ART and adverse birth outcomes in Botswana

Polly Clayden, HIV i-Base

Data describing the association between adverse birth outcomes – preterm delivery (PTD), small for gestational age (SGA) and stillbirth (SB) – and ART are conflicting.

The association between PTD and protease inhibitors has also been observed in some studies but not others. An article in the 1st December 2012 issue of the Journal of Infectious Diseases presents findings from the largest surveillance study of birth outcomes among HIV positive women receiving ART to date. The study was conducted in Botswana during 2009-2011.

Women who delivered live births or stillbirths at 20 weeks gestation or more at six public hospitals – chosen to include geographic diversity and primary and tertiary levels of obstetric care – were included in this analysis. Data were obtained from obstetrical records on discharge from maternity wards.

During the study period women with CD4 counts <250 cells/mm3 were eligible for ART – usually nevirapine (NVP) plus AZT/3TC. Women with CD4 counts >250 cells/mm3 received AZT monotherapy for PMTCT. Starting in late October 2009, a limited number of women received ART with CD4 counts >250 cells/mm3 through a pilot programme. This regimen was lopinavir/ritonavir (LPV/r) plus AZT/3TC.

The investigators reported, of 33,148 women, an impressive 32,113 (97%) were tested for HIV, and 9504 (30%) tested were HIV positive. In multivariate analysis, HIV was significantly associated with SB (AOR 1.5; 95% CI 1.3 – 1.7), PTD (AOR 1.3; 95% CI 1.3 – 1.4), SGA (AOR 1.8; 95% CI 1.7 – 1.9), and neonatal death (NND) (AOR 1.4; 95% CI 1.2 – 1.7) in HIV positive compared to HIV negative women. The majority (96%) of 9504 HIV positive women had a recorded date for initiation of antiretroviral drugs in pregnancy. Of 9149 women, 2189 (24%) continued ART from before pregnancy, 1101 (12%) started ART in pregnancy, 4625 (51%) started AZT in pregnancy, and 1234 (13%) received no antiretrovirals.

Only a small proportion (9%) of all women receiving ART received LPV/r-based regimens, the majority received NVP-based regimens or had no regimen specified (and were assumed to have received NVP).

Women starting ART in pregnancy did so at a median gestational age of 25 weeks and those starting AZT at a median of 29 weeks. The overall rate of PTD in HIV positive women was 24% occurring at a median gestational age of 34 weeks. Compared with all other HIV positive women, continuing ART from before pregnancy was significantly associated with PTD (AOR 1.2; 95% CI 1.1 – 1.4). Compared with AZT monotherapy, starting ART in pregnancy was also significantly associated with PTD (AOR, 1.4; 95% CI, 1.2, 1.8). Maternal hypertension and anaemia in pregnancy were also significant independent risk factors for PTD for all HIV positive women.

The rate of SGA among HIV positive women was 18% at a median gestational age of 39 weeks. Similarly, continued ART from before pregnancy was significantly associated with SGA (AOR 1.8; 95% CI, 1.6 – 2.1) among all HIV positive women. Starting ART in pregnancy compared to AZT was also associated (AOR 1.5; 95% CI, 1.2, 1.9) with higher rates of this adverse outcome. Among women receiving ART, continuing treatment was associated with higher risk of SGA than starting in pregnancy (AOR 1.3; 95% CI 1.0 – 1.5). Maternal hypertension and CD4 count <200 cells/mm3 were also independently associated with SGA infants for all HIV positive women.

There was a 5% rate of SB in HIV positive women in this cohort at a median gestational age of 32 weeks. Continuing ART from before pregnancy was associated with higher risk of SB (AOR 1.5; 95% CI, 1.2, – 1.8) among all HIV positive pregnant women. Starting ART in pregnancy compared to AZT was also associated with SB (AOR 2.5; 95% CI, 1.6 – 3.9). Maternal hypertension and CD4 count <200 cells/mm3 were also additional risk factors.

Neonatal death (NND) occurred in 2.3% of infants born to HIV positive women. In univariate analysis, the rate was significantly in higher infants born preterm compared to those at term (7% vs 0.8%, p<0.0001) and SGA infants were at higher risk than those with appropriate weights for their gestational age (3.5% versus 1.5, p<0.0001). The investigators did not find higher rates of NND in women who continued ART from before pregnancy compared to other HIV positive women but women who started ART versus AZT in pregnancy had a higher risk (1.9% vs 0.8%). Because of the small numbers of events and the potential for multiple interactions with PTD, SGA and NND, the investigators did not perform multivariate analyses for this outcome.

One of the limitations of this study is that CD4 counts were not recorded for 51% of HIV positive women but when the analyses were limited to those with available data, the investigators observed no differences in their findings. Further sensitivity analyses included an evaluation of the association between PI-based ART and PTD. This analysis found 20 of 45 (42%) women who continued PI-based ART had a PTD compared to 522 of 1998 (26%) women who continued non-PI-based ART (OR 2.0; 95% CI, 1.1 – 3.6). A further 44 of 178 (25%) women starting PI-based ART in pregnancy had a PTD compared to 131 of 654 (20%) initiating non-PI-based ART (OR 1.2; 95% CI, 0.9 – 1.9).

The investigators noted that previous conflicting results from other observational studies might be due to their limited power and differing exposure categories and comparisons.


In an accompanying editorial, Heather Watts and Lynne Mofenson note that the increased risks of coinfections such as TB and malaria are also associated with adverse pregnancy outcomes. They also remind us that the pathogenesis of preterm delivery among all women and the potential increased risk among HIV positive women are not well understood.

As ART in pregnancy is rolled out more widely, they stress the importance of monitoring pregnancy outcomes to determine optimal regimens for improving maternal health and maximising HIV-free survival in infants.


  1. Jennifer Y. Chen JY et al. Highly active antiretroviral therapy and adverse birth outcomes among HIV-infected women in Botswana. Journal of Infectious Diseases Volume 206 Issue 11 December 1, 2012.
  2. Watts DH and Mofenson LM. Antiretrovirals in pregnancy: A note of caution. Journal of Infectious Diseases Volume 206 Issue 11 December 1, 2012.

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