SSRIs and Pregnancy: Increase in Septal Heart Defects

Pharmacology Watch

In this issue: Depression and pregnancy, new vaccine recommendations from the CDC, cortico-steroids and/or antivirals for Bell's palsy, rasagiline and Parkinson's disease, and FDA Actions.

Use of SSRIs during pregnancy

Depression is common in pregnancy, affecting up to 20% of women, with about 13% taking an antidepressant during pregnancy. A new study from Denmark suggests that use of sertraline (Zoloft®) and citalopram (Celexa®) by mothers during pregnancy is associated with an increased risk of septal heart defects in their children. Researchers utilized the Danish nationwide registry to review nearly 500,000 births from 1996 to 2003. Selective serotonin reuptake inhibitors (SSRIs) in general were not associated with major malformations, but were associated with septal heart defects. Among the individual drugs, sertraline conveyed the highest risk (odds ratio [OR], 3.25; confidence interval [CI], 1.21-8.75), followed by citalopram (OR, 2.52; CI, 1.04-6.10). Use of more than one SSRI was associated with an OR of 4.70 (CI, 1.74-12.7). The absolute prevalence of septal heart defects was 0.5% among unexposed children, 0.9% among children whose mothers received any SSRI, and 2.1% among children whose mother were prescribed more than one SSRI (BMJ 2009:339:b3569; Epub ahead of print 23 Sept 2009). Significant in this study was the low overall rate of heart defects and the lack of association of heart defects with paroxetine (Paxil®) or fluoxetine (Prozac®), although the authors consider this a "class effect," and the greatest risk was noted if more than one drug was used during pregnancy.

CDC issues new vaccine recommendations

The Centers for Disease Control and Prevention has recently revised several vaccine recommendations:

Quadravalent meningococcal conjugate vaccine. The Advisory Committee on Immunization Practices (ACIP) is recommending revaccination of persons at prolonged increased risk for meningococcal disease. In a statement in the September 25th Morbidity and Mortality Weekly Report, ACIP is recommending that persons with increased susceptibility to meningococcal disease, such as those with persistent complement component deficiencies, functional asplenia, prolonged exposure such as those traveling to or living in nations where the disease is epidemic or hyperendemic, should receive a booster with the quadravalent meningococcal conjugate vaccine 5 years after their previous vaccination if they received it at age 7 or older. Children who received the first vaccine between ages 2 and 6 should be revaccinated after 3 years. Those who remain at high risk should continue to be revaccinated every 5 years. The recommended booster vaccine is the MCV4 vaccine (Menactra®).

Haemophilus influenzae type b vaccine. The FDA recently approved Hiberix® for Haemophilus influenzae type b (Hib) ending a prolonged shortage of the Hib vaccine. Hiberix is approved as a booster for children ages 15 months to 4 years who have received a primary series of shots. The Centers for Disease Control and Prevention has now issued recommendations that the vaccine can be given as early as age 12 months to facilitate timely booster vaccination. Children who missed a booster because of the recent shortage should receive a booster with any of the Hib vaccines, including Hiberix, at the earliest opportunity.

Hepatitis A vaccine. Hepatitis A vaccine is now recommended for all close household contacts and international adoptees when the children are from intermediate-risk or high-risk areas, with an initial dose being given at least 2 weeks before the child's arrival.

Quadravalent human papilloma virus vaccine. In related news, an FDA advisory panel is recommending that the quadravalent human papilloma virus vaccine (Gardasil®) be approved for males ages 9-26 to prevent genital warts. The vaccine is currently approved only for females in that age group. Meanwhile, the same FDA advisory panel has endorsed the approval of GlaxoSmithKline's Cervarix®, a bivalent HPV vaccine which targets HPV 16 and HPV 18, leading causes of cervical cancer. If approved it would also be recommended in women ages 10-25. The new vaccine protects against 2 of the HPV strains covered by Gardasil, but also contains an adjuvant, which is designed to enhance the immune system's response to these HPV strains. Whether this imparts clinical difference is yet to be seen. The FDA is yet to act on the advisory committee's recommendations.

Bell's palsy: Corticosteroids and/or antivirals?

For treatment of Bell's palsy, corticosteroids with or without antivirals have been the subject of much debate. A new meta-analysis suggests that combination therapy may lead to better outcomes. The review included 18 trials with 2786 patients. The outcomes were unsatisfactory facial recovery at 4 months, unsatisfactory short-term recovery, synkinesis and autonomic dysfunction, or adverse effects. Combination therapy with corticosteroids and antivirals resulted in slightly better outcome than steroids alone (P = 0.05). Antiviral agents alone did not show a benefit (JAMA 2009;302:985-993). At least one source (UpToDate) recommends a typical treatment regimen for Bell's palsy of prednisone 60-80 mg per day along with valacyclovir 1000 mg three times a day for 1 week.

Rasagiline and Parkinson's disease

Does rasagiline slow the progression of Parkinson's disease? A recent study suggests lower doses of the drug may be beneficial. In this multinational study, 1176 subjects with untreated Parkinson's disease were randomized to rasagiline 1 mg or 2 mg per day for 72 weeks or placebo for 36 weeks followed by rasagiline for 36 weeks. Disease progression was rated on a standard rating scale. Patients who were started at baseline on rasagiline 1 mg met all endpoints in the primary analysis: a slower rate of worsening between weeks 12 and 36 (P = 0.01), less worsening of the score between baseline and week 72 (P = 0.02), and non-inferiority between weeks 48 and 72 (P ≤ 0.001). Interestingly, all 3 endpoints were not met with the higher dose of 2 mg per day. The authors conclude that early treatment with rasagiline at a dose of 1 mg per day provided a possible disease-modifying effect, but suggested the results must be interpreted with caution (N Engl J Med 2009;361:1268-1278). Although the findings of this paper are somewhat confusing, it offers some hope since there is currently no effective therapy to slow or stop disease progression in Parkinson's disease.

FDA Actions

The FDA has approved asenapine (Saphris®) for the treatment of schizophrenia and bipolar I disorder in adults. The drug is approved for first-line treatment of both conditions. Schering-Plough provided the agency with safety data in 4500 patients, some of whom were treated for more than 2 years. Like other antipsychotics, asenapine will carry a warning regarding increased mortality in elderly patients with dementia-related psychosis. The drug is expected to be available in the fourth quarter of 2009.

The FDA has lowered the approved age limit for levocetirizine (Xyzal®) to 6 months for children with chronic hives and perennial allergic rhinitis and 2 years for children with seasonal allergic rhinitis. Previously the drug had been approved for children 6 years and older. Levocetirizine is marketed by UCB and Sanofi Aventis.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5468. E-mail: