Is protease inhibitor use during pregnancy linked to premature delivery?

An observational study from the University of Miami has found that the use of protease inhibitor-based antiretroviral therapy during pregnancy is associated with an increased risk of premature delivery. The study’s findings were published in the 1^st May edition of The Journal of Infectious Diseases.

The use of antiretroviral therapy during pregnancy has dramatically improved the health of women and reduced the levels of mother-to-child transmission of HIV. However, the safety and efficacy of most anti-HIV drugs have not been formally tested in randomised clinical trials.

In the absence of randomised trials, a number of observational studies have examined the effects of anti-HIV treatment on the outcomes of pregnancy, with diverging conclusions. For example, a large European cohort of 2300 women found that exposure to antiretroviral therapy containing a protease inhibitor more than doubled the risk of preterm delivery. In contrast, a recent study of 2120 women from the United States found no link between combination antiretroviral therapy and either preterm delivery or low birth weight.

To gain a better understanding of the effect of antiretroviral therapy during pregnancy, investigators from Miami carried out an analysis of their data on outcomes in 1337 HIV-positive women. Although some of these women were included in the American study above, the investigators wished to restrict their analysis to one site, in order to ensure that all women included were treated according to the same protocols and standards of care.

The study, which ran from 1990 to 2002, included 999 women who received anti-HIV therapy. Of these, 492 received one anti-HIV drug, 373 received combination therapy without a protease inhibitor and 134 received protease inhibitor-based combination therapy. An additional 338 women did not receive therapy.

The investigators found that use of a combination including a protease inhibitor led to an elevated risk of delivery before 37 weeks’ gestation, compared to combination therapy without a protease inhibitor (odds ratio: 1.8; p = 0.03). This was determined after correction for a range of risk factors, including drug and alcohol use, smoking and previous preterm delivery.

Preterm delivery was also associated with a history of previous preterm delivery (p

In contrast, there were no significant differences in birth weight or rates of stillbirth between treatment groups.

The authors claim that their results show that there is a risk to protease inhibitor use during pregnancy. “Although it is reassuring that there does not appear to be an increased risk of adverse pregnancy outcome associated with monotherapy or combination therapy without a protease inhibitor, we believe that protease inhibitors should be used with caution,” they write.

“The results of the present study suggest that a decision to initiate combination therapy with a protease inhibitor during pregnancy should be made with caution and emphasise the importance of counselling patients about the risks of prematurity before the initiation of therapy,” they add.

However, in an accompanying editorial commentary, Ruth Tuomala and Sigal Yawetz of Brigham and Women’s Hospital, Boston, argue that the divergent conclusions of the Miami study and other similar studies could be due to their observational design.

The two doctors point out that the mothers prescribed protease inhibitors during the Miami study took these drugs because they had low CD4 cell counts or because they had experienced failure of a previous protease inhibitor-sparing regimen. The large European study, which had similar conclusions to the results from Miami, had similar criteria for protease inhibitor use.

Tuomala and Yawetz argue that the health of the mothers could be more directly linked to premature delivery than the drugs themselves. “It is likely that the finding of an effect on preterm delivery of combination antiretroviral therapy that includes protease inhibitors is unavoidably and inextricably confounded by indication for therapy of maternal disease,” they write.

The doctors make a strong case for future studies being randomised and controlled, in order to provide clearer information on the effects of protease inhibitors on the outcomes of pregnancy.

In addition, they suggest that these be limited to mothers who do not need treatment themselves, in order to determine the effects of treatment on the outcomes of pregnancy independently of the mothers’ state of health. Although these studies may be difficult to carry out because of ethical considerations, they would help to clear up some of the confusion around the risks of HIV treatment during pregnancy.

“The true association between protease inhibitor use and adverse pregnancy outcome is unlikely to be determined by further analysis of observational data,” they write. “It is time to facilitate large-scale, randomised, controlled clinical trials aimed at carefully defining the risks associated with combination antiretroviral therapy regimens used during pregnancy by women receiving antiretroviral therapy for foetal protection and whose HIV disease would not otherwise require therapy.”