Effect of weekly 17-hydroxyprogesterone caproate on small for gestational age among pregnant women with HIV in Zambia.

The IPOP trial demonstrated a reduced risk of severe small for gestational age among infants born to women with HIV who received weekly intramuscular 17 alpha-hydroxyprogesterone caproate. This secondary analysis examined the 17P treatment effect in subgroups of maternal BMI, parity, timing of antiretroviral therapy (ART) initiation, and ART regimen. We found that 17P was more effective among nulliparous women, women who started ART before pregnancy, and those taking protease inhibitors.

Risk of Adverse Birth Outcomes in Two Cohorts of Pregnant Women With HIV in Zambia.

BACKGROUND: A trial of progesterone to prevent preterm birth among HIV-infected Zambian women [Improving Pregnancy Outcomes with Progesterone (IPOP)] found no treatment effect, but the risk of the primary outcome was among the lowest ever documented in women with HIV. In this secondary analysis, we compare the risks of preterm birth (<37 weeks), stillbirth, and a composite primary outcome comprising the two in IPOP versus an observational pregnancy cohort [Zambian Preterm Birth Prevention Study (ZAPPS)] in Zambia, to evaluate reasons for the low risk in IPOP. METHODS: Both studies enrolled women before 24 gestational weeks, during August 2015-September 2017 (ZAPPS) and February 2018-January 2020 (IPOP). We used linear probability and log-binomial regression to estimate risk differences and risk ratios (RR), before and after restriction and standardization with inverse probability weights. RESULTS: The unadjusted risk of composite outcome was 18% in ZAPPS (N = 1450) and 9% in IPOP (N = 791) (RR = 2.0; 95% CI = 1.6, 2.6). After restricting and standardizing the ZAPPS cohort to the distribution of IPOP baseline characteristics, the risk remained higher in ZAPPS (RR = 1.6; 95% CI = 1.0, 2.4). The lower risk of preterm/stillbirth in IPOP was only partially explained by measured risk factors. CONCLUSIONS: Possible benefits in IPOP of additional monetary reimbursement, more frequent visits, and group-based care warrant further investigation.

AI Estimation of Gestational Age from Blind Ultrasound Sweeps in Low-Resource Settings.

BACKGROUND: Ultrasound is indispensable to gestational age estimation and thus to quality obstetrical care, yet high equipment cost and the need for trained sonographers limit its use in low-resource settings. METHODS: From September 2018 through June 2021, we recruited 4695 pregnant volunteers in North Carolina and Zambia and obtained blind ultrasound sweeps (cineloop videos) of the gravid abdomen alongside standard fetal biometry. We trained a neural network to estimate gestational age from the sweeps and, in three test data sets, assessed the performance of the artificial intelligence (AI) model and biometry against previously established gestational age. RESULTS: In our main test set, the mean absolute error (MAE) (±SE) was 3.9±0.12 days for the model versus 4.7±0.15 days for biometry (difference, -0.8 days; 95% confidence interval [CI], -1.1 to -0.5; P<0.001). The results were similar in North Carolina (difference, -0.6 days; 95% CI, -0.9 to -0.2) and Zambia (-1.0 days; 95% CI, -1.5 to -0.5). Findings were supported in the test set of women who conceived by in vitro fertilization (MAE of 2.8±0.28 vs. 3.6±0.53 days for the model vs. biometry; difference, -0.8 days; 95% CI, -1.7 to 0.2) and in the set of women from whom sweeps were collected by untrained users with low-cost, battery-powered devices (MAE of 4.9±0.29 vs. 5.4±0.28 days for the model vs. biometry; difference, -0.6; 95% CI, -1.3 to 0.1). CONCLUSIONS: When provided blindly obtained ultrasound sweeps of the gravid abdomen, our AI model estimated gestational age with accuracy similar to that of trained sonographers conducting standard fetal biometry. Model performance appears to extend to blind sweeps collected by untrained providers in Zambia using low-cost devices. (Funded by the Bill and Melinda Gates Foundation.).

Limiting adverse birth outcomes in resource-limited settings (LABOR): protocol of a prospective intrapartum cohort study.

Background: Each year, nearly 300,000 women and 5 million fetuses or neonates die during childbirth or shortly thereafter, a burden concentrated disproportionately in low- and middle-income countries. Identifying women and their fetuses at risk for intrapartum-related morbidity and death could facilitate early intervention. Methods: The Limiting Adverse Birth Outcomes in Resource-Limited Settings (LABOR) Study is a multi-country, prospective, observational cohort designed to exhaustively document the course and outcomes of labor, delivery, and the immediate postpartum period in settings where adverse outcomes are frequent. The study is conducted at four hospitals across three countries in Ghana, India, and Zambia. We will enroll approximately 12,000 women at presentation to the hospital for delivery and follow them and their fetuses/newborns throughout their labor and delivery course, postpartum hospitalization, and up to 42 days thereafter. The co-primary outcomes are composites of maternal (death, hemorrhage, hypertensive disorders, infection) and fetal/neonatal adverse events (death, encephalopathy, sepsis) that may be attributed to the intrapartum period. The study collects extensive physiologic data through the use of physiologic sensors and employs medical scribes to document examination findings, diagnoses, medications, and other interventions in real time. Discussion: The goal of this research is to produce a large, sharable dataset that can be used to build statistical algorithms to prospectively stratify parturients according to their risk of adverse outcomes. We anticipate this research will inform the development of new tools to reduce peripartum morbidity and mortality in low-resource settings.

Weekly 17 alpha-hydroxyprogesterone caproate to prevent preterm birth among women living with HIV: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Women with HIV face an increased risk of preterm birth. 17 alpha-hydroxyprogesterone caproate (17P) has been shown in some trials to reduce early delivery among women with a history of spontaneous preterm birth. We investigated whether 17P would reduce this risk among women with HIV. METHODS: We did a randomised, double-blind, placebo-controlled trial in pregnant women with HIV at the University Teaching Hospital and Kamwala District Health Centre in Lusaka, Zambia. Eligible patients were women aged 18 years or older with confirmed HIV-1 infection, viable intrauterine singleton pregnancy at less than 24 weeks of gestation, and were receiving or intending to commence antiretroviral therapy during pregnancy. Exclusion criteria were major uterine or fetal anomaly; planned or in situ cervical cerclage; evidence of threatened miscarriage, preterm labour, or ruptured membranes at screening; medical contraindication to 17P; previous participation in the trial; or history of spontaneous preterm birth. Eligible participants provided written informed consent and were randomly assigned (1:1) to receive 250 mg intramuscular 17P or placebo once per week, starting between 16 and 24 weeks of gestation until delivery, stillbirth, or reaching term (37 weeks). Participants and study staff were masked to assignment, except for pharmacy staff who did random assignment and prepared injections but did not interact with participants. The primary outcome was a composite of delivery before 37 weeks or stillbirth at any gestational age. Patients attended weekly visits for study drug injections and antenatal care. We estimated the absolute and relative difference in risk of the primary outcome and safety events between treatment groups by intention to treat. This trial is registered with ClinicalTrials.gov, NCT03297216, and is complete. FINDINGS: Between Feb 7, 2018 and Jan 13, 2020, we assessed 1042 women for inclusion into the study. 242 women were excluded after additional assessments, and 800 eligible patients were enrolled and randomly assigned to receive intramuscular 17P (n=399) or placebo (n=401). Baseline characteristics were similar between groups. Adherence to study drug injections was 98% in both groups, no patients were lost to follow-up, and the final post-partum visit was on Aug 6, 2020. 36 (9%) of 399 participants assigned to 17P had preterm birth or stillbirth, compared with 36 (9%) of 401 patients assigned to placebo (risk difference 0·1, 95% CI -3·9 to 4·0; relative risk 1·0, 95% CI 0·6 to 1·6; p=0·98). Intervention-related adverse events were reported by 140 (18%) of 800 participants and occurred in similar proportions in both randomisation groups. No serious adverse events were reported. INTERPRETATION: Although 17P seems to be safe and acceptable to participants, available data do not support the use of the drug to prevent preterm birth among women whose risk derives solely from HIV infection. The low risk of preterm birth in both randomisation groups warrants further investigation. FUNDING: US National Institutes of Health and the Bill and Melinda Gates Foundation.

Acceptability of a trial of vaginal progesterone for the prevention of preterm birth among HIV-infected women in Lusaka, Zambia: A mixed methods study.

Antenatal progesterone prevents preterm birth (PTB) in women with a short cervix or prior PTB in daily vaginal or weekly injectable formulations, respectively. Neither has been tested for the indication of maternal HIV, which is associated with an elevated risk of PTB. The Vaginal Progesterone (VP) Trial was a pilot feasibility study of VP to prevent HIV-related PTB in Lusaka, Zambia. Using mixed methods, we concurrently evaluated the acceptability of the trial and the study product among participants. Over a 1-year period, we enrolled 140 pregnant women living with HIV into a double-masked, placebo-controlled, randomized trial of daily self-administered VP or placebo. We administered an endline questionnaire to all participants and conducted in-depth interviews with 30 participants to assess barriers and facilitators to uptake and retention in the trial and to study product adherence. All interviews were audiotaped, transcribed, translated into English as needed, and independently coded by two analysts to capture emerging themes. Of 131 participants who completed the questionnaire, 128 (98%) reported that nothing was difficult when asked the hardest part about using the study product. When given a hypothetical choice between vaginal and injectable progesterone, 97 (74%) chose vaginal, 31 (24%) injectable, and 3 (2%) stated no preference. Most interviewees reported no difficulties with using the study product; others cited minor side effects and surmountable challenges. Strategies that supported adherence included setting alarms, aligning dosing with antiretrovirals, receiving encouragement from friends and family, sensing a benefit to their unborn baby, and positive feedback from study staff. Participants who reported preference of a vaginal medication over injectable described familiarity with the vaginal product, a fear of needles and resulting pain, and inconvenience of a weekly clinic visit. Those who would prefer weekly injections cited fewer doses to remember. Perceived barriers to study participation included mistrust about the motivations behind research, suspicion of Satanism, and futility or possible harm from a placebo. We report key influences on acceptability of a randomized trial of VP to prevent PTB among HIV-infected women in Zambia, which should inform methods to promote uptake, adherence, and retention in a full-scale trial.

Vaginal progesterone to prevent preterm delivery among HIV-infected pregnant women in Zambia: A feasibility study.

Antenatal vaginal progesterone (VP) reduces the risk of preterm birth (PTB) in women with shortened cervical length, and we hypothesize that it may also prevent PTB in women with HIV as their primary risk factor. We conducted a pilot feasibility study in Lusaka, Zambia to investigate uptake, adherence, and retention in preparation for a future efficacy trial. This was a double-masked, placebo-controlled, randomized trial of 200mg daily self-administered VP suppository or placebo. Pregnant women with HIV who were initiating or continuing antiretroviral therapy were eligible for participation. Potential participants underwent ultrasound to assess eligibility; we excluded those ≥24 gestational weeks, with non-viable, multiple gestation, or extrauterine pregnancies, with short cervix (<2.0cm), or with prior spontaneous PTB. Participants initiated study product between 20-24 weeks of gestation and continued to 37 weeks (or delivery, if sooner). The primary outcome was adherence (proportion achieving ≥80% study product use), assessed by dye stain assay of returned single-use vaginal applicators. Secondary outcomes with pre-defined feasibility targets were: uptake (≥50% eligible participants enrolled) and retention (≥90% ascertainment of delivery outcomes). We also evaluated preliminary efficacy by comparing the risk of spontaneous PTB <37 weeks between groups. From July 2017 to June 2018, 208 HIV-infected pregnant women were eligible for screening and 140 (uptake = 67%) were randomly allocated to VP (n = 70) or placebo (n = 70). Mean adherence was 94% (SD±9.4); 91% (n = 125/137) achieved overall adherence ≥80%. Delivery outcomes were ascertained from 134 (96%) participants. Spontaneous PTB occurred in 10 participants (15%) receiving placebo and 8 (12%) receiving progesterone (RR 0.82; 95%CI:0.34-1.97). Spontaneous PTB < 34 weeks occurred in 6 (9%) receiving placebo and 4 (6%) receiving progesterone (RR 0.67; 95%CI:0.20-2.67). In contrast to findings from vaginal microbicide studies in HIV-uninfected, non-pregnant women, our trial participants were highly adherent to daily self-administered vaginal progesterone. The study's a priori criteria for uptake, adherence, and retention were met, indicating that a phase III efficacy trial would be feasible.

Intramuscular 17-hydroxyprogesterone caproate to prevent preterm birth among HIV-infected women in Zambia: study protocol of the IPOP randomized trial.

BACKGROUND: Each year, an estimated 15 million babies are born preterm, a global burden borne disproportionately by families in lower-income countries. Maternal HIV infection increases a woman's risk of delivering prematurely, and antiretroviral therapy (ART) may compound this risk. While prenatal progesterone prophylaxis prevents preterm birth among some high-risk women, it is unknown whether HIV-infected women could benefit from this therapy. We are studying the efficacy of progesterone supplementation to reduce the risk of preterm birth among pregnant women with HIV in Lusaka, Zambia. METHODS: The Improving Pregnancy Outcomes with Progesterone (IPOP) study is a Phase III double-masked, placebo-controlled, randomized trial of intramuscular 17-alpha hydroxprogesterone caproate (17P) to prevent preterm birth in HIV-infected women. A total of 800 women will be recruited prior to 24 weeks of gestation and randomly allocated to 17P or placebo administered by weekly intramuscular injection. The primary outcome will be a composite of live birth prior to 37 completed gestational weeks or stillbirth at any gestational age. Secondary outcomes will include very preterm birth (< 34 weeks), extreme preterm birth (< 28 weeks), small for gestational age (<10th centile), low birth weight (< 2500 g), and neonatal outcomes. In secondary analysis, we will assess whether specific HIV-related covariates, including the timing of maternal ART initiation relative to conception, is associated with progesterone's prophylactic efficacy, if any. DISCUSSION: We hypothesize that weekly prenatal 17P will reduce the risk of HIV-related preterm birth. An inexpensive intervention to prevent preterm birth among pregnant women with HIV could have substantial global public health impact. TRIAL REGISTRATION: NCT03297216 ; September 29, 2017.

Adverse birth outcomes and their clinical phenotypes in an urban Zambian cohort.

Background: Few cohort studies of pregnancy in sub-Saharan Africa use rigorous gestational age dating and clinical phenotyping. As a result, incidence and risk factors of adverse birth outcomes are inadequately characterized. Methods: The Zambian Preterm Birth Prevention Study (ZAPPS) is a prospective observational cohort established to investigate adverse birth outcomes at a referral hospital in urban Lusaka. This report describes ZAPPS phase I, enrolled August 2015 to September 2017. Women were followed through pregnancy and 42 days postpartum. At delivery, study staff assessed neonatal vital status, birthweight, and sex, and assigned a delivery phenotype. Primary outcomes were: (1) preterm birth (PTB; delivery <37 weeks), (2) small-for-gestational-age (SGA; <10 th percentile weight-for-age at birth), and (3) stillbirth (SB; delivery of an infant without signs of life). Results: ZAPPS phase I enrolled 1450 women with median age 27 years (IQR 23-32). Most participants (68%) were multiparous, of whom 41% reported a prior PTB and 14% reported a prior stillbirth. Twins were present in 3% of pregnancies, 3% of women had short cervix (<25mm), 24% of women were HIV seropositive, and 5% were syphilis seropositive. Of 1216 (84%) retained at delivery, 15% were preterm, 18% small-for-gestational-age, and 4% stillborn. PTB risk was higher with prior PTB (aRR 1.88; 95%CI 1.32-2.68), short cervix (aRR 2.62; 95%CI 1.68-4.09), twins (aRR 5.22; 95%CI 3.67-7.43), and antenatal hypertension (aRR 2.04; 95%CI 1.43-2.91). SGA risk was higher with twins (aRR 2.75; 95%CI 1.81-4.18) and antenatal hypertension (aRR 1.62; 95%CI 1.16-2.26). SB risk was higher with short cervix (aRR 6.42; 95%CI 2.56-16.1). Conclusio ns: This study confirms high rates of PTB, SGA, and SB among pregnant women in Lusaka, Zambia. Accurate gestational age dating and careful ascertainment of delivery data are critical to understanding the scope of adverse birth outcomes in low-resource settings.

The Zambian Preterm Birth Prevention Study (ZAPPS): Cohort characteristics at enrollment.

Background:Sub-Saharan Africa bears a disproportionate burden of preterm birth and other adverse outcomes. A better understanding of the demographic, clinical, and biologic underpinnings of these adverse outcomes is urgently needed to plan interventions and inform new discovery.  Methods:The Zambian Preterm Birth Prevention Study (ZAPPS) is a prospective observational cohort established at the Women and Newborn Hospital (WNH) in Lusaka, Zambia. We recruit pregnant women from district health centers and the WNH and offer ultrasound examination to determine eligibility. Participants receive routine obstetrical care, lab testing, midtrimester cervical length measurement, and serial fetal growth monitoring. At delivery, we assess gestational age, birthweight, vital status, and sex and assign a delivery phenotype. We collect blood, urine, and vaginal swab specimens at scheduled visits and store them in an on-site biorepository. In September 2017, enrollment of the ZAPPS Phase 1 - the subject of this report - was completed. Phase 2 - which is limited to HIV-uninfected women - reopened in January 2018.  Results:Between August 2015 and September 2017, we screened 1784 women, of whom 1450 (81.2%) met inclusion criteria and were enrolled. The median age at enrollment was 27 years (IQR 23-32) and thee median gestational age was 16 weeks (IQR 13-18). Among parous women (N=866; 64%), 21% (N=182) reported a prior miscarriage, 49% (N=424) reported a prior preterm birth, and 13% (N=116) reported a prior stillbirth. The HIV seroprevalence was 24%. Discussion:We have established a large cohort of pregnant women and newborns at the WHN to characterize the determinants of adverse birth outcomes in Lusaka, Zambia. Our overarching goal is to elucidate biological mechanisms in an effort to identify new strategies for early detection and prevention of adverse outcomes. We hope that findings from this cohort will help guide future studies, clinical care, and policy.

Vaginal progesterone to reduce preterm birth among HIV-infected pregnant women in Zambia: a feasibility study protocol.

BACKGROUND: Women infected with HIV have a risk of preterm birth (PTB) that is twice that among uninfected women, and treatment with antiretroviral therapy (ART) may further increase this risk. Progesterone supplementation reduces the risk of preterm delivery in women who have a shortened cervix in the midtrimester. We propose to study the feasibility of a trial of vaginal progesterone (VP) to prevent PTB among HIV-infected women receiving ART in pregnancy. Given low adherence among women self-administering vaginal study product in recent microbicide trials, we plan to investigate whether adequate adherence to VP can be achieved prior to launching a full-scale efficacy trial. METHODS AND DESIGN: One hundred forty HIV-infected pregnant women in Lusaka, Zambia, will be randomly allocated to daily self-administration of either VP or matched placebo, starting between 20 and 24 gestational weeks. The primary outcome will be adherence, defined as the proportion of participants who achieve at least 80% use of study product, assessed objectively with a validated dye stain assay that confirms vaginal insertion of returned single-use applicators. Secondary outcomes will be study uptake, retention, and preliminary efficacy. We will concurrently perform semi-structured interviews with participants enrolled in the study and with women who decline enrollment to assess the acceptability of VP to prevent PTB and of enrollment to a randomized controlled trial. DISCUSSION: We hypothesize that VP could prevent PTB among women receiving ART in pregnancy. In preparation for a trial to test this hypothesis, we plan to assess whether participants will be adherent to study product and protocol. TRIAL REGISTRATION: ClinicalTrial.gov, NCT02970552.

Managing multiple funding streams and agendas to achieve local and global health and research objectives: lessons from the field.

Multiple funding sources provide research and program implementation organizations a broader base of funding and facilitate synergy, but also entail challenges that include varying stakeholder expectations, unaligned grant cycles, and highly variable reporting requirements. Strong governance and strategic planning are essential to ensure alignment of goals and agendas. Systems to track budgets and outputs, as well as procurement and human resources are required. A major goal of funders is to transition leadership and operations to local ownership. This article details successful approaches used by the newly independent nongovernmental organization, the Centre for Infectious Disease Research in Zambia.