Evidence-Based Reviews

Treating anxiety during pregnancy: Just how safe are SSRIs?

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

References

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A rational approach

Both benzodiazepines and SSRIs are associated with low but demonstrated risks to the fetus when used during pregnancy (Table 2).^{19,20,23,25,30,33} Use these medications to manage a patient’s anxiety only if the clinical benefit to the mother justifies the potential risks to the fetus.²⁹

A staggered combination of SSRIs during the first 2 trimesters and benzodiazepines during the last 2 trimesters can help balance the risks and benefits of pharmacotherapy of anxiety disorders during pregnancy (Table 3).

Frankly discuss with your patient the risks and benefits in the context of her perceived need for symptom control to sustain her level of functioning. You could document this discussion in the progress note as “R, B, A, and pt C,” signifying that risks, benefits, and alternatives were discussed, and the patient consented. If possible, include the patient’s husband, partner, or parent in this discussion.

Table 2

Risks of SSRIs vs benzodiazepines during pregnancy stages

Pregnancy stage when given	Fetal risk	SSRIs	Benzodiazepines
First trimester*	Teratogenicity	Paroxetine use associated with 2-fold increased risk of major congenital anomalies and 3-fold increased risk of major cardiac anomalies;¹⁹ meta-analysis calculated significant risk of cardiac malformations (odds ratio 1.72; population prevalence = 13.4/1,000 births)^20,33	Meta-analysis of case control studies showed increased risk of major malformations/cleft palate (odds ratio 3.01; population prevalence = 10 to 20/1,000 births); no association seen in cohort studies³⁰
Third trimester	PPHN	Case control study showed 3.7% of infants with PPHN were exposed to SSRIs vs 0.7% of controls; adjusted odds ratio 6.1, absolute risk to exposed population = 6 to 12/1,000 births)²³
Perinatal and long-term effects	Toxicity/withdrawal syndromes	Cohort study of 60 infants concluded prevalence of discontinuation syndromes is 30% in neonates with third trimester SSRI exposure²⁵	Neonatal toxicity (“floppy infant syndrome”) and neonatal withdrawal reported with maternal benzodiazepine use in late third trimester; prevalence unknown^†
	Preterm birth, serotonin withdrawal syndromes, CNS effects, long-term neurobehavioral effects	Unknown^†	Unknown^†
PPHN: persistent pulmonary hypertension of the newborn; SSRIs: selective serotonin reuptake inhibitors
* Available data indicate that first-trimester exposure to SSRIs (other than paroxetine) and benzodiazepines may increase the relative risk for congenital anomalies, but the absolute risk of having a child with an anomaly is small.
^† Some case reports, but published literature is insufficient to determine prevalence or magnitude of risk.

Table 3

Staggered, combination therapy for anxiety disorders during pregnancy

Pregnancy stage	Recommended to manage risks to mother and fetus
First trimester	SSRI (not paroxetine) No benzodiazepines Nondrug therapies*
Second trimester	SSRI (not paroxetine) Can use benzodiazepine if needed Nondrug therapies*
Third trimester	Taper off SSRI by 1 to 2 months before due date Can use benzodiazepine until 2 weeks before due date Nondrug therapies*
SSRI: selective serotonin reuptake inhibitor
* Nondrug therapies can include prenatal exercise, sleep hygiene, relaxation, and psychotherapy (cognitive-behavioral therapy, interpersonal therapy, supportive therapy, family/couples therapy)

CASE CONTINUED: CBT plus medication

Ms. K and her husband are open to adding weekly cognitive-behavioral therapy (CBT) for anxiety as long as she can continue her medications. You discuss the evidence regarding potential neonatal risks with paroxetine and clonazepam treatment. Because Ms. K is 6 weeks pregnant, you outline a plan for a rapid cross-taper off paroxetine and onto fluoxetine, 10 to 30 mg/d, explaining that paroxetine might pose a greater first-trimester risk of major congenital malformations and cardiac malformations. You discuss possible side effects of fluoxetine and explain a plan to taper off fluoxetine during the third trimester to reduce the risk of PPHN, early delivery, and withdrawal in the newborn.

Clinical Point

Benzodiazepines can be restarted in the second trimester, if needed, but taper them off completely 2 weeks before the patient’s due date

Because Ms. K has been taking clonazepam at only 0.5 mg 1 to 2 times per week, you instruct her to stop taking the benzodiazepine for the next 6 weeks until she is through her first trimester. You also reassure her that she can use clonazepam after the first trimester, if necessary, as long as she agrees to taper off completely 1 to 2 weeks before to her due date.

You refer her to a CBT therapist and emphasize the importance of CBT, relaxation, and sleep hygiene—as well as support from her husband, family, and friends—to reduce her stress and facilitate the medication taper during her third trimester. You plan to see her monthly and co-manage her care with the CBT therapist and Ob/Gyn. You document this discussion in her medical record as evidence of informed consent.

Related resources

Baby Center. Managing stress and anxiety during pregnancy. Patient information. www.babycenter.com/0_managing-stress-and-anxiety-during-pregnancy_1683.bc.
Organization of Teratology Information Specialists (OTIS). www.otispregnancy.org.

Drug brand names

Clonazepam • Klonopin
Paroxetine • Paxil
Fluoxetine • Prozac
Sertraline • Zoloft

Disclosures

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.