Publications by authors named "Jeffrey S A Stringer"

167 Publications

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

Lancet HIV 2021 Sep 9. Epub 2021 Sep 9.

Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, NC, USA.

Background: Women with HIV face an increased risk of preterm birth. 17 alpha-hydroxyprogesterone caproate (17P) has been shown in some trials to reduce early delivery among women with a history of spontaneous preterm birth. We investigated whether 17P would reduce this risk among women with HIV.

Methods: We did a randomised, double-blind, placebo-controlled trial in pregnant women with HIV at the University Teaching Hospital and Kamwala District Health Centre in Lusaka, Zambia. Eligible patients were women aged 18 years or older with confirmed HIV-1 infection, viable intrauterine singleton pregnancy at less than 24 weeks of gestation, and were receiving or intending to commence antiretroviral therapy during pregnancy. Exclusion criteria were major uterine or fetal anomaly; planned or in situ cervical cerclage; evidence of threatened miscarriage, preterm labour, or ruptured membranes at screening; medical contraindication to 17P; previous participation in the trial; or history of spontaneous preterm birth. Eligible participants provided written informed consent and were randomly assigned (1:1) to receive 250 mg intramuscular 17P or placebo once per week, starting between 16 and 24 weeks of gestation until delivery, stillbirth, or reaching term (37 weeks). Participants and study staff were masked to assignment, except for pharmacy staff who did random assignment and prepared injections but did not interact with participants. The primary outcome was a composite of delivery before 37 weeks or stillbirth at any gestational age. Patients attended weekly visits for study drug injections and antenatal care. We estimated the absolute and relative difference in risk of the primary outcome and safety events between treatment groups by intention to treat. This trial is registered with ClinicalTrials.gov, NCT03297216, and is complete.

Findings: Between Feb 7, 2018 and Jan 13, 2020, we assessed 1042 women for inclusion into the study. 242 women were excluded after additional assessments, and 800 eligible patients were enrolled and randomly assigned to receive intramuscular 17P (n=399) or placebo (n=401). Baseline characteristics were similar between groups. Adherence to study drug injections was 98% in both groups, no patients were lost to follow-up, and the final post-partum visit was on Aug 6, 2020. 36 (9%) of 399 participants assigned to 17P had preterm birth or stillbirth, compared with 36 (9%) of 401 patients assigned to placebo (risk difference 0·1, 95% CI -3·9 to 4·0; relative risk 1·0, 95% CI 0·6 to 1·6; p=0·98). Intervention-related adverse events were reported by 140 (18%) of 800 participants and occurred in similar proportions in both randomisation groups. No serious adverse events were reported.

Interpretation: Although 17P seems to be safe and acceptable to participants, available data do not support the use of the drug to prevent preterm birth among women whose risk derives solely from HIV infection. The low risk of preterm birth in both randomisation groups warrants further investigation.

Funding: US National Institutes of Health and the Bill and Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S2352-3018(21)00150-8DOI Listing
September 2021

Association of mid-trimester maternal angiogenic biomarkers with small-for-gestational-age infants in an urban Zambian cohort: a nested case-control study.

Int J Gynaecol Obstet 2021 Aug 6. Epub 2021 Aug 6.

University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Objective: To investigate whether angiogenic biomarker concentrations differ between women who deliver small-for-gestational-age (SGA) infants (<10th centile birth weight for gestational age) compared with controls, because identifying SGA risk early could improve outcomes.

Methods: This case-control study compared serum concentrations of angiogenic biomarkers before 24 weeks of pregnancy from 62 women who delivered SGA infants (cases) and 62 control women from an urban Zambian cohort. Odds of delivering an SGA infant were calculated using conditional logistic regression.

Results: Placental growth factor (PlGF), soluble fms-like tyrosine kinase (sFLT-1) and soluble endoglin (sEng) in controls were 37.74 pg/mL (interquartile range [IQR] 23.12-63.15), 2525.18 pg/mL (IQR 1502.21-4265.54) and 2408.18 pg/mL (IQR 1854.87-3017.94), respectively. SGA cases had higher PlGF (40.50 pg/mL, IQR 22.81-67.94) and sFLT-1 (2613.06 pg/mL, IQR 1720.58-3722.50), and lower sEng (2038.06 pg/mL, IQR 1445.25-3372.26). Participants with sEng concentration below and concomitant sFLT-1 concentration above their respective thresholds (n = 40) had five-fold higher odds of SGA (adjusted odds ratio 4.77, 95% confidence interval 1.61-14.1; P = 0.005).

Conclusion: Biomarker concentrations were similar between cases and controls. Participants with concomitant low sEng and high sFLT-1 had the highest odds of SGA, suggesting that a combination of biomarkers may better for predicting SGA than single biomarkers.
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http://dx.doi.org/10.1002/ijgo.13860DOI Listing
August 2021

Circulating angiogenic factors and HIV among pregnant women in Zambia: a nested case-control study.

BMC Pregnancy Childbirth 2021 Jul 28;21(1):534. Epub 2021 Jul 28.

Division of Global Women's Health, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Background: Maternal HIV increases the risk of adverse birth outcomes including preterm birth, fetal growth restriction, and stillbirth, but the biological mechanism(s) underlying this increased risk are not well understood. We hypothesized that maternal HIV may lead to adverse birth outcomes through an imbalance in angiogenic factors involved in the vascular endothelial growth factor (VEGF) signaling pathway.

Methods: In a case-control study nested within an ongoing cohort in Zambia, our primary outcomes were serum concentrations of VEGF-A, soluble endoglin (sEng), placental growth factor (PlGF), and soluble fms-like tyrosine kinase-1 (sFLT-1). These were measured in 57 women with HIV (cases) and 57 women without HIV (controls) before 16 gestational weeks. We used the Wilcoxon rank-sum and linear regression controlling for maternal body mass index (BMI) and parity to assess the difference in biomarker concentrations between cases and controls. We also used logistic regression to test for associations between biomarker concentration and adverse pregnancy outcomes (preeclampsia, preterm birth, small for gestational age, stillbirth, and a composite of preterm birth or stillbirth).

Results: Compared to controls, women with HIV had significantly lower median concentrations of PlGF (7.6 vs 10.2 pg/mL, p = 0.02) and sFLT-1 (1647.9 vs 2055.6 pg/mL, p = 0.04), but these findings were not confirmed in adjusted analysis. PlGF concentration was lower among women who delivered preterm compared to those who delivered at term (6.7 vs 9.6 pg/mL, p = 0.03) and among those who experienced the composite adverse birth outcome (6.2 vs 9.8 pg/mL, p = 0.02). Median sFLT-1 concentration was lower among participants with the composite outcome (1621.0 vs 1945.9 pg/mL, p = 0.04), but the association was not significant in adjusted analysis. sEng was not associated with either adverse birth outcomes or HIV. VEGF-A was undetectable by Luminex in all specimens.

Conclusions: We present preliminary findings that HIV is associated with a shift in the VEGF signaling pathway in early pregnancy, although adjusted analyses were inconclusive. We confirm an association between angiogenic biomarkers and adverse birth outcomes in our population. Larger studies are needed to further elucidate the role of HIV on placental angiogenesis and adverse birth outcomes.
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http://dx.doi.org/10.1186/s12884-021-03965-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317322PMC
July 2021

Comprehensive pregnancy monitoring with a network of wireless, soft, and flexible sensors in high- and low-resource health settings.

Proc Natl Acad Sci U S A 2021 May;118(20)

Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;

Vital signs monitoring is a fundamental component of ensuring the health and safety of women and newborns during pregnancy, labor, and childbirth. This monitoring is often the first step in early detection of pregnancy abnormalities, providing an opportunity for prompt, effective intervention to prevent maternal and neonatal morbidity and mortality. Contemporary pregnancy monitoring systems require numerous devices wired to large base units; at least five separate devices with distinct user interfaces are commonly used to detect uterine contractility, maternal blood oxygenation, temperature, heart rate, blood pressure, and fetal heart rate. Current monitoring technologies are expensive and complex with implementation challenges in low-resource settings where maternal morbidity and mortality is the greatest. We present an integrated monitoring platform leveraging advanced flexible electronics, wireless connectivity, and compatibility with a wide range of low-cost mobile devices. Three flexible, soft, and low-profile sensors offer comprehensive vital signs monitoring for both women and fetuses with time-synchronized operation, including advanced parameters such as continuous cuffless blood pressure, electrohysterography-derived uterine monitoring, and automated body position classification. Successful field trials of pregnant women between 25 and 41 wk of gestation in both high-resource settings ( = 91) and low-resource settings ( = 485) demonstrate the system's performance, usability, and safety.
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http://dx.doi.org/10.1073/pnas.2100466118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157941PMC
May 2021

An automated framework for image classification and segmentation of fetal ultrasound images for gestational age estimation.

Proc SPIE Int Soc Opt Eng 2021 Feb 15;11596. Epub 2021 Feb 15.

Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill.

Accurate assessment of fetal gestational age (GA) is critical to the clinical management of pregnancy. Industrialized countries rely upon obstetric ultrasound (US) to make this estimate. In low- and middle- income countries, automatic measurement of fetal structures using a low-cost obstetric US may assist in establishing GA without the need for skilled sonographers. In this report, we leverage a large database of obstetric US images acquired, stored and annotated by expert sonographers to train algorithms to classify, segment, and measure several fetal structures: biparietal diameter (BPD), head circumference (HC), crown rump length (CRL), abdominal circumference (AC), and femur length (FL). We present a technique for generating raw images suitable for model training by removing caliper and text annotation and describe a fully automated pipeline for image classification, segmentation, and structure measurement to estimate the GA. The resulting framework achieves an average accuracy of 93% in classification tasks, a mean Intersection over Union accuracy of 0.91 during segmentation tasks, and a mean measurement error of 1.89 centimeters, finally leading to a 1.4 day mean average error in the predicted GA compared to expert sonographer GA estimate using the Hadlock equation.
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http://dx.doi.org/10.1117/12.2582243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086527PMC
February 2021

Wireless skin sensors for physiological monitoring of infants in low-income and middle-income countries.

Lancet Digit Health 2021 04 24;3(4):e266-e273. Epub 2021 Feb 24.

Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, USA; Department of Chemistry, Northwestern University, Evanston, IL, USA; Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, USA; Department of Materials Science and Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, USA; Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. Electronic address:

Globally, neonatal mortality remains unacceptability high. Physiological monitoring is foundational to the care of these vulnerable patients to assess neonatal cardiopulmonary status, guide medical intervention, and determine readiness for safe discharge. However, most existing physiological monitoring systems require multiple electrodes and sensors, which are linked to wires tethered to wall-mounted display units, to adhere to the skin. For neonates, these systems can cause skin injury, prevent kangaroo mother care, and complicate basic clinical care. Novel, wireless, and biointegrated sensors provide opportunities to enhance monitoring capabilities, reduce iatrogenic injuries, and promote family-centric care. Early validation data have shown performance equivalent to (and sometimes exceeding) standard-of-care monitoring systems in premature neonates cared for in high-income countries. The reusable nature of these sensors and compatibility with low-cost mobile phones have the future potential to enable substantially lower monitoring costs compared with existing systems. Deployment at scale, in low-income countries, holds the promise of substantial improvements in neonatal outcomes.
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http://dx.doi.org/10.1016/S2589-7500(21)00001-7DOI Listing
April 2021

Maternal HIV Infection and Spontaneous Versus Provider-Initiated Preterm Birth in an Urban Zambian Cohort.

J Acquir Immune Defic Syndr 2021 06;87(2):860-868

University of North Carolina Global Projects Zambia, Lusaka, Zambia; and.

Objective: We investigated the effect of maternal HIV and its treatment on spontaneous and provider-initiated preterm birth (PTB) in an urban African cohort.

Methods: The Zambian Preterm Birth Prevention Study enrolled pregnant women at their first antenatal visit in Lusaka. Participants underwent ultrasound, laboratory testing, and clinical phenotyping of delivery outcomes. Key exposures were maternal HIV serostatus and timing of antiretroviral therapy initiation. We defined the primary outcome, PTB, as delivery between 16 and 37 weeks' gestational age, and differentiated spontaneous from provider-initiated parturition.

Results: Of 1450 pregnant women enrolled, 350 (24%) had HIV. About 1216 (84%) were retained at delivery, 3 of whom delivered <16 weeks. Of 181 (15%) preterm deliveries, 120 (66%) were spontaneous, 56 (31%) were provider-initiated, and 5 (3%) were unclassified. In standardized analyses using inverse probability weighting, maternal HIV increased the risk of spontaneous PTB [RR 1.68; 95% confidence interval (CI): 1.12 to 2.52], but this effect was mitigated on overall PTB [risk ratio (RR) 1.31; 95% CI: 0.92 to 1.86] owing to a protective effect against provider-initiated PTB. HIV reduced the risk of preeclampsia (RR 0.32; 95% CI: 0.11 to 0.91), which strongly predicted provider-initiated PTB (RR 17.92; 95% CI: 8.13 to 39.53). The timing of antiretroviral therapy start did not affect the relationship between HIV and PTB.

Conclusion: The risk of HIV on spontaneous PTB seems to be opposed by a protective effect of HIV on provider-initiated PTB. These findings support an inflammatory mechanism underlying HIV-related PTB and suggest that published estimates of PTB risk overall underestimate the risk of spontaneous PTB.
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http://dx.doi.org/10.1097/QAI.0000000000002654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131221PMC
June 2021

Performance Enhanced Ultrasound Probe Tracking With a Hemispherical Marker Rigid Body.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 06 25;68(6):2155-2163. Epub 2021 May 25.

Among tracking techniques applied in the 3-D freehand ultrasound (US), the camera-based tracking method is relatively mature and reliable. However, constrained by manufactured marker rigid bodies, the US probe is usually limited to operate within a narrow rotational range before occlusion issues affect accurate and robust tracking performance. Thus, this study proposed a hemispherical marker rigid body to hold passive noncoplanar markers so that the markers could be identified by the camera, mitigating self-occlusion. The enlarged rotational range provides greater freedom for sonographers while performing examinations. The single-axis rotational and translational tracking performances of the system, equipped with the newly designed marker rigid body, were investigated and evaluated. Tracking with the designed marker rigid body achieved high tracking accuracy with 0.57° for the single-axis rotation and 0.01 mm for the single-axis translation for sensor distance between 1.5 and 2 m. In addition to maintaining high accuracy, the system also possessed an enhanced ability to capture over 99.76% of the motion data in the experiments. The results demonstrated that with the designed marker rigid body, the missing data were remarkably reduced from over 15% to less than 0.5%, which enables interpolation in the data postprocessing. An imaging test was further conducted, and the volume reconstruction of a four-month fetal phantom was demonstrated using the motion data obtained from the tracking system.
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http://dx.doi.org/10.1109/TUFFC.2021.3058145DOI Listing
June 2021

Metabolic gestational age assessment in low resource settings: a validation protocol.

Gates Open Res 2020 28;4:150. Epub 2021 Jan 28.

Clinical Epidemiology Program, Ottawa Health Research Institute, Ottawa, ON, Canada.

Preterm birth is the leading global cause of neonatal morbidity and mortality. Reliable gestational age estimates are useful for quantifying population burdens of preterm birth and informing allocation of resources to address the problem. However, evaluating gestational age in low-resource settings can be challenging, particularly in places where access to ultrasound is limited. Our group has developed an algorithm using newborn screening analyte values derived from dried blood spots from newborns born in Ontario, Canada for estimating gestational age within one to two weeks. The primary objective of this study is to validate a program that derives gestational age estimates from dried blood spot samples (heel-prick or cord blood) collected from health and demographic surveillance sites and population representative health facilities in low-resource settings in Zambia, Kenya, Bangladesh and Zimbabwe. We will also pilot the use of an algorithm to identify birth percentiles based on gestational age estimates and weight to identify small for gestational age infants. Once collected from local sites, samples will be tested by the Newborn Screening Ontario laboratory at the Children's Hospital of Eastern Ontario (CHEO) in Ottawa, Canada. Analyte values will be obtained through laboratory analysis for estimation of gestational age as well as screening for other diseases routinely conducted at Ontario's newborn screening program. For select conditions, abnormal screening results will be reported back to the sites in real time to facilitate counseling and future clinical management. We will determine the accuracy of our existing algorithm for estimation of gestational age in these newborn samples. Results from this research hold the potential to create a feasible method to assess gestational age at birth in low- and middle-income countries where reliable estimation may be otherwise unavailable.
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http://dx.doi.org/10.12688/gatesopenres.13155.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801859.2PMC
January 2021

Neurodevelopmental Outcomes of Children Following In Utero Exposure to Zika in Nicaragua.

Clin Infect Dis 2021 03;72(5):e146-e153

Department of Microbiology, Faculty of Medical Science, National Autonomous University of Nicaragua at León, Managua, Nicaragua.

Background: Neurodevelopmental outcomes of asymptomatic children exposed to Zika virus (ZIKV) in utero are not well characterized.

Methods: We prospectively followed 129 newborns without evidence of congenital Zika syndrome (CZS) up to 24 months of age. Participants were classified as ZIKV exposed or ZIKV unexposed. The Mullen Scales of Early Learning (MSEL) was administered in the participants' homes at 6, 12, 15, 18, 21, and 24 months of age by trained psychologists. Sociodemographic data, medical history, and infant anthropometry at birth were collected at each home visit. Our primary outcome was the Mullen Early Learning Composite Score (ECL) at 24 months of age between our 2 exposure groups. Secondary outcomes were differences in MSEL subscales over time and at 24 months.

Results: Of 129 infants in whom exposure status could be ascertained, 32 (24.8%) met criteria for in utero ZIKV exposure and 97 (75.2%) did not. There were no differences in maternal age, maternal educational attainment, birthweight, or gestational age at birth between the 2 exposure groups. The adjusted means and standard errors (SEs) for the ELC score between the ZIKV-exposed children compared to ZIKV-unexposed children were 91.4 (SE, 3.1) vs 96.8 (SE, 2.4) at 12 months and 93.3 (SE, 2.9) vs 95.9 (SE, 2.3) at 24 months. In a longitudinal mixed model, infants born to mothers with an incident ZIKV infection (P = .01) and low-birthweight infants (<2500 g) (P = .006) had lower composite ECL scores.

Conclusions: In this prospective cohort of children without CZS, children with in utero ZIKV exposure had lower neurocognitive scores at 24 months.
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http://dx.doi.org/10.1093/cid/ciaa1833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935385PMC
March 2021

Non-communicable Diseases in Pregnant and Postpartum Women Living with HIV: Implications for Health Throughout the Life Course.

Curr HIV/AIDS Rep 2021 02 5;18(1):73-86. Epub 2021 Jan 5.

Division of Infectious Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Ave 37-121 CHS, Los Angeles, CA, 90095, USA.

Purpose Of Review: The development of non-communicable diseases (NCDs) in pregnant women living with HIV can be a harbinger of future NCD-related morbidity and mortality. This review focuses on the NCDs that complicate pregnancy and the postpartum period, including hypertensive complications, hyperglycemic disorders, excessive gestational weight gain, and bone mineral density losses. For each disease process, we explore the role of HIV as a possible driver of excess risk, the immediate consequences of these complications on pregnancy outcomes and maternal and infant health, and possible implications for long-term women's health.

Recent Findings: Countries with the highest burden of HIV also shoulder a high burden of NCDs that complicate pregnancy, including hypertensive disorders, hyperglycemic disorders, weight gain, and osteopenia. This double burden of disease is a significant public health threat for reproductive-age women, with the potential for serious short- and long-term consequences for both women and their infants. Additionally, as the global first-line antiretroviral therapy regimens increasingly include integrase inhibitors, unhealthy weight gain associated with this drug class poses additional risk for NCD-related pregnancy complications and their persistence postpartum. Further research is needed to better define prevalence of NCD complications in pregnancy, elucidate HIV-specific and traditional factors associated with poor outcomes, and to develop interventions to reduce risk and avoid downstream complications in those at highest risk.
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http://dx.doi.org/10.1007/s11904-020-00539-6DOI Listing
February 2021

Maternal HIV, antiretroviral timing, and spontaneous preterm birth in an urban Zambian cohort: the role of local and systemic inflammation.

AIDS 2021 03;35(4):555-565

University of North Carolina at Chapel Hill, Chapel Hill, USA.

Objective: To assess plasma and vaginal inflammation in three antenatal groups (HIV-uninfected women, HIV-infected women entering care on preconceptional ART, and HIV-infected women not on preconceptional ART) and whether these measures are associated with spontaneous preterm birth (sPTB).

Design: Case--control study nested within a pregnancy cohort in Lusaka, Zambia.

Methods: We analyzed 11 pro-inflammatory and two anti-inflammatory markers in 207 women with paired plasma and vaginal specimens collected between 16 and 20 gestational weeks. Among 51 HIV-infected women, we repeated the assays in 24-34-week samples. We used confirmatory factor analysis to create inflammation scores and compared them among the three groups.

Results: At baseline, HIV-infected women not on ART had higher vaginal pro-inflammatory scores than HIV-uninfected women [mean 0.37 (95% CI -0.06 to 0.80) vs. -0.02 (-0.32 to 0.27), P = 0.02]. In repeat testing, women not on preconceptional ART had an increase in vaginal inflammation between the baseline and 24-34-week visits compared with those continuing preconceptional ART [mean 0.62 (95% CI -0.80 to 4.20) vs. -0.07 (-2.78 to 2.11), P = 0.04]. In multivariate analyses, baseline vaginal inflammation predicted sPTB (aOR 1.5; 95% CI 1.0-2.3; P = 0.02). Plasma inflammation did not differ by HIV or ART exposure and was not associated with sPTB.

Conclusion: Women not receiving ART at entry into pregnancy care had more vaginal inflammation than women entering on treatment. They also experienced an increase in vaginal inflammation between the two sampling timepoints, possibly as a consequence of ART initiation. Vaginal (but not systemic) inflammation was associated with sPTB and offers a potential mechanistic insight into this important adverse birth outcome.
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http://dx.doi.org/10.1097/QAD.0000000000002808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944942PMC
March 2021

Antenatal Glucocorticoids in Low-Resource Settings - Who, When, and Where?

N Engl J Med 2020 12;383(26):2584-2585

From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Providence, RI (D.J.R.); and the Division of Global Women's Health, Department of Obstetrics and Gynecology, University of North Carolina School of Medicine, Chapel Hill (J.S.A.S.).

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http://dx.doi.org/10.1056/NEJMe2032499DOI Listing
December 2020

Multiomics Characterization of Preterm Birth in Low- and Middle-Income Countries.

JAMA Netw Open 2020 12 1;3(12):e2029655. Epub 2020 Dec 1.

Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan.

Importance: Worldwide, preterm birth (PTB) is the single largest cause of deaths in the perinatal and neonatal period and is associated with increased morbidity in young children. The cause of PTB is multifactorial, and the development of generalizable biological models may enable early detection and guide therapeutic studies.

Objective: To investigate the ability of transcriptomics and proteomics profiling of plasma and metabolomics analysis of urine to identify early biological measurements associated with PTB.

Design, Setting, And Participants: This diagnostic/prognostic study analyzed plasma and urine samples collected from May 2014 to June 2017 from pregnant women in 5 biorepository cohorts in low- and middle-income countries (LMICs; ie, Matlab, Bangladesh; Lusaka, Zambia; Sylhet, Bangladesh; Karachi, Pakistan; and Pemba, Tanzania). These cohorts were established to study maternal and fetal outcomes and were supported by the Alliance for Maternal and Newborn Health Improvement and the Global Alliance to Prevent Prematurity and Stillbirth biorepositories. Data were analyzed from December 2018 to July 2019.

Exposures: Blood and urine specimens that were collected early during pregnancy (median sampling time of 13.6 weeks of gestation, according to ultrasonography) were processed, stored, and shipped to the laboratories under uniform protocols. Plasma samples were assayed for targeted measurement of proteins and untargeted cell-free ribonucleic acid profiling; urine samples were assayed for metabolites.

Main Outcomes And Measures: The PTB phenotype was defined as the delivery of a live infant before completing 37 weeks of gestation.

Results: Of the 81 pregnant women included in this study, 39 had PTBs (48.1%) and 42 had term pregnancies (51.9%) (mean [SD] age of 24.8 [5.3] years). Univariate analysis demonstrated functional biological differences across the 5 cohorts. A cohort-adjusted machine learning algorithm was applied to each biological data set, and then a higher-level machine learning modeling combined the results into a final integrative model. The integrated model was more accurate, with an area under the receiver operating characteristic curve (AUROC) of 0.83 (95% CI, 0.72-0.91) compared with the models derived for each independent biological modality (transcriptomics AUROC, 0.73 [95% CI, 0.61-0.83]; metabolomics AUROC, 0.59 [95% CI, 0.47-0.72]; and proteomics AUROC, 0.75 [95% CI, 0.64-0.85]). Primary features associated with PTB included an inflammatory module as well as a metabolomic module measured in urine associated with the glutamine and glutamate metabolism and valine, leucine, and isoleucine biosynthesis pathways.

Conclusions And Relevance: This study found that, in LMICs and high PTB settings, major biological adaptations during term pregnancy follow a generalizable model and the predictive accuracy for PTB was augmented by combining various omics data sets, suggesting that PTB is a condition that manifests within multiple biological systems. These data sets, with machine learning partnerships, may be a key step in developing valuable predictive tests and intervention candidates for preventing PTB.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.29655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749442PMC
December 2020

Travel Medicine: Clinical Updates in Women's Health Care Primary and Preventive Care Review.

Obstet Gynecol 2020 Nov;136(5):1074

Travel is an increasingly common aspect of modern life, and the practicing obstetrician-gynecologist needs a good understanding of the health- and safety-related issues it presents for patients. This monograph examines the environmental data that support individual risk assessment and provides guidance on how to eliminate or mitigate those risks, including recommendations for immunization and chemoprophylaxis for women traveling to areas with endemic infectious disease. Management approaches for travel-related diseases, such as traveler's diarrhea, altitude sickness, and location-specific diseases, are reviewed as are special considerations for pregnant and breastfeeding women and women who are attempting pregnancy. Evaluation and management of the returned traveler also is addressed. The recommendations in this document cite resources available from the United States federal government; therefore, they are applicable to women seeking care in the United States.
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http://dx.doi.org/10.1097/AOG.0000000000004136DOI Listing
November 2020

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

PLoS One 2020 24;15(9):e0238748. Epub 2020 Sep 24.

Department of Health Behavior, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

Antenatal progesterone prevents preterm birth (PTB) in women with a short cervix or prior PTB in daily vaginal or weekly injectable formulations, respectively. Neither has been tested for the indication of maternal HIV, which is associated with an elevated risk of PTB. The Vaginal Progesterone (VP) Trial was a pilot feasibility study of VP to prevent HIV-related PTB in Lusaka, Zambia. Using mixed methods, we concurrently evaluated the acceptability of the trial and the study product among participants. Over a 1-year period, we enrolled 140 pregnant women living with HIV into a double-masked, placebo-controlled, randomized trial of daily self-administered VP or placebo. We administered an endline questionnaire to all participants and conducted in-depth interviews with 30 participants to assess barriers and facilitators to uptake and retention in the trial and to study product adherence. All interviews were audiotaped, transcribed, translated into English as needed, and independently coded by two analysts to capture emerging themes. Of 131 participants who completed the questionnaire, 128 (98%) reported that nothing was difficult when asked the hardest part about using the study product. When given a hypothetical choice between vaginal and injectable progesterone, 97 (74%) chose vaginal, 31 (24%) injectable, and 3 (2%) stated no preference. Most interviewees reported no difficulties with using the study product; others cited minor side effects and surmountable challenges. Strategies that supported adherence included setting alarms, aligning dosing with antiretrovirals, receiving encouragement from friends and family, sensing a benefit to their unborn baby, and positive feedback from study staff. Participants who reported preference of a vaginal medication over injectable described familiarity with the vaginal product, a fear of needles and resulting pain, and inconvenience of a weekly clinic visit. Those who would prefer weekly injections cited fewer doses to remember. Perceived barriers to study participation included mistrust about the motivations behind research, suspicion of Satanism, and futility or possible harm from a placebo. We report key influences on acceptability of a randomized trial of VP to prevent PTB among HIV-infected women in Zambia, which should inform methods to promote uptake, adherence, and retention in a full-scale trial.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238748PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7514015PMC
November 2020

Is Group B Streptococcus Colonization Associated with Maternal Peripartum Infection in an Era of Routine Prophylaxis?

Am J Perinatol 2021 08 23;38(S 01):e262-e268. Epub 2020 May 23.

Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Duke University, Durham, North Carolina.

Objective: This study aimed to assess whether colonization with group B streptococcus (GBS) is associated with maternal peripartum infection in an era of routine prophylaxis.

Study Design: This study presented a secondary analysis of women delivering ≥37 weeks who underwent a trial of labor from the U.S. Consortium on Safe Labor (CSL) study. The exposure was maternal GBS colonization and the outcome was a diagnosis of chorioamnionitis, and secondarily, analyses were restricted to deliveries not admitted in labor and measures of postpartum infection (postpartum fever, endometritis, and surgical site infection). Logistic regression with generalized estimating equations was used accounting for within-woman correlations. Models adjusted for maternal age, parity, race, prepregnancy body mass index, pregestational diabetes, insurance status, study site/region, year of delivery, number of vaginal exams from admission to delivery, and time (in hours) from admission to delivery.

Results: Among 170,804 assessed women, 33,877 (19.8%) were colonized with GBS and 5,172 (3.0%) were diagnosed with chorioamnionitis. While the frequency of GBS colonization did not vary by chorioamnionitis status (3.0% in both groups), in multivariable analyses, GBS colonization was associated with slightly lower odds of chorioamnionitis (adjusted odds ratio [AOR]: 0.89; 95% confidence interval [CI]: 0.83-0.96). In secondary analyses, this association held regardless of spontaneous labor on admission; and the odds of postpartum infectious outcomes were not higher with GBS colonization.

Conclusion: In contrast to historical data, GBS colonization was associated with lower odds of chorioamnionitis in an era of routine GBS screening and prophylaxis.

Key Points: · Data in an era prior to routine group B streptococcus (GBS) screening and prophylaxis showed that maternal GBS colonization was associated with a higher frequency of maternal peripartum infection.. · In the current study, GBS colonization was associated with lower odds of chorioamnionitis in an era of routine GBS screening and prophylaxis.. · The results highlight potential benefits of GBS screening and intrapartum antibiotic prophylaxis beyond neonatal disease prevention, including mitigating the risk of maternal infectious morbidity..
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http://dx.doi.org/10.1055/s-0040-1709666DOI Listing
August 2021

Effects of Depot Medroxyprogesterone Acetate, Copper Intrauterine Devices, and Levonorgestrel Implants on Early HIV Disease Progression.

AIDS Res Hum Retroviruses 2020 08 2;36(8):632-640. Epub 2020 Jun 2.

Setshaba Research Center, Soshanguve, South Africa.

Limited data exist on the effects of contraceptives on HIV disease progression. We studied the association between intramuscular injectable depot medroxyprogesterone acetate (DMPA-IM), the copper intrauterine device (IUD), and the levonorgestrel (LNG) implant on markers of HIV disease progression at the time of HIV detection and 3 months postdetection and time from detection to CD4 count <350 cells/mm. Among women initiating antiretroviral therapy (ART), we studied the effect of contraceptive group on time from ART initiation to viral load (VL) <40 copies/mL. We included women 16-35 years randomized to DMPA-IM, copper IUD, or LNG implant with incident HIV infection during the Evidence for Contraceptive Options and HIV Outcomes (ECHO) trial ( = 382). We analyzed HIV VL and CD4 cell count according to participants' randomized method and also conducted a "continuous use" analysis that excluded follow-up time after method discontinuation. We used adjusted linear models to compare mean VL and CD4 cell levels by contraceptive group up to the time of ART initiation. We compared time from HIV detection to CD4 count <350 cells/mm and, following ART initiation, time to viral suppression (VL <40 copies/mL) using Cox proportional hazards models. At HIV detection, women allocated to DMPA-IM had lower VL relative to copper IUD (-0.28 log copies/mL; 95% confidence interval [CI]: -0.55 to -0.01) and LNG implant (-0.27, CI: -0.55 to 0.02) and higher mean CD4 than copper IUD users by 66 cells/mm (CI: 11-121). In continuous use analyses women allocated to DMPA-IM progressed to CD4 < 350 cells/mm slower than copper IUD users (hazard ratio [HR] = 0.6, CI: 0.3-1.1), whereas copper IUD users progressed faster than LNG implant users (HR = 1.8, CI: 1.0-3.3). Time to viral suppression was faster for DMPA-IM than copper IUD (HR = 1.5, CI: 1.0-2.3) and LNG implant 1.4 (CI: 0.9-2.2) users. We found no evidence of more rapid early HIV disease progression among women using DMPA-IM than among women using copper IUD or LNG implant. Our finding of more rapid progression among copper IUD compared with DMPA-IM users should be interpreted cautiously.
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http://dx.doi.org/10.1089/AID.2020.0015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414801PMC
August 2020

Association Between Maternal Obesity and Group B Streptococcus Colonization in a National U.S. Cohort.

J Womens Health (Larchmt) 2020 12 4;29(12):1507-1512. Epub 2020 May 4.

Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Duke University, Durham, North Carolina, USA.

To investigate the association between maternal obesity as measured by prepregnancy body mass index (BMI) and group B streptococcus (GBS) colonization. We conducted a secondary analysis from the Consortium on Safe Labor Study (CSL) in the United States cohort study (2002-2008). Pregnant women with deliveries at ≥37 weeks of gestation who attempted labor were included (115,070 assessed deliveries). The association between maternal prepregnancy BMI, categorized as normal weight or below (<25 kg/m), overweight (25 to <30 kg/m), class I obesity (30 to <35 kg/m), class II obesity (35 to <40 kg/m), and class III obesity (≥40 kg/m), and GBS colonization was modeled using logistic regression with generalized estimating equations. Models adjusted for maternal age, parity, race, pregestational diabetes, insurance status, study site/region, and year of delivery. The overall prevalence of GBS colonization was 20.5% (23,625/115,070), which increased with rising maternal BMI, normal weight 19.3% (13,543/70,098), overweight 20.8% (5,353/25,733), class I obesity 23.0% (2,596/11,275), class II obesity 26.1% (1,270/4,850), and class III obesity 27.7% (863/3,114). In multivariable analysis, increasing maternal obesity severity was associated with higher odds of GBS colonization, namely overweight (adjusted odds ratio [AOR]: 1.09, 95% confidence interval [CI]: 1.05-1.13), class I obesity (AOR: 1.20, 95% CI: 1.15-1.26), class II obesity (AOR: 1.42, 95% CI: 1.33-1.51), and class III obesity (AOR: 1.50; 95% CI: 1.38-1.62) compared with normal weight. In secondary analyses, these associations persisted when stratified by maternal race. In a national U.S. sample, increasing maternal obesity severity as assessed by prepregnancy BMI was associated with a higher likelihood of maternal GBS colonization during pregnancy.
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http://dx.doi.org/10.1089/jwh.2019.8139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757598PMC
December 2020

Machine Learning and Statistical Models to Predict Postpartum Hemorrhage.

Obstet Gynecol 2020 04;135(4):935-944

Departments of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, Duke University, Durham, Wake Forest University, Winston-Salem, North Carolina.

Objective: To predict a woman's risk of postpartum hemorrhage at labor admission using machine learning and statistical models.

Methods: Predictive models were constructed and compared using data from 10 of 12 sites in the U.S. Consortium for Safe Labor Study (2002-2008) that consistently reported estimated blood loss at delivery. The outcome was postpartum hemorrhage, defined as an estimated blood loss at least 1,000 mL. Fifty-five candidate risk factors routinely available on labor admission were considered. We used logistic regression with and without lasso regularization (lasso regression) as the two statistical models, and random forest and extreme gradient boosting as the two machine learning models to predict postpartum hemorrhage. Model performance was measured by C statistics (ie, concordance index), calibration, and decision curves. Models were constructed from the first phase (2002-2006) and externally validated (ie, temporally) in the second phase (2007-2008). Further validation was performed combining both temporal and site-specific validation.

Results: Of the 152,279 assessed births, 7,279 (4.8%, 95% CI 4.7-4.9) had postpartum hemorrhage. All models had good-to-excellent discrimination. The extreme gradient boosting model had the best discriminative ability to predict postpartum hemorrhage (C statistic: 0.93; 95% CI 0.92-0.93), followed by random forest (C statistic: 0.92; 95% CI 0.91-0.92). The lasso regression model (C statistic: 0.87; 95% CI 0.86-0.88) and logistic regression (C statistic: 0.87; 95% CI 0.86-0.87) had lower-but-good discriminative ability. The above results held with validation across both time and sites. Decision curve analysis demonstrated that, although all models provided superior net benefit when clinical decision thresholds were between 0% and 80% predicted risk, the extreme gradient boosting model provided the greatest net benefit.

Conclusion: Postpartum hemorrhage on labor admission can be predicted with excellent discriminative ability using machine learning and statistical models. Further clinical application is needed, which may assist health care providers to be prepared and triage at-risk women.
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http://dx.doi.org/10.1097/AOG.0000000000003759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236480PMC
April 2020

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

PLoS One 2020 29;15(1):e0224874. Epub 2020 Jan 29.

Division of Global Women's Health, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

Antenatal vaginal progesterone (VP) reduces the risk of preterm birth (PTB) in women with shortened cervical length, and we hypothesize that it may also prevent PTB in women with HIV as their primary risk factor. We conducted a pilot feasibility study in Lusaka, Zambia to investigate uptake, adherence, and retention in preparation for a future efficacy trial. This was a double-masked, placebo-controlled, randomized trial of 200mg daily self-administered VP suppository or placebo. Pregnant women with HIV who were initiating or continuing antiretroviral therapy were eligible for participation. Potential participants underwent ultrasound to assess eligibility; we excluded those ≥24 gestational weeks, with non-viable, multiple gestation, or extrauterine pregnancies, with short cervix (<2.0cm), or with prior spontaneous PTB. Participants initiated study product between 20-24 weeks of gestation and continued to 37 weeks (or delivery, if sooner). The primary outcome was adherence (proportion achieving ≥80% study product use), assessed by dye stain assay of returned single-use vaginal applicators. Secondary outcomes with pre-defined feasibility targets were: uptake (≥50% eligible participants enrolled) and retention (≥90% ascertainment of delivery outcomes). We also evaluated preliminary efficacy by comparing the risk of spontaneous PTB <37 weeks between groups. From July 2017 to June 2018, 208 HIV-infected pregnant women were eligible for screening and 140 (uptake = 67%) were randomly allocated to VP (n = 70) or placebo (n = 70). Mean adherence was 94% (SD±9.4); 91% (n = 125/137) achieved overall adherence ≥80%. Delivery outcomes were ascertained from 134 (96%) participants. Spontaneous PTB occurred in 10 participants (15%) receiving placebo and 8 (12%) receiving progesterone (RR 0.82; 95%CI:0.34-1.97). Spontaneous PTB < 34 weeks occurred in 6 (9%) receiving placebo and 4 (6%) receiving progesterone (RR 0.67; 95%CI:0.20-2.67). In contrast to findings from vaginal microbicide studies in HIV-uninfected, non-pregnant women, our trial participants were highly adherent to daily self-administered vaginal progesterone. The study's a priori criteria for uptake, adherence, and retention were met, indicating that a phase III efficacy trial would be feasible.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224874PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988922PMC
March 2020

Association between HIV antiretroviral therapy and preterm birth based on antenatal ultrasound gestational age determination: a comparative analysis.

AIDS 2019 12;33(15):2403-2413

aDivision of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of North Carolina School of Medicine, Chapel Hill, North Carolina bHarvard T.H. Chan School of Public Health, Center for Biostatistics in AIDS Research, Boston, Massachusetts, USA cCentre for AIDS Research in South Africa and Department of Obstetrics and Gynecology, School of Clinical Medicine, University of KwaZulu Natal, Durban, South Africa dByramiee Jeejeebhoy Government Medical College, Pune, India eMakerere University, Kampala, Uganda fWits Reproductive Health and HIV Institute, University of the Witwatersrand, Johannesburg, South Africa gDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland hDivision of Global Women's Health, Department of Obstetrics and Gynecology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.

Objective: To evaluate the association between HIV antiretroviral therapy (ART) and preterm birth (PTB), when defined by gold standard antenatal ultrasound versus newborn exam.

Design: A secondary analysis of the PROMISE 1077BF/1077FF randomized controlled trial, which compared antiretroviral strategies to reduce perinatal HIV transmission and improve maternal health. The trial used newborn exam (i.e. New Ballard Score, NBS) to assess gestational age. This analysis included liveborn singleton pregnancies with both newborn exam and ultrasound data. The primary exposure was the trial's antiretroviral strategies: zidovudine with intrapartum nevirapine ('ZDV alone'); zidovudine/lamivudine/lopinavir-ritonavir ('ZDV-based ART'); or tenofovir/emtricitabine/lopinavir-ritonavir ('TDF-based ART'). The primary outcome was PTB less than 37 and less than 34 weeks based on the gold standard of ultrasound dating. We evaluated the association between antiretroviral strategy and PTB. We fit multivariable logistic regression models, adjusting for maternal characteristics, obstetric history, and HIV disease severity.

Results: Among 720 assessed pregnant women, PTB less than 37 weeks was 15.4% by NBS and 18.3% by ultrasound. The NBS was specific but not sensitive for PTB less than 37 weeks (92.0% and 48.5%). Women receiving ZDV-based and TDF-based ART had significantly higher odds of PTB less than 37 by ultrasound compared with ZDV alone (adjusted odds ratios: 1.68; 95% confidence interval 1.10-2.57, and 2.71; 95% confidence interval 1.39-5.29), as well as for PTB less than 34 weeks. These results held for ultrasounds performed less than 24 weeks, and were generally consistent with prior analyses from the PROMISE trial using the NBS.

Conclusion: Women starting HIV ART in pregnancy remained at higher risk of PTB when determined by ultrasound, consistent with prior data using newborn exam. However, newborn exam misclassified cases of PTB compared with gold standard ultrasound.
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http://dx.doi.org/10.1097/QAD.0000000000002367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293898PMC
December 2019

Cervical Cancer as a Global Concern: Contributions of the Dual Epidemics of HPV and HIV.

JAMA 2019 10;322(16):1558-1560

Division of Global Women's Health, Department of Obstetrics and Gynecology, University of North Carolina School of Medicine, Chapel Hill.

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http://dx.doi.org/10.1001/jama.2019.16176DOI Listing
October 2019

Highly diverse anaerobe-predominant vaginal microbiota among HIV-infected pregnant women in Zambia.

PLoS One 2019 2;14(10):e0223128. Epub 2019 Oct 2.

Division of Global Women's Health, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, United States of America.

Vaginal dysbiosis has been shown to increase the risk of some adverse birth outcomes. HIV infection may be associated with shifts in the vaginal microbiome. We characterized microbial communities in vaginal swabs collected between 16-20 gestational weeks in the Zambian Preterm Birth Prevention Study to investigate whether HIV and its treatment alter the microbiome in pregnancy. We quantified relative abundance and diversity of bacterial taxa by whole-genome shotgun sequencing and identified community state types (CST) by hierarchical clustering. Associations between exposures-HIV serostatus (HIV+ vs HIV-) and preconceptional ART (ART+ vs ART-)-and microbiome characteristics were tested with rank-sum, and by linear and logistic regression, accounting for sampling by inverse-probability weighting. Of 261 vaginal swabs, 256 (98%) had evaluable sequences; 98 (38%) were from HIV+ participants, 55 (56%) of whom had preconceptional ART exposure. Major CSTs were dominated by: L. crispatus (CST 1; 17%), L.] iners (CST 3; 32%), Gardnerella vaginalis (CST 4-I; 37%), G. vaginalis & Atopobium vaginae (CST 4-II; 5%), and other mixed anaerobes (CST 4-III; 9%). G. vaginalis was present in 95%; mean relative abundance was higher in HIV+ (0.46±0.29) compared to HIV- participants (0.35±0.33; rank-sum p = .01). Shannon diversity was higher in HIV+/ART+ (coeff 0.17; 95%CI (0.01,0.33), p = .04) and HIV+/ART- (coeff 0.37; 95%CI (0.19,0.55), p < .001) participants compared to HIV-. Anaerobe-dominant CSTs were more prevalent in HIV+/ART+ (63%, AOR 3.11; 95%CI: 1.48,6.55, p = .003) and HIV+/ART- (85%, AOR 7.59; 95%CI (2.80,20.6), p < .001) compared to HIV- (45%). Restricting the comparison to 111 women in either CST 3 (L. iners dominance) or CST 1 (L. crispatus dominance), CST 3 frequency was similar in HIV- (63%) and HIV+/ART- participants (67%, AOR 1.31; 95%CI: (0.25,6.90), p = .7), but higher in HIV+/ART+ (89%, AOR 6.44; 95%CI: (1.12,37.0), p = .04). Pregnant women in Zambia, particularly those with HIV, had diverse anaerobe-dominant vaginal microbiota.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223128PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774526PMC
March 2020

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

Gates Open Res 2018 15;2:25. Epub 2019 Jul 15.

University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Sub-Saharan Africa bears a disproportionate burden of preterm birth and other adverse outcomes. A better understanding of the demographic, clinical, and biologic underpinnings of these adverse outcomes is urgently needed to plan interventions and inform new discovery.  The Zambian Preterm Birth Prevention Study (ZAPPS) is a prospective observational cohort established at the Women and Newborn Hospital (WNH) in Lusaka, Zambia. We recruit pregnant women from district health centers and the WNH and offer ultrasound examination to determine eligibility. Participants receive routine obstetrical care, lab testing, midtrimester cervical length measurement, and serial fetal growth monitoring. At delivery, we assess gestational age, birthweight, vital status, and sex and assign a delivery phenotype. We collect blood, urine, and vaginal swab specimens at scheduled visits and store them in an on-site biorepository. In September 2017, enrollment of the ZAPPS Phase 1-the subject of this report-was completed. Phase 2, which is limited to HIV-uninfected women, reopened in January 2018.  Between August 2015 and September 2017, we screened 1784 women, of whom 1450 (81.2%) met inclusion criteria and were enrolled. The median age at enrollment was 27 years (IQR 23-32) and median gestational age was 16 weeks (IQR 13-18). Among women with a previous pregnancy (n=1042), 19% (n=194) reported a prior miscarriage.  Among parous women (n=992), 41% (n=411) reported a prior preterm birth and 14% (n=126) reported a prior stillbirth. The HIV seroprevalence was 24%. We have established a large cohort of pregnant women and newborns at the WNH to characterize the determinants of adverse birth outcomes in Lusaka, Zambia. Our overarching goal is to elucidate biological mechanisms in an effort to identify new strategies for early detection and prevention of adverse outcomes. We hope that findings from this cohort will help guide future studies, clinical care, and policy.
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http://dx.doi.org/10.12688/gatesopenres.12820.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350406PMC
July 2019

Risk Factors for Adverse Birth Outcomes in the PROMISE 1077BF/1077FF Trial.

J Acquir Immune Defic Syndr 2019 08;81(5):521-532

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD.

Background: In the multicountry PROMISE 1077BF/1077FF trial, the risk of low birth weight (LBW; <2500 g) and preterm delivery (PTD; <37 weeks) was significantly higher among women initiating a protease inhibitor-based antiretroviral treatment (ART) regimen than those receiving ZDV alone. Among those assigned to a protease inhibitor regimen, tenofovir/emtricitabine was associated with the more severe outcomes of very LBW (<1500 g) and very PTD (<34 weeks) compared with zidovudine/lamivudine.

Methods: We used multivariate logistic regression to further explore these treatment findings, taking into account demographic baseline clinical and postentry obstetrical factors. We evaluated individual adverse outcomes and composites that included stillbirth and early loss/spontaneous abortion.

Results: Among 3333 women delivering at least 1 live infant, median maternal age at enrollment was 26 years; 661 (20%) were primiparous, and 110 (3.3%) reported at least 1 previous PTD. Seventeen percent of newborns were LBW, 1% were very LBW, 17% had PTD, and 3% had very PTD. Treatment allocation remained strongly associated with multiple adverse outcomes after controlling for other risk factors with both ART regimens exhibiting increased risk relative to ZDV alone. Other risk factors remaining significant in at least one of the multivariate models included the following: country, gestational age at entry, maternal age, maternal body mass index, previous PTD, history of alcohol use, baseline HIV viral titer, multiple gestation, and several obstetric risk factors.

Conclusions: ART effects on adverse pregnancy outcomes reported in the randomized PROMISE trial remained strongly significant even after controlling for demographic, baseline clinical, and obstetrical risk factors, which were also associated with these outcomes.
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http://dx.doi.org/10.1097/QAI.0000000000002072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702964PMC
August 2019

HIV serostatus, viral load, and midtrimester cervical length in a Zambian prenatal cohort.

Int J Gynaecol Obstet 2019 Aug 29;146(2):206-211. Epub 2019 Apr 29.

Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Objective: To evaluate whether maternal HIV serostatus and plasma viral load (VL) are associated with midtrimester cervical length (CL).

Methods: The Zambian Preterm Birth Prevention Study (ZAPPS) is an ongoing prospective cohort that began enrolling in Lusaka in August 2015. Pregnant women undergo ultrasound to determine gestational age and return for CL measurement at 16-28 weeks. We evaluated crude and adjusted associations between dichotomous indicators and short cervix (≤2.5 cm) via logistic regression, and between VL and CL as a continuous variable via linear regression.

Results: This analysis includes 1171 women enrolled between August 2015 and September 2017. Of 294 (25.1%) HIV-positive women, 275 (93.5%) had viral load performed close to CL measurement; of these, 148 (53.8%) had undetectable virus. Median CL was 3.6 cm (IQR 3.5-4.0) and was similar in HIV-infected (3.7 cm, IQR 3.5-4.0) versus uninfected (3.6 cm, IQR 3.5-4.0) participants (P=0.273). The odds of short CL were similar by HIV serostatus (OR 0.64; P=0.298) and detectable VL among those infected (OR 2.37, P=0.323). We observed no association between log VL and CL via linear regression (-0.12 cm; P=0.732).

Conclusion: We found no evidence of association between HIV infection and short CL.
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http://dx.doi.org/10.1002/ijgo.12823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610732PMC
August 2019

Reducing the global burden of preterm births.

Lancet Glob Health 2019 04;7(4):e415

Department of Obstetrics and Gynaeocology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address:

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http://dx.doi.org/10.1016/S2214-109X(19)30060-9DOI Listing
April 2019

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

BMC Pregnancy Childbirth 2019 Feb 27;19(1):81. Epub 2019 Feb 27.

Division of Global Women's Health, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, 3009 Old Clinic Building, Campus Box 7577, Chapel Hill, NC, 27599-7577, USA.

Background: Each year, an estimated 15 million babies are born preterm, a global burden borne disproportionately by families in lower-income countries. Maternal HIV infection increases a woman's risk of delivering prematurely, and antiretroviral therapy (ART) may compound this risk. While prenatal progesterone prophylaxis prevents preterm birth among some high-risk women, it is unknown whether HIV-infected women could benefit from this therapy. We are studying the efficacy of progesterone supplementation to reduce the risk of preterm birth among pregnant women with HIV in Lusaka, Zambia.

Methods: The Improving Pregnancy Outcomes with Progesterone (IPOP) study is a Phase III double-masked, placebo-controlled, randomized trial of intramuscular 17-alpha hydroxprogesterone caproate (17P) to prevent preterm birth in HIV-infected women. A total of 800 women will be recruited prior to 24 weeks of gestation and randomly allocated to 17P or placebo administered by weekly intramuscular injection. The primary outcome will be a composite of live birth prior to 37 completed gestational weeks or stillbirth at any gestational age. Secondary outcomes will include very preterm birth (< 34 weeks), extreme preterm birth (< 28 weeks), small for gestational age (<10th centile), low birth weight (< 2500 g), and neonatal outcomes. In secondary analysis, we will assess whether specific HIV-related covariates, including the timing of maternal ART initiation relative to conception, is associated with progesterone's prophylactic efficacy, if any.

Discussion: We hypothesize that weekly prenatal 17P will reduce the risk of HIV-related preterm birth. An inexpensive intervention to prevent preterm birth among pregnant women with HIV could have substantial global public health impact.

Trial Registration: NCT03297216 ; September 29, 2017.
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http://dx.doi.org/10.1186/s12884-019-2224-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391830PMC
February 2019

Improving preterm newborn identification in low-resource settings with machine learning.

PLoS One 2019 27;14(2):e0198919. Epub 2019 Feb 27.

University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States.

Background: Globally, preterm birth is the leading cause of neonatal death with estimated prevalence and associated mortality highest in low- and middle-income countries (LMICs). Accurate identification of preterm infants is important at the individual level for appropriate clinical intervention as well as at the population level for informed policy decisions and resource allocation. As early prenatal ultrasound is commonly not available in these settings, gestational age (GA) is often estimated using newborn assessment at birth. This approach assumes last menstrual period to be unreliable and birthweight to be unable to distinguish preterm infants from those that are small for gestational age (SGA). We sought to leverage machine learning algorithms incorporating maternal factors associated with SGA to improve accuracy of preterm newborn identification in LMIC settings.

Methods And Findings: This study uses data from an ongoing obstetrical cohort in Lusaka, Zambia that uses early pregnancy ultrasound to estimate GA. Our intent was to identify the best set of parameters commonly available at delivery to correctly categorize births as either preterm (<37 weeks) or term, compared to GA assigned by early ultrasound as the gold standard. Trained midwives conducted a newborn assessment (<72 hours) and collected maternal and neonatal data at the time of delivery or shortly thereafter. New Ballard Score (NBS), last menstrual period (LMP), and birth weight were used individually to assign GA at delivery and categorize each birth as either preterm or term. Additionally, machine learning techniques incorporated combinations of these measures with several maternal and newborn characteristics associated with prematurity and SGA to develop GA at delivery and preterm birth prediction models. The distribution and accuracy of all models were compared to early ultrasound dating. Within our live-born cohort to date (n = 862), the median GA at delivery by early ultrasound was 39.4 weeks (IQR: 38.3-40.3). Among assessed newborns with complete data included in this analysis (n = 468), the median GA by ultrasound was 39.6 weeks (IQR: 38.4-40.3). Using machine learning, we identified a combination of six accessible parameters (LMP, birth weight, twin delivery, maternal height, hypertension in labor, and HIV serostatus) that can be used by machine learning to outperform current GA prediction methods. For preterm birth prediction, this combination of covariates correctly classified >94% of newborns and achieved an area under the curve (AUC) of 0.9796.

Conclusions: We identified a parsimonious list of variables that can be used by machine learning approaches to improve accuracy of preterm newborn identification. Our best-performing model included LMP, birth weight, twin delivery, HIV serostatus, and maternal factors associated with SGA. These variables are all easily collected at delivery, reducing the skill and time required by the frontline health worker to assess GA.

Trial Registration: ClinicalTrials.gov Identifier: NCT02738892.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198919PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392324PMC
December 2019
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