How do you counsel patients about taking medications for depression during pregnancy?

Sophia is a 33-year-old woman with a history of major depressive disorder (MDD). She is currently euthymic and taking sertraline 100mg daily. She has had 3 lifetime severe major depressive episodes and has taken sertraline on and off for the past 13 years. She has never participated in psychotherapy. During your most recent visit, she tells you that she is hoping to become pregnant within the next year. She asks for your opinion and guidance around the sertraline. What should she do? 

How do you counsel your patient on the risks and benefits of treating MDD with antidepressants during pregnancy?

There are no randomized controlled trials looking at the treatment of MDD with antidepressants in pregnant women.* Furthermore, many studies that look at the risks of antidepressants in pregnancy compare those with depression to those without depression, rather than looking at those with depression treated with medication v. those with depression not treated with medication. Confounding is a significant issue. 

And yet, 12% of pregnant women are depressed, with 1.8-8% taking antidepressant medications during pregnancy (Bayrampour 2020). Although our literature has limitations, we still need to make clinical recommendations. Fortunately, there are systematic reviews and observational studies to offer some guidance; both the USPSTF and American College of Obstetrics and Gynecology (ACOG) have established guidelines on the treatment of MDD in pregnancy. 

I will summarize the relevant literature and guidelines so that you have the necessary information to support an individualized risk-risk conversation with patients.

What are the risks of undertreated depression for women and infants?

Maternal depression, like many other significant illnesses, can exert negative effects on a mother’s health, on pregnancy, and on the infant. Perinatal depression is associated with maternal suffering and a 3x higher risk of suicidal behavior compared to pregnancy without perinatal depression (Yu 2024). Undertreatment of depression in pregnant women is also associated with reduced engagement in medical care during pregnancy, increased substance use by pregnant mothers, postpartum depression, impaired infant attachment, and disrupted relationships between parental partners (ACOG 2023).  

Depression during pregnancy and postpartum is also associated with preterm birth and may disrupt neurocognitive changes that prepare mothers to fully respond to their infants (Grote 2010, Grigoriadis 2013, Pearson 2012). A 2020 meta-analysis showed small associations between perinatal depression and infant dysregulation, delayed infant motor ability, and social-emotional development (Roger 2020). Children of women who were depressed peripartum had increased anxiety and higher levels of internalizing behavior at ages 3, 6, and 12 (Hutchison 2023).  

What are the benefits of treatment with antidepressants for women and infants?

Treating women with MDD with antidepressants may reduce the risk of the negative sequelae of depression described above. Treatment for depression with antidepressants reduces the risk for depressive relapse in women with a history of recurrent or severe MDD (RR=2.30; 95% CI, 1.58 to 3.35), but not in women with mild or moderate depression (RR=1.59; 95% CI, 0.83 to 3.04) (Bayrampour 2020). Women with recurrent, severe MDD have a good indication for their own health to continue antidepressants. These data also remind us that antidepressants are no more effective for mild depression than placebo pills. 

What are the risks of treatment with antidepressants for the mother?

The risks of treatment with antidepressants are similar for pregnant and non-pregnant individuals. Counseling should include a discussion of the typical side effects of antidepressants

What are the risks of treatment with SSRIs and SNRIs for the baby?

Antidepressant use (SSRIs and SNRIs) is likely not associated with congenital malformations; a recent meta-analysis found no increased risk of congenital malformations in children exposed to antidepressants in utero when maternal depression is factored into the analysis (Gao 2018). Antidepressant use during pregnancy is associated with preterm birth and low Apgar scores in an individual participant data meta-analysis (Vlenterie 2021). However, pregnancies in women with depressive symptoms who were not taking antidepressants are also associated with preterm birth, suggesting that this association is likely secondary to the illness rather than the medications (Grote 2010, Grigoriadis 2013, Vlenterie 2021). 

There may be a small increased risk of persistent pulmonary hypertension of the newborn (PPHN) in infants exposed to antidepressants compared to non-exposed infants, but the absolute risk remains very small; in a 2015 meta-analysis, in women with a depression diagnosis, the OR for PPHN in the newborn was 1.36 (95% CI, 1.18-1.57) for SSRI-exposed infants compared to non-exposed infants. Of note, the authors also found an increased OR for PPHN and maternal diabetes (OR, 2.93; 95% CI, 2.72-3.15), obesity (OR, 2.02; 95% CI, 1.88-2.17), and cesarean delivery (OR, 3.20; 95% CI, 3.06-3.35) (Huybrechts 2015).

In utero exposure to SSRIs and SNRIs is associated with neonatal adaptation syndrome in 25% of exposed neonates. A meta-analysis of 8 studies found an OR for neonatal adaptation syndrome and exposure to any antidepressant of 5.07 (95% CI 3.25-7.90, p<0.0001) (Grigoriadis 2013). This syndrome can include irritability, agitation, tremors, hyperreflexia, hypoglycemia, hypothermia, sleep disruption, and poor feeding. It is self limited and generally resolves within 2 weeks. In an attempt to reduce the risk of neonatal adaptation syndrome, some providers have recommended tapering antidepressants in the third trimester. ACOG and perinatal psychiatrists strongly recommend against this practice. The data we have suggest that tapering antidepressants before birth does not result in improved neonatal outcomes, but does set a woman up for a higher risk of postpartum depression at the height of vulnerability (the first month after birth) (Warburton 2010).  

Researchers have looked for an association between in-utero SSRI exposure and future neurodevelopmental disease. While there have been no consistent findings that associate SSRI exposure in utero to negative long-term outcomes for children, there are many studies with inconsistent results. For example, a 2021 study found children exposed to SSRIs in utero performed better in some but worse in other sensorimotor testing compared with both children of mothers with untreated depression and mothers without depression (Galbally 2021). At the same time, a 2021 study demonstrated that children exposed to SSRIs in utero performed slightly worse on standardized mathematics tests but not language tests compared to children who were not exposed to antidepressants (Christensen 2021). These authors caution that maternal depression, its associated behaviors, and the environment may result in residual confounding leading to these results. A study of 2 large cohorts of parent-child pairs found no increased risk for the development of learning disorders or ADHD among children of the same parent, one with in-utero antidepressant exposure and one without (Suarez 2022).

Risk-risk conversation

Ultimately, we are faced with a risk-risk conversation, the risk of under-treated depression for the mother and baby compared to the risk of treatment itself for the mother and baby. The risk of untreated depression in persons with recurrent or severe depression is well documented: relapse of depression during pregnancy may result in maternal suffering and self-harm, difficulty engaging with the medical system during pregnancy and challenges engaging with the newborn infant after birth. There are also risks of taking SSRIs/SNRIs during pregnancy, in particular a risk of neonatal adaptation syndrome. The strength of research is limited by the lack of randomized control trials, confounding by the effects of depression (preterm birth occurs in women with depression, both on and off antidepressants), and inconsistencies in results (neurodevelopmental disorders and development).

Let’s put this all together for Sophia. Pregnancy is a vulnerable time; as much as possible, it is important to strengthen Sophia’s pregnancy environment, including managing her depression. Sophia has severe recurrent major depression that responds well to sertraline. I would offer her the option to continue this medication during pregnancy, describing both the risks of stopping the medication and of continuing it. If she asks for my specific recommendation, I would tell her that given the severity and persistence of her depression, it seems like the potential benefits of taking sertraline for her and for a future baby outweigh the risks. Ultimately, it is her decision, and I will of course support her in whatever she decides. I would also strongly encourage psychotherapy during pregnancy; the USPSTF recommends therapy for all pregnant patients with depression (O’Connor 2016). Regular exercise, adequate sleep, and increased family/social support may also help.

*Studies on pregnancy and depression refer to the subjects with gendered pronouns and descriptions; I use “maternal depression,” “pregnant women,” and “mother” in line with this research.

Resources:

  • Mother to Baby: patient-facing information on all pregnancy related concerns including mental health.
  • MGH Center for Women’s Mental Health: short reviews from Mass General Hospital of current research on women’s mental health, including pregnancy, with recommendations.

Key Points

  1. Treatment for depression during pregnancy is available: ACOG recommends psychotherapy and the continuation of antidepressants in women who have recurrent and/or severe depression.
  2. There is risk associated with discontinuing treatment with antidepressants in pregnant women for both the pregnant person and their child, driven by the sequelae of undertreated depression. There is also risk associated with treatment with antidepressants, specifically the increased risk of neonatal adaptation syndrome and, possibly, PPHN. 
  3. Engage your patient in a risk-risk conversation, informing them of the lack of well-designed research on this topic, the reality and consequences of maternal depression on pregnancy and parenting, and the low likelihood of infant neurodevelopmental disease associated with in utero exposure to antidepressants.

References:

Bayrampour, H., Kapoor, A., Bunka, M., & Ryan, D. (2020). The Risk of Relapse of Depression During Pregnancy After Discontinuation of Antidepressants: A Systematic Review and Meta-Analysis. The Journal of Clinical Psychiatry, 81(4). https://doi.org/10.4088/JCP.19r13134

Christensen, J., Trabjerg, B. B., Sun, Y., & Dreier, J. W. (2021). Association of Maternal Antidepressant Prescription During Pregnancy With Standardized Test Scores of Danish School-aged Children. JAMA, 326(17), 1725. https://doi.org/10.1001/jama.2021.17380

Gao, S.-Y., Wu, Q.-J., Sun, C., Zhang, T.-N., Shen, Z.-Q., Liu, C.-X., Gong, T.-T., Xu, X., Ji, C., Huang, D.-H., Chang, Q., & Zhao, Y.-H. (2018). Selective serotonin reuptake inhibitor use during early pregnancy and congenital malformations: A systematic review and meta-analysis of cohort studies of more than 9 million births. BMC Medicine, 16(1), 205. https://doi.org/10.1186/s12916-018-1193-5

Grigoriadis, S., VonderPorten, E. H., Mamisashvili, L., Eady, A., Tomlinson, G., Dennis, C.-L., Koren, G., Steiner, M., Mousmanis, P., Cheung, A., & Ross, L. E. (2013). The Effect of Prenatal Antidepressant Exposure on Neonatal Adaptation: A Systematic Review and Meta-Analysis. The Journal of Clinical Psychiatry, 74(04), e309–e320. https://doi.org/10.4088/JCP.12r07967

Grigoriadis, S., VonderPorten, E. H., Mamisashvili, L., Tomlinson, G., Dennis, C.-L., Koren, G., Steiner, M., Mousmanis, P., Cheung, A., Radford, K., Martinovic, J., & Ross, L. E. (2013). The Impact of Maternal Depression During Pregnancy on Perinatal Outcomes: A Systematic Review and Meta-Analysis. The Journal of Clinical Psychiatry, 74(04), e321–e341. https://doi.org/10.4088/JCP.12r07968

Grote, N. K., Bridge, J. A., Gavin, A. R., Melville, J. L., Iyengar, S., & Katon, W. J. (2010). A Meta-analysis of Depression During Pregnancy and the Risk of Preterm Birth, Low Birth Weight, and Intrauterine Growth Restriction. Archives of General Psychiatry, 67(10), 1012. https://doi.org/10.1001/archgenpsychiatry.2010.111

Hutchison, S. M., Brain, U., Grunau, R. E., Kuzeljevic, B., Irvine, M., Mâsse, L. C., & Oberlander, T. F. (2023). Associations between maternal depressive symptoms and selective serotonin reuptake inhibitor antidepressant treatment on internalising and anxiety behaviours in children: 12-year longitudinal study. BJPsych Open, 9(2), e26. https://doi.org/10.1192/bjo.2022.623

Huybrechts, K. F., Bateman, B. T., Palmsten, K., Desai, R. J., Patorno, E., Gopalakrishnan, C., Levin, R., Mogun, H., & Hernandez-Diaz, S. (2015). Antidepressant Use Late in Pregnancy and Risk of Persistent Pulmonary Hypertension of the Newborn. JAMA, 313(21), 2142. https://doi.org/10.1001/jama.2015.5605

Megan Galbally, Stuart J. Watson, Olav Spigset, Philip Boyce, Tim F. Oberlander, & Andrew J. Lewis. (2021). Antidepressant exposure in pregnancy and child sensorimotor and visuospatial development. Journal of Psychiatric Research, 143, 485–491.

Moses-Kolko, E. L., Bogen, D., Perel, J., Bregar, A., Uhl, K., Levin, B., & Wisner, K. L. (n.d.). Neonatal Signs After Late In Utero Exposure to Serotonin Reuptake Inhibitors.

O’Connor, E., Rossom, R. C., Henninger, M., Groom, H. C., & Burda, B. U. (2016). Primary Care Screening for and Treatment of Depression in Pregnant and Postpartum Women: Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA, 315(4), 388. https://doi.org/10.1001/jama.2015.18948

Pearson, R. M., Melotti, R., Heron, J., Joinson, C., Stein, A., Ramchandani, P. G., & Evans, J. (2012). Disruption to the development of maternal responsiveness? The impact of prenatal depression on mother–infant interactions. Infant Behavior and Development, 35(4), 613–626. https://doi.org/10.1016/j.infbeh.2012.07.020

Rogers, A., Obst, S., Teague, S. J., Rossen, L., Spry, E. A., Macdonald, J. A., Sunderland, M., Olsson, C. A., Youssef, G., & Hutchinson, D. (2020). Association Between Maternal Perinatal Depression and Anxiety and Child and Adolescent Development: A Meta-analysis. JAMA Pediatrics, 174(11), 1082. https://doi.org/10.1001/jamapediatrics.2020.2910

Suarez, E. A., Bateman, B. T., Hernández-Díaz, S., Straub, L., Wisner, K. L., Gray, K. J., Pennell, P. B., Lester, B., McDougle, C. J., Zhu, Y., Mogun, H., & Huybrechts, K. F. (2022). Association of Antidepressant Use During Pregnancy With Risk of Neurodevelopmental Disorders in Children. JAMA Internal Medicine, 182(11), 1149. https://doi.org/10.1001/jamainternmed.2022.4268

Treatment and Management of Mental Health Conditions During Pregnancy and Postpartum: 

ACOG Clinical Practice Guideline No. 5: (2023). Obstetrics & Gynecology, 141(6), 1262–1288. https://doi.org/10.1097/AOG.0000000000005202

Vlenterie, R., Van Gelder, M. M. H. J., Anderson, H. R., Andersson, L., Broekman, B. F. P., Dubnov-Raz, G., El Marroun, H., Ferreira, E., Fransson, E., Van Der Heijden, F. M. M. A., Holzman, C. B., Kim, J. J., Khashan, A. S., Kirkwood, B. R., Kuijpers, H. J. H., Lahti-Pulkkinen, M., Mason, D., Misra, D., Niemi, M., … Roeleveld, N. (2021). Associations Between Maternal Depression, Antidepressant Use During Pregnancy, and Adverse Pregnancy Outcomes: An Individual Participant Data Meta-analysis. Obstetrics & Gynecology, 138(4), 633–646. https://doi.org/10.1097/AOG.0000000000004538

Warburton, W., C. Hertzman, and T. F. Oberlander. A register study of the impact of stopping third trimester selective serotonin reuptake inhibitor exposure on neonatal health. Acta Psychiatrica Scandinavica 121.6 (2010): 471-479.

Yu, H., Shen, Q., Bränn, E., Yang, Y., Oberg, A. S., Valdimarsdóttir, U. A., & Lu, D. (2024). Perinatal Depression and Risk of Suicidal Behavior. JAMA Network Open, 7(1), e2350897. https://doi.org/10.1001/jamanetworkopen.2023.50897