Christina Chambers, PhD, MPH.

The need for more and better quality data on medication safety in human pregnancy has been in the public and regulatory spotlight for decades. The issue is becoming even more urgent with the impending revisions to the product label format that will eliminate the traditional A, B, C, D, X pregnancy categories, and substitute more data-driven narratives.

In response to this need, over the last several years there has been a steady increase in the number of regulatory requests/requirements for postmarketing surveillance studies for new medications likely to be used by women of reproductive age or by pregnant women. These requests most often have been fulfilled by the initiation of pregnancy registries. However, concern has been raised that pregnancy registries by and large have been challenged to recruit sufficient numbers of study subjects, and the time to completion of these studies is typically longer than desirable. Other questions have been raised about the adequacy of pregnancy registries alone (especially those with small sample sizes and no internal comparison groups) to test hypotheses related to birth outcomes.

In May 2014, the Food and Drug Administration hosted a public meeting to highlight some of these issues and to seek advice and solutions, titled "Study Approaches and Methods to Evaluate the Safety of Drugs and Biological Products During Pregnancy in the Post-Approval Setting." Panelists included representation from federal agencies including the Centers for Disease Control and Prevention, Department of Defense Naval Health Research Center, the Agency for Healthcare Research and Quality, and the Food and Drug Administration. Other panelists represented academic and HMO-based research networks, contract research organizations, the pharmaceutical industry, obstetric providers, and patients. Comments also were provided by audience members who represented a variety of entities including academic societies, professional associations, and advocacy groups.

Specific strategies for obtaining better data in a more timely fashion were presented by the panelists. These included the value and efficiency of utilizing large administrative claims databases or systemwide electronic capture of pregnancy exposure and outcome data. Using this approach, representative samples of patients can be accrued while not requiring individual active informed consent. Limitations of such sources of data also were mentioned, including inability to validate that the pregnant woman actually took a medication of interest, when, and at what dose, and the usual absence of information in claims data on some important confounders such as alcohol use and folic acid supplementation.

Panelists representing various pregnancy registry study designs described approaches to addressing some of the limitations of these studies. For example, some panelists emphasized that "disease-based" registries that involve examination of birth outcomes for several medications used for the treatment of one or more similar maternal conditions have several distinct advantages. These include a more streamlined referral process, whereby clinicians can more easily identify and refer all pregnant patients who have the same underlying condition, irrespective of treatment with any specific medication under study. Examples of successful disease-based approaches that were highlighted by panelists included the Antiretroviral Drugs in Pregnancy Registry, the North American Antiepileptic Drug Pregnancy Registry, and the OTIS/MotherToBaby Autoimmune Diseases in Pregnancy Project. Each of these studies allows for comparison of outcomes across various treatments, while accounting for the possible contribution of the underlying maternal condition to adverse pregnancy outcomes.

Panelists also emphasized that more effective methods are needed for raising awareness of the existence and value of pregnancy registries for providers and consumers alike, including more efficient and extensive use of social media. Panelists, and in particular obstetric providers, indicated a need for better methods of identifying women who are eligible for participation in a pregnancy study, and facilitating the referral process. The obstetric provider panelist suggested that existing electronic medical records systems could be adapted to generate automated alerts to providers regarding patients who qualify for referral to a registry.

The patient representative panelist emphasized the need to engage the pregnant woman in the research process. This was confirmed by research groups whose primary interaction in pregnancy studies is with the pregnant woman herself, resulting in minimal loss-to-follow-up and high participant satisfaction.

Last, there was extensive discussion about the use of other alternative study designs, such as case-control studies, that could help address the limitations of pregnancy registries, especially in terms of statistical power for evaluating rare outcomes such as specific birth defects. The Vaccines and Medications in Pregnancy Surveillance System (VAMPSS) was described as one such alternative, combining the benefits of a cohort (registry-type) study with a concurrent case-control study to address the same exposures in pregnancy.

There was general consensus among panel members that no single approach to postmarketing safety studies would likely be sufficient to evaluate new or existing products, and that complementary approaches are needed.

A complete set of the panelists’ slide presentations from the public meeting as well as webcasts of the 2-day proceedings in their entirety are available for viewing here.

Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She said that she had no relevant financial disclosures. To comment, e-mail her at [email protected].

The need for more and better quality data on medication safety in human pregnancy has been in the public and regulatory spotlight for decades. The issue is becoming even more urgent with the impending revisions to the product label format that will eliminate the traditional A, B, C, D, X pregnancy categories, and substitute more data-driven narratives.

In response to this need, over the last several years there has been a steady increase in the number of regulatory requests/requirements for postmarketing surveillance studies for new medications likely to be used by women of reproductive age or by pregnant women. These requests most often have been fulfilled by the initiation of pregnancy registries. However, concern has been raised that pregnancy registries by and large have been challenged to recruit sufficient numbers of study subjects, and the time to completion of these studies is typically longer than desirable. Other questions have been raised about the adequacy of pregnancy registries alone (especially those with small sample sizes and no internal comparison groups) to test hypotheses related to birth outcomes.

In May 2014, the Food and Drug Administration hosted a public meeting to highlight some of these issues and to seek advice and solutions, titled "Study Approaches and Methods to Evaluate the Safety of Drugs and Biological Products During Pregnancy in the Post-Approval Setting." Panelists included representation from federal agencies including the Centers for Disease Control and Prevention, Department of Defense Naval Health Research Center, the Agency for Healthcare Research and Quality, and the Food and Drug Administration. Other panelists represented academic and HMO-based research networks, contract research organizations, the pharmaceutical industry, obstetric providers, and patients. Comments also were provided by audience members who represented a variety of entities including academic societies, professional associations, and advocacy groups.

Specific strategies for obtaining better data in a more timely fashion were presented by the panelists. These included the value and efficiency of utilizing large administrative claims databases or systemwide electronic capture of pregnancy exposure and outcome data. Using this approach, representative samples of patients can be accrued while not requiring individual active informed consent. Limitations of such sources of data also were mentioned, including inability to validate that the pregnant woman actually took a medication of interest, when, and at what dose, and the usual absence of information in claims data on some important confounders such as alcohol use and folic acid supplementation.

Panelists representing various pregnancy registry study designs described approaches to addressing some of the limitations of these studies. For example, some panelists emphasized that "disease-based" registries that involve examination of birth outcomes for several medications used for the treatment of one or more similar maternal conditions have several distinct advantages. These include a more streamlined referral process, whereby clinicians can more easily identify and refer all pregnant patients who have the same underlying condition, irrespective of treatment with any specific medication under study. Examples of successful disease-based approaches that were highlighted by panelists included the Antiretroviral Drugs in Pregnancy Registry, the North American Antiepileptic Drug Pregnancy Registry, and the OTIS/MotherToBaby Autoimmune Diseases in Pregnancy Project. Each of these studies allows for comparison of outcomes across various treatments, while accounting for the possible contribution of the underlying maternal condition to adverse pregnancy outcomes.

Panelists also emphasized that more effective methods are needed for raising awareness of the existence and value of pregnancy registries for providers and consumers alike, including more efficient and extensive use of social media. Panelists, and in particular obstetric providers, indicated a need for better methods of identifying women who are eligible for participation in a pregnancy study, and facilitating the referral process. The obstetric provider panelist suggested that existing electronic medical records systems could be adapted to generate automated alerts to providers regarding patients who qualify for referral to a registry.

The patient representative panelist emphasized the need to engage the pregnant woman in the research process. This was confirmed by research groups whose primary interaction in pregnancy studies is with the pregnant woman herself, resulting in minimal loss-to-follow-up and high participant satisfaction.

Last, there was extensive discussion about the use of other alternative study designs, such as case-control studies, that could help address the limitations of pregnancy registries, especially in terms of statistical power for evaluating rare outcomes such as specific birth defects. The Vaccines and Medications in Pregnancy Surveillance System (VAMPSS) was described as one such alternative, combining the benefits of a cohort (registry-type) study with a concurrent case-control study to address the same exposures in pregnancy.

There was general consensus among panel members that no single approach to postmarketing safety studies would likely be sufficient to evaluate new or existing products, and that complementary approaches are needed.

A complete set of the panelists’ slide presentations from the public meeting as well as webcasts of the 2-day proceedings in their entirety are available for viewing here.

Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She said that she had no relevant financial disclosures. To comment, e-mail her at [email protected].

The need for more and better quality data on medication safety in human pregnancy has been in the public and regulatory spotlight for decades. The issue is becoming even more urgent with the impending revisions to the product label format that will eliminate the traditional A, B, C, D, X pregnancy categories, and substitute more data-driven narratives.

In response to this need, over the last several years there has been a steady increase in the number of regulatory requests/requirements for postmarketing surveillance studies for new medications likely to be used by women of reproductive age or by pregnant women. These requests most often have been fulfilled by the initiation of pregnancy registries. However, concern has been raised that pregnancy registries by and large have been challenged to recruit sufficient numbers of study subjects, and the time to completion of these studies is typically longer than desirable. Other questions have been raised about the adequacy of pregnancy registries alone (especially those with small sample sizes and no internal comparison groups) to test hypotheses related to birth outcomes.

In May 2014, the Food and Drug Administration hosted a public meeting to highlight some of these issues and to seek advice and solutions, titled "Study Approaches and Methods to Evaluate the Safety of Drugs and Biological Products During Pregnancy in the Post-Approval Setting." Panelists included representation from federal agencies including the Centers for Disease Control and Prevention, Department of Defense Naval Health Research Center, the Agency for Healthcare Research and Quality, and the Food and Drug Administration. Other panelists represented academic and HMO-based research networks, contract research organizations, the pharmaceutical industry, obstetric providers, and patients. Comments also were provided by audience members who represented a variety of entities including academic societies, professional associations, and advocacy groups.

Specific strategies for obtaining better data in a more timely fashion were presented by the panelists. These included the value and efficiency of utilizing large administrative claims databases or systemwide electronic capture of pregnancy exposure and outcome data. Using this approach, representative samples of patients can be accrued while not requiring individual active informed consent. Limitations of such sources of data also were mentioned, including inability to validate that the pregnant woman actually took a medication of interest, when, and at what dose, and the usual absence of information in claims data on some important confounders such as alcohol use and folic acid supplementation.

Panelists representing various pregnancy registry study designs described approaches to addressing some of the limitations of these studies. For example, some panelists emphasized that "disease-based" registries that involve examination of birth outcomes for several medications used for the treatment of one or more similar maternal conditions have several distinct advantages. These include a more streamlined referral process, whereby clinicians can more easily identify and refer all pregnant patients who have the same underlying condition, irrespective of treatment with any specific medication under study. Examples of successful disease-based approaches that were highlighted by panelists included the Antiretroviral Drugs in Pregnancy Registry, the North American Antiepileptic Drug Pregnancy Registry, and the OTIS/MotherToBaby Autoimmune Diseases in Pregnancy Project. Each of these studies allows for comparison of outcomes across various treatments, while accounting for the possible contribution of the underlying maternal condition to adverse pregnancy outcomes.

Panelists also emphasized that more effective methods are needed for raising awareness of the existence and value of pregnancy registries for providers and consumers alike, including more efficient and extensive use of social media. Panelists, and in particular obstetric providers, indicated a need for better methods of identifying women who are eligible for participation in a pregnancy study, and facilitating the referral process. The obstetric provider panelist suggested that existing electronic medical records systems could be adapted to generate automated alerts to providers regarding patients who qualify for referral to a registry.

The patient representative panelist emphasized the need to engage the pregnant woman in the research process. This was confirmed by research groups whose primary interaction in pregnancy studies is with the pregnant woman herself, resulting in minimal loss-to-follow-up and high participant satisfaction.

Last, there was extensive discussion about the use of other alternative study designs, such as case-control studies, that could help address the limitations of pregnancy registries, especially in terms of statistical power for evaluating rare outcomes such as specific birth defects. The Vaccines and Medications in Pregnancy Surveillance System (VAMPSS) was described as one such alternative, combining the benefits of a cohort (registry-type) study with a concurrent case-control study to address the same exposures in pregnancy.

There was general consensus among panel members that no single approach to postmarketing safety studies would likely be sufficient to evaluate new or existing products, and that complementary approaches are needed.

A complete set of the panelists’ slide presentations from the public meeting as well as webcasts of the 2-day proceedings in their entirety are available for viewing here.

Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She said that she had no relevant financial disclosures. To comment, e-mail her at [email protected].

It is estimated that 30%-70% of children diagnosed with attention-deficit/hyperactivity disorder will continue to experience symptoms as they grow older. The prevalence of the disorder in adults is thought to be 3%-4%.

For these reasons, therapeutic use of stimulants to treat attention-deficit/hyperactivity disorder (ADHD) among adults has increased sharply in recent years. This leads to the increasing possibility that pregnant women will either intentionally or inadvertently be treated with ADHD medications during some period of gestation (J. Clin. Psychiatry 2014;75:e88-93); (Can. Fam. Physician 2007;53:1153-5). Yet, there are limited human data regarding the use of these medications with respect to fetal safety.

Of the various medications currently marketed for the treatment of ADHD, the stimulant medication methylphenidate is the single drug with the largest amount of published human pregnancy safety data. The Swedish Medical Birth Register holds reports on 104 children exposed to methylphenidate in early pregnancy. Three children had congenital malformations (two to three expected), all of which were heart defects (Basic Clin. Pharmacol. Toxicol. 2013;112:73-6).

Another register-based study, conducted in Denmark between 1998 and 2010, identified 480 pregnancies in which women had redeemed at least one prescription for an ADHD medication; 81.9% of these prescriptions were for methylphenidate (Pharmacoepidemiol. Drug Saf. 2014 Mar 4 [doi: 10.1002/pds.3600]). Women treated with an ADHD medication in pregnancy were more likely to be younger, single, less educated, and primiparous, and to have used other psychotherapeutic medications. Methylphenidate-exposed women were more likely to experience an induced or spontaneous abortion than other pregnant women in the population, but no more likely to have a child with a congenital anomaly (adjusted odds ratio, 0.48; 95% confidence interval, 0.15, 1.53).

A third study, also from Denmark, identified 240 pregnancies with a prescription dispensed for methylphenidate in the first trimester and linked them to live birth outcomes between 2005 and 2012. It is unclear how much overlap there was with the pregnancies reported in the previously mentioned Danish study from the same data source. Methylphenidate-exposed pregnancies in this analysis were compared with propensity score–matched pregnancies presumed to be unexposed to the drug, to address confounding by age, education, tobacco, and other drug use that differed between the groups. Among the exposed, 3.2% of pregnancies resulted in a child with a major malformation, which is within the expected range in the population. The point prevalence ratio for major birth defects comparing the methylphenidate-exposed women to the matched controls was 0.8 (95% confidence interval, 0.3-1.8) (J. Clin. Psychiatry 2014;75:e88-93).

Finally, a study from Israel (published as an abstract only) identified 54 methylphenidate-exposed pregnancies of which 52 were exposed in the first trimester and compared outcomes with 54 unexposed pregnancies. There were no congenital malformations reported in the exposed group; there were no significant differences in abortion rates, and no significant differences in gestational age at delivery or mean birth weight between the groups (Reprod. Toxicol. 2011;31:267).

Other than the concern for pregnancy loss, which could be explained in part by other characteristics of the mothers who were taking methylphenidate early in pregnancy, the limited data to date have been generally reassuring, with no suggestion of an overall increased risk for major congenital malformations or a specific pattern of defects. However, the number of exposed pregnancies followed in controlled studies that have been published in the literature to date are too few to allow firm conclusions. Additional data are needed for this drug as well as alternative stimulant and nonstimulant medications used to treat ADHD, particularly in light of the fact that it is evident that an increasing number of women will continue to be treated into their reproductive years.

Dr. Chambers is professor of pediatrics and family and preventive medicine at the University of California, San Diego. She is director of the California Teratogen Information Service and Clinical Research Program. Dr. Chambers is a past president of the Organization of Teratology Information Specialists and past president of the Teratology Society. She said that she had no relevant financial disclosures. To comment, e-mail her at [email protected].

It is estimated that 30%-70% of children diagnosed with attention-deficit/hyperactivity disorder will continue to experience symptoms as they grow older. The prevalence of the disorder in adults is thought to be 3%-4%.

For these reasons, therapeutic use of stimulants to treat attention-deficit/hyperactivity disorder (ADHD) among adults has increased sharply in recent years. This leads to the increasing possibility that pregnant women will either intentionally or inadvertently be treated with ADHD medications during some period of gestation (J. Clin. Psychiatry 2014;75:e88-93); (Can. Fam. Physician 2007;53:1153-5). Yet, there are limited human data regarding the use of these medications with respect to fetal safety.

Of the various medications currently marketed for the treatment of ADHD, the stimulant medication methylphenidate is the single drug with the largest amount of published human pregnancy safety data. The Swedish Medical Birth Register holds reports on 104 children exposed to methylphenidate in early pregnancy. Three children had congenital malformations (two to three expected), all of which were heart defects (Basic Clin. Pharmacol. Toxicol. 2013;112:73-6).

Another register-based study, conducted in Denmark between 1998 and 2010, identified 480 pregnancies in which women had redeemed at least one prescription for an ADHD medication; 81.9% of these prescriptions were for methylphenidate (Pharmacoepidemiol. Drug Saf. 2014 Mar 4 [doi: 10.1002/pds.3600]). Women treated with an ADHD medication in pregnancy were more likely to be younger, single, less educated, and primiparous, and to have used other psychotherapeutic medications. Methylphenidate-exposed women were more likely to experience an induced or spontaneous abortion than other pregnant women in the population, but no more likely to have a child with a congenital anomaly (adjusted odds ratio, 0.48; 95% confidence interval, 0.15, 1.53).

A third study, also from Denmark, identified 240 pregnancies with a prescription dispensed for methylphenidate in the first trimester and linked them to live birth outcomes between 2005 and 2012. It is unclear how much overlap there was with the pregnancies reported in the previously mentioned Danish study from the same data source. Methylphenidate-exposed pregnancies in this analysis were compared with propensity score–matched pregnancies presumed to be unexposed to the drug, to address confounding by age, education, tobacco, and other drug use that differed between the groups. Among the exposed, 3.2% of pregnancies resulted in a child with a major malformation, which is within the expected range in the population. The point prevalence ratio for major birth defects comparing the methylphenidate-exposed women to the matched controls was 0.8 (95% confidence interval, 0.3-1.8) (J. Clin. Psychiatry 2014;75:e88-93).

Finally, a study from Israel (published as an abstract only) identified 54 methylphenidate-exposed pregnancies of which 52 were exposed in the first trimester and compared outcomes with 54 unexposed pregnancies. There were no congenital malformations reported in the exposed group; there were no significant differences in abortion rates, and no significant differences in gestational age at delivery or mean birth weight between the groups (Reprod. Toxicol. 2011;31:267).

Other than the concern for pregnancy loss, which could be explained in part by other characteristics of the mothers who were taking methylphenidate early in pregnancy, the limited data to date have been generally reassuring, with no suggestion of an overall increased risk for major congenital malformations or a specific pattern of defects. However, the number of exposed pregnancies followed in controlled studies that have been published in the literature to date are too few to allow firm conclusions. Additional data are needed for this drug as well as alternative stimulant and nonstimulant medications used to treat ADHD, particularly in light of the fact that it is evident that an increasing number of women will continue to be treated into their reproductive years.

Dr. Chambers is professor of pediatrics and family and preventive medicine at the University of California, San Diego. She is director of the California Teratogen Information Service and Clinical Research Program. Dr. Chambers is a past president of the Organization of Teratology Information Specialists and past president of the Teratology Society. She said that she had no relevant financial disclosures. To comment, e-mail her at [email protected].

It is estimated that 30%-70% of children diagnosed with attention-deficit/hyperactivity disorder will continue to experience symptoms as they grow older. The prevalence of the disorder in adults is thought to be 3%-4%.

For these reasons, therapeutic use of stimulants to treat attention-deficit/hyperactivity disorder (ADHD) among adults has increased sharply in recent years. This leads to the increasing possibility that pregnant women will either intentionally or inadvertently be treated with ADHD medications during some period of gestation (J. Clin. Psychiatry 2014;75:e88-93); (Can. Fam. Physician 2007;53:1153-5). Yet, there are limited human data regarding the use of these medications with respect to fetal safety.

Of the various medications currently marketed for the treatment of ADHD, the stimulant medication methylphenidate is the single drug with the largest amount of published human pregnancy safety data. The Swedish Medical Birth Register holds reports on 104 children exposed to methylphenidate in early pregnancy. Three children had congenital malformations (two to three expected), all of which were heart defects (Basic Clin. Pharmacol. Toxicol. 2013;112:73-6).

Another register-based study, conducted in Denmark between 1998 and 2010, identified 480 pregnancies in which women had redeemed at least one prescription for an ADHD medication; 81.9% of these prescriptions were for methylphenidate (Pharmacoepidemiol. Drug Saf. 2014 Mar 4 [doi: 10.1002/pds.3600]). Women treated with an ADHD medication in pregnancy were more likely to be younger, single, less educated, and primiparous, and to have used other psychotherapeutic medications. Methylphenidate-exposed women were more likely to experience an induced or spontaneous abortion than other pregnant women in the population, but no more likely to have a child with a congenital anomaly (adjusted odds ratio, 0.48; 95% confidence interval, 0.15, 1.53).

A third study, also from Denmark, identified 240 pregnancies with a prescription dispensed for methylphenidate in the first trimester and linked them to live birth outcomes between 2005 and 2012. It is unclear how much overlap there was with the pregnancies reported in the previously mentioned Danish study from the same data source. Methylphenidate-exposed pregnancies in this analysis were compared with propensity score–matched pregnancies presumed to be unexposed to the drug, to address confounding by age, education, tobacco, and other drug use that differed between the groups. Among the exposed, 3.2% of pregnancies resulted in a child with a major malformation, which is within the expected range in the population. The point prevalence ratio for major birth defects comparing the methylphenidate-exposed women to the matched controls was 0.8 (95% confidence interval, 0.3-1.8) (J. Clin. Psychiatry 2014;75:e88-93).

Finally, a study from Israel (published as an abstract only) identified 54 methylphenidate-exposed pregnancies of which 52 were exposed in the first trimester and compared outcomes with 54 unexposed pregnancies. There were no congenital malformations reported in the exposed group; there were no significant differences in abortion rates, and no significant differences in gestational age at delivery or mean birth weight between the groups (Reprod. Toxicol. 2011;31:267).

Other than the concern for pregnancy loss, which could be explained in part by other characteristics of the mothers who were taking methylphenidate early in pregnancy, the limited data to date have been generally reassuring, with no suggestion of an overall increased risk for major congenital malformations or a specific pattern of defects. However, the number of exposed pregnancies followed in controlled studies that have been published in the literature to date are too few to allow firm conclusions. Additional data are needed for this drug as well as alternative stimulant and nonstimulant medications used to treat ADHD, particularly in light of the fact that it is evident that an increasing number of women will continue to be treated into their reproductive years.

Dr. Chambers is professor of pediatrics and family and preventive medicine at the University of California, San Diego. She is director of the California Teratogen Information Service and Clinical Research Program. Dr. Chambers is a past president of the Organization of Teratology Information Specialists and past president of the Teratology Society. She said that she had no relevant financial disclosures. To comment, e-mail her at [email protected].

One of the most common conditions that complicate pregnancy is maternal asthma. Evidence continues to mount that adequate control of asthma, including appropriate use of medications, is the best approach to optimizing outcomes. Yet questions persist about the effect of asthma itself, as well as specific medications and the risk for major congenital malformations. As with any exposure during pregnancy, answering these questions is challenging because of the rarity of specific birth defects and the various and increasing number of medications that might be used to treat or prevent asthma symptoms.

Previously in this column ("Beta2-agonists for asthma, December 2011), we reviewed two studies that suggested short-acting beta-agonists used for the treatment of asthma were associated with an increased risk of oral clefts and that long-acting beta-agonists might be associated with an increased risk of cardiac anomalies (Hum. Reprod. 2011;26:3147-54; Birth Defects Res. A. Clin. Mol. Teratol. 2011;91:937-47).

What have we learned since then? Two studies published in 2013 add to the body of knowledge. The first, a database analysis using the United Kingdom’s General Practice Research Database, assessed pregnancy outcomes between 1991 and 2002 in 7,911 women exposed to asthma medications in the first trimester of pregnancy and 15,840 women who were not exposed (Pharmacotherapy 2013;33:363-8). Major anomalies were identified up to 1 year of age. Minor anomalies, chromosomal anomalies, and those associated with prematurity were excluded.

The overall risk for any exposure, compared with no exposure, for any congenital anomaly was 1.1 (95% confidence interval [CI], 1.0-1.3). No significant differences were found by class of asthma medication. Specific categories of defects also were evaluated, including musculoskeletal anomalies, oral clefts, cardiovascular defects, and multiple anomalies. Some estimates were elevated for specific medication classes.

For example, the relative risk (RR) of cleft lip or palate associated with exposure to long-acting beta-agonists was 2.4, but the confidence interval included 1 (0.3-21.8) based on 424 exposed pregnancies. The authors concluded that they found no significant increased risk of congenital anomalies associated with exposure to asthma, asthma medications, or any specific asthma medication classes in the first trimester. Limitations of the study included the inability to verify that exposure took place and insufficient data to adjust for confounding by vitamin supplementation, alcohol use, socioeconomic status, or markers of disease severity (other than number of medications prescribed).

The second study addressed the issue of maternal asthma itself and the risk for congenital anomalies (BJOG 2013;120:812-22). Using a meta-analysis approach, 21 cohort studies published between 1975 and 2012 met the criteria for inclusion. Combining major and minor congenital anomalies, the authors found a slight but statistically significant increased risk for any defect (RR, 1.11; 95% CI, 1.01-1.68), but when the analysis was restricted to major defects alone, the summary estimate was elevated but no longer significant (RR, 1.31; 95% CI, 0.57-3.02). When the specific defect grouping of oral clefts was examined, however, there was a significantly elevated overall relative risk of 1.30 (95% CI, 1.01-1.68). Limitations of this study include differing quality of studies and the appropriateness of combining data to derive a summary estimate.

Although both studies provide reassurance about the overall risk of major defects in the offspring of women with asthma, both suggest that more work needs to be done to follow up on the risk for oral clefts and whether this is linked to underlying disease severity and/or use of specific medications. Furthermore, safety of specific long-acting beta-agonist medications in pregnancy should be further examined.

The take-home message, however, continues to be that the risk for major defects in the offspring of pregnant women with asthma appears to be low, which supports the recommendation to follow guidelines for appropriate treatment of women with asthma both during and outside of pregnancy to control symptoms.

Dr. Chambers is professor of pediatrics and family and preventive medicine at the University of California, San Diego. She is director of the California Teratogen Information Service and Clinical Research Program. Dr. Chambers is a past president of the Organization of Teratology Information Specialists and past president of the Teratology Society. She said that she had no relevant financial disclosures. 

One of the most common conditions that complicate pregnancy is maternal asthma. Evidence continues to mount that adequate control of asthma, including appropriate use of medications, is the best approach to optimizing outcomes. Yet questions persist about the effect of asthma itself, as well as specific medications and the risk for major congenital malformations. As with any exposure during pregnancy, answering these questions is challenging because of the rarity of specific birth defects and the various and increasing number of medications that might be used to treat or prevent asthma symptoms.

Previously in this column ("Beta2-agonists for asthma, December 2011), we reviewed two studies that suggested short-acting beta-agonists used for the treatment of asthma were associated with an increased risk of oral clefts and that long-acting beta-agonists might be associated with an increased risk of cardiac anomalies (Hum. Reprod. 2011;26:3147-54; Birth Defects Res. A. Clin. Mol. Teratol. 2011;91:937-47).

What have we learned since then? Two studies published in 2013 add to the body of knowledge. The first, a database analysis using the United Kingdom’s General Practice Research Database, assessed pregnancy outcomes between 1991 and 2002 in 7,911 women exposed to asthma medications in the first trimester of pregnancy and 15,840 women who were not exposed (Pharmacotherapy 2013;33:363-8). Major anomalies were identified up to 1 year of age. Minor anomalies, chromosomal anomalies, and those associated with prematurity were excluded.

The overall risk for any exposure, compared with no exposure, for any congenital anomaly was 1.1 (95% confidence interval [CI], 1.0-1.3). No significant differences were found by class of asthma medication. Specific categories of defects also were evaluated, including musculoskeletal anomalies, oral clefts, cardiovascular defects, and multiple anomalies. Some estimates were elevated for specific medication classes.

For example, the relative risk (RR) of cleft lip or palate associated with exposure to long-acting beta-agonists was 2.4, but the confidence interval included 1 (0.3-21.8) based on 424 exposed pregnancies. The authors concluded that they found no significant increased risk of congenital anomalies associated with exposure to asthma, asthma medications, or any specific asthma medication classes in the first trimester. Limitations of the study included the inability to verify that exposure took place and insufficient data to adjust for confounding by vitamin supplementation, alcohol use, socioeconomic status, or markers of disease severity (other than number of medications prescribed).

The second study addressed the issue of maternal asthma itself and the risk for congenital anomalies (BJOG 2013;120:812-22). Using a meta-analysis approach, 21 cohort studies published between 1975 and 2012 met the criteria for inclusion. Combining major and minor congenital anomalies, the authors found a slight but statistically significant increased risk for any defect (RR, 1.11; 95% CI, 1.01-1.68), but when the analysis was restricted to major defects alone, the summary estimate was elevated but no longer significant (RR, 1.31; 95% CI, 0.57-3.02). When the specific defect grouping of oral clefts was examined, however, there was a significantly elevated overall relative risk of 1.30 (95% CI, 1.01-1.68). Limitations of this study include differing quality of studies and the appropriateness of combining data to derive a summary estimate.

Although both studies provide reassurance about the overall risk of major defects in the offspring of women with asthma, both suggest that more work needs to be done to follow up on the risk for oral clefts and whether this is linked to underlying disease severity and/or use of specific medications. Furthermore, safety of specific long-acting beta-agonist medications in pregnancy should be further examined.

The take-home message, however, continues to be that the risk for major defects in the offspring of pregnant women with asthma appears to be low, which supports the recommendation to follow guidelines for appropriate treatment of women with asthma both during and outside of pregnancy to control symptoms.

Dr. Chambers is professor of pediatrics and family and preventive medicine at the University of California, San Diego. She is director of the California Teratogen Information Service and Clinical Research Program. Dr. Chambers is a past president of the Organization of Teratology Information Specialists and past president of the Teratology Society. She said that she had no relevant financial disclosures. 

One of the most common conditions that complicate pregnancy is maternal asthma. Evidence continues to mount that adequate control of asthma, including appropriate use of medications, is the best approach to optimizing outcomes. Yet questions persist about the effect of asthma itself, as well as specific medications and the risk for major congenital malformations. As with any exposure during pregnancy, answering these questions is challenging because of the rarity of specific birth defects and the various and increasing number of medications that might be used to treat or prevent asthma symptoms.

Previously in this column ("Beta2-agonists for asthma, December 2011), we reviewed two studies that suggested short-acting beta-agonists used for the treatment of asthma were associated with an increased risk of oral clefts and that long-acting beta-agonists might be associated with an increased risk of cardiac anomalies (Hum. Reprod. 2011;26:3147-54; Birth Defects Res. A. Clin. Mol. Teratol. 2011;91:937-47).

What have we learned since then? Two studies published in 2013 add to the body of knowledge. The first, a database analysis using the United Kingdom’s General Practice Research Database, assessed pregnancy outcomes between 1991 and 2002 in 7,911 women exposed to asthma medications in the first trimester of pregnancy and 15,840 women who were not exposed (Pharmacotherapy 2013;33:363-8). Major anomalies were identified up to 1 year of age. Minor anomalies, chromosomal anomalies, and those associated with prematurity were excluded.

The overall risk for any exposure, compared with no exposure, for any congenital anomaly was 1.1 (95% confidence interval [CI], 1.0-1.3). No significant differences were found by class of asthma medication. Specific categories of defects also were evaluated, including musculoskeletal anomalies, oral clefts, cardiovascular defects, and multiple anomalies. Some estimates were elevated for specific medication classes.

For example, the relative risk (RR) of cleft lip or palate associated with exposure to long-acting beta-agonists was 2.4, but the confidence interval included 1 (0.3-21.8) based on 424 exposed pregnancies. The authors concluded that they found no significant increased risk of congenital anomalies associated with exposure to asthma, asthma medications, or any specific asthma medication classes in the first trimester. Limitations of the study included the inability to verify that exposure took place and insufficient data to adjust for confounding by vitamin supplementation, alcohol use, socioeconomic status, or markers of disease severity (other than number of medications prescribed).

The second study addressed the issue of maternal asthma itself and the risk for congenital anomalies (BJOG 2013;120:812-22). Using a meta-analysis approach, 21 cohort studies published between 1975 and 2012 met the criteria for inclusion. Combining major and minor congenital anomalies, the authors found a slight but statistically significant increased risk for any defect (RR, 1.11; 95% CI, 1.01-1.68), but when the analysis was restricted to major defects alone, the summary estimate was elevated but no longer significant (RR, 1.31; 95% CI, 0.57-3.02). When the specific defect grouping of oral clefts was examined, however, there was a significantly elevated overall relative risk of 1.30 (95% CI, 1.01-1.68). Limitations of this study include differing quality of studies and the appropriateness of combining data to derive a summary estimate.

Although both studies provide reassurance about the overall risk of major defects in the offspring of women with asthma, both suggest that more work needs to be done to follow up on the risk for oral clefts and whether this is linked to underlying disease severity and/or use of specific medications. Furthermore, safety of specific long-acting beta-agonist medications in pregnancy should be further examined.

The take-home message, however, continues to be that the risk for major defects in the offspring of pregnant women with asthma appears to be low, which supports the recommendation to follow guidelines for appropriate treatment of women with asthma both during and outside of pregnancy to control symptoms.

Dr. Chambers is professor of pediatrics and family and preventive medicine at the University of California, San Diego. She is director of the California Teratogen Information Service and Clinical Research Program. Dr. Chambers is a past president of the Organization of Teratology Information Specialists and past president of the Teratology Society. She said that she had no relevant financial disclosures. 

One of the most common conditions that complicate pregnancy is maternal asthma. Evidence continues to mount that adequate control of asthma, including appropriate use of medications, is the best approach to optimizing outcomes. Yet questions persist about the effect of asthma itself, as well as specific medications and the risk for major congenital malformations. As with any exposure during pregnancy, answering these questions is challenging because of the rarity of specific birth defects and the various and increasing number of medications that might be used to treat or prevent asthma symptoms.

Previously in this column ("Beta2-agonists for asthma, December 2011), we reviewed two studies that suggested short-acting beta-agonists used for the treatment of asthma were associated with an increased risk of oral clefts and that long-acting beta-agonists might be associated with an increased risk of cardiac anomalies (Hum. Reprod. 2011;26:3147-54; Birth Defects Res. A. Clin. Mol. Teratol. 2011;91:937-47).

What have we learned since then? Two studies published in 2013 add to the body of knowledge. The first, a database analysis using the United Kingdom’s General Practice Research Database, assessed pregnancy outcomes between 1991 and 2002 in 7,911 women exposed to asthma medications in the first trimester of pregnancy and 15,840 women who were not exposed (Pharmacotherapy 2013;33:363-8). Major anomalies were identified up to 1 year of age. Minor anomalies, chromosomal anomalies, and those associated with prematurity were excluded.

The overall risk for any exposure, compared with no exposure, for any congenital anomaly was 1.1 (95% confidence interval [CI], 1.0-1.3). No significant differences were found by class of asthma medication. Specific categories of defects also were evaluated, including musculoskeletal anomalies, oral clefts, cardiovascular defects, and multiple anomalies. Some estimates were elevated for specific medication classes.

For example, the relative risk (RR) of cleft lip or palate associated with exposure to long-acting beta-agonists was 2.4, but the confidence interval included 1 (0.3-21.8) based on 424 exposed pregnancies. The authors concluded that they found no significant increased risk of congenital anomalies associated with exposure to asthma, asthma medications, or any specific asthma medication classes in the first trimester. Limitations of the study included the inability to verify that exposure took place and insufficient data to adjust for confounding by vitamin supplementation, alcohol use, socioeconomic status, or markers of disease severity (other than number of medications prescribed).

The second study addressed the issue of maternal asthma itself and the risk for congenital anomalies (BJOG 2013;120:812-22). Using a meta-analysis approach, 21 cohort studies published between 1975 and 2012 met the criteria for inclusion. Combining major and minor congenital anomalies, the authors found a slight but statistically significant increased risk for any defect (RR, 1.11; 95% CI, 1.01-1.68), but when the analysis was restricted to major defects alone, the summary estimate was elevated but no longer significant (RR, 1.31; 95% CI, 0.57-3.02). When the specific defect grouping of oral clefts was examined, however, there was a significantly elevated overall relative risk of 1.30 (95% CI, 1.01-1.68). Limitations of this study include differing quality of studies and the appropriateness of combining data to derive a summary estimate.

Although both studies provide reassurance about the overall risk of major defects in the offspring of women with asthma, both suggest that more work needs to be done to follow up on the risk for oral clefts and whether this is linked to underlying disease severity and/or use of specific medications. Furthermore, safety of specific long-acting beta-agonist medications in pregnancy should be further examined.

The take-home message, however, continues to be that the risk for major defects in the offspring of pregnant women with asthma appears to be low, which supports the recommendation to follow guidelines for appropriate treatment of women with asthma both during and outside of pregnancy to control symptoms.

Dr. Chambers is professor of pediatrics and family and preventive medicine at the University of California, San Diego. She is director of the California Teratogen Information Service and Clinical Research Program. Dr. Chambers is a past president of the Organization of Teratology Information Specialists and past president of the Teratology Society. She said that she had no relevant financial disclosures. 

One of the most common conditions that complicate pregnancy is maternal asthma. Evidence continues to mount that adequate control of asthma, including appropriate use of medications, is the best approach to optimizing outcomes. Yet questions persist about the effect of asthma itself, as well as specific medications and the risk for major congenital malformations. As with any exposure during pregnancy, answering these questions is challenging because of the rarity of specific birth defects and the various and increasing number of medications that might be used to treat or prevent asthma symptoms.

Previously in this column ("Beta2-agonists for asthma, December 2011), we reviewed two studies that suggested short-acting beta-agonists used for the treatment of asthma were associated with an increased risk of oral clefts and that long-acting beta-agonists might be associated with an increased risk of cardiac anomalies (Hum. Reprod. 2011;26:3147-54; Birth Defects Res. A. Clin. Mol. Teratol. 2011;91:937-47).

What have we learned since then? Two studies published in 2013 add to the body of knowledge. The first, a database analysis using the United Kingdom’s General Practice Research Database, assessed pregnancy outcomes between 1991 and 2002 in 7,911 women exposed to asthma medications in the first trimester of pregnancy and 15,840 women who were not exposed (Pharmacotherapy 2013;33:363-8). Major anomalies were identified up to 1 year of age. Minor anomalies, chromosomal anomalies, and those associated with prematurity were excluded.

The overall risk for any exposure, compared with no exposure, for any congenital anomaly was 1.1 (95% confidence interval [CI], 1.0-1.3). No significant differences were found by class of asthma medication. Specific categories of defects also were evaluated, including musculoskeletal anomalies, oral clefts, cardiovascular defects, and multiple anomalies. Some estimates were elevated for specific medication classes.

For example, the relative risk (RR) of cleft lip or palate associated with exposure to long-acting beta-agonists was 2.4, but the confidence interval included 1 (0.3-21.8) based on 424 exposed pregnancies. The authors concluded that they found no significant increased risk of congenital anomalies associated with exposure to asthma, asthma medications, or any specific asthma medication classes in the first trimester. Limitations of the study included the inability to verify that exposure took place and insufficient data to adjust for confounding by vitamin supplementation, alcohol use, socioeconomic status, or markers of disease severity (other than number of medications prescribed).

The second study addressed the issue of maternal asthma itself and the risk for congenital anomalies (BJOG 2013;120:812-22). Using a meta-analysis approach, 21 cohort studies published between 1975 and 2012 met the criteria for inclusion. Combining major and minor congenital anomalies, the authors found a slight but statistically significant increased risk for any defect (RR, 1.11; 95% CI, 1.01-1.68), but when the analysis was restricted to major defects alone, the summary estimate was elevated but no longer significant (RR, 1.31; 95% CI, 0.57-3.02). When the specific defect grouping of oral clefts was examined, however, there was a significantly elevated overall relative risk of 1.30 (95% CI, 1.01-1.68). Limitations of this study include differing quality of studies and the appropriateness of combining data to derive a summary estimate.

Although both studies provide reassurance about the overall risk of major defects in the offspring of women with asthma, both suggest that more work needs to be done to follow up on the risk for oral clefts and whether this is linked to underlying disease severity and/or use of specific medications. Furthermore, safety of specific long-acting beta-agonist medications in pregnancy should be further examined.

The take-home message, however, continues to be that the risk for major defects in the offspring of pregnant women with asthma appears to be low, which supports the recommendation to follow guidelines for appropriate treatment of women with asthma both during and outside of pregnancy to control symptoms.

Dr. Chambers is professor of pediatrics and family and preventive medicine at the University of California, San Diego. She is director of the California Teratogen Information Service and Clinical Research Program. Dr. Chambers is a past president of the Organization of Teratology Information Specialists and past president of the Teratology Society. She said that she had no relevant financial disclosures. 

One of the most common conditions that complicate pregnancy is maternal asthma. Evidence continues to mount that adequate control of asthma, including appropriate use of medications, is the best approach to optimizing outcomes. Yet questions persist about the effect of asthma itself, as well as specific medications and the risk for major congenital malformations. As with any exposure during pregnancy, answering these questions is challenging because of the rarity of specific birth defects and the various and increasing number of medications that might be used to treat or prevent asthma symptoms.

Previously in this column ("Beta2-agonists for asthma, December 2011), we reviewed two studies that suggested short-acting beta-agonists used for the treatment of asthma were associated with an increased risk of oral clefts and that long-acting beta-agonists might be associated with an increased risk of cardiac anomalies (Hum. Reprod. 2011;26:3147-54; Birth Defects Res. A. Clin. Mol. Teratol. 2011;91:937-47).

What have we learned since then? Two studies published in 2013 add to the body of knowledge. The first, a database analysis using the United Kingdom’s General Practice Research Database, assessed pregnancy outcomes between 1991 and 2002 in 7,911 women exposed to asthma medications in the first trimester of pregnancy and 15,840 women who were not exposed (Pharmacotherapy 2013;33:363-8). Major anomalies were identified up to 1 year of age. Minor anomalies, chromosomal anomalies, and those associated with prematurity were excluded.

The overall risk for any exposure, compared with no exposure, for any congenital anomaly was 1.1 (95% confidence interval [CI], 1.0-1.3). No significant differences were found by class of asthma medication. Specific categories of defects also were evaluated, including musculoskeletal anomalies, oral clefts, cardiovascular defects, and multiple anomalies. Some estimates were elevated for specific medication classes.

For example, the relative risk (RR) of cleft lip or palate associated with exposure to long-acting beta-agonists was 2.4, but the confidence interval included 1 (0.3-21.8) based on 424 exposed pregnancies. The authors concluded that they found no significant increased risk of congenital anomalies associated with exposure to asthma, asthma medications, or any specific asthma medication classes in the first trimester. Limitations of the study included the inability to verify that exposure took place and insufficient data to adjust for confounding by vitamin supplementation, alcohol use, socioeconomic status, or markers of disease severity (other than number of medications prescribed).

The second study addressed the issue of maternal asthma itself and the risk for congenital anomalies (BJOG 2013;120:812-22). Using a meta-analysis approach, 21 cohort studies published between 1975 and 2012 met the criteria for inclusion. Combining major and minor congenital anomalies, the authors found a slight but statistically significant increased risk for any defect (RR, 1.11; 95% CI, 1.01-1.68), but when the analysis was restricted to major defects alone, the summary estimate was elevated but no longer significant (RR, 1.31; 95% CI, 0.57-3.02). When the specific defect grouping of oral clefts was examined, however, there was a significantly elevated overall relative risk of 1.30 (95% CI, 1.01-1.68). Limitations of this study include differing quality of studies and the appropriateness of combining data to derive a summary estimate.

Although both studies provide reassurance about the overall risk of major defects in the offspring of women with asthma, both suggest that more work needs to be done to follow up on the risk for oral clefts and whether this is linked to underlying disease severity and/or use of specific medications. Furthermore, safety of specific long-acting beta-agonist medications in pregnancy should be further examined.

The take-home message, however, continues to be that the risk for major defects in the offspring of pregnant women with asthma appears to be low, which supports the recommendation to follow guidelines for appropriate treatment of women with asthma both during and outside of pregnancy to control symptoms.

Dr. Chambers is professor of pediatrics and family and preventive medicine at the University of California, San Diego. She is director of the California Teratogen Information Service and Clinical Research Program. Dr. Chambers is a past president of the Organization of Teratology Information Specialists and past president of the Teratology Society. She said that she had no relevant financial disclosures. 

Approximately 75% of all pregnancies are estimated to be complicated by maternal nausea and vomiting, or nausea alone. Although nausea and vomiting are associated with a decreased risk of miscarriage, persistent or more severe symptoms can negatively impact the pregnant woman’s ability to work, as well as her quality of life. In a small subset of women (0.3%-1.0%), nausea and vomiting will progress to hyperemesis gravidarum, potentially leading to maternal dehydration, weight loss, hospitalization and adverse infant outcomes (N. Engl. J. Med. 2010;363:1544-50).

Although dietary modifications can be effective, pharmacologic therapy for nausea and vomiting of pregnancy may be needed. For more than 25 years, Bendectin was available in the United States, and was widely used as an effective treatment for nausea and vomiting of pregnancy. However, in 1983 the drug was voluntarily removed from the market by the manufacturer on the basis of the extensive business costs and negative publicity associated with allegations of teratogenicity. In the ensuing 27 years, the drug has never been reintroduced into the U.S. market, despite the fact that the safety of Bendectin exposure in pregnancy has been extensively studied, and the overwhelming evidence does not support any teratogenic effect.

In recognition of the strong safety profile and effectiveness of the ingredients in Bendectin, present-day American College of Obstetricians and Gynecologists practice guidelines recommend first-line treatment for nausea and vomiting with a combination of vitamin B6 and doxylamine (the formulation of Bendectin when it was removed from the market). This combination of ingredients, although not labeled for the indication of nausea and vomiting in pregnancy, is available in the United States as an over-the-counter product under the brand name Unisom SleepTabs. At the same time, a sustained-release formulation of the ingredients in Bendectin (Diclectin) has been approved in Canada specifically for the indication of nausea and vomiting in pregnancy, and has been widely used in that country for many years.

A further chapter was recently added to the long history of Bendectin. In a double-blind, randomized clinical trial conducted at three centers in the United States, the Canadian sustained-release formulation of Diclectin was compared with placebo for the treatment of nausea and vomiting (Am. J. Obstet. Gynecol. 2010 [doi:10.1016/j.ajog.2010.07.030]).

In this trial, the final sample included 256 pregnant women who met baseline criteria for severity and frequency of nausea and vomiting of pregnancy. The women enrolled in the trial at a mean gestational age of approximately 9 weeks, and were treated with Diclectin or placebo for 15 days.

Using intent-to-treat analysis, a significant reduction in the study measure of frequency and intensity of nausea and vomiting was reported in the treated group, compared with the placebo arm. There was a similarly significant improvement in the treated group’s global assessment of well-being over the course of treatment. Furthermore, there was no significant excess of serious or nonserious adverse events reported in the treated group vs. the placebo group during the period of the intervention.

Because of the study design, women tended to enroll at the peak time in gestation for symptoms of nausea and vomiting to occur. Thus, although the mean reduction in symptom score from baseline was 23% greater in the treated group than in the placebo group, there were substantial (close to 50%) mean reductions in symptom score from baseline in both groups by the end of the 2-week trial. This undoubtedly was due in part to the natural decline in symptoms with or without treatment as women in both arms approached the end of the first trimester. Had women been able to be randomized closer to the onset of symptoms (approximately 5-6 weeks’ gestation), the treatment effect might have been stronger.

In addition, had earlier enrollment been possible, thereby allowing for a greater number of days of follow-up during the critical window of peak symptoms, the investigators might have been able to more effectively evaluate the economic impact of treatment on number of lost days of work due to nausea.

The study was not designed to test the hypothesis that early, effective treatment can reduce the rate of progression from nausea and vomiting to hyperemesis gravidarum in the small subset of women who are susceptible to this condition. However, ecological data suggest that this might be possible, given the approximate doubling of the incidence of hospitalizations due to hyperemesis following withdrawal of Bendectin from the market.

Adding to the large volume of safety data for Bendectin, this study provides evidence of the safety and effectiveness of the sustained-release product for the labeled indication, an extremely common condition of pregnancy.

Dr. Chambers is associate professor of pediatrics and family and preventive medicine at the University of California, San Diego. She is director of the California Teratogen Information Service and Clinical Research Program. Dr. Chambers is a past president of the Organization of Teratology Information Specialists (www.otispregnancy.org) and past president of the Teratology Society. She had no conflicts to disclose related to the topic of this column. To comment, e-mail her at [email protected].

Approximately 75% of all pregnancies are estimated to be complicated by maternal nausea and vomiting, or nausea alone. Although nausea and vomiting are associated with a decreased risk of miscarriage, persistent or more severe symptoms can negatively impact the pregnant woman’s ability to work, as well as her quality of life. In a small subset of women (0.3%-1.0%), nausea and vomiting will progress to hyperemesis gravidarum, potentially leading to maternal dehydration, weight loss, hospitalization and adverse infant outcomes (N. Engl. J. Med. 2010;363:1544-50).

Although dietary modifications can be effective, pharmacologic therapy for nausea and vomiting of pregnancy may be needed. For more than 25 years, Bendectin was available in the United States, and was widely used as an effective treatment for nausea and vomiting of pregnancy. However, in 1983 the drug was voluntarily removed from the market by the manufacturer on the basis of the extensive business costs and negative publicity associated with allegations of teratogenicity. In the ensuing 27 years, the drug has never been reintroduced into the U.S. market, despite the fact that the safety of Bendectin exposure in pregnancy has been extensively studied, and the overwhelming evidence does not support any teratogenic effect.

In recognition of the strong safety profile and effectiveness of the ingredients in Bendectin, present-day American College of Obstetricians and Gynecologists practice guidelines recommend first-line treatment for nausea and vomiting with a combination of vitamin B6 and doxylamine (the formulation of Bendectin when it was removed from the market). This combination of ingredients, although not labeled for the indication of nausea and vomiting in pregnancy, is available in the United States as an over-the-counter product under the brand name Unisom SleepTabs. At the same time, a sustained-release formulation of the ingredients in Bendectin (Diclectin) has been approved in Canada specifically for the indication of nausea and vomiting in pregnancy, and has been widely used in that country for many years.

A further chapter was recently added to the long history of Bendectin. In a double-blind, randomized clinical trial conducted at three centers in the United States, the Canadian sustained-release formulation of Diclectin was compared with placebo for the treatment of nausea and vomiting (Am. J. Obstet. Gynecol. 2010 [doi:10.1016/j.ajog.2010.07.030]).

In this trial, the final sample included 256 pregnant women who met baseline criteria for severity and frequency of nausea and vomiting of pregnancy. The women enrolled in the trial at a mean gestational age of approximately 9 weeks, and were treated with Diclectin or placebo for 15 days.

Using intent-to-treat analysis, a significant reduction in the study measure of frequency and intensity of nausea and vomiting was reported in the treated group, compared with the placebo arm. There was a similarly significant improvement in the treated group’s global assessment of well-being over the course of treatment. Furthermore, there was no significant excess of serious or nonserious adverse events reported in the treated group vs. the placebo group during the period of the intervention.

Because of the study design, women tended to enroll at the peak time in gestation for symptoms of nausea and vomiting to occur. Thus, although the mean reduction in symptom score from baseline was 23% greater in the treated group than in the placebo group, there were substantial (close to 50%) mean reductions in symptom score from baseline in both groups by the end of the 2-week trial. This undoubtedly was due in part to the natural decline in symptoms with or without treatment as women in both arms approached the end of the first trimester. Had women been able to be randomized closer to the onset of symptoms (approximately 5-6 weeks’ gestation), the treatment effect might have been stronger.

In addition, had earlier enrollment been possible, thereby allowing for a greater number of days of follow-up during the critical window of peak symptoms, the investigators might have been able to more effectively evaluate the economic impact of treatment on number of lost days of work due to nausea.

The study was not designed to test the hypothesis that early, effective treatment can reduce the rate of progression from nausea and vomiting to hyperemesis gravidarum in the small subset of women who are susceptible to this condition. However, ecological data suggest that this might be possible, given the approximate doubling of the incidence of hospitalizations due to hyperemesis following withdrawal of Bendectin from the market.

Adding to the large volume of safety data for Bendectin, this study provides evidence of the safety and effectiveness of the sustained-release product for the labeled indication, an extremely common condition of pregnancy.

Dr. Chambers is associate professor of pediatrics and family and preventive medicine at the University of California, San Diego. She is director of the California Teratogen Information Service and Clinical Research Program. Dr. Chambers is a past president of the Organization of Teratology Information Specialists (www.otispregnancy.org) and past president of the Teratology Society. She had no conflicts to disclose related to the topic of this column. To comment, e-mail her at [email protected].

Approximately 75% of all pregnancies are estimated to be complicated by maternal nausea and vomiting, or nausea alone. Although nausea and vomiting are associated with a decreased risk of miscarriage, persistent or more severe symptoms can negatively impact the pregnant woman’s ability to work, as well as her quality of life. In a small subset of women (0.3%-1.0%), nausea and vomiting will progress to hyperemesis gravidarum, potentially leading to maternal dehydration, weight loss, hospitalization and adverse infant outcomes (N. Engl. J. Med. 2010;363:1544-50).

Although dietary modifications can be effective, pharmacologic therapy for nausea and vomiting of pregnancy may be needed. For more than 25 years, Bendectin was available in the United States, and was widely used as an effective treatment for nausea and vomiting of pregnancy. However, in 1983 the drug was voluntarily removed from the market by the manufacturer on the basis of the extensive business costs and negative publicity associated with allegations of teratogenicity. In the ensuing 27 years, the drug has never been reintroduced into the U.S. market, despite the fact that the safety of Bendectin exposure in pregnancy has been extensively studied, and the overwhelming evidence does not support any teratogenic effect.

In recognition of the strong safety profile and effectiveness of the ingredients in Bendectin, present-day American College of Obstetricians and Gynecologists practice guidelines recommend first-line treatment for nausea and vomiting with a combination of vitamin B6 and doxylamine (the formulation of Bendectin when it was removed from the market). This combination of ingredients, although not labeled for the indication of nausea and vomiting in pregnancy, is available in the United States as an over-the-counter product under the brand name Unisom SleepTabs. At the same time, a sustained-release formulation of the ingredients in Bendectin (Diclectin) has been approved in Canada specifically for the indication of nausea and vomiting in pregnancy, and has been widely used in that country for many years.

A further chapter was recently added to the long history of Bendectin. In a double-blind, randomized clinical trial conducted at three centers in the United States, the Canadian sustained-release formulation of Diclectin was compared with placebo for the treatment of nausea and vomiting (Am. J. Obstet. Gynecol. 2010 [doi:10.1016/j.ajog.2010.07.030]).

In this trial, the final sample included 256 pregnant women who met baseline criteria for severity and frequency of nausea and vomiting of pregnancy. The women enrolled in the trial at a mean gestational age of approximately 9 weeks, and were treated with Diclectin or placebo for 15 days.

Using intent-to-treat analysis, a significant reduction in the study measure of frequency and intensity of nausea and vomiting was reported in the treated group, compared with the placebo arm. There was a similarly significant improvement in the treated group’s global assessment of well-being over the course of treatment. Furthermore, there was no significant excess of serious or nonserious adverse events reported in the treated group vs. the placebo group during the period of the intervention.

Because of the study design, women tended to enroll at the peak time in gestation for symptoms of nausea and vomiting to occur. Thus, although the mean reduction in symptom score from baseline was 23% greater in the treated group than in the placebo group, there were substantial (close to 50%) mean reductions in symptom score from baseline in both groups by the end of the 2-week trial. This undoubtedly was due in part to the natural decline in symptoms with or without treatment as women in both arms approached the end of the first trimester. Had women been able to be randomized closer to the onset of symptoms (approximately 5-6 weeks’ gestation), the treatment effect might have been stronger.

In addition, had earlier enrollment been possible, thereby allowing for a greater number of days of follow-up during the critical window of peak symptoms, the investigators might have been able to more effectively evaluate the economic impact of treatment on number of lost days of work due to nausea.

The study was not designed to test the hypothesis that early, effective treatment can reduce the rate of progression from nausea and vomiting to hyperemesis gravidarum in the small subset of women who are susceptible to this condition. However, ecological data suggest that this might be possible, given the approximate doubling of the incidence of hospitalizations due to hyperemesis following withdrawal of Bendectin from the market.

Adding to the large volume of safety data for Bendectin, this study provides evidence of the safety and effectiveness of the sustained-release product for the labeled indication, an extremely common condition of pregnancy.

Dr. Chambers is associate professor of pediatrics and family and preventive medicine at the University of California, San Diego. She is director of the California Teratogen Information Service and Clinical Research Program. Dr. Chambers is a past president of the Organization of Teratology Information Specialists (www.otispregnancy.org) and past president of the Teratology Society. She had no conflicts to disclose related to the topic of this column. To comment, e-mail her at [email protected].