Lee Cohen, MD

The last decade has brought much attention to the risks of fetal exposure to antidepressant medications, with numerous studies describing the risks of adverse outcomes that range from congenital malformations, persistent pulmonary hypertension of the newborn (PPHN), and neonatal adaptation syndrome, to preterm birth and spontaneous abortion. It has been challenging for clinicians to make clinical sense out of these studies, which vary in their methodologic rigor, and to determine how to fit these data into the treatment algorithm for managing depression during pregnancy.

To date, rigorous studies evaluating whether treatment with antidepressants during pregnancy increases the risk of spontaneous abortion have been relatively sparse. The available data, largely from small cohort studies, have suggested that selective serotonin reuptake inhibitor (SSRI) exposure during pregnancy is associated with an increased risk of spontaneous abortion relative to unexposed pregnancies – but the increases have been relatively modest and rates typically have not exceeded estimated rates in the general population. Cohort studies are often underpowered with a small sample of women, hindering the ability to show a statistical difference for an uncommon outcome like spontaneous abortion. And even if there is a statistical difference, a critical issue to consider is whether that difference is clinically meaningfu

Studies using large administrative databases both in the United States and internationally have provided the capacity to look at exposure to psychiatric and other medications during pregnancy in large numbers of women. But many have not adequately addressed the problem of "confounding by indication," because they compare women taking the antidepressant to untreated women who do not have the underlying disorder for which the medication is used. This is critical because depression may be independently associated with some of the adverse obstetrical and neonatal outcomes that have been ascribed to exposure to antidepressants (Arch. Gen. Psychiatr. 2010;67:1012-24).

But a population-based study published last year using data from the Danish birth, hospital, and psychiatric registries from February 1997 to December 2008 addressed the confounding issue in more than 1 million pregnancies and represents an incremental contribution to the literature on this topic (PLoS One 2013;8:e72095 [doi: 10.1371/journal.pone.0072095]).

Of about 1,005,000 pregnancies, the rate of spontaneous abortion (before 22 weeks’ gestation) was 11%. The risk of spontaneous abortion among pregnancies in women with depression treated with an antidepressant in early pregnancy (22,061 pregnancies) was compared with the risk among pregnancies in women with depression who did not report use of antidepressants (1,843 pregnancies) and in women with no diagnosis of depression and no antidepressant use (981,415). The antidepressants included SSRIs, serotonin-norepinephrine reuptake inhibitors, and tricyclics, and the risk ratios were adjusted for maternal age, education, and other factors.

The risk of spontaneous abortion associated with the use of antidepressants was slightly higher compared with no antidepressant use, with a relative risk of 1.14. However, when the analysis was restricted to women diagnosed with depressive disorder, as documented in the psychiatric registry (which includes information on all admissions to psychiatric hospitals and outpatient treatments in Denmark), the risk associated with antidepressant use dropped to 1.0.

Essentially, after adjustment for the depression diagnosis, the risk moves toward the null, and spontaneous abortion rates are comparable between unexposed and exposed pregnancies. This has never been shown in such a large study, and is a critical finding because this represents an effort in a very large dataset to parse out the relative effects of exposure to the disease versus exposure to the medicine.

When considered in the context of previously available data, where do these results leave the clinician and their patients? Women with depression often ask about the risks of preterm birth and spontaneous abortion associated with antidepressants. This concern is particularly relevant for women with depression undergoing assisted reproductive technology procedures for infertility.

Patients and clinicians can be somewhat reassured by the findings of this study, which indicate that even if there is a risk of increased spontaneous abortion, it is a very small one, and it appears to be even smaller when factoring in the depression diagnosis.

There is no perfect decision with respect to the challenging question of whether to use an antidepressant in women with significant psychological distress, including major affective disorder. Women with the same illness history presented with the same information may make different decisions about psychiatric medication use during pregnancy, and some women may choose not to use an antidepressant.

Finally, this study highlights the importance of factoring in the effect of the underlying illness for which the patient is being treated in clinical studies that examine the fetal effects of exposure to psychiatric medications, as well as for other classes of medications for other nonpsychiatric illnesses. In large datasets, it is challenging to adjust for variables that are relevant to the outcome of interest, and this could explain some of the disparate findings of studies regarding spontaneous abortion and other obstetrical and neonatal outcomes.

When we see large studies with large numbers of patients, while exciting, we need to be more critical in interpreting the results, paying attention to the comparison groups and whether the study adjusts for the variables that can be very relevant to the outcome of interest.

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 has been a consultant to manufacturers of antidepressant medications, and the Danish study was funded with one of the author’s post doc grants from the Danish Council for Independent Research Companies. To comment, e-mail him at [email protected].

The last decade has brought much attention to the risks of fetal exposure to antidepressant medications, with numerous studies describing the risks of adverse outcomes that range from congenital malformations, persistent pulmonary hypertension of the newborn (PPHN), and neonatal adaptation syndrome, to preterm birth and spontaneous abortion. It has been challenging for clinicians to make clinical sense out of these studies, which vary in their methodologic rigor, and to determine how to fit these data into the treatment algorithm for managing depression during pregnancy.

To date, rigorous studies evaluating whether treatment with antidepressants during pregnancy increases the risk of spontaneous abortion have been relatively sparse. The available data, largely from small cohort studies, have suggested that selective serotonin reuptake inhibitor (SSRI) exposure during pregnancy is associated with an increased risk of spontaneous abortion relative to unexposed pregnancies – but the increases have been relatively modest and rates typically have not exceeded estimated rates in the general population. Cohort studies are often underpowered with a small sample of women, hindering the ability to show a statistical difference for an uncommon outcome like spontaneous abortion. And even if there is a statistical difference, a critical issue to consider is whether that difference is clinically meaningfu

Studies using large administrative databases both in the United States and internationally have provided the capacity to look at exposure to psychiatric and other medications during pregnancy in large numbers of women. But many have not adequately addressed the problem of "confounding by indication," because they compare women taking the antidepressant to untreated women who do not have the underlying disorder for which the medication is used. This is critical because depression may be independently associated with some of the adverse obstetrical and neonatal outcomes that have been ascribed to exposure to antidepressants (Arch. Gen. Psychiatr. 2010;67:1012-24).

But a population-based study published last year using data from the Danish birth, hospital, and psychiatric registries from February 1997 to December 2008 addressed the confounding issue in more than 1 million pregnancies and represents an incremental contribution to the literature on this topic (PLoS One 2013;8:e72095 [doi: 10.1371/journal.pone.0072095]).

Of about 1,005,000 pregnancies, the rate of spontaneous abortion (before 22 weeks’ gestation) was 11%. The risk of spontaneous abortion among pregnancies in women with depression treated with an antidepressant in early pregnancy (22,061 pregnancies) was compared with the risk among pregnancies in women with depression who did not report use of antidepressants (1,843 pregnancies) and in women with no diagnosis of depression and no antidepressant use (981,415). The antidepressants included SSRIs, serotonin-norepinephrine reuptake inhibitors, and tricyclics, and the risk ratios were adjusted for maternal age, education, and other factors.

The risk of spontaneous abortion associated with the use of antidepressants was slightly higher compared with no antidepressant use, with a relative risk of 1.14. However, when the analysis was restricted to women diagnosed with depressive disorder, as documented in the psychiatric registry (which includes information on all admissions to psychiatric hospitals and outpatient treatments in Denmark), the risk associated with antidepressant use dropped to 1.0.

Essentially, after adjustment for the depression diagnosis, the risk moves toward the null, and spontaneous abortion rates are comparable between unexposed and exposed pregnancies. This has never been shown in such a large study, and is a critical finding because this represents an effort in a very large dataset to parse out the relative effects of exposure to the disease versus exposure to the medicine.

When considered in the context of previously available data, where do these results leave the clinician and their patients? Women with depression often ask about the risks of preterm birth and spontaneous abortion associated with antidepressants. This concern is particularly relevant for women with depression undergoing assisted reproductive technology procedures for infertility.

Patients and clinicians can be somewhat reassured by the findings of this study, which indicate that even if there is a risk of increased spontaneous abortion, it is a very small one, and it appears to be even smaller when factoring in the depression diagnosis.

There is no perfect decision with respect to the challenging question of whether to use an antidepressant in women with significant psychological distress, including major affective disorder. Women with the same illness history presented with the same information may make different decisions about psychiatric medication use during pregnancy, and some women may choose not to use an antidepressant.

Finally, this study highlights the importance of factoring in the effect of the underlying illness for which the patient is being treated in clinical studies that examine the fetal effects of exposure to psychiatric medications, as well as for other classes of medications for other nonpsychiatric illnesses. In large datasets, it is challenging to adjust for variables that are relevant to the outcome of interest, and this could explain some of the disparate findings of studies regarding spontaneous abortion and other obstetrical and neonatal outcomes.

When we see large studies with large numbers of patients, while exciting, we need to be more critical in interpreting the results, paying attention to the comparison groups and whether the study adjusts for the variables that can be very relevant to the outcome of interest.

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 has been a consultant to manufacturers of antidepressant medications, and the Danish study was funded with one of the author’s post doc grants from the Danish Council for Independent Research Companies. To comment, e-mail him at [email protected].

The last decade has brought much attention to the risks of fetal exposure to antidepressant medications, with numerous studies describing the risks of adverse outcomes that range from congenital malformations, persistent pulmonary hypertension of the newborn (PPHN), and neonatal adaptation syndrome, to preterm birth and spontaneous abortion. It has been challenging for clinicians to make clinical sense out of these studies, which vary in their methodologic rigor, and to determine how to fit these data into the treatment algorithm for managing depression during pregnancy.

To date, rigorous studies evaluating whether treatment with antidepressants during pregnancy increases the risk of spontaneous abortion have been relatively sparse. The available data, largely from small cohort studies, have suggested that selective serotonin reuptake inhibitor (SSRI) exposure during pregnancy is associated with an increased risk of spontaneous abortion relative to unexposed pregnancies – but the increases have been relatively modest and rates typically have not exceeded estimated rates in the general population. Cohort studies are often underpowered with a small sample of women, hindering the ability to show a statistical difference for an uncommon outcome like spontaneous abortion. And even if there is a statistical difference, a critical issue to consider is whether that difference is clinically meaningfu

Studies using large administrative databases both in the United States and internationally have provided the capacity to look at exposure to psychiatric and other medications during pregnancy in large numbers of women. But many have not adequately addressed the problem of "confounding by indication," because they compare women taking the antidepressant to untreated women who do not have the underlying disorder for which the medication is used. This is critical because depression may be independently associated with some of the adverse obstetrical and neonatal outcomes that have been ascribed to exposure to antidepressants (Arch. Gen. Psychiatr. 2010;67:1012-24).

But a population-based study published last year using data from the Danish birth, hospital, and psychiatric registries from February 1997 to December 2008 addressed the confounding issue in more than 1 million pregnancies and represents an incremental contribution to the literature on this topic (PLoS One 2013;8:e72095 [doi: 10.1371/journal.pone.0072095]).

Of about 1,005,000 pregnancies, the rate of spontaneous abortion (before 22 weeks’ gestation) was 11%. The risk of spontaneous abortion among pregnancies in women with depression treated with an antidepressant in early pregnancy (22,061 pregnancies) was compared with the risk among pregnancies in women with depression who did not report use of antidepressants (1,843 pregnancies) and in women with no diagnosis of depression and no antidepressant use (981,415). The antidepressants included SSRIs, serotonin-norepinephrine reuptake inhibitors, and tricyclics, and the risk ratios were adjusted for maternal age, education, and other factors.

The risk of spontaneous abortion associated with the use of antidepressants was slightly higher compared with no antidepressant use, with a relative risk of 1.14. However, when the analysis was restricted to women diagnosed with depressive disorder, as documented in the psychiatric registry (which includes information on all admissions to psychiatric hospitals and outpatient treatments in Denmark), the risk associated with antidepressant use dropped to 1.0.

Essentially, after adjustment for the depression diagnosis, the risk moves toward the null, and spontaneous abortion rates are comparable between unexposed and exposed pregnancies. This has never been shown in such a large study, and is a critical finding because this represents an effort in a very large dataset to parse out the relative effects of exposure to the disease versus exposure to the medicine.

When considered in the context of previously available data, where do these results leave the clinician and their patients? Women with depression often ask about the risks of preterm birth and spontaneous abortion associated with antidepressants. This concern is particularly relevant for women with depression undergoing assisted reproductive technology procedures for infertility.

Patients and clinicians can be somewhat reassured by the findings of this study, which indicate that even if there is a risk of increased spontaneous abortion, it is a very small one, and it appears to be even smaller when factoring in the depression diagnosis.

There is no perfect decision with respect to the challenging question of whether to use an antidepressant in women with significant psychological distress, including major affective disorder. Women with the same illness history presented with the same information may make different decisions about psychiatric medication use during pregnancy, and some women may choose not to use an antidepressant.

Finally, this study highlights the importance of factoring in the effect of the underlying illness for which the patient is being treated in clinical studies that examine the fetal effects of exposure to psychiatric medications, as well as for other classes of medications for other nonpsychiatric illnesses. In large datasets, it is challenging to adjust for variables that are relevant to the outcome of interest, and this could explain some of the disparate findings of studies regarding spontaneous abortion and other obstetrical and neonatal outcomes.

When we see large studies with large numbers of patients, while exciting, we need to be more critical in interpreting the results, paying attention to the comparison groups and whether the study adjusts for the variables that can be very relevant to the outcome of interest.

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 has been a consultant to manufacturers of antidepressant medications, and the Danish study was funded with one of the author’s post doc grants from the Danish Council for Independent Research Companies. To comment, e-mail him at [email protected].

Over the past decade, there has been a steady stream of information and published studies on the safety of antidepressants during pregnancy. Despite small sample sizes, methodological flaws, and other limitations of many published studies, we were grateful for useful information on the reproductive safety of antidepressants, primarily selective serotonin reuptake inhibitors.

Compared with those early years, we now have a vast amount of data and numerous published studies on the subject, providing us with more information regarding the spectrum of outcomes associated with prenatal exposure to SSRIs. Analyses of those data have become more sophisticated, with the appreciation that any assessment of reproductive safety must take into account both the potential risks of exposure to the medication and the risks of untreated psychiatric illness.

In this column, I will not review the extent to which SSRI exposure increases the risk of major congenital malformations, addressed in previous columns. Based on the literature over the last 10-15 years, it is reasonable to conclude that, if the risk of major congenital malformations following first-trimester exposure to SSRIs is increased, the increase is small (N. Engl. J. Med. 2007;356:2732-3).

The effects of SSRI exposure on other outcomes such as preterm delivery, birth weight, and Apgar scores have been less clear. These outcomes are gaining an increased presence in the literature, and interpretation of the data from either small cohort studies or large administrative databases can be extremely confusing for both biostatistician and clinician alike.

An important study, a meta-analysis of 23 studies published online in February, rigorously evaluated pregnancy and delivery outcomes following prenatal exposure to antidepressants (including SSRIs, tricyclics, and monoamine oxidase [MAO] inhibitors) – mostly SSRIs – factoring in the risk of untreated psychiatric illness on these outcomes. There were no significant associations between prenatal exposure to antidepressant medications and the risk of spontaneous abortion, with no significant differences among exposed vs. nonexposed pregnancies (JAMA Psychiatry 2013 Feb. 27:1-8 [doi:10.1001/jamapsychiatry.2013.684]).

There were, however, significant associations between prenatal antidepressant exposure and gestational age, preterm delivery, lower birth weight, and lower Apgar scores. Antidepressant exposure was significantly associated with a shorter gestation, and preterm delivery was more common among women taking antidepressants, whether or not they were compared with all women not exposed to antidepressants or just depressed women who did not take antidepressants during pregnancy.

Similarly, prenatal antidepressant exposure was significantly associated with lower birth weight (a mean difference of 74 g) when compared with birth weights of babies with no prenatal exposure. But when the comparison was limited to depressed mothers with no exposure to antidepressants, the association was no longer significant.

Antidepressant exposure also was significantly associated with lower Apgar scores at 1 and 5 minutes when compared with all the unexposed mothers and to only the mothers who were depressed but did not take antidepressants. (The study was funded by Canadian government grants, and 4 of the 11 authors disclosed having received honoraria, an unrestricted educational grant, and/or research support from companies that included antidepressant manufacturers).

What do these results mean to the clinician trying to translate these scientific findings into clinical practice? For the clinician, the most critical issue to consider is that, even when there were observed differences in outcomes between exposed and nonexposed pregnancies, those differences were small. Gestational age was less than half a week shorter, and the differences in the mean 1- and 5-minute Apgar scores were less than half a point and the scores were considered excellent.

These results are reassuring because the clinical relevance of the cited differences between the two groups is exceedingly small. Perhaps the most critical finding in this published analysis is that even a statistically significant difference in an outcome only has relevance if the difference informs clinical care. This is not an Olympic downhill ski race, where a hundredth of a second can make a critical difference.

Dr. Cohen is the director of the Center for Women’s Mental Health at the Massachusetts General Hospital in Boston, which provides information about pregnancy and mental health at www.womensmentalhealth.org. He has been a consultant to manufacturers of SSRIs.

Over the past decade, there has been a steady stream of information and published studies on the safety of antidepressants during pregnancy. Despite small sample sizes, methodological flaws, and other limitations of many published studies, we were grateful for useful information on the reproductive safety of antidepressants, primarily selective serotonin reuptake inhibitors.

Compared with those early years, we now have a vast amount of data and numerous published studies on the subject, providing us with more information regarding the spectrum of outcomes associated with prenatal exposure to SSRIs. Analyses of those data have become more sophisticated, with the appreciation that any assessment of reproductive safety must take into account both the potential risks of exposure to the medication and the risks of untreated psychiatric illness.

In this column, I will not review the extent to which SSRI exposure increases the risk of major congenital malformations, addressed in previous columns. Based on the literature over the last 10-15 years, it is reasonable to conclude that, if the risk of major congenital malformations following first-trimester exposure to SSRIs is increased, the increase is small (N. Engl. J. Med. 2007;356:2732-3).

The effects of SSRI exposure on other outcomes such as preterm delivery, birth weight, and Apgar scores have been less clear. These outcomes are gaining an increased presence in the literature, and interpretation of the data from either small cohort studies or large administrative databases can be extremely confusing for both biostatistician and clinician alike.

An important study, a meta-analysis of 23 studies published online in February, rigorously evaluated pregnancy and delivery outcomes following prenatal exposure to antidepressants (including SSRIs, tricyclics, and monoamine oxidase [MAO] inhibitors) – mostly SSRIs – factoring in the risk of untreated psychiatric illness on these outcomes. There were no significant associations between prenatal exposure to antidepressant medications and the risk of spontaneous abortion, with no significant differences among exposed vs. nonexposed pregnancies (JAMA Psychiatry 2013 Feb. 27:1-8 [doi:10.1001/jamapsychiatry.2013.684]).

There were, however, significant associations between prenatal antidepressant exposure and gestational age, preterm delivery, lower birth weight, and lower Apgar scores. Antidepressant exposure was significantly associated with a shorter gestation, and preterm delivery was more common among women taking antidepressants, whether or not they were compared with all women not exposed to antidepressants or just depressed women who did not take antidepressants during pregnancy.

Similarly, prenatal antidepressant exposure was significantly associated with lower birth weight (a mean difference of 74 g) when compared with birth weights of babies with no prenatal exposure. But when the comparison was limited to depressed mothers with no exposure to antidepressants, the association was no longer significant.

Antidepressant exposure also was significantly associated with lower Apgar scores at 1 and 5 minutes when compared with all the unexposed mothers and to only the mothers who were depressed but did not take antidepressants. (The study was funded by Canadian government grants, and 4 of the 11 authors disclosed having received honoraria, an unrestricted educational grant, and/or research support from companies that included antidepressant manufacturers).

What do these results mean to the clinician trying to translate these scientific findings into clinical practice? For the clinician, the most critical issue to consider is that, even when there were observed differences in outcomes between exposed and nonexposed pregnancies, those differences were small. Gestational age was less than half a week shorter, and the differences in the mean 1- and 5-minute Apgar scores were less than half a point and the scores were considered excellent.

These results are reassuring because the clinical relevance of the cited differences between the two groups is exceedingly small. Perhaps the most critical finding in this published analysis is that even a statistically significant difference in an outcome only has relevance if the difference informs clinical care. This is not an Olympic downhill ski race, where a hundredth of a second can make a critical difference.

Dr. Cohen is the director of the Center for Women’s Mental Health at the Massachusetts General Hospital in Boston, which provides information about pregnancy and mental health at www.womensmentalhealth.org. He has been a consultant to manufacturers of SSRIs.

Over the past decade, there has been a steady stream of information and published studies on the safety of antidepressants during pregnancy. Despite small sample sizes, methodological flaws, and other limitations of many published studies, we were grateful for useful information on the reproductive safety of antidepressants, primarily selective serotonin reuptake inhibitors.

Compared with those early years, we now have a vast amount of data and numerous published studies on the subject, providing us with more information regarding the spectrum of outcomes associated with prenatal exposure to SSRIs. Analyses of those data have become more sophisticated, with the appreciation that any assessment of reproductive safety must take into account both the potential risks of exposure to the medication and the risks of untreated psychiatric illness.

In this column, I will not review the extent to which SSRI exposure increases the risk of major congenital malformations, addressed in previous columns. Based on the literature over the last 10-15 years, it is reasonable to conclude that, if the risk of major congenital malformations following first-trimester exposure to SSRIs is increased, the increase is small (N. Engl. J. Med. 2007;356:2732-3).

The effects of SSRI exposure on other outcomes such as preterm delivery, birth weight, and Apgar scores have been less clear. These outcomes are gaining an increased presence in the literature, and interpretation of the data from either small cohort studies or large administrative databases can be extremely confusing for both biostatistician and clinician alike.

An important study, a meta-analysis of 23 studies published online in February, rigorously evaluated pregnancy and delivery outcomes following prenatal exposure to antidepressants (including SSRIs, tricyclics, and monoamine oxidase [MAO] inhibitors) – mostly SSRIs – factoring in the risk of untreated psychiatric illness on these outcomes. There were no significant associations between prenatal exposure to antidepressant medications and the risk of spontaneous abortion, with no significant differences among exposed vs. nonexposed pregnancies (JAMA Psychiatry 2013 Feb. 27:1-8 [doi:10.1001/jamapsychiatry.2013.684]).

There were, however, significant associations between prenatal antidepressant exposure and gestational age, preterm delivery, lower birth weight, and lower Apgar scores. Antidepressant exposure was significantly associated with a shorter gestation, and preterm delivery was more common among women taking antidepressants, whether or not they were compared with all women not exposed to antidepressants or just depressed women who did not take antidepressants during pregnancy.

Similarly, prenatal antidepressant exposure was significantly associated with lower birth weight (a mean difference of 74 g) when compared with birth weights of babies with no prenatal exposure. But when the comparison was limited to depressed mothers with no exposure to antidepressants, the association was no longer significant.

Antidepressant exposure also was significantly associated with lower Apgar scores at 1 and 5 minutes when compared with all the unexposed mothers and to only the mothers who were depressed but did not take antidepressants. (The study was funded by Canadian government grants, and 4 of the 11 authors disclosed having received honoraria, an unrestricted educational grant, and/or research support from companies that included antidepressant manufacturers).

What do these results mean to the clinician trying to translate these scientific findings into clinical practice? For the clinician, the most critical issue to consider is that, even when there were observed differences in outcomes between exposed and nonexposed pregnancies, those differences were small. Gestational age was less than half a week shorter, and the differences in the mean 1- and 5-minute Apgar scores were less than half a point and the scores were considered excellent.

These results are reassuring because the clinical relevance of the cited differences between the two groups is exceedingly small. Perhaps the most critical finding in this published analysis is that even a statistically significant difference in an outcome only has relevance if the difference informs clinical care. This is not an Olympic downhill ski race, where a hundredth of a second can make a critical difference.

Dr. Cohen is the director of the Center for Women’s Mental Health at the Massachusetts General Hospital in Boston, which provides information about pregnancy and mental health at www.womensmentalhealth.org. He has been a consultant to manufacturers of SSRIs.

Over the last decade, attention in the medical literature has gathered logarithmically to focus on potentially efficacious treatments for perinatal depression. Studies of relevant databases, editorials, and various reviews have addressed the reproductive safety concerns of antidepressant treatments, particularly selective serotonin reuptake inhibitors (SSRIs) on one hand, and the impact of untreated maternal psychiatric illness on fetal and maternal well-being on the other.

Depression clusters in women across the childbearing years, and growing numbers of women in this group are being treated with antidepressants. Historically, pregnancy had been considered a time of emotional well-being, but it now is generally accepted that pregnancy does not confer protection against psychiatric disorder. This is particularly the case for women with histories of depression; for women with histories of depression who are on maintenance therapy with antidepressants to sustain emotional well-being, discontinuation of these medications proximate to or during pregnancy is associated with a high risk of depressive relapse. This appears to be the case particularly among women with histories of severe depression.

So what is the most appropriate treatment of depression during pregnancy? Navigating the growing literature on relative risks of antidepressant treatment during pregnancy can be particularly burdensome for clinicians. While clearly the amount of data is vast, the quality of these data is highly variable. Randomized controlled clinical trials of antidepressant use during pregnancy are not performed for obvious ethical reasons, and reports of outcomes of fetal exposure to psychiatric medications including antidepressants frequently derive from analyses of data from small cohort studies or from administrative databases, which are limited by serious methodologic difficulties – small numbers of exposed cases, problems ascertaining reliable information regarding actual medication exposure, comorbid substance use, or the presence of active psychiatric disorder across pregnancy. These factors make reliable assessment of risk that much more difficult, and determination of clinical implications of such findings even more challenging. Variable interpretations of the same literature make it even more difficult for clinicians in the community to know how to proceed with the patient presenting for guidance about appropriate use of antidepressants during pregnancy or alternative evidence-based management strategies for perinatal depression.

A recently published article addressing the risks of SSRIs in infertile women, which discusses, among other issues, the risk of SSRIs during pregnancy across outcomes of miscarriage, birth defects, neonatal side effects (so-called neonatal adaptation syndrome), and persistent pulmonary hypertension of the newborn (PPHN), is an example of how published reports and reviews frequently confuse more than they inform. The authors offer the following conclusions: Antidepressants are not effective for most women with depression; a strong signal for teratogenicity is evident for SSRIs; and outcomes such as preterm birth, PPHN, and poor neonatal adaptation are common after prenatal exposure to SSRIs. (The review was published online in October 2012 in Human Reproduction [doi: 10.1093/humrep/des383], and no external funding or conflicts of interest of the authors are noted.) The review, described as "systematic," appears to be relatively selective with respect to data presented, and as such, many of the conclusions are not uniformly supported by the data in the literature; hence its conclusions should be put in perspective.

As an example, more data support the absence of a strong teratogenic signal with first-trimester exposure to SSRIs than for almost any other medicine taken by pregnant women. This was the main point made in an editorial published in the New England Journal of Medicine in 2007, titled "Teratogenicity of SSRIs – serious concern or much ado about little?" The editorial refers to two studies published in the same issue, and states that the reports "together with other available information, do suggest that any increased risks of these malformations in association with the use of SSRIs are likely to be small in terms of absolute risks" (N. Engl. J. Med. 2007;356:2732-3).

Certainly, over the last decade, efforts have been made to refine the risk-benefit decision regarding antidepressant use during pregnancy by a better understanding of the vast data on the impact of SSRIs on fetal well-being and outcomes such as malformations, as well as the effects of untreated depression on fetal and neonatal well-being. Across the review noted above, the numerous studies citing adverse effects of untreated depression on obstetrical and neonatal well-being are not discussed. Most critical is the omission of a meta-analysis of adverse effects of depression during pregnancy, which identified an increased risk of preterm delivery and low birth weight associated with prenatal depression (Arch. Gen. Psych. 2010;67:1012-24).

Also omitted is what is one the most pivotal studies published to date on the long-term neurobehavioral follow-up of children exposed to antidepressants during pregnancy. This study followed children exposed to fluoxetine (Prozac) or a tricyclic antidepressant for a period of up to 72 months and compared outcomes including IQ, reactivity, temperament, mood, or distractibility to a matched group of nonexposed children; no differences were noted between the groups (N. Engl. J. Med. 1997;336:258-62). Other studies of long-term neurocognitive sequelae of fetal exposure to antidepressants will lay the groundwork for the most critical refinement of guidelines for the use of antidepressants during pregnancy.

The decision to use antidepressants during pregnancy needs to be made with great care and scrutiny, particularly among those who suffer from more mild to moderate depression where nonpharmacologic interventions, such as cognitive behavioral therapy (CBT), are appropriate and may, in some cases, be used as a first-line treatment. However, the greatest concern for those clinicians who manage the care of women who suffer from depression before or during pregnancy centers on extrapolation of the same treatment algorithm used for women with mild depression to those with more refractory disease. Indeed, the clinical scale is weighted toward antidepressant treatment for women with more malignant refractory depression, whose journey to emotional well-being has been long and arduous, and where maintenance antidepressant therapy has been a cornerstone of treatment. Given the small absolute risk associated with SSRI use during pregnancy, our threshold to threaten that well-being should be very high. Relapse or new onset of depression during pregnancy is of great importance because no factor more strongly predicts postpartum depression than depression during pregnancy – and the adverse effects of postpartum depression on long-term development of children and the well-being of the mother and her family are substantial.

The debate over the most appropriate use of SSRIs during pregnancy will invariably continue. Careful reading of the relevant data and appreciating the conclusions made that are justified and, conversely, where the data fail to absolutely inform leaves clinicians in a position to share with patients what we know and what we don’t know. Clinicians then can tailor ultimate decisions based on available information from the scientific literature, patient’s wishes, and individual clinical histories.

Dr. Cohen is the director of the Center for Women’s Mental Health at the Massachusetts General Hospital in Boston, which provides information about pregnancy and mental health here. He has been a consultant to manufacturers of SSRIs.

Over the last decade, attention in the medical literature has gathered logarithmically to focus on potentially efficacious treatments for perinatal depression. Studies of relevant databases, editorials, and various reviews have addressed the reproductive safety concerns of antidepressant treatments, particularly selective serotonin reuptake inhibitors (SSRIs) on one hand, and the impact of untreated maternal psychiatric illness on fetal and maternal well-being on the other.

Depression clusters in women across the childbearing years, and growing numbers of women in this group are being treated with antidepressants. Historically, pregnancy had been considered a time of emotional well-being, but it now is generally accepted that pregnancy does not confer protection against psychiatric disorder. This is particularly the case for women with histories of depression; for women with histories of depression who are on maintenance therapy with antidepressants to sustain emotional well-being, discontinuation of these medications proximate to or during pregnancy is associated with a high risk of depressive relapse. This appears to be the case particularly among women with histories of severe depression.

So what is the most appropriate treatment of depression during pregnancy? Navigating the growing literature on relative risks of antidepressant treatment during pregnancy can be particularly burdensome for clinicians. While clearly the amount of data is vast, the quality of these data is highly variable. Randomized controlled clinical trials of antidepressant use during pregnancy are not performed for obvious ethical reasons, and reports of outcomes of fetal exposure to psychiatric medications including antidepressants frequently derive from analyses of data from small cohort studies or from administrative databases, which are limited by serious methodologic difficulties – small numbers of exposed cases, problems ascertaining reliable information regarding actual medication exposure, comorbid substance use, or the presence of active psychiatric disorder across pregnancy. These factors make reliable assessment of risk that much more difficult, and determination of clinical implications of such findings even more challenging. Variable interpretations of the same literature make it even more difficult for clinicians in the community to know how to proceed with the patient presenting for guidance about appropriate use of antidepressants during pregnancy or alternative evidence-based management strategies for perinatal depression.

A recently published article addressing the risks of SSRIs in infertile women, which discusses, among other issues, the risk of SSRIs during pregnancy across outcomes of miscarriage, birth defects, neonatal side effects (so-called neonatal adaptation syndrome), and persistent pulmonary hypertension of the newborn (PPHN), is an example of how published reports and reviews frequently confuse more than they inform. The authors offer the following conclusions: Antidepressants are not effective for most women with depression; a strong signal for teratogenicity is evident for SSRIs; and outcomes such as preterm birth, PPHN, and poor neonatal adaptation are common after prenatal exposure to SSRIs. (The review was published online in October 2012 in Human Reproduction [doi: 10.1093/humrep/des383], and no external funding or conflicts of interest of the authors are noted.) The review, described as "systematic," appears to be relatively selective with respect to data presented, and as such, many of the conclusions are not uniformly supported by the data in the literature; hence its conclusions should be put in perspective.

As an example, more data support the absence of a strong teratogenic signal with first-trimester exposure to SSRIs than for almost any other medicine taken by pregnant women. This was the main point made in an editorial published in the New England Journal of Medicine in 2007, titled "Teratogenicity of SSRIs – serious concern or much ado about little?" The editorial refers to two studies published in the same issue, and states that the reports "together with other available information, do suggest that any increased risks of these malformations in association with the use of SSRIs are likely to be small in terms of absolute risks" (N. Engl. J. Med. 2007;356:2732-3).

Certainly, over the last decade, efforts have been made to refine the risk-benefit decision regarding antidepressant use during pregnancy by a better understanding of the vast data on the impact of SSRIs on fetal well-being and outcomes such as malformations, as well as the effects of untreated depression on fetal and neonatal well-being. Across the review noted above, the numerous studies citing adverse effects of untreated depression on obstetrical and neonatal well-being are not discussed. Most critical is the omission of a meta-analysis of adverse effects of depression during pregnancy, which identified an increased risk of preterm delivery and low birth weight associated with prenatal depression (Arch. Gen. Psych. 2010;67:1012-24).

Also omitted is what is one the most pivotal studies published to date on the long-term neurobehavioral follow-up of children exposed to antidepressants during pregnancy. This study followed children exposed to fluoxetine (Prozac) or a tricyclic antidepressant for a period of up to 72 months and compared outcomes including IQ, reactivity, temperament, mood, or distractibility to a matched group of nonexposed children; no differences were noted between the groups (N. Engl. J. Med. 1997;336:258-62). Other studies of long-term neurocognitive sequelae of fetal exposure to antidepressants will lay the groundwork for the most critical refinement of guidelines for the use of antidepressants during pregnancy.

The decision to use antidepressants during pregnancy needs to be made with great care and scrutiny, particularly among those who suffer from more mild to moderate depression where nonpharmacologic interventions, such as cognitive behavioral therapy (CBT), are appropriate and may, in some cases, be used as a first-line treatment. However, the greatest concern for those clinicians who manage the care of women who suffer from depression before or during pregnancy centers on extrapolation of the same treatment algorithm used for women with mild depression to those with more refractory disease. Indeed, the clinical scale is weighted toward antidepressant treatment for women with more malignant refractory depression, whose journey to emotional well-being has been long and arduous, and where maintenance antidepressant therapy has been a cornerstone of treatment. Given the small absolute risk associated with SSRI use during pregnancy, our threshold to threaten that well-being should be very high. Relapse or new onset of depression during pregnancy is of great importance because no factor more strongly predicts postpartum depression than depression during pregnancy – and the adverse effects of postpartum depression on long-term development of children and the well-being of the mother and her family are substantial.

The debate over the most appropriate use of SSRIs during pregnancy will invariably continue. Careful reading of the relevant data and appreciating the conclusions made that are justified and, conversely, where the data fail to absolutely inform leaves clinicians in a position to share with patients what we know and what we don’t know. Clinicians then can tailor ultimate decisions based on available information from the scientific literature, patient’s wishes, and individual clinical histories.

Dr. Cohen is the director of the Center for Women’s Mental Health at the Massachusetts General Hospital in Boston, which provides information about pregnancy and mental health here. He has been a consultant to manufacturers of SSRIs.

Over the last decade, attention in the medical literature has gathered logarithmically to focus on potentially efficacious treatments for perinatal depression. Studies of relevant databases, editorials, and various reviews have addressed the reproductive safety concerns of antidepressant treatments, particularly selective serotonin reuptake inhibitors (SSRIs) on one hand, and the impact of untreated maternal psychiatric illness on fetal and maternal well-being on the other.

Depression clusters in women across the childbearing years, and growing numbers of women in this group are being treated with antidepressants. Historically, pregnancy had been considered a time of emotional well-being, but it now is generally accepted that pregnancy does not confer protection against psychiatric disorder. This is particularly the case for women with histories of depression; for women with histories of depression who are on maintenance therapy with antidepressants to sustain emotional well-being, discontinuation of these medications proximate to or during pregnancy is associated with a high risk of depressive relapse. This appears to be the case particularly among women with histories of severe depression.

So what is the most appropriate treatment of depression during pregnancy? Navigating the growing literature on relative risks of antidepressant treatment during pregnancy can be particularly burdensome for clinicians. While clearly the amount of data is vast, the quality of these data is highly variable. Randomized controlled clinical trials of antidepressant use during pregnancy are not performed for obvious ethical reasons, and reports of outcomes of fetal exposure to psychiatric medications including antidepressants frequently derive from analyses of data from small cohort studies or from administrative databases, which are limited by serious methodologic difficulties – small numbers of exposed cases, problems ascertaining reliable information regarding actual medication exposure, comorbid substance use, or the presence of active psychiatric disorder across pregnancy. These factors make reliable assessment of risk that much more difficult, and determination of clinical implications of such findings even more challenging. Variable interpretations of the same literature make it even more difficult for clinicians in the community to know how to proceed with the patient presenting for guidance about appropriate use of antidepressants during pregnancy or alternative evidence-based management strategies for perinatal depression.

A recently published article addressing the risks of SSRIs in infertile women, which discusses, among other issues, the risk of SSRIs during pregnancy across outcomes of miscarriage, birth defects, neonatal side effects (so-called neonatal adaptation syndrome), and persistent pulmonary hypertension of the newborn (PPHN), is an example of how published reports and reviews frequently confuse more than they inform. The authors offer the following conclusions: Antidepressants are not effective for most women with depression; a strong signal for teratogenicity is evident for SSRIs; and outcomes such as preterm birth, PPHN, and poor neonatal adaptation are common after prenatal exposure to SSRIs. (The review was published online in October 2012 in Human Reproduction [doi: 10.1093/humrep/des383], and no external funding or conflicts of interest of the authors are noted.) The review, described as "systematic," appears to be relatively selective with respect to data presented, and as such, many of the conclusions are not uniformly supported by the data in the literature; hence its conclusions should be put in perspective.

As an example, more data support the absence of a strong teratogenic signal with first-trimester exposure to SSRIs than for almost any other medicine taken by pregnant women. This was the main point made in an editorial published in the New England Journal of Medicine in 2007, titled "Teratogenicity of SSRIs – serious concern or much ado about little?" The editorial refers to two studies published in the same issue, and states that the reports "together with other available information, do suggest that any increased risks of these malformations in association with the use of SSRIs are likely to be small in terms of absolute risks" (N. Engl. J. Med. 2007;356:2732-3).

Certainly, over the last decade, efforts have been made to refine the risk-benefit decision regarding antidepressant use during pregnancy by a better understanding of the vast data on the impact of SSRIs on fetal well-being and outcomes such as malformations, as well as the effects of untreated depression on fetal and neonatal well-being. Across the review noted above, the numerous studies citing adverse effects of untreated depression on obstetrical and neonatal well-being are not discussed. Most critical is the omission of a meta-analysis of adverse effects of depression during pregnancy, which identified an increased risk of preterm delivery and low birth weight associated with prenatal depression (Arch. Gen. Psych. 2010;67:1012-24).

Also omitted is what is one the most pivotal studies published to date on the long-term neurobehavioral follow-up of children exposed to antidepressants during pregnancy. This study followed children exposed to fluoxetine (Prozac) or a tricyclic antidepressant for a period of up to 72 months and compared outcomes including IQ, reactivity, temperament, mood, or distractibility to a matched group of nonexposed children; no differences were noted between the groups (N. Engl. J. Med. 1997;336:258-62). Other studies of long-term neurocognitive sequelae of fetal exposure to antidepressants will lay the groundwork for the most critical refinement of guidelines for the use of antidepressants during pregnancy.

The decision to use antidepressants during pregnancy needs to be made with great care and scrutiny, particularly among those who suffer from more mild to moderate depression where nonpharmacologic interventions, such as cognitive behavioral therapy (CBT), are appropriate and may, in some cases, be used as a first-line treatment. However, the greatest concern for those clinicians who manage the care of women who suffer from depression before or during pregnancy centers on extrapolation of the same treatment algorithm used for women with mild depression to those with more refractory disease. Indeed, the clinical scale is weighted toward antidepressant treatment for women with more malignant refractory depression, whose journey to emotional well-being has been long and arduous, and where maintenance antidepressant therapy has been a cornerstone of treatment. Given the small absolute risk associated with SSRI use during pregnancy, our threshold to threaten that well-being should be very high. Relapse or new onset of depression during pregnancy is of great importance because no factor more strongly predicts postpartum depression than depression during pregnancy – and the adverse effects of postpartum depression on long-term development of children and the well-being of the mother and her family are substantial.

The debate over the most appropriate use of SSRIs during pregnancy will invariably continue. Careful reading of the relevant data and appreciating the conclusions made that are justified and, conversely, where the data fail to absolutely inform leaves clinicians in a position to share with patients what we know and what we don’t know. Clinicians then can tailor ultimate decisions based on available information from the scientific literature, patient’s wishes, and individual clinical histories.

Dr. Cohen is the director of the Center for Women’s Mental Health at the Massachusetts General Hospital in Boston, which provides information about pregnancy and mental health here. He has been a consultant to manufacturers of SSRIs.