In this issue: SSRIs are safer in pregnancy than previously thought; Estrogen therapy in younger women may be of benefit in preventing cardiovascular disease; Warfarin is substantially better than antiplatelet therapy in preventing stroke in patients with atrial fibrillation; The FDA tightens regulations regarding dietary supplements, Lyrica is approved for treatment of fibromyalgia.

SSRIs are associated with a low rate of birth defects according to 2 new studies in the New England Journal of Medicine. SSRIs are often taken by women in their childbearing years, but the risk of birth defects has been unclear. Paroxetine (Paxil) specifically has been associated with omphalocele and heart defects, but there is little data on the risk of other SSRIs. In the first study from Boston University and Harvard, researchers assessed the association between first-trimester maternal use of SSRI and birth defects among nearly 10,000 infants with and over 5,800 infants without birth defects who participated in the Sloan Epidemiology Center Birth Defects Study. Use of SSRIs was not associated with significantly increased risk of craniosynostosis (odds ratio 0.8), omphalocele (odds ratio 1.4), or heart defects overall (odds ratio 1.2). Analysis of specific SSRIs and specific deficits showed significant associations between use of sertraline (Zoloft) and omphalocele (odds ratio 5.7) and septal defects (odds ratio 2.0) and between use of paroxetine and right ventricular outflow tract obstruction defects (odds ratio 3.3). There were no significant associations with other defects with other SSRIs or non-SSRI antidepressants. In the other study, researchers from the CDC and University of British Columbia looked at data obtained on 9,622 infants with major birth defects and 4,092 control infants born between 1997 and 2002. Records were obtained from birth defects surveillance systems in 8 U.S. states and controls were selected randomly from the same geographic areas. Mothers were interviewed regarding exposure to potential risk factors including medications before and during pregnancy. No significant associations were found between maternal use of SSRIs overall during early pregnancy and congenital heart defects or most other categories or subcategories categories of birth defects. Maternal SSRI use was associated with amencephaly (odds ratio 2.4), craniosynostosis (odds ratio 2.5) and omphalocele (odds ratio 2.8). Their conclusion was that maternal use of SSRIs during early pregnancy was not associated with significantly increased risk of congenital heart defects or most other categories or birth defects. There was an association with SSRI use and 3 types of birth defects, but the absolute risk was small and further studies are warranted (N Engl J Med 2007; 356:2675- 2683, 2684-2692). An accompanying editorial points out that 2 previous studies had suggested a relationship between paroxetine and cardiac malformations including ventricular septal defects, an association that was not found in these current studies. Although a small rate of congenital heart malformations, including right ventricular outflow tract lesions, were found the rate was still low, less than 1%. The editorialists, Dr. Michael Green from Massachusetts General states, "The 2 reports in this issue of the Journal, together with other available information, do suggest that any increased risks of these malformations in association with the use of SSRIs are likely to be small in terms of absolute risks." (N Engl J Med 2007; 356:2732-2733).

Estrogen for Younger Postmenopausal Women

Another follow-up study from the Women's Health Initiative suggests that estrogen therapy in younger postmenopausal women may be of benefit in preventing cardiovascular disease. Analysis was done on the "estrogen-only" wing of WHI in women who had undergone hysterectomy prior to enrolling in the study and were not treated with progesterone. Women age 50 to 59 were treated with 0.625 mg per day of conjugated equine estrogens or placebo. CT heart scanning was done at entry to the study and after a mean of 7.4 years of treatment and 1.3 years after the trial was completed. The endpoint of mean coronary-artery calcium scores was lower among women receiving estrogen (83.1) than those receiving placebo (123.1) (P = 0.02 by rank test). After adjusting for coronary risk factors, the odds ratios for coronary-artery calcium scores of more than 0, 10 or more, and 100 or more in the group receiving estrogen as compared to placebo were respectively 0.78, 0.74, and 0.69. The corresponding odds ratios among women with at least 80% adherence to the study estrogen or placebo were 0.64 (P = 0.01), 0.55 (P < 0.001), and 0.46 (P = 0.001). For women who had calcium scores greater than 300 the multivariate odds ratio was 0.58 (P = 0.03) in an intention-to-treat analysis and 0.39 (P = 0.004) among women with at least 80% adherence. The authors conclude that in women age 50 to 59 years old at enrollment, estrogen treatment resulted in a lower calcified plaque burden in the coronary arteries compared to placebo. They also point out that estrogen has complex biological effects and may influence the risk of cardiovascular events and other outcomes through multiple pathways (N Engl J Med 2007; 356:2591-2602). An accompanying editorial points out that not only did women in this analysis who were treated with estrogen have lower calcium scores, women in whom hormone replacement therapy was initiated at a younger age also had a 30% reduction in total mortality and did not have significant increases in any adverse outcomes examined. This supports the "timing hypothesis" for hormone replacement therapy that suggests that the cardiovascular benefits of hormone replacement are only evident if treatment is started before atherosclerosis develops. (N Engl J Med 2007;356:2639-2641).

Warfarin Better for Atrial Fibrillation Patients

Recent meta-analysis has confirmed the value of warfarin in preventing stroke in patients with nonvalvular atrial fibrillation. Twenty-nine trials involving more than 28,000 patients were reviewed. Compared with control, warfarin and antiplatelet agents reduce stroke by 64% (95% CI, 49% to 74%) and 22% (CI, 6% to 35%) respectively. Adjusted-dose warfarin was substantially more efficacious than antiplatelet therapy, and increases in extracranial hemorrhage assisted with warfarin were small. The authors conclude that warfarin is substantially more efficacious at preventing stroke in patients with a fibrillation than is antiplatelet therapy (by approximately 40%). (Ann Int Med 2007; 146: 857-867).

FDA Actions

The FDA has strengthened its regulations regarding dietary supplements, issuing a "final rule" requiring current good manufacturing practices for dietary supplements. The rule ensures the supplements are produced in a quality manner, do not contain contaminants or impurities, and are accurately labeled. Manufacturers will also be required to report all serious dietary supplement-related adverse events to the FDA by the end of the year.

Pregabalin (Lyrica-Pfizer) has been approved for the treatment of fibromyalgia, the first drug approved for this indication. Fibromyalgia, which is characterized by pain, fatigue, and sleep problems, affects up to 6 million people in United States. Approval was based on 2 double-blind, controlled trials involving 1,800 patients that showed improvement in pain symptoms at doses of 300 mg or 450 mg per day. The drug has already been approved for partial seizures, postherpetic neuralgia, and diabetic neuropathy.

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) 262-5431. E-mail: