In high HIV prevalence regions, women are at high risk for HIV during pregnancy and breastfeeding. To protect women and reach elimination of mother-to-child HIV transmissions targets, the World Health Organization recommends offering oral pre-exposure prophylaxis (PrEP) to HIV-negative pregnant/postpartum women in high-burden settings. To date, no large-scale longitudinal safety evaluation of prenatal PrEP use has been conducted and there are no long-term data beyond 12 months. The proposed study aims to quantify infant pre- and postnatal PrEP exposure and evaluate birth, bone, growth, and neurocognitive outcomes following PrEP exposure through the child’s 5th birthday. Our overall goal is to define a comprehensive safety profile of prenatal/postpartum PrEP in a unique ongoing cluster-RCT in Kenya that compares PrEP delivery approaches in >4500 pregnant women (PrIMA Study, R01AI125498, MPI: John-Stewart/Baeten). By leveraging existing PrIMA infrastructure, extending follow up from 9 to 60 months, and collecting new outcome data in this unprecedented cohort, we are uniquely positioned to assess infant PrEP exposure and outcomes. Our aims: Aim 1-Quantify infant PrEP exposure in utero and via breastmilk through a paired analysis of mother-infant hair samples. Hair samples will be collected from mother-infant pairs enrolled in PrIMA to assess PrEP exposure in utero through breastfeeding cessation. PrEP concentrations in hair will be quantified using validated LC-MS/MS methods. Ratios of infant-to-maternal hair concentrations of PrEP (representing degree of maternal-to-infant transfer) will be assessed. We will also determine whether duration of PrEP use, gestational age at PrEP initiation, maternal age, and infant sex are associated with hair levels and ratios. Hypothesis: PrEP will be detectable in infant hair at delivery and will correlate with levels in maternal hair. Infant PrEP levels will peak at birth and decrease when exposure is limited to breastmilk. Aim 2–Determine whether prenatal PrEP exposure is associated adverse birth and infant outcomes. We will compare frequency of miscarriage, stillbirth, preterm birth, low birth birthweight, and small-for-gestational age, and infant growth by any prenatal PrEP exposure, trimester of exposure, and quantity of exposure measured by maternal PrEP drug levels. Hypothesis: Prenatal PrEP use will not be associated with adverse outcomes. Aim 3–Evaluate whether PrEP exposure during pregnancy and breastfeeding is associated with infant and child bone development, neurocognitive, or growth outcomes up to 60 months. We will measure bone mineral density using dual energy x-ray absorptiometry, conduct neurocognitive assessments, and measure growth in an extension cohort of mother-infant pairs in PrIMA to detect differences by PrEP exposure (binary and strata of PrEP drug levels). Hypothesis: Maternal PrEP will not result in changes in early childhood outcomes. These highly innovative studies will provide comprehensive, long-term outcome data, with precise exposure quantification in the largest PrEP in pregnancy evaluation to date.

Pregnancy and breastfeeding are periods of high HIV acquisition risk for African women. The World Health Organization recommends offering oral pre-exposure prophylaxis (PrEP) to HIV-negative pregnant and postpartum women in HIV high-burden settings, while advocating for continued comprehensive longitudinal safety evaluation during implementation. Our proposed work will provide important new data by systematically quantifying infant pre- and postnatal PrEP exposure and assessing birth, bone, growth, and neurocognitive, outcomes following PrEP exposure through the child’s 5th birthday in the largest PrEP in pregnancy evaluation to date.