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Background: We investigated the impact of Drug-Drug Interactions (DDIs) on virologic control among HIV-positive pregnant women initiating antiretroviral therapy while identifying drivers for Traditional Medicine (TM) use and exploring the nature and extent of TM-related DDIs., Methods: Employing a three-pronged approach, we examined DDIs arising from comedication, including TM, in ART. The DolPHIN-2 trial (NCT03249181) randomized 268 HIV-positive pregnant women in Uganda and South Africa to dolutegravir (DTG)-based (135) or efavirenz-based (133) regimens while systematically recording comedications and screening for DDIs. We used Cox regression models to compare time-to-virologic control between participants with and without DDIs. We conducted in-depth interviews and focus group discussions among 37 and 67 women with and without HIV, respectively, to explore reasons for TM use during pregnancy. Additionally, in-vitro and in-vivo studies evaluated the composition and impact of clay-based TM, mumbwa, on DTG plasma exposure., Results: The baseline prevalence of DDIs was 67.2%, with TM use prevalent in 34% of participants, with mumbwa being the most frequent (76%, 69/91). There was no difference in virologic response between participants with and without DDIs. Fetal health and cultural norms were among the reasons cited for TM use. Analysis of mumbwa rods confirmed significant amounts of aluminium (8.4%-13.9%) and iron (4%-6%). In Balb-C mice, coadministration of mumbwa led to a reduction in DTG exposure observed in the AUC0-24 (-21%; P = 0.0271) and C24 (-53%; P = 0.0028)., Conclusions: The widespread use of clay-based TM may compromise HIV treatment, necessitating medication screening and counselling to manage DDIs in pregnant women., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. 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.)

This prospective cohort study investigated the mobility patterns of 200 pregnant and postpartum women living with HIV in South Africa. Participants were enrolled during their third trimester from routine antenatal care near Cape Town, South Africa, and followed for six months postpartum. Quantitative data were collected at enrollment and follow-up. Mobility (self-reported) was common among the participants, despite the brief study period and the concurrent COVID-19 pandemic. While most reported stability in their current residence, 71% had a second main residence, primarily in the Eastern Cape (EC). Participants had a median of two lifetime moves, motivated by work, education, and family life. During the study period, 20% of participants met the study definition of travel (>7 days and >50 km), with trips predominantly to the EC, lasting a median duration of 30 days. Over one-third of participants with other living children reported that these children lived apart from them, with the mother's family being primary caregivers. These findings emphasize the need for targeted interventions to support continuity of care for mobile populations, particularly peripartum women living with HIV. The study contributes valuable insights into mobility dynamics and highlights unique barriers faced by this population, contributing to improved HIV care in resource-limited settings.

Introduction: Outside of pregnancy, evidence shows that persons with HIV initiating or switching to dolutegravir (DTG)-based antiretroviral therapy (ART) experience greater weight gain compared to those on other ART classes. However, there are few data on the impact of DTG-based ART on gestational weight gain (GWG) in sub-Saharan Africa where HIV is most common. According to the National Academy of Medicine (NAM), GWG below and above NAM guidelines is associated with adverse birth outcomes. Therefore, the objective of this study was to describe GWG by HIV status and ART regimen, and examine the associations with adverse birth outcomes., Methods: We enrolled pregnant women with HIV (WHIV) and without HIV (≥18 years) in a peri-urban primary healthcare facility in Cape Town, South Africa between 2019 and 2022. GWG was study-measured at 24-28 (baseline) and 33-38 weeks gestation and converted to GWG rate (kg/week) in accordance with NAM guidelines. GWG z-scores were generated using the INTEGROWTH-21 and US standards to account for differing lengths of gestation. Birth outcome data were obtained from medical records. Associations of GWG z-score with adverse birth outcomes were assessed using multivariable linear or log-binomial regression., Results: Among 292 participants (48% WHIV), median age was 29 years (IQR, 25-33), median pre-pregnancy body mass index (BMI) was 31 kg/m 2 (IQR, 26-36) and 20% were primiparous at baseline. The median weekly rate of GWG was 0.30 kg/week (IQR, 0.12-0.50), 35% had GWG below NAM standards (59% WHIV) and 48% had GWG above NAM standards (36% WHIV). WHIV gained weight more slowly (0.25 vs. 0.37 kg/week, p<0.01) than women without HIV. Weekly rate of GWG did not differ by ART regimen (DTG-based ART 0.25 vs. efavirenz-based ART 0.27 kg/week, p = 0.80). In multivariable analyses, GWG z-score was positively associated with continuous birth weight (mean difference = 68.53 95% CI 8.96, 128.10) and categorical high birth weight of >4000 g (RR = 2.18 95% CI 1.18, 4.01)., Conclusions: Despite slower GWG among WHIV, nearly half of all women gained weight faster than recommended by the NAM. GWG was positively associated with infant birth weight. Interventions to support healthy GWG in sub-Saharan Africa are urgently needed., (© 2024 The Author(s). Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Competing Interests: We declare no competing interests.

Introduction: In recent years, the expansion of HIV treatment eligibility has resulted in an increase in people with antiretroviral therapy (ART) experience prior to pregnancy but little is known about postpartum engagement in care in this population. We examined differences in disengagement from HIV care after delivery by maternal ART history before conception., Methods: We analysed data from people living with HIV (aged 15-49) in Khayelitsha, South Africa, with ≥1 live birth between April 2013 and March 2019. We described trends over time in ART history prior to estimated conception, classifying ART history groups as: (A) on ART with no disengagement (>270 days with no evidence of HIV care); (B) returned before pregnancy following disengagement; (C) restarted ART in pregnancy after disengagement; and (D) ART new start in pregnancy. We used Kaplan-Meier curves and proportional-hazards models (adjusted for maternal age, number of pregnancy records and year of delivery) to examine the time to disengagement from delivery to 2 years postpartum., Results: Among 7309 pregnancies (in 6680 individuals), the proportion on ART (A) increased from 19% in 2013 to 41% in 2019. The proportions of those who returned (B) and restarted (C) increased from 2% to 13% and from 2% to 10%, respectively. There was a corresponding decline in the proportion of new starts (D) from 77% in 2013 to 36% in 2019. In the first recorded pregnancy per person in the study period, 26% (95% CI 25-27%) had disengaged from care by 1 year and 34% (95% CI 33-36%) by 2 years postpartum. Individuals who returned (B: aHR 2.10, 95% CI 1.70-2.60), restarted (C: aHR 3.32, 95% CI 2.70-4.09) and newly started ART (D: aHR 2.41, 95% CI 2.12-2.74) had increased hazards of postpartum disengagement compared to those on ART (A)., Conclusions: There is a growing population of people with ART experience prior to conception and postpartum disengagement varies substantially by ART history. Antenatal care presents an important opportunity to understand prior ART experiences and an entry into interventions for strengthened engagement in HIV care., (© 2024 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Introduction: We evaluated associations of HIV and antiretroviral therapy (ART) with birth and maternal outcomes at a province-wide-level in the Western Cape, South Africa, in a recent cohort before dolutegravir-based first-line ART implementation., Methods: This retrospective cohort study included pregnant people delivering in 2018-2019 with data in the Western Cape Provincial Health Data Centre which integrates individual-level data on all public sector patients from multiple electronic platforms using unique identifiers. Adverse birth outcomes (stillbirth, low birth weight (LBW), very LBW (VLBW)) and maternal outcomes (early and late pregnancy-related deaths, early and late hospitalizations) were compared by HIV/ART status and adjusted prevalence ratios (aPRs) calculated using log-binomial regression., Results: Overall 171,960 pregnant people and their singleton newborns were included, 19% (N = 32 015) identified with HIV. Amongst pregnant people with HIV (PPHIV), 60% (N = 19 157) were on ART preconception, 29% (N = 9276) initiated ART during pregnancy and 11% (N = 3582) had no ART. Adjusted for maternal age, multiparity, hypertensive disorders and residential district, stillbirths were higher only for PPHIV not on ART [aPR 1.31 (95%CI 1.04-1.66)] compared to those without HIV. However, LBW and VLBW were higher among all PPHIV, with aPRs of 1.11-1.22 for LBW and 1.14-1.54 for VLBW. Pregnancy-initiated ART was associated with early pregnancy-related death (aPR 3.21; 95%CI 1.55-6.65), and HIV with or without ART was associated with late pregnancy-related death (aPRs 7.89-9.01)., Conclusions: Even in the universal ART era, PPHIV experienced higher rates of LBW and VLBW newborns, and higher late pregnancy-related death regardless of ART status than pregnant people without HIV., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: While Option B + has made great strides in eliminating vertical transmission of HIV and improving access to lifelong antiretroviral therapy (ART) for women, the postpartum period remains a risk period for disengagement from HIV care and non-adherence., Methods: Longitudinal qualitative data was collected from 30 women living with HIV in Cape Town, South Africa from pregnancy through 1 year postpartum to examine key barriers and facilitators to HIV treatment adherence across this transition. Participants were also asked about their preferences for behavioral intervention content, format, and scope. The intervention development process was guided by Fernandez et al.'s Intervention Mapping process and was informed by the qualitative data, the wider literature on ART adherence, and Transition Theory., Results: The Womandla Health Intervention is a multicomponent intervention consisting of four individual sessions with a lay health worker and four peer group sessions, which span late pregnancy and early postpartum. These sessions are guided by Transition Theory and utilize motivational interviewing techniques to empower women to ascertain their own individual barriers to HIV care and identify solutions and strategies to overcome these barriers., Conclusions: This intervention will be tested in a small scale RCT. If successful, findings will provide an innovative approach to HIV treatment by capitalizing on the transition into motherhood to bolster self-care behaviors, focusing on ART adherence and also women's overall postpartum health and psychosocial needs., (© 2023. The Author(s).)

Background: Despite the overall reduction in the HIV mother-to-child transmission (MTCT) rate in South Africa, poor adherence and retention in care during breastfeeding contribute to this period being a major driver of MTCT in South Africa. To improve this retention, postnatal clubs were created as an integrated, differentiated model of care providing psychosocial support and comprehensive care for the mother-infant pairs (MIP), including HIV and under-5-child services. We describe the implementation of these facility-based clubs and examine its health outcomes in a peri-urban primary health care setting in Cape Town, South Africa., Methods: In this prospective cohort study, conducted between June 2016 and December 2019, MIPs were recruited into postnatal clubs between 6 weeks and 6 months of age and followed-up until 18 months of age. Outcomes including maternal Viral Load (VL), and children's HIV testing were compared to a historical control group. Children's immunizations and maternal sexual and reproductive health outcomes are also described., Results: During the implementation of the postnatal club study period, 484 MIP were recruited with 84% overall attendance, 95% overall viral load suppression, and 98% overall uptake of HIV infant testing. Compared to historical controls, the club infant rapid test uptake was 1.6 times higher (95% CI: 1.4-1.9) at 9 months and 2.0 times higher at 18 months (95% CI: 1.6-2.6). Through 12 months and between 12-18 months, maternal VL monitoring was higher in the club group compared to the historical control by 1.5 times (95% CI: 1.3-1.6) and 2.6 times (95% CI: 2.1-3.2), respectively, with similar maternal VL suppression. Of 105 infants attending the 12 months visit, 99% were fully vaccinated by one year., Conclusion: MIP in the postnatal clubs showed better PMTCT outcomes than historical controls with high levels of retention in care. Other outcomes such as immunisation results suggest that integration of services, such as in the postnatal club, is feasible and beneficial for MIPs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Nelson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Several HIV-related syndemics have been described among adults. We investigated syndemic vulnerability to hazardous drinking (HD), intimate partner violence (IPV) and household food insecurity (HFIS) in breastfed children born without HIV in urban South Africa. We compared those who were perinatally HIV exposed (CHEU) to those who were not (CHU), under conditions of universal maternal antiretroviral therapy (ART) and breastfeeding., Methods: A prospective cohort of pregnant women living with HIV (WLHIV), and without HIV, were enrolled and followed with their infants for 12 months postpartum (2013-2017). All WLHIV initiated antenatal efavirenz-based ART. Measurements of growth (∼3 monthly), infectious cause hospitalisation, ambulatory childhood illness (2-week recall) and neurodevelopment (BSID-III, measured at ∼12 months' age) were compared across bio-social strata using generalised linear regression models, with interaction terms; maternal data included interview-based measures for HD (AUDIT-C), IPV (WHO VAW) and HFIS., Results: Among 872 breastfeeding mother-infant pairs (n = 461 CHEU, n = 411 CHU), WLHIV (vs. HIV negative) reported more unemployment (279/461, 60% vs. 217/411, 53%; p = 0.02), incomplete secondary education (347/461, 75% vs. 227/411, 55%; p < 0.0001), HD (25%, 117/459 vs. 7%, 30/411; p < 0.0001) and IPV (22%, 101/457 vs. 8%, 32/411; p < 0.0001) at enrolment; and HFIS at 12 months (45%, 172/386 vs. 30%, 105/352; p > 0.0001). There were positive interactions between maternal HIV and other characteristics. Compared to food secure CHU, the mean difference (95% CI) in weight-for-age Z-score (WAZ) was 0.06 (-0.14; 0.25) for food insecure CHU; -0.26 (-0.42; -0.10) for food secure CHEU; and -0.43 (-0.61; -0.25), for food insecure CHEU. Results were similar for underweight (WAZ < -2), infectious-cause hospitalisation, cognitive and motor delay. HIV-IPV interactions were evident for ambulatory diarrhoea and motor delay. There were HIV-HD interactions for odds of underweight, stunting, cognitive and motor delay. Compared to HD-unexposed CHU, the odds ratios (95% CI) of underweight were 2.31 (1.11; 4.82) for HD-exposed CHU; 3.57 (0.84; 15.13) for HD-unexposed CHEU and 6.01 (2.22; 16.22) for HD-exposed CHEU., Conclusions: These data suggest that maternal HIV-related syndemics may partly drive excess CHEU health risks, highlighting an urgent need for holistic maternal and family care and support alongside ART to optimise the health of CHEU., (© 2023 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Introduction: CHERISH is designed to establish a long-term sustainable system for measurement of in utero and postnatal exposures and outcomes in children who are HIV-exposed uninfected (HEU) and HIV-unexposed to compare survival, hospitalisation, growth and neurodevelopment in the Western Cape, South Africa., Methods and Analysis: During 2022-2025, the CHERISH dynamic cohort is prospectively enrolling pregnant people with and without HIV at 24-36 weeks gestation from one urban and one rural community, following mother-child pairs, including children who are HEU (target N=1200) and HIV-unexposed (target N=600) for 3 years from the child's birth. In-person visits occur at enrolment, delivery, 12 months, 24 months and 36 months with intervening 3-monthly telephone data collection. Children and mothers without HIV are tested for HIV at all in-person visits. Data on exposures and outcomes are collected from routine standardised healthcare documentation, maternal interview, measurement (growth and neurodevelopment) at in-person visits and linkage to the Western Cape Provincial Health Data Centre (survival and hospitalisation). A priori adverse birth outcomes, advanced maternal HIV and maternal mental health are considered potential mediators of outcome disparities in children who are HEU and will be evaluated as such in multivariable models appropriate for each outcome., Ethics and Dissemination: Mothers interested in joining the study are taken through a visual informed consent document for their and their child's participation, with the option to consent to anonymised de-identified data being contributed to a public data repository. All data is captured directly into an electronic database using alphanumeric identifiers devoid of identifying information. The cohort study is approved by Human Research Ethics Committees of Stellenbosch University (N20/08/084), University of Cape Town (723/2021) and Western Cape Government (WC&#95;2021&#95;09&#95;007). Findings will be shared with participants, participating communities, local and provincial stakeholders, child health clinicians, researchers and policymakers at local, national and international forums and submitted for publication in peer-reviewed journals., Competing Interests: Competing interests: M-AD receives funding from ViiV Healthcare for an unrelated project. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Few data are available on COVID-19 outcomes among pregnant women in sub-Saharan Africa (SSA), where high-risk comorbidities are prevalent. We investigated the impact of pregnancy on SARS-CoV-2 infection and of SARS-CoV-2 infection on pregnancy to generate evidence for health policy and clinical practice., Methods: We conducted a 6-country retrospective cohort study among hospitalized women of childbearing age between 1 March 2020 and 31 March 2021. Exposures were (1) pregnancy and (2) a positive SARS-CoV-2 RT-PCR test. The primary outcome for both analyses was intensive care unit (ICU) admission. Secondary outcomes included supplemental oxygen requirement, mechanical ventilation, adverse birth outcomes, and in-hospital mortality. We used log-binomial regression to estimate the effect between pregnancy and SARS-CoV-2 infection. Factors associated with mortality were evaluated using competing-risk proportional subdistribution hazards models., Results: Our analyses included 1315 hospitalized women: 510 pregnant women with SARS-CoV-2, 403 nonpregnant women with SARS-CoV-2, and 402 pregnant women without SARS-CoV-2 infection. Among women with SARS-CoV-2 infection, pregnancy was associated with increased risk for ICU admission (adjusted risk ratio [aRR]: 2.38; 95% CI: 1.42-4.01), oxygen supplementation (aRR: 1.86; 95% CI: 1.44-2.42), and hazard of in-hospital death (adjusted sub-hazard ratio [aSHR]: 2.00; 95% CI: 1.08-3.70). Among pregnant women, SARS-CoV-2 infection increased the risk of ICU admission (aRR: 2.0; 95% CI: 1.20-3.35), oxygen supplementation (aRR: 1.57; 95% CI: 1.17-2.11), and hazard of in-hospital death (aSHR: 5.03; 95% CI: 1.79-14.13)., Conclusions: Among hospitalized women in SSA, both SARS-CoV-2 infection and pregnancy independently increased risks of ICU admission, oxygen supplementation, and death. These data support international recommendations to prioritize COVID-19 vaccination among pregnant women., Competing Interests: Potential conflicts of interest. J. B. N. is an infectious disease internist and epidemiologist and Principal Investigator (PI) of NIH/FIC grant numbers 1R25TW011217-01, 1R21TW011706-01, and 1D43TW010937-01A1; and payment to University of Pittsburgh. N. A. S.-A. is a clinician-scientist in Pediatric Infectious Diseases and implementation research; she is supported by the NIH National Institute of Child Health and Human Development (NICHD) grant number R01HD089866; by an NIH/FIC award through the Adolescent HIV Prevention and Treatment Implementation Science Alliance (AHISA) for the Central and West Africa Implementation Science Alliance (CAWISA) (payment to institution); and by NIH/FIC grant number 1D43TW012280-01. F. S., N. K. S., and A. P. are supported as PIs by NIH/FIC grant number 1R25TW011217-01. A. Z. is PIs of the Pan-African Network on Emerging and Re-Emerging Infections (PANDORA-ID-NET; https://www.pandora-id.net) funded by the European Developing Countries Clinical Trial Partnership (EDCTP) and the European Union Horizon 2020 Framework Program for Research and Innovation, paid to institution (University College London, London, UK). R. N. M. reports grants or contracts unrelated to this work, and payment to their institution: NIH/FIC1D43TW010547-01—The African Center for Biostatistical Excellence (ACBE). P. J. R. reports the following grants or contracts unrelated to this work and paid to their institution: 5R01AI075045-12, 5R01AI139179-04, and 5R01AI117001-07. E. R. S. reports a Bill and Melinda Gates Foundation grant for a prospective meta-analysis of COVID-19 in pregnancy, unrelated to this work, and payment to George Washington University. A. B. reports grants or contracts unrelated to this work—NIH: IMPAACT Vice-chair Funding for P1106; and UNITAID: Benefit KIDS funding for PETITE Study. P. A. reports grants or contracts unrelated to this work and paid to the University of Ibadan, Nigeria: NIH/FIC R25 grant number 1R25TW011217-01 to AFREhealth. J. W. N. reports grants paid to the University of Pittsburgh from the NIH to the Pitt-Ohio State Clinical Trials Unit (UM1 AI068636), the University of Pittsburgh Virology Support Laboratory (UM1 AI106701), the I4C Martin Delaney Collaboratory for an HIV Cure (UM1 AI126603), the REACH Martin Delaney Collaboratory for HIV Cure (UM1 AI164565), and from the National Cancer Institute through Leidos contract numbers HHSN261200800001E and 75N91019D00024 USAID; Gilead Sciences, Inc; and Janssen Pharmaceuticals. J. W. N. also reports consulting fees from Gilead Sciences, Inc (Scientific Advisory Board), Accelevir Diagnostics (Consulting Agreement), and Merck (Consulting Agreement); shares from Abound Bio, Inc, share options from Co-Crystal Pharma, Inc, and share options from Infectious Diseases Connect; a consulting agreement with Xi’an Yufan Biotechnologies; and employment with the University of Pittsburgh. M. S. reports grants or contracts unrelated to this work and paid to their institution (MGH-Boston, MA, USA): NIH/NIA R01AG059504-03 and NIH/NHLBI R01 HL141053-04. A.-P. K. reports research support unrelate to this work paid to their institution (South African Medical Research Council): NIH/FIC 1R21TW011706-01-Dolutegravir, Weight Gain and Metabolic Outcomes in South Africa. L. M. reports consulting fees from the World Health Organization on COVID in pregnancy and mother to child SARS-CoV-2 transmission (this contract is now completed); and payment from Virology Education for a talk on SARS-CoV-2 in pregnancy and possibility of mother-to-child SARS-CoV-2 transmission for continuing education sponsored by Virology Education. M. Y. is PI of the NIH/National Institute of Allergy and Infectious Diseases (NIH/NIAID) grant number 5U01AI096299-13 of the Central Africa-International epidemiology to Evaluate AIDS (CA-IeDEA). M. Y. also reports grants or contracts unrelated to this work and paid to their institution: NIH grant numbers 5U01AI096299 (NIAID), R01HD087993 (NICHD), U54CA254568 (National Cancer Institute), and R01HD105526 (NICHD). All other authors report no potential conflicts. 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) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Background: Many women in sub-Saharan Africa initiate antenatal care (ANC) late in pregnancy, undermining optimal prevention of mother-to-child-transmission (PMTCT) of HIV. Questions remain about whether and how late initiation of ANC in pregnancy is related to adherence to antiretroviral therapy (ART) in the era of national dolutegravir roll-out., Methods: This study employed a qualitative design involving individual interviews and focus group discussions conducted between August 2018 and March 2019. We interviewed 37 pregnant and lactating women living with HIV selected purposively for early or late presentation to ANC from poor urban communities in South Africa and Uganda. Additionally, we carried out seven focused group discussions involving 67 participants in both countries. Data were analysed thematically in NVivo12., Results: Women described common underlying factors influencing both late ANC initiation and poor ART adherence in South Africa and Uganda. These included poverty and time constraints; inadequate health knowledge; perceived low health risk; stigma of HIV in pregnancy; lack of disclosure; and negative provider attitudes. Most late ANC presenters reported relationship problems, lack of autonomy and the limited ability to dialogue with their partners to influence household decisions on health and resource allocation. Perception of poor privacy and confidentiality in maternity clinics was rife among women in both study settings and compounded risks associated with early disclosure of pregnancy and HIV. Women who initiated ANC late and were then diagnosed with HIV appeared to be more susceptible to poor ART adherence. They were often reprimanded by health workers for presenting late which hampered their participation in treatment counselling and festered provider mistrust and subsequent disengagement in care. Positive HIV diagnosis in late pregnancy complicated women's ability to disclose their status to significant others which deprived them of essential social support for treatment adherence. Further, it appeared to adversely affect women's mental health and treatment knowledge and self-efficacy., Conclusions: We found clear links between late initiation of ANC and the potential for poor adherence to ART based on common structural barriers shaping both health seeking behaviours, and the adverse impact of late HIV diagnosis on women's mental health and treatment knowledge and efficacy. Women who present late are a potential target group for better access to antiretrovirals that are easy to take and decrease viral load rapidly, and counselling support with adherence and partner disclosure. A combination of strengthened health literacy, economic empowerment, improved privacy and patient-provider relationships as well as community interventions that tackle inimical cultural practices on pregnancy and unfair gender norms may be required., (© 2022. The Author(s).)

Background: Early-life metabolic derangements in HIV-exposed uninfected (HEU) infants have been reported., Methods: Pregnant women with HIV and HIV-uninfected pregnant women were enrolled with their newborns in a US cohort from 2011 to 2015. We measured cord insulin, C-peptide, and metabolic cytokines of HEU and HIV-unexposed uninfected (HUU) newborns using ELISA and metabolites, lipid subspecies, and eicosanoids via liquid chromatography/mass spectrometry. Linear regression was employed to assess the association of intrauterine HIV/ART with insulin and C-peptide. Graphical lasso regression was used to identify differences between metabolite/lipid subspecies networks associated with C-peptide., Results: Of 118 infants, 56 were HEU, ART exposed. In adjusted analyses, mean cord insulin (β = 0.295, p = 0.03) and C-peptide (β = 0.522, p < 0.01) were significantly higher in HEU vs. HUU newborns. HEU neonates exhibited primarily positive associations between complex lipids and C-peptide, indicative of fuel storage, and augmented associations between cord eicosanoids and cytokines. HUU neonates exhibited negative associations with lipids and C-peptide indicative of increased fuel utilization., Conclusion: Higher cord insulin and C-peptide in HEU vs. HUU newborns as well as differences in cord metabolites, metabolic-related cytokines, and eicosanoids may reflect a propensity for fuel storage and an inflammatory milieu suggestive of fetal metabolic changes associated with in utero HIV/ART exposure., Impact: There is a paucity of studies assessing cord blood and neonatal metabolic health in HIV-exposed uninfected (HEU) newborns, an increasing population worldwide. Compared to HIV-unexposed uninfected (HUU) newborns, HEU newborns exhibit alterations in fuel homeostasis and an inflammatory milieu associated with in utero HIV/antiretroviral therapy (ART) exposure. The long-term implications of these neonatal findings are as yet unknown, but merit continued evaluation as this important and growing population ages into adulthood., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Introduction: Women who are pregnant or who could become pregnant experience delayed access to or underinformed use of important new antiretroviral (ARV) drugs because of traditional drug development processes that ostensibly aim to reduce potential harm but effectively fail to ensure that timely information about safe and effective use in pregnancy is available., Discussion: The World Health Organization and International Maternal, Pediatric, Adolescent Antiretroviral Clinical Trials Network convened a year-long workshop on "Approaches to Enhance and Accelerate Study of New Drugs for HIV and Associated Infections in Pregnant Women." Workshop participants were tasked with defining key principles and optimal approaches to including pregnant women in pre- and post-licensure trials in order to accelerate the availability of pharmacokinetic and safety data for new ARV agents in pregnancy. ARV efficacy in pregnancy and ARV efficacy for prevention of vertical transmission can be extrapolated from proof of efficacy in non-pregnant adults, provided that drug levels in pregnancy are similar. However, short-term safety and pharmacokinetics must be studied directly in pregnant women and should be conducted and included in initial licensure for all new ARVs. Accelerating the timeline for completion of pre-clinical studies is essential for pregnancy short-term safety and pharmacokinetic studies to be safely completed by the time a drug is licensed. Composite key pregnancy, birth and neonatal outcomes are critical for drugs expected to have broad use, and studies should be initiated at or soon after drug licensure. Teratogenicity risk cannot be feasibly assessed before drug licensure and will depend on robust post-marketing surveillance systems. With some modifications, these principles will apply to ARVs used for prevention, two-drug regimens, long-acting ARVs and ARVs administered through novel delivery systems., Conclusions: Implementation of the proposed principles and framework will enhance and accelerate the study of new ARVs in pregnancy, resulting in more timely, equitable and informed access to new ARVs for pregnant women., (© 2022 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Background: Antiretroviral therapy (ART) use during pregnancy may be associated with adverse outcomes, but findings have been inconsistent, at least in part due to unreliably estimated gestational age., Objective: To quantify the association between HIV status, ART initiation timing and adverse birth outcomes, with reliably assessed gestational age at booking, in a public sector primary care facility in Cape Town, South Africa., Methods: Pregnant women, HIV-negative or living with HIV (WLHIV), were enrolled at first antenatal care visit and followed through delivery. Ultrasound-assessed gestational age was deemed the gold standard. Based on quantitative bias analysis for outcome misclassification, gestational age by non-ultrasound assessment was corrected using multiple overimputation, which deals with missing data and measurement error simultaneously. Using bias-corrected gestational age, birth outcomes were compared between WLHIV and HIV-negative women, and among WLHIV who initiated ART before versus during pregnancy, further divided into trimesters., Results: Of 3952 women enrolled, 37% were WLHIV (mostly using tenofovir + emtricitabine + efavirenz). Last menstrual period (LMP)-based gestational age was identified to be biased, and LMP measures were thus corrected using multiple overimputation. Comparing WLHIV and HIV-negative women, adjusted risk ratio (aRR) of overall pregnancy loss was 1.26 (95% confidence interval [CI] 0.98, 1.61); aRR of preterm delivery was 1.02 (95% CI 0.88, 1.20); aRR of small for gestational age infants was 1.43 (95% CI 1.14, 1.80). Among WLHIV, outcomes were similar by ART initiation timing., Conclusions: In this routine care cohort, risk of SGA, and possibly of pregnancy loss, was increased in WLHIV compared with HIV-negative women, with no evidence of increased risk of preterm delivery. Further research is needed to improve mechanistic understanding of the contribution of ART to adverse birth outcomes to optimize treatment for pregnant WLHIV and ensure optimal maternal and infant outcomes., (© 2021 John Wiley & Sons Ltd.)

Introduction: Pregnant women are routinely excluded from clinical trials, leading to the absence or delay in even the most basic pharmacokinetic (PK) information needed for dosing in pregnancy. When available, pregnancy PK studies use a small sample size, resulting in limited safety information. We discuss key study design elements that may enhance the timely availability of pregnancy data, including the role and timing of randomized controlled trials (RCTs) to evaluate pregnancy safety; efficacy and safety outcome measures; stand-alone protocols, platform trials, single arm studies, sample size and the effect that follow-up time during gestation has on analysis interpretations; and observational studies., Discussion: Pregnancy PK should be studied during drug development, after dosing in non-pregnant persons is established (unless non-clinical or other data raise pregnancy concerns). RCTs should evaluate the safety during pregnancy of priority new HIV agents that are likely to be used by large numbers of females of childbearing age. Key endpoints for pregnancy safety studies include birth outcomes (prematurity, small for gestational age and stillbirth) and neonatal death, with traditional adverse events and infant growth also measured (congenital anomalies are best studied through surveillance). We recommend that viral efficacy be studied as a secondary endpoint of pregnancy RCTs, once PK studies confirm adequate drug exposure in pregnancy. RCTs typically use a stand-alone protocol for new agents. In contrast, master protocols using a platform design can add agents over time, possibly speeding safety data ascertainment. To speed accrual, stand-alone pregnancy trial protocols can include pre-specified starting rules based upon adequate PK levels in pregnancy; and seamless master protocols or platform trials can include a pregnancy PK and safety component. When RCTs are unethical or cost-prohibitive, observational studies should be conducted, preferably using target trial emulation to avoid bias., Conclusions: Pregnancy PK needs to be obtained earlier in drug evaluation. Timely RCTs are needed to understand safety in pregnancy for high-priority new HIV agents. RCTs that enrol pregnant women should focus on outcomes unique to pregnancy, and observational studies should focus on questions that RCTs are not equipped to answer., (© 2022 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Background: Maternal HIV and antiretroviral therapy (ART) exposure in utero may influence infant weight, but the contribution of maternal y body mass index (BMI) to early life overweight and obesity is not clear., Objective: To estimate associations between maternal BMI at entry to antenatal care (ANC) and infant weight through approximately 1 year of age and to evaluate whether associations were modified by maternal HIV status, maternal HIV and viral load, breastfeeding intensity through 6 months or timing of entry into ANC., Methods: We followed HIV-uninfected and -infected pregnant women initiating efavirenz-based ART from first antenatal visit through 12 months postpartum. Infant weight was assessed via World Health Organization BMI and weight-for-length z-scores (WLZ) at 6 weeks, 3, 6, 9 and 12 months. We used multivariable linear mixed-effects models to estimate associations between maternal BMI and infant z-scores over time., Results: In 861 HIV-uninfected infants (454 HIV-exposed; 407 HIV-unexposed), nearly 20% of infants were overweight or obese by 12 months of age, regardless of HIV exposure status. In multivariable analyses, increasing maternal BMI category was positively associated with higher infant BMIZ and WLZ scores between 6 weeks and 12 months of age and did not differ by HIV exposure status. However, HIV-exposed infants had slightly lower BMIZ and WLZ trajectories through 12 months of age, compared with HIV-unexposed infants across all maternal BMI categories. Differences in BMIZ and WLZ scores by HIV exposure were not explained by timing of entry into ANC or maternal viral load pre-ART initiation, but z-scores were slightly higher for HIV-exposed infants who were predominantly or exclusively versus partially breastfed., Conclusions: These findings suggest maternal BMI influences early infant weight gain, regardless of infant HIV exposure status. Intervention to reduce maternal BMI may help to address growing concerns about obesity among HIV-uninfected children., (© 2021 John Wiley & Sons Ltd.)

Background: In the absence of clinical trials, data on the safety of medicine exposures in pregnancy are dependent on observational studies conducted after the agent has been licensed for use. This requires an accurate history of antenatal medicine use to determine potential risks. Medication use is commonly determined by self-report, clinician records, and electronic pharmacy data; different data sources may be more informative for different types of medication and resources may differ by setting. We compared three methods to determine antenatal medicine use (self-report, clinician records and electronic pharmacy dispensing records [EDR]) in women attending antenatal care at a primary care facility in Cape Town, South Africa in a setting with high HIV prevalence., Methods: Structured, interview-administered questionnaires recorded self-reported medicine use. Data were collected from clinician records and EDR on the same participants. We determined agreement between these data sources using Cohen's kappa and, lacking a gold standard, used Latent Class Analysis to estimate sensitivity, specificity and positive predictive value (PPV) for each data source., Results: Between 55% and 89% of 967 women had any medicine use documented depending on the data source (median number of medicines/participant = 5 [IQR 3-6]). Agreement between the datasets was poor regardless of class except for antiretroviral therapy (ART; kappa 0.6-0.71). Overall, agreement was better between the EDR and self-report than with either dataset and the clinician records. Sensitivity and PPV were higher for self-report and the EDR and were similar for the two. Self-report was the best source for over-the-counter, traditional and complementary medicines; clinician records for vaccines and supplements; and EDR for chronic medicines., Conclusions: Medicine use in pregnancy was common and no single data source included all the medicines used. ART was the most consistently reported across all three datasets but otherwise agreement between them was poor and dependent on class. Using a single data collection method will under-estimate medicine use in pregnancy and the choice of data source should be guided by the class of the agents being investigated., (© 2022. The Author(s).)

Background: Sexually transmitted infections (STIs) during pregnancy may increase the risk of adverse pregnancy outcomes. STI syndromic management is standard of care in South Africa but has its limitations. We evaluated the impact of diagnosing and treating curable STIs during pregnancy on adverse pregnancy and birth outcomes., Methods: We combined data from two prospective studies of pregnant women attending public sector antenatal care (ANC) clinics in Tshwane District and Cape Town, South Africa. Pregnant women were enrolled, tested and treated for STIs. We evaluated the association between any STI at the first ANC visit and a composite adverse pregnancy outcome (miscarriage, stillbirth, preterm birth, early neonatal death, or low birthweight) using modified Poisson regression models, stratifying by HIV infection and adjusting for maternal characteristics., Results: Among 619 women, 61% (n = 380) were from Tshwane District and 39% (n = 239) from Cape Town; 79% (n = 486) were women living with HIV. The prevalence of any STI was 37% (n = 228); C. trachomatis, 26% (n = 158), T. vaginalis, 18% (n = 120) and N. gonorrhoeae, 6% (n = 40). There were 93% (n = 574) singleton live births, 5% (n = 29) miscarriages and 2% (n = 16) stillbirths. Among the live births, there were 1% (n = 3) neonatal deaths, 7% (n = 35) low birthweight in full-term babies and 10% (n = 62) preterm delivery. There were 24% (n = 146) for the composite adverse pregnancy outcome. Overall, any STI diagnosis and treatment at first ANC visit was not associated with adverse outcomes in women living with HIV (adjusted relative risk (aRR); 1.43, 95% CI: 0.95-2.16) or women without HIV (aRR; 2.11, 95% CI: 0.89-5.01). However, C. trachomatis (aRR; 1.57, 95% CI: 1.04-2.39) and N. gonorrhoeae (aRR; 1.69, 95% CI: 1.09-3.08), were each independently associated with the composite adverse outcome in women living with HIV., Conclusion: Treated STIs at the first ANC visit were not associated with adverse pregnancy outcome overall. In women living with HIV, C. trachomatis or N. gonorrhoeae at first ANC were each independently associated with adverse pregnancy outcome. Our results highlights complex interactions between the timing of STI detection and treatment, HIV infection and pregnancy outcomes, which warrants further investigation., (© 2022. The Author(s).)

Rationale: Adherence to antiretroviral therapy (ART) is a global concern among pregnant and postpartum women living with HIV (WLHIV). Research focusing on peripartum WLHIV and how they balance adherence, engaging in HIV care, and other forms of self-care is limited. Women's empowerment theories have been applied to myriad health behaviors to understand patterns, establish mechanisms, and develop interventions; yet empowerment theory as applied to ART is under-researched., Objective: Seeking deeper insight into peripartum health behaviors, we examine these factors using Naila Kabeer's (1999) women's empowerment theory, which denotes resources, agency, and achievements as three primary and interrelated components of empowerment., Methods: Data were collected in Gugulethu, South Africa, between March and July 2018. Thirty in-depth interviews were conducted with WLHIV at 32-35 weeks of pregnancy, with topics including experiences related to ART adherence and meanings of empowerment in motherhood. Analyses had two phases: (1) inductive open-coding for emergent themes; and (2) classifying themes into Kabeer's empowerment theory., Results: Participants expressed that resources play a critical role in adherence, ranging from practical support to motivational support provided by both family and partners. Agency is experienced as a desire to be an independent mother in the often-expected event that partners withdraw support. Participants described achievements as time-oriented goals, ranging from having a baby born without HIV to living a long and productive life., Conclusions: These findings suggest that a promising and innovative approach to improving ART adherence across the peripartum transition would focus on understanding resources as an enabling environment, build on existing feelings of agency, and highlight the lifelong goals achievable with high levels of adherence. A better understanding of how women's empowerment evolves over the course of pregnancy and into the postpartum period will support intervention development aimed at improving ART adherence and potentially additional peripartum health behaviors., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Infants born HIV-exposed yet remain uninfected (HEU) are at increased risk of poorer growth and health compared to infants born HIV-unexposed (HU). Whether maternal antiretroviral treatment (ART) in pregnancy ameliorates this risk of poorer growth is not well understood. Furthermore, whether risks are similar across high burden HIV settings has not been extensively explored., Methods: We harmonized data from two prospective observational studies conducted in Cape Town, South Africa, and Lusaka, Zambia, to compare weight-for-age (WAZ), length-for-age (LAZ) and weight-for-length (WLZ) Z-scores between infants who were HEU and HU, converting infant anthropometric measures using World Health Organisation Growth Standards adjusted for age and sex. Linear mixed effects models were fit to identify risk factors for differences in anthropometrics at 6-10 weeks and 6 months by infant HIV exposures status and by timing of exposure to maternal ART, either from conception or later in gestation., Results: Overall 773 mother-infant pairs were included across two countries: women living with HIV (WLHIV), 51% (n = 395) with 65% on ART at conception and 35% initiating treatment in pregnancy. In linear mixed effects models, WAZ and WLZ at 6-10 weeks were lower among infants who were HEU vs HU [β = - 0.29 (95% CI: - 0.46, - 0.12) and [β = - 0.42 (95% CI: - 0.68, - 0.16)] respectively after adjusting for maternal characteristics and infant feeding with a random intercept for country. At 6 months, LAZ was lower [β = - 0.28 CI: - 0.50, - 0.06)] among infants who were HEU, adjusting for the same variables, with no differences in WAZ and WLZ. Within cohort evaluations identified different results with higher LAZ among infants who were HEU from Zambia at 6-10 weeks, [β = + 0.34 CI: + 0.01, + 0.68)] and lower LAZ among infants who were HEU from South Africa [β = - 0.30 CI: - 0.59, - 0.01)] at 6 months, without other anthropometric differences at either site., Conclusion: Infant growth trajectories differed by country, highlighting the importance of studying contextual influences on outcomes of infants who were HEU., (© 2022. The Author(s).)

Background: Mechanisms underlying an association between human immunodeficiency virus (HIV) or antiretroviral therapy (ART) during pregnancy with risk of preterm delivery (PTD) and small-for-gestational-age (SGA) remain unclear. We explored the association between cellular immune activation and PTD or SGA in women with HIV initiating ART during or before pregnancy., Methods: Women with HIV enrolled at median 15 weeks' gestation, were analyzed for immune markers, and matched on ART initiation timing (15 women initiated pre- and 15 during pregnancy). There were 30 PTD (delivery <37 weeks), 30 SGA (weight for age ≤10th percentile) cases, and 30 controls (term, weight for gestational age >25th percentile) as outcomes. Lymphocytes, monocytes, and dendritic cell populations and their activation status or functionality were enumerated by flow cytometry., Results: PTD cases initiating ART in pregnancy showed decreased CD8+ T cell, monocyte, and dendritic cell activation; increased classical (CD14+CD16-) and intermediate (CD14+CD16+) monocyte frequencies; and decreased inflammatory monocytes (CD14dimCD16+) compared with SGA cases and term controls (all P < .05). Allowing for baseline viral load, the immune markers remained significantly associated with PTD but only in women initiating ART in pregnancy. Lower monocyte activation was predictive of PTD. TLR ligand-induced interferon-α and macrophage inflammatory protein-1β levels in monocytes were significantly lower in PTD women initiating ART in pregnancy., Conclusion: Low immune activation, skewing toward anti-inflammatory monocytes, and lower monocyte cytokine production in response to TLR ligand stimulation were associated with PTD but not SGA among women initiating ART in, but not before, pregnancy, suggesting immune anergy to microbial stimulation as a possible underlying mechanism for PTD in women initiating ART in pregnancy., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Implementation of universal antiretroviral therapy (ART) has significantly lowered vertical transmission rates but has also increased numbers of human immunodeficiency virus (HIV)-exposed uninfected children, who remain vulnerable to morbid effects. In the current study, we investigated whether T-cell alterations in the placenta contribute to altered immune status in HIV-exposed uninfected., Methods: We analyzed T cells from term placenta decidua and villous tissue and paired cord blood from pregnant women living with HIV (PWH) who initiated ART late in pregnancy (n = 21) with pregnant women not living with HIV (PWNH) (n = 9)., Results: Placentas from PWH showed inverted CD4/CD8 ratios and higher proportions of tissue resident CD8+ T cells in villous tissue relative to control placentas. CD8+ T cells in the fetal capillaries, which were of fetal origin, were positively correlated with maternal plasma viremia before ART initiation, implying that imbalanced T cells persisted throughout pregnancy. In addition, the expanded memory differentiation of CD8+ T cells was confined to the fetal placental compartment and cord blood but was not observed in the maternal decidua., Conclusions: T-cell homeostatic imbalance in the blood circulation of PWH is reflected in the placenta. The placenta may be a causal link between HIV-induced maternal immune changes during gestation and altered immunity in newborn infants in the absence of vertical transmission., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: During pregnancy and postpartum period, the sexual behaviors of women and their partners change in ways that may either increase or reduce HIV risks. Pregnant women are a priority population for reducing both horizontal and vertical HIV transmission., Setting: Nine sites in 4 South African provinces., Methods: Women aged 18-30 years were randomized to receive pericoital tenofovir 1% gel or placebo gel and required to use reliable modern contraception. We compared HIV incidence in women before, during, and after pregnancy and used multivariate Cox Proportional hazards models to compare HIV incidence by pregnancy status., Results: Rates of pregnancy were 7.1 per 100 woman-years (95% confidence interval [CI]: 6.3 to 8.1) and highest in those who reported oral contraceptive use (25.1 per 100 woman-years; adjusted hazard ratio 22.97 higher than other women; 95% CI: 5.0 to 105.4) or had 2 children. Birth outcomes were similar between trial arms, with 59.8% having full-term live births. No difference was detected in incident HIV during pregnancy compared with nonpregnant women (2.1 versus 4.3%; hazard ratio = 0.56, 95% CI: 0.14 to 2.26). Sexual activity was low in pregnancy and the early postpartum period, as was consistent condom use., Conclusions: Pregnancy incidence was high despite trial participation being contingent on contraceptive use. We found no evidence that rates of HIV acquisition were elevated in pregnancy when compared with those in nonpregnant women. Risks from reductions in condom use may be offset by reduced sexual activity. Nevertheless, high HIV incidence in both pregnant and nonpregnant women supports consideration of introducing antiretroviral-containing pre-exposure prophylaxis for pregnant and nonpregnant women in high HIV prevalence settings., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Increased risk of morbidity and hospitalization has been observed in children who are HIV-exposed uninfected (HEU) compared with HIV-unexposed uninfected (HUU). Studies in the era of universal maternal antiretroviral treatment (ART) are limited., Design: Prospective cohort., Methods: We investigated hospitalization between 29 days and 12 months of life in a South African cohort of infants born between February 2017 and January 2019 (HEU = 455; HUU = 458). All mothers known with HIV during pregnancy received ART. We reviewed hospital records and classified and graded infectious diagnoses using a standardized tool. We examined factors associated with infectious-cause hospitalization using mixed-effects Poisson regression., Results: Infants HEU vs. HUU had higher all-cause and infectious-cause hospitalization (13 vs. 7%, P = 0.004 and 10 vs. 6%, P = 0.014, respectively). Infectious causes accounted for most hospitalizations (77%). More infants HEU were hospitalized with severe or very severe infections than those HUU (9 vs. 6%; P = 0.031). Mortality (<1%) did not differ between groups. HIV exposure was a significant risk factor for infectious-cause hospitalization [adjusted incidence rate ratios (aIRRs) = 2.8; 95% confidence interval (CI) 1.5-5.4]. Although increased incidence of preterm birth (14 vs. 10%; P < 0.05) and shorter duration of breastfeeding (44 vs. 68% breastfed for ≥3 months, P < 0.001) among infants HEU vs. HUU contributed to increased hospitalization, they did not account for all the increased risk., Conclusion: Infectious-cause hospitalization incidence was higher among infants HEU vs. HUU, likely partly because of higher incidence of preterm birth and lower breastfeeding rates among infants HEU. The increased infectious disease burden in HEU infants has important implications for health services in sub-Saharan Africa., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Prematurity Immunology in Mothers living with HIV and their infants Study (PIMS) is a prospective cohort study in South Africa investigating the association between antiretroviral therapy (ART) use, preterm delivery (PTD) and small-for-gestational age (SGA) live births. PIMS main hypotheses are that ART initiation in pregnancy and ART-induced hypertension are associated with PTD and SGA respectively and that reconstitution of cellular immune responses in women on ART from before pregnancy results in increases in PTD of GA infants., Participants: Pregnant women (n=3972) aged ≥18 years regardless of HIV status recruited from 2015 to 2016 into the overall PIMS cohort (2517 HIV-negative, 1455 living with HIV). A nested cohort contained 551 women living with HIV who were ≤24 weeks' GA on ultrasound: 261 initiated ART before pregnancy, 290 initiated during the pregnancy., Findings to Date: Women in the overall cohort were followed antenatally through to delivery using routine clinical records; further women in the nested cohort were actively followed up until 12 months post partum, with data collected on maternal health (HIV care and ART use, clinical care and intercurrent clinical history). Other procedures conducted on the nested cohort included physical examinations (anthropometry, blood pressure measurement), assessment of fetal growth (ultrasound), maternal and infant phlebotomy for storage of plasma, RNA and peripheral blood mononuclear cells, collection of delivery specimens (placenta and cord blood) and infant 12-month developmental assessment. Preliminary findings have contributed to our understanding of risk factors for adverse birth outcomes, and the relationship between pregnancy immunology, HIV/ART and adverse birth outcomes., Future Plans: Using specimens collected from study participants living with HIV throughout pregnancy and first year of life, the PIMS provides a valuable platform for answering a variety of research questions focused on temporal changes of immunology markers in women whose immune status is altered by HIV infection, and how ART initiated during the pregnancy affects immune responses. The relationship between these immunological changes with adverse birth outcomes as well as possible longer-term impact of exposure to ART in fetal and early life will be explored. Additionally, further active and passive follow-up of mothers and their infants is planned at school-going age and beyond to chart growth, morbidity and development, as well as changes in family circumstances., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Enhanced postnatal prophylaxis is recommended in infants of women with viremia during labor, as identified by viral load (VL) testing late in pregnancy. However, data on the use of antenatal VL to predict peripartum viremia are few, particularly in women starting antiretroviral therapy (ART) in pregnancy who experience initial VL declines., Methods: Between January 2016 and August 2017, we identified HIV-infected women who initiated ART (tenofovir, emtricitabine, and efavirenz) antenatally and had a VL <400 copies/mL before delivery in Cape Town, South Africa. VLs were repeated postdelivery, and sensitivity, specificity, and positive and negative likelihood ratios (LR+ and LR-) for antenatal VL <100 copies/mL in predicting peripartum VLs <100 and <400 copies/mL were calculated., Results: Among 322 women (median age 29 years, 44% with a history of ART use, median gestation of antenatal VL 33 weeks), antenatal VL was <100 copies/mL in 89% and 100-400 copies/mL in 11%. At a median 9 days postpartum, 91%, 7%, and 2% of women had a VL <100, 100-400, and >400 copies/mL, respectively. Sensitivity of antenatal VL <100 copies/mL in predicting peripartum VL <100 copies/mL was 0.95 (95% confidence interval: 0.92 to 0.97), and specificity was 0.71 (95% confidence interval: 0.51 to 0.87; LR+ 3.28, LR- 0.07). Performance was slightly weaker to detect peripartum VL <400 copies/mL but was similar across strata of gestation at antenatal VL and history of ART use., Discussion: Antenatal VL is a useful predictor of peripartum viremia in women who started ART in pregnancy and attained a VL <400 copies/mL antenatally and may be used to target enhanced postnatal prophylaxis interventions., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: STIs during pregnancy increase adverse pregnancy and birth outcomes and may increase HIV risk. STI syndromic management is standard of care in South Africa. Our study evaluated the prevalence and incidence of STIs in pregnant women and the associated risk factors., Methods: We combined data from two prospective observational studies of pregnant women enrolled while attending their first antenatal clinic (ANC) visit in Tshwane District and Cape Town. Women ≥18 years were tested at first ANC visit and at their first postpartum visit for Chlamydia trachomatis , Neisseria gonorrhoeae and Trichomonas vaginalis using Xpert assays (Cepheid, USA). We evaluated the prevalence and incidence of STI and the associated risk factors using multivariable regression models., Results: We enrolled 669 pregnant women, 64% (n=427) from Tshwane District and 36% (n=242) from Cape Town; 80% (n=534) were women living with HIV (WLHIV) and 20% (n=135) without HIV. At enrolment, 37% (n=250) were diagnosed with at least one STI, of which 76% (n=190) were asymptomatic. STI prevalence was 40% (n=213) in WLHIV and 27% (n=37) in women without HIV (p=0.01). Baseline STI infection was associated with younger age (OR=0.95 per year, 95% CI 0.92 to 0.98), higher gestational age (adjusted OR (aOR)=1.03 per week, 95% CI 1.00 to 1.05), single relationship status (aOR=1.53, 95% CI 1.09 to 2.15) and HIV status (aOR=1.86, 95% CI 1.17 to 2.95). Of 419 participants with no STI at baseline, 21 had an incident STI during follow-up, with a mean follow-up time of 140 days. The incidence rate of STI during pregnancy and early post partum was 15 infections per 100 women-years (95% CI 9 to 23). Younger age was associated with STI incidence., Conclusion: Our study shows high prevalence and incidence of STIs in pregnancy, especially in WLHIV, demonstrating the need for STI screening in ANC to prevent adverse pregnancy and birth outcomes. Most STI cases were asymptomatic and would have gone untreated with syndromic management. Aetiological STI screening is urgently needed to reduce the burden of STIs in pregnancy., Competing Interests: Competing interests: The authors received a donation of STI Xpert assays from Cepheid (California, USA)., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

Objective: To examine the association between timing of antiretroviral treatment (ART) initiation in HIV-infected women and placental histopathology., Design: A nested substudy in a larger cohort of HIV-infected women which examined the association between ART status and birth outcomes., Methods: Placentas (n = 130) were examined for histopathology from two ART groups: stable (n = 53), who initiated ART before conception and initiating (n = 77), who started ART during pregnancy [median (interquartile range) 15 weeks gestation (11-18)]. Using binomial regression we quantified associations between ART initiation timing with placental histopathology and pregnancy outcomes., Results: One-third of all placentas were less than 10th percentile weight-for-gestation and there was no significant difference between ART groups. Placental diameter, thickness, cord insertion position and foetal-placental weight ratio were also similar by group. However, placentas from the stable group showed increased maternal vascular malperfusion (MVM) (39.6 vs. 19.4%), and decreased weight (392 vs. 422 g, P = 0.09). MVM risk was twice as high [risk ratios 2.03 (95% confidence interval: 1.16-3.57); P = 0.01] in the stable group; the increased risk remaining significant when adjusting for maternal age [risk ratios 2.04 (95% confidence interval: 1.12-3.72); P = 0.02]. Furthermore, MVM was significantly associated with preterm delivery and low birth weight (P = 0.002 and <0.0001, respectively)., Conclusion: Preconception initiation of ART was associated with an increased MVM risk, and may contribute to placental dysfunction. The association between MVM with preterm delivery and low birth weight suggests that a placenta-mediated mechanism likely links the putative association between long-term use of ART and adverse birth outcomes., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To compare the unit and total costs of three models of ART care for mother-infant pairs during the postpartum phase from provider and patient's perspectives: (i) local standard of care with women in general ART services and infants at well-baby clinics; (ii) women and infants continue to receive care through an integrated maternal and child care approach during the postpartum breastfeeding period; and (iii) referral of women directly to community adherence clubs with their infants receiving care at well-baby clinics., Methods: Capital and recurrent cost data (relating to buildings, furniture, equipment, personnel, overheads, maintenance, medication, diagnostic tests and immunisations) were collected from a provider's perspective at six sites in Cape Town, South Africa. Patient time, collected via time-and-motion observation and questionnaires, was used to estimate patient perspective costs and is comprised of lost productivity time, time spent travelling and the direct cost of travelling., Results: The cost of postpartum ART visits under models I, II and III was US $13, US $10 and US $7 per visit for a mother-infant pair, respectively, in 2018 US$. The annual costs for the mother-infant pair utilising the average visit frequencies (a mean of 4.5, 6.9 and 6.7 visits postpartum for models I, II and III, respectively) including costs for infant immunisations, visits, medication and diagnostic tests for both mothers and infants were: I - US $222, II - US $335 and III - US $249. Sensitivity analysis to assess the impact of visit frequency on visit cost showed that Model I annual costs would be most costly if visit frequency was equalised., Conclusion: This comparative analysis of three models of care provides novel data on unit costs and insight into the costs to provide ART and care to mother-infant pairs during the delicate postpartum phase. These costs may be used to help make decisions around integrated services models and differentiated service delivery for postpartum WLH and their children., (© 2020 The Authors Tropical Medicine & International Health Published by John Wiley & Sons Ltd.)

Background: Evidence shows that antiretroviral (ART) exposure is associated with neurodevelopmental delays in human immunodeficiency virus (HIV)-exposed uninfected (HEU) children. However, there are few insights into modifiable maternal and child factors that may play a role in improving neurodevelopment in HEU children. We used a parent-centric neurodevelopment tool, Ages & Stages Questionnaire (ASQ) to examined neurodevelopment in HEU children at 12-24 months of age, and associations with maternal and child factors., Methods: 505 HIV-infected women (initiated ART pre- or during pregnancy) with live singleton births attending primary health care were enrolled; 355 of their HEU children were assessed for neurodevelopment (gross motor, fine motor, communication, problem solving and personal-social domains) at 12-24 months using age-specific ASQ administered by a trained fieldworker. Associations with maternal and child factors were examined using logistic regression models., Results: Among mothers (median age 30 years, IQR, 26-34), 52% initiated ART during pregnancy; the median CD4 count was 436 cells/μl (IQR, 305-604). Most delayed neurodevelopment in HEU children was in gross (9%) and fine motor (5%) functions. In adjusted models, maternal socio-economic status (aOR 0.42, 95% CI 0.24-0.76) was associated with reduced odds of delayed gross-fine motor neurodevelopment. Maternal age ≥35 years (aOR 0.22, 95% CI 0.05-0.89) and maternal body mass index (BMI) <18.5 (aOR 6.76, 95% CI 1.06-43.13) were associated with delayed communication-problem-solving-personal-social neurodevelopment. There were no differences in odds for either domain by maternal ART initiation timing., Conclusions: Delayed neurodevelopment was detected in both gross and fine motor functions in this cohort of HEU children, with strong maternal predictors that may be explored as potentially modifiable factors associated with neurodevelopment at one to two years of age., Competing Interests: Co-author Landon Myer has served as an editor for PLOS ONE in the past. The authors confirm that this does not alter their adherence to all the PLOS ONE policies on sharing data and materials.

Curable sexually transmitted infections (STIs) including Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), and Trichomonas vaginalis (TV) are associated with adverse pregnancy outcomes. Partner notification is an important component of STI control as it has been shown to prevent re-infection and reduce infectious burden. Between October 2017 and February 2019, we conducted a cohort study of women attending antenatal care in Cape Town, South Africa. Self-collected vulvovaginal swabs were tested for CT, NG, and TV using Xpert® assays at first antenatal visit, during the third trimester, and postpartum. At the visit following a positive diagnosis, women were asked if they notified their partner and if their partner was treated. Among 242 participants, 97% reported being willing to notify partners if they tested positive and 78% thought their partner would be willing to treat the STI. Of the 73 women who were diagnosed with one or more STIs and reported having a sex partner, 93% reported notifying their partner and 63% reported their partner was treated. Younger maternal age was associated with partner notification and treatment (OR = 3.82; 95%CI = 1.34-10.90). Acceptability of partner notification was high in pregnant women, but partner treatment was low. Future interventions to improve partner notification and treatment are needed.

Objective: Mycoplasma genitalium (MG) is a sexually transmitted organism associated with cervicitis and pelvic inflammatory disease in women and has been shown to increase the risk of HIV acquisition and transmission. Little is known about the prevalence and incidence of MG in pregnant women. Our study sought to evaluate the prevalence and incidence of MG infection in HIV-infected and HIV-uninfected pregnant women., Methods: We conducted a cohort study of 197 women ≥18 years receiving antenatal care in South Africa from November 2017 to February 2019. We over-recruited HIV-infected pregnant women to compare MG by HIV infection status. Self-collected vaginal swabs, performed at the first antenatal visit, third trimester and within 1 week post partum, were tested for MG using the Aptima assay (Hologic, USA). We report on the prevalence and incidence of MG and used multivariable logistic regression to describe correlates of MG and adverse pregnancy and birth outcomes (preterm delivery, miscarriage and vertical HIV transmission), adjusting for maternal age and HIV infection status., Results: At first antenatal visit, the median age was 29 years (IQR=24-34) and the gestational age was 19 weeks (IQR=14-23); 47% of women enrolled in the study were HIV-infected. MG prevalence was 24% (95% CI 16% to 34%, n=22) in HIV-infected and 12% (95% CI 6.8% to 20%, n=13) in HIV-uninfected pregnant women. MG incidence during pregnancy and early post partum was 4.7 infections per 100 woman-years (95% CI 1.2 to 12.9) or 3.9 per 1000 woman-months (95% CI 1.0 to 10.7). Adjusting for maternal age, HIV-infected women had over three times the odds of being infected with MG (adjusted OR=3.09, 95% CI 1.36 to 7.06)., Conclusion: We found a high prevalence and incidence of MG in pregnant women. Younger maternal age and HIV infection were associated with MG infection in pregnancy. Further research into birth outcomes of women infected with MG, including vertical transmission of HIV infection, is needed., Competing Interests: Competing interests: We received STI testing kits from Cepheid and Hologic., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Postpartum HIV care retention rates are well below retention rates of the general adult population. The Maternal-Child Health Antiretroviral Therapy (MCH-ART) trial tested the benefit of integrating postpartum maternal ART and pediatric care through the end of breastfeeding compared to the standard of care of immediate postpartum referral of mother and infant to separate services. After the trial, twenty-one participants completed in-depth interviews to understand the acceptability of the service integration and the potentially differing "lived" experiences of the women randomized to the two conditions. Key findings include: (1) the MCH-ART integrated service was found to be acceptable, (2) women in the intervention condition expressed more negative feelings around the need to be transferred to general ART services and (3) women in the intervention condition perceived that they had more influence in selecting the clinic to which they would be transferred compared to those in the control group, although there was no actual difference by study design. Future work should more directly evaluate the impact of shared decision-making and long-term relationships with clinic staff on patient engagement and retention in HIV care.

Background: Improving maternal antiretroviral therapy (ART) retention and adherence is a critical challenge facing prevention of mother-to-child transmission (PMTCT) of HIV programs. There is an urgent need for evidence-based, cost-effective, and scalable interventions to improve maternal adherence and retention that can be feasibly implemented in overburdened health systems. Brief video-based interventions are a promising but underutilized approach to this crisis. We describe a trial protocol to evaluate the effectiveness and implementation of a standardized educational video-based intervention targeting HIV-infected pregnant women that seeks to optimize their ART retention and adherence by providing a VITAL Start (Video intervention to Inspire Treatment Adherence for Life) before committing to lifelong ART., Methods: This study is a multisite parallel group, randomized controlled trial assessing the effectiveness of a brief facility-based video intervention to optimize retention and adherence to ART among pregnant women living with HIV in Malawi. A total of 892 pregnant women living with HIV and not yet on ART will be randomized to standard-of-care pre-ART counseling or VITAL Start. The primary outcome is a composite of retention and adherence (viral load < 1000 copies/ml) 12 months after starting ART. Secondary outcomes include assessments of behavioral adherence (self-reported adherence, pharmacy refill, and tenofovir diphosphate concentration), psychosocial impact, and resource utilization. We will also examine the implementation of VITAL Start via surveys and qualitative interviews with patients, partners, and health care workers and conduct cost-effectiveness analyses., Discussion: This is a robust evaluation of an innovative facility-based video intervention for pregnant women living with HIV, with the potential to improve maternal and infant outcomes., Trial Registration: ClinicalTrials.gov, NCT03654898. Registered on 31 August 2018.

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.

Introduction: HIV incidence is high during pregnancy and breastfeeding with HIV acquisition risk more than doubling during pregnancy and the postpartum period compared to when women are not pregnant. The World Health Organization recommends offering pre-exposure prophylaxis (PrEP) to pregnant and postpartum women at substantial risk of HIV infection. However, maternal PrEP national guidelines differ and most countries with high maternal HIV incidence are not offering PrEP. We conducted a systematic review of recent research on PrEP safety in pregnancy to inform national policy and rollout., Methods: We used a standard Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) approach to conduct a systematic review by searching for completed, ongoing, or planned PrEP in pregnancy projects or studies from clinicaltrials.gov, PubMed and NIH RePORTER from 2014 to March 2019. We performed a systematic review of studies that assess tenofovir disoproxil fumarate (TDF)-based oral PrEP safety in pregnant and breastfeeding HIV-uninfected women., Results and Discussion: We identified 14 completed (n = 5) and ongoing/planned (n = 9) studies that evaluate maternal and/or infant outcomes following PrEP exposure during pregnancy or breastfeeding. None of the completed studies found differences in pregnancy or perinatal outcomes associated with PrEP exposure. Nine ongoing studies, to be completed by 2022, will provide data on >6200 additional PrEP-exposed pregnancies and assess perinatal, infant growth and bone health outcomes, expanding by sixfold the data on PrEP safety in pregnancy. Research gaps include limited data on (1) accurately measured PrEP exposure within maternal and infant populations including drug levels needed for maternal protection; (2) uncommon perinatal outcomes (e.g. congenital anomalies); (3) infant outcomes such as bone growth beyond one year following PrEP exposure; (4) outcomes in HIV-uninfected women who use PrEP during pregnancy and/or lactation., Conclusions: Expanding delivery of PrEP is an essential strategy to reduce HIV incidence in pregnancy and breastfeeding women. Early safety studies of PrEP among pregnant women without HIV infection are reassuring and ongoing/planned studies will contribute extensive new data to bolster the safety profile of PrEP use in pregnancy. However, addressing research gaps is essential to expanding PrEP delivery for women in the context of pregnancy., (© 2020 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Objectives: The coverage of prevention of mother-to-child transmission (PMTCT) services in South Africa is variable. Identifying gaps in the implementation of these services is necessary to isolate steps needed to further reduce paediatric infections and eliminate transmission., Setting: Two primary care clinics in Paarl, South Africa., Participants: 1225 pregnant women; inclusion criteria were 18 years or older, clinic attendance and remaining in area for at least 1 year., Methods: Data were collected through the Drakenstein Child Health Study, a population-based birth cohort in a periurban area of the Western Cape, South Africa. A combination of clinic records, hospital records, national database searches and maternal self-report were collected during the study., Results: Of the 1225 mothers enrolled in the cohort between 2012 and 2015, 260 (21%) were confirmed HIV infected antenatally and 1 mother tested positive in the postnatal period. Of those with documentation (n=250/260, 96%), the majority (99%) received antiretroviral prophylaxis or therapy (ART) before labour; however, there was a high rate of defaulting from ART noted during pregnancy (20%). All HIV-exposed infants with data received antiretroviral prophylaxis, 35% were exclusively breast fed until 6 weeks and 16% for 6 months. There were two cases of infant HIV infection (0.8%) who were initiated on ART but had complicated histories., Conclusion: Despite the low transmission rate in this cohort, reaching elimination will require further work, and this study illustrates several areas to improve implementation of PMTCT services and reduce paediatric infections including retesting at-risk HIV-negative mothers through the duration of breast feeding, infant HIV testing at any admission in addition to routine testing and improved counselling to prevent defaulting from treatment. Better data surveillance systems are essential for determining the implementation of PMTCT guidelines., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Background: HIV infection is known to cause developmental delay, but the effects of HIV exposure without infection during pregnancy on child development are unclear. We compared the neurodevelopmental outcomes of HIV-exposed uninfected and HIV-unexposed children during their first 2 years of life., Methods: Pregnant women (>18 years of age) at 20-28 weeks' gestation were enrolled into the Drakenstein Child Health cohort study while attending routine antenatal appointments at one of two peri-urban community-based clinics in Paarl, South Africa. Livebirths born to enrolled women during follow-up were included in the birth cohort. Mothers and infants received antenatal and postnatal HIV testing and antiretroviral therapy per local guidelines. Developmental assessments on the Bayley Scales of Infant and Toddler Development, third edition (BSID-III), were done in a subgroup of infants at 6 months of age, and in the full cohort at 24 months of age, with assessors masked to HIV exposure status. Mean raw scores and the proportions of children categorised as having a delay (scores <-2 SDs from the reference mean) on BSID-III were compared between HIV-exposed uninfected and HIV-unexposed children., Findings: 1225 women were enrolled between March 5, 2012, and March 31, 2015. Of 1143 livebirths, 1065 (93%) children were in follow-up at 6 months and 1000 (87%) at 24 months. Two children were diagnosed with HIV infection between birth and 24-month follow-up and were excluded from the analysis. BSID-III assessments were done in 260 (24%) randomly selected children (61 HIV-exposed uninfected, 199 HIV-unexposed) at 6 months and in 732 (73%) children (168 HIV-exposed uninfected, 564 HIV-unexposed) at 24 months. All HIV-exposed uninfected children were exposed to antiretrovirals (88% to maternal triple antiretroviral therapy). BSID-III outcomes did not significantly differ between HIV-exposed uninfected and HIV-unexposed children at 6 months. At 24 months, HIV-exposed uninfected children scored lower than HIV-unexposed for receptive language (adjusted mean difference -1·03 [95% CI -1·69 to -0·37]) and expressive language (-1·17 [-2·09 to -0·24]), whereas adjusted differences in cognitive (-0·45 [-1·32 to 0·43]), fine motor (0·09 [-0·49 to 0·66]), and gross motor (-0·41 [-1·09 to 0·27]) domain scores between groups were not significant. Correspondingly, the proportions of HIV-exposed uninfected children with developmental delay were higher than those of HIV-unexposed children for receptive language (adjusted odds ratio 1·96 [95% CI 1·09 to 3·52]) and expressive language (2·14 [1·11 to 4·15])., Interpretation: Uninfected children exposed to maternal HIV infection and antiretroviral therapy have increased odds of receptive and expressive language delays at 2 years of age. Further long-term work is needed to understand developmental outcomes of HIV-exposed uninfected children, especially in regions such as sub-Saharan Africa that have a high prevalence of HIV exposure among children., Funding: Bill & Melinda Gates Foundation, SA Medical Research Council, Wellcome Trust., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: Recruitment and retention present major challenges to longitudinal research in maternal and child health, yet there are few insights into optimal strategies that can be employed in low-resource settings. Following prior participation in a longitudinal study following women living with HIV through pregnancy and breastfeeding in Cape Town, women were re-contacted at least 18 months after the last study contact and were invited to attend an additional follow-up visit. We describe lessons learnt and offer recommendations for a multiphase recruitment approach., Results: Using telephone calls, home visits, clinic tracing and Facebook/WhatsApp messages, we located 387 of the 463 eligible women and successfully enrolled 353 (91% of those contacted). Phone calls were the most successful strategy, yielding 67% of enrolments. Over half of the women had changed their contact information since participation in the previous study. We recommend that researchers collect multiple contact details and use several recruitment strategies in parallel from the start of a study. Participants in longitudinal studies may require frequent contact to update contact information, particularly in settings where mobility is common.

Objectives: Sexually transmitted infections (STIs) are associated with adverse outcomes in pregnancy, including mother-to-child HIV transmission. Yet there are limited data on the prevalence and correlates of STI in pregnant women by HIV status in low- and middle-income countries, where syndromic STI management is routine., Methods: Between November 2017 and July 2018, we conducted a cross-sectional study of consecutive pregnant women making their first visit to a public sector antenatal clinic (ANC) in Cape Town. We interviewed women ≥18 years and tested them for Chlamydia trachomatis (CT), Neisseria gonorrhoea (NG) and Trichomonas vaginalis (TV) using Xpert assays (Cepheid, USA); results of syphilis serology came from routine testing records. We used multivariable logistic regression to identify correlates of STI in pregnancy., Results: In 242 women (median age 29 years [IQR = 24-34], median gestation 19 weeks [IQR = 14-24]) 44% were HIV-infected. Almost all reported vaginal sex during pregnancy (93%). Prevalence of any STI was 32%: 39% in HIV-infected women vs. 28% in HIV-uninfected women (p = 0.036). The most common infection was CT (20%) followed by TV (15%), then NG (5.8%). Of the 78 women diagnosed with a STI, 7 (9%) were identified and treated syndromically in ANC. Adjusting for age and gestational age, HIV-infection (aOR = 1.89; 95% CI = 1.02-3.67), being unmarried or not cohabiting with the fetus' father (aOR = 2.19; 95% CI = 1.16-4.12), and having STI symptoms in the past three days (aOR = 6.60; 95% CI = 2.08-20.95) were associated with STI diagnosis., Conclusion: We found a high prevalence of treatable STIs in pregnancy among pregnant women, especially in HIV-infected women. Few women were identified and treated in pregnancy., Competing Interests: The authors have declared that no competing interests exist.

Objective: HIV-uninfected pregnant and breastfeeding women are at high risk of HIV acquisition, contributing to vertical transmission of HIV. Preexposure prophylaxis (PrEP) is safe in pregnancy, but PrEP in pregnancy is not policy in many countries including South Africa. We evaluated the potential impact of providing PrEP for pregnant/breastfeeding women using a HIV model for South Africa., Methods: Our model considers two scenarios: a conservative scenario that matches the experience reported in the Kenyan PrEP programme for pregnant women (probability of uptake = 32% and 11% in high-risk and low-risk women, respectively); and an optimistic scenario with PrEP initiated by 80% of all pregnant women. We compared this with PrEP for female sex workers, MSM and adolescent girls/young women. Women are assumed to remain on PrEP throughout pregnancy and breastfeeding, and an equivalent average PrEP duration (2 years) is assumed in other scenarios., Results: Between 2020 and 2030, if PrEP is provided to pregnant/breastfeeding mothers, we project a 2.5% reduction in total HIV transmission [95% credibility interval (CI): 2.4-2.6%] in the conservative scenario and 7.2% (95% CI: 6.8-7.5%) in the optimistic scenario, which is similar to that in the female sex worker and MSM PrEP scenarios (1.9% and 3.0%, respectively). Without PrEP, 76 000 (95% CI: 64 000-90 000) new cases of vertical transmission are expected; PrEP provision may reduce these infections by 13% (95% CI: 13-14%) in the conservative scenario and 41% (95% CI: 39-44%) in the optimistic scenario., Conclusion: High levels of uptake of and adherence to PrEP among pregnant/breastfeeding women could substantially reduce maternal and infant HIV acquisition in South Africa.

Introduction : The advent of policies promoting lifelong antiretroviral therapy (ART) for all pregnant and postpartum women living with HIV has shifted focus from short-term prevention of mother-to-child transmission (PMTCT) to lifelong engagement in ART services. However, disengagement from care threatens the long-term treatment and prevention benefits of lifelong ART. Areas covered : A framework for considering the unique aspects of ART for pregnant and postpartum women is presented along with a review of the literature on maternal engagement in care in sub-Saharan Africa and a discussion of potential interventions to sustain engagement in lifelong ART. Expert opinion : Engaging women and mothers in ART services for life is critical for maternal health, PMTCT, and prevention of sexual transmission. Evidence-based interventions exist to support engagement in care but most focus on periods of mother-to-child transmission risk. In the long term, life transitions and health-care transfers are inevitable. Thus, interventions that can reach beyond a single facility or provide a bridge between health services should be prioritized. Multicomponent interventions will also be essential to address the numerous intersecting barriers to sustained engagement in ART services.

Background: Prevention of mother-to-child transmission (PMTCT) across sub-Saharan Africa has rapidly shifted towards Option B+, an approach in which all HIV+ pregnant and breastfeeding women initiate lifelong antiretroviral therapy (ART) independent of CD4+ count. Healthcare workers (HCW) are critical to the success of Option B+, yet little is known regarding HCW acceptability of Option B+, particularly over time., Methods: Ten health facilities in the Manzini and Lubombo regions of eSwatini transitioned from Option A to Option B+ between 2013 and 2014 as part of the Safe Generations study examining PMTCT retention. Fifty HCWs (5 per facility) completed questionnaires assessing feasibility and acceptability: (1) prior to transitioning to Option B+, (2) two months post transition, and (3) approximately 2 years post Option B+ transition. This analysis describes HCW perceptions and experiences two years after transitioning to Option B+., Results: Two years after transition, 80% of HCWs surveyed reported that Option B+ was easy for HCWs, noting that it was particularly easy to explain and coordinate. Immediate ART initiation also reduced delays by eliminating need for laboratory tests prior to ART initiation. Additionally, HCWs reported ease of patient follow-up (58%), documentation (56%), and counseling (58%) under Option B+. Findings also indicate that a majority of HCWs reported that their workloads increased under Option B+. Sixty-eight percent of HCWs at two years post-transition reported more work under Option B+, specifically noting increased involvement in adherence counseling, prescribing/monitoring medications, and appointment scheduling/tracking. Some HCWs attributed their higher workloads to increased client loads, now that all HIV-positive women were initiated on ART. New barriers to patient uptake, and issues related to retention, adherence, and follow-up were also noted as challenges face by HCW when implementing Option B+., Conclusions: Overall, HCWs found Option B+ to be acceptable and feasible while providing critical insights into the practical issues of universal ART. Further strengthening of the healthcare system may be necessary to alleviate worker burden and to ensure effective monitoring of client retention and adherence. HCW perceptions and experiences with Option B+ should be considered more broadly as countries implement Option B+ and consider universal treatment for all HIV+ individuals., Trial Registration: http://clinicaltrials.gov NCT01891799 , registered on July 3, 2013.

Objective: Unintended pregnancies are common among women living with HIV, but there are no data on their long-term impact on treatment outcomes. In a cohort of women initiating antiretroviral therapy (ART) during pregnancy, we examined the association between the intendedness of the current pregnancy, measured antenatally, and elevated viral load up to 5 years postpartum., Design: Prospective study with enrolment at entry into antenatal care and follow-up at study visits separate from routine care., Methods: At enrolment women completed the London Measure of Unplanned Pregnancy. Mixed effects models examined the impact of the intendedness of the pregnancy (planned versus each of unplanned or ambivalent, respectively) on viral load 50 or more copies/ml across postpartum study visits., Results: Overall, 459 women were followed for a median of 43 months postpartum, contributing 2535 viral load measures (median per woman: 6). Ambivalent and unplanned pregnancy were commonly reported (20 and 60%, respectively), and the proportion of women with elevated viral load increased over time (16% at 6 weeks to 43% by 36-60 months postpartum). Compared with those reporting a planned pregnancy, elevated viral load was more common among women reporting an unplanned pregnancy (odds ratio: 2.87; 95% confidence interval: 1.46-5.64), with a trend towards a higher odds among those reporting ambivalence (odds ratio: 2.19; 95% confidence interval: 0.97-4.82); associations persisted after adjustment for a wide range of demographic, clinical and psychosocial factors., Conclusion: These novel data suggest that unplanned pregnancy may be a prevalent and persistent predictor of poor ART outcomes among women initiating ART during pregnancy.