Evidence-Based Reviews

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

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

Overall risks are low, and fears of lawsuits should not deter appropriate care

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.

30. Henshaw SK. Unintended pregnancy in the United States. Fam Plann Perspect. 1998;30(1):24-29 46.

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

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Recently there has been an increase in advertising soliciting participants for class-action lawsuits involving birth defects and antidepressants, particularly sertraline. Many psychiatrists are unsure why these ads are running in seemingly every medium because there has been no change in the FDA pregnancy classification for most selective serotonin reuptake inhibitors (SSRIs), except for paroxetine going from a C to a D rating in 2005.¹ Some studies have found SSRIs increase the risk of adverse birth outcomes and others have not, which makes it difficult for clinicians to know what to discuss with patients regarding the risks and benefits of using antidepressants during pregnancy, as well as the risks of untreated major depressive disorder (MDD).

It can be hard to encourage some patients to take necessary medications in the best of circumstances, let alone suggest that a pregnant woman take a medication that has been labeled “dangerous.” This article seeks to alleviate physicians’ fears about being caught in a no-win situation by:

explaining factors that may have led to this increase in class-action lawsuits
clarifying the risks of using certain medications and not treating depression
suggesting ways physicians can protect themselves and their patients.

The FDA’s position

In July 2006, the FDA issued a public health advisory regarding SSRI use during pregnancy and the possibility of persistent pulmonary hypertension (PPHN).² This warning was based on a single study that found the risk of developing PPHN (baseline rate: 1 to 2 per 1,000 births) was 6 times greater for fetuses exposed to SSRIs in late pregnancy.³ Many legal websites highlight this 2006 warning as proof of SSRIs’ danger. However, because subsequent studies have had conflicting results, the FDA’s current position is that the risks of using SSRIs during pregnancy are “unknown” (Box).^1-4

Box

FDA statements about antidepressant use during pregnancy

2006: In a warning about the risk of persistent pulmonary hypertension (PPHN) with antidepressant use during pregnancy, the FDA acknowledged “decisions about how to treat depression in pregnant women are increasingly complex.”² The FDA issued the warning based on a study by Chambers et al,³ noting that the study was “too small” to look at individual medications.

This warning also cited a study by Cohen et al⁴ that found “women who stopped their [antidepressant] medicine were five times more likely to have a relapse of depression during their pregnancy than were the women who continued to take their antidepressant medicine while pregnant.”² Although the warning identified a potential “rare” danger, the FDA guidance was that “women who are pregnant or thinking about becoming pregnant should not stop any antidepressant without first consulting their physician. The decision to continue medication or not should be made only after there has been careful consideration of the potential benefits and risks of the medication for each individual pregnant patient.”

2011: In this communication,¹ the FDA stated “the initial Public Health Advisory in July 2006 on this potential risk was based on a single published study. Since then, there have been conflicting findings from new studies evaluating this potential risk, making it unclear whether use of [selective serotonin reuptake inhibitors (SSRIs)] during pregnancy can cause PPHN.” The FDA also said that the “potential risk with SSRI use during pregnancy remains unknown.”

Risks of depression

Although most physicians know the risks of untreated MDD, they tend to minimize or forget these risks when a woman becomes pregnant. Pregnant women with MDD face not only the expected risks of their psychiatric illness but additionally face risks of pre-eclampsia, suicide (20% of deaths in the postpartum period are due to suicide), and infanticide.^5-10 Risks to the fetus include poor prenatal care, increased risk of intrauterine exposure to drugs or alcohol, increased exposure to maternal cortisol with resulting neurodevelopmental changes, preterm delivery, low birth weight, and failure to thrive.^6-8 Later difficulties for the child of a mother with untreated depression may include poor stress adaptation, decreased cognitive performance, and behavioral difficulties because of poor mother-child bonding and other factors.⁶

See Table 1 for key statistics regarding pregnancy and depression.

Table 1

Statistics on pregnancy and depression

There are approximately 6 million pregnancies each year in the United States^a
There are approximately 4 million live births each year in the United States^a
Two percent to 3% of healthy pregnancies result in a birth defect or miscarriage^b-d
Sixty percent to 70% of birth complications occur due to an unknown cause^d
Rates of depression during pregnancy are 7% to 25%^b,e,f
Approximately 13% of pregnant women take an antidepressant during pregnancy^e
Fifteen percent of women with untreated depression in pregnancy attempt suicide^b
Twenty percent of deaths in the postpartum period are due to suicide^e
Women who discontinue antidepressants are 5 times more likely than women who continue medications in pregnancy to have a relapse of depression^g,h
SSRIs are the antidepressant class most frequently prescribed to pregnant womenⁱ
Sertraline is one of the most frequently prescribed antidepressants perinatally and has low concentration in breast milk and infant serum^j,k
SSRIs: selective serotonin reuptake inhibitors American Pregnancy Association. Statistics. http://www.americanpregnancy.org/main/statistics.html. Accessed December 20, 2012. Hasser C, Brizendine L, Spielvogel A. SSRI use during pregnancy. Current Psychiatry. 2006;5(4):31-40. Altshuler L, Richards M, Yonkers K. Treating bipolar disorder during pregnancy. Current Psychiatry. 2003;2(7):14-26. Cott A, Wisner K. Psychiatric disorders during pregnancy. Internat Rev Psychiatry. 2003;15(3):217-230. Meltzer-Brody S. New insights into perinatal depression: pathogenesis and treatment during pregnancy and postpartum. Dialogues Clin Neurosci. 2011;13(1):89-100. 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. 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/PostmarketDrugSafetyInformationforPatientsandProviders /DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm124348.htm. Published July 19, 2006. Accessed December 20, 2012. 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. 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. Berle JO, Spigset O. Antidepressant use during breastfeeding. Curr Womens Health Rev. 2011;7(1):28-34. Friedman SH, Nagle-Yang S, Parsons S. Maternal mental health in the neonatal intensive care unit. NeoReviews. 2011;12(2):e85-e93.