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.

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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.

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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.

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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.

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Toxicity and withdrawal syndromes. Infants of women who continue to take SSRIs just before delivery can develop toxicity or withdrawal syndromes. Occurrence of either syndrome depends on SSRI half-life, serum concentration, and the pharmacodynamics of other medications given during pregnancy and labor.²⁴

Discontinuation syndromes can occur in SSRI-exposed neonates within a few hours or days after birth and last up to 1 month after delivery, depending on the infant’s susceptibility.²⁵ Nearly two-thirds of suspected SSRI-induced neonatal withdrawal syndromes have been associated with paroxetine, although all SSRIs appear be associated with some risk.²⁶ Several trials, including a recent prospective study, found prenatal antidepressant use associated with lower gestational age at birth and increased risk of preterm birth.²⁷

Clinical Point

Taper and discontinue SSRI use during the third trimester, then restart after delivery to prevent anxiety symptom recurrence

A prospective study compared the effects of maternal SSRI use on behavioral state, sleep, motor activity, and heart rate variability in 17 exposed vs 17 nonexposed matched neonates. In the first 1 to 2 weeks of life, SSRI-exposed neonates showed:

greater tremulousness
less flexible and dampened state regulation
more time in uninterrupted REM sleep
more frequent startles or sudden arousals
greater generalized motor activity
greater autonomic dysregulation.²⁸

In a cohort study of 60 neonates exposed to SSRIs in utero, 30% met diagnostic criteria for neonatal abstinence syndrome. The most common discontinuation symptoms were:

tremor (37/60)
GI disturbances (34/60)—including exaggerated sucking, poor feeding, regurgitation, vomiting, and loose stools
sleep disturbance (21/60).

Other symptoms included irritability, constant crying, shivering, increased tone, convulsions, jitteriness, poor gaze control, vomiting, myoclonus, and lethargy.²⁵

Recommendations. The perception that SSRIs have low fetal toxicity has guided prescribing practices in recent years. Newer evidence shows, however, that fetal exposure to SSRIs may have some adverse effects, including lower birth weight and early delivery. First-trimester paroxetine use has been associated with increased risk for fetal ventricular and/or atrial septal defects.

Discuss these risks with the patient when you consider starting or continuing SSRI use during pregnancy.²⁴ If you prescribe an SSRI, use the minimum effective dosage and avoid paroxetine during pregnancy.¹⁸

To reduce the risk for PPHN, early delivery, and neonatal withdrawal syndromes, taper and discontinue the SSRI during the third trimester. Restarting the SSRI soon after delivery is the most effective way to prevent recurrence of anxiety symptoms or postpartum depression.

Benzodiazepines

Teratogenicity. Like SSRIs, benzodiazepines cross the placenta to the fetus.²⁹ Benzodiazepine teratogenicity remains controversial.⁸ Some—but not all—data show a small but significant increased risk for major malformations/oral cleft malformations with first-trimester benzodiazepine exposure.

A Medline literature search from 1966 to 2000 found not enough information to determine whether potential benefits of benzodiazepines to the mother outweigh risks to the fetus.²⁹ An ambitious meta-analysis of >1,400 studies by Dolovich et al³⁰ found a small association between fetal exposure to benzodiazepines and major malformations/cleft palate, but only in pooled data from case-controlled studies. No association was found between fetal exposure to benzodiazepines and malformations/cleft palate in pooled data from cohort studies.

A 32-month, hospital-based surveillance program of 28,565 births found no increase in the rate of major malformations in 43 infants exposed to clonazepam monotherapy—33 (77%) in the first trimester.³¹ Thus, the risk of major malformations/cleft palate with the use of benzodiazepines in the first trimester appears to be low.

Clinical Point

Discuss the risks, benefits, and alternatives with the patient and (if possible) the patient’s husband, partner, or parent

Toxicity and withdrawal syndromes. Neonatal benzodiazepine toxicity and withdrawal syndromes have been reported in studies and case reports. Although these syndromes occur, they do not affect all infants with late third-trimester benzodiazepine exposure. Prevalence rates have not been calculated.³²

Neonatal toxicity (“floppy infant syndrome”)—characterized by hypothermia, lethargy, poor respiratory effort, and feeding difficulties—occurs after maternal benzodiazepine use just before delivery.⁸
Neonatal withdrawal may be caused by very late, third trimester exposure to benzodiazepines. Symptoms—which can persist ≤3 months after delivery—include restlessness, irritability, abnormal sleep patterns, suckling difficulties, growth retardation, hypertonia, hyperreflexia, tremulousness, apnea, diarrhea, and vomiting.^8,29

Recommendations. When possible, avoid benzodiazepines in the first trimester because of possible teratogenicity and then again late in the third trimester before delivery because of neonatal withdrawal syndromes. To reduce as much as possible the small risk of a benzodiazepine-related fetal malformation/cleft palate, wean the mother from benzodiazepines before conception. After the first trimester, the benzodiazepine can be restarted if necessary.²⁹

To minimize neonatal withdrawal, gradually taper the mother’s benzodiazepine before delivery.²⁹ Because the baby’s due date is calculated to be ±2 weeks before delivery, begin this taper 3 to 4 weeks before the due date and discontinue at least 1 week before delivery. Breastfeeding while taking benzodiazepines is not recommended because of the risk of over-sedating the infant.