Treatment with a protease inhibitor during the first trimester of pregnancy increases the risk of pre-term birth

Further evidence has emerged from research in the United States that antiretroviral therapy based on a protease inhibitor (PI) during the first three months of pregnancy is associated with an increased risk of pre-term delivery. The study is published in the advance, online edition of the Journal of Infectious Diseases.

“We found that PI-based combination regimen use in the first trimester was associated with both total and spontaneous preterm birth risk,” write the investigators. “HIV disease progression or effects of combination ARV [antiretroviral therapy] on the immune system among women with indications for initiation of therapy before pregnancy may contribute to increasing preterm birth risk.”

Appropriate use of antiretroviral treatment during pregnancy can reduce the risk of mother-to-child transmission of HIV to below 1% and combination antiretroviral therapy is recommended for all HIV-positive pregnant women who are ill because of HIV or who have a CD4 cell count below 350 cells/mm³.

Treatment has undoubted benefits, reducing the risk of transmission and protecting the health of the mother. However, its risks are less certain. Research conducted in Europe – but not the US – showed that combination HIV therapy during pregnancy increases the risk of pre-term delivery, especially if it is based on a protease inhibitor. The overall findings of a meta-analysis of 14 studies showed treatment during pregnancy did not increase the risk of premature delivery. Nevertheless, it also found that treatment with a protease inhibitor during the first trimester was a risk factor for premature delivery.

Given this uncertainty, investigators from the US Pediatric HIV/AIDS Cohort Study (PHACS) wanted to establish a clearer understanding of the risks associated with protease inhibitor therapy during pregnancy. They therefore looked at maternal use of antiretroviral therapy among women enrolled in the Surveillance Monitoring for Antiretroviral Therapy Toxicities (SMARTT) study and its association with pre-term delivery and birth weight.

“The large size of the study, which includes detailed information on the specific type and timing of ARV drug regimens and other potential risk factors in pregnancy allowed us to control for many potential confounding factors and to assess combinations of factors that may influence the risk of preterm delivery,” comment the authors.

The analysis was limited to singleton births with maternal enrolment before 31 October 2010. Pre-term birth was defined as delivery before the completion of 37 weeks of pregnancy; very pre-term birth was defined as delivery before the end of week 32. Infants were small for gestational age if their birth weight was < 10^th percentile for gestational age.

A total of 1869 live, HIV-negative infants born to 1506 mothers were included in the study. There were 346 (19%) pre-term births, and 55% of these were spontaneous. There were 37 (2%) very pre-term births and 135 infants (7%) were small for gestational age.

Most of the mothers (89%) used antiretroviral therapy during pregnancy, with 40% treated with anti-HIV drugs during the first trimester.

Preliminary analysis showed that a number of factors were associated with an increased risk of pre-term delivery. These included black race, income below $20,000 per year and a CD4 cell count below 200 cells/mm³ late in pregnancy.

Taking these factors into account, the investigators looked at the relationship between the pre-term delivery and the type and timing of antiretroviral treatment.

Their first analysis showed a marginal association between use of protease inhibitor-based treatment and premature birth (OR = 1.60; 95% CI, 0.96-2.67, p = 0.07) as compared to other types of therapy.

Evaluation of timing of treatment showed that use of a protease inhibitor during the first trimester increased the risk of pre-term delivery significantly (AOR = 1.55; 95% CI, 1.16-2.07, p = 0.003). Treatment with a protease inhibitor during the first three months of pregnancy also increased the risk of a spontaneous premature delivery (AOR = 1.59; 95% CI, 1.10-2.30, p = 0.014).

“The association between first trimester PI combination drug exposure and increased preterm birth risk…raises concerns which warrant further study,” comment the researchers.     

Individual protease inhibitors associated with a pre-term birth were saquinavir (Invirase), ritonavir (Norvir) and lopinavir/ritonavir (Kaletra).

There was no relationship between infant size and use of combination HIV therapy at any time during pregnancy.

“We have observed that although combination ARV use later in pregnancy is not associated with an increased risk of preterm delivery, use in the first trimester of PI-containing combination ARV regimens may contribute to an increased risk,” the investigators conclude. “The mechanism of first trimester effect is unclear but could be related to changes in immune and inflammatory mediators. Further studies are needed to elucidate the specific drug effects and the interaction of the many factors that determine pregnancy outcome.”