HIV-infected women in Botswana, starting combination antiretroviral therapy during pregnancy was associated with an
increased risk for adverse birth outcomes, including pre-term delivery, small for
gestational age, stillbirth and neonatal death, researchers report in the
largest study of birth outcomes to date among HIV-positive women with access to
ART in pregnancy.
The study is published in the advance online edition of the Journal of Infectious Diseases.
risk for adverse birth outcomes was also seen among HIV-positive women exposed
to ART started before they became pregnant, compared to all HIV-positive women.
HIV infection was significantly associated
with an increased risk for stillbirth, pre-term delivery, small for gestational
age and neonatal death, with adjusted odd ratios (AORs) ranging from 1.3 to 1.8,
Jennifer Y Chen and colleagues write in this analysis of over 33,000 records of
women delivering at six government hospitals over a two-year period.
an accompanying editorial, Heather Watts and Lynne Mofenson note such adverse
pregnancy outcomes are not surprising since HIV-positive women are additionally
at increased risk for co-infections, including tuberculosis and malaria, which
are also associated with adverse pregnancy outcomes.
“The pathogenesis of preterm delivery among all women and the potential
increased risk among HIV-infected women are not well understood.”
resource-rich settings, Watts and Mofenson
note, the effect of pre-term delivery on infant death and
disease may be limited because of the level of care available. However, in resource-poor settings any increased
risk for pre-term delivery because of ART “could have enormous impact, because
options for care of preterm infants is limited and millions of HIV-infected
women become pregnant each year”.
findings from studies, mostly in resource-rich settings, may be the result of
small sample size, differences in population and exposure categories and
availability of care and treatment before delivery, note the authors.
address these limitations, they undertook the largest surveillance study to date
and restricted their analyses to ART exposure at conception, or to a
time-limited comparison of ART with zidovudine during pregnancy with similar
opportunities for outcomes. Comparisons were adjusted for CD4 cell count.
all analyses, ART exposure was significantly associated with adverse birth
outcomes, independent of CD4 cell count. Yet the association appeared greater
in those with CD4 cell counts over 200, leading Watts
and Mofenson to suggest that not all outcomes could be the result of women on
ART with more advanced illness.
findings support previous studies in West Africa and Botswana showing a link between ART
and pre-term delivery.
and Mofenson acknowledge the appeal of the programmatic and operational
advantages of the recent guidance from WHO for resource-poor settings of using
a single ART regimen for the lifelong treatment of all HIV-positive women and
prevention of mother-to-child transmission (Option B+). Additionally. this approach will
ensure women with more advanced illness can be treated without waiting for CD4
implementation of this strategy, they add, critically requires monitoring the
rate of HIV-free survival and infant HIV infection because an increase in
pre-term delivery in resource-poor settings may lead to increased infant death,
undermining the benefits of preventing mother-to-child transmission.
increased risk for pre-term delivery with women starting combination ART compared to zidovudine
treatment is concerning, they note. Triple-drug ART was associated with a significantly
elevated risk of pre-term delivery (AOR 1.4), small for gestational age (AOR 1.5)
and stillbirth (AOR 2.5), when compared to exposure to zidovudine prophylaxis
alone. There was also an increased rate of neonatal death (1.9% compared to
0.8%, p=0.002) among this group; CD4 count made no difference.
authors note that, while the severity of pre-term delivery and small for gestational
age may reflect the rate of neonatal death, it may also differ by the level of
obstetrical and neonatal care.
Watts and Mofenson note it is unclear how this
difference will translate into overall infant mortality. They cite a previous
study that showed twice the risk of pre-term delivery in women with CD4 counts over 200, randomised
to zidovudine, lamivudine and lopinavir/ritonavir compared to zidovudine,
lamivudine and abacavir, but no differences in infant hospitalisation or death
by six months of age.
Watts and Mofenson
stress the need for more data on the potential benefits and risks of combination ART and
zidovudine; the efficacy of both options is equivalent (assuming appropriate
use) in women not needing treatment for their own health (those with CD4 cell
counts at or above 350 cells/mm3).
Watts and Mofenson
highlight the clear benefit of combination ART among women with CD4 cell counts under 350
“because 92% of maternal mortality and 88% of perinatal and breastfeeding
transmission occur in this group, and these rates can be reduced with the
prompt start of ART. Any increased risk of PTD would need to be very high to
outweigh benefits for this group of women.”
class of drug used may also affect the risk of pre-term delivery. Conflicting results between
protease-inhibitor-based ART regimens and nevirapine- or efavirenz-based ART
regimens further complicate any assessment.
Watts and Mofenson
advocate for conducting surveillance of rates of adverse events to determine
the best ART regimen for use in pregnancy for maternal and infant health.
between the causes of pre-term birth can help focus research into the
pathogenesis of pre-term delivery in HIV-positive women, they suggest.
hypertension to be a strong predictor for all adverse birth outcomes, the
authors advocate for prioritising management of hypertension in pregnancy for
all high-risk women, including those receiving ART.
authors conclude, “although these data are observational they…underscore the
need for further research into potential mechanisms by which ART may affect
birth outcomes as well as investigation of the safest antiretroviral regimens
for use during pregnancy…As more women gain access to ART during pregnancy [in
resource-limited settings] additional efforts are needed to identify those at
high risk for adverse outcomes and provide intensified support systems that
address modifiable risk factors…in pregnancy.”