Elizabeth M. McClure

Postpartum anemia affects approximately 75% of women in India. We conducted this implementation research (IR) related to the use of ferric carboxymaltose (FCM) intravenous (IV) iron as part of a trial in anemic postpartum women. The aim of the IR study was to understand potential facilitators and barriers to implementation of single-dose FCM IV iron. This is a mixed-methods study in three secondary-level healthcare facilities in Belagavi, India, designed to explore selected Consolidated Framework for Implementation Research constructs and Proctor’s framework elements. Quantitative data were gathered via surveys of postpartum women who received IV FCM (n = 308) and from healthcare workers and administrators (n = 16). Qualitative data included in-depth interviews with 15 women who received IV FCM, 15 family members of women, and 15 healthcare workers and administrators. Quantitative data were analyzed descriptively, and interview transcripts underwent directed content analysis to augment survey findings. Nearly all women believed IV iron made anemia symptoms better, 76% felt the single infusion process was very easy, 58% completely agreed to receive treatment again, and 69% were very likely to recommend treatment to family or friends. Family members were supportive of women receiving FCM. Health workers felt that single dose FCM had comparative advantages over oral iron; however, 4/10 health workers said giving FCM IV iron is harder than oral iron because of the patient monitoring involved and 8/16 health workers and administrators felt there were not enough trained staff to provide the service. Fewer than half of health workers and administrators (7/16) believed their hospital had enough resources to implement IV FCM infusions, and 9/16 said getting the necessary supplies would be a moderate or major barrier. In conclusion, the intervention was well accepted by women and their families and feasible for government health staff within the context of a trial. Future scale up of FCM IV iron would require out-of-pocket costs to be covered by public funding, staff training on the intervention, and strategies, such as dedicated staff or task shifting, to allow for monitoring during and after the infusion.

Objectives: Limited population‐based data have evaluated COVID‐19 infections during pregnancy in low‐ and middle‐income countries (LMICs). We updated COVID‐19 antibody positivity rates and relationships to pregnancy outcomes in unvaccinated women in LMICs. Design: COVID‐19 antibody testing was conducted for pregnant women at delivery. We evaluated pregnancy outcomes using data collected in a prospective registry. Setting: The Maternal and Newborn Health Registry (MNHR) is a prospective, population‐based study in specific geographic communities in Kenya, Zambia, the Democratic Republic of the Congo (DRC), Bangladesh, Pakistan, India, and Guatemala. Methods: From October 2020 to October 2021, we conducted COVID‐19 antibody testing at delivery among women enrolled in the MNHR ( n = 14 015). Results include women delivering from November 2021 to July 2022 ( n = 8204). Outcomes among women who were COVID‐19 positive versus negative at delivery were compared among women unvaccinated for COVID‐19. Outcome Measures: COVID‐19 antibody positivity rates, stillbirth, neonatal mortality, maternal mortality, and morbidity. Results: Vaccination among pregnant women increased from < 1% (October 2020–October 2021) to 30.4% (November 2021–June 2022). In the final period, COVID‐19 vaccination rates ranged from 0.1% in DRC to 67.4% in Guatemala. Among unvaccinated women, the antibody positivity rate overall was 14.0% (October 2020–December 2020), increasing to 69.5% during May–July 2022. Over time, antibody positivity rates increased until January 2022 for women in all sites, when the positivity rates remained relatively stable through July 2022. In the final period, antibody positivity rates ranged from 59.4% (DRC) to 88.0% (India). After adjusting for site and maternal characteristics, antibody positivity was not associated with any adverse fetal/neonatal outcome. Conclusions: In the pregnant populations across seven LMICs, COVID‐19 infections occurred in over 50% of unvaccinated women overall. Adverse pregnancy outcomes, including preterm birth, low birthweight, stillbirth, neonatal death, and antepartum hemorrhage, were not increased in women who were antibody positive compared to women who were antibody negative in either time period.

Objective: To evaluate if the effect of low‐dose aspirin (LDA) commenced between 6 and 13 weeks of gestational age (GA) on preterm delivery (PTD) is modified by total exposure. Design: Post hoc analysis of a randomized controlled trial. Setting: Hospitals in low‐resource settings in Africa, Asia and Latin America. Population: Outcomes were obtained for 11 908/11943 women at 6 0/7 to 13 6/7 weeks' GA randomized. Methods: Women received prepackaged two‐week medication allotments. Adherence was assessed by pill counts every 2 weeks. Estimated relative risk and 95% confidence interval data for each outcome at each GA of treatment initiation weeks were obtained by fitting a Poisson model to each outcome, adjusting for site, treatment arm and GA at treatment initiation. Main Outcomes Measures: The primary outcome was PTD. Secondary outcomes included PTD < 34 weeks and perinatal mortality including analysis by region. Results: The median gestational age at treatment initiation was 10.1 weeks (IQR 8.6, 12.0). 85.5% of the mothers had over 90% adherence to treatment. For each 1 week increase of GA at treatment initiation, the treatment risk ratio did not change for PTD [RR 0.97 (95% CI, 0.93, 1.02)], PTD < 34 weeks [< 0.98 (0.89, 1.07)] or perinatal mortality [1.04 (0.96, 1.12)], with no evidence of effect modification. For each 5% increase in adherence, the treatment risk ratio did not change for PTD [1.01 (0.99, 1.04)], PTD < 34 weeks [< 0.99 (0.95, 1.03)] or perinatal mortality [1.02 (0.98, 1.06)], indicating no meaningful interaction with adherence. There was no effect modification by region. Conclusions: This analysis shows that the results of PTD, PTD < 34 weeks and perinatal mortality were not dependent on the timing of the initiation or adherence to treatment. Trial Registration: ClinicalTrials.gov identifier: NCT02409680

Objective: The randomized trial of azithromycin to reduce maternal and neonatal sepsis (the A‐PLUS Trial) found substantial reduction in maternal sepsis among women receiving azithromycin and substantial non‐study antibiotic use. This secondary analysis explored the effect modification of non‐study antibiotics on azithromycin versus placebo on maternal and newborn infection among A‐PLUS participants. Methods: Women ≥28 weeks gestation in labor and planning a vaginal delivery at a study hospital in seven low‐ and middle‐income countries (Bangladesh, India [two sites], Pakistan, Guatemala, Kenya, Democratic Republic of Congo, and Zambia) were eligible for inclusion. Non‐study antibiotic use was collected prospectively. We estimated the interaction of non‐study antibiotics with azithromycin versus placebo on maternal and newborn sepsis. Results: A total of 29 287 participants were randomized (14 590 to azithromycin; 14 688 to placebo). Maternal infection was reduced among the azithromycin group compared to placebo among those who did not receive non‐study antibiotics, with estimated relative risk (RR) 0.58 (95% confidence interval [CI] 0.48, 0.70), and among those who received non‐study antibiotics, with RR 0.80 (95% CI 0.70, 0.91). Similar results were observed for maternal sepsis. Neonatal infection was not significantly reduced in any group. These results were similar when stratified by African and Asian region but not statistically significant. Conclusion: Our results suggest a benefit of azithromycin in reducing maternal infection or sepsis across all groups, with a larger reduction in risk among participants who had not received other antibiotics. Given the concerns of inappropriate use of antibiotics, further research is warranted to determine the most effective strategies of reducing risk of infection.

Objective: A multi‐centre international trial (A‐PLUS), demonstrated that a single dose of 2 g oral azithromycin in labour reduced the risk of maternal sepsis or death, but not neonatal mortality. We aimed to determine whether the efficacy of azithromycin in prevention of any maternal infection or neonatal infection varied by time interval from azithromycin administration to delivery. Design: This is a secondary analysis of a randomized controlled trial. Setting: Multi‐centre international randomized controlled trial. Population: Pregnant patients ≥ 28 weeks gestation (singleton or multiple gestation) presenting in labour for planned vaginal delivery. Outcomes: The primary outcome for this secondary analysis was maternal infection and the secondary outcome was any neonatal infection. Methods: The estimated relative risks (and 95% confidence interval) of any maternal or neonatal infection comparing azithromycin to placebo were obtained by fitting a Poisson model adjusting for site, treatment arm, hours between drug administration and delivery (as continuous measure, and ≤ 12 or > 12 h for maternal and ≤ 9 or > 9 h for neonatal), and the two‐way interaction between treatment arm and hours between drug administration and delivery. Results: Included in the analysis were n = 14 569 randomized to azithromycin and n = 14 667 to placebo. There was no evidence that the benefit of azithromycin on reducing the risk of any maternal infection varied by time from dose to delivery (RR 0.71 (0.64–0.79) and RR 0.71 (0.54–0.94) for ≤ 12 and > 12 h respectively, interaction p = 0.987), although there was an observed interaction in Sub‐Saharan Africa subgroup with reduced risk observed with administration > 12 vs. ≤ 12 (RR 0.21 (0.08–0.54) vs. RR 0.52 (0.41–0.66), interaction p = 0.03). There was no benefit observed in prevention of infant infection regardless of time from dose to delivery (≤ 9 or > 9 h) (RR 1.00 (0.95–1.06) and RR 1.01 (0.88–1.15) interaction p = 0.997). Conclusion: The benefit observed with a single intrapartum dose of azithromycin for prevention of any maternal infection in the setting of planned vaginal delivery was not observed to vary by time interval from azithromycin administration to delivery, although in some populations there may be greater benefit with delivery > 12 h from administration. Pregnant patients presenting for planned vaginal birth benefit from a single dose of 2 g azithromycin regardless of how soon delivery is anticipated.

Background The Azithromycin Prevention in Labor Use Study (A-PLUS), a large, multi-national randomized trial, was performed to evaluate the improvement of maternal and newborn outcomes following a single dose of azithromycin (AZ) given during labor. However, the immediate and long-term impact of this single dose on the microbiome and the development or prevalence of antimicrobial resistance are unknown. We designed a sub-study to assess AZ resistance of bacterial isolates from clinical infections and of three target bacteria (Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli) from the serial surveillance of the nasopharynx and rectum. Additionally, the serially surveilled samples will be evaluated for changes to the microbiome and the resistome of the nasopharynx and rectum. Methods and Analysis As part of the large, randomized APLUS trial, maternal and neonatal clinical infections were monitored for up to 42 days postpartum, and samples collected for culture using site-specific routine methods. For this sub-study, cultured bacterial isolates will be assessed for AZ resistance using an antibiotic susceptibility method. Additionally, a random subset of maternal-neonatal dyads from the main trial will be selected for serial surveillance with aseptic swab collections of the nasopharynx and the rectum at baseline, and subsequently at 1-week, 6-weeks, 3-months, 6-months, and 12-months postpartum. The serial samples will undergo selective culturing of sentinel bacterial species and screened for AZ resistance. An additional set of serial samples will be stored for future microbiome and resistome analyses. Ethics and Dissemination The study protocol was reviewed, and ethics approval obtained from all the relevant ethical review boards at each research site. All participants will provide informed written consent prior to their enrollment. Results of the trial will be disseminated through peer-reviewed publications, presentations at relevant conferences, and at dissemination meetings with the ministries of health and local stakeholders at each research site. Trial Registration NCT03871491.

Objective: To evaluate similarities in pathways leading to preterm stillbirth and preterm neonatal death. Design: Prospective observational study. Setting: Study hospitals in India and Pakistan. Population: Preterm stillbirths and neonatal deaths ≥ 1000 g delivered in a study facility and evaluated by an expert panel for cause of death. Methods: An observational study of stillbirths and preterm neonatal deaths. Main Outcome Measures: Asphyxia, placental maternal vascular malperfusion (MVM), maternal hypertension, fetal growth restriction (FGR). Results: There were 398 preterm stillbirths and 582 preterm neonatal deaths in our study population. Of these, the panel determined asphyxia as a cause of death for 80.2% of the preterm stillbirths and 57.4% of the preterm neonatal deaths. Of the 319 preterm stillbirths with asphyxia, 62.4% also had placental MVM, while only 38.0% of the preterm stillbirths without birth asphyxia had MVM. Maternal hypertension was present among 44.5% of the stillbirths and FGR in 35.2%. Among the stillbirths with hypertension, 64.4% had asphyxia and MVM compared to 38.5% among those without hypertension. Similar patterns were seen among neonatal deaths. Conclusions: Both MVM and birth asphyxia were commonly present among stillbirths and neonatal deaths, especially those associated with hypertension and FGR compared to stillbirths and neonatal deaths without those conditions. These findings suggest that MVM and fetal asphyxia are part of a common pathway for stillbirth and preterm neonatal deaths.

Background Anemia among women of reproductive age has remained highly prevalent globally. Intravenous (IV) iron is well tolerated and proven effective for treating postpartum iron deficiency anemia in high-income countries, but evidence from LMICs, where oral iron is standard treatment, is limited. The PRIORITY trial will test the effectiveness of IV iron compared to oral iron for postpartum women with moderate anemia in eight LMIC sites. An implementation research (IR) study will be conducted alongside the PRIORITY trial in India and Pakistan to gather information on the intervention characteristics and the implementation process, and to assess feasibility, acceptability, fidelity, and cost of implementation for providing IV iron to postpartum women with moderate iron deficiency anemia. Methods The PRIORITY IR study will use a mixed methods convergent parallel design guided by two frameworks: the Consolidated Framework for Implementation Research and Proctor’s implementation outcomes. The IR study will be conducted in the Belagavi, India and Karachi, Pakistan PRIORITY trial sites. Participants will include postpartum women in the IV iron intervention arm of the trial, family members, health workers administering IV iron, hospital administrators, postpartum women who refuse to be part of the trial (Pakistan only), and postpartum women in the oral iron arm of the trial (India only). Data collection methods will include surveys, in-depth interviews, a supervision checklist, and a cost assessment. Survey and supervision checklist data will be analyzed descriptively. Interview data will be analyzed using a directed content analysis approach. Discussion The PRIORITY IR study will contribute important information about implementation processes and strategies and feasibility, acceptability, fidelity, and costs for postpartum IV iron implementation. Results of the study can provide guidance for implementing effective anemia treatment in LMIC contexts with a high anemia burden. Registration NCT05590260 (21/10/2022), CTRI/2022/10/046632 (19/10/2022), CTRI/2023/05/053302 (31/05/2023).