Antiretroviral therapy during pregnancy is
associated with an increased risk of premature delivery, French researchers
report in Clinical Infectious Diseases.
The large study showed that treatment with a ritonavir-boosted protease
inhibitor was especially associated with prematurity.
“Our findings suggest a relationship
between cARV [combination antiretroviral] use and preterm delivery,” comment
the authors. “Our most important finding was a significant association between
prematurity and ritonavir-boosted PI [protease inhibitor] therapy.”
The authors of an editorial which
accompanies the study suggest that it “advances our understanding of the
relationship between ART [antiretroviral therapy] in pregnancy and preterm
delivery by addressing some of the limitations of earlier studies”.
The risk of mother-to-child transmission of
HIV can be reduced to less than 1% by the use of antiretroviral therapy during
pregnancy. This treatment can cause side-effects and there are therefore
concerns about its implications for both maternal and infant health.
Nevertheless, the risks of therapy are
outweighed by its benefits. Despite this, European research has consistently
shown a relationship between antiretroviral treatment during pregnancy and an
increased risk of prematurity. It is important to note that most US research
has failed to find this association.
French investigators wanted to establish a
clearer understanding of this issue. They therefore studied all singleton
pregnancies (a pregnancy with one baby) in HIV-positive women in France between 1990 and 2009. A
sub-analysis focused on women who started antiretroviral treatment based on a
protease inhibitor during pregnancy between 2005 and 2009.
Factors other than HIV therapy that can
increase the risk of prematurity were controlled for in the investigators’ analysis.
A total of 13,271 pregnancies were included
in the study; the results showed that the overall prematurity rate increased
significantly between 1990 and 2009.
Between 1990 and 1993, when no treatment
was used to reduce the risk of vertical transmission, the prematurity rate was
9.2%. This increased to 9.6% between 1994 and 1996, when AZT monotherapy was
the standard of care during pregnancy. A further increase to 12.4% was observed
between 1997 and 1999, a time when dual nucleoside reverse transcriptase
inhibitor (NRTI) treatment was the standard of care. In the era of modern
triple-drug therapy (2005 to 2009), the prematurity rate was 14%. These
increases were highly significant (p < 0.01).
After controlling for other factors that
can increase the risk of prematurity, the use of combination antiretroviral
therapy during pregnancy was significantly associated with preterm delivery
(adjusted hazard ratio [aHR] = 1.69; 95% CI, 1.38-2.07).
The risk of premature delivery was higher
for women who were already taking HIV therapy when they became pregnant,
compared to those who started therapy during pregnancy (aHR = 1.31; 95% CI,
Analysis was then restricted to the 1253
women who started therapy based on a protease inhibitor between 2005 and 2009.
Most of these women (85%) were treated with a ritonavir-boosted protease
inhibitor. The most frequently used drug of this type was lopinavir/ritonavir
(Kaletra, 81%), and the most commonly prescribed non-boosted protease inhibitor was
nelfinavir (prior to its withdrawal: 92%).
The overall rate of prematurity was 13.6%.
It was higher for the women treated with a boosted protease inhibitor compared
to those taking a non-boosted protease inhibitor (14.4 vs 9.1%, p = 0.053).
The rate of severe prematurity was approximately 3% for both treatment groups.
Initial analysis showed a strong
association between treatment with a ritonavir-boosted protease inhibitor and
an increased risk of premature delivery (aHR = 2.03; 95% CI, 1.06-3.89, p =
0.03). However, this association weakened when hepatitis C co-infection, viral
load and time of treatment initiation were excluded (aHR = 1.76; 95% CI,
0.97-3.19, p = 0.06).
Type of premature delivery differed
according to the use of boosted and non-boosted protease inhibitors.
The risk of a spontaneous preterm delivery
did not differ between the two types of protease inhibitor.
However, women taking a ritonavir booster
were more likely to have an induced premature delivery.
Moreover, women treated with this class of
drug were also significantly more likely to experience a complication during
pregnancy requiring hospitalisation (p = 0.003).
“Ritonavir is associated with complex
metabolic changes and could interfere with the adrenal systems of both the
mother and fetus,” suggest the authors. “Because these adrenal systems are
involved in the spontaneous onset of labour, ritonavir-boosted protease
inhibitors may influence its timing.”
They also offer an explanation for the
increased risk of induced preterm delivery associated with ritonavir: “Patients
treated with ritonavir had more maternal metabolic and vascular complications,
leading to an increase in induced premature births.”
authors conclude, “Our findings suggest a plausible explanation or the
association between cARV therapy and prematurity that merits further
investigation. Because boosted protease inhibitor therapies are standard of
care during pregnancy, this may have important clinical implications."