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Objective: To evaluate the accuracy of two portable ultrasound machines (PUM) in assessing fetal biometry and estimated gestational age (EGA)., Methods: This was a secondary analysis of data from the Fetal Age Machine Learning Initiative, an observational study of pregnant women in the USA and Zambia. Each participant underwent ultrasound assessment by an experienced sonographer using both a high-specification ultrasound machine (HSUM) and a PUM (Butterfly iQ or Clarius C3) to measure fetal biometry and calculate EGA at each visit. By comparing paired PUM and HSUM scans, we estimated agreement between individual biometry measurements and aggregate gestational age estimates by reporting mean difference, intraclass correlation coefficient (ICC) and Bland-Altman plots, adjusting for trend., Results: Between April and December 2021, 818 participants contributed 1386 paired PUM-HSUM ultrasound investigations, of which 991 PUM scans were obtained using the Butterfly iQ device and 395 using the Clarius C3 device. Gestational age at scan ranged from 7 to 38 weeks. Compared with HSUM, the Butterfly iQ PUM had a mean difference of -0.20 (95% CI, -0.60 to 0.20) days in the first trimester and -0.68 (95% CI, -0.93 to -0.44) days in the second/third trimesters. Compared with HSUM, the Clarius C3 PUM had a mean difference of -0.47 (95% CI, -1.11 to 0.18) days in the first trimester and -1.67 (95% CI, -2.10 to -1.25) days in the second/third trimesters. ICCs were 0.989 or greater throughout. Increasing gestational age was associated with increasing error and absolute error in EGA and fetal biometry. Both PUM devices demonstrated a modest trend toward underestimation of EGA with advancing gestational age in second/third-trimester scans, compared with HSUM., Conclusion: The Butterfly iQ and Clarius C3 PUM devices were highly accurate in performing fetal biometry in a diverse population from the USA and Zambia. © 2023 International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: To compare the performance of mid upper arm circumference (MUAC) and body mass index (BMI) for prediction of small for gestational age (SGA) in Zambia., Methods: This is a secondary analysis of an ongoing clinical cohort that included women with a single gestation and MUAC measured before 24 weeks of pregnancy. We assessed relationships between maternal MUAC and birth weight centile using regression. The performance of MUAC and BMI to predict SGA was compared using receiver operating characteristic curves and the effect of maternal HIV was investigated in sub-group analyses., Results: Of 1117 participants, 847 (75%) were HIV-negative (HIV-) and 270 (24%) were HIV-positive (HIV+). Seventy-four (7%) delivered severe SGA infants (<3rd centile), of whom 56 (76%) were HIV- and 18 (24%) were HIV+ (odds ratio [OR] 1.01, 95% confidence interval [CI] 0.58-1.75). MUAC was associated with higher birth weight centile (+1.2 centile points, 95% CI 0.7-1.6; P < 0.001); this relationship was stronger among HIV+ women (+1.7 centile points, 95% CI 0.8-2.6; P < 0.001) than HIV- women (+0.9 centile points, 95% CI 0.4-1.4; P = 0.001). The discriminatory power was similar, albeit poor (area under the curve [AUC] < 0.7), between MUAC and BMI for the prediction of SGA. In stratified analysis, MUAC and BMI showed excellent discrimination predicting severe SGA among HIV+ (AUC 0.83 and 0.81, respectively) but not among HIV- women (AUC 0.64 and 0.63, respectively)., Conclusion: Maternal HIV infection increased the discrimination of both early pregnancy MUAC and BMI for prediction of severe SGA in Zambia., Clinical Trial Number: ClinicalTrials.gov (NCT02738892)., (© 2022 International Federation of Gynecology and Obstetrics.)

Background: Since the declaration of COVID-19 as a global pandemic, several studies have been conducted to examine associated factors. However, few studies have focused on pregnant women infected with COVID-19 in sub-Saharan Africa. Therefore, this study investigated the prevalence and factors associated with COVID-19 infection among pregnant women at the Levy Mwanawasa University Teaching Hospital and Women and Newborn Hospital of the University Teaching Hospitals in Lusaka, Zambia., Methods: A cross-sectional study was conducted between March and July 2021. Women were recruited as they presented for antenatal care. Data was collected using a structured questionnaire to capture variables of interest (socio-demographic, clinical and obstetric). COVID-19 diagnosis was made using a nasopharyngeal swab by PCR test. Multivariable logistic regression was used to control for confounding and calculate the odds ratios for each explanatory variable and respective 95% confidence intervals., Results: The study enrolled 352 participants with a mean (standard deviation [SD]) age of 30.1 years (5.6). One hundred thirty of 352 (36.9%; 95% CI: 31.9 to 42.2) participants had a confirmed positive SARS-CoV-2 test result. At univariable analysis, factors associated with COVID-19 were increased gestational age, education status and maternal HIV serostatus. Women with a secondary level of education were less likely to have COVID-19 infection than those with a primary level of education (AOR = 0.23, 95% CI: 0.09-0.63). On the other hand, a one-week increase in gestational age was associated with higher odds of COVID-19 infection (AOR = 1.03, 95% CI: 1.01-1.06)., Conclusion: The results showed that the prevalence of COVID-19 infection among pregnant women was 36.9% and was associated with increased gestational age and a lower level of education. To mitigate adverse maternal outcomes, there is a need to screen for COVID-19 strictly and broadly monitor prenatal women presenting for healthcare., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: Accurate estimates of gestational age (GA) at birth are important for preterm birth surveillance but can be challenging to obtain in low income countries. Our objective was to develop machine learning models to accurately estimate GA shortly after birth using clinical and metabolomic data., Methods: We derived three GA estimation models using ELASTIC NET multivariable linear regression using metabolomic markers from heel-prick blood samples and clinical data from a retrospective cohort of newborns from Ontario, Canada. We conducted internal model validation in an independent cohort of Ontario newborns, and external validation in heel prick and cord blood sample data collected from newborns from prospective birth cohorts in Lusaka, Zambia and Matlab, Bangladesh. Model performance was measured by comparing model-derived estimates of GA to reference estimates from early pregnancy ultrasound., Results: Samples were collected from 311 newborns from Zambia and 1176 from Bangladesh. The best-performing model accurately estimated GA within about 6 days of ultrasound estimates in both cohorts when applied to heel prick data (MAE 0.79 weeks (95% CI 0.69, 0.90) for Zambia; 0.81 weeks (0.75, 0.86) for Bangladesh), and within about 7 days when applied to cord blood data (1.02 weeks (0.90, 1.15) for Zambia; 0.95 weeks (0.90, 0.99) for Bangladesh)., Conclusions: Algorithms developed in Canada provided accurate estimates of GA when applied to external cohorts from Zambia and Bangladesh. Model performance was superior in heel prick data as compared to cord blood data., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Hawken 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.)

Objective: To illustrate the difference between exposure effects and population attributable effects., Methods: We examined the effect of mid-pregnancy short cervical length (<25 mm) on preterm birth using data from a prospective cohort of pregnant women in Lusaka, Zambia. Preterm birth was live birth or stillbirth before 37 weeks of pregnancy. For estimation, we used multivariable regression and parametric g-computation., Results: Among 1409 women included in the analysis, short cervix was rare (2.4%); 13.6% of births were preterm. Exposure effect estimates were large (marginal risk ratio 2.86, 95% confidence interval [CI] 1.80-4.54), indicating that the preterm birth risk was substantially higher among women with a short cervix compared with women without a short cervix. However, the population attributable effect estimates were close to the null (risk ratio 1.06, 95% CI 1.02-1.10), indicating that an intervention to counteract the impact of short cervix on preterm birth would have minimal effect on the population risk of preterm birth., Conclusion: Although authors often refer to "the" effect, there are actually different types of effects, as we have illustrated here. In planning research, it is important to consider which effect to estimate to ensure that the estimate aligns with the research objective., (© 2022 International Federation of Gynecology and Obstetrics.)

The IPOP trial demonstrated a reduced risk of severe small for gestational age among infants born to women with HIV who received weekly intramuscular 17 alpha-hydroxyprogesterone caproate. This secondary analysis examined the 17P treatment effect in subgroups of maternal BMI, parity, timing of antiretroviral therapy (ART) initiation, and ART regimen. We found that 17P was more effective among nulliparous women, women who started ART before pregnancy, and those taking protease inhibitors., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Postpartum depression (PPD) is a prevalent and debilitating disease that may affect medication adherence and thus maternal health and vertical transmission among women with HIV. We assessed the feasibility of a trial of interpersonal psychotherapy (IPT) versus antidepressant medication (ADM) to treat PPD and/or anxiety among postpartum women with HIV in Lusaka, Zambia., Methods: Between 29 October 2019 and 8 September 2020, we pre-screened women 6-8 weeks after delivery with the Edinburgh Postnatal Depression Scale (EPDS) and diagnosed PPD or anxiety with the Mini International Neuropsychiatric Interview. Consenting participants were randomized 1:1 to up to 11 sessions of IPT or daily self-administered sertraline and followed for 24 weeks. We assessed EPDS score, Clinical Global Impression-Severity of Illness (CGI-S) and medication side effects at each visit and measured maternal HIV viral load at baseline and final study visit. Retention, visit adherence, change in EPDS, CGI-S and log viral load were compared between groups with t-tests and Wilcoxon signed rank tests; we report mean differences, relative risks and 95% confidence intervals. A participant satisfaction survey assessed trial acceptability., Results: 78/80 (98%) participants were retained at the final study visit. In the context of the COVID-19 pandemic, visit adherence was greater among women allocated to ADM (9.9 visits, SD 2.2) versus IPT (8.9 visits, SD 2.4; p = 0.06). EPDS scores decreased from baseline to final visit overall, though mean change was greater in the IPT group (-13.8 points, SD 4.7) compared to the ADM group (-11.4 points, SD 5.5; p = 0.04). Both groups showed similar changes in mean log viral load from baseline to final study visit (mean difference -0.43, 95% CI -0.32, 1.18; p = 0.48). In the IPT group, viral load decreased significantly from baseline (0.9 log copies/ml, SD 1.7) to final visit (0.2 log copies/ml, SD 0.9; p = 0.01)., Conclusions: This pilot study demonstrates that a trial of two forms of PPD treatment is feasible and acceptable among women with HIV in Zambia. IPT and ADM both improved measures of depression severity; however, a full-scale trial is required to determine whether treatment of PPD and anxiety improves maternal-infant HIV outcomes., (© 2022 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

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., (© 2021 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

A Lactobacillus-deficient, anaerobe-rich vaginal microbiome has been associated with local inflammation and spontaneous preterm birth (sPTB), but few studies have assessed this association in the setting of HIV. We performed metagenomic sequencing and inflammatory marker assays on vaginal swabs collected in pregnancy. We grouped samples into 7 metagenomic clusters (mgClust) using the non-redundant VIRGO catalogue, and derived inflammatory scores by factor analysis. Of 221 participants, median Shannon diversity index (SDI) was highest in HIV+ with detectable viral load (1.31, IQR: 0.85-1.66; p < 0.001) and HIV+ with undetectable virus (1.17, IQR: 0.51-1.66; p = 0.01) compared to HIV- (0.74, IQR: 0.35-1.26). Inflammatory scores positively correlated with SDI (+ 0.66, 95%CI 0.28, 1.03; p = 0.001), highest among anaerobe-rich mgClust2-mgClust6. HIV was associated with predominance of anaerobe-rich mgClust5 (17% vs. 6%; p = 0.02) and mgClust6 (27% vs. 11%; p = 0.002). Relative abundance of a novel Gardnerella metagenomic subspecies > 50% predicted sPTB (RR 2.6; 95%CI: 1.1, 6.4) and was higher in HIV+ (23% vs. 10%; p = 0.001). A novel Gardnerella metagenomic subspecies more abundant in women with HIV predicted sPTB. The risk of sPTB among women with HIV may be mediated by the vaginal microbiome and inflammation, suggesting potential targets for prevention., (© 2022. The Author(s).)

Background: A trial of progesterone to prevent preterm birth among HIV-infected Zambian women [Improving Pregnancy Outcomes with Progesterone (IPOP)] found no treatment effect, but the risk of the primary outcome was among the lowest ever documented in women with HIV. In this secondary analysis, we compare the risks of preterm birth (<37 weeks), stillbirth, and a composite primary outcome comprising the two in IPOP versus an observational pregnancy cohort [Zambian Preterm Birth Prevention Study (ZAPPS)] in Zambia, to evaluate reasons for the low risk in IPOP., Methods: Both studies enrolled women before 24 gestational weeks, during August 2015-September 2017 (ZAPPS) and February 2018-January 2020 (IPOP). We used linear probability and log-binomial regression to estimate risk differences and risk ratios (RR), before and after restriction and standardization with inverse probability weights., Results: The unadjusted risk of composite outcome was 18% in ZAPPS (N = 1450) and 9% in IPOP (N = 791) (RR = 2.0; 95% CI = 1.6, 2.6). After restricting and standardizing the ZAPPS cohort to the distribution of IPOP baseline characteristics, the risk remained higher in ZAPPS (RR = 1.6; 95% CI = 1.0, 2.4). The lower risk of preterm/stillbirth in IPOP was only partially explained by measured risk factors., Conclusions: Possible benefits in IPOP of additional monetary reimbursement, more frequent visits, and group-based care warrant further investigation., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: There is a paucity of data on the psychosocial issues and coping mechanisms among pregnant and postnatal women with COVID-19 infection. We, therefore, aimed to explore the psychosocial issues and coping mechanisms of pregnant and postnatal women diagnosed with COVID-19 at tertiary-level hospitals., Methods: This was a qualitative phenomenological study conducted in 2021 with a sample size of 16 women admitted at two referral hospitals serving as COVID-19 admission facilities for pregnant and postnatal women in Lusaka, Zambia. In-depth interviews were conducted via telephone to understand what these women experienced when diagnosed with COVID-19. All the interviews were audio-recorded and transcribed verbatim. Thematic analysis was conducted using the six steps approach to develop emerging themes., Results: Two major themes emerged: psychosocial issues and coping mechanisms. The primary psychosocial issues were worry and stigma. Women worried about infecting their unborn baby or neonate, being separated from the baby, the general safety of the baby, and the health of other family members. Women also worried about the attitude of health care providers and faced discrimination or stigma because of their infection. Thus, some coping mechanisms were developed that helped them, such as a positive attitude, keeping the disease secret, reliance on family members for support and using positive information from social media., Conclusion: This study provides unique insights into the psychosocial experiences of pregnant and postnatal women diagnosed with COVID-19. Women were particularly concerned about the unborn baby's well-being and discrimination.This study suggests the need for policy and clinical practice to consider the integration of effective mental health services into the provision of maternal health and COVID-19 services.

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., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 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.)

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., (© 2021. The Author(s).)

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., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: The authors have declared that no competing interests exist.

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., Competing Interests: The authors have declared that no competing interests exist.

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., Competing Interests: The authors have declared that no competing interests exist.

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., (© 2019 International Federation of Gynecology and Obstetrics.)

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., Competing Interests: The authors have declared that no competing interests exist.

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.

Objective: To quantify differences in assessing preterm delivery when calculating gestational age from last menstrual period (LMP) versus ultrasonography biometry., Methods: The Zambian Preterm Birth Prevention Study is an ongoing prospective cohort study that commenced enrolment in August 2015 at Women and Newborn Hospital of University Teaching Hospital in Lusaka, Zambia. Women at less than 20 weeks of pregnancy who were enrolled between August 17, 2015, and August 31, 2017, and underwent ultrasonography examination were included in the present analysis. The primary outcome was the difference between ultrasonography- and LMP-based estimated gestational age. Associations between baseline predictors and outcomes were assessed using simple regression. The proportion of preterm deliveries using LMP- and ultrasonography-derived gestational dating was calculated using Kaplan-Meier analysis., Results: The analysis included 942 women. The discrepancy between estimating gestational age using ultrasonography and LMP increased with greater gestational age at presentation and among patients with no history of preterm delivery. In a Kaplan-Meier analysis of 692 deliveries, 140 (20.2%, 95% confidence interval [CI] 17.7-23.0) and 79 (11.4%, 95% CI 9.6-13.6) deliveries were classified as preterm by LMP and ultrasonography estimates, respectively., Conclusion: Taking ultrasonography as a standard, a bias was observed in LMP-based gestational age estimates, which increased with advancing gestation at presentation. This resulted in misclassification of term deliveries as preterm., (© 2018 International Federation of Gynecology and Obstetrics.)

Background: Lifelong antiretroviral therapy (ART) is now recommended for all human immunodeficiency virus (HIV)-infected pregnant and breastfeeding women; however, few have described overall infant outcomes in this new era for the prevention of mother-to-child HIV transmission (PMTCT)., Methods: As part of an assessment of PMTCT program impact, we enrolled a prospective cohort study in 4 predominantly rural districts in Zambia. HIV-infected mothers and their newborns (≤30 days old) were recruited and followed at 6 weeks, 6 months and 12 months postpartum; infant specimens were tested via HIV DNA polymerase chain reaction. In Kaplan-Meier analyses, we estimated overall infant HIV-free survival and then stratified by district, community and maternal ART use. We investigated the relationship between community-level 12-month, self-reported maternal ART use and infant HIV-free survival via linear regression., Results: From June 2014 to November 2015, we enrolled 827 mother-infant pairs in 33 communities. At 12 months, small proportions of infants had died (2.8%), were HIV-infected (3.0%) or were lost to follow-up (4.3%). Overall, infant HIV-free survival was 99.0% [95% confidence interval (CI): 98.0%-99.5%] at 6 weeks, 97.5% (95% CI: 96.1%-98.4%) at 6 months and 96.3% (95% CI: 94.8%-97.4%) at 12 months. Women reporting ART use at enrollment had higher infant HIV-free survival than those who did not (97.4% vs. 89.0%, P = 0.01). Differences were noted at the district and site levels (P = 0.01). In community-level analysis, no relationship was observed between 12-month infant HIV-free survival and self-reported maternal ART use (P = 0.65)., Conclusion: Although encouraging, these findings highlight the need for rigorous monitoring and evaluation of PMTCT services at the population level.

Introduction: Zambia has made substantial investments in health systems capacity, yet it remains unclear whether improved service quality improves outcomes. We investigated the association between health system capacity and use of prevention of mother-to-child HIV transmission (PMTCT) services in Zambia., Materials and Methods: We analyzed data from two studies conducted in rural and semi-urban Lusaka Province in 2014-2015. Health system capacity, our primary exposure, was measured with a validated balanced scorecard approach. Based on WHO building blocks for health systems strengthening, we derived overall and domain-specific facility scores (range: 0-100), with higher scores indicating greater capacity. Our outcome, community-level maternal antiretroviral drug use at 12 months postpartum, was measured via self-report in a large cohort study evaluating PMTCT program impact. Associations between health systems capacity and our outcome were analyzed via linear regression., Results: Among 29 facilities, median overall facility score was 72 (IQR:67-74). Median domain scores were: patient satisfaction 75 (IQR 71-78); human resources 85 (IQR:63-87); finance 50 (IQR:50-67); governance 82 (IQR:74-91); service capacity 77 (IQR:68-79); service provision 60 (IQR:52-76). Our programmatic outcome was measured from 804 HIV-infected mothers. Median community-level antiretroviral use at 12 months was 81% (IQR:69-89%). Patient satisfaction was the only domain score significantly associated with 12-month maternal antiretroviral use (β:0.22; p = 0.02). When we excluded the human resources and finance domains, we found a positive association between composite 4-domain facility score and 12-month maternal antiretroviral use in peri-urban but not rural facilities., Conclusions: In these Zambian health facilities, patient satisfaction was positively associated with maternal antiretroviral 12 months postpartum. The association between overall health system capacity and maternal antiretroviral drug use was stronger in peri-urban versus rural facilities. Additional work is needed to guide strategic investments for improved outcomes in HIV and broader maternal-child health region-wide., Competing Interests: The authors declare that no competing interests exist.