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

PLOS ONE RESEARCH ARTICLE Maternal biomarkers of endothelial dysfunction and pregnancy outcomes in women with and without HIV in Botswana Gaerolwe Masheto ID1,2*, Sikhulile Moyo1,2,3, Terence Mohammed1, Christine Banda1, Charlene Raphaka1, Gloria Mayondi1, Joseph Makhema1,2, Roger Shapiro1,2,4, Mosepele Mosepele1,2,5, Rebecca Zash1,6,7, Shahin Lockman1,2,6,7 a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 1 Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana, 2 Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, United States of America, 3 Faculty of Health Sciences, School of Allied Health Professions, University of Botswana, Gaborone, Botswana, 4 Beth Israel Deaconess Medical Center, Boston, MA, United States of America, 5 Faculty of Medicine, University of Botswana, Gaborone, Botswana, 6 Brigham and Women’s Hospital, Boston, MA, United States of America, 7 Harvard Medical School, Boston, MA, United States of America * Abstract OPEN ACCESS Citation: Masheto G, Moyo S, Mohammed T, Banda C, Raphaka C, Mayondi G, et al. (2023) Maternal biomarkers of endothelial dysfunction and pregnancy outcomes in women with and without HIV in Botswana. PLoS ONE 18(2): e0281910. https://doi.org/10.1371/journal.pone.0281910 Editor: Ashish K. C., Uppsala University: Uppsala Universitet, SWEDEN Received: June 21, 2021 Accepted: February 5, 2023 Published: February 23, 2023 Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: https://doi.org/10.1371/journal.pone.0281910 Copyright: © 2023 Masheto 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. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Background Women living with HIV-1 (WLHIV) are at higher risk of having an adverse birth outcome, but the underlying mechanism(s) are unknown. We hypothesized that HIV-associated endothelial activation could adversely impact placental function and lead to impaired fetal growth or stillbirth. Methods We used stored samples from WLHIV and HIV-negative women who had enrolled during pregnancy in the observational Botswana Tshipidi cohort. Written informed consent was obtained from the participants. We measured plasma levels of markers of endothelial activation (soluble vascular adhesion molecule 1 [VCAM-1], intercellular adhesion molecule 1 [ICAM-1] and E-selectin) from samples taken during pregnancy. We compared log10 biomarker levels by maternal HIV status and by the timing of ART initiation (ART prior to conception vs. during pregnancy; ART prior to sample collection vs. no ART prior to sampling) using t-tests and the Kruskal-Wallis rank test. We evaluated the association between these biomarkers and adverse birth outcomes (composite of stillbirth or small for gestational age [SGA]) using univariate and multivariate log-binomial regression controlling for maternal age (continuous) and timing of ART start. We also used generalized linear models (GLM) to evaluate the association between continuous birthweight (in grams) and gestational age (in weeks) and markers of endothelial dysfunction, adjusting for maternal age (continuous) and timing of ART relative to sample collection. Results Specimens collected before delivery were available for 414 women (372 WLHIV and 42 HIV-negative women), with a median age of 28 years and median gestational age at sample PLOS ONE | https://doi.org/10.1371/journal.pone.0281910 February 23, 2023 1 / 10 PLOS ONE Funding: Dr. Gaerolwe Masheto was supported by the Harvard University Center for AIDS Research (CFAR), an NIH-funded program (P30 AI060354), which is supported by the following NIH CoFunding and Participating Institutes and Centers: National Institute of Allergy and Infectious Diseases, National Cancer Institute, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Heart, Lung, and Blood Institute, National Institute on Drug Abuse, National Institute of Mental Health, National Institute on Aging, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of General Medical Sciences, National Institute on Minority Health and Health Disparities, National Institute of Dental and Craniofacial Research, Office of AIDS Research, and Fogarty International Center. Dr. Sikhulile Moyo was partially supported through the Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE 2.0), by Bill and Melinda Gates Foundation (INV-033558) and the National Institutes of Health NIH Fogarty International Center K43 TW012350-01. Dr. Shahin Lockman was supported by the National Institutes of Health NIH/ National Institute of Allergy and Infectious Diseases K24 mentoring grant - NIH K24 AI131928. Competing interests: The authors have declared that no compering interest exist. Maternal biomarkers of endothelial dysfunction and pregnancy outcomes in women with and without HIV collection of 30 weeks (range 26, 35 weeks). WLHIV had significantly higher median VCAM1 (p = 0.002) than HIV-negative women, but HIV-negative women had higher median ICAM1 (p = 0.01); e-Selectin levels did not differ by maternal HIV status. Women starting ART during pregnancy had higher log10 VCAM1 levels than those on ART before conception, regardless of whether the sample was collected before (p = 0.02) or after (p = 0.03) ART initiation. However, ICAM1 and e-Selectin did not differ significantly by ART status or ART timing. Ninety-eight women (91 WLHIV and 7 HIV-negative), or 9 (2%) and 89 (22%) included in this study, had a stillborn or SGA baby respectively. Univariate and adjusted analyses did not show significant associations between levels of any of the biomarkers with these adverse birth outcomes. However, lower birthweight (p = 0.03) and lower gestational age at delivery were associated e-Selectin and ICAM (p = 0.008), respectively. Conclusion Maternal HIV infection and lack of ART (or recent ART initiation) were associated with one marker of greater endothelial activation (VCAM-1), but not with other markers (ICAM-1 nor E-selectin) in pregnancy. e-Selectin was associated with lower birthweight and every unit increase in log ICAM-1 at delivery was associated with lower gestation age at delivery. Introduction Increased access to 3-drug antiretroviral therapy (ART) during pregnancy has dramatically reduced new pediatric HIV infections globally and has improved maternal health [1–4]. However, women living with HIV (WLHIV) who take ART are at significantly higher risk of having a (...truncated)