Yes or No: Prescribing Antidepressants to Pregnant Patients

Despite antidepressants being one of the most-studied classes of medications used during pregnancy, their use during pregnancy remains controversial. Numerous studies have explored the association between antidepressants and a variety of outcomes in the neonate including cardiac malformations, preterm birth, persistent pulmonary hypertension (PPHN), poor neonatal adaptation syndrome, and most recently autism.

Many of these studies have resulted in sensational headlines when there have been positive findings; however, there are a number of limitations in these studies that, when taken into account with other studies, resulted in negative findings that do not seem to make it into the headlines.

One significant limitation of the literature in this area is that the use of antidepressants during pregnancy can be considered a “marker” for a population of women that have very different associated behaviors and risk factors than the general population of pregnant women. These risk factors, if not controlled for, may influence the outcomes of studies attempting to examine the risks of in utero exposure of antidepressants. For example, diabetes, obesity, smoking, and substance use are more common in patients with a history of depression than in the general population of pregnant women.

Studies that have not controlled for the underlying psychiatric illness and its attendant risks may find associations between antidepressants and outcomes that are not caused by exposure to the medication itself, but by the presence of other risk factors that are highly prevalent in the population of patients who take antidepressants during pregnancy. Many published studies essentially compare “apples” with “oranges” and do not control for factors that are associated with the psychiatric illness itself.

A good example of this phenomenon is the literature examining the risk of cardiovascular malformations with in utero exposure to selective serotonin reuptake inhibitors (SSRIs). The literature examining links between SSRI use during pregnancy and cardiovascular malformations in exposed infants is discrepant, and several studies have demonstrated that the association between antidepressants and cardiac defects is likely secondary to other underlying risk factors in the population of women with depression.

Jimenez-Solem and colleagues (1) found an increased risk of cardiovascular malformations in babies whose mothers had a diagnosis of depression, but deferred antidepressant treatment during pregnancy. This finding suggests that the risk is associated with the illness, not the antidepressant exposure. The largest study to date (2), with a sample size of over 900,000 women, did not find an association between antidepressant exposure and cardiac malformations when the analyses controlled for depression. A recent meta-analysis (3) found no association between SSRI use and heart defects when comparing women with depression who took SSRIs during the first trimester with women with depression who did not take antidepressants during pregnancy. The overall consensus in the field is that the risk of major organ malformations, if it exists, is small, having a risk of less than 1 percent (4).

A similar pattern appears in the literature on the risk for PPHN in antidepressant-exposed newborns. PPHN is a failure of the pulmonary vasculature to decrease resistance at birth resulting in breathing difficulties for the infant, leading to hypoxia and often the need for intubation. PPHN has a 10 percent to 20 percent mortality rate (5) and has been associated with a number of maternal factors that are more common in women with depression (6) including obesity, smoking (7), diabetes, and C-section.

There have been seven studies on the association between SSRIs and PPHN with conflicting results. The first, published in 2006 (8), found an adjusted (for maternal diabetes, race, and body-mass index) odds ratio of 6.1. Since this first study, six additional studies have been conducted: three found no association between SSRI exposure and PPHN (9-11) and three found an association (12-14), although with lower odds ratios than 6.1. The most recent (14) analyzed nearly 3.8 million pregnancies, including 128,950 women who took an antidepressant during pregnancy, and found an odds ratio of 1.51 (CI 1.35-1.69) for an association between SSRI exposure and PPHN. However, when the analyses were adjusted for potential confounders, the odds ratio became insignificant (odds ratio 1.10 [0.94-1.29]).

The importance of controlling for confounding risk factors is driven home by Kieler and colleagues, who found an increased risk of PPHN in infants of mothers who had a history of psychiatric hospitalization but did not take antidepressants during pregnancy (13). Again, the risk of PPHN, if real, is extremely small with less than 1 percent of exposed infants developing the condition.

From a purely clinical perspective, it is important not to overlook the risks of untreated maternal psychiatric illness to both the mother and child. When considering the risks and benefits of taking antidepressants during pregnancy, women and their physicians should compare the risk of exposure to medication—not with the risk of no exposure, but with the risks of exposure to maternal psychiatric illness, which are not benign for either mother or child.

There is a strong literature demonstrating that untreated maternal psychiatric illness during pregnancy is associated with poorer outcomes for the mother and the exposed child, including low maternal weight gain and increased rates of preterm birth (15); low birth weight; increased rates of substance use (16); increased ambivalence about the pregnancy; and overall worse health status (17), including higher rates of preeclampsia and gestational diabetes (18, 19).

The literature regarding postpartum depression is even stronger, with adverse outcomes including lower IQ, slower language development, increased risk of attention-deficit disorder, and increased risk of behavioral issues and psychiatric illness in the exposed offspring (20). These findings often seem to get lost in the debate of whether to use psychiatric medications during pregnancy.

Depression is not a benign illness for either mother or child that can be ignored and untreated during pregnancy. When considered as a whole, the literature supports the use of antidepressants in pregnancy in appropriate cases. In most cases, the benefits of treating maternal depression outweigh the minimal and rare risks of in utero exposure to antidepressants. ■

1) Jimenez-Solem E, Andersen JT, Petersen M, Broedbaek K, Jensen JK, Afzal S, et al. Exposure to Selective Serotonin Reuptake Inhibitors and the Risk of Congenital Malformations: A Nationwide Cohort Study. BMJ Open. 2012;18;2(3):pii:e001148.

2) Huybrechts KF, Sanghani RS, Avorn J, Urato AC. Preterm Birth and Antidepressant Medication Use During Pregnancy: A Systematic Review and Meta-Analysis. PLoS One. 2014;9(3):e92778.

3) Wang S, Yang L, Wang L, Gao L, Xu B, Xiong Y. Selective Serotonin Reuptake Inhibitors (SSRIs) and the Risk of Congenital Heart Defects: A Meta-Analysis of Prospective Cohort Studies. J Am Heart Assoc. 2015;May 19;4(5):pii: e001681.

4) Yonkers KA, Wisner KL, Stewart DE, Oberlander TF, Dell DL, Stotland N, et al. The Management of Depression During Pregnancy: A Report From the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Gen Hosp Psychiatry. 2009;31:403-13.

5) Walsh-Sukys MC, Tyson JE, Wright LL, Bauer CR, Korones SB, Stevenson DK, et al. Persistent Pulmonary Hypertension of the Newborn in the Era Before Nitric Oxide: Practice Variation and Outcomes. Pediatrics. 2000;105(1 Pt 1):14-20.

6) Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Mitchell AA. Risk Factors for Persistent Pulmonary Hypertension of the Newborn. Pediatrics. 2007;120(2):e272-82.

7) Bearer C, Emerson RK, O'Riordan MA, Roitman E, Shackleton C. Maternal Tobacco Smoke Exposure and Persistent Pulmonary Hypertension of the Newborn. Environ Health Perspect. 1997;105(2):202-6.

8) Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, et al. Selective Serotonin-Reuptake Inhibitors and Risk of Persistent Pulmonary Hypertension of the Newborn. N Engl J Med. 2006; 354(6):579-87.

9) Andrade SE, McPhillips H, Loren D, Raebel MA, Lane K, Livingston J, et al. Antidepressant Medication Use and Risk of Persistent Pulmonary Hypertension of the Newborn. Pharmacoepidemiol Drug Saf. 2009;18(3):246-52.

10) Wichman CL, Moore KM, Lang TR, St Sauver JL, Heise RH,Jr, Watson WJ. Congenital Heart Disease Associated With Selective Serotonin Reuptake Inhibitor Use During Pregnancy. Mayo Clin Proc. 2009;84(1):23-7.

11) Wilson KL, Zelig CM, Harvey JP, Cunningham BS, Dolinsky BM, Napolitano PG. Persistent Pulmonary Hypertension of the Newborn is Associated With Mode of Delivery and Not With Maternal Use of Selective Serotonin Reuptake Inhibitors. Am J Perinatol. 2011;28(1):19-24.

12) Kallen B, Olausson PO. Maternal Use of Selective Serotonin Re-Uptake Inhibitors and Persistent Pulmonary Hypertension of the Newborn. Pharmacoepidemiol Drug Saf. 2008;Aug;17(8):801-6.

13) Kieler H, Artama M, Engeland A, Ericsson O, Furu K, Gissler M, et al. Selective Serotonin Reuptake Inhibitors During Pregnancy and Risk of Persistent Pulmonary Hypertension in the Newborn: Population Based Cohort Study From the Five Nordic Countries. BMJ. 2012; Jan 12;344:d8012.

14) Huybrechts KF, Bateman BT, Palmsten K, Desai RJ, Patorno E, Gopalakrishnan C, et al. Antidepressant Use Late in Pregnancy and Risk of Persistent Pulmonary Hypertension of the Newborn. JAMA. 2015;313(21):2142-51.

15) Li D, Liu L, Odouli R. Presence of Depressive Symptoms During Early Pregnancy and the Risk of Preterm Delivery: A Prospective Cohort Study. Hum Reprod. 2009;24(1):146-53.

16) Zuckerman B, Amaro H, Bauchner H, Cabral H. Depressive Symptoms During Pregnancy: Relationship to Poor Health Behaviors. Am J Obstet Gynecol. 1989;160(5 Pt 1):1107-11.

17) Orr ST, Blazer DG, James SA, Reiter JP. Depressive Symptoms and Indicators of Maternal Health Status During Pregnancy. J Womens Health (Larchmt). 2007;16(4):535-42.

18) Field T, Diego M, Hernandez-Reif M. Prenatal Depression Effects on the Fetus and Newborn: A Review. Infant Behav Dev. 2006;29(3):445-55.

19) Field T, Diego M, Hernandez-Reif M. Prenatal Depression Effects and Interventions: A Review. Infant Behav Dev. 2010;33(4):409-18.

20) Grace SL, Evindar A, Stewart DE. The Effect of Postpartum Depression on Child Cognitive Development and Behavior: A Review and Critical Analysis of the Literature. Arch Womens Ment Health. 2003;6(4):263-74.