Evidence-Based Reviews

Antidepressant use during pregnancy: How to avoid clinical and legal pitfalls

Current Psychiatry. 2013 February;12(2):10-17

References

1. U.S. Food and Drug Administration. FDA drug safety communication: selective serotonin reuptake inhibitor (SSRI) antidepressant use during pregnancy and reports of a rare heart and lung condition in newborn babies. http://www.fda.gov/Drugs/DrugSafety/ucm283375.htm. Published December 14, 2011. Accessed December 20, 2012.

2. U.S. Food and Drug Administration. Public health advisory: treatment challenges of depression in pregnancy and the possibility of persistent pulmonary hypertension in newborns. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsand
Providers/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/
ucm124348.htm. Published July 19, 2006. Accessed December 20, 2012.

3. Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med. 2006;354(6):579-587.

4. Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006;295(5):499-507.

5. Muzik M, Hamilton S. Psychiatric illness during pregnancy. Current Psychiatry. 2012;11(2):23-32.

6. Hasser C, Brizendine L, Spielvogel A. SSRI use during pregnancy. Current Psychiatry. 2006;5(4):31-40.

7. Wisner KL, Sit DK, Hanusa BH, et al. Major depression and antidepressant treatment: impact on pregnancy and neonatal outcomes. Am J Psychiatry. 2009;166(5):557-566.

8. Friedman SH, Resnick PJ. Postpartum depression: an update. Women’s Health (Lond Engl). 2009;5(3):287-295.

9. Meltzer-Brody S. New insights into perinatal depression: pathogenesis and treatment during pregnancy and postpartum. Dialogues Clin Neurosci. 2011;13(1):89-100.

10. Friedman SH, Hall RCW. Treatment of mental illness in pregnancy and malpractice concerns. News Amer Acad Psychiatry Law. 2012;37(2):21-22.

11. Yonkers KA, Wisner KL, Stewart DE, 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(5):403-413.

12. Bar-Oz B, Einarson T, Einarson A, et al. Paroxetine and congenital malformations: meta-analysis and consideration of potential confounding factors. Clin Ther. 2007;29(5):918-926.

13. Wilson KL, Zelig CM, Harvey JP. 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.

14. Silvani P, Camporesi A. Drug-induced pulmonary hypertension in newborns: a review. Curr Vasc Pharmacol. 2007;5(2):129-133.

15. Occhiogrosso M, Omran SS, Altemus M. Persistent pulmonary hypertension of the newborn and selective serotonin reuptake inhibitors: lessons from clinical and translational studies. Am J Psychiatry. 2012;169(2):134-140.

16. Delaney C, Cornfield D. Risk factors for persistent pulmonary hypertension of the newborn. Pulm Circ. 2012;2(1):15-20.

17. Centers for Disease Control and Prevention. Key findings: updated national birth prevalence estimates for selected birth defects in the United States 2004-2006. http://www.cdc.gov/ncbddd/features/birthdefects-keyfindings.html. Published September 28, 2010. Accessed December 20, 2012.

18. Einarson A, Choi J, Einarson TR, et al. Incidence of major malformations in infants following antidepressant exposure in pregnancy: results of a large prospective cohort study. Can J Psychiatry. 2009;54(4):242-246.

19. Alwan S, Reefhuis J, Rasmussen SA, et al. National Birth Defects Prevention Study. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med. 2007;356(26):2684-2692.

20. Andrade SE, McPhillips H, Loren D. Antidepressant medication use and risk of persistent pulmonary hypertension of the newborn. Pharmacoepidemiol Drug Saf. 2009;18(3):246-252.

21. U.S. Food and Drug Administration. FDA advising of risk of birth defects with paxil. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2005/ucm108527.htm. Published December 8, 2005. Accessed December 20, 2012.

22. Koren G, Boucher N. Adverse effects in neonates exposed to SSRIs and SNRI in late gestation-Motherisk Update 2008. Can J Clin Pharmacol. 2009;16(1):e66-e67.

23. Pederson LH, Henriksen TB, Vestergaard M, et al. Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population based cohort study. BMJ. 2009;339:b3569.-doi:10.1136/bmj.b3569.

24. Kieler H, Artama M, Engeland A, 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;344:d8012.-doi:10.1136/bmj.d801.

25. Wyeth v Levine, 555 US 555 (2009).

26. PLIVA, Inc. v Mensing, 588 F3d 603, 593 F3d 428 (2011).

27. Greenwood K. The mysteries of pregnancy: the role of law in solving the problem of unknown but knowable maternal–fetal medication risk. University of Cincinnati Law Review. 2011;79(1):267-322.

28. Lyam Kilker v SmithKline Beecham Corporation, Philadelphia Court of Common Pleas (2009).

29. Mulder E, Davis A, Gawley L, et al. Negative impact of non-evidence-based information received by women taking antidepressants during pregnancy from health care providers and others. J Obstet Gynaecol Can. 2012;34(1):66-71.

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31. Altshuler L, Richards M, Yonkers K. Treating bipolar disorder during pregnancy. Current Psychiatry. 2003;2(7):14-26.

Limitations of research

Because of ethical difficulties in studying MDD treatment during pregnancy, most data are retrospective and prone to detection and confounding biases, such as^11-15:

the risks associated with depression
comorbid conditions such as obesity
maternal age
poor prenatal care
how the baby was delivered (eg, Caesarean sections have higher rates of PPHN)¹³
illicit substance use
effects of other medications (80% of pregnant women use medications, including nonsteroidal anti-inflammatory drugs [NSAIDs], which are associated with PPHN).^11,16

Clinical Point

Ethical difficulties in studying MDD treatment during pregnancy means most studies have been retrospective and prone to biases

No medication is 100% safe during pregnancy and all pregnancies have risks. In the United States, 2% to 3% of pregnancies produce infants with malformations,¹⁷ which makes it hard to determine if a defect is caused by a medication or occurred spontaneously. This is the baseline risk of all malformations; individual malformations are rare and it is difficult to conduct studies that have adequate power to demonstrate the risk for a specific malformation.

There are several potential adverse outcomes to consider when prescribing psychotropics to a pregnant woman, including miscarriage, malformation, preterm delivery, perinatal toxicity, and behavioral teratogenesis (Table 2).^6,7 SSRIs have been implicated in adverse outcomes, but there is no strong evidence that they increase the miscarriage rate, and several studies found no increase in birth defects.^6,13,18-20 Regarding teratogenesis, the FDA switched paroxetine from class C to class D because of a potential 1.5% to 2% risk of fetal cardiac malformation, compared with a 1% baseline rate in the general population.²¹ Drug toxicity or withdrawal in a neonate also is a risk; however, this condition is self-limited and managed supportively by neonatology.²² Behavioral teratogenesis—neurobehavioral problems that develop later in a child’s life—remains a hypothetical concern; research has been conflicting, and studies often used flawed methodology.

Clinical Point

SSRIs have been implicated in adverse birth outcomes but several studies found no increase in birth defects

Evidence linking SSRIs to an increased risk of adverse birth outcomes often has been based on large, retrospective health system database cohort studies looking at SSRI exposure and associations with conditions such as PPHN, cardiac anomalies, attention-deficit/hyperactivity disorder, and autism.^10,23,24 However, correlation is not the same as causation. It is difficult to prove or disprove the causative factor of adverse outcomes in these studies because:

these databases were not designed to answer these types of exposure questions (eg, limitations in data collected, such as other potential causes not recorded)
they have many confounding biases (undocumented illicit substance use, possible minimization of smoking history, publication basis for positive findings, etc.)
individuals who provided the data did not follow a standardized method (eg, variability among individual clinicians).

Many of these limitations are evident in a 2009 study by Pedersen et al,²³ who reported the prevalence of septal heart defects was 0.5% (2,315/493,113) among unexposed children and 0.9% (12/1,370) among children exposed to 1 SSRI during early pregnancy (odds ratio [OR]=1.99 [1.13 to 3.53]). Based on this study’s data, the number needed to harm—the number of patients you would need to treat to encounter 1 adverse outcome—was 246, which suggests a relatively low risk. When data for the entire study is reviewed, the ORs for either minor birth defects (control: 7,373/493,113 vs SSRI exposed: 39/1,370; OR=0.88 [0.54 to 1.41]) or major birth defects (control: 15,518/493,113 vs SSRI exposed: 55/1,370; OR 1.21 [0.91 to 1.62]) were not statistically significant (major and minor malformations were defined using European Surveillance of Congenital Anomalies coding).

Not to case aspersions on this group’s work, it should be noted that this study had limitations, including that the researchers:

did not take into account SSRI dosage
did not measure depression severity or remittance
were not able to fully account for potential exposures (eg, over-the-counter NSAIDs)
were unable to confirm that patients took their medications because the variable measured was prescriptions filled
did not interview participants about their medication use or symptoms.

In addition, researchers noted that mothers who filled their antidepressant prescription at least twice also were likely to have other factors that put them at higher risk for having a child with birth defects—such as older age or smoking. The biggest problem with the study was a lack of a control group, such as depressed women who did not receive medication (eg, the risk of depression itself could explain the rise, or those with more severe depression could be prescribed antidepressants).¹⁵

In a more recent study,²⁴ 33 of 11,014 infants exposed to SSRIs after gestational week 20 developed PPHN (absolute risk: 3 per 1,000 births, compared with an incidence of 1.2 per 1,000 births in the general population), with an adjusted OR of 2.1 (95% CI 1.5 to 3.0). Although the authors warned that the results suggest a “class effect,” the rate of PPHN also was higher for mothers with a history of a psychiatric hospitalization within the last 10 years who were not taking medication (OR=1.3, 95% CI 1.0 to 1.6) and the OR for escitalopram (1.5, CI 0.2 to 10.5) was not statistically significant. This study did include a control group, but the 10-year window may have been too wide to represent a group with similar comorbid risks. Similar to the previously discussed study, mothers prescribed SSRIs were older, 1.7 times more likely to be smokers, and twice as likely to be prescribed NSAIDs. The study did not analyze the risk factors of smoking and body mass index because of an initial subset analysis (which was not reported) finding that these known risk factors for PPHN “did not confound the results.”²⁴