Cleveland Clinic Journal of Medicine

A 51-year-old man with type 2 diabetes was referred to our hospital because of liver dysfunction and nonpruritic exanthema, with papulosquamous, scaly, papular and macular lesions on his trunk and extremities, including his palms (Figure 1) and soles. Also noted were tiny grayish mucus patches on the oral mucosa. Axillary and inguinal superficial lymph nodes were palpable.

Laboratory testing revealed elevated serum levels of markers of liver disease, ie:

• Total bilirubin 9.8 mg/dL (reference range 0.2–1.3)
• Direct bilirubin 8.0 mg/dL (< 0.2)
• Aspartate aminotransferase 57 IU/L (13–35)
• Alanine aminotransferase 90 IU/L (10–54)
• Alkaline phosphatase 4,446 IU/L (36–108).

Possible causes of liver dysfunction such as legal and illicit drugs, alcohol abuse, obstructive biliary tract or liver disease, viral hepatitis, and primary biliary cirrhosis were ruled out by history, serologic testing, abdominal ultrasonography, and computed tomography.

Secondary syphilis was suspected in view of the characteristic distribution of exanthema involving the trunk and extremities, especially the palms and soles. On questioning, the patient admitted to having had unprotected sex with a female sex worker, which also raised the probability of syphilis infection.

The rapid plasma reagin test was positive at a titer of 1:16, and the Treponema pallidum agglutination test was positive at a signal-to-cutoff ratio of 27.02. Antibody testing for human immunodeficiency virus (HIV) was negative.

The patient was started on penicillin G, but 4 hours later, he developed a fever with a temperature of 100.2°F (37.9°C), which was assumed to be a Jarisch-Herxheimer reaction. The fever resolved by the next morning without further treatment.

His course was otherwise uneventful. The exanthema resolved within 3 months, and his liver function returned to normal. Five months later, the rapid plasma reagin test was repeated on an outpatient basis, and the result was normal.

SYPHILIS IS NOT A DISEASE OF THE PAST

Syphilis is caused by T pallidum and is mainly transmitted by sexual contact.¹

The incidence of syphilis has substantially increased in recent years in Japan^2,3 and worldwide.⁴ The typical patient is a young man who has sex with men, is infected with HIV, and has a history of syphilis infection.³ However, the rapid increase in syphilis infections in Japan in recent years is largely because of an increase in heterosexual transmission.³

Infectious in its early stages

Syphilis is potentially infectious in its early (primary, secondary, and early latent) stages.^1,5 The secondary stage generally begins 6 to 8 weeks after the primary infection¹ and presents with diverse symptoms, including arthralgia, condylomata lata, generalized lymphaden­opathy, maculopapular and papulosquamous exanthema, myalgia, and pharyngitis.¹

Liver dysfunction in secondary syphilis

Liver dysfunction is common in secondary syphilis, occurring in 25% to 50% of cases.⁵ The liver enzyme pattern in most cases is a disproportionate increase in the alkaline phosphatase level compared with modest elevations of aminotransferases and bilirubin.^2,5 However, some cases may show predominant hepatocellular damage (with prominent elevations in aminotransferase levels), and others may present with severe cholestasis (with prominent elevations in alkaline phosphatase and bilirubin) or even fulminant hepatic failure.^2,5

The diagnostic criteria for syphilitic hepatitis are abnormal liver enzyme levels, serologic evidence of syphilis in conjunction with acute clinical presentation of secondary syphilis, exclusion of alternative causes of liver dysfunction, and prompt recovery of liver function after antimicrobial therapy.^2,5

Pathogenic mechanisms in syphilitic hepatitis include direct portal venous inoculation and immune complex-mediated disease.² However, direct hepatotoxicity of the microorganism seems unlikely, as spirochetes are rarely detected in liver specimens.^2,5

Jarisch-Herxheimer reaction

The Jarisch-Herxheimer reaction is an acute febrile illness during the first 24 hours of antimicrobial treatment.^1,6 It is assumed to be due to lysis of large numbers of spirochetes, releasing lipopolysaccharides (endotoxins) that further incite the release of a range of cytokines, resulting in symptoms such as fever, chills, myalgias, headache, tachycardia, hyperventilation, vasodilation with flushing, and mild hypotension.^6,7

The frequency of Jarisch-Herxheimer reaction in syphilis and other spirochetal infections has varied widely in different reports.⁸ It is common in primary and secondary syphilis but usually does not occur in latent syphilis.⁶

Consider the diagnosis

Physicians should consider secondary syphilis in patients who present with characteristic generalized reddish macules and papules with papulosquamous lesions, including on the palms and soles as in our patient, and also in patients who have had unprotected sexual contact. Syphilis is not a disease of the past.

Acknowledgment: The authors thank Dr. Joel Branch, Shonan Kamakura General Hospital, Japan, for his editorial assistance.

A 51-year-old man with type 2 diabetes was referred to our hospital because of liver dysfunction and nonpruritic exanthema, with papulosquamous, scaly, papular and macular lesions on his trunk and extremities, including his palms (Figure 1) and soles. Also noted were tiny grayish mucus patches on the oral mucosa. Axillary and inguinal superficial lymph nodes were palpable.

Laboratory testing revealed elevated serum levels of markers of liver disease, ie:

• Total bilirubin 9.8 mg/dL (reference range 0.2–1.3)
• Direct bilirubin 8.0 mg/dL (< 0.2)
• Aspartate aminotransferase 57 IU/L (13–35)
• Alanine aminotransferase 90 IU/L (10–54)
• Alkaline phosphatase 4,446 IU/L (36–108).

Possible causes of liver dysfunction such as legal and illicit drugs, alcohol abuse, obstructive biliary tract or liver disease, viral hepatitis, and primary biliary cirrhosis were ruled out by history, serologic testing, abdominal ultrasonography, and computed tomography.

Secondary syphilis was suspected in view of the characteristic distribution of exanthema involving the trunk and extremities, especially the palms and soles. On questioning, the patient admitted to having had unprotected sex with a female sex worker, which also raised the probability of syphilis infection.

The rapid plasma reagin test was positive at a titer of 1:16, and the Treponema pallidum agglutination test was positive at a signal-to-cutoff ratio of 27.02. Antibody testing for human immunodeficiency virus (HIV) was negative.

The patient was started on penicillin G, but 4 hours later, he developed a fever with a temperature of 100.2°F (37.9°C), which was assumed to be a Jarisch-Herxheimer reaction. The fever resolved by the next morning without further treatment.

His course was otherwise uneventful. The exanthema resolved within 3 months, and his liver function returned to normal. Five months later, the rapid plasma reagin test was repeated on an outpatient basis, and the result was normal.

SYPHILIS IS NOT A DISEASE OF THE PAST

Syphilis is caused by T pallidum and is mainly transmitted by sexual contact.¹

The incidence of syphilis has substantially increased in recent years in Japan^2,3 and worldwide.⁴ The typical patient is a young man who has sex with men, is infected with HIV, and has a history of syphilis infection.³ However, the rapid increase in syphilis infections in Japan in recent years is largely because of an increase in heterosexual transmission.³

Infectious in its early stages

Syphilis is potentially infectious in its early (primary, secondary, and early latent) stages.^1,5 The secondary stage generally begins 6 to 8 weeks after the primary infection¹ and presents with diverse symptoms, including arthralgia, condylomata lata, generalized lymphaden­opathy, maculopapular and papulosquamous exanthema, myalgia, and pharyngitis.¹

Liver dysfunction in secondary syphilis

Liver dysfunction is common in secondary syphilis, occurring in 25% to 50% of cases.⁵ The liver enzyme pattern in most cases is a disproportionate increase in the alkaline phosphatase level compared with modest elevations of aminotransferases and bilirubin.^2,5 However, some cases may show predominant hepatocellular damage (with prominent elevations in aminotransferase levels), and others may present with severe cholestasis (with prominent elevations in alkaline phosphatase and bilirubin) or even fulminant hepatic failure.^2,5

The diagnostic criteria for syphilitic hepatitis are abnormal liver enzyme levels, serologic evidence of syphilis in conjunction with acute clinical presentation of secondary syphilis, exclusion of alternative causes of liver dysfunction, and prompt recovery of liver function after antimicrobial therapy.^2,5

Pathogenic mechanisms in syphilitic hepatitis include direct portal venous inoculation and immune complex-mediated disease.² However, direct hepatotoxicity of the microorganism seems unlikely, as spirochetes are rarely detected in liver specimens.^2,5

Jarisch-Herxheimer reaction

The Jarisch-Herxheimer reaction is an acute febrile illness during the first 24 hours of antimicrobial treatment.^1,6 It is assumed to be due to lysis of large numbers of spirochetes, releasing lipopolysaccharides (endotoxins) that further incite the release of a range of cytokines, resulting in symptoms such as fever, chills, myalgias, headache, tachycardia, hyperventilation, vasodilation with flushing, and mild hypotension.^6,7

The frequency of Jarisch-Herxheimer reaction in syphilis and other spirochetal infections has varied widely in different reports.⁸ It is common in primary and secondary syphilis but usually does not occur in latent syphilis.⁶

Consider the diagnosis

Physicians should consider secondary syphilis in patients who present with characteristic generalized reddish macules and papules with papulosquamous lesions, including on the palms and soles as in our patient, and also in patients who have had unprotected sexual contact. Syphilis is not a disease of the past.

Acknowledgment: The authors thank Dr. Joel Branch, Shonan Kamakura General Hospital, Japan, for his editorial assistance.

A 51-year-old man with type 2 diabetes was referred to our hospital because of liver dysfunction and nonpruritic exanthema, with papulosquamous, scaly, papular and macular lesions on his trunk and extremities, including his palms (Figure 1) and soles. Also noted were tiny grayish mucus patches on the oral mucosa. Axillary and inguinal superficial lymph nodes were palpable.

Laboratory testing revealed elevated serum levels of markers of liver disease, ie:

• Total bilirubin 9.8 mg/dL (reference range 0.2–1.3)
• Direct bilirubin 8.0 mg/dL (< 0.2)
• Aspartate aminotransferase 57 IU/L (13–35)
• Alanine aminotransferase 90 IU/L (10–54)
• Alkaline phosphatase 4,446 IU/L (36–108).

Possible causes of liver dysfunction such as legal and illicit drugs, alcohol abuse, obstructive biliary tract or liver disease, viral hepatitis, and primary biliary cirrhosis were ruled out by history, serologic testing, abdominal ultrasonography, and computed tomography.

Secondary syphilis was suspected in view of the characteristic distribution of exanthema involving the trunk and extremities, especially the palms and soles. On questioning, the patient admitted to having had unprotected sex with a female sex worker, which also raised the probability of syphilis infection.

The rapid plasma reagin test was positive at a titer of 1:16, and the Treponema pallidum agglutination test was positive at a signal-to-cutoff ratio of 27.02. Antibody testing for human immunodeficiency virus (HIV) was negative.

The patient was started on penicillin G, but 4 hours later, he developed a fever with a temperature of 100.2°F (37.9°C), which was assumed to be a Jarisch-Herxheimer reaction. The fever resolved by the next morning without further treatment.

His course was otherwise uneventful. The exanthema resolved within 3 months, and his liver function returned to normal. Five months later, the rapid plasma reagin test was repeated on an outpatient basis, and the result was normal.

SYPHILIS IS NOT A DISEASE OF THE PAST

Syphilis is caused by T pallidum and is mainly transmitted by sexual contact.¹

The incidence of syphilis has substantially increased in recent years in Japan^2,3 and worldwide.⁴ The typical patient is a young man who has sex with men, is infected with HIV, and has a history of syphilis infection.³ However, the rapid increase in syphilis infections in Japan in recent years is largely because of an increase in heterosexual transmission.³

Infectious in its early stages

Syphilis is potentially infectious in its early (primary, secondary, and early latent) stages.^1,5 The secondary stage generally begins 6 to 8 weeks after the primary infection¹ and presents with diverse symptoms, including arthralgia, condylomata lata, generalized lymphaden­opathy, maculopapular and papulosquamous exanthema, myalgia, and pharyngitis.¹

Liver dysfunction in secondary syphilis

Liver dysfunction is common in secondary syphilis, occurring in 25% to 50% of cases.⁵ The liver enzyme pattern in most cases is a disproportionate increase in the alkaline phosphatase level compared with modest elevations of aminotransferases and bilirubin.^2,5 However, some cases may show predominant hepatocellular damage (with prominent elevations in aminotransferase levels), and others may present with severe cholestasis (with prominent elevations in alkaline phosphatase and bilirubin) or even fulminant hepatic failure.^2,5

The diagnostic criteria for syphilitic hepatitis are abnormal liver enzyme levels, serologic evidence of syphilis in conjunction with acute clinical presentation of secondary syphilis, exclusion of alternative causes of liver dysfunction, and prompt recovery of liver function after antimicrobial therapy.^2,5

Pathogenic mechanisms in syphilitic hepatitis include direct portal venous inoculation and immune complex-mediated disease.² However, direct hepatotoxicity of the microorganism seems unlikely, as spirochetes are rarely detected in liver specimens.^2,5

Jarisch-Herxheimer reaction

The Jarisch-Herxheimer reaction is an acute febrile illness during the first 24 hours of antimicrobial treatment.^1,6 It is assumed to be due to lysis of large numbers of spirochetes, releasing lipopolysaccharides (endotoxins) that further incite the release of a range of cytokines, resulting in symptoms such as fever, chills, myalgias, headache, tachycardia, hyperventilation, vasodilation with flushing, and mild hypotension.^6,7

The frequency of Jarisch-Herxheimer reaction in syphilis and other spirochetal infections has varied widely in different reports.⁸ It is common in primary and secondary syphilis but usually does not occur in latent syphilis.⁶

Consider the diagnosis

Physicians should consider secondary syphilis in patients who present with characteristic generalized reddish macules and papules with papulosquamous lesions, including on the palms and soles as in our patient, and also in patients who have had unprotected sexual contact. Syphilis is not a disease of the past.

Acknowledgment: The authors thank Dr. Joel Branch, Shonan Kamakura General Hospital, Japan, for his editorial assistance.

A 20-year-old woman had a 4-month history of painful red erosions around the mouth. She had no dysphagia or fatigue and no history of diarrhea, gluten intolerance, or diabetes mellitus. An antifungal-antibacterial ointment prescribed by her dentist had provided no relief.

• Hemoglobin 8.0 g/dL (reference range for females 12.3–15.3)
• Mean corpuscular volume 62 fL (80–100)
• Serum ferritin 1.3 ng/mL (15–200)
• Reticulocyte count 0.86% (0.5–1.5)
• White blood cell count 9.8 × 10⁹/L (4.5–11.0)
• Platelet count 450 × 10⁹/L (150–400).

Vitamin B₁₂ and folate levels were normal, and tests for antitissue transglutaminase and antinuclear antibodies were negative.

Based on these results, the diagnosis was angular cheilitis from iron deficiency anemia. Treatment with oral ferrous gluconate 300 mg twice daily cleared the cheilitis, and after 4 weeks of this treatment, the hemoglobin level increased to 9.8 g/dL, the serum ferritin increased to 7 ng/mL, and the reticulocyte count increased to 2.6%. She was advised to continue taking oral iron tablets for another 3 months until the hemoglobin level reached 12.0 g/dL.

During 2 years of follow-up, she had no recurrence of angular cheilitis, and her hemoglobin and serum ferritin levels remained normal. Ferrous gluconate was her only medication from the time of her diagnosis.

A BROAD DIFFERENTIAL DIAGNOSIS

Angular cheilitis (perlèche) is an inflammatory condition characterized by erosive inflammation at one or both angles of the mouth. It typically presents as erythema, scaling, fissuring, and ulceration. A wide variety of factors, including nutritional deficiencies, local and systemic factors, and drug side effects, may produce cheilitis.^1,2

Nutritional deficiencies account for 25% of all cases of angular cheilitis³ and include iron deficiency and deficiencies of the B vitamins riboflavin (B₂), niacin (B₃), pyridoxine (B₆), and cyanocobalamin (B₁₂).¹

Local causes include infection with Candida albicans or Staphylococcus aureus and allergic contact dermatitis. Common causes of allergic contact dermatitis include lipstick, toothpaste, mouthwash, cosmetics, sunscreen, fragrance, metals such as nickel, and dental appliances.¹

Systemic diseases associated with angular cheilitis include xerostomia, inflammatory bowel disease, Sjögren syndrome, glucagonoma, and human immunodeficiency virus.¹

Drugs that cause angular cheilitis include isotretinoin, sorafenib (antineoplastic kinase inhibitor), and ointments or creams such as neomycin sulfate–polymyxin B sulfate, bacitracin, idoxuridine, and steroids.^1,4

Conditions that mimic angular cheilitis include herpes simplex type 1 (herpes labialis) and actinic cheilitis. Herpes labialis, characterized by burning sensation, itching, or paresthesia, usually precedes a recurrence of vesicles that eventually ulcerate or form a crust and heal without a crust. Herpes labialis often recurs, affecting the vermilion border and lasting approximately 1 week.

Actinic cheilitis, a premalignant condition that commonly involves the lower lip with sparing of the corners of the mouth, is caused by excessive sun exposure. Patients often have persistent dryness and cracking of the lips.

In our patient, angular cheilitis was the main clinical manifestation of iron deficiency anemia, highlighting the importance of looking for iron deficiency in affected patients without a more obvious cause.

A 20-year-old woman had a 4-month history of painful red erosions around the mouth. She had no dysphagia or fatigue and no history of diarrhea, gluten intolerance, or diabetes mellitus. An antifungal-antibacterial ointment prescribed by her dentist had provided no relief.

• Hemoglobin 8.0 g/dL (reference range for females 12.3–15.3)
• Mean corpuscular volume 62 fL (80–100)
• Serum ferritin 1.3 ng/mL (15–200)
• Reticulocyte count 0.86% (0.5–1.5)
• White blood cell count 9.8 × 10⁹/L (4.5–11.0)
• Platelet count 450 × 10⁹/L (150–400).

Vitamin B₁₂ and folate levels were normal, and tests for antitissue transglutaminase and antinuclear antibodies were negative.

Based on these results, the diagnosis was angular cheilitis from iron deficiency anemia. Treatment with oral ferrous gluconate 300 mg twice daily cleared the cheilitis, and after 4 weeks of this treatment, the hemoglobin level increased to 9.8 g/dL, the serum ferritin increased to 7 ng/mL, and the reticulocyte count increased to 2.6%. She was advised to continue taking oral iron tablets for another 3 months until the hemoglobin level reached 12.0 g/dL.

During 2 years of follow-up, she had no recurrence of angular cheilitis, and her hemoglobin and serum ferritin levels remained normal. Ferrous gluconate was her only medication from the time of her diagnosis.

A BROAD DIFFERENTIAL DIAGNOSIS

Angular cheilitis (perlèche) is an inflammatory condition characterized by erosive inflammation at one or both angles of the mouth. It typically presents as erythema, scaling, fissuring, and ulceration. A wide variety of factors, including nutritional deficiencies, local and systemic factors, and drug side effects, may produce cheilitis.^1,2

Nutritional deficiencies account for 25% of all cases of angular cheilitis³ and include iron deficiency and deficiencies of the B vitamins riboflavin (B₂), niacin (B₃), pyridoxine (B₆), and cyanocobalamin (B₁₂).¹

Local causes include infection with Candida albicans or Staphylococcus aureus and allergic contact dermatitis. Common causes of allergic contact dermatitis include lipstick, toothpaste, mouthwash, cosmetics, sunscreen, fragrance, metals such as nickel, and dental appliances.¹

Systemic diseases associated with angular cheilitis include xerostomia, inflammatory bowel disease, Sjögren syndrome, glucagonoma, and human immunodeficiency virus.¹

Drugs that cause angular cheilitis include isotretinoin, sorafenib (antineoplastic kinase inhibitor), and ointments or creams such as neomycin sulfate–polymyxin B sulfate, bacitracin, idoxuridine, and steroids.^1,4

Conditions that mimic angular cheilitis include herpes simplex type 1 (herpes labialis) and actinic cheilitis. Herpes labialis, characterized by burning sensation, itching, or paresthesia, usually precedes a recurrence of vesicles that eventually ulcerate or form a crust and heal without a crust. Herpes labialis often recurs, affecting the vermilion border and lasting approximately 1 week.

Actinic cheilitis, a premalignant condition that commonly involves the lower lip with sparing of the corners of the mouth, is caused by excessive sun exposure. Patients often have persistent dryness and cracking of the lips.

In our patient, angular cheilitis was the main clinical manifestation of iron deficiency anemia, highlighting the importance of looking for iron deficiency in affected patients without a more obvious cause.

A 20-year-old woman had a 4-month history of painful red erosions around the mouth. She had no dysphagia or fatigue and no history of diarrhea, gluten intolerance, or diabetes mellitus. An antifungal-antibacterial ointment prescribed by her dentist had provided no relief.

• Hemoglobin 8.0 g/dL (reference range for females 12.3–15.3)
• Mean corpuscular volume 62 fL (80–100)
• Serum ferritin 1.3 ng/mL (15–200)
• Reticulocyte count 0.86% (0.5–1.5)
• White blood cell count 9.8 × 10⁹/L (4.5–11.0)
• Platelet count 450 × 10⁹/L (150–400).

Vitamin B₁₂ and folate levels were normal, and tests for antitissue transglutaminase and antinuclear antibodies were negative.

Based on these results, the diagnosis was angular cheilitis from iron deficiency anemia. Treatment with oral ferrous gluconate 300 mg twice daily cleared the cheilitis, and after 4 weeks of this treatment, the hemoglobin level increased to 9.8 g/dL, the serum ferritin increased to 7 ng/mL, and the reticulocyte count increased to 2.6%. She was advised to continue taking oral iron tablets for another 3 months until the hemoglobin level reached 12.0 g/dL.

During 2 years of follow-up, she had no recurrence of angular cheilitis, and her hemoglobin and serum ferritin levels remained normal. Ferrous gluconate was her only medication from the time of her diagnosis.

A BROAD DIFFERENTIAL DIAGNOSIS

Angular cheilitis (perlèche) is an inflammatory condition characterized by erosive inflammation at one or both angles of the mouth. It typically presents as erythema, scaling, fissuring, and ulceration. A wide variety of factors, including nutritional deficiencies, local and systemic factors, and drug side effects, may produce cheilitis.^1,2

Nutritional deficiencies account for 25% of all cases of angular cheilitis³ and include iron deficiency and deficiencies of the B vitamins riboflavin (B₂), niacin (B₃), pyridoxine (B₆), and cyanocobalamin (B₁₂).¹

Local causes include infection with Candida albicans or Staphylococcus aureus and allergic contact dermatitis. Common causes of allergic contact dermatitis include lipstick, toothpaste, mouthwash, cosmetics, sunscreen, fragrance, metals such as nickel, and dental appliances.¹

Systemic diseases associated with angular cheilitis include xerostomia, inflammatory bowel disease, Sjögren syndrome, glucagonoma, and human immunodeficiency virus.¹

Drugs that cause angular cheilitis include isotretinoin, sorafenib (antineoplastic kinase inhibitor), and ointments or creams such as neomycin sulfate–polymyxin B sulfate, bacitracin, idoxuridine, and steroids.^1,4

Conditions that mimic angular cheilitis include herpes simplex type 1 (herpes labialis) and actinic cheilitis. Herpes labialis, characterized by burning sensation, itching, or paresthesia, usually precedes a recurrence of vesicles that eventually ulcerate or form a crust and heal without a crust. Herpes labialis often recurs, affecting the vermilion border and lasting approximately 1 week.

Actinic cheilitis, a premalignant condition that commonly involves the lower lip with sparing of the corners of the mouth, is caused by excessive sun exposure. Patients often have persistent dryness and cracking of the lips.

In our patient, angular cheilitis was the main clinical manifestation of iron deficiency anemia, highlighting the importance of looking for iron deficiency in affected patients without a more obvious cause.

A 29-year-old nulliparous woman presents for a routine checkup. She has hypertension and type 2 diabetes mellitus. Her current medications are chlorpropamide 500 mg daily, metformin 500 mg twice a day, lisinopril 40 mg daily, simvastatin 40 mg daily, and aspirin 81 mg daily. Her body mass index is 37 kg/m² and her blood pressure is 130/80 mm Hg. Her hemoglobin A_1c level is 7.8% and her low-density lipoprotein cholesterol 90 mg/dL.

She is considering pregnancy. How would you counsel her?

DEFINING DIABETES IN PREGNANCY

Diabetes in pregnant women, both gestational and pregestational, is the most common medical complication associated with pregnancy.¹

• Gestational diabetes is defined as diabetes that is diagnosed during the second or third trimester of pregnancy and that is not clearly pregestational.²
• Pregestational diabetes exists before pregnancy and can be either type 1 or type 2.

Most cases of diabetes diagnosed during the first trimester reflect pregestational diabetes, as gestational diabetes occurs when insulin resistance increases in the later trimesters.

Type 1 diabetes involves autoimmune destruction of pancreatic islet cells, leading to insulin deficiency and the need for insulin therapy. Type 2 diabetes is characterized by insulin resistance rather than overall insulin deficiency. Type 2 diabetes tends to be associated with comorbidities such as obesity and hypertension, which are independent risk factors for adverse perinatal outcomes.^3,4

Gestational diabetes accounts for most cases of diabetes during pregnancy. Although both pregestational and gestational diabetes increase the risk of maternal and fetal complications, pregestational diabetes is associated with significantly greater risks.¹

IMPACT OF DIABETES ON THE MOTHER

Pregnancy increases the risk of maternal hypoglycemia, especially during the first trimester in patients with type 1 diabetes, as insulin sensitivity increases in early pregnancy.¹ Pregnant women with diabetes may also have an altered counterregulatory response and less hypoglycemic awareness.¹ Insulin resistance rises during the second and early third trimesters, increasing the risk of hyperglycemia in women with diabetes.¹

Glycemic control during pregnancy is usually easier to achieve in patients with type 2 diabetes than with type 1, but it may require much higher insulin doses.

Because pregnancy is inherently a ketogenic state, women with type 1 diabetes are at higher risk of diabetic ketoacidosis, particularly during the second and third trimesters.¹ There are reports of euglycemic diabetic ketoacidosis in pregnant women with either gestational or pregestational diabetes.⁵

Diabetes is associated with a risk of preeclampsia 4 times higher than in nondiabetic women.⁶ Other potential pregnancy-related complications include infections, polyhydram­nios, spontaneous abortion, and cesarean delivery.^1,7 The risk of pregnancy loss is similar in women with either type 1 or type 2 diabetes (2.6% and 3.7%, respectively), but the causes are different.⁸ Although preexisting diabetic complications such as retinopathy, nephropathy, and gastroparesis can be exacerbated during pregnancy,¹ only severe gastroparesis and advanced renal disease are considered relative contraindications to pregnancy.

IMPACT OF DIABETES ON THE FETUS

Fetal complications of maternal diabetes include embryopathy (fetal malformations) and fetopathy (overgrowth, ie, fetus large for gestational age, and increased risk of fetal death or distress). Maternal hyperglycemia is associated with diabetic embryopathy, resulting in major birth defects in 5% to 25% of pregnancies and spontaneous abortions in 15% to 20%.^9,10 There is a 2- to 6-fold increase in risk of congenital malformations.6

The most common diabetes-associated congenital malformations affect the cardiovascular system. Congenital heart disease includes tetralogy of Fallot, transposition of the great vessels, septal defects, and anomalous pulmonary venous return. Other relatively common defects involve the fetal central nervous system, spine, orofacial system, kidneys, urogenital system, gastrointestinal tract, and skeleton.¹¹

The risk of fetopathy is proportional to the degree of maternal hyperglycemia. Excess maternal glucose and fatty acid levels can lead to fetal hyperglycemia and overgrowth, which increases fetal oxygen requirements. Erythro­poietin levels rise, causing an increase in red cell mass, with subsequent hyperviscosity within the placenta and higher risk of fetal death.

Other complications include intrauterine growth restriction, prematurity, and preterm delivery. Fetal macrosomia (birth weight > 90th percentile or 4 kg, approximately 8 lb, 13 oz) occurs in 27% to 62% of children born to mothers with diabetes, a rate 10 times higher than in patients without diabetes. It contributes to shoulder dystocia (risk 2 to 4 times higher in diabetic pregnancies) and cesarean delivery.⁶ Infants born to mothers with diabetes also have higher risks of neonatal hypoglycemia, erythrocytosis, hyperbilirubinemia, hypocalcemia, respiratory distress, cardiomyopathy, and death, as well as for developing diabetes, obesity, and other adverse cardiometabolic outcomes later in life.¹¹

Nearly half of pregnancies in the general population are unplanned,¹⁵ so preconception diabetes assessment needs to be part of routine medical care for all reproductive-age women. Because most organogenesis occurs during the first 5 to 8 weeks after fertilization—potentially before a woman realizes she is pregnant—achieving optimal glycemic control before conception is necessary to improve pregnancy outcomes.¹

EVERY VISIT IS AN OPPORTUNITY

Every medical visit with a reproductive-age woman with diabetes is an opportunity for counseling about pregnancy. Topics that need to be discussed include the risks of unplanned pregnancy and of poor metabolic control, and the benefits of improved maternal and fetal outcomes with appropriate pregnancy planning and diabetes management.

Referral to a registered dietitian for individualized counseling about proper nutrition, particularly during pregnancy, has been associated with positive outcomes.¹⁶ Patients with diabetes and at high risk of pregnancy complications should be referred to a clinic that specializes in high-risk pregnancies.

Practitioners also should emphasize the importance of regular exercise and encourage patients to maintain or achieve a medically optimal weight before conception. Ideally, this would be a normal body mass index; however, this is not always possible.

In women who are planning pregnancy or are not on effective contraception, medications should be reviewed for potential teratogenicity. If needed, discuss alternative medications or switch to safer ones. However, these changes should not interrupt diabetes treatment.

In addition, ensure that the patient is up to date on age- and disease-appropriate preventive care (eg, immunizations, screening for sexually transmitted disease and malignancy). Counseling and intervention for use of tobacco, alcohol, and recreational drugs are also important. As with any preconception counseling, the patient (and her partner, if possible) should be advised to avoid travel to areas where Zika virus is endemic, and informed about the availability of expanded carrier genetic screening through her obstetric provider.

Finally, pregnant women with diabetes benefit from screening for diabetic complications including hypertension, retinopathy, cardiovascular disease, neuropathy, and nephropathy.

ASSESSING RISKS

Blood pressure

Chronic (preexisting) hypertension is defined as a systolic pressure 140 mm Hg or higher or a diastolic pressure 90 mm Hg or higher, or both, that antedates pregnancy or is present before the 20th week of pregnancy.³ Chronic hypertension has been reported in up to 5% of pregnant women and is associated with increased risk of preterm delivery, superimposed preeclampsia, low birth weight, and perinatal death.³

Reproductive-age women with diabetes and high blood pressure benefit from lifestyle and behavioral modifications.¹⁷ If drug therapy is needed, antihypertensive drugs that are safe for the fetus should be used. Treatment of mild or moderate hypertension during pregnancy reduces the risk of progression to severe hypertension but may not improve obstetric outcomes.

Diabetic retinopathy

Diabetic retinopathy can significantly worsen during pregnancy: the risk of progression is double that in the nonpregnant state.¹⁸ Women with diabetes who are contemplating pregnancy should have a comprehensive eye examination before conception, and any active proliferative retinopathy needs to be treated. These patients may require ophthalmologic monitoring and treatment during pregnancy. (Note: laser photocoagulation is not contraindicated during pregnancy.)

Cardiovascular disease

Cardiovascular physiology changes dramatically during pregnancy. Cardiovascular disease, especially when superimposed on diabetes, can increase the risk of maternal death. Thus, evaluation for cardiovascular risk factors as well as cardiovascular system integrity before conception is important. Listen for arterial bruits and murmurs, and assess peripheral pulses. Consideration should be given to obtaining a preconception resting electrocardiogram in women with diabetes who are over age 35 or who are suspected of having cardiovascular disease.¹⁶

Neurologic disorders

Peripheral neuropathy, the most common neurologic complication of diabetes, is associated with injury and infection.¹⁹

Autonomic neuropathy is associated with decreased cardiac responsiveness and orthostatic hypotension.¹⁹ Diabetic gastroparesis alone can precipitate serious complications during pregnancy, including extreme hypoglycemia and hyperglycemia, increased risk of diabetic ketoacidosis, weight loss, malnutrition, frequent hospitalizations, and increased requirement for parenteral nutrition.²⁰

Although diabetic neuropathy does not significantly worsen during pregnancy, women with preexisting gastroparesis should be counseled on the substantial risks associated with pregnancy. Screening for neuropathy should be part of all diabetic preconception examinations.

Renal complications

Pregnancy in women with diabetes and preexisting renal dysfunction increases their risk of accelerated progression of diabetic kidney disease.²¹ Preexisting renal dysfunction also increases the risk of pregnancy-related complications, such as stillbirth, intrauterine growth restriction, gestational hypertension, preeclampsia, and preterm delivery.^19,21,22 Further, the risk of pregnancy complications correlates directly with the severity of renal dysfunction.²²

Psychiatric disorders

Emotional wellness is essential for optimal diabetes management. It is important to recognize the emotional impact of diabetes in pregnant women and to conduct routine screening for depression, anxiety, stress, and eating disorders.¹⁶

Hemoglobin A_1c. The general consensus is to achieve the lowest hemoglobin A_1c level possible that does not increase the risk of hypoglycemia. The American Diabetes Association (ADA) recommends that, before attempting to conceive, women should lower their hemoglobin A_1c to below 6.5%.¹

Thyroid measures. Autoimmune thyroid disease is the most common autoimmune disorder associated with diabetes and has been reported in 35% to 40% of women with type 1 diabetes.²³ Recommendations are to check thyroid-stimulating hormone and thyroid peroxidase antibody levels before conception or early in pregnancy in all women with diabetes.^1,24 Overt hypothyroidism should be treated before conception, given that early fetal brain development depends on maternal thyroxine.

Renal function testing. Preconception assessment of renal function is important for counseling and risk stratification. This assessment should include serum creatinine level, estimated glomerular filtration rate, and urinary albumin excretion.²¹

Celiac screening. Because women with type 1 diabetes are more susceptible to autoimmune diseases, they should be screened for celiac disease before conception, with testing for  immunoglobulin A (IgA) and tissue transglutaminase antibodies, with or without IgA endomysial antibodies.^16,25,26 An estimated 6% of patients with type 1 diabetes have celiac disease vs 1% of the general population.²⁵ Celiac disease is 2 to 3 times more common in women, and asymptomatic people with type 1 diabetes are considered at increased risk for celiac disease.²⁶

The association between type 1 diabetes and celiac disease most likely relates to the overlap in human leukocyte antigens of the diseases. There is no established link between type 2 diabetes and celiac disease.²⁵

Undiagnosed celiac disease increases a woman’s risk of obstetric complications such as preterm birth, low birth weight, and stillbirth.²⁶ The most likely explanation for these adverse effects is nutrient malabsorption, which is characteristic of celiac disease. Adherence to a gluten-free diet before and during gestation may reduce the risk of preterm delivery by as much as 20%.²⁶

Vitamin B₁₂ level. Celiac disease interferes with the absorption of vitamin B₁₂-instrinsic factor in the ileum, which can lead to vitamin B₁₂ deficiency. Therefore, baseline vitamin B₁₂ levels should be checked before conception in women with celiac disease. Levels should also be checked in women taking metformin, which also decreases vitamin B₁₂ absorption. Of note, increased folate levels due to taking supplements can potentially mask vitamin B₁₂ deficiency.

MEDICATIONS TO REVIEW FOR PREGNANCY INTERACTIONS

Diabetic medications

Insulin is the first-line pharmacotherapy for pregnant patients with type 1, type 2, or gestational diabetes. Insulin does not cross the placenta to a measurable extent, and most insulin preparations have been classified as category B,¹ meaning no risks to the fetus have been found in humans.

Insulin dosing during pregnancy is not static. Beginning around mid-gestation, insulin requirements increase,^28,29 but after 32 weeks the need may decrease. These changes require practitioners to closely monitor blood glucose throughout pregnancy.

Both basal-bolus injections and continuous subcutaneous infusion are reasonable options during pregnancy.³⁰ However, the need for multiple and potentially painful insulin injections daily can lead to poor compliance. This inconvenience has led to studies using oral hypoglycemic medications instead of insulin for patients with gestational and type 2 diabetes.

Metformin is an oral biguanide that decreases hepatic gluconeogenesis and intestinal glucose absorption while peripherally increasing glucose utilization and uptake. Metformin does not pose a risk of hypoglycemia because its mechanism of action does not involve increased insulin production.⁷

Metformin does cross the placenta, resulting in umbilical cord blood levels higher than maternal levels. Nevertheless, studies support the efficacy and short-term safety of metformin use during a pregnancy complicated by gestational or type 2 diabetes.^7,31 Moreover, metformin has been associated with a lower risk of neonatal hypoglycemia and maternal weight gain than insulin.³² However, this agent should be used with caution, as long-term data are not yet available, and it may slightly increase the risk of premature delivery.

Glyburide is another oral hypoglycemic medication that has been used during pregnancy. This second-generation sulfonylurea enhances the release of insulin from the pancreas by binding beta islet cell ATP-calcium channel receptors. Compared with other sulfonylureas, glyburide has the lowest rate of maternal-to-fetal transfer, with umbilical cord plasma concentrations 70% of maternal levels.³³ Although some trials support the efficacy and short-term safety of glyburide treatment for gestational diabetes,³⁴ recent studies have associated glyburide use during pregnancy with a higher rate of neonatal hypoglycemia, neonatal respiratory distress, macrosomia, and neonatal intensive care unit admissions than insulin and metformin.^1,35

Patients treated with oral agents should be informed that these drugs cross the placenta, and that although no adverse effects on the fetus have been demonstrated, long-term safety data are lacking. In addition, oral agents are ineffective in type 1 diabetes and may be insufficient to overcome the insulin resistance in type 2 diabetes.

Antihypertensive drugs

All antihypertensive drugs cross the placenta, but several have an acceptable safety profile in pregnancy, including methyldopa, labeta­lol, clonidine, prazosin, and nifedipine. Hydralazine and labetalol are short-acting, come in intravenous formulations, and can be used for urgent blood pressure control during pregnancy. Diltiazem may be used for heart rate control during pregnancy, and it has been shown to lower blood pressure and proteinuria in pregnant patients with underlying renal disease.^36,37 The ADA recommends against chronic use of diuretics during pregnancy because of potential reductions in maternal plasma volume and uteroplacental perfusion.¹

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and direct renin inhibitors are contraindicated during pregnancy because of the risk of fetal defects, particularly in the renal system.^21,38 Although there is evidence to question the association between first semester exposure and fetotoxicity,³⁹ we avoid these drugs during pregnancy and switch to a different agent in women planning pregnancy.

Other drugs

Statins are contraindicated in pregnancy because they interfere with the development of the fetal nervous system.²¹ Although preliminary data from a small study did not identify safety risks associated with pravastatin use after 12 weeks of gestation,⁴⁰ we recommend discontinuing statins in women attempting pregnancy.

Aspirin. The US Preventive Services Task Force41 recommends low-dose aspirin (81 mg/day) after 12 weeks of gestation for women with type 1 or type 2 diabetes, as well as those with renal disease or chronic hypertension, to prevent preeclampsia. Of note, higher doses need to be used with caution during pregnancy because fetal abnormalities have been reported, such as disruption of fetal vasculature (mesenteric vessels), gastroschisis, and small intestinal atresia.¹⁶

Folate supplementation (0.6–4 mg/day) is recommended in women with celiac disease to prevent neural tube defects in the offspring, and the US Preventive Services Task Force recommends 0.4 mg daily of folic acid supplementation for all women planning or capable of pregnancy.^42–44 Higher doses, ranging from 0.6 to 5 mg/day, have been proposed for patients with diabetes,¹³ and we recommend at least 1 mg for this group, based on data suggesting that higher doses further reduce the risk of neural tube defects.⁴³

Maternal diabetes, insulin therapy, and oral hypoglycemic agents are not contraindications to breastfeeding. The US Preventive Services Task Force recommends interventions by primary care physicians to promote and support breastfeeding.⁴⁵ Breastfeeding is encouraged based on various short- and long-term health benefits for both breastfed infants and breastfeeding mothers. Breastfeeding decreases a woman’s insulin requirements and increases the risk for hypoglycemia, especially in patients with insulin-dependent type 1 diabetes.¹

Additionally, insulin sensitivity increases immediately following delivery of the placenta.¹ Therefore, it is prudent to adjust insulin doses postpartum, especially while a patient is breastfeeding, or to suggest high-carbohydrate snacks before feeds.^9,29

Antihypertensive drugs considered safe to use during lactation include captopril, enalapril, quinapril, labetalol, propranolol, nifedipine, and hydralazine.^21,46 Methyldopa is not contraindicated, but it causes fatigue and worsened postpartum depression and should not be used as first-line therapy. Diuretics and ARBs are not recommended during lactation.²¹ Both metformin and glyburide enter breast milk in small enough amounts that they are not contraindicated during breastfeeding.¹⁶ The Lactmed database (www.toxnet.nlm.nih.gov) provides information about drugs and breastfeeding.

WHAT ABOUT CONTRACEPTIVES?

The ADA recommends contraception for women with diabetes because, just as in women without diabetes, the risks of unplanned pregnancy outweigh those of contraceptives.¹

We recommend low-dose combination estrogen-progestin oral contraceptives to normotensive women under age 35 with diabetes but without underlying microvascular disease. For women over age 35 or for those with microvascular disease, additional options include intrauterine devices or progestin implants. We prefer not to use injectable depot medroxyprogesterone acetate because of its side effects of insulin resistance and weight gain.⁴⁷

CASE DISCUSSION: NEXT STEPS

Our patient’s interest in family planning presents an opportunity for preconception counseling. We recommend a prenatal folic acid supplement, diet and regular exercise for weight loss, and screening tests including a comprehensive metabolic panel, hemoglobin A_1c, thyroid-stimulating hormone, and dilated eye examination. We make sure she is up to date on her indicated health maintenance (eg, immunizations, disease screening), and we review her medications for potential teratogens. She denies any recreational drug use. Also, she has no plans for long-distance travel.

Our counseling includes discussions of pregnancy risks associated with pregestational diabetes and suboptimal glycemic control. We encourage her to use effective contraception until she is “medically optimized” for pregnancy—ie, until her hemoglobin A_1c is lower than 6.5% and she has achieved a medically optimal weight. If feasible, a reduction of weight (7% or so) through lifestyle modification should be attempted, and if her hemoglobin A_1c remains elevated, adding insulin would be recommended.

Pregnant patients or patients contemplating pregnancy are usually motivated to modify their behavior, making this a good time to reinforce lifestyle modifications. Many patients benefit from individualized counseling by a registered dietitian to help achieve the recommended weight and glycemic control.

Our physical examination in this patient includes screening for micro- and macrovascular complications of diabetes, and the test results are negative. Patients with active proliferative retinopathy should be referred to an ophthalmologist for assessment and treatment.

We review her medications for potential teratogenic effects and stop her ACE inhibitor (lisinopril) and statin (simvastatin). We switch her from a first-generation sulfonylurea (chlorpropamide) to glyburide, a second-generation sulfonylurea. Second-generation sulfonylureas are considered more “fetus-friendly” because first-generation sulfonylureas cross the placenta more easily and can cause fetal hyperinsulinemia, leading to macrosomia and neonatal hypoglycemia.⁷

The management of diabetes during pregnancy leans toward insulin use, given the lack of information regarding long-term outcomes with oral agents. If insulin is needed, it is best to initiate it before the patient conceives, and then to stop other diabetes medications. We would not make any changes to her aspirin or metformin use.

Educating the patient and her family about prevention, recognition, and treatment of hypoglycemia is important to prevent and manage the increased risk of hypoglycemia with insulin therapy and in early pregnancy.¹ Consideration should be given to providing ketone strips as well as education on diabetic ketoacidosis prevention and detection.¹ If the patient conceives, begin prenatal care early to allow adequate planning for care of her disease and evaluation of the fetus. Because of the complexity of insulin management in pregnancy, the ADA recommends referral, if possible, to a center offering team-based care, including an obstetrician specialized in high-risk pregnancies, an endocrinologist, and a dietitian.¹

A 29-year-old nulliparous woman presents for a routine checkup. She has hypertension and type 2 diabetes mellitus. Her current medications are chlorpropamide 500 mg daily, metformin 500 mg twice a day, lisinopril 40 mg daily, simvastatin 40 mg daily, and aspirin 81 mg daily. Her body mass index is 37 kg/m² and her blood pressure is 130/80 mm Hg. Her hemoglobin A_1c level is 7.8% and her low-density lipoprotein cholesterol 90 mg/dL.

She is considering pregnancy. How would you counsel her?

DEFINING DIABETES IN PREGNANCY

Diabetes in pregnant women, both gestational and pregestational, is the most common medical complication associated with pregnancy.¹

• Gestational diabetes is defined as diabetes that is diagnosed during the second or third trimester of pregnancy and that is not clearly pregestational.²
• Pregestational diabetes exists before pregnancy and can be either type 1 or type 2.

Most cases of diabetes diagnosed during the first trimester reflect pregestational diabetes, as gestational diabetes occurs when insulin resistance increases in the later trimesters.

Type 1 diabetes involves autoimmune destruction of pancreatic islet cells, leading to insulin deficiency and the need for insulin therapy. Type 2 diabetes is characterized by insulin resistance rather than overall insulin deficiency. Type 2 diabetes tends to be associated with comorbidities such as obesity and hypertension, which are independent risk factors for adverse perinatal outcomes.^3,4

Gestational diabetes accounts for most cases of diabetes during pregnancy. Although both pregestational and gestational diabetes increase the risk of maternal and fetal complications, pregestational diabetes is associated with significantly greater risks.¹

IMPACT OF DIABETES ON THE MOTHER

Pregnancy increases the risk of maternal hypoglycemia, especially during the first trimester in patients with type 1 diabetes, as insulin sensitivity increases in early pregnancy.¹ Pregnant women with diabetes may also have an altered counterregulatory response and less hypoglycemic awareness.¹ Insulin resistance rises during the second and early third trimesters, increasing the risk of hyperglycemia in women with diabetes.¹

Glycemic control during pregnancy is usually easier to achieve in patients with type 2 diabetes than with type 1, but it may require much higher insulin doses.

Because pregnancy is inherently a ketogenic state, women with type 1 diabetes are at higher risk of diabetic ketoacidosis, particularly during the second and third trimesters.¹ There are reports of euglycemic diabetic ketoacidosis in pregnant women with either gestational or pregestational diabetes.⁵

Diabetes is associated with a risk of preeclampsia 4 times higher than in nondiabetic women.⁶ Other potential pregnancy-related complications include infections, polyhydram­nios, spontaneous abortion, and cesarean delivery.^1,7 The risk of pregnancy loss is similar in women with either type 1 or type 2 diabetes (2.6% and 3.7%, respectively), but the causes are different.⁸ Although preexisting diabetic complications such as retinopathy, nephropathy, and gastroparesis can be exacerbated during pregnancy,¹ only severe gastroparesis and advanced renal disease are considered relative contraindications to pregnancy.

IMPACT OF DIABETES ON THE FETUS

Fetal complications of maternal diabetes include embryopathy (fetal malformations) and fetopathy (overgrowth, ie, fetus large for gestational age, and increased risk of fetal death or distress). Maternal hyperglycemia is associated with diabetic embryopathy, resulting in major birth defects in 5% to 25% of pregnancies and spontaneous abortions in 15% to 20%.^9,10 There is a 2- to 6-fold increase in risk of congenital malformations.6

The most common diabetes-associated congenital malformations affect the cardiovascular system. Congenital heart disease includes tetralogy of Fallot, transposition of the great vessels, septal defects, and anomalous pulmonary venous return. Other relatively common defects involve the fetal central nervous system, spine, orofacial system, kidneys, urogenital system, gastrointestinal tract, and skeleton.¹¹

The risk of fetopathy is proportional to the degree of maternal hyperglycemia. Excess maternal glucose and fatty acid levels can lead to fetal hyperglycemia and overgrowth, which increases fetal oxygen requirements. Erythro­poietin levels rise, causing an increase in red cell mass, with subsequent hyperviscosity within the placenta and higher risk of fetal death.

Other complications include intrauterine growth restriction, prematurity, and preterm delivery. Fetal macrosomia (birth weight > 90th percentile or 4 kg, approximately 8 lb, 13 oz) occurs in 27% to 62% of children born to mothers with diabetes, a rate 10 times higher than in patients without diabetes. It contributes to shoulder dystocia (risk 2 to 4 times higher in diabetic pregnancies) and cesarean delivery.⁶ Infants born to mothers with diabetes also have higher risks of neonatal hypoglycemia, erythrocytosis, hyperbilirubinemia, hypocalcemia, respiratory distress, cardiomyopathy, and death, as well as for developing diabetes, obesity, and other adverse cardiometabolic outcomes later in life.¹¹

Nearly half of pregnancies in the general population are unplanned,¹⁵ so preconception diabetes assessment needs to be part of routine medical care for all reproductive-age women. Because most organogenesis occurs during the first 5 to 8 weeks after fertilization—potentially before a woman realizes she is pregnant—achieving optimal glycemic control before conception is necessary to improve pregnancy outcomes.¹

EVERY VISIT IS AN OPPORTUNITY

Every medical visit with a reproductive-age woman with diabetes is an opportunity for counseling about pregnancy. Topics that need to be discussed include the risks of unplanned pregnancy and of poor metabolic control, and the benefits of improved maternal and fetal outcomes with appropriate pregnancy planning and diabetes management.

Referral to a registered dietitian for individualized counseling about proper nutrition, particularly during pregnancy, has been associated with positive outcomes.¹⁶ Patients with diabetes and at high risk of pregnancy complications should be referred to a clinic that specializes in high-risk pregnancies.

Practitioners also should emphasize the importance of regular exercise and encourage patients to maintain or achieve a medically optimal weight before conception. Ideally, this would be a normal body mass index; however, this is not always possible.

In women who are planning pregnancy or are not on effective contraception, medications should be reviewed for potential teratogenicity. If needed, discuss alternative medications or switch to safer ones. However, these changes should not interrupt diabetes treatment.

In addition, ensure that the patient is up to date on age- and disease-appropriate preventive care (eg, immunizations, screening for sexually transmitted disease and malignancy). Counseling and intervention for use of tobacco, alcohol, and recreational drugs are also important. As with any preconception counseling, the patient (and her partner, if possible) should be advised to avoid travel to areas where Zika virus is endemic, and informed about the availability of expanded carrier genetic screening through her obstetric provider.

Finally, pregnant women with diabetes benefit from screening for diabetic complications including hypertension, retinopathy, cardiovascular disease, neuropathy, and nephropathy.

ASSESSING RISKS

Blood pressure

Chronic (preexisting) hypertension is defined as a systolic pressure 140 mm Hg or higher or a diastolic pressure 90 mm Hg or higher, or both, that antedates pregnancy or is present before the 20th week of pregnancy.³ Chronic hypertension has been reported in up to 5% of pregnant women and is associated with increased risk of preterm delivery, superimposed preeclampsia, low birth weight, and perinatal death.³

Reproductive-age women with diabetes and high blood pressure benefit from lifestyle and behavioral modifications.¹⁷ If drug therapy is needed, antihypertensive drugs that are safe for the fetus should be used. Treatment of mild or moderate hypertension during pregnancy reduces the risk of progression to severe hypertension but may not improve obstetric outcomes.

Diabetic retinopathy

Diabetic retinopathy can significantly worsen during pregnancy: the risk of progression is double that in the nonpregnant state.¹⁸ Women with diabetes who are contemplating pregnancy should have a comprehensive eye examination before conception, and any active proliferative retinopathy needs to be treated. These patients may require ophthalmologic monitoring and treatment during pregnancy. (Note: laser photocoagulation is not contraindicated during pregnancy.)

Cardiovascular disease

Cardiovascular physiology changes dramatically during pregnancy. Cardiovascular disease, especially when superimposed on diabetes, can increase the risk of maternal death. Thus, evaluation for cardiovascular risk factors as well as cardiovascular system integrity before conception is important. Listen for arterial bruits and murmurs, and assess peripheral pulses. Consideration should be given to obtaining a preconception resting electrocardiogram in women with diabetes who are over age 35 or who are suspected of having cardiovascular disease.¹⁶

Neurologic disorders

Peripheral neuropathy, the most common neurologic complication of diabetes, is associated with injury and infection.¹⁹

Autonomic neuropathy is associated with decreased cardiac responsiveness and orthostatic hypotension.¹⁹ Diabetic gastroparesis alone can precipitate serious complications during pregnancy, including extreme hypoglycemia and hyperglycemia, increased risk of diabetic ketoacidosis, weight loss, malnutrition, frequent hospitalizations, and increased requirement for parenteral nutrition.²⁰

Although diabetic neuropathy does not significantly worsen during pregnancy, women with preexisting gastroparesis should be counseled on the substantial risks associated with pregnancy. Screening for neuropathy should be part of all diabetic preconception examinations.

Renal complications

Pregnancy in women with diabetes and preexisting renal dysfunction increases their risk of accelerated progression of diabetic kidney disease.²¹ Preexisting renal dysfunction also increases the risk of pregnancy-related complications, such as stillbirth, intrauterine growth restriction, gestational hypertension, preeclampsia, and preterm delivery.^19,21,22 Further, the risk of pregnancy complications correlates directly with the severity of renal dysfunction.²²

Psychiatric disorders

Emotional wellness is essential for optimal diabetes management. It is important to recognize the emotional impact of diabetes in pregnant women and to conduct routine screening for depression, anxiety, stress, and eating disorders.¹⁶

Hemoglobin A_1c. The general consensus is to achieve the lowest hemoglobin A_1c level possible that does not increase the risk of hypoglycemia. The American Diabetes Association (ADA) recommends that, before attempting to conceive, women should lower their hemoglobin A_1c to below 6.5%.¹

Thyroid measures. Autoimmune thyroid disease is the most common autoimmune disorder associated with diabetes and has been reported in 35% to 40% of women with type 1 diabetes.²³ Recommendations are to check thyroid-stimulating hormone and thyroid peroxidase antibody levels before conception or early in pregnancy in all women with diabetes.^1,24 Overt hypothyroidism should be treated before conception, given that early fetal brain development depends on maternal thyroxine.

Renal function testing. Preconception assessment of renal function is important for counseling and risk stratification. This assessment should include serum creatinine level, estimated glomerular filtration rate, and urinary albumin excretion.²¹

Celiac screening. Because women with type 1 diabetes are more susceptible to autoimmune diseases, they should be screened for celiac disease before conception, with testing for  immunoglobulin A (IgA) and tissue transglutaminase antibodies, with or without IgA endomysial antibodies.^16,25,26 An estimated 6% of patients with type 1 diabetes have celiac disease vs 1% of the general population.²⁵ Celiac disease is 2 to 3 times more common in women, and asymptomatic people with type 1 diabetes are considered at increased risk for celiac disease.²⁶

The association between type 1 diabetes and celiac disease most likely relates to the overlap in human leukocyte antigens of the diseases. There is no established link between type 2 diabetes and celiac disease.²⁵

Undiagnosed celiac disease increases a woman’s risk of obstetric complications such as preterm birth, low birth weight, and stillbirth.²⁶ The most likely explanation for these adverse effects is nutrient malabsorption, which is characteristic of celiac disease. Adherence to a gluten-free diet before and during gestation may reduce the risk of preterm delivery by as much as 20%.²⁶

Vitamin B₁₂ level. Celiac disease interferes with the absorption of vitamin B₁₂-instrinsic factor in the ileum, which can lead to vitamin B₁₂ deficiency. Therefore, baseline vitamin B₁₂ levels should be checked before conception in women with celiac disease. Levels should also be checked in women taking metformin, which also decreases vitamin B₁₂ absorption. Of note, increased folate levels due to taking supplements can potentially mask vitamin B₁₂ deficiency.

MEDICATIONS TO REVIEW FOR PREGNANCY INTERACTIONS

Diabetic medications

Insulin is the first-line pharmacotherapy for pregnant patients with type 1, type 2, or gestational diabetes. Insulin does not cross the placenta to a measurable extent, and most insulin preparations have been classified as category B,¹ meaning no risks to the fetus have been found in humans.

Insulin dosing during pregnancy is not static. Beginning around mid-gestation, insulin requirements increase,^28,29 but after 32 weeks the need may decrease. These changes require practitioners to closely monitor blood glucose throughout pregnancy.

Both basal-bolus injections and continuous subcutaneous infusion are reasonable options during pregnancy.³⁰ However, the need for multiple and potentially painful insulin injections daily can lead to poor compliance. This inconvenience has led to studies using oral hypoglycemic medications instead of insulin for patients with gestational and type 2 diabetes.

Metformin is an oral biguanide that decreases hepatic gluconeogenesis and intestinal glucose absorption while peripherally increasing glucose utilization and uptake. Metformin does not pose a risk of hypoglycemia because its mechanism of action does not involve increased insulin production.⁷

Metformin does cross the placenta, resulting in umbilical cord blood levels higher than maternal levels. Nevertheless, studies support the efficacy and short-term safety of metformin use during a pregnancy complicated by gestational or type 2 diabetes.^7,31 Moreover, metformin has been associated with a lower risk of neonatal hypoglycemia and maternal weight gain than insulin.³² However, this agent should be used with caution, as long-term data are not yet available, and it may slightly increase the risk of premature delivery.

Glyburide is another oral hypoglycemic medication that has been used during pregnancy. This second-generation sulfonylurea enhances the release of insulin from the pancreas by binding beta islet cell ATP-calcium channel receptors. Compared with other sulfonylureas, glyburide has the lowest rate of maternal-to-fetal transfer, with umbilical cord plasma concentrations 70% of maternal levels.³³ Although some trials support the efficacy and short-term safety of glyburide treatment for gestational diabetes,³⁴ recent studies have associated glyburide use during pregnancy with a higher rate of neonatal hypoglycemia, neonatal respiratory distress, macrosomia, and neonatal intensive care unit admissions than insulin and metformin.^1,35

Patients treated with oral agents should be informed that these drugs cross the placenta, and that although no adverse effects on the fetus have been demonstrated, long-term safety data are lacking. In addition, oral agents are ineffective in type 1 diabetes and may be insufficient to overcome the insulin resistance in type 2 diabetes.

Antihypertensive drugs

All antihypertensive drugs cross the placenta, but several have an acceptable safety profile in pregnancy, including methyldopa, labeta­lol, clonidine, prazosin, and nifedipine. Hydralazine and labetalol are short-acting, come in intravenous formulations, and can be used for urgent blood pressure control during pregnancy. Diltiazem may be used for heart rate control during pregnancy, and it has been shown to lower blood pressure and proteinuria in pregnant patients with underlying renal disease.^36,37 The ADA recommends against chronic use of diuretics during pregnancy because of potential reductions in maternal plasma volume and uteroplacental perfusion.¹

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and direct renin inhibitors are contraindicated during pregnancy because of the risk of fetal defects, particularly in the renal system.^21,38 Although there is evidence to question the association between first semester exposure and fetotoxicity,³⁹ we avoid these drugs during pregnancy and switch to a different agent in women planning pregnancy.

Other drugs

Statins are contraindicated in pregnancy because they interfere with the development of the fetal nervous system.²¹ Although preliminary data from a small study did not identify safety risks associated with pravastatin use after 12 weeks of gestation,⁴⁰ we recommend discontinuing statins in women attempting pregnancy.

Aspirin. The US Preventive Services Task Force41 recommends low-dose aspirin (81 mg/day) after 12 weeks of gestation for women with type 1 or type 2 diabetes, as well as those with renal disease or chronic hypertension, to prevent preeclampsia. Of note, higher doses need to be used with caution during pregnancy because fetal abnormalities have been reported, such as disruption of fetal vasculature (mesenteric vessels), gastroschisis, and small intestinal atresia.¹⁶

Folate supplementation (0.6–4 mg/day) is recommended in women with celiac disease to prevent neural tube defects in the offspring, and the US Preventive Services Task Force recommends 0.4 mg daily of folic acid supplementation for all women planning or capable of pregnancy.^42–44 Higher doses, ranging from 0.6 to 5 mg/day, have been proposed for patients with diabetes,¹³ and we recommend at least 1 mg for this group, based on data suggesting that higher doses further reduce the risk of neural tube defects.⁴³

Maternal diabetes, insulin therapy, and oral hypoglycemic agents are not contraindications to breastfeeding. The US Preventive Services Task Force recommends interventions by primary care physicians to promote and support breastfeeding.⁴⁵ Breastfeeding is encouraged based on various short- and long-term health benefits for both breastfed infants and breastfeeding mothers. Breastfeeding decreases a woman’s insulin requirements and increases the risk for hypoglycemia, especially in patients with insulin-dependent type 1 diabetes.¹

Additionally, insulin sensitivity increases immediately following delivery of the placenta.¹ Therefore, it is prudent to adjust insulin doses postpartum, especially while a patient is breastfeeding, or to suggest high-carbohydrate snacks before feeds.^9,29

Antihypertensive drugs considered safe to use during lactation include captopril, enalapril, quinapril, labetalol, propranolol, nifedipine, and hydralazine.^21,46 Methyldopa is not contraindicated, but it causes fatigue and worsened postpartum depression and should not be used as first-line therapy. Diuretics and ARBs are not recommended during lactation.²¹ Both metformin and glyburide enter breast milk in small enough amounts that they are not contraindicated during breastfeeding.¹⁶ The Lactmed database (www.toxnet.nlm.nih.gov) provides information about drugs and breastfeeding.

WHAT ABOUT CONTRACEPTIVES?

The ADA recommends contraception for women with diabetes because, just as in women without diabetes, the risks of unplanned pregnancy outweigh those of contraceptives.¹

We recommend low-dose combination estrogen-progestin oral contraceptives to normotensive women under age 35 with diabetes but without underlying microvascular disease. For women over age 35 or for those with microvascular disease, additional options include intrauterine devices or progestin implants. We prefer not to use injectable depot medroxyprogesterone acetate because of its side effects of insulin resistance and weight gain.⁴⁷

CASE DISCUSSION: NEXT STEPS

Our patient’s interest in family planning presents an opportunity for preconception counseling. We recommend a prenatal folic acid supplement, diet and regular exercise for weight loss, and screening tests including a comprehensive metabolic panel, hemoglobin A_1c, thyroid-stimulating hormone, and dilated eye examination. We make sure she is up to date on her indicated health maintenance (eg, immunizations, disease screening), and we review her medications for potential teratogens. She denies any recreational drug use. Also, she has no plans for long-distance travel.

Our counseling includes discussions of pregnancy risks associated with pregestational diabetes and suboptimal glycemic control. We encourage her to use effective contraception until she is “medically optimized” for pregnancy—ie, until her hemoglobin A_1c is lower than 6.5% and she has achieved a medically optimal weight. If feasible, a reduction of weight (7% or so) through lifestyle modification should be attempted, and if her hemoglobin A_1c remains elevated, adding insulin would be recommended.

Pregnant patients or patients contemplating pregnancy are usually motivated to modify their behavior, making this a good time to reinforce lifestyle modifications. Many patients benefit from individualized counseling by a registered dietitian to help achieve the recommended weight and glycemic control.

Our physical examination in this patient includes screening for micro- and macrovascular complications of diabetes, and the test results are negative. Patients with active proliferative retinopathy should be referred to an ophthalmologist for assessment and treatment.

We review her medications for potential teratogenic effects and stop her ACE inhibitor (lisinopril) and statin (simvastatin). We switch her from a first-generation sulfonylurea (chlorpropamide) to glyburide, a second-generation sulfonylurea. Second-generation sulfonylureas are considered more “fetus-friendly” because first-generation sulfonylureas cross the placenta more easily and can cause fetal hyperinsulinemia, leading to macrosomia and neonatal hypoglycemia.⁷

The management of diabetes during pregnancy leans toward insulin use, given the lack of information regarding long-term outcomes with oral agents. If insulin is needed, it is best to initiate it before the patient conceives, and then to stop other diabetes medications. We would not make any changes to her aspirin or metformin use.

Educating the patient and her family about prevention, recognition, and treatment of hypoglycemia is important to prevent and manage the increased risk of hypoglycemia with insulin therapy and in early pregnancy.¹ Consideration should be given to providing ketone strips as well as education on diabetic ketoacidosis prevention and detection.¹ If the patient conceives, begin prenatal care early to allow adequate planning for care of her disease and evaluation of the fetus. Because of the complexity of insulin management in pregnancy, the ADA recommends referral, if possible, to a center offering team-based care, including an obstetrician specialized in high-risk pregnancies, an endocrinologist, and a dietitian.¹

A 29-year-old nulliparous woman presents for a routine checkup. She has hypertension and type 2 diabetes mellitus. Her current medications are chlorpropamide 500 mg daily, metformin 500 mg twice a day, lisinopril 40 mg daily, simvastatin 40 mg daily, and aspirin 81 mg daily. Her body mass index is 37 kg/m² and her blood pressure is 130/80 mm Hg. Her hemoglobin A_1c level is 7.8% and her low-density lipoprotein cholesterol 90 mg/dL.

She is considering pregnancy. How would you counsel her?

DEFINING DIABETES IN PREGNANCY

Diabetes in pregnant women, both gestational and pregestational, is the most common medical complication associated with pregnancy.¹

• Gestational diabetes is defined as diabetes that is diagnosed during the second or third trimester of pregnancy and that is not clearly pregestational.²
• Pregestational diabetes exists before pregnancy and can be either type 1 or type 2.

Most cases of diabetes diagnosed during the first trimester reflect pregestational diabetes, as gestational diabetes occurs when insulin resistance increases in the later trimesters.

Type 1 diabetes involves autoimmune destruction of pancreatic islet cells, leading to insulin deficiency and the need for insulin therapy. Type 2 diabetes is characterized by insulin resistance rather than overall insulin deficiency. Type 2 diabetes tends to be associated with comorbidities such as obesity and hypertension, which are independent risk factors for adverse perinatal outcomes.^3,4

Gestational diabetes accounts for most cases of diabetes during pregnancy. Although both pregestational and gestational diabetes increase the risk of maternal and fetal complications, pregestational diabetes is associated with significantly greater risks.¹

IMPACT OF DIABETES ON THE MOTHER

Pregnancy increases the risk of maternal hypoglycemia, especially during the first trimester in patients with type 1 diabetes, as insulin sensitivity increases in early pregnancy.¹ Pregnant women with diabetes may also have an altered counterregulatory response and less hypoglycemic awareness.¹ Insulin resistance rises during the second and early third trimesters, increasing the risk of hyperglycemia in women with diabetes.¹

Glycemic control during pregnancy is usually easier to achieve in patients with type 2 diabetes than with type 1, but it may require much higher insulin doses.

Because pregnancy is inherently a ketogenic state, women with type 1 diabetes are at higher risk of diabetic ketoacidosis, particularly during the second and third trimesters.¹ There are reports of euglycemic diabetic ketoacidosis in pregnant women with either gestational or pregestational diabetes.⁵

Diabetes is associated with a risk of preeclampsia 4 times higher than in nondiabetic women.⁶ Other potential pregnancy-related complications include infections, polyhydram­nios, spontaneous abortion, and cesarean delivery.^1,7 The risk of pregnancy loss is similar in women with either type 1 or type 2 diabetes (2.6% and 3.7%, respectively), but the causes are different.⁸ Although preexisting diabetic complications such as retinopathy, nephropathy, and gastroparesis can be exacerbated during pregnancy,¹ only severe gastroparesis and advanced renal disease are considered relative contraindications to pregnancy.

IMPACT OF DIABETES ON THE FETUS

Fetal complications of maternal diabetes include embryopathy (fetal malformations) and fetopathy (overgrowth, ie, fetus large for gestational age, and increased risk of fetal death or distress). Maternal hyperglycemia is associated with diabetic embryopathy, resulting in major birth defects in 5% to 25% of pregnancies and spontaneous abortions in 15% to 20%.^9,10 There is a 2- to 6-fold increase in risk of congenital malformations.6

The most common diabetes-associated congenital malformations affect the cardiovascular system. Congenital heart disease includes tetralogy of Fallot, transposition of the great vessels, septal defects, and anomalous pulmonary venous return. Other relatively common defects involve the fetal central nervous system, spine, orofacial system, kidneys, urogenital system, gastrointestinal tract, and skeleton.¹¹

The risk of fetopathy is proportional to the degree of maternal hyperglycemia. Excess maternal glucose and fatty acid levels can lead to fetal hyperglycemia and overgrowth, which increases fetal oxygen requirements. Erythro­poietin levels rise, causing an increase in red cell mass, with subsequent hyperviscosity within the placenta and higher risk of fetal death.

Other complications include intrauterine growth restriction, prematurity, and preterm delivery. Fetal macrosomia (birth weight > 90th percentile or 4 kg, approximately 8 lb, 13 oz) occurs in 27% to 62% of children born to mothers with diabetes, a rate 10 times higher than in patients without diabetes. It contributes to shoulder dystocia (risk 2 to 4 times higher in diabetic pregnancies) and cesarean delivery.⁶ Infants born to mothers with diabetes also have higher risks of neonatal hypoglycemia, erythrocytosis, hyperbilirubinemia, hypocalcemia, respiratory distress, cardiomyopathy, and death, as well as for developing diabetes, obesity, and other adverse cardiometabolic outcomes later in life.¹¹

Nearly half of pregnancies in the general population are unplanned,¹⁵ so preconception diabetes assessment needs to be part of routine medical care for all reproductive-age women. Because most organogenesis occurs during the first 5 to 8 weeks after fertilization—potentially before a woman realizes she is pregnant—achieving optimal glycemic control before conception is necessary to improve pregnancy outcomes.¹

EVERY VISIT IS AN OPPORTUNITY

Every medical visit with a reproductive-age woman with diabetes is an opportunity for counseling about pregnancy. Topics that need to be discussed include the risks of unplanned pregnancy and of poor metabolic control, and the benefits of improved maternal and fetal outcomes with appropriate pregnancy planning and diabetes management.

Referral to a registered dietitian for individualized counseling about proper nutrition, particularly during pregnancy, has been associated with positive outcomes.¹⁶ Patients with diabetes and at high risk of pregnancy complications should be referred to a clinic that specializes in high-risk pregnancies.

Practitioners also should emphasize the importance of regular exercise and encourage patients to maintain or achieve a medically optimal weight before conception. Ideally, this would be a normal body mass index; however, this is not always possible.

In women who are planning pregnancy or are not on effective contraception, medications should be reviewed for potential teratogenicity. If needed, discuss alternative medications or switch to safer ones. However, these changes should not interrupt diabetes treatment.

In addition, ensure that the patient is up to date on age- and disease-appropriate preventive care (eg, immunizations, screening for sexually transmitted disease and malignancy). Counseling and intervention for use of tobacco, alcohol, and recreational drugs are also important. As with any preconception counseling, the patient (and her partner, if possible) should be advised to avoid travel to areas where Zika virus is endemic, and informed about the availability of expanded carrier genetic screening through her obstetric provider.

Finally, pregnant women with diabetes benefit from screening for diabetic complications including hypertension, retinopathy, cardiovascular disease, neuropathy, and nephropathy.

ASSESSING RISKS

Blood pressure

Chronic (preexisting) hypertension is defined as a systolic pressure 140 mm Hg or higher or a diastolic pressure 90 mm Hg or higher, or both, that antedates pregnancy or is present before the 20th week of pregnancy.³ Chronic hypertension has been reported in up to 5% of pregnant women and is associated with increased risk of preterm delivery, superimposed preeclampsia, low birth weight, and perinatal death.³

Reproductive-age women with diabetes and high blood pressure benefit from lifestyle and behavioral modifications.¹⁷ If drug therapy is needed, antihypertensive drugs that are safe for the fetus should be used. Treatment of mild or moderate hypertension during pregnancy reduces the risk of progression to severe hypertension but may not improve obstetric outcomes.

Diabetic retinopathy

Diabetic retinopathy can significantly worsen during pregnancy: the risk of progression is double that in the nonpregnant state.¹⁸ Women with diabetes who are contemplating pregnancy should have a comprehensive eye examination before conception, and any active proliferative retinopathy needs to be treated. These patients may require ophthalmologic monitoring and treatment during pregnancy. (Note: laser photocoagulation is not contraindicated during pregnancy.)

Cardiovascular disease

Cardiovascular physiology changes dramatically during pregnancy. Cardiovascular disease, especially when superimposed on diabetes, can increase the risk of maternal death. Thus, evaluation for cardiovascular risk factors as well as cardiovascular system integrity before conception is important. Listen for arterial bruits and murmurs, and assess peripheral pulses. Consideration should be given to obtaining a preconception resting electrocardiogram in women with diabetes who are over age 35 or who are suspected of having cardiovascular disease.¹⁶

Neurologic disorders

Peripheral neuropathy, the most common neurologic complication of diabetes, is associated with injury and infection.¹⁹

Autonomic neuropathy is associated with decreased cardiac responsiveness and orthostatic hypotension.¹⁹ Diabetic gastroparesis alone can precipitate serious complications during pregnancy, including extreme hypoglycemia and hyperglycemia, increased risk of diabetic ketoacidosis, weight loss, malnutrition, frequent hospitalizations, and increased requirement for parenteral nutrition.²⁰

Although diabetic neuropathy does not significantly worsen during pregnancy, women with preexisting gastroparesis should be counseled on the substantial risks associated with pregnancy. Screening for neuropathy should be part of all diabetic preconception examinations.

Renal complications

Pregnancy in women with diabetes and preexisting renal dysfunction increases their risk of accelerated progression of diabetic kidney disease.²¹ Preexisting renal dysfunction also increases the risk of pregnancy-related complications, such as stillbirth, intrauterine growth restriction, gestational hypertension, preeclampsia, and preterm delivery.^19,21,22 Further, the risk of pregnancy complications correlates directly with the severity of renal dysfunction.²²

Psychiatric disorders

Emotional wellness is essential for optimal diabetes management. It is important to recognize the emotional impact of diabetes in pregnant women and to conduct routine screening for depression, anxiety, stress, and eating disorders.¹⁶

Hemoglobin A_1c. The general consensus is to achieve the lowest hemoglobin A_1c level possible that does not increase the risk of hypoglycemia. The American Diabetes Association (ADA) recommends that, before attempting to conceive, women should lower their hemoglobin A_1c to below 6.5%.¹

Thyroid measures. Autoimmune thyroid disease is the most common autoimmune disorder associated with diabetes and has been reported in 35% to 40% of women with type 1 diabetes.²³ Recommendations are to check thyroid-stimulating hormone and thyroid peroxidase antibody levels before conception or early in pregnancy in all women with diabetes.^1,24 Overt hypothyroidism should be treated before conception, given that early fetal brain development depends on maternal thyroxine.

Renal function testing. Preconception assessment of renal function is important for counseling and risk stratification. This assessment should include serum creatinine level, estimated glomerular filtration rate, and urinary albumin excretion.²¹

Celiac screening. Because women with type 1 diabetes are more susceptible to autoimmune diseases, they should be screened for celiac disease before conception, with testing for  immunoglobulin A (IgA) and tissue transglutaminase antibodies, with or without IgA endomysial antibodies.^16,25,26 An estimated 6% of patients with type 1 diabetes have celiac disease vs 1% of the general population.²⁵ Celiac disease is 2 to 3 times more common in women, and asymptomatic people with type 1 diabetes are considered at increased risk for celiac disease.²⁶

The association between type 1 diabetes and celiac disease most likely relates to the overlap in human leukocyte antigens of the diseases. There is no established link between type 2 diabetes and celiac disease.²⁵

Undiagnosed celiac disease increases a woman’s risk of obstetric complications such as preterm birth, low birth weight, and stillbirth.²⁶ The most likely explanation for these adverse effects is nutrient malabsorption, which is characteristic of celiac disease. Adherence to a gluten-free diet before and during gestation may reduce the risk of preterm delivery by as much as 20%.²⁶

Vitamin B₁₂ level. Celiac disease interferes with the absorption of vitamin B₁₂-instrinsic factor in the ileum, which can lead to vitamin B₁₂ deficiency. Therefore, baseline vitamin B₁₂ levels should be checked before conception in women with celiac disease. Levels should also be checked in women taking metformin, which also decreases vitamin B₁₂ absorption. Of note, increased folate levels due to taking supplements can potentially mask vitamin B₁₂ deficiency.

MEDICATIONS TO REVIEW FOR PREGNANCY INTERACTIONS

Diabetic medications

Insulin is the first-line pharmacotherapy for pregnant patients with type 1, type 2, or gestational diabetes. Insulin does not cross the placenta to a measurable extent, and most insulin preparations have been classified as category B,¹ meaning no risks to the fetus have been found in humans.

Insulin dosing during pregnancy is not static. Beginning around mid-gestation, insulin requirements increase,^28,29 but after 32 weeks the need may decrease. These changes require practitioners to closely monitor blood glucose throughout pregnancy.

Both basal-bolus injections and continuous subcutaneous infusion are reasonable options during pregnancy.³⁰ However, the need for multiple and potentially painful insulin injections daily can lead to poor compliance. This inconvenience has led to studies using oral hypoglycemic medications instead of insulin for patients with gestational and type 2 diabetes.

Metformin is an oral biguanide that decreases hepatic gluconeogenesis and intestinal glucose absorption while peripherally increasing glucose utilization and uptake. Metformin does not pose a risk of hypoglycemia because its mechanism of action does not involve increased insulin production.⁷

Metformin does cross the placenta, resulting in umbilical cord blood levels higher than maternal levels. Nevertheless, studies support the efficacy and short-term safety of metformin use during a pregnancy complicated by gestational or type 2 diabetes.^7,31 Moreover, metformin has been associated with a lower risk of neonatal hypoglycemia and maternal weight gain than insulin.³² However, this agent should be used with caution, as long-term data are not yet available, and it may slightly increase the risk of premature delivery.

Glyburide is another oral hypoglycemic medication that has been used during pregnancy. This second-generation sulfonylurea enhances the release of insulin from the pancreas by binding beta islet cell ATP-calcium channel receptors. Compared with other sulfonylureas, glyburide has the lowest rate of maternal-to-fetal transfer, with umbilical cord plasma concentrations 70% of maternal levels.³³ Although some trials support the efficacy and short-term safety of glyburide treatment for gestational diabetes,³⁴ recent studies have associated glyburide use during pregnancy with a higher rate of neonatal hypoglycemia, neonatal respiratory distress, macrosomia, and neonatal intensive care unit admissions than insulin and metformin.^1,35

Patients treated with oral agents should be informed that these drugs cross the placenta, and that although no adverse effects on the fetus have been demonstrated, long-term safety data are lacking. In addition, oral agents are ineffective in type 1 diabetes and may be insufficient to overcome the insulin resistance in type 2 diabetes.

Antihypertensive drugs

All antihypertensive drugs cross the placenta, but several have an acceptable safety profile in pregnancy, including methyldopa, labeta­lol, clonidine, prazosin, and nifedipine. Hydralazine and labetalol are short-acting, come in intravenous formulations, and can be used for urgent blood pressure control during pregnancy. Diltiazem may be used for heart rate control during pregnancy, and it has been shown to lower blood pressure and proteinuria in pregnant patients with underlying renal disease.^36,37 The ADA recommends against chronic use of diuretics during pregnancy because of potential reductions in maternal plasma volume and uteroplacental perfusion.¹

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and direct renin inhibitors are contraindicated during pregnancy because of the risk of fetal defects, particularly in the renal system.^21,38 Although there is evidence to question the association between first semester exposure and fetotoxicity,³⁹ we avoid these drugs during pregnancy and switch to a different agent in women planning pregnancy.

Other drugs

Statins are contraindicated in pregnancy because they interfere with the development of the fetal nervous system.²¹ Although preliminary data from a small study did not identify safety risks associated with pravastatin use after 12 weeks of gestation,⁴⁰ we recommend discontinuing statins in women attempting pregnancy.

Aspirin. The US Preventive Services Task Force41 recommends low-dose aspirin (81 mg/day) after 12 weeks of gestation for women with type 1 or type 2 diabetes, as well as those with renal disease or chronic hypertension, to prevent preeclampsia. Of note, higher doses need to be used with caution during pregnancy because fetal abnormalities have been reported, such as disruption of fetal vasculature (mesenteric vessels), gastroschisis, and small intestinal atresia.¹⁶

Folate supplementation (0.6–4 mg/day) is recommended in women with celiac disease to prevent neural tube defects in the offspring, and the US Preventive Services Task Force recommends 0.4 mg daily of folic acid supplementation for all women planning or capable of pregnancy.^42–44 Higher doses, ranging from 0.6 to 5 mg/day, have been proposed for patients with diabetes,¹³ and we recommend at least 1 mg for this group, based on data suggesting that higher doses further reduce the risk of neural tube defects.⁴³

Maternal diabetes, insulin therapy, and oral hypoglycemic agents are not contraindications to breastfeeding. The US Preventive Services Task Force recommends interventions by primary care physicians to promote and support breastfeeding.⁴⁵ Breastfeeding is encouraged based on various short- and long-term health benefits for both breastfed infants and breastfeeding mothers. Breastfeeding decreases a woman’s insulin requirements and increases the risk for hypoglycemia, especially in patients with insulin-dependent type 1 diabetes.¹

Additionally, insulin sensitivity increases immediately following delivery of the placenta.¹ Therefore, it is prudent to adjust insulin doses postpartum, especially while a patient is breastfeeding, or to suggest high-carbohydrate snacks before feeds.^9,29

Antihypertensive drugs considered safe to use during lactation include captopril, enalapril, quinapril, labetalol, propranolol, nifedipine, and hydralazine.^21,46 Methyldopa is not contraindicated, but it causes fatigue and worsened postpartum depression and should not be used as first-line therapy. Diuretics and ARBs are not recommended during lactation.²¹ Both metformin and glyburide enter breast milk in small enough amounts that they are not contraindicated during breastfeeding.¹⁶ The Lactmed database (www.toxnet.nlm.nih.gov) provides information about drugs and breastfeeding.

WHAT ABOUT CONTRACEPTIVES?

The ADA recommends contraception for women with diabetes because, just as in women without diabetes, the risks of unplanned pregnancy outweigh those of contraceptives.¹

We recommend low-dose combination estrogen-progestin oral contraceptives to normotensive women under age 35 with diabetes but without underlying microvascular disease. For women over age 35 or for those with microvascular disease, additional options include intrauterine devices or progestin implants. We prefer not to use injectable depot medroxyprogesterone acetate because of its side effects of insulin resistance and weight gain.⁴⁷

CASE DISCUSSION: NEXT STEPS

Our patient’s interest in family planning presents an opportunity for preconception counseling. We recommend a prenatal folic acid supplement, diet and regular exercise for weight loss, and screening tests including a comprehensive metabolic panel, hemoglobin A_1c, thyroid-stimulating hormone, and dilated eye examination. We make sure she is up to date on her indicated health maintenance (eg, immunizations, disease screening), and we review her medications for potential teratogens. She denies any recreational drug use. Also, she has no plans for long-distance travel.

Our counseling includes discussions of pregnancy risks associated with pregestational diabetes and suboptimal glycemic control. We encourage her to use effective contraception until she is “medically optimized” for pregnancy—ie, until her hemoglobin A_1c is lower than 6.5% and she has achieved a medically optimal weight. If feasible, a reduction of weight (7% or so) through lifestyle modification should be attempted, and if her hemoglobin A_1c remains elevated, adding insulin would be recommended.

Pregnant patients or patients contemplating pregnancy are usually motivated to modify their behavior, making this a good time to reinforce lifestyle modifications. Many patients benefit from individualized counseling by a registered dietitian to help achieve the recommended weight and glycemic control.

Our physical examination in this patient includes screening for micro- and macrovascular complications of diabetes, and the test results are negative. Patients with active proliferative retinopathy should be referred to an ophthalmologist for assessment and treatment.

We review her medications for potential teratogenic effects and stop her ACE inhibitor (lisinopril) and statin (simvastatin). We switch her from a first-generation sulfonylurea (chlorpropamide) to glyburide, a second-generation sulfonylurea. Second-generation sulfonylureas are considered more “fetus-friendly” because first-generation sulfonylureas cross the placenta more easily and can cause fetal hyperinsulinemia, leading to macrosomia and neonatal hypoglycemia.⁷

The management of diabetes during pregnancy leans toward insulin use, given the lack of information regarding long-term outcomes with oral agents. If insulin is needed, it is best to initiate it before the patient conceives, and then to stop other diabetes medications. We would not make any changes to her aspirin or metformin use.

Educating the patient and her family about prevention, recognition, and treatment of hypoglycemia is important to prevent and manage the increased risk of hypoglycemia with insulin therapy and in early pregnancy.¹ Consideration should be given to providing ketone strips as well as education on diabetic ketoacidosis prevention and detection.¹ If the patient conceives, begin prenatal care early to allow adequate planning for care of her disease and evaluation of the fetus. Because of the complexity of insulin management in pregnancy, the ADA recommends referral, if possible, to a center offering team-based care, including an obstetrician specialized in high-risk pregnancies, an endocrinologist, and a dietitian.¹

Travel, once reserved for wealthy vacationers and high-level executives, has become a regular experience for many people. The US Travel and Tourism Overview reported that US domestic travel climbed to more than 2.25 billion person-trips in 2017.¹ The US Centers for Disease Control and Prevention (CDC) and the US Travel Association suggest that, based on this frequency and the known rate of diabetes, 17 million people with diabetes travel annually for leisure and 5.6 million for business, and these numbers are expected to increase.²

It stands to reason that as the number of people who travel continues to increase, so too will the number of patients with diabetes seeking medical travel advice. Despite resources available to travelers with diabetes, researchers at the 2016 meeting of the American Diabetes Association noted that only 30% of patients with diabetes who responded to a survey reported being satisfied with the resources available to help them manage their diabetes while traveling.² This article discusses how clinicians can help patients manage their diabetes while traveling, address common travel questions, and prepare patients for emergencies that may arise while traveling.

PRE-TRIP PREPARATION

Provider visit before travel: Checking the bases

Advise patients to schedule an appointment 4 to 6 weeks before their trip.³ At this appointment, give the patient a healthcare provider travel letter (Figure 1) and prescriptions that the patient can hand-carry en route.³ The provider letter should state that the patient has diabetes and should list all supplies the patient needs. The letter should also include specific medications used by the patient and the devices that deliver these medications, eg, Humalog insulin and U-100 syringes⁴ to administer insulin, as well as any food and medication allergies.

Prescriptions should be written for patients to use in the event of an emergency during travel. Prescriptions for diabetes medications should be written with generic names to minimize confusion for those traveling internationally. Additionally, all prescriptions should provide enough medication to last throughout the trip.⁴

Advise patients that rules for filling prescriptions may vary between states and countries.³ Also, the strength of insulin may vary between the United States and other countries. Patients should understand that if they fill their insulin prescription in a foreign country, they may need to purchase new syringes to match the insulin dose. For example, if patients use U-100 syringes and purchase U-40 insulin, they will need to buy U-40 syringes or risk taking too little of a dose.

Remind patients that prescriptions are not necessary for all diabetes supplies but are essential for coverage by insurance companies. Blood glucose testing supplies, ketone strips, and glucose tablets may be purchased in a pharmacy without a prescription. Human insulin may also be purchased over the counter. However, oral medications, glucagon, and analog insulins require a prescription. We suggest that patients who travel have their prescriptions on file at a chain pharmacy rather than an independent one. If they are in the United States, they can go to any branch of the chain pharmacy and easily fill a prescription.

Work with the patient to compile a separate document that details the medication dosing, correction-scale instructions, carbohydrate-to-insulin ratios, and pump settings (basal rates, insulin sensitivity, active insulin time).⁴ Patients who use an insulin pump should record all pump settings in the event that they need to convert to insulin injections during travel.⁴ We suggest that all patients with an insulin pump have an alternate insulin method (eg, pens, vials) and that they carry this with them along with basal insulin in case the pump fails. This level of preparation empowers the patient to assume responsibility for his or her own care if a healthcare provider is not available during travel.

Like all travelers, patients with diabetes should confirm that their immunizations are up to date. Encourage patients to the CDC’s page (wwwnc.cdc.gov/travel) to check the list of vaccines necessary for their region of travel.^4,5 Many special immunizations can be acquired only from a public health department and not from a clinician’s office.

Additionally, depending on the region of travel, prescribing antibiotics or antidiarrheal medications may be necessary to ensure patient safety and comfort. We also recommend that patients with type 1 diabetes obtain a supply of antibiotics and antidiarrheals because they can become sick quickly.

Packing with diabetes: Double is better

The American Diabetes Association recommends that patients pack at least twice the medication and blood-testing supplies they anticipate needing.³ Reinforce to patients the need to pack all medications and supplies in their carry-on bag and to keep this bag in their possession at all times to avoid damage, loss, and extreme changes in temperature and air pressure, which can adversely affect the activity and stability of insulin.

Ask patients about the activities they plan to participate in and how many days they will be traveling, and then recommend shoes that will encourage appropriate foot care.⁴ Patients with diabetes should choose comfort over style when selecting footwear. All new shoes should be purchased and “broken in” 2 to 3 weeks before the trip. Alternating shoes decreases the risk of blisters and calluses.⁴

Emergency abroad: Planning to be prepared

It is crucial to counsel patients on how to respond in an emergency.

Encourage patients with diabetes, especially those who use insulin, to obtain a medical identification bracelet, necklace, or in some cases, a tattoo, that states they use insulin and discloses any allergies.³ This ensures that emergency medical personnel will be aware of the patient’s condition when providing care. Also suggest that your patients have emergency contact information available on their person and their cell phone to expedite assistance in an emergency (Table 2).

Urge patients to determine prior to their departure if their health coverage will change once they leave the state or the country. Some insurance companies require patients to go to a specific healthcare system while others regulate the amount of time a patient can be in the hospital before being transferred home. It is important for patients to be aware of these terms in the event of hospitalization.⁴ Travel insurance should be considered for international travel.

AIRPORT SECURITY: WHAT TO EXPECT WITH DIABETES

The American Diabetes Association works with the US Transportation Security Administration (TSA) to ensure that passengers with diabetes have access to supplies. Travelers with diabetes are allowed to apply for an optional disability notification card, which discreetly informs officers that the passenger has a condition or device that may affect screening procedures.⁶

The TSA suggests that, before going through airport screening, patients with diabetes separate their diabetes supplies from their luggage and declare all items.⁶ Including prescription labels for medications and medical devices helps speed up the security process. Advise patients to carry glucose tablets and other solid foods for treating hypoglycemia when passing through airport security checkpoints.⁷

Since 2016, the TSA has allowed all diabetes-related supplies, medications, and equipment, including liquids and devices, through security after they have been screened by the x-ray scanner or by hand.⁷ People with diabetes are allowed to carry insulin and other liquid medications in amounts greater than 3.4 ounces (100 mLs) through airport security checkpoints.

Insulin can pass safely through x-ray scanners, but if patients are concerned, they may request that their insulin be inspected by hand.⁷ Patients must inform airport security of this decision before the screening process begins. A hand inspection may include swabbing for explosives.

Patients with an insulin pump and a continuous glucose monitoring device may feel uncomfortable during x-ray screening and special security screenings. Remind patients that it is TSA policy that patients do not need to disconnect their devices and can request screening by pat-down rather than x-ray scanner.⁶ It is the responsibility of the patient to research whether the pump can pass through x-ray scanners.

All patients have the right to request a pat-down and can opt out of passing through the x-ray scanner.⁶ However, patients need to inform officers about a pump before screening and must understand that the pump may be subject to further inspection. Usually, this additional inspection includes swabbing the patient’s hands to check for explosive material and a simple pat-down of the insulin pump.⁷

IN-FLIGHT TIPS

Time zones and insulin dosing

Diabetes management is often based on a 24-hour medication schedule. Travel can disrupt this schedule, making it challenging for patients to determine the appropriate medication adjustments. With some assistance, the patient can determine the best course of action based on the direction of travel and the number of time zones crossed.

According to Chandran and Edelman,⁷ medication adjustments are needed only when the patient is traveling east or west, not north or south. As time zones change, day length changes and, consequently, so does the 24-hour regimen many patients follow. As a general rule, traveling east results in a shortened day, requiring a potential reduction in insulin, while traveling west results in a longer day, possibly requiring an increase in insulin dose.⁷ However, this is a guideline and may not be applicable to all patients.⁷

Advise patients to follow local time to administer medications beginning the morning after arrival.⁷ It is not uncommon, due to changes in meal schedules and dosing, for patients to experience hyperglycemia during travel. They should be prepared to correct this if necessary.

Patients using insulin injections should plan to adjust to the new time zone as soon as possible. If the time change is only 1 or 2 hours, they should take their medications before departure according to their normal home time.⁷ Upon arrival, they should resume their insulin regimen based on the local time.

Westward travel. If the patient is traveling west with a time change of 3 or more hours, additional changes may be necessary. Advise patients to take their insulin according to their normal home time before departure. The change in dosing and schedule will depend largely on current glucose control, time of travel, and availability of food and glucose during travel. Encourage patients to discuss these matters with you in advance of any long travel.

Eastward travel. When the patient is traveling east with a time change greater than 3 hours, the day will be consequently shortened. On the day of travel, patients should take their morning dose according to home time. If they are concerned about hypoglycemia, suggest that they decrease the dose by 10%.⁶ On arrival, they should adhere to the new time zone and base insulin dosing on local time.

Advice for insulin pump users. Patients with an insulin pump need make only minimal changes to their dosing schedule. They should continue their routine of basal and bolus doses and change the time on their insulin pump to local time when they arrive. Insulin pump users should bring insulin and syringes as backup; in the event of pump malfunction, the patient should continue to use the same amount of bolus insulin to correct glucose readings and to cover meals.⁷ As for the basal dose, patients can administer a once-daily injection of long-acting insulin, which can be calculated from their pump or accessed from the list they created as part of their pre-travel preparation.⁷

Advice for patients on oral diabetes medications

If a patient is taking an oral medication, it is less crucial to adhere to a time schedule. In fact, in some cases it may be preferable to skip a dose and risk slight hyperglycemia for a few hours rather than take medication too close in time and risk hypoglycemia.⁷

Remind patients to anticipate a change in their oral medication regimen if they travel farther than 5 time zones.⁷ Encourage patients to research time changes and discuss the necessary changes in medication dosage on the day of travel as well as the specific aspects of their trip. A time-zone converter can be found at www.timeanddate.com.⁸

Insulin 101

Storing insulin at the appropriate temperature may be a concern. Insulin should be kept between 40°F and 86°F (4°C–30°C).⁴ Remind patients to carry their insulin with them at all times and to not store it in a car glove compartment or backpack where it can be exposed to excessive sun. The Frio cold pack (ReadyCare, Walnut Creek, CA) is a helpful alternative to refrigeration and can be used to cool insulin when hiking or participating in activities where insulin can overheat. These cooling gel packs are activated when exposed to cold water for 5 to 7 minutes⁵ and are reusable.

Alert patients that insulin names and concentrations may vary among countries. Most insulins are U-100 concentration, which means that for every 1 mL of liquid there are 100 units of insulin. This is the standard insulin concentration used in the United States. There are U-200, U-300, and U-500 insulins as well. In Europe, the standard concentration is U-40 insulin. Syringe sizes are designed to accommodate either U-100 or U-40 insulin. Review these differences with patients and explain the consequences of mixing insulin concentration with syringes of different sizes. Figure 2 shows how to calculate equivalent doses.

Resort tips: Food, drinks, and excursions

A large component of travel is indulging in local cuisine. Patients with diabetes need to be aware of how different foods can affect their diabetes control. Encourage them to research the foods common to the local cuisine. Websites such as Calorie King, MyFitnessPal, Lose it!, and Nutrition Data can help identify the caloric and nutritional makeup of foods.⁹

Advise patients to actively monitor how their blood glucose is affected by new foods by checking blood glucose levels before and after each meal.⁹ Opting for vegetables and protein sources minimizes glucose fluctuations. Remind patients that drinks at resorts may contain more sugar than advertised. Patients should continue to manage their blood glucose by checking levels and by making appropriate insulin adjustments based on the readings. We often advise patients to pack a jar of peanut butter when traveling to ensure a ready source of protein.

Patients who plan to participate in physically challenging activities while travelling should inform all relevant members of the activity staff of their condition. In case of an emergency, hotel staff and guides will be better equipped to help with situations such as hypoglycemia. As noted above, patients should always carry snacks and supplies to treat hypoglycemia in case no alternative food options are available during an excursion. Also, warn patients to avoid walking barefoot. Water shoes are a good alternative to protect feet from cuts and sores.

Patients should inquire about the safety of high-elevation activities. With many glucose meters, every 1,000 feet of elevation results in a 1% to 2% underestimation of blood glucose,¹⁰ which could result in an inaccurate reading. If high-altitude activities are planned, advise patients to bring multiple meters to cross-check glucose readings in cases where inaccuracies (due to elevation) are possible.

Travel, once reserved for wealthy vacationers and high-level executives, has become a regular experience for many people. The US Travel and Tourism Overview reported that US domestic travel climbed to more than 2.25 billion person-trips in 2017.¹ The US Centers for Disease Control and Prevention (CDC) and the US Travel Association suggest that, based on this frequency and the known rate of diabetes, 17 million people with diabetes travel annually for leisure and 5.6 million for business, and these numbers are expected to increase.²

It stands to reason that as the number of people who travel continues to increase, so too will the number of patients with diabetes seeking medical travel advice. Despite resources available to travelers with diabetes, researchers at the 2016 meeting of the American Diabetes Association noted that only 30% of patients with diabetes who responded to a survey reported being satisfied with the resources available to help them manage their diabetes while traveling.² This article discusses how clinicians can help patients manage their diabetes while traveling, address common travel questions, and prepare patients for emergencies that may arise while traveling.

PRE-TRIP PREPARATION

Provider visit before travel: Checking the bases

Advise patients to schedule an appointment 4 to 6 weeks before their trip.³ At this appointment, give the patient a healthcare provider travel letter (Figure 1) and prescriptions that the patient can hand-carry en route.³ The provider letter should state that the patient has diabetes and should list all supplies the patient needs. The letter should also include specific medications used by the patient and the devices that deliver these medications, eg, Humalog insulin and U-100 syringes⁴ to administer insulin, as well as any food and medication allergies.

Prescriptions should be written for patients to use in the event of an emergency during travel. Prescriptions for diabetes medications should be written with generic names to minimize confusion for those traveling internationally. Additionally, all prescriptions should provide enough medication to last throughout the trip.⁴

Advise patients that rules for filling prescriptions may vary between states and countries.³ Also, the strength of insulin may vary between the United States and other countries. Patients should understand that if they fill their insulin prescription in a foreign country, they may need to purchase new syringes to match the insulin dose. For example, if patients use U-100 syringes and purchase U-40 insulin, they will need to buy U-40 syringes or risk taking too little of a dose.

Remind patients that prescriptions are not necessary for all diabetes supplies but are essential for coverage by insurance companies. Blood glucose testing supplies, ketone strips, and glucose tablets may be purchased in a pharmacy without a prescription. Human insulin may also be purchased over the counter. However, oral medications, glucagon, and analog insulins require a prescription. We suggest that patients who travel have their prescriptions on file at a chain pharmacy rather than an independent one. If they are in the United States, they can go to any branch of the chain pharmacy and easily fill a prescription.

Work with the patient to compile a separate document that details the medication dosing, correction-scale instructions, carbohydrate-to-insulin ratios, and pump settings (basal rates, insulin sensitivity, active insulin time).⁴ Patients who use an insulin pump should record all pump settings in the event that they need to convert to insulin injections during travel.⁴ We suggest that all patients with an insulin pump have an alternate insulin method (eg, pens, vials) and that they carry this with them along with basal insulin in case the pump fails. This level of preparation empowers the patient to assume responsibility for his or her own care if a healthcare provider is not available during travel.

Like all travelers, patients with diabetes should confirm that their immunizations are up to date. Encourage patients to the CDC’s page (wwwnc.cdc.gov/travel) to check the list of vaccines necessary for their region of travel.^4,5 Many special immunizations can be acquired only from a public health department and not from a clinician’s office.

Additionally, depending on the region of travel, prescribing antibiotics or antidiarrheal medications may be necessary to ensure patient safety and comfort. We also recommend that patients with type 1 diabetes obtain a supply of antibiotics and antidiarrheals because they can become sick quickly.

Packing with diabetes: Double is better

The American Diabetes Association recommends that patients pack at least twice the medication and blood-testing supplies they anticipate needing.³ Reinforce to patients the need to pack all medications and supplies in their carry-on bag and to keep this bag in their possession at all times to avoid damage, loss, and extreme changes in temperature and air pressure, which can adversely affect the activity and stability of insulin.

Ask patients about the activities they plan to participate in and how many days they will be traveling, and then recommend shoes that will encourage appropriate foot care.⁴ Patients with diabetes should choose comfort over style when selecting footwear. All new shoes should be purchased and “broken in” 2 to 3 weeks before the trip. Alternating shoes decreases the risk of blisters and calluses.⁴

Emergency abroad: Planning to be prepared

It is crucial to counsel patients on how to respond in an emergency.

Encourage patients with diabetes, especially those who use insulin, to obtain a medical identification bracelet, necklace, or in some cases, a tattoo, that states they use insulin and discloses any allergies.³ This ensures that emergency medical personnel will be aware of the patient’s condition when providing care. Also suggest that your patients have emergency contact information available on their person and their cell phone to expedite assistance in an emergency (Table 2).

Urge patients to determine prior to their departure if their health coverage will change once they leave the state or the country. Some insurance companies require patients to go to a specific healthcare system while others regulate the amount of time a patient can be in the hospital before being transferred home. It is important for patients to be aware of these terms in the event of hospitalization.⁴ Travel insurance should be considered for international travel.

AIRPORT SECURITY: WHAT TO EXPECT WITH DIABETES

The American Diabetes Association works with the US Transportation Security Administration (TSA) to ensure that passengers with diabetes have access to supplies. Travelers with diabetes are allowed to apply for an optional disability notification card, which discreetly informs officers that the passenger has a condition or device that may affect screening procedures.⁶

The TSA suggests that, before going through airport screening, patients with diabetes separate their diabetes supplies from their luggage and declare all items.⁶ Including prescription labels for medications and medical devices helps speed up the security process. Advise patients to carry glucose tablets and other solid foods for treating hypoglycemia when passing through airport security checkpoints.⁷

Since 2016, the TSA has allowed all diabetes-related supplies, medications, and equipment, including liquids and devices, through security after they have been screened by the x-ray scanner or by hand.⁷ People with diabetes are allowed to carry insulin and other liquid medications in amounts greater than 3.4 ounces (100 mLs) through airport security checkpoints.

Insulin can pass safely through x-ray scanners, but if patients are concerned, they may request that their insulin be inspected by hand.⁷ Patients must inform airport security of this decision before the screening process begins. A hand inspection may include swabbing for explosives.

Patients with an insulin pump and a continuous glucose monitoring device may feel uncomfortable during x-ray screening and special security screenings. Remind patients that it is TSA policy that patients do not need to disconnect their devices and can request screening by pat-down rather than x-ray scanner.⁶ It is the responsibility of the patient to research whether the pump can pass through x-ray scanners.

All patients have the right to request a pat-down and can opt out of passing through the x-ray scanner.⁶ However, patients need to inform officers about a pump before screening and must understand that the pump may be subject to further inspection. Usually, this additional inspection includes swabbing the patient’s hands to check for explosive material and a simple pat-down of the insulin pump.⁷

IN-FLIGHT TIPS

Time zones and insulin dosing

Diabetes management is often based on a 24-hour medication schedule. Travel can disrupt this schedule, making it challenging for patients to determine the appropriate medication adjustments. With some assistance, the patient can determine the best course of action based on the direction of travel and the number of time zones crossed.

According to Chandran and Edelman,⁷ medication adjustments are needed only when the patient is traveling east or west, not north or south. As time zones change, day length changes and, consequently, so does the 24-hour regimen many patients follow. As a general rule, traveling east results in a shortened day, requiring a potential reduction in insulin, while traveling west results in a longer day, possibly requiring an increase in insulin dose.⁷ However, this is a guideline and may not be applicable to all patients.⁷

Advise patients to follow local time to administer medications beginning the morning after arrival.⁷ It is not uncommon, due to changes in meal schedules and dosing, for patients to experience hyperglycemia during travel. They should be prepared to correct this if necessary.

Patients using insulin injections should plan to adjust to the new time zone as soon as possible. If the time change is only 1 or 2 hours, they should take their medications before departure according to their normal home time.⁷ Upon arrival, they should resume their insulin regimen based on the local time.

Westward travel. If the patient is traveling west with a time change of 3 or more hours, additional changes may be necessary. Advise patients to take their insulin according to their normal home time before departure. The change in dosing and schedule will depend largely on current glucose control, time of travel, and availability of food and glucose during travel. Encourage patients to discuss these matters with you in advance of any long travel.

Eastward travel. When the patient is traveling east with a time change greater than 3 hours, the day will be consequently shortened. On the day of travel, patients should take their morning dose according to home time. If they are concerned about hypoglycemia, suggest that they decrease the dose by 10%.⁶ On arrival, they should adhere to the new time zone and base insulin dosing on local time.

Advice for insulin pump users. Patients with an insulin pump need make only minimal changes to their dosing schedule. They should continue their routine of basal and bolus doses and change the time on their insulin pump to local time when they arrive. Insulin pump users should bring insulin and syringes as backup; in the event of pump malfunction, the patient should continue to use the same amount of bolus insulin to correct glucose readings and to cover meals.⁷ As for the basal dose, patients can administer a once-daily injection of long-acting insulin, which can be calculated from their pump or accessed from the list they created as part of their pre-travel preparation.⁷

Advice for patients on oral diabetes medications

If a patient is taking an oral medication, it is less crucial to adhere to a time schedule. In fact, in some cases it may be preferable to skip a dose and risk slight hyperglycemia for a few hours rather than take medication too close in time and risk hypoglycemia.⁷

Remind patients to anticipate a change in their oral medication regimen if they travel farther than 5 time zones.⁷ Encourage patients to research time changes and discuss the necessary changes in medication dosage on the day of travel as well as the specific aspects of their trip. A time-zone converter can be found at www.timeanddate.com.⁸

Insulin 101

Storing insulin at the appropriate temperature may be a concern. Insulin should be kept between 40°F and 86°F (4°C–30°C).⁴ Remind patients to carry their insulin with them at all times and to not store it in a car glove compartment or backpack where it can be exposed to excessive sun. The Frio cold pack (ReadyCare, Walnut Creek, CA) is a helpful alternative to refrigeration and can be used to cool insulin when hiking or participating in activities where insulin can overheat. These cooling gel packs are activated when exposed to cold water for 5 to 7 minutes⁵ and are reusable.

Alert patients that insulin names and concentrations may vary among countries. Most insulins are U-100 concentration, which means that for every 1 mL of liquid there are 100 units of insulin. This is the standard insulin concentration used in the United States. There are U-200, U-300, and U-500 insulins as well. In Europe, the standard concentration is U-40 insulin. Syringe sizes are designed to accommodate either U-100 or U-40 insulin. Review these differences with patients and explain the consequences of mixing insulin concentration with syringes of different sizes. Figure 2 shows how to calculate equivalent doses.

Resort tips: Food, drinks, and excursions

A large component of travel is indulging in local cuisine. Patients with diabetes need to be aware of how different foods can affect their diabetes control. Encourage them to research the foods common to the local cuisine. Websites such as Calorie King, MyFitnessPal, Lose it!, and Nutrition Data can help identify the caloric and nutritional makeup of foods.⁹

Advise patients to actively monitor how their blood glucose is affected by new foods by checking blood glucose levels before and after each meal.⁹ Opting for vegetables and protein sources minimizes glucose fluctuations. Remind patients that drinks at resorts may contain more sugar than advertised. Patients should continue to manage their blood glucose by checking levels and by making appropriate insulin adjustments based on the readings. We often advise patients to pack a jar of peanut butter when traveling to ensure a ready source of protein.

Patients who plan to participate in physically challenging activities while travelling should inform all relevant members of the activity staff of their condition. In case of an emergency, hotel staff and guides will be better equipped to help with situations such as hypoglycemia. As noted above, patients should always carry snacks and supplies to treat hypoglycemia in case no alternative food options are available during an excursion. Also, warn patients to avoid walking barefoot. Water shoes are a good alternative to protect feet from cuts and sores.

Patients should inquire about the safety of high-elevation activities. With many glucose meters, every 1,000 feet of elevation results in a 1% to 2% underestimation of blood glucose,¹⁰ which could result in an inaccurate reading. If high-altitude activities are planned, advise patients to bring multiple meters to cross-check glucose readings in cases where inaccuracies (due to elevation) are possible.

Travel, once reserved for wealthy vacationers and high-level executives, has become a regular experience for many people. The US Travel and Tourism Overview reported that US domestic travel climbed to more than 2.25 billion person-trips in 2017.¹ The US Centers for Disease Control and Prevention (CDC) and the US Travel Association suggest that, based on this frequency and the known rate of diabetes, 17 million people with diabetes travel annually for leisure and 5.6 million for business, and these numbers are expected to increase.²

It stands to reason that as the number of people who travel continues to increase, so too will the number of patients with diabetes seeking medical travel advice. Despite resources available to travelers with diabetes, researchers at the 2016 meeting of the American Diabetes Association noted that only 30% of patients with diabetes who responded to a survey reported being satisfied with the resources available to help them manage their diabetes while traveling.² This article discusses how clinicians can help patients manage their diabetes while traveling, address common travel questions, and prepare patients for emergencies that may arise while traveling.

PRE-TRIP PREPARATION

Provider visit before travel: Checking the bases

Advise patients to schedule an appointment 4 to 6 weeks before their trip.³ At this appointment, give the patient a healthcare provider travel letter (Figure 1) and prescriptions that the patient can hand-carry en route.³ The provider letter should state that the patient has diabetes and should list all supplies the patient needs. The letter should also include specific medications used by the patient and the devices that deliver these medications, eg, Humalog insulin and U-100 syringes⁴ to administer insulin, as well as any food and medication allergies.

Prescriptions should be written for patients to use in the event of an emergency during travel. Prescriptions for diabetes medications should be written with generic names to minimize confusion for those traveling internationally. Additionally, all prescriptions should provide enough medication to last throughout the trip.⁴

Advise patients that rules for filling prescriptions may vary between states and countries.³ Also, the strength of insulin may vary between the United States and other countries. Patients should understand that if they fill their insulin prescription in a foreign country, they may need to purchase new syringes to match the insulin dose. For example, if patients use U-100 syringes and purchase U-40 insulin, they will need to buy U-40 syringes or risk taking too little of a dose.

Remind patients that prescriptions are not necessary for all diabetes supplies but are essential for coverage by insurance companies. Blood glucose testing supplies, ketone strips, and glucose tablets may be purchased in a pharmacy without a prescription. Human insulin may also be purchased over the counter. However, oral medications, glucagon, and analog insulins require a prescription. We suggest that patients who travel have their prescriptions on file at a chain pharmacy rather than an independent one. If they are in the United States, they can go to any branch of the chain pharmacy and easily fill a prescription.

Work with the patient to compile a separate document that details the medication dosing, correction-scale instructions, carbohydrate-to-insulin ratios, and pump settings (basal rates, insulin sensitivity, active insulin time).⁴ Patients who use an insulin pump should record all pump settings in the event that they need to convert to insulin injections during travel.⁴ We suggest that all patients with an insulin pump have an alternate insulin method (eg, pens, vials) and that they carry this with them along with basal insulin in case the pump fails. This level of preparation empowers the patient to assume responsibility for his or her own care if a healthcare provider is not available during travel.

Like all travelers, patients with diabetes should confirm that their immunizations are up to date. Encourage patients to the CDC’s page (wwwnc.cdc.gov/travel) to check the list of vaccines necessary for their region of travel.^4,5 Many special immunizations can be acquired only from a public health department and not from a clinician’s office.

Additionally, depending on the region of travel, prescribing antibiotics or antidiarrheal medications may be necessary to ensure patient safety and comfort. We also recommend that patients with type 1 diabetes obtain a supply of antibiotics and antidiarrheals because they can become sick quickly.

Packing with diabetes: Double is better

The American Diabetes Association recommends that patients pack at least twice the medication and blood-testing supplies they anticipate needing.³ Reinforce to patients the need to pack all medications and supplies in their carry-on bag and to keep this bag in their possession at all times to avoid damage, loss, and extreme changes in temperature and air pressure, which can adversely affect the activity and stability of insulin.

Ask patients about the activities they plan to participate in and how many days they will be traveling, and then recommend shoes that will encourage appropriate foot care.⁴ Patients with diabetes should choose comfort over style when selecting footwear. All new shoes should be purchased and “broken in” 2 to 3 weeks before the trip. Alternating shoes decreases the risk of blisters and calluses.⁴

Emergency abroad: Planning to be prepared

It is crucial to counsel patients on how to respond in an emergency.

Encourage patients with diabetes, especially those who use insulin, to obtain a medical identification bracelet, necklace, or in some cases, a tattoo, that states they use insulin and discloses any allergies.³ This ensures that emergency medical personnel will be aware of the patient’s condition when providing care. Also suggest that your patients have emergency contact information available on their person and their cell phone to expedite assistance in an emergency (Table 2).

Urge patients to determine prior to their departure if their health coverage will change once they leave the state or the country. Some insurance companies require patients to go to a specific healthcare system while others regulate the amount of time a patient can be in the hospital before being transferred home. It is important for patients to be aware of these terms in the event of hospitalization.⁴ Travel insurance should be considered for international travel.

AIRPORT SECURITY: WHAT TO EXPECT WITH DIABETES

The American Diabetes Association works with the US Transportation Security Administration (TSA) to ensure that passengers with diabetes have access to supplies. Travelers with diabetes are allowed to apply for an optional disability notification card, which discreetly informs officers that the passenger has a condition or device that may affect screening procedures.⁶

The TSA suggests that, before going through airport screening, patients with diabetes separate their diabetes supplies from their luggage and declare all items.⁶ Including prescription labels for medications and medical devices helps speed up the security process. Advise patients to carry glucose tablets and other solid foods for treating hypoglycemia when passing through airport security checkpoints.⁷

Since 2016, the TSA has allowed all diabetes-related supplies, medications, and equipment, including liquids and devices, through security after they have been screened by the x-ray scanner or by hand.⁷ People with diabetes are allowed to carry insulin and other liquid medications in amounts greater than 3.4 ounces (100 mLs) through airport security checkpoints.

Insulin can pass safely through x-ray scanners, but if patients are concerned, they may request that their insulin be inspected by hand.⁷ Patients must inform airport security of this decision before the screening process begins. A hand inspection may include swabbing for explosives.

Patients with an insulin pump and a continuous glucose monitoring device may feel uncomfortable during x-ray screening and special security screenings. Remind patients that it is TSA policy that patients do not need to disconnect their devices and can request screening by pat-down rather than x-ray scanner.⁶ It is the responsibility of the patient to research whether the pump can pass through x-ray scanners.

All patients have the right to request a pat-down and can opt out of passing through the x-ray scanner.⁶ However, patients need to inform officers about a pump before screening and must understand that the pump may be subject to further inspection. Usually, this additional inspection includes swabbing the patient’s hands to check for explosive material and a simple pat-down of the insulin pump.⁷

IN-FLIGHT TIPS

Time zones and insulin dosing

Diabetes management is often based on a 24-hour medication schedule. Travel can disrupt this schedule, making it challenging for patients to determine the appropriate medication adjustments. With some assistance, the patient can determine the best course of action based on the direction of travel and the number of time zones crossed.

According to Chandran and Edelman,⁷ medication adjustments are needed only when the patient is traveling east or west, not north or south. As time zones change, day length changes and, consequently, so does the 24-hour regimen many patients follow. As a general rule, traveling east results in a shortened day, requiring a potential reduction in insulin, while traveling west results in a longer day, possibly requiring an increase in insulin dose.⁷ However, this is a guideline and may not be applicable to all patients.⁷

Advise patients to follow local time to administer medications beginning the morning after arrival.⁷ It is not uncommon, due to changes in meal schedules and dosing, for patients to experience hyperglycemia during travel. They should be prepared to correct this if necessary.

Patients using insulin injections should plan to adjust to the new time zone as soon as possible. If the time change is only 1 or 2 hours, they should take their medications before departure according to their normal home time.⁷ Upon arrival, they should resume their insulin regimen based on the local time.

Westward travel. If the patient is traveling west with a time change of 3 or more hours, additional changes may be necessary. Advise patients to take their insulin according to their normal home time before departure. The change in dosing and schedule will depend largely on current glucose control, time of travel, and availability of food and glucose during travel. Encourage patients to discuss these matters with you in advance of any long travel.

Eastward travel. When the patient is traveling east with a time change greater than 3 hours, the day will be consequently shortened. On the day of travel, patients should take their morning dose according to home time. If they are concerned about hypoglycemia, suggest that they decrease the dose by 10%.⁶ On arrival, they should adhere to the new time zone and base insulin dosing on local time.

Advice for insulin pump users. Patients with an insulin pump need make only minimal changes to their dosing schedule. They should continue their routine of basal and bolus doses and change the time on their insulin pump to local time when they arrive. Insulin pump users should bring insulin and syringes as backup; in the event of pump malfunction, the patient should continue to use the same amount of bolus insulin to correct glucose readings and to cover meals.⁷ As for the basal dose, patients can administer a once-daily injection of long-acting insulin, which can be calculated from their pump or accessed from the list they created as part of their pre-travel preparation.⁷

Advice for patients on oral diabetes medications

If a patient is taking an oral medication, it is less crucial to adhere to a time schedule. In fact, in some cases it may be preferable to skip a dose and risk slight hyperglycemia for a few hours rather than take medication too close in time and risk hypoglycemia.⁷

Remind patients to anticipate a change in their oral medication regimen if they travel farther than 5 time zones.⁷ Encourage patients to research time changes and discuss the necessary changes in medication dosage on the day of travel as well as the specific aspects of their trip. A time-zone converter can be found at www.timeanddate.com.⁸

Insulin 101

Storing insulin at the appropriate temperature may be a concern. Insulin should be kept between 40°F and 86°F (4°C–30°C).⁴ Remind patients to carry their insulin with them at all times and to not store it in a car glove compartment or backpack where it can be exposed to excessive sun. The Frio cold pack (ReadyCare, Walnut Creek, CA) is a helpful alternative to refrigeration and can be used to cool insulin when hiking or participating in activities where insulin can overheat. These cooling gel packs are activated when exposed to cold water for 5 to 7 minutes⁵ and are reusable.

Alert patients that insulin names and concentrations may vary among countries. Most insulins are U-100 concentration, which means that for every 1 mL of liquid there are 100 units of insulin. This is the standard insulin concentration used in the United States. There are U-200, U-300, and U-500 insulins as well. In Europe, the standard concentration is U-40 insulin. Syringe sizes are designed to accommodate either U-100 or U-40 insulin. Review these differences with patients and explain the consequences of mixing insulin concentration with syringes of different sizes. Figure 2 shows how to calculate equivalent doses.

Resort tips: Food, drinks, and excursions

A large component of travel is indulging in local cuisine. Patients with diabetes need to be aware of how different foods can affect their diabetes control. Encourage them to research the foods common to the local cuisine. Websites such as Calorie King, MyFitnessPal, Lose it!, and Nutrition Data can help identify the caloric and nutritional makeup of foods.⁹

Advise patients to actively monitor how their blood glucose is affected by new foods by checking blood glucose levels before and after each meal.⁹ Opting for vegetables and protein sources minimizes glucose fluctuations. Remind patients that drinks at resorts may contain more sugar than advertised. Patients should continue to manage their blood glucose by checking levels and by making appropriate insulin adjustments based on the readings. We often advise patients to pack a jar of peanut butter when traveling to ensure a ready source of protein.

Patients who plan to participate in physically challenging activities while travelling should inform all relevant members of the activity staff of their condition. In case of an emergency, hotel staff and guides will be better equipped to help with situations such as hypoglycemia. As noted above, patients should always carry snacks and supplies to treat hypoglycemia in case no alternative food options are available during an excursion. Also, warn patients to avoid walking barefoot. Water shoes are a good alternative to protect feet from cuts and sores.

Patients should inquire about the safety of high-elevation activities. With many glucose meters, every 1,000 feet of elevation results in a 1% to 2% underestimation of blood glucose,¹⁰ which could result in an inaccurate reading. If high-altitude activities are planned, advise patients to bring multiple meters to cross-check glucose readings in cases where inaccuracies (due to elevation) are possible.

In June 2017, a 4-year-old boy died 1 week after being knocked over and briefly submerged while playing in knee-deep water. This story was widely reported as a case of a rare occurrence called “dry” or “secondary” drowning, depending on the source.¹ The media accounts went viral, spreading fear in parents and others learning about these alleged conditions from the news and social media.

Many alleged cases of dry drowning are reported every year, but each has been found to have a recognized medical source that has a legitimate medically recognized diagnosis (which dry and secondary drowning are not).

Drowning is one of the most common causes of death in children, and so we ought to make sure that the information we share about it is accurate, as it is vital to effective prevention, rescue, and treatment.

Unfortunately, medical providers, medical journals, and the mass media continue to disseminate misinformation on drowning.² These reports often prevail over updated information and hinder accurate understanding of the drowning problem and its solutions.

Every death is tragic, especially the death of a child, and our heartfelt sympathies go out to the family in this alleged drowning case, as well as to all families suffering the loss of a loved one to drowning. However, in the 2017 case, the cause of death was found on autopsy to be myocarditis not related in any way to drowning. As often happens in such situations, this clarification did not receive any media attention, despite the wide reporting and penetration of the original, erroneous story.

We hope our review will reduce misunderstanding among the public and healthcare providers, contribute to improved data collection, and help to promote interventions aimed at prevention, rescue, and mitigation of drowning incidents.

WHAT IS DROWNING?

A consensus committee of the World Health Organization defined drowning as “the process of experiencing respiratory impairment from submersion/immersion in liquid.”³ The process begins when the victim’s airway goes below the surface of the liquid (submersion) or when water splashes over the face (immersion). If the victim is rescued at any time, the process is interrupted, and this is termed a nonfatal drowning. If the victim dies at any time, this is a fatal drowning. Any water-distress incident without evidence of respiratory impairment (ie, without aspiration) should be considered a water rescue and not a drowning.

Rarely do minimally symptomatic cases progress to death, just as most cases of chest pain do not progress to cardiac arrest.⁴ Nonetheless, rescued drowning victims can deteriorate, which is why we encourage people to seek medical care immediately upon warning signs, as we do with chest pain. For drowning, such warning signs are any water distress followed by difficulty breathing, excessive coughing, foam in the mouth, or abnormal behavior.

A SERIOUS PUBLIC HEALTH ISSUE

Drowning is a serious and neglected public health issue, claiming the lives of 372,000 people a year worldwide.⁵ It is a leading cause of death in children ages 1 to 14. The toll continues largely unabated, and in low- and middle-income nations it does not attract the levels of funding that go to other forms of injury prevention, such as road safety.

Nonfatal drowning—with symptoms ranging from mild cough to severe pulmonary edema, and complications ranging from none to severe neurologic impairment—is far more common than fatal drowning.⁶ For every fatal drowning, there are at least 5 nonfatal drowning incidents in which medical care is needed, and 200 rescues are performed.^7–10

In the United States, drowning accounts for almost 13,000 emergency department visits per year and about 3,500 deaths.^7,8

In Brazil, with two-thirds the population of the United States, drowning accounts for far fewer hospital visits but about twice as many deaths. In Rio de Janeiro, where a highly effective and specialized prehospital service is provided at 3 drowning resuscitation centers staffed by medical doctors, an analysis of the 46,060 cases of rescue in 10 years from 1991 to 2000 showed that medical assistance was needed in only 930 cases (2%).¹⁰ The preventive and rescue actions of parents, bystanders, lifeguards, and prehospital rescue services significantly reduce the number of drowning deaths, but these groups do not consistently gather data on nonfatal drowning that can be included in a comprehensive database.

DROWNING IS A PROCESS

When a person in the water can no longer keep the airway clear, water that enters the mouth is voluntarily spit out or swallowed. Within a few seconds to minutes, the person can no longer clear the airways and water is aspirated, stimulating the cough reflex. Laryngo­spasm, another myth concerning drowning, is presumed to protect the airways but does not, as it is rare, occurring in less than 2% of cases.^11,12

If the person is not rescued, aspiration of water continues, and hypoxemia leads to loss of consciousness and apnea within seconds to a few minutes, followed by cardiac arrest. As a consequence, hypoxemic cardiac arrest generally occurs after a period of tachycardia followed by bradycardia and pulseless electrical activity, usually leading to asystole.^13,14

The entire drowning process, from water distress to cardiac arrest, usually takes a few minutes, but in rare situations, such as rapid hypothermia, it can go on for up to an hour.¹⁵ Most drowning patients have an otherwise healthy heart, and the apnea and hypoxemia precede the cardiac arrest by only a few seconds to minutes; thus, cardiac arrest is caused by the hypoxemic insult and not by ventricular dysrhythmias.^6,16

Drowning can be interrupted at any point between distress and death. If the person is rescued early, the clinical picture is determined by the reactivity of the airway and the amount of water that has been aspirated, but not by the type of water (salt or fresh).

Another myth is that drowning in salt water is different from drowning in fresh water. Both salt water and fresh water cause similar surfactant destruction and washout and disrupt the alveolar-capillary membrane. Disruption of the alveolar-capillary membrane increases its permeability and exacerbates shifting of fluid, plasma, and electrolytes into the alveoli.¹³ The clinical picture of the damage is one of regional or generalized pulmonary edema, which interferes with gas exchange in the lungs.^6,13,17

Animal studies by Modell et al showed that aspiration of just 2.2 mL of water per kilogram of body weight is sufficient to cause severe disturbances in oxygen exchange,¹⁷ reflected in a rise in arterial pH and a drop in partial pressure of oxygen. The situation must be similar in humans. In a 70-kg person, this is only about 154 mL of water—about two-thirds of a cup.

The combined effects of fluid in the lungs, the loss of surfactant, and the increase in capillary-alveolar permeability can result in decreased lung compliance, increased right-to-left shunting in the lungs, atelectasis, alveolitis, hypoxemia, and cerebral hypoxia.¹³

If the victim needs cardiopulmonary resuscitation, the possibility of neurologic damage is similar to that in other cardiac arrest situations, but exceptions exist. For example, in rare cases, hypothermia provides a protective mechanism that allows victims to survive prolonged submersion.^4,15

The duration of submersion is the best predictor of death.¹⁸ Underwater, people are not taking in oxygen, and cerebral hypoxia causes both morbidity and death. For this reason, reversing cerebral hypoxia with effective ventilation, oxygen, and chest compression is the priority of treatment.

“Near drowning,” “dry drowning,” “wet drowning,” “delayed drowning,” and “secondary drowning” are not medically accepted diagnoses,^3,4,19 and many organizations and lifesaving institutions around the world discourage the use of these terms.^19,20 Unfortunately, these terms still slip past the editors of medical journals and are thus perpetuated. The terms are most pervasive in the nonmedical media, where drowning seems to be synonymous with death.^3,19,21 We urge all authors and stakeholders to abandon these terms in favor of understanding and communicating drowning as a process that can vary in severity and have a fatal or nonfatal outcome.

Near-drowning

Historically, drowning meant death, while near-drowning meant the victim survived, at least initially (usually for at least 24 hours).

Before 2002, there were 13 different published definitions of near-drowning.^21,22 This variability has caused a great deal of confusion when trying to describe and monitor drowning.

A person can drown and survive, just as a person can have cardiac arrest and survive.^4,21 Just as there is no recognized condition of “near-cardiac arrest,” there is also no condition of near-drowning. Using near-drowning as a medical diagnosis hides the true burden of drowning and consequently amplifies difficulties in developing effective prevention, rescue, and treatment programs.

Dry drowning

Dry drowning has never been an accepted medical term, although it has been used to describe different parts of the drowning process. While many authors use it as a synonym for secondary drowning (described below), in the past it was usually used in cases in which no water was found in the lungs at autopsy in persons who were found dead in the water.^2–4,21 This occurred in about 10% to 15% of cases and was also called drowning “without water aspiration.”

Perhaps some victims suffer sudden cardiac death. It happens on land—why not in the water? Modell et al stated, “In the absence of the common finding of significant pulmonary edema in the victim’s respiratory system, to conclude his or her death was caused by ‘drowning without aspiration’ is unwise.”²³

Laryngospasm is another proposed explanation. It could play a role in the fewer than 2% of cases in which no other cause of death is found on clinical examination or autopsy,^11,12,19,23 but it does not occur in most cases of drowning, or it is brief and is terminated by the respiratory movements that allow the air in the lung to escape and water to be inhaled.

The problem with the term dry drowning is the harm caused by misdiagnosing cases of sudden death as drowning, when an alternative cause is present. Most importantly, the management is the same if small amounts of water are present or not; therefore, no clinical distinction is made between wet and dry drowning.

Secondary drowning

Secondary drowning, sometimes called delayed drowning, is another term that is not medically accepted. The historical use of this term reflects the reality that some patients may worsen due to pulmonary edema after aspirating small amounts of water.

Drowning starts with aspiration, and few or only mild symptoms may be present as soon as the person is removed from the water. Either the small amount of water in the lungs is absorbed and causes no complications or, rarely, the patient’s condition becomes progressively worse over the next few hours as the alveoli become inflamed and the alveolar-capillary membrane is disrupted. But people do not unexpectedly die of drowning days or weeks later with no preceding symptoms. The lungs and heart do not “fill up with water,” and water does not need to be pumped out of the lungs.

There has never been a case published in the medical literature of a patient who underwent clinical evaluation, was initially without symptoms, and later deteriorated and died more than 8 hours after the incident.^6,10,21 People who have drowned and have minimal symptoms get better (usually) or worse (rarely) within 4 to 8 hours. In a study of more than 41,000 lifeguard rescues, only 0.5% of symptomatic patients died.⁶

Drowning secondary to injury or sudden illness

Any injury, trauma, or sudden illness that can cause loss of consciousness or mental or physical weakness can lead to drowning. Physicians need to recognize these situations to treat them appropriately. Drowning that is secondary to other primary insults can be classified as²⁴:

• Drowning caused by injury or trauma (eg, a surfing, boating, or a hang-gliding accident)
• Drowning caused by a sudden illness such as cardiac disease (eg, myocardial ischemia, arrhythmias, prolonged QT syndrome, hypertrophic cardiomyopathy) or neurologic disease (eg, epilepsy, stroke)
• Diving disease (eg, decompression sickness, pulmonary overpressurization syndrome, compression barotrauma, narcosis [“rapture of the deep”], shallow water blackout, immersion pulmonary edema).

PREVENTION IS BEST

Drowning is a leading and preventable cause of death worldwide and for people of all ages. The danger is real, not esoteric or rare, and healthcare providers should use any opportunity to discuss with patients, parents, and the media the most important tool for treating drowning: primary prevention.

For example, small children should be continuously and uninterruptedly supervised within arm’s reach while in the water, even if a lifeguard is present. Other preventive measures are lifejackets, fences completely enclosing pools or ponds, and swimming and water safety lessons. Drowning often occurs in a deceptively pleasant environment that may not seem dangerous.

When preventive measures fail, responders (usually a health professional is involved) need to be able to perform the necessary steps to interrupt the drowning process.

The first challenge is to recognize when someone in the water is at risk of drowning and needs to be rescued.²⁵ Early self-rescue or rescue by others may stop the drowning process and prevent most cases of initial and subsequent water aspiration, respiratory distress, and medical complications.

DON’T BECOME A VICTIM

Rescuers must take care not to become victims themselves. Panicked swimmers can thrash about and injure the rescuer or clutch at anything they encounter, dragging the rescuer under. And the rescuer can succumb to the same hazards that got the victim into trouble, such as strong currents, deep water, or underwater hazards.

Certified lifeguards are trained to get victims out of the water safely. The American Red Cross slogan “Reach or throw, don’t go” means “Reach out with a pole or other object or throw something that floats; don’t get in the water yourself.”

WHAT TO TELL THE PUBLIC

While some journalists acknowledge that the terms dry drowning and secondary drowning are medically discredited, they still use them in their reports. The novelty of this story—and its appeal to media outlets—is precisely the unfamiliarity of these terms to the general public and the perceived mysterious, looming threat.

We often hear that these terms are more familiar to the public, which is likely true. More concerning, some physicians continue to use them (and older definitions of drowning that equate it with death) in media interviews, clinical care, and publications. The paradox is that we, the medical community, invented these terms, not patients or the media.

As clinicians and researchers, we should drive popular culture definitions, not the other way around. Rather than dismiss these terms as “semantics” or “technicalities,” we should take the opportunity to highlight the dangers of drowning and the importance of prevention, and to promote simpler language that is easier for us and our patients to understand.^19,21

Healthcare providers should understand and share modern drowning science and best practices, which will reduce fear, improve resource utilization, and prevent potentially deadly consequences due to misunderstanding or misinterpretation of incorrect terminology.

WHEN PATIENTS SHOULD SEEK CARE

Anyone who experiences cough, breathless­ness, or other worrisome symptoms such as abnormal mentation within 8 hours of a drowning incident (using the modern definition above) should seek medical advice immediately.

We tell people to seek care if symptoms seem any worse than the experience of a drink “going down the wrong pipe” at the dinner table.²¹ But symptoms can be minimal. Careful attention should be given to mild symptoms that get progressively worse during that time. These cases can rarely progress to acute respiratory distress syndrome.

Table 1 explores who needs further medical help after being rescued from the water.²⁶

In most of these cases, it is most appropriate to call an ambulance, but care may involve seeing a doctor depending on the severity of the symptoms.^6,21 Usually, drowning patients are observed for 4 to 8 hours in an emergency department and are discharged if normal. Symptoms that are more significant include persistent cough, foam at the mouth or nose, confusion, or abnormal behavior, and these require further medical evaluation.

Patients should also seek medical care even if they are 100% normal upon exiting the water but develop worrisome symptoms more than 8 hours later, and providers should consider diagnoses other than primary drowning. Spontaneous pneumothorax, chemical pneumonitis, bacterial or viral pneumonia, head injury, asthma, chest trauma, and acute respiratory distress syndrome have been mislabeled as delayed, dry, or secondary drowning.^3,4,19,21

In June 2017, a 4-year-old boy died 1 week after being knocked over and briefly submerged while playing in knee-deep water. This story was widely reported as a case of a rare occurrence called “dry” or “secondary” drowning, depending on the source.¹ The media accounts went viral, spreading fear in parents and others learning about these alleged conditions from the news and social media.

Many alleged cases of dry drowning are reported every year, but each has been found to have a recognized medical source that has a legitimate medically recognized diagnosis (which dry and secondary drowning are not).

Drowning is one of the most common causes of death in children, and so we ought to make sure that the information we share about it is accurate, as it is vital to effective prevention, rescue, and treatment.

Unfortunately, medical providers, medical journals, and the mass media continue to disseminate misinformation on drowning.² These reports often prevail over updated information and hinder accurate understanding of the drowning problem and its solutions.

Every death is tragic, especially the death of a child, and our heartfelt sympathies go out to the family in this alleged drowning case, as well as to all families suffering the loss of a loved one to drowning. However, in the 2017 case, the cause of death was found on autopsy to be myocarditis not related in any way to drowning. As often happens in such situations, this clarification did not receive any media attention, despite the wide reporting and penetration of the original, erroneous story.

We hope our review will reduce misunderstanding among the public and healthcare providers, contribute to improved data collection, and help to promote interventions aimed at prevention, rescue, and mitigation of drowning incidents.

WHAT IS DROWNING?

A consensus committee of the World Health Organization defined drowning as “the process of experiencing respiratory impairment from submersion/immersion in liquid.”³ The process begins when the victim’s airway goes below the surface of the liquid (submersion) or when water splashes over the face (immersion). If the victim is rescued at any time, the process is interrupted, and this is termed a nonfatal drowning. If the victim dies at any time, this is a fatal drowning. Any water-distress incident without evidence of respiratory impairment (ie, without aspiration) should be considered a water rescue and not a drowning.

Rarely do minimally symptomatic cases progress to death, just as most cases of chest pain do not progress to cardiac arrest.⁴ Nonetheless, rescued drowning victims can deteriorate, which is why we encourage people to seek medical care immediately upon warning signs, as we do with chest pain. For drowning, such warning signs are any water distress followed by difficulty breathing, excessive coughing, foam in the mouth, or abnormal behavior.

A SERIOUS PUBLIC HEALTH ISSUE

Drowning is a serious and neglected public health issue, claiming the lives of 372,000 people a year worldwide.⁵ It is a leading cause of death in children ages 1 to 14. The toll continues largely unabated, and in low- and middle-income nations it does not attract the levels of funding that go to other forms of injury prevention, such as road safety.

Nonfatal drowning—with symptoms ranging from mild cough to severe pulmonary edema, and complications ranging from none to severe neurologic impairment—is far more common than fatal drowning.⁶ For every fatal drowning, there are at least 5 nonfatal drowning incidents in which medical care is needed, and 200 rescues are performed.^7–10

In the United States, drowning accounts for almost 13,000 emergency department visits per year and about 3,500 deaths.^7,8

In Brazil, with two-thirds the population of the United States, drowning accounts for far fewer hospital visits but about twice as many deaths. In Rio de Janeiro, where a highly effective and specialized prehospital service is provided at 3 drowning resuscitation centers staffed by medical doctors, an analysis of the 46,060 cases of rescue in 10 years from 1991 to 2000 showed that medical assistance was needed in only 930 cases (2%).¹⁰ The preventive and rescue actions of parents, bystanders, lifeguards, and prehospital rescue services significantly reduce the number of drowning deaths, but these groups do not consistently gather data on nonfatal drowning that can be included in a comprehensive database.

DROWNING IS A PROCESS

When a person in the water can no longer keep the airway clear, water that enters the mouth is voluntarily spit out or swallowed. Within a few seconds to minutes, the person can no longer clear the airways and water is aspirated, stimulating the cough reflex. Laryngo­spasm, another myth concerning drowning, is presumed to protect the airways but does not, as it is rare, occurring in less than 2% of cases.^11,12

If the person is not rescued, aspiration of water continues, and hypoxemia leads to loss of consciousness and apnea within seconds to a few minutes, followed by cardiac arrest. As a consequence, hypoxemic cardiac arrest generally occurs after a period of tachycardia followed by bradycardia and pulseless electrical activity, usually leading to asystole.^13,14

The entire drowning process, from water distress to cardiac arrest, usually takes a few minutes, but in rare situations, such as rapid hypothermia, it can go on for up to an hour.¹⁵ Most drowning patients have an otherwise healthy heart, and the apnea and hypoxemia precede the cardiac arrest by only a few seconds to minutes; thus, cardiac arrest is caused by the hypoxemic insult and not by ventricular dysrhythmias.^6,16

Drowning can be interrupted at any point between distress and death. If the person is rescued early, the clinical picture is determined by the reactivity of the airway and the amount of water that has been aspirated, but not by the type of water (salt or fresh).

Another myth is that drowning in salt water is different from drowning in fresh water. Both salt water and fresh water cause similar surfactant destruction and washout and disrupt the alveolar-capillary membrane. Disruption of the alveolar-capillary membrane increases its permeability and exacerbates shifting of fluid, plasma, and electrolytes into the alveoli.¹³ The clinical picture of the damage is one of regional or generalized pulmonary edema, which interferes with gas exchange in the lungs.^6,13,17

Animal studies by Modell et al showed that aspiration of just 2.2 mL of water per kilogram of body weight is sufficient to cause severe disturbances in oxygen exchange,¹⁷ reflected in a rise in arterial pH and a drop in partial pressure of oxygen. The situation must be similar in humans. In a 70-kg person, this is only about 154 mL of water—about two-thirds of a cup.

The combined effects of fluid in the lungs, the loss of surfactant, and the increase in capillary-alveolar permeability can result in decreased lung compliance, increased right-to-left shunting in the lungs, atelectasis, alveolitis, hypoxemia, and cerebral hypoxia.¹³

If the victim needs cardiopulmonary resuscitation, the possibility of neurologic damage is similar to that in other cardiac arrest situations, but exceptions exist. For example, in rare cases, hypothermia provides a protective mechanism that allows victims to survive prolonged submersion.^4,15

The duration of submersion is the best predictor of death.¹⁸ Underwater, people are not taking in oxygen, and cerebral hypoxia causes both morbidity and death. For this reason, reversing cerebral hypoxia with effective ventilation, oxygen, and chest compression is the priority of treatment.