Principal Investigator: Chelsea Morroni, MPH, MPhil, PhD, MBChB, DTM&H, DFSRH

Study Objectives:

Specific Aim 1. Evaluate the effectiveness of an antenatal combination regimen of daily low dose aspirin, daily multiple micronutrients, and single dose azithromycin, initiated < 20 weeks’ gestation to reduce the risk of preterm birth, small for gestational age, or low birthweight.

Specific Aim 2. Evaluate the effectiveness of an antenatal combination regimen of daily low dose aspirin and daily multiple micronutrients, initiated initiated < 20 weeks’ gestation to reduce the risk of preterm birth, small for gestational age, or low birthweight.

Specific Aim 3. Evaluate the effectiveness of single dose azithromycin administered empirically initiated < 20 weeks’ gestation to reduce the risk of preterm birth, small for gestational age, or low birthweight.

Specific Aim 4. Comprehensively assess the sociodemographic, behavioral, and environmental predictors of small vulnerable newborn births among pregnant women, comparing those who receive or do not receive each of the three study interventions. This is to a) generate robust meaningful data on the breadth of factors influencing adverse birth outcomes within each study setting, and b) develop a highly predictive risk stratification index for targeted antenatal care in post-trial contexts.

Specific Aim 5. Estimate the cost effectiveness of the intervention, including the cost per disability-adjusted life years averted.

Study Design:

A 2x2 factorial design will be employed to efficiently achieve comparison of the two distinct study regimens, and their combination, compared to routine antenatal care

Study population:

The study will enroll pregnant women <= 20 weeks gestation and aged 18 and above. See inclusion criteria below.

Sample size:

Sample size and power calculations were done using PASS 2023 (NCSS, LLC, Kayesville, UT) — Multi-Arm Tests for Treatment and Control Proportions, adjusted for multiple comparisons. The primary aim of this study is to evaluate the effectiveness of one combination antenatal regimen (daily aspirin + micronutrients, and single-dose azithromycin) and two of its components (daily aspirin + micronutrients, or single dose azithromycin) in reducing adverse birth outcomes when compared to the current antenatal care among pregnant mothers in Botswana. The primary study outcome comprises a dichotomous composite frequency of preterm birth, small for gestational age, and/or low birth weight (i.e., a birth with any of these characteristics would be classified as ‘adverse’ or a ‘small vulnerable newborn.’) We considered a baseline frequency in small vulnerable newborn births raging from 15% to 30%, estimated based on prior studies and surveillance data in Botswana.96,97 We considered a reduction in the risk of the outcome ranging from 20-30% for either of the three intervention regimens.

Assuming 80% power, an overall Type I error rate of 5%, a conservative 15% baseline small vulnerable newborn birth rate, and at least 25% risk reduction for the least effective intervention, 3,276 pregnant women are required (819 per arm). Assuming a 20% follow-up attrition rate, 3,931 participants will be required. Thus, we will enroll a total of 4000 pregnant women.

Study duration: The study is expected to take 7 years from pre-implementation to study close-out and dissemination of findings. Participants will be enrolled at their first ANC visit and followed up until 18 months post-delivery

Sponsor: : Botswana Harvard Health Partnership