OBG Management

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EXPERT COMMENTARY

Influenza can be a serious, even life-threatening infection, especially in pregnant women and their newborn infants.¹ For that reason, the Centers for Disease Control and Prevention (CDC) and the American College of Obstetricians and Gynecologists (ACOG) strongly recommend that all pregnant women receive the inactivated influenza vaccine at the start of each flu season, regardless of trimester of exposure.

The most widely-used vaccine in the United States is the inactivated quadrivalent vaccine, which is intended for intramuscular administration in a single dose. The 2017-2018 version of this vaccine includes 2 influenza A antigens and 2 influenza B antigens. The first of the A antigens differs from last year's vaccine. The other 3 antigens are the same as in the 2016-2017 vaccine:

• A/Michigan/45/2015 (H1N1) pdm09-like virus
• A/Hong Kong/4801/2014 (H3N2)-like virus  
• B/Brisbane/60/2008-like virus
• B/Phuket/3073/2013-like virus (B/Yamagota)

Several recent reports in large, diverse populations^2-5 have demonstrated that the vaccine does not increase the risk of spontaneous abortion, stillbirth, preterm delivery, or congenital anomalies. Therefore, a recent report by Donahue and colleagues⁶ is surprising and is certainly worthy of our attention. 

Related article:
Does influenza immunization during pregnancy confer flu protection to newborns?

Details of the study

Donahue and colleagues, experienced investigators, were tasked by the CDC with using information from the Vaccine Safety Datalink to specifically assess the safety of the influenza vaccine when administered early in pregnancy. They evaluated 485 women who had experienced a spontaneous abortion in 1 of 2 time periods: September 1, 2010 to April 28, 2011 and September 1, 2011 to April 28, 2012. These women were matched by last menstrual period with controls who subsequently had a liveborn infant or stillbirth at greater than 20 weeks of gestation. The exposure of interest was receipt of the monovalent H1N1 vaccine (H1N1pdm09), the inactivated trivalent vaccine (A/California/7/2009 H1N1 pdm09-like, A/Perth/16/2009 H3N2-like, and B/Brisbane/60/2008-like), or both in the 28 days immediately preceding the spontaneous abortion. The investigators also considered 2 other windows of exposure: 29 to 56 days and greater than 56 days. In addition, they controlled for the following potential confounding variables: maternal age, smoking history, presence of type 1 or 2 diabetes, prepregnancy BMI, and previous health care utilization. 

Cases were significantly older than controls. They also were more likely to be African-American, to have had a history of greater than or equal to 2 spontaneous abortions, and to have smoked during pregnancy. The median gestational age at the time of spontaneous abortion was 7 weeks. Overall, the adjusted odds ratio (aOR) of spontaneous abortion within the 1- to 28-day window was 2.0 (95% confidence interval [CI], 1.1-3.6). There was not even a weak association in the other 2 windows of exposure. However, in women who received the pH1N1 vaccine in the previous flu season, the aOR was 7.7 (95% CI, 2.2-27.3). When women who had experienced 2 or more spontaneous abortions were excluded, the aOR remained significantly elevated at 6.5 (95% CI, 1.7-24.3). The aOR was 1.3 (95% CI, 0.7-2.7) in women who were not vaccinated with the pH1N1 vaccine in the previous flu season.

Donahue and colleagues⁶ offered several possible explanations for their observations. They noted that the pH1N1 vaccine seemed to cause at least mild increases in pro-inflammatory cytokines, particularly in pregnant compared with nonpregnant women. In addition, infection with the pH1N1 virus or vaccination with the pH1N1 vaccine induces an increase in T helper type-1 cells, which exert a pro-inflammatory effect. Excessive inflammation, in turn, may cause spontaneous abortion.

Related article:
5 ways to reduce infection risk during pregnancy

Study limitations

This study has several important limitations. First, the vaccine used in the investigation is not identical to the one used most commonly today. Second, although the number of women with spontaneous abortions is relatively large, the number who received the pH1N1-containing vaccine in consecutive years was relatively small. Third, this case-control study was able to estimate an odds ratio for the adverse outcome, but it could not prove causation, nor could it provide a precise estimate of absolute risk for a spontaneous miscarriage following the influenza vaccine. Finally, the authors, understandably,were unable to control for all the myriad factors that may increase the risk for spontaneous abortion.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Influenza can be a serious, even life-threatening infection, especially in pregnant women and their newborn infants.¹ For that reason, the Centers for Disease Control and Prevention (CDC) and the American College of Obstetricians and Gynecologists (ACOG) strongly recommend that all pregnant women receive the inactivated influenza vaccine at the start of each flu season, regardless of trimester of exposure.

The most widely-used vaccine in the United States is the inactivated quadrivalent vaccine, which is intended for intramuscular administration in a single dose. The 2017-2018 version of this vaccine includes 2 influenza A antigens and 2 influenza B antigens. The first of the A antigens differs from last year's vaccine. The other 3 antigens are the same as in the 2016-2017 vaccine:

• A/Michigan/45/2015 (H1N1) pdm09-like virus
• A/Hong Kong/4801/2014 (H3N2)-like virus  
• B/Brisbane/60/2008-like virus
• B/Phuket/3073/2013-like virus (B/Yamagota)

Several recent reports in large, diverse populations^2-5 have demonstrated that the vaccine does not increase the risk of spontaneous abortion, stillbirth, preterm delivery, or congenital anomalies. Therefore, a recent report by Donahue and colleagues⁶ is surprising and is certainly worthy of our attention. 

Related article:
Does influenza immunization during pregnancy confer flu protection to newborns?

Details of the study

Donahue and colleagues, experienced investigators, were tasked by the CDC with using information from the Vaccine Safety Datalink to specifically assess the safety of the influenza vaccine when administered early in pregnancy. They evaluated 485 women who had experienced a spontaneous abortion in 1 of 2 time periods: September 1, 2010 to April 28, 2011 and September 1, 2011 to April 28, 2012. These women were matched by last menstrual period with controls who subsequently had a liveborn infant or stillbirth at greater than 20 weeks of gestation. The exposure of interest was receipt of the monovalent H1N1 vaccine (H1N1pdm09), the inactivated trivalent vaccine (A/California/7/2009 H1N1 pdm09-like, A/Perth/16/2009 H3N2-like, and B/Brisbane/60/2008-like), or both in the 28 days immediately preceding the spontaneous abortion. The investigators also considered 2 other windows of exposure: 29 to 56 days and greater than 56 days. In addition, they controlled for the following potential confounding variables: maternal age, smoking history, presence of type 1 or 2 diabetes, prepregnancy BMI, and previous health care utilization. 

Cases were significantly older than controls. They also were more likely to be African-American, to have had a history of greater than or equal to 2 spontaneous abortions, and to have smoked during pregnancy. The median gestational age at the time of spontaneous abortion was 7 weeks. Overall, the adjusted odds ratio (aOR) of spontaneous abortion within the 1- to 28-day window was 2.0 (95% confidence interval [CI], 1.1-3.6). There was not even a weak association in the other 2 windows of exposure. However, in women who received the pH1N1 vaccine in the previous flu season, the aOR was 7.7 (95% CI, 2.2-27.3). When women who had experienced 2 or more spontaneous abortions were excluded, the aOR remained significantly elevated at 6.5 (95% CI, 1.7-24.3). The aOR was 1.3 (95% CI, 0.7-2.7) in women who were not vaccinated with the pH1N1 vaccine in the previous flu season.

Donahue and colleagues⁶ offered several possible explanations for their observations. They noted that the pH1N1 vaccine seemed to cause at least mild increases in pro-inflammatory cytokines, particularly in pregnant compared with nonpregnant women. In addition, infection with the pH1N1 virus or vaccination with the pH1N1 vaccine induces an increase in T helper type-1 cells, which exert a pro-inflammatory effect. Excessive inflammation, in turn, may cause spontaneous abortion.

Related article:
5 ways to reduce infection risk during pregnancy

Study limitations

This study has several important limitations. First, the vaccine used in the investigation is not identical to the one used most commonly today. Second, although the number of women with spontaneous abortions is relatively large, the number who received the pH1N1-containing vaccine in consecutive years was relatively small. Third, this case-control study was able to estimate an odds ratio for the adverse outcome, but it could not prove causation, nor could it provide a precise estimate of absolute risk for a spontaneous miscarriage following the influenza vaccine. Finally, the authors, understandably,were unable to control for all the myriad factors that may increase the risk for spontaneous abortion.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Influenza can be a serious, even life-threatening infection, especially in pregnant women and their newborn infants.¹ For that reason, the Centers for Disease Control and Prevention (CDC) and the American College of Obstetricians and Gynecologists (ACOG) strongly recommend that all pregnant women receive the inactivated influenza vaccine at the start of each flu season, regardless of trimester of exposure.

The most widely-used vaccine in the United States is the inactivated quadrivalent vaccine, which is intended for intramuscular administration in a single dose. The 2017-2018 version of this vaccine includes 2 influenza A antigens and 2 influenza B antigens. The first of the A antigens differs from last year's vaccine. The other 3 antigens are the same as in the 2016-2017 vaccine:

• A/Michigan/45/2015 (H1N1) pdm09-like virus
• A/Hong Kong/4801/2014 (H3N2)-like virus  
• B/Brisbane/60/2008-like virus
• B/Phuket/3073/2013-like virus (B/Yamagota)

Several recent reports in large, diverse populations^2-5 have demonstrated that the vaccine does not increase the risk of spontaneous abortion, stillbirth, preterm delivery, or congenital anomalies. Therefore, a recent report by Donahue and colleagues⁶ is surprising and is certainly worthy of our attention. 

Related article:
Does influenza immunization during pregnancy confer flu protection to newborns?

Details of the study

Donahue and colleagues, experienced investigators, were tasked by the CDC with using information from the Vaccine Safety Datalink to specifically assess the safety of the influenza vaccine when administered early in pregnancy. They evaluated 485 women who had experienced a spontaneous abortion in 1 of 2 time periods: September 1, 2010 to April 28, 2011 and September 1, 2011 to April 28, 2012. These women were matched by last menstrual period with controls who subsequently had a liveborn infant or stillbirth at greater than 20 weeks of gestation. The exposure of interest was receipt of the monovalent H1N1 vaccine (H1N1pdm09), the inactivated trivalent vaccine (A/California/7/2009 H1N1 pdm09-like, A/Perth/16/2009 H3N2-like, and B/Brisbane/60/2008-like), or both in the 28 days immediately preceding the spontaneous abortion. The investigators also considered 2 other windows of exposure: 29 to 56 days and greater than 56 days. In addition, they controlled for the following potential confounding variables: maternal age, smoking history, presence of type 1 or 2 diabetes, prepregnancy BMI, and previous health care utilization. 

Cases were significantly older than controls. They also were more likely to be African-American, to have had a history of greater than or equal to 2 spontaneous abortions, and to have smoked during pregnancy. The median gestational age at the time of spontaneous abortion was 7 weeks. Overall, the adjusted odds ratio (aOR) of spontaneous abortion within the 1- to 28-day window was 2.0 (95% confidence interval [CI], 1.1-3.6). There was not even a weak association in the other 2 windows of exposure. However, in women who received the pH1N1 vaccine in the previous flu season, the aOR was 7.7 (95% CI, 2.2-27.3). When women who had experienced 2 or more spontaneous abortions were excluded, the aOR remained significantly elevated at 6.5 (95% CI, 1.7-24.3). The aOR was 1.3 (95% CI, 0.7-2.7) in women who were not vaccinated with the pH1N1 vaccine in the previous flu season.

Donahue and colleagues⁶ offered several possible explanations for their observations. They noted that the pH1N1 vaccine seemed to cause at least mild increases in pro-inflammatory cytokines, particularly in pregnant compared with nonpregnant women. In addition, infection with the pH1N1 virus or vaccination with the pH1N1 vaccine induces an increase in T helper type-1 cells, which exert a pro-inflammatory effect. Excessive inflammation, in turn, may cause spontaneous abortion.

Related article:
5 ways to reduce infection risk during pregnancy

Study limitations

This study has several important limitations. First, the vaccine used in the investigation is not identical to the one used most commonly today. Second, although the number of women with spontaneous abortions is relatively large, the number who received the pH1N1-containing vaccine in consecutive years was relatively small. Third, this case-control study was able to estimate an odds ratio for the adverse outcome, but it could not prove causation, nor could it provide a precise estimate of absolute risk for a spontaneous miscarriage following the influenza vaccine. Finally, the authors, understandably,were unable to control for all the myriad factors that may increase the risk for spontaneous abortion.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

One-third of patients who visit a gynecologist are there because of abnormal uterine bleeding (AUB), which is believed to account for more than 70% of gyneco¬logic consults in perimenopausal and postmenopausal women. The American College of Obstetricians and Gynecologists Practice Bulle¬tin on AUB now states that a negative blind endometrial biopsy is not a stopping point in persistent bleeding.

In this supplement, learn about the advantages of diagnosing AUB using a hysteroscope.

Authors:

Steven R. Goldstein, MD, CCD, NCMP, FACOG

New York University Medical Center New York, New York

Ted L. Anderson, MD, PhD

Vanderbilt University Medical School Nashville, Tennessee

 

Click here to read this supplement.

To access the posttest and evaluation, visit
www.worldclasscme.com/endometrialevaluation

One-third of patients who visit a gynecologist are there because of abnormal uterine bleeding (AUB), which is believed to account for more than 70% of gyneco¬logic consults in perimenopausal and postmenopausal women. The American College of Obstetricians and Gynecologists Practice Bulle¬tin on AUB now states that a negative blind endometrial biopsy is not a stopping point in persistent bleeding.

In this supplement, learn about the advantages of diagnosing AUB using a hysteroscope.

Authors:

Steven R. Goldstein, MD, CCD, NCMP, FACOG

New York University Medical Center New York, New York

Ted L. Anderson, MD, PhD

Vanderbilt University Medical School Nashville, Tennessee

 

Click here to read this supplement.

To access the posttest and evaluation, visit
www.worldclasscme.com/endometrialevaluation

One-third of patients who visit a gynecologist are there because of abnormal uterine bleeding (AUB), which is believed to account for more than 70% of gyneco¬logic consults in perimenopausal and postmenopausal women. The American College of Obstetricians and Gynecologists Practice Bulle¬tin on AUB now states that a negative blind endometrial biopsy is not a stopping point in persistent bleeding.

In this supplement, learn about the advantages of diagnosing AUB using a hysteroscope.

Authors:

Steven R. Goldstein, MD, CCD, NCMP, FACOG

New York University Medical Center New York, New York

Ted L. Anderson, MD, PhD

Vanderbilt University Medical School Nashville, Tennessee

 

Click here to read this supplement.

To access the posttest and evaluation, visit
www.worldclasscme.com/endometrialevaluation

A) Dermoid plug CORRECT
The most common appearance of an ovarian dermoid is a cystic lesion with a focal echogenic nodule protruding into the cyst (Rokitansky nodule).¹

A) Dermoid plug CORRECT
The most common appearance of an ovarian dermoid is a cystic lesion with a focal echogenic nodule protruding into the cyst (Rokitansky nodule).¹

A) Dermoid plug CORRECT
The most common appearance of an ovarian dermoid is a cystic lesion with a focal echogenic nodule protruding into the cyst (Rokitansky nodule).¹

In 2015 more than 30,000 deaths from opioid overdose were reported (FIGURE).¹ More than 50% of the deaths were due to prescription opioids. The opioid crisis is a public health emergency and clinicians are diligently working to reduce both the number of opioid prescriptions and the doses prescribed per prescription.

In obstetrics, there is growing concern that narcotics used for the treatment of pain in women who are breastfeeding may increase the risk of adverse effects in newborns, including excessive sedation and respiratory depression. The American Academy of Pediatrics (AAP), the US Food and Drug Administration (FDA) and the American College of Obstetricians and Gynecologists (ACOG) recommend against the use of codeine and tramadol in women who are breastfeeding because their newborns may have adverse reactions, including excessive sleepiness, difficulty breathing, and potentially fatal breathing problems.^2–4 In addition, there is growing concern that the use of oxycodone and hydrocodone should also be limited in women who are breastfeeding. In this article, I discuss the rationale for these recommendations.

Related article:
Landmark women’s health care remains law of the land

Codeine

Codeine is metabolized to morphine by CYP2D6 and CYP2D7. Both codeine and morphine are excreted into breast milk. Some women are ultrarapid metabolizers of codeine because of high levels of CYP2D6, resulting in higher concentrations of morphine in their breast milk and their breast fed newborn.^2,5 In many women who are ultra-rapid metabolizers of codeine, CYP2D6 gene duplication or multiplication is the cause of the increased enzyme activity.⁶ Genotyping can identify some women who are ultrarapid metabolizers, but it is not currently utilized widely in clinical practice.

In the United States approximately 5% of women express high levels of CYP2D6 and are ultra-rapid metabolizers of codeine.⁴ In Ethiopia as many as 29% of women are ultrarapid metabolizers.⁷ Newborn central nervous system (CNS) depression is the most common adverse effect of fetal ingestion of excessive codeine and mor-phine from breast milk and may present as sedation, apnea, bradycardia, or cyanosis.⁸ Multiple newborn fatalities have been re-ported in the literature when lactating mothers who were ultrarapid metabolizers took co-deine. The FDA and ACOG recommend against the use of codeine in lactating women.

Hydrocodone

Hydrocodone, a hydrogenated ketone derivative of codeine, is metabolized by CYP2D6 to hydromorphone. Both hydrocodone and hydromorphone are present in breast milk. In lactating mothers taking hydrocodone, up to 9% of the dose may be ingested by the breastfeeding newborn.⁹ There is concern that hydrocodone use by women who are breastfeeding and are ultrarapid metabolizers may cause increased fetal consumption of hydromorphone resulting in adverse outcomes in the newborn. The AAP cautions against the use of hydrocodone.²

Oxycodone

Oxycodone is metabolized by CYP2D6 to oxymorphone and is concentrated into breast milk.¹⁰ Oxymorphone is more than 10 times more potent than oxycodone. In one study of lactating women taking oxycodone, codeine, or acetaminophen, the rates of neonate CNS depression were 20%, 17%, and 0.5%, respectively.¹¹ The authors concluded that for mothers who are breastfeeding oxycodone was no safer than codeine because both medications were associated with a high rate of depression in the neonate. Newborns who develop CNS depression from exposure to oxycodone in breast milk will respond to naloxone treatment.¹² The AAP recommends against prescribing oxycodone for women who are breastfeeding their infants.²

In a recent communication, the Society for Obstetric Anesthesia and Perinatology (SOAP) observed that in the United States, following cesarean delivery the majority of women receive oxycodone or hydrocodone.¹³ SOAP disagreed with the AAP recommendation against the use of oxycodone or hydrocodone in breastfeeding women. SOAP noted that all narcotics can produce adverse effects in newborns of breastfeeding women and that there are no good data that the prescription of oxycodone or hydrocodone is more risky than morphine or hydromorphone. However, based on their assessment of risk and benefit, pediatricians prioritize the use of acetaminophen and morphine and seldom use oxycodone or hydrocodone to treat moderate to severe pain in babies and children.

Tramadol

Tramadol is metabolized by CYP2D6 to O-desmethyltramadol. Both tramadol and O-desmethyltramadol are excreted into breast milk. In ultrarapid metabolizers, a greater concentration of O-desmethyltramadol is excreted into breast milk. The FDA reported that they identified no serious neonatal adverse events in the literature due to the use of tramadol by women who are breastfeeding. However, given that tramadol and its CYP2D6 metabolite enter breast milk and the potential for life-threatening respiratory de-pression in the infant, the FDA included tramadol in its warning about codeine.³

Codeine, hydrocodone, oxycodone, and tramadol are all metabolized to more potent metabolites by the CYP2D6 enzyme. Individuals with low CYP2D6 activity, representing about 5% of the US population, cannot fully activate these narcotics. Hence they may not get adequate pain relief when treated with codeine, oxycodone, hydrocodone, or tramadol. Given their resistance to these medications they may first be placed on a higher dose of the narcotic and then switched from a high ineffective dose of one of the agents activated by CYP2D6 to a high dose of morphine or hydromorphone. This can be dangerous because they may then receive an excessive dose of narcotic and develop respiratory depression.¹⁴

Read about how other pain medications affect breast milk.

Aspirin

There are very little high quality data about the use of aspirin in women breastfeeding and the effect on the neonate. If a mother takes aspirin, the drug will enter breast milk. It is estimated that the nursing baby receives about 4% to 8% of the mother’s dose. The World Health Organization recommends that aspirin is compatible with breastfeeding in occasional small doses, but repeated administration of aspirin in normal doses should be avoided in women who are breastfeeding. If chronic or high-dose aspirin therapy is recommended, the infant should be monitored for side effects including metabolic acidosis¹⁵ and coagulation disorders.¹⁶ The National Reye’s Syndrome Foundation recommends against the use of aspirin in women who are breastfeeding because of the theoretical risk of triggering Reye syndrome.¹⁷ Acetaminophen and ibuprofen are recommended by the WHO for chronic treatment of pain during breastfeeding.¹⁶

Acetaminophen and ibuprofen

For the medication treatment of pain in women who are breastfeeding, the WHO recommends the use of acetaminophen and ibuprofen.¹⁶ Acetaminophen is transferred from the maternal circulation into breast milk, but it is estimated that the dose to the nursing neonate is <0.3% of the maternal dose.¹⁸ In mothers taking ibuprofen 1600 mg daily, the concentration of ibuprofen in breast milk was below the level of laboratory detection (<1 mg/L).¹⁹ Ibuprofen treatment is thought to be safe for women who are breastfeeding because of its short half-life (2 hours), low excretion into milk, and few reported adverse effects in infants.

Morphine

Morphine is not metabolized by CYP2D6 and is excreted into breast milk. Many experts believe that women who are breastfeeding may take standard doses of oral morphine with few adverse effects in the newborn.^20,21 For the treatment of moderate to severe pain in opioid-naive adults, morphine doses in the range of 10 mg orally every 4 hours up to 30 mg orally every 4 hours are prescribed. When using a solution of morphine, standard doses are 10 mg to 20 mg every 4 hours, as needed to treat pain. When using morphine tablets, standard doses are 15 mg to 30 mg every 4 hours. The WHO states that occasional doses of morphine are usually safe for women breastfeeding their newborn.¹⁶ The AAP recommends the use of morphine and hydromorphone when narcotic agents are needed to treat pain in breastfeeding women.²

Hydromorphone

Hydromorphone, a hydrogenated ketone derivative of morphine, is not metabolized by CYP2D6 and is excreted into breast milk. There are limited data on the safety of hydromorphone during breastfeeding. Breast milk concentrations of hydromorphone are low, and an occasional dose is likely associated with few adverse effects in the breastfeeding newborn.²² For the treatment of moderate to severe pain in opioid-naive adults, hydromorphone doses in the range of 2 mg orally every 4 hours up to 4 mg orally every 4 hours are prescribed. Like all narcotics, hydromorphone can result in central nervous system depression. If a mother ingests sufficient quantities of hydromorphone, respiratory depression in the breastfeeding newborn can occur. In one case report, a nursing mother was taking hydromorphone 4 mg every 4 hours for pain following a cesarean delivery. On day 6 following birth, her newborn was lethargic and she brought the infant to an emergency room. In the emergency room the infant became apneic and was successfully treated with naloxone, suggesting anarcotic overdose due to the presence of hydromorphone in breast milk.²³ Hydromorphone should only be used at the lowest effective dose and for the shortest time possible.

Related article:
Should coffee consumption be added as an adjunct to the postoperative care of gynecologic oncology patients?

The bottom line

Pediatricians seldom prescribe codeine, oxycodone, hydrocodone, or tramadol for the treatment of pain in newborns or children. Pediatricians generally use acetaminophen and morphine for the treatment of pain in newborns. Although data from large, high quality clinical trials are not available, expert opinion recommends that acetaminophen and ibuprofen should be prescribed as first-line medications for the treatment of pain in women who are breastfeeding. Use of narcotics that are metabolized by CYP2D6 should be minimized or avoided in women who are breastfeeding. If narcotic medication is necessary, the lowest effective dose of morphine or hy-dromorphone should be prescribed for the shortest time possible. If morphine is prescribed to wo-men who are breastfeeding, they should be advised to observe their baby for signs of narcotic excess, including drowsiness, poor nursing, slow breathing, or low heart rate.

The goal of reducing morbidity and mortality from opioid use is a top public health priority. Obstetrician-gynecologists can contribute through the optimal use of opioid analgesics. Reducing the number of opioid prescriptions and the quantity of medication prescribed per prescription is an important first step in our effort to reduce opioid-related deaths.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

In 2015 more than 30,000 deaths from opioid overdose were reported (FIGURE).¹ More than 50% of the deaths were due to prescription opioids. The opioid crisis is a public health emergency and clinicians are diligently working to reduce both the number of opioid prescriptions and the doses prescribed per prescription.

In obstetrics, there is growing concern that narcotics used for the treatment of pain in women who are breastfeeding may increase the risk of adverse effects in newborns, including excessive sedation and respiratory depression. The American Academy of Pediatrics (AAP), the US Food and Drug Administration (FDA) and the American College of Obstetricians and Gynecologists (ACOG) recommend against the use of codeine and tramadol in women who are breastfeeding because their newborns may have adverse reactions, including excessive sleepiness, difficulty breathing, and potentially fatal breathing problems.^2–4 In addition, there is growing concern that the use of oxycodone and hydrocodone should also be limited in women who are breastfeeding. In this article, I discuss the rationale for these recommendations.

Related article:
Landmark women’s health care remains law of the land

Codeine

Codeine is metabolized to morphine by CYP2D6 and CYP2D7. Both codeine and morphine are excreted into breast milk. Some women are ultrarapid metabolizers of codeine because of high levels of CYP2D6, resulting in higher concentrations of morphine in their breast milk and their breast fed newborn.^2,5 In many women who are ultra-rapid metabolizers of codeine, CYP2D6 gene duplication or multiplication is the cause of the increased enzyme activity.⁶ Genotyping can identify some women who are ultrarapid metabolizers, but it is not currently utilized widely in clinical practice.

In the United States approximately 5% of women express high levels of CYP2D6 and are ultra-rapid metabolizers of codeine.⁴ In Ethiopia as many as 29% of women are ultrarapid metabolizers.⁷ Newborn central nervous system (CNS) depression is the most common adverse effect of fetal ingestion of excessive codeine and mor-phine from breast milk and may present as sedation, apnea, bradycardia, or cyanosis.⁸ Multiple newborn fatalities have been re-ported in the literature when lactating mothers who were ultrarapid metabolizers took co-deine. The FDA and ACOG recommend against the use of codeine in lactating women.

Hydrocodone

Hydrocodone, a hydrogenated ketone derivative of codeine, is metabolized by CYP2D6 to hydromorphone. Both hydrocodone and hydromorphone are present in breast milk. In lactating mothers taking hydrocodone, up to 9% of the dose may be ingested by the breastfeeding newborn.⁹ There is concern that hydrocodone use by women who are breastfeeding and are ultrarapid metabolizers may cause increased fetal consumption of hydromorphone resulting in adverse outcomes in the newborn. The AAP cautions against the use of hydrocodone.²

Oxycodone

Oxycodone is metabolized by CYP2D6 to oxymorphone and is concentrated into breast milk.¹⁰ Oxymorphone is more than 10 times more potent than oxycodone. In one study of lactating women taking oxycodone, codeine, or acetaminophen, the rates of neonate CNS depression were 20%, 17%, and 0.5%, respectively.¹¹ The authors concluded that for mothers who are breastfeeding oxycodone was no safer than codeine because both medications were associated with a high rate of depression in the neonate. Newborns who develop CNS depression from exposure to oxycodone in breast milk will respond to naloxone treatment.¹² The AAP recommends against prescribing oxycodone for women who are breastfeeding their infants.²

In a recent communication, the Society for Obstetric Anesthesia and Perinatology (SOAP) observed that in the United States, following cesarean delivery the majority of women receive oxycodone or hydrocodone.¹³ SOAP disagreed with the AAP recommendation against the use of oxycodone or hydrocodone in breastfeeding women. SOAP noted that all narcotics can produce adverse effects in newborns of breastfeeding women and that there are no good data that the prescription of oxycodone or hydrocodone is more risky than morphine or hydromorphone. However, based on their assessment of risk and benefit, pediatricians prioritize the use of acetaminophen and morphine and seldom use oxycodone or hydrocodone to treat moderate to severe pain in babies and children.

Tramadol

Tramadol is metabolized by CYP2D6 to O-desmethyltramadol. Both tramadol and O-desmethyltramadol are excreted into breast milk. In ultrarapid metabolizers, a greater concentration of O-desmethyltramadol is excreted into breast milk. The FDA reported that they identified no serious neonatal adverse events in the literature due to the use of tramadol by women who are breastfeeding. However, given that tramadol and its CYP2D6 metabolite enter breast milk and the potential for life-threatening respiratory de-pression in the infant, the FDA included tramadol in its warning about codeine.³

Codeine, hydrocodone, oxycodone, and tramadol are all metabolized to more potent metabolites by the CYP2D6 enzyme. Individuals with low CYP2D6 activity, representing about 5% of the US population, cannot fully activate these narcotics. Hence they may not get adequate pain relief when treated with codeine, oxycodone, hydrocodone, or tramadol. Given their resistance to these medications they may first be placed on a higher dose of the narcotic and then switched from a high ineffective dose of one of the agents activated by CYP2D6 to a high dose of morphine or hydromorphone. This can be dangerous because they may then receive an excessive dose of narcotic and develop respiratory depression.¹⁴

Read about how other pain medications affect breast milk.

Aspirin

There are very little high quality data about the use of aspirin in women breastfeeding and the effect on the neonate. If a mother takes aspirin, the drug will enter breast milk. It is estimated that the nursing baby receives about 4% to 8% of the mother’s dose. The World Health Organization recommends that aspirin is compatible with breastfeeding in occasional small doses, but repeated administration of aspirin in normal doses should be avoided in women who are breastfeeding. If chronic or high-dose aspirin therapy is recommended, the infant should be monitored for side effects including metabolic acidosis¹⁵ and coagulation disorders.¹⁶ The National Reye’s Syndrome Foundation recommends against the use of aspirin in women who are breastfeeding because of the theoretical risk of triggering Reye syndrome.¹⁷ Acetaminophen and ibuprofen are recommended by the WHO for chronic treatment of pain during breastfeeding.¹⁶

Acetaminophen and ibuprofen

For the medication treatment of pain in women who are breastfeeding, the WHO recommends the use of acetaminophen and ibuprofen.¹⁶ Acetaminophen is transferred from the maternal circulation into breast milk, but it is estimated that the dose to the nursing neonate is <0.3% of the maternal dose.¹⁸ In mothers taking ibuprofen 1600 mg daily, the concentration of ibuprofen in breast milk was below the level of laboratory detection (<1 mg/L).¹⁹ Ibuprofen treatment is thought to be safe for women who are breastfeeding because of its short half-life (2 hours), low excretion into milk, and few reported adverse effects in infants.

Morphine

Morphine is not metabolized by CYP2D6 and is excreted into breast milk. Many experts believe that women who are breastfeeding may take standard doses of oral morphine with few adverse effects in the newborn.^20,21 For the treatment of moderate to severe pain in opioid-naive adults, morphine doses in the range of 10 mg orally every 4 hours up to 30 mg orally every 4 hours are prescribed. When using a solution of morphine, standard doses are 10 mg to 20 mg every 4 hours, as needed to treat pain. When using morphine tablets, standard doses are 15 mg to 30 mg every 4 hours. The WHO states that occasional doses of morphine are usually safe for women breastfeeding their newborn.¹⁶ The AAP recommends the use of morphine and hydromorphone when narcotic agents are needed to treat pain in breastfeeding women.²

Hydromorphone

Hydromorphone, a hydrogenated ketone derivative of morphine, is not metabolized by CYP2D6 and is excreted into breast milk. There are limited data on the safety of hydromorphone during breastfeeding. Breast milk concentrations of hydromorphone are low, and an occasional dose is likely associated with few adverse effects in the breastfeeding newborn.²² For the treatment of moderate to severe pain in opioid-naive adults, hydromorphone doses in the range of 2 mg orally every 4 hours up to 4 mg orally every 4 hours are prescribed. Like all narcotics, hydromorphone can result in central nervous system depression. If a mother ingests sufficient quantities of hydromorphone, respiratory depression in the breastfeeding newborn can occur. In one case report, a nursing mother was taking hydromorphone 4 mg every 4 hours for pain following a cesarean delivery. On day 6 following birth, her newborn was lethargic and she brought the infant to an emergency room. In the emergency room the infant became apneic and was successfully treated with naloxone, suggesting anarcotic overdose due to the presence of hydromorphone in breast milk.²³ Hydromorphone should only be used at the lowest effective dose and for the shortest time possible.

Related article:
Should coffee consumption be added as an adjunct to the postoperative care of gynecologic oncology patients?

The bottom line

Pediatricians seldom prescribe codeine, oxycodone, hydrocodone, or tramadol for the treatment of pain in newborns or children. Pediatricians generally use acetaminophen and morphine for the treatment of pain in newborns. Although data from large, high quality clinical trials are not available, expert opinion recommends that acetaminophen and ibuprofen should be prescribed as first-line medications for the treatment of pain in women who are breastfeeding. Use of narcotics that are metabolized by CYP2D6 should be minimized or avoided in women who are breastfeeding. If narcotic medication is necessary, the lowest effective dose of morphine or hy-dromorphone should be prescribed for the shortest time possible. If morphine is prescribed to wo-men who are breastfeeding, they should be advised to observe their baby for signs of narcotic excess, including drowsiness, poor nursing, slow breathing, or low heart rate.

The goal of reducing morbidity and mortality from opioid use is a top public health priority. Obstetrician-gynecologists can contribute through the optimal use of opioid analgesics. Reducing the number of opioid prescriptions and the quantity of medication prescribed per prescription is an important first step in our effort to reduce opioid-related deaths.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

In 2015 more than 30,000 deaths from opioid overdose were reported (FIGURE).¹ More than 50% of the deaths were due to prescription opioids. The opioid crisis is a public health emergency and clinicians are diligently working to reduce both the number of opioid prescriptions and the doses prescribed per prescription.

In obstetrics, there is growing concern that narcotics used for the treatment of pain in women who are breastfeeding may increase the risk of adverse effects in newborns, including excessive sedation and respiratory depression. The American Academy of Pediatrics (AAP), the US Food and Drug Administration (FDA) and the American College of Obstetricians and Gynecologists (ACOG) recommend against the use of codeine and tramadol in women who are breastfeeding because their newborns may have adverse reactions, including excessive sleepiness, difficulty breathing, and potentially fatal breathing problems.^2–4 In addition, there is growing concern that the use of oxycodone and hydrocodone should also be limited in women who are breastfeeding. In this article, I discuss the rationale for these recommendations.

Related article:
Landmark women’s health care remains law of the land

Codeine

Codeine is metabolized to morphine by CYP2D6 and CYP2D7. Both codeine and morphine are excreted into breast milk. Some women are ultrarapid metabolizers of codeine because of high levels of CYP2D6, resulting in higher concentrations of morphine in their breast milk and their breast fed newborn.^2,5 In many women who are ultra-rapid metabolizers of codeine, CYP2D6 gene duplication or multiplication is the cause of the increased enzyme activity.⁶ Genotyping can identify some women who are ultrarapid metabolizers, but it is not currently utilized widely in clinical practice.

In the United States approximately 5% of women express high levels of CYP2D6 and are ultra-rapid metabolizers of codeine.⁴ In Ethiopia as many as 29% of women are ultrarapid metabolizers.⁷ Newborn central nervous system (CNS) depression is the most common adverse effect of fetal ingestion of excessive codeine and mor-phine from breast milk and may present as sedation, apnea, bradycardia, or cyanosis.⁸ Multiple newborn fatalities have been re-ported in the literature when lactating mothers who were ultrarapid metabolizers took co-deine. The FDA and ACOG recommend against the use of codeine in lactating women.

Hydrocodone

Hydrocodone, a hydrogenated ketone derivative of codeine, is metabolized by CYP2D6 to hydromorphone. Both hydrocodone and hydromorphone are present in breast milk. In lactating mothers taking hydrocodone, up to 9% of the dose may be ingested by the breastfeeding newborn.⁹ There is concern that hydrocodone use by women who are breastfeeding and are ultrarapid metabolizers may cause increased fetal consumption of hydromorphone resulting in adverse outcomes in the newborn. The AAP cautions against the use of hydrocodone.²

Oxycodone

Oxycodone is metabolized by CYP2D6 to oxymorphone and is concentrated into breast milk.¹⁰ Oxymorphone is more than 10 times more potent than oxycodone. In one study of lactating women taking oxycodone, codeine, or acetaminophen, the rates of neonate CNS depression were 20%, 17%, and 0.5%, respectively.¹¹ The authors concluded that for mothers who are breastfeeding oxycodone was no safer than codeine because both medications were associated with a high rate of depression in the neonate. Newborns who develop CNS depression from exposure to oxycodone in breast milk will respond to naloxone treatment.¹² The AAP recommends against prescribing oxycodone for women who are breastfeeding their infants.²

In a recent communication, the Society for Obstetric Anesthesia and Perinatology (SOAP) observed that in the United States, following cesarean delivery the majority of women receive oxycodone or hydrocodone.¹³ SOAP disagreed with the AAP recommendation against the use of oxycodone or hydrocodone in breastfeeding women. SOAP noted that all narcotics can produce adverse effects in newborns of breastfeeding women and that there are no good data that the prescription of oxycodone or hydrocodone is more risky than morphine or hydromorphone. However, based on their assessment of risk and benefit, pediatricians prioritize the use of acetaminophen and morphine and seldom use oxycodone or hydrocodone to treat moderate to severe pain in babies and children.

Tramadol

Tramadol is metabolized by CYP2D6 to O-desmethyltramadol. Both tramadol and O-desmethyltramadol are excreted into breast milk. In ultrarapid metabolizers, a greater concentration of O-desmethyltramadol is excreted into breast milk. The FDA reported that they identified no serious neonatal adverse events in the literature due to the use of tramadol by women who are breastfeeding. However, given that tramadol and its CYP2D6 metabolite enter breast milk and the potential for life-threatening respiratory de-pression in the infant, the FDA included tramadol in its warning about codeine.³

Codeine, hydrocodone, oxycodone, and tramadol are all metabolized to more potent metabolites by the CYP2D6 enzyme. Individuals with low CYP2D6 activity, representing about 5% of the US population, cannot fully activate these narcotics. Hence they may not get adequate pain relief when treated with codeine, oxycodone, hydrocodone, or tramadol. Given their resistance to these medications they may first be placed on a higher dose of the narcotic and then switched from a high ineffective dose of one of the agents activated by CYP2D6 to a high dose of morphine or hydromorphone. This can be dangerous because they may then receive an excessive dose of narcotic and develop respiratory depression.¹⁴

Read about how other pain medications affect breast milk.

Aspirin

There are very little high quality data about the use of aspirin in women breastfeeding and the effect on the neonate. If a mother takes aspirin, the drug will enter breast milk. It is estimated that the nursing baby receives about 4% to 8% of the mother’s dose. The World Health Organization recommends that aspirin is compatible with breastfeeding in occasional small doses, but repeated administration of aspirin in normal doses should be avoided in women who are breastfeeding. If chronic or high-dose aspirin therapy is recommended, the infant should be monitored for side effects including metabolic acidosis¹⁵ and coagulation disorders.¹⁶ The National Reye’s Syndrome Foundation recommends against the use of aspirin in women who are breastfeeding because of the theoretical risk of triggering Reye syndrome.¹⁷ Acetaminophen and ibuprofen are recommended by the WHO for chronic treatment of pain during breastfeeding.¹⁶

Acetaminophen and ibuprofen

For the medication treatment of pain in women who are breastfeeding, the WHO recommends the use of acetaminophen and ibuprofen.¹⁶ Acetaminophen is transferred from the maternal circulation into breast milk, but it is estimated that the dose to the nursing neonate is <0.3% of the maternal dose.¹⁸ In mothers taking ibuprofen 1600 mg daily, the concentration of ibuprofen in breast milk was below the level of laboratory detection (<1 mg/L).¹⁹ Ibuprofen treatment is thought to be safe for women who are breastfeeding because of its short half-life (2 hours), low excretion into milk, and few reported adverse effects in infants.

Morphine

Morphine is not metabolized by CYP2D6 and is excreted into breast milk. Many experts believe that women who are breastfeeding may take standard doses of oral morphine with few adverse effects in the newborn.^20,21 For the treatment of moderate to severe pain in opioid-naive adults, morphine doses in the range of 10 mg orally every 4 hours up to 30 mg orally every 4 hours are prescribed. When using a solution of morphine, standard doses are 10 mg to 20 mg every 4 hours, as needed to treat pain. When using morphine tablets, standard doses are 15 mg to 30 mg every 4 hours. The WHO states that occasional doses of morphine are usually safe for women breastfeeding their newborn.¹⁶ The AAP recommends the use of morphine and hydromorphone when narcotic agents are needed to treat pain in breastfeeding women.²

Hydromorphone

Hydromorphone, a hydrogenated ketone derivative of morphine, is not metabolized by CYP2D6 and is excreted into breast milk. There are limited data on the safety of hydromorphone during breastfeeding. Breast milk concentrations of hydromorphone are low, and an occasional dose is likely associated with few adverse effects in the breastfeeding newborn.²² For the treatment of moderate to severe pain in opioid-naive adults, hydromorphone doses in the range of 2 mg orally every 4 hours up to 4 mg orally every 4 hours are prescribed. Like all narcotics, hydromorphone can result in central nervous system depression. If a mother ingests sufficient quantities of hydromorphone, respiratory depression in the breastfeeding newborn can occur. In one case report, a nursing mother was taking hydromorphone 4 mg every 4 hours for pain following a cesarean delivery. On day 6 following birth, her newborn was lethargic and she brought the infant to an emergency room. In the emergency room the infant became apneic and was successfully treated with naloxone, suggesting anarcotic overdose due to the presence of hydromorphone in breast milk.²³ Hydromorphone should only be used at the lowest effective dose and for the shortest time possible.

Related article:
Should coffee consumption be added as an adjunct to the postoperative care of gynecologic oncology patients?

The bottom line

Pediatricians seldom prescribe codeine, oxycodone, hydrocodone, or tramadol for the treatment of pain in newborns or children. Pediatricians generally use acetaminophen and morphine for the treatment of pain in newborns. Although data from large, high quality clinical trials are not available, expert opinion recommends that acetaminophen and ibuprofen should be prescribed as first-line medications for the treatment of pain in women who are breastfeeding. Use of narcotics that are metabolized by CYP2D6 should be minimized or avoided in women who are breastfeeding. If narcotic medication is necessary, the lowest effective dose of morphine or hy-dromorphone should be prescribed for the shortest time possible. If morphine is prescribed to wo-men who are breastfeeding, they should be advised to observe their baby for signs of narcotic excess, including drowsiness, poor nursing, slow breathing, or low heart rate.

The goal of reducing morbidity and mortality from opioid use is a top public health priority. Obstetrician-gynecologists can contribute through the optimal use of opioid analgesics. Reducing the number of opioid prescriptions and the quantity of medication prescribed per prescription is an important first step in our effort to reduce opioid-related deaths.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Photo: Shutterstock

Many hospitals across the country have received designation as “Baby Friendly”; many other hospitals are in the process of seeking this designation. In order to be Baby Friendly, a hospital or birth center must prove they have implemented a set of 10 rules to encourage breastfeeding. As Baby Friendly USA puts it in their byline, it has become the gold standard of care.

Importantly, Baby Friendly fails to recognize that there is another equally crucial participant in any childbirth experience—the woman. Although childbirth is natural and usually healthy, it is not easy. Women commonly lose up to 1 L of blood during childbirth.¹ Labor can take 18 to 24 hours for a first-timer and about 12 to 18 hours for an encore performance, often disrupting at least1 entire night of sleep. The minimally invasive cesarean delivery continues to elude us, and women undergoing cesarean delivery must contend with a sizable incision and the additional pain and associated recovery.

Hospitals adopting the Baby Friendly rules must not allow formula, must prohibit pacifier use, and must go to great lengths to encourage rooming-in. Rooming-in means that the baby shares the same room as the new mother around-the-clock, which is reported to help the new mother distinguish sounds that indicate “feed me” from those that indicate a cool breeze. Rooming-in has been shown to be associated with a modest increase in breastfeeding²; however, women who are committed to breastfeeding likely room-in more often than women less committed to breastfeeding. Whether or not forcing the woman who is less committed to breastfeeding or the woman highly committed to breastfeeding who just wants a good night’s rest to room-in with her baby has a meaningful impact on breastfeeding remains unknown.

Are we violating ethics rules?

When hospitals adopt the Baby Friendly rules—policies that limit women’s choices for themselves and for their baby—we violate medical ethics principles regarding respect for autonomy, beneficence, and truthfulness. For instance, women are told that if they breastfeed their babies will be smarter, healthier, and have stronger emotional bonds. However, when research studies control for factors such as mothers’ education level or the amount of time spent talking to the baby, the effect of breastfeeding on intelligence “washes out.”³ Babies who are formula-fed but cuddled experience the same degree of bonding with their mothers as breast-fed babies.^4,5

Although breast is best, the reported benefits that underlie Baby Friendly are overblown and oversold. When we explain to a woman why her newborn cannot spend a few hours in the nursery or why we cannot allow a pacifier, we are denying her the right to parent and make choices for herself and her baby, not acting in the best interest of the woman. We are in fact misrepresenting the truth. We are also acting paternalistic, propagating the long tradition of telling women that we know better about their reproductive health and choices.

Related article:
Women’s Preventive Services Initiative Guidelines provide consensus for practicing ObGyns

Breastfeeding still not fully accepted outside the hospital

The Baby Friendly rules restrict autonomy and prod women to breastfeed for the few days that they remain in the hospital postpartum. However, these women go home to societal and institutional systems that are deeply unsupportive of breastfeeding. In addition to being the birthplace for 98% of babies born in the United States, the health care industry is the single largest employer of US women.^6,7 There are 5 academic hospitals in the Boston area. After contacting the human resources department at each, I found that only 1 has a policy for their breastfeeding employees.

Women should not be forced to choose between breastfeeding and working, between taking a longer maternity leave (often unpaid and professionally detrimental) and shelving the breast pump. What we invest in reveals our values. When we require women to room-in without respecting their choices or needs, and when workplaces fail to provide reasonable flexibility and private space for breast-pumping employees, our values as a society are revealed.

Women and men, hospital users and hospital employees, need to insist that the principles of autonomy, respect for persons, truthfulness, and justice guide breastfeeding policy both within our hospitals and within our workplaces. We need to respect women and the choices that they make for themselves and their families. We need to allow women to decide to recover from their delivery without their baby constantly in arms’ reach. We need to ensure that our counseling and our policies are rooted in sound science and not influenced by passionate but biased perspectives.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Photo: Shutterstock

Many hospitals across the country have received designation as “Baby Friendly”; many other hospitals are in the process of seeking this designation. In order to be Baby Friendly, a hospital or birth center must prove they have implemented a set of 10 rules to encourage breastfeeding. As Baby Friendly USA puts it in their byline, it has become the gold standard of care.

Importantly, Baby Friendly fails to recognize that there is another equally crucial participant in any childbirth experience—the woman. Although childbirth is natural and usually healthy, it is not easy. Women commonly lose up to 1 L of blood during childbirth.¹ Labor can take 18 to 24 hours for a first-timer and about 12 to 18 hours for an encore performance, often disrupting at least1 entire night of sleep. The minimally invasive cesarean delivery continues to elude us, and women undergoing cesarean delivery must contend with a sizable incision and the additional pain and associated recovery.

Hospitals adopting the Baby Friendly rules must not allow formula, must prohibit pacifier use, and must go to great lengths to encourage rooming-in. Rooming-in means that the baby shares the same room as the new mother around-the-clock, which is reported to help the new mother distinguish sounds that indicate “feed me” from those that indicate a cool breeze. Rooming-in has been shown to be associated with a modest increase in breastfeeding²; however, women who are committed to breastfeeding likely room-in more often than women less committed to breastfeeding. Whether or not forcing the woman who is less committed to breastfeeding or the woman highly committed to breastfeeding who just wants a good night’s rest to room-in with her baby has a meaningful impact on breastfeeding remains unknown.

Are we violating ethics rules?

When hospitals adopt the Baby Friendly rules—policies that limit women’s choices for themselves and for their baby—we violate medical ethics principles regarding respect for autonomy, beneficence, and truthfulness. For instance, women are told that if they breastfeed their babies will be smarter, healthier, and have stronger emotional bonds. However, when research studies control for factors such as mothers’ education level or the amount of time spent talking to the baby, the effect of breastfeeding on intelligence “washes out.”³ Babies who are formula-fed but cuddled experience the same degree of bonding with their mothers as breast-fed babies.^4,5

Although breast is best, the reported benefits that underlie Baby Friendly are overblown and oversold. When we explain to a woman why her newborn cannot spend a few hours in the nursery or why we cannot allow a pacifier, we are denying her the right to parent and make choices for herself and her baby, not acting in the best interest of the woman. We are in fact misrepresenting the truth. We are also acting paternalistic, propagating the long tradition of telling women that we know better about their reproductive health and choices.

Related article:
Women’s Preventive Services Initiative Guidelines provide consensus for practicing ObGyns

Breastfeeding still not fully accepted outside the hospital

The Baby Friendly rules restrict autonomy and prod women to breastfeed for the few days that they remain in the hospital postpartum. However, these women go home to societal and institutional systems that are deeply unsupportive of breastfeeding. In addition to being the birthplace for 98% of babies born in the United States, the health care industry is the single largest employer of US women.^6,7 There are 5 academic hospitals in the Boston area. After contacting the human resources department at each, I found that only 1 has a policy for their breastfeeding employees.

Women should not be forced to choose between breastfeeding and working, between taking a longer maternity leave (often unpaid and professionally detrimental) and shelving the breast pump. What we invest in reveals our values. When we require women to room-in without respecting their choices or needs, and when workplaces fail to provide reasonable flexibility and private space for breast-pumping employees, our values as a society are revealed.

Women and men, hospital users and hospital employees, need to insist that the principles of autonomy, respect for persons, truthfulness, and justice guide breastfeeding policy both within our hospitals and within our workplaces. We need to respect women and the choices that they make for themselves and their families. We need to allow women to decide to recover from their delivery without their baby constantly in arms’ reach. We need to ensure that our counseling and our policies are rooted in sound science and not influenced by passionate but biased perspectives.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Photo: Shutterstock

Many hospitals across the country have received designation as “Baby Friendly”; many other hospitals are in the process of seeking this designation. In order to be Baby Friendly, a hospital or birth center must prove they have implemented a set of 10 rules to encourage breastfeeding. As Baby Friendly USA puts it in their byline, it has become the gold standard of care.

Importantly, Baby Friendly fails to recognize that there is another equally crucial participant in any childbirth experience—the woman. Although childbirth is natural and usually healthy, it is not easy. Women commonly lose up to 1 L of blood during childbirth.¹ Labor can take 18 to 24 hours for a first-timer and about 12 to 18 hours for an encore performance, often disrupting at least1 entire night of sleep. The minimally invasive cesarean delivery continues to elude us, and women undergoing cesarean delivery must contend with a sizable incision and the additional pain and associated recovery.

Hospitals adopting the Baby Friendly rules must not allow formula, must prohibit pacifier use, and must go to great lengths to encourage rooming-in. Rooming-in means that the baby shares the same room as the new mother around-the-clock, which is reported to help the new mother distinguish sounds that indicate “feed me” from those that indicate a cool breeze. Rooming-in has been shown to be associated with a modest increase in breastfeeding²; however, women who are committed to breastfeeding likely room-in more often than women less committed to breastfeeding. Whether or not forcing the woman who is less committed to breastfeeding or the woman highly committed to breastfeeding who just wants a good night’s rest to room-in with her baby has a meaningful impact on breastfeeding remains unknown.

Are we violating ethics rules?

When hospitals adopt the Baby Friendly rules—policies that limit women’s choices for themselves and for their baby—we violate medical ethics principles regarding respect for autonomy, beneficence, and truthfulness. For instance, women are told that if they breastfeed their babies will be smarter, healthier, and have stronger emotional bonds. However, when research studies control for factors such as mothers’ education level or the amount of time spent talking to the baby, the effect of breastfeeding on intelligence “washes out.”³ Babies who are formula-fed but cuddled experience the same degree of bonding with their mothers as breast-fed babies.^4,5

Although breast is best, the reported benefits that underlie Baby Friendly are overblown and oversold. When we explain to a woman why her newborn cannot spend a few hours in the nursery or why we cannot allow a pacifier, we are denying her the right to parent and make choices for herself and her baby, not acting in the best interest of the woman. We are in fact misrepresenting the truth. We are also acting paternalistic, propagating the long tradition of telling women that we know better about their reproductive health and choices.

Related article:
Women’s Preventive Services Initiative Guidelines provide consensus for practicing ObGyns

Breastfeeding still not fully accepted outside the hospital

The Baby Friendly rules restrict autonomy and prod women to breastfeed for the few days that they remain in the hospital postpartum. However, these women go home to societal and institutional systems that are deeply unsupportive of breastfeeding. In addition to being the birthplace for 98% of babies born in the United States, the health care industry is the single largest employer of US women.^6,7 There are 5 academic hospitals in the Boston area. After contacting the human resources department at each, I found that only 1 has a policy for their breastfeeding employees.

Women should not be forced to choose between breastfeeding and working, between taking a longer maternity leave (often unpaid and professionally detrimental) and shelving the breast pump. What we invest in reveals our values. When we require women to room-in without respecting their choices or needs, and when workplaces fail to provide reasonable flexibility and private space for breast-pumping employees, our values as a society are revealed.

Women and men, hospital users and hospital employees, need to insist that the principles of autonomy, respect for persons, truthfulness, and justice guide breastfeeding policy both within our hospitals and within our workplaces. We need to respect women and the choices that they make for themselves and their families. We need to allow women to decide to recover from their delivery without their baby constantly in arms’ reach. We need to ensure that our counseling and our policies are rooted in sound science and not influenced by passionate but biased perspectives.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

The International Continence Society (ICS) defines overactive bladder (OAB) as a syndrome of "urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence (UUI), in the absence of urinary tract infection [UTI] or obvious pathology."¹ The Agency for Healthcare Research and Quality (AHRQ) reported OAB prevalence to be 15% in US women, with 11% reporting UUI.² OAB represents a significant health care burden that impacts nearly every aspect of life, including physical, emotional, and psychological domains.^3,4 The economic impact is notable; the projected cost is estimated to reach $82.6 billion annually by 2020.⁵

The American Urological Association (AUA) and the Society for Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (SUFU) have endorsed an algorithm for use in the evaluation of idiopathic OAB (FIGURE).⁶ If the patient's symptoms are certain, minimal evaluation is needed and it is reasonable to proceed with first-line therapy, which includes fluid management (decreasing caffeine intake and limiting evening fluid intake), bladder retraining drills such as timed voiding, and improving pelvic floor muscles with the use of biofeedback and functional electrical stimulation.^6,7 Pelvic floor muscle training can be facilitated with a referral to a physical therapist trained in pelvic floor muscle education.

If treatment goals are not met with first-line strategies, second-line therapy may be initiated with anticholinergic or β3-adrenergic receptor agonist medications. If symptoms persist after 4 to 8 weeks of pharmacologic therapy, clinicians are encouraged to reassess or refer the patient to a specialist. Further evaluation may include a bladder diary in which the patient documents voided volumes, voiding frequency, and number of incontinent episodes; symptom-specific questionnaires; and/or urodynamic testing.

Related article:
The latest treatments for urinary and fecal incontinence: Which hold water?

Based on that evaluation, the patient may be a candidate for third-line therapy with either intradetrusor onabotulinumtoxinA, posterior tibial nerve stimulation (PTNS), or sacral neuromodulation.

There is a paucity of information comparing third-line therapies. In this Update, we focus on 4 randomized clinical trials that compare third-line treatment options for idiopathic OAB.

Read about how anticholinergic medication and onabotulinumtoxinA compare for treating UUI.

Anticholinergic therapy and onabotulinumtoxinA produce equivalent reductions in the frequency of daily UUI episodes

Visco AG, Brubaker L, Richter HE, et al; for the Pelvic Floor Disorders Network. Anticholinergic therapy vs onabotulinumtoxinA for urgency urinary incontinence. N Engl J Med. 2012;367(19):1803-1813.

In a double-blind, double-placebo-controlled randomized trial, Visco and colleagues compared anticholinergic medication with onabotulinumtoxinA 100 U for the treatment of women with UUI.

Details of the study

Two hundred forty-one women with moderate to severe UUI received either 6 months of oral anticholinergic therapy (solifenacin 5 mg daily with the option of dose escalation to 10 mg daily or change to trospium XR 60 mg daily based on the Patient Global Symptom Control score) plus a single intradetrusor injection of saline, or a single intradetrusor injection of onabotulinumtoxinA 100 U plus a 6-month oral placebo regimen.

Inclusion criteria were 5 or more UUI episodes on a 3-day diary, insufficient resolution of symptoms after 2 medications, or being drug naive. Exclusions included a postvoid residual (PVR) urine volume greater than 150 mL or previous therapy with onabotulinumtoxinA.

Participants were scheduled for follow up every 2 to 6 months post randomization, at which time all study medications were discontinued. The primary outcome was reduction from baseline in the mean number of UUI episodes per day over the 6-month period, as recorded in the monthly 3-day bladder diaries. Secondary outcomes included the proportion of participants with complete resolution of UUI, the proportion of participants with 75% or more reduction in UUI episodes, Overactive Bladder Questionnaire Short Form (OABq-SF) scores, other symptom-specific questionnaire scores, and adverse events.

Related article:
Which treatments for pelvic floor disorders are backed by evidence?

Both treatments significantly reduced UUI episodes

At baseline, participants reported a mean (SD) of 5.0 (2.7) UUI episodes per day, and 41% of participants were drug naive. Both treatment groups experienced significant reductions compared with baseline in mean UUI episodes, and the reductions were similar between the 2 groups (reduction of 3.4 episodes per day in the anticholinergic group, reduction of 3.3 episodes in the onabotulinumtoxinA group; P = .81). Complete resolution of UUI was more common in the onabotulinumtoxinA group (27%) as compared with the anticholinergic group (13%) (P = .003). There were no differences in improvement in OABq-SF scores (37.05 in the anticholinergic group vs 37.13 in the onabotulinumtoxinA group; P = .98) or other quality-of-life measures.

Adverse events. The anticholinergic group experienced a higher rate of dry mouth compared with the onabotulinumtoxinA group (46% vs 31%; P = .02) but had lower rates of intermittent catheterization use at 2 months (0% vs 5%, P = .01) and UTIs (13% vs 33%, P<.001).

Strengths and limitations. This was a well-designed, multicenter, randomized double-blind, double placebo-controlled trial. The study design allowed for dose escalation and change to another medication for inadequate symptom control and included drug-naive participants, which increases the generalizability of the results. However, current guidelines recommend reserving onabotulinumtoxinA therapy for third-line therapy, thus deterring this treatment's use in the drug-naive population. Additionally, the lack of a pure placebo arm makes it difficult to interpret the extent to which a placebo effect contributed to observed improvements in clinical symptoms.

Read: onabotulinumtoxinA vs PTNS for OAB.

OnabotulinumtoxinA has greater 9-month durability for OAB symptoms compared with12 weeks of PTNS

Sherif H, Khalil M, Omar R. Management of refractory idiopathic overactive bladder: intradetrusor injection of botulinum toxin type A versus posterior tibial nerve stimulation. Can J Urol. 2017;24(3):8838-8846.

In this randomized clinical trial, Sherif and colleagues compared the safety and efficacy of a single intradetrusor injection of onabotulinumtoxinA 100 U with that of PTNS for OAB.

Details of the study

Sixty adult men and women with OAB who did not respond to medical therapy were randomly assigned to treatment with either onabotulinumtoxinA 100 U or PTNS. Criteria for exclusion were current UTI, PVR urine volume of more than 150 mL, previous radiation therapy or chemotherapy, previous incontinence surgery or bladder malignancy, or presence of mixed urinary incontinence.

At baseline, participants completed a 3-day bladder diary, an OAB symptom score (OABSS) questionnaire, and urodynamic testing. The OABSS questionnaire included 7 questions (scoring range, 0-28), with higher scores indicating worse symptoms, and included subscales for urgency and quality-of-life measures. Total OABSS, urgency score, quality-of-life score, bladder diary records, and urodynamic testing parameters were assessed at 6, 12, 24, and 36 weeks, along with adverse events.

OnabotulinumtoxinA injections were performed under spinal anesthesia. If PVR urine volume was greater than 200 mL at any follow-up visit, participants were instructed to begin clean intermittent self-catheterization. PTNS was administered as weekly 30-minute sessions for 12 consecutive weeks.

Participants' baseline demographics and symptoms were similar. Average age was 45 years. Averages (SD) for duration of anticholinergic use was 13 (0.8) weeks, UUI episode score was 4.5 (1) on 3-day bladder diary, and OABSS was 22 (2.7). Nine-month data were available for 29 participants in the onabotulinumtoxinA group and for 8 in the PTNS group.

Related article:
Update on pelvic floor dysfunction: Focus on urinary incontinence

OnabotulinumtoxinA treatment benefits sustained for 9 months

Through 6 months, compared with baseline assessments, both treatment groups had significant improvements in clinical symptoms and OABSS total score, as well as urgency and quality-of-life subscales. At 3 months, urodynamic study parameters were similarly improved from baseline in both groups.

At 9 months, however, only the onabotulinumtoxinA group, compared with the PTNS group, maintained the significant improvement from baseline in 3-day bladder diary voiding episodes (average [SD], 10.7 [1.01] vs 11.6 [1.09]; P = .009), 3-day bladder diary nocturia episodes (average [SD], 3.8 [1.09] vs 4.4 [0.8]; P = .02), and average [SD] UUI episodes over 3 days (3.5 [1.2] vs 4.2 [1.04]; P = .02). Similarly, onabotulinumtoxinA-treated participants, compared with those treated with PTNS, maintained improvements at 9 months in average (SD): OABSS total score (19.2 [2.4] vs 20.4 [1.7]; P = .03), urgency scores (10.9 [1.3] vs 11.8 [1.4]; P = .009), urine volume at first desire (177.8 [9.2] vs 171.8 [7.7]), maximum cystometric capacity (304 [17.6] vs 290 [13.1]), and Qmax (mL/sec) (20.7 [1.6] vs 22.2 [1.2]).

Adverse events. Average PVR urine volumes were higher in the onabotulinumtoxinA group compared with the PTNS group (36.8 [2.7] vs 32.4 [3.03]; P = .0001) at all time points, and self-catheterization was required in 6.6% of onabotulinumtoxinA-treated participants. Urinary tract infection occurred in 6.6% of participants in the onabotulinumtoxinA group and in none of the PTNS group. In the PTNS group, few experienced pain and minor bleeding at the needle site.

Strengths and limitations. This randomized, open-label trial comparing treatment with onabotulinumtoxinA 100 U and PTNS included both men and women with idiopathic OAB symptoms. The participants were assessed at regular intervals with various measures, and follow-up adherence was good. The sample size was small, so the study may not have been powered to see differences prior to 9 months.

Although at 9 months only the onabotulinumtoxinA group maintained significant improvement over baseline levels, the improvement was diminished, and therefore the clinical meaningfulness is uncertain. Further, participants in the PTNS group did not undergo monthly maintenance therapy after 3 months, which is recommended for those with a 12-week therapeutic response; this may have affected 9-month outcomes in this group. Since the one-time onabotulinumtoxinA 100 U injection was performed under spinal anesthesia, cost comparisons should be considered, since future onabotulinumtoxinA injections would be necessary. 

Read about using different doses of onabotulinumtoxinA for OAB.

OnabotulinumtoxinA 200-U injection provides longer OAB symptom  improvement than 100-U injection

Abdelwahab O, Sherif H, Soliman T, Elbarky I, Eshazly A. Efficacy of botulinum toxin type A 100 units versus 200 units for treatment of refractory idiopathic overactive bladder. Int Braz J Urol. 2015;41(6):1132-1140.

Abdelwahab and colleagues conducted a single-center, randomized clinical trial to investigate the safety and efficacy of a single injection of intradetrusor onabotulinumtoxinA in 2 different doses (100 U and 200 U) for treatment of OAB.

Details of the study

Eighty adults (63 women, 17 men) who did not benefit from anticholinergic medication during the previous 3 months were randomly assigned to receive either a 100-U (n = 40) or a 200-U (n = 40) injection of onabotulinumtoxinA. Exclusion criteria were PVR urine volume greater than 150 mL and previous radiation therapy or chemotherapy.

Initial assessments -- completed at baseline and at 1, 3, 6, and 9 months -- included the health-related quality-of-life (HR-QOL) questionnaire (maximum score, 100; higher score indicates better quality of life), an abbreviated OABSS questionnaire (4 questions; score range, 0-15; higher score indicates more severe symptoms), and urodynamic evaluation. Outcomes included OABSS, HR-QOL score, and urodynamic parameters at the various time points.

Related article:
Is there a link between impaired mobility and urinary incontinence in elderly, community-dwelling women?

Higher dose, greater symptom improvement and higher adverse event rate

At baseline, participants (average age, 31 years) had an average (SD) OABSS of 1.7 (1.6). OnabotulinumtoxinA treatment with both a 100-U and a 200-U dose resulted in significant improvements (compared with baseline levels) in frequency, nocturia, UUI episodes, OABSS, and urodynamic parameters throughout the 9 months. At 9 months, however, the group treated with the 200-U dose had greater improvements, compared with the group who received a 100-U dose, in urinary frequency symptom scores (mean [SD], 0.32 [0.47] vs 1.1 [0.51]; P<.05), nocturia symptom scores (mean [SD], 0.13 [0.34] vs 0.36 [0.49]; P<.05), UUI symptom scores (mean [SD], 0.68 [0.16] vs 1.26 [1.1]; P<.05), and mean (SD) total OABSS (2.6 [2.31] vs 5.3 [2.11]; P<.05). Similarly, at 9 months the 200-U dose resulted in greater improvements in volume at first desire (mean [SD], 291.8 [42.8] vs 246.8 [53.8] mL; P<.05), volume at strong desire (mean [SD], 392.1 [37.3] vs 313.1 [67.4] mL; P<.05), detrusor pressure (mean [SD], 10.4 [4.0] vs 19.2 [7.8] cm H₂O; P<.05), and maximum cystometric capacity (mean [SD], 430.5 [34.2] vs 350 [69.1] mL; P<.05) compared with the 100-U dose.

Adverse events. No participant had a PVR urine volume greater than 100 mL at any follow-up visit. Postoperative hematuria occurred in 23% of the group treated with onabotulinumtoxinA 200 U versus in 15% of those treated with a 100-U dose. Similarly, UTIs occurred in 17.5% of the 200-U dose group and in 7.5% of the 100-U dose group. Dysuria was reported in 37.5% and 15% of the 200-U and 100-U dose groups, respectively.

Strengths and limitations. This randomized, open-label trial comparing a single injection of 100 U versus 200 U of onabotulinumtoxinA included mostly women. OAB symptoms and urodynamic parameters improved after treatment with both dose levels, but a longer duration of improvement was seen with the 200-U dose. The cohort had a low baseline OAB severity, based on the OABSS questionnaire, and a young average age of participants, which limits the generalizability of the study results to a population with refractory OAB. The 0% rate of clean intermittent self-catheterization postinjection might be based on the study's criteria for requiring clean intermittent catheterization. In addition, the initial postinjection visit occurred at 1 month, possibly missing participants who had symptoms of retention soon after injection.

Read: onabotulinumtoxinA vs sacral neuromodulation therapy for UUI.

Treatment with onabotulinumtoxinA may control UUI symptoms better than sacral neuromodulation therapy

Amundsen CL, Richter HE, Menefee SA, et al; Pelvic Floor Disorders Network. OnabotulinumtoxinA vs sacral neuromodulation on refractory urgency urinary incontinence in women: a randomized clinical trial. JAMA. 2016;316(13):1366-1374.

In this multicenter open-label randomized trial, Amundsen and colleagues compared the efficacy and safety of onabotulinumtoxinA 200 U with that of sacral neuromodulation.

Details of the study

Three hundred sixty-four women with UUI had data available for primary analysis at  6 months. Women were considered eligible for the study if they had 6 or more UUI episodes on a 3-day bladder diary, persistent symptoms despite anticholinergic therapy, a PVR urine volume of less than 150 mL, and had never previously received either study treatment.

There were no differences in baseline characteristics of the participants. The average (SD) age of the study population was 63 (11.6) years, with an average (SD) daily number of UUI episodes of 5.3 (2.8). The average (SD) body mass index was 32 (8) kg/m².

Participants were randomly assigned to undergo either sacral neuromodulation (n = 174) or intradetrusor injection of onabotulinumtoxinA 200 U (n = 190). The primary outcome was change from baseline in mean number of daily UUI episodes averaged over 6 months as recorded on a monthly 3-day bladder diary. Secondary outcomes included complete resolution of urgency incontinence, 75% or more reduction in UUI episodes, the Overactive Bladder Questionnaire Short Form (SF) score (range, 0-100; higher score indicates higher symptom severity), the Overactive Bladder Satisfaction of Treatment questionnaire (range, 0-100; higher score indicates better satisfaction), other quality-of-life measures, and adverse events.

Related article:
2015 Update on pelvic floor dysfunction: Bladder pain syndrome

Greater symptom bother improvement, treatment satisfaction with onabotulinumtoxinA 200 U

Participants treated with onabotulinumtoxinA had a greater mean reduction of 3.9 UUI episodes per day than the sacral neuromodulation group's reduction of 3.3 UUI episodes per day (mean difference, 0.63; 95% confidence interval [CI], 0.13-1.14; P = .01). In addition, complete UUI resolution was higher in the onabotulinumtoxinA group as compared with the sacral neuromodulation group (20% vs 4%; P<.001). The onabotulinumtoxinA group also had higher rates of 75% or more reduction of UUI episodes compared with the sacral neuromodulation group (46% vs 26%; P<.001). Over 6 months, both groups had improvements in all quality-of-life measures, but the onabotulinumtoxinA group had greater improvement in symptom bother compared with the sacral neuromodulation group (-46.7 vs -38.6; mean difference, 8.1; 95% CI, 3.0-13.3; P = .002). Furthermore, the onabotulinumtoxinA group had greater treatment satisfaction compared with the sacral neuromodulation group (mean difference, 7.8; 95% CI, 1.6-14.1; P = .01).

Adverse events. Six women (3%) underwent sacral neuromodulation device revision or removal. Approximately 8% of onabotulinumtoxinA-treated participants required intermittent self-catheterization at 1 month, 4% at 3 months, and 2% at 6 months. The risk of UTI was higher in the onabotulinumtoxinA group compared with the sacral neuromodulation group (35% vs 11%; risk difference, 23%; 95% CI, -33% to -13%; P<.001).

Strengths and limitations. This is a well-designed randomized clinical trial comparing clinical outcomes and adverse events after treatment with onabotulinumtoxinA 200-U versus sacral neuromodulation. The interventions were standardized across investigators at multiple sites, and the study design required close follow-up to assess efficacy and adverse events. The study used a 200-U dose based on reported durability of effect at that time and findings of equivalency between onabotulinumtoxinA 100 U and anticholinergic therapy. The US Food and Drug Administration's recommendation to use a 100-U dose in all patients with idiopathic OAB might dissuade clinicians from considering the higher dose of onabotulinumtoxinA. The study was limited by the lack of a placebo group.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

The International Continence Society (ICS) defines overactive bladder (OAB) as a syndrome of "urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence (UUI), in the absence of urinary tract infection [UTI] or obvious pathology."¹ The Agency for Healthcare Research and Quality (AHRQ) reported OAB prevalence to be 15% in US women, with 11% reporting UUI.² OAB represents a significant health care burden that impacts nearly every aspect of life, including physical, emotional, and psychological domains.^3,4 The economic impact is notable; the projected cost is estimated to reach $82.6 billion annually by 2020.⁵

The American Urological Association (AUA) and the Society for Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (SUFU) have endorsed an algorithm for use in the evaluation of idiopathic OAB (FIGURE).⁶ If the patient's symptoms are certain, minimal evaluation is needed and it is reasonable to proceed with first-line therapy, which includes fluid management (decreasing caffeine intake and limiting evening fluid intake), bladder retraining drills such as timed voiding, and improving pelvic floor muscles with the use of biofeedback and functional electrical stimulation.^6,7 Pelvic floor muscle training can be facilitated with a referral to a physical therapist trained in pelvic floor muscle education.

If treatment goals are not met with first-line strategies, second-line therapy may be initiated with anticholinergic or β3-adrenergic receptor agonist medications. If symptoms persist after 4 to 8 weeks of pharmacologic therapy, clinicians are encouraged to reassess or refer the patient to a specialist. Further evaluation may include a bladder diary in which the patient documents voided volumes, voiding frequency, and number of incontinent episodes; symptom-specific questionnaires; and/or urodynamic testing.

Related article:
The latest treatments for urinary and fecal incontinence: Which hold water?

Based on that evaluation, the patient may be a candidate for third-line therapy with either intradetrusor onabotulinumtoxinA, posterior tibial nerve stimulation (PTNS), or sacral neuromodulation.

There is a paucity of information comparing third-line therapies. In this Update, we focus on 4 randomized clinical trials that compare third-line treatment options for idiopathic OAB.

Read about how anticholinergic medication and onabotulinumtoxinA compare for treating UUI.

Anticholinergic therapy and onabotulinumtoxinA produce equivalent reductions in the frequency of daily UUI episodes

Visco AG, Brubaker L, Richter HE, et al; for the Pelvic Floor Disorders Network. Anticholinergic therapy vs onabotulinumtoxinA for urgency urinary incontinence. N Engl J Med. 2012;367(19):1803-1813.

In a double-blind, double-placebo-controlled randomized trial, Visco and colleagues compared anticholinergic medication with onabotulinumtoxinA 100 U for the treatment of women with UUI.

Details of the study

Two hundred forty-one women with moderate to severe UUI received either 6 months of oral anticholinergic therapy (solifenacin 5 mg daily with the option of dose escalation to 10 mg daily or change to trospium XR 60 mg daily based on the Patient Global Symptom Control score) plus a single intradetrusor injection of saline, or a single intradetrusor injection of onabotulinumtoxinA 100 U plus a 6-month oral placebo regimen.

Inclusion criteria were 5 or more UUI episodes on a 3-day diary, insufficient resolution of symptoms after 2 medications, or being drug naive. Exclusions included a postvoid residual (PVR) urine volume greater than 150 mL or previous therapy with onabotulinumtoxinA.

Participants were scheduled for follow up every 2 to 6 months post randomization, at which time all study medications were discontinued. The primary outcome was reduction from baseline in the mean number of UUI episodes per day over the 6-month period, as recorded in the monthly 3-day bladder diaries. Secondary outcomes included the proportion of participants with complete resolution of UUI, the proportion of participants with 75% or more reduction in UUI episodes, Overactive Bladder Questionnaire Short Form (OABq-SF) scores, other symptom-specific questionnaire scores, and adverse events.

Related article:
Which treatments for pelvic floor disorders are backed by evidence?

Both treatments significantly reduced UUI episodes

At baseline, participants reported a mean (SD) of 5.0 (2.7) UUI episodes per day, and 41% of participants were drug naive. Both treatment groups experienced significant reductions compared with baseline in mean UUI episodes, and the reductions were similar between the 2 groups (reduction of 3.4 episodes per day in the anticholinergic group, reduction of 3.3 episodes in the onabotulinumtoxinA group; P = .81). Complete resolution of UUI was more common in the onabotulinumtoxinA group (27%) as compared with the anticholinergic group (13%) (P = .003). There were no differences in improvement in OABq-SF scores (37.05 in the anticholinergic group vs 37.13 in the onabotulinumtoxinA group; P = .98) or other quality-of-life measures.

Adverse events. The anticholinergic group experienced a higher rate of dry mouth compared with the onabotulinumtoxinA group (46% vs 31%; P = .02) but had lower rates of intermittent catheterization use at 2 months (0% vs 5%, P = .01) and UTIs (13% vs 33%, P<.001).

Strengths and limitations. This was a well-designed, multicenter, randomized double-blind, double placebo-controlled trial. The study design allowed for dose escalation and change to another medication for inadequate symptom control and included drug-naive participants, which increases the generalizability of the results. However, current guidelines recommend reserving onabotulinumtoxinA therapy for third-line therapy, thus deterring this treatment's use in the drug-naive population. Additionally, the lack of a pure placebo arm makes it difficult to interpret the extent to which a placebo effect contributed to observed improvements in clinical symptoms.

Read: onabotulinumtoxinA vs PTNS for OAB.

OnabotulinumtoxinA has greater 9-month durability for OAB symptoms compared with12 weeks of PTNS

Sherif H, Khalil M, Omar R. Management of refractory idiopathic overactive bladder: intradetrusor injection of botulinum toxin type A versus posterior tibial nerve stimulation. Can J Urol. 2017;24(3):8838-8846.

In this randomized clinical trial, Sherif and colleagues compared the safety and efficacy of a single intradetrusor injection of onabotulinumtoxinA 100 U with that of PTNS for OAB.

Details of the study

Sixty adult men and women with OAB who did not respond to medical therapy were randomly assigned to treatment with either onabotulinumtoxinA 100 U or PTNS. Criteria for exclusion were current UTI, PVR urine volume of more than 150 mL, previous radiation therapy or chemotherapy, previous incontinence surgery or bladder malignancy, or presence of mixed urinary incontinence.

At baseline, participants completed a 3-day bladder diary, an OAB symptom score (OABSS) questionnaire, and urodynamic testing. The OABSS questionnaire included 7 questions (scoring range, 0-28), with higher scores indicating worse symptoms, and included subscales for urgency and quality-of-life measures. Total OABSS, urgency score, quality-of-life score, bladder diary records, and urodynamic testing parameters were assessed at 6, 12, 24, and 36 weeks, along with adverse events.

OnabotulinumtoxinA injections were performed under spinal anesthesia. If PVR urine volume was greater than 200 mL at any follow-up visit, participants were instructed to begin clean intermittent self-catheterization. PTNS was administered as weekly 30-minute sessions for 12 consecutive weeks.

Participants' baseline demographics and symptoms were similar. Average age was 45 years. Averages (SD) for duration of anticholinergic use was 13 (0.8) weeks, UUI episode score was 4.5 (1) on 3-day bladder diary, and OABSS was 22 (2.7). Nine-month data were available for 29 participants in the onabotulinumtoxinA group and for 8 in the PTNS group.

Related article:
Update on pelvic floor dysfunction: Focus on urinary incontinence

OnabotulinumtoxinA treatment benefits sustained for 9 months

Through 6 months, compared with baseline assessments, both treatment groups had significant improvements in clinical symptoms and OABSS total score, as well as urgency and quality-of-life subscales. At 3 months, urodynamic study parameters were similarly improved from baseline in both groups.

At 9 months, however, only the onabotulinumtoxinA group, compared with the PTNS group, maintained the significant improvement from baseline in 3-day bladder diary voiding episodes (average [SD], 10.7 [1.01] vs 11.6 [1.09]; P = .009), 3-day bladder diary nocturia episodes (average [SD], 3.8 [1.09] vs 4.4 [0.8]; P = .02), and average [SD] UUI episodes over 3 days (3.5 [1.2] vs 4.2 [1.04]; P = .02). Similarly, onabotulinumtoxinA-treated participants, compared with those treated with PTNS, maintained improvements at 9 months in average (SD): OABSS total score (19.2 [2.4] vs 20.4 [1.7]; P = .03), urgency scores (10.9 [1.3] vs 11.8 [1.4]; P = .009), urine volume at first desire (177.8 [9.2] vs 171.8 [7.7]), maximum cystometric capacity (304 [17.6] vs 290 [13.1]), and Qmax (mL/sec) (20.7 [1.6] vs 22.2 [1.2]).

Adverse events. Average PVR urine volumes were higher in the onabotulinumtoxinA group compared with the PTNS group (36.8 [2.7] vs 32.4 [3.03]; P = .0001) at all time points, and self-catheterization was required in 6.6% of onabotulinumtoxinA-treated participants. Urinary tract infection occurred in 6.6% of participants in the onabotulinumtoxinA group and in none of the PTNS group. In the PTNS group, few experienced pain and minor bleeding at the needle site.

Strengths and limitations. This randomized, open-label trial comparing treatment with onabotulinumtoxinA 100 U and PTNS included both men and women with idiopathic OAB symptoms. The participants were assessed at regular intervals with various measures, and follow-up adherence was good. The sample size was small, so the study may not have been powered to see differences prior to 9 months.

Although at 9 months only the onabotulinumtoxinA group maintained significant improvement over baseline levels, the improvement was diminished, and therefore the clinical meaningfulness is uncertain. Further, participants in the PTNS group did not undergo monthly maintenance therapy after 3 months, which is recommended for those with a 12-week therapeutic response; this may have affected 9-month outcomes in this group. Since the one-time onabotulinumtoxinA 100 U injection was performed under spinal anesthesia, cost comparisons should be considered, since future onabotulinumtoxinA injections would be necessary. 

Read about using different doses of onabotulinumtoxinA for OAB.

OnabotulinumtoxinA 200-U injection provides longer OAB symptom  improvement than 100-U injection

Abdelwahab O, Sherif H, Soliman T, Elbarky I, Eshazly A. Efficacy of botulinum toxin type A 100 units versus 200 units for treatment of refractory idiopathic overactive bladder. Int Braz J Urol. 2015;41(6):1132-1140.

Abdelwahab and colleagues conducted a single-center, randomized clinical trial to investigate the safety and efficacy of a single injection of intradetrusor onabotulinumtoxinA in 2 different doses (100 U and 200 U) for treatment of OAB.

Details of the study

Eighty adults (63 women, 17 men) who did not benefit from anticholinergic medication during the previous 3 months were randomly assigned to receive either a 100-U (n = 40) or a 200-U (n = 40) injection of onabotulinumtoxinA. Exclusion criteria were PVR urine volume greater than 150 mL and previous radiation therapy or chemotherapy.

Initial assessments -- completed at baseline and at 1, 3, 6, and 9 months -- included the health-related quality-of-life (HR-QOL) questionnaire (maximum score, 100; higher score indicates better quality of life), an abbreviated OABSS questionnaire (4 questions; score range, 0-15; higher score indicates more severe symptoms), and urodynamic evaluation. Outcomes included OABSS, HR-QOL score, and urodynamic parameters at the various time points.

Related article:
Is there a link between impaired mobility and urinary incontinence in elderly, community-dwelling women?

Higher dose, greater symptom improvement and higher adverse event rate

At baseline, participants (average age, 31 years) had an average (SD) OABSS of 1.7 (1.6). OnabotulinumtoxinA treatment with both a 100-U and a 200-U dose resulted in significant improvements (compared with baseline levels) in frequency, nocturia, UUI episodes, OABSS, and urodynamic parameters throughout the 9 months. At 9 months, however, the group treated with the 200-U dose had greater improvements, compared with the group who received a 100-U dose, in urinary frequency symptom scores (mean [SD], 0.32 [0.47] vs 1.1 [0.51]; P<.05), nocturia symptom scores (mean [SD], 0.13 [0.34] vs 0.36 [0.49]; P<.05), UUI symptom scores (mean [SD], 0.68 [0.16] vs 1.26 [1.1]; P<.05), and mean (SD) total OABSS (2.6 [2.31] vs 5.3 [2.11]; P<.05). Similarly, at 9 months the 200-U dose resulted in greater improvements in volume at first desire (mean [SD], 291.8 [42.8] vs 246.8 [53.8] mL; P<.05), volume at strong desire (mean [SD], 392.1 [37.3] vs 313.1 [67.4] mL; P<.05), detrusor pressure (mean [SD], 10.4 [4.0] vs 19.2 [7.8] cm H₂O; P<.05), and maximum cystometric capacity (mean [SD], 430.5 [34.2] vs 350 [69.1] mL; P<.05) compared with the 100-U dose.

Adverse events. No participant had a PVR urine volume greater than 100 mL at any follow-up visit. Postoperative hematuria occurred in 23% of the group treated with onabotulinumtoxinA 200 U versus in 15% of those treated with a 100-U dose. Similarly, UTIs occurred in 17.5% of the 200-U dose group and in 7.5% of the 100-U dose group. Dysuria was reported in 37.5% and 15% of the 200-U and 100-U dose groups, respectively.

Strengths and limitations. This randomized, open-label trial comparing a single injection of 100 U versus 200 U of onabotulinumtoxinA included mostly women. OAB symptoms and urodynamic parameters improved after treatment with both dose levels, but a longer duration of improvement was seen with the 200-U dose. The cohort had a low baseline OAB severity, based on the OABSS questionnaire, and a young average age of participants, which limits the generalizability of the study results to a population with refractory OAB. The 0% rate of clean intermittent self-catheterization postinjection might be based on the study's criteria for requiring clean intermittent catheterization. In addition, the initial postinjection visit occurred at 1 month, possibly missing participants who had symptoms of retention soon after injection.

Read: onabotulinumtoxinA vs sacral neuromodulation therapy for UUI.

Treatment with onabotulinumtoxinA may control UUI symptoms better than sacral neuromodulation therapy

Amundsen CL, Richter HE, Menefee SA, et al; Pelvic Floor Disorders Network. OnabotulinumtoxinA vs sacral neuromodulation on refractory urgency urinary incontinence in women: a randomized clinical trial. JAMA. 2016;316(13):1366-1374.

In this multicenter open-label randomized trial, Amundsen and colleagues compared the efficacy and safety of onabotulinumtoxinA 200 U with that of sacral neuromodulation.

Details of the study

Three hundred sixty-four women with UUI had data available for primary analysis at  6 months. Women were considered eligible for the study if they had 6 or more UUI episodes on a 3-day bladder diary, persistent symptoms despite anticholinergic therapy, a PVR urine volume of less than 150 mL, and had never previously received either study treatment.

There were no differences in baseline characteristics of the participants. The average (SD) age of the study population was 63 (11.6) years, with an average (SD) daily number of UUI episodes of 5.3 (2.8). The average (SD) body mass index was 32 (8) kg/m².

Participants were randomly assigned to undergo either sacral neuromodulation (n = 174) or intradetrusor injection of onabotulinumtoxinA 200 U (n = 190). The primary outcome was change from baseline in mean number of daily UUI episodes averaged over 6 months as recorded on a monthly 3-day bladder diary. Secondary outcomes included complete resolution of urgency incontinence, 75% or more reduction in UUI episodes, the Overactive Bladder Questionnaire Short Form (SF) score (range, 0-100; higher score indicates higher symptom severity), the Overactive Bladder Satisfaction of Treatment questionnaire (range, 0-100; higher score indicates better satisfaction), other quality-of-life measures, and adverse events.

Related article:
2015 Update on pelvic floor dysfunction: Bladder pain syndrome

Greater symptom bother improvement, treatment satisfaction with onabotulinumtoxinA 200 U

Participants treated with onabotulinumtoxinA had a greater mean reduction of 3.9 UUI episodes per day than the sacral neuromodulation group's reduction of 3.3 UUI episodes per day (mean difference, 0.63; 95% confidence interval [CI], 0.13-1.14; P = .01). In addition, complete UUI resolution was higher in the onabotulinumtoxinA group as compared with the sacral neuromodulation group (20% vs 4%; P<.001). The onabotulinumtoxinA group also had higher rates of 75% or more reduction of UUI episodes compared with the sacral neuromodulation group (46% vs 26%; P<.001). Over 6 months, both groups had improvements in all quality-of-life measures, but the onabotulinumtoxinA group had greater improvement in symptom bother compared with the sacral neuromodulation group (-46.7 vs -38.6; mean difference, 8.1; 95% CI, 3.0-13.3; P = .002). Furthermore, the onabotulinumtoxinA group had greater treatment satisfaction compared with the sacral neuromodulation group (mean difference, 7.8; 95% CI, 1.6-14.1; P = .01).

Adverse events. Six women (3%) underwent sacral neuromodulation device revision or removal. Approximately 8% of onabotulinumtoxinA-treated participants required intermittent self-catheterization at 1 month, 4% at 3 months, and 2% at 6 months. The risk of UTI was higher in the onabotulinumtoxinA group compared with the sacral neuromodulation group (35% vs 11%; risk difference, 23%; 95% CI, -33% to -13%; P<.001).

Strengths and limitations. This is a well-designed randomized clinical trial comparing clinical outcomes and adverse events after treatment with onabotulinumtoxinA 200-U versus sacral neuromodulation. The interventions were standardized across investigators at multiple sites, and the study design required close follow-up to assess efficacy and adverse events. The study used a 200-U dose based on reported durability of effect at that time and findings of equivalency between onabotulinumtoxinA 100 U and anticholinergic therapy. The US Food and Drug Administration's recommendation to use a 100-U dose in all patients with idiopathic OAB might dissuade clinicians from considering the higher dose of onabotulinumtoxinA. The study was limited by the lack of a placebo group.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

The International Continence Society (ICS) defines overactive bladder (OAB) as a syndrome of "urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence (UUI), in the absence of urinary tract infection [UTI] or obvious pathology."¹ The Agency for Healthcare Research and Quality (AHRQ) reported OAB prevalence to be 15% in US women, with 11% reporting UUI.² OAB represents a significant health care burden that impacts nearly every aspect of life, including physical, emotional, and psychological domains.^3,4 The economic impact is notable; the projected cost is estimated to reach $82.6 billion annually by 2020.⁵

The American Urological Association (AUA) and the Society for Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (SUFU) have endorsed an algorithm for use in the evaluation of idiopathic OAB (FIGURE).⁶ If the patient's symptoms are certain, minimal evaluation is needed and it is reasonable to proceed with first-line therapy, which includes fluid management (decreasing caffeine intake and limiting evening fluid intake), bladder retraining drills such as timed voiding, and improving pelvic floor muscles with the use of biofeedback and functional electrical stimulation.^6,7 Pelvic floor muscle training can be facilitated with a referral to a physical therapist trained in pelvic floor muscle education.

If treatment goals are not met with first-line strategies, second-line therapy may be initiated with anticholinergic or β3-adrenergic receptor agonist medications. If symptoms persist after 4 to 8 weeks of pharmacologic therapy, clinicians are encouraged to reassess or refer the patient to a specialist. Further evaluation may include a bladder diary in which the patient documents voided volumes, voiding frequency, and number of incontinent episodes; symptom-specific questionnaires; and/or urodynamic testing.

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Based on that evaluation, the patient may be a candidate for third-line therapy with either intradetrusor onabotulinumtoxinA, posterior tibial nerve stimulation (PTNS), or sacral neuromodulation.

There is a paucity of information comparing third-line therapies. In this Update, we focus on 4 randomized clinical trials that compare third-line treatment options for idiopathic OAB.

Read about how anticholinergic medication and onabotulinumtoxinA compare for treating UUI.

Anticholinergic therapy and onabotulinumtoxinA produce equivalent reductions in the frequency of daily UUI episodes

Visco AG, Brubaker L, Richter HE, et al; for the Pelvic Floor Disorders Network. Anticholinergic therapy vs onabotulinumtoxinA for urgency urinary incontinence. N Engl J Med. 2012;367(19):1803-1813.

In a double-blind, double-placebo-controlled randomized trial, Visco and colleagues compared anticholinergic medication with onabotulinumtoxinA 100 U for the treatment of women with UUI.

Details of the study

Two hundred forty-one women with moderate to severe UUI received either 6 months of oral anticholinergic therapy (solifenacin 5 mg daily with the option of dose escalation to 10 mg daily or change to trospium XR 60 mg daily based on the Patient Global Symptom Control score) plus a single intradetrusor injection of saline, or a single intradetrusor injection of onabotulinumtoxinA 100 U plus a 6-month oral placebo regimen.

Inclusion criteria were 5 or more UUI episodes on a 3-day diary, insufficient resolution of symptoms after 2 medications, or being drug naive. Exclusions included a postvoid residual (PVR) urine volume greater than 150 mL or previous therapy with onabotulinumtoxinA.

Participants were scheduled for follow up every 2 to 6 months post randomization, at which time all study medications were discontinued. The primary outcome was reduction from baseline in the mean number of UUI episodes per day over the 6-month period, as recorded in the monthly 3-day bladder diaries. Secondary outcomes included the proportion of participants with complete resolution of UUI, the proportion of participants with 75% or more reduction in UUI episodes, Overactive Bladder Questionnaire Short Form (OABq-SF) scores, other symptom-specific questionnaire scores, and adverse events.

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Both treatments significantly reduced UUI episodes

At baseline, participants reported a mean (SD) of 5.0 (2.7) UUI episodes per day, and 41% of participants were drug naive. Both treatment groups experienced significant reductions compared with baseline in mean UUI episodes, and the reductions were similar between the 2 groups (reduction of 3.4 episodes per day in the anticholinergic group, reduction of 3.3 episodes in the onabotulinumtoxinA group; P = .81). Complete resolution of UUI was more common in the onabotulinumtoxinA group (27%) as compared with the anticholinergic group (13%) (P = .003). There were no differences in improvement in OABq-SF scores (37.05 in the anticholinergic group vs 37.13 in the onabotulinumtoxinA group; P = .98) or other quality-of-life measures.

Adverse events. The anticholinergic group experienced a higher rate of dry mouth compared with the onabotulinumtoxinA group (46% vs 31%; P = .02) but had lower rates of intermittent catheterization use at 2 months (0% vs 5%, P = .01) and UTIs (13% vs 33%, P<.001).

Strengths and limitations. This was a well-designed, multicenter, randomized double-blind, double placebo-controlled trial. The study design allowed for dose escalation and change to another medication for inadequate symptom control and included drug-naive participants, which increases the generalizability of the results. However, current guidelines recommend reserving onabotulinumtoxinA therapy for third-line therapy, thus deterring this treatment's use in the drug-naive population. Additionally, the lack of a pure placebo arm makes it difficult to interpret the extent to which a placebo effect contributed to observed improvements in clinical symptoms.

Read: onabotulinumtoxinA vs PTNS for OAB.

OnabotulinumtoxinA has greater 9-month durability for OAB symptoms compared with12 weeks of PTNS

Sherif H, Khalil M, Omar R. Management of refractory idiopathic overactive bladder: intradetrusor injection of botulinum toxin type A versus posterior tibial nerve stimulation. Can J Urol. 2017;24(3):8838-8846.

In this randomized clinical trial, Sherif and colleagues compared the safety and efficacy of a single intradetrusor injection of onabotulinumtoxinA 100 U with that of PTNS for OAB.

Details of the study

Sixty adult men and women with OAB who did not respond to medical therapy were randomly assigned to treatment with either onabotulinumtoxinA 100 U or PTNS. Criteria for exclusion were current UTI, PVR urine volume of more than 150 mL, previous radiation therapy or chemotherapy, previous incontinence surgery or bladder malignancy, or presence of mixed urinary incontinence.

At baseline, participants completed a 3-day bladder diary, an OAB symptom score (OABSS) questionnaire, and urodynamic testing. The OABSS questionnaire included 7 questions (scoring range, 0-28), with higher scores indicating worse symptoms, and included subscales for urgency and quality-of-life measures. Total OABSS, urgency score, quality-of-life score, bladder diary records, and urodynamic testing parameters were assessed at 6, 12, 24, and 36 weeks, along with adverse events.

OnabotulinumtoxinA injections were performed under spinal anesthesia. If PVR urine volume was greater than 200 mL at any follow-up visit, participants were instructed to begin clean intermittent self-catheterization. PTNS was administered as weekly 30-minute sessions for 12 consecutive weeks.

Participants' baseline demographics and symptoms were similar. Average age was 45 years. Averages (SD) for duration of anticholinergic use was 13 (0.8) weeks, UUI episode score was 4.5 (1) on 3-day bladder diary, and OABSS was 22 (2.7). Nine-month data were available for 29 participants in the onabotulinumtoxinA group and for 8 in the PTNS group.

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OnabotulinumtoxinA treatment benefits sustained for 9 months

Through 6 months, compared with baseline assessments, both treatment groups had significant improvements in clinical symptoms and OABSS total score, as well as urgency and quality-of-life subscales. At 3 months, urodynamic study parameters were similarly improved from baseline in both groups.

At 9 months, however, only the onabotulinumtoxinA group, compared with the PTNS group, maintained the significant improvement from baseline in 3-day bladder diary voiding episodes (average [SD], 10.7 [1.01] vs 11.6 [1.09]; P = .009), 3-day bladder diary nocturia episodes (average [SD], 3.8 [1.09] vs 4.4 [0.8]; P = .02), and average [SD] UUI episodes over 3 days (3.5 [1.2] vs 4.2 [1.04]; P = .02). Similarly, onabotulinumtoxinA-treated participants, compared with those treated with PTNS, maintained improvements at 9 months in average (SD): OABSS total score (19.2 [2.4] vs 20.4 [1.7]; P = .03), urgency scores (10.9 [1.3] vs 11.8 [1.4]; P = .009), urine volume at first desire (177.8 [9.2] vs 171.8 [7.7]), maximum cystometric capacity (304 [17.6] vs 290 [13.1]), and Qmax (mL/sec) (20.7 [1.6] vs 22.2 [1.2]).

Adverse events. Average PVR urine volumes were higher in the onabotulinumtoxinA group compared with the PTNS group (36.8 [2.7] vs 32.4 [3.03]; P = .0001) at all time points, and self-catheterization was required in 6.6% of onabotulinumtoxinA-treated participants. Urinary tract infection occurred in 6.6% of participants in the onabotulinumtoxinA group and in none of the PTNS group. In the PTNS group, few experienced pain and minor bleeding at the needle site.

Strengths and limitations. This randomized, open-label trial comparing treatment with onabotulinumtoxinA 100 U and PTNS included both men and women with idiopathic OAB symptoms. The participants were assessed at regular intervals with various measures, and follow-up adherence was good. The sample size was small, so the study may not have been powered to see differences prior to 9 months.

Although at 9 months only the onabotulinumtoxinA group maintained significant improvement over baseline levels, the improvement was diminished, and therefore the clinical meaningfulness is uncertain. Further, participants in the PTNS group did not undergo monthly maintenance therapy after 3 months, which is recommended for those with a 12-week therapeutic response; this may have affected 9-month outcomes in this group. Since the one-time onabotulinumtoxinA 100 U injection was performed under spinal anesthesia, cost comparisons should be considered, since future onabotulinumtoxinA injections would be necessary. 

Read about using different doses of onabotulinumtoxinA for OAB.

OnabotulinumtoxinA 200-U injection provides longer OAB symptom  improvement than 100-U injection

Abdelwahab O, Sherif H, Soliman T, Elbarky I, Eshazly A. Efficacy of botulinum toxin type A 100 units versus 200 units for treatment of refractory idiopathic overactive bladder. Int Braz J Urol. 2015;41(6):1132-1140.

Abdelwahab and colleagues conducted a single-center, randomized clinical trial to investigate the safety and efficacy of a single injection of intradetrusor onabotulinumtoxinA in 2 different doses (100 U and 200 U) for treatment of OAB.

Details of the study

Eighty adults (63 women, 17 men) who did not benefit from anticholinergic medication during the previous 3 months were randomly assigned to receive either a 100-U (n = 40) or a 200-U (n = 40) injection of onabotulinumtoxinA. Exclusion criteria were PVR urine volume greater than 150 mL and previous radiation therapy or chemotherapy.

Initial assessments -- completed at baseline and at 1, 3, 6, and 9 months -- included the health-related quality-of-life (HR-QOL) questionnaire (maximum score, 100; higher score indicates better quality of life), an abbreviated OABSS questionnaire (4 questions; score range, 0-15; higher score indicates more severe symptoms), and urodynamic evaluation. Outcomes included OABSS, HR-QOL score, and urodynamic parameters at the various time points.

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Higher dose, greater symptom improvement and higher adverse event rate

At baseline, participants (average age, 31 years) had an average (SD) OABSS of 1.7 (1.6). OnabotulinumtoxinA treatment with both a 100-U and a 200-U dose resulted in significant improvements (compared with baseline levels) in frequency, nocturia, UUI episodes, OABSS, and urodynamic parameters throughout the 9 months. At 9 months, however, the group treated with the 200-U dose had greater improvements, compared with the group who received a 100-U dose, in urinary frequency symptom scores (mean [SD], 0.32 [0.47] vs 1.1 [0.51]; P<.05), nocturia symptom scores (mean [SD], 0.13 [0.34] vs 0.36 [0.49]; P<.05), UUI symptom scores (mean [SD], 0.68 [0.16] vs 1.26 [1.1]; P<.05), and mean (SD) total OABSS (2.6 [2.31] vs 5.3 [2.11]; P<.05). Similarly, at 9 months the 200-U dose resulted in greater improvements in volume at first desire (mean [SD], 291.8 [42.8] vs 246.8 [53.8] mL; P<.05), volume at strong desire (mean [SD], 392.1 [37.3] vs 313.1 [67.4] mL; P<.05), detrusor pressure (mean [SD], 10.4 [4.0] vs 19.2 [7.8] cm H₂O; P<.05), and maximum cystometric capacity (mean [SD], 430.5 [34.2] vs 350 [69.1] mL; P<.05) compared with the 100-U dose.

Adverse events. No participant had a PVR urine volume greater than 100 mL at any follow-up visit. Postoperative hematuria occurred in 23% of the group treated with onabotulinumtoxinA 200 U versus in 15% of those treated with a 100-U dose. Similarly, UTIs occurred in 17.5% of the 200-U dose group and in 7.5% of the 100-U dose group. Dysuria was reported in 37.5% and 15% of the 200-U and 100-U dose groups, respectively.

Strengths and limitations. This randomized, open-label trial comparing a single injection of 100 U versus 200 U of onabotulinumtoxinA included mostly women. OAB symptoms and urodynamic parameters improved after treatment with both dose levels, but a longer duration of improvement was seen with the 200-U dose. The cohort had a low baseline OAB severity, based on the OABSS questionnaire, and a young average age of participants, which limits the generalizability of the study results to a population with refractory OAB. The 0% rate of clean intermittent self-catheterization postinjection might be based on the study's criteria for requiring clean intermittent catheterization. In addition, the initial postinjection visit occurred at 1 month, possibly missing participants who had symptoms of retention soon after injection.

Read: onabotulinumtoxinA vs sacral neuromodulation therapy for UUI.

Treatment with onabotulinumtoxinA may control UUI symptoms better than sacral neuromodulation therapy

Amundsen CL, Richter HE, Menefee SA, et al; Pelvic Floor Disorders Network. OnabotulinumtoxinA vs sacral neuromodulation on refractory urgency urinary incontinence in women: a randomized clinical trial. JAMA. 2016;316(13):1366-1374.

In this multicenter open-label randomized trial, Amundsen and colleagues compared the efficacy and safety of onabotulinumtoxinA 200 U with that of sacral neuromodulation.

Details of the study

Three hundred sixty-four women with UUI had data available for primary analysis at  6 months. Women were considered eligible for the study if they had 6 or more UUI episodes on a 3-day bladder diary, persistent symptoms despite anticholinergic therapy, a PVR urine volume of less than 150 mL, and had never previously received either study treatment.

There were no differences in baseline characteristics of the participants. The average (SD) age of the study population was 63 (11.6) years, with an average (SD) daily number of UUI episodes of 5.3 (2.8). The average (SD) body mass index was 32 (8) kg/m².

Participants were randomly assigned to undergo either sacral neuromodulation (n = 174) or intradetrusor injection of onabotulinumtoxinA 200 U (n = 190). The primary outcome was change from baseline in mean number of daily UUI episodes averaged over 6 months as recorded on a monthly 3-day bladder diary. Secondary outcomes included complete resolution of urgency incontinence, 75% or more reduction in UUI episodes, the Overactive Bladder Questionnaire Short Form (SF) score (range, 0-100; higher score indicates higher symptom severity), the Overactive Bladder Satisfaction of Treatment questionnaire (range, 0-100; higher score indicates better satisfaction), other quality-of-life measures, and adverse events.

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Greater symptom bother improvement, treatment satisfaction with onabotulinumtoxinA 200 U

Participants treated with onabotulinumtoxinA had a greater mean reduction of 3.9 UUI episodes per day than the sacral neuromodulation group's reduction of 3.3 UUI episodes per day (mean difference, 0.63; 95% confidence interval [CI], 0.13-1.14; P = .01). In addition, complete UUI resolution was higher in the onabotulinumtoxinA group as compared with the sacral neuromodulation group (20% vs 4%; P<.001). The onabotulinumtoxinA group also had higher rates of 75% or more reduction of UUI episodes compared with the sacral neuromodulation group (46% vs 26%; P<.001). Over 6 months, both groups had improvements in all quality-of-life measures, but the onabotulinumtoxinA group had greater improvement in symptom bother compared with the sacral neuromodulation group (-46.7 vs -38.6; mean difference, 8.1; 95% CI, 3.0-13.3; P = .002). Furthermore, the onabotulinumtoxinA group had greater treatment satisfaction compared with the sacral neuromodulation group (mean difference, 7.8; 95% CI, 1.6-14.1; P = .01).

Adverse events. Six women (3%) underwent sacral neuromodulation device revision or removal. Approximately 8% of onabotulinumtoxinA-treated participants required intermittent self-catheterization at 1 month, 4% at 3 months, and 2% at 6 months. The risk of UTI was higher in the onabotulinumtoxinA group compared with the sacral neuromodulation group (35% vs 11%; risk difference, 23%; 95% CI, -33% to -13%; P<.001).

Strengths and limitations. This is a well-designed randomized clinical trial comparing clinical outcomes and adverse events after treatment with onabotulinumtoxinA 200-U versus sacral neuromodulation. The interventions were standardized across investigators at multiple sites, and the study design required close follow-up to assess efficacy and adverse events. The study used a 200-U dose based on reported durability of effect at that time and findings of equivalency between onabotulinumtoxinA 100 U and anticholinergic therapy. The US Food and Drug Administration's recommendation to use a 100-U dose in all patients with idiopathic OAB might dissuade clinicians from considering the higher dose of onabotulinumtoxinA. The study was limited by the lack of a placebo group.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.