Does mother's ART during pregnancy impede uninfected children's growth?

Children born to HIV-positive women who take antiretroviral therapy (ART) during pregnancy are significantly smaller in terms of height, weight and head circumference compared with children born to HIV-positive women not on ART, or who took monotherapy, according the results of a European study examining the effects of ART on uninfected childrens' growth up to the age of 18 months. Although the authors of the study, published in the November issue of the Journal of Acquired Immune Deficiency Syndromes, say that these growth differences are "marginal and unlikely to be clinically relevant at this age", and that the benefits of ART outweigh the risks, further long-term follow-up is warranted.

Thanks to the advent of both prophylactic therapy and ART to prevent HIV transmission, mother-to-child transmission rates are now less than two percent in Europe. Consequently, whilst most children born to HIV-positive women are uninfected with HIV, they are exposed to antiretrovirals.

There is currently only limited data on whether this exposure affects children's growth, and this is based on short-term exposure to AZT (zidovudine, Retrovir). However, since many women now take a combination of three or more antiretrovirals (HAART) throughout their pregnancy, researchers from the European Collaborative Study sought to investigate whether there was, indeed, a difference between the growth of children exposed to dual therapy or ART compared with those who were not exposed to dual therapy or ART over the first 18 months of life.

The European Collaborative Study is a cohort study at 13 centres in nine countries and it has prospectively followed HIV-positive pregnant women since 1985. By December 2003, 1912 uninfected (those with a negative HIV antibody or RNA test at or after 18 months-old) and presumed uninfected (those under 18 months-old with at least two negative HIV RNA tests) children born to 1728 mothers (median age at delivery 27.9 years) were enrolled in the study.

Just over 81% (1513) of the mothers gave birth at full term (over 37 weeks) and 14% (266) gave birth after 34-36 weeks' gestation. Of the 4% (78) that gave birth earlier than 34 weeks, four gave birth at 27-28 weeks, thirteen at 29-30 weeks, and 61 and 31-133 weeks.

More than half of the mothers (52%; 987) were not exposed to any antiretrovirals; 17% (317) took monotherapy; 7% (125) took dual therapy and 25% (483) took ART during their pregnancy. Of note, 16% (295) of mothers were current injection drug users (IDUs) and 26% (469) had been IDUs in the past.

The median birth weight of the children was 2960g (range 795-4740g) and the median head circumference was 34.0cm (range 24.0-39.5cm). In univariate analysis, researchers found that were no significant differences seen between children exposed or not exposed to antiretrovirals in either weight (p=0.524) or head circumference (p=0.121) during the first 18 months of life. In fact, children exposed to antiretrovirals and who were born after 37 weeks' gestation were significantly heavier than those whose mothers took no therapy or monotherapy at three months (p=0.004) and 18 months (0.001).

However, they did find that, at three months, children exposed to antiretrovirals and who were born before 34 weeks had, on average, a smaller head circumference (p=0.027) over and above that of gestational age compared to those not exposed to antiretrovirals.

In multivariate analysis, adjusting for weight, height, head circumference, gestational age, and material IDU, the researchers found that children exposed to dual therapy or ART were significantly smaller in terms of weight (p=0.019), height (p=0.008) and head circumference (p=0.0001) than those not exposed.

However, they write in the discussion that "this effect was marginal and unlikely to be clinically relevant at this age." They add that "the effect was much smaller than that of maternal IDU, for which we confirm that children of mothers with reported drug use in pregnancy were significantly smaller in terms of weight, height, and [head circumference] than those of mothers with no reported drug use."

Although ART use has been associated with prematurity, the researchers found that those children born earlier than 37 weeks and exposed to dual therapy or ART tended to reach a certain point in weight and height measurements earlier than premature babies not exposed to antiretrovirals. They explain these findings by suggesting that they are consistent with the hypothesis that prematurity during ART is due to an imbalance of cytokines rather than the failure of the placenta or infant factors.

The authors' conclusions are cautiously optimistic. Although they do say that they "found a minimal effect of combination antiretroviral therapy on growth up to 18 months of age," they add that "the subsequent clinical implications of this finding are unclear."

They note that a previous report from their study group published in AIDS last year found that neutrophil cell counts were reduced in uninfected children exposed to antiretrovirals up to the age of eight, "although, again," they write, "the clinical implications are not clear."

They conclude: "Although not denying the great benefits of ART in the prevention of mother-to-child transmission, these suggestions of potential long-term effects warrant the monitoring of antiretroviral-exposed uninfected children in the long term."