Neonatal mortality risk of vulnerable newborns by fine stratum of gestational age and birthweight for 230 679 live births in nine low- and middle-income countries, 2000-2017.

OBJECTIVE: To describe the mortality risks by fine strata of gestational age and birthweight among 230 679 live births in nine low- and middle-income countries (LMICs) from 2000 to 2017. DESIGN: Descriptive multi-country secondary data analysis. SETTING: Nine LMICs in sub-Saharan Africa, Southern and Eastern Asia, and Latin America. POPULATION: Liveborn infants from 15 population-based cohorts. METHODS: Subnational, population-based studies with high-quality birth outcome data were invited to join the Vulnerable Newborn Measurement Collaboration. All studies included birthweight, gestational age measured by ultrasound or last menstrual period, infant sex and neonatal survival. We defined adequate birthweight as 2500-3999 g (reference category), macrosomia as ≥4000 g, moderate low as 1500-2499 g and very low birthweight as <1500 g. We analysed fine strata classifications of preterm, term and post-term: ≥42+0 , 39+0 -41+6 (reference category), 37+0 -38+6 , 34+0 -36+6 ,34+0 -36+6 ,32+0 -33+6 , 30+0 -31+6 , 28+0 -29+6 and less than 28 weeks. MAIN OUTCOME MEASURES: Median and interquartile ranges by study for neonatal mortality rates (NMR) and relative risks (RR). We also performed meta-analysis for the relative mortality risks with 95% confidence intervals (CIs) by the fine categories, stratified by regional study setting (sub-Saharan Africa and Southern Asia) and study-level NMR (≤25 versus >25 neonatal deaths per 1000 live births). RESULTS: We found a dose-response relationship between lower gestational ages and birthweights with increasing neonatal mortality risks. The highest NMR and RR were among preterm babies born at <28 weeks (median NMR 359.2 per 1000 live births; RR 18.0, 95% CI 8.6-37.6) and very low birthweight (462.8 per 1000 live births; RR 43.4, 95% CI 29.5-63.9). We found no statistically significant neonatal mortality risk for macrosomia (RR 1.1, 95% CI 0.6-3.0) but a statistically significant risk for all preterm babies, post-term babies (RR 1.3, 95% CI 1.1-1.5) and babies born at 370 -386 weeks (RR 1.2, 95% CI 1.0-1.4). There were no statistically significant differences by region or underlying neonatal mortality. CONCLUSIONS: In addition to tracking vulnerable newborn types, monitoring finer categories of birthweight and gestational age will allow for better understanding of the predictors, interventions and health outcomes for vulnerable newborns. It is imperative that all newborns from live births and stillbirths have an accurate recorded weight and gestational age to track maternal and neonatal health and optimise prevention and care of vulnerable newborns.

Weight changes and adverse pregnancy outcomes with dolutegravir- and tenofovir alafenamide fumarate-containing antiretroviral treatment regimens during pregnancy and postpartum.

BACKGROUND: We evaluated associations between antepartum weight change and adverse pregnancy outcomes and between antiretroviral therapy (ART) regimens and week-50 postpartum body mass index in IMPAACT 2010. METHODS: Women with HIV-1 in 9 countries were randomized 1:1:1 at 14-28 weeks gestational age (GA) to start dolutegravir(DTG)+emtricitabine(FTC)/tenofovir alafenamide fumarate(TAF) versus DTG+FTC/tenofovir disoproxil fumarate(TDF) versus efavirenz (EFV)/FTC/TDF. Insufficient antepartum weight gain was defined using IOM guidelines. Cox-proportional hazards regression models were used to evaluate the association between antepartum weight change and adverse pregnancy outcomes: stillbirth (≥20 weeks GA), preterm delivery (<37 weeks GA), small for gestational age (SGA<10th percentile), and a composite of these endpoints. RESULTS: 643 participants were randomized: 217 in DTG+FTC/TAF, 215 in DTG+FTC/TDF, and 211 in EFV/FTC/TDF arms. Baseline medians were: GA 21.9 weeks, HIV RNA 903 copies/mL, CD4 count 466 cells/uL. Insufficient weight gain was least frequent with DTG+FTC/TAF (15.0%) versus DTG+FTC/TDF (23.6%) and EFV/FTC/TDF (30.4%). Women in the DTG+FTC/TAF arm had the lowest rate of composite adverse pregnancy outcome. Low antepartum weight gain was associated with higher hazard of composite adverse pregnancy outcome (HR 1.44, 95%CI 1.04, 2.00) and SGA (HR 1.48, 95%CI 0.99, 2.22). More women in the DTG+FTC/TAF arm had body mass index ≥25 kg/m2 at 50 weeks postpartum (54.7%) versus the DTG+FTC/TDF (45.2%) and EFV/FTC/TDF (34.2%) arms. CONCLUSIONS: Antepartum weight gain on DTG regimens was protective against adverse pregnancy outcomes traditionally associated with insufficient weight gain, supportive of guidelines recommending DTG-based ART for women starting ART during pregnancy. Interventions to mitigate postpartum weight gain are needed.

The impact of free antiretroviral therapy for pregnant non-citizens and their infants in Botswana.

INTRODUCTION: In December 2019, the Botswana government expanded free antiretroviral therapy (ART) to include non-citizens. We evaluated the impact of this policy change on antenatal care (ANC), antiretroviral therapy coverage and adverse birth outcomes. METHODS: The Tsepamo Surveillance study collects data at up to 18 delivery sites in Botswana. We compared outcomes in citizens and non-citizens living with HIV before and after antiretroviral therapy expansion to non-citizens. Adverse birth outcomes included preterm delivery (PTD) <37 weeks, very preterm delivery (VPTD) <32 weeks, small for gestational age (SGA) <10th percentile, very small for gestational age (VSGA) <3rd percentile, stillbirth and neonatal death. Log-binomial regression models were constructed to generate risk ratios. RESULTS: From August 2014 to September 2021, 45,576 (96.5%) citizens and 1513 (3.2%) non-citizens living with HIV delivered; 954 (62.9%) non-citizen deliveries were before the antiretroviral therapy expansion, and 562 (37.1%) were after. Non-citizen ANC attendance among pregnant people living with HIV increased from 79.2% pre-expansion to 87.2% post-expansion (p<0.001), and became more similar to citizens (96.0% post-expansion). Non-citizens receiving any antenatal antiretroviral therapy increased from 65.5% pre-expansion to 89.9% post-expansion (p < 0.001), also more similar to citizens (97.2% post-expansion). Infants born to non-citizens with singleton gestations in the pre-expansion period had significantly greater risk of PTD (aRR = 1.28, 95% CI, 1.11, 1.46), VPTD (aRR = 1.89, 95% CI, 1.43, 2.44) and neonatal death (aRR = 1.69, 95% CI, 1.03, 2.60), but reduced SGA risk (aRR = 0.75; 95% CI, 0.62, 0.89) compared with citizens. Post-expansion, greater declines in most adverse outcomes were observed in non-citizens, with largely similar outcomes between non-citizens and citizens. Non-significant differences were observed for non-citizenship in PTD (aRR = 0.84, 95% CI, 0.66, 1.06), VPTD (aRR = 0.57, 95% CI, 0.28, 1.01), SGA (aRR = 0.91, 95% CI, 0.72, 1.13), VSGA (aRR = 0.87, 95% CI, 0.58, 1.25), stillbirth (aRR = 0.71, 95% CI, 0.35, 1.27) and neonatal death (aRR = 1.35, 95% CI, 0.60, 2.62). CONCLUSIONS: Following the expansion of free antiretroviral therapy to non-citizens, gaps narrowed in ANC and antiretroviral therapy use in pregnancy between citizens and non-citizens living with HIV. Disparities in adverse birth outcomes were no longer observed.

Metabolic implications and safety of dolutegravir use in pregnancy.

Dolutegravir is recommended for all people living with HIV because of its efficacy, high barrier to resistance, favourable safety and tolerability profile, and affordability. Dolutegravir has the highest rates of viral suppression in pregnancy, therefore preventing perinatal HIV transmission. In view of these benefits, particularly for pregnant women, an important question is if dolutegravir is safe in pregnancy. Dolutegravir has been associated with metabolic complications, including weight gain and rare events of hyperglycaemia, that could affect maternal, fetal, and postnatal health. We review the current clinically and experimentally based literature on the implications of dolutegravir use for pregnant women and for developing embryos and fetuses. Possible effects on folate status, energy metabolism, adipogenesis, and oxidative stress are considered. In many instances, insufficient data are available, pointing to the need for additional research in this important area of HIV treatment.

Evaluating the association of antiretroviral therapy and immune status with hypertensive disorders of pregnancy among people with HIV.

OBJECTIVE: The aim of this study was to examine the association of timing of antiretroviral therapy (ART) initiation and ART class with risk of new-onset hypertensive disorders of pregnancy (HDP) among people with HIV (PWH). DESIGN: An observational study of participants in the multisite Surveillance Monitoring for ART Toxicities (SMARTT) study. METHODS: Data were abstracted from medical records of pregnant PWH enrolled in SMARTT (January 30, 2015 to March 25, 2019). New-onset HDP included gestational hypertension, preeclampsia/eclampsia, or HELLP syndrome. We examined the associations of clinical risk factors and three exposures of interest, each in a separate model, with risk of new-onset HDP. Log-binomial regression models were fit using generalized estimating equations to account for correlations within people. Exposures included timing of ART initiation, antiretroviral class among those on therapy at conception, and antiretroviral class among those initiating treatment during pregnancy. RESULTS: Of 1038 pregnancies in this cohort, 973 were singletons with complete data on HDP, with ART use in 948. Overall, 9% had a new-onset HDP, 10% had chronic hypertension, and 81% had no hypertension. Diabetes [adjusted relative risk (aRR) 2.44, 95% confidence interval (95% CI) 1.42-4.21] and first/second trimester CD4 + cell count less than 200 cells/µl (aRR 1.99, 95% CI 1.21-3.27) were associated with a greater risk of new-onset HDP. Risk of new-onset HDP was similar by antiretroviral class, but those initiating ART after 20 weeks' gestation had a greater risk (aRR 1.93, 95% CI 1.12-3.30) compared with those receiving ART at conception. CONCLUSION: In this large, diverse cohort of pregnant PWH, worse early pregnancy immune status and later ART initiation were associated with an increased risk of HDP while ART class was not.

The burden, prevention and care of infants and children with congenital anomalies in sub-Saharan Africa: A scoping review.

The aim of this scoping review was to determine the scope, objectives and methodology of contemporary published research on congenital anomalies (CAs) in sub-Saharan Africa (SSA), to inform activities of the newly established sub-Saharan African Congenital Anomaly Network (sSCAN). MEDLINE was searched for CA-related articles published between January 2016 and June 2021. Articles were classified into four main areas (public health burden, surveillance, prevention, care) and their objectives and methodologies summarized. Of the 532 articles identified, 255 were included. The articles originated from 22 of the 49 SSA countries, with four countries contributing 60% of the articles: Nigeria (22.0%), Ethiopia (14.1%), Uganda (11.7%) and South Africa (11.7%). Only 5.5% of studies involved multiple countries within the region. Most articles included CA as their primary focus (85%), investigated a single CA (88%), focused on CA burden (56.9%) and care (54.1%), with less coverage of surveillance (3.5%) and prevention (13.3%). The most common study designs were case studies/case series (26.6%), followed by cross-sectional surveys (17.6%), retrospective record reviews (17.3%), and cohort studies (17.2%). Studies were mainly derived from single hospitals (60.4%), with only 9% being population-based studies. Most data were obtained from retrospective review of clinical records (56.1%) or via caregiver interviews (34.9%). Few papers included stillbirths (7.5%), prenatally diagnosed CAs (3.5%) or terminations of pregnancy for CA (2.4%).This first-of-a-kind-scoping review on CA in SSA demonstrated an increasing level of awareness and recognition among researchers in SSA of the contribution of CAs to under-5 mortality and morbidity in the region. The review also highlighted the need to address diagnosis, prevention, surveillance and care to meet Sustainable Development Goals 3.2 and 3.8. The SSA sub-region faces unique challenges, including fragmentation of efforts that we hope to surmount through sSCAN via a multidisciplinary and multi-stakeholder approach.

Neonatal mortality risk of vulnerable newborns: A descriptive analysis of subnational, population-based birth cohorts for 238 203 live births in low- and middle-income settings from 2000 to 2017.

OBJECTIVE: We aimed to understand the mortality risks of vulnerable newborns (defined as preterm and/or born weighing smaller or larger compared to a standard population), in low- and middle-income countries (LMICs). DESIGN: Descriptive multi-country, secondary analysis of individual-level study data of babies born since 2000. SETTING: Sixteen subnational, population-based studies from nine LMICs in sub-Saharan Africa, Southern and Eastern Asia, and Latin America. POPULATION: Live birth neonates. METHODS: We categorically defined five vulnerable newborn types based on size (large- or appropriate- or small-for-gestational age [LGA, AGA, SGA]), and term (T) and preterm (PT): T + LGA, T + SGA, PT + LGA, PT + AGA, and PT + SGA, with T + AGA (reference). A 10-type definition included low birthweight (LBW) and non-LBW, and a four-type definition collapsed AGA/LGA into one category. We performed imputation for missing birthweights in 13 of the studies. MAIN OUTCOME MEASURES: Median and interquartile ranges by study for the prevalence, mortality rates and relative mortality risks for the four, six and ten type classification. RESULTS: There were 238 203 live births with known neonatal status. Four of the six types had higher mortality risk: T + SGA (median relative risk [RR] 2.6, interquartile range [IQR] 2.0-2.9), PT + LGA (median RR 7.3, IQR 2.3-10.4), PT + AGA (median RR 6.0, IQR 4.4-13.2) and PT + SGA (median RR 10.4, IQR 8.6-13.9). T + SGA, PT + LGA and PT + AGA babies who were LBW, had higher risk compared with non-LBW babies. CONCLUSIONS: Small and/or preterm babies in LIMCs have a considerably increased mortality risk compared with babies born at term and larger. This classification system may advance the understanding of the social determinants and biomedical risk factors along with improved treatment that is critical for newborn health.

Maternal biomarkers of endothelial dysfunction and pregnancy outcomes in women with and without HIV in Botswana.

BACKGROUND: Women living with HIV-1 (WLHIV) are at higher risk of having an adverse birth outcome, but the underlying mechanism(s) are unknown. We hypothesized that HIV-associated endothelial activation could adversely impact placental function and lead to impaired fetal growth or stillbirth. METHODS: We used stored samples from WLHIV and HIV-negative women who had enrolled during pregnancy in the observational Botswana Tshipidi cohort. Written informed consent was obtained from the participants. We measured plasma levels of markers of endothelial activation (soluble vascular adhesion molecule 1 [VCAM-1], intercellular adhesion molecule 1 [ICAM-1] and E-selectin) from samples taken during pregnancy. We compared log10 biomarker levels by maternal HIV status and by the timing of ART initiation (ART prior to conception vs. during pregnancy; ART prior to sample collection vs. no ART prior to sampling) using t-tests and the Kruskal-Wallis rank test. We evaluated the association between these biomarkers and adverse birth outcomes (composite of stillbirth or small for gestational age [SGA]) using univariate and multivariate log-binomial regression controlling for maternal age (continuous) and timing of ART start. We also used generalized linear models (GLM) to evaluate the association between continuous birthweight (in grams) and gestational age (in weeks) and markers of endothelial dysfunction, adjusting for maternal age (continuous) and timing of ART relative to sample collection. RESULTS: Specimens collected before delivery were available for 414 women (372 WLHIV and 42 HIV-negative women), with a median age of 28 years and median gestational age at sample collection of 30 weeks (range 26, 35 weeks). WLHIV had significantly higher median VCAM1 (p = 0.002) than HIV-negative women, but HIV-negative women had higher median ICAM1 (p = 0.01); e-Selectin levels did not differ by maternal HIV status. Women starting ART during pregnancy had higher log10 VCAM1 levels than those on ART before conception, regardless of whether the sample was collected before (p = 0.02) or after (p = 0.03) ART initiation. However, ICAM1 and e-Selectin did not differ significantly by ART status or ART timing. Ninety-eight women (91 WLHIV and 7 HIV-negative), or 9 (2%) and 89 (22%) included in this study, had a stillborn or SGA baby respectively. Univariate and adjusted analyses did not show significant associations between levels of any of the biomarkers with these adverse birth outcomes. However, lower birthweight (p = 0.03) and lower gestational age at delivery were associated e-Selectin and ICAM (p = 0.008), respectively. CONCLUSION: Maternal HIV infection and lack of ART (or recent ART initiation) were associated with one marker of greater endothelial activation (VCAM-1), but not with other markers (ICAM-1 nor E-selectin) in pregnancy. e-Selectin was associated with lower birthweight and every unit increase in log ICAM-1 at delivery was associated with lower gestation age at delivery.

Emulating Target Trials to Avoid Immortal Time Bias - An Application to Antibiotic Initiation and Preterm Delivery.

BACKGROUND: Randomized trials in pregnancy are extremely challenging, and observational studies are often the only option to evaluate medication safety during pregnancy. However, such studies are often susceptible to immortal time bias if treatment initiation occurs after time zero of follow-up. We describe how emulating a sequence of target trials avoids immortal time bias and apply the approach to estimate the safety of antibiotic initiation between 24 and 37 weeks gestation on preterm delivery. METHODS: The Tsepamo Study captured birth outcomes at hospitals throughout Botswana from 2014 to 2021. We emulated 13 sequential target trials of antibiotic initiation versus no initiation among individuals presenting to care <24 weeks, one for each week from 24 to 37 weeks. For each trial, eligible individuals had not previously initiated antibiotics. We also conducted an analysis susceptible to immortal time bias by defining time zero as 24 weeks and exposure as antibiotic initiation between 24 and 37 weeks. We calculated adjusted risk ratios (RR) and 95% confidence intervals (CI) for preterm delivery. RESULTS: Of 111,403 eligible individuals, 17,009 (15.3%) initiated antibiotics between 24 and 37 weeks. In the sequence of target trials, RRs (95% CIs) ranged from 1.04 (0.90, 1.19) to 1.24 (1.11, 1.39) (pooled RR: 1.11 [1.06, 1.15]). In the analysis susceptible to immortal time bias, the RR was 0.90 (0.86, 0.94). CONCLUSIONS: Defining exposure as antibiotic initiation at any time during follow-up after time zero resulted in substantial immortal time bias, making antibiotics appear protective against preterm delivery. Conducting a sequence of target trials can avoid immortal time bias in pregnancy studies.

Incident HIV acquisition among pregnant women in Botswana: findings from the Tsepamo birth outcomes surveillance study.

INTRODUCTION: In Botswana, where almost all pregnant women known to have HIV receive antiretroviral therapy, a large proportion of vertical HIV transmission may occur among women with incident undiagnosed HIV infection during pregnancy. Botswana guidelines recommend repeat HIV testing every 3 months in pregnancy, with at least one test in the third trimester. We evaluated the rate of repeat HIV testing, calculated HIV incidence during pregnancy and estimated missed seroconversions. METHODS: In the Botswana Tsepamo Study, we abstracted HIV test dates and results from obstetric records of all women who delivered at maternity wards in 18 communities between 7th May 2017 and 20th August 2021. We defined seroconversion as an initial negative/indeterminate HIV test in pregnancy followed by a positive test during pregnancy/at delivery. The incidence rate (IR) of seroconversion was calculated among women with > = 2 known test dates. Missed seroconversions were estimated among women without a test in the third trimester by applying the IR to the time after the last HIV test until delivery. RESULTS: Among 103,529 women delivering in the study period testing negative at the first test and with known conception and HIV test dates, 29,085 (28%) were tested in one trimester of pregnancy, 73,156 (71%) were tested in ≥ 2 trimesters of pregnancy and 9628 (9%) had a test in all trimesters. A total of 78,162 (75%) women had a third-trimester test. There were 223 seroconversions (2.58/1000 pregnancies, 0.26%) among those with ≥ 2 known HIV test dates, yielding an IR of 0.69/100 person-years. Among 25,289 women who did not have a test in the third trimester, we estimate approximately 58 seroconversions may have been missed during pregnancy due to a lack of repeat testing. Factors associated with seroconversion during pregnancy included younger age, less education and not being married. CONCLUSIONS: More than two-thirds of women had repeat HIV testing in pregnancy and HIV incidence was low. However, an estimated 21% of seroconversions in pregnancy were likely missed due to a lack of re-testing. To reach the goal of zero new paediatric HIV infections, Botswana will need to intensify repeat HIV testing in the third trimester of pregnancy.

Association of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection With Maternal Mortality and Neonatal Birth Outcomes in Botswana by Human Immunodeficiency Virus Status.

OBJECTIVE: To evaluate the combined association of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human immunodeficiency virus (HIV) infection on adverse birth outcomes in an HIV-endemic region. METHODS: The Tsepamo Study abstracts data from antenatal and obstetric records in government maternity wards across Botswana. We assessed maternal mortality and adverse birth outcomes for all singleton pregnancies from September 2020 to mid-November 2021 at 13 Tsepamo sites among individuals with documented SARS-CoV-2 screening tests and known HIV status. RESULTS: Of 20,410 individuals who gave birth, 11,483 (56.3%) were screened for SARS-CoV-2 infection; 4.7% tested positive. People living with HIV were more likely to test positive (144/2,421, 5.9%) than those without HIV (392/9,030, 4.3%) (P=.001). Maternal deaths occurred in 3.7% of those who had a positive SARS-CoV-2 test result compared with 0.1% of those who tested negative (adjusted relative risk [aRR] 31.6, 95% CI 15.4-64.7). Maternal mortality did not differ by HIV status. The offspring of individuals with SARS-CoV-2 infection experienced more overall adverse birth outcomes (34.5% vs 26.6%; aRR 1.2, 95% CI 1.1-1.4), severe adverse birth outcomes (13.6% vs 9.8%; aRR 1.2, 95% CI 1.0-1.5), preterm delivery (21.4% vs 13.4%; aRR 1.4, 95% CI 1.2-1.7), and stillbirth (5.6% vs 2.7%; aRR 1.7 95% CI 1.2-2.5). Neonates exposed to SARS-CoV-2 and HIV infection had the highest prevalence of adverse birth outcomes (43.1% vs 22.6%; aRR 1.7, 95% CI 1.4-2.0). CONCLUSION: Infection with SARS-CoV-2 at the time of delivery was associated with 3.7% maternal mortality and 5.6% stillbirth in Botswana. Most adverse birth outcomes were worse among neonates exposed to both SARS-CoV-2 and HIV infection.

Impact of prophylactic antimalarials in pregnant women living with Human Immunodeficiency Virus on birth outcomes in Botswana.

OBJECTIVES: Until late 2015, Botswana recommended preventive treatment for pregnant women in malarial regions with chloroquine and proguanil (CP). The guideline change provided an opportunity to evaluate CP and adverse birth outcomes. METHODS: The Tsepamo Study performed birth outcomes surveillance at large delivery centres throughout Botswana. We evaluated adverse birth outcomes from 2015 to 2017 at three hospitals where 93% of CP use was recorded. Outcomes included neonatal death (NND), small for gestational age (SGA), very SGA, stillbirth (SB), preterm delivery (PTD) and very PTD. Logistic regression analysis (unadjusted and adjusted) was conducted for each adverse birth outcome. RESULTS: During the study period, 5883 (26%) of 23,033 deliveries were exposed to CP, with the majority (65%) in the most malaria-endemic region. At this site, there was a trend or an association between CP use and reduction of three adverse birth outcomes: PTD (aOR 0.85, 95% CI 0.76-0.96), vPTD (aOR 0.83, 95% CI 0.68-1.01) and NND (aOR 0.65, 95% CI 0.42-1.00). However, at the least malaria-endemic site, the association was in the opposite direction for SB (aOR 1.54, 95% CI 1.08-2.22), SGA (aOR 1.24, 95% CI 1.06-1.44) and vSGA (aOR 1.42, 95% CI 1.14-1.77). The association between CP and reduced PTD was present among women without HIV (aOR 0.77, 95% CI 0.67-0.89) but not among women with HIV (aOR 1.09, 95% CI 0.78-1.35). CONCLUSIONS: Antimalarial prophylaxis was associated with improved birth outcomes in the most malaria-endemic region of Botswana, but not elsewhere. This finding supports current WHO guidance to use prophylaxis strategies among pregnant women in highly malaria-endemic regions. Further studies of the risks and benefits of specific antimalarial regimens in pregnancy are warranted, particularly in areas with lower incidence of malaria.

Dolutegravir in Pregnancy as Compared with Current HIV Regimens in the United States.

BACKGROUND: Data on the effectiveness and safety of dolutegravir-based antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infection in pregnancy as compared with other ART regimens commonly used in the United States and Europe, particularly when initiated before conception, are limited. METHODS: We conducted a study involving pregnancies in persons with HIV-1 infection in the Pediatric HIV/AIDS Cohort Study whose initial ART in pregnancy included dolutegravir, atazanavir-ritonavir, darunavir-ritonavir, oral rilpivirine, raltegravir, or elvitegravir-cobicistat. Viral suppression at delivery and the risks of infants being born preterm, having low birth weight, and being small for gestational age were compared between each non-dolutegravir-based ART regimen and dolutegravir-based ART. Supplementary analyses that included participants in the Swiss Mother and Child HIV Cohort Study were conducted to improve the precision of our results. RESULTS: Of the pregnancies in the study, 120 were in participants who received dolutegravir, 464 in those who received atazanavir-ritonavir, 185 in those who received darunavir-ritonavir, 243 in those who received rilpivirine, 86 in those who received raltegravir, and 159 in those who received elvitegravir-cobicistat. The median age at conception was 29 years; 51% of the pregnancies were in participants who started ART before conception. Viral suppression was present at delivery in 96.7% of the pregnancies in participants who received dolutegravir; corresponding percentages were 84.0% for atazanavir-ritonavir, 89.2% for raltegravir, and 89.8% for elvitegravir-cobicistat (adjusted risk differences vs. dolutegravir, -13.0 percentage points [95% confidence interval {CI}, -17.0 to -6.1], -17.0 percentage points [95% CI, -27.0 to -2.4], and -7.0 percentage points [95% CI, -13.3 to -0.0], respectively). The observed risks of preterm birth were 13.6 to 17.6%. Adjusted risks of infants being born preterm, having low birth weight, or being small for gestational age did not differ substantially between non-dolutegravir-based ART and dolutegravir. Results of supplementary analyses were similar. CONCLUSIONS: Atazanavir-ritonavir and raltegravir were associated with less frequent viral suppression at delivery than dolutegravir. No clear differences in adverse birth outcomes were observed with dolutegravir-based ART as compared with non-dolutegravir-based ART, although samples were small. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).

Iron, folic acid, and multiple micronutrient supplementation strategies during pregnancy and adverse birth outcomes in Botswana.

BACKGROUND: Antenatal multiple micronutrient supplementation (MMS) with iron, folic acid, and other micronutrients might improve birth outcomes, but it is not currently universally recommended by WHO. METHODS: In this observational cohort study, we surveyed pregnancies for adverse birth outcomes at eight hospitals from July, 2014, to July, 2018, and 18 hospitals from August, 2018, to December, 2020, in Botswana to assess four routine supplementation strategies in women presenting before 24 weeks' gestation: folic acid only, iron only, iron and folic acid supplementation (IFAS), and MMS. Women with singleton pregnancies; a known HIV status, age, and delivery site; haemoglobin measured within 7 days of presenting to antenatal care; and weight measured within 31 days of presenting to care were included in our analysis. Data were abstracted from the maternity obstetric record (a record of antenatal care) at the time of birth from all women giving birth at selected hospitals throughout the country. We estimated risk differences overall and in key subgroups, adjusting for demographic and clinical factors. FINDINGS: Between July 6, 2014, and Dec 8, 2020, 96 341 eligible women (21 659 [22·5%] of whom had HIV) were included in the study. 36 334 (37·7%) women initiated iron only supplementation, 1133 (11·8%) initiated folic acid only supplementation, 23 101 (24·0%) initiated IFAS, and 31 588 (32·8%) women initiated MMS. Women who initiated iron only and folic acid only supplementation had higher risks of stillbirth, preterm birth, very preterm birth, low and very low birthweight, and neonatal death compared with women who received IFAS (adjusted risk differences for iron only supplementation vs IFAS ranged from 0·22% [95% CI 0·04 to 0·40] for neonatal death to 2·39% [1·78 to 3·00] for preterm birth; and adjusted risk differences for folic acid only supplementation vs IFAS ranged from 0·77% [-0·80 to 2·34] for neonatal death to 5·75% [1·38 to 10·13] for preterm birth), with greater difference in women with HIV and those aged 35 years and older. Compared with IFAS, women who initiated MMS had lower risks of preterm and very preterm births, and low and very low birthweight (adjusted risk differences ranged from -0·50% [-0·77 to 0·23] for very preterm birth to -1·06% [-1·69 to -0·42] for preterm birth). INTERPRETATION: Nationwide data from Botswana support improved birth outcomes with MMS compared with IFAS. FUNDING: National Institutes of Health, National Institute of Child Health and Human Development, and National Institute of Allergy and Infectious Diseases.

Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial.

HIV-1 therapy with single or dual broadly neutralizing antibodies (bNAbs) has shown viral escape, indicating that at least a triple bNAb therapy may be needed for robust suppression of viremia. We performed a two-part study consisting of a single-center, randomized, double-blind, dose-escalation, placebo-controlled first-in-human trial of the HIV-1 V2-glycan-specific antibody PGDM1400 alone or in combination with the V3-glycan-specific antibody PGT121 in 24 adults without HIV in part 1, as well as a multi-center, open-label trial of the combination of PGDM1400, PGT121 and the CD4-binding-site antibody VRC07-523LS in five viremic adults living with HIV not on antiretroviral therapy (ART) in part 2 ( NCT03205917 ). The primary endpoints were safety, tolerability and pharmacokinetics for both parts and antiviral activity among viremic adults living with HIV and not on ART for part 2 of the study. The secondary endpoints were changes in CD4+ T cell counts and development of HIV-1 sequence variations associated with PGDM1400, PGT121 and VRC07-523LS resistance in part 2. Intravenously administered PGDM1400 was safe and well-tolerated at doses up to 30 mg kg-1 and when given in combination with PGT121 and VRC07-523LS. A single intravenous infusion of 20 mg kg-1 of each of the three antibodies reduced plasma HIV RNA levels in viremic individuals by a maximum mean of 2.04 log10 copies per ml; however, viral rebound occurred in all participants within a median of 20 days after nadir. Rebound viruses demonstrated partial to complete resistance to PGDM1400 and PGT121 in vitro, whereas susceptibility to VRC07-523LS was preserved. Viral rebound occurred despite mean VRC07-523LS serum concentrations of 93 µg ml-1. The trial met the pre-specified endpoints. Our data suggest that future bNAb combinations likely need to achieve broad antiviral activity, while also maintaining high serum concentrations, to mediate viral control.

High risk of adverse birth outcomes among adolescents living with HIV in Botswana compared to adult women living with HIV and adolescents without HIV.

BACKGROUND: Adolescent girls are three times more likely to be living with HIV than boys of the same age. Prior studies have found associations between adolescent pregnancies and increased maternal morbidity and infant mortality, but few studies have assessed the impact of HIV infection on maternal and infant outcomes in adolescents. METHODS: The Tsepamo Study abstracts maternal and infant data from obstetric records in government maternity wards in Botswana. We assessed maternal complications and adverse birth outcomes for all singleton pregnancies from August 2014 to August 2020 at eighteen Tsepamo sites among adolescents (defined as 10-19 years of age) and adults (defined as 20-35 years of age), by HIV status. Univariate and multivariate logistic regression using a complete case analysis method were used to evaluate differences in outcomes. RESULTS: This analysis included 142,258 singleton births, 21,133 (14.9%) to adolescents and 121,125 (85.1%) to adults. The proportion of adults living with HIV (N = 22,114, 22.5%) was higher than adolescents (N = 1593, 7.6%). The proportion of most adverse birth outcomes was higher in adolescents. Among adolescents, those with HIV had increased likelihoods of anemia (aOR = 1.89, 95%CI 1.66, 2.15) and cesarean sections (aOR = 1.49, 95%CI 1.3,1.72), and infants with preterm birth (aOR = 1.15, 95%CI 1.0, 1.32), very preterm birth (aOR = 1.35, 95%CI 1.0,1.8), small for gestational age (aOR = 1.37, 95%CI 1.20,1.58), and very small for gestational age (aOR = 1.46, 95%CI 1.20, 1.79). CONCLUSIONS: Adolescent pregnancy and adolescent HIV infection remain high in Botswana. Adolescents have higher risk of adverse maternal and infant birth outcomes than adults, with the worst outcomes among adolescents living with HIV. Linking HIV prevention and family planning strategies for this age group may help minimize the number of infants with poor birth outcomes among this already vulnerable population.

Cross-sectional trends in HIV prevalence among pregnant women in Botswana: an opportunity for PrEP?

INTRODUCTION: Young women in sub-Saharan Africa are at particularly high risk of HIV acquisition. Recent shifts towards "test and treat" strategies have potential to reduce transmission in this age group but have not been widely studied outside of clinical trials. Using data from nationwide surveillance among pregnant women in Botswana, where a "test and treat" program was implemented in 2016, we describe trends in HIV prevalence over time and highlight opportunities for targeted prevention. METHODS: The Tsepamo study abstracted data from obstetric records of all women delivering at eight government hospitals in Botswana between 2015 and 2019, accounting for 45% of all births in the country (n = 120,755). We used a stratified analysis to identify prevalence trends and evaluated decreases in HIV prevalence over time using the Cochrane-Armitage test for linear trend. A multivariable logistic regression analysis was also performed to identify factors associated with declines in HIV prevalence. RESULTS: Overall HIV prevalence was 24.1% among 120,755 women who delivered during the study period. Prevalence differed by site of delivery, ranging from 16.1% to 28.2%, and increased markedly with age. Lower educational attainment (adjusted odds ratio [aOR] = 3.28; 95% confidence interval [CI] 3.07-3.50) and being unmarried (aOR = 1.98; 95% CI 1.88-2.08) were associated with HIV infection. HIV prevalence was 10.0% with a first pregnancy, 21.0% with a second and 39.2% with a third or greater (aOR = 2.20; for any prior pregnancy; 95% CI 2.10-2.29). The same age-adjusted trends were seen when data were limited to women aged 15-24, with a two- to three-fold increase in HIV prevalence between a first and third pregnancy. Prevalence decreased linearly during the 5-year study period from 25.8% to 22.7% (p <0.001). Among age-specific strata, the greatest absolute decline occurred in those aged 35-39, with an 8.7% absolute decrease in HIV prevalence from 2015 to 2019. Minimal declines were seen in those 15-24, with a decrease of only 1.5% over the same period. CONCLUSIONS: While overall trends in Botswana show HIV prevalence declining among pregnant women, prevalence among the youngest age group has remained stagnant. Preventative interventions utilizing pre-exposure prophylaxis should be prioritized during the high-risk period surrounding a woman's first pregnancy.

Anti-hypertensive use for non-severe gestational hypertension in Botswana: A case-control study.

OBJECTIVE: The fetal risks and benefits of antihypertensives to treat gestational hypertension in pregnancy are understudied, particularly in low- and middle-income countries. METHODS: We performed a nested case-control study within a retrospective cohort of obstetrical patients in Botswana from 2014 to 2019. We included women carrying singletons who developed new onset non-severe hypertension (140-159 mm Hg systolic or 90-109 mm Hg diastolic blood pressure) after 20 weeks of pregnancy. Cases were defined as women with either small-for-gestational-age (SGA) infants or stillbirth, analyzed separately; controls were otherwise similar women without the adverse outcome in each analysis. RESULTS: We identified 1932 cases of SGA (7925 controls) and 316 cases of stillbirth (9619 controls). Cases with SGA were more likely to have used an anti-hypertensive than controls (33% vs 29%, adjusted odds ratio [aOR] 1.28, 95% confidence interval [CI] 1.15-1.43). Cases with stillbirth were more likely to have used an anti-hypertensive than controls (42% versus 29%, aOR 1.45, 95% CI 1.14-1.83). CONCLUSION: Anti-hypertensive use for new-onset gestational hypertension was associated with an increased risk of having an SGA infant or a stillbirth among women who never developed severe hypertension. These data support conduct of a randomized clinical trial to determine the appropriate use of anti-hypertensives in non-severe gestational hypertension.

Are morbidity and mortality estimates from randomized controlled trials externally valid? A comparison of outcomes among infants enrolled into an RCT or a cohort study in Botswana.

BACKGROUND: The external validity of the randomized controlled trial (RCT) refers to the extent to which the results of the RCT apply to the relevant, non-trial population and is impacted by its eligibility criteria, its organization, and its delivery of the intervention. Here, we compared the outcomes of mortality and hospitalization between an RCT and a cohort study that concurrently enrolled HIV-exposed uninfected (HEU) newborns in Botswana. METHODS: The Mpepu Study (the RCT) was a clinical trial which determined that co-trimoxazole (CTX) provided no survival benefit for HEUs, allowing both arms of the RCT to be used. The Maikaelelo study (the cohort study) was a prospective observational study that enrolled HEU newborns with telephone follow-up and no in-person visits. Rates of death and hospitalization in the pooled population, were modeled using cox-proportional hazards models for time to death or time to first hospitalization, with study setting (RCT vs. cohort study) as an independent variable. The causal effect of study setting on morbidity and mortality was obtained through a treatment effects approach. RESULTS: In total, 4,010 infants were included; 1,306 were enrolled into the cohort study and 2,704 were enrolled into the RCT. No significant differences in mortality were observed between the two study settings (HR: 1.28, 95% CI: 0.76, 2.13), but RCT participants had a lower risk of hospitalization (HR: 0.72, 95% CI: 0.58, 0.89) that decreased with age. However, RCT participants had a higher risk of hospitalization within the first six months of life. The causal risk difference in hospitalizations attributable to the RCT setting was -0.03 (95% CI: -0.05, -0.01). CONCLUSIONS: Children in an RCT with rigorous application of national standard of care guidelines experienced a significantly lower risk of hospitalization than children participating in a cohort study that did not alter clinical care. Future research is needed to further investigate outcome disparities when real-world results fail to mirror those achieved in a clinical trial. Trial registration The Mpepu Trial was funded by the U.S. National Institutes of Health (No. NCT01229761) and the Maikaelelo Study was funded primarily by the U.S. Centers for Disease Control and Prevention (32AI007433-21).