Evidence-Based Reviews

Treating anxiety during pregnancy: Just how safe are SSRIs?

Current Psychiatry. 2008 February;7(2):39-52

References

1. Ross LE, McLean LM. Anxiety disorders during pregnancy and the postpartum period: a systematic review. J Clin Psychiatry 2006;67(8):1285-98.

2. Labad J, Menchon JM, Alonso P, et al. Female reproductive cycle and obsessive-compulsive disorder. J Clin Psychiatry 2005;66(4):428-35.

3. Adewuya AO, Ola BA, Aloba OO, Mapayi BM. Anxiety disorders among Nigerian women in late pregnancy: a controlled study. Arch Womens Ment Health 2006;9(6):325-8.

4. Field T, Hernandez-Reif M, Diego M, et al. Stability of mood states and biochemistry across pregnancy. Infant Behav Dev 2006;29(2):262-7.

5. Teixeira JM, Fisk NM, Glover V. Association between maternal anxiety in pregnancy and increased uterine artery resistance index: cohort based study. BMJ 1999;318(7177):153-7.

6. Monk C, Myers MM, Sloan RP, et al. Effects of women’s stress-elicited physiological activity and chronic anxiety on fetal heart rate. J Dev Behav Pediatr 2003;24(1):32-8.

7. Egliston KA, McMahon C, Austin MP. Stress in pregnancy and infant HPA axis function: conceptual and methodological issues relating to the use of salivary cortisol as an outcome measure. Psychoneuroendocrinology 2007;32(1):1-13.

8. Levey L, Ragan K, Hower-Hartley A, et al. Psychiatric disorders in pregnancy. Neurol Clin 2004;22(4):863-93.

9. Oberlander TF, Reebye P, Misri S, et al. Externalizing and attentional behaviors in children of depressed mothers treated with a selective serotonin reuptake inhibitor antidepressant during pregnancy. Arch Pediatr Adolesc Med 2007;161(1):22-9.

10. Misri S, Reebye P, Kendrick K, et al. Internalizing behaviors in 4-year-old children exposed in utero to psychotropic medications. Am J Psychiatry 2006;163(6):1026-32.

11. Copper RL, Goldenberg RL, Das A, et al. The Preterm Prediction Study: maternal stress is associated with spontaneous preterm birth at less than thirty-five weeks’ gestation. Am J Obstet Gynecol 1996;175(5):1286-92.

12. Sutter-Dallay AL, Giaconne-Marcesche V, Glatigny-Dallay E, Verdoux H. Women with anxiety disorders during pregnancy are at increased risk of intense postnatal depressive symptoms: a prospective survey of the MATQUID cohort. Eur Psychiatry 2004;19(8):459-63.

13. Nierop A, Bratsikas A, Zimmermann R, Ehlert U. Are stress-induced cortisol changes during pregnancy associated with postpartum depressive symptoms? Psychosom Med 2006;68(6):931-7.

14. Weissman MM. Recent non-medication trials of interpersonal psychotherapy for depression. Int J Neuropsychopharmacology 2007;10(1):117-22.

15. Ward RK, Zamorski MA. Benefits and risks of psychiatric medications during pregnancy. Am Fam Physician 2002;66(4):629-36.

16. Bastani F, Hidarnia A, Montgomery KS, et al. Does relaxation education in anxious primigravid Iranian women influence adverse pregnancy outcomes? A randomized controlled trial. J Perinat Neonatal Nurs 2006;20(2):138-46.

17. Fricchione G. Generalized anxiety disorder. N Engl J Med 2004;351(7):675-82.

18. Källén BA, Otterblad Olausson P. Maternal use of selective serotonin re-uptake inhibitors in early pregnancy and infant congenital malformations. Birth Defects Res A Clin Mol Teratol 2007;79(4):301-8.

19. Berard A, Ramos E, Rey E, et al. First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage. Birth Defects Res B Dev Reprod Toxicol 2007;80(1):18-27.

20. Bar-Oz B, Einarson T, Einarson A, et al. Paroxetine and congenital malformations: meta-analysis and consideration of potential confounding factors. Clin Ther 2005;29(5):918-26.

21. Malm H, Klaukka T, Neuvonen PJ. Risks associated with selective serotonin reuptake inhibitors in pregnancy. Obstet Gynecol 2005;106(6):1289-96.

22. 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(11):1889-95.

23. 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.

24. Haddad PM, Pal BR, Clarke P, et al. Neonatal symptoms following maternal paroxetine treatment: serotonin toxicity or paroxetine discontinuation syndrome? J Psychopharmacology 2005;19(5):554-7.

25. Levinson-Castiel R, Merlob P, Linder N, et al. Neonatal abstinence syndrome after in utero exposure to selective serotonin reuptake inhibitors in term infants. Arch Pediatr Adolesc Med 2006;160(2):173-6.

26. Sanz EJ, De-las-Cuevas C, Kiuru A, et al. Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis. Lancet 2005;365(9458):482-7.

27. Suri R, Altshuler L, Hellemann G, et al. Effects of antenatal depression and antidepressant treatment on gestational age at birth and risk of preterm birth. Am J Psychiatry 2007;164(8):1206-13.

28. Zeskind PS, Stephens LE. Maternal selective serotonin reuptake inhibitor use during pregnancy and newborn neurobehavior. Pediatrics 2004;113(2):368-75.

29. Iqbal MM, Sobhan T, Ryals T. Effects of commonly used benzodiazepines on the fetus, the neonate, and the nursing infant. Psychiatr Serv 2002;53(1):39-49.

30. Dolovich LR, Addis A, Vaillancourt JM, et al. Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and case-control studies. BMJ 1998;317(7162):839-43.

31. McElhatton PR. The effects of benzodiazepine use during pregnancy. Reprod Toxicol 1994;8(6):461-75.

32. Lin AE, Peller AJ, Westgate MN, et al. Clonazepam use in pregnancy and the risk of malformations. Birth Defects Res A Clin Mol Teratol 2004;70(8):534-6.

33. Levy M, James MS, Erickson JD, McClearn AB. Prevalence of birth defects. Birth outcomes Centers for Disease Control and Prevention. Available at: http://www.cdc.gov/reproductivehealth/Products&Pubs/DatatoAction/pdf/birout4.pdf. Accessed January 9, 2008.

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CASE CONTINUED: ‘Stay the course’

Ms. K worries that she could not tolerate recurrence of her anxiety symptoms and wishes to continue both medications. Her husband concurs, but they want to minimize potential risks to their baby. You discuss the options for treating anxiety symptoms during pregnancy, including medications, psychotherapy, and behavioral treatments.

Treatment decisions

Ideally you’ll begin treating anxiety disorders in women of childbearing age with preconception psychoeducation. Explaining the risks of medications if she were to become pregnant and asking about the contraception she is using are de rigueur. Psychotherapy is low risk to the fetus and is considered first choice for treating mild to moderate anxiety in women of childbearing age who plan to become pregnant (Box).^1,14-17

Box

Psychotherapy: First choice for anxiety during pregnancy

No studies directly address the efficacy or outcome of any psychotherapy for anxiety in pregnancy. Even so:

For mild to moderate anxiety, psychotherapy is the first-line treatment for pregnant women.
Interpersonal psychotherapy (IPT) without medications can reduce depressive symptoms in pregnant women with depression.¹⁴
Cognitive-behavioral therapy (CBT) without medications has shown efficacy for anxiety disorders in psychiatric populations.^15,16

Because no evidence suggests that pregnant women require different psychotherapeutic recommendations than other psychiatric patients, consider a course of CBT that targets anxiety symptoms or IPT for a pregnant patient with an anxiety disorder.

Relaxation therapy also has shown efficacy in treating anxiety disorders. In a randomized controlled trial of 110 pregnant women with high-level anxiety, 7 weeks of applied relaxation training sessions was associated with significant reductions in low-weight births, cesarean sections, and instrumental extractions.^16,17

Because poor marital relationships are consistent psychosocial predictors of anxiety during pregnancy and postpartum depression,¹ recommend family or marital therapy when appropriate.

Psychotherapy alone is inadequate, however, for the many patients—such as Ms. K—who present already pregnant with a history of moderate to severe anxiety. Adjunctive psychotropic therapy—along with various nonmedication therapies—is warranted for patients whose social or occupational functioning would be substantially impaired by suboptimal control of anxiety during pregnancy.

Because Ms. K wishes to continue taking paroxetine and clonazepam, what can you tell her about the risks and benefits of SSRIs and benzodiazepines during pregnancy?

SSRIs in pregnancy

Teratogenicity. Compared with benzodiazepines, SSRIs have been considered agents of choice for use during pregnancy because of a lower risk of teratogenic effects.¹⁵ Paroxetine, however, appears to pose a greater risk for teratogenicity than other SSRIs.

Clinical Point

Paroxetine appears to pose a greater risk for teratogenicity (specifically cardiac malformations) than other SSRIs

An increased risk for fetal ventricular and/or atrial septal defects has been associated with first-trimester exposure to paroxetine, but no other SSRI.¹⁸ First trimester exposure to paroxetine at doses averaging 25 mg/d has been associated with statistically significant risks of major congenital anomalies (2-fold increase) and major cardiac anomalies (3-fold increase),¹⁹ although other studies have failed to reproduce this finding. A meta-analysis of 7 studies by Bar-Oz et al²⁰ found an association between first-trimester paroxetine exposure and a significant increase in risk for cardiac malformations (odds ratio [OR] 1.72; 95% CI,1.22-2.42).

The overall rate of fetal malformations from SSRIs appears to be low, although most studies have examined only fluoxetine or paroxetine. Some studies have reported various malformations with fluoxetine or sertraline, but others have not. In Finland, a population-based study found no increase in rate of major congenital malformations in offspring of 1,782 women who filled prescriptions for SSRIs during pregnancy, compared with the general population rate of 1% to 3%.²¹

Neurobehavioral effects. SSRI exposure during fetal life has shown no long-term neurobehavioral effects. A blinded prospective study by Nulman et al²² found no differences in global IQ scores, language development, or behavioral development among children age ≤5 who were exposed in utero to fluoxetine (n=40) or a tricyclic antidepressant (n=46), compared with unexposed children of nondepressed mothers (n=36). Similarly, using reports from teachers and clinical measures of internalizing behaviors, Misri et al¹⁰ found no increase in depression, anxiety, or withdrawal in 4-year-olds with prenatal exposure to SSRIs (n=22), compared with nonexposed children (n=14).

Pulmonary hypertension. SSRI exposure in later pregnancy may increase the rate of persistent pulmonary hypertension of the newborn (PPHN), which occurs in 1 to 2 infants per 1,000 live births. PPHN showed a statistically significant association with late prenatal SSRI exposure (OR 6.1) in a study that controlled for maternal smoking, body mass index, and diabetes.²³ PPHN occurred in approximately 1% of infants exposed to SSRIs in late pregnancy. PPHN rates were not affected by maternal depression/anxiety, non-SSRI antidepressant exposure throughout pregnancy, or SSRI exposure during early pregnancy only.