third trimester of pregnancy, on a randomized basis, to receive either AZT or a placebo until the birth of the child. The newborn would then receive the same medication as the mother for an additional 6 weeks after birth. This design was chosen to decrease the risk of fetal malformation by starting therapy well after organ development was complete. Study organizers believed that the risk of giving AZT to an uninfected fetus was acceptable because of the inability to identify such fetuses and the relatively high likelihood of transmission. Thus, the pediatricians who designed the trial believed the study to be timely and ethical.
Criticism of the design, however, was immediate and severe. Advocates of women with HIV disease and some AIDS Clinical Trials Group investigators argued that the focus of the protocol, including any risk-benefit analysis, should be the pregnant woman, not the fetus. Previously expressed concerns that women were considered of importance in the epidemic only in relation to their role as "vectors" of disease to their unborn children or as sexual partners seemed to them to be borne out by the design of protocol 076 (Mitchell, 1988). Critics also pointed out that AZT had been demonstrated to prolong life in patients with AIDS and to delay progression to AIDS in asymptomatic HIV-infected individuals with CD4 counts below 500. They argued that by randomizing pregnant women to receive AZT or a placebo, the design would deny some women essential therapy in order to determine the effects of the drug on preventing fetal transmission. To meet concerns that in this protocol, and others, decisions regarding the treatment of women were not being addressed by those qualified to make them, a working group composed of obstetrician-gynecologists, internists, and pediatricians was established within the AIDS Clinical Trials Group. The working group has since been raised to the level of a full scientific committee and presumably will be consulted regarding all studies in which pregnant women will be enrolled.
Ultimately, the FDA asked its Anti-Viral Advisory Committee to review protocol 076. That review, in September 1990, resulted in recommendations to radically redesign the study. In general, the recommendations supported the view that women should be the focus of the trial. Thus, the committee recommended that women with AIDS or severe immune dysfunction be excluded and given AZT. Women with moderate immune dysfunction, although eligible, would be told that if they were not pregnant, AZT would often be recommended, although the risk of delaying therapy for 6 months was believed to be small. Randomization much earlier, just after the first trimester, was recommended to maximize the possible benefit in preventing fetal transmission.
Advocates have recently voiced new doubts about the ethical propriety of the protocol. They point out that the carcinogenic effects of AZT in women are unknown because studies of AZT have included very few women.