Selective Serotonin Reuptake Inhibitors (SSRIs) in Pregnancy: An Updated Review on Risks to Mother, Fetus, and Child

Abstract

Purpose of Review

To provide an updated summary and appraisal of work from 2019 to 2022 examining risks of selective serotonin reuptake inhibitor (SSRI) use in pregnancy.

Recent Findings

Perinatal SSRI exposure does not increase risk of major malformations or gestational diabetes after accounting for underlying maternal illness. SSRIs are associated with small increase in risk of pre-eclampsia, postpartum hemorrhage, preterm delivery, persistent pulmonary hypertension of the newborn, and neonatal intensive care unit admissions, though absolute risk of these outcomes is low. While data suggests no increased risk of neurodevelopmental disorders in offspring, mixed evidence indicates increased risk of adverse cognitive outcomes and affective disorders.

Summary

Recent evidence suggest low absolute risk of clinically relevant negative outcomes with perinatal SSRI exposure when compared to untreated perinatal depression. However, study design and ability to control for confounding remains an ongoing research challenge, highlighting need for ongoing rigorous study design and analysis.

Introduction

Perinatal mood and anxiety disorders (PMADs) affect an estimated 10–20% of women during their reproductive years and lead to adverse effects on both mother and infant [1]. PMADs can increase risk of negative pregnancy outcomes (e.g., preterm birth, low birth weight), maternal substance use, maternal suicide, impaired mother-infant attachment, and behavioral/psychiatric disorders in children [2]. As a result, treatment to prevent these negative effects is a key public health goal [2]. While mild mood and anxiety symptoms may be addressed with evidence-based therapy or lifestyle interventions, moderate to severe symptoms often require psychopharmacologic treatment.

Selective serotonin reuptake inhibitors (SSRIs) are considered first-line psychopharmacologic treatment for numerous mood and anxiety disorders and are the most commonly used antidepressants in pregnancy [3]. Prevalence rates of SSRI use in pregnancy have increased fourfold between 1996 and 2005 with recent estimated international prevalence of 3% and US prevalence of 6% respectively [3–5]. SSRIs as a class have been more extensively studied than other psychotropic medications in pregnancy [6]. However, research on SSRIs in pregnancy has been complicated by research methodology challenges, leading to inconsistent results and confusion for clinicians.

Randomized controlled trials of SSRI use in pregnancy are not performed due to ethical issues involved in studying pregnant patients. As a result, all studies examining SSRI use in pregnancy are observational studies, which have inherent limitations [7]. Specifically, it can be challenging to determine whether observed outcomes are due to medication exposure, the underlying mental health disorder, or other confounding variables. Even when women on antidepressants are compared to women with depression not on medication (or those on differing doses), there is still question of confounding related to illness severity. One large cohort study found that women who continue antidepressants in pregnancy are more likely to have an inpatient hospitalization for depression compared to women who discontinued medication [8]. This study emphasizes the possibility that women who continue antidepressants in pregnancy (or those who take a higher dose of medication) may have more severe illness compared to those that discontinue medication. As such, both confounding by indication and illness severity can complicate interpretation of observational studies. Due to these limitations, ongoing characterization of the reproductive safety profile of SSRIs remains an active area of research.

This review summarizes the current state of knowledge on the safety of SSRIs in pregnancy by reviewing and critically appraising studies on perinatal SSRI use published from 2019 to 2022. The term “antidepressant exposure” is used for studies evaluating any antidepressant including SSRI and non-SSRI antidepressants. The term “SSRI exposure” refers to studies evaluating SSRIs as a group. If an individual SSRI is associated with significant findings in a study, this is highlighted. Subsections focus on key areas of clinical relevance: congenital malformations, maternal/obstetric outcomes, fetal and neonatal outcomes, and long-term neurodevelopmental outcomes.

Congenital Malformations

Prior to 2019, some studies raised concern for a potential association between specific SSRIs, notably paroxetine, and cardiac malformations [9–11]. Conversely, other studies including large administrative database studies did not observe such associations, even with paroxetine [12, 13]. Generally speaking, the studies that have not identified a significant association between SSRIs and cardiac defects better controlled for underlying confounding by indication through use of more applicable control groups (e.g., women with depression not on medication vs non-depressed women) and high-quality methods to adjust for residual confounding (e.g., propensity score matching). Nevertheless, researchers continue to examine the question of whether or not SSRIs increase risk of major malformations in pregnancy.

In 2020, Anderson et al. conducted a multisite case–control study, the National Birth Defects Prevention Study, examining associations between individual antidepressants and specific birth defects [14••]. Researchers identified 30,630 case mothers of infants with birth defects and 11,478 randomly sampled control mothers of infants without any major birth defects. To determine exposure, mothers were contacted up to 2 years after delivery and asked about antidepressant use both before and during pregnancy. First trimester antidepressant exposure occurred in 1562 case mothers (5.1%) and 467 control mothers (4.1%). While unadjusted analyses showed elevated odds ratios for several individual SSRIs and congenital heart defects, these associations attenuated after accounting for underlying conditions. Interestingly, the researchers found a significant association between citalopram and diaphragmatic hernia (aOR 5.11, 95% CI 1.29–20.04), which persisted after adjustment for confounders. This particular finding has not been observed in any other studies to date.

The design of this study has multiple limitations, as described in an accompanying article by Wisner et al. [15]. First, recall bias is a concern since mothers were asked about exposure up to 2 years after delivery. Women whose infants have a congenital malformation may be more likely to recall medication exposure vs mothers of healthy infants. Variable recall can lead to exposure misclassification and overestimation of risk. Second, to control for confounding by indication, the comparison group included women treated with antidepressants 2 to 3 months before and/or after embryogenesis (months 4–9). However, there are likely fundamental differences between women who continued a medication throughout pregnancy and those who successfully stopped the medication, notably the severity of the underlying mental illness. Lastly, there may be residual confounding variables (e.g., adherence to prenatal care, socioeconomic status) that are not fully accounted for in the adjusted analysis. Nonetheless, the results generally mirror what has been found in large, well-designed studies showing no association between major malformations and SSRI use in pregnancy. The association between citalopram and diaphragmatic hernia is of unclear clinical significance, since the number of cases was small (7) and the large confidence interval (1.29–20.04) suggests statistical uncertainty of the finding.

Both a 2021 meta-analysis of twenty studies [16] and a 2020 umbrella review of 22 meta-analyses [17] found significant associations between first trimester SSRI exposure and congenital heart defects. However, most of the studies included in the meta-analyses were vulnerable to confounding by indication, using a comparison group of women without depression who did not take medications in pregnancy rather than including a subcohort of women with depression not on medications.

Highlighting the potential implications of confounding by indication, a 2021 Australian retrospective cohort study found that mood disorders alone may increase the risk for congenital heart defects [18]. Exposure factors were compared in 30,842 general obstetric patients and 470 obstetric patients with a fetus with congenital heart defects. Notably, they separated out the group of women with depression or anxiety disorders not on medications in the first trimester in their analysis. Multivariate analysis showed increased relative risk of congenital heart defects for women taking SSRIs in the first trimester (RR 4.41, 95% CI 2.58–6.65), women with a history of anxiety or mood disorder with no SSRI use in the first trimester (RR 2.2, 95% CI 1.77–2.74), and women with maternal age > 40 (RR 02.30, 95% CI 1.57–3.38). The finding suggests that mood disorders themselves (or factors associated with mood disorders) may negatively impact fetal heart development. Importantly, this study provides critique of prior associations between SSRIs and congenital heart defect that did not have a mood disorder comparison group.

In sum, recent studies do not markedly alter our understanding of the body of literature to date. While some studies have observed an association between SSRIs and cardiac malformations, these findings generally attenuate when the underlying mental illness severity is adequately accounted for.

Maternal Outcomes

Fewer studies have examined maternal outcomes related to SSRI use in pregnancy, with research predominantly focused on risks to the fetus and neonate [19]. Of the available literature prior to 2019, some studies observed increased risk of gestational hypertension [20], pre-eclampsia [20], placental abnormalities [21], and postpartum hemorrhage with SSRI use [21–23]. However, other studies did not find such associations [24, 25]. Additionally, underlying depression and anxiety alone appear to increase the risk of these adverse maternal outcomes [26, 27].

Postpartum Hemorrhage (PPH)

After vascular injury, platelets release serotonin, which promotes platelet aggregation and vasoconstriction, leading to hemostasis. SSRIs may interfere with normal platelet function and hemostasis by inhibiting serotonin reuptake in platelets. Several studies of SSRIs have observed an increased risk of bleeding in non-perinatal settings (e.g., during surgery, in patients at risk for GI bleed) [28, 29]. In addition to the impact on platelet-mediated hemostasis, serotonin may also negatively impact myometrial contraction, which could increase risk of PPH [22].

Using data from the Swedish Pregnancy Register, Skalkidou et al. [30] conducted a retrospective cohort study comparing women who received an SSRI during pregnancy, those with past or current major mental illness who did not take an SSRI during pregnancy, and healthy controls. After adjustment for confounders including maternal age, body mass index, and smoking status, SSRI-exposed women were at small but significantly increased risk of PPH (OR 1.34, 95%CI 1.24–1.44). Women with psychiatric illness but no medication exposure also were at increased risk of PPH (OR 1.09, 95% CI 1.04–1.14), though to a lesser degree compared to SSRI-exposed women.

Palmsten et al. [31••] attempted to better control for underlying psychiatric illness using a group of women with history of depression or anxiety disorder with low antidepressant exposure with dosage reduction or discontinuation in the first trimester as the control group. Using a large healthcare claims database to identify pregnancies with antidepressant exposure, the authors separated them into groups based on antidepressant dose. Compared to the control group, women who took SSRIs throughout the pregnancy had a small, dose-dependent increase in risk for PPH (low dose RR 1.32, 95% CI 1.05–1.66; moderate dose RR 1.35, 95% CI 1.03–1.78; and high dose RR 2.51, 95% CI 1.69–3.71).

Ultimately, these studies suggest a possible small increase in the risk of PPH associated with SSRI use. However, the clinical significance of these findings remains unclear, and it is not currently recommended to discontinue or taper off medications in the third trimester to reduce risk of PPH [32, 33]. Notably, non-serotonergic antidepressants have also been associated with increased risk of PPH, despite less biological plausibility, increasing the possibility that psychiatric illness or other associated behaviors are contributing to the risk [34]. When weighed against the risks of untreated perinatal depression or anxiety, it is recommended that women continue SSRIs at lowest, effective dose in pregnancy.

Pre-Eclampsia/Gestational HTN

Serotonin is thought to play a role in the pathogenesis of pre-eclampsia via its vascular and hemostatic effects [35]. Because SSRIs can modulate serotonin levels in the body and inhibit synthesis of the vasodilator nitric oxide, it is thought that they may increase risk of pre-eclampsia [36, 37]. Simultaneously, mood and anxiety disorders alone have been shown to increase risk of pre-eclampsia, possibly through their vascular effects [26, 27].

The 2020 Palmsten health claims database study, which looked at risk of PPH with SSRI use, also examined risk of pre-eclampsia with SSRI use [31••]. Similar to the PPH results, researchers identified a small, dose-dependent increase in risk for pre-eclampsia with SSRI exposure (low dose RR 1.17, 95% CI 1.01–1.34; moderate dose RR 1.31, 95% CI 1.12–1.54; and high dose 1.41, 95% I 1.05–1.90). This study indicates that women with SSRI exposure are at small increased risk for pre-eclampsia.

Gestational Diabetes

Antidepressants have been correlated with increased risk of type II diabetes mellitus in the non-perinatal population [38]. Because pregnancy can increase risk of insulin resistance and lead to gestational diabetes mellitus (GDM), it is useful to understand how antidepressants may impact this risk. Two earlier studies examining this outcomes identified a moderate risk of GDM with antidepressant exposure, though notably the control group were women with no history of psychiatric illness [21, 39].

Two studies published in 2019 did not identify an increased risk of GDM with SSRI exposure, using a comparator group of women with depression [40, 41]. A 2022 study by Lupatelli et al. found that antidepressants with low H1 receptor affinity (which included all SSRIs) were not significantly associated with GDM risk (RR 0.69, 95% CI 0.31–1.51) [42•]. However, an increased risk was found for agents with high affinity for the H1 receptor (i.e., mirtazapine). These recent studies indicate that SSRIs do not increase risk of GDM in pregnancy.

Fetal and Neonatal Outcomes

Prior to 2019, studies examining SSRI use in pregnancy and subsequent fetal and neonatal outcomes showed mixed results. Some studies observed significant associations with preterm birth [43–45], low birth weight [45], neonatal adaptation syndrome [46], and persistent pulmonary hypertension of the newborn (PPHN) [47]. Conversely, other studies saw either no associations or lower risk of adverse outcomes than initially described [48, 49].

Studies Assessing Multiple Outcomes

In 2019, Fitton et al. conducted a systematic review of 16 studies assessing fetal and neonatal outcomes after perinatal antidepressant exposure compared to a comparison group of women with untreated perinatal depression [50]. SSRI exposure was associated with an increased risk of preterm birth, decreased birth weight, lower Apgar scores, and increased hospital admissions after birth compared to women with untreated depression [50].

A 2020 umbrella review of meta-analyses by Biffi et al. found small but significant associations with SSRIs and risk of preterm birth (RR 1.43, 95% CI 1.22–1.37) and respiratory distress (RR 1.33; 95% CI 1.14–1.55) [17]. However, the authors noted that none of their analyses was supported by convincing, high-quality evidence that adequately accounted for residual confounding, had well-defined a priori outcomes, and guarded against exposure misclassification. They concluded that larger, prospective studies and comprehensive standardized reporting of analyses are needed to accurately characterize risk of perinatal SSRI exposure.

Using data from a Swedish national registry, Wolgast et al. compared women with MDD on an antidepressant before pregnancy, women with MDD on an antidepressant before and during pregnancy, and healthy controls without MDD or antidepressant exposure [51]. They found that the “before pregnancy” and “before and during pregnancy” groups were at elevated risk of several adverse fetal/neonatal outcomes compared to the control group. Specifically, both groups showed increased odds of c-section (aOR 1.19, 95% CI 1.12–1.27 for the “before pregnancy” group; aOR 1.38, 95% CI 1.28–1.48 for the “before and during pregnancy” group) and neonatal intensive care unit (NICU) admission (aOR 1.51, 95% CI 1.17–1.95; aOR 1.55, 95% 1.14–2.11 respectively). Compared to the “before pregnancy” group, women who continued antidepressants during pregnancy also had higher odds of hyperemesis in pregnancy (aOR 1.93, 95% CI 1.60–2.32), c-section delivery (aOR 1.17, 95% CI 1.06–1.29), and preterm delivery (aOR 1.53, 95% CI 1.28–1.81). The results of this study suggest that both patients with MDD and patients with MDD on antidepressants in pregnancy are at increased risk of multiple adverse fetal and neonatal outcomes, though patients who continued antidepressants had a slightly higher risk of adverse obstetric and neonatal outcomes compared to those who discontinued. The authors conclude that the clinical relevance of this differential risk increase among women who continued antidepressants is small.

In 2021, Vlenterie et al. performed an individual participant data meta-analysis examining the various fetal and neonatal outcomes associated with antidepressant use in the perinatal period [52]. Individual participant meta-analyses can facilitate standardization of analyses across studies, leading to more reliable results than aggregate data meta-analyses [52]. When the analyses were restricted to women with a diagnosis of depression, there were no associations between any neonatal or fetal outcome (including preterm birth and low APGAR scores). Importantly, women with depression were also observed to have increased risk of preterm birth (OR 2.2, 95% CI 1.7–3.0), highlighting the risks of untreated depression in pregnancy and suggesting low absolute risks of SSRI use in pregnancy.

Studies Assessing Persistent Pulmonary Hypertension of the Newborn

Persistent pulmonary hypertension of the newborn is a potential neonatal outcome with serious morbidity and mortality. Though the 2006 study by Chambers et al. suggested a 1% absolute risk of PPHN in SSRI-exposed infants [47], subsequent studies have shown much lower risk of PPHN, ranging from 0.2 to 0.3% absolute risk [53].

In 2019, Marasawa et al. attempted to clarify the relationship between PPHN and perinatal exposure to SSRIs and SNRIs by conducting a network meta-analysis of 11 studies [54•]. Of 156,978 women exposed to SSRIs or SNRIs in pregnancy, 452 infants developed PPHN, which equates to an incidence rate of 2.9 cases per 1000 live birth. The risk for PPHN was significantly increased in infants exposed to SSRIs/SNRIs in pregnancy (OR 1.82, 95% CI 1.31–2.54), though similar to prior studies, the absolute risk is still quite low. Sertraline had the lowest risk of PPHN compared to other antidepressant, supporting it as a preferred antidepressant in pregnancy for treatment-naïve patients.

Ng et al. came to similar conclusions regarding risk of PPHN with SSRI exposure in pregnancy [55]. Specifically, they observed a pooled OR of 1.516 (95% CI 1.035–1.997) with number needed to harm of 1615 and absolute risk of 0.18%. They concluded that the clinical relevance of this finding is outweighed by the significant risks associated with untreated perinatal depression. These recent studies support the findings of prior studies showing low absolute risk of this outcome with SSRI exposure.

Long-Term Neurodevelopmental Outcomes

Data on long-term neurodevelopmental outcomes related to perinatal SSRI use remains more limited to date. This is in part due to the logistical challenges of conducting long-term developmental studies and adequately controlling for environmental confounders and the impact of maternal mental illness. Animal studies indicate that perinatal antidepressant exposure can change offspring behavior and brain structure [56, 57]. Studies prior to 2019 show mixed evidence around risk of adverse cognitive outcomes and developmental delay in SSRI-exposed offspring [58–60]. Concerns around long-term risks of medication exposure must also be weighed against the clear negative neurodevelopmental impact of exposure to maternal psychiatric illness [61].

Dragioti et al. examined 45 meta-analyses of observational studies and ranked evidence of association according to established criteria: convincing, highly suggestive, suggestive, or not significant [62••]. They found “convincing” evidence of the association between SSRI use in pregnancy and autism spectrum disorder (ASD) [62••]. However, after accounting for confounding by indication, this finding did not remain at the “convincing” evidence level. The authors concluded that their results did not reflect a causal relationship between perinatal SSRI exposure and ASD, but were rather due to confounding by indication and/or other methodologic limitations of observational studies.

A 2021 multisite case–control study by Ames et al. attempted to further clarify the associations between maternal psychiatric illness, perinatal SSRI exposure, and risk of neurodevelopmental disorders in offspring [63•]. The authors restricted their analyses to mothers with psychiatric conditions in pregnancy. They found that odds of ASD was significantly increased in both mothers with psychiatric illness not on SSRIs (aOR 1.81, 95% CI 1.44–2.27) and mothers who took SSRIs in pregnancy (aOR 2.05, 95% CI 1.5–2.8) compared to mothers without a psychiatric condition. In the restricted analysis of women with psychiatric conditions, mothers who took SSRIs did not have elevated odds of ASD in offspring (aOR 1.145, 95% CI 0.8–1.62) compared to those who did not. The authors concluded that maternal psychiatric illness and not medication exposure significantly increased risk of neurodevelopmental disorders in offspring.

Rommel et al. examined 34 observational studies assessing physical, neurodevelopmental, and psychiatric outcomes of children age 4 years and older following in utero antidepressant exposure [64•]. Among 18 studies focused on neurodevelopmental outcomes (e.g., cognition, behavior, IQ, motor development, speech, language), no consistent associations were identified after adjustment for confounding. Among 11 studies focused on psychiatric outcomes (e.g., affective disorders, autism spectrum disorders, and attention-deficit/hyperactivity disorder), in utero antidepressant exposure was associated with an increased risk of affective disorders.

Lupatelli et al. conducted a large cohort study to assess risk of ADHD in children following perinatal exposure to SSRIs and SNRIs [65]. They found no difference in ADHD risk between antidepressant-exposed children vs non-exposed children whose mothers had depression/anxiety (HR 1.07, 95% CI 0.76–1.51). Importantly, they found that maternal anxiety and depression before pregnancy were also independently associated with childhood ADHD. Though the average hazard ratio over the duration of the study’s follow-up period showed no antidepressant association with ADHD, an increased risk of ADHD emerged when analysis was restricted to children at age 7–9 years only. Inattention is more easily measured in older children, so there may be a possible association between perinatal antidepressant exposure and a predominantly inattentive type of ADHD, though this association requires further inquiry.

Very few studies have focused on cognitive outcomes and school performance in exposed children. A 2020 retrospective cohort study by Singal et al. used a large administrative dataset to assess whether exposure to perinatal antidepressants, specifically SSRIs or SNRIs, impacts risk of developmental delay in kindergarten children [66•]. Restricting their analysis to mothers with mood or anxiety disorder diagnosis, the authors found that children with perinatal antidepressant exposure had increased odds of scoring in bottom 10th percentile in two or more domains on the Early Developmental Instrument (EDI) (aOR 1.43, 95% CI 1.08–1.9). The exposed group also had increased risk of vulnerability in language and/or cognition (aOR 1.4, 95% CI 1.03–1.90).

A large retrospective cohort 2021 study by Christensen et al. also looked at the association between maternal antidepressant exposure (which included SSRIs, SNRIs, TCAs, and atypical antidepressants) in pregnancy and subsequent cognitive outcomes in Danish school-aged children ranging from 8 to 15 years old [67•]. Children whose mothers received antidepressants in pregnancy had small but statistically significant decrease in mathematics test scores compared to children whose mothers did not receive antidepressants in pregnancy. The difference in the math scores between the exposed and unexposed groups was small (2 points out of 100) and is likely of minimal clinical relevance. The SSRI-restricted cohort showed a similar 2-point decrease in math scores. There was no difference in language scores between the exposed and unexposed groups, which is in contrast to the findings of Singal et al. described above.

In sum, recent studies mirror the results of prior large, well-designed studies which have not found an association between perinatal SSRI exposure and neurodevelopmental disorders including ASD and ADHD [58, 68–72]. There may be a negative impact of SSRI exposure on cognitive outcomes and risk of psychiatric illness in children. However, further study is needed to clarify this risk and its relation to underlying maternal mental illness, which can lead to residual confounding by indication in studies examining risks of antidepressant exposure in pregnancy. Notably, parental genetic factors have been shown to increase risk of psychiatric illness in offspring [73], so it is possible that mothers with PMADs have genetic loading that increases vulnerability to psychiatric illness in their offspring. Other potential confounders related to maternal mental illness and risk of neuropsychiatric disorders in offspring include parenting practices and environmental stress in the postpartum [74–76].

Conclusion

Studies from 2019 to 2022 examining the reproductive safety of SSRIs continue to exhibit the same methodologic limitations of prior observational studies, notably difficulty controlling for confounding by indication and unmeasured confounders associated with maternal mental illness. Nevertheless, the majority of recent studies, particularly those with higher quality designs, are reassuring regarding the safety of SSRIs as a class in pregnancy and suggest low absolute risk.

Studies that have better controlled for confounding by indication have not observed increased risk of major malformations for SSRIs as a class. Studies focused on maternal outcomes in SSRI-exposed women show no increased risk of gestational diabetes, but a possible small increased risk of postpartum hemorrhage and pre-eclampsia. Studies on adverse fetal and neonatal outcomes indicate that women with underlying psychiatric illness, regardless of SSRI exposure, are at elevated risk of preterm birth, low birth weight, and NICU admissions. However, the risk associated with SSRI exposure appears to be slightly higher compared to the non-exposed patients. The literature on neurodevelopmental outcomes is more limited overall, but generally suggests modest risk of clinically relevant adverse outcomes, particularly when contrasted with the clear negative impact of untreated perinatal depression on neurodevelopment in offspring [61].

Current consensus in much of the reproductive psychiatry suggests that the risks of SSRIs in pregnancy are justified when juxtaposed next to the risks of more severe untreated mental illness [77, 78]. However, it is important that each patient come to an individualized risk–benefit decision regarding the use of SSRI in pregnancy. In addition to known and unknown risks of SSRI use, patients and clinicians should consider the severity of the patient’s illness when untreated and relapse risk off medications, as well as access and response to non-medication treatments. With recent studies suggesting increased risks of adverse maternal outcomes with higher doses of antidepressants [31••], it is also prudent that clinicians remember to use the lowest effective dose when choosing to continue an SSRI in pregnancy. In guiding patients through these conversations, clinicians must be able to describe the strengths and limitations of the available literature on perinatal SSRI exposure in order to optimize collaborative decision-making and improve treatment outcomes.

Future research on the reproductive safety of SSRIs should focus on using innovative, rigorous methodology to control for confounding by indication, since it is unlikely that RCTs will be conducted in this patient population. Additionally, due to the relative lack of studies on maternal outcomes and long-term neurodevelopmental outcomes, future research should continue to explore these areas of clinical relevance. More high-quality data in these domains will help clinicians and patients in their decision-making regarding SSRIs during pregnancy.