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Registry Sees No Increased Overall Birth Defect Risk With First-Trimester Antiretrovirals
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1st International Workshop on HIV and Women, January 10-11, 2011, Washington, DC
Mark Mascolini
Ongoing international reporting to the Antiretroviral Pregnancy Registry discerned no greater risk of birth defects among women taking antiretrovirals during the first trimester than among women taking antiretrovirals later in pregnancy [1]. Among drugs with at least 200 reports in the registry, didanosine and nelfinavir carried a slightly but significantly higher birth defect risk with first-trimester exposure compared with a general-population group.
The Antiretroviral Pregnancy Registry is a prospective exposure-registration cohort in which physicians report cases of antiretroviral exposure throughout pregnancy--before the birth outcome is known. Physicians then report fetal or neonatal outcomes. An expert reviews any defects that occur, and an independent advisory committee scrutinizes all submitted data twice yearly. Birth defect prevalence is calculated as defects after 20 weeks gestation per live births. This rate is compared with a general-population birth defect survey in the Atlanta area managed by the Centers for Disease Control (CDC), and first-trimester antiretroviral exposures in the registry are compared with second- and third-trimester exposures.
Antiretroviral manufacturers jointly sponsor the registry, which is overseen by a panel of independent specialists and representatives from the CDC, the National Institutes of Health, and the FDA. Almost 79% of reported cases come from the United States, though the registry is working to increase international representation. Brazil contributes 6% of cases, the United Kingdom 3.2%, Argentina 2.7%, Uganda 1.9%, and South Africa 1.7%. The registry has an 80% power to detect a doubling of overall birth defect risk.
Since 1989 the registry has enrolled 15,101 women, of which 13,298 (88%) could be evaluated through July 31, 2010. About one quarter of these women (28%) had a CD4 count above 500, 43% had 200 to 499 CD4s, 16% had fewer than 200 CD4s, and the rest had missing data. While 6005 women (45%) were enrolled in their first trimester, 5388 (41%) were enrolled in their second trimester and 1903 (14%) in their third. Because 238 women delivered two or more children, there were 13,538 pregnancy outcomes, including 12,652 live births (94%), 180 stillbirths (1%), 390 induced abortions (3%), and 316 spontaneous abortions (2%).
Among cases with follow-up data through July 31, 2010, the overall birth defect rate was 3% and did not differ substantially with first-trimester exposure versus second/third-trimester exposure:
-- First trimester: defects in 159 of 5348 cases (3.0%, 95% confidence interval [CI] 2.5 to 3.5)
-- Second/third trimester: defects in 202 of 7302 cases (2.8%, 95% CI 2.4 to 3.2)
-- Any trimester: defects in 363 of 12,652 cases (2.9%, 95% CI 2.6 to 3.2)
The registry includes 200 or more first-trimester exposures of 14 antiretrovirals: lamivudine, zidovudine, nelfinavir, ritonavir, nevirapine, stavudine, tenofovir, abacavir, efavirenz, lopinavir, didanosine, emtricitabine, atazanavir, and indinavir. Exposure to only two of those drugs, didanosine and nelfinavir, resulted in "modest but statistically significant elevations of overall [birth defect] rates" compared with the general-population Atlanta cohort: didanosine (19 of 404 first-trimester exposures, 4.7%, 95% CI 2.8 to 7.3) and nelfinavir (45 of 1182 first-trimester exposures, 3.8%, 95% CI 2.8% to 5.1%). Heather Watts of NIH, who presented the findings, said registry analysts could find no specific defect pattern with these drugs. The didanosine cases, she noted, may reflect use of the drug by older women with a longer HIV duration.
The registry offers this conclusion based on the analysis to date: "In reviewing all reported defects from the prospective registry, informed by clinical studies and retrospective reports of antiretroviral exposure, the Registry finds that the defects reported show no apparent increases in frequency with first trimester versus later exposures and no pattern to suggest a common cause."
The statement goes on to caution that the number of cases may to too small to identify an increased risk of relatively rare defects. With that caveat in mind, registry officials propose, "these findings should provide some assurance when counseling patients."
Anyone can check details of registry methods and specific findings by going to www.APRegistry.com, clicking on "Healthcare Professionals," and then clicking on "Interim Report." Physicians can download forms to register patients by clicking on "Registration."
Reference
1. Watts DH, Vannappagari V, Seekins DW, et al. Monitoring for birth defects among infants born to antiretroviral-exposed pregnant women: the Antiretroviral Pregnancy Registry. 1st International Workshop on HIV and Women. January 10-11, 2011. Washington, DC. Abstract O_19.
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