Antiretroviral therapy in pregnant women and pregnancy outcomes in Abidjan, Cote D’Ivoire
Polly Clayden HIV i-Base
The association between HAART use in pregnancy and adverse infant outcomes, particularly preterm delivery (PTD) is controversial. An association has been demonstrated in some studies but not others and data from Africa is lacking.
Didier Koumavi Ekouevi and co-workers compared pregnancy outcomes in two sequential programmes conducted at the same antenatal clinic in Abidjan. The programmes were: the ANRS Ditrame Plus study, conducted between March 2001 and July 2003 (when HAART was not yet available, and not recommended by WHO) and the MTCT Plus programme between August 2003 and August 2007.
In Ditrame Plus women eligible for HAART, by WHO criteria, received a short-course of either AZT from 36 weeks or AZT+3TC from 32 weeks plus single dose NVP for mother-to-child transmission prophylaxis (PMTCT group). The women who met the criteria for starting treatment in MTCT Plus received HAART (HAART group).
The HAART group included both women who had started treatment before they became pregnant and women eligible for HAART who started during pregnancy. All infants received AZT for 7 days and single dose NVP. Women were counselled either to replacement feed or exclusive breast feed for 4-6 months. Formula was provided free in the PMTCT group but not in the HAART group.
There were 358 HIV-positive women eligible for HAART enrolled in this study. Their median age at enrolment was 28 years (IQR, 25-32 and median CD4 cell count 179 cells/mm3 (IQR 120-252). The median maternal BMI at delivery was 23.8 kg/m2 (IQR 21.8-26.3).
The women in the PMTCT (n=90) and HAART (n=168; 34 starting HAART before pregnancy) groups had similar characteristics except more women were at WHO stage 3 and 4 in the PMTCT group (59.4%) than the HAART group (39.7%), p=<0.001 and there was a difference in parity, p=0.001 and age, p=0.039.
The median duration of HAART before delivery was 11.9 weeks and the median duration of prophylaxis was 4.9 weeks. The most frequent regimens were: AZT+3TC+NVP (87%) in the HAART group and AZT+sdNVP in the PMTCT group.
Of 326 singleton infants (175 in PMTCT and 151 in HAART groups), the overall rate of stillbirth (fetal death any time after 20 weeks of pregnancy) was 3.1% (CI 1.5-5.6). There was no significant difference between the HAART and PMTCT groups (3.3 vs. 2.9%, p=0.85).
Among the 309 infants for whom data were available, the investigators found the median birth weight was 3000g (IQR 2700-3250). There were 52 (16.8%) infants with low birth weight (LBW) (<2500 g). The frequency was higher in the HAART group than the PMTCT group (22.3 vs. 12.4%, p=0.02). The frequency was similar in the PMTCT group between the two regimens (12.3% with short course AZT+3TC+sdNVP and 9.4% with short course AZT+sdNVP, p=0.60). It was also similar between women who started HAART before and during pregnancy in the HAART group (25.0 vs 21.5%, p=0.68). There was no difference between the rate of very low birth weight (VLBW) (<2000g) between the two groups, p=0.279.
There were 28/305 infants identified as HIV-infected at 12 months (9.6%, 95% CI 6.7-13.7%). The estimated transmission risk was 2.3% (95% CI 0.7-6.9%) in the HAART group, and 16.1% (95% CI 11.2-22.9%) in the PMTCT group p<0.001. In the HAART, group 65% of the women breast fed for a median of 4.7 months (IQR 3.3-6.3), compared to 48% in the PMTCT group for a median of 4.3 months (IQR 3.5-6.5).
In multivariate analysis, the authors found HAART initiated before pregnancy (AOR 2.88, 95% CI 1.10-7.51) and during pregnancy (AOR 2.12, 95% CI 1.15-4.65) and maternal BMI (<25 kg/m2) (AOR 2.43, 95% CI 1.20-4.91), to be associated with LBW.
The overall infant survival rate among uninfected infants was 0.93 (95% CI 0.87-0.96) and was similar in the two groups, p=0.78. Neither LBW (AOR 1.5, p=0.38) nor maternal HAART exposure (AOR 1.1, p=0.85) were associated with infant mortality in these infants. The only factor associated with infant mortality in this analysis was paediatric HIV infection (AOR 11.9, 95% CI 4.8-29.5); after adjustment for infant feeding, LBW, exposure to HAART regimens, and maternal characteristics at enrolment.
The authors note that they were unable to study PTD rates to try and explain rate of LBW because the majority of HIV-infected women did not know the date of their last menstruation and did not have an ultrasound examination in the first trimester.
They wrote: “Further larger scale international pharmacovigilance systems should be established to access pregnancy outcomes in the context of this wider use of antiretroviral regimen in pregnant women.”
The controversy surrounding HAART and preterm delivery should not obscure the need for careful assessment of birth weight and gestational age at delivery in all babies exposed to HAART in pregnancy. In this study low birth weight was not associated with infant mortality – only HIV infection. This is the most important point, but as rates of HIV infection become lower, determining the safest way to achieve this becomes even more important. In European studies a significant proportion of preterm deliveries have been before 32 weeks and such babies frequently require special care facilities that may not always be available.
So far there are limited data from Africa. Preliminary data from a review of obstetrical records in Botswana also suggest possible associations between maternal disease status, HAART, and adverse pregnancy outcomes and this calls, as Ekouevi et al stress, for the establishment of good pharmacovigilance systems as HAART becomes more available and widely used in pregnancy in resource limited settings.
Ekouevi DK, Patrick A. Coffiea PA et al. Antiretroviral therapy in pregnant women with advanced HIV disease and pregnancy outcomes in Abidjan, Cote d’Ivoire. AIDS 2008, Vol 22 No 14. 1815-1820.