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.

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.

Table 2

Potential concerns when treating pregnant women with psychotropics

Miscarriage (spontaneous abortion)
Malformation (teratogenesis)
Preterm delivery
Perinatal syndrome (toxicity or withdrawal in neonate; usually self-limited and related to serotonin overstimulation or withdrawal; symptoms may include disrupted sleep irritability jitteriness or abnormal breathing)
Behavioral teratogenesis (later behavioral problems in child eg lower IQ developmental delays or autism)
Lactation compatibility or plans to bottle-feed
Source: References 6,7

The basis of class-action lawsuits

Interest in class-action lawsuits involving birth defects and antidepressants, particularly sertraline, appears to be increasing. Many websites advertising these lawsuits quote unnamed articles from reputable medical journals to support the claim that the medications are dangerous and cause a wide range of birth defects. Although some of the birth defects mentioned are specific, others (eg, “breathing problems” or “gastrointestinal side effects”) are so broad that any problem or complication could conceivably be attributed to the antidepressant. The degree of causation—if any at all—for many of these conditions has not been determined. A national advertising campaign looking for any problem may be occurring because the exact risks are “unknown.”¹

The 2009 U.S. Supreme Court ruling in Wyeth v Levine²⁵ allows individuals to sue manufacturers of branded medications in state and federal court for lack of proper labeling. However, the 2011 U.S. Supreme Court case of PLIVA, Inc. v Mensing²⁶ prohibits state lawsuits against manufacturers of generic medications over labeling because by federal (superseding) law, generic manufacturers must use the same warnings as the branded medication. This may in part explain why many medications targeted in commercials and websites for class-action lawsuits are branded products, even though generics are available.

Clinical Point

The U.S. Supreme Court has prohibited state lawsuits against manufacturers of generic agents

The focus of these types of lawsuits has been on drug manufacturers, in part because of the success of past litigation. Past class- and single-action lawsuits involving birth defects against pharmaceutical companies, such as Richardson-Merrell Inc.—the manufacturer of thalidomide and Bendectin, the branded version of a combination of pyridoxine and doxylamine used to treat nausea and vomiting during pregnancy—were successful. Although limb defects with thalidomide were scientifically proven, Bendectin was never conclusively shown to cause birth defects even though it had been prescribed to 40% of pregnant women at one point. The legal theory behind the lawsuits is that the manufacturers should have done more research to determine the potential for birth defects.²⁷ In a case against SmithKline Beecham Corporation,²⁸ which makes Paxil, the branded version of the SSRI paroxetine, a jury found the manufacturer negligent for failing to warn about Paxil’s association with cardiac defects. The result was a $2.5 million jury verdict. Since that case, the manufacturer has settled >800 additional suits for >$1 billion. Because this risk of using paroxetine has been established, physicians should discuss this risk with their patients as part of an informed consent because they could be liable if they don’t.²¹ This legal concept is known as the “learned intermediary doctrine,” which states that once the risk is known, the intermediary (eg, the physician) is responsible to ensure that a product (eg, medication) is used appropriately. The 2011 FDA statement saying the risk for SSRIs during pregnancy is unknown¹ is important because it removes physicians as “learned intermediaries.”

Protect your patient and yourself

An estimated 13% of pregnant women take antidepressants; SSRIs are the most commonly used antidepressant during and after pregnancy.⁹ Although not every depressed pregnant woman requires medication, those with moderate to severe depression often do. Rational medication decisions, informed consent, and good documentation are important when treating these women. Discuss the risks of untreated illness as well as the risks of medications to ensure that the patient understands that avoiding medication does not guarantee a safe pregnancy. Suggest psychotherapy and electroconvulsive therapy as options when appropriate. When possible, include the patient’s partner and family in the discussion to help improve compliance and potentially reduce strife.²⁹ The psychiatrist or patient should discuss the medication plan with the patient’s obstetrician or family physician.

Clinical Point

Ensure that pregnant patients understand the risks of untreated depression as well as the risks of medication

Whenever possible, consider using monotherapy, continuing a previously “successful” medication, and using the lowest effective dose.⁵ Clinicians may “underdose” medications because they believe this will lessen the risk from exposure, but this is risky because the fetus is still being exposed to the medication as well as the negative effects of undertreated MDD. If SSRIs are used throughout the pregnancy, the newborn may require additional observation to monitor for potential perinatal syndromes or PPHN.