Paroxetine in pregnancy?
FDA advisory flunks as evidence-based medicine.
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.
8 published studies: No significant increase in birth defects with SSRIs
SSRI exposure (# of patients)
Risk of major malformation
Pastuszak et al3
Prospective cohort, controlled
Chambers et al4
Prospective cohort, controlled
Goldstein et al5
SSRI: 3.6% (ns)
1998/USA, Canada, Brazil
Kulin et al6
Prospective cohort, controlled
Total SSRI: 4.1%
Ericson et al7
Simon et al9
Total SSRI: 6.5%
Hendrick et al10
Total SSRI: 1.4% (ns)
Hallberg et al8
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
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.
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:
- 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 cardiovascular malformation rate associated with paroxetine was significantly higher than the rates seen with other SSRIs examined in the databases.
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.
In the first abstract, a U.S. case-control study showed an increased risk of major malformations in 5,357 infants of women who took SSRIs in the first trimester, compared with 3,366 normal controls.14 Specific birth defects included:
- 161 infants with omphalocele (bowel protrusion through an abdominal wall defect) (OR, 3.0; 95% CI, 1.4-6.1)
- 372 infants with craniosynostosis (deformities caused by premature closure of skull sutures) (OR, 1.8; 95% CI, 1.0-3.2).
Paroxetine was associated with an increased risk of omphalocele (OR, 6.3; CI, 2.0-19.6) but no significant risk of cardiovascular defects. The authors stated that the associations need to be confirmed in other data sets, but this had not been done when FDA issued its warning.
In the second abstract, Wogelius et al15 examined a Danish prescription database and found a slightly increased risk for congenital malformation (OR, 1.4; 95% CI, 1.1-1.9) and specifically cardiac malformation (OR, 1.6; 95% CI, 1.0-2.6) with SSRIs during pregnancy. This study included 1,054 women who filled SSRI prescriptions within a window of 30 days before conception to the end of the first trimester. The authors compared these malformation rates with those in 150,908 controls (women who did not fill an SSRI prescription in this period before and during pregnancy).
This cohort study did not report specific data about paroxetine, nor whether the women took the SSRIs they acquired.
Epidemiologic studies. The FDA also cited two unpublished epidemiologic studies.
The first analyzed a Swedish national registry database and found that infants whose mothers received paroxetine in early pregnancy had a 2% risk of cardiac defect, compared with a 1% risk among all registry infants. Although the FDA advisory does not cite a reference, the data may be from the same registry in which previous studies have shown no significant difference in malformations when comparing paroxetine-exposed infants with controls.7,8
The second epidemiologic study used a U.S. insurance claims database and found that infants of women who received paroxetine in early pregnancy had a 1.5% risk of cardiac defect, compared with 1% among infants whose mothers took other antidepressants.
Unfortunately, FDA has refused to release information about these studies beyond what it gave in the advisory, stating simply that the studies are unpublished. Evidence-based medicine can be difficult to practice if clinicians can’t access the evidence to assess its quality.
In clinical practice
Evidence from five peer-reviewed, published studies contradict the FDA advisory on increased risk for congenital cardiac malformations with paroxetine use during pregnancy. So, when prescribing antidepressants for depressed pregnant women, do we rely on the five negative studies or practice defensive medicine and choose SSRIs other than paroxetine?
We have good reasons to question the FDA advisory’s scientific validity, but our patients—and our lawyers—will be more comfortable if we avoid paroxetine in women of child-bearing potential for now. Excluding paroxetine and relying on other SSRIs when necessary to treat major depression during pregnancy is hardly evidence-based medicine, but it’s a legitimate practice of legally-defensive medicine.
This answers our question about how to respond to Mrs. J’s concerns:
- First, she and I would decide if she needs an antidepressant during pregnancy.
- Then, after reviewing with her the FDA warning on paroxetine and discussing its questionable scientific validity, I would recommend that she switch to another SSRI.
- If she chooses to continue paroxetine, I would ask her to sign the note that documents our discussion of the pros and cons of choosing paroxetine instead of alternatives.
- GlaxoSmithKline letter to clinicians about paroxetine during pregnancy, September 2005. www.fda.gov/medwatch/safety/2005/Paxil_dearhcp_letter.pdf
- Food and Drug Administration advisory on paroxetine during pregnancy, December 2005 (full text). www.fda.gov/cder/drug/advisory/paroxetine200512.htm.
Drug brand names
- Citalopram • Celexa
- Fluoxetine • Prozac
- Fluvoxamine • Luvox
- Paroxetine • Paxil, Paxil CR, Pexeva
- Sertraline • Zoloft
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
1. Fleming N. Depression drugs ‘can raise birth defect risk.’ News.telegraph. Available at: www.telegraph.co.uk/news/main.jhtml?xml=/news/2005/09/01/wdep01.xml&sSheet=/news/2005/09/01/ixworld.html. Accessed February 22, 2006.
2. Lamberg L. Risks and benefits key to psychotropic drug use during pregnancy and postpartum period. JAMA 2005;294(13):1604-8.
3. Pastuszak A, Zuber C, et al. Pregnancy outcome following first trimester exposure to fluoxetine. JAMA 1993;269:2246-8.
4. Chambers CD, Johnson KA, Dick LM, et al. Birth outcomes in pregnant women taking fluoxetine. N Engl J Med 1996;335:1010-5.
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10. Hendrick V, Smith LM, Suri R, et al. Birth outcomes after prenatal exposure to antidepressant medication. Am J Obstet Gynecol 2003;188:812-5.
11. Einarson TR, Einarson A. Newer antidepressants in pregnancy and rates of major malformations: a meta-analysis of prospective comparative studies. Pharmacoepidemiol Drug Saf 2005;14(12):823-7.
12. GlaxoSmithKline study EPIP083. GSK medicine: bupropion 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 February 22, 2006.
13. Honein MA, Paulozzi LJ, Cragan JD, Correa A. Evaluation of selected characteristics of pregnancy drug registries. Teratology 1999;60:356-64.
14. Alwan S, Reefhuis J, Rasmussen S, et al. Maternal use of selective serotonin re-uptake inhibitors and risk for birth defects. Birth Defects Research (Part A). Clin Molecular Teratology 2005;731:291-S143.
15. Wogelius P, Norgaard M, Muff Munk E, et al. Maternal use of selective serotonin reuptake inhibitors and risk of adverse pregnancy outcomes. Pharmacoepidemiol Drug Saf 2005;14:S143.-Available at: www.laegemiddelstyrelsen.dk/db/filarkiv/5611/Pharmacoepidemiology_2005.pdf. Accessed February 22, 2006.