Adverse effects of ART use in pregnancy: prematurity continues to raise concerns

Premature births in HIV-positive women continue to be a concern, and need to anticipated and managed actively in developing countries, researchers said last week at the 18th Conference on Retroviruses and Opportunistic Infections in Boston.

Conflicting findings persist over the use of antiretroviral therapy, especially use of protease inhibitors, during pregnancy and its adverse effects on infants including pre-term birth. Premature birth and low birth weight increase the risks for death and disease in both low-resource and high-resource settings.

Some studies have shown an elevated risk of premature delivery among women who receive ritonavir-boosted protease inhibitors during pregnancy.

An ANRS French Perinatal Cohort French study presented at the conference showed that women who received a ritonavir-boosted protease inhibitor (PI) were almost twice as likely to deliver prematurely compared to those getting non-boosted PI during pregnancy: 14.4% compared to 9.1%; adjusted hazard ratio=2.0(1.1-3.9); p=0.03.

The increased risk and mostly induced pre-term delivery could be explained, perhaps, she noted, by more toxicity in the third trimester.

However, Maria Isabel González-Tomé, reporting at the same session on a prospective cohort study from 2000 to 2008 among 803 children born to HIV-positive women in seven Spanish hospitals, found that while the rate of pre-term birth and low-birth weight was high it was not linked to any combination of ART regimen. In fact mothers not on ART were at the greatest risk for pre-term delivery and low-birth weight (RR 2.064, 95% CI: 1.262-3.376; p=0.006).

Claire Thorne of University College, London, a co-discussant during the poster presentation session, stated that pre-term delivery is incompletely understood.

Noting that populations selected and methods used are critical to interpretation of the diverse and often conflicting findings she added “Striking inequalities exist in survival chances of a preterm infant between developed and developing countries and possible adverse effects of ART use in pregnancy may be more difficult to manage in resource-poor settings.”

Not surprisingly both studies found that older age, intravenous drug use, tobacco use, no antenatal care/late access to care increased the risks for pre-term delivery and low birth weight. In the Spanish study hepatitis C co-infection (RR1.703, 1.31-2.207, p=0.001), low CD4 cell count and high viral load at delivery also increased the risks.

Two other presentations in this session reported on these issues in a developing country with a generalised HIV epidemic, Botswana.

In a first report of its kind Natasha Parekh and colleagues looked at the risk factors including the use of ART for very premature and very-small-for-age infants born to HIV-positive mothers in six hospitals across Botswana.

Among 16,203 live births from October 2007 to March 2010, 28% (4343) were born to HIV-positive women of which 4.3% were very pre-term delivery and 3.7% were very small for gestational age. The associated rates of neonatal deaths were 26% and 8%, respectively.

Very pre-term was defined as a birth at under 32 weeks of pregnancy; very small for age at birth was defined as under 3^rd percentile for Botswana-specific norms.

Maternal high blood pressure, HIV infection and a history of poor obstetric outcomes that included still birth, pre-term delivery or low birth weight were linked to both very pre-term delivery and very small for gestational age.

Continued use of antiretrovirals starting before conception was associated with very small for gestational age (AOR 1.75, 95% CI: 1.21-2.52) and high blood pressure during pregnancy (AOR 1.34, 95% CI: 1.00-1.77) but not with very pre-term delivery (AOR: 0.78, 95% CI: 0.49-1.26).

Dr. Parekh suggested that control of hypertension in pregnancy may improve outcomes.

Kathleen Powis presented data on the effect of protease inhibitor-based ART on pre-term delivery from the first randomised trial comparing antiretroviral regimens among pregnant women.

HIV-infected women with CD4 cell counts under or equal to 200 cells/mm³ were randomised between 26 and 34 weeks of gestation to a PI-based (lopinavir/ritonavir/zidovudine/lamivudine) or triple nucleoside reverse transcriptase inhibitor-based regimen (abacavir/zidovudine/lamivudine) in a clinical trial designed to prevent mother–to-child transmission.

88 (16.7%) of the 530 women (267 in the PI group and 263 in the NRTI group) who got ART, for a median of 11.3 weeks before delivery, delivered pre-term. Women in the PI group were almost twice as likely to deliver pre-term (21.4% compared to 11.8%, p=0.003);(OR 2.03, 95% CI: 1.26-3.27).

Those in the PI group gained less weight than those in the NRTI group. However, weight change was not a significant risk for pre-term delivery.

Infant hospitalisations and infant deaths (12.7% and 14.8% and 1.5% and 1.1%, in the PI and NRTI groups, respectively) while highest in the first six months of life did not differ significantly according to maternal ART regimen.

These two studies highlight the importance of prioritising high-risk antenatal and neonatal services in countries like Botswana with generalised HIV epidemics where ART regimens are used for PMTCT.

And, as Dr.Powis said “we need to be concerned that PI-based ART carries a higher risk for pre-term delivery in resource-poor settings and [we] need to be prepared to deal with it.”

Didier Ekouévi, co-discussant, of the University of Bordeaux, France and of the ANRS Abidjan, Côte d’Ivoire, concluded that while ART reduces MTCT rate to 1% it also induces preterm delivery (11%-20%), as a result of which 6% of infants will die within the first six months.

He proposed: “the urgent need to put in place a ‘pregnancy register’ in low-income countries to better describe

• Frequency of pre-term delivery

• Relation to type of ART started

• Long term follow-up data (death/growth)

• Haematological and neuro-development disorders

He added that the register should include data from HIV-infected pregnant women as well as from the general population.

Sibiude J et al. Large increase in prematurity between 1990 and 2009 in HIv-infected women in the national French perinatal cohort: does ritonavir boost play a role. Eighteenth Conference on Retroviruses and Opportunistic Infections, Boston, Abstract 743, 2011. (View abstract here).

González-Tomé MI et al. Risk factors of preterm delivery and low birth weight in a multicentre cohort of HIV + pregnant women.Eighteenth Conference on Retroviruses and Opportunistic Infections, Boston, Abstract 744, 2011. (View abstract here).

Parekh N et al. Risk factors for very premature and very small for gestational age infants in Botswana. Eighteenth Conference on Retroviruses and Opportunistic Infections, Boston, Abstract 745, 2011. (View poster here).

Powis K et al. Protease inhibitor-based ART was associated with pre-term delivery, but not adverse infant outcomes, in a randomized MTCT prevention study in Botswana. Eighteenth Conference on Retroviruses and Opportunistic Infections, Boston, Abstract 746, 2011. (View poster here).