Use of Multiple Anti-HIV Drugs Does Not Raise Risk of Adverse Birth Outcomes
Among HIV-infected pregnant women, those who receive combination antiretroviral drug therapy have rates of premature delivery and stillbirth similar to those receiving monotherapy or no therapy, and they are no more likely to deliver a baby with low birth weight or low Apgar scores, according to a combined analysis of multiple studies performed in the United States.1 Furthermore, women who take protease inhibitors as part of their combined drug regimen are no more likely to have a premature or very premature delivery or a low-birth-weight infant than are women who use combination therapy without these drugs, monotherapy or no therapy. Among women receiving combination therapy, however, users of protease inhibitors may be more likely than nonusers to have a very low birth weight infant (odds ratio, 3.6).
HIV-infected pregnant women can take antiretroviral drugs to improve their health and decrease the likelihood of mother-to-child HIV transmission, but the impact of these drugs on pregnancy outcomes has not been determined. To examine the effects of antiretroviral treatment on the risks of adverse outcomes, researchers analyzed data from seven clinical studies of HIV-1-positive pregnant women who delivered their infants from 1990 through 1998. The researchers studied the women's characteristics and type of antiretroviral therapy used, as well as the following outcomes for singleton births: premature or very premature delivery (at less than 37 or 32 weeks' gestation, respectively), low or very low birth weight (less than 2,500 g or 1,500 g, respectively), possibly or definitely abnormal Apgar scores (less than seven or four, respectively) at one minute and five minutes, and stillbirth.
Of the 3,266 women identified, 1,590 had received zidovudine monotherapy, 533 had received a combination of antiretroviral drugs (396 whose treatment included protease inhibitors and 137 whose treatment did not) and 1,143 had not received any antiretroviral drugs. Compared with women who had received monotherapy, those who had received any combination therapy were generally older (median age, 28 vs. 27), had lower median CD4+ cell counts (286 vs. 358 per cubic millimeter) and were less likely to have used illicit drugs during pregnancy (16% vs. 25%). Women who had received antiretroviral treatment had lower median CD4+ cell counts than did untreated women (343 vs. 450 per cubic millimeter) and were also less likely to have used tobacco (34% vs. 55%), alcohol (23% vs. 41%) or illicit drugs (23% vs. 42%) during pregnancy.
There were no significant differences in the frequencies of stillbirth or other adverse pregnancy outcomes between women who had received monotherapy and those who had received multiple drug treatment. Commonly encountered complications were low birth weight (13-17%), premature delivery (15-16%) and possibly abnormal one-minute Apgar score (11-12%). Among women who had used combined drug therapy, the rates of adverse outcomes for those who had taken protease inhibitors and those who had not were similar, with the exception of the rate of low birth weight, which was higher among users of protease inhibitors (20% vs. 11%). The stillbirth and complication rates of treated and untreated women were also similar; only the rate of premature delivery differed significantly between groups (16% vs. 20%). However, after adjustment for CD4+ cell count and use of tobacco, alcohol and illicit drugs, all rates were similar for those who had received any drug treatment, any combination therapy or no treatment.
Logistic regression analyses that corrected for risk factors such as CD4+ cell count, age, race or ethnicity, and use of tobacco, alcohol or illicit drugs revealed that the risks of premature or very premature delivery and low or very low birth weight for women who had used any combined drug regimen were similar to those for women who had used monotherapy. The risks of premature and very premature delivery that were associated with the use of regimens containing protease inhibitors were similar to those conferred by use of monotherapy or combination therapy without protease inhibitors. Compared with women who had used monotherapy, those who had received combination therapy without protease inhibitors had a lower risk of delivering a low-birth-weight infant (odds ratio, 0.6), whereas women whose regimen had included these drugs had an increased risk of having a very low birth weight infant (2.9). However, these results became nonsignificant after further adjustment for prior premature delivery. Among women who had been given combination therapy, users of protease inhibitors were more likely than nonusers to deliver a baby of low birth weight or very low birth weight (2.3 and 3.2, respectively); the odds of very low birth weight remained elevated when results were adjusted for prior premature delivery (3.6).
Finally, the investigators compared treated and untreated women and found that those who had used monotherapy or combination therapy with or without protease inhibitors were, in general, as likely as untreated women to have a premature or very premature delivery or a baby of low or very low birth weight. Although users of combination therapy that included protease inhibitors had an elevated likelihood of delivering a baby of very low birth weight (3.2), this result became nonsignificant after adjustment for prior premature delivery. Women whose combination treatment did not include protease inhibitors had a lower likelihood of low birth weight than did untreated women (0.4), even after correction for prior premature delivery (0.5).
According to the authors, the study shows that the risk of adverse birth outcomes associated with administration of antiretroviral combination therapy to manage HIV infection during pregnancy is no greater than the risks associated with monotherapy or no therapy. Among women who use combination therapy, however, users of protease inhibitors may be at an increased risk of very low birth weight--a finding that the analysts suggest requires confirmation because of its wide confidence interval, the small number of infants involved (a total of 16) and the lack of adjustment for the different study sources. The authors also note that they did not consider other factors such as maternal disease status, HIV viral load, and the precise timing and duration of therapy. They conclude, nevertheless, that "the risks of adverse outcomes of pregnancy that are attributable to antiretroviral therapy are low and are likely to be outweighed by the recognized benefits of such therapy during pregnancy."--T. Lane
1. Tuomala RE et al., Antiretroviral therapy during pregnancy and the risk of an adverse outcome, New England Journal of Medicine, 2002, 346(24):1863-1870.