Mrs. J, age 24, has a history of recurrent major depression, for which you have prescribed paroxetine. Newly pregnant, she brings you Internet articles with headlines such as “Depression drugs ‘can raise birth defect risks.’”SSRI use during pregnancy: Do antidepressants’ benefits outweigh the risks?).
FDA recommends avoiding paroxetine in women of child-bearing age. How does this advisory change the way we manage depression in pregnancy? How strong is the evidence supporting it?
SSRIs and birth defect risk
Eight prospective or case-control studies of SSRIs in >5,400 pregnant women have been published since 1993 (Table).3-10 Five included paroxetine.6-10 The studies ranged from small to large, and none showed a significant increase in major malformations with any SSRI. Even in a study of >2,500 women, no single malformation was overrepresented.8
In addition, a recent meta-analysis11 of 7 prospective comparative cohort studies involving 1,774 pregnant women showed no increased risk of major birth defects from exposure to any of the 8 antidepressants studied, including 4 SSRIs used during the first trimester. The review identified no specific malformation or cluster of malformations associated with first-trimester antidepressant use.
Table
8 published studies: No significant increase in birth defects with SSRIs
| Year/location | Authors | Study design | SSRI exposure (# of patients) | Risk of major malformation |
|---|---|---|---|---|
| 1993/USA, Canada | Pastuszak et al3 | Prospective cohort, controlled | Fluoxetine (98) | SSRI: 2% Control: 1.8% (ns) |
| 1996/USA | Chambers et al4 | Prospective cohort, controlled | Fluoxetine (174) | SSRI: 3.4% Control: 2.7% (ns) |
| 1997/worldwide | Goldstein et al5 | Clinical trial | Fluoxetine (28) | SSRI: 3.6% (ns) |
| 1998/USA, Canada, Brazil | Kulin et al6 | Prospective cohort, controlled | Paroxetine (97) | Total SSRI: 4.1% Control: 3.8% (ns) |
| Sertraline (147) | ||||
| Fluvoxamine (26) | ||||
| 1999/Sweden | Ericson et al7 | Case-control | Citalopram (364) | Citalopram: 3.9% Total risk of remaining SSRIs: 3.8% (ns) |
| Paroxetine (118) | ||||
| Sertraline (32) | ||||
| Fluoxetine (15) | ||||
| 2002/USA | Simon et al9 | Case-control | Fluoxetine (129) | Total SSRI: 6.5% Control: 4.9% (ns) |
| Sertraline (32) | ||||
| Paroxetine (28) | ||||
| 2003/USA | Hendrick et al10 | Prospective, uncontrolled | Fluoxetine (13) | Total SSRI: 1.4% (ns) |
| Paroxetine (19) | ||||
| Sertraline (36) | ||||
| 2005/Sweden | Hallberg et al8 | Case-control | Citalopram (1,696) | Citalopram: 3.1% |
| Paroxetine (708) | Paroxetine: 3.4% | |||
| Sertraline (1,067) | Sertraline: 2.0% | |||
| Fluoxetine (574) | Fluoxetine: 3.3% (ns) | |||
| ns: No statistically significant difference | ||||
Evidence cited by FDA
FDA’s advisory (Box) came 3 months after GSK notified health professionals that fetuses exposed to paroxetine during organogenesis may be at increased risk of developing malformations, particularly ventricular septal defect (see Related resources).
Paroxetine in pregnancy:
What FDA recommends to you and your patients
GSK’s study. GSK conducted a retrospective cohort study of major congenital malformations in children of women who had taken antidepressants in the first trimester.12 The study used data from two Ingenix databases of United Healthcare medical insurance information. Malformation rates were compared with those in the general population, as determined by a 1999 Centers for Disease Control and Prevention study of four pregnancy registries and a population-based birth-defect surveillance system.13 After adjustments were made for other antidepressants and known teratogenic drugs the women took while pregnant, the study showed:What FDA recommends to you and your patients
The FDA is awaiting the final results of the recent studies and accruing additional data related to the use of paroxetine in pregnancy in order to better characterize the risk for congenital malformations associated with paroxetine. In the interim, FDA recommends the following:
Physicians who are caring for women receiving paroxetine should alert them to the potential risk to the fetus if they plan to become pregnant or are currently in their first trimester of pregnancy. Discontinuing paroxetine therapy should be considered for these patients. In individual cases, the benefits of continuing paroxetine may outweigh the potential risk to the fetus. If the decision is made to discontinue paroxetine and switch to another antidepressant or cease antidepressant therapy, paroxetine discontinuation should be undertaken only as directed in the prescribing information. Paroxetine should generally not be initiated in women who are in their first trimester of pregnancy or in women who plan to become pregnant in the near future.
Women who are pregnant, or planning a pregnancy, and currently taking paroxetine should consult with their physician about whether to continue taking it. Women should not stop the drug without discussing the best way to do that with their physician.
Source: Verbatim from FDA advisory, December 2005.
- Major congenital defects occurred in 4% of 527 pregnancies during which women used paroxetine, (adjusted odds ratios [OR], 2.20; 95% CI, 1.34-3.63), compared with 3% prevalence in the general population.
- Cardiovascular malformations occurred at an adjusted rate of 2% (OR, 2.08; 95% CI, 1.03-4.23), compared with 1% in the general population.
- 10 of the 14 cardiovascular malformations were ventricular septal defects.
The GSK investigation was an unpublished retrospective study without peer review when FDA issued its advisory about paroxetine.
Two abstracts. The FDA alert also cited two abstracts that were not peer-reviewed and whose findings were inconsistent with those of GSK.