The incidence of maternal asthma is rising. Based on US national health surveys, the prevalence of asthma during pregnancy is between 3.7% and 8.4%.¹ It is the most common respiratory illness of pregnancy.² Hence, clinicians need to know how asthma affects the mother and the fetus. Appropriate care of asthma during pregnancy is based on several management principles, as reviewed here, and is key to ensuring good outcomes for the mother and the baby.

EFFECT OF PREGNANCY ON ASTHMA CONTROL

Asthma control can vary in pregnancy. About a third of asthmatic women experience a worsening of asthma control with pregnancy, a third remain unchanged, and another third have improvement in asthma symptoms.³ The peak worsening of asthma tends to occur in the sixth month.⁴ Asthma control also tends to be better in the last month of pregnancy.³

The peak expiratory flow rate was noted to increase with each trimester in a small study of 43 women.⁵ The authors speculated that a rising progesterone level stimulates cyclic adenosine monophosphate to cause bronchodilation, thereby improving the expiratory flow rate and asthma control. Asthma control tends to follow the pattern experienced in the previous pregnancy: ie, if asthma worsened during the previous pregnancy, the same will be likely in the subsequent pregnancy.³

Two maternal factors that adversely affect asthma severity during pregnancy are the use of asthma medications contrary to guidelines such as those of the Global Initiative for Asthma (http://ginasthma.org/2017-gina-report-global-strategy-for-asthma-management-and-prevention) and inadquate control of asthma before becoming pregnant.⁶ Pregnancy can bring on stress, and stress is known to worsen asthma. In addition, when patients themselves were interviewed to elucidate the reasons for poor adherence to asthma medications during pregnancy, concerns about medication use, especially corticosteroids, stood out.⁷ A study based on prescription claims data showed that in the first trimester, there was a significant decline in asthma prescription medications (a 23% decline in inhaled corticosteroids, a 13% decline in short-acting bronchodilator agents, and a 54% decline in rescue corticosteroids).⁸ Lack of physician education about management of asthma in pregnancy and discomfort with prescribing to pregnant women also affect asthma control.

EFFECT OF ASTHMA ON MATERNAL AND FETAL OUTCOMES

Studies of the effects of asthma on fetal and maternal outcomes have yielded mixed and conflicting results.⁹ Adverse outcomes that have been shown to be associated with maternal asthma are listed in Table 1. Other studies have not demonstrated an association between asthma in pregnancy and maternal or fetal adverse events.⁹ Such discrepant findings are due to differences in study population characteristics that make comparisons difficult. A meta-analysis involving more than 1.6 million asthmatic women showed maternal asthma was associated with a 40% greater risk of low birth weight and preterm delivery, a 50% greater risk of preeclampsia, and a 20% greater risk of the baby being small for its gestational age.¹⁰

The association of maternal asthma and preterm birth may pose short-term and long-term health risks to the child associated with prematurity.⁹ Short-term risks with prematurity include infection, respiratory distress syndrome, brain injury, and necrotizing enterocolitis. Long-term risks include neuro­developmental and behavioral sequelae. Furthermore, asthma exacerbations during pregnancy are associated with a twofold higher risk of low birth weight.¹¹ The benefits of good adherence to asthma regimens during pregnancy outweigh the risks associated with frequent symptoms and exacerbations caused by untreated asthma.¹²

OUTPATIENT MANAGEMENT OF MATERNAL ASTHMA

Goals

In the 2004 update of the National Asthma Education and Prevention Program (NAEPP) Working Group Report on Managing Asthma During Pregnancy, goals focused mainly on adequate asthma control for maternal health and quality of life, as well as normal fetal maturation (Table 2),¹² goals similar to those in nonpregnant asthmatic women.

Assessment and monitoring

Monthly physician visits during pregnancy are recommended for assessment of symptoms and pulmonary function. If symptoms are uncontrolled, therapy must be stepped up, and any trigger for exacerbation, such as gastroesophageal reflux disease (GERD), exposure, or rhinitis, must be treated and eliminated. NAEPP guidelines recommend baseline spirometry at the time of initial assessment.¹² At follow-up visits, spirometry is preferred, but measurement of the peak expiratory flow rate usually suffices. Such objective data can help differentiate dyspnea from asthma and from dyspnea that usually accompanies the physiologic changes of pregnancy. In addition, patients should be advised to monitor for adequate fetal activity. If asthma is uncontrolled or poorly controlled, serial fetal ultrasonography should be considered from 32 weeks of gestation, as well as after recovery from an asthma exacerbation. Regular monitoring of the pregnant asthmatic patient by a multidisciplinary team can improve outcomes.¹³

Avoiding triggers

Patients should be advised to avoid asthma triggers such as pet dander, dust mites, pollen, smoke, mold, and perfumes, as this can decrease symptoms and allow for use of lower doses of medications.¹² Additionally, smoking cessation must be strongly encouraged, not only to control maternal asthma, but also to prevent harm to the fetus.

MANAGEMENT OF SPECIFIC TRIGGERS

GERD

Reflux disease often worsens during pregnancy, and it can coexist with asthma and can also exacerbate it.¹⁴ Optimal control of GERD helps maintain adequate asthma control. For mild reflux symptoms, lifestyle modifications such as elevating the head of bed, avoiding eating too close to bedtime, and avoiding foods that cause heartburn may be adequate.^15,16 If medications are needed, antacids (but not sodium bicarbonate, for fear of metabolic alkalosis) and sucralfate should be considered before using a histamine 2 receptor antagonist such as ranitidine. Proton pump inhibitors should be considered only if reflux symptoms are refractory to other therapies.

Allergic rhinitis

Intranasal corticosteroids are effective against allergic rhinitis in pregnancy (Table 3).¹² Montelukast, a leukotriene receptor antagonist, can be used, but data to support its use for allergic rhinitis in pregnancy are limited.

Among antihistamines, second-generation drugs such as cetirizine or loratadine can be considered.¹² Oral decongestants such as pseudoephedrine in early pregnancy are associated with a rare congenital fetal abnormality called gastroschisis, caused by vascular disruption.¹⁷ Hence, if a nasal decongestant is required in early pregnancy, a local therapy such as an intranasal corticosteroid, short-term oxymetazoline, or an external nasal dilator may be considered.¹² These therapies must be combined with avoidance of allergens whenever possible.

Allergies

Diagnostic allergy and skin tests during pregnancy pose a risk of anaphylaxis and thus should be avoided. Instead, the focus should be on obtaining a thorough medical history about exposures and eliminating specific asthma triggers. It is also inadvisable to start allergen immunotherapy during pregnancy because of the risk of anaphylaxis and the effect of treatment on the mother and fetus.¹⁸ However, maintenance doses of allergen immunotherapy can be continued during pregnancy.¹⁸

Patient education

Because of concern about the risks of taking medications during pregnancy, many women with asthma stop using their inhalers during pregnancy, thus compromising asthma control.^8,13 The physician and multidisciplinary team must use every opportunity to emphasize the importance of good asthma control during pregnancy. Inhaler technique should also be reviewed and, if defective, corrected. Again, trigger avoidance and tobacco cessation should be addressed.

Drugs

The NAEPP recommendations state that asthma therapy should be continued during pregnancy, as it is safer both for mother and fetus to avoid exacerbations and uncontrolled asthma.¹² Despite this, 25% of primary care physicians instruct their patients to decrease or discontinue their inhaled corticosteroid during pregnancy.¹⁹ As with asthma in general, treatment should involve using the lowest dose of drugs that achieves adequate control of symptoms.

In 2015, the US Food and Drug Administration (FDA) amended the labeling rule for medications used in pregnancy and lactation. The previous risk categories A (safest), B, C, D, and X (highest risk) are in the process of being removed from labels for all human prescription drugs and biologic products, to be replaced with a summary of the risks of taking the drug during pregnancy and lactation, a discussion of the data supporting the use, and relevant information to help healthcare providers make prescribing decisions and counsel women about the use of drugs during pregnancy and lactation (www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm).

ROLES OF CONTROLLER THERAPY AND RESCUE THERAPY

Inhaled corticosteroids

Inhaled corticosteroids are the mainstay of asthma controller therapy during pregnancy. A meta-analysis of 16 studies showed no increased risk of congenital malformations, cesarean delivery, or stillbirth among mothers who used these agents during pregnancy.²⁰ Because there are more safety data for budesonide, it is currently the preferred inhaled corticosteroid during pregnancy.⁹ However, if a patient’s asthma is controlled with a different corticosteroid before pregnancy, that agent may be continued during pregnancy, especially if it is thought that switching formulations could adversely affect asthma control.¹² This is mainly because current data do not prove that other inhaled corticosteroids are unsafe.

Inhaled beta-agonists

Inhaled beta-agonists, both short-acting and long-acting, are used for rescue therapy. Al­buterol is the preferred short-acting agent for rescue therapy in pregnant women with asthma.¹² Meta-analysis has shown no increased risk of major or minor congenital malformations in pregnant patients who use bronchodilators.²⁰ Long-acting beta-agonists typically are used as add-on therapy when asthma cannot be controlled by an inhaled corticosteroid. They should not be used without a controller medication (ie, an inhaled corticosteroid).

Guidelines for rescue therapy are similar to those for nonpregnant asthmatic patients. Although data are limited as to the gestational effects of long-acting beta-agonists (ie, formoterol, salmeterol), it can be assumed that the toxicologic and pharmacologic profiles are similar to those of the short-acting bronchodilators. Thus, the safety of albuterol can be extended potentially to the long-acting beta-agonists.¹²

Combining controller and rescue therapy

When asthma is not adequately controlled on inhaled corticosteroids, a long-acting beta-agonist can be added or the dose of corticosteroid can be increased. The 2004 NAEPP guidelines stated that based on available literature, there was no clear advantage of one option over the other.¹² A study that compared the 2 approaches found no difference in rates of congenital malformations.²¹

Leukotriene receptor antagonists

There is little in the literature regarding the use of leukotriene receptor antagonists during pregnancy. However, animal safety data are reassuring,¹² and human studies have not found a higher risk of major congenital malformations.^22,23 Thus, they are an alternative for patients whose asthma has been well controlled on these agents before pregnancy. Montelukast and zafirlukast are in former FDA pregnancy risk factor category B (probably safe) (Table 3). However, 5-lipoxygenase inhibitors such as zileuton are contraindicated based on animal studies showing teratogenicity.²⁴

Omalizumab

Omalizumab, a recombinant anti-immunoglobulin E antibody, can be used for allergic asthma not controlled with inhaled corticosteroids (Table 3). An analysis of the omalizumab pregnancy registry²⁵ found no significant increase in the rate of major congenital malformations, prematurity, or babies small for gestational age in asthmatic women taking omalizumab 8 weeks before conception or during pregnancy vs pregnant asthmatic women not taking omalizumab. However, this drug carries a risk of anaphylaxis and so should not be started during pregnancy.²⁵

Theophylline

Because of potential toxicity, use of theophylline during pregnancy requires careful monitoring to ensure the serum concentration remains between 5 and 12 µg/mL.¹² Drug interactions are also common: for example, alcohol may increase the serum concentration of theophylline, and theophylline may increase the toxic effect of formoterol.

Systemic corticosteroids

Pregnant women with asthma that is not well controlled despite the therapies described above may require a daily oral corticosteroid such as prednisone to achieve adequate control. Oral steroids are also a mainstay of treatment of asthma exacerbation.

Although use of corticosteroids in the first trimester was associated with orofacial cleft in infants,¹² these studies did not include many women with asthma. In 2011, a nationwide cohort study from Denmark showed no increase in the risk of orofacial cleft with the use of corticosteroids during pregnancy.²⁶

Preeclampsia, low birth weight, and preterm delivery have been described with corticosteroid use in pregnancy. It is not known whether these problems were a result of corticosteroid use or were due to the uncontrolled nature of the underlying condition that led to the steroid use. Since the risk of uncontrolled asthma to mother and fetus outweighs the risk of systemic corticosteroids, these drugs are recommended when indicated for management of maternal asthma.¹²

ACUTE EXACERBATIONS REQUIRE AGGRESSIVE MANAGEMENT

Based on a systematic review, 20% of pregnant women with asthma require some intervention for an asthma exacerbation during pregnancy, and 5.8% are admitted to the hospital for an exacerbation.¹¹ Exacerbations were associated with a higher risk of low birth weight compared with rates in women without asthma.

Exacerbations are more common late in the second trimester and are unlikely to occur during labor and delivery.²  The incidence of exacerbations increases with the severity of asthma, from 8% in mild asthma, to 47% in moderate asthma, to 65% in severe asthma.²⁷ Risk factors for exacerbations include poor prenatal care, obesity, and lack of appropriate treatment with inhaled corticosteroids.² The main triggers are viral respiratory infections and noncompliance with inhaled corticosteroid therapy.¹¹

Asthma exacerbations during pregnancy should be managed aggressively (Table 4),¹² as the risk to the fetus of hypoxia far outweighs any risk from asthma medications. Close collaboration between the primary care physician and the obstetrician allows closer monitoring of mother and fetus.

The goal oxygen saturation must be above 95%.¹² Signs of acute respiratory failure in a pregnant patient include a partial pressure of arterial oxygen less than 70 mm Hg or a partial pressure of carbon dioxide greater than 35 mm Hg.

In a multicenter study comparing nonpregnant and pregnant women visiting the emergency room for asthma exacerbations,²⁸ pregnant women were less likely to be prescribed systemic corticosteroids either in the emergency room or at the time of hospital discharge, and they were also more likely to describe an ongoing exacerbation at 2-week follow-up. However, a recent study showed a significant increase in systemic corticosteroid treatment in the emergency room (51% to 78% across the time periods, odds ratio 3.11, 95% confidence interval 1.27–7.60, P = .01). There was also an increase in steroid treatment at discharge (42% to 63%, odds ratio 2.49, 95% confidence interval 0.97–6.37, P = .054), though the increase was not statistically significant.²⁹ Although emergency room care for pregnant asthmatic women has improved, this group concluded that further improvement is still warranted, as 1 in 3 women is discharged without corticosteroid treatment.

The incidence of maternal asthma is rising. Based on US national health surveys, the prevalence of asthma during pregnancy is between 3.7% and 8.4%.¹ It is the most common respiratory illness of pregnancy.² Hence, clinicians need to know how asthma affects the mother and the fetus. Appropriate care of asthma during pregnancy is based on several management principles, as reviewed here, and is key to ensuring good outcomes for the mother and the baby.

EFFECT OF PREGNANCY ON ASTHMA CONTROL

Asthma control can vary in pregnancy. About a third of asthmatic women experience a worsening of asthma control with pregnancy, a third remain unchanged, and another third have improvement in asthma symptoms.³ The peak worsening of asthma tends to occur in the sixth month.⁴ Asthma control also tends to be better in the last month of pregnancy.³

The peak expiratory flow rate was noted to increase with each trimester in a small study of 43 women.⁵ The authors speculated that a rising progesterone level stimulates cyclic adenosine monophosphate to cause bronchodilation, thereby improving the expiratory flow rate and asthma control. Asthma control tends to follow the pattern experienced in the previous pregnancy: ie, if asthma worsened during the previous pregnancy, the same will be likely in the subsequent pregnancy.³

Two maternal factors that adversely affect asthma severity during pregnancy are the use of asthma medications contrary to guidelines such as those of the Global Initiative for Asthma (http://ginasthma.org/2017-gina-report-global-strategy-for-asthma-management-and-prevention) and inadquate control of asthma before becoming pregnant.⁶ Pregnancy can bring on stress, and stress is known to worsen asthma. In addition, when patients themselves were interviewed to elucidate the reasons for poor adherence to asthma medications during pregnancy, concerns about medication use, especially corticosteroids, stood out.⁷ A study based on prescription claims data showed that in the first trimester, there was a significant decline in asthma prescription medications (a 23% decline in inhaled corticosteroids, a 13% decline in short-acting bronchodilator agents, and a 54% decline in rescue corticosteroids).⁸ Lack of physician education about management of asthma in pregnancy and discomfort with prescribing to pregnant women also affect asthma control.

EFFECT OF ASTHMA ON MATERNAL AND FETAL OUTCOMES

Studies of the effects of asthma on fetal and maternal outcomes have yielded mixed and conflicting results.⁹ Adverse outcomes that have been shown to be associated with maternal asthma are listed in Table 1. Other studies have not demonstrated an association between asthma in pregnancy and maternal or fetal adverse events.⁹ Such discrepant findings are due to differences in study population characteristics that make comparisons difficult. A meta-analysis involving more than 1.6 million asthmatic women showed maternal asthma was associated with a 40% greater risk of low birth weight and preterm delivery, a 50% greater risk of preeclampsia, and a 20% greater risk of the baby being small for its gestational age.¹⁰

The association of maternal asthma and preterm birth may pose short-term and long-term health risks to the child associated with prematurity.⁹ Short-term risks with prematurity include infection, respiratory distress syndrome, brain injury, and necrotizing enterocolitis. Long-term risks include neuro­developmental and behavioral sequelae. Furthermore, asthma exacerbations during pregnancy are associated with a twofold higher risk of low birth weight.¹¹ The benefits of good adherence to asthma regimens during pregnancy outweigh the risks associated with frequent symptoms and exacerbations caused by untreated asthma.¹²

OUTPATIENT MANAGEMENT OF MATERNAL ASTHMA

Goals

In the 2004 update of the National Asthma Education and Prevention Program (NAEPP) Working Group Report on Managing Asthma During Pregnancy, goals focused mainly on adequate asthma control for maternal health and quality of life, as well as normal fetal maturation (Table 2),¹² goals similar to those in nonpregnant asthmatic women.

Assessment and monitoring

Monthly physician visits during pregnancy are recommended for assessment of symptoms and pulmonary function. If symptoms are uncontrolled, therapy must be stepped up, and any trigger for exacerbation, such as gastroesophageal reflux disease (GERD), exposure, or rhinitis, must be treated and eliminated. NAEPP guidelines recommend baseline spirometry at the time of initial assessment.¹² At follow-up visits, spirometry is preferred, but measurement of the peak expiratory flow rate usually suffices. Such objective data can help differentiate dyspnea from asthma and from dyspnea that usually accompanies the physiologic changes of pregnancy. In addition, patients should be advised to monitor for adequate fetal activity. If asthma is uncontrolled or poorly controlled, serial fetal ultrasonography should be considered from 32 weeks of gestation, as well as after recovery from an asthma exacerbation. Regular monitoring of the pregnant asthmatic patient by a multidisciplinary team can improve outcomes.¹³

Avoiding triggers

Patients should be advised to avoid asthma triggers such as pet dander, dust mites, pollen, smoke, mold, and perfumes, as this can decrease symptoms and allow for use of lower doses of medications.¹² Additionally, smoking cessation must be strongly encouraged, not only to control maternal asthma, but also to prevent harm to the fetus.

MANAGEMENT OF SPECIFIC TRIGGERS

GERD

Reflux disease often worsens during pregnancy, and it can coexist with asthma and can also exacerbate it.¹⁴ Optimal control of GERD helps maintain adequate asthma control. For mild reflux symptoms, lifestyle modifications such as elevating the head of bed, avoiding eating too close to bedtime, and avoiding foods that cause heartburn may be adequate.^15,16 If medications are needed, antacids (but not sodium bicarbonate, for fear of metabolic alkalosis) and sucralfate should be considered before using a histamine 2 receptor antagonist such as ranitidine. Proton pump inhibitors should be considered only if reflux symptoms are refractory to other therapies.

Allergic rhinitis

Intranasal corticosteroids are effective against allergic rhinitis in pregnancy (Table 3).¹² Montelukast, a leukotriene receptor antagonist, can be used, but data to support its use for allergic rhinitis in pregnancy are limited.

Among antihistamines, second-generation drugs such as cetirizine or loratadine can be considered.¹² Oral decongestants such as pseudoephedrine in early pregnancy are associated with a rare congenital fetal abnormality called gastroschisis, caused by vascular disruption.¹⁷ Hence, if a nasal decongestant is required in early pregnancy, a local therapy such as an intranasal corticosteroid, short-term oxymetazoline, or an external nasal dilator may be considered.¹² These therapies must be combined with avoidance of allergens whenever possible.

Allergies

Diagnostic allergy and skin tests during pregnancy pose a risk of anaphylaxis and thus should be avoided. Instead, the focus should be on obtaining a thorough medical history about exposures and eliminating specific asthma triggers. It is also inadvisable to start allergen immunotherapy during pregnancy because of the risk of anaphylaxis and the effect of treatment on the mother and fetus.¹⁸ However, maintenance doses of allergen immunotherapy can be continued during pregnancy.¹⁸

Patient education

Because of concern about the risks of taking medications during pregnancy, many women with asthma stop using their inhalers during pregnancy, thus compromising asthma control.^8,13 The physician and multidisciplinary team must use every opportunity to emphasize the importance of good asthma control during pregnancy. Inhaler technique should also be reviewed and, if defective, corrected. Again, trigger avoidance and tobacco cessation should be addressed.

Drugs

The NAEPP recommendations state that asthma therapy should be continued during pregnancy, as it is safer both for mother and fetus to avoid exacerbations and uncontrolled asthma.¹² Despite this, 25% of primary care physicians instruct their patients to decrease or discontinue their inhaled corticosteroid during pregnancy.¹⁹ As with asthma in general, treatment should involve using the lowest dose of drugs that achieves adequate control of symptoms.

In 2015, the US Food and Drug Administration (FDA) amended the labeling rule for medications used in pregnancy and lactation. The previous risk categories A (safest), B, C, D, and X (highest risk) are in the process of being removed from labels for all human prescription drugs and biologic products, to be replaced with a summary of the risks of taking the drug during pregnancy and lactation, a discussion of the data supporting the use, and relevant information to help healthcare providers make prescribing decisions and counsel women about the use of drugs during pregnancy and lactation (www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm).

ROLES OF CONTROLLER THERAPY AND RESCUE THERAPY

Inhaled corticosteroids

Inhaled corticosteroids are the mainstay of asthma controller therapy during pregnancy. A meta-analysis of 16 studies showed no increased risk of congenital malformations, cesarean delivery, or stillbirth among mothers who used these agents during pregnancy.²⁰ Because there are more safety data for budesonide, it is currently the preferred inhaled corticosteroid during pregnancy.⁹ However, if a patient’s asthma is controlled with a different corticosteroid before pregnancy, that agent may be continued during pregnancy, especially if it is thought that switching formulations could adversely affect asthma control.¹² This is mainly because current data do not prove that other inhaled corticosteroids are unsafe.

Inhaled beta-agonists

Inhaled beta-agonists, both short-acting and long-acting, are used for rescue therapy. Al­buterol is the preferred short-acting agent for rescue therapy in pregnant women with asthma.¹² Meta-analysis has shown no increased risk of major or minor congenital malformations in pregnant patients who use bronchodilators.²⁰ Long-acting beta-agonists typically are used as add-on therapy when asthma cannot be controlled by an inhaled corticosteroid. They should not be used without a controller medication (ie, an inhaled corticosteroid).

Guidelines for rescue therapy are similar to those for nonpregnant asthmatic patients. Although data are limited as to the gestational effects of long-acting beta-agonists (ie, formoterol, salmeterol), it can be assumed that the toxicologic and pharmacologic profiles are similar to those of the short-acting bronchodilators. Thus, the safety of albuterol can be extended potentially to the long-acting beta-agonists.¹²

Combining controller and rescue therapy

When asthma is not adequately controlled on inhaled corticosteroids, a long-acting beta-agonist can be added or the dose of corticosteroid can be increased. The 2004 NAEPP guidelines stated that based on available literature, there was no clear advantage of one option over the other.¹² A study that compared the 2 approaches found no difference in rates of congenital malformations.²¹

Leukotriene receptor antagonists

There is little in the literature regarding the use of leukotriene receptor antagonists during pregnancy. However, animal safety data are reassuring,¹² and human studies have not found a higher risk of major congenital malformations.^22,23 Thus, they are an alternative for patients whose asthma has been well controlled on these agents before pregnancy. Montelukast and zafirlukast are in former FDA pregnancy risk factor category B (probably safe) (Table 3). However, 5-lipoxygenase inhibitors such as zileuton are contraindicated based on animal studies showing teratogenicity.²⁴

Omalizumab

Omalizumab, a recombinant anti-immunoglobulin E antibody, can be used for allergic asthma not controlled with inhaled corticosteroids (Table 3). An analysis of the omalizumab pregnancy registry²⁵ found no significant increase in the rate of major congenital malformations, prematurity, or babies small for gestational age in asthmatic women taking omalizumab 8 weeks before conception or during pregnancy vs pregnant asthmatic women not taking omalizumab. However, this drug carries a risk of anaphylaxis and so should not be started during pregnancy.²⁵

Theophylline

Because of potential toxicity, use of theophylline during pregnancy requires careful monitoring to ensure the serum concentration remains between 5 and 12 µg/mL.¹² Drug interactions are also common: for example, alcohol may increase the serum concentration of theophylline, and theophylline may increase the toxic effect of formoterol.

Systemic corticosteroids

Pregnant women with asthma that is not well controlled despite the therapies described above may require a daily oral corticosteroid such as prednisone to achieve adequate control. Oral steroids are also a mainstay of treatment of asthma exacerbation.

Although use of corticosteroids in the first trimester was associated with orofacial cleft in infants,¹² these studies did not include many women with asthma. In 2011, a nationwide cohort study from Denmark showed no increase in the risk of orofacial cleft with the use of corticosteroids during pregnancy.²⁶

Preeclampsia, low birth weight, and preterm delivery have been described with corticosteroid use in pregnancy. It is not known whether these problems were a result of corticosteroid use or were due to the uncontrolled nature of the underlying condition that led to the steroid use. Since the risk of uncontrolled asthma to mother and fetus outweighs the risk of systemic corticosteroids, these drugs are recommended when indicated for management of maternal asthma.¹²

ACUTE EXACERBATIONS REQUIRE AGGRESSIVE MANAGEMENT

Based on a systematic review, 20% of pregnant women with asthma require some intervention for an asthma exacerbation during pregnancy, and 5.8% are admitted to the hospital for an exacerbation.¹¹ Exacerbations were associated with a higher risk of low birth weight compared with rates in women without asthma.

Exacerbations are more common late in the second trimester and are unlikely to occur during labor and delivery.²  The incidence of exacerbations increases with the severity of asthma, from 8% in mild asthma, to 47% in moderate asthma, to 65% in severe asthma.²⁷ Risk factors for exacerbations include poor prenatal care, obesity, and lack of appropriate treatment with inhaled corticosteroids.² The main triggers are viral respiratory infections and noncompliance with inhaled corticosteroid therapy.¹¹

Asthma exacerbations during pregnancy should be managed aggressively (Table 4),¹² as the risk to the fetus of hypoxia far outweighs any risk from asthma medications. Close collaboration between the primary care physician and the obstetrician allows closer monitoring of mother and fetus.

The goal oxygen saturation must be above 95%.¹² Signs of acute respiratory failure in a pregnant patient include a partial pressure of arterial oxygen less than 70 mm Hg or a partial pressure of carbon dioxide greater than 35 mm Hg.

In a multicenter study comparing nonpregnant and pregnant women visiting the emergency room for asthma exacerbations,²⁸ pregnant women were less likely to be prescribed systemic corticosteroids either in the emergency room or at the time of hospital discharge, and they were also more likely to describe an ongoing exacerbation at 2-week follow-up. However, a recent study showed a significant increase in systemic corticosteroid treatment in the emergency room (51% to 78% across the time periods, odds ratio 3.11, 95% confidence interval 1.27–7.60, P = .01). There was also an increase in steroid treatment at discharge (42% to 63%, odds ratio 2.49, 95% confidence interval 0.97–6.37, P = .054), though the increase was not statistically significant.²⁹ Although emergency room care for pregnant asthmatic women has improved, this group concluded that further improvement is still warranted, as 1 in 3 women is discharged without corticosteroid treatment.

The incidence of maternal asthma is rising. Based on US national health surveys, the prevalence of asthma during pregnancy is between 3.7% and 8.4%.¹ It is the most common respiratory illness of pregnancy.² Hence, clinicians need to know how asthma affects the mother and the fetus. Appropriate care of asthma during pregnancy is based on several management principles, as reviewed here, and is key to ensuring good outcomes for the mother and the baby.

EFFECT OF PREGNANCY ON ASTHMA CONTROL

Asthma control can vary in pregnancy. About a third of asthmatic women experience a worsening of asthma control with pregnancy, a third remain unchanged, and another third have improvement in asthma symptoms.³ The peak worsening of asthma tends to occur in the sixth month.⁴ Asthma control also tends to be better in the last month of pregnancy.³

The peak expiratory flow rate was noted to increase with each trimester in a small study of 43 women.⁵ The authors speculated that a rising progesterone level stimulates cyclic adenosine monophosphate to cause bronchodilation, thereby improving the expiratory flow rate and asthma control. Asthma control tends to follow the pattern experienced in the previous pregnancy: ie, if asthma worsened during the previous pregnancy, the same will be likely in the subsequent pregnancy.³

Two maternal factors that adversely affect asthma severity during pregnancy are the use of asthma medications contrary to guidelines such as those of the Global Initiative for Asthma (http://ginasthma.org/2017-gina-report-global-strategy-for-asthma-management-and-prevention) and inadquate control of asthma before becoming pregnant.⁶ Pregnancy can bring on stress, and stress is known to worsen asthma. In addition, when patients themselves were interviewed to elucidate the reasons for poor adherence to asthma medications during pregnancy, concerns about medication use, especially corticosteroids, stood out.⁷ A study based on prescription claims data showed that in the first trimester, there was a significant decline in asthma prescription medications (a 23% decline in inhaled corticosteroids, a 13% decline in short-acting bronchodilator agents, and a 54% decline in rescue corticosteroids).⁸ Lack of physician education about management of asthma in pregnancy and discomfort with prescribing to pregnant women also affect asthma control.

EFFECT OF ASTHMA ON MATERNAL AND FETAL OUTCOMES

Studies of the effects of asthma on fetal and maternal outcomes have yielded mixed and conflicting results.⁹ Adverse outcomes that have been shown to be associated with maternal asthma are listed in Table 1. Other studies have not demonstrated an association between asthma in pregnancy and maternal or fetal adverse events.⁹ Such discrepant findings are due to differences in study population characteristics that make comparisons difficult. A meta-analysis involving more than 1.6 million asthmatic women showed maternal asthma was associated with a 40% greater risk of low birth weight and preterm delivery, a 50% greater risk of preeclampsia, and a 20% greater risk of the baby being small for its gestational age.¹⁰

The association of maternal asthma and preterm birth may pose short-term and long-term health risks to the child associated with prematurity.⁹ Short-term risks with prematurity include infection, respiratory distress syndrome, brain injury, and necrotizing enterocolitis. Long-term risks include neuro­developmental and behavioral sequelae. Furthermore, asthma exacerbations during pregnancy are associated with a twofold higher risk of low birth weight.¹¹ The benefits of good adherence to asthma regimens during pregnancy outweigh the risks associated with frequent symptoms and exacerbations caused by untreated asthma.¹²

OUTPATIENT MANAGEMENT OF MATERNAL ASTHMA

Goals

In the 2004 update of the National Asthma Education and Prevention Program (NAEPP) Working Group Report on Managing Asthma During Pregnancy, goals focused mainly on adequate asthma control for maternal health and quality of life, as well as normal fetal maturation (Table 2),¹² goals similar to those in nonpregnant asthmatic women.

Assessment and monitoring

Monthly physician visits during pregnancy are recommended for assessment of symptoms and pulmonary function. If symptoms are uncontrolled, therapy must be stepped up, and any trigger for exacerbation, such as gastroesophageal reflux disease (GERD), exposure, or rhinitis, must be treated and eliminated. NAEPP guidelines recommend baseline spirometry at the time of initial assessment.¹² At follow-up visits, spirometry is preferred, but measurement of the peak expiratory flow rate usually suffices. Such objective data can help differentiate dyspnea from asthma and from dyspnea that usually accompanies the physiologic changes of pregnancy. In addition, patients should be advised to monitor for adequate fetal activity. If asthma is uncontrolled or poorly controlled, serial fetal ultrasonography should be considered from 32 weeks of gestation, as well as after recovery from an asthma exacerbation. Regular monitoring of the pregnant asthmatic patient by a multidisciplinary team can improve outcomes.¹³

Avoiding triggers

Patients should be advised to avoid asthma triggers such as pet dander, dust mites, pollen, smoke, mold, and perfumes, as this can decrease symptoms and allow for use of lower doses of medications.¹² Additionally, smoking cessation must be strongly encouraged, not only to control maternal asthma, but also to prevent harm to the fetus.

MANAGEMENT OF SPECIFIC TRIGGERS

GERD

Reflux disease often worsens during pregnancy, and it can coexist with asthma and can also exacerbate it.¹⁴ Optimal control of GERD helps maintain adequate asthma control. For mild reflux symptoms, lifestyle modifications such as elevating the head of bed, avoiding eating too close to bedtime, and avoiding foods that cause heartburn may be adequate.^15,16 If medications are needed, antacids (but not sodium bicarbonate, for fear of metabolic alkalosis) and sucralfate should be considered before using a histamine 2 receptor antagonist such as ranitidine. Proton pump inhibitors should be considered only if reflux symptoms are refractory to other therapies.

Allergic rhinitis

Intranasal corticosteroids are effective against allergic rhinitis in pregnancy (Table 3).¹² Montelukast, a leukotriene receptor antagonist, can be used, but data to support its use for allergic rhinitis in pregnancy are limited.

Among antihistamines, second-generation drugs such as cetirizine or loratadine can be considered.¹² Oral decongestants such as pseudoephedrine in early pregnancy are associated with a rare congenital fetal abnormality called gastroschisis, caused by vascular disruption.¹⁷ Hence, if a nasal decongestant is required in early pregnancy, a local therapy such as an intranasal corticosteroid, short-term oxymetazoline, or an external nasal dilator may be considered.¹² These therapies must be combined with avoidance of allergens whenever possible.

Allergies

Diagnostic allergy and skin tests during pregnancy pose a risk of anaphylaxis and thus should be avoided. Instead, the focus should be on obtaining a thorough medical history about exposures and eliminating specific asthma triggers. It is also inadvisable to start allergen immunotherapy during pregnancy because of the risk of anaphylaxis and the effect of treatment on the mother and fetus.¹⁸ However, maintenance doses of allergen immunotherapy can be continued during pregnancy.¹⁸

Patient education

Because of concern about the risks of taking medications during pregnancy, many women with asthma stop using their inhalers during pregnancy, thus compromising asthma control.^8,13 The physician and multidisciplinary team must use every opportunity to emphasize the importance of good asthma control during pregnancy. Inhaler technique should also be reviewed and, if defective, corrected. Again, trigger avoidance and tobacco cessation should be addressed.

Drugs

The NAEPP recommendations state that asthma therapy should be continued during pregnancy, as it is safer both for mother and fetus to avoid exacerbations and uncontrolled asthma.¹² Despite this, 25% of primary care physicians instruct their patients to decrease or discontinue their inhaled corticosteroid during pregnancy.¹⁹ As with asthma in general, treatment should involve using the lowest dose of drugs that achieves adequate control of symptoms.

In 2015, the US Food and Drug Administration (FDA) amended the labeling rule for medications used in pregnancy and lactation. The previous risk categories A (safest), B, C, D, and X (highest risk) are in the process of being removed from labels for all human prescription drugs and biologic products, to be replaced with a summary of the risks of taking the drug during pregnancy and lactation, a discussion of the data supporting the use, and relevant information to help healthcare providers make prescribing decisions and counsel women about the use of drugs during pregnancy and lactation (www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm).

ROLES OF CONTROLLER THERAPY AND RESCUE THERAPY

Inhaled corticosteroids

Inhaled corticosteroids are the mainstay of asthma controller therapy during pregnancy. A meta-analysis of 16 studies showed no increased risk of congenital malformations, cesarean delivery, or stillbirth among mothers who used these agents during pregnancy.²⁰ Because there are more safety data for budesonide, it is currently the preferred inhaled corticosteroid during pregnancy.⁹ However, if a patient’s asthma is controlled with a different corticosteroid before pregnancy, that agent may be continued during pregnancy, especially if it is thought that switching formulations could adversely affect asthma control.¹² This is mainly because current data do not prove that other inhaled corticosteroids are unsafe.

Inhaled beta-agonists

Inhaled beta-agonists, both short-acting and long-acting, are used for rescue therapy. Al­buterol is the preferred short-acting agent for rescue therapy in pregnant women with asthma.¹² Meta-analysis has shown no increased risk of major or minor congenital malformations in pregnant patients who use bronchodilators.²⁰ Long-acting beta-agonists typically are used as add-on therapy when asthma cannot be controlled by an inhaled corticosteroid. They should not be used without a controller medication (ie, an inhaled corticosteroid).

Guidelines for rescue therapy are similar to those for nonpregnant asthmatic patients. Although data are limited as to the gestational effects of long-acting beta-agonists (ie, formoterol, salmeterol), it can be assumed that the toxicologic and pharmacologic profiles are similar to those of the short-acting bronchodilators. Thus, the safety of albuterol can be extended potentially to the long-acting beta-agonists.¹²

Combining controller and rescue therapy

When asthma is not adequately controlled on inhaled corticosteroids, a long-acting beta-agonist can be added or the dose of corticosteroid can be increased. The 2004 NAEPP guidelines stated that based on available literature, there was no clear advantage of one option over the other.¹² A study that compared the 2 approaches found no difference in rates of congenital malformations.²¹

Leukotriene receptor antagonists

There is little in the literature regarding the use of leukotriene receptor antagonists during pregnancy. However, animal safety data are reassuring,¹² and human studies have not found a higher risk of major congenital malformations.^22,23 Thus, they are an alternative for patients whose asthma has been well controlled on these agents before pregnancy. Montelukast and zafirlukast are in former FDA pregnancy risk factor category B (probably safe) (Table 3). However, 5-lipoxygenase inhibitors such as zileuton are contraindicated based on animal studies showing teratogenicity.²⁴

Omalizumab

Omalizumab, a recombinant anti-immunoglobulin E antibody, can be used for allergic asthma not controlled with inhaled corticosteroids (Table 3). An analysis of the omalizumab pregnancy registry²⁵ found no significant increase in the rate of major congenital malformations, prematurity, or babies small for gestational age in asthmatic women taking omalizumab 8 weeks before conception or during pregnancy vs pregnant asthmatic women not taking omalizumab. However, this drug carries a risk of anaphylaxis and so should not be started during pregnancy.²⁵

Theophylline

Because of potential toxicity, use of theophylline during pregnancy requires careful monitoring to ensure the serum concentration remains between 5 and 12 µg/mL.¹² Drug interactions are also common: for example, alcohol may increase the serum concentration of theophylline, and theophylline may increase the toxic effect of formoterol.

Systemic corticosteroids

Pregnant women with asthma that is not well controlled despite the therapies described above may require a daily oral corticosteroid such as prednisone to achieve adequate control. Oral steroids are also a mainstay of treatment of asthma exacerbation.

Although use of corticosteroids in the first trimester was associated with orofacial cleft in infants,¹² these studies did not include many women with asthma. In 2011, a nationwide cohort study from Denmark showed no increase in the risk of orofacial cleft with the use of corticosteroids during pregnancy.²⁶

Preeclampsia, low birth weight, and preterm delivery have been described with corticosteroid use in pregnancy. It is not known whether these problems were a result of corticosteroid use or were due to the uncontrolled nature of the underlying condition that led to the steroid use. Since the risk of uncontrolled asthma to mother and fetus outweighs the risk of systemic corticosteroids, these drugs are recommended when indicated for management of maternal asthma.¹²

ACUTE EXACERBATIONS REQUIRE AGGRESSIVE MANAGEMENT

Based on a systematic review, 20% of pregnant women with asthma require some intervention for an asthma exacerbation during pregnancy, and 5.8% are admitted to the hospital for an exacerbation.¹¹ Exacerbations were associated with a higher risk of low birth weight compared with rates in women without asthma.

Exacerbations are more common late in the second trimester and are unlikely to occur during labor and delivery.²  The incidence of exacerbations increases with the severity of asthma, from 8% in mild asthma, to 47% in moderate asthma, to 65% in severe asthma.²⁷ Risk factors for exacerbations include poor prenatal care, obesity, and lack of appropriate treatment with inhaled corticosteroids.² The main triggers are viral respiratory infections and noncompliance with inhaled corticosteroid therapy.¹¹

Asthma exacerbations during pregnancy should be managed aggressively (Table 4),¹² as the risk to the fetus of hypoxia far outweighs any risk from asthma medications. Close collaboration between the primary care physician and the obstetrician allows closer monitoring of mother and fetus.

The goal oxygen saturation must be above 95%.¹² Signs of acute respiratory failure in a pregnant patient include a partial pressure of arterial oxygen less than 70 mm Hg or a partial pressure of carbon dioxide greater than 35 mm Hg.

In a multicenter study comparing nonpregnant and pregnant women visiting the emergency room for asthma exacerbations,²⁸ pregnant women were less likely to be prescribed systemic corticosteroids either in the emergency room or at the time of hospital discharge, and they were also more likely to describe an ongoing exacerbation at 2-week follow-up. However, a recent study showed a significant increase in systemic corticosteroid treatment in the emergency room (51% to 78% across the time periods, odds ratio 3.11, 95% confidence interval 1.27–7.60, P = .01). There was also an increase in steroid treatment at discharge (42% to 63%, odds ratio 2.49, 95% confidence interval 0.97–6.37, P = .054), though the increase was not statistically significant.²⁹ Although emergency room care for pregnant asthmatic women has improved, this group concluded that further improvement is still warranted, as 1 in 3 women is discharged without corticosteroid treatment.

Helicobacter pylori infection is an infectious disease and should be treated like one, with due consideration of antibiotic resistance and stewardship.^1–4

This was the consensus of the 2015 Kyoto H pylori conference,² and it signaled a fundamental shift in thinking. Up to now, H pylori treatment has not been based on infectious disease principles, leading to suboptimal results and antibiotic resistance. In addition, the conference recommended that H pylori infection be treated whenever it is found unless there are compelling reasons not to.

Here we review current and possible future regimens for eradicating H pylori that we hope will be more effective and will lead to less resistance than in the past.

H PYLORI AS AN INFECTIOUS DISEASE

Not until the late 1980s was H pylori recognized as the cause of peptic ulcer disease, which until then accounted for hundreds of thousands of hospitalizations and more than 100,000 surgical procedures each year.⁵ Now, peptic ulcer disease is routinely treated by eradicating H pylori. In addition, the World Health Organization has recommended considering H pylori eradication to reduce the risk of gastric cancer,⁶ which causes 738,000 deaths worldwide per year.⁷

The problems of how to diagnose and treat H pylori infection were taken on by gastroenterologists, and not by specialists in infectious disease.¹ Even now, almost all the major reviews and consensus statements on H pylori come from gastroenterologists and are published in gastroenterology journals.^2,8,9

But infectious diseases differ from most gastrointestinal diseases. In gastrointestinal problems such as constipation or inflammatory bowel disease,¹⁰ the causes are generally unknown, and there is a large placebo response to therapy. In contrast, in infectious diseases, the cause is generally known, there is no placebo response, and treatment success depends on susceptibility of the organism. Failure of proven regimens is generally due to resistant organisms, poor adherence, or, in the case of H pylori, poorly designed regimens in terms of doses, frequency of administration, or duration of therapy.

The differences extend to clinical trials of treatment.³ In other infectious diseases, treatment is based on susceptibility. The usual comparative approach in infectious diseases is a noninferiority trial in which the new treatment is compared with standard care, ie, a regimen that reliably achieves nearly 100% cure rates. Not so with H pylori. Most trials of H pylori therapy compared regimens in populations with high but unknown prevalences of resistance and therefore are of limited or no help to the clinician in choosing the best regimen for an individual patient.³

Many thousands of H pylori-infected patients participated in clinical trials in which the results would have been predictable if the researchers had assessed susceptibility before giving the drugs.^11–13 Worse, many patients were also randomized to receive regimens that the investigators knew provided poor cure rates in the population being studied. This knowledge was generally not shared with the patients. This approach was used to demonstrate that a new regimen was superior to an old one, even though the new one was already known to be less affected by resistance to the key element in the comparator.

Clinicians generally do not test for susceptibility when treating H pylori, one reason being that such testing is often unavailable.³ However, almost every hospital, clinic, and major laboratory in the world provides susceptibility testing for other common local pathogens. H pylori is easy to grow, and laboratories could test for susceptibility if we asked them to.

Current H pylori recommendations may also contribute to the global increase in antimicrobal resistance.

As discussed below, all recent guidelines have recommended 4-drug non-bismuth-containing concomitant therapy as first-line therapy. An infectious disease colleague described it as a “hope therapy” because the prescriber hoped that the infection would be susceptible to either metronidazole or clarithromycin. All who receive this combination receive an antibiotic they do not need. This is an expedient rather than a medically rational choice resulting from failure to deal with H pylori as an infectious disease.

H PYLORI THERAPIES

Conceptually, treating infectious disease is straightforward: one should prescribe antimicrobial drugs to which the organism is susceptible³ (Table 1). However, clinical success lies in the details, which include the doses, frequency of doses, duration of therapy, timing of doses in relation to meals, and use of adjuvants such as antisecretory drugs, antacids, and probiotics. A number of regimens reliably yield high cure rates—95% or higher—if the organism is susceptible and the patients are adherent.

The effectiveness of any regimen may vary depending on the population it is used in, due to polymorphisms in drug-metabolizing enzymes such as CYP2C19.

Sequential therapy is obsolete

Sequential therapy for H pylori infection consisted of amoxicillin plus a proton pump inhibitor for 7 days, followed by clarithromycin, tinidazole, or metronidazole plus a proton pump inhibitor for a further 7 days. This regimen should not be used any more because concomitant therapy will always be superior (see below).

 

 

Need for 14 days of therapy

H pylori occupies a number of different niches in the body ranging from gastric mucus (which is technically outside the body) to inside gastric epithelial cells. As a general rule, 14-day therapy provides the best results, in part because the longer duration helps kill the organisms that persist in different niches.^14,15

In addition, proton pump inhibitors, which are part of all the currently recommended regimens, require 3 or more days to reach their full antisecretory effectiveness, which further limits the effectiveness of short-duration therapies.

Shorter regimens should be used only if they are proved to be as good as 14-day regimens and if both achieve 95% or greater cure rates with susceptible infections.

How to choose a therapy

Since rational infectious-disease therapy is based on susceptibility, one should start by considering the susceptibility pattern in the local population and, therefore, the likely susceptibility in the patient in front of us.

Unfortunately, we do not yet have local or regional susceptibility data on H pylori for most locales. Until those data are available, we must use the indirect information that is available, such as the patient’s history of antibiotic use.

Triple therapy should not be used empirically

Triple therapy (Table 1) consists of the combination of:

• Clarithromycin or metronidazole or a fluoroquinolone
• Amoxicillin
• A proton pump inhibitor.

However, prior use of a macrolide (eg, erythromycin, clarithromycin, or azithromycin), metronidazole, or a fluoroquinolone (eg, ciprofloxacin, levofloxacin) almost guarantees resistance to those drugs. In the United States, resistance to clarithromycin, metronidazole, levofloxacin, and related drugs is already widespread, and none should be used empirically in triple therapies. In contrast, amoxicillin, tetracycline, and furazolidone can often be used again, as resistance to them is rare even with prior use.

For example, 14 days of clarithromycin triple therapy (clarithromycin, amoxicillin, and a proton pump inhibitor) can be expected to cure more than 95% of patients who have susceptible infections and about 20% of those with resistant infections.¹⁶ This 20% is due to the proton pump inhibitor and amoxicillin, as the contribution to the cure rate from clarithromycin is close to zero.

If the prevalence of resistance to clarithromycin is 25%, the cure rate in the entire population will be a little more than 75%—97% in the 75% of the population with susceptible infections and 20% in patients who previously received clarithromycin (Figure 1).

Based on Graham DY. Hp-normogram (normo-graham) for assessing the outcome of H. pylori therapy: effect of resistance, duration, and CYP2C19 genotype. Helicobacter 2015; 21:85–90.

If we know that our patient has an infection that is susceptible to clarithromycin, metronidazole, or levofloxacin, good results could be achieved with triple therapy that includes a proton pump inhibitor, for 14 days. Fluoroquinolones have a number of black-box warnings from the US Food and Drug Administration (www.fda.gov/Drugs/DrugSafety/ucm500143.htm) and should always be a last choice. However, in the United States, lacking definite data about susceptibility to clarithromycin, metronidazole, and levofloxacin, we should assume resistance is present and use a 4-drug regimen (eg, concomitant therapy or bismuth quadruple therapy).

Concomitant therapy is preferred

Concomitant therapy is the combination of:

• Amoxicillin
• Metronidazole
• Clarithromycin
• A proton pump inhibitor.

Functionally, this is a combination of clarithromycin and metronidazole triple therapies, given simultaneously.¹⁷ The premise is that even though the prevalence of metronidazole resistance in the United States is high (20%–40%), and so is the prevalence of clarithromycin resistance (about 20%), the prevalence of resistance to both drugs at the same time is expected to be low (eg, 0.4 × 0.2 = 0.08, or 8%) unless the drugs had previously been used together, as in some older regimens that contained both. Thus, the metronidazole will kill the clarithromycin-resistant but metronidazole-susceptible strains, and the clarithromycin will kill the clarithromycin-susceptible, metronidazole-resistant strains. Only with dual resistant strains will this regimen fail (with a 20% cure rate due to the proton pump inhibitor and amoxicillin and a population cure rate of slightly more than 90%).

The downside of this highly recommended therapy is that all who receive it are getting an antibiotic that they don’t need, which is, in a global sense, inappropriate. In other words, all those who are cured by clarithromycin also receive metronidazole, which plays no role in treatment success, and those cured by metronidazole receive unneeded clarithromycin (Figure 2). Had susceptibility testing been available, those with susceptible strains would have received appropriate triple therapies, and those with dual resistance would not have received either antibiotic.

Thus, while we recommend concomitant therapy as an empiric regimen in populations that do not have high levels of resistance to metronidazole or clarithromycin (as those would also have a high prevalence of dual resistance), one must be aware of the “dirty little secret” of inappropriate antibiotic use that accompanies it and some other H pylori therapies (eg, vonoprazan triple therapy in Japan).^18–20

 

 

Bismuth quadruple therapy is an alternative

Bismuth quadruple therapy (Table 1) consists of:

• Bismuth
• Tetracycline
• Metronidazole
• A proton pump inhibitor.

This was the first truly effective regimen for H pylori. Its advantage is that it can partially or completely overcome metronidazole resistance.^21,22 As such, it is potentially ideal, as it should be effective despite resistance to clarithromycin, metronidazole, or levofloxacin, and it can be used in patients allergic to penicillin.

The major downside is a high frequency of side effects, particularly abdominal pain, nausea, and vomiting, often resulting in poor adherence. Most regimens that contain antibiotics have side effects, but adherence seems to be more of a problem with bismuth quadruple therapy, probably because of the combination of the high doses of metronidazole and tetracycline.²² In our experience, this regimen can be effective if the physician takes the time to explain to the patient that side effects are common but treatment success depends on completing the full course of 14 days.

Another problem is that tetracycline has become difficult to obtain in many areas, and doxycycline cannot be substituted in those with metronidazole resistance. To date, it has been difficult or impossible to obtain the same excellent results with doxycycline as can be obtained with tetracycline. It is not clear why.²¹

To use bismuth quadruple therapy one must often use a name-brand product, Pylera. Pylera is packaged as a 10-day course, which is effective against metronidazole-susceptible infections. However, 14 days are generally required to achieve a high cure rate with metronidazole-resistant infections, which are the main indication for use of this product. Moreover, Pylera does not include a proton pump inhibitor, which must be prescribed separately.

In the United States, Pylera is expensive, costing $740 to $790 with a coupon for a 10-day supply and proportionally more for the required 14-day supply (www.goodrx.com/pylera?drug-name=pylera), whereas in Europe it costs less than 70 Euros ($73).²¹ If generic tetracycline is available, the US cost for 14 days of generic bismuth quadruple therapy is less than $50.

An alternate and simpler approach is to substitute amoxicillin for tetracycline.²³ This regimen has been used successfully in China and was shown to be noninferior to the tetracycline-containing regimen in a head-to-head comparison.²⁴

Recent studies have confirmed earlier Italian studies suggesting that twice-a-day bismuth and tetracycline is effective, which would further simplify therapy and possibly reduce side effects.^21,23,24 These variations on bismuth quadruple therapy have not yet been optimized to where one can reliably achieve 95% or greater cure rates, and further studies are needed.

Why include more than 1 antibiotic?

The H pylori load in the stomach is typically large, which increases the odds that a subpopulation of resistant organisms is present. Resistance may be due to a relatively high rate of mutation in certain bacterial genes.²⁵ This is particularly a problem with clarithromycin, metronidazole, and fluoroquinolones and is reflected in a high rate of resistance among patients for whom single-drug regimens have failed. These drugs are always given with a second antimicrobial to which H pylori rarely becomes resistant, such as amoxicillin or tetracycline.

Why include a proton pump inhibitor?

An antisecretory drug is needed to increase the gastric pH, which makes antimicrobial therapy more effective. It also decreases antibiotic washout from the stomach and likely protects and increases the gastric concentration of some antibiotics.

The activities of amoxicillin, fluoroquinolones, and to a lesser degree clarithromycin are pH-dependent. For example, keeping the gastric pH above 6.0 promotes H pylori replication,^26,27 making it is more susceptible to amoxicillin (reviewed in detail by Dore et al²¹). A gastric pH of 6.0 or more is very difficult to achieve with proton pump inhibitors, and has been accomplished regularly only in people who metabolize these drugs slowly (“slow metabolizers”) who received both the proton pump inhibitor and amoxicillin every 6 hours for 14 days.²¹

With standard clarithromycin, metronidazole, or fluoroquinolone triple therapy, proton pump inhibitors appear to provide satisfactory cure rates when given for 14 days in standard doses. However, double doses (eg, 40 mg of omeprazole or an equivalent) may be slightly better, especially in the presence of resistance.

The cure rate reflects the sum of the 2 populations of organisms: the susceptible and the resistant. In triple therapy, increasing the gastric pH with a proton pump inhibitor makes the amoxicillin component of the regimen more effective against resistant organisms and thus increases the cure rate. For example, in Western countries, esomeprazole  40 mg (approximately equivalent to rabeprazole 40 mg, omeprazole or lansoprazole 60 mg, or pantoprazole 240 mg)²⁸ given twice a day in a 14-day triple therapy regimen cures about 40% to 50% of resistant infections. This benefit will be evident in an improvement in cure rates in populations in which resistance has reduced the average cure rate. This is also why meta-analyses have shown better results with second-generation proton pump inhibitors and with longer duration of therapy.^29,30

Generally, we recommend omeprazole 40 mg twice a day or an equivalent (Tables 1–3).

Would a potassium-competitive acid blocker be better than a proton pump inhibitor?

Vonoprazan is a potassium-competitive acid blocker. It does not require intermediate complex formation and is stable at low pH. It has a longer half-life than proton pump inhibitors, and its bioavailability is unaffected by food.³¹ It was recently approved in Japan for H pylori eradication in combination with clarithromycin or metronidazole plus amoxicillin.¹⁸

Vonoprazan is more effective than current proton pump inhibitors for keeping the gastric pH high. There are no published studies of vonoprazan dual therapy in Western countries, but given twice a day for 7 days along with twice-daily amoxicillin it cured only approximately 80% of clarithromycin-resistant strains. Further studies are needed to identify the optimum proton pump inhibitor or potassium-competitive acid blocker, dose, and duration.

 

 

Misuse of antibiotics

In triple therapy, the second antimicrobial drug (eg, amoxicillin) is given in part to prevent resistance from developing. It is not clear whether the combination is additive or synergistic, but until we can reliably maintain the intragastric pH above 6.0, which would increase the effectiveness of the amoxicillin component of the regimen, this practice cannot be considered as misuse of antibiotics.

In contrast, in the 4-drug nonbismuth combinations (concomitant, sequential, and hybrid therapies) and the new vonoprazan, clarithromycin, and metronidazole triple therapies, 1 of the antibiotics provides no benefit to some, often most, of the patients.^18–20,32 This practice should end when susceptibility data become more widely available and when vonoprazan becomes available, so that we can deliver effective vonoprazan-amoxicillin dual therapy.

First-, second-, and third-line therapies

Many recommendations give advice in terms of first-, second-, and third-line therapies. In practice, a physician should have at least 2 first-line regimens (a first and a second choice). Both should be proven highly successful as empiric therapies in one’s patient population but differ in terms of primary antibiotics. This approach allows the clinician to tailor therapy depending on whether he or she suspects antibiotic resistance (eg, if the patient has taken clarithromycin before) or the patient is allergic or cannot take 1 or more drugs.

Two treatment failures with 2 different regimens known to be effective suggest poor compliance (a difficult patient) or a multiple-drug-resistant infection (a difficult infection). That patient would require salvage therapy (Table 2), which logically should be based on antimicrobial testing or, at a minimum, consultation with someone who frequently deals with this problem.

Test of cure

Monitoring the outcome of therapy (testing for cure) is essential, as it provides a reliable measure of the local effectiveness of particular therapies and also serves as an early warning of development of resistance in one’s patient population.¹⁴

Unless there are compelling reasons, testing for cure should use noninvasive testing with the urea breath test or stool antigen test. It is recommended that this be delayed at least 4 weeks to allow the organisms if still present to repopulate the stomach sufficiently for the tests to become positive. Because antibiotics, bismuth, and proton pump inhibitors reduce the bacterial load, they should be withheld at least 2 weeks before testing. Histamine-2 receptor antagonists can be substituted for proton pump inhibitors if antisecretory therapy is needed for symptoms, and continued up to the day before testing. The urea breath test should contain citric acid to overcome any residual pH effects. Physician groups should share their experience so as to alert the community about which therapies should likely be avoided.³³

Salvage therapy

Salvage therapy is given after 2 or more treatment failures with different antibiotics. Ideally, the regimen should be based on the results of antimicrobial testing. Current regimens include rifabutin triple therapy, dual therapy (a protein pump inhibitor or vonoprazan and amoxicillin), or furazolidone quadruple therapy (Table 2).

Furazolidone is a synthetic nitrofuran derivative that is effective against many enteric organisms, including gram-negative bacteria and protozoa. It is not available in most Western countries but is available in many other parts of the world.^34,35 It is also a monoamine oxidase inhibitor and thus interacts with many drugs and foods (eg, soy sauce, aged cheeses), leading to a relatively high rate of side effects such as fever, palpitations, and skin rash.

Rifabutin-containing regimens, generally, a proton pump inhibitor, amoxicillin 1 g, and rifabutin 150 mg, all twice a day (Table 3) provide average cure rates of less than 80% (typically in the mid-70% range).³⁶ Borody et al³⁷ reported greater than 95% success with a 12-day regimen consisting of rifabutin 150 mg once daily (half-dose), amoxicillin 1.5 g 3 times a day, and pantoprazole 80 mg (approximately equivalent to omeprazole 20 mg) 3 times a day. Ciccaglione et al,³⁸ in a small study, used a 10-day quadruple regimen containing a proton pump inhibitor, amoxicillin, rifabutin, and bismuth (all twice a day), with high cure rates. The results of these studies are yet to be confirmed, and the optimal rifabutin-containing regimen remains to be determined.

PROBIOTICS

There is considerable interest in using probiotics to enhance the effectiveness of antimicrobial therapy for H pylori by increasing tolerability, reducing side effects, and therefore improving compliance.^39,40

In a meta-analysis of 14 randomized trials (N = 1,671), when probiotics were added, pooled H pylori eradication rates were only slightly improved: 83.6% (95% CI 80.5%–86.7%) with probiotics and 74.8% (95% CI 71.1%–78.5%) without probiotics by intent-to-treat analysis.⁴¹

Another meta-analysis of probiotics suggested that those containing Saccharomyces boulardii, Lactobacillus, and Bifidobacterium significantly increased the eradication rate of triple therapy in populations with high rates of antimicrobial resistance and reduced the risk of overall H pylori therapy-related adverse effects, especially diarrhea.^42,43

At present, we recommend that probiotics be considered only for patients who are likely not to comply with treatment (eg, those with irritable bowel syndrome or difficulty taking antibiotics), to try to take advantage of their ability to improve antibiotic tolerability.

Helicobacter pylori infection is an infectious disease and should be treated like one, with due consideration of antibiotic resistance and stewardship.^1–4

This was the consensus of the 2015 Kyoto H pylori conference,² and it signaled a fundamental shift in thinking. Up to now, H pylori treatment has not been based on infectious disease principles, leading to suboptimal results and antibiotic resistance. In addition, the conference recommended that H pylori infection be treated whenever it is found unless there are compelling reasons not to.

Here we review current and possible future regimens for eradicating H pylori that we hope will be more effective and will lead to less resistance than in the past.

H PYLORI AS AN INFECTIOUS DISEASE

Not until the late 1980s was H pylori recognized as the cause of peptic ulcer disease, which until then accounted for hundreds of thousands of hospitalizations and more than 100,000 surgical procedures each year.⁵ Now, peptic ulcer disease is routinely treated by eradicating H pylori. In addition, the World Health Organization has recommended considering H pylori eradication to reduce the risk of gastric cancer,⁶ which causes 738,000 deaths worldwide per year.⁷

The problems of how to diagnose and treat H pylori infection were taken on by gastroenterologists, and not by specialists in infectious disease.¹ Even now, almost all the major reviews and consensus statements on H pylori come from gastroenterologists and are published in gastroenterology journals.^2,8,9

But infectious diseases differ from most gastrointestinal diseases. In gastrointestinal problems such as constipation or inflammatory bowel disease,¹⁰ the causes are generally unknown, and there is a large placebo response to therapy. In contrast, in infectious diseases, the cause is generally known, there is no placebo response, and treatment success depends on susceptibility of the organism. Failure of proven regimens is generally due to resistant organisms, poor adherence, or, in the case of H pylori, poorly designed regimens in terms of doses, frequency of administration, or duration of therapy.

The differences extend to clinical trials of treatment.³ In other infectious diseases, treatment is based on susceptibility. The usual comparative approach in infectious diseases is a noninferiority trial in which the new treatment is compared with standard care, ie, a regimen that reliably achieves nearly 100% cure rates. Not so with H pylori. Most trials of H pylori therapy compared regimens in populations with high but unknown prevalences of resistance and therefore are of limited or no help to the clinician in choosing the best regimen for an individual patient.³

Many thousands of H pylori-infected patients participated in clinical trials in which the results would have been predictable if the researchers had assessed susceptibility before giving the drugs.^11–13 Worse, many patients were also randomized to receive regimens that the investigators knew provided poor cure rates in the population being studied. This knowledge was generally not shared with the patients. This approach was used to demonstrate that a new regimen was superior to an old one, even though the new one was already known to be less affected by resistance to the key element in the comparator.

Clinicians generally do not test for susceptibility when treating H pylori, one reason being that such testing is often unavailable.³ However, almost every hospital, clinic, and major laboratory in the world provides susceptibility testing for other common local pathogens. H pylori is easy to grow, and laboratories could test for susceptibility if we asked them to.

Current H pylori recommendations may also contribute to the global increase in antimicrobal resistance.

As discussed below, all recent guidelines have recommended 4-drug non-bismuth-containing concomitant therapy as first-line therapy. An infectious disease colleague described it as a “hope therapy” because the prescriber hoped that the infection would be susceptible to either metronidazole or clarithromycin. All who receive this combination receive an antibiotic they do not need. This is an expedient rather than a medically rational choice resulting from failure to deal with H pylori as an infectious disease.

H PYLORI THERAPIES

Conceptually, treating infectious disease is straightforward: one should prescribe antimicrobial drugs to which the organism is susceptible³ (Table 1). However, clinical success lies in the details, which include the doses, frequency of doses, duration of therapy, timing of doses in relation to meals, and use of adjuvants such as antisecretory drugs, antacids, and probiotics. A number of regimens reliably yield high cure rates—95% or higher—if the organism is susceptible and the patients are adherent.

The effectiveness of any regimen may vary depending on the population it is used in, due to polymorphisms in drug-metabolizing enzymes such as CYP2C19.

Sequential therapy is obsolete

Sequential therapy for H pylori infection consisted of amoxicillin plus a proton pump inhibitor for 7 days, followed by clarithromycin, tinidazole, or metronidazole plus a proton pump inhibitor for a further 7 days. This regimen should not be used any more because concomitant therapy will always be superior (see below).

 

 

Need for 14 days of therapy

H pylori occupies a number of different niches in the body ranging from gastric mucus (which is technically outside the body) to inside gastric epithelial cells. As a general rule, 14-day therapy provides the best results, in part because the longer duration helps kill the organisms that persist in different niches.^14,15

In addition, proton pump inhibitors, which are part of all the currently recommended regimens, require 3 or more days to reach their full antisecretory effectiveness, which further limits the effectiveness of short-duration therapies.

Shorter regimens should be used only if they are proved to be as good as 14-day regimens and if both achieve 95% or greater cure rates with susceptible infections.

How to choose a therapy

Since rational infectious-disease therapy is based on susceptibility, one should start by considering the susceptibility pattern in the local population and, therefore, the likely susceptibility in the patient in front of us.

Unfortunately, we do not yet have local or regional susceptibility data on H pylori for most locales. Until those data are available, we must use the indirect information that is available, such as the patient’s history of antibiotic use.

Triple therapy should not be used empirically

Triple therapy (Table 1) consists of the combination of:

• Clarithromycin or metronidazole or a fluoroquinolone
• Amoxicillin
• A proton pump inhibitor.

However, prior use of a macrolide (eg, erythromycin, clarithromycin, or azithromycin), metronidazole, or a fluoroquinolone (eg, ciprofloxacin, levofloxacin) almost guarantees resistance to those drugs. In the United States, resistance to clarithromycin, metronidazole, levofloxacin, and related drugs is already widespread, and none should be used empirically in triple therapies. In contrast, amoxicillin, tetracycline, and furazolidone can often be used again, as resistance to them is rare even with prior use.

For example, 14 days of clarithromycin triple therapy (clarithromycin, amoxicillin, and a proton pump inhibitor) can be expected to cure more than 95% of patients who have susceptible infections and about 20% of those with resistant infections.¹⁶ This 20% is due to the proton pump inhibitor and amoxicillin, as the contribution to the cure rate from clarithromycin is close to zero.

If the prevalence of resistance to clarithromycin is 25%, the cure rate in the entire population will be a little more than 75%—97% in the 75% of the population with susceptible infections and 20% in patients who previously received clarithromycin (Figure 1).

Based on Graham DY. Hp-normogram (normo-graham) for assessing the outcome of H. pylori therapy: effect of resistance, duration, and CYP2C19 genotype. Helicobacter 2015; 21:85–90.

If we know that our patient has an infection that is susceptible to clarithromycin, metronidazole, or levofloxacin, good results could be achieved with triple therapy that includes a proton pump inhibitor, for 14 days. Fluoroquinolones have a number of black-box warnings from the US Food and Drug Administration (www.fda.gov/Drugs/DrugSafety/ucm500143.htm) and should always be a last choice. However, in the United States, lacking definite data about susceptibility to clarithromycin, metronidazole, and levofloxacin, we should assume resistance is present and use a 4-drug regimen (eg, concomitant therapy or bismuth quadruple therapy).

Concomitant therapy is preferred

Concomitant therapy is the combination of:

• Amoxicillin
• Metronidazole
• Clarithromycin
• A proton pump inhibitor.

Functionally, this is a combination of clarithromycin and metronidazole triple therapies, given simultaneously.¹⁷ The premise is that even though the prevalence of metronidazole resistance in the United States is high (20%–40%), and so is the prevalence of clarithromycin resistance (about 20%), the prevalence of resistance to both drugs at the same time is expected to be low (eg, 0.4 × 0.2 = 0.08, or 8%) unless the drugs had previously been used together, as in some older regimens that contained both. Thus, the metronidazole will kill the clarithromycin-resistant but metronidazole-susceptible strains, and the clarithromycin will kill the clarithromycin-susceptible, metronidazole-resistant strains. Only with dual resistant strains will this regimen fail (with a 20% cure rate due to the proton pump inhibitor and amoxicillin and a population cure rate of slightly more than 90%).

The downside of this highly recommended therapy is that all who receive it are getting an antibiotic that they don’t need, which is, in a global sense, inappropriate. In other words, all those who are cured by clarithromycin also receive metronidazole, which plays no role in treatment success, and those cured by metronidazole receive unneeded clarithromycin (Figure 2). Had susceptibility testing been available, those with susceptible strains would have received appropriate triple therapies, and those with dual resistance would not have received either antibiotic.

Thus, while we recommend concomitant therapy as an empiric regimen in populations that do not have high levels of resistance to metronidazole or clarithromycin (as those would also have a high prevalence of dual resistance), one must be aware of the “dirty little secret” of inappropriate antibiotic use that accompanies it and some other H pylori therapies (eg, vonoprazan triple therapy in Japan).^18–20

 

 

Bismuth quadruple therapy is an alternative

Bismuth quadruple therapy (Table 1) consists of:

• Bismuth
• Tetracycline
• Metronidazole
• A proton pump inhibitor.

This was the first truly effective regimen for H pylori. Its advantage is that it can partially or completely overcome metronidazole resistance.^21,22 As such, it is potentially ideal, as it should be effective despite resistance to clarithromycin, metronidazole, or levofloxacin, and it can be used in patients allergic to penicillin.

The major downside is a high frequency of side effects, particularly abdominal pain, nausea, and vomiting, often resulting in poor adherence. Most regimens that contain antibiotics have side effects, but adherence seems to be more of a problem with bismuth quadruple therapy, probably because of the combination of the high doses of metronidazole and tetracycline.²² In our experience, this regimen can be effective if the physician takes the time to explain to the patient that side effects are common but treatment success depends on completing the full course of 14 days.

Another problem is that tetracycline has become difficult to obtain in many areas, and doxycycline cannot be substituted in those with metronidazole resistance. To date, it has been difficult or impossible to obtain the same excellent results with doxycycline as can be obtained with tetracycline. It is not clear why.²¹

To use bismuth quadruple therapy one must often use a name-brand product, Pylera. Pylera is packaged as a 10-day course, which is effective against metronidazole-susceptible infections. However, 14 days are generally required to achieve a high cure rate with metronidazole-resistant infections, which are the main indication for use of this product. Moreover, Pylera does not include a proton pump inhibitor, which must be prescribed separately.

In the United States, Pylera is expensive, costing $740 to $790 with a coupon for a 10-day supply and proportionally more for the required 14-day supply (www.goodrx.com/pylera?drug-name=pylera), whereas in Europe it costs less than 70 Euros ($73).²¹ If generic tetracycline is available, the US cost for 14 days of generic bismuth quadruple therapy is less than $50.

An alternate and simpler approach is to substitute amoxicillin for tetracycline.²³ This regimen has been used successfully in China and was shown to be noninferior to the tetracycline-containing regimen in a head-to-head comparison.²⁴

Recent studies have confirmed earlier Italian studies suggesting that twice-a-day bismuth and tetracycline is effective, which would further simplify therapy and possibly reduce side effects.^21,23,24 These variations on bismuth quadruple therapy have not yet been optimized to where one can reliably achieve 95% or greater cure rates, and further studies are needed.

Why include more than 1 antibiotic?

The H pylori load in the stomach is typically large, which increases the odds that a subpopulation of resistant organisms is present. Resistance may be due to a relatively high rate of mutation in certain bacterial genes.²⁵ This is particularly a problem with clarithromycin, metronidazole, and fluoroquinolones and is reflected in a high rate of resistance among patients for whom single-drug regimens have failed. These drugs are always given with a second antimicrobial to which H pylori rarely becomes resistant, such as amoxicillin or tetracycline.

Why include a proton pump inhibitor?

An antisecretory drug is needed to increase the gastric pH, which makes antimicrobial therapy more effective. It also decreases antibiotic washout from the stomach and likely protects and increases the gastric concentration of some antibiotics.

The activities of amoxicillin, fluoroquinolones, and to a lesser degree clarithromycin are pH-dependent. For example, keeping the gastric pH above 6.0 promotes H pylori replication,^26,27 making it is more susceptible to amoxicillin (reviewed in detail by Dore et al²¹). A gastric pH of 6.0 or more is very difficult to achieve with proton pump inhibitors, and has been accomplished regularly only in people who metabolize these drugs slowly (“slow metabolizers”) who received both the proton pump inhibitor and amoxicillin every 6 hours for 14 days.²¹

With standard clarithromycin, metronidazole, or fluoroquinolone triple therapy, proton pump inhibitors appear to provide satisfactory cure rates when given for 14 days in standard doses. However, double doses (eg, 40 mg of omeprazole or an equivalent) may be slightly better, especially in the presence of resistance.

The cure rate reflects the sum of the 2 populations of organisms: the susceptible and the resistant. In triple therapy, increasing the gastric pH with a proton pump inhibitor makes the amoxicillin component of the regimen more effective against resistant organisms and thus increases the cure rate. For example, in Western countries, esomeprazole  40 mg (approximately equivalent to rabeprazole 40 mg, omeprazole or lansoprazole 60 mg, or pantoprazole 240 mg)²⁸ given twice a day in a 14-day triple therapy regimen cures about 40% to 50% of resistant infections. This benefit will be evident in an improvement in cure rates in populations in which resistance has reduced the average cure rate. This is also why meta-analyses have shown better results with second-generation proton pump inhibitors and with longer duration of therapy.^29,30

Generally, we recommend omeprazole 40 mg twice a day or an equivalent (Tables 1–3).

Would a potassium-competitive acid blocker be better than a proton pump inhibitor?

Vonoprazan is a potassium-competitive acid blocker. It does not require intermediate complex formation and is stable at low pH. It has a longer half-life than proton pump inhibitors, and its bioavailability is unaffected by food.³¹ It was recently approved in Japan for H pylori eradication in combination with clarithromycin or metronidazole plus amoxicillin.¹⁸

Vonoprazan is more effective than current proton pump inhibitors for keeping the gastric pH high. There are no published studies of vonoprazan dual therapy in Western countries, but given twice a day for 7 days along with twice-daily amoxicillin it cured only approximately 80% of clarithromycin-resistant strains. Further studies are needed to identify the optimum proton pump inhibitor or potassium-competitive acid blocker, dose, and duration.

 

 

Misuse of antibiotics

In triple therapy, the second antimicrobial drug (eg, amoxicillin) is given in part to prevent resistance from developing. It is not clear whether the combination is additive or synergistic, but until we can reliably maintain the intragastric pH above 6.0, which would increase the effectiveness of the amoxicillin component of the regimen, this practice cannot be considered as misuse of antibiotics.

In contrast, in the 4-drug nonbismuth combinations (concomitant, sequential, and hybrid therapies) and the new vonoprazan, clarithromycin, and metronidazole triple therapies, 1 of the antibiotics provides no benefit to some, often most, of the patients.^18–20,32 This practice should end when susceptibility data become more widely available and when vonoprazan becomes available, so that we can deliver effective vonoprazan-amoxicillin dual therapy.

First-, second-, and third-line therapies

Many recommendations give advice in terms of first-, second-, and third-line therapies. In practice, a physician should have at least 2 first-line regimens (a first and a second choice). Both should be proven highly successful as empiric therapies in one’s patient population but differ in terms of primary antibiotics. This approach allows the clinician to tailor therapy depending on whether he or she suspects antibiotic resistance (eg, if the patient has taken clarithromycin before) or the patient is allergic or cannot take 1 or more drugs.

Two treatment failures with 2 different regimens known to be effective suggest poor compliance (a difficult patient) or a multiple-drug-resistant infection (a difficult infection). That patient would require salvage therapy (Table 2), which logically should be based on antimicrobial testing or, at a minimum, consultation with someone who frequently deals with this problem.

Test of cure

Monitoring the outcome of therapy (testing for cure) is essential, as it provides a reliable measure of the local effectiveness of particular therapies and also serves as an early warning of development of resistance in one’s patient population.¹⁴

Unless there are compelling reasons, testing for cure should use noninvasive testing with the urea breath test or stool antigen test. It is recommended that this be delayed at least 4 weeks to allow the organisms if still present to repopulate the stomach sufficiently for the tests to become positive. Because antibiotics, bismuth, and proton pump inhibitors reduce the bacterial load, they should be withheld at least 2 weeks before testing. Histamine-2 receptor antagonists can be substituted for proton pump inhibitors if antisecretory therapy is needed for symptoms, and continued up to the day before testing. The urea breath test should contain citric acid to overcome any residual pH effects. Physician groups should share their experience so as to alert the community about which therapies should likely be avoided.³³

Salvage therapy

Salvage therapy is given after 2 or more treatment failures with different antibiotics. Ideally, the regimen should be based on the results of antimicrobial testing. Current regimens include rifabutin triple therapy, dual therapy (a protein pump inhibitor or vonoprazan and amoxicillin), or furazolidone quadruple therapy (Table 2).

Furazolidone is a synthetic nitrofuran derivative that is effective against many enteric organisms, including gram-negative bacteria and protozoa. It is not available in most Western countries but is available in many other parts of the world.^34,35 It is also a monoamine oxidase inhibitor and thus interacts with many drugs and foods (eg, soy sauce, aged cheeses), leading to a relatively high rate of side effects such as fever, palpitations, and skin rash.

Rifabutin-containing regimens, generally, a proton pump inhibitor, amoxicillin 1 g, and rifabutin 150 mg, all twice a day (Table 3) provide average cure rates of less than 80% (typically in the mid-70% range).³⁶ Borody et al³⁷ reported greater than 95% success with a 12-day regimen consisting of rifabutin 150 mg once daily (half-dose), amoxicillin 1.5 g 3 times a day, and pantoprazole 80 mg (approximately equivalent to omeprazole 20 mg) 3 times a day. Ciccaglione et al,³⁸ in a small study, used a 10-day quadruple regimen containing a proton pump inhibitor, amoxicillin, rifabutin, and bismuth (all twice a day), with high cure rates. The results of these studies are yet to be confirmed, and the optimal rifabutin-containing regimen remains to be determined.

PROBIOTICS

There is considerable interest in using probiotics to enhance the effectiveness of antimicrobial therapy for H pylori by increasing tolerability, reducing side effects, and therefore improving compliance.^39,40

In a meta-analysis of 14 randomized trials (N = 1,671), when probiotics were added, pooled H pylori eradication rates were only slightly improved: 83.6% (95% CI 80.5%–86.7%) with probiotics and 74.8% (95% CI 71.1%–78.5%) without probiotics by intent-to-treat analysis.⁴¹

Another meta-analysis of probiotics suggested that those containing Saccharomyces boulardii, Lactobacillus, and Bifidobacterium significantly increased the eradication rate of triple therapy in populations with high rates of antimicrobial resistance and reduced the risk of overall H pylori therapy-related adverse effects, especially diarrhea.^42,43

At present, we recommend that probiotics be considered only for patients who are likely not to comply with treatment (eg, those with irritable bowel syndrome or difficulty taking antibiotics), to try to take advantage of their ability to improve antibiotic tolerability.

Helicobacter pylori infection is an infectious disease and should be treated like one, with due consideration of antibiotic resistance and stewardship.^1–4

This was the consensus of the 2015 Kyoto H pylori conference,² and it signaled a fundamental shift in thinking. Up to now, H pylori treatment has not been based on infectious disease principles, leading to suboptimal results and antibiotic resistance. In addition, the conference recommended that H pylori infection be treated whenever it is found unless there are compelling reasons not to.

Here we review current and possible future regimens for eradicating H pylori that we hope will be more effective and will lead to less resistance than in the past.

H PYLORI AS AN INFECTIOUS DISEASE

Not until the late 1980s was H pylori recognized as the cause of peptic ulcer disease, which until then accounted for hundreds of thousands of hospitalizations and more than 100,000 surgical procedures each year.⁵ Now, peptic ulcer disease is routinely treated by eradicating H pylori. In addition, the World Health Organization has recommended considering H pylori eradication to reduce the risk of gastric cancer,⁶ which causes 738,000 deaths worldwide per year.⁷

The problems of how to diagnose and treat H pylori infection were taken on by gastroenterologists, and not by specialists in infectious disease.¹ Even now, almost all the major reviews and consensus statements on H pylori come from gastroenterologists and are published in gastroenterology journals.^2,8,9

But infectious diseases differ from most gastrointestinal diseases. In gastrointestinal problems such as constipation or inflammatory bowel disease,¹⁰ the causes are generally unknown, and there is a large placebo response to therapy. In contrast, in infectious diseases, the cause is generally known, there is no placebo response, and treatment success depends on susceptibility of the organism. Failure of proven regimens is generally due to resistant organisms, poor adherence, or, in the case of H pylori, poorly designed regimens in terms of doses, frequency of administration, or duration of therapy.

The differences extend to clinical trials of treatment.³ In other infectious diseases, treatment is based on susceptibility. The usual comparative approach in infectious diseases is a noninferiority trial in which the new treatment is compared with standard care, ie, a regimen that reliably achieves nearly 100% cure rates. Not so with H pylori. Most trials of H pylori therapy compared regimens in populations with high but unknown prevalences of resistance and therefore are of limited or no help to the clinician in choosing the best regimen for an individual patient.³

Many thousands of H pylori-infected patients participated in clinical trials in which the results would have been predictable if the researchers had assessed susceptibility before giving the drugs.^11–13 Worse, many patients were also randomized to receive regimens that the investigators knew provided poor cure rates in the population being studied. This knowledge was generally not shared with the patients. This approach was used to demonstrate that a new regimen was superior to an old one, even though the new one was already known to be less affected by resistance to the key element in the comparator.

Clinicians generally do not test for susceptibility when treating H pylori, one reason being that such testing is often unavailable.³ However, almost every hospital, clinic, and major laboratory in the world provides susceptibility testing for other common local pathogens. H pylori is easy to grow, and laboratories could test for susceptibility if we asked them to.

Current H pylori recommendations may also contribute to the global increase in antimicrobal resistance.

As discussed below, all recent guidelines have recommended 4-drug non-bismuth-containing concomitant therapy as first-line therapy. An infectious disease colleague described it as a “hope therapy” because the prescriber hoped that the infection would be susceptible to either metronidazole or clarithromycin. All who receive this combination receive an antibiotic they do not need. This is an expedient rather than a medically rational choice resulting from failure to deal with H pylori as an infectious disease.

H PYLORI THERAPIES

Conceptually, treating infectious disease is straightforward: one should prescribe antimicrobial drugs to which the organism is susceptible³ (Table 1). However, clinical success lies in the details, which include the doses, frequency of doses, duration of therapy, timing of doses in relation to meals, and use of adjuvants such as antisecretory drugs, antacids, and probiotics. A number of regimens reliably yield high cure rates—95% or higher—if the organism is susceptible and the patients are adherent.

The effectiveness of any regimen may vary depending on the population it is used in, due to polymorphisms in drug-metabolizing enzymes such as CYP2C19.

Sequential therapy is obsolete

Sequential therapy for H pylori infection consisted of amoxicillin plus a proton pump inhibitor for 7 days, followed by clarithromycin, tinidazole, or metronidazole plus a proton pump inhibitor for a further 7 days. This regimen should not be used any more because concomitant therapy will always be superior (see below).

 

 

Need for 14 days of therapy

H pylori occupies a number of different niches in the body ranging from gastric mucus (which is technically outside the body) to inside gastric epithelial cells. As a general rule, 14-day therapy provides the best results, in part because the longer duration helps kill the organisms that persist in different niches.^14,15

In addition, proton pump inhibitors, which are part of all the currently recommended regimens, require 3 or more days to reach their full antisecretory effectiveness, which further limits the effectiveness of short-duration therapies.

Shorter regimens should be used only if they are proved to be as good as 14-day regimens and if both achieve 95% or greater cure rates with susceptible infections.

How to choose a therapy

Since rational infectious-disease therapy is based on susceptibility, one should start by considering the susceptibility pattern in the local population and, therefore, the likely susceptibility in the patient in front of us.

Unfortunately, we do not yet have local or regional susceptibility data on H pylori for most locales. Until those data are available, we must use the indirect information that is available, such as the patient’s history of antibiotic use.

Triple therapy should not be used empirically

Triple therapy (Table 1) consists of the combination of:

• Clarithromycin or metronidazole or a fluoroquinolone
• Amoxicillin
• A proton pump inhibitor.

However, prior use of a macrolide (eg, erythromycin, clarithromycin, or azithromycin), metronidazole, or a fluoroquinolone (eg, ciprofloxacin, levofloxacin) almost guarantees resistance to those drugs. In the United States, resistance to clarithromycin, metronidazole, levofloxacin, and related drugs is already widespread, and none should be used empirically in triple therapies. In contrast, amoxicillin, tetracycline, and furazolidone can often be used again, as resistance to them is rare even with prior use.

For example, 14 days of clarithromycin triple therapy (clarithromycin, amoxicillin, and a proton pump inhibitor) can be expected to cure more than 95% of patients who have susceptible infections and about 20% of those with resistant infections.¹⁶ This 20% is due to the proton pump inhibitor and amoxicillin, as the contribution to the cure rate from clarithromycin is close to zero.

If the prevalence of resistance to clarithromycin is 25%, the cure rate in the entire population will be a little more than 75%—97% in the 75% of the population with susceptible infections and 20% in patients who previously received clarithromycin (Figure 1).

Based on Graham DY. Hp-normogram (normo-graham) for assessing the outcome of H. pylori therapy: effect of resistance, duration, and CYP2C19 genotype. Helicobacter 2015; 21:85–90.

If we know that our patient has an infection that is susceptible to clarithromycin, metronidazole, or levofloxacin, good results could be achieved with triple therapy that includes a proton pump inhibitor, for 14 days. Fluoroquinolones have a number of black-box warnings from the US Food and Drug Administration (www.fda.gov/Drugs/DrugSafety/ucm500143.htm) and should always be a last choice. However, in the United States, lacking definite data about susceptibility to clarithromycin, metronidazole, and levofloxacin, we should assume resistance is present and use a 4-drug regimen (eg, concomitant therapy or bismuth quadruple therapy).

Concomitant therapy is preferred

Concomitant therapy is the combination of:

• Amoxicillin
• Metronidazole
• Clarithromycin
• A proton pump inhibitor.

Functionally, this is a combination of clarithromycin and metronidazole triple therapies, given simultaneously.¹⁷ The premise is that even though the prevalence of metronidazole resistance in the United States is high (20%–40%), and so is the prevalence of clarithromycin resistance (about 20%), the prevalence of resistance to both drugs at the same time is expected to be low (eg, 0.4 × 0.2 = 0.08, or 8%) unless the drugs had previously been used together, as in some older regimens that contained both. Thus, the metronidazole will kill the clarithromycin-resistant but metronidazole-susceptible strains, and the clarithromycin will kill the clarithromycin-susceptible, metronidazole-resistant strains. Only with dual resistant strains will this regimen fail (with a 20% cure rate due to the proton pump inhibitor and amoxicillin and a population cure rate of slightly more than 90%).

The downside of this highly recommended therapy is that all who receive it are getting an antibiotic that they don’t need, which is, in a global sense, inappropriate. In other words, all those who are cured by clarithromycin also receive metronidazole, which plays no role in treatment success, and those cured by metronidazole receive unneeded clarithromycin (Figure 2). Had susceptibility testing been available, those with susceptible strains would have received appropriate triple therapies, and those with dual resistance would not have received either antibiotic.

Thus, while we recommend concomitant therapy as an empiric regimen in populations that do not have high levels of resistance to metronidazole or clarithromycin (as those would also have a high prevalence of dual resistance), one must be aware of the “dirty little secret” of inappropriate antibiotic use that accompanies it and some other H pylori therapies (eg, vonoprazan triple therapy in Japan).^18–20

 

 

Bismuth quadruple therapy is an alternative

Bismuth quadruple therapy (Table 1) consists of:

• Bismuth
• Tetracycline
• Metronidazole
• A proton pump inhibitor.

This was the first truly effective regimen for H pylori. Its advantage is that it can partially or completely overcome metronidazole resistance.^21,22 As such, it is potentially ideal, as it should be effective despite resistance to clarithromycin, metronidazole, or levofloxacin, and it can be used in patients allergic to penicillin.

The major downside is a high frequency of side effects, particularly abdominal pain, nausea, and vomiting, often resulting in poor adherence. Most regimens that contain antibiotics have side effects, but adherence seems to be more of a problem with bismuth quadruple therapy, probably because of the combination of the high doses of metronidazole and tetracycline.²² In our experience, this regimen can be effective if the physician takes the time to explain to the patient that side effects are common but treatment success depends on completing the full course of 14 days.

Another problem is that tetracycline has become difficult to obtain in many areas, and doxycycline cannot be substituted in those with metronidazole resistance. To date, it has been difficult or impossible to obtain the same excellent results with doxycycline as can be obtained with tetracycline. It is not clear why.²¹

To use bismuth quadruple therapy one must often use a name-brand product, Pylera. Pylera is packaged as a 10-day course, which is effective against metronidazole-susceptible infections. However, 14 days are generally required to achieve a high cure rate with metronidazole-resistant infections, which are the main indication for use of this product. Moreover, Pylera does not include a proton pump inhibitor, which must be prescribed separately.

In the United States, Pylera is expensive, costing $740 to $790 with a coupon for a 10-day supply and proportionally more for the required 14-day supply (www.goodrx.com/pylera?drug-name=pylera), whereas in Europe it costs less than 70 Euros ($73).²¹ If generic tetracycline is available, the US cost for 14 days of generic bismuth quadruple therapy is less than $50.

An alternate and simpler approach is to substitute amoxicillin for tetracycline.²³ This regimen has been used successfully in China and was shown to be noninferior to the tetracycline-containing regimen in a head-to-head comparison.²⁴

Recent studies have confirmed earlier Italian studies suggesting that twice-a-day bismuth and tetracycline is effective, which would further simplify therapy and possibly reduce side effects.^21,23,24 These variations on bismuth quadruple therapy have not yet been optimized to where one can reliably achieve 95% or greater cure rates, and further studies are needed.

Why include more than 1 antibiotic?

The H pylori load in the stomach is typically large, which increases the odds that a subpopulation of resistant organisms is present. Resistance may be due to a relatively high rate of mutation in certain bacterial genes.²⁵ This is particularly a problem with clarithromycin, metronidazole, and fluoroquinolones and is reflected in a high rate of resistance among patients for whom single-drug regimens have failed. These drugs are always given with a second antimicrobial to which H pylori rarely becomes resistant, such as amoxicillin or tetracycline.

Why include a proton pump inhibitor?

An antisecretory drug is needed to increase the gastric pH, which makes antimicrobial therapy more effective. It also decreases antibiotic washout from the stomach and likely protects and increases the gastric concentration of some antibiotics.

The activities of amoxicillin, fluoroquinolones, and to a lesser degree clarithromycin are pH-dependent. For example, keeping the gastric pH above 6.0 promotes H pylori replication,^26,27 making it is more susceptible to amoxicillin (reviewed in detail by Dore et al²¹). A gastric pH of 6.0 or more is very difficult to achieve with proton pump inhibitors, and has been accomplished regularly only in people who metabolize these drugs slowly (“slow metabolizers”) who received both the proton pump inhibitor and amoxicillin every 6 hours for 14 days.²¹

With standard clarithromycin, metronidazole, or fluoroquinolone triple therapy, proton pump inhibitors appear to provide satisfactory cure rates when given for 14 days in standard doses. However, double doses (eg, 40 mg of omeprazole or an equivalent) may be slightly better, especially in the presence of resistance.

The cure rate reflects the sum of the 2 populations of organisms: the susceptible and the resistant. In triple therapy, increasing the gastric pH with a proton pump inhibitor makes the amoxicillin component of the regimen more effective against resistant organisms and thus increases the cure rate. For example, in Western countries, esomeprazole  40 mg (approximately equivalent to rabeprazole 40 mg, omeprazole or lansoprazole 60 mg, or pantoprazole 240 mg)²⁸ given twice a day in a 14-day triple therapy regimen cures about 40% to 50% of resistant infections. This benefit will be evident in an improvement in cure rates in populations in which resistance has reduced the average cure rate. This is also why meta-analyses have shown better results with second-generation proton pump inhibitors and with longer duration of therapy.^29,30

Generally, we recommend omeprazole 40 mg twice a day or an equivalent (Tables 1–3).

Would a potassium-competitive acid blocker be better than a proton pump inhibitor?

Vonoprazan is a potassium-competitive acid blocker. It does not require intermediate complex formation and is stable at low pH. It has a longer half-life than proton pump inhibitors, and its bioavailability is unaffected by food.³¹ It was recently approved in Japan for H pylori eradication in combination with clarithromycin or metronidazole plus amoxicillin.¹⁸

Vonoprazan is more effective than current proton pump inhibitors for keeping the gastric pH high. There are no published studies of vonoprazan dual therapy in Western countries, but given twice a day for 7 days along with twice-daily amoxicillin it cured only approximately 80% of clarithromycin-resistant strains. Further studies are needed to identify the optimum proton pump inhibitor or potassium-competitive acid blocker, dose, and duration.

 

 

Misuse of antibiotics

In triple therapy, the second antimicrobial drug (eg, amoxicillin) is given in part to prevent resistance from developing. It is not clear whether the combination is additive or synergistic, but until we can reliably maintain the intragastric pH above 6.0, which would increase the effectiveness of the amoxicillin component of the regimen, this practice cannot be considered as misuse of antibiotics.

In contrast, in the 4-drug nonbismuth combinations (concomitant, sequential, and hybrid therapies) and the new vonoprazan, clarithromycin, and metronidazole triple therapies, 1 of the antibiotics provides no benefit to some, often most, of the patients.^18–20,32 This practice should end when susceptibility data become more widely available and when vonoprazan becomes available, so that we can deliver effective vonoprazan-amoxicillin dual therapy.

First-, second-, and third-line therapies

Many recommendations give advice in terms of first-, second-, and third-line therapies. In practice, a physician should have at least 2 first-line regimens (a first and a second choice). Both should be proven highly successful as empiric therapies in one’s patient population but differ in terms of primary antibiotics. This approach allows the clinician to tailor therapy depending on whether he or she suspects antibiotic resistance (eg, if the patient has taken clarithromycin before) or the patient is allergic or cannot take 1 or more drugs.

Two treatment failures with 2 different regimens known to be effective suggest poor compliance (a difficult patient) or a multiple-drug-resistant infection (a difficult infection). That patient would require salvage therapy (Table 2), which logically should be based on antimicrobial testing or, at a minimum, consultation with someone who frequently deals with this problem.

Test of cure

Monitoring the outcome of therapy (testing for cure) is essential, as it provides a reliable measure of the local effectiveness of particular therapies and also serves as an early warning of development of resistance in one’s patient population.¹⁴

Unless there are compelling reasons, testing for cure should use noninvasive testing with the urea breath test or stool antigen test. It is recommended that this be delayed at least 4 weeks to allow the organisms if still present to repopulate the stomach sufficiently for the tests to become positive. Because antibiotics, bismuth, and proton pump inhibitors reduce the bacterial load, they should be withheld at least 2 weeks before testing. Histamine-2 receptor antagonists can be substituted for proton pump inhibitors if antisecretory therapy is needed for symptoms, and continued up to the day before testing. The urea breath test should contain citric acid to overcome any residual pH effects. Physician groups should share their experience so as to alert the community about which therapies should likely be avoided.³³

Salvage therapy

Salvage therapy is given after 2 or more treatment failures with different antibiotics. Ideally, the regimen should be based on the results of antimicrobial testing. Current regimens include rifabutin triple therapy, dual therapy (a protein pump inhibitor or vonoprazan and amoxicillin), or furazolidone quadruple therapy (Table 2).

Furazolidone is a synthetic nitrofuran derivative that is effective against many enteric organisms, including gram-negative bacteria and protozoa. It is not available in most Western countries but is available in many other parts of the world.^34,35 It is also a monoamine oxidase inhibitor and thus interacts with many drugs and foods (eg, soy sauce, aged cheeses), leading to a relatively high rate of side effects such as fever, palpitations, and skin rash.

Rifabutin-containing regimens, generally, a proton pump inhibitor, amoxicillin 1 g, and rifabutin 150 mg, all twice a day (Table 3) provide average cure rates of less than 80% (typically in the mid-70% range).³⁶ Borody et al³⁷ reported greater than 95% success with a 12-day regimen consisting of rifabutin 150 mg once daily (half-dose), amoxicillin 1.5 g 3 times a day, and pantoprazole 80 mg (approximately equivalent to omeprazole 20 mg) 3 times a day. Ciccaglione et al,³⁸ in a small study, used a 10-day quadruple regimen containing a proton pump inhibitor, amoxicillin, rifabutin, and bismuth (all twice a day), with high cure rates. The results of these studies are yet to be confirmed, and the optimal rifabutin-containing regimen remains to be determined.

PROBIOTICS

There is considerable interest in using probiotics to enhance the effectiveness of antimicrobial therapy for H pylori by increasing tolerability, reducing side effects, and therefore improving compliance.^39,40

In a meta-analysis of 14 randomized trials (N = 1,671), when probiotics were added, pooled H pylori eradication rates were only slightly improved: 83.6% (95% CI 80.5%–86.7%) with probiotics and 74.8% (95% CI 71.1%–78.5%) without probiotics by intent-to-treat analysis.⁴¹

Another meta-analysis of probiotics suggested that those containing Saccharomyces boulardii, Lactobacillus, and Bifidobacterium significantly increased the eradication rate of triple therapy in populations with high rates of antimicrobial resistance and reduced the risk of overall H pylori therapy-related adverse effects, especially diarrhea.^42,43

At present, we recommend that probiotics be considered only for patients who are likely not to comply with treatment (eg, those with irritable bowel syndrome or difficulty taking antibiotics), to try to take advantage of their ability to improve antibiotic tolerability.

Bariatric surgery, though beneficial, is associated with complications, one of which is post-gastric bypass hypoglycemia (PGBH).¹ The mean time from gastric bypass to documented hypoglycemia is about 28 months.²

PGBH is probably more common than initially thought. In older reports, the prevalence was only 0.1% to 0.36%.^1,3 In contrast, in a mail survey in 2015,⁴ one-third of bariatric surgery patients reported symptoms that raised the suspicion of hypoglycemia. Those with suspicious symptoms were more likely to have undergone Roux-en-Y surgery, to have had no preoperative diabetes, to have had a longer interval since surgery, and to be female. Restricting the suspicion of postprandial hypoglycemia to those who reported more serious symptoms, including needing third-party assistance, the prevalence was 11.6%.

Kefurt et al⁵ followed Roux-en-Y patients who wore a continuous glucose monitor for 86 months after surgery and found that 38% had hypoglycemia; however, symptoms of hypoglycemia were not discussed.

Thus, the exact prevalence is currently unknown. But as time goes by and more procedures are performed, the incidence will likely rise.

OBESITY IS ON THE RISE, AND SO IS WEIGHT-LOSS SURGERY

Obesity is rampant, and its prevalence continues to rise. In 2011–2012, more than two-thirds of adults in the United States were reported as obese.⁶ Complications of obesity such as cardiac disease, diabetes, and cancer lead to increased mortality risk.⁷ Obesity is difficult to reverse, as many people fail to lose weight with diet, exercise, and pharmacotherapy.

Given the difficulty of losing weight and the complications that arise from obesity, bariatric surgery has become increasingly popular. Not only do patients lose significantly more weight with bariatric surgery than with conventional measures, but surgery also reduces and often cures conditions associated with obesity.⁸

Nguyen et al⁹ reported that 671,959 patients underwent gastric bypass procedures in the United States from 2003 to 2008. In a registry maintained by the American Society for Metabolic and Bariatric Surgery¹⁰ from June 2007 to May 2009, the most common bariatric procedure in the United States was Roux-en-Y gastric bypass, followed by sleeve gastrectomy.

DIFFERENTIAL DIAGNOSIS AND DEFINITIONS

The differential diagnosis for hyperinsulinemic hypoglycemia after gastric bypass surgery includes exogenous and endogenous causes (Table 1). Exogenous causes include abuse of insulin secretagogues such as sulfonylureas or meglitinides and abuse of insulin, which may occur in patients with Munchausen syndrome, Munchausen syndrome by proxy, or malingering. Endogenous causes include insulinoma, early and late dumping syndromes, and PGBH.

When differentiating endogenous from exogenous hypoglycemia, insulin and C-peptide levels are useful (Table 2). The pancreas produces proinsulin, which is broken down into insulin and C-peptide. Since exogenous insulin does not have a C-peptide component, people abusing insulin have elevated insulin levels with a low C-peptide level.¹¹ Insulin secretagogues cause endogenous insulin secretion, resulting in elevated levels of both insulin and C-peptide. Thus, a screen for these medications is necessary to determine this as the cause.

Differentiating endogenous causes of hypoglycemia

Differentiating the endogenous causes (insulinoma, early or late dumping syndrome, and PGBH) can be challenging, as all 3 have similar biochemical profiles (Table 2).

Insulinoma is a tumor of pancreatic beta cells that produces excessive amounts of insulin. Unlike dumping syndrome, which only occurs postprandially, insulinoma primarily causes fasting hypoglycemia, although postprandial hypoglycemia can occur less commonly. Insulinoma after Roux-en-Y is rare. Only 7 cases have been reported.¹²

Dumping syndrome is classified as either early or late.

Early dumping syndrome usually occurs within 20 minutes of eating. The rapid transit of carbohydrates into the small intestine results in a fluid shift and a sympathetic response characterized by tachycardia, nausea, and diarrhea. Hypoglycemia is not present. Early dumping syndrome usually arises during the first few months after surgery.¹³

Late dumping syndrome usually occurs 1 to 4 hours after ingestion of a carbohydrate load, with symptoms of diaphoresis, dizziness, and fatigue caused by hypoglycemia from an excessive insulin release in response to the carbohydrates.¹³ It does not tend to cause neuroglycopenic symptoms.¹⁴ We define late dumping syndrome as postprandial hypoglycemic symptoms that occur after eating simple sugars and that resolve with dietary changes alone.

Differentiating late dumping syndrome from PGBH is difficult, as the line between the 2 processes is blurred.¹³

PGBH is defined as postprandial hypoglycemia (although it can be fasting in severe cases), often with neuroglycopenic symptoms, that occurs despite adherence to an acceptable bariatric diet (outlined in Table 3). We categorize PGBH as mild, moderate, or severe. Mild PGBH resolves with dietary changes with or without an alpha-glucosidase inhibitor. Moderate PGBH does not respond to an alpha-glucosidase inhibitor and dietary changes, and alternative or additional medication or medications are needed for resolution. Severe PGBH does not respond to dietary or medical interventions, and patients experience persistent episodes of neuroglycopenia.

THE EXACT MECHANISM IS UNCERTAIN

Patients with PGBH have a significant postprandial rise in glucose (often with levels > 200 mg/dL), leading to a robust insulin response and a subsequent drop in blood glucose.¹⁵

The exact mechanisms causing hypoglycemia are unknown, but excessive release of the incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) are thought to contribute. GLP-1 is primarily secreted in the gut in response to nutrients, causing a glucose-dependent release of insulin and suppression of glucagon, as well as a delay in gastric emptying and motility. Salehi et al¹⁶ demonstrated excessive GLP-1 and insulin release after glucose administration in postbypass patients, with a more exaggerated response in those experiencing postprandial hypoglycemia.

Excessive incretin hormones may also contribute to pancreatic islet cell hyperplasia, leading to hyperinsulinism.¹⁷ Other proposed mechanisms of PGBH are the lack of a decrease in beta cell mass after gastric bypass, a postoperative increase in insulin sensitivity, a decrease in ghrelin (an insulin counterregulatory hormone), and an abnormal glucagon response.^13,17

Pathologic changes vary widely

PGBH is a challenging diagnosis to make pathologically. On review of pancreatic tissue from 36 patients undergoing partial pancreatectomy for PGBH, the pancreatic islet cells of the PGBH group were larger and more irregular compared with controls.^18,19 This histologic condition with islet-cell hypertrophy, hyperplasia, and other changes has been termed nesidioblastosis.^11,14,20 However, the pancreatic tissue appears grossly normal. The histopathologic findings can vary greatly in individual cases and in one-third of cases the pancreatic changes can be minimal, so that “normal” and PGBH cells can be nearly impossible to distinguish from each other.²¹

DIAGNOSIS AND TREATMENT

We recommend a stepwise approach to evaluating and treating PGBH (Figures 1 and 2).

Step 1: Evaluate blood glucose and Whipple triad

The first step is a thorough history, including food consumption and timing of hypoglycemic symptoms. Give the patient a glucometer to take home, with instructions to check blood glucose levels when hypoglycemic symptoms occur. The patient should keep a log documenting time tested, food consumed, symptoms, and blood glucose data.

Hypoglycemic symptoms are categorized as autonomic and neuroglycopenic. Autonomic symptoms include anxiety, palpitations, tremulousness, and diaphoresis. Neuroglycopenic symptoms include confusion, falls, seizures, and loss of consciousness.¹²

There are degrees of hypoglycemia and hypoglycemic symptoms. Clinical hypoglycemia—a blood glucose level low enough to cause signs or symptoms—can be confirmed by the Whipple triad:

• Measured low blood glucose
• Symptoms of low blood glucose
• Relief of symptoms when low blood glucose is corrected.

Hypoglycemic symptoms can occur when the blood glucose level falls to less than 55 mg/dL in healthy people, but this cutoff can shift lower in someone who has recurrent hypoglycemia.

When the Whipple triad is documented, rule out nonhyperinsulinemic causes of hypoglycemia such as hypothyroidism, adrenal insufficiency, underlying organ dysfunction (ie, liver disease), and medications that cause hypoglycemia.

Step 2: Modify the diet

If postprandial hypoglycemia is occurring, the next step is dietary modification. Two studies showed that a low-carbohydrate diet prevented hypoglycemia; however, these diets contained nearly no carbohydrates (with meals consisting of eggs, sausage, cheese, and black coffee or tea).^15,22

Instruct patients to never eat pure carbohydrates without fat or protein, as this can result in a more severe hypoglycemic response.²² In addition, foods with a high glycemic index (a measure of how a carbohydrate-containing food raises blood sugar) should be avoided, and a low glycemic index diet is recommended.²³ High glycemic index foods include white bread, bagels, pretzels, and pineapple. Low glycemic index foods include 100% stone-ground whole wheat or pumpernickel bread, lima beans, butter beans, peas, legumes, lentils, and nonstarchy vegetables.

Our bariatric surgeons provide all postbariatric surgery patients with the dietary guidelines shown in Table 3.²⁴ We also ask our patients with PGBH to limit carbohydrates to 15 to 30 g per meal and to limit added sugars to less than 4 g per meal, including regular and sugar alcohols (polyols). Snacks should contain only protein and fat. In severe cases, we further limit the diet to 15 g of carbohydrate per meal, with no added sugars.

The hypoglycemia occurring with PGBH is treated differently than the hypoglycemia that occurs in diabetic patients. Advise patients with PGBH to treat their hypoglycemic episodes with a simple sugar combined with a protein or fat (eg, a small handful of candy with a spoonful of peanut butter), as they will often have recurrent hypoglycemia if a simple sugar is used alone. If patients regain weight, ask them about frequent eating, which would be related to self-treatment of hypoglycemia.

Step 3: Start an alpha-glucosidase inhibitor

If postprandial hypoglycemia persists despite dietary modification, then start an alpha-glucosidase inhibitor such as acarbose. Acarbose inhibits carbohydrate absorption, resulting in a decreased insulin response; thus, it blunts the decline in postprandial blood glucose.

Unfortunately, gastrointestinal side effects such as flatulence, diarrhea, and abdominal pain occur in up to 20% of patients who take acarbose, often leading to its discontinuation.²⁵ To minimize gastrointestinal side effects, we usually start with 25 mg of acarbose with 1 meal daily for 1 week, then increase the dosage weekly to 25 mg with the other 2 meals. If tolerated, acarbose can be increased to 50 to 100 mg with 3 meals daily.

Step 4: Obtain a mixed meal tolerance test or a provocation meal test

If dietary changes and an alpha-glucosidase inhibitor do not prevent postprandial hypoglycemia from recurring, then confirmation of PGBH is needed, using a mixed meal tolerance test or a provocation meal test.

In a mixed meal tolerance test, the meal consists of 55% carbohydrate, 30% fat, and 15% protein. Patients with hyperinsulinemic hypoglycemia have a rapid rise in blood glucose (> 200 mg/dL) with a robust insulin response that is often followed by hypoglycemia after ingesting a meal containing carbohydrates in this test. Insulin levels that remain elevated after the plasma glucose level falls to less than 55 mg/dL indicate hyperinsulinism.¹¹

Nevertheless, a mixed meal tolerance test will not always induce hypoglycemia. In a study of 51 patients with PGBH, all wore a continuous glucose monitor, were instructed to follow their normal diet for 5 days, and then underwent a mixed meal tolerance test on day 6. The glucose monitor revealed hypoglycemia in 75% of patients, while the mixed meal tolerance test was positive in only 29%.⁵

Moreover, to date, there is no standardized mixed meal.^5,15 This might also explain the difference in prevalence of hypoglycemia detected by this test.

Based on these conflicting findings, we recommend a provocation meal test—ie, the patient is given foods that have induced hypoglycemia earlier.

Of note, the Endocrine Society guidelines on hypoglycemia state that an oral glucose tolerance test should never be used to document postprandial hypoglycemia.²⁶ Lev-Ran and Anderson²⁷ found that an oral glucose tolerance test could be positive in at least 10% of normal people.

Step 5: Consider other pharmacotherapy

For moderate to severe PGBH in which dietary modification and acarbose have failed, additional medical therapy is the next step. Medical therapies include calcium channel blockers, somatostatin analogues (eg, octreotide), and diazoxide.

Calcium channel blockers inhibit insulin release from beta cells²⁸ but at the risk of hypotension. Mordes and Alonso²⁹ treated 6 PGBH patients with nifedipine or verapamil with or without acarbose, and symptoms resolved in 5 of the 6 patients.

When we treat PGBH, we often add a calcium channel blocker as the next step in therapy if the patient has hypertension or if the blood pressure can tolerate this. If the patient’s blood pressure is low, then avoiding calcium channel blocker therapy may be necessary. The next step would be octreotide and then diazoxide.

Somatostatin analogues such as octreotide inhibit GLP-1 and insulin release.³⁰ The most common side effects of octreotide are diarrhea and abdominal pain. Bile stone formation can also occur, but this is not common.

Diazoxide opens adenosine triphosphate-sensitive potassium channels and reduces the opening of calcium channels, inhibiting insulin release and raising blood glucose. In a study of 6 Japanese patients with inoperable insulinoma, diazoxide was used to treat hypoglycemia.³¹ Unfortunately, the doses required to control the low blood sugars also led to adverse reactions, most of which involved edema secondary to volume overload and other heart failure symptoms. Diazoxide also commonly causes hypotension and hirsutism.

Step 6: 72-hour fast

A 72-hour fast is recommended in severe cases of PGBH in patients for whom dietary modification and the additional pharmacotherapy outlined in step 5 have failed. A 72-hour fast is always indicated in evaluating confirmed fasting hypoglycemia. People with insulinoma usually have fasting hypoglycemia, while patients with dumping syndrome do not. Patients with PGBH usually do not have fasting hypoglycemia, but they can in severe cases.¹¹

For safety, this test should be done in the hospital. Baseline plasma levels of insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and glucose should be obtained. The patient then fasts, consuming only noncaloric and noncaffeinated beverages for 72 hours. During this time, capillary glucose checks are performed every 6 hours. If the capillary glucose level falls below 55 mg/dL,^11,26 then the baseline tests are redrawn along with a sulfonylurea screen. To reduce costs and unnecessary testing, the tests are not sent for laboratory processing unless the plasma glucose is less than 55 mg/dL.

When the plasma glucose is less than 55 mg/dL, insulin production should cease. Elevated insulin levels and insulin byproducts raise concern for hyperinsulinism. These values confirm hyperinsulinemic hypoglycemia²⁶:

• Glucose < 55 mg/dL
• Insulin ≥ 3 µU/mL
• C-peptide ≥ 0.2 nmol/L
• Proinsulin ≥ 5.0 pmol/L.

After hypoglycemia is confirmed, 1 mg of glucagon is given intravenously, and plasma glucose levels are obtained at 10, 20, and 30 minutes.^11,26 A rise in plasma glucose of at least 25 mg/dL after intravenous glucagon injection indicates hypoglycemia due to hyperinsulinemia. Two-thirds of patients with insulinoma experience hypoglycemia within the first 24 hours, and nearly all experience hypoglycemia within 48 hours.²⁶

Step 7: Obtain pancreatic imaging

If fasting hypoglycemia is present and hyperinsulinemic hypoglycemia is confirmed during a 72-hour fast, then pancreatic imaging should be obtained to evaluate for an insulinoma. We also recommend pancreatic imaging to rule out insulinoma when severe PGBH has not responded to dietary modification or pharmacotherapy.

Imaging is not recommended in PGBH that has been successfully treated with dietary modification with or without pharmacotherapy.

Endoscopic ultrasonography alone has 80% to 92% sensitivity for localizing a pancreatic mass as small as 5 mm. However, when coupled with computed tomography or magnetic resonance imaging, the sensitivity increases to nearly 100%.¹²

Step 8: Selective arterial calcium stimulation test

If a patient is found to have hyperinsulinemic hypoglycemia during a 72-hour fast but pancreatic imaging is negative, then selective arterial calcium stimulation testing (SACST) and hepatic vein sampling should be performed. Also, for severe PGBH, in which hypoglycemia has persisted despite dietary modification and pharmacotherapy, SACST can be performed to evaluate for possible localization of hyperinsulinism in patients considering surgery. For mild and moderate cases of PGBH, in which the hypoglycemia has been successfully treated with dietary changes with or without pharmacotherapy, SACST is not necessary.

This test can localize the area of excess insulin production in the pancreas in patients with an insulinoma. Patients with severe PGBH usually have diffuse hyperinsulinism without localization on SACST.^32,33

When SACST is performed, a sampling catheter is placed in the femoral vein. Calcium gluconate is injected into the major arteries of the pancreas (superior mesenteric, gastroduodenal, and splenic arteries). Calcium stimulates release of insulin from an insulinoma or hyperplastic beta cells. Resultant insulin levels are measured in the hepatic vein. If there is a greater than twofold increase in insulin release from 2 segments, then the test is considered positive.

Thompson et al³⁴ documented that insulin release from insulinoma is almost 4 times higher than in diffuse nesidioblastosis. SACST has a sensitivity of 96% for detecting insulinomas.³⁵

Step 9: Other alternatives and surgery

In patients with severe PGBH for whom dietary modification and all pharmacotherapy have failed and who continue to have debilitating neuroglycopenia, there are options before proceeding with surgery, the last resort in this condition.

Continuous glucose monitoring is helpful in many patients with severe PGBH. Many of them have hypoglycemia unawareness, and the monitor alerts them when their blood sugar is low. In addition, the monitor indicates when the blood sugar is dropping, so that intervention can occur before hypoglycemia occurs.

Unfortunately, insurance coverage for continuous monitors in this patient population is limited. We argue that insurance should cover the cost for these severe cases.

Pasireotide, a somatostatin analogue that is longer-acting than octreotide, is approved for use in Cushing disease and acromegaly and actually causes hyperglycemia. In a case report of a 50-year-old woman, pasireotide resulted in less hypoglycemia and higher glucagon levels then octreotide.³⁶ Pasireotide is available from Novartis for compassionate use in patients with severe PGBH.

Glucocorticoids are another off-label option. However, in excess, they can lead to iatrogenic Cushing syndrome, which has its own complications. Prednisone and diazoxide have been used together to help prevent hypoglycemia in a patients with inoperable insulinoma.³¹

Tube feeding. Some researchers have studied altering nutrition access through surgical means. McLaughlin et al³⁷ discussed a case of gastric tube insertion into the remnant stomach of a patient with PGBH, with resolution of hypoglycemic symptoms and hypoglycemia; however, this does not always provide complete resolution of symptoms.^37,38 If gastric bypass reversal is being considered, a trial of solely remnant stomach tube feeds (with no oral intake) should be pursued first. If this ameliorates the hypoglycemia, then gastric bypass reversal may be of benefit.

Surgery is the last resort if all of the above treatments have failed and severe debilitating neuroglycopenia persists. However, surgery poses risks, and the success rate in correcting hypoglycemia is not ideal. Surgical options include Roux-en-Y reversal, gastric pouch resection, and pancreatic resection.

In a review by Mala,² 75 patients with documented PGBH underwent surgical therapy. Hypoglycemic symptoms resolved in 34 of 51 pancreatic resections, 13 of 17 Roux-en-Y reversals, and 9 of 11 gastric pouch resections. However, the follow-up period was short.

As noted above, we recommend calcium stimulation testing only for severe cases of PGBH when surgery is being considered to evaluate for possible localization of hyperinsulinism for which partial pancreatectomy would be of benefit. Since there is no localization in many PGBH cases and the success rates are slightly higher in gastric bypass reversal, bypass reversal is usually preferred over partial or complete pancreatectomy.^2,32,33

POTENTIAL FUTURE THERAPIES

Given the elevated GLP-1 levels and robust insulin response to glucose observed in PGBH, blocking GLP-1 may provide clinical benefit. Salehi et al¹⁶ found that a GLP-1 antagonist prevented surges in GLP-1 and reduced hypoglycemic episodes in patients with PGBH. Unfortunately, the medication they used was given as a continuous infusion and is not currently available.

Conversely, a GLP-1 agonist showed benefit in a series of 5 cases of PGBH.³⁹ In addition, an insulin receptor antibody is undergoing phase 2 trials and has been shown to reverse insulin-induced hypoglycemia in rodents and humans; it may be a novel therapy in the future for hyperinsulinemic hypoglycemia.⁴⁰

MORE STUDY NEEDED

As the prevalence of obesity continues to rise and more people opt for bariatric surgery for weight loss, we will likely continue to see an increase in PGBH, since the onset of PGBH can be delayed for many years after surgery.²⁸

Unfortunately, the disease process involved in PGBH is not well understood. For example, we do not know why GLP-1 elevations or a robust insulin response causing hypoglycemia occurs in some but not all gastric bypass patients. Study is needed to elucidate the pathophysiology to further understand why most patients have no hypoglycemia after gastric bypass, some have mild to moderate PGBH, and a small percentage have severe PGBH with debilitating neuroglycopenia unresponsive to dietary changes and medications.     

Bariatric surgery, though beneficial, is associated with complications, one of which is post-gastric bypass hypoglycemia (PGBH).¹ The mean time from gastric bypass to documented hypoglycemia is about 28 months.²

PGBH is probably more common than initially thought. In older reports, the prevalence was only 0.1% to 0.36%.^1,3 In contrast, in a mail survey in 2015,⁴ one-third of bariatric surgery patients reported symptoms that raised the suspicion of hypoglycemia. Those with suspicious symptoms were more likely to have undergone Roux-en-Y surgery, to have had no preoperative diabetes, to have had a longer interval since surgery, and to be female. Restricting the suspicion of postprandial hypoglycemia to those who reported more serious symptoms, including needing third-party assistance, the prevalence was 11.6%.

Kefurt et al⁵ followed Roux-en-Y patients who wore a continuous glucose monitor for 86 months after surgery and found that 38% had hypoglycemia; however, symptoms of hypoglycemia were not discussed.

Thus, the exact prevalence is currently unknown. But as time goes by and more procedures are performed, the incidence will likely rise.

OBESITY IS ON THE RISE, AND SO IS WEIGHT-LOSS SURGERY

Obesity is rampant, and its prevalence continues to rise. In 2011–2012, more than two-thirds of adults in the United States were reported as obese.⁶ Complications of obesity such as cardiac disease, diabetes, and cancer lead to increased mortality risk.⁷ Obesity is difficult to reverse, as many people fail to lose weight with diet, exercise, and pharmacotherapy.

Given the difficulty of losing weight and the complications that arise from obesity, bariatric surgery has become increasingly popular. Not only do patients lose significantly more weight with bariatric surgery than with conventional measures, but surgery also reduces and often cures conditions associated with obesity.⁸

Nguyen et al⁹ reported that 671,959 patients underwent gastric bypass procedures in the United States from 2003 to 2008. In a registry maintained by the American Society for Metabolic and Bariatric Surgery¹⁰ from June 2007 to May 2009, the most common bariatric procedure in the United States was Roux-en-Y gastric bypass, followed by sleeve gastrectomy.

DIFFERENTIAL DIAGNOSIS AND DEFINITIONS

The differential diagnosis for hyperinsulinemic hypoglycemia after gastric bypass surgery includes exogenous and endogenous causes (Table 1). Exogenous causes include abuse of insulin secretagogues such as sulfonylureas or meglitinides and abuse of insulin, which may occur in patients with Munchausen syndrome, Munchausen syndrome by proxy, or malingering. Endogenous causes include insulinoma, early and late dumping syndromes, and PGBH.

When differentiating endogenous from exogenous hypoglycemia, insulin and C-peptide levels are useful (Table 2). The pancreas produces proinsulin, which is broken down into insulin and C-peptide. Since exogenous insulin does not have a C-peptide component, people abusing insulin have elevated insulin levels with a low C-peptide level.¹¹ Insulin secretagogues cause endogenous insulin secretion, resulting in elevated levels of both insulin and C-peptide. Thus, a screen for these medications is necessary to determine this as the cause.

Differentiating endogenous causes of hypoglycemia

Differentiating the endogenous causes (insulinoma, early or late dumping syndrome, and PGBH) can be challenging, as all 3 have similar biochemical profiles (Table 2).

Insulinoma is a tumor of pancreatic beta cells that produces excessive amounts of insulin. Unlike dumping syndrome, which only occurs postprandially, insulinoma primarily causes fasting hypoglycemia, although postprandial hypoglycemia can occur less commonly. Insulinoma after Roux-en-Y is rare. Only 7 cases have been reported.¹²

Dumping syndrome is classified as either early or late.

Early dumping syndrome usually occurs within 20 minutes of eating. The rapid transit of carbohydrates into the small intestine results in a fluid shift and a sympathetic response characterized by tachycardia, nausea, and diarrhea. Hypoglycemia is not present. Early dumping syndrome usually arises during the first few months after surgery.¹³

Late dumping syndrome usually occurs 1 to 4 hours after ingestion of a carbohydrate load, with symptoms of diaphoresis, dizziness, and fatigue caused by hypoglycemia from an excessive insulin release in response to the carbohydrates.¹³ It does not tend to cause neuroglycopenic symptoms.¹⁴ We define late dumping syndrome as postprandial hypoglycemic symptoms that occur after eating simple sugars and that resolve with dietary changes alone.

Differentiating late dumping syndrome from PGBH is difficult, as the line between the 2 processes is blurred.¹³

PGBH is defined as postprandial hypoglycemia (although it can be fasting in severe cases), often with neuroglycopenic symptoms, that occurs despite adherence to an acceptable bariatric diet (outlined in Table 3). We categorize PGBH as mild, moderate, or severe. Mild PGBH resolves with dietary changes with or without an alpha-glucosidase inhibitor. Moderate PGBH does not respond to an alpha-glucosidase inhibitor and dietary changes, and alternative or additional medication or medications are needed for resolution. Severe PGBH does not respond to dietary or medical interventions, and patients experience persistent episodes of neuroglycopenia.

THE EXACT MECHANISM IS UNCERTAIN

Patients with PGBH have a significant postprandial rise in glucose (often with levels > 200 mg/dL), leading to a robust insulin response and a subsequent drop in blood glucose.¹⁵

The exact mechanisms causing hypoglycemia are unknown, but excessive release of the incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) are thought to contribute. GLP-1 is primarily secreted in the gut in response to nutrients, causing a glucose-dependent release of insulin and suppression of glucagon, as well as a delay in gastric emptying and motility. Salehi et al¹⁶ demonstrated excessive GLP-1 and insulin release after glucose administration in postbypass patients, with a more exaggerated response in those experiencing postprandial hypoglycemia.

Excessive incretin hormones may also contribute to pancreatic islet cell hyperplasia, leading to hyperinsulinism.¹⁷ Other proposed mechanisms of PGBH are the lack of a decrease in beta cell mass after gastric bypass, a postoperative increase in insulin sensitivity, a decrease in ghrelin (an insulin counterregulatory hormone), and an abnormal glucagon response.^13,17

Pathologic changes vary widely

PGBH is a challenging diagnosis to make pathologically. On review of pancreatic tissue from 36 patients undergoing partial pancreatectomy for PGBH, the pancreatic islet cells of the PGBH group were larger and more irregular compared with controls.^18,19 This histologic condition with islet-cell hypertrophy, hyperplasia, and other changes has been termed nesidioblastosis.^11,14,20 However, the pancreatic tissue appears grossly normal. The histopathologic findings can vary greatly in individual cases and in one-third of cases the pancreatic changes can be minimal, so that “normal” and PGBH cells can be nearly impossible to distinguish from each other.²¹

DIAGNOSIS AND TREATMENT

We recommend a stepwise approach to evaluating and treating PGBH (Figures 1 and 2).

Step 1: Evaluate blood glucose and Whipple triad

The first step is a thorough history, including food consumption and timing of hypoglycemic symptoms. Give the patient a glucometer to take home, with instructions to check blood glucose levels when hypoglycemic symptoms occur. The patient should keep a log documenting time tested, food consumed, symptoms, and blood glucose data.

Hypoglycemic symptoms are categorized as autonomic and neuroglycopenic. Autonomic symptoms include anxiety, palpitations, tremulousness, and diaphoresis. Neuroglycopenic symptoms include confusion, falls, seizures, and loss of consciousness.¹²

There are degrees of hypoglycemia and hypoglycemic symptoms. Clinical hypoglycemia—a blood glucose level low enough to cause signs or symptoms—can be confirmed by the Whipple triad:

• Measured low blood glucose
• Symptoms of low blood glucose
• Relief of symptoms when low blood glucose is corrected.

Hypoglycemic symptoms can occur when the blood glucose level falls to less than 55 mg/dL in healthy people, but this cutoff can shift lower in someone who has recurrent hypoglycemia.

When the Whipple triad is documented, rule out nonhyperinsulinemic causes of hypoglycemia such as hypothyroidism, adrenal insufficiency, underlying organ dysfunction (ie, liver disease), and medications that cause hypoglycemia.

Step 2: Modify the diet

If postprandial hypoglycemia is occurring, the next step is dietary modification. Two studies showed that a low-carbohydrate diet prevented hypoglycemia; however, these diets contained nearly no carbohydrates (with meals consisting of eggs, sausage, cheese, and black coffee or tea).^15,22

Instruct patients to never eat pure carbohydrates without fat or protein, as this can result in a more severe hypoglycemic response.²² In addition, foods with a high glycemic index (a measure of how a carbohydrate-containing food raises blood sugar) should be avoided, and a low glycemic index diet is recommended.²³ High glycemic index foods include white bread, bagels, pretzels, and pineapple. Low glycemic index foods include 100% stone-ground whole wheat or pumpernickel bread, lima beans, butter beans, peas, legumes, lentils, and nonstarchy vegetables.

Our bariatric surgeons provide all postbariatric surgery patients with the dietary guidelines shown in Table 3.²⁴ We also ask our patients with PGBH to limit carbohydrates to 15 to 30 g per meal and to limit added sugars to less than 4 g per meal, including regular and sugar alcohols (polyols). Snacks should contain only protein and fat. In severe cases, we further limit the diet to 15 g of carbohydrate per meal, with no added sugars.

The hypoglycemia occurring with PGBH is treated differently than the hypoglycemia that occurs in diabetic patients. Advise patients with PGBH to treat their hypoglycemic episodes with a simple sugar combined with a protein or fat (eg, a small handful of candy with a spoonful of peanut butter), as they will often have recurrent hypoglycemia if a simple sugar is used alone. If patients regain weight, ask them about frequent eating, which would be related to self-treatment of hypoglycemia.

Step 3: Start an alpha-glucosidase inhibitor

If postprandial hypoglycemia persists despite dietary modification, then start an alpha-glucosidase inhibitor such as acarbose. Acarbose inhibits carbohydrate absorption, resulting in a decreased insulin response; thus, it blunts the decline in postprandial blood glucose.

Unfortunately, gastrointestinal side effects such as flatulence, diarrhea, and abdominal pain occur in up to 20% of patients who take acarbose, often leading to its discontinuation.²⁵ To minimize gastrointestinal side effects, we usually start with 25 mg of acarbose with 1 meal daily for 1 week, then increase the dosage weekly to 25 mg with the other 2 meals. If tolerated, acarbose can be increased to 50 to 100 mg with 3 meals daily.

Step 4: Obtain a mixed meal tolerance test or a provocation meal test

If dietary changes and an alpha-glucosidase inhibitor do not prevent postprandial hypoglycemia from recurring, then confirmation of PGBH is needed, using a mixed meal tolerance test or a provocation meal test.

In a mixed meal tolerance test, the meal consists of 55% carbohydrate, 30% fat, and 15% protein. Patients with hyperinsulinemic hypoglycemia have a rapid rise in blood glucose (> 200 mg/dL) with a robust insulin response that is often followed by hypoglycemia after ingesting a meal containing carbohydrates in this test. Insulin levels that remain elevated after the plasma glucose level falls to less than 55 mg/dL indicate hyperinsulinism.¹¹

Nevertheless, a mixed meal tolerance test will not always induce hypoglycemia. In a study of 51 patients with PGBH, all wore a continuous glucose monitor, were instructed to follow their normal diet for 5 days, and then underwent a mixed meal tolerance test on day 6. The glucose monitor revealed hypoglycemia in 75% of patients, while the mixed meal tolerance test was positive in only 29%.⁵

Moreover, to date, there is no standardized mixed meal.^5,15 This might also explain the difference in prevalence of hypoglycemia detected by this test.

Based on these conflicting findings, we recommend a provocation meal test—ie, the patient is given foods that have induced hypoglycemia earlier.

Of note, the Endocrine Society guidelines on hypoglycemia state that an oral glucose tolerance test should never be used to document postprandial hypoglycemia.²⁶ Lev-Ran and Anderson²⁷ found that an oral glucose tolerance test could be positive in at least 10% of normal people.

Step 5: Consider other pharmacotherapy

For moderate to severe PGBH in which dietary modification and acarbose have failed, additional medical therapy is the next step. Medical therapies include calcium channel blockers, somatostatin analogues (eg, octreotide), and diazoxide.

Calcium channel blockers inhibit insulin release from beta cells²⁸ but at the risk of hypotension. Mordes and Alonso²⁹ treated 6 PGBH patients with nifedipine or verapamil with or without acarbose, and symptoms resolved in 5 of the 6 patients.

When we treat PGBH, we often add a calcium channel blocker as the next step in therapy if the patient has hypertension or if the blood pressure can tolerate this. If the patient’s blood pressure is low, then avoiding calcium channel blocker therapy may be necessary. The next step would be octreotide and then diazoxide.

Somatostatin analogues such as octreotide inhibit GLP-1 and insulin release.³⁰ The most common side effects of octreotide are diarrhea and abdominal pain. Bile stone formation can also occur, but this is not common.

Diazoxide opens adenosine triphosphate-sensitive potassium channels and reduces the opening of calcium channels, inhibiting insulin release and raising blood glucose. In a study of 6 Japanese patients with inoperable insulinoma, diazoxide was used to treat hypoglycemia.³¹ Unfortunately, the doses required to control the low blood sugars also led to adverse reactions, most of which involved edema secondary to volume overload and other heart failure symptoms. Diazoxide also commonly causes hypotension and hirsutism.

Step 6: 72-hour fast

A 72-hour fast is recommended in severe cases of PGBH in patients for whom dietary modification and the additional pharmacotherapy outlined in step 5 have failed. A 72-hour fast is always indicated in evaluating confirmed fasting hypoglycemia. People with insulinoma usually have fasting hypoglycemia, while patients with dumping syndrome do not. Patients with PGBH usually do not have fasting hypoglycemia, but they can in severe cases.¹¹

For safety, this test should be done in the hospital. Baseline plasma levels of insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and glucose should be obtained. The patient then fasts, consuming only noncaloric and noncaffeinated beverages for 72 hours. During this time, capillary glucose checks are performed every 6 hours. If the capillary glucose level falls below 55 mg/dL,^11,26 then the baseline tests are redrawn along with a sulfonylurea screen. To reduce costs and unnecessary testing, the tests are not sent for laboratory processing unless the plasma glucose is less than 55 mg/dL.

When the plasma glucose is less than 55 mg/dL, insulin production should cease. Elevated insulin levels and insulin byproducts raise concern for hyperinsulinism. These values confirm hyperinsulinemic hypoglycemia²⁶:

• Glucose < 55 mg/dL
• Insulin ≥ 3 µU/mL
• C-peptide ≥ 0.2 nmol/L
• Proinsulin ≥ 5.0 pmol/L.

After hypoglycemia is confirmed, 1 mg of glucagon is given intravenously, and plasma glucose levels are obtained at 10, 20, and 30 minutes.^11,26 A rise in plasma glucose of at least 25 mg/dL after intravenous glucagon injection indicates hypoglycemia due to hyperinsulinemia. Two-thirds of patients with insulinoma experience hypoglycemia within the first 24 hours, and nearly all experience hypoglycemia within 48 hours.²⁶

Step 7: Obtain pancreatic imaging

If fasting hypoglycemia is present and hyperinsulinemic hypoglycemia is confirmed during a 72-hour fast, then pancreatic imaging should be obtained to evaluate for an insulinoma. We also recommend pancreatic imaging to rule out insulinoma when severe PGBH has not responded to dietary modification or pharmacotherapy.

Imaging is not recommended in PGBH that has been successfully treated with dietary modification with or without pharmacotherapy.

Endoscopic ultrasonography alone has 80% to 92% sensitivity for localizing a pancreatic mass as small as 5 mm. However, when coupled with computed tomography or magnetic resonance imaging, the sensitivity increases to nearly 100%.¹²

Step 8: Selective arterial calcium stimulation test

If a patient is found to have hyperinsulinemic hypoglycemia during a 72-hour fast but pancreatic imaging is negative, then selective arterial calcium stimulation testing (SACST) and hepatic vein sampling should be performed. Also, for severe PGBH, in which hypoglycemia has persisted despite dietary modification and pharmacotherapy, SACST can be performed to evaluate for possible localization of hyperinsulinism in patients considering surgery. For mild and moderate cases of PGBH, in which the hypoglycemia has been successfully treated with dietary changes with or without pharmacotherapy, SACST is not necessary.

This test can localize the area of excess insulin production in the pancreas in patients with an insulinoma. Patients with severe PGBH usually have diffuse hyperinsulinism without localization on SACST.^32,33

When SACST is performed, a sampling catheter is placed in the femoral vein. Calcium gluconate is injected into the major arteries of the pancreas (superior mesenteric, gastroduodenal, and splenic arteries). Calcium stimulates release of insulin from an insulinoma or hyperplastic beta cells. Resultant insulin levels are measured in the hepatic vein. If there is a greater than twofold increase in insulin release from 2 segments, then the test is considered positive.

Thompson et al³⁴ documented that insulin release from insulinoma is almost 4 times higher than in diffuse nesidioblastosis. SACST has a sensitivity of 96% for detecting insulinomas.³⁵

Step 9: Other alternatives and surgery

In patients with severe PGBH for whom dietary modification and all pharmacotherapy have failed and who continue to have debilitating neuroglycopenia, there are options before proceeding with surgery, the last resort in this condition.

Continuous glucose monitoring is helpful in many patients with severe PGBH. Many of them have hypoglycemia unawareness, and the monitor alerts them when their blood sugar is low. In addition, the monitor indicates when the blood sugar is dropping, so that intervention can occur before hypoglycemia occurs.

Unfortunately, insurance coverage for continuous monitors in this patient population is limited. We argue that insurance should cover the cost for these severe cases.

Pasireotide, a somatostatin analogue that is longer-acting than octreotide, is approved for use in Cushing disease and acromegaly and actually causes hyperglycemia. In a case report of a 50-year-old woman, pasireotide resulted in less hypoglycemia and higher glucagon levels then octreotide.³⁶ Pasireotide is available from Novartis for compassionate use in patients with severe PGBH.

Glucocorticoids are another off-label option. However, in excess, they can lead to iatrogenic Cushing syndrome, which has its own complications. Prednisone and diazoxide have been used together to help prevent hypoglycemia in a patients with inoperable insulinoma.³¹

Tube feeding. Some researchers have studied altering nutrition access through surgical means. McLaughlin et al³⁷ discussed a case of gastric tube insertion into the remnant stomach of a patient with PGBH, with resolution of hypoglycemic symptoms and hypoglycemia; however, this does not always provide complete resolution of symptoms.^37,38 If gastric bypass reversal is being considered, a trial of solely remnant stomach tube feeds (with no oral intake) should be pursued first. If this ameliorates the hypoglycemia, then gastric bypass reversal may be of benefit.

Surgery is the last resort if all of the above treatments have failed and severe debilitating neuroglycopenia persists. However, surgery poses risks, and the success rate in correcting hypoglycemia is not ideal. Surgical options include Roux-en-Y reversal, gastric pouch resection, and pancreatic resection.

In a review by Mala,² 75 patients with documented PGBH underwent surgical therapy. Hypoglycemic symptoms resolved in 34 of 51 pancreatic resections, 13 of 17 Roux-en-Y reversals, and 9 of 11 gastric pouch resections. However, the follow-up period was short.

As noted above, we recommend calcium stimulation testing only for severe cases of PGBH when surgery is being considered to evaluate for possible localization of hyperinsulinism for which partial pancreatectomy would be of benefit. Since there is no localization in many PGBH cases and the success rates are slightly higher in gastric bypass reversal, bypass reversal is usually preferred over partial or complete pancreatectomy.^2,32,33

POTENTIAL FUTURE THERAPIES

Given the elevated GLP-1 levels and robust insulin response to glucose observed in PGBH, blocking GLP-1 may provide clinical benefit. Salehi et al¹⁶ found that a GLP-1 antagonist prevented surges in GLP-1 and reduced hypoglycemic episodes in patients with PGBH. Unfortunately, the medication they used was given as a continuous infusion and is not currently available.

Conversely, a GLP-1 agonist showed benefit in a series of 5 cases of PGBH.³⁹ In addition, an insulin receptor antibody is undergoing phase 2 trials and has been shown to reverse insulin-induced hypoglycemia in rodents and humans; it may be a novel therapy in the future for hyperinsulinemic hypoglycemia.⁴⁰

MORE STUDY NEEDED

As the prevalence of obesity continues to rise and more people opt for bariatric surgery for weight loss, we will likely continue to see an increase in PGBH, since the onset of PGBH can be delayed for many years after surgery.²⁸

Unfortunately, the disease process involved in PGBH is not well understood. For example, we do not know why GLP-1 elevations or a robust insulin response causing hypoglycemia occurs in some but not all gastric bypass patients. Study is needed to elucidate the pathophysiology to further understand why most patients have no hypoglycemia after gastric bypass, some have mild to moderate PGBH, and a small percentage have severe PGBH with debilitating neuroglycopenia unresponsive to dietary changes and medications.     

Bariatric surgery, though beneficial, is associated with complications, one of which is post-gastric bypass hypoglycemia (PGBH).¹ The mean time from gastric bypass to documented hypoglycemia is about 28 months.²

PGBH is probably more common than initially thought. In older reports, the prevalence was only 0.1% to 0.36%.^1,3 In contrast, in a mail survey in 2015,⁴ one-third of bariatric surgery patients reported symptoms that raised the suspicion of hypoglycemia. Those with suspicious symptoms were more likely to have undergone Roux-en-Y surgery, to have had no preoperative diabetes, to have had a longer interval since surgery, and to be female. Restricting the suspicion of postprandial hypoglycemia to those who reported more serious symptoms, including needing third-party assistance, the prevalence was 11.6%.

Kefurt et al⁵ followed Roux-en-Y patients who wore a continuous glucose monitor for 86 months after surgery and found that 38% had hypoglycemia; however, symptoms of hypoglycemia were not discussed.

Thus, the exact prevalence is currently unknown. But as time goes by and more procedures are performed, the incidence will likely rise.

OBESITY IS ON THE RISE, AND SO IS WEIGHT-LOSS SURGERY

Obesity is rampant, and its prevalence continues to rise. In 2011–2012, more than two-thirds of adults in the United States were reported as obese.⁶ Complications of obesity such as cardiac disease, diabetes, and cancer lead to increased mortality risk.⁷ Obesity is difficult to reverse, as many people fail to lose weight with diet, exercise, and pharmacotherapy.

Given the difficulty of losing weight and the complications that arise from obesity, bariatric surgery has become increasingly popular. Not only do patients lose significantly more weight with bariatric surgery than with conventional measures, but surgery also reduces and often cures conditions associated with obesity.⁸

Nguyen et al⁹ reported that 671,959 patients underwent gastric bypass procedures in the United States from 2003 to 2008. In a registry maintained by the American Society for Metabolic and Bariatric Surgery¹⁰ from June 2007 to May 2009, the most common bariatric procedure in the United States was Roux-en-Y gastric bypass, followed by sleeve gastrectomy.

DIFFERENTIAL DIAGNOSIS AND DEFINITIONS

The differential diagnosis for hyperinsulinemic hypoglycemia after gastric bypass surgery includes exogenous and endogenous causes (Table 1). Exogenous causes include abuse of insulin secretagogues such as sulfonylureas or meglitinides and abuse of insulin, which may occur in patients with Munchausen syndrome, Munchausen syndrome by proxy, or malingering. Endogenous causes include insulinoma, early and late dumping syndromes, and PGBH.

When differentiating endogenous from exogenous hypoglycemia, insulin and C-peptide levels are useful (Table 2). The pancreas produces proinsulin, which is broken down into insulin and C-peptide. Since exogenous insulin does not have a C-peptide component, people abusing insulin have elevated insulin levels with a low C-peptide level.¹¹ Insulin secretagogues cause endogenous insulin secretion, resulting in elevated levels of both insulin and C-peptide. Thus, a screen for these medications is necessary to determine this as the cause.

Differentiating endogenous causes of hypoglycemia

Differentiating the endogenous causes (insulinoma, early or late dumping syndrome, and PGBH) can be challenging, as all 3 have similar biochemical profiles (Table 2).

Insulinoma is a tumor of pancreatic beta cells that produces excessive amounts of insulin. Unlike dumping syndrome, which only occurs postprandially, insulinoma primarily causes fasting hypoglycemia, although postprandial hypoglycemia can occur less commonly. Insulinoma after Roux-en-Y is rare. Only 7 cases have been reported.¹²

Dumping syndrome is classified as either early or late.

Early dumping syndrome usually occurs within 20 minutes of eating. The rapid transit of carbohydrates into the small intestine results in a fluid shift and a sympathetic response characterized by tachycardia, nausea, and diarrhea. Hypoglycemia is not present. Early dumping syndrome usually arises during the first few months after surgery.¹³

Late dumping syndrome usually occurs 1 to 4 hours after ingestion of a carbohydrate load, with symptoms of diaphoresis, dizziness, and fatigue caused by hypoglycemia from an excessive insulin release in response to the carbohydrates.¹³ It does not tend to cause neuroglycopenic symptoms.¹⁴ We define late dumping syndrome as postprandial hypoglycemic symptoms that occur after eating simple sugars and that resolve with dietary changes alone.

Differentiating late dumping syndrome from PGBH is difficult, as the line between the 2 processes is blurred.¹³

PGBH is defined as postprandial hypoglycemia (although it can be fasting in severe cases), often with neuroglycopenic symptoms, that occurs despite adherence to an acceptable bariatric diet (outlined in Table 3). We categorize PGBH as mild, moderate, or severe. Mild PGBH resolves with dietary changes with or without an alpha-glucosidase inhibitor. Moderate PGBH does not respond to an alpha-glucosidase inhibitor and dietary changes, and alternative or additional medication or medications are needed for resolution. Severe PGBH does not respond to dietary or medical interventions, and patients experience persistent episodes of neuroglycopenia.

THE EXACT MECHANISM IS UNCERTAIN

Patients with PGBH have a significant postprandial rise in glucose (often with levels > 200 mg/dL), leading to a robust insulin response and a subsequent drop in blood glucose.¹⁵

The exact mechanisms causing hypoglycemia are unknown, but excessive release of the incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) are thought to contribute. GLP-1 is primarily secreted in the gut in response to nutrients, causing a glucose-dependent release of insulin and suppression of glucagon, as well as a delay in gastric emptying and motility. Salehi et al¹⁶ demonstrated excessive GLP-1 and insulin release after glucose administration in postbypass patients, with a more exaggerated response in those experiencing postprandial hypoglycemia.

Excessive incretin hormones may also contribute to pancreatic islet cell hyperplasia, leading to hyperinsulinism.¹⁷ Other proposed mechanisms of PGBH are the lack of a decrease in beta cell mass after gastric bypass, a postoperative increase in insulin sensitivity, a decrease in ghrelin (an insulin counterregulatory hormone), and an abnormal glucagon response.^13,17

Pathologic changes vary widely

PGBH is a challenging diagnosis to make pathologically. On review of pancreatic tissue from 36 patients undergoing partial pancreatectomy for PGBH, the pancreatic islet cells of the PGBH group were larger and more irregular compared with controls.^18,19 This histologic condition with islet-cell hypertrophy, hyperplasia, and other changes has been termed nesidioblastosis.^11,14,20 However, the pancreatic tissue appears grossly normal. The histopathologic findings can vary greatly in individual cases and in one-third of cases the pancreatic changes can be minimal, so that “normal” and PGBH cells can be nearly impossible to distinguish from each other.²¹

DIAGNOSIS AND TREATMENT

We recommend a stepwise approach to evaluating and treating PGBH (Figures 1 and 2).

Step 1: Evaluate blood glucose and Whipple triad

The first step is a thorough history, including food consumption and timing of hypoglycemic symptoms. Give the patient a glucometer to take home, with instructions to check blood glucose levels when hypoglycemic symptoms occur. The patient should keep a log documenting time tested, food consumed, symptoms, and blood glucose data.

Hypoglycemic symptoms are categorized as autonomic and neuroglycopenic. Autonomic symptoms include anxiety, palpitations, tremulousness, and diaphoresis. Neuroglycopenic symptoms include confusion, falls, seizures, and loss of consciousness.¹²

There are degrees of hypoglycemia and hypoglycemic symptoms. Clinical hypoglycemia—a blood glucose level low enough to cause signs or symptoms—can be confirmed by the Whipple triad:

• Measured low blood glucose
• Symptoms of low blood glucose
• Relief of symptoms when low blood glucose is corrected.

Hypoglycemic symptoms can occur when the blood glucose level falls to less than 55 mg/dL in healthy people, but this cutoff can shift lower in someone who has recurrent hypoglycemia.

When the Whipple triad is documented, rule out nonhyperinsulinemic causes of hypoglycemia such as hypothyroidism, adrenal insufficiency, underlying organ dysfunction (ie, liver disease), and medications that cause hypoglycemia.

Step 2: Modify the diet

If postprandial hypoglycemia is occurring, the next step is dietary modification. Two studies showed that a low-carbohydrate diet prevented hypoglycemia; however, these diets contained nearly no carbohydrates (with meals consisting of eggs, sausage, cheese, and black coffee or tea).^15,22

Instruct patients to never eat pure carbohydrates without fat or protein, as this can result in a more severe hypoglycemic response.²² In addition, foods with a high glycemic index (a measure of how a carbohydrate-containing food raises blood sugar) should be avoided, and a low glycemic index diet is recommended.²³ High glycemic index foods include white bread, bagels, pretzels, and pineapple. Low glycemic index foods include 100% stone-ground whole wheat or pumpernickel bread, lima beans, butter beans, peas, legumes, lentils, and nonstarchy vegetables.

Our bariatric surgeons provide all postbariatric surgery patients with the dietary guidelines shown in Table 3.²⁴ We also ask our patients with PGBH to limit carbohydrates to 15 to 30 g per meal and to limit added sugars to less than 4 g per meal, including regular and sugar alcohols (polyols). Snacks should contain only protein and fat. In severe cases, we further limit the diet to 15 g of carbohydrate per meal, with no added sugars.

The hypoglycemia occurring with PGBH is treated differently than the hypoglycemia that occurs in diabetic patients. Advise patients with PGBH to treat their hypoglycemic episodes with a simple sugar combined with a protein or fat (eg, a small handful of candy with a spoonful of peanut butter), as they will often have recurrent hypoglycemia if a simple sugar is used alone. If patients regain weight, ask them about frequent eating, which would be related to self-treatment of hypoglycemia.

Step 3: Start an alpha-glucosidase inhibitor

If postprandial hypoglycemia persists despite dietary modification, then start an alpha-glucosidase inhibitor such as acarbose. Acarbose inhibits carbohydrate absorption, resulting in a decreased insulin response; thus, it blunts the decline in postprandial blood glucose.

Unfortunately, gastrointestinal side effects such as flatulence, diarrhea, and abdominal pain occur in up to 20% of patients who take acarbose, often leading to its discontinuation.²⁵ To minimize gastrointestinal side effects, we usually start with 25 mg of acarbose with 1 meal daily for 1 week, then increase the dosage weekly to 25 mg with the other 2 meals. If tolerated, acarbose can be increased to 50 to 100 mg with 3 meals daily.

Step 4: Obtain a mixed meal tolerance test or a provocation meal test

If dietary changes and an alpha-glucosidase inhibitor do not prevent postprandial hypoglycemia from recurring, then confirmation of PGBH is needed, using a mixed meal tolerance test or a provocation meal test.

In a mixed meal tolerance test, the meal consists of 55% carbohydrate, 30% fat, and 15% protein. Patients with hyperinsulinemic hypoglycemia have a rapid rise in blood glucose (> 200 mg/dL) with a robust insulin response that is often followed by hypoglycemia after ingesting a meal containing carbohydrates in this test. Insulin levels that remain elevated after the plasma glucose level falls to less than 55 mg/dL indicate hyperinsulinism.¹¹

Nevertheless, a mixed meal tolerance test will not always induce hypoglycemia. In a study of 51 patients with PGBH, all wore a continuous glucose monitor, were instructed to follow their normal diet for 5 days, and then underwent a mixed meal tolerance test on day 6. The glucose monitor revealed hypoglycemia in 75% of patients, while the mixed meal tolerance test was positive in only 29%.⁵

Moreover, to date, there is no standardized mixed meal.^5,15 This might also explain the difference in prevalence of hypoglycemia detected by this test.

Based on these conflicting findings, we recommend a provocation meal test—ie, the patient is given foods that have induced hypoglycemia earlier.

Of note, the Endocrine Society guidelines on hypoglycemia state that an oral glucose tolerance test should never be used to document postprandial hypoglycemia.²⁶ Lev-Ran and Anderson²⁷ found that an oral glucose tolerance test could be positive in at least 10% of normal people.

Step 5: Consider other pharmacotherapy

For moderate to severe PGBH in which dietary modification and acarbose have failed, additional medical therapy is the next step. Medical therapies include calcium channel blockers, somatostatin analogues (eg, octreotide), and diazoxide.

Calcium channel blockers inhibit insulin release from beta cells²⁸ but at the risk of hypotension. Mordes and Alonso²⁹ treated 6 PGBH patients with nifedipine or verapamil with or without acarbose, and symptoms resolved in 5 of the 6 patients.

When we treat PGBH, we often add a calcium channel blocker as the next step in therapy if the patient has hypertension or if the blood pressure can tolerate this. If the patient’s blood pressure is low, then avoiding calcium channel blocker therapy may be necessary. The next step would be octreotide and then diazoxide.

Somatostatin analogues such as octreotide inhibit GLP-1 and insulin release.³⁰ The most common side effects of octreotide are diarrhea and abdominal pain. Bile stone formation can also occur, but this is not common.

Diazoxide opens adenosine triphosphate-sensitive potassium channels and reduces the opening of calcium channels, inhibiting insulin release and raising blood glucose. In a study of 6 Japanese patients with inoperable insulinoma, diazoxide was used to treat hypoglycemia.³¹ Unfortunately, the doses required to control the low blood sugars also led to adverse reactions, most of which involved edema secondary to volume overload and other heart failure symptoms. Diazoxide also commonly causes hypotension and hirsutism.

Step 6: 72-hour fast

A 72-hour fast is recommended in severe cases of PGBH in patients for whom dietary modification and the additional pharmacotherapy outlined in step 5 have failed. A 72-hour fast is always indicated in evaluating confirmed fasting hypoglycemia. People with insulinoma usually have fasting hypoglycemia, while patients with dumping syndrome do not. Patients with PGBH usually do not have fasting hypoglycemia, but they can in severe cases.¹¹

For safety, this test should be done in the hospital. Baseline plasma levels of insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and glucose should be obtained. The patient then fasts, consuming only noncaloric and noncaffeinated beverages for 72 hours. During this time, capillary glucose checks are performed every 6 hours. If the capillary glucose level falls below 55 mg/dL,^11,26 then the baseline tests are redrawn along with a sulfonylurea screen. To reduce costs and unnecessary testing, the tests are not sent for laboratory processing unless the plasma glucose is less than 55 mg/dL.

When the plasma glucose is less than 55 mg/dL, insulin production should cease. Elevated insulin levels and insulin byproducts raise concern for hyperinsulinism. These values confirm hyperinsulinemic hypoglycemia²⁶:

• Glucose < 55 mg/dL
• Insulin ≥ 3 µU/mL
• C-peptide ≥ 0.2 nmol/L
• Proinsulin ≥ 5.0 pmol/L.

After hypoglycemia is confirmed, 1 mg of glucagon is given intravenously, and plasma glucose levels are obtained at 10, 20, and 30 minutes.^11,26 A rise in plasma glucose of at least 25 mg/dL after intravenous glucagon injection indicates hypoglycemia due to hyperinsulinemia. Two-thirds of patients with insulinoma experience hypoglycemia within the first 24 hours, and nearly all experience hypoglycemia within 48 hours.²⁶

Step 7: Obtain pancreatic imaging

If fasting hypoglycemia is present and hyperinsulinemic hypoglycemia is confirmed during a 72-hour fast, then pancreatic imaging should be obtained to evaluate for an insulinoma. We also recommend pancreatic imaging to rule out insulinoma when severe PGBH has not responded to dietary modification or pharmacotherapy.

Imaging is not recommended in PGBH that has been successfully treated with dietary modification with or without pharmacotherapy.

Endoscopic ultrasonography alone has 80% to 92% sensitivity for localizing a pancreatic mass as small as 5 mm. However, when coupled with computed tomography or magnetic resonance imaging, the sensitivity increases to nearly 100%.¹²

Step 8: Selective arterial calcium stimulation test

If a patient is found to have hyperinsulinemic hypoglycemia during a 72-hour fast but pancreatic imaging is negative, then selective arterial calcium stimulation testing (SACST) and hepatic vein sampling should be performed. Also, for severe PGBH, in which hypoglycemia has persisted despite dietary modification and pharmacotherapy, SACST can be performed to evaluate for possible localization of hyperinsulinism in patients considering surgery. For mild and moderate cases of PGBH, in which the hypoglycemia has been successfully treated with dietary changes with or without pharmacotherapy, SACST is not necessary.

This test can localize the area of excess insulin production in the pancreas in patients with an insulinoma. Patients with severe PGBH usually have diffuse hyperinsulinism without localization on SACST.^32,33

When SACST is performed, a sampling catheter is placed in the femoral vein. Calcium gluconate is injected into the major arteries of the pancreas (superior mesenteric, gastroduodenal, and splenic arteries). Calcium stimulates release of insulin from an insulinoma or hyperplastic beta cells. Resultant insulin levels are measured in the hepatic vein. If there is a greater than twofold increase in insulin release from 2 segments, then the test is considered positive.

Thompson et al³⁴ documented that insulin release from insulinoma is almost 4 times higher than in diffuse nesidioblastosis. SACST has a sensitivity of 96% for detecting insulinomas.³⁵

Step 9: Other alternatives and surgery

In patients with severe PGBH for whom dietary modification and all pharmacotherapy have failed and who continue to have debilitating neuroglycopenia, there are options before proceeding with surgery, the last resort in this condition.

Continuous glucose monitoring is helpful in many patients with severe PGBH. Many of them have hypoglycemia unawareness, and the monitor alerts them when their blood sugar is low. In addition, the monitor indicates when the blood sugar is dropping, so that intervention can occur before hypoglycemia occurs.

Unfortunately, insurance coverage for continuous monitors in this patient population is limited. We argue that insurance should cover the cost for these severe cases.

Pasireotide, a somatostatin analogue that is longer-acting than octreotide, is approved for use in Cushing disease and acromegaly and actually causes hyperglycemia. In a case report of a 50-year-old woman, pasireotide resulted in less hypoglycemia and higher glucagon levels then octreotide.³⁶ Pasireotide is available from Novartis for compassionate use in patients with severe PGBH.

Glucocorticoids are another off-label option. However, in excess, they can lead to iatrogenic Cushing syndrome, which has its own complications. Prednisone and diazoxide have been used together to help prevent hypoglycemia in a patients with inoperable insulinoma.³¹

Tube feeding. Some researchers have studied altering nutrition access through surgical means. McLaughlin et al³⁷ discussed a case of gastric tube insertion into the remnant stomach of a patient with PGBH, with resolution of hypoglycemic symptoms and hypoglycemia; however, this does not always provide complete resolution of symptoms.^37,38 If gastric bypass reversal is being considered, a trial of solely remnant stomach tube feeds (with no oral intake) should be pursued first. If this ameliorates the hypoglycemia, then gastric bypass reversal may be of benefit.

Surgery is the last resort if all of the above treatments have failed and severe debilitating neuroglycopenia persists. However, surgery poses risks, and the success rate in correcting hypoglycemia is not ideal. Surgical options include Roux-en-Y reversal, gastric pouch resection, and pancreatic resection.

In a review by Mala,² 75 patients with documented PGBH underwent surgical therapy. Hypoglycemic symptoms resolved in 34 of 51 pancreatic resections, 13 of 17 Roux-en-Y reversals, and 9 of 11 gastric pouch resections. However, the follow-up period was short.

As noted above, we recommend calcium stimulation testing only for severe cases of PGBH when surgery is being considered to evaluate for possible localization of hyperinsulinism for which partial pancreatectomy would be of benefit. Since there is no localization in many PGBH cases and the success rates are slightly higher in gastric bypass reversal, bypass reversal is usually preferred over partial or complete pancreatectomy.^2,32,33

POTENTIAL FUTURE THERAPIES

Given the elevated GLP-1 levels and robust insulin response to glucose observed in PGBH, blocking GLP-1 may provide clinical benefit. Salehi et al¹⁶ found that a GLP-1 antagonist prevented surges in GLP-1 and reduced hypoglycemic episodes in patients with PGBH. Unfortunately, the medication they used was given as a continuous infusion and is not currently available.

Conversely, a GLP-1 agonist showed benefit in a series of 5 cases of PGBH.³⁹ In addition, an insulin receptor antibody is undergoing phase 2 trials and has been shown to reverse insulin-induced hypoglycemia in rodents and humans; it may be a novel therapy in the future for hyperinsulinemic hypoglycemia.⁴⁰

MORE STUDY NEEDED

As the prevalence of obesity continues to rise and more people opt for bariatric surgery for weight loss, we will likely continue to see an increase in PGBH, since the onset of PGBH can be delayed for many years after surgery.²⁸

Unfortunately, the disease process involved in PGBH is not well understood. For example, we do not know why GLP-1 elevations or a robust insulin response causing hypoglycemia occurs in some but not all gastric bypass patients. Study is needed to elucidate the pathophysiology to further understand why most patients have no hypoglycemia after gastric bypass, some have mild to moderate PGBH, and a small percentage have severe PGBH with debilitating neuroglycopenia unresponsive to dietary changes and medications.     

A   43-year-old woman presented to the  clinic complaining of bilateral ankle joint pain for 2 months. She denied a history of fever, weight loss, addictions, cough, or trauma. On physical examinatio, she had swelling of the ankle and wrist joints and digital clubbing (Figure 1). Active movement of the ankles and wrists was restricted due to pain. The examination was otherwise unremarkable.

Radiography of both ankles showed a lamellar type periosteal reaction suggestive of periostitis (Figure 2). Computed tomography of the chest revealed a spiculated mass over the right lower lobe. Biopsy study of the mass was positive for squamous cell carcinoma. She was referred to the oncology center for further management.

FEATURES OF HYPERTROPHIC OSTEOARTHROPATHY

Digital clubbing is one of the oldest signs in clinical medicine. It is characterized by bulbous enlargement of the terminal segments of the fingers and toes due to proliferation of subungual connective tissue. It usually appears as a painless finger deformity and is clinically appreciated as a loss of the normal angle between the nail bed and proximal nail fold.

Hypertrophic osteoarthropathy is a symptomatic form of clubbing associated with proliferative periostosis of the distal end of long tubular bones, commonly those adjacent to the wrist and ankle joints.¹ The laminated appearance of these bones on radiography is due to the excess connective tissue secondary to new osteoid material deposited under the periosteum.

There is evidence to suggest that clubbing and hypertrophic osteoarthropathy represent different stages of the same disease process.² In most cases, finger deformity is the first manifestation; as the disease progresses, periostosis becomes evident.

Hypertrophic osteoarthropathy can be classified as primary or secondary. The primary form, also known as primary pachydermoperiostosis, is rare and constitutes only 3% of all cases.³ The exact cause is not yet known; it occurs as a hereditary disease with autosomal dominant inheritance with variable penetrance. Congenital clubbing without periostosis is of no clinical significance.⁴

CONDITIONS ASSOCIATED WITH CLUBBING

Primary bronchogenic carcinoma is the most common cause of clubbing and hypertrophic osteoarthropathy. In one retrospective series, 4.5% of patients with lung cancer had radiologic evidence of hypertrophic osteoarthropathy.⁵ Other malignancies associated with this condition are mesothelioma, hepatocellular carcinoma, and certain types of gastrointestinal adenocarcinoma.

Other conditions associated with clubbing include:

• Cardiovascular disease such as congenital cyanotic heart disease and infective endocarditis
• Gastrointestinal conditions such as cirrhosis, primary sclerosing cholangitis, Crohn disease, and ulcerative colitis
• Infections such as lung abscess and empyema.

Clubbing is generally bilaterally symmetrical. Asymmetric clubbing is rare and usually indicates impaired regional blood flow due to vascular disease. Unilateral clubbing or hypertrophic osteoarthropathy restricted to 1 upper limb can result from an anomaly of the aortic arch or from a subclavian or brachial artery aneurysm. Clubbing affecting predominantly the lower limbs has been reported in coarctation of aorta and patent ductus arteriosus.⁶ Rare cases of unidigital clubbing are reported in sarcoidosis.⁷

The importance of recognizing hypertrophic osteoarthropathy cannot be overemphasized. If any of the manifestations of the syndrome become evident in a previously healthy person, a thorough evaluation for an underlying disease should be done.

Clubbing should be differentiated from pseudoclubbing, which is seen in conditions such as hyperparathyroidism and scleroderma. The central mechanism for nail deformity in pseudoclubbing is acro-osteolysis with the resulting collapse of the subungual soft tissues. The important features differentiating it from true clubbing are preservation of the angle between the nail bed and proximal nail fold and asymmetric finger involvement.⁸

MANAGEMENT

The management of primary hypertrophic osteoarthropathy focuses on relieving the symptoms of periosteitis. Secondary forms require a detailed evaluation to rule out the underlying disease. In refractory cases, a bone-modifying agent (eg, zoledronic acid),⁹ octreotide,¹⁰ nonsteroidal anti-inflammatory drugs, or vagotomy¹¹ may help.

A   43-year-old woman presented to the  clinic complaining of bilateral ankle joint pain for 2 months. She denied a history of fever, weight loss, addictions, cough, or trauma. On physical examinatio, she had swelling of the ankle and wrist joints and digital clubbing (Figure 1). Active movement of the ankles and wrists was restricted due to pain. The examination was otherwise unremarkable.

Radiography of both ankles showed a lamellar type periosteal reaction suggestive of periostitis (Figure 2). Computed tomography of the chest revealed a spiculated mass over the right lower lobe. Biopsy study of the mass was positive for squamous cell carcinoma. She was referred to the oncology center for further management.

FEATURES OF HYPERTROPHIC OSTEOARTHROPATHY

Digital clubbing is one of the oldest signs in clinical medicine. It is characterized by bulbous enlargement of the terminal segments of the fingers and toes due to proliferation of subungual connective tissue. It usually appears as a painless finger deformity and is clinically appreciated as a loss of the normal angle between the nail bed and proximal nail fold.

Hypertrophic osteoarthropathy is a symptomatic form of clubbing associated with proliferative periostosis of the distal end of long tubular bones, commonly those adjacent to the wrist and ankle joints.¹ The laminated appearance of these bones on radiography is due to the excess connective tissue secondary to new osteoid material deposited under the periosteum.

There is evidence to suggest that clubbing and hypertrophic osteoarthropathy represent different stages of the same disease process.² In most cases, finger deformity is the first manifestation; as the disease progresses, periostosis becomes evident.

Hypertrophic osteoarthropathy can be classified as primary or secondary. The primary form, also known as primary pachydermoperiostosis, is rare and constitutes only 3% of all cases.³ The exact cause is not yet known; it occurs as a hereditary disease with autosomal dominant inheritance with variable penetrance. Congenital clubbing without periostosis is of no clinical significance.⁴

CONDITIONS ASSOCIATED WITH CLUBBING

Primary bronchogenic carcinoma is the most common cause of clubbing and hypertrophic osteoarthropathy. In one retrospective series, 4.5% of patients with lung cancer had radiologic evidence of hypertrophic osteoarthropathy.⁵ Other malignancies associated with this condition are mesothelioma, hepatocellular carcinoma, and certain types of gastrointestinal adenocarcinoma.

Other conditions associated with clubbing include:

• Cardiovascular disease such as congenital cyanotic heart disease and infective endocarditis
• Gastrointestinal conditions such as cirrhosis, primary sclerosing cholangitis, Crohn disease, and ulcerative colitis
• Infections such as lung abscess and empyema.

Clubbing is generally bilaterally symmetrical. Asymmetric clubbing is rare and usually indicates impaired regional blood flow due to vascular disease. Unilateral clubbing or hypertrophic osteoarthropathy restricted to 1 upper limb can result from an anomaly of the aortic arch or from a subclavian or brachial artery aneurysm. Clubbing affecting predominantly the lower limbs has been reported in coarctation of aorta and patent ductus arteriosus.⁶ Rare cases of unidigital clubbing are reported in sarcoidosis.⁷

The importance of recognizing hypertrophic osteoarthropathy cannot be overemphasized. If any of the manifestations of the syndrome become evident in a previously healthy person, a thorough evaluation for an underlying disease should be done.

Clubbing should be differentiated from pseudoclubbing, which is seen in conditions such as hyperparathyroidism and scleroderma. The central mechanism for nail deformity in pseudoclubbing is acro-osteolysis with the resulting collapse of the subungual soft tissues. The important features differentiating it from true clubbing are preservation of the angle between the nail bed and proximal nail fold and asymmetric finger involvement.⁸

MANAGEMENT

The management of primary hypertrophic osteoarthropathy focuses on relieving the symptoms of periosteitis. Secondary forms require a detailed evaluation to rule out the underlying disease. In refractory cases, a bone-modifying agent (eg, zoledronic acid),⁹ octreotide,¹⁰ nonsteroidal anti-inflammatory drugs, or vagotomy¹¹ may help.

A   43-year-old woman presented to the  clinic complaining of bilateral ankle joint pain for 2 months. She denied a history of fever, weight loss, addictions, cough, or trauma. On physical examinatio, she had swelling of the ankle and wrist joints and digital clubbing (Figure 1). Active movement of the ankles and wrists was restricted due to pain. The examination was otherwise unremarkable.

Radiography of both ankles showed a lamellar type periosteal reaction suggestive of periostitis (Figure 2). Computed tomography of the chest revealed a spiculated mass over the right lower lobe. Biopsy study of the mass was positive for squamous cell carcinoma. She was referred to the oncology center for further management.

FEATURES OF HYPERTROPHIC OSTEOARTHROPATHY

Digital clubbing is one of the oldest signs in clinical medicine. It is characterized by bulbous enlargement of the terminal segments of the fingers and toes due to proliferation of subungual connective tissue. It usually appears as a painless finger deformity and is clinically appreciated as a loss of the normal angle between the nail bed and proximal nail fold.

Hypertrophic osteoarthropathy is a symptomatic form of clubbing associated with proliferative periostosis of the distal end of long tubular bones, commonly those adjacent to the wrist and ankle joints.¹ The laminated appearance of these bones on radiography is due to the excess connective tissue secondary to new osteoid material deposited under the periosteum.

There is evidence to suggest that clubbing and hypertrophic osteoarthropathy represent different stages of the same disease process.² In most cases, finger deformity is the first manifestation; as the disease progresses, periostosis becomes evident.

Hypertrophic osteoarthropathy can be classified as primary or secondary. The primary form, also known as primary pachydermoperiostosis, is rare and constitutes only 3% of all cases.³ The exact cause is not yet known; it occurs as a hereditary disease with autosomal dominant inheritance with variable penetrance. Congenital clubbing without periostosis is of no clinical significance.⁴

CONDITIONS ASSOCIATED WITH CLUBBING

Primary bronchogenic carcinoma is the most common cause of clubbing and hypertrophic osteoarthropathy. In one retrospective series, 4.5% of patients with lung cancer had radiologic evidence of hypertrophic osteoarthropathy.⁵ Other malignancies associated with this condition are mesothelioma, hepatocellular carcinoma, and certain types of gastrointestinal adenocarcinoma.

Other conditions associated with clubbing include:

• Cardiovascular disease such as congenital cyanotic heart disease and infective endocarditis
• Gastrointestinal conditions such as cirrhosis, primary sclerosing cholangitis, Crohn disease, and ulcerative colitis
• Infections such as lung abscess and empyema.

Clubbing is generally bilaterally symmetrical. Asymmetric clubbing is rare and usually indicates impaired regional blood flow due to vascular disease. Unilateral clubbing or hypertrophic osteoarthropathy restricted to 1 upper limb can result from an anomaly of the aortic arch or from a subclavian or brachial artery aneurysm. Clubbing affecting predominantly the lower limbs has been reported in coarctation of aorta and patent ductus arteriosus.⁶ Rare cases of unidigital clubbing are reported in sarcoidosis.⁷

The importance of recognizing hypertrophic osteoarthropathy cannot be overemphasized. If any of the manifestations of the syndrome become evident in a previously healthy person, a thorough evaluation for an underlying disease should be done.

Clubbing should be differentiated from pseudoclubbing, which is seen in conditions such as hyperparathyroidism and scleroderma. The central mechanism for nail deformity in pseudoclubbing is acro-osteolysis with the resulting collapse of the subungual soft tissues. The important features differentiating it from true clubbing are preservation of the angle between the nail bed and proximal nail fold and asymmetric finger involvement.⁸

MANAGEMENT

The management of primary hypertrophic osteoarthropathy focuses on relieving the symptoms of periosteitis. Secondary forms require a detailed evaluation to rule out the underlying disease. In refractory cases, a bone-modifying agent (eg, zoledronic acid),⁹ octreotide,¹⁰ nonsteroidal anti-inflammatory drugs, or vagotomy¹¹ may help.

We thank those who reviewed manuscripts submitted to the Cleveland Clinic Journal of Medicine in the year ending December 31, 2016. Reviewing papers for scientific journals is an arduous task and involves considerable time and effort. We are grateful to these reviewers for contributing their expertise this past year.

—Brian F. Mandell, MD, PhD, Editor in Chief

We thank those who reviewed manuscripts submitted to the Cleveland Clinic Journal of Medicine in the year ending December 31, 2016. Reviewing papers for scientific journals is an arduous task and involves considerable time and effort. We are grateful to these reviewers for contributing their expertise this past year.

—Brian F. Mandell, MD, PhD, Editor in Chief

We thank those who reviewed manuscripts submitted to the Cleveland Clinic Journal of Medicine in the year ending December 31, 2016. Reviewing papers for scientific journals is an arduous task and involves considerable time and effort. We are grateful to these reviewers for contributing their expertise this past year.

—Brian F. Mandell, MD, PhD, Editor in Chief

Cervical dysplasia is a condition commonly encountered by the gynecologist. It is either treated (with excision or ablation) or monitored, depending on the lesion grade, cytologic history, medical history, and reproductive goals. Cervical dysplasia commonly arises in women of reproductive age. Therefore, consider reproductive effects when deciding whether to treat or monitor, as well as when choosing the treatment modality.

Background

Approximately two-thirds of human papillomavirus infections resolve within a year, and more than 90% resolve within 2 years. Similarly, low-grade cervical intraepithelial neoplasia (CIN 1) lesions frequently resolve. High-grade (CIN 2 and CIN 3) lesions regress less commonly, with 5% and 12%-40% progressing to invasive cancer, respectively. Therefore, treatment is typically recommended.

Obstetric implications

Potential obstetric risks of treatment for CIN include infertility, spontaneous abortion, preterm premature rupture of membranes (PPROM), preterm delivery, and perinatal/neonatal mortality. These risks are discussed individually below. Mechanisms that have been suggested for such complications include decreased cervical mucous, cervical scarring impeding conception or dilation, loss of cervical volume, collagen breakdown, and immunologic processes due to decreased physical defenses or microbiome shifts.

Fertility

Studies have shown that treatment does not appear to impede conception. The overall pregnancy rate is higher among treated women than untreated women. Pregnancy rates are not different among women intending to conceive or among women attempting conception for more than 12 months, with the caveat being that these studies are heterogenous.^2,3

Miscarriage

No difference has been observed in total (less than 24 weeks) miscarriage rate or first trimester (less than 12 weeks) miscarriage rate among treated and untreated women. However, the second trimester miscarriage rate is significantly higher among treated women (risk ratio, 2.60).² This risk is most notable following laser conization or LEEP.⁴ There may also be an association between ablation and pregnancy loss.

Preterm birth and PPROM

Several studies and meta-analyses show an association between preterm birth and treatment for CIN using LEEP or CKC. There is an increased risk of severe preterm delivery (relative risk, 2.78), extreme preterm delivery (relative risk, 5.33), and low birth weight (relative risk, 2.86) with CKC.⁵ LEEP is associated with the same outcomes, albeit the risk is lower than with CKC.⁶ The risk of preterm birth is even lower for ablation.⁷

Other complications

Ectopic pregnancy and termination rates may be higher in treated women, compared with untreated women.² However, there does not appear to be an increased risk for perinatal/neonatal mortality, cesarean section, or neonatal intensive care unit admission among women treated with excisional procedures.⁶

Pointers for practice

• Due to the potential for adverse obstetric complications following excisional procedures for cervical dysplasia, gynecologists should closely adhere to the American Society for Colposcopy and Cervical Pathology guidelines when determining the appropriateness of dysplasia interventions. The decision to treat, versus monitor, dysplasia in a woman who plans future childbearing should be made with the patient after thorough discussion of the risks and benefits of each path.
• Women younger than age 30 years should not be screened for high-risk human papillomavirus because of both its high incidence and its high rate of spontaneous resolution.
• For reproductive-aged women with CIN 2 and adequate colposcopy, the American Society for Colposcopy and Cervical Pathology supports either monitoring with cytology and colposcopy every 6 months for a year or excisional treatment. However, women with CIN 3, inadequate colposcopy, prior cervical cancer, diethylstilbestrol exposure, or decreased immunity should undergo excisional treatment.
• When selecting an excisional method (LEEP or CKC), surgeons should choose the most appropriate technique for the patient’s pathology but should acknowledge the observed higher rates of PPROM, preterm birth, and low-birth-weight infants among those receiving CKC, and tailor the size of the excision to the specific lesion.
• Consider recommending a 12-month interval between treatment and pregnancy to ensure resolution of high-grade dysplasia. Furthermore, obstetric risk may be increased within 12 months following treatment.

Dr. Robbins is a resident in the department of obstetrics and gynecology at the University of North Carolina, Chapel Hill. Dr. Rossi is an assistant professor in the division of gynecologic oncology at UNC, Chapel Hill. They reported having no relevant financial disclosures.

References

1. Am J Obstet Gynecol. 2011 Jul;205(1):19-27.

2. Cochrane Database Syst Rev. 2015 Sep 29;(9):CD008478.

3. BMJ. 2014 Oct 28;349:g6192.

4. Obstet Gynecol. 2016 Dec;128(6):1265-73.

5. BMJ. 2008 Sep 18;337:a1284.

6. Arch Gynecol Obstet. 2014 Jan;289(1):85-99.

7. BJOG. 2011 Aug;118(9):1031-41.

8. Obstet Gynecol. 2013 May;121(5):1063-8.

9. Lancet. 2006 Feb 11;367(9509):489-98.

10. Gynecol Obstet Invest. 2014;77(4):240-4.

Cervical dysplasia is a condition commonly encountered by the gynecologist. It is either treated (with excision or ablation) or monitored, depending on the lesion grade, cytologic history, medical history, and reproductive goals. Cervical dysplasia commonly arises in women of reproductive age. Therefore, consider reproductive effects when deciding whether to treat or monitor, as well as when choosing the treatment modality.

Background

Approximately two-thirds of human papillomavirus infections resolve within a year, and more than 90% resolve within 2 years. Similarly, low-grade cervical intraepithelial neoplasia (CIN 1) lesions frequently resolve. High-grade (CIN 2 and CIN 3) lesions regress less commonly, with 5% and 12%-40% progressing to invasive cancer, respectively. Therefore, treatment is typically recommended.

Obstetric implications

Potential obstetric risks of treatment for CIN include infertility, spontaneous abortion, preterm premature rupture of membranes (PPROM), preterm delivery, and perinatal/neonatal mortality. These risks are discussed individually below. Mechanisms that have been suggested for such complications include decreased cervical mucous, cervical scarring impeding conception or dilation, loss of cervical volume, collagen breakdown, and immunologic processes due to decreased physical defenses or microbiome shifts.

Fertility

Studies have shown that treatment does not appear to impede conception. The overall pregnancy rate is higher among treated women than untreated women. Pregnancy rates are not different among women intending to conceive or among women attempting conception for more than 12 months, with the caveat being that these studies are heterogenous.^2,3

Miscarriage

No difference has been observed in total (less than 24 weeks) miscarriage rate or first trimester (less than 12 weeks) miscarriage rate among treated and untreated women. However, the second trimester miscarriage rate is significantly higher among treated women (risk ratio, 2.60).² This risk is most notable following laser conization or LEEP.⁴ There may also be an association between ablation and pregnancy loss.

Preterm birth and PPROM

Several studies and meta-analyses show an association between preterm birth and treatment for CIN using LEEP or CKC. There is an increased risk of severe preterm delivery (relative risk, 2.78), extreme preterm delivery (relative risk, 5.33), and low birth weight (relative risk, 2.86) with CKC.⁵ LEEP is associated with the same outcomes, albeit the risk is lower than with CKC.⁶ The risk of preterm birth is even lower for ablation.⁷

Other complications

Ectopic pregnancy and termination rates may be higher in treated women, compared with untreated women.² However, there does not appear to be an increased risk for perinatal/neonatal mortality, cesarean section, or neonatal intensive care unit admission among women treated with excisional procedures.⁶

Pointers for practice

• Due to the potential for adverse obstetric complications following excisional procedures for cervical dysplasia, gynecologists should closely adhere to the American Society for Colposcopy and Cervical Pathology guidelines when determining the appropriateness of dysplasia interventions. The decision to treat, versus monitor, dysplasia in a woman who plans future childbearing should be made with the patient after thorough discussion of the risks and benefits of each path.
• Women younger than age 30 years should not be screened for high-risk human papillomavirus because of both its high incidence and its high rate of spontaneous resolution.
• For reproductive-aged women with CIN 2 and adequate colposcopy, the American Society for Colposcopy and Cervical Pathology supports either monitoring with cytology and colposcopy every 6 months for a year or excisional treatment. However, women with CIN 3, inadequate colposcopy, prior cervical cancer, diethylstilbestrol exposure, or decreased immunity should undergo excisional treatment.
• When selecting an excisional method (LEEP or CKC), surgeons should choose the most appropriate technique for the patient’s pathology but should acknowledge the observed higher rates of PPROM, preterm birth, and low-birth-weight infants among those receiving CKC, and tailor the size of the excision to the specific lesion.
• Consider recommending a 12-month interval between treatment and pregnancy to ensure resolution of high-grade dysplasia. Furthermore, obstetric risk may be increased within 12 months following treatment.

Dr. Robbins is a resident in the department of obstetrics and gynecology at the University of North Carolina, Chapel Hill. Dr. Rossi is an assistant professor in the division of gynecologic oncology at UNC, Chapel Hill. They reported having no relevant financial disclosures.

References

1. Am J Obstet Gynecol. 2011 Jul;205(1):19-27.

2. Cochrane Database Syst Rev. 2015 Sep 29;(9):CD008478.

3. BMJ. 2014 Oct 28;349:g6192.

4. Obstet Gynecol. 2016 Dec;128(6):1265-73.

5. BMJ. 2008 Sep 18;337:a1284.

6. Arch Gynecol Obstet. 2014 Jan;289(1):85-99.

7. BJOG. 2011 Aug;118(9):1031-41.

8. Obstet Gynecol. 2013 May;121(5):1063-8.

9. Lancet. 2006 Feb 11;367(9509):489-98.

10. Gynecol Obstet Invest. 2014;77(4):240-4.

Cervical dysplasia is a condition commonly encountered by the gynecologist. It is either treated (with excision or ablation) or monitored, depending on the lesion grade, cytologic history, medical history, and reproductive goals. Cervical dysplasia commonly arises in women of reproductive age. Therefore, consider reproductive effects when deciding whether to treat or monitor, as well as when choosing the treatment modality.

Background

Approximately two-thirds of human papillomavirus infections resolve within a year, and more than 90% resolve within 2 years. Similarly, low-grade cervical intraepithelial neoplasia (CIN 1) lesions frequently resolve. High-grade (CIN 2 and CIN 3) lesions regress less commonly, with 5% and 12%-40% progressing to invasive cancer, respectively. Therefore, treatment is typically recommended.

Obstetric implications

Potential obstetric risks of treatment for CIN include infertility, spontaneous abortion, preterm premature rupture of membranes (PPROM), preterm delivery, and perinatal/neonatal mortality. These risks are discussed individually below. Mechanisms that have been suggested for such complications include decreased cervical mucous, cervical scarring impeding conception or dilation, loss of cervical volume, collagen breakdown, and immunologic processes due to decreased physical defenses or microbiome shifts.

Fertility

Studies have shown that treatment does not appear to impede conception. The overall pregnancy rate is higher among treated women than untreated women. Pregnancy rates are not different among women intending to conceive or among women attempting conception for more than 12 months, with the caveat being that these studies are heterogenous.^2,3

Miscarriage

No difference has been observed in total (less than 24 weeks) miscarriage rate or first trimester (less than 12 weeks) miscarriage rate among treated and untreated women. However, the second trimester miscarriage rate is significantly higher among treated women (risk ratio, 2.60).² This risk is most notable following laser conization or LEEP.⁴ There may also be an association between ablation and pregnancy loss.

Preterm birth and PPROM

Several studies and meta-analyses show an association between preterm birth and treatment for CIN using LEEP or CKC. There is an increased risk of severe preterm delivery (relative risk, 2.78), extreme preterm delivery (relative risk, 5.33), and low birth weight (relative risk, 2.86) with CKC.⁵ LEEP is associated with the same outcomes, albeit the risk is lower than with CKC.⁶ The risk of preterm birth is even lower for ablation.⁷

Other complications

Ectopic pregnancy and termination rates may be higher in treated women, compared with untreated women.² However, there does not appear to be an increased risk for perinatal/neonatal mortality, cesarean section, or neonatal intensive care unit admission among women treated with excisional procedures.⁶

Pointers for practice

• Due to the potential for adverse obstetric complications following excisional procedures for cervical dysplasia, gynecologists should closely adhere to the American Society for Colposcopy and Cervical Pathology guidelines when determining the appropriateness of dysplasia interventions. The decision to treat, versus monitor, dysplasia in a woman who plans future childbearing should be made with the patient after thorough discussion of the risks and benefits of each path.
• Women younger than age 30 years should not be screened for high-risk human papillomavirus because of both its high incidence and its high rate of spontaneous resolution.
• For reproductive-aged women with CIN 2 and adequate colposcopy, the American Society for Colposcopy and Cervical Pathology supports either monitoring with cytology and colposcopy every 6 months for a year or excisional treatment. However, women with CIN 3, inadequate colposcopy, prior cervical cancer, diethylstilbestrol exposure, or decreased immunity should undergo excisional treatment.
• When selecting an excisional method (LEEP or CKC), surgeons should choose the most appropriate technique for the patient’s pathology but should acknowledge the observed higher rates of PPROM, preterm birth, and low-birth-weight infants among those receiving CKC, and tailor the size of the excision to the specific lesion.
• Consider recommending a 12-month interval between treatment and pregnancy to ensure resolution of high-grade dysplasia. Furthermore, obstetric risk may be increased within 12 months following treatment.

Dr. Robbins is a resident in the department of obstetrics and gynecology at the University of North Carolina, Chapel Hill. Dr. Rossi is an assistant professor in the division of gynecologic oncology at UNC, Chapel Hill. They reported having no relevant financial disclosures.

References

1. Am J Obstet Gynecol. 2011 Jul;205(1):19-27.

2. Cochrane Database Syst Rev. 2015 Sep 29;(9):CD008478.

3. BMJ. 2014 Oct 28;349:g6192.

4. Obstet Gynecol. 2016 Dec;128(6):1265-73.

5. BMJ. 2008 Sep 18;337:a1284.

6. Arch Gynecol Obstet. 2014 Jan;289(1):85-99.

7. BJOG. 2011 Aug;118(9):1031-41.

8. Obstet Gynecol. 2013 May;121(5):1063-8.

9. Lancet. 2006 Feb 11;367(9509):489-98.

10. Gynecol Obstet Invest. 2014;77(4):240-4.

Electronic fetal monitoring (EFM) is the most commonly used instrument in obstetrics and is the perceived standard of care. However, the U.S. Preventive Services Task Force recommended against its use in low-risk women in 1996 (a “D” rating) – signifying the lack of evidence for benefit and the potential for harm – and said there was insufficient evidence to recommend for or against its use in high-risk women (a “C” rating).

Today, available data still suggest that EFM does not reduce overall perinatal mortality or the risk of cerebral palsy. Moreover, its use is associated with increased operative vaginal deliveries and cesarean deliveries.

Emerging research

An abnormal or indeterminate fetal heart rate tracing is the second most common indication for primary cesarean, after labor arrest, according to a study published in 2011 of more than 32,000 live births. Given the rarity of category III tracings (“abnormal”), it is likely that category II tracings (“indeterminate”) account for most of the cesarean deliveries performed out of concern for fetal acidemia (Obstet Gynecol. 2011 Jul;118[1]:29-38).

Until recently, we’ve known very little about the patterns contained within category II of our current three-tier system for categorizing fetal heart rate patterns. The system was defined by the 2008 consensus workshop sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine (Obstet Gynecol. 2008 Sep;112[3]:661-6).

We have reasonable data to know that the vast majority of patients with category I fetal heart rate tracings will have a normal pH. We also have reasonable data showing us that patients with category III tracings have a high risk of acidemia and morbidity. However, the majority of tracings we see during labor at term fall into category II, with no clear indication of risk and characterized most often by the presence of decelerations.

As we’ve delved more deeply into the highly variable and complex category II tracings defined in 2008, we’ve begun to demonstrate that tracings can have different meanings for different patients, and that particular clinical factors can make EFM patterns more informative and predictive. In other words, EFM patterns may require different interpretations based on a priori risk and clinical factors.

One of these factors may be the presence of meconium. In a prospective cohort of more than 3,000 women with category II tracings, the presence of meconium – especially thick meconium – was associated with a higher risk of acidemia and neonatal morbidity than when meconium was absent. Interestingly, the negative predictive value was higher than the overall predictive ability in this cohort, which suggests that the absence of meconium in the setting of a category II tracing can be considered a reassuring feature (Am J Obstet Gynecol. 2014;211:644.e1-8).

We have also found through retrospective cohort studies that magnesium sulfate can impact fetal heart rate tracings, causing a transient decrease in variability (Obstet Gynecol. 2012 Jun;119[6]:1129-36 and Am J Perinatol. 2014 Nov;31[10]:869-74). In addition, intrauterine growth restricted fetuses have a higher risk of decelerations without a commensurate higher risk of morbidity (Am J Perinatol. 2015 Jul;32[9]:873-8).

Such findings need to be reproduced, expanded, and further analyzed to show us how the risk of acidemia can be better predicted. For now, just as we increasingly appreciate that tracings have a transient nature and should be considered with two lenses – one looking back in time and one looking forward – we have a growing sense that EFM should not be interpreted without consideration of clinical factors.

Research at our institution and others has shown that acidemia is more significantly associated with non-NICHD measures of fetal heart rate deceleration than with each of the main deceleration types defined by the 2008 NICHD system (i.e., repetitive variable, repetitive late, and repetitive prolonged).

For instance, Emily Hamilton, MD, and her colleagues at PeriGen, a perinatal software company, found that only prolonged decelerations, in addition to the variability within the deceleration and a depth below 60 beats per minute for more than 60 seconds, could discriminate between cases of metabolic acidosis and those with normal umbilical artery gases (J Matern Fetal Neonatal Med. 2012 Jun;25[6]:648-53).

In a 4-year retrospective cohort study of nearly 5,340 consecutive singleton, term, nonanomalous gestations, we found acidemia was most significantly associated with a calculation of the “total deceleration area” – the sum of the estimates of area within all the decelerations. This measure accounted for the frequency, depth, and duration of all decelerations in the final 30 minutes of EFM.

Each of the NICHD deceleration types was associated in our study with acidemia after adjustment for fever, obesity, prolonged first stage, and nulliparity. However, total deceleration area had superior predictive ability. After the same adjustments were made, an abnormal total deceleration area (greater than the 95th percentile) was significantly associated with an increased risk for acidemia (odds ratio, 3.79) (Am J Obstet Gynecol. 2012 Sep;207[3]:206.e1-8).

Pathophysiologically, it seems logical that the total area is most predictive, as it captures both the temporal and dose effect of decelerations. At this point, however, we can only apply this concept crudely at the bedside. There is more work to do to translate such findings into software-driven bedside tools.

Gaining reassurance

Although efforts to manage intrapartum fetal heart rate tracings focus largely on attempting to better predict who is at greatest risk for acidemia, it is important and worthwhile that we also attempt to determine whether a fetus with a category II tracing is not acidotic.

Research has consistently shown that the presence of accelerations, whether spontaneous or stimulated, is a highly reliable indicator of normal neonatal umbilical cord pH. It is therefore reasonable, when faced with indeterminate tracings (e.g., minimal variability), to consider scalp stimulation to elicit fetal heart rate acceleration. Scalp stimulation is the easiest noninvasive tool to employ to quickly secure clinical reassurance – within a couple of minutes – that the fetus is not acidotic.

For guidance on managing repetitive variable decelerations, amnioinfusion with normal saline is similarly worthy of consideration. It has been demonstrated (Level A evidence) to resolve variable fetal heart rate decelerations and reduce the incidence of cesarean delivery for nonreassuring fetal heart rate patterns. Both amnioinfusion and scalp stimulation are recommended in the 2014 ACOG/SMFM consensus statement on “Safe Prevention of the Primary Cesarean Delivery” (Obstet Gynecol. 2014 Mar;123[3]:693-711).

Oxygen administration, on the other hand, is ingrained in practice and is included in the American College of Obstetricians and Gynecologists’ practice bulletin on managing intrapartum fetal rate tracings. It is listed as a possible resuscitative measure for category II or III tracings, despite the fact that there are extremely limited data for its effectiveness or safety in labor.

Maureen S. Hamel, MD, and her colleagues at the Warren Albert Medical School at Brown University reviewed the literature and concluded that the only two randomized trials investigating the use of maternal oxygen supplementation in laboring women do not support the idea that supplementation may benefit the fetus. Moreover, they contended that oxygen supplementation may even be harmful (Am J Obstet Gynecol. 2014 Aug;211[2]:124-7).

If supplemental oxygen were a medication, we would want to know the dose, as well as the length and duration of administration before fetal heart rate tracing improved. We don’t know the answers to these questions.

There is research ongoing, both observational studies and at least one registered randomized clinical trial, that should provide more information and guidance on the impact of supplemental oxygen in the setting of category II fetal heart rate patterns. I do not expect these findings to resolve all the questions. We’re going to need a thorough body of work to provide us with definitive answers.
 

Dr. Cahill is the chief of the division of maternal-fetal medicine at Washington University in St. Louis. She reported having no financial disclosures relevant to this Master Class.

Electronic fetal monitoring (EFM) is the most commonly used instrument in obstetrics and is the perceived standard of care. However, the U.S. Preventive Services Task Force recommended against its use in low-risk women in 1996 (a “D” rating) – signifying the lack of evidence for benefit and the potential for harm – and said there was insufficient evidence to recommend for or against its use in high-risk women (a “C” rating).

Today, available data still suggest that EFM does not reduce overall perinatal mortality or the risk of cerebral palsy. Moreover, its use is associated with increased operative vaginal deliveries and cesarean deliveries.

Emerging research

An abnormal or indeterminate fetal heart rate tracing is the second most common indication for primary cesarean, after labor arrest, according to a study published in 2011 of more than 32,000 live births. Given the rarity of category III tracings (“abnormal”), it is likely that category II tracings (“indeterminate”) account for most of the cesarean deliveries performed out of concern for fetal acidemia (Obstet Gynecol. 2011 Jul;118[1]:29-38).

Until recently, we’ve known very little about the patterns contained within category II of our current three-tier system for categorizing fetal heart rate patterns. The system was defined by the 2008 consensus workshop sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine (Obstet Gynecol. 2008 Sep;112[3]:661-6).

We have reasonable data to know that the vast majority of patients with category I fetal heart rate tracings will have a normal pH. We also have reasonable data showing us that patients with category III tracings have a high risk of acidemia and morbidity. However, the majority of tracings we see during labor at term fall into category II, with no clear indication of risk and characterized most often by the presence of decelerations.

As we’ve delved more deeply into the highly variable and complex category II tracings defined in 2008, we’ve begun to demonstrate that tracings can have different meanings for different patients, and that particular clinical factors can make EFM patterns more informative and predictive. In other words, EFM patterns may require different interpretations based on a priori risk and clinical factors.

One of these factors may be the presence of meconium. In a prospective cohort of more than 3,000 women with category II tracings, the presence of meconium – especially thick meconium – was associated with a higher risk of acidemia and neonatal morbidity than when meconium was absent. Interestingly, the negative predictive value was higher than the overall predictive ability in this cohort, which suggests that the absence of meconium in the setting of a category II tracing can be considered a reassuring feature (Am J Obstet Gynecol. 2014;211:644.e1-8).

We have also found through retrospective cohort studies that magnesium sulfate can impact fetal heart rate tracings, causing a transient decrease in variability (Obstet Gynecol. 2012 Jun;119[6]:1129-36 and Am J Perinatol. 2014 Nov;31[10]:869-74). In addition, intrauterine growth restricted fetuses have a higher risk of decelerations without a commensurate higher risk of morbidity (Am J Perinatol. 2015 Jul;32[9]:873-8).

Such findings need to be reproduced, expanded, and further analyzed to show us how the risk of acidemia can be better predicted. For now, just as we increasingly appreciate that tracings have a transient nature and should be considered with two lenses – one looking back in time and one looking forward – we have a growing sense that EFM should not be interpreted without consideration of clinical factors.

Research at our institution and others has shown that acidemia is more significantly associated with non-NICHD measures of fetal heart rate deceleration than with each of the main deceleration types defined by the 2008 NICHD system (i.e., repetitive variable, repetitive late, and repetitive prolonged).

For instance, Emily Hamilton, MD, and her colleagues at PeriGen, a perinatal software company, found that only prolonged decelerations, in addition to the variability within the deceleration and a depth below 60 beats per minute for more than 60 seconds, could discriminate between cases of metabolic acidosis and those with normal umbilical artery gases (J Matern Fetal Neonatal Med. 2012 Jun;25[6]:648-53).

In a 4-year retrospective cohort study of nearly 5,340 consecutive singleton, term, nonanomalous gestations, we found acidemia was most significantly associated with a calculation of the “total deceleration area” – the sum of the estimates of area within all the decelerations. This measure accounted for the frequency, depth, and duration of all decelerations in the final 30 minutes of EFM.

Each of the NICHD deceleration types was associated in our study with acidemia after adjustment for fever, obesity, prolonged first stage, and nulliparity. However, total deceleration area had superior predictive ability. After the same adjustments were made, an abnormal total deceleration area (greater than the 95th percentile) was significantly associated with an increased risk for acidemia (odds ratio, 3.79) (Am J Obstet Gynecol. 2012 Sep;207[3]:206.e1-8).

Pathophysiologically, it seems logical that the total area is most predictive, as it captures both the temporal and dose effect of decelerations. At this point, however, we can only apply this concept crudely at the bedside. There is more work to do to translate such findings into software-driven bedside tools.

Gaining reassurance

Although efforts to manage intrapartum fetal heart rate tracings focus largely on attempting to better predict who is at greatest risk for acidemia, it is important and worthwhile that we also attempt to determine whether a fetus with a category II tracing is not acidotic.

Research has consistently shown that the presence of accelerations, whether spontaneous or stimulated, is a highly reliable indicator of normal neonatal umbilical cord pH. It is therefore reasonable, when faced with indeterminate tracings (e.g., minimal variability), to consider scalp stimulation to elicit fetal heart rate acceleration. Scalp stimulation is the easiest noninvasive tool to employ to quickly secure clinical reassurance – within a couple of minutes – that the fetus is not acidotic.

For guidance on managing repetitive variable decelerations, amnioinfusion with normal saline is similarly worthy of consideration. It has been demonstrated (Level A evidence) to resolve variable fetal heart rate decelerations and reduce the incidence of cesarean delivery for nonreassuring fetal heart rate patterns. Both amnioinfusion and scalp stimulation are recommended in the 2014 ACOG/SMFM consensus statement on “Safe Prevention of the Primary Cesarean Delivery” (Obstet Gynecol. 2014 Mar;123[3]:693-711).

Oxygen administration, on the other hand, is ingrained in practice and is included in the American College of Obstetricians and Gynecologists’ practice bulletin on managing intrapartum fetal rate tracings. It is listed as a possible resuscitative measure for category II or III tracings, despite the fact that there are extremely limited data for its effectiveness or safety in labor.

Maureen S. Hamel, MD, and her colleagues at the Warren Albert Medical School at Brown University reviewed the literature and concluded that the only two randomized trials investigating the use of maternal oxygen supplementation in laboring women do not support the idea that supplementation may benefit the fetus. Moreover, they contended that oxygen supplementation may even be harmful (Am J Obstet Gynecol. 2014 Aug;211[2]:124-7).

If supplemental oxygen were a medication, we would want to know the dose, as well as the length and duration of administration before fetal heart rate tracing improved. We don’t know the answers to these questions.

There is research ongoing, both observational studies and at least one registered randomized clinical trial, that should provide more information and guidance on the impact of supplemental oxygen in the setting of category II fetal heart rate patterns. I do not expect these findings to resolve all the questions. We’re going to need a thorough body of work to provide us with definitive answers.
 

Dr. Cahill is the chief of the division of maternal-fetal medicine at Washington University in St. Louis. She reported having no financial disclosures relevant to this Master Class.

Electronic fetal monitoring (EFM) is the most commonly used instrument in obstetrics and is the perceived standard of care. However, the U.S. Preventive Services Task Force recommended against its use in low-risk women in 1996 (a “D” rating) – signifying the lack of evidence for benefit and the potential for harm – and said there was insufficient evidence to recommend for or against its use in high-risk women (a “C” rating).

Today, available data still suggest that EFM does not reduce overall perinatal mortality or the risk of cerebral palsy. Moreover, its use is associated with increased operative vaginal deliveries and cesarean deliveries.

Emerging research

An abnormal or indeterminate fetal heart rate tracing is the second most common indication for primary cesarean, after labor arrest, according to a study published in 2011 of more than 32,000 live births. Given the rarity of category III tracings (“abnormal”), it is likely that category II tracings (“indeterminate”) account for most of the cesarean deliveries performed out of concern for fetal acidemia (Obstet Gynecol. 2011 Jul;118[1]:29-38).

Until recently, we’ve known very little about the patterns contained within category II of our current three-tier system for categorizing fetal heart rate patterns. The system was defined by the 2008 consensus workshop sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine (Obstet Gynecol. 2008 Sep;112[3]:661-6).

We have reasonable data to know that the vast majority of patients with category I fetal heart rate tracings will have a normal pH. We also have reasonable data showing us that patients with category III tracings have a high risk of acidemia and morbidity. However, the majority of tracings we see during labor at term fall into category II, with no clear indication of risk and characterized most often by the presence of decelerations.

As we’ve delved more deeply into the highly variable and complex category II tracings defined in 2008, we’ve begun to demonstrate that tracings can have different meanings for different patients, and that particular clinical factors can make EFM patterns more informative and predictive. In other words, EFM patterns may require different interpretations based on a priori risk and clinical factors.

One of these factors may be the presence of meconium. In a prospective cohort of more than 3,000 women with category II tracings, the presence of meconium – especially thick meconium – was associated with a higher risk of acidemia and neonatal morbidity than when meconium was absent. Interestingly, the negative predictive value was higher than the overall predictive ability in this cohort, which suggests that the absence of meconium in the setting of a category II tracing can be considered a reassuring feature (Am J Obstet Gynecol. 2014;211:644.e1-8).

We have also found through retrospective cohort studies that magnesium sulfate can impact fetal heart rate tracings, causing a transient decrease in variability (Obstet Gynecol. 2012 Jun;119[6]:1129-36 and Am J Perinatol. 2014 Nov;31[10]:869-74). In addition, intrauterine growth restricted fetuses have a higher risk of decelerations without a commensurate higher risk of morbidity (Am J Perinatol. 2015 Jul;32[9]:873-8).

Such findings need to be reproduced, expanded, and further analyzed to show us how the risk of acidemia can be better predicted. For now, just as we increasingly appreciate that tracings have a transient nature and should be considered with two lenses – one looking back in time and one looking forward – we have a growing sense that EFM should not be interpreted without consideration of clinical factors.

Research at our institution and others has shown that acidemia is more significantly associated with non-NICHD measures of fetal heart rate deceleration than with each of the main deceleration types defined by the 2008 NICHD system (i.e., repetitive variable, repetitive late, and repetitive prolonged).

For instance, Emily Hamilton, MD, and her colleagues at PeriGen, a perinatal software company, found that only prolonged decelerations, in addition to the variability within the deceleration and a depth below 60 beats per minute for more than 60 seconds, could discriminate between cases of metabolic acidosis and those with normal umbilical artery gases (J Matern Fetal Neonatal Med. 2012 Jun;25[6]:648-53).

In a 4-year retrospective cohort study of nearly 5,340 consecutive singleton, term, nonanomalous gestations, we found acidemia was most significantly associated with a calculation of the “total deceleration area” – the sum of the estimates of area within all the decelerations. This measure accounted for the frequency, depth, and duration of all decelerations in the final 30 minutes of EFM.

Each of the NICHD deceleration types was associated in our study with acidemia after adjustment for fever, obesity, prolonged first stage, and nulliparity. However, total deceleration area had superior predictive ability. After the same adjustments were made, an abnormal total deceleration area (greater than the 95th percentile) was significantly associated with an increased risk for acidemia (odds ratio, 3.79) (Am J Obstet Gynecol. 2012 Sep;207[3]:206.e1-8).

Pathophysiologically, it seems logical that the total area is most predictive, as it captures both the temporal and dose effect of decelerations. At this point, however, we can only apply this concept crudely at the bedside. There is more work to do to translate such findings into software-driven bedside tools.

Gaining reassurance

Although efforts to manage intrapartum fetal heart rate tracings focus largely on attempting to better predict who is at greatest risk for acidemia, it is important and worthwhile that we also attempt to determine whether a fetus with a category II tracing is not acidotic.

Research has consistently shown that the presence of accelerations, whether spontaneous or stimulated, is a highly reliable indicator of normal neonatal umbilical cord pH. It is therefore reasonable, when faced with indeterminate tracings (e.g., minimal variability), to consider scalp stimulation to elicit fetal heart rate acceleration. Scalp stimulation is the easiest noninvasive tool to employ to quickly secure clinical reassurance – within a couple of minutes – that the fetus is not acidotic.

For guidance on managing repetitive variable decelerations, amnioinfusion with normal saline is similarly worthy of consideration. It has been demonstrated (Level A evidence) to resolve variable fetal heart rate decelerations and reduce the incidence of cesarean delivery for nonreassuring fetal heart rate patterns. Both amnioinfusion and scalp stimulation are recommended in the 2014 ACOG/SMFM consensus statement on “Safe Prevention of the Primary Cesarean Delivery” (Obstet Gynecol. 2014 Mar;123[3]:693-711).

Oxygen administration, on the other hand, is ingrained in practice and is included in the American College of Obstetricians and Gynecologists’ practice bulletin on managing intrapartum fetal rate tracings. It is listed as a possible resuscitative measure for category II or III tracings, despite the fact that there are extremely limited data for its effectiveness or safety in labor.

Maureen S. Hamel, MD, and her colleagues at the Warren Albert Medical School at Brown University reviewed the literature and concluded that the only two randomized trials investigating the use of maternal oxygen supplementation in laboring women do not support the idea that supplementation may benefit the fetus. Moreover, they contended that oxygen supplementation may even be harmful (Am J Obstet Gynecol. 2014 Aug;211[2]:124-7).

If supplemental oxygen were a medication, we would want to know the dose, as well as the length and duration of administration before fetal heart rate tracing improved. We don’t know the answers to these questions.

There is research ongoing, both observational studies and at least one registered randomized clinical trial, that should provide more information and guidance on the impact of supplemental oxygen in the setting of category II fetal heart rate patterns. I do not expect these findings to resolve all the questions. We’re going to need a thorough body of work to provide us with definitive answers.
 

Dr. Cahill is the chief of the division of maternal-fetal medicine at Washington University in St. Louis. She reported having no financial disclosures relevant to this Master Class.

There is no question that we are living in the information age where “big data” isn’t just reserved for scientists but is accessible to everyone. Wearable devices have revolutionized when and how often we exercise. Smartphones have changed the way in which we consume news, watch television, take photographs, and record home movies. Online video chatting has allowed people who live miles – or even countries – away to connect on a whole new level. Today’s 7-year-olds have never lived in a world without iPhones and don’t know what life is like without iPads. Technology has improved our daily lives in countless ways. However, is “too much of a good thing” ever just too much?

Last year, we looked back over the preceding 5 decades of ob.gyn. practice. This retrospective analysis demonstrated that today’s practitioners have infinitely more tools at their disposal than many of their mentors did to ensure the best pregnancy outcomes. From prenatal diagnostic approaches, such as ultrasonography and genetic screening, to in utero surgical interventions, our discipline has advanced in leaps and bounds, all over the course of one person’s lifetime.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

There is no question that we are living in the information age where “big data” isn’t just reserved for scientists but is accessible to everyone. Wearable devices have revolutionized when and how often we exercise. Smartphones have changed the way in which we consume news, watch television, take photographs, and record home movies. Online video chatting has allowed people who live miles – or even countries – away to connect on a whole new level. Today’s 7-year-olds have never lived in a world without iPhones and don’t know what life is like without iPads. Technology has improved our daily lives in countless ways. However, is “too much of a good thing” ever just too much?

Last year, we looked back over the preceding 5 decades of ob.gyn. practice. This retrospective analysis demonstrated that today’s practitioners have infinitely more tools at their disposal than many of their mentors did to ensure the best pregnancy outcomes. From prenatal diagnostic approaches, such as ultrasonography and genetic screening, to in utero surgical interventions, our discipline has advanced in leaps and bounds, all over the course of one person’s lifetime.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

There is no question that we are living in the information age where “big data” isn’t just reserved for scientists but is accessible to everyone. Wearable devices have revolutionized when and how often we exercise. Smartphones have changed the way in which we consume news, watch television, take photographs, and record home movies. Online video chatting has allowed people who live miles – or even countries – away to connect on a whole new level. Today’s 7-year-olds have never lived in a world without iPhones and don’t know what life is like without iPads. Technology has improved our daily lives in countless ways. However, is “too much of a good thing” ever just too much?

Last year, we looked back over the preceding 5 decades of ob.gyn. practice. This retrospective analysis demonstrated that today’s practitioners have infinitely more tools at their disposal than many of their mentors did to ensure the best pregnancy outcomes. From prenatal diagnostic approaches, such as ultrasonography and genetic screening, to in utero surgical interventions, our discipline has advanced in leaps and bounds, all over the course of one person’s lifetime.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

The Food and Drug Administration approved 22 new drug products in 12 pharmacologic classes in 2016. Additionally, daclizumab (Zenapax), which was approved several years ago for prophylaxis of acute organ rejection in patients receiving renal transplants, was approved for multiple sclerosis treatment (Zinbryta) last year, and sofosbuvir (Sovaldi), which was approved in 2013 for the treatment of hepatitis C virus, is now combined with velpatasvir (Epclusa) to treat all six major forms of hepatitis C.

There are 22 drugs that can be considered novel drugs. As defined by the FDA, novel drugs have never been approved for human use. There are no human pregnancy data for any of the newly approved drugs or drug combinations. As such, it is important to consider that high molecular weight drugs that probably do not cross the placenta in the first half of pregnancy may do so in late pregnancy.

Antineoplastics

Atezolizumab (Tecentriq) is a programmed death ligand–blocking antibody that is indicated for locally advanced or metastatic urothelial carcinoma and metastatic nonsmall cell lung cancer following platinum-containing chemotherapy. Animal reproduction studies have not been conducted, but, based on its mechanism of action, fetal exposure may increase the risk of developing immune-mediated disorders or altering the normal immune response. The molecular weight is high (145,000) and the terminal half-life is long (27 days).

Olaratumab (Lartruvo) is a platelet-derived growth factor receptor– alpha-blocking antibody. It is indicated, in combination with doxorubicin, for the treatment of soft tissue sarcoma. Although the estimated elimination half-life is long (about 11 days with a range of 6-24 days), the high molecular weight (about 154,000) should limit fetal exposure, at least in the first half of pregnancy. The drug should be avoided in pregnancy, however, based on the animal data, the mechanism of action, and its combination with doxorubicin.

Rucaparib (Rubraca) is a poly (adenosine diphosphate–ribose) polymerase inhibitor indicated for the treatment of ovarian cancer. The drug could cause human fetal harm based on the animal data, mechanism of action, relatively low molecular weight (about 556), and terminal half-life (17 hours).

Venetoclax (Venclexta) is a B-cell lymphoma 2 inhibitor indicated for the treatment of chronic lymphocytic leukemia. Although the animal data, molecular weight (about 868), and elimination half-life (about 26 hours) suggest embryo-fetal risk, the high plasma protein binding (99.9%) should limit the amount crossing the placenta.

Anti-infectives

There are two new monoclonal antibodies in this class. Bezlotoxumab (Zinplava) is used to reduce recurrence of Clostridium difficile. Animal reproduction studies have not been conducted. As the molecular weight is about 148,000, the drug will not cross the placenta, at least not in the first half of pregnancy. However, the drug has a long elimination half-life (about 19 days), so, depending on when it was given, it could cross in late pregnancy. Obiltoxaximab (Anthim), administered as a single IV dose, is indicated for the treatment of inhaled anthrax due to Bacillus anthracis. No fetal harm was observed in animal reproduction studies. The high molecular weight (about 148,000) suggests that the drug will not cross to the embryo and/or fetus, at least not in the first part of pregnancy.

Elbasvir/Grazoprevir (Zepatier) is indicated for the treatment of chronic hepatitis C virus genotype 1 or 4. Animal reproduction studies found no evidence of adverse developmental outcomes. The molecular weights of the two components are about 882 and 767, respectively. Both are extensively bound to plasma proteins, 99.9% and 98.8%, respectively, and the terminal half-lives are 24 and 31 hours. Thus, the product appears to be low risk if used in human pregnancy. However, it is contraindicated if given with ribavirin.

moodboard/Thinkstock

Central nervous system agents

Brivaracetam (Briviact) is an anticonvulsant used to treat partial-onset seizures. Animal reproduction studies suggest moderate risk. The molecular weight (about 212), low plasma protein binding (less than or equal to 20%), and terminal plasma half-life of about 9 hours suggest that the drug will cross the placenta. The manufacturer recommends that the drug should be used in pregnancy only if the potential benefit justifies the potential risk to the embryo/fetus.

Pimavanserin (Nuplazid) is an atypical antipsychotic indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. Reproduction studies in animals suggest low risk. The molecular weight of the free base (about 428) and the long mean plasma half-lives of the parent drug and active metabolite (57 and 200 hours) suggest that the drug will cross the placenta. However, the high plasma protein binding (about 95%) may limit the exposure. Nevertheless, avoiding the period of organogenesis appears to be best.

Dermatologic agents

Crisaborole (Eucrisa) is indicated for topical treatment of mild to moderate atopic dermatitis. In 33 pediatric subjects (aged 2-17 years) who applied the ointment twice daily for 8 days, low amounts were absorbed systemically with plasma concentrations in the nanogram/milliliter range. Plasma protein binding was 97%. With oral formulations of the drug, animal reproduction studies suggest low risk. Taken in sum, the human pregnancy risk appears to be low.

Ixekizumab (Taltz) is a humanized interleukin-17A antagonist, administered subcutaneously, that is indicated for the treatment of adults with moderate to severe plaque psoriasis. The drug did not cause developmental toxicity in monkeys. The molecular weight for the drug’s protein backbone is 146,158, and the mean elimination half-life was 13 days. The human embryo-fetal risk in the first half of pregnancy appears to be low.

Diagnostic agents

Fluciclovine F 18 (Axumin) is a radioactive diagnostic agent indicated for positron emission tomography imaging in men with suspected prostate cancer. Since the agent is only used in men, there are no human or animal pregnancy data.

Gallium GA 68 dotatate injection, a diagnostic imaging agent to detect rare neuroendocrine tumors, is not yet on the market.

Endocrine/metabolic agents

Lixisenatide (Adlyxin) is a glucagon-like–peptide-1 receptor agonist that is administered subcutaneously. It is indicated as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes. The drug was teratogenic in two animal species. The molecular weight is about 4,859, and the mean terminal half-life was about 3 hours. Since tight control of glucose levels in type 2 diabetes is required during pregnancy, insulin is the treatment of choice. Consequently, lixisenatide should not be used during pregnancy.

Gastrointestinal agents

Obeticholic acid (Ocaliva) is a farnesoid X receptor agonist that is given orally for the treatment of primary biliary cholangitis, in combination with ursodiol, or ursodeoxycholic acid. I have classified ursodiol as compatible in pregnancy in the 10th edition of “Drugs in Pregnancy and Lactation” (2011: Wolters Kluwer Health). The animal reproduction data for both drugs suggest low risk. Based on the molecular weight of obeticholic (about 421), the drug will probably cross to the embryo/fetus, but the high plasma protein binding (greater than 99%) may limit exposure. The elimination half-life is apparently unknown.

Hematologic agents

Defibrotide sodium (Defitelio), given as an intravenous infusion, is an oligonucleotide mixture. It is indicated for the treatment of hepatic veno-occlusive disease, also known as sinusoidal obstruction syndrome, with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation. Animal reproduction studies in two species suggest risk. The mean molecular weight is 13,000-20,000. Plasma protein binding is an average 93%, and the elimination half-life is less than 2 hours. It is doubtful if the drug crosses the placenta, especially in the first half of pregnancy. If possible, avoid the drug in the second half of pregnancy.

Immunologics

Two indications have been approved for daclizumab. The first was in 2005 for the prophylaxis of acute organ rejection of renal transplants (Zenapax), and the second was in 2016 for the treatment of relapsing forms of multiple sclerosis (Zinbryta). Reproduction studies in monkeys with Zinbryta can be classified as low risk. The molecular weight (about 144,000) suggests that the drug will not cross the placenta, at least in the first half of pregnancy. However, depending on when the drug is given, the long elimination half-life of 21 days might allow the drug to cross in late pregnancy. Regardless, if the perceived maternal benefit exceeds the potential embryo-fetal risk, the drug should not be withheld because of pregnancy.

Muscular disorder agents

Eteplirsen (Exondys 51) is an antisense oligonucleotide that is given intravenously. It is indicated for the treatment of Duchenne muscular dystrophy in patients who have a confirmed mutation of the related gene, which is amenable to exon 51 skipping. There are no animal reproduction data. The molecular weight is about 10,306. This suggests that the drug will not cross the placenta, at least in the first half of pregnancy. The elimination half-life is 3-4 hours, and the plasma concentration 24 hours after a dose was 0.07% of the peak plasma concentration. The drug is given once weekly, and waiting for 24 hours or slightly longer after a dose should reduce the exposure, if any, of the embryo-fetus during the first half of pregnancy.

Nusinersen (Spinraza), a survival motor neuron 2 directed–antisense oligonucleotide, is given as an intrathecal dose. It is indicated for the treatment of spinal muscular atrophy. Subcutaneous doses in two animal species caused no developmental toxicity. The molecular weight of 7,501 suggests that the drug will not cross the human placenta, at least not in the first half of pregnancy. The mean terminal elimination half-life in cerebrospinal fluid was 135-177 days and 63-87 days in plasma.

Ophthalmic agents

Lifitegrast (Xiidra) is an ophthalmic solution of a lymphocyte function-associated–antigen-1 antagonist. It is indicated for the treatment of the signs and symptoms of dry eye disease. The animal reproduction data suggest low risk. The molecular weight is about 616, suggesting that the drug would cross the placenta. However, in a Phase III trial conducted before FDA approval, 47 patients with dry eye disease were given 1 drop twice daily for periods up to 360 days. Nine patients (19%) had plasma predose (trough) concentrations above 0.5 ng/mL, the lower limit of quantitation. Trough plasma concentrations in these patients ranged from 0.55 ng/mL to 3.74 ng/mL. These amounts do not appear to represent an embryo-fetal risk.

Respiratory agents

Reslizumab (Cinqair), an interleukin-5 antagonist monoclonal antibody, is given intravenously. It is indicated for add-on maintenance treatment of severe asthma in patients with an eosinophilic phenotype. Animal data in two species suggest low risk. The molecular weight is about 147,000, and the elimination half-life is about 24 days. This suggests that exposure of the embryo and fetus will be minimal, at least in the first half of pregnancy. The maternal benefit appears to outweigh the unknown embryo-fetal risk.

Lactation

None of the above drugs have been studied during breastfeeding. Many drugs, regardless of their molecular weight, will cross into milk in small amounts during the first postpartum week. The effects of this exposure on a nursing infant are unknown. Based on the potential for nursing infant harm, the drugs that probably should not be given during breastfeeding include the four antineoplastics, the atypical antipsychotic pimavanserin, and the diabetes injection lixisenatide.

Mr. Briggs is a clinical professor of pharmacy at the University of California, San Francisco, and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, and at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation,” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.

The Food and Drug Administration approved 22 new drug products in 12 pharmacologic classes in 2016. Additionally, daclizumab (Zenapax), which was approved several years ago for prophylaxis of acute organ rejection in patients receiving renal transplants, was approved for multiple sclerosis treatment (Zinbryta) last year, and sofosbuvir (Sovaldi), which was approved in 2013 for the treatment of hepatitis C virus, is now combined with velpatasvir (Epclusa) to treat all six major forms of hepatitis C.

There are 22 drugs that can be considered novel drugs. As defined by the FDA, novel drugs have never been approved for human use. There are no human pregnancy data for any of the newly approved drugs or drug combinations. As such, it is important to consider that high molecular weight drugs that probably do not cross the placenta in the first half of pregnancy may do so in late pregnancy.

Antineoplastics

Atezolizumab (Tecentriq) is a programmed death ligand–blocking antibody that is indicated for locally advanced or metastatic urothelial carcinoma and metastatic nonsmall cell lung cancer following platinum-containing chemotherapy. Animal reproduction studies have not been conducted, but, based on its mechanism of action, fetal exposure may increase the risk of developing immune-mediated disorders or altering the normal immune response. The molecular weight is high (145,000) and the terminal half-life is long (27 days).

Olaratumab (Lartruvo) is a platelet-derived growth factor receptor– alpha-blocking antibody. It is indicated, in combination with doxorubicin, for the treatment of soft tissue sarcoma. Although the estimated elimination half-life is long (about 11 days with a range of 6-24 days), the high molecular weight (about 154,000) should limit fetal exposure, at least in the first half of pregnancy. The drug should be avoided in pregnancy, however, based on the animal data, the mechanism of action, and its combination with doxorubicin.

Rucaparib (Rubraca) is a poly (adenosine diphosphate–ribose) polymerase inhibitor indicated for the treatment of ovarian cancer. The drug could cause human fetal harm based on the animal data, mechanism of action, relatively low molecular weight (about 556), and terminal half-life (17 hours).

Venetoclax (Venclexta) is a B-cell lymphoma 2 inhibitor indicated for the treatment of chronic lymphocytic leukemia. Although the animal data, molecular weight (about 868), and elimination half-life (about 26 hours) suggest embryo-fetal risk, the high plasma protein binding (99.9%) should limit the amount crossing the placenta.

Anti-infectives

There are two new monoclonal antibodies in this class. Bezlotoxumab (Zinplava) is used to reduce recurrence of Clostridium difficile. Animal reproduction studies have not been conducted. As the molecular weight is about 148,000, the drug will not cross the placenta, at least not in the first half of pregnancy. However, the drug has a long elimination half-life (about 19 days), so, depending on when it was given, it could cross in late pregnancy. Obiltoxaximab (Anthim), administered as a single IV dose, is indicated for the treatment of inhaled anthrax due to Bacillus anthracis. No fetal harm was observed in animal reproduction studies. The high molecular weight (about 148,000) suggests that the drug will not cross to the embryo and/or fetus, at least not in the first part of pregnancy.

Elbasvir/Grazoprevir (Zepatier) is indicated for the treatment of chronic hepatitis C virus genotype 1 or 4. Animal reproduction studies found no evidence of adverse developmental outcomes. The molecular weights of the two components are about 882 and 767, respectively. Both are extensively bound to plasma proteins, 99.9% and 98.8%, respectively, and the terminal half-lives are 24 and 31 hours. Thus, the product appears to be low risk if used in human pregnancy. However, it is contraindicated if given with ribavirin.

moodboard/Thinkstock

Central nervous system agents

Brivaracetam (Briviact) is an anticonvulsant used to treat partial-onset seizures. Animal reproduction studies suggest moderate risk. The molecular weight (about 212), low plasma protein binding (less than or equal to 20%), and terminal plasma half-life of about 9 hours suggest that the drug will cross the placenta. The manufacturer recommends that the drug should be used in pregnancy only if the potential benefit justifies the potential risk to the embryo/fetus.

Pimavanserin (Nuplazid) is an atypical antipsychotic indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. Reproduction studies in animals suggest low risk. The molecular weight of the free base (about 428) and the long mean plasma half-lives of the parent drug and active metabolite (57 and 200 hours) suggest that the drug will cross the placenta. However, the high plasma protein binding (about 95%) may limit the exposure. Nevertheless, avoiding the period of organogenesis appears to be best.

Dermatologic agents

Crisaborole (Eucrisa) is indicated for topical treatment of mild to moderate atopic dermatitis. In 33 pediatric subjects (aged 2-17 years) who applied the ointment twice daily for 8 days, low amounts were absorbed systemically with plasma concentrations in the nanogram/milliliter range. Plasma protein binding was 97%. With oral formulations of the drug, animal reproduction studies suggest low risk. Taken in sum, the human pregnancy risk appears to be low.

Ixekizumab (Taltz) is a humanized interleukin-17A antagonist, administered subcutaneously, that is indicated for the treatment of adults with moderate to severe plaque psoriasis. The drug did not cause developmental toxicity in monkeys. The molecular weight for the drug’s protein backbone is 146,158, and the mean elimination half-life was 13 days. The human embryo-fetal risk in the first half of pregnancy appears to be low.

Diagnostic agents

Fluciclovine F 18 (Axumin) is a radioactive diagnostic agent indicated for positron emission tomography imaging in men with suspected prostate cancer. Since the agent is only used in men, there are no human or animal pregnancy data.

Gallium GA 68 dotatate injection, a diagnostic imaging agent to detect rare neuroendocrine tumors, is not yet on the market.

Endocrine/metabolic agents

Lixisenatide (Adlyxin) is a glucagon-like–peptide-1 receptor agonist that is administered subcutaneously. It is indicated as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes. The drug was teratogenic in two animal species. The molecular weight is about 4,859, and the mean terminal half-life was about 3 hours. Since tight control of glucose levels in type 2 diabetes is required during pregnancy, insulin is the treatment of choice. Consequently, lixisenatide should not be used during pregnancy.

Gastrointestinal agents

Obeticholic acid (Ocaliva) is a farnesoid X receptor agonist that is given orally for the treatment of primary biliary cholangitis, in combination with ursodiol, or ursodeoxycholic acid. I have classified ursodiol as compatible in pregnancy in the 10th edition of “Drugs in Pregnancy and Lactation” (2011: Wolters Kluwer Health). The animal reproduction data for both drugs suggest low risk. Based on the molecular weight of obeticholic (about 421), the drug will probably cross to the embryo/fetus, but the high plasma protein binding (greater than 99%) may limit exposure. The elimination half-life is apparently unknown.

Hematologic agents

Defibrotide sodium (Defitelio), given as an intravenous infusion, is an oligonucleotide mixture. It is indicated for the treatment of hepatic veno-occlusive disease, also known as sinusoidal obstruction syndrome, with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation. Animal reproduction studies in two species suggest risk. The mean molecular weight is 13,000-20,000. Plasma protein binding is an average 93%, and the elimination half-life is less than 2 hours. It is doubtful if the drug crosses the placenta, especially in the first half of pregnancy. If possible, avoid the drug in the second half of pregnancy.

Immunologics

Two indications have been approved for daclizumab. The first was in 2005 for the prophylaxis of acute organ rejection of renal transplants (Zenapax), and the second was in 2016 for the treatment of relapsing forms of multiple sclerosis (Zinbryta). Reproduction studies in monkeys with Zinbryta can be classified as low risk. The molecular weight (about 144,000) suggests that the drug will not cross the placenta, at least in the first half of pregnancy. However, depending on when the drug is given, the long elimination half-life of 21 days might allow the drug to cross in late pregnancy. Regardless, if the perceived maternal benefit exceeds the potential embryo-fetal risk, the drug should not be withheld because of pregnancy.

Muscular disorder agents

Eteplirsen (Exondys 51) is an antisense oligonucleotide that is given intravenously. It is indicated for the treatment of Duchenne muscular dystrophy in patients who have a confirmed mutation of the related gene, which is amenable to exon 51 skipping. There are no animal reproduction data. The molecular weight is about 10,306. This suggests that the drug will not cross the placenta, at least in the first half of pregnancy. The elimination half-life is 3-4 hours, and the plasma concentration 24 hours after a dose was 0.07% of the peak plasma concentration. The drug is given once weekly, and waiting for 24 hours or slightly longer after a dose should reduce the exposure, if any, of the embryo-fetus during the first half of pregnancy.

Nusinersen (Spinraza), a survival motor neuron 2 directed–antisense oligonucleotide, is given as an intrathecal dose. It is indicated for the treatment of spinal muscular atrophy. Subcutaneous doses in two animal species caused no developmental toxicity. The molecular weight of 7,501 suggests that the drug will not cross the human placenta, at least not in the first half of pregnancy. The mean terminal elimination half-life in cerebrospinal fluid was 135-177 days and 63-87 days in plasma.

Ophthalmic agents

Lifitegrast (Xiidra) is an ophthalmic solution of a lymphocyte function-associated–antigen-1 antagonist. It is indicated for the treatment of the signs and symptoms of dry eye disease. The animal reproduction data suggest low risk. The molecular weight is about 616, suggesting that the drug would cross the placenta. However, in a Phase III trial conducted before FDA approval, 47 patients with dry eye disease were given 1 drop twice daily for periods up to 360 days. Nine patients (19%) had plasma predose (trough) concentrations above 0.5 ng/mL, the lower limit of quantitation. Trough plasma concentrations in these patients ranged from 0.55 ng/mL to 3.74 ng/mL. These amounts do not appear to represent an embryo-fetal risk.

Respiratory agents

Reslizumab (Cinqair), an interleukin-5 antagonist monoclonal antibody, is given intravenously. It is indicated for add-on maintenance treatment of severe asthma in patients with an eosinophilic phenotype. Animal data in two species suggest low risk. The molecular weight is about 147,000, and the elimination half-life is about 24 days. This suggests that exposure of the embryo and fetus will be minimal, at least in the first half of pregnancy. The maternal benefit appears to outweigh the unknown embryo-fetal risk.

Lactation

None of the above drugs have been studied during breastfeeding. Many drugs, regardless of their molecular weight, will cross into milk in small amounts during the first postpartum week. The effects of this exposure on a nursing infant are unknown. Based on the potential for nursing infant harm, the drugs that probably should not be given during breastfeeding include the four antineoplastics, the atypical antipsychotic pimavanserin, and the diabetes injection lixisenatide.

Mr. Briggs is a clinical professor of pharmacy at the University of California, San Francisco, and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, and at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation,” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.

The Food and Drug Administration approved 22 new drug products in 12 pharmacologic classes in 2016. Additionally, daclizumab (Zenapax), which was approved several years ago for prophylaxis of acute organ rejection in patients receiving renal transplants, was approved for multiple sclerosis treatment (Zinbryta) last year, and sofosbuvir (Sovaldi), which was approved in 2013 for the treatment of hepatitis C virus, is now combined with velpatasvir (Epclusa) to treat all six major forms of hepatitis C.

There are 22 drugs that can be considered novel drugs. As defined by the FDA, novel drugs have never been approved for human use. There are no human pregnancy data for any of the newly approved drugs or drug combinations. As such, it is important to consider that high molecular weight drugs that probably do not cross the placenta in the first half of pregnancy may do so in late pregnancy.

Antineoplastics

Atezolizumab (Tecentriq) is a programmed death ligand–blocking antibody that is indicated for locally advanced or metastatic urothelial carcinoma and metastatic nonsmall cell lung cancer following platinum-containing chemotherapy. Animal reproduction studies have not been conducted, but, based on its mechanism of action, fetal exposure may increase the risk of developing immune-mediated disorders or altering the normal immune response. The molecular weight is high (145,000) and the terminal half-life is long (27 days).

Olaratumab (Lartruvo) is a platelet-derived growth factor receptor– alpha-blocking antibody. It is indicated, in combination with doxorubicin, for the treatment of soft tissue sarcoma. Although the estimated elimination half-life is long (about 11 days with a range of 6-24 days), the high molecular weight (about 154,000) should limit fetal exposure, at least in the first half of pregnancy. The drug should be avoided in pregnancy, however, based on the animal data, the mechanism of action, and its combination with doxorubicin.

Rucaparib (Rubraca) is a poly (adenosine diphosphate–ribose) polymerase inhibitor indicated for the treatment of ovarian cancer. The drug could cause human fetal harm based on the animal data, mechanism of action, relatively low molecular weight (about 556), and terminal half-life (17 hours).

Venetoclax (Venclexta) is a B-cell lymphoma 2 inhibitor indicated for the treatment of chronic lymphocytic leukemia. Although the animal data, molecular weight (about 868), and elimination half-life (about 26 hours) suggest embryo-fetal risk, the high plasma protein binding (99.9%) should limit the amount crossing the placenta.

Anti-infectives

There are two new monoclonal antibodies in this class. Bezlotoxumab (Zinplava) is used to reduce recurrence of Clostridium difficile. Animal reproduction studies have not been conducted. As the molecular weight is about 148,000, the drug will not cross the placenta, at least not in the first half of pregnancy. However, the drug has a long elimination half-life (about 19 days), so, depending on when it was given, it could cross in late pregnancy. Obiltoxaximab (Anthim), administered as a single IV dose, is indicated for the treatment of inhaled anthrax due to Bacillus anthracis. No fetal harm was observed in animal reproduction studies. The high molecular weight (about 148,000) suggests that the drug will not cross to the embryo and/or fetus, at least not in the first part of pregnancy.

Elbasvir/Grazoprevir (Zepatier) is indicated for the treatment of chronic hepatitis C virus genotype 1 or 4. Animal reproduction studies found no evidence of adverse developmental outcomes. The molecular weights of the two components are about 882 and 767, respectively. Both are extensively bound to plasma proteins, 99.9% and 98.8%, respectively, and the terminal half-lives are 24 and 31 hours. Thus, the product appears to be low risk if used in human pregnancy. However, it is contraindicated if given with ribavirin.

moodboard/Thinkstock

Central nervous system agents

Brivaracetam (Briviact) is an anticonvulsant used to treat partial-onset seizures. Animal reproduction studies suggest moderate risk. The molecular weight (about 212), low plasma protein binding (less than or equal to 20%), and terminal plasma half-life of about 9 hours suggest that the drug will cross the placenta. The manufacturer recommends that the drug should be used in pregnancy only if the potential benefit justifies the potential risk to the embryo/fetus.

Pimavanserin (Nuplazid) is an atypical antipsychotic indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. Reproduction studies in animals suggest low risk. The molecular weight of the free base (about 428) and the long mean plasma half-lives of the parent drug and active metabolite (57 and 200 hours) suggest that the drug will cross the placenta. However, the high plasma protein binding (about 95%) may limit the exposure. Nevertheless, avoiding the period of organogenesis appears to be best.

Dermatologic agents

Crisaborole (Eucrisa) is indicated for topical treatment of mild to moderate atopic dermatitis. In 33 pediatric subjects (aged 2-17 years) who applied the ointment twice daily for 8 days, low amounts were absorbed systemically with plasma concentrations in the nanogram/milliliter range. Plasma protein binding was 97%. With oral formulations of the drug, animal reproduction studies suggest low risk. Taken in sum, the human pregnancy risk appears to be low.

Ixekizumab (Taltz) is a humanized interleukin-17A antagonist, administered subcutaneously, that is indicated for the treatment of adults with moderate to severe plaque psoriasis. The drug did not cause developmental toxicity in monkeys. The molecular weight for the drug’s protein backbone is 146,158, and the mean elimination half-life was 13 days. The human embryo-fetal risk in the first half of pregnancy appears to be low.

Diagnostic agents

Fluciclovine F 18 (Axumin) is a radioactive diagnostic agent indicated for positron emission tomography imaging in men with suspected prostate cancer. Since the agent is only used in men, there are no human or animal pregnancy data.

Gallium GA 68 dotatate injection, a diagnostic imaging agent to detect rare neuroendocrine tumors, is not yet on the market.

Endocrine/metabolic agents

Lixisenatide (Adlyxin) is a glucagon-like–peptide-1 receptor agonist that is administered subcutaneously. It is indicated as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes. The drug was teratogenic in two animal species. The molecular weight is about 4,859, and the mean terminal half-life was about 3 hours. Since tight control of glucose levels in type 2 diabetes is required during pregnancy, insulin is the treatment of choice. Consequently, lixisenatide should not be used during pregnancy.

Gastrointestinal agents

Obeticholic acid (Ocaliva) is a farnesoid X receptor agonist that is given orally for the treatment of primary biliary cholangitis, in combination with ursodiol, or ursodeoxycholic acid. I have classified ursodiol as compatible in pregnancy in the 10th edition of “Drugs in Pregnancy and Lactation” (2011: Wolters Kluwer Health). The animal reproduction data for both drugs suggest low risk. Based on the molecular weight of obeticholic (about 421), the drug will probably cross to the embryo/fetus, but the high plasma protein binding (greater than 99%) may limit exposure. The elimination half-life is apparently unknown.

Hematologic agents

Defibrotide sodium (Defitelio), given as an intravenous infusion, is an oligonucleotide mixture. It is indicated for the treatment of hepatic veno-occlusive disease, also known as sinusoidal obstruction syndrome, with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation. Animal reproduction studies in two species suggest risk. The mean molecular weight is 13,000-20,000. Plasma protein binding is an average 93%, and the elimination half-life is less than 2 hours. It is doubtful if the drug crosses the placenta, especially in the first half of pregnancy. If possible, avoid the drug in the second half of pregnancy.

Immunologics

Two indications have been approved for daclizumab. The first was in 2005 for the prophylaxis of acute organ rejection of renal transplants (Zenapax), and the second was in 2016 for the treatment of relapsing forms of multiple sclerosis (Zinbryta). Reproduction studies in monkeys with Zinbryta can be classified as low risk. The molecular weight (about 144,000) suggests that the drug will not cross the placenta, at least in the first half of pregnancy. However, depending on when the drug is given, the long elimination half-life of 21 days might allow the drug to cross in late pregnancy. Regardless, if the perceived maternal benefit exceeds the potential embryo-fetal risk, the drug should not be withheld because of pregnancy.

Muscular disorder agents

Eteplirsen (Exondys 51) is an antisense oligonucleotide that is given intravenously. It is indicated for the treatment of Duchenne muscular dystrophy in patients who have a confirmed mutation of the related gene, which is amenable to exon 51 skipping. There are no animal reproduction data. The molecular weight is about 10,306. This suggests that the drug will not cross the placenta, at least in the first half of pregnancy. The elimination half-life is 3-4 hours, and the plasma concentration 24 hours after a dose was 0.07% of the peak plasma concentration. The drug is given once weekly, and waiting for 24 hours or slightly longer after a dose should reduce the exposure, if any, of the embryo-fetus during the first half of pregnancy.

Nusinersen (Spinraza), a survival motor neuron 2 directed–antisense oligonucleotide, is given as an intrathecal dose. It is indicated for the treatment of spinal muscular atrophy. Subcutaneous doses in two animal species caused no developmental toxicity. The molecular weight of 7,501 suggests that the drug will not cross the human placenta, at least not in the first half of pregnancy. The mean terminal elimination half-life in cerebrospinal fluid was 135-177 days and 63-87 days in plasma.

Ophthalmic agents

Lifitegrast (Xiidra) is an ophthalmic solution of a lymphocyte function-associated–antigen-1 antagonist. It is indicated for the treatment of the signs and symptoms of dry eye disease. The animal reproduction data suggest low risk. The molecular weight is about 616, suggesting that the drug would cross the placenta. However, in a Phase III trial conducted before FDA approval, 47 patients with dry eye disease were given 1 drop twice daily for periods up to 360 days. Nine patients (19%) had plasma predose (trough) concentrations above 0.5 ng/mL, the lower limit of quantitation. Trough plasma concentrations in these patients ranged from 0.55 ng/mL to 3.74 ng/mL. These amounts do not appear to represent an embryo-fetal risk.

Respiratory agents

Reslizumab (Cinqair), an interleukin-5 antagonist monoclonal antibody, is given intravenously. It is indicated for add-on maintenance treatment of severe asthma in patients with an eosinophilic phenotype. Animal data in two species suggest low risk. The molecular weight is about 147,000, and the elimination half-life is about 24 days. This suggests that exposure of the embryo and fetus will be minimal, at least in the first half of pregnancy. The maternal benefit appears to outweigh the unknown embryo-fetal risk.

Lactation

None of the above drugs have been studied during breastfeeding. Many drugs, regardless of their molecular weight, will cross into milk in small amounts during the first postpartum week. The effects of this exposure on a nursing infant are unknown. Based on the potential for nursing infant harm, the drugs that probably should not be given during breastfeeding include the four antineoplastics, the atypical antipsychotic pimavanserin, and the diabetes injection lixisenatide.

Mr. Briggs is a clinical professor of pharmacy at the University of California, San Francisco, and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, and at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation,” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.

Although it is often taken for granted, the ability to initiate and maintain sleep throughout the night is elusive for many. About one-third of adults experience a troublesome episode of insomnia.¹ In most, it is transient, but in 10% to 15% (roughly 30 million people), the problem becomes self-perpetuating and chronic.² Chronic insomnia is one of the most prevalent conditions that family physicians (FPs) encounter, a function of it being so closely associated with comorbid conditions that FPs deal with every day, such as depression, chronic pain, and polypharmacy.^3,4

Insomnia can be vexing for a number of reasons. Because it is not acutely dangerous, patients may present it as an “add-on” concern at the end of an already lengthy visit. And because insomnia is often a symptom of multiple underlying physiologic and psychological factors, it requires the FP to engage in a thorough and time-consuming exploration of possible causes and comorbidities. Finally, standard treatment options have drawbacks: reports show that use of pharmacotherapy is troubling to prescribers primarily because of concerns about adverse effects and dependence;^5-7 the other major therapeutic avenue, cognitive behavioral therapy for insomnia (CBT-I), requires training and is time-consuming to deliver in the context of an office visit.^8,9

Despite these obstacles, successful evaluation and treatment of insomnia can be highly rewarding. Chronic insomnia is associated with great individual misery and negative consequences for long-term health. Specifically, it is associated with reduced quality of life and daytime functioning,¹⁰ depression,^11,12 hypertension,^13,14 increased workplace accidents and absenteeism,^15-17 and exacerbations of chronic pain.¹⁸ And while the evaluation and management of insomnia can be laborious, a systematic method can streamline the process.

Insomnia: Symptom or cause?

The International Classification of Sleep Disorders defines chronic insomnia as an inability to sleep sufficiently despite creating adequate opportunity. It occurs at least 3 nights per week for >3 months with perceived negative consequences during the day. Patients typically complain about symptoms including fatigue, diminished cog­nitive performance, and mood disturbance.¹⁹ Acute insomnia triggered by one or more biopsychosocial stresses is, by definition, self-limited and has different underlying mechanisms. As such, it will not be described in this review.

The chief risk factors are female gender, low socioeconomic status, and increasing age.²⁰ However, cohorts of healthy seniors show preserved good sleep; the increase in prevalence of insomnia in the elderly is likely linked more specifically to age-related accumulation of medical/mental health disorders and polypharmacy than aging per se.²¹

Research over the past 20 years has shown that comorbidities have a bidirectional relationship with insomnia, rather than a one-way cause and effect.

In the past, insomnia was viewed as a symptom, occurring secondarily to an underlying cause, usually an acute biopsychosocial stressor or depression. It was assumed that if the primary cause was effectively treated, then healthy sleep would return.

But research over the past 20 years has changed this paradigm in 2 ways. First, when comorbidities such as depression or chronic pain are present, they have a bidirectional relationship with insomnia rather than a one-way cause and effect. For example, instead of depression being a primary disorder from which insomnia can result, it is now recognized that insomnia can be present first and is a risk factor for new-onset depression. When depression and insomnia coexist, they may exacerbate each other in a bidirectional pattern.

Secondly, an estimated 15% of chronic insomnia sufferers have no targetable comorbidity; rather, they are unable to get sufficient sleep in large part because of a trait-like predisposition to fragile sleep, called hyperarousal brain physiology.²² These people used to be described as having “primary insomnia,” although the term has been dropped from the 5th edition of The Diagnostic and Statistical Manual of Mental Disorders (DSM).²³

Assess comorbidities, obtain sleep logs

The evaluation of the chronic form of insomnia should begin with a thorough medical his­tory to assess for comorbid conditions that can exacerbate disturbed sleep. These are generally grouped into medical disorders (TABLE 1²⁰), medications/substances (eg, antidepressants, stimulants, decongestants, narcotic analgesics, cardiovascular drugs, pulmonary agents, alcohol), and mental health disorders (especially depression and anxiety). It’s important to consider whether such comorbidities are contributing to the insomnia and optimize treatment that addresses them.

Take particular care to evaluate signs and symptoms of comorbid primary sleep disorders such as obstructive sleep apnea, restless legs syndrome (RLS), and circadian rhythm disorders since any of these can present with a complaint of insomnia. RLS, usually classified as a sleep disorder because of its circadian pattern (it is experienced more at night than during the day), is present to a troublesome degree in about 3% to 4% of all adults.²⁴ It is important to inquire about symptoms of RLS (urge to move legs in the night more than during the day; relieved with movement; worsened with inactivity) so as not to miss this treatable cause of insomnia.

The physical exam should focus on signs that suggest sleep-disordered breathing—obesity, large neck girth, hypertension, and crowded oropharynx—because people with sleep apnea often present with the complaint of frequent awakenings.

Sleep logs can present a powerful picture

In addition to a history and physical exam, physicians should ask their patients with chronic insomnia to complete sleep logs for 2 to 3 weeks.²⁰ A sleep log with midnight near the middle of the page is preferred by many because it places the typical sleeping hours in the middle of the page, showing relevant information in a way that can be grasped immediately (FIGURE 1). To save time, nurses can provide sleep logs to patients along with instructions about how to complete them.

Patient-completed sleep logs often illuminate obvious detrimental behaviors that reinforce insomnia (eg, spending excessive time in bed, having irregular bed/wake times, daytime napping that diminishes sleep drive in the evening). In addition, they sometimes reveal circadian rhythm abnormalities such as delayed sleep phase syndrome in which the patient attempts to sleep at a normal bedtime, but exhibits a marked delay in falling asleep/waking up compared to societal norms. Seeing such information graphically represented is often a powerful learning experience for both physician and patient.

Sleep studies aren't usually warranted

In its most recent (2008) clinical guideline on the evaluation and management of chronic insomnia, the American Academy of Sleep Medicine (AASM) stated that “routine testing in the sleep lab is not warranted for most cases of insomnia.” Instead, it is reserved for individuals in whom there is a suspicion of a comorbid sleep disorder. FPs should refer patients for formal sleep studies only if, in addition to the insomnia complaint, there is suspicion of:²⁰

• obstructive sleep apnea (based upon some combination of loud snoring, obesity, hypertension, and/or excessive daytime sleepiness),
• narcolepsy (based upon excessive daytime sleepiness without a readily identifiable cause), or
• arousals with the potential for self-injurious behavior (parasomnias).

Treatments: Sleep hygiene, CBT-I, and medication

Sleep hygiene, cognitive/behavioral techniques, and pharmacotherapy serve as the core of therapy for chronic insomnia.

Sleep hygiene: Common-sense strategies

Most FPs are familiar with sleep hygiene instructions; these are simple, common-sense behavioral techniques such as limiting caffeine and screen (television, computer) time at night, avoiding daytime naps, and maintaining regular bed- and out-of-bed times. (See “A sleep hygiene checklist.”) Although it is a logical starting point for behavioral modification, sleep hygiene has not been studied rigorously as a monotherapy for insomnia and, therefore, doesn’t have an evidence rating in terms of effectiveness.²⁰

CBT-I: Treatment of choice

CBT-I seeks to lower cognitive and somatic arousal. Taken together, cognitive and behavioral techniques are effective in 70% to 80% of people, whether they have primary insomnia or comorbidities.^25-27 Furthermore, the benefits are sustained with the passage of time.²⁷ CBT-I is regarded as the treatment of choice for chronic insomnia.²⁰

An experience of successful sleep initiation and maintenance is important psychologically: It renews patients' confidence in the ability to sleep.

When provided by a highly trained mental health professional, CBT-I usually takes the form of a series of 6 to 8 weekly appointments. Descriptions and manuals for CBT-I abound and online programs have also proliferated.^28,29 However, there is a shortage of highly trained providers, and most FPs do not feel proficient to engage fully in CBT-I.^8,9 Nevertheless, some behavioral elements of CBT-I, such as stimulus control and sleep restriction, can be utilized in the family medicine setting and may be effective for a significant subset of patients.

Stimulus control and sleep restriction. Two behavioral techniques for insomnia that can be applied in the family medicine setting are stimulus control and sleep restriction therapy.²⁰

With stimulus control, patients attempt to eliminate stimuli that weaken the psychological association between the bed and successful sleep, namely wakeful activities in bed such as watching television, reading, or even “tossing and turning.” Instead, they are instructed to use their bed only for sleep (and intimacy), to vacate it if awake and not clearly on the verge of sleep, and to avoid looking at a clock during the night. Patients are also advised to sleep only in their own bed and not in other places in their home.

Sleep restriction is predicated on the observation that many people with insomnia habitually spend too much time awake in bed, and this creates a conditioned arousal response to the bed. With sleep restriction, the patient is assigned a narrow window of “allowed time in bed,” usually a 6-hour interval of their choosing, and is instructed to adhere to this schedule for a period of 2 to 4 weeks. Many patients find that they fall asleep more rapidly and stay asleep longer after a few weeks. This experience of “successful” sleep initiation and maintenance is important psychologically; it renews their confidence in their ability to sleep, which is missing in most people with chronic insomnia.

If you use this approach with a patient, be sure to acknowledge that sleep restriction usually engenders some sleep deprivation in the first few weeks. But it is only a short-term intervention designed to change the expectation of nightly insomnia that is so ingrained in these patients. While they engage in sleep restriction, patients should keep sleep logs to track their “sleep efficiency” (ie, estimated time asleep vs time in bed). Once good sleep efficiency (>85%) is achieved, they may gradually lengthen their allowed time in bed by 15 minutes each week until they are obtaining 7 to 9 hours of sleep per night. (See “Breaking the cycle of insomnia by employing sleep restriction.”)

Cognitive therapy. Cognitive therapies for insomnia are usually provided by psychologists with special training. Three specific techniques that have evidence ratings* from the AASM are:²⁰

1. Relaxation training, including progressive muscle relaxation, guided imagery, and abdominal breathing to lower somatic and cognitive arousal states that interfere with sleep (strength of recommendation [SOR]: A).
2. Biofeedback therapy trains patients to control some physiologic variable through visual or auditory feedback. The objective is to reduce somatic arousal (SOR: B).
3. Paradoxical intention in which the patient is trained to confront the fear of staying awake and its potential effects. The objective is to eliminate a patient’s anxiety about sleep performance (SOR: B).

Pharmacotherapy: Overused? Addictive?

For patients who continue to struggle with insomnia despite attempting CBT-I, or for those who prefer a different approach, pharmacotherapy is a reasonable therapeutic option. While hypnotic medications are no guarantee of success, they sometimes provide meaningful benefit when supplied to a patient who has successfully established good cognitive and behavioral techniques, but is still struggling with insomnia.

Use of hypnotic medications has increased dramatically in recent years. Prescriptions for sleep medications approached 60 million in 2008, up 54% from 2004, with sales topping $2 billion.^30,31 A National Health and Nutrition Examination Survey looking at the period between 2005 and 2010 found that about 4% of adults ages 20 and older used prescription sleep aids in the past month.³²

Meta-analyses of pharmacotherapy for chronic insomnia show small to moderate effect sizes for sleep variables such as latency to sleep onset, total sleep time, and wake time after sleep onset.^33,34 Treatment of chronic insomnia with hypnotic medications is of comparable effectiveness to CBT-I in the early phase, but the benefits of CBT-I are more enduring.²⁷

A controversial approach. The appropriateness of hypnotic medications for chronic insomnia is controversial. While their use by health care professionals has been increasing, some authors have raised concerns about sleeping pills, citing a lack of effectiveness and possible adverse effects such as falls, driving impairment, and the potential for addiction, tolerance, and dependence.^33,35 The Beers Criteria of the American Geriatric Society recommends against the use of benzodiazepines in the elderly due to the risks of falls, cognitive impairment, and motor vehicle accidents and advises against the use of benzodiazepine agonists (such as zolpidem) for >90 days.³⁶

Two behavioral techniques for insomnia that can be easily applied in the family medicine setting are stimulus control and sleep restriction therapy.

Despite these concerns, the potential benefits of hypnotic medications for chronic insomnia should not be dismissed. The common strategy of simply addressing comorbidities and advising good sleep hygiene is insufficient for many patients. And some patients prefer the ease of using a hypnotic agent to the commitment required by CBT-I. Several reports suggest that the risk of hypnotic medication misuse in people with no history of substance abuse is overestimated.^37,38 And a panel of insomnia experts convened for the New Clinical Drug Evaluation Unit symposium in 2001 concluded, “Patients with chronic insomnia tend to exhibit therapy-seeking behavior, not drug-seeking behavior.”³⁹

Which hypnotic agent to choose?

US Food and Drug Administration (FDA)-approved hypnotic medications fall into 5 families (TABLE 2⁴⁰): benzodiazepines (BDZs), benzodiazepine agonists (BDZAs, sometimes called “Z drugs”), melatonin agonists (eg, ramelteon), tricyclic antidepressants (eg, low-dose doxepin), and orexin antagonists (eg, suvorexant). BDZs, BDZAs, and melatonin agonists potentiate sleep-promoting systems, while orexin antagonists and antihistaminergics suppress wake-promoting systems.

"Patients with chronic insomnia tend to exhibit therapy-seeking behavior, not drug-seeking behavior."

Studies of physician prescribing patterns show that among prescription medications for insomnia, zolpidem is the most popular, followed by trazodone (off-label use), other benzodiazepines, quetiapine (off-label use), and doxepin.⁴¹ Overall, over-the-counter melatonin may be more widely used than any of the prescription choices.⁴²

One useful basis for selection of an agent is whether the patient complains of difficulty with sleep initiation at the beginning of the night vs sleep maintenance, or both. For sleep initiation complaints, short-acting/sleep-promoting agents are preferred. For sleep maintenance complaints, longer-acting/wake-inhibiting medications that work at the end of the sleep phase may be necessary.

The AASM has recently concluded an exhaustive review of the literature regarding hypnotic medications for chronic insomnia.⁴³ The authors acknowledge important methodologic limitations, most notably a paucity of data on effectiveness and adverse effects, along with industry sponsorship of most studies and publication bias. Nevertheless, their conclusions favor the use of FDA-approved agents to off-label use of trazodone or over-the-counter use of melatonin or diphenhydramine. To summarize the AASM guidelines:³⁸

1. Medications recommended for sleep onset insomnia include: eszopiclone, ramelteon, temazepam, triazolam, zaleplon, and zolpidem.
2. Medications recommended for treating sleep maintenance insomnia include: doxepin, eszopiclone, suvorexant, zolpidem, and temazepam.
3. Medications not recommended for treating either sleep initiation or sleep maintenance insomnia include: diphenhydramine, melatonin, tiagabine, trazodone, tryptophan, and valerian.

These recommendations are similar to a review of hypnotics published by The Medical Letter in 2015.⁴⁰
 

Trazodone, an antidepressant medication with sedating properties, is not FDA-approved for the treatment of insomnia, yet ranks second to zolpidem in the number of prescriptions written for insomnia. Its popularity may be due to a perception of safety implied by its unscheduled FDA status and the lack of restrictions on prescribing duration. However, several reviews point out that its evidence base is weak.^44,45 There is only one placebo-controlled study involving trazodone use for "primary insomnia" (other studies have been in people with comorbid depression) and it showed insignificant improvements in sleep parameters and less effectiveness compared to zolpidem.⁴⁶

Trazadone, an antidepressant with sedating properties, is not FDA-approved for the treatment of insomnia, yet ranks second to zolpidem in the number of prescriptions written for insomnia.

Trazodone’s mechanisms of action are thought to be serotonin reuptake inhibition and alpha blockade, which might explain adverse effects such as orthostatic hypotension and psychomotor impairment. The frequency of such adverse effects is difficult to estimate since most studies of trazodone have used higher doses than are commonly used for insomnia in order to address comorbid depression. However, some experts have cautioned against its use—especially in the elderly.

The AASM guidelines recommend against use of trazodone. Others assert that it is probably best reserved for people in whom the complaint of insomnia is linked to comorbid depression.^43,44 

Is long-term use ever appropriate? There are no published guidelines about dosing strategies for hypnotics and whether nightly or intermittent use is preferred. All FDA-approved hypnotic agents are for short-term use, but this designation stems from a lack of long-term studies demonstrating continuing efficacy rather than actual proof of loss of effect. Although tolerance to over-the-counter sleep aids does occur, it has not been demonstrated to occur with FDA-approved agents. Studies of eszopiclone and zolpidem indicate continuing effectiveness as hypnotics with nightly use over a time-frame of several months to one year.^47,48

Regarding the thorny question of long-term use of hypnotics for chronic insomnia, the AASM concluded that long-term use should be reserved for “individuals in whom CBT-I is inaccessible or ineffective, who have been appropriately screened for contraindications to such treatment, who maintain long-term gains with medication, and who are followed regularly.”⁴³

CORRESPONDENCE
Adam J. Sorscher, MD, Dartmouth-Hitchcock Medical Center, 18 Old Etna Road, Lebanon, NH 03766; [email protected].

Although it is often taken for granted, the ability to initiate and maintain sleep throughout the night is elusive for many. About one-third of adults experience a troublesome episode of insomnia.¹ In most, it is transient, but in 10% to 15% (roughly 30 million people), the problem becomes self-perpetuating and chronic.² Chronic insomnia is one of the most prevalent conditions that family physicians (FPs) encounter, a function of it being so closely associated with comorbid conditions that FPs deal with every day, such as depression, chronic pain, and polypharmacy.^3,4

Insomnia can be vexing for a number of reasons. Because it is not acutely dangerous, patients may present it as an “add-on” concern at the end of an already lengthy visit. And because insomnia is often a symptom of multiple underlying physiologic and psychological factors, it requires the FP to engage in a thorough and time-consuming exploration of possible causes and comorbidities. Finally, standard treatment options have drawbacks: reports show that use of pharmacotherapy is troubling to prescribers primarily because of concerns about adverse effects and dependence;^5-7 the other major therapeutic avenue, cognitive behavioral therapy for insomnia (CBT-I), requires training and is time-consuming to deliver in the context of an office visit.^8,9

Despite these obstacles, successful evaluation and treatment of insomnia can be highly rewarding. Chronic insomnia is associated with great individual misery and negative consequences for long-term health. Specifically, it is associated with reduced quality of life and daytime functioning,¹⁰ depression,^11,12 hypertension,^13,14 increased workplace accidents and absenteeism,^15-17 and exacerbations of chronic pain.¹⁸ And while the evaluation and management of insomnia can be laborious, a systematic method can streamline the process.

Insomnia: Symptom or cause?

The International Classification of Sleep Disorders defines chronic insomnia as an inability to sleep sufficiently despite creating adequate opportunity. It occurs at least 3 nights per week for >3 months with perceived negative consequences during the day. Patients typically complain about symptoms including fatigue, diminished cog­nitive performance, and mood disturbance.¹⁹ Acute insomnia triggered by one or more biopsychosocial stresses is, by definition, self-limited and has different underlying mechanisms. As such, it will not be described in this review.

The chief risk factors are female gender, low socioeconomic status, and increasing age.²⁰ However, cohorts of healthy seniors show preserved good sleep; the increase in prevalence of insomnia in the elderly is likely linked more specifically to age-related accumulation of medical/mental health disorders and polypharmacy than aging per se.²¹

Research over the past 20 years has shown that comorbidities have a bidirectional relationship with insomnia, rather than a one-way cause and effect.

In the past, insomnia was viewed as a symptom, occurring secondarily to an underlying cause, usually an acute biopsychosocial stressor or depression. It was assumed that if the primary cause was effectively treated, then healthy sleep would return.

But research over the past 20 years has changed this paradigm in 2 ways. First, when comorbidities such as depression or chronic pain are present, they have a bidirectional relationship with insomnia rather than a one-way cause and effect. For example, instead of depression being a primary disorder from which insomnia can result, it is now recognized that insomnia can be present first and is a risk factor for new-onset depression. When depression and insomnia coexist, they may exacerbate each other in a bidirectional pattern.

Secondly, an estimated 15% of chronic insomnia sufferers have no targetable comorbidity; rather, they are unable to get sufficient sleep in large part because of a trait-like predisposition to fragile sleep, called hyperarousal brain physiology.²² These people used to be described as having “primary insomnia,” although the term has been dropped from the 5th edition of The Diagnostic and Statistical Manual of Mental Disorders (DSM).²³

Assess comorbidities, obtain sleep logs

The evaluation of the chronic form of insomnia should begin with a thorough medical his­tory to assess for comorbid conditions that can exacerbate disturbed sleep. These are generally grouped into medical disorders (TABLE 1²⁰), medications/substances (eg, antidepressants, stimulants, decongestants, narcotic analgesics, cardiovascular drugs, pulmonary agents, alcohol), and mental health disorders (especially depression and anxiety). It’s important to consider whether such comorbidities are contributing to the insomnia and optimize treatment that addresses them.

Take particular care to evaluate signs and symptoms of comorbid primary sleep disorders such as obstructive sleep apnea, restless legs syndrome (RLS), and circadian rhythm disorders since any of these can present with a complaint of insomnia. RLS, usually classified as a sleep disorder because of its circadian pattern (it is experienced more at night than during the day), is present to a troublesome degree in about 3% to 4% of all adults.²⁴ It is important to inquire about symptoms of RLS (urge to move legs in the night more than during the day; relieved with movement; worsened with inactivity) so as not to miss this treatable cause of insomnia.

The physical exam should focus on signs that suggest sleep-disordered breathing—obesity, large neck girth, hypertension, and crowded oropharynx—because people with sleep apnea often present with the complaint of frequent awakenings.

Sleep logs can present a powerful picture

In addition to a history and physical exam, physicians should ask their patients with chronic insomnia to complete sleep logs for 2 to 3 weeks.²⁰ A sleep log with midnight near the middle of the page is preferred by many because it places the typical sleeping hours in the middle of the page, showing relevant information in a way that can be grasped immediately (FIGURE 1). To save time, nurses can provide sleep logs to patients along with instructions about how to complete them.

Patient-completed sleep logs often illuminate obvious detrimental behaviors that reinforce insomnia (eg, spending excessive time in bed, having irregular bed/wake times, daytime napping that diminishes sleep drive in the evening). In addition, they sometimes reveal circadian rhythm abnormalities such as delayed sleep phase syndrome in which the patient attempts to sleep at a normal bedtime, but exhibits a marked delay in falling asleep/waking up compared to societal norms. Seeing such information graphically represented is often a powerful learning experience for both physician and patient.

Sleep studies aren't usually warranted

In its most recent (2008) clinical guideline on the evaluation and management of chronic insomnia, the American Academy of Sleep Medicine (AASM) stated that “routine testing in the sleep lab is not warranted for most cases of insomnia.” Instead, it is reserved for individuals in whom there is a suspicion of a comorbid sleep disorder. FPs should refer patients for formal sleep studies only if, in addition to the insomnia complaint, there is suspicion of:²⁰

• obstructive sleep apnea (based upon some combination of loud snoring, obesity, hypertension, and/or excessive daytime sleepiness),
• narcolepsy (based upon excessive daytime sleepiness without a readily identifiable cause), or
• arousals with the potential for self-injurious behavior (parasomnias).

Treatments: Sleep hygiene, CBT-I, and medication

Sleep hygiene, cognitive/behavioral techniques, and pharmacotherapy serve as the core of therapy for chronic insomnia.

Sleep hygiene: Common-sense strategies

Most FPs are familiar with sleep hygiene instructions; these are simple, common-sense behavioral techniques such as limiting caffeine and screen (television, computer) time at night, avoiding daytime naps, and maintaining regular bed- and out-of-bed times. (See “A sleep hygiene checklist.”) Although it is a logical starting point for behavioral modification, sleep hygiene has not been studied rigorously as a monotherapy for insomnia and, therefore, doesn’t have an evidence rating in terms of effectiveness.²⁰

CBT-I: Treatment of choice

CBT-I seeks to lower cognitive and somatic arousal. Taken together, cognitive and behavioral techniques are effective in 70% to 80% of people, whether they have primary insomnia or comorbidities.^25-27 Furthermore, the benefits are sustained with the passage of time.²⁷ CBT-I is regarded as the treatment of choice for chronic insomnia.²⁰

An experience of successful sleep initiation and maintenance is important psychologically: It renews patients' confidence in the ability to sleep.

When provided by a highly trained mental health professional, CBT-I usually takes the form of a series of 6 to 8 weekly appointments. Descriptions and manuals for CBT-I abound and online programs have also proliferated.^28,29 However, there is a shortage of highly trained providers, and most FPs do not feel proficient to engage fully in CBT-I.^8,9 Nevertheless, some behavioral elements of CBT-I, such as stimulus control and sleep restriction, can be utilized in the family medicine setting and may be effective for a significant subset of patients.

Stimulus control and sleep restriction. Two behavioral techniques for insomnia that can be applied in the family medicine setting are stimulus control and sleep restriction therapy.²⁰

With stimulus control, patients attempt to eliminate stimuli that weaken the psychological association between the bed and successful sleep, namely wakeful activities in bed such as watching television, reading, or even “tossing and turning.” Instead, they are instructed to use their bed only for sleep (and intimacy), to vacate it if awake and not clearly on the verge of sleep, and to avoid looking at a clock during the night. Patients are also advised to sleep only in their own bed and not in other places in their home.

Sleep restriction is predicated on the observation that many people with insomnia habitually spend too much time awake in bed, and this creates a conditioned arousal response to the bed. With sleep restriction, the patient is assigned a narrow window of “allowed time in bed,” usually a 6-hour interval of their choosing, and is instructed to adhere to this schedule for a period of 2 to 4 weeks. Many patients find that they fall asleep more rapidly and stay asleep longer after a few weeks. This experience of “successful” sleep initiation and maintenance is important psychologically; it renews their confidence in their ability to sleep, which is missing in most people with chronic insomnia.

If you use this approach with a patient, be sure to acknowledge that sleep restriction usually engenders some sleep deprivation in the first few weeks. But it is only a short-term intervention designed to change the expectation of nightly insomnia that is so ingrained in these patients. While they engage in sleep restriction, patients should keep sleep logs to track their “sleep efficiency” (ie, estimated time asleep vs time in bed). Once good sleep efficiency (>85%) is achieved, they may gradually lengthen their allowed time in bed by 15 minutes each week until they are obtaining 7 to 9 hours of sleep per night. (See “Breaking the cycle of insomnia by employing sleep restriction.”)

Cognitive therapy. Cognitive therapies for insomnia are usually provided by psychologists with special training. Three specific techniques that have evidence ratings* from the AASM are:²⁰

1. Relaxation training, including progressive muscle relaxation, guided imagery, and abdominal breathing to lower somatic and cognitive arousal states that interfere with sleep (strength of recommendation [SOR]: A).
2. Biofeedback therapy trains patients to control some physiologic variable through visual or auditory feedback. The objective is to reduce somatic arousal (SOR: B).
3. Paradoxical intention in which the patient is trained to confront the fear of staying awake and its potential effects. The objective is to eliminate a patient’s anxiety about sleep performance (SOR: B).

Pharmacotherapy: Overused? Addictive?

For patients who continue to struggle with insomnia despite attempting CBT-I, or for those who prefer a different approach, pharmacotherapy is a reasonable therapeutic option. While hypnotic medications are no guarantee of success, they sometimes provide meaningful benefit when supplied to a patient who has successfully established good cognitive and behavioral techniques, but is still struggling with insomnia.

Use of hypnotic medications has increased dramatically in recent years. Prescriptions for sleep medications approached 60 million in 2008, up 54% from 2004, with sales topping $2 billion.^30,31 A National Health and Nutrition Examination Survey looking at the period between 2005 and 2010 found that about 4% of adults ages 20 and older used prescription sleep aids in the past month.³²

Meta-analyses of pharmacotherapy for chronic insomnia show small to moderate effect sizes for sleep variables such as latency to sleep onset, total sleep time, and wake time after sleep onset.^33,34 Treatment of chronic insomnia with hypnotic medications is of comparable effectiveness to CBT-I in the early phase, but the benefits of CBT-I are more enduring.²⁷

A controversial approach. The appropriateness of hypnotic medications for chronic insomnia is controversial. While their use by health care professionals has been increasing, some authors have raised concerns about sleeping pills, citing a lack of effectiveness and possible adverse effects such as falls, driving impairment, and the potential for addiction, tolerance, and dependence.^33,35 The Beers Criteria of the American Geriatric Society recommends against the use of benzodiazepines in the elderly due to the risks of falls, cognitive impairment, and motor vehicle accidents and advises against the use of benzodiazepine agonists (such as zolpidem) for >90 days.³⁶

Two behavioral techniques for insomnia that can be easily applied in the family medicine setting are stimulus control and sleep restriction therapy.

Despite these concerns, the potential benefits of hypnotic medications for chronic insomnia should not be dismissed. The common strategy of simply addressing comorbidities and advising good sleep hygiene is insufficient for many patients. And some patients prefer the ease of using a hypnotic agent to the commitment required by CBT-I. Several reports suggest that the risk of hypnotic medication misuse in people with no history of substance abuse is overestimated.^37,38 And a panel of insomnia experts convened for the New Clinical Drug Evaluation Unit symposium in 2001 concluded, “Patients with chronic insomnia tend to exhibit therapy-seeking behavior, not drug-seeking behavior.”³⁹

Which hypnotic agent to choose?

US Food and Drug Administration (FDA)-approved hypnotic medications fall into 5 families (TABLE 2⁴⁰): benzodiazepines (BDZs), benzodiazepine agonists (BDZAs, sometimes called “Z drugs”), melatonin agonists (eg, ramelteon), tricyclic antidepressants (eg, low-dose doxepin), and orexin antagonists (eg, suvorexant). BDZs, BDZAs, and melatonin agonists potentiate sleep-promoting systems, while orexin antagonists and antihistaminergics suppress wake-promoting systems.

"Patients with chronic insomnia tend to exhibit therapy-seeking behavior, not drug-seeking behavior."

Studies of physician prescribing patterns show that among prescription medications for insomnia, zolpidem is the most popular, followed by trazodone (off-label use), other benzodiazepines, quetiapine (off-label use), and doxepin.⁴¹ Overall, over-the-counter melatonin may be more widely used than any of the prescription choices.⁴²

One useful basis for selection of an agent is whether the patient complains of difficulty with sleep initiation at the beginning of the night vs sleep maintenance, or both. For sleep initiation complaints, short-acting/sleep-promoting agents are preferred. For sleep maintenance complaints, longer-acting/wake-inhibiting medications that work at the end of the sleep phase may be necessary.

The AASM has recently concluded an exhaustive review of the literature regarding hypnotic medications for chronic insomnia.⁴³ The authors acknowledge important methodologic limitations, most notably a paucity of data on effectiveness and adverse effects, along with industry sponsorship of most studies and publication bias. Nevertheless, their conclusions favor the use of FDA-approved agents to off-label use of trazodone or over-the-counter use of melatonin or diphenhydramine. To summarize the AASM guidelines:³⁸

1. Medications recommended for sleep onset insomnia include: eszopiclone, ramelteon, temazepam, triazolam, zaleplon, and zolpidem.
2. Medications recommended for treating sleep maintenance insomnia include: doxepin, eszopiclone, suvorexant, zolpidem, and temazepam.
3. Medications not recommended for treating either sleep initiation or sleep maintenance insomnia include: diphenhydramine, melatonin, tiagabine, trazodone, tryptophan, and valerian.

These recommendations are similar to a review of hypnotics published by The Medical Letter in 2015.⁴⁰
 

Trazodone, an antidepressant medication with sedating properties, is not FDA-approved for the treatment of insomnia, yet ranks second to zolpidem in the number of prescriptions written for insomnia. Its popularity may be due to a perception of safety implied by its unscheduled FDA status and the lack of restrictions on prescribing duration. However, several reviews point out that its evidence base is weak.^44,45 There is only one placebo-controlled study involving trazodone use for "primary insomnia" (other studies have been in people with comorbid depression) and it showed insignificant improvements in sleep parameters and less effectiveness compared to zolpidem.⁴⁶

Trazadone, an antidepressant with sedating properties, is not FDA-approved for the treatment of insomnia, yet ranks second to zolpidem in the number of prescriptions written for insomnia.

Trazodone’s mechanisms of action are thought to be serotonin reuptake inhibition and alpha blockade, which might explain adverse effects such as orthostatic hypotension and psychomotor impairment. The frequency of such adverse effects is difficult to estimate since most studies of trazodone have used higher doses than are commonly used for insomnia in order to address comorbid depression. However, some experts have cautioned against its use—especially in the elderly.

The AASM guidelines recommend against use of trazodone. Others assert that it is probably best reserved for people in whom the complaint of insomnia is linked to comorbid depression.^43,44 

Is long-term use ever appropriate? There are no published guidelines about dosing strategies for hypnotics and whether nightly or intermittent use is preferred. All FDA-approved hypnotic agents are for short-term use, but this designation stems from a lack of long-term studies demonstrating continuing efficacy rather than actual proof of loss of effect. Although tolerance to over-the-counter sleep aids does occur, it has not been demonstrated to occur with FDA-approved agents. Studies of eszopiclone and zolpidem indicate continuing effectiveness as hypnotics with nightly use over a time-frame of several months to one year.^47,48

Regarding the thorny question of long-term use of hypnotics for chronic insomnia, the AASM concluded that long-term use should be reserved for “individuals in whom CBT-I is inaccessible or ineffective, who have been appropriately screened for contraindications to such treatment, who maintain long-term gains with medication, and who are followed regularly.”⁴³

CORRESPONDENCE
Adam J. Sorscher, MD, Dartmouth-Hitchcock Medical Center, 18 Old Etna Road, Lebanon, NH 03766; [email protected].

Although it is often taken for granted, the ability to initiate and maintain sleep throughout the night is elusive for many. About one-third of adults experience a troublesome episode of insomnia.¹ In most, it is transient, but in 10% to 15% (roughly 30 million people), the problem becomes self-perpetuating and chronic.² Chronic insomnia is one of the most prevalent conditions that family physicians (FPs) encounter, a function of it being so closely associated with comorbid conditions that FPs deal with every day, such as depression, chronic pain, and polypharmacy.^3,4

Insomnia can be vexing for a number of reasons. Because it is not acutely dangerous, patients may present it as an “add-on” concern at the end of an already lengthy visit. And because insomnia is often a symptom of multiple underlying physiologic and psychological factors, it requires the FP to engage in a thorough and time-consuming exploration of possible causes and comorbidities. Finally, standard treatment options have drawbacks: reports show that use of pharmacotherapy is troubling to prescribers primarily because of concerns about adverse effects and dependence;^5-7 the other major therapeutic avenue, cognitive behavioral therapy for insomnia (CBT-I), requires training and is time-consuming to deliver in the context of an office visit.^8,9

Despite these obstacles, successful evaluation and treatment of insomnia can be highly rewarding. Chronic insomnia is associated with great individual misery and negative consequences for long-term health. Specifically, it is associated with reduced quality of life and daytime functioning,¹⁰ depression,^11,12 hypertension,^13,14 increased workplace accidents and absenteeism,^15-17 and exacerbations of chronic pain.¹⁸ And while the evaluation and management of insomnia can be laborious, a systematic method can streamline the process.

Insomnia: Symptom or cause?

The International Classification of Sleep Disorders defines chronic insomnia as an inability to sleep sufficiently despite creating adequate opportunity. It occurs at least 3 nights per week for >3 months with perceived negative consequences during the day. Patients typically complain about symptoms including fatigue, diminished cog­nitive performance, and mood disturbance.¹⁹ Acute insomnia triggered by one or more biopsychosocial stresses is, by definition, self-limited and has different underlying mechanisms. As such, it will not be described in this review.

The chief risk factors are female gender, low socioeconomic status, and increasing age.²⁰ However, cohorts of healthy seniors show preserved good sleep; the increase in prevalence of insomnia in the elderly is likely linked more specifically to age-related accumulation of medical/mental health disorders and polypharmacy than aging per se.²¹

Research over the past 20 years has shown that comorbidities have a bidirectional relationship with insomnia, rather than a one-way cause and effect.

In the past, insomnia was viewed as a symptom, occurring secondarily to an underlying cause, usually an acute biopsychosocial stressor or depression. It was assumed that if the primary cause was effectively treated, then healthy sleep would return.

But research over the past 20 years has changed this paradigm in 2 ways. First, when comorbidities such as depression or chronic pain are present, they have a bidirectional relationship with insomnia rather than a one-way cause and effect. For example, instead of depression being a primary disorder from which insomnia can result, it is now recognized that insomnia can be present first and is a risk factor for new-onset depression. When depression and insomnia coexist, they may exacerbate each other in a bidirectional pattern.

Secondly, an estimated 15% of chronic insomnia sufferers have no targetable comorbidity; rather, they are unable to get sufficient sleep in large part because of a trait-like predisposition to fragile sleep, called hyperarousal brain physiology.²² These people used to be described as having “primary insomnia,” although the term has been dropped from the 5th edition of The Diagnostic and Statistical Manual of Mental Disorders (DSM).²³

Assess comorbidities, obtain sleep logs

The evaluation of the chronic form of insomnia should begin with a thorough medical his­tory to assess for comorbid conditions that can exacerbate disturbed sleep. These are generally grouped into medical disorders (TABLE 1²⁰), medications/substances (eg, antidepressants, stimulants, decongestants, narcotic analgesics, cardiovascular drugs, pulmonary agents, alcohol), and mental health disorders (especially depression and anxiety). It’s important to consider whether such comorbidities are contributing to the insomnia and optimize treatment that addresses them.

Take particular care to evaluate signs and symptoms of comorbid primary sleep disorders such as obstructive sleep apnea, restless legs syndrome (RLS), and circadian rhythm disorders since any of these can present with a complaint of insomnia. RLS, usually classified as a sleep disorder because of its circadian pattern (it is experienced more at night than during the day), is present to a troublesome degree in about 3% to 4% of all adults.²⁴ It is important to inquire about symptoms of RLS (urge to move legs in the night more than during the day; relieved with movement; worsened with inactivity) so as not to miss this treatable cause of insomnia.

The physical exam should focus on signs that suggest sleep-disordered breathing—obesity, large neck girth, hypertension, and crowded oropharynx—because people with sleep apnea often present with the complaint of frequent awakenings.

Sleep logs can present a powerful picture

In addition to a history and physical exam, physicians should ask their patients with chronic insomnia to complete sleep logs for 2 to 3 weeks.²⁰ A sleep log with midnight near the middle of the page is preferred by many because it places the typical sleeping hours in the middle of the page, showing relevant information in a way that can be grasped immediately (FIGURE 1). To save time, nurses can provide sleep logs to patients along with instructions about how to complete them.

Patient-completed sleep logs often illuminate obvious detrimental behaviors that reinforce insomnia (eg, spending excessive time in bed, having irregular bed/wake times, daytime napping that diminishes sleep drive in the evening). In addition, they sometimes reveal circadian rhythm abnormalities such as delayed sleep phase syndrome in which the patient attempts to sleep at a normal bedtime, but exhibits a marked delay in falling asleep/waking up compared to societal norms. Seeing such information graphically represented is often a powerful learning experience for both physician and patient.

Sleep studies aren't usually warranted

In its most recent (2008) clinical guideline on the evaluation and management of chronic insomnia, the American Academy of Sleep Medicine (AASM) stated that “routine testing in the sleep lab is not warranted for most cases of insomnia.” Instead, it is reserved for individuals in whom there is a suspicion of a comorbid sleep disorder. FPs should refer patients for formal sleep studies only if, in addition to the insomnia complaint, there is suspicion of:²⁰

• obstructive sleep apnea (based upon some combination of loud snoring, obesity, hypertension, and/or excessive daytime sleepiness),
• narcolepsy (based upon excessive daytime sleepiness without a readily identifiable cause), or
• arousals with the potential for self-injurious behavior (parasomnias).

Treatments: Sleep hygiene, CBT-I, and medication

Sleep hygiene, cognitive/behavioral techniques, and pharmacotherapy serve as the core of therapy for chronic insomnia.

Sleep hygiene: Common-sense strategies

Most FPs are familiar with sleep hygiene instructions; these are simple, common-sense behavioral techniques such as limiting caffeine and screen (television, computer) time at night, avoiding daytime naps, and maintaining regular bed- and out-of-bed times. (See “A sleep hygiene checklist.”) Although it is a logical starting point for behavioral modification, sleep hygiene has not been studied rigorously as a monotherapy for insomnia and, therefore, doesn’t have an evidence rating in terms of effectiveness.²⁰

CBT-I: Treatment of choice

CBT-I seeks to lower cognitive and somatic arousal. Taken together, cognitive and behavioral techniques are effective in 70% to 80% of people, whether they have primary insomnia or comorbidities.^25-27 Furthermore, the benefits are sustained with the passage of time.²⁷ CBT-I is regarded as the treatment of choice for chronic insomnia.²⁰

An experience of successful sleep initiation and maintenance is important psychologically: It renews patients' confidence in the ability to sleep.

When provided by a highly trained mental health professional, CBT-I usually takes the form of a series of 6 to 8 weekly appointments. Descriptions and manuals for CBT-I abound and online programs have also proliferated.^28,29 However, there is a shortage of highly trained providers, and most FPs do not feel proficient to engage fully in CBT-I.^8,9 Nevertheless, some behavioral elements of CBT-I, such as stimulus control and sleep restriction, can be utilized in the family medicine setting and may be effective for a significant subset of patients.

Stimulus control and sleep restriction. Two behavioral techniques for insomnia that can be applied in the family medicine setting are stimulus control and sleep restriction therapy.²⁰

With stimulus control, patients attempt to eliminate stimuli that weaken the psychological association between the bed and successful sleep, namely wakeful activities in bed such as watching television, reading, or even “tossing and turning.” Instead, they are instructed to use their bed only for sleep (and intimacy), to vacate it if awake and not clearly on the verge of sleep, and to avoid looking at a clock during the night. Patients are also advised to sleep only in their own bed and not in other places in their home.

Sleep restriction is predicated on the observation that many people with insomnia habitually spend too much time awake in bed, and this creates a conditioned arousal response to the bed. With sleep restriction, the patient is assigned a narrow window of “allowed time in bed,” usually a 6-hour interval of their choosing, and is instructed to adhere to this schedule for a period of 2 to 4 weeks. Many patients find that they fall asleep more rapidly and stay asleep longer after a few weeks. This experience of “successful” sleep initiation and maintenance is important psychologically; it renews their confidence in their ability to sleep, which is missing in most people with chronic insomnia.

If you use this approach with a patient, be sure to acknowledge that sleep restriction usually engenders some sleep deprivation in the first few weeks. But it is only a short-term intervention designed to change the expectation of nightly insomnia that is so ingrained in these patients. While they engage in sleep restriction, patients should keep sleep logs to track their “sleep efficiency” (ie, estimated time asleep vs time in bed). Once good sleep efficiency (>85%) is achieved, they may gradually lengthen their allowed time in bed by 15 minutes each week until they are obtaining 7 to 9 hours of sleep per night. (See “Breaking the cycle of insomnia by employing sleep restriction.”)

Cognitive therapy. Cognitive therapies for insomnia are usually provided by psychologists with special training. Three specific techniques that have evidence ratings* from the AASM are:²⁰

1. Relaxation training, including progressive muscle relaxation, guided imagery, and abdominal breathing to lower somatic and cognitive arousal states that interfere with sleep (strength of recommendation [SOR]: A).
2. Biofeedback therapy trains patients to control some physiologic variable through visual or auditory feedback. The objective is to reduce somatic arousal (SOR: B).
3. Paradoxical intention in which the patient is trained to confront the fear of staying awake and its potential effects. The objective is to eliminate a patient’s anxiety about sleep performance (SOR: B).

Pharmacotherapy: Overused? Addictive?

For patients who continue to struggle with insomnia despite attempting CBT-I, or for those who prefer a different approach, pharmacotherapy is a reasonable therapeutic option. While hypnotic medications are no guarantee of success, they sometimes provide meaningful benefit when supplied to a patient who has successfully established good cognitive and behavioral techniques, but is still struggling with insomnia.

Use of hypnotic medications has increased dramatically in recent years. Prescriptions for sleep medications approached 60 million in 2008, up 54% from 2004, with sales topping $2 billion.^30,31 A National Health and Nutrition Examination Survey looking at the period between 2005 and 2010 found that about 4% of adults ages 20 and older used prescription sleep aids in the past month.³²

Meta-analyses of pharmacotherapy for chronic insomnia show small to moderate effect sizes for sleep variables such as latency to sleep onset, total sleep time, and wake time after sleep onset.^33,34 Treatment of chronic insomnia with hypnotic medications is of comparable effectiveness to CBT-I in the early phase, but the benefits of CBT-I are more enduring.²⁷

A controversial approach. The appropriateness of hypnotic medications for chronic insomnia is controversial. While their use by health care professionals has been increasing, some authors have raised concerns about sleeping pills, citing a lack of effectiveness and possible adverse effects such as falls, driving impairment, and the potential for addiction, tolerance, and dependence.^33,35 The Beers Criteria of the American Geriatric Society recommends against the use of benzodiazepines in the elderly due to the risks of falls, cognitive impairment, and motor vehicle accidents and advises against the use of benzodiazepine agonists (such as zolpidem) for >90 days.³⁶

Two behavioral techniques for insomnia that can be easily applied in the family medicine setting are stimulus control and sleep restriction therapy.

Despite these concerns, the potential benefits of hypnotic medications for chronic insomnia should not be dismissed. The common strategy of simply addressing comorbidities and advising good sleep hygiene is insufficient for many patients. And some patients prefer the ease of using a hypnotic agent to the commitment required by CBT-I. Several reports suggest that the risk of hypnotic medication misuse in people with no history of substance abuse is overestimated.^37,38 And a panel of insomnia experts convened for the New Clinical Drug Evaluation Unit symposium in 2001 concluded, “Patients with chronic insomnia tend to exhibit therapy-seeking behavior, not drug-seeking behavior.”³⁹

Which hypnotic agent to choose?

US Food and Drug Administration (FDA)-approved hypnotic medications fall into 5 families (TABLE 2⁴⁰): benzodiazepines (BDZs), benzodiazepine agonists (BDZAs, sometimes called “Z drugs”), melatonin agonists (eg, ramelteon), tricyclic antidepressants (eg, low-dose doxepin), and orexin antagonists (eg, suvorexant). BDZs, BDZAs, and melatonin agonists potentiate sleep-promoting systems, while orexin antagonists and antihistaminergics suppress wake-promoting systems.

"Patients with chronic insomnia tend to exhibit therapy-seeking behavior, not drug-seeking behavior."

Studies of physician prescribing patterns show that among prescription medications for insomnia, zolpidem is the most popular, followed by trazodone (off-label use), other benzodiazepines, quetiapine (off-label use), and doxepin.⁴¹ Overall, over-the-counter melatonin may be more widely used than any of the prescription choices.⁴²

One useful basis for selection of an agent is whether the patient complains of difficulty with sleep initiation at the beginning of the night vs sleep maintenance, or both. For sleep initiation complaints, short-acting/sleep-promoting agents are preferred. For sleep maintenance complaints, longer-acting/wake-inhibiting medications that work at the end of the sleep phase may be necessary.

The AASM has recently concluded an exhaustive review of the literature regarding hypnotic medications for chronic insomnia.⁴³ The authors acknowledge important methodologic limitations, most notably a paucity of data on effectiveness and adverse effects, along with industry sponsorship of most studies and publication bias. Nevertheless, their conclusions favor the use of FDA-approved agents to off-label use of trazodone or over-the-counter use of melatonin or diphenhydramine. To summarize the AASM guidelines:³⁸

1. Medications recommended for sleep onset insomnia include: eszopiclone, ramelteon, temazepam, triazolam, zaleplon, and zolpidem.
2. Medications recommended for treating sleep maintenance insomnia include: doxepin, eszopiclone, suvorexant, zolpidem, and temazepam.
3. Medications not recommended for treating either sleep initiation or sleep maintenance insomnia include: diphenhydramine, melatonin, tiagabine, trazodone, tryptophan, and valerian.

These recommendations are similar to a review of hypnotics published by The Medical Letter in 2015.⁴⁰
 

Trazodone, an antidepressant medication with sedating properties, is not FDA-approved for the treatment of insomnia, yet ranks second to zolpidem in the number of prescriptions written for insomnia. Its popularity may be due to a perception of safety implied by its unscheduled FDA status and the lack of restrictions on prescribing duration. However, several reviews point out that its evidence base is weak.^44,45 There is only one placebo-controlled study involving trazodone use for "primary insomnia" (other studies have been in people with comorbid depression) and it showed insignificant improvements in sleep parameters and less effectiveness compared to zolpidem.⁴⁶

Trazadone, an antidepressant with sedating properties, is not FDA-approved for the treatment of insomnia, yet ranks second to zolpidem in the number of prescriptions written for insomnia.

Trazodone’s mechanisms of action are thought to be serotonin reuptake inhibition and alpha blockade, which might explain adverse effects such as orthostatic hypotension and psychomotor impairment. The frequency of such adverse effects is difficult to estimate since most studies of trazodone have used higher doses than are commonly used for insomnia in order to address comorbid depression. However, some experts have cautioned against its use—especially in the elderly.

The AASM guidelines recommend against use of trazodone. Others assert that it is probably best reserved for people in whom the complaint of insomnia is linked to comorbid depression.^43,44 

Is long-term use ever appropriate? There are no published guidelines about dosing strategies for hypnotics and whether nightly or intermittent use is preferred. All FDA-approved hypnotic agents are for short-term use, but this designation stems from a lack of long-term studies demonstrating continuing efficacy rather than actual proof of loss of effect. Although tolerance to over-the-counter sleep aids does occur, it has not been demonstrated to occur with FDA-approved agents. Studies of eszopiclone and zolpidem indicate continuing effectiveness as hypnotics with nightly use over a time-frame of several months to one year.^47,48

Regarding the thorny question of long-term use of hypnotics for chronic insomnia, the AASM concluded that long-term use should be reserved for “individuals in whom CBT-I is inaccessible or ineffective, who have been appropriately screened for contraindications to such treatment, who maintain long-term gains with medication, and who are followed regularly.”⁴³

CORRESPONDENCE
Adam J. Sorscher, MD, Dartmouth-Hitchcock Medical Center, 18 Old Etna Road, Lebanon, NH 03766; [email protected].