| Summary: | In 2015, the majority (80%) of the 1.2 million HIV-positive pregnant women globally, most of whom reside in sub-Saharan Africa (91%), received antiretroviral treatment (ART) for the prevention-of- mother-to-child-transmission (PMTCT). The use of Highly Active Antiretroviral Treatment (HAART) during pregnancy improves maternal health, reduces mother-to-child-transmission to <1%, and reduces horizontal HIV-transmission to serodiscordant couples. Consequently, in 2016, WHO recommended that all HIV-positive women of reproductive age initiate lifelong HAART. Despite the benefits of ART, an increasing body of conflicting evidence continue to report high rates of adverse perinatal outcomes in HIV-positive pregnant women, with no clarity on whether this is attributable to HIV-infection, ART or underlying confounding. This thesis explored the association between maternal HIV-infection, ART and perinatal outcomes, using 3 rigorous methods. A systematic review and pairwise meta-analysis showed that ART-naà ̄ve maternal HIV-infection significantly increased the risk of preterm birth (PTB), low birthweight (LBW), small for gestational age (SGA), and stillbirth. This effect was most prominent in sub-Saharan Africa, it persisted after adjustment for confounders and was directly correlated with the clinical stage of disease. Secondly, a systematic review and network meta-analysis of randomised control trials showed PI-based HAART and NNRTI-based HAART, both of which are recommended for PMTCT in developed and developing countries, to be the most efficacious ART for PMTCT but also associated with the highest risks of PTB, spontaneous PTB, LBW and very LBW compared to other commonly used ART. Lastly, prospectively collected data on a South African cohort of HIV-negative and HIV- positive women on a predominantly NNRTI-based HAART regimen, with pregnancies dated by early ultrasound (<l14 weeks gestation), was used to determine the association between HIV/ART and perinatal outcomes in a 'real-world' context. The limited power of the study, and high background incidence of adverse perinatal outcomes in HIV-negative women prevented multivariate analyses from detecting an independent association between maternal HIV/ART and PTB, LBW or SGA. The findings of this thesis highlight the importance of recent efforts by national governments and international stakeholders (WHO, USAID, UNAIDS) to accelerate ART coverage in HIV-positive women of reproductive age; however, it also shows that an unintended negative consequence of the current HAART regimens recommended for PMTCT will be a significant increase in the burden of adverse perinatal outcomes that directly contribute to neonatal and under-5 mortality, particularly in sub-Saharan Africa.
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