American Foundation for AIDS Research, January 2002
Gretchen Schmelz

One of HIV medicine's greatest achievements was the almost complete eradication of mother-to-child transmission of HIV in the United States. In the year 2000, only about 6% of mothers known to have HIV passed the virus on to their newborns. At the same time, the extent to which antiretroviral therapy also causes birth defects has proved difficult to determine.

The Centers for Disease Control and Prevention (CDC) used to fund the Survey of Childbearing Women, a population-based HIV transmission survey that tracked the number of babies born [quote]to HIV-positive women. The survey ended for political reasons in 1997. In addition, not every state has considered HIV infection to be a reportable condition. These two factors combined have hampered a population-based surveillance system.

Recording possible treatment-associated cases of birth defects has been left to industry. In 1989, GlaxoWellcome began the Zidovudine in Pregnancy Registry to receive doctors' reports on the experience of pregnant women and their infants. As the FDA approved more antiretrovirals, more companies became involved, and in 1993 the database became the “Antiretroviral Pregnancy Registry." It is now sponsored by Abbott, Agouron, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Hoffmann-LaRoche, and Merck. The Registry is international, but most reports come from the U.S. (88.5%). PharmaResearch Corporation of Wilmington, North Carolina manages the data collection, which is reviewed every six months by an independent steering committee.

Last December, Dr. Patricia Garcia of Northwestern University presented the Registry's current data set, including cases registered between January 1989 and July 2001, at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Her report included exposure to all approved antiretrovirals, excluding tenofovir.

Of the 2,851 pregnancies documented in the Registry, 2,174 (76%) were included in the July 2001 analysis. (Excluded cases had incomplete data.) Garcia reported that the prevalence of birth defects was 2.4 per 100 live births (20 of 819) among women with a first-trimester exposure. Including all women with antiretroviral exposure at any time during pregnancy, the prevalence was 2.3 per 100 live births (46 of 2,026). The birth defect rate among offspring exposed in their first three months of fetal development did not differ significantly from those first exposed during the second and/or third trimester.

The investigators concluded that, compared to the general HIV-negative population, birth defects were no more common in babies whose mothers took anti-HIV medications during the first trimester of pregnancy. This was true for all antiretrovirals in the aggregate and for AZT or 3TC in particular. For any AZT or 3TC first-trimester exposure (used alone or in combination with other antiretrovirals) there were, respectively, 13 defects in 590 live births (2.2 per 100) and 15 defects in 564 (2.7 per 100).

It is difficult to know what proportion of antiretroviral-exposed offspring are included in the Registry. Without knowing the exact number of babies born to HIV-positive women, one can only estimate. The experts' best guess relies heavily on the Survey of Childbearing Women, last updated in 1997, which indicated that 5,000 to 7,000 babies were born every year to HIV-positive women. Between July 2000 and July 2001, clinicians prospectively submitted 876 reports to the Registry. Simple math shows that the Registry captures only a small portion of infants exposed to HIV medications-between 13% and 18% - and that is assuming every HIV positive mother receives treatment.

The information from the Registry must be interpreted with caution. The voluntary Registry compares its prevalence rates against the CDC's population-based surveillance system, which does not rely on voluntary reports. Voluntary reporting invites selection bias, since some doctors may preferentially register certain types of cases over others and certain sets of doctors may not register any patients at all.

The small number of registrants and unsystematic follow-up create an inherent mathematical problem. Upticks in rare defects, those that usually occur once in ten thousand or more births, are virtually undetectable.

Collecting data from children who may have defects that were not immediately apparent after birth is another problem. Clinicians report major structural defects and major malformations readily apparent at birth, but subtle defects are less likely to be reported. Tracking long-term effects is difficult because the Registry does not actively follow each case after the initial assessment.

Despite the limitations, Garcia is hopeful that, with help, the Registry will provide answers to these questions. “We need to encourage providers to prospectively report exposures and we must get the obstetric and HIV communities involved, so we don't have to wait another three, four, five years for a decent denominator," she said.

"The registry clearly doesn't capture all of the antiretroviral exposures in the U.S.," said Dr. Lynne Mofenson, Branch Chief of the Pediatric, Adolescent, and Maternal AIDS Branch of the National Institute of Child Health and Human Development. "It provides us with some information regarding the potential for birth defects. We can say with some certainty that the rate of birth defects does not increase with exposure to zidovudine, and with a little less certainty, with zidovudine and lamivudine. But there are insufficient data to make that claim about combination therapy, nor about the long-term affects of therapy."

Mofenson stressed that one has to look at the whole picture. "Based on what we know today - that one in four children contract HIV without treatment, but with treatment, that number drops by 70% or even more - that benefit is greater than the dangers of birth defects."

For more information about the Antiretroviral Pregnancy Registry, call 800/258-4263. An Internet site is also available: www.APRegistry.com.

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