SSRI exposure during pregnancy: What’s enough data?

Numerous studies on the reproductive safety of selective serotonin reuptake inhibitors (SSRIs) have been published, particularly over the last decade. With the different methodologies used and often disparate results, the extensive data now available in the medical literature can be overwhelming for clinicians and researchers to sort through. Many of the most recently published studies derive from analyses using large administrative databases, from sources such as Medicare, Medicaid, or large HMO databases. Less common are prospective cohort studies, where patients with or without a history of exposure to SSRIs are followed across pregnancy in real time.

Studies over the past 5-10 years have consistently suggested that the risk of major congenital malformations associated with fetal exposure to SSRIs is nonexistent or modest. A major criticism of this literature has been that much of the data are derived from claims databases, which do not adequately account for the potential confounding effect of major depression – so-called “confounding by indication.”

While the consensus is that fetal exposure to SSRIs is not associated with a significant overall risk for major congenital malformations, questions have lingered about whether antidepressant exposure during pregnancy increases risk for cardiac defects. This had been a particular concern with respect to paroxetine, which in 2006 was changed from a pregnancy category C to D because of a purported increase in risk of heart defects associated with first-trimester exposure to this medication.

This issue was addressed again in a large population cohort study published this past June, using Medicaid data from 2000-2007. The study, in which I participated, involved a collaboration of investigators representing epidemiology, teratology, and reproductive psychiatry (N. Engl. J. Med. 2014;370:2397-2407). The study compared the risk of major cardiac defects in babies with and without exposure to antidepressants during the first trimester, providing a risk estimate unadjusted for depression, and an analysis that adjusted for the potential effect of depression and other potential confounders using propensity score adjustment methodology. (Propensity scores are an analytic tool that makes it possible to match groups with the exception of the variable being scrutinized, to minimize confounding.)

Results indicated that the increased risk identified in the unadjusted analysis is attenuated when factoring in depression: Compared with those not exposed to SSRIs, the unadjusted relative risk of any cardiac defect associated with SSRI exposure was 1.25. But with the fully adjusted analysis, the relative risk approached the null, at 1.06, and is not significant. The results are noteworthy because of the large sample size and the effort to control for relevant confounding factors, relevant to many other previously published studies evaluating risk of fetal SSRI exposure.

One would imagine that the increasing number of studies such as this one would be helpful to clinicians. But it can be very challenging for clinicians and even clinical researchers to navigate the growing literature and to attempt to parse out the methodologic strengths and limitations of the various analyses put forth. What makes interpretation of these growing data even more complicated is that reviews of this topic frequently are selective, and reflect what the author chooses to highlight, with resulting conclusions about safety that may be incomplete. The issue is relevant with respect to the medical literature and even the more general media.

An example is the recent publication of an article in the New York Times about whether antidepressants are safe during pregnancy. The article elicited volley after volley of diverse replies, expressing both outrage at the selective reference of studies associating antidepressants with increased fetal risk, as well as criticism of potential cavalier prescribing and use of antidepressants during pregnancy, with their risks still not absolutely quantified. The New York Times public editor also weighed in with a response, writing in a column that “readers – many of them doctors – wrote to complain that the article was inappropriately alarmist, and that the idea behind it was dangerous for pregnant women suffering from depression.”

As my colleagues and I wrote in a response to the article in a blog, whatever the reason for the brevity, a “cursory presentation of the complexity of decisions made around antidepressant use during pregnancy” can potentially be harmful to patients, and at best “is just incomplete; at its worst, it is irresponsible.”

Perhaps of even greater concern than the selective discussion of studies was the implication in the article that the decision to take antidepressants during pregnancy is similar to the decision to give up wine, caffeine, and ripened cheese across such an important time. The decision is certainly not that simple. After more than 2 decades and thousands of consults with women contemplating the decision of whether to take an SSRI during pregnancy or not, I remain impressed with the bind faced by patients with major depression who are trying to make this decision with their doctors and partners, applying their own private calculus to the question of whether to use antidepressants during pregnancy.

What is also ironic is that there is common use of other medications during pregnancy for which there are vastly less available reproductive safety data. These medicines would include, for example, sedative hypnotics or antibiotics; so why the enormous concern about SSRIs? One has to wonder whether the scrutiny about SSRIs is not about using the medication but is related to bias regarding the use of a medicine during pregnancy to treat an illness such as depression, where many people, including clinicians, would discount the devastating effect of depression on women’s lives – as well as the evolving data on the impact of untreated psychiatric illness on fetal well-being, and the well-documented association between psychiatric illness during pregnancy and increased risk for postpartum depression.

Ironically, the availability of more data has not made it easier for the clinician but has brought about a need for greater scrutiny; the conversation about this issue is probably good for the field. Ultimately, decisions about what women choose to do will be made on a case-by-case basis, as individuals make the decision with their doctors and partners using available data in the context of their individual clinical situations, factoring in severity of illness as well as their own individual wishes.

Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information about reproductive mental health at www.womensmentalhealth.org. He is a consultant to manufacturers of antidepressant medications. He was an author of the NEJM study, which was funded by the U.S. Agency for Healthcare Research and Quality and the National Institutes of Health. To comment, e-mail him at obnews@frontlinemedcom.com.

Numerous studies on the reproductive safety of selective serotonin reuptake inhibitors (SSRIs) have been published, particularly over the last decade. With the different methodologies used and often disparate results, the extensive data now available in the medical literature can be overwhelming for clinicians and researchers to sort through. Many of the most recently published studies derive from analyses using large administrative databases, from sources such as Medicare, Medicaid, or large HMO databases. Less common are prospective cohort studies, where patients with or without a history of exposure to SSRIs are followed across pregnancy in real time.

Studies over the past 5-10 years have consistently suggested that the risk of major congenital malformations associated with fetal exposure to SSRIs is nonexistent or modest. A major criticism of this literature has been that much of the data are derived from claims databases, which do not adequately account for the potential confounding effect of major depression – so-called “confounding by indication.”

While the consensus is that fetal exposure to SSRIs is not associated with a significant overall risk for major congenital malformations, questions have lingered about whether antidepressant exposure during pregnancy increases risk for cardiac defects. This had been a particular concern with respect to paroxetine, which in 2006 was changed from a pregnancy category C to D because of a purported increase in risk of heart defects associated with first-trimester exposure to this medication.

This issue was addressed again in a large population cohort study published this past June, using Medicaid data from 2000-2007. The study, in which I participated, involved a collaboration of investigators representing epidemiology, teratology, and reproductive psychiatry (N. Engl. J. Med. 2014;370:2397-2407). The study compared the risk of major cardiac defects in babies with and without exposure to antidepressants during the first trimester, providing a risk estimate unadjusted for depression, and an analysis that adjusted for the potential effect of depression and other potential confounders using propensity score adjustment methodology. (Propensity scores are an analytic tool that makes it possible to match groups with the exception of the variable being scrutinized, to minimize confounding.)

Results indicated that the increased risk identified in the unadjusted analysis is attenuated when factoring in depression: Compared with those not exposed to SSRIs, the unadjusted relative risk of any cardiac defect associated with SSRI exposure was 1.25. But with the fully adjusted analysis, the relative risk approached the null, at 1.06, and is not significant. The results are noteworthy because of the large sample size and the effort to control for relevant confounding factors, relevant to many other previously published studies evaluating risk of fetal SSRI exposure.

One would imagine that the increasing number of studies such as this one would be helpful to clinicians. But it can be very challenging for clinicians and even clinical researchers to navigate the growing literature and to attempt to parse out the methodologic strengths and limitations of the various analyses put forth. What makes interpretation of these growing data even more complicated is that reviews of this topic frequently are selective, and reflect what the author chooses to highlight, with resulting conclusions about safety that may be incomplete. The issue is relevant with respect to the medical literature and even the more general media.

An example is the recent publication of an article in the New York Times about whether antidepressants are safe during pregnancy. The article elicited volley after volley of diverse replies, expressing both outrage at the selective reference of studies associating antidepressants with increased fetal risk, as well as criticism of potential cavalier prescribing and use of antidepressants during pregnancy, with their risks still not absolutely quantified. The New York Times public editor also weighed in with a response, writing in a column that “readers – many of them doctors – wrote to complain that the article was inappropriately alarmist, and that the idea behind it was dangerous for pregnant women suffering from depression.”

As my colleagues and I wrote in a response to the article in a blog, whatever the reason for the brevity, a “cursory presentation of the complexity of decisions made around antidepressant use during pregnancy” can potentially be harmful to patients, and at best “is just incomplete; at its worst, it is irresponsible.”

Perhaps of even greater concern than the selective discussion of studies was the implication in the article that the decision to take antidepressants during pregnancy is similar to the decision to give up wine, caffeine, and ripened cheese across such an important time. The decision is certainly not that simple. After more than 2 decades and thousands of consults with women contemplating the decision of whether to take an SSRI during pregnancy or not, I remain impressed with the bind faced by patients with major depression who are trying to make this decision with their doctors and partners, applying their own private calculus to the question of whether to use antidepressants during pregnancy.

What is also ironic is that there is common use of other medications during pregnancy for which there are vastly less available reproductive safety data. These medicines would include, for example, sedative hypnotics or antibiotics; so why the enormous concern about SSRIs? One has to wonder whether the scrutiny about SSRIs is not about using the medication but is related to bias regarding the use of a medicine during pregnancy to treat an illness such as depression, where many people, including clinicians, would discount the devastating effect of depression on women’s lives – as well as the evolving data on the impact of untreated psychiatric illness on fetal well-being, and the well-documented association between psychiatric illness during pregnancy and increased risk for postpartum depression.

Ironically, the availability of more data has not made it easier for the clinician but has brought about a need for greater scrutiny; the conversation about this issue is probably good for the field. Ultimately, decisions about what women choose to do will be made on a case-by-case basis, as individuals make the decision with their doctors and partners using available data in the context of their individual clinical situations, factoring in severity of illness as well as their own individual wishes.

Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information about reproductive mental health at www.womensmentalhealth.org. He is a consultant to manufacturers of antidepressant medications. He was an author of the NEJM study, which was funded by the U.S. Agency for Healthcare Research and Quality and the National Institutes of Health. To comment, e-mail him at obnews@frontlinemedcom.com.

Numerous studies on the reproductive safety of selective serotonin reuptake inhibitors (SSRIs) have been published, particularly over the last decade. With the different methodologies used and often disparate results, the extensive data now available in the medical literature can be overwhelming for clinicians and researchers to sort through. Many of the most recently published studies derive from analyses using large administrative databases, from sources such as Medicare, Medicaid, or large HMO databases. Less common are prospective cohort studies, where patients with or without a history of exposure to SSRIs are followed across pregnancy in real time.

Studies over the past 5-10 years have consistently suggested that the risk of major congenital malformations associated with fetal exposure to SSRIs is nonexistent or modest. A major criticism of this literature has been that much of the data are derived from claims databases, which do not adequately account for the potential confounding effect of major depression – so-called “confounding by indication.”

While the consensus is that fetal exposure to SSRIs is not associated with a significant overall risk for major congenital malformations, questions have lingered about whether antidepressant exposure during pregnancy increases risk for cardiac defects. This had been a particular concern with respect to paroxetine, which in 2006 was changed from a pregnancy category C to D because of a purported increase in risk of heart defects associated with first-trimester exposure to this medication.

This issue was addressed again in a large population cohort study published this past June, using Medicaid data from 2000-2007. The study, in which I participated, involved a collaboration of investigators representing epidemiology, teratology, and reproductive psychiatry (N. Engl. J. Med. 2014;370:2397-2407). The study compared the risk of major cardiac defects in babies with and without exposure to antidepressants during the first trimester, providing a risk estimate unadjusted for depression, and an analysis that adjusted for the potential effect of depression and other potential confounders using propensity score adjustment methodology. (Propensity scores are an analytic tool that makes it possible to match groups with the exception of the variable being scrutinized, to minimize confounding.)

Results indicated that the increased risk identified in the unadjusted analysis is attenuated when factoring in depression: Compared with those not exposed to SSRIs, the unadjusted relative risk of any cardiac defect associated with SSRI exposure was 1.25. But with the fully adjusted analysis, the relative risk approached the null, at 1.06, and is not significant. The results are noteworthy because of the large sample size and the effort to control for relevant confounding factors, relevant to many other previously published studies evaluating risk of fetal SSRI exposure.

One would imagine that the increasing number of studies such as this one would be helpful to clinicians. But it can be very challenging for clinicians and even clinical researchers to navigate the growing literature and to attempt to parse out the methodologic strengths and limitations of the various analyses put forth. What makes interpretation of these growing data even more complicated is that reviews of this topic frequently are selective, and reflect what the author chooses to highlight, with resulting conclusions about safety that may be incomplete. The issue is relevant with respect to the medical literature and even the more general media.

An example is the recent publication of an article in the New York Times about whether antidepressants are safe during pregnancy. The article elicited volley after volley of diverse replies, expressing both outrage at the selective reference of studies associating antidepressants with increased fetal risk, as well as criticism of potential cavalier prescribing and use of antidepressants during pregnancy, with their risks still not absolutely quantified. The New York Times public editor also weighed in with a response, writing in a column that “readers – many of them doctors – wrote to complain that the article was inappropriately alarmist, and that the idea behind it was dangerous for pregnant women suffering from depression.”

As my colleagues and I wrote in a response to the article in a blog, whatever the reason for the brevity, a “cursory presentation of the complexity of decisions made around antidepressant use during pregnancy” can potentially be harmful to patients, and at best “is just incomplete; at its worst, it is irresponsible.”

Perhaps of even greater concern than the selective discussion of studies was the implication in the article that the decision to take antidepressants during pregnancy is similar to the decision to give up wine, caffeine, and ripened cheese across such an important time. The decision is certainly not that simple. After more than 2 decades and thousands of consults with women contemplating the decision of whether to take an SSRI during pregnancy or not, I remain impressed with the bind faced by patients with major depression who are trying to make this decision with their doctors and partners, applying their own private calculus to the question of whether to use antidepressants during pregnancy.

What is also ironic is that there is common use of other medications during pregnancy for which there are vastly less available reproductive safety data. These medicines would include, for example, sedative hypnotics or antibiotics; so why the enormous concern about SSRIs? One has to wonder whether the scrutiny about SSRIs is not about using the medication but is related to bias regarding the use of a medicine during pregnancy to treat an illness such as depression, where many people, including clinicians, would discount the devastating effect of depression on women’s lives – as well as the evolving data on the impact of untreated psychiatric illness on fetal well-being, and the well-documented association between psychiatric illness during pregnancy and increased risk for postpartum depression.

Ironically, the availability of more data has not made it easier for the clinician but has brought about a need for greater scrutiny; the conversation about this issue is probably good for the field. Ultimately, decisions about what women choose to do will be made on a case-by-case basis, as individuals make the decision with their doctors and partners using available data in the context of their individual clinical situations, factoring in severity of illness as well as their own individual wishes.

Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information about reproductive mental health at www.womensmentalhealth.org. He is a consultant to manufacturers of antidepressant medications. He was an author of the NEJM study, which was funded by the U.S. Agency for Healthcare Research and Quality and the National Institutes of Health. To comment, e-mail him at obnews@frontlinemedcom.com.