Gideon Koren, MD

Up to 80% of women experience morning sickness, and about 25% of them continue to experience symptoms through the second and third trimesters. The delayed-release combination of the antihistamine doxylamine and vitamin B₆ (pyridoxine hydrochloride) is the only drug approved to treat nausea and vomiting in pregnancy (NVP) in the United States (Diclegis) and Canada (Diclectin). Despite Food and Drug Administration approval and solid evidence demonstrating that this antihistamine-based treatment is safe and effective during pregnancy, many women are afraid to take it due to misperception of risk.

What can help clinicians who are reassuring their pregnant patients to use medications when needed are the numerous studies documenting that NVP is associated with reduced rates of congenital malformations, prematurity, and miscarriage.

In a recent analysis of studies from Sweden, the United States, and Hungary – which measured different outcomes – we found a consistent, favorable effect of NVP on birth outcomes, including lower rates of miscarriages, congenital malformations, and prematurity, as well as neurodevelopmental outcomes.

These studies include a U.S. study of about 2,400 pregnant women between 2000 and 2004, which found that the miscarriage risk was reduced among most age groups of women who experienced NVP for at least half of their pregnancy, with the greatest effects (an 80% reduced risk) among the oldest women. Among those who did not have symptoms, the risk for miscarriage was increased by about threefold (Hum. Reprod. 2010;25:2907-12).

A prospective Swedish study that evaluated the effects of antihistamines in early pregnancy provides even stronger evidence for a protective effect of NVP. This study compared delivery outcomes in more than 17,000 women who took antihistamines early in pregnancy for allergies or for morning sickness. A protective effect was demonstrated in the group with NVP, with a significantly lower rate of preterm births, low birth weight, and small for gestational age among singletons. But in the group of women who took the medication for allergies, there was a neutral effect on delivery outcomes, with no protective effect observed (J. Matern. Fetal Neonatal Med. 2002;11:146-52).

Other studies include the following:

• In a prospective study of 849 pregnant women in Ecuador, the risk of miscarriage was significantly reduced by 55% among those with nausea only, and by 34% among those with nausea and vomiting (J. Perinat. Med. 2006;34: 115-22).

•A study using data from the Hungarian Case-Control Surveillance System of Congenital Abnormalities between 1980 and 1996 found that overall, mothers of babies with congenital abnormalities were 26% less likely to have experienced severe NVP in early pregnancy compared with the mothers of controls with no congenital abnormalities (Am. Med. Genet. A 2006;140:453-62). In another study of more than 38,000 women who were controls in this registry, who did not have babies with congenital abnormalities, 6.4% of those with medically documented and treated NVP had preterm births vs. 9.5% among those who did not have NVP (Paediatr. Perinat. Epidemiol. 2004;18:253-9).

• In a Swedish study, the rate of congenital malformations was 9% lower in a group of more than 16,000 women who said they had used meclozine (the antihistamine most often used for NVP in Sweden) early in pregnancy, compared with all women who gave birth. Rates of preterm birth, low birth weight, and small head circumference were lower among those who had taken meclozine (Eur. J. Epidemiol. 2003;18: 665-9).

• In a Motherisk study that compared the neurodevelopment of 121 children aged 3-7 years, those whose mothers had NVP scored higher in some areas compared with women not experiencing NVP. The severity of NVP and maternal IQ were predictors of improved results (J. Pediatr. 2009;155:45-50).

The underlying hypothesis is that the protective effect of NVP is related to a more favorable hormonal milieu during pregnancy. Although estrogen, progesterone and beta-HCG levels are increased during pregnancy, the effect cannot be attributed to any one hormone, and some believe it may be an as-of-yet unidentified hormone. Many women who have morning sickness until they deliver often say that symptoms entirely resolve within minutes of the delivery of the placenta, suggesting that a hormone – or another compound or combination of compounds – produced by the placenta causes these symptoms.

The Motherisk NVP Line (800-436-8477) encourages women who need pharmacotherapy that there are safe medications for this condition, and that the protective effect of NVP on pregnancy outcome should encourage them to effectively treat their symptoms.

Dr. Koren is professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk Program. He also holds the Ivey Chair in Molecular Toxicology at the department of medicine, University of Western Ontario, London. Dr. Koren was a principal investigator in the U.S. study that resulted in the approval of Diclegis, marketed by Duchesnay USA, and he has served as a consultant to Duchesnay. E-mail him at [email protected].

Up to 80% of women experience morning sickness, and about 25% of them continue to experience symptoms through the second and third trimesters. The delayed-release combination of the antihistamine doxylamine and vitamin B₆ (pyridoxine hydrochloride) is the only drug approved to treat nausea and vomiting in pregnancy (NVP) in the United States (Diclegis) and Canada (Diclectin). Despite Food and Drug Administration approval and solid evidence demonstrating that this antihistamine-based treatment is safe and effective during pregnancy, many women are afraid to take it due to misperception of risk.

What can help clinicians who are reassuring their pregnant patients to use medications when needed are the numerous studies documenting that NVP is associated with reduced rates of congenital malformations, prematurity, and miscarriage.

In a recent analysis of studies from Sweden, the United States, and Hungary – which measured different outcomes – we found a consistent, favorable effect of NVP on birth outcomes, including lower rates of miscarriages, congenital malformations, and prematurity, as well as neurodevelopmental outcomes.

These studies include a U.S. study of about 2,400 pregnant women between 2000 and 2004, which found that the miscarriage risk was reduced among most age groups of women who experienced NVP for at least half of their pregnancy, with the greatest effects (an 80% reduced risk) among the oldest women. Among those who did not have symptoms, the risk for miscarriage was increased by about threefold (Hum. Reprod. 2010;25:2907-12).

A prospective Swedish study that evaluated the effects of antihistamines in early pregnancy provides even stronger evidence for a protective effect of NVP. This study compared delivery outcomes in more than 17,000 women who took antihistamines early in pregnancy for allergies or for morning sickness. A protective effect was demonstrated in the group with NVP, with a significantly lower rate of preterm births, low birth weight, and small for gestational age among singletons. But in the group of women who took the medication for allergies, there was a neutral effect on delivery outcomes, with no protective effect observed (J. Matern. Fetal Neonatal Med. 2002;11:146-52).

Other studies include the following:

• In a prospective study of 849 pregnant women in Ecuador, the risk of miscarriage was significantly reduced by 55% among those with nausea only, and by 34% among those with nausea and vomiting (J. Perinat. Med. 2006;34: 115-22).

•A study using data from the Hungarian Case-Control Surveillance System of Congenital Abnormalities between 1980 and 1996 found that overall, mothers of babies with congenital abnormalities were 26% less likely to have experienced severe NVP in early pregnancy compared with the mothers of controls with no congenital abnormalities (Am. Med. Genet. A 2006;140:453-62). In another study of more than 38,000 women who were controls in this registry, who did not have babies with congenital abnormalities, 6.4% of those with medically documented and treated NVP had preterm births vs. 9.5% among those who did not have NVP (Paediatr. Perinat. Epidemiol. 2004;18:253-9).

• In a Swedish study, the rate of congenital malformations was 9% lower in a group of more than 16,000 women who said they had used meclozine (the antihistamine most often used for NVP in Sweden) early in pregnancy, compared with all women who gave birth. Rates of preterm birth, low birth weight, and small head circumference were lower among those who had taken meclozine (Eur. J. Epidemiol. 2003;18: 665-9).

• In a Motherisk study that compared the neurodevelopment of 121 children aged 3-7 years, those whose mothers had NVP scored higher in some areas compared with women not experiencing NVP. The severity of NVP and maternal IQ were predictors of improved results (J. Pediatr. 2009;155:45-50).

The underlying hypothesis is that the protective effect of NVP is related to a more favorable hormonal milieu during pregnancy. Although estrogen, progesterone and beta-HCG levels are increased during pregnancy, the effect cannot be attributed to any one hormone, and some believe it may be an as-of-yet unidentified hormone. Many women who have morning sickness until they deliver often say that symptoms entirely resolve within minutes of the delivery of the placenta, suggesting that a hormone – or another compound or combination of compounds – produced by the placenta causes these symptoms.

The Motherisk NVP Line (800-436-8477) encourages women who need pharmacotherapy that there are safe medications for this condition, and that the protective effect of NVP on pregnancy outcome should encourage them to effectively treat their symptoms.

Dr. Koren is professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk Program. He also holds the Ivey Chair in Molecular Toxicology at the department of medicine, University of Western Ontario, London. Dr. Koren was a principal investigator in the U.S. study that resulted in the approval of Diclegis, marketed by Duchesnay USA, and he has served as a consultant to Duchesnay. E-mail him at [email protected].

Up to 80% of women experience morning sickness, and about 25% of them continue to experience symptoms through the second and third trimesters. The delayed-release combination of the antihistamine doxylamine and vitamin B₆ (pyridoxine hydrochloride) is the only drug approved to treat nausea and vomiting in pregnancy (NVP) in the United States (Diclegis) and Canada (Diclectin). Despite Food and Drug Administration approval and solid evidence demonstrating that this antihistamine-based treatment is safe and effective during pregnancy, many women are afraid to take it due to misperception of risk.

What can help clinicians who are reassuring their pregnant patients to use medications when needed are the numerous studies documenting that NVP is associated with reduced rates of congenital malformations, prematurity, and miscarriage.

In a recent analysis of studies from Sweden, the United States, and Hungary – which measured different outcomes – we found a consistent, favorable effect of NVP on birth outcomes, including lower rates of miscarriages, congenital malformations, and prematurity, as well as neurodevelopmental outcomes.

These studies include a U.S. study of about 2,400 pregnant women between 2000 and 2004, which found that the miscarriage risk was reduced among most age groups of women who experienced NVP for at least half of their pregnancy, with the greatest effects (an 80% reduced risk) among the oldest women. Among those who did not have symptoms, the risk for miscarriage was increased by about threefold (Hum. Reprod. 2010;25:2907-12).

A prospective Swedish study that evaluated the effects of antihistamines in early pregnancy provides even stronger evidence for a protective effect of NVP. This study compared delivery outcomes in more than 17,000 women who took antihistamines early in pregnancy for allergies or for morning sickness. A protective effect was demonstrated in the group with NVP, with a significantly lower rate of preterm births, low birth weight, and small for gestational age among singletons. But in the group of women who took the medication for allergies, there was a neutral effect on delivery outcomes, with no protective effect observed (J. Matern. Fetal Neonatal Med. 2002;11:146-52).

Other studies include the following:

• In a prospective study of 849 pregnant women in Ecuador, the risk of miscarriage was significantly reduced by 55% among those with nausea only, and by 34% among those with nausea and vomiting (J. Perinat. Med. 2006;34: 115-22).

•A study using data from the Hungarian Case-Control Surveillance System of Congenital Abnormalities between 1980 and 1996 found that overall, mothers of babies with congenital abnormalities were 26% less likely to have experienced severe NVP in early pregnancy compared with the mothers of controls with no congenital abnormalities (Am. Med. Genet. A 2006;140:453-62). In another study of more than 38,000 women who were controls in this registry, who did not have babies with congenital abnormalities, 6.4% of those with medically documented and treated NVP had preterm births vs. 9.5% among those who did not have NVP (Paediatr. Perinat. Epidemiol. 2004;18:253-9).

• In a Swedish study, the rate of congenital malformations was 9% lower in a group of more than 16,000 women who said they had used meclozine (the antihistamine most often used for NVP in Sweden) early in pregnancy, compared with all women who gave birth. Rates of preterm birth, low birth weight, and small head circumference were lower among those who had taken meclozine (Eur. J. Epidemiol. 2003;18: 665-9).

• In a Motherisk study that compared the neurodevelopment of 121 children aged 3-7 years, those whose mothers had NVP scored higher in some areas compared with women not experiencing NVP. The severity of NVP and maternal IQ were predictors of improved results (J. Pediatr. 2009;155:45-50).

The underlying hypothesis is that the protective effect of NVP is related to a more favorable hormonal milieu during pregnancy. Although estrogen, progesterone and beta-HCG levels are increased during pregnancy, the effect cannot be attributed to any one hormone, and some believe it may be an as-of-yet unidentified hormone. Many women who have morning sickness until they deliver often say that symptoms entirely resolve within minutes of the delivery of the placenta, suggesting that a hormone – or another compound or combination of compounds – produced by the placenta causes these symptoms.

The Motherisk NVP Line (800-436-8477) encourages women who need pharmacotherapy that there are safe medications for this condition, and that the protective effect of NVP on pregnancy outcome should encourage them to effectively treat their symptoms.

Dr. Koren is professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk Program. He also holds the Ivey Chair in Molecular Toxicology at the department of medicine, University of Western Ontario, London. Dr. Koren was a principal investigator in the U.S. study that resulted in the approval of Diclegis, marketed by Duchesnay USA, and he has served as a consultant to Duchesnay. E-mail him at [email protected].

For some time, the potent antiemetic ondansetron, a 5-HT₃ receptor antagonist approved for preventing nausea and vomiting related to cancer chemotherapy and surgery, has been used to treat morning sickness, mostly for severe cases of nausea and vomiting in pregnancy (NVP). Ondansetron, which blocks the action of serotonin, is marketed as Zofran in the United States and Canada, and is also available in generic formulations.

Like most drugs, ondansetron is not labeled for use in pregnancy. But until recently, the limited reproductive safety data available on ondansetron have been somewhat reassuring. The first published report was a Motherisk study comparing pregnancy outcomes of three groups of women who called a teratogen information service. My colleagues and I found no increase in the major malformation rate among the 176 pregnancies of women exposed to ondansetron (a 3.6% rate of major malformations), compared with the rates among women exposed to other antiemetics and those exposed to drugs known not be teratogenic (BJOG 2004;111:940-3). However, this sample size could not rule out less than a threefold increase in malformation rates.

More reassuring data became available earlier this year with the publication of a study using data from Danish pregnancy, birth, and prescription registries. The study compared pregnancy outcomes among almost 2,000 women exposed to ondansetron in pregnancy, and women not exposed to the drug between 2004 and 2011. Exposure to ondansetron was not associated with an increased rate of major malformations (at about 3%), or other adverse fetal outcomes, including stillbirth, preterm delivery, and low birth weight, compared with the unexposed pregnancies (N. Engl. J. Med. 2013;368:814-23).

However, the mean gestational age of exposure was 10 weeks, so half the women who took ondansetron started treatment after that time, past the window of risk for malformations, which may have diluted the risk, if it existed. Still, this limitation did not deter from the strength of the conclusions of the study.

But new and troubling evidence suggesting that the drug may be associated with increased risks during pregnancy – both maternal and fetal – has recently become available in the medical literature and elsewhere.

In August 2013, at the International Society of Pharmacoepidemiology meeting in Montreal, the results of a different group of Danish researchers using data from the same national registries employed in the study published in February, but with more pregnancies (almost 900,000) over a longer period (1997 to 2010), detected a twofold increase in congenital heart defects associated with ondansetron during the first trimester of pregnancy. Of the 1,248 women who filled a prescription for ondansetron during the first trimester, 4.7% (58) had a baby with a congenital malformation, compared with 3.5% (31,357) of those who were not exposed to ondansetron; this represented a 30% increased risk (adjusted odds ratio, 1.3). The increased risk was mostly due to the increased prevalence of heart defects. There was no association with congenital malformations and first-trimester prescriptions for metoclopramide, another drug used to treat hyperemesis gravidarum.

In January 2012, a study from the Center for Birth Defects Research and Prevention identified a twofold increased risk for cleft palate associated with ondansetron exposure used for NVP in the first trimester. There were over 9,000 pregnant women in the study overall, both cases and controls; 67% reported NVP and 15% used some kind of agent to treat NVP. The study used data from the National Birth Defects Prevention Study, looking at the association between NVP and treatments for NVP and cleft palate, and other noncardiac birth detects (Birth Defects Res. A Clin. Mol. Teratol. 2012;94:22-30).

With these recent studies, we are left with contradictory results regarding the risk of birth defects associated with ondansetron exposure in the first trimester, and more studies may be needed.

Importantly, potential risks of ondansetron, namely, cardiac arrhythmias and serotonin syndrome – which can be harmful to both the mother and fetus – also should be considered. In June 2012, the Food and Drug Administration (FDA) issued an updated warning about the possible increased risk of prolongation of the QT interval, which can result in the potentially fatal arrhythmia Torsade de pointes, associated with ondansetron. The warning advised against using ondansetron in patients with congenital long-QT syndrome, and recommended ECG monitoring for certain patients on ondansetron, including those with electrolyte abnormalities, such as hypokalemia or hypomagnesemia.

Based on what we hear from women who have been treated with ondansetron during pregnancy and contact Motherisk, most clinicians are not following these recommendations in pregnant women. But monitoring pregnant women taking ondansetron for NVP for these adverse effects is just as important – particularly because they are prone to electrolyte imbalances, including hypokalemia and hypomagnesemia, specified in the FDA warning.

Another recent development is the FDA’s announcement in May 2013 that an increased risk for serotonin syndrome in patients taking 5-HT₃ receptor antagonists, including Zofran, has been identified as a "potential safety issue" in the FDA’s adverse event reporting database during the first quarter of 2013, and that the agency was investigating this possible association further.

Typically, serotonin syndrome occurs with the coadministration of two or more dugs that affect serotonin, usually selective serotonin reuptake inhibitors (SSRIs) or monoamine oxidase (MAO) inhibitors. Cases of possible or probable serotonin syndrome have been reported with the use of ondansetron, and because many pregnant women are treated with SSRIs during pregnancy, the potential for serotonin syndrome with an SSRI and ondansetron should be considered. Therefore, life-threatening serotonin syndrome – characterized by a triad of cognitive or behavioral changes, such as confusion or agitation; autonomic instability; and neuromuscular changes – should be kept in mind as another potential risk for pregnant women taking ondansetron.

Based on the available data, one therefore needs to be cautious with ondansetron, considering the potential risks of cardiac malformations and oral clefts with first-trimester exposure, which needs to be studied further, and the maternal risks of serotonin syndrome and cardiac arrhythmias.

For about 30 years, there was no drug labeled in the United States for morning sickness, after the unjustified removal of Bendectin (doxylamine-pyridoxine). Hence, ondansetron has been increasingly used off-label for this indication. But now that the FDA has approved Diclegis (doxylamine succinate and pyridoxine hydrochloride) for morning sickness – the doxylamine-pyridoxine combination that has been studied in hundreds of thousands of pregnant women and is a pregnancy category A drug – there is now a safer option for women with NVP. Therefore, ondansetron should be used cautiously in pregnant women, and only after drugs with a more established safety record – particularly doxylamine-pyridoxine – have been prescribed.

Dr. Koren is professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk Program. He also holds the Ivey Chair in Molecular Toxicology at the department of medicine, University of Western Ontario, London. Dr. Koren was a principal investigator in the U.S. study that resulted in the approval of Diclegis, marketed by Duchesnay USA, and he has served as a consultant to Duchesnay. E-mail him at [email protected].

For some time, the potent antiemetic ondansetron, a 5-HT₃ receptor antagonist approved for preventing nausea and vomiting related to cancer chemotherapy and surgery, has been used to treat morning sickness, mostly for severe cases of nausea and vomiting in pregnancy (NVP). Ondansetron, which blocks the action of serotonin, is marketed as Zofran in the United States and Canada, and is also available in generic formulations.

Like most drugs, ondansetron is not labeled for use in pregnancy. But until recently, the limited reproductive safety data available on ondansetron have been somewhat reassuring. The first published report was a Motherisk study comparing pregnancy outcomes of three groups of women who called a teratogen information service. My colleagues and I found no increase in the major malformation rate among the 176 pregnancies of women exposed to ondansetron (a 3.6% rate of major malformations), compared with the rates among women exposed to other antiemetics and those exposed to drugs known not be teratogenic (BJOG 2004;111:940-3). However, this sample size could not rule out less than a threefold increase in malformation rates.

More reassuring data became available earlier this year with the publication of a study using data from Danish pregnancy, birth, and prescription registries. The study compared pregnancy outcomes among almost 2,000 women exposed to ondansetron in pregnancy, and women not exposed to the drug between 2004 and 2011. Exposure to ondansetron was not associated with an increased rate of major malformations (at about 3%), or other adverse fetal outcomes, including stillbirth, preterm delivery, and low birth weight, compared with the unexposed pregnancies (N. Engl. J. Med. 2013;368:814-23).

However, the mean gestational age of exposure was 10 weeks, so half the women who took ondansetron started treatment after that time, past the window of risk for malformations, which may have diluted the risk, if it existed. Still, this limitation did not deter from the strength of the conclusions of the study.

But new and troubling evidence suggesting that the drug may be associated with increased risks during pregnancy – both maternal and fetal – has recently become available in the medical literature and elsewhere.

In August 2013, at the International Society of Pharmacoepidemiology meeting in Montreal, the results of a different group of Danish researchers using data from the same national registries employed in the study published in February, but with more pregnancies (almost 900,000) over a longer period (1997 to 2010), detected a twofold increase in congenital heart defects associated with ondansetron during the first trimester of pregnancy. Of the 1,248 women who filled a prescription for ondansetron during the first trimester, 4.7% (58) had a baby with a congenital malformation, compared with 3.5% (31,357) of those who were not exposed to ondansetron; this represented a 30% increased risk (adjusted odds ratio, 1.3). The increased risk was mostly due to the increased prevalence of heart defects. There was no association with congenital malformations and first-trimester prescriptions for metoclopramide, another drug used to treat hyperemesis gravidarum.

In January 2012, a study from the Center for Birth Defects Research and Prevention identified a twofold increased risk for cleft palate associated with ondansetron exposure used for NVP in the first trimester. There were over 9,000 pregnant women in the study overall, both cases and controls; 67% reported NVP and 15% used some kind of agent to treat NVP. The study used data from the National Birth Defects Prevention Study, looking at the association between NVP and treatments for NVP and cleft palate, and other noncardiac birth detects (Birth Defects Res. A Clin. Mol. Teratol. 2012;94:22-30).

With these recent studies, we are left with contradictory results regarding the risk of birth defects associated with ondansetron exposure in the first trimester, and more studies may be needed.

Importantly, potential risks of ondansetron, namely, cardiac arrhythmias and serotonin syndrome – which can be harmful to both the mother and fetus – also should be considered. In June 2012, the Food and Drug Administration (FDA) issued an updated warning about the possible increased risk of prolongation of the QT interval, which can result in the potentially fatal arrhythmia Torsade de pointes, associated with ondansetron. The warning advised against using ondansetron in patients with congenital long-QT syndrome, and recommended ECG monitoring for certain patients on ondansetron, including those with electrolyte abnormalities, such as hypokalemia or hypomagnesemia.

Based on what we hear from women who have been treated with ondansetron during pregnancy and contact Motherisk, most clinicians are not following these recommendations in pregnant women. But monitoring pregnant women taking ondansetron for NVP for these adverse effects is just as important – particularly because they are prone to electrolyte imbalances, including hypokalemia and hypomagnesemia, specified in the FDA warning.

Another recent development is the FDA’s announcement in May 2013 that an increased risk for serotonin syndrome in patients taking 5-HT₃ receptor antagonists, including Zofran, has been identified as a "potential safety issue" in the FDA’s adverse event reporting database during the first quarter of 2013, and that the agency was investigating this possible association further.

Typically, serotonin syndrome occurs with the coadministration of two or more dugs that affect serotonin, usually selective serotonin reuptake inhibitors (SSRIs) or monoamine oxidase (MAO) inhibitors. Cases of possible or probable serotonin syndrome have been reported with the use of ondansetron, and because many pregnant women are treated with SSRIs during pregnancy, the potential for serotonin syndrome with an SSRI and ondansetron should be considered. Therefore, life-threatening serotonin syndrome – characterized by a triad of cognitive or behavioral changes, such as confusion or agitation; autonomic instability; and neuromuscular changes – should be kept in mind as another potential risk for pregnant women taking ondansetron.

Based on the available data, one therefore needs to be cautious with ondansetron, considering the potential risks of cardiac malformations and oral clefts with first-trimester exposure, which needs to be studied further, and the maternal risks of serotonin syndrome and cardiac arrhythmias.

For about 30 years, there was no drug labeled in the United States for morning sickness, after the unjustified removal of Bendectin (doxylamine-pyridoxine). Hence, ondansetron has been increasingly used off-label for this indication. But now that the FDA has approved Diclegis (doxylamine succinate and pyridoxine hydrochloride) for morning sickness – the doxylamine-pyridoxine combination that has been studied in hundreds of thousands of pregnant women and is a pregnancy category A drug – there is now a safer option for women with NVP. Therefore, ondansetron should be used cautiously in pregnant women, and only after drugs with a more established safety record – particularly doxylamine-pyridoxine – have been prescribed.

Dr. Koren is professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk Program. He also holds the Ivey Chair in Molecular Toxicology at the department of medicine, University of Western Ontario, London. Dr. Koren was a principal investigator in the U.S. study that resulted in the approval of Diclegis, marketed by Duchesnay USA, and he has served as a consultant to Duchesnay. E-mail him at [email protected].

For some time, the potent antiemetic ondansetron, a 5-HT₃ receptor antagonist approved for preventing nausea and vomiting related to cancer chemotherapy and surgery, has been used to treat morning sickness, mostly for severe cases of nausea and vomiting in pregnancy (NVP). Ondansetron, which blocks the action of serotonin, is marketed as Zofran in the United States and Canada, and is also available in generic formulations.

Like most drugs, ondansetron is not labeled for use in pregnancy. But until recently, the limited reproductive safety data available on ondansetron have been somewhat reassuring. The first published report was a Motherisk study comparing pregnancy outcomes of three groups of women who called a teratogen information service. My colleagues and I found no increase in the major malformation rate among the 176 pregnancies of women exposed to ondansetron (a 3.6% rate of major malformations), compared with the rates among women exposed to other antiemetics and those exposed to drugs known not be teratogenic (BJOG 2004;111:940-3). However, this sample size could not rule out less than a threefold increase in malformation rates.

More reassuring data became available earlier this year with the publication of a study using data from Danish pregnancy, birth, and prescription registries. The study compared pregnancy outcomes among almost 2,000 women exposed to ondansetron in pregnancy, and women not exposed to the drug between 2004 and 2011. Exposure to ondansetron was not associated with an increased rate of major malformations (at about 3%), or other adverse fetal outcomes, including stillbirth, preterm delivery, and low birth weight, compared with the unexposed pregnancies (N. Engl. J. Med. 2013;368:814-23).

However, the mean gestational age of exposure was 10 weeks, so half the women who took ondansetron started treatment after that time, past the window of risk for malformations, which may have diluted the risk, if it existed. Still, this limitation did not deter from the strength of the conclusions of the study.

But new and troubling evidence suggesting that the drug may be associated with increased risks during pregnancy – both maternal and fetal – has recently become available in the medical literature and elsewhere.

In August 2013, at the International Society of Pharmacoepidemiology meeting in Montreal, the results of a different group of Danish researchers using data from the same national registries employed in the study published in February, but with more pregnancies (almost 900,000) over a longer period (1997 to 2010), detected a twofold increase in congenital heart defects associated with ondansetron during the first trimester of pregnancy. Of the 1,248 women who filled a prescription for ondansetron during the first trimester, 4.7% (58) had a baby with a congenital malformation, compared with 3.5% (31,357) of those who were not exposed to ondansetron; this represented a 30% increased risk (adjusted odds ratio, 1.3). The increased risk was mostly due to the increased prevalence of heart defects. There was no association with congenital malformations and first-trimester prescriptions for metoclopramide, another drug used to treat hyperemesis gravidarum.

In January 2012, a study from the Center for Birth Defects Research and Prevention identified a twofold increased risk for cleft palate associated with ondansetron exposure used for NVP in the first trimester. There were over 9,000 pregnant women in the study overall, both cases and controls; 67% reported NVP and 15% used some kind of agent to treat NVP. The study used data from the National Birth Defects Prevention Study, looking at the association between NVP and treatments for NVP and cleft palate, and other noncardiac birth detects (Birth Defects Res. A Clin. Mol. Teratol. 2012;94:22-30).

With these recent studies, we are left with contradictory results regarding the risk of birth defects associated with ondansetron exposure in the first trimester, and more studies may be needed.

Importantly, potential risks of ondansetron, namely, cardiac arrhythmias and serotonin syndrome – which can be harmful to both the mother and fetus – also should be considered. In June 2012, the Food and Drug Administration (FDA) issued an updated warning about the possible increased risk of prolongation of the QT interval, which can result in the potentially fatal arrhythmia Torsade de pointes, associated with ondansetron. The warning advised against using ondansetron in patients with congenital long-QT syndrome, and recommended ECG monitoring for certain patients on ondansetron, including those with electrolyte abnormalities, such as hypokalemia or hypomagnesemia.

Based on what we hear from women who have been treated with ondansetron during pregnancy and contact Motherisk, most clinicians are not following these recommendations in pregnant women. But monitoring pregnant women taking ondansetron for NVP for these adverse effects is just as important – particularly because they are prone to electrolyte imbalances, including hypokalemia and hypomagnesemia, specified in the FDA warning.

Another recent development is the FDA’s announcement in May 2013 that an increased risk for serotonin syndrome in patients taking 5-HT₃ receptor antagonists, including Zofran, has been identified as a "potential safety issue" in the FDA’s adverse event reporting database during the first quarter of 2013, and that the agency was investigating this possible association further.

Typically, serotonin syndrome occurs with the coadministration of two or more dugs that affect serotonin, usually selective serotonin reuptake inhibitors (SSRIs) or monoamine oxidase (MAO) inhibitors. Cases of possible or probable serotonin syndrome have been reported with the use of ondansetron, and because many pregnant women are treated with SSRIs during pregnancy, the potential for serotonin syndrome with an SSRI and ondansetron should be considered. Therefore, life-threatening serotonin syndrome – characterized by a triad of cognitive or behavioral changes, such as confusion or agitation; autonomic instability; and neuromuscular changes – should be kept in mind as another potential risk for pregnant women taking ondansetron.

Based on the available data, one therefore needs to be cautious with ondansetron, considering the potential risks of cardiac malformations and oral clefts with first-trimester exposure, which needs to be studied further, and the maternal risks of serotonin syndrome and cardiac arrhythmias.

For about 30 years, there was no drug labeled in the United States for morning sickness, after the unjustified removal of Bendectin (doxylamine-pyridoxine). Hence, ondansetron has been increasingly used off-label for this indication. But now that the FDA has approved Diclegis (doxylamine succinate and pyridoxine hydrochloride) for morning sickness – the doxylamine-pyridoxine combination that has been studied in hundreds of thousands of pregnant women and is a pregnancy category A drug – there is now a safer option for women with NVP. Therefore, ondansetron should be used cautiously in pregnant women, and only after drugs with a more established safety record – particularly doxylamine-pyridoxine – have been prescribed.

Dr. Koren is professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk Program. He also holds the Ivey Chair in Molecular Toxicology at the department of medicine, University of Western Ontario, London. Dr. Koren was a principal investigator in the U.S. study that resulted in the approval of Diclegis, marketed by Duchesnay USA, and he has served as a consultant to Duchesnay. E-mail him at [email protected].

Until the early 1980s, the combination of the antihistamine doxylamine succinate and the vitamin B₆ analog pyridoxine hydrochloride was marketed in the United States as Bendectin to treat nausea and vomiting of pregnancy – the same combination that was approved by the Food and Drug Administration in April and is being marketed as Diclegis.

Bendectin was taken off the U.S. market, not due to an FDA decision to remove the drug, but because of the lawsuits filed against the manufacturer alleging that the drug had caused birth defects. Despite periodic reaffirmations by the FDA that there was no evidence that it was teratogenic, women in the United States have been left without an FDA-approved drug for morning sickness for over 30 years.

Soon after Bendectin was taken off the market, a study found the rate of hospitalizations for severe morning sickness in the United States increased threefold (Can. J. Public Health 1995;86:66-70).

So clearly, the removal of a drug taken by up to 40% of pregnant women in the United States during the late 1970s was not warranted, and women have suffered as a result. Because it was off-patent, a Canadian company, Duchesnay, began manufacturing the drug and marketed it as Diclectin in Canada, where it remained available and has been widely used, with a solid safety profile and no evidence of an increased risk of congenital malformations/teratogenicity.

Overall, there has been no evidence of an increased malformation risk in over 250,000 women treated during pregnancy – far more than any other drug used in pregnancy. In addition, more studies have confirmed the fetal safety of the combination, including three meta-analyses of studies of over 200,000 women that found no increased risk of congenital malformations in general, or specific malformations in particular, associated with prenatal exposure to Bendectin (Drug Intell. Clin. Pharm. 1988;22:813-24).

Another meta-analysis published in 1994 of 16 cohort and 11 case-control studies found no difference in the risk of birth defects among the babies exposed to Bendectin in the first trimester and those with no such exposure (Teratology 1994;50:27-37).

In another study that followed the neurodevelopment of children whose mothers had called Motherisk about nausea and vomiting of pregnancy (NVP) while pregnant, we found no evidence of an adverse effect of Diclectin exposure on neurodevelopment up through age 7 years (J. Pediatr. 2009;155:45-50, 50.e1-2).

The U.S. approval of doxylamine-pyridoxine in April 2013 is a major milestone, particularly because it is indicated for use in pregnancy and the FDA has labeled it a pregnancy category A drug – the strongest evidence of fetal safety. For approval, the FDA required a new phase III placebo-controlled study conducted in the United States. The study, in which I was an investigator, enrolled over 200 adult women at 7-14 weeks’ gestation experiencing NVP, at medical centers in Galveston, Pittsburgh, and Washington, D.C. It found that treatment with the doxylamine-pyridoxine combination was significantly superior at improving symptoms over placebo, and that it improved quality of life, after 2 weeks of treatment. Women on the drug required fewer alternative treatments, more asked to continue treatment than did those on placebo, and they missed less time from work (Am. J. Obstet. Gynecol. 2010;203:571.e1-571.e7).

Older antihistamines such as doxylamine tend to cause CNS depression, but in the U.S. study, those who received the active drug did not have more sedation than those on placebo. The experience in Canada has been similar.

After 30 years of experience in Canada, quite a few Canadian physicians give more than the four tablets recommended in the label, which may be necessary to achieve the therapeutic effects for women who have severe symptoms, are overweight, or are obese. In a study, my colleagues and I found no increased risk of malformations or developmental issues associated with prenatal exposure to the higher-than-standard doses, more than four tablets a day (J. Clin. Pharmacol. 2001;41:842-5).

We recently published a study showing the benefits of preemptive treatment with Diclectin in women who had experienced severe nausea and vomiting during a previous pregnancy: Those who commenced treatment with Diclectin before symptoms started had significantly fewer cases of moderate to severe NVP than those who started treatment once they started to experience symptoms (Obstet. Gynecol. Int. 2013 [doi: 10.1155/2013/809787]).

In summary, the introduction of Diclegis in the United States is a major victory for American women and their health care providers, after being orphaned from this FDA-approved medication for NVP for 30 years.

Dr. Koren is professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk Program. He also holds the Ivey Chair in Molecular Toxicology at the department of medicine, University of Western Ontario, London. Dr. Koren was a principal investigator in the U.S. study that resulted in the approval of Diclegis, marketed by Duchesnay USA, has participated in other studies of Diclectin, and has served as a consultant to Duchesnay. E-mail him at [email protected].

Until the early 1980s, the combination of the antihistamine doxylamine succinate and the vitamin B₆ analog pyridoxine hydrochloride was marketed in the United States as Bendectin to treat nausea and vomiting of pregnancy – the same combination that was approved by the Food and Drug Administration in April and is being marketed as Diclegis.

Bendectin was taken off the U.S. market, not due to an FDA decision to remove the drug, but because of the lawsuits filed against the manufacturer alleging that the drug had caused birth defects. Despite periodic reaffirmations by the FDA that there was no evidence that it was teratogenic, women in the United States have been left without an FDA-approved drug for morning sickness for over 30 years.

Soon after Bendectin was taken off the market, a study found the rate of hospitalizations for severe morning sickness in the United States increased threefold (Can. J. Public Health 1995;86:66-70).

So clearly, the removal of a drug taken by up to 40% of pregnant women in the United States during the late 1970s was not warranted, and women have suffered as a result. Because it was off-patent, a Canadian company, Duchesnay, began manufacturing the drug and marketed it as Diclectin in Canada, where it remained available and has been widely used, with a solid safety profile and no evidence of an increased risk of congenital malformations/teratogenicity.

Overall, there has been no evidence of an increased malformation risk in over 250,000 women treated during pregnancy – far more than any other drug used in pregnancy. In addition, more studies have confirmed the fetal safety of the combination, including three meta-analyses of studies of over 200,000 women that found no increased risk of congenital malformations in general, or specific malformations in particular, associated with prenatal exposure to Bendectin (Drug Intell. Clin. Pharm. 1988;22:813-24).

Another meta-analysis published in 1994 of 16 cohort and 11 case-control studies found no difference in the risk of birth defects among the babies exposed to Bendectin in the first trimester and those with no such exposure (Teratology 1994;50:27-37).

In another study that followed the neurodevelopment of children whose mothers had called Motherisk about nausea and vomiting of pregnancy (NVP) while pregnant, we found no evidence of an adverse effect of Diclectin exposure on neurodevelopment up through age 7 years (J. Pediatr. 2009;155:45-50, 50.e1-2).

The U.S. approval of doxylamine-pyridoxine in April 2013 is a major milestone, particularly because it is indicated for use in pregnancy and the FDA has labeled it a pregnancy category A drug – the strongest evidence of fetal safety. For approval, the FDA required a new phase III placebo-controlled study conducted in the United States. The study, in which I was an investigator, enrolled over 200 adult women at 7-14 weeks’ gestation experiencing NVP, at medical centers in Galveston, Pittsburgh, and Washington, D.C. It found that treatment with the doxylamine-pyridoxine combination was significantly superior at improving symptoms over placebo, and that it improved quality of life, after 2 weeks of treatment. Women on the drug required fewer alternative treatments, more asked to continue treatment than did those on placebo, and they missed less time from work (Am. J. Obstet. Gynecol. 2010;203:571.e1-571.e7).

Older antihistamines such as doxylamine tend to cause CNS depression, but in the U.S. study, those who received the active drug did not have more sedation than those on placebo. The experience in Canada has been similar.

After 30 years of experience in Canada, quite a few Canadian physicians give more than the four tablets recommended in the label, which may be necessary to achieve the therapeutic effects for women who have severe symptoms, are overweight, or are obese. In a study, my colleagues and I found no increased risk of malformations or developmental issues associated with prenatal exposure to the higher-than-standard doses, more than four tablets a day (J. Clin. Pharmacol. 2001;41:842-5).

We recently published a study showing the benefits of preemptive treatment with Diclectin in women who had experienced severe nausea and vomiting during a previous pregnancy: Those who commenced treatment with Diclectin before symptoms started had significantly fewer cases of moderate to severe NVP than those who started treatment once they started to experience symptoms (Obstet. Gynecol. Int. 2013 [doi: 10.1155/2013/809787]).

In summary, the introduction of Diclegis in the United States is a major victory for American women and their health care providers, after being orphaned from this FDA-approved medication for NVP for 30 years.

Dr. Koren is professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk Program. He also holds the Ivey Chair in Molecular Toxicology at the department of medicine, University of Western Ontario, London. Dr. Koren was a principal investigator in the U.S. study that resulted in the approval of Diclegis, marketed by Duchesnay USA, has participated in other studies of Diclectin, and has served as a consultant to Duchesnay. E-mail him at [email protected].

Until the early 1980s, the combination of the antihistamine doxylamine succinate and the vitamin B₆ analog pyridoxine hydrochloride was marketed in the United States as Bendectin to treat nausea and vomiting of pregnancy – the same combination that was approved by the Food and Drug Administration in April and is being marketed as Diclegis.

Bendectin was taken off the U.S. market, not due to an FDA decision to remove the drug, but because of the lawsuits filed against the manufacturer alleging that the drug had caused birth defects. Despite periodic reaffirmations by the FDA that there was no evidence that it was teratogenic, women in the United States have been left without an FDA-approved drug for morning sickness for over 30 years.

Soon after Bendectin was taken off the market, a study found the rate of hospitalizations for severe morning sickness in the United States increased threefold (Can. J. Public Health 1995;86:66-70).

So clearly, the removal of a drug taken by up to 40% of pregnant women in the United States during the late 1970s was not warranted, and women have suffered as a result. Because it was off-patent, a Canadian company, Duchesnay, began manufacturing the drug and marketed it as Diclectin in Canada, where it remained available and has been widely used, with a solid safety profile and no evidence of an increased risk of congenital malformations/teratogenicity.

Overall, there has been no evidence of an increased malformation risk in over 250,000 women treated during pregnancy – far more than any other drug used in pregnancy. In addition, more studies have confirmed the fetal safety of the combination, including three meta-analyses of studies of over 200,000 women that found no increased risk of congenital malformations in general, or specific malformations in particular, associated with prenatal exposure to Bendectin (Drug Intell. Clin. Pharm. 1988;22:813-24).

Another meta-analysis published in 1994 of 16 cohort and 11 case-control studies found no difference in the risk of birth defects among the babies exposed to Bendectin in the first trimester and those with no such exposure (Teratology 1994;50:27-37).

In another study that followed the neurodevelopment of children whose mothers had called Motherisk about nausea and vomiting of pregnancy (NVP) while pregnant, we found no evidence of an adverse effect of Diclectin exposure on neurodevelopment up through age 7 years (J. Pediatr. 2009;155:45-50, 50.e1-2).

The U.S. approval of doxylamine-pyridoxine in April 2013 is a major milestone, particularly because it is indicated for use in pregnancy and the FDA has labeled it a pregnancy category A drug – the strongest evidence of fetal safety. For approval, the FDA required a new phase III placebo-controlled study conducted in the United States. The study, in which I was an investigator, enrolled over 200 adult women at 7-14 weeks’ gestation experiencing NVP, at medical centers in Galveston, Pittsburgh, and Washington, D.C. It found that treatment with the doxylamine-pyridoxine combination was significantly superior at improving symptoms over placebo, and that it improved quality of life, after 2 weeks of treatment. Women on the drug required fewer alternative treatments, more asked to continue treatment than did those on placebo, and they missed less time from work (Am. J. Obstet. Gynecol. 2010;203:571.e1-571.e7).

Older antihistamines such as doxylamine tend to cause CNS depression, but in the U.S. study, those who received the active drug did not have more sedation than those on placebo. The experience in Canada has been similar.

After 30 years of experience in Canada, quite a few Canadian physicians give more than the four tablets recommended in the label, which may be necessary to achieve the therapeutic effects for women who have severe symptoms, are overweight, or are obese. In a study, my colleagues and I found no increased risk of malformations or developmental issues associated with prenatal exposure to the higher-than-standard doses, more than four tablets a day (J. Clin. Pharmacol. 2001;41:842-5).

We recently published a study showing the benefits of preemptive treatment with Diclectin in women who had experienced severe nausea and vomiting during a previous pregnancy: Those who commenced treatment with Diclectin before symptoms started had significantly fewer cases of moderate to severe NVP than those who started treatment once they started to experience symptoms (Obstet. Gynecol. Int. 2013 [doi: 10.1155/2013/809787]).

In summary, the introduction of Diclegis in the United States is a major victory for American women and their health care providers, after being orphaned from this FDA-approved medication for NVP for 30 years.

Dr. Koren is professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk Program. He also holds the Ivey Chair in Molecular Toxicology at the department of medicine, University of Western Ontario, London. Dr. Koren was a principal investigator in the U.S. study that resulted in the approval of Diclegis, marketed by Duchesnay USA, has participated in other studies of Diclectin, and has served as a consultant to Duchesnay. E-mail him at [email protected].

The new Centers for Disease Control and Prevention immunization schedule, released in late January, recommends that a dose of the Tdap vaccine be administered to all women during each pregnancy, whether or not she has received the vaccine previously (Pediatrics 2013;131:397-404 [doi: 10.1542/peds.2012-3706]). This is a change from the 2011 recommendation that only women who have not had the Tdap vaccine should be vaccinated during pregnancy, preferably during the third or late second trimester. Like the 2011 recommendation, the 2013 recommendation states that a dose of Tdap should be administered immediately after delivery if a woman has not received the vaccine during pregnancy.

This recommendation for a Tdap dose during every pregnancy may initially strike both clinicians and patients as somewhat extreme, but the basis of the new recommendation is quite clear: A huge pertussis epidemic is currently affecting parts of the United States, with more than 41,000 cases reported last year and infants disproportionately affected. Most pertussis deaths and hospitalizations between 2000 and 2012 occurred among children under age 3 months, according to the Centers for Disease Control and Prevention (CDC).

Logically, the CDC’s Advisory Committee for Immunization Practices (ACIP) Pertussis Working Group concluded that one dose during one pregnancy was not sufficient to provide protection during subsequent pregnancies, and revised the recommendation based on considerations that included the continued high number of pertussis cases, evidence that less than 3% of women are getting the vaccine during pregnancy as recommended, and hesitancy of health care providers to vaccinate when a patient’s Tdap vaccine history is not known.

To highlight the importance of this new guideline, the working group described a 40-day-old baby who died from pertussis, whose mother had received a postpartum Tdap dose 2 years earlier but developed a cough illness a week before delivery. A dose of Tdap in the late second or third trimester provides immunity to the mother, with effective antibody response and placental transfer of pertussis antibodies, and is likely to provide passive immunity for infants until the first Tdap dose given to them becomes protective. This is a powerful example of the "cocooning" strategy, whereby the mother is vaccinated to allow protection of the newborn.

Other examples of cocooning include tetanus toxoid vaccination during pregnancy (two doses during the first pregnancy and one dose during other pregnancies), recommended in countries where tetanus is endemic to protect newborns from tetanus; and trivalent influenza vaccine administered during pregnancy.

While both clinicians and parents may be concerned about potential, unknown risks, particularly with repeated vaccination in subsequent pregnancies, the risk of pertussis in the newborn and young infants is by far greater. As painfully demonstrated in the present epidemic, the increased risk of respiratory failure and death associated with pertussis in infants is not theoretical.

To date, there are no data to suggest increased fetal, maternal, or pregnancy risks with exposure to the vaccine. Moreover, the recommendation is that the vaccine be administered in the second or third trimester, after the completion of embryogenesis. In March 2012, the ACOG Committee on Obstetric Practice’s Opinion on Tdap Vaccination stated that "there is no evidence of adverse fetal effects from the vaccination of pregnant women with an inactivated virus, bacterial vaccine, or toxoid, and these should be administered as indicated" (Committee Opinion No. 521. March 2012).

As for the safety of repeated vaccination, there is no biological basis for concern, although no data have yet been collected. The working group described the safety data on two Tdap doses as "reassuring," noting that the tetanus toxoid vaccine has not been associated with an excess risk of adverse events. Recently published studies in nonpregnant adults and adolescents found that a repeat Tdap dose 5 or 10 years after the first dose was well tolerated and immunogenic. In addition, the risk of severe hypersensitivity reactions associated with multiple Tdap doses in pregnancy is "unlikely," based on a recent study of tetanus and diphtheria toxoids (Vaccine 2012;30:974-82; Vaccine 2011;29:8459-65).

In reality, most women are not likely to receive more than two doses, and only about 5% of women would receive four or more doses, based on U.S. data indicating that most women who have children have fewer than three.

The safety of Tdap given during pregnancy should continue to be closely monitored with good pharmacovigilance through the Food and Drug Administration’s Vaccine Safety Datalink and studies evaluating adverse pregnancy and birth outcomes. In Motherisk, we plan to follow up women who receive the Tdap in pregnancy.

In summary, all health care professionals caring for pregnant women should adopt these new guidelines to ensure that the epidemic outbreak of this old disease that kills newborn babies is prevented.

Dr. Koren is professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk Program. He also holds the Ivey Chair in Molecular Toxicology at the department of medicine, University of Western Ontario, London. Dr. Koren said he had no relevant financial disclosures. E-mail him at [email protected].

The new Centers for Disease Control and Prevention immunization schedule, released in late January, recommends that a dose of the Tdap vaccine be administered to all women during each pregnancy, whether or not she has received the vaccine previously (Pediatrics 2013;131:397-404 [doi: 10.1542/peds.2012-3706]). This is a change from the 2011 recommendation that only women who have not had the Tdap vaccine should be vaccinated during pregnancy, preferably during the third or late second trimester. Like the 2011 recommendation, the 2013 recommendation states that a dose of Tdap should be administered immediately after delivery if a woman has not received the vaccine during pregnancy.

This recommendation for a Tdap dose during every pregnancy may initially strike both clinicians and patients as somewhat extreme, but the basis of the new recommendation is quite clear: A huge pertussis epidemic is currently affecting parts of the United States, with more than 41,000 cases reported last year and infants disproportionately affected. Most pertussis deaths and hospitalizations between 2000 and 2012 occurred among children under age 3 months, according to the Centers for Disease Control and Prevention (CDC).

Logically, the CDC’s Advisory Committee for Immunization Practices (ACIP) Pertussis Working Group concluded that one dose during one pregnancy was not sufficient to provide protection during subsequent pregnancies, and revised the recommendation based on considerations that included the continued high number of pertussis cases, evidence that less than 3% of women are getting the vaccine during pregnancy as recommended, and hesitancy of health care providers to vaccinate when a patient’s Tdap vaccine history is not known.

To highlight the importance of this new guideline, the working group described a 40-day-old baby who died from pertussis, whose mother had received a postpartum Tdap dose 2 years earlier but developed a cough illness a week before delivery. A dose of Tdap in the late second or third trimester provides immunity to the mother, with effective antibody response and placental transfer of pertussis antibodies, and is likely to provide passive immunity for infants until the first Tdap dose given to them becomes protective. This is a powerful example of the "cocooning" strategy, whereby the mother is vaccinated to allow protection of the newborn.

Other examples of cocooning include tetanus toxoid vaccination during pregnancy (two doses during the first pregnancy and one dose during other pregnancies), recommended in countries where tetanus is endemic to protect newborns from tetanus; and trivalent influenza vaccine administered during pregnancy.

While both clinicians and parents may be concerned about potential, unknown risks, particularly with repeated vaccination in subsequent pregnancies, the risk of pertussis in the newborn and young infants is by far greater. As painfully demonstrated in the present epidemic, the increased risk of respiratory failure and death associated with pertussis in infants is not theoretical.

To date, there are no data to suggest increased fetal, maternal, or pregnancy risks with exposure to the vaccine. Moreover, the recommendation is that the vaccine be administered in the second or third trimester, after the completion of embryogenesis. In March 2012, the ACOG Committee on Obstetric Practice’s Opinion on Tdap Vaccination stated that "there is no evidence of adverse fetal effects from the vaccination of pregnant women with an inactivated virus, bacterial vaccine, or toxoid, and these should be administered as indicated" (Committee Opinion No. 521. March 2012).

As for the safety of repeated vaccination, there is no biological basis for concern, although no data have yet been collected. The working group described the safety data on two Tdap doses as "reassuring," noting that the tetanus toxoid vaccine has not been associated with an excess risk of adverse events. Recently published studies in nonpregnant adults and adolescents found that a repeat Tdap dose 5 or 10 years after the first dose was well tolerated and immunogenic. In addition, the risk of severe hypersensitivity reactions associated with multiple Tdap doses in pregnancy is "unlikely," based on a recent study of tetanus and diphtheria toxoids (Vaccine 2012;30:974-82; Vaccine 2011;29:8459-65).

In reality, most women are not likely to receive more than two doses, and only about 5% of women would receive four or more doses, based on U.S. data indicating that most women who have children have fewer than three.

The safety of Tdap given during pregnancy should continue to be closely monitored with good pharmacovigilance through the Food and Drug Administration’s Vaccine Safety Datalink and studies evaluating adverse pregnancy and birth outcomes. In Motherisk, we plan to follow up women who receive the Tdap in pregnancy.

In summary, all health care professionals caring for pregnant women should adopt these new guidelines to ensure that the epidemic outbreak of this old disease that kills newborn babies is prevented.

Dr. Koren is professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk Program. He also holds the Ivey Chair in Molecular Toxicology at the department of medicine, University of Western Ontario, London. Dr. Koren said he had no relevant financial disclosures. E-mail him at [email protected].

The new Centers for Disease Control and Prevention immunization schedule, released in late January, recommends that a dose of the Tdap vaccine be administered to all women during each pregnancy, whether or not she has received the vaccine previously (Pediatrics 2013;131:397-404 [doi: 10.1542/peds.2012-3706]). This is a change from the 2011 recommendation that only women who have not had the Tdap vaccine should be vaccinated during pregnancy, preferably during the third or late second trimester. Like the 2011 recommendation, the 2013 recommendation states that a dose of Tdap should be administered immediately after delivery if a woman has not received the vaccine during pregnancy.

This recommendation for a Tdap dose during every pregnancy may initially strike both clinicians and patients as somewhat extreme, but the basis of the new recommendation is quite clear: A huge pertussis epidemic is currently affecting parts of the United States, with more than 41,000 cases reported last year and infants disproportionately affected. Most pertussis deaths and hospitalizations between 2000 and 2012 occurred among children under age 3 months, according to the Centers for Disease Control and Prevention (CDC).

Logically, the CDC’s Advisory Committee for Immunization Practices (ACIP) Pertussis Working Group concluded that one dose during one pregnancy was not sufficient to provide protection during subsequent pregnancies, and revised the recommendation based on considerations that included the continued high number of pertussis cases, evidence that less than 3% of women are getting the vaccine during pregnancy as recommended, and hesitancy of health care providers to vaccinate when a patient’s Tdap vaccine history is not known.

To highlight the importance of this new guideline, the working group described a 40-day-old baby who died from pertussis, whose mother had received a postpartum Tdap dose 2 years earlier but developed a cough illness a week before delivery. A dose of Tdap in the late second or third trimester provides immunity to the mother, with effective antibody response and placental transfer of pertussis antibodies, and is likely to provide passive immunity for infants until the first Tdap dose given to them becomes protective. This is a powerful example of the "cocooning" strategy, whereby the mother is vaccinated to allow protection of the newborn.

Other examples of cocooning include tetanus toxoid vaccination during pregnancy (two doses during the first pregnancy and one dose during other pregnancies), recommended in countries where tetanus is endemic to protect newborns from tetanus; and trivalent influenza vaccine administered during pregnancy.

While both clinicians and parents may be concerned about potential, unknown risks, particularly with repeated vaccination in subsequent pregnancies, the risk of pertussis in the newborn and young infants is by far greater. As painfully demonstrated in the present epidemic, the increased risk of respiratory failure and death associated with pertussis in infants is not theoretical.

To date, there are no data to suggest increased fetal, maternal, or pregnancy risks with exposure to the vaccine. Moreover, the recommendation is that the vaccine be administered in the second or third trimester, after the completion of embryogenesis. In March 2012, the ACOG Committee on Obstetric Practice’s Opinion on Tdap Vaccination stated that "there is no evidence of adverse fetal effects from the vaccination of pregnant women with an inactivated virus, bacterial vaccine, or toxoid, and these should be administered as indicated" (Committee Opinion No. 521. March 2012).

As for the safety of repeated vaccination, there is no biological basis for concern, although no data have yet been collected. The working group described the safety data on two Tdap doses as "reassuring," noting that the tetanus toxoid vaccine has not been associated with an excess risk of adverse events. Recently published studies in nonpregnant adults and adolescents found that a repeat Tdap dose 5 or 10 years after the first dose was well tolerated and immunogenic. In addition, the risk of severe hypersensitivity reactions associated with multiple Tdap doses in pregnancy is "unlikely," based on a recent study of tetanus and diphtheria toxoids (Vaccine 2012;30:974-82; Vaccine 2011;29:8459-65).

In reality, most women are not likely to receive more than two doses, and only about 5% of women would receive four or more doses, based on U.S. data indicating that most women who have children have fewer than three.

The safety of Tdap given during pregnancy should continue to be closely monitored with good pharmacovigilance through the Food and Drug Administration’s Vaccine Safety Datalink and studies evaluating adverse pregnancy and birth outcomes. In Motherisk, we plan to follow up women who receive the Tdap in pregnancy.

In summary, all health care professionals caring for pregnant women should adopt these new guidelines to ensure that the epidemic outbreak of this old disease that kills newborn babies is prevented.

Dr. Koren is professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk Program. He also holds the Ivey Chair in Molecular Toxicology at the department of medicine, University of Western Ontario, London. Dr. Koren said he had no relevant financial disclosures. E-mail him at [email protected].