Evidence-Based Reviews

SSRI use during pregnancy

Current Psychiatry. 2006 April;5(4):31-40

Caitlin Hasser, MD

Louann Brizendine, MD

Anna Spielvogel, MD, PhD

Do antidepressants’ benefits outweigh the risks?

PDF Download

References

1. Bonari L, Koren G, Einarson TR, et al. Use of antidepressants by pregnant women: evaluation of perception of risk, efficacy of evidence-based counseling, and determinants of decision making. Arch Women Ment Health 2005;8:214-20.

2. Hallberg P, Joblom V. The use of selective serotonin reuptake inhibitors during pregnancy and breast-feeding: a review and clinical aspects. J Clin Psychopharmacol 2005;25:59-73.

3. Larsson C, Sydsjo G, Josefsson A. Health, sociodemographic data, and pregnancy outcome in women with antepartum depressive symptoms. Obstet Gynecol 2004;104(3):469-66.

4. Bonari L, Pinto N, Ahn E, et al. Perinatal risks of untreated depression during pregnancy. Can J Psychiatry 2004;49(11):726-35.

5. Cohen L, 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.

6. Hendrick V, Altshuler L. Management of major depression during pregnancy. Am J Psychiatry 2002;159:1667-73.

7. Sandman CA, Glynn L, Wadhwa PD, et al. Maternal hypothalamic-pituitary-adrenal dysregulation during the third trimester influences human fetal responses. Dev Neurosci 2003;25(1):41-9.

8. Huot RL, Brennan PA, Stowe ZN, et al. Negative affect in offspring of depressed mothers is predicted by infant cortisol levels at 6 months and maternal depression during pregnancy, but not postpartum. Ann NY Acad Sci 2004;1032:234-6.

9. Gutteling BM, de Weerth C, Buitelaar JK. Prenatal stress and children’s cortisol reaction to the first day of school. Psychoneuroendocrinology 2005;20:541-9.

10. Hendrick V, Stowe ZN, Altshuler LL, et al. Placental passage of antidepressant medications. Am J Psychiatry 2003;5:993-6.

11. GlaxoSmithKline study EPIP083. GSK medicine: buproprion and paroxetine. Epidemiology study: preliminary report on bupropion in pregnancy and the occurrence of cardiovascular and major congenital malformation. Available at: http://ctr.gsk.co.uk/summary/paroxetine/epip083.pdf. Accessed March 13, 2006.

12. Ericson A, Kallen B, Wiholm BE. Delivery outcome after the use of antidepressants in early pregnancy. Eur J Clin Pharmacol 1999;55:503-8.

13. Kulin NA, Pastuszak A, Sage S, et al. Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors. A prospective controlled multicenter study. JAMA 1998;279:609-10.

14. Kallen BA, Otterblad Olausson P. Maternal drug use in early pregnancy and infant cardiovascular defect. Reprod Toxicol 2003;17:255-61.

15. Lattimore K, Donn S, Kaciroti N, et al. Selective serotonin reuptake inhibitor use during pregnancy and effects on the fetus and newborn: a meta-analysis. J Perinatol 2005;25:595-604.

16. Levy L, Ragan K, Hower-Hartley A, et al. Psychiatric disorders in pregnancy. Neurol Clin 2004;22:863-93.

17. Nordeng H, Spigset O. Treatment with selective serotonin reuptake inhibitors in the third trimester of pregnancy: effects on the infant. Drug Saf 2005;28(7):565-81.

18. Levinson-Castiel R, Merlob P, Linder N, et al. Neonatal abstinence syndrome after in utero exposure to selective serotonin reuptake inhibitors to term infants. Arch Pediatr Adolesc Med 2006;160:173-6.

19. Oberlander TF, Misri S, Fitzgerald CE, et al. Pharmacologic factors associated with transient neonatal symptoms following prenatal psychotropic medication exposure. J Clin Psychiatry 2004;65(2):230-7.

20. Zeskind PS, Stephens L. Maternal selective serotonin reuptake inhibitor use during pregnancy and newborn neurobehavior. Pediatrics 2004;113:368-75.

21. Moses-Kolko E, Bogen D, Perel J, et al. Neonatal signs after late in utero exposure to serotonin reuptake inhibitors. JAMA 2005;293:2372-83.

22. 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):579-87.

23. Nulman I, Rovet J, Stewart DE, et al. Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a prospective, controlled study. Am J Psychiatry 2002;159:1889-95.

24. Casper RC, Fleisher BE, Lee-Ancajas JC, et al. Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy. J Pediatr 2003;4(142):402-8.

25. Spinelli M, Endicott J. Controlled clinical trial of interpersonal psychotherapy versus parenting education program for depressed pregnant women. Am J Psychiatry 2003;160:555-62.

26. Oren D, Wisner K, Spinelli M, et al. An open trial of morning light therapy for treatment of antepartum depression. Am J Psychiatry 2002;159:666-9.

Untreated depression can have serious consequences, but many pregnant women resist taking antidepressants because they overestimate the risk of birth defects.^{Paroxetine in pregnancy”). Further study is needed to define the risks of teratogenesis with paroxetine compared with other antidepressants.}

Third-trimester exposure

In a recent meta-analysis, infants exposed to SSRIs in utero showed an increased risk for prematurity (OR; 2.03) and low birth weight (OR; 2.37).¹⁵ Other studies, however, showed no differences in these risks in SSRI-exposed infants or attributed the results to untreated maternal depression or smoking.¹⁶

A Medline search across the last 20 years¹⁷ found 26 case reports, three prospective controlled cohort studies, and other records of >400 women who received fluoxetine, sertraline, or paroxetine in the third trimester. The authors found the evidence “ambiguous” as to the cause of adverse events and concluded that the risk of not treating major depression with adequate SSRI therapy at that stage of pregnancy “most likely” outweighs the risk of harm to infants.

Transient neonatal complications. Thirty percent of neonates exposed to SSRIs in the third trimester experience transient adaptation problems, which peak 48 hours after birth¹⁸ (Table 3). Symptoms may include initial lack of crying, increased muscle tonus, flush, irritability, jitteriness, hypothermia, abnormal breathing, and disrupted sleep and motor activity.^2,19,20

Transient neonatal symptoms from SSRI exposure are thought to be a serotonin withdrawal syndrome or serotonin overstimulation.²¹ The syndrome is usually mild, self-limited, and requires only supportive treatments. All antidepressants’ labels warn of these effects.

Table 3

Neonatal SSRI withdrawal: Symptoms, causes, and treatment

Symptoms	Initial lack of crying
	Increased muscle tonus
	Irritability, jitteriness
	Abnormal breathing pattern
	Disrupted sleep and motor activity
Hypotheses of cause	Serotonin overstimulation or withdrawal
Treatment	Close observation
Treatment	Supportive measures

Pulmonary hypertension. An increased risk of persistent pulmonary hypertension of the newborn (PPHN) has been shown in infants exposed to SSRIs after 20 weeks’ gestation. A retrospective case-control study concluded that the absolute risk of PPHN with SSRIs is relatively low (6 to 12 cases per 1,000 pregnancies).²²

Recommendation. Some authors have recommended tapering antidepressants in the third trimester, but the risk of postpartum depression appears to outweigh any potential benefit from discontinuation. Because birth timing is unpredictable, some women whose antidepressants are tapered off could be without medication for a long time.

Thus, we recommend:

continuing SSRIs during late pregnancy
monitoring the newborn for 48 hours for transient neonatal adaptation symptoms or PPHN.^2,17,18

Long-term effects of SSRI exposure

Do SSRIs during pregnancy have long-term effects on infants’ neurodevelopment? Study results are mixed. For example:

A prospective, controlled, cohort trial found no adverse effects on IQ, language, or behavioral development in children ages 15 months to 6 years whose mothers took tricyclic antidepressants (N=46) or fluoxetine (N=40) during pregnancy, compared with 36 unexposed controls.²³
Another prospective study showed lower Bayley Psychomotor Developmental Index scores in 31 SSRI-exposed infants compared with 13 infants born to depressed mothers not on antidepressants. Reduced body control, coordination, and fine motor skills might suggest possible subtle effects of SSRIs on motor development in exposed infants, the authors concluded.²⁴

Case continued: A healthy delivery

Ms. P’s depression improves a few weeks after she restarts an SSRI. She delivers a healthy term baby with Apgar score of 7. The baby initially does not cry, awakens easily, and shows mild irritability. His mother’s SSRI use, her severe depression during part of the pregnancy, or some other factor may have caused his mild neonatal complications.

Nursing staff carefully observe the infant for 2 days in the newborn nursery, and his irritability fades away. Ms. P decides to continue taking antidepressants to care for herself and the baby.

Weighing treatment options

For each woman with a history of depression who is pregnant or intends to conceive, we recommend a risk-benefit analysis of her depression severity and need for an antidepressant:

Mild depression (BDI 25,26

Moderate to severe depression (history of recurrent depressive episodes, hospitalization, or suicidality). Strongly consider medication. If your patient is taking an SSRI, counsel her about:

the 70% risk of depression relapse if she stops the medication, even for the first trimester
risks of untreated depression during pregnancy (poor self-care, preterm labor, birth complications, and increased risk for poor stress adaptations in children).

If she refuses antidepressant treatment, monitor her for suicidal tendencies, deteriorating social function, psychosis, and inability to comply with prenatal care during the pregnancy and postpartum.

Choosing an SSRI. No one SSRI is the safest choice for all women, especially when data on breast-feeding come into play.

Fluoxetine has been studied more than other SSRIs during pregnancy; most evidence is reassuring, except for transient neonatal complications. With its long half-life, fluoxetine is not recommended during breastfeeding because it may accumulate in infant sera.
Sertraline has shown low umbilical cord to maternal serum ratios in small samples and has reassuring breast-feeding data.
Citalopram, compared with sertraline, has been studied more in pregnancy but has a higher fetal-to-maternal serum ratio (as does escitalopram). These SSRIs are usually second-line for starting a new antidepressant during pregnancy but could be first-line if they have worked well for a patient or she has had adverse effects with fluoxetine or sertraline.