Adverse birth outcomes more frequent in women exposed to ART during pregnancy, largest-ever study confirms

Among 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.

Increased 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.

Maternal 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.

In 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. 

Importantly, “The pathogenesis of preterm delivery among all women and the potential increased risk among HIV-infected women are not well understood.”

In 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”.

Conflicting 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.

To 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.

In 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.

These findings support previous studies in West Africa and Botswana showing a link between ART and pre-term delivery.

Watts 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 cell counts.

Nonetheless, 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.

The 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.

The 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.

Yet 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.”

The 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.

Distinguishing between the causes of pre-term birth can help focus research into the pathogenesis of pre-term delivery in HIV-positive women, they suggest.

Finding 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.

The 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.”

Chen JY et al. Highly active antiretroviral therapy and adverse birth outcomes among HIV-infected women in Botswana J Infect Dis October 12, doi: 10.1093/infdis/jis553, 2012.

Watts DH and Mofenson LM Antiretrovirals in pregnancy: a note of caution J Infect Dis Editorial Commentary, October 12, doi: 10.1093/infdis/jis581, 2012.