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
“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 < 10th percentile for
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
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
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.”