Perinatal outcomes in treated, HIV-positive pregnant women

Globally, 1.4 million HIV-positive women become pregnant annually, of whom 92% reside in sub-Saharan Africa and 23% in South Africa. In 2019, 87% of HIV-positive pregnant women in sub-Saharan Africa and >97% in South Africa received lifelong antiretroviral therapy (ART) for the prevention of mother-to-child transmission (MTCT). However, the evidence regarding the association between maternal HIV/ART and perinatal outcomes has been inconsistent. This is partly due to the reliance on observational data and the use of sub-optimal methods to estimate gestational age and measure birth weight. Furthermore, the effect of maternal HIV/ART on fetal growth patterns has never been evaluated. This thesis, therefore, aimed to explore the effect of maternal HIV/ART on perinatal outcomes and fetal growth patterns. First, a systematic review and pairwise meta-analysis of observational studies was performed. Data from a prospective longitudinal study in South Africa were then analysed to assess those effects in a “real world” context. Gestational age was accurately estimated using first trimester ultrasound (<14 weeks’ gestation). Fetal biometric parameters (biparietal diameter [BPD], head circumference [HC], abdominal circumference [AC] and femur length [FL]) were measured serially from 14 weeks’ gestation to delivery. Birth weight was measured in a standardised manner within 24h of birth. The systematic review and meta-analysis showed that treated maternal HIV infection was associated with an increased risk of preterm birth (PTB), spontaneous PTB (sPTB), very PTB (VPTB), low birth weight (LBW) and small for gestational age (SGA) compared with HIV-negativity. However, treated maternal HIV infection was associated with a reduced risk of PTB, LBW and very LBW (VLBW) compared with untreated maternal HIV infection. Among treated HIV-positive women: 1) highly active antiretroviral therapy (HAART) was associated with PTB, LBW and SGA; 2) protease inhibitor (PI)-based ART was associated with PTB, and 3) pre-conception initiation of ART was associated with PTB and VPTB. Secondly, based on accurately determined gestational age and birth weight in the longitudinal study, the overlap between PTB and LBW was substantial, i.e. it is not worthwhile to analyse them separately. Thirdly, the multiple logistic regression showed a significant association between maternal HIV/ART and SGA and neonatal death. Risk factors for adverse perinatal outcomes were also identified: in HIV-positive women, these were dominated by nutritional factors. Lastly, the growth trajectories of fetal BPD, HC, AC and FL were similar between treated HIV-positive and HIV-negative women. Given the clear benefits of ART for improving maternal health and reducing MTCT risk, the expansion of ART coverage in women of reproductive age should be accelerated. However, the present findings of an unintended negative effect of maternal HIV/ART on perinatal outcomes highlight the importance of ongoing surveillance to assess the safety of in utero ART exposure. Accurate measurement of perinatal outcomes is essential to provide better evidence. Therefore, expansion of ultrasound access and standardised birth weight measurement within 24h of birth should be promoted, particularly in HIV-endemic settings with poor perinatal outcomes and the highest fertility rates, i.e. sub-Saharan Africa.