Perinatal Nutrition and Infection Interventions in Sub-Saharan Africa: Timing and Mechanisms of Action

Abstract

The United Nations Sustainable Development Goals call on all countries to end preventable deaths of newborns and children under 5 years of age by 2030 and reduce the neonatal mortality below 12 per 1000 live births and mortality under the age of five (U5) to less than 25 per 1000 live births. In 2018, the global U5 mortality rate was 39 per 1000 and neonatal deaths accounted for 47% of these deaths. As a result, meeting the SDGs target of will require countries to expand and strengthen perinatal interventions to reduce stillbirths and improve neonatal health. However, there are still key knowledge gaps in understanding the mechanisms of action and timing of these interventions. My three papers use epidemiologic methods to investigate three perinatal interventions: antenatal maternal micronutrient supplements (MMS), antiretroviral therapy for pregnant women living with HIV, and neonatal vitamin A supplementation (NVAS), with specific focus on timing of administration, potential interactions between interventions, and better understanding of the mechanisms of their effects through evaluation of potential mediators. Women in low- and middle-income countries (LMICs) often have multiple concurrent micronutrient deficiencies and as a result MMS has been explored in pregnancy to improve maternal and perinatal health. MMS in pregnancy has been shown to improve birthweight among infants and survival among subgroups of infants in LMIC. Recent evidence suggests that the survival benefits of MMS are greater for female infants as compared to males, but the biological mechanisms leading to the sex differential effect remains unclear. I utilized data from a randomized, double-blind, placebo-controlled trial of MMS conducted in Tanzania to examine birthweight and other birth outcomes as potential mediators of the effect of MMS on six-week infant mortality. Causal mediation analyses were conducted to assess mediation through birth weight, gestational age, weight for gestational age, and the joint effect of gestational age and weight for gestational age. This analysis found that the potential sex-specific effects of MMS on mortality may be due to differences in mechanisms related to birth outcomes. In the context of the Tanzanian trial, the observed effect of MMS on 6-week mortality for female infants was entirely mediated by increased gestation duration and improved intrauterine growth, while these mechanisms did not appear to be major contributors among male infants. Combination antiretroviral therapy (cART) for pregnant women living with HIV is associated with very low rates of HIV transmission from mother to newborn; however, an unintended adverse consequence of some cART regimens may be increased risks of fetal loss and preterm birth. While analyses have been conducted to compare the relative safety of different regimens during pregnancy, it remains unclear whether these risks vary by timing of treatment initiation during pregnancy. Data from a prospective cohort of women living with HIV in Tanzania was used to analyze of timing of cART initiation on pregnancy loss and birth outcomes. This study did not demonstrate any increased risk of stillbirth based on timing of cART initiation, and there were no associations between preconception cART initiation as compared to post-conception cART initiation with adverse birth outcomes. However, starting cART before 20 weeks of gestation was associated with an increased risk of preterm birth, but decreased risk of small for gestational age birth compared to initiating after 20 weeks. With increasing use of cART preconception and early in pregnancy as a result of global recommendations, clinicians should be aware of both the benefits and risks of cART in relation to adverse birth outcomes to most effectively optimize regimens for maternal and child health. NVAS has been hypothesized to have negative effects for female infant survival for those who receive the diphtheria-tetanus-pertussis (DTP) vaccine. The proposed biological mechanism is that NVAS may amplify negative nonspecific effects of DTP vaccination. The first aim of the study was to assess the potential nonspecific effects of Bacillus Calmette-Guérin (BCG) and DTP vaccines on infant mortality in two large birth cohorts from Ghana and Tanzania and secondly to determine whether non-specific effects of vaccination are modified the by NVAS and infant sex. I found that both BCG and DTP vaccination were associated with a lower risk of mortality and found no evidence interaction of vitamin A with DTP or BCG vaccination on infant survival, supporting global recommendations on BCG and DTP vaccination and programmatic efforts to ensure all children have access to these vaccines. Together, these three papers provide a demonstration of how studies of timing, mediation, and interaction can be used to optimize interventions and inform interventions design and program planning to maximize impact of perinatal intervention. The results of this thesis provide key information to assist in global recommendations on MMS, NVAS, and antenatal cART provision for the prevention of perinatal death.