Background Implementation of 3-drug antiretroviral therapy (ART) for prevention of mother to child transmission of HIV (PMTCT) has dramatically decreased vertical transmission of HIV globally. However, recent evidence suggests that women on ART have exceptionally high risk of stillbirth, preterm delivery and small for gestational age infants. Though reasons for adverse birth outcomes are unknown, a growing number of studies have found that hypertension is an important risk factor, leading us to hypothesize that maternal endothelial dysfunction causes adverse birth outcomes among HIV-infected women on ART. Candidate I first contributed to the field of PMTCT 16 years ago when I lived in South Africa and ran the first local NGO to provide antiretroviral prophylaxis in pregnancy. I decided to pursue a research career in PMTCT and adverse birth outcomes during my Infectious Diseases fellowship, after performing a large birth surveillance study in Botswana that found strikingly high rates of adverse birth outcomes and hypertension among women with well-controlled HIV. I am applying for a 5-year K23 Career Development Award that builds on findings from my fellowship study. A K23 award will provide the necessary training and experience needed to become an independent investigator studying drug safety in pregnancy, identifying mechanisms underlying adverse birth outcomes and testing interventions to improve pregnancy outcomes among HIV-infected women. Mentoring My primary mentor, Dr. Roger Shapiro, has conducted clinical trials, research on childhood mortality, and birth outcomes research in Botswana for more than 15 years and has been my research mentor since residency. Together we have identified an excellent mentoring team including Dr. Paige Williams (a biostatistician with expertise in studies of drug safety in pregnancy) and Dr. Raina Fichorova (an OB/GYN with 20 years experience running a lab in obstetric immunology). Research Using data collected in an ongoing large birth surveillance study in Botswana, and creating a nested cohort within this surveillance study, my study will 1) establish the role of hypertension in adverse pregnancy outcomes and 2) evaluate the role of low progesterone and chronic inflammation as mechanisms of adverse birth outcomes. I will evaluate whether HIV-status, specific ART regimens and/or the timing of ART initiation influence hypertension, progesterone level and markers of chronic inflammation. These combined analyses are critical first steps in the design of a larger longitudinal cohort to further elucidate mechanisms of adverse birth outcomes among HIV-infected women on ART. This will lead to interventions to improve birth outcomes among HIV-infected women. Training The research objectives are supported by a training plan that includes obtaining an MSc in Epidemiology, further training in the pathophysiology of adverse birth outcomes and a grant support and development program through Harvard Catalyst.
A growing body of evidence suggests that maternal antiretroviral exposure is associated with an increased risk of adverse birth outcomes including preterm delivery, stillbirth and low birth weight/small for gestational age infants though the mechanism for this increased risk is not understood. As the world moves to a `treat all' ART strategy and PMTCT programs provide universal ART for pregnant women with continuation of this ART for life (WHO Option B+), an increase in adverse birth outcomes has the potential to negate improvements in infant morbidity and mortality from decreased vertical HIV transmission. This research will identify underlying pathways that threaten normal pregnancy outcomes among HIV-infected women on ART, and will determine if these pathways are amenable to future interventions.
