We have received many emails and calls from colleagues and patients regarding the recent article on the safety of SSRI use during pregnancy published in the New York Times. In this article, health writer Roni Caryn Rabin, detailed the risks associated with the use of antidepressants during pregnancy.
Many have been incensed by the implication that the decision to take antidepressants during pregnancy is not given much thought and is (to paraphrase Ms. Rabin) similar to skipping a double tall latte or politely refusing unpasteurized cheese. As clinicians who have worked with this population over the last several decades, we have seen thousands of women who have struggled to make the best choices for themselves and their babies. Making this sort of decision involves weighing the risks of untreated illness in the mother against the potential risks of medication exposure to the fetus. This decision is by no means simple.
Ms. Rabin seems to trivialize depression, making it seem more like acne or athlete’s foot. Yes, for some women, depression may be a mild and circumscribed illness, amenable to treatment with a variety of interventions and may not require long-term treatment with an antidepressant. However, for many women, depression is a severe, recurrent, and occasionally fatal illness that impacts all areas of life and health. Often these women have tried many different types of interventions, including medication and psychotherapy. Often they have tried unsuccessfully on multiple occasions to stop their medications.
For women with histories of depression, pregnancy is not a time of emotional well-being. What the research shows us is that about 15% of all women suffer from depression during pregnancy. Many of these women have had depression prior to pregnancy, and it appears that women who discontinue antidepressants proximate to conception are particularly vulnerable. One study demonstrated that women who discontinued antidepressant were 5 times as likely to relapse as compared to women who maintained their antidepressant treatment across pregnancy. That meant that about two-thirds of the women were depressed during pregnancy.
Given that risk of depression is so high in women in the setting of antidepressant medication, it would be ill-advised and irresponsible to reflexively recommend that all women who are either pregnant or planning to conceive should forgo treatment with antidepressants. Instead we must counsel women regarding the potential risks associated with treatment and help them to choose the most effective options that carry the lowest risk with regard to her pregnancy.
Over the last two decades, numerous studies have addressed the reproductive safety of antidepressants; ironically, it seems that having more data has actually made the decision-making process regarding the use of antidepressants during pregnancy even more complicated. Research regarding the reproductive safety of the SSRIs has yielded conflicting and often inconsistent results. While some studies suggest that SSRIs increase the risk of certain types of malformations – for example, cardiac septal defects – most studies do not demonstrate a link between SSRIs and congenital malformations. While some studies report serious adverse effects related to exposure to SSRIs late in pregnancy, such as pulmonary hypertension of the newborn (PPHN), most studies describe a more benign and self-limited pattern of symptoms, labeled as “poor neonatal adaptation”.
Often the information yielded by these studies is so nuanced and complex that it is extremely difficult for patients and their doctors to fully understand the clinical implications, leaving them confused about their treatment options. The situation is worsened by the distribution of articles, such as the one by Ms. Rabin, that either sensationalize bad outcomes or present only some of the available scientific data.
In an effort to answer some of the questions and concerns our patients and colleagues have raised over the last few days, we have responded to some of the claims made in this article. It is our hope that by focusing on the breadth of data available we can help women to make the best decisions regarding their treatment.
Use of Antidepressants during Pregnancy: Ms. Rabin states, “Up to 14 percent of pregnant women take antidepressants, and the Food and Drug Administration has issued strong warnings that one of them, paroxetine (Paxil), may cause birth defects.”
- Patterns of medication use during pregnancy vary widely. For example, studies from the Nordic countries have reported that less than 2% of women use antidepressants during pregnancy whereas one study in a Medicaid population in Tennessee reported antidepressant use in 13.4% of all pregnancies. The most recent study on this topic which gathered data from a private insurance database including 70 million Americans indicates that the use of antidepressants from 2007 to 2011 has remained fairly steady, ranging from 6.4% to 6.7%. Rates of antidepressant use in this study dropped below 4% after the first trimester, suggesting that many women stopped their medication after discovering they were pregnant.
- While these studies suggest that a sizeable percentage of women take antidepressants during pregnancy, multiple studies have observed that the majority of women who suffer from depression during pregnancy receive no treatment.
Effects of Untreated Antenatal Depression: But the prevailing attitude among doctors has been that depression during pregnancy is more dangerous to mother and child than any drug could be. Now a growing number of critics are challenging that assumption.
- There is an accumulating body of literature which indicates that untreated depression in the mother may have negative consequences for the pregnancy and the developing fetus. (Reviewed by Field 2006 (full text available), Field 2011.)
- In addition, women who are depressed are more likely to smoke, drink alcohol, and use illicit drugs. All of these factors are associated with worse pregnancy outcomes and can affect fetal neurodevelopment.
- Some but not all studies have shown increased risk of preterm birth and low birth weight among depressed mothers.
- Several studies have shown an increased risk of pre-eclampsia among women with antenatal depression.
- More recent studies actually show that depression during pregnancy (in the absence of antidepressant treatment) can actually change the architecture of the fetal brain. Researchers observed alterations in the microstructure of the right amygdala, a brain region associated with stress reactivity and vulnerability to mood and anxiety disorders.
- There is also evidence that what happens in utero, while the fetus is developing, may predispose a child to certain illnesses later on in life. It has been hypothesized that alterations of the maternal hypothalamic-pituitary-adrenal (HPA) axis may influence the development of the fetal HPA axis. When dysregulation of the maternal HPA axis occurs — as a result of exposure to stressful life events or the experience of anxiety or depressive symptoms during pregnancy – this may lead to long-standing alterations in the fetal HPA axis, making the child more susceptible to depression or anxiety as an adult.
Risk of Congenital Malformations: Babies exposed to S.S.R.I.s prenatally are more likely to be born with congenital heart defects, other rare birth defects, clubfoot and a serious lung condition called persistent pulmonary hypertension, several studies have found.
- Over the last few years, several studies have suggested an increased risk of certain types of cardiovascular malformations among children exposed to selective serotonin reuptake inhibitors (SSRIs) during pregnancy. The first reports suggested a link between cardiac septal defects and exposure to paroxetine; other, but not all, studies have also shown an elevated risk of cardiac defects in children with prenatal exposure to other SSRIs.
- A recent study published in the New England Journal of Medicine included of total of 64,389 women who used antidepressants during the first trimester of pregnancy and indicated no substantial increase in the risk of cardiac malformations attributable to antidepressant use during the first trimester of pregnancy.
Risk of Adverse Pregnancy Outcomes: Another study concluded that the babies of treated mothers also had lower Apgar scores, a measure of a newborn’s well-being. Yet another found these infants were more likely to be underweight.
- While some studies have shown an association between in utero exposure to antidepressants and various pregnancy outcomes, including preterm delivery, low birth weight, and lower Apgar scores, these outcomes have also been linked to untreated maternal depression. Thus, it has been difficult to determine if there is a causal relationship between antidepressant exposure and negative pregnancy outcomes or whether maternal depression is itself responsible for these negative outcomes.
- A recent meta-analysis demonstrated statistically significant differences between exposed and non-exposed children with regard to gestational age, birth weight, and Apgar scores. However, it is reassuring that the observed effects were small: about 3 days shorter gestational age, 75 g lower birth weight, and less than half a point on the 1- and 5-minute Apgar scores. Furthermore, these values typically fall within the normal range. The clinical significance of these findings is unclear.
Risk of Neonatal Symptoms: Like babies born to drug addicts, newborns may display S.S.R.I. withdrawal symptoms. One study found that S.S.R.I.s disrupt fetal non-R.E.M. sleep, the deep sleep that is important for healthy growth.
- Several recent studies have suggested that exposure to SSRIs near the time of delivery may be associated with poor perinatal outcomes. Attention has focused on a range of transient neonatal distress syndromes associated with exposure to (or withdrawal from) antidepressants in utero. These syndromes appear to affect about 25% of babies exposed to antidepressants late in pregnancy. The most commonly reported symptoms in newborns include tremor, restlessness, increased muscle tone, and increased crying. Reassuringly, these syndromes appear to be relatively benign and short-lived, resolving within 1 to 4 days after birth without any specific medical intervention.
- Another concern has been that maternal SSRI use may be associated with a higher than expected number of cases of persistent pulmonary hypertension of the newborn (PPHN). Use of an SSRI antidepressant after the 20th week of gestation was associated with a six-fold greater risk of PPHN. Since the initial report on this topic, three studies have found no association between antidepressant use during pregnancy and PPHN, and one study showed a much lower risk than the 1% originally reported. These findings taken together bring into question whether there is an association at all and suggest that, if there is a risk, it is much lower than that reported in the original 2006 report.
Risk of Developmental Delays: A large Norwegian study, reported in April, that looked at a registry of more than 51,000 babies found that prolonged use of S.S.R.I.s during pregnancy was associated with lower language competence by age 3, an effect the researchers said was independent of the mothers’ depression.
- In this study from Norway, prolonged use of an SSRI during pregnancy was associated with lower language competence in children at age three. Having symptoms of depression throughout pregnancy was also associated with lower language competence. Although the authors stated that the effect of SSRIs was independent of maternal depression, it was more marked in women with prolonged (as opposed to short-term) SSRI exposure. It is possible that the women with prolonged exposure had more severe depressive symptoms, and thus it may be the severity of the depression that accounts for the difference.
- Another study examined 31 mother-child pairs exposed prenatally to SSRIs and 52 mother-child pairs who were non-exposed at ten months of age. Infants exposed prenatally to SSRIs scored significantly lower than non-exposed infants on gross motor (P=0.03), social-emotional (P=0.04) and adaptive behavior (P=0.05) subscales of the Bayley Scales of Infant Development (BSID-III). No significant differences in any of the BSID-III subscales were observed between infants exposed and infants not exposed to pre and postnatal maternal depressed mood (P>0.05), suggesting that these findings could not be attributed to maternal depression.
- Different results were observed in a landmark study from Nulman and colleagues (1997) which followed a cohort of preschool children who had been exposed to either tricyclic antidepressants (n=80) or fluoxetine (n=55) during pregnancy (most commonly during the first trimester) and compared these subjects to a cohort of non-exposed controls (n=84). Results indicated no significant differences in IQ, temperament, behavior, reactivity, mood, distractibility, or activity level between exposed and non-exposed children. A more recent report from the same group which followed a cohort of children exposed to fluoxetine (n= 40) or tricyclic antidepressants (n=47) for the entire duration of the pregnancy yielded similar results (Nulman et al, 2002).
Risk of Autism: Researchers at Johns Hopkins University reported in April that boys with autism were nearly three times more likely to have been exposed to S.S.R.I.s before birth than typically developing boys.
- Two recent epidemiologic studies have demonstrated an association between prenatal exposure to selective serotonin reuptake inhibitor antidepressants (SSRIs) with autism spectrum disorders (ASD; Croen et al 2011, Rai et al, 2013). One important limitation of these two studies is that parental psychiatric disorder in itself is associated with an increased risk of ASD in the offspring, and these studies could not distinguish between the effects of drug exposure and the consequences of the underlying maternal psychiatric illness.
- Two other studies, however, suggest that the association between prenatal antidepressant exposure and ASD in the offspring observed in previous studies may, all or in part, be the result of confounding factors, specifically the underlying indication for antidepressant use or other unmeasured factors related to maternal illness during pregnancy. Researchers also observed that the risk of having a child with autism spectrum disorder was also elevated among women who received SSRIs before – but not during — pregnancy (adjusted odds ratio of 1.46; 95% CI, 1.17 to 1.81), further supporting the notion that other environmental or genetic factors – as opposed to antidepressant exposure – may modulate risk for autism.
Undoubtedly all women, if given the choice, would prefer to avoid taking any medications during pregnancy. Many women, unfortunately, suffer from depression during pregnancy and deferring treatment with antidepressants may not be the best option for them. As a field, we cannot conclude that fetal exposure to antidepressants – or any other medications for that matter — is totally free of risk. No clinical decision, particularly one of this complexity, is risk free or perfect. However, we do have considerable data to indicate that many antidepressants, especially the SSRIs, may be thoughtfully used during pregnancy.
Oversimplification of a continually growing and complicated literature such as use of psychiatric medication during pregnancy may be pursued by some. Whether presented under the aegis of journalistic freedom or a word count limit in a discussion section of a scientific paper, cursory presentation of the complexity of decisions made around antidepressant use during pregnancy has the real potential to place patients in harm’s way. At best, such presentation is just incomplete; at its worst, it is irresponsible. As those who try to help women navigate these complex decisions, our goal should be to present a balanced picture of the information we do have, so that women may make thoughtful and well-informed decisions based on their own clinical situation and their personal wishes.
Ruta Nonacs, MD PhD
Lee S. Cohen, MD
Marlene Freeman, MD