Some, but not all, studies have shown an association between in utero exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants and adverse pregnancy outcomes, including preterm delivery, low birth weight, and lower Apgar scores.  

One of the difficulties in estimating the risk for adverse outcomes in this population is that studies have used varying methodologies and have relied on different means of identifying and classifying neonatal outcomes.  Furthermore, many of these studies have not taken into consideration other variables that may affect neonatal outcomes, including the use of other medications, smoking, and maternal mental illness.  

We often question whether depression itself (as opposed to the antidepressants used to treat it) may contribute to adverse outcomes.  This question stems from early research conducted by Steer and colleagues (1992) and Orr and Miller (1995).  Steer observed that the risk of a poor pregnancy outcome rose by 5-7% for each point increase on the Beck Depression Inventory (BDI).  Women with a score greater than 21 on the BDI, a score suggestive of clinical depression, experienced:

A 3.97-fold increase in risk of delivering a low birth weight infant (< 2500 g)

A 3.39-fold increase in risk of having a preterm delivery (< 37 weeks’ gestation)

A 3.02-fold increase in risk of having a small-for-gestational-age infant (< 10th percentile)

These outcomes were observed in the absence of antidepressant treatment.

Exposure to Antidepressant vs. Exposure to Maternal Psychiatric Illness: Which is Worse?

Several recent studies have attempted to distinguish the impact of maternal depression from that of antidepressant exposure.  

In one study from the University of Iowa, International Classification of Diseases (ICD)-9 codes for depression were used to identify women with depression. Data were extracted from linked maternal and neonatal records for all women with an ICD-9 code for depression and an equal number of women without ICD-9 codes for depression.

Of the 3,695 women who delivered between 2009 and 2011, 238 had an ICD-9 code for depression; 126 of these women (50%) were treated with an SSRI and 23 (9%) received a non-SSRI antidepressant.  When the researchers compared outcomes in depressed vs. non-depressed women, the mean duration of gestation was more than one week shorter in the infants born to depressed mothers. When corrected for gestational age at delivery, birth weight was not significantly affected by maternal depression. The frequency of NICU admission was nearly double for infants born to mothers with depression; this increase was driven by admissions for respiratory distress.

When they looked specifically at pregnancies in mothers with depression, SSRI use did not significantly alter the timing of delivery, birth weight, or the rate of NICU admission.  Using logistic regression to identify predictors of NICU admission, tobacco use, obesity, and diagnosis of depression, but not SSRI use, were independently associated with NICU admission.

Treating Depression May Actually Reduce the Risk of Adverse Outcomes

The most recent study (Malm et al, 2015) was a large population-based prospective birth cohort study which used national register data and included a total of 845,345 offspring.  The researchers compared outcomes across three groups:

Pregnancies exposed to SSRIs (N=15,729; SSRI + illness)

Pregnancies with no SSRI exposure but mother with psychiatric diagnosis (N=9,652; no SSRI + illness)

Pregnancies with no medication exposure and no psychiatric diagnosis (N=31,394; no SSRI + no illness).

Compared to the offspring of unexposed mothers (no SSRI + no illness), the offspring exposed to SSRI + illness and the offspring of mothers no SSRI + illness were at increased risk for several adverse pregnancy outcomes, including cesarean section and monitoring in a neonatal care unit.

However, when compared to the offspring of mothers with exposure to no SSRI + illness, the offspring of mothers who received SSRIs during pregnancy actually had a lower risk for late preterm birth (odds ratio=0.84, 95% CI=0.74–0.96), lower risk of very preterm birth (odds ratio=0.52, 95% CI=0.37–0.74), and lower risk of cesarean section (odds ratio=0.70, 95% CI=0.66-0.75).  SSRI-treated mothers were more likely to have offspring with neonatal complications, including lower Apgar score (odds ratio=1.68, 95% CI=1.34–2.12) and monitoring in a neonatal care unit (odds ratio=1.24, 95% CI=1.14–1.35).

The authors speculate that antidepressant treatment may mitigate the physiologic effects of depression and may thus improve certain outcomes. “Prenatal stress, associated with maternal depression, affects regulation of the hypothalamic-pituitary-adrenal axis, resulting in increased corticosteroid production and release of vasoactive amines, potentially reducing umbilical blood flow and predisposing to hypoxia and preterm birth. Hence, the protective effect observed in our cohort could be related to relief of symptoms and stress secondary to the antidepressant effect of SSRIs, and it may be consistent with the increased risk of preterm birth in mothers with untreated depression, which was also observed in our study.”

It is becoming increasingly clear that studies which compare outcomes in antidepressant-treated women to those in healthy non-depressed women without antidepressant exposure may yield results that are potentially misleading. Needless to say, pregnancy is a complicated series of events, where multiple factors influence outcomes.  While we cannot say that antidepressants are completely free of risk, we must take into consideration the impact of untreated depression on the well-being of the mother and her pregnancy.  

Ruta Nonacs, MD PhD

Engelstad HJ, Roghair RD, Calarge CA, Colaizy TT, Stuart S, Haskell SE.  Perinatal outcomes of pregnancies complicated by maternal depression with or without selective serotonin reuptake inhibitor therapy.  Neonatology. 2014;105(2):149-54.

Malm H, Sourander A, Gissler M, et al.  Pregnancy Complications Following Prenatal Exposure to SSRIs or Maternal Psychiatric Disorders: Results From Population-Based National Register Data.  Am J Psychiatry. 2015 Aug 4:appiajp201514121575. [Epub ahead of print]

Orr ST, Miller CA.  Maternal depressive symptoms and the risk of poor pregnancy outcome. Review of the literature and preliminary findings.  Epidemiol Rev. 1995;17(1):165-71. 

Steer RA, Scholl TO, Hediger ML, Fischer RL.  Self-reported depression and negative pregnancy outcomes.  J Clin Epidemiol. 1992 Oct; 45(10):1093-9.

 Suri R, Lin AS, Cohen LS, Altshuler LL.  Acute and long-term behavioral outcome of infants and children exposed in utero to either maternal depression or antidepressants: a review of the literature.  J Clin Psychiatry. 2014 Oct;75(10): e1142-52.


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