First-trimester antiretrovirals a 'possible' risk for genital abnormalities in male babies

According to an analysis of over fourteen years of data, antiretroviral therapy (ART) has not generally increased the rate of birth defects in children born to HIV-positive mothers (compared to mothers not taking ART). However, genital malformations called hypospadias were seen more frequently in male children born to women taking antiretrovirals during the first trimester. The review was published in the March 1^st issue of the Journal of Acquired Immune Deficiency Syndromes.

With the specific exception of efavirenz (Sustiva), which has caused birth defects in animal tests and is contraindicated for pregnant women, antiretroviral use during pregnancy has not been generally shown to cause birth defects.

In this study, a group of US researchers analysed data from the Women and Infants Transmission Study (WITS), a cohort study enrolling pregnant women and their babies at centres in several major US cities and San Juan, Puerto Rico. The data published in this report were gathered from 2,527 live births among 2,353 women between January 1st 1990 and June 30th 2004. (There were 230 stillbirths, miscarriages and abortions during the time period observed.)

Comparisons were made between women who did not use antiretrovirals at all during pregnancy, those who took them during the first trimester (defined as up to 13 weeks), and during the second (14 through 26 weeks, and third trimester, 27 weeks until delivery.

Characteristics of the three groups of women were significantly different. Women who used antiretrovirals during the first trimester were generally more sick, and so presumably did so out of need: 16.0% had CD4 cell counts below 50 cells/mm³ (compared to 12.2% in the second/third trimester group and 9.2% in the non-ART users). First-trimester ART users were also much more likely to be on prophylaxis for opportunistic infections: 17.3% vs. 5.4% and 4.2% in the other groups, respectively. Women who did not use ART during pregnancy were more likely to have smoked and used alcohol and recreational drugs during pregnancy. (p<.001 all="" factors.="" for="">

When grouped according to antiretroviral use, birth defect rates were as follows:

Most commonly observed birth defects were extra fingers and toes, club feet and cleft palate, and in general birth defects did not exceed the rates seen in the general population.

Rates of birth defects did not show a correlation with antiretroviral use, with the single exception of the genital defects. By univariate analysis, first-trimester antiretroviral exposure was a risk factor for these hypospadias; by multivariate analysis, only first-trimester AZT (zidovudine, Retrovir)use was a risk (odds ratio 10.68; 95% CI 2.11 to 54.13; p=.004).

The report points out that the numbers studied were too small to detect all changes in risk: numbers were “inadequate for many of the newer antiretroviral agents to detect even a tripling of risk”. Statistically, the study was most sensitive to drug-specific birth defects from AZT and 3TC: even for those, it was only powered to detect an overall twofold increased risk, which was not seen except as noted for the hypospadias.

Nevertheless, the researchers believe their data “are reassuring regarding antiretroviral use and detection of birth defects… [t]he single notable finding, an increase in the risk of hypospadias after first-trimester antiretroviral exposure, requires confirmation, because numbers are small, it has not been noted in other studies, and there are plausible alternate explanations for the finding.”

The authors note that the rate of hypospadias has been rising in the general population since the 1970s in the United States, and that it has been attributed by some researchers to exposure to endocrine disrupters, suggesting that the association with antiretroviral therapy may be coincidental.