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Background: There are limited data on the epidemiology of sexually transmitted infections (STI) and their contribution to adverse birth outcomes (ABO) in sub-Saharan Africa (SSA). We performed a case-control study to assess the prevalence of STI and their association with ABO among women attending Queen Elizabeth Central Hospital, Blantyre, Malawi., Methods: A composite case definition for ABO included stillborn, preterm and low birthweight infants and infants admitted to neonatal intensive care unit within 24 hours of birth. Following recruitment of an infant with an ABO, the next born healthy infant was recruited as a control. Multiplex PCR for Neisseria gonorrhoeae (NG), Chlamydia trachomatis (CT) and Trichomonas vaginalis (TV) was performed on maternal vaginal swabs. HIV and syphilis status was determined on maternal and infant serum. For syphilis, we used combined treponemal/non-treponemal rapid point-of-care tests in parallel with rapid plasma reagin tests, PCR for Treponema pallidum and clinical parameters to diagnose and stage the infection. We compared STI positivity between cases and controls., Results: We included 259 cases and 251 controls. Maternal prevalence of STI was 3.1%, 2.7% and 17.1% for NG, CT and TV, respectively. Maternal prevalence of untreated syphilis was 2.0% and 6.1% for early stage and late/unknown stage, respectively; prevalence of treated syphilis was 2.7%. The HIV prevalence was 16.5%. HIV infection significantly increased the odds for ABO (OR=3.31; 95% CI 1.10 to 9.91) as did NG positivity (OR=4.30; 95% CI 1.16 to 15.99). We observed higher rates of ABO among women with untreated maternal syphilis (early: OR=7.13; 95% CI 0.87 to 58.39, late/unknown stage: OR=1.43; 95% CI 0.65 to 3.15). Maternal TV and CT infections were not associated with ABO., Conclusion: STI prevalence among pregnant women in Malawi is comparable to other SSA countries. HIV, NG and untreated syphilis prevalence was higher among women with ABO compared with women with healthy infants., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: In the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) 2010/VESTED study, pregnant women were randomized to initiate dolutegravir (DTG) + emtricitabine (FTC)/tenofovir alafenamide (TAF), DTG + FTC/tenofovir disoproxil fumarate (TDF), or efavirenz (EFV)/FTC/TDF., Methods: We assessed red blood cell (RBC) folate concentrations at maternal study entry and delivery, and infant birth. RBC folate outcomes were (1) maternal change entry to delivery (trajectory), (2) infant, and (3) ratio of infant-to-maternal delivery. Generalized estimating equation models for each log(folate) outcome were fit to estimate adjusted geometric mean ratio (Adj-GMR)/GMR trajectories (Adj-GMRTs) of each arm comparison in 340 mothers and 310 infants., Results: Overall, 90% of mothers received folic acid supplements and 78% lived in Africa. At entry, median maternal age was 25 years, gestational age was 22 weeks, CD4 count was 482 cells/μL, and log10 HIV RNA was 3 copies/mL. Entry RBC folate was similar across arms. Adj-GMRT of maternal folate was 3% higher in the DTG + FTC/TAF versus EFV/FTC/TDF arm (1.03 [95% confidence interval {CI}, 1.00-1.06]). The DTG + FTC/TAF arm had an 8% lower infant-maternal folate ratio (0.92 [95% CI, .78-1.09]) versus EFV/FTC/TDF., Conclusions: Results are consistent, with no clinically meaningful differences between arms for all RBC folate outcomes, and they suggest that cellular uptake of folate and folate transport to the infant do not differ in pregnant women starting DTG- versus EFV-based antiretroviral therapy., Clinical Trials Registration: NCT03048422., Competing Interests: Potential conflicts of interest. P. D. and S. B. have received funds from ViiV/GSK that were paid to Harvard. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Women with HIV (WHIV) have higher risks of adverse pregnancy outcomes, particularly in the absence of antiretroviral treatment(ART), and timing of ART may impact risk., Methods: In IMPAACT 2010 (VESTED), 643 pregnant WHIV in 9 countries were randomized 1:1:1 to initiate ART: dolutegravir (DTG)+emtricitabine(FTC)/tenofovir alafenamide(TAF); DTG+FTC/tenofovir disoproxil fumarate (TDF) or efavirenz (EFV)/FTC/TDF. We describe adverse pregnancy outcomes in women with a subsequent pregnancy during 50 weeks of postpartum follow-up: spontaneous abortion (<20 weeks), stillbirth (≥20 weeks), preterm delivery (<37 weeks) and small-for-gestational-age (SGA)., Results: Of 643 women, 19 (3%) had 20 subsequent pregnancies while receiving ART at conception: DTG/FTC/TAF(3), DTG/FTC/TDF(2), EFV/FTC or lamivudine(3TC)/TDF(12), EFV/abacavir/3TC (1) and no ART(1). Four spontaneous abortions, 3 stillbirths, and 1 induced abortion occurred. Three (25%) of 12 liveborn infants were preterm (24-, 26- and 36-weeks' gestation). Only 12 (60%) subsequent pregnancies resulted in live birth, and at least 1 adverse pregnancy outcome occurred in 11/19 (58%) (induced abortion excluded). Of 7 women who experienced spontaneous abortion/stillbirth in the subsequent pregnancy, 4 experienced a stillbirth and 1 a neonatal death as outcomes of their earlier index pregnancy. No congenital anomalies were reported., Conclusions: Adverse pregnancy outcomes were common in this cohort of WHIV who conceived on ART shortly after an index pregnancy, 35% ended in stillbirth or spontaneous abortion. The majority of fetal losses occurred in women with recent prior pregnancy loss. Data from larger cohorts of WHIV conceiving on ART and surveillance are needed to elucidate rates and predictors of adverse pregnancy outcome. (249 words)., Competing Interests: Competing interests SB and LZ received NIH funding and ViiV Healthcare funding, both paid to their institution. RH serves on the editorial board for Elsevier’s Clinical Key, a clinical resource for clinicians.

Objective: To evaluate the impact of screening and treating asymptomatic pregnant women for Chlamydia (C.) trachomatis and Neisseria (N.) gonorrhoeae infections on the frequency of preterm birth or low birthweight infants in Botswana., Design: Non-randomised, cluster-controlled trial., Setting: Four antenatal care clinics in Gaborone, Botswana., Population: Pregnant women aged ≥15 years, attending a first antenatal care visit, ≤27 weeks of gestation and without urogenital symptoms were eligible., Methods: Participants in the intervention clinics received screening (GeneXpert®, Cepheid) during pregnancy and at the postnatal visit. Participants in the standard-of-care clinics received screening at the postnatal visit only. We used multivariable logistic regression and post-estimation predictive margins analysis. Post-hoc analysis was conducted among sub-samples stratified by parity., Main Outcome Measures: Preterm birth (<37 weeks of gestation) and low birthweight (<2500 g)., Results: After controlling for parity, hypertension, antenatal care visits and clinic site, the predicted prevalence of preterm birth or low birthweight was lower in the intervention arm (11%) compared with the standard-of-care arm (16%) (adjusted odds ratio [aOR] 0.59; 95% confidence interval [CI] 0.28-1.24). In post-hoc analysis, the intervention was more effective than the standard-of-care (aOR 0.20; 95% CI 0.07-0.64) among nulliparous participants., Conclusion: A C. trachomatis and N. gonorrhoeae infection screening and treatment intervention among asymptomatic pregnant women may have reduced preterm birth or low birthweight outcomes, but results were not statistically significant. Post-hoc analysis found that the intervention reduced adverse outcomes among nulliparous participants., (© 2024 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Background: Mother-to-child transmission of syphilis remains high especially in the WHO AFRO region with a prevalence of 1.62%, resulting in a congenital syphilis rate of 1,119 per 100,000 live births. Elimination efforts can be supported by an understanding of the spatial and temporal changes in disease over time, which can identify priority areas for targeted interventions aimed at reducing transmission., Methods: We collated routine surveillance data from health facilities and covariate data from demographic and health surveys conducted in Malawi between 2014 and 2022. We fitted a Bayesian hierarchical mixed model with spatial and temporally structured random effects to model the district-level monthly counts of maternal syphilis notifications as a function of individual- and district-level predictors. We then generated district-level spatiotemporally explicit risk profiles to estimate the effect of individual- and district-level covariates on maternal syphilis notifications and to identify hotspot areas., Results: Overall, the national prevalence of maternal syphilis increased from 0.28% (95% CI: 0.27-0.29%) in 2014 to peaking in 2021 at 1.92% (95% CI: 1.89-1.96%). Between 2020 and 2022, there was a decline in prevalence, with the most significant decline seen in Zomba District (1.40, 95% CI: 1.12-1.66%). In regression models, a one percentage point increase in district-level antenatal HIV prevalence was associated with increased maternal syphilis (prevalence ratio [PR]: 1.15, 95% credible interval [CrI]: 1.10-1.21). There was also an increased prevalence of maternal syphilis associated with an increased district-level mean number of sex partners (PR: 1.05, 95% CrI: 0.80-1.37). The number of districts with a high prevalence of maternal syphilis also increased between 2014 and 2022, especially in the southern region, where most had a high probability (approaching 100%) of having high maternal syphilis (defined as relative risk >1 compared to the standard population of women aged 15-49 years) in 2022., Conclusion: Maternal syphilis prevalence in Malawi shows an increasing upward trend, with an estimated six times relative increase between 2014 and 2022 (0.28% to 1.73%) and strong associations with higher district-level HIV prevalence. Controlling syphilis depends on reaching vulnerable populations at the sub-national level, which may be disproportionately affected. Our findings support the move to integrate the elimination of mother-to-child transmission (EMTCT) of syphilis programs with existing prevention of mother-to-child transmission (PMTCT) of HIV programs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chirombo, Majamanda, Gunsaru, Yosefe, Ozituosauka, Mchoma, Morroni, Chipeta, MacPherson and Freyne.)

Objectives: Women are under-represented in clinical trials and must often commit to using contraception to enroll. We sought to determine the incidence and predictors of pregnancy in women participating in HIV treatment trials., Design: Individual participant data meta-analysis., Methods: We included data from multicountry HIV treatment trials conducted during the period 2005-2019 by the AIDS Clinical Trials Group that included females with HIV who were of reproductive potential, did not intend to become pregnant, and agreed to use effective contraception during study treatment. We extracted data from all female participants of age 18-55 years, including occurrence and dates of pregnancy on-study; however, only a few incident pregnancy predictor variables were available for analysis., Results: One thousand six hundred twenty-six women from 4 trials were included. Over a median of 28 months (6461 person-years) of follow-up, 143 (9%) women became pregnant, for an overall incidence of 2.2 pregnancies/100 person-years (range 0.5-3/100 person-years, by study). In multivariable analysis including baseline age, type of regimen, and country as predictor variables, younger age remained the strongest predictor of incident pregnancy ( P < 0.0001 adjusted for country and antiretroviral treatment regimen). CD4 and HIV-1 RNA were not associated with pregnancy incidence., Conclusions: Pregnancy incidence was 2.2/100 person-years in female participants of HIV treatment trials. Rather than leading to exclusion of young women from trials, this finding should prompt appropriate adaptations in study design and analysis for earlier generation of pregnancy safety information for drugs., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Chlamydia trachomatis ( C. trachomatis ) and Neisseria gonorrhoeae ( N. gonorrhoeae ) are curable sexually transmitted infections (STIs) that cause adverse pregnancy and neonatal outcomes. Most countries, including Botswana, do not offer C. trachomatis or N. gonorrhoeae screening during antenatal care (ANC) and instead use a syndromic approach for management of STIs., Methods: The Maduo Study is a prospective, cluster-controlled trial in Botswana evaluating the impact of diagnostic screening for antenatal C. trachomatis and N. gonorrhoeae infections to prevent adverse neonatal outcomes. Using baseline data from the Maduo Study (March 2021-March 2022), we determined the prevalence of C. trachomatis and N. gonorrhoeae infection among asymptomatic pregnant women in Botswana and correlates of infection using multivariable logistic regression., Results: Of 251 women who underwent C. trachomatis and N. gonorrhoeae screening at first ANC visit, 55 (21.9%, 95%CI 17.0-27.5) tested positive for C. trachomatis , 1 (0.4%, 95%CI 0-2.2) for N. gonorrhoeae ; and 2 (0.8%, 95%CI 0-2.8) for dual C. trachomatis and N. gonorrhoeae infection. Older age was associated with lower odds (aOR 0.93; 95%CI 0.88-0.98; p = 0.011) while any alcohol use during pregnancy was associated with higher odds (aOR = 3.53; 95%CI 1.22-10.16; p = 0.020) of testing positive for C. trachomatis or N. gonorrhoeae ., Conclusions: A high frequency of C. trachomatis infections was detected among asymptomatic pregnant women in Botswana indicating that many antenatal STIs are missed by the syndromic management approach. Our results highlight the need for diagnostic C. trachomatis screening during ANC in Botswana and other low- and middle-income countries that rely solely on the syndromic approach for management of STIs.

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., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2022 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

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., (© 2022 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

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., (© 2022 The Authors Tropical Medicine & International Health Published by John Wiley & Sons Ltd.)

Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

Background: Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) are extremely common sexually transmitted infections (STIs) that are associated with adverse birth and neonatal outcomes, and the risk of vertical transmission of CT and NG during delivery is high. The majority of CT and NG infections are asymptomatic and missed by the standard of care in most countries (treatment based on symptoms). Thus, it is likely that missed maternal CT and NG infections contribute to preventable adverse health outcomes among women and children globally. This study aims to assess the effectiveness of CT and NG testing for asymptomatic pregnant women to prevent adverse neonatal outcomes, understand the inflammatory response linking CT and NG infections to adverse neonatal outcomes, and conduct an economic analysis of the CT and NG testing intervention., Methods: The Maduo ("results" in Setswana) is a prospective, cluster-controlled trial in Gaborone, Botswana to compare a near point-of-care CT and NG testing and treatment intervention implemented in "study clinics" with standard antenatal care (World Health Organization-endorsed "syndromic management" strategy based on signs and symptoms without laboratory confirmation) implemented in "standard of care clinics" among asymptomatic pregnant women. The primary outcome is vertical transmission of CT/NG infection. Secondary outcomes include preterm birth (delivery < 37 completed weeks of gestation) and/or low birth weight (< 2500 g). The trial will also evaluate immunological and inflammatory markers of adverse neonatal outcomes, as well as the costs and cost-effectiveness of the intervention compared with standard care., Discussion: The Maduo study will improve our understanding of the effectiveness and cost-effectiveness of CT and NG testing among asymptomatic pregnant women. It will also increase knowledge about the CT/NG-related immune responses that might drive adverse neonatal outcomes. Further, results from this study could encourage expansion of STI testing during antenatal care in low resource settings and improve maternal and neonatal health globally., Trial Registration: This trial is registered with ClinicalTrials.gov (Identifier NCT04955717, First posted: July 9, 2021))., (© 2022. The Author(s).)

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., (© 2022 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Background: Successful scale-up of antiretroviral therapy (ART) during pregnancy has minimized infant HIV acquisition, and over 1 million infants are born HIV-exposed but uninfected (HEU), with an increasing proportion also exposed in utero to maternal ART. While benefits of ART in pregnancy outweigh risks, some studies have reported associations between in utero ART exposure and impaired fetal growth, highlighting the need to identify the safest ART regimens for use in pregnancy., Methods: We compared birth anthropometrics of infants who were HEU with those HIV-unexposed (HU) in Cape Town, South Africa. Pregnant women had gestational age assessed by ultrasound at enrolment. Women living with HIV were on ART (predominately tenofovir-emtricitabine-efavirenz) either prior to conception or initiated during pregnancy. Birth weights and lengths were converted to weight-for-age (WAZ) and length-for-age (LAZ) z-scores using Intergrowth-21st software. Linear regression was used to compare mean z-scores adjusting for maternal and pregnancy characteristics., Results: Among 888 infants, 49% (n = 431) were HEU and 51% (n = 457) HU. Of 431 HEU infants, 62% (n = 268) were exposed to HIV and antiretrovirals (ARVs) from conception and 38% (n = 163) were exposed to ARVs during gestation but after conception (median fetal ARV exposure of 21 weeks [IQR; 17-26]). In univariable analysis, infants who were HEU had lower mean WAZ compared with HU [β = - 0.15 (95% Confidence Interval (CI): - 0.28, - 0.020)]. After adjustment for maternal age, gravidity, alcohol use, marital and employment status the effect remained [adjusted β - 0.14 (95%CI: - 0.28, - 0.01]. Similar differences were noted for mean LAZ in univariable [β - 0.20 (95%CI: - 0.42, - 0.01] but not multivariable analyses [adjusted β - 0.18 (95%CI: - 0.41, + 0.04] after adjusting for the same variables. Mean WAZ and LAZ did not vary by in utero ARV exposure duration among infants who were HEU., Conclusion: In a cohort with high prevalence of ART exposure in pregnancy, infants who were HEU had lower birth WAZ compared with those HU. Studies designed to identify the mechanisms and clinical significance of these disparities, and to establish the safest ART for use in pregnancy are urgently needed.

Background: Maternal human immunodeficiency virus (HIV) infection is associated with lower placental transfer of antibodies specific to several childhood pathogens. Our objective for this study was to evaluate the effect of maternal HIV infection on the placental transfer of respiratory syncytial virus (RSV)-neutralizing antibodies., Methods: We conducted a cross-sectional study of mothers and their newborn infants at a tertiary hospital in Gaborone, Botswana, between March 2015 and December 2015. We measured serum RSV antibody levels by using a microneutralization assay. We used multivariable linear regression to evaluate the effect of maternal HIV infection on maternal RSV antibody levels, placental transfer of RSV antibodies, and newborn RSV antibody levels., Results: Of 316 mothers, 154 (49%) were infected with HIV. The placental transfer ratios for RSV antibodies to HIV-exposed, uninfected (HEU) and HIV-unexposed, uninfected infants were 1.02 and 1.15, respectively. The geometric mean titer (95% confidence interval) of RSV-neutralizing antibodies was 2657 (2251-3136) among HEU newborns and 2911 (2543-3331) among HIV-unexposed, uninfected newborns. In multivariable analyses, maternal HIV infection was associated with lower placental transfer of RSV antibodies (P = .02) and a lower level of RSV antibodies among newborns (P = .002). Among HEU newborns, higher birth weight (P = .004) and an undetectable maternal antenatal viral load (P = .01) were associated with more effective placental transfer of RSV antibodies., Conclusions: Maternal human immunodeficiency virus (HIV) infection is associated with lower mother-to-fetus transfer of serum RSV-neutralizing antibodies. HEU infants should be prioritized for preventive interventions for RSV. Maternal viral suppression through combination antiretroviral therapy has the potential to improve immunity to RSV among HIV-exposed infants., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Intensified viral load monitoring for pregnant and breastfeeding women has been proposed to help address concerns around antiretroviral therapy (ART) adherence, viraemia and transmission risk, but there have been no systematic evaluations of existing policies., Methods: We used an individual Monte Carlo simulation to describe longitudinal ART adherence and viral load from conception until 2 years' postpartum. We applied national and international guidelines for viral load monitoring to the simulated data. We compared guidelines on the percentage of women receiving viral load monitoring and the percentage of women monitored at the time of elevated viral load., Results: Coverage of viral load monitoring in pregnancy and breastfeeding varied markedly, with between 14% and 100% of women monitored antenatally and 38-98% monitored during breastfeeding. Specific recommendations for testing at either a fixed gestation or a short, fixed period after ART initiation achieved more than 95% testing in pregnancy but this was much lower (14-83%) among guidelines with no special stipulations. By the end of breastfeeding, only a small proportion of simulated episodes of elevated viral load more than 1000 copies/ml were successfully detected by monitoring (range, 20-50%)., Discussion: Although further research is needed to understand optimal viral load frequency and timing in this population, these results suggest that current policies yield suboptimal detection of elevated viral load in pregnant and breastfeeding women.

Background: HIV-infected, postpartum women on antiretroviral therapy (ART) have high rates of viremia. We examined predictors of postpartum viremia in the PROMISE study., Methods: Women with pre-ART CD4 T-cell counts ≥400 cells/mm who started ART during pregnancy were randomized postpartum to continue ART (CTART) or discontinue ART (DCART). Viral load and self-reported adherence were collected every 12 weeks, up to 144 weeks. Women in DCART reinitiated therapy when clinically indicated. Viremia was defined as 2 consecutive viral loads >1000 copies/mL after 24 weeks on ART. Adherence was dichotomized as missing versus not missing ART doses in the past 4 weeks. Predictors of viremia were examined using Cox proportional hazards regression with adherence as a time-varying covariate., Results: Among 802 women in the CTART arm, median age at entry was 27 years and median CD4 T-cell count 696 cells/mm. Of 175 women in CTART with viremia (22%), 141 had resistance data, and 12% had resistance to their current regimen. There was an estimated 0.12 probability of viremia by week 48 and 0.25 by week 144. Predictors of viremia included missed ART doses within the past 4 weeks, younger age, shorter duration of pre-entry ART, and being from the South American/Caribbean region. Of 137 women in DCART who reinitiated therapy, probability of viremia was similar to CTART (0.24 by week 96; 0.27 by week 144)., Conclusions: Rates of postpartum viremia are high and viremia is more likely in younger postpartum women who start ART later in pregnancy. Interventions should target these higher-risk women.

Background: The safety, efficacy, and appropriate timing of isoniazid therapy to prevent tuberculosis in pregnant women with human immunodeficiency virus (HIV) infection who are receiving antiretroviral therapy are unknown., Methods: In this multicenter, double-blind, placebo-controlled, noninferiority trial, we randomly assigned pregnant women with HIV infection to receive isoniazid preventive therapy for 28 weeks, initiated either during pregnancy (immediate group) or at week 12 after delivery (deferred group). Mothers and infants were followed through week 48 after delivery. The primary outcome was a composite of treatment-related maternal adverse events of grade 3 or higher or permanent discontinuation of the trial regimen because of toxic effects. The noninferiority margin was an upper boundary of the 95% confidence interval for the between-group difference in the rate of the primary outcome of less than 5 events per 100 person-years., Results: A total of 956 women were enrolled. A primary outcome event occurred in 72 of 477 women (15.1%) in the immediate group and in 73 of 479 (15.2%) in the deferred group (incidence rate, 15.03 and 14.93 events per 100 person-years, respectively; rate difference, 0.10; 95% confidence interval [CI], -4.77 to 4.98, which met the criterion for noninferiority). Two women in the immediate group and 4 women in the deferred group died (incidence rate, 0.40 and 0.78 per 100 person-years, respectively; rate difference, -0.39; 95% CI, -1.33 to 0.56); all deaths occurred during the postpartum period, and 4 were from liver failure (2 of the women who died from liver failure had received isoniazid [1 in each group]). Tuberculosis developed in 6 women (3 in each group); the incidence rate was 0.60 per 100 person-years in the immediate group and 0.59 per 100 person-years in the deferred group (rate difference, 0.01; 95% CI, -0.94 to 0.96). There was a higher incidence in the immediate group than in the deferred group of an event included in the composite adverse pregnancy outcome (stillbirth or spontaneous abortion, low birth weight in an infant, preterm delivery, or congenital anomalies in an infant) (23.6% vs. 17.0%; difference, 6.7 percentage points; 95% CI, 0.8 to 11.9)., Conclusions: The risks associated with initiation of isoniazid preventive therapy during pregnancy appeared to be greater than those associated with initiation of therapy during the postpartum period. (Funded by the National Institutes of Health; IMPAACT P1078 TB APPRISE ClinicalTrials.gov number, NCT01494038.)., (Copyright © 2019 Massachusetts Medical Society.)

The PROMISE trial enrolled asymptomatic HIV-infected pregnant and postpartum women not eligible for antiretroviral treatment (ART) per local guidelines and randomly assigned proven antiretroviral strategies to assess relative efficacy for perinatal prevention plus maternal/infant safety and maternal health. The START study subsequently demonstrated clear benefit in initiating ART regardless of CD4 count. Active PROMISE participants were informed of results and women not receiving ART were strongly recommended to immediately initiate treatment to optimize their own health. We recorded their decision and the primary reason given for accepting or rejecting the universal ART offer after receiving the START information. One-third of participants did not initiate ART after the initial session, wanting more time to consider. Six sessions were required to attain 95% uptake. The slow uptake of universal ART highlights the need to prepare individuals and sensitize communities regarding the personal and population benefits of the "Treat All" strategy.

Background: A preliminary safety signal for neural-tube defects was previously reported in association with dolutegravir exposure from the time of conception, which has affected choices of antiretroviral treatment (ART) for human immunodeficiency virus (HIV)-infected women of reproductive potential. The signal can now be evaluated with data from follow-up of additional pregnancies., Methods: We conducted birth-outcomes surveillance at hospitals throughout Botswana, expanding from 8 to 18 sites in 2018. Trained midwives performed surface examinations of all live-born and stillborn infants. Research assistants photographed abnormalities after maternal consent was obtained. The prevalence of neural-tube defects and major external structural defects according to maternal HIV infection and ART exposure status was determined. In the primary analyses, we used the Newcombe method to evaluate differences in prevalence with 95% confidence intervals., Results: From August 2014 through March 2019, surveillance captured 119,477 deliveries; 119,033 (99.6%) had an infant surface examination that could be evaluated, and 98 neural-tube defects were identified (0.08% of deliveries). Among 1683 deliveries in which the mother was taking dolutegravir at conception, 5 neural-tube defects were found (0.30% of deliveries); the defects included two instances of myelomeningocele, one of anencephaly, one of encephalocele, and one of iniencephaly. In comparison, 15 neural-tube defects were found among 14,792 deliveries (0.10%) in which the mother was taking any non-dolutegravir ART at conception, 3 among 7959 (0.04%) in which the mother was taking efavirenz at conception, 1 among 3840 (0.03%) in which the mother started dolutegravir treatment during pregnancy, and 70 among 89,372 (0.08%) in HIV-uninfected mothers. The prevalence of neural-tube defects was higher in association with dolutegravir treatment at conception than with non-dolutegravir ART at conception (difference, 0.20 percentage points; 95% confidence interval [CI], 0.01 to 0.59) or with other types of ART exposure. Major external structural defects were found in 0.95% of deliveries among women exposed to dolutegravir at conception and 0.68% of those among women exposed to non-dolutegravir ART at conception (difference, 0.27 percentage points; 95% CI, -0.13 to 0.87)., Conclusions: The prevalence of neural-tube defects was slightly higher in association with dolutegravir exposure at conception than with other types of ART exposure at conception (3 per 1000 deliveries vs. 1 per 1000 deliveries). (Funded by the National Institutes of Health.)., (Copyright © 2019 Massachusetts Medical Society.)

Background: Little is known about the combined impact of HIV/syphilis coinfection on birth outcomes., Methods: Antenatal HIV and syphilis test results, obstetric history, and infant birth outcomes were collected from obstetric records in maternity wards in Botswana between 2008 and 2011 (5 sites) and 2014 and 2016 (8 sites). We used logistic regression to compare adverse birth outcomes by HIV and syphilis status. Outcomes included stillbirth, preterm delivery, low birth weight, and in-hospital neonatal death., Results: Of 76,466 women, 75,770 (99.1%) had HIV test results, and 20,520 (27.1%) were HIV positive. Syphilis test results were available for 67,290 (88.0%), and 697 (1.0%) had reactive rapid plasma reagin. Among 692 women with syphilis and an HIV test result, 261 (37.7%) were coinfected. HIV-infected women were more likely to be infected with syphilis than HIV-uninfected women [odds ratio (OR) = 1.68; 95% confidence interval (CI): 1.44 to 1.96]. From 2008-2011 to 2014-2016, the proportion of women with syphilis remained constant (1.1% vs. 1.0%, P = 0.41), but HIV/syphilis coinfection declined from 45% to 27% (P < 0.0001). Stillbirth occurred in 5.8% of coinfected women, compared with 1.9% with no HIV/syphilis (OR = 3.09; 95% CI: 1.83 to 5.23); 3.4% with HIV alone (OR = 1.75; 95% CI: 1.03 to 2.97), or 3.7% with syphilis alone (OR = 1.58; 95% CI: 0.77 to 3.25). Low birth weight occurred in 24.1% of coinfected women, compared with 12.1% with no HIV/syphilis (OR 2.31; 95% CI: 1.74 to 3.08; 20% with HIV alone (OR = 1.27; 95% CI: 0.96 to 1.69); or 14.6% with syphilis alone (OR = 1.85; 95% CI: 1.26 to 2.74)., Conclusions: Although HIV/syphilis coinfection in pregnancy has declined in the past decade, coinfection was associated with adverse birth outcomes.

Competing Interests: Competing interests: We have read and understood BMJ policy on declaration of interests and declare no competing interests. This article was funded by the South African Medical Research Council and Unicef. Research reported in this publication was also supported by the Fogarty International Center of the National Institutes of Health under Award Number 1K43TW010683 to ALS and the Eunice Kennedy Shriver National Institute of Child Health and Human Development under Award Number 1R21HD093531 to KMP. ALS receives salary support through the CIPHER Grantee Programme of the International AIDS Society (2017/518-SLO) while VR receives support from the SAMRC Intramural Postdoctoral Fellowship Programme. The content of this paper is the sole responsibility of the authors and does not necessarily represent the official views of the organisations and funders.

Background: Minimal data exist related to neurodevelopment after in utero exposure to Efavirenz (EFV). We sought to compare neurodevelopmental outcomes in HIV-exposed/uninfected (HEU) children with in utero exposure to EFV-based triple antiretroviral treatment (ART) versus non-EFV-based ART, and to examine whether timing of initial EFV exposure is associated with neurodevelopment deficits., Methods: Women living with HIV who had received EFV-based ART during pregnancy and whose HEU newborn participated in a prior study were reconsented for their HEU toddler to undergo neurodevelopmental testing at 24 months old. We administered the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), Developmental Milestones Checklist (DMC) and Profile of Social Emotional Development (PSED). We compared outcomes to previously-collected data from a cohort of 24-month-old HEU children with in utero exposure to non-EFV-based ART. Adjusted general linear models were used to compare mean outcomes., Results: Our analysis included 493 HEU children (126 EFV-exposed, 367 EFV-unexposed). Adjusted mean scores for the EFV-exposed group were worse than the EFV-unexposed group on BSID-III Receptive Language (adjusted means = 21.5 vs. 22.5, P = 0.05), DMC Locomotor (30.7 vs. 32.0, P < 0.01) and Fine Motor scales (17.8 vs. 19.2, P < 0.01); and PSED (11.7 vs. 9.9, P = 0.02); but better on the DMC Language scale (17.6 vs. 16.5, P = 0.01). Earlier (vs. later) EFV exposure was associated with worse scores on the BSID-III Receptive Language scale (20.7 vs. 22.2, P = 0.02)., Conclusions: HEU children exposed in utero to EFV-based ART may be at higher risk for neurodevelopmental and social-emotional deficits than HEU children exposed to non-EFV-based ART.

Objectives: To prospectively assess rates and detailed predictors of morbidity and mortality among HIV-exposed uninfected children and HIV-unexposed children in Botswana in a more recent era., Study Design: We enrolled HIV-infected and HIV-uninfected mothers and their children in the prospective observational Tshipidi study at 2 sites (1 city and 1 village) in Botswana from May 2010-July 2012. Live-born children and their mothers were followed for 24 months postpartum. Detailed sociodemographic data, health, and psychosocial characteristics were collected at baseline and prospectively, and health outcomes ascertained. Mothers chose infant feeding method with counselling., Results: A total of 893 live-born HIV-uninfected children (436 HIV-exposed uninfected, 457 HIV-unexposed) were followed. HIV-infected mothers had a median CD4 count of 410 cells/mm 3 , 32% took 3-drug antiretroviral treatment during pregnancy, 67% took only zidovudine, and 1% took <2 weeks of any antiretrovirals antepartum. Twenty four-month vital status was available for 888 (99.4%) children. HIV-exposed uninfected children had a significantly higher risk of death compared with children of HIV-uninfected mothers (5.0% vs 1.8%) (adjusted hazard ratio 3.27, 95% CI 1.44-7.40). High collinearity between maternal HIV status and child feeding method precluded analysis of these factors as independent predictors of mortality. Preterm birth, low birth weight, and congenital anomaly were also associated with mortality (in separate analyses), but maternal socioeconomic factors, depression, substance use, and social support were not significant predictors., Conclusions: The strongest predictors of 24-month mortality among children in Botswana were HIV exposure and formula feeding, although the relative contribution of these factors to child health could not be separated., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: In utero exposure to nucleoside reverse transcriptase inhibitor (NRTI)-containing antiretroviral treatment (ART) regimens may be associated with poor neurodevelopmental functioning in children of HIV-infected mothers. We investigated neurodevelopmental outcomes of HIV-exposed uninfected (HEU) children of HIV-infected women enrolled in a randomized trial of abacavir/zidovudine/lamivudine (triple-NRTI regimen) vs. lopinavir/ritonavir/zidovudine/lamivudine [dual-NRTI + protease inhibitor (PI) regimen]., Setting: The Mma Bana randomized trial was conducted in urban and rural sites in Botswana., Methods: The Mma Bana study randomized HIV-infected pregnant women with CD4 ≥200 cells per mm to a triple-NRTI vs. dual-NRTI + PI regimen from 26- to 34-week gestation through planned weaning at 6-month postpartum. Partway through the study, neurodevelopmental assessments were added at 24 months of age, including the Developmental Milestones Checklist, the Bayley Scales of Infant and Toddler Development third edition, Ten Questions Questionnaire, and Profile of Social Emotional Development. We evaluated differences in mean scores between the 2 arms using unadjusted and adjusted linear regression., Results: A total of 197 HEU infants (48% male) completed a neurodevelopmental assessment (101 in triple-NRTI arm and 96 in dual-NRTI + PI-exposed arm). Mean values for all neurodevelopmental outcomes were similar for children of mothers randomized to either ART regimen, with no significant differences in either unadjusted or adjusted models (estimated effect sizes ranging from -0.12 to 0.14)., Conclusions: Neurodevelopmental outcomes in 24-month-old HEU children of HIV-infected mothers with baseline CD4 ≥200 were similar in those randomized to a dual-NRTI + PI-based vs. a triple-NRTI-based ART regimen, suggestive of lack of short-term toxicity. Monitoring of long-term toxicity and newer regimens is warranted.

Among human immunodeficiency virus-positive women in Botswana on the recommended first-line antiretroviral therapy regimen, tenofovir-emtricitabine-efavirenz, initiated within the first or early second trimester, we found no increased risk of stillbirth, neonatal death, preterm/very preterm delivery, or the infant being born small or very small for gestational age. Treatment with tenofovir-emtricitabine-efavirenz <1 year before conception increased the risk of preterm delivery slightly over late-second-trimester treatment initiation (adjusted risk ratio, 1.33 [95% confidence interval, 1.04-1.70]).

Almost 25 years since antiretroviral therapy (ART) was first shown to prevent mother-to-child transmission of HIV, 76% of pregnant women living with HIV (over 1 million women) receive ART annually. This number is the result of successes in universal ART scale-up in low-income and middle-income countries. Despite unprecedented ART-related benefits to maternal and child health, challenges remain related to ART adherence, retention in care, and unequal access to ART. Implementation research is ongoing to understand and to address obstacles that lead to loss to follow-up. The biological mechanisms that underlie observed associations between antenatal ART and adverse outcomes in pregnancy and birth are not completely understood, with further research needed as well as strengthening of the systems to assess safety of antiretroviral drugs for the mother and HIV-exposed child. In the treat-all era, as duration of treatment and options for ART expand, pregnant women will remain a priority population for treatment optimisation to promote their health and that of their ART-exposed children., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Global rollout of dolutegravir-based antiretroviral therapy (ART) has been hampered in part by insufficient safety data in pregnancy. We compared birth outcomes among women initiating dolutegravir-based ART with those among women initiating efavirenz-based ART in pregnancy in Botswana., Methods: In this observational study, we captured birth outcome data at eight government hospitals throughout Botswana (~45% of all deliveries in the country) in an ongoing study that started on Aug 15, 2014. In 2016, Botswana changed first-line ART from efavirenz-tenofovir-emtricitabine to dolutegravir-tenofovir-emtricitabine, including for pregnant women. This analysis includes women starting either efavirenz-based ART or dolutegravir-based ART during singleton pregnancy (regimen started and delivery occurring between Aug 15, 2014, and Aug 15, 2016, for efavirenz-based ART and between Nov 1, 2016, and Sept 30, 2017, for dolutegravir-based ART). We excluded births to mothers who had switched regimen or stopped ART. The primary outcomes were the combined endpoints of any adverse outcome (stillbirth, preterm birth [<37 weeks' gestation], small for gestational age [SGA; less than the tenth percentile of birthweight by gestational age], or neonatal death [within 28 days of age]) and severe adverse outcomes (stillbirth, neonatal death, very preterm birth [<32 weeks' gestation], and very SGA [less than the third percentile of birthweight by gestational age]). We fitted log-binomial regression models, controlling for maternal age, gravidity, and education, to estimate adjusted risk ratios (aRRs)., Findings: Our analysis included 1729 pregnant women who initiated dolutegravir-based ART and 4593 who initiated efavirenz-based ART. The risk for any adverse birth outcome among women on dolutegravir versus efavirenz was similar (33·2% vs 35·0%; aRR 0·95, 95% CI 0·88-1·03), as was the risk of any severe birth outcome (10·7% vs 11·3%; 0·94, 0·81-1·11). We found no significant differences by regimen in the individual outcomes of stillbirth, neonatal death, preterm birth, very preterm birth, SGA, or very SGA., Interpretation: Adverse birth outcomes were similar among pregnant women who initiated dolutegravir-based and efavirenz-based ART. Dolutegravir-based ART can be safely initiated in pregnancy., Funding: National Institutes of Health., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: Conflicting data exist regarding the impact of in-utero exposure to maternal combination antiretrovirals. We compared neurodevelopmental outcomes between HIV-exposed-uninfected (HEU) children exposed in utero to three-drug combination antiretroviral therapy (ART) vs. zidovudine (ZDV) monotherapy., Design: Prospective study of child neurodevelopment, nested within two cohorts of HIV-infected mothers and their children in Botswana (one observational, one interventional)., Methods: The Tshipidi and Mma Bana studies enrolled HIV-infected women during pregnancy and followed their HEU children for 24 months. Mothers took three-drug ART or ZDV during pregnancy. ART-exposed babies were mostly breastfed, and ZDV-exposed were formula-fed. Neurodevelopmental outcomes, measured at 24 months using Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III) and Development Milestones Checklist (DMC), were compared in adjusted linear regression according to antiretroviral exposure., Results: Of 598 HEU children with valid neurodevelopment assessments, 382 were ART-exposed and 210 were ZDV-exposed. Adjusted mean Bayley-III scores were similar among ART-exposed vs. ZDV-exposed, with adjusted mean differences (95% confidence interval): Bayley-III Cognitive: -0.3 (-1.4, 0.9); Gross Motor: 0.8 (-0.1, 1.7); Fine Motor: 0.5 (-0.2, 1.3); Expressive Language: 0.7 (-0.3, 1.7); Receptive Language: 0.1 (-0.7, 0.8); and DMC Locomotor: 0.0 (-0.5, 0.6); Fine Motor: 0.3 (-0.3, 0.8); Language: -0.1 (-0.5, 0.4); Personal-Social: 0.2 (-0.7, 1.1). Similarly, when restricted to formula-fed children in one cohort (Tshipidi), there were no differences in adjusted mean scores., Conclusion: Neurodevelopmental outcomes at 24 months of age were similar in ART-exposed vs. ZDV-exposed HEU children. Maternal ART with breastfeeding does not appear to have an adverse effect on neurodevelopment.

Background: We sought to determine if HIV-exposed uninfected (HEU) children had worse neurodevelopmental outcomes at 24 months compared with HIV-unexposed uninfected (HUU) children in Botswana., Methods: HIV-infected and uninfected mothers enrolled in a prospective observational study ("Tshipidi") in Botswana from May 2010 to July 2012. Child neurodevelopment was assessed at 24 months with the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III: cognitive, gross motor, fine motor, expressive language, and receptive language domains) and the Development Milestones Checklist (DMC), a caregiver-completed questionnaire (locomotor, fine motor, language and personal-social domains). We used linear regression models to estimate the association of in-utero HIV exposure with neurodevelopment, adjusting for socioeconomic and maternal health characteristics., Results: We evaluated 670 children (313 HEU, 357 HUU) with ≥1 valid Bayley-III domain assessed and 723 children (337 HEU, 386 HUU) with a DMC. Among the 337 HEU children with either assessment, 122 (36%) were exposed in utero to maternal 3-drug antiretroviral treatment and 214 (64%) to zidovudine. Almost all HUU children (99.5%) breastfed, compared with only 9% of HEU children. No domain score was significantly lower among HEU children in adjusted analyses. Bayley-III cognitive and DMC personal-social domain scores were significantly higher in HEU children than in HUU children, but differences were small., Conclusions: HEU children performed equally well on neurodevelopmental assessments at 24 months of age compared with HUU children. Given the global expansion of the HEU population, results suggesting no adverse impact of in-utero HIV and antiretroviral exposure on early neurodevelopment are reassuring., (Copyright © 2017 by the American Academy of Pediatrics.)

Background: HIV point-of-care (POC) testing allows for early infant HIV diagnosis and treatment, but POC accuracy at birth and in the setting of antiretroviral prophylaxis for the prevention of mother-to-child HIV transmission is unknown., Methods: We evaluated the Cepheid Xpert HIV-1 Qual POC test against the Roche Taqman HIV-1 DNA polymerase chain reaction (PCR) platform using dried blood spots from 15 HIV-infected and 75 HIV-exposed uninfected newborns. These infants were screened for HIV at <96 hours of life at 5 hospital maternity wards in Botswana; all infants received postexposure antiretroviral prophylaxis with single-dose nevirapine and zidovudine, and most mothers received 3-drug antiretroviral therapy in pregnancy and at delivery., Results: Fourteen of the 15 PCR positive samples tested positive by Cepheid POC, yielding a sensitivity of 93.3% (95% confidence interval: 68.1 to 99.8). Baseline viral load among positive infants ranged from <40 to >10,000,000 copies/mL, with a median of 2403 copies/mL. The HIV RNA for the infant with false-negative POC testing was 1661 copies/mL. Of note, 2 infants with low HIV RNA (<40 and 272 copies/mL) were correctly identified as HIV positive by Cepheid POC. All the 75 PCR-negative samples tested negative by Cepheid POC, yielding a specificity of 100% (95% confidence interval: 96.1 to 100)., Discussion: Our study demonstrates high sensitivity and specificity for the Cepheid POC assay in the first week of life despite early infection and antiretroviral prophylaxis. This platform may be a useful approach for adding early infant HIV diagnosis to current testing programs.

Background: Co-trimoxazole prophylaxis reduces mortality among HIV-infected children, but efficacy in HIV-exposed but uninfected (HEU) children in a non-malarial, low-breastfeeding setting with a low risk of mother-to-child transmission of HIV is unclear., Methods: HEU children in Botswana were randomly assigned to receive co-trimoxazole (100 mg/20 mg once daily until age 6 months and 200 mg/40 mg once daily thereafter) or placebo from age 14-34 days to age 15 months. Mothers chose whether to breastfeed or formula feed their children. Breastfed children were randomly assigned to breastfeeding for 6 months (Botswana guidelines) or 12 months (WHO guidelines). The primary outcome, analysed by a modified intention-to-treat approach, was cumulative child mortality from treatment assignment to age 18 months. We also assessed HIV-free survival by duration of breastfeeding. This trial is registered with ClinicalTrials.gov, number NCT01229761., Findings: From June 7, 2011, to April 2, 2015, 2848 HEU children were randomly assigned to receive co-trimoxazole (n=1423) or placebo (n=1425). The data and safety monitoring board stopped the study early because of a low likelihood of benefit with co-trimoxazole. Only 153 (5%) children were lost to follow-up (76 in the co-trimoxazole group and 77 in the placebo group), and 2053 (72%) received treatment continuously to age 15 months, death, or study closure. Mortality after the start of study treatment was similar in the two study groups: 30 children died in the co-trimoxazole group, compared with 34 in the placebo group (estimated mortality at 18 months 2·4% vs 2·6%; difference -0·2%, 95% CI -1·5 to 1·0, p=0·70). We saw no difference in hospital admissions between groups (12·5% in the co-trimoxazole group vs 17·4% in the placebo group, p=0·19) or grade 3-4 clinical adverse events (16·5% vs 18·4%, p=0·18). Grade 3-4 anaemia did not differ between groups (8·1% vs 8·3%, p=0·93), but grade 3-4 neutropenia was more frequent in the co-trimoxazole group than in the placebo group (8·1% vs 5·8%, p=0·03). More co-trimoxazole resistance in commensal Escherichia coli isolated from stool samples was seen in children aged 3 or 6 months in the co-trimoxazole group than in the placebo group (p=0·001 and p=0·01, respectively). 572 (20%) children were breastfed. HIV infection and mortality did not differ significantly by duration of breastfeeding (3·9% for 6 months vs 1·9% for 12 months, p=0·21)., Interpretation: Prophylactic co-trimoxazole seems to offer no survival benefit among HEU children in non-malarial, low-breastfeeding areas with a low risk of mother-to-child transmission of HIV., Funding: US National Institutes of Health., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND license. Published by Elsevier Ltd.. All rights reserved.)

Mortality in the postpartum period may be impacted by antiretroviral therapy (ART) received in pregnancy, and whether ART is continued in the postpartum period. HIV-infected and HIV-uninfected mothers were enrolled within 48 h of delivery at five public hospital maternity wards throughout Botswana and followed for 24 months. Maternal deaths were reported by one of the approved contacts given by the mother at enrollment. Detailed information on the cause of death was not available. Risk factors for 24-month mortality were assessed using Cox proportional hazard models. From February 2012 to March 2013, 3000 mothers (1499 HIV infected and 1501 HIV uninfected) were enrolled, and 2985 (99.5%) were followed to 24 months or death, or until the death of their child. There were 26 total maternal deaths through 24 months postpartum [439 per 100,000 person-years (p-y)], 22 among HIV-infected women (758 per 100,000 p-y) and 4 among HIV-uninfected women (132 per 100,000 p-y). Maternal HIV-infection (aHR 5.0, 95% CI 1.6-15.2) and infant birth injury (aHR 3.8, 95% CI 1.3-11.4) were independent risk factors for maternal death. Universal ART in pregnancy became the standard-of-care after June 2012, and 978 (65%) women received ART in pregnancy; by 24 months postpartum or end of follow-up, 1148 (79%) had started ART overall. There was no significant difference in 24-month mortality among HIV-infected women who took ART in pregnancy and continued throughout the follow-up period compared with HIV-infected women who took ART or zidovudine in pregnancy and stopped postpartum (aHR 0.6, 95% CI 0.2-1.7). Despite high uptake of ART in pregnancy and postpartum, women with HIV infection in Botswana are five times more likely to die than HIV-uninfected women in the 24 months postpartum., Competing Interests: Author Disclosure Statement No competing financial interests exist.

: Botswana was one of the first African countries to transition from WHO Option A to Option B for prevention of mother-to-child HIV transmission (MTCT). We evaluated the impact of this transition on projected MTCT risk through review of 10,681 obstetric records of HIV-infected women delivering at 6 maternity wards. Compared with Option A, women receiving antenatal care under Option B were more likely to receive combination antiretroviral therapy (ART), adjusted odds ratio (aOR): 2.59 (95% confidence interval: 2.25 to 2.98), but they were also more likely to receive no antenatal antiretrovirals, aOR: 2.10 (95% confidence interval: 1.74 to 2.53). Consequently, initial implementation of Option B was associated with increased projected MTCT at 6 months of age, 3.79% under Option A and 4.69% under Option B (P < 0.001). Successful implementation of Option B or B+ may require that ART can be initiated within antenatal clinics, and novel strategies to remove barriers to rapid ART initiation.

Background: Low maternal 25(OH)D (vitamin D) values have been associated with higher mortality and impaired growth among HIV-exposed uninfected (HEU) infants of antiretroviral (ART)-naive women. These associations have not been studied among HEU infants of women receiving ART., Methods: We performed a nested case-control study in the Botswana Mma Bana Study, a study providing ART to women during pregnancy and breastfeeding. Median maternal vitamin D values, and the proportion with maternal vitamin D insufficiency, were compared between women whose HEU infants experienced morbidity/mortality during 24 months of follow-up and women with nonhospitalized HEU infants. Growth faltering was assessed for never hospitalized infants attending the 24-month-of-life visit. Multivariate logistic regression models determined associations between maternal vitamin D insufficiency and infant morbidity/mortality and growth faltering., Results: Delivery plasma was available and vitamin D levels assayable from 119 (86%) of 139 cases and 233 (84%) of 278 controls, and did not differ significantly between cases and controls [median: 36.7 ng/mL, interquartile range (IQR): 29.1-44.7 vs. 37.1 ng/mL, IQR: 30.0-47.2, P = 0.32]. Vitamin D insufficiency (<32 ng/mL) was recorded among 112 (31.8%) of 352 women at delivery and occurred most frequently among women delivering in winter. Multivariate logistic regression models adjusted for maternal HIV disease progression did not show associations between maternal vitamin D insufficiency at delivery and child morbidity/mortality, or 24-month-of-life growth faltering., Conclusions: Vitamin D insufficiency was common among ART-treated pregnant women in Botswana, but was not associated with morbidity, mortality or growth impairment in their HIV-uninfected children.