Expert Commentary

EXPERT COMMENTARY

Lower urinary tract infection (UTI) is one of the most common medical complications of pregnancy. Approximately 5% to 10% of all pregnant women have asymptomatic bacteriuria, which usually antedates the pregnancy and is detected at the time of the first prenatal appointment. Another 2% to 3% develop acute cystitis during pregnancy. The dominant organisms that cause lower UTIs in pregnant women are Escherichia coli, Klebsiella pneumoniae, Proteus species, group B streptococci, enterococci, and Staphylococcus saprophyticus.

One goal of treating asymptomatic bacteriuria and acute cystitis is to prevent ascending infection (pyelonephritis), which can be associated with preterm delivery, sepsis, and adult respiratory distress syndrome. Another key goal is to use an antibiotic that eradicates the uropathogen without causing harm to either the mother or fetus.

In 2009, Crider and colleagues reported that 2 of the most commonly used antibiotics for UTIs, sulfonamides and nitrofurantoin, were associated with a disturbing spectrum of birth defects.¹ Following that report, in 2011 the American College of Obstetricians and Gynecologists (ACOG) published a committee opinion that recommended against the use of these 2 agents in the first trimester of pregnancy unless other antibiotics were unlikely to be effective.²

Details of the study

Centers for Disease Control and Prevention investigators recently conducted a study to assess the effect of these ACOG recommendations on clinical practice. Ailes and co-workers used the Truven Health MarketScan Commercial Database to examine antibiotic prescriptions filled by pregnant women with UTIs.

The database included 482,917 pregnancies in 2014 eligible for analysis. A total of 7.2% (n = 34,864) of pregnant women were treated as outpatients for a UTI within the 90-day interval before the last menstrual period or during the pregnancy. Among these women, the most commonly prescribed antibiotics during the first trimester were nitrofurantoin (34.7%), ciprofloxacin (10.5%), cephalexin (10.3%), and trimethoprim-sulfamethoxazole (7.6%).

The authors concluded that 43% of women used an antibiotic (nitrofurantoin or trimethoprim-sulfamethoxazole) in the first trimester that had potential teratogenicity, despite the precautionary statement articulated in the ACOG committee opinion.²

Antibiotic-associated effects

Of all the antibiotics that could be used to treat a lower UTI in pregnancy, nitrofurantoin probably has the greatest appeal. The drug is highly concentrated in the urine and is very active against all the common uropathogens except Proteus species. It is not absorbed significantly outside the lower urinary tract, and thus it does not alter the natural flora of the bowel or vagina (such alteration would predispose the patient to antibiotic-associated diarrhea or vulvovaginal candidiasis). Nitrofurantoin is inexpensive and usually is very well tolerated.

In the National Birth Defects Prevention Study by Crider and colleagues, nitrofurantoin was associated with anophthalmia or microphthalmos (adjusted odds ratio [AOR], 3.7; 95% confidence interval [CI], 1.1–12.2), hypoplastic left heart syndrome (AOR, 4.2; 95% CI, 1.9–9.1), atrial septal defects (AOR, 1.9; 95% CI, 1.1–3.4), and cleft lip with cleft palate (AOR, 2.1; 95% CI, 1.2–3.9).¹ Other investigations, including one published as recently as 2013, have not documented these same associations.³

Similarly, the combination of trimethoprim-sulfamethoxazole also has considerable appeal for treating lower UTIs in pregnancy because it is highly active against most uropathogens, is inexpensive, and usually is very well tolerated. The report by Crider and colleagues, however, was even more worrisome with respect to the possible teratogenicity of this antibiotic.¹ The authors found that use of this antibiotic in the first trimester was associated with anencephaly (AOR, 3.4; 95% CI, 1.3–8.8), coarctation of the aorta (AOR, 2.7; 95% CI, 1.3–5.6), hypoplastic left heart (AOR, 3.2; 95% CI, 1.3–7.6), choanal atresia (AOR, 8.0; 95% CI, 2.7–23.5), transverse limb deficiency (AOR, 2.5; 95% CI, 1.0–5.9), and diaphragmatic hernia (AOR, 2.4; 95% CI, 1.1–5.4). Again, other authors, using different epidemiologic methods, have not found the same associations.³

Study strengths and weaknesses

The National Birth Defects Prevention Study by Crider and colleagues was a large, well-funded, and well-designed epidemiologic study. It included more than 13,000 patients from 10 different states.

Nevertheless, the study had certain limitations.⁴ The findings are subject to recall bias because the investigators questioned patients about antibiotic use after, rather than during, pregnancy. Understandably, the investigators were not able to verify the prescriptions for antibiotics by reviewing each individual medical record. In fact, one-third of study participants were unable to recall the exact name of the antibiotic they received. The authors did not precisely distinguish between single-agent sulfonamides and the combination drug, trimethoprim-sulfamethoxazole, although it seems reasonable to assume that the majority of the prescriptions were for the latter. Finally, given the observational nature of the study, the authors could not be certain that the observed associations were due to the antibiotic, the infection for which the drug was prescribed, or another confounding factor.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Lower urinary tract infection (UTI) is one of the most common medical complications of pregnancy. Approximately 5% to 10% of all pregnant women have asymptomatic bacteriuria, which usually antedates the pregnancy and is detected at the time of the first prenatal appointment. Another 2% to 3% develop acute cystitis during pregnancy. The dominant organisms that cause lower UTIs in pregnant women are Escherichia coli, Klebsiella pneumoniae, Proteus species, group B streptococci, enterococci, and Staphylococcus saprophyticus.

One goal of treating asymptomatic bacteriuria and acute cystitis is to prevent ascending infection (pyelonephritis), which can be associated with preterm delivery, sepsis, and adult respiratory distress syndrome. Another key goal is to use an antibiotic that eradicates the uropathogen without causing harm to either the mother or fetus.

In 2009, Crider and colleagues reported that 2 of the most commonly used antibiotics for UTIs, sulfonamides and nitrofurantoin, were associated with a disturbing spectrum of birth defects.¹ Following that report, in 2011 the American College of Obstetricians and Gynecologists (ACOG) published a committee opinion that recommended against the use of these 2 agents in the first trimester of pregnancy unless other antibiotics were unlikely to be effective.²

Details of the study

Centers for Disease Control and Prevention investigators recently conducted a study to assess the effect of these ACOG recommendations on clinical practice. Ailes and co-workers used the Truven Health MarketScan Commercial Database to examine antibiotic prescriptions filled by pregnant women with UTIs.

The database included 482,917 pregnancies in 2014 eligible for analysis. A total of 7.2% (n = 34,864) of pregnant women were treated as outpatients for a UTI within the 90-day interval before the last menstrual period or during the pregnancy. Among these women, the most commonly prescribed antibiotics during the first trimester were nitrofurantoin (34.7%), ciprofloxacin (10.5%), cephalexin (10.3%), and trimethoprim-sulfamethoxazole (7.6%).

The authors concluded that 43% of women used an antibiotic (nitrofurantoin or trimethoprim-sulfamethoxazole) in the first trimester that had potential teratogenicity, despite the precautionary statement articulated in the ACOG committee opinion.²

Antibiotic-associated effects

Of all the antibiotics that could be used to treat a lower UTI in pregnancy, nitrofurantoin probably has the greatest appeal. The drug is highly concentrated in the urine and is very active against all the common uropathogens except Proteus species. It is not absorbed significantly outside the lower urinary tract, and thus it does not alter the natural flora of the bowel or vagina (such alteration would predispose the patient to antibiotic-associated diarrhea or vulvovaginal candidiasis). Nitrofurantoin is inexpensive and usually is very well tolerated.

In the National Birth Defects Prevention Study by Crider and colleagues, nitrofurantoin was associated with anophthalmia or microphthalmos (adjusted odds ratio [AOR], 3.7; 95% confidence interval [CI], 1.1–12.2), hypoplastic left heart syndrome (AOR, 4.2; 95% CI, 1.9–9.1), atrial septal defects (AOR, 1.9; 95% CI, 1.1–3.4), and cleft lip with cleft palate (AOR, 2.1; 95% CI, 1.2–3.9).¹ Other investigations, including one published as recently as 2013, have not documented these same associations.³

Similarly, the combination of trimethoprim-sulfamethoxazole also has considerable appeal for treating lower UTIs in pregnancy because it is highly active against most uropathogens, is inexpensive, and usually is very well tolerated. The report by Crider and colleagues, however, was even more worrisome with respect to the possible teratogenicity of this antibiotic.¹ The authors found that use of this antibiotic in the first trimester was associated with anencephaly (AOR, 3.4; 95% CI, 1.3–8.8), coarctation of the aorta (AOR, 2.7; 95% CI, 1.3–5.6), hypoplastic left heart (AOR, 3.2; 95% CI, 1.3–7.6), choanal atresia (AOR, 8.0; 95% CI, 2.7–23.5), transverse limb deficiency (AOR, 2.5; 95% CI, 1.0–5.9), and diaphragmatic hernia (AOR, 2.4; 95% CI, 1.1–5.4). Again, other authors, using different epidemiologic methods, have not found the same associations.³

Study strengths and weaknesses

The National Birth Defects Prevention Study by Crider and colleagues was a large, well-funded, and well-designed epidemiologic study. It included more than 13,000 patients from 10 different states.

Nevertheless, the study had certain limitations.⁴ The findings are subject to recall bias because the investigators questioned patients about antibiotic use after, rather than during, pregnancy. Understandably, the investigators were not able to verify the prescriptions for antibiotics by reviewing each individual medical record. In fact, one-third of study participants were unable to recall the exact name of the antibiotic they received. The authors did not precisely distinguish between single-agent sulfonamides and the combination drug, trimethoprim-sulfamethoxazole, although it seems reasonable to assume that the majority of the prescriptions were for the latter. Finally, given the observational nature of the study, the authors could not be certain that the observed associations were due to the antibiotic, the infection for which the drug was prescribed, or another confounding factor.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Lower urinary tract infection (UTI) is one of the most common medical complications of pregnancy. Approximately 5% to 10% of all pregnant women have asymptomatic bacteriuria, which usually antedates the pregnancy and is detected at the time of the first prenatal appointment. Another 2% to 3% develop acute cystitis during pregnancy. The dominant organisms that cause lower UTIs in pregnant women are Escherichia coli, Klebsiella pneumoniae, Proteus species, group B streptococci, enterococci, and Staphylococcus saprophyticus.

One goal of treating asymptomatic bacteriuria and acute cystitis is to prevent ascending infection (pyelonephritis), which can be associated with preterm delivery, sepsis, and adult respiratory distress syndrome. Another key goal is to use an antibiotic that eradicates the uropathogen without causing harm to either the mother or fetus.

In 2009, Crider and colleagues reported that 2 of the most commonly used antibiotics for UTIs, sulfonamides and nitrofurantoin, were associated with a disturbing spectrum of birth defects.¹ Following that report, in 2011 the American College of Obstetricians and Gynecologists (ACOG) published a committee opinion that recommended against the use of these 2 agents in the first trimester of pregnancy unless other antibiotics were unlikely to be effective.²

Details of the study

Centers for Disease Control and Prevention investigators recently conducted a study to assess the effect of these ACOG recommendations on clinical practice. Ailes and co-workers used the Truven Health MarketScan Commercial Database to examine antibiotic prescriptions filled by pregnant women with UTIs.

The database included 482,917 pregnancies in 2014 eligible for analysis. A total of 7.2% (n = 34,864) of pregnant women were treated as outpatients for a UTI within the 90-day interval before the last menstrual period or during the pregnancy. Among these women, the most commonly prescribed antibiotics during the first trimester were nitrofurantoin (34.7%), ciprofloxacin (10.5%), cephalexin (10.3%), and trimethoprim-sulfamethoxazole (7.6%).

The authors concluded that 43% of women used an antibiotic (nitrofurantoin or trimethoprim-sulfamethoxazole) in the first trimester that had potential teratogenicity, despite the precautionary statement articulated in the ACOG committee opinion.²

Antibiotic-associated effects

Of all the antibiotics that could be used to treat a lower UTI in pregnancy, nitrofurantoin probably has the greatest appeal. The drug is highly concentrated in the urine and is very active against all the common uropathogens except Proteus species. It is not absorbed significantly outside the lower urinary tract, and thus it does not alter the natural flora of the bowel or vagina (such alteration would predispose the patient to antibiotic-associated diarrhea or vulvovaginal candidiasis). Nitrofurantoin is inexpensive and usually is very well tolerated.

In the National Birth Defects Prevention Study by Crider and colleagues, nitrofurantoin was associated with anophthalmia or microphthalmos (adjusted odds ratio [AOR], 3.7; 95% confidence interval [CI], 1.1–12.2), hypoplastic left heart syndrome (AOR, 4.2; 95% CI, 1.9–9.1), atrial septal defects (AOR, 1.9; 95% CI, 1.1–3.4), and cleft lip with cleft palate (AOR, 2.1; 95% CI, 1.2–3.9).¹ Other investigations, including one published as recently as 2013, have not documented these same associations.³

Similarly, the combination of trimethoprim-sulfamethoxazole also has considerable appeal for treating lower UTIs in pregnancy because it is highly active against most uropathogens, is inexpensive, and usually is very well tolerated. The report by Crider and colleagues, however, was even more worrisome with respect to the possible teratogenicity of this antibiotic.¹ The authors found that use of this antibiotic in the first trimester was associated with anencephaly (AOR, 3.4; 95% CI, 1.3–8.8), coarctation of the aorta (AOR, 2.7; 95% CI, 1.3–5.6), hypoplastic left heart (AOR, 3.2; 95% CI, 1.3–7.6), choanal atresia (AOR, 8.0; 95% CI, 2.7–23.5), transverse limb deficiency (AOR, 2.5; 95% CI, 1.0–5.9), and diaphragmatic hernia (AOR, 2.4; 95% CI, 1.1–5.4). Again, other authors, using different epidemiologic methods, have not found the same associations.³

Study strengths and weaknesses

The National Birth Defects Prevention Study by Crider and colleagues was a large, well-funded, and well-designed epidemiologic study. It included more than 13,000 patients from 10 different states.

Nevertheless, the study had certain limitations.⁴ The findings are subject to recall bias because the investigators questioned patients about antibiotic use after, rather than during, pregnancy. Understandably, the investigators were not able to verify the prescriptions for antibiotics by reviewing each individual medical record. In fact, one-third of study participants were unable to recall the exact name of the antibiotic they received. The authors did not precisely distinguish between single-agent sulfonamides and the combination drug, trimethoprim-sulfamethoxazole, although it seems reasonable to assume that the majority of the prescriptions were for the latter. Finally, given the observational nature of the study, the authors could not be certain that the observed associations were due to the antibiotic, the infection for which the drug was prescribed, or another confounding factor.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Realistic prospective performance data are needed to quantify the additional benefit of the cytology component of cotesting on top of what is already known to be highly sensitive molecular HPV testing. While the addition of cytology to HPV testing can add performance, it also can add further costs and the potential for unnecessary colposcopies for what are merely cytomorphologic manifestations of an active HPV infection. Frequent invasive procedures such as colposcopy, which can be costly and lead to anxiety and distress in generally young women and the potential for overtreatment of likely regressive lesions, has been defined as a harm of screening by the US Preventive Services Task Force (USPSTF).

Details of the study

In a cohort from Kaiser Permanente Northern California, 1,208,710 women aged 30 years or older were screened with cotesting from 2003 to 2015. Those who cotested HPV negative and cytology negative were offered triennial screening. Positive cotest results were managed according to Kaiser protocol. Women with cytologic abnormalities were referred for colposcopy. Those with HPV positive/cytology negative results or HPV negative/cytology equivocal results underwent accelerated testing at 1 year. A total of 623 cervical cancers were identified and included in the analyses.

Using multiple analyses, Schiffman and colleagues demonstrated the sensitivity advantage of HPV testing. They clearly showed that the cytology component to cotesting performance over many years is very limited for detecting precancers and early curable cancers. For example, prediagnostic HPV testing (76.7%) was more likely to be positive than cytology (59.1%; P<.001 for paired comparison); 82.6% of all prediagnostic cotests were positive by HPV and/or cytology; and only 5.9% of the cotests were positive by cytology alone (HPV negative.)

Primary HPV testing is recommended as a potential screening strategy by an interim guidance group led by the Society of Gynecologic Oncology and the American Society for Colposcopy and Cervical Pathology, and it is the primary cervical cancer screening recommendation of USPSTF draft guidelines.¹ There have been reports that reliance on primary HPV testing would encourage cervical cancer mortality; Schiffman and colleagues point out, however, that according to their study data, such reports are overstated.

Despite these data, practically speaking, shifting away from standard cotesting poses numerous challenges for clinicians and laboratories alike; however, these data clearly show the limited value of cytology and, due to the overtreatment of likely regressive cervical intraepithelial neoplasia grade 2, the possible increased risk of preterm birth and its subsequent harm as well.

Study strengths and weaknesses

The authors examined the long-term relative history of HPV testing and cytology prior to cancer diagnosis in a large, prospectively followed US cohort where hundreds of women in this cohort developed cancer. There will not be a validation study of this size and scale in the near future. Further, the authors showed that the relative value of cytology to cotesting is minimal. Multiple subsequent rounds of cotesting after negative results also can be questioned. 

One weakness of the study is that the data were collected from only one health care system and therefore may not be representative of all populations. Additionally, cotesting was performed on 2 separately collected specimens, which may have reduced HPV testing performance.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Realistic prospective performance data are needed to quantify the additional benefit of the cytology component of cotesting on top of what is already known to be highly sensitive molecular HPV testing. While the addition of cytology to HPV testing can add performance, it also can add further costs and the potential for unnecessary colposcopies for what are merely cytomorphologic manifestations of an active HPV infection. Frequent invasive procedures such as colposcopy, which can be costly and lead to anxiety and distress in generally young women and the potential for overtreatment of likely regressive lesions, has been defined as a harm of screening by the US Preventive Services Task Force (USPSTF).

Details of the study

In a cohort from Kaiser Permanente Northern California, 1,208,710 women aged 30 years or older were screened with cotesting from 2003 to 2015. Those who cotested HPV negative and cytology negative were offered triennial screening. Positive cotest results were managed according to Kaiser protocol. Women with cytologic abnormalities were referred for colposcopy. Those with HPV positive/cytology negative results or HPV negative/cytology equivocal results underwent accelerated testing at 1 year. A total of 623 cervical cancers were identified and included in the analyses.

Using multiple analyses, Schiffman and colleagues demonstrated the sensitivity advantage of HPV testing. They clearly showed that the cytology component to cotesting performance over many years is very limited for detecting precancers and early curable cancers. For example, prediagnostic HPV testing (76.7%) was more likely to be positive than cytology (59.1%; P<.001 for paired comparison); 82.6% of all prediagnostic cotests were positive by HPV and/or cytology; and only 5.9% of the cotests were positive by cytology alone (HPV negative.)

Primary HPV testing is recommended as a potential screening strategy by an interim guidance group led by the Society of Gynecologic Oncology and the American Society for Colposcopy and Cervical Pathology, and it is the primary cervical cancer screening recommendation of USPSTF draft guidelines.¹ There have been reports that reliance on primary HPV testing would encourage cervical cancer mortality; Schiffman and colleagues point out, however, that according to their study data, such reports are overstated.

Despite these data, practically speaking, shifting away from standard cotesting poses numerous challenges for clinicians and laboratories alike; however, these data clearly show the limited value of cytology and, due to the overtreatment of likely regressive cervical intraepithelial neoplasia grade 2, the possible increased risk of preterm birth and its subsequent harm as well.

Study strengths and weaknesses

The authors examined the long-term relative history of HPV testing and cytology prior to cancer diagnosis in a large, prospectively followed US cohort where hundreds of women in this cohort developed cancer. There will not be a validation study of this size and scale in the near future. Further, the authors showed that the relative value of cytology to cotesting is minimal. Multiple subsequent rounds of cotesting after negative results also can be questioned. 

One weakness of the study is that the data were collected from only one health care system and therefore may not be representative of all populations. Additionally, cotesting was performed on 2 separately collected specimens, which may have reduced HPV testing performance.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Realistic prospective performance data are needed to quantify the additional benefit of the cytology component of cotesting on top of what is already known to be highly sensitive molecular HPV testing. While the addition of cytology to HPV testing can add performance, it also can add further costs and the potential for unnecessary colposcopies for what are merely cytomorphologic manifestations of an active HPV infection. Frequent invasive procedures such as colposcopy, which can be costly and lead to anxiety and distress in generally young women and the potential for overtreatment of likely regressive lesions, has been defined as a harm of screening by the US Preventive Services Task Force (USPSTF).

Details of the study

In a cohort from Kaiser Permanente Northern California, 1,208,710 women aged 30 years or older were screened with cotesting from 2003 to 2015. Those who cotested HPV negative and cytology negative were offered triennial screening. Positive cotest results were managed according to Kaiser protocol. Women with cytologic abnormalities were referred for colposcopy. Those with HPV positive/cytology negative results or HPV negative/cytology equivocal results underwent accelerated testing at 1 year. A total of 623 cervical cancers were identified and included in the analyses.

Using multiple analyses, Schiffman and colleagues demonstrated the sensitivity advantage of HPV testing. They clearly showed that the cytology component to cotesting performance over many years is very limited for detecting precancers and early curable cancers. For example, prediagnostic HPV testing (76.7%) was more likely to be positive than cytology (59.1%; P<.001 for paired comparison); 82.6% of all prediagnostic cotests were positive by HPV and/or cytology; and only 5.9% of the cotests were positive by cytology alone (HPV negative.)

Primary HPV testing is recommended as a potential screening strategy by an interim guidance group led by the Society of Gynecologic Oncology and the American Society for Colposcopy and Cervical Pathology, and it is the primary cervical cancer screening recommendation of USPSTF draft guidelines.¹ There have been reports that reliance on primary HPV testing would encourage cervical cancer mortality; Schiffman and colleagues point out, however, that according to their study data, such reports are overstated.

Despite these data, practically speaking, shifting away from standard cotesting poses numerous challenges for clinicians and laboratories alike; however, these data clearly show the limited value of cytology and, due to the overtreatment of likely regressive cervical intraepithelial neoplasia grade 2, the possible increased risk of preterm birth and its subsequent harm as well.

Study strengths and weaknesses

The authors examined the long-term relative history of HPV testing and cytology prior to cancer diagnosis in a large, prospectively followed US cohort where hundreds of women in this cohort developed cancer. There will not be a validation study of this size and scale in the near future. Further, the authors showed that the relative value of cytology to cotesting is minimal. Multiple subsequent rounds of cotesting after negative results also can be questioned. 

One weakness of the study is that the data were collected from only one health care system and therefore may not be representative of all populations. Additionally, cotesting was performed on 2 separately collected specimens, which may have reduced HPV testing performance.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Hormonal contraception (HC) has long been utilized safely in this country for a variety of indications, including pregnancy prevention, timing pregnancy appropriately, management of symptoms (dysmenorrhea, irregular menstrual cycles, heavy menstrual bleeding), and to prevent serious diseases (such as ovarian cancer, uterine cancer, osteoporosis in women with premature menopause). Like most prescription medications, there are potential adverse effects. With HC, side effects such as venous thromboembolism, a slight increase in liver cancer, and a possible increase in breast cancer risk have long been recognized.

Danish study compared HC use with breast cancer risk
In the December 7, 2017, issue of New England Journal of Medicine,¹ investigators in Denmark published a study of women using HC (oral, transdermal, intravaginal routes, and levonorgestrel intrauterine device [LNG-IUD]) and breast cancer risk compared with women who did not use HC. This retrospective observational country-wide study was very large (1.8 million women followed over an average of 10.9 years), which allowed for the detection of even small changes in breast cancer risk.

Putting results in perspective
It is important to point out that this is an observational study, and small effect sizes (1 in 7,600) should be interpreted with caution. Observational studies can introduce many different types of bias (prescribing bias, confounding bias, etc). Of note, while the LNG-IUD was associated with a small increased risk of breast cancer (relative risk [RR], 1.21; 95% confidence interval [CI], 1.11-1.33]), the higher dose continuous progestin administration (medroxyprogesterone) was not (RR, 0.95; 95% CI, 0.40-2.29).¹

Nonetheless, providing patients with a balanced summary of this new study along with other published and reliable information about HC that conveys both benefits and risks is important to assure that each woman makes a decision regarding HC that achieves her health and life goals. See "Counseling talking points" below.

Bottom line

This recent study demonstrated that in Denmark, a woman's risk of developing breast cancer is very slightly elevated on HC¹:

• 1 in 7,690 users overall
• 1 in 50,000 women older than age 35 years.

By comparison, the risk of maternal mortality in the United States is 1 in 3,788.² A substantial reduction in HC use would likely increase unintended and mistimed pregnancies with a potential substantial negative impact on quality of life and personal/societal cost.

The best available data indicate that a woman's risk of developing any cancer is slightly less on HC than not on HC, even with this incremental breast cancer increase.^3,4

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Hormonal contraception (HC) has long been utilized safely in this country for a variety of indications, including pregnancy prevention, timing pregnancy appropriately, management of symptoms (dysmenorrhea, irregular menstrual cycles, heavy menstrual bleeding), and to prevent serious diseases (such as ovarian cancer, uterine cancer, osteoporosis in women with premature menopause). Like most prescription medications, there are potential adverse effects. With HC, side effects such as venous thromboembolism, a slight increase in liver cancer, and a possible increase in breast cancer risk have long been recognized.

Danish study compared HC use with breast cancer risk
In the December 7, 2017, issue of New England Journal of Medicine,¹ investigators in Denmark published a study of women using HC (oral, transdermal, intravaginal routes, and levonorgestrel intrauterine device [LNG-IUD]) and breast cancer risk compared with women who did not use HC. This retrospective observational country-wide study was very large (1.8 million women followed over an average of 10.9 years), which allowed for the detection of even small changes in breast cancer risk.

Putting results in perspective
It is important to point out that this is an observational study, and small effect sizes (1 in 7,600) should be interpreted with caution. Observational studies can introduce many different types of bias (prescribing bias, confounding bias, etc). Of note, while the LNG-IUD was associated with a small increased risk of breast cancer (relative risk [RR], 1.21; 95% confidence interval [CI], 1.11-1.33]), the higher dose continuous progestin administration (medroxyprogesterone) was not (RR, 0.95; 95% CI, 0.40-2.29).¹

Nonetheless, providing patients with a balanced summary of this new study along with other published and reliable information about HC that conveys both benefits and risks is important to assure that each woman makes a decision regarding HC that achieves her health and life goals. See "Counseling talking points" below.

Bottom line

This recent study demonstrated that in Denmark, a woman's risk of developing breast cancer is very slightly elevated on HC¹:

• 1 in 7,690 users overall
• 1 in 50,000 women older than age 35 years.

By comparison, the risk of maternal mortality in the United States is 1 in 3,788.² A substantial reduction in HC use would likely increase unintended and mistimed pregnancies with a potential substantial negative impact on quality of life and personal/societal cost.

The best available data indicate that a woman's risk of developing any cancer is slightly less on HC than not on HC, even with this incremental breast cancer increase.^3,4

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Hormonal contraception (HC) has long been utilized safely in this country for a variety of indications, including pregnancy prevention, timing pregnancy appropriately, management of symptoms (dysmenorrhea, irregular menstrual cycles, heavy menstrual bleeding), and to prevent serious diseases (such as ovarian cancer, uterine cancer, osteoporosis in women with premature menopause). Like most prescription medications, there are potential adverse effects. With HC, side effects such as venous thromboembolism, a slight increase in liver cancer, and a possible increase in breast cancer risk have long been recognized.

Danish study compared HC use with breast cancer risk
In the December 7, 2017, issue of New England Journal of Medicine,¹ investigators in Denmark published a study of women using HC (oral, transdermal, intravaginal routes, and levonorgestrel intrauterine device [LNG-IUD]) and breast cancer risk compared with women who did not use HC. This retrospective observational country-wide study was very large (1.8 million women followed over an average of 10.9 years), which allowed for the detection of even small changes in breast cancer risk.

Putting results in perspective
It is important to point out that this is an observational study, and small effect sizes (1 in 7,600) should be interpreted with caution. Observational studies can introduce many different types of bias (prescribing bias, confounding bias, etc). Of note, while the LNG-IUD was associated with a small increased risk of breast cancer (relative risk [RR], 1.21; 95% confidence interval [CI], 1.11-1.33]), the higher dose continuous progestin administration (medroxyprogesterone) was not (RR, 0.95; 95% CI, 0.40-2.29).¹

Nonetheless, providing patients with a balanced summary of this new study along with other published and reliable information about HC that conveys both benefits and risks is important to assure that each woman makes a decision regarding HC that achieves her health and life goals. See "Counseling talking points" below.

Bottom line

This recent study demonstrated that in Denmark, a woman's risk of developing breast cancer is very slightly elevated on HC¹:

• 1 in 7,690 users overall
• 1 in 50,000 women older than age 35 years.

By comparison, the risk of maternal mortality in the United States is 1 in 3,788.² A substantial reduction in HC use would likely increase unintended and mistimed pregnancies with a potential substantial negative impact on quality of life and personal/societal cost.

The best available data indicate that a woman's risk of developing any cancer is slightly less on HC than not on HC, even with this incremental breast cancer increase.^3,4

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Citation: Heazell HE, et al. Association between maternal sleep practices and late stillbirth – findings from a stillbirth case-control study. Published online November 20, 2017. DOI: 10.1111/1471-0528.14967.

Citation: Heazell HE, et al. Association between maternal sleep practices and late stillbirth – findings from a stillbirth case-control study. Published online November 20, 2017. DOI: 10.1111/1471-0528.14967.

Citation: Heazell HE, et al. Association between maternal sleep practices and late stillbirth – findings from a stillbirth case-control study. Published online November 20, 2017. DOI: 10.1111/1471-0528.14967.

EXPERT COMMENTARY

Although the incidence of lower urinary tract and ureteral injury following gynecologic surgery is low, intraoperative identification of ureteral patency can prevent serious long-term sequelae. Since the indigo carmine shortage in 2014, US surgeons have searched for multiple alternative agents. Intravenous methylene blue is suboptimal due to its systemic adverse effects and the length of time for dye excretion in the urine.

Grimes and colleagues conducted a study to determine if there was any significant difference in surgeon satisfaction among 4 different alternatives to indigo carmine for intraoperative ureteral patency evaluation.

Related article:
Farewell to indigo carmine

Details of the study

The investigators conducted a randomized clinical trial of 130 women undergoing benign gynecologic or pelvic reconstructive surgery. Four different regimens were used for intraoperative ureteral evaluation: 1) oral phenazopyridine 200 mg, 2) intravenous sodium fluorescein 25 mg, 3) mannitol bladder distention, and 4) normal saline bladder distention.

Study outcomes. The primary outcome was surgeon satisfaction based on a 0 to 100 point visual analog scale rating (with 0 indicating strong agreement, 100 indicating disagreement). Secondary outcomes included ease of ureteral jet visualization, time to surgeon confidence of ureteral patency, and occurrence of adverse events over 6 weeks.

Surgeon satisfaction rating. The investigators found statistically significant physician satisfaction with the use of mannitol as a bladder distention medium over oral phenazopyridine, and slightly better satisfaction compared with the use of intravenous sodium fluorescein or normal saline distention. The median (range) visual analog scores for ureteral patency were phenazopyridine, 48 (0–83); sodium fluorescein 20 (0–82); mannitol, 0 (0–44); and normal saline, 23 (3–96) (P<.001).

There was no difference across the 4 groups in the timing to surgeon confidence of ureteral patency, length of cystoscopy (on average, 3 minutes), and development of postoperative urinary tract infections (UTIs).

Most dissatisfaction related to phenazopyridine is the fact that the resulting orange-stained urine can obscure the bladder mucosa.

One significant adverse event was a protocol deviation in which 1 patient received an incorrect dose of IV sodium fluorescein (500 mg) instead of the recommended 25-mg dose.

Related article:
Alternative options for visualizing ureteral patency during intraoperative cystoscopy

Study strengths and weaknesses

The strength of this study is in its randomized design and power. Its major weakness is surgeon bias, since the surgeons could not possibly be blinded to the method used.

The study confirms the problem that phenazopyridine makes the urine so orange that bladder mucosal lesions and de novo hematuria could be difficult to detect. Recommending mannitol as a hypertonic distending medium (as it is used in hysteroscopy procedures), however, may be premature. Prior studies have shown increased postoperative UTIs when 50% and 10% dextrose was used versus normal saline for cystoscopy.^1,2 Since the Grimes study protocol did not include postoperative urine collection for cultures, more research on UTIs after mannitol use would be needed before surgeons confidently could use it routinely.

In our practice, surgeons prefer that intravenous sodium fluorescein be administered just prior to cystoscopy and oral phenazopyridine en route to the operating room. I agree that a major disadvantage to phenazopyridine is the heavy orange staining that obscures visualization.

Finally, this study did not account for cost of the various methods; standard normal saline would be cheapest, followed by phenazopyridine.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Although the incidence of lower urinary tract and ureteral injury following gynecologic surgery is low, intraoperative identification of ureteral patency can prevent serious long-term sequelae. Since the indigo carmine shortage in 2014, US surgeons have searched for multiple alternative agents. Intravenous methylene blue is suboptimal due to its systemic adverse effects and the length of time for dye excretion in the urine.

Grimes and colleagues conducted a study to determine if there was any significant difference in surgeon satisfaction among 4 different alternatives to indigo carmine for intraoperative ureteral patency evaluation.

Related article:
Farewell to indigo carmine

Details of the study

The investigators conducted a randomized clinical trial of 130 women undergoing benign gynecologic or pelvic reconstructive surgery. Four different regimens were used for intraoperative ureteral evaluation: 1) oral phenazopyridine 200 mg, 2) intravenous sodium fluorescein 25 mg, 3) mannitol bladder distention, and 4) normal saline bladder distention.

Study outcomes. The primary outcome was surgeon satisfaction based on a 0 to 100 point visual analog scale rating (with 0 indicating strong agreement, 100 indicating disagreement). Secondary outcomes included ease of ureteral jet visualization, time to surgeon confidence of ureteral patency, and occurrence of adverse events over 6 weeks.

Surgeon satisfaction rating. The investigators found statistically significant physician satisfaction with the use of mannitol as a bladder distention medium over oral phenazopyridine, and slightly better satisfaction compared with the use of intravenous sodium fluorescein or normal saline distention. The median (range) visual analog scores for ureteral patency were phenazopyridine, 48 (0–83); sodium fluorescein 20 (0–82); mannitol, 0 (0–44); and normal saline, 23 (3–96) (P<.001).

There was no difference across the 4 groups in the timing to surgeon confidence of ureteral patency, length of cystoscopy (on average, 3 minutes), and development of postoperative urinary tract infections (UTIs).

Most dissatisfaction related to phenazopyridine is the fact that the resulting orange-stained urine can obscure the bladder mucosa.

One significant adverse event was a protocol deviation in which 1 patient received an incorrect dose of IV sodium fluorescein (500 mg) instead of the recommended 25-mg dose.

Related article:
Alternative options for visualizing ureteral patency during intraoperative cystoscopy

Study strengths and weaknesses

The strength of this study is in its randomized design and power. Its major weakness is surgeon bias, since the surgeons could not possibly be blinded to the method used.

The study confirms the problem that phenazopyridine makes the urine so orange that bladder mucosal lesions and de novo hematuria could be difficult to detect. Recommending mannitol as a hypertonic distending medium (as it is used in hysteroscopy procedures), however, may be premature. Prior studies have shown increased postoperative UTIs when 50% and 10% dextrose was used versus normal saline for cystoscopy.^1,2 Since the Grimes study protocol did not include postoperative urine collection for cultures, more research on UTIs after mannitol use would be needed before surgeons confidently could use it routinely.

In our practice, surgeons prefer that intravenous sodium fluorescein be administered just prior to cystoscopy and oral phenazopyridine en route to the operating room. I agree that a major disadvantage to phenazopyridine is the heavy orange staining that obscures visualization.

Finally, this study did not account for cost of the various methods; standard normal saline would be cheapest, followed by phenazopyridine.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Although the incidence of lower urinary tract and ureteral injury following gynecologic surgery is low, intraoperative identification of ureteral patency can prevent serious long-term sequelae. Since the indigo carmine shortage in 2014, US surgeons have searched for multiple alternative agents. Intravenous methylene blue is suboptimal due to its systemic adverse effects and the length of time for dye excretion in the urine.

Grimes and colleagues conducted a study to determine if there was any significant difference in surgeon satisfaction among 4 different alternatives to indigo carmine for intraoperative ureteral patency evaluation.

Related article:
Farewell to indigo carmine

Details of the study

The investigators conducted a randomized clinical trial of 130 women undergoing benign gynecologic or pelvic reconstructive surgery. Four different regimens were used for intraoperative ureteral evaluation: 1) oral phenazopyridine 200 mg, 2) intravenous sodium fluorescein 25 mg, 3) mannitol bladder distention, and 4) normal saline bladder distention.

Study outcomes. The primary outcome was surgeon satisfaction based on a 0 to 100 point visual analog scale rating (with 0 indicating strong agreement, 100 indicating disagreement). Secondary outcomes included ease of ureteral jet visualization, time to surgeon confidence of ureteral patency, and occurrence of adverse events over 6 weeks.

Surgeon satisfaction rating. The investigators found statistically significant physician satisfaction with the use of mannitol as a bladder distention medium over oral phenazopyridine, and slightly better satisfaction compared with the use of intravenous sodium fluorescein or normal saline distention. The median (range) visual analog scores for ureteral patency were phenazopyridine, 48 (0–83); sodium fluorescein 20 (0–82); mannitol, 0 (0–44); and normal saline, 23 (3–96) (P<.001).

There was no difference across the 4 groups in the timing to surgeon confidence of ureteral patency, length of cystoscopy (on average, 3 minutes), and development of postoperative urinary tract infections (UTIs).

Most dissatisfaction related to phenazopyridine is the fact that the resulting orange-stained urine can obscure the bladder mucosa.

One significant adverse event was a protocol deviation in which 1 patient received an incorrect dose of IV sodium fluorescein (500 mg) instead of the recommended 25-mg dose.

Related article:
Alternative options for visualizing ureteral patency during intraoperative cystoscopy

Study strengths and weaknesses

The strength of this study is in its randomized design and power. Its major weakness is surgeon bias, since the surgeons could not possibly be blinded to the method used.

The study confirms the problem that phenazopyridine makes the urine so orange that bladder mucosal lesions and de novo hematuria could be difficult to detect. Recommending mannitol as a hypertonic distending medium (as it is used in hysteroscopy procedures), however, may be premature. Prior studies have shown increased postoperative UTIs when 50% and 10% dextrose was used versus normal saline for cystoscopy.^1,2 Since the Grimes study protocol did not include postoperative urine collection for cultures, more research on UTIs after mannitol use would be needed before surgeons confidently could use it routinely.

In our practice, surgeons prefer that intravenous sodium fluorescein be administered just prior to cystoscopy and oral phenazopyridine en route to the operating room. I agree that a major disadvantage to phenazopyridine is the heavy orange staining that obscures visualization.

Finally, this study did not account for cost of the various methods; standard normal saline would be cheapest, followed by phenazopyridine.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.