Chemoprevention for malaria with monthly intermittent preventive treatment with dihydroartemisinin-piperaquine in pregnant women living with HIV on daily co-trimoxazole in Kenya and Malawi: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The efficacy of daily co-trimoxazole, an antifolate used for malaria chemoprevention in pregnant women living with HIV, is threatened by cross-resistance of Plasmodium falciparum to the antifolate sulfadoxine-pyrimethamine. We assessed whether addition of monthly dihydroartemisinin-piperaquine to daily co-trimoxazole is more effective at preventing malaria infection than monthly placebo plus daily co-trimoxazole in pregnant women living with HIV. METHODS: We did an individually randomised, two-arm, placebo-controlled trial in areas with high-grade sulfadoxine-pyrimethamine resistance in Kenya and Malawi. Pregnant women living with HIV on dolutegravir-based combination antiretroviral therapy (cART) who had singleton pregnancies between 16 weeks' and 28 weeks' gestation were randomly assigned (1:1) by computer-generated block randomisation, stratified by site and HIV status (known positive vs newly diagnosed), to daily co-trimoxazole plus monthly dihydroartemisinin-piperaquine (three tablets of 40 mg dihydroartemisinin and 320 mg piperaquine given daily for 3 days) or daily co-trimoxazole plus monthly placebo. Daily co-trimoxazole consisted of one tablet of 160 mg sulfamethoxazole and 800 mg trimethoprim. The primary endpoint was the incidence of Plasmodium infection detected in the peripheral (maternal) or placental (maternal) blood or tissue by PCR, microscopy, rapid diagnostic test, or placental histology (active infection) from 2 weeks after the first dose of dihydroartemisinin-piperaquine or placebo to delivery. Log-binomial regression was used for binary outcomes, and Poisson regression for count outcomes. The primary analysis was by modified intention to treat, consisting of all randomised eligible participants with primary endpoint data. The safety analysis included all women who received at least one dose of study drug. All investigators, laboratory staff, data analysts, and participants were masked to treatment assignment. This trial is registered with ClinicalTrials.gov, NCT04158713. FINDINGS: From Nov 11, 2019, to Aug 3, 2021, 904 women were enrolled and randomly assigned to co-trimoxazole plus dihydroartemisinin-piperaquine (n=448) or co-trimoxazole plus placebo (n=456), of whom 895 (99%) contributed to the primary analysis (co-trimoxazole plus dihydroartemisinin-piperaquine, n=443; co-trimoxazole plus placebo, n=452). The cumulative risk of any malaria infection during pregnancy or delivery was lower in the co-trimoxazole plus dihydroartemisinin-piperaquine group than in the co-trimoxazole plus placebo group (31 [7%] of 443 women vs 70 [15%] of 452 women, risk ratio 0·45, 95% CI 0·30-0·67; p=0·0001). The incidence of any malaria infection during pregnancy or delivery was 25·4 per 100 person-years in the co-trimoxazole plus dihydroartemisinin-piperaquine group versus 77·3 per 100 person-years in the co-trimoxazole plus placebo group (incidence rate ratio 0·32, 95% CI 0·22-0·47, p<0·0001). The number needed to treat to avert one malaria infection per pregnancy was 7 (95% CI 5-10). The incidence of serious adverse events was similar between groups in mothers (17·7 per 100 person-years in the co-trimoxazole plus dihydroartemisinin-piperaquine group [23 events] vs 17·8 per 100 person-years in the co-trimoxazole group [25 events]) and infants (45·4 per 100 person-years [23 events] vs 40·2 per 100 person-years [21 events]). Nausea within the first 4 days after the start of treatment was reported by 29 (7%) of 446 women in the co-trimoxazole plus dihydroartemisinin-piperaquine group versus 12 (3%) of 445 women in the co-trimoxazole plus placebo group. The risk of adverse pregnancy outcomes did not differ between groups. INTERPRETATION: Addition of monthly intermittent preventive treatment with dihydroartemisinin-piperaquine to the standard of care with daily unsupervised co-trimoxazole in areas of high antifolate resistance substantially improves malaria chemoprevention in pregnant women living with HIV on dolutegravir-based cART and should be considered for policy. FUNDING: European and Developing Countries Clinical Trials Partnership 2; UK Joint Global Health Trials Scheme (UK Foreign, Commonwealth and Development Office; Medical Research Council; National Institute for Health Research; Wellcome); and Swedish International Development Cooperation Agency.

Effect of monthly intermittent preventive treatment with dihydroartemisinin-piperaquine with and without azithromycin versus monthly sulfadoxine-pyrimethamine on adverse pregnancy outcomes in Africa: a double-blind randomised, partly placebo-controlled trial.

BACKGROUND: Intermittent preventive treatment in pregnancy (IPTp) with dihydroartemisinin-piperaquine is more effective than IPTp with sulfadoxine-pyrimethamine at reducing malaria infection during pregnancy in areas with high-grade resistance to sulfadoxine-pyrimethamine by Plasmodium falciparum in east Africa. We aimed to assess whether IPTp with dihydroartemisinin-piperaquine, alone or combined with azithromycin, can reduce adverse pregnancy outcomes compared with IPTp with sulfadoxine-pyrimethamine. METHODS: We did an individually randomised, double-blind, three-arm, partly placebo-controlled trial in areas of high sulfadoxine-pyrimethamine resistance in Kenya, Malawi, and Tanzania. HIV-negative women with a viable singleton pregnancy were randomly assigned (1:1:1) by computer-generated block randomisation, stratified by site and gravidity, to receive monthly IPTp with sulfadoxine-pyrimethamine (500 mg of sulfadoxine and 25 mg of pyrimethamine for 1 day), monthly IPTp with dihydroartemisinin-piperaquine (dosed by weight; three to five tablets containing 40 mg of dihydroartemisinin and 320 mg of piperaquine once daily for 3 consecutive days) plus a single treatment course of placebo, or monthly IPTp with dihydroartemisinin-piperaquine plus a single treatment course of azithromycin (two tablets containing 500 mg once daily for 2 consecutive days). Outcome assessors in the delivery units were masked to treatment group. The composite primary endpoint was adverse pregnancy outcome, defined as fetal loss, adverse newborn baby outcomes (small for gestational age, low birthweight, or preterm), or neonatal death. The primary analysis was by modified intention to treat, consisting of all randomised participants with primary endpoint data. Women who received at least one dose of study drug were included in the safety analyses. This trial is registered with ClinicalTrials.gov, NCT03208179. FINDINGS: From March-29, 2018, to July 5, 2019, 4680 women (mean age 25·0 years [SD 6·0]) were enrolled and randomly assigned: 1561 (33%; mean age 24·9 years [SD 6·1]) to the sulfadoxine-pyrimethamine group, 1561 (33%; mean age 25·1 years [6·1]) to the dihydroartemisinin-piperaquine group, and 1558 (33%; mean age 24·9 years [6.0]) to the dihydroartemisinin-piperaquine plus azithromycin group. Compared with 335 (23·3%) of 1435 women in the sulfadoxine-pyrimethamine group, the primary composite endpoint of adverse pregnancy outcomes was reported more frequently in the dihydroartemisinin-piperaquine group (403 [27·9%] of 1442; risk ratio 1·20, 95% CI 1·06-1·36; p=0·0040) and in the dihydroartemisinin-piperaquine plus azithromycin group (396 [27·6%] of 1433; 1·16, 1·03-1·32; p=0·017). The incidence of serious adverse events was similar in mothers (sulfadoxine-pyrimethamine group 17·7 per 100 person-years, dihydroartemisinin-piperaquine group 14·8 per 100 person-years, and dihydroartemisinin-piperaquine plus azithromycin group 16·9 per 100 person-years) and infants (sulfadoxine-pyrimethamine group 49·2 per 100 person-years, dihydroartemisinin-piperaquine group 42·4 per 100 person-years, and dihydroartemisinin-piperaquine plus azithromycin group 47·8 per 100 person-years) across treatment groups. 12 (0·2%) of 6685 sulfadoxine-pyrimethamine, 19 (0·3%) of 7014 dihydroartemisinin-piperaquine, and 23 (0·3%) of 6849 dihydroartemisinin-piperaquine plus azithromycin treatment courses were vomited within 30 min. INTERPRETATION: Monthly IPTp with dihydroartemisinin-piperaquine did not improve pregnancy outcomes, and the addition of a single course of azithromycin did not enhance the effect of monthly IPTp with dihydroartemisinin-piperaquine. Trials that combine sulfadoxine-pyrimethamine and dihydroartemisinin-piperaquine for IPTp should be considered. FUNDING: European & Developing Countries Clinical Trials Partnership 2, supported by the EU, and the UK Joint-Global-Health-Trials-Scheme of the Foreign, Commonwealth and Development Office, Medical Research Council, Department of Health and Social Care, Wellcome, and the Bill-&-Melinda-Gates-Foundation.

Chemoprevention of malaria with long-acting oral and injectable drugs: an updated target product profile.

Malaria is preventable, but the burden of disease remains high with over 249 million cases and 608,000 deaths reported in 2022. Historically, the most important protective interventions have been vector control and chemopreventive medicines with over 50 million children receiving seasonal malaria chemoprevention in the year 2023. Two vaccines are approved and starting to be deployed, bringing additional protection for children up to 36 months. However, the impact of these currently available tools is somewhat limited on various fronts. Vaccines exhibit partial efficacy, are relatively costly, and not accessible in all settings. The challenges encountered with chemoprevention are barriers to acceptability and feasibility, including frequency of dosing, and the lack of options in the first trimester of pregnancy and for women living with HIV. Also, the emergence of resistance against chemopreventive medicines is concerning. To address these limitations, a target product profile (TPP) is proposed as a road map to guide innovation and to boost the quest for novel chemopreventive alternatives. This TPP describes the ideal product attributes, while acknowledging potential trade-offs that may be needed. Critically, it considers the target populations most at risk; primarily infants, children, and pregnant women. Malaria control and elimination requires appropriate chemoprevention, not only in areas of high endemicity and transmission, but also in lower transmission areas where immunity is declining, as well as for travellers from areas where malaria has been eliminated. New medicines should show acceptable safety and tolerability, with high and long protective efficacy. Formulations and costs need to support operational adherence, access, and effectiveness. Next generation long-acting oral and injectable drugs are likely to constitute the backbone of malaria prevention. Therefore, the perspectives of front-line experts in malaria prevention, researchers, and those involved in drug development are captured in the TPP. This inclusive approach aims at concentrating efforts and aligning responses across the community to develop new and transformative medicines.

Four antenatal care visits by four months of pregnancy and four vital tests for pregnant mothers: impact of a community-facility health systems strengthening intervention in Migori County, Kenya.

BACKGROUND: Early attendance at antenatal care (ANC), coupled with good-quality care, is essential for improving maternal and child health outcomes. However, achieving these outcomes in sub-Saharan Africa remains a challenge. This study examines the effects of a community-facility health system strengthening model (known as 4byFour) on early ANC attendance, testing for four conditions by four months of pregnancy, and four ANC clinic visits in Migori county, western Kenya. METHODS: We conducted a mixed methods quasi-experimental study with a before-after interventional design to assess the impact of the 4byFour model on ANC attendance. Data were collected between August 2019 and December 2020 from two ANC hospitals. Using quantitative data obtained from facility ANC registers, we analysed 707 baseline and 894 endline unique ANC numbers (attendances) based on negative binomial regression. Logistic regression models were used to determine the impact of patient factors on outcomes with Akaike Information Criterion (AIC) and likelihood ratio testing used to compare models. Regular facility stock checks were undertaken at the study sites to assess the availability of ANC profile tests. Analysis of the quantitative data was conducted in R v4.1.1 software. Additionally, qualitative in-depth interviews were conducted with 37 purposively sampled participants, including pregnant mothers, community health volunteers, facility staff, and senior county health officials to explore outcomes of the intervention. The interview data were audio-recorded, transcribed, and coded; and thematic analysis was conducted in NVivo. RESULTS: There was a significant 26% increase in overall ANC uptake in both facilities following the intervention. Early ANC attendance improved for all age groups, including adolescents, from 22% (baseline) to 33% (endline, p = 0.002). Logistic regression models predicting early booking were a better fit to data when patient factors were included (age, parity, and distance to clinic, p = 0.004 on likelihood ratio testing), suggesting that patient factors were associated with early booking.The proportion of women receiving all four tests by four months increased to 3% (27/894), with haemoglobin and malaria testing rates rising to 8% and 4%, respectively. Despite statistical significance (p < 0.001), the rates of testing remained low. Testing uptake in ANC was hampered by frequent shortage of profile commodities not covered by buffer stock and low ANC attendance during the first trimester. Qualitative data highlighted how community health volunteer-enhanced health education improved understanding and motivated early ANC-seeking. Community pregnancy testing facilitated early detection and referral, particularly for adolescent mothers. Challenges to optimal ANC attendance included insufficient knowledge about the ideal timing for ANC initiation, financial constraints, and long distances to facilities. CONCLUSION: The 4byFour model of community-facility health system strengthening has the potential to improve early uptake of ANC and testing in pregnancy. Sustained improvement in ANC attendance requires concerted efforts to improve care quality, consistent availability of ANC commodities, understand motivating factors, and addressing barriers to ANC. Research involving randomised control trials is needed to strengthen the evidence on the model's effectiveness and inform potential scale up.

Improving birth weight measurement and recording practices in Kenya and Tanzania: a prospective intervention study with historical controls.

BACKGROUND: Low birth weight (LBW) is a significant public health concern given its association with early-life mortality and other adverse health consequences that can impact the entire life cycle. In many countries, accurate estimates of LBW prevalence are lacking due to inaccuracies in collection and gaps in available data. Our study aimed to determine LBW prevalence among facility-born infants in selected areas of Kenya and Tanzania and to assess whether the introduction of an intervention to improve the accuracy of birth weight measurement would result in a meaningfully different estimate of LBW prevalence than current practice. METHODS: We carried out a historically controlled intervention study in 22 health facilities in Kenya and three health facilities in Tanzania. The intervention included: provision of high-quality digital scales, training of nursing staff on accurate birth weight measurement, recording and scale calibration practices, and quality maintenance support that consisted of enhanced supervision and feedback (prospective arm). The historically controlled data were birth weights from the same facilities recorded in maternity registers for the same calendar months from the previous year measured using routine practices and manual scales. We calculated mean birth weight (95% confidence interval CI), mean difference in LBW prevalence, and respective risk ratio (95% CI) between study arms. RESULTS: Between October 2019 and February 2020, we prospectively collected birth weights from 8441 newborns in Kenya and 4294 in Tanzania. Historical data were available from 9318 newborns in Kenya and 12,007 in Tanzania. In the prospective sample, the prevalence of LBW was 12.6% (95% confidence intervals [CI]: 10.9%-14.4%) in Kenya and 18.2% (12.2%-24.2%) in Tanzania. In the historical sample, the corresponding prevalence estimates were 7.8% (6.5%-9.2%) and 10.0% (8.6%-11.4%). Compared to the retrospective sample, the LBW prevalence in the prospective sample was 4.8% points (3.2%-6.4%) higher in Kenya and 8.2% points (2.3%-14.0%) higher in Tanzania, corresponding to a risk ratio of 1.61 (1.38-1.88) in Kenya and 1.81 (1.30-2.52) in Tanzania. CONCLUSION: Routine birth weight records underestimate the risk of LBW among facility-born infants in Kenya and Tanzania. The quality of birth weight data can be improved by a simple intervention consisting of provision of digital scales and supportive training.

Delivery effectiveness of and adherence to intermittent preventive treatment for malaria in pregnancy with dihydroartemisinin-piperaquine with or without targeted information transfer or sulfadoxine-pyrimethamine in western Kenya: a three-armed, pragmatic, open-label, cluster-randomised trial.

BACKGROUND: High-level resistance to sulfadoxine-pyrimethamine threatens the efficacy of WHO-recommended intermittent preventive treatment in pregnancy (IPTp) with single-dose sulfadoxine-pyrimethamine to prevent malaria. Monthly IPTp with dihydroartemisinin-piperaquine, a 3-day regimen, is an emerging alternative, but this regimen poses potential implementation and adherence challenges. We aimed to assess adherence to a multiday IPTp with dihydroartemisinin-piperaquine regimen and its delivery effectiveness in routine antenatal care settings in western Kenya. METHODS: We conducted a pragmatic, three-armed, open-label, cluster-randomised trial in antenatal clinics in 18 health-care facilities (six facilities per group) in Kisumu County and Homa Bay County in western Kenya. Clusters were facilities offering routine antenatal care services provided by trained Ministry of Health staff with 100 or more antenatal clinic attendances per month between July, 2018, and June, 2019. Private or mission hospitals, dispensaries, referral hospitals, and trial sites were excluded. Individuals in their first trimester, living with HIV, or who were not attending a scheduled antenatal clinic visit were excluded. The 18 antenatal clinics were grouped into matched triplets stratified by location and clinics in each matched triplet were randomly assigned to one of the three study groups (1:1:1). Masking was not possible. Two groups were given IPTp with dihydroartemisinin-piperaquine (one group with a targeted information transfer intervention and one group without any additional interventions) and one group was given the standard of care (ie, IPTp with sulfadoxine-pyrimethamine). The primary endpoint, adherence, was defined as the proportion of participants completing their most recent 3-day IPTp with dihydroartemisinin-piperaquine regimen. This completion was verified by pill counts during home visits no more than 2 days after participants' 3-day regimens ended. The secondary endpoint, delivery effectiveness, was defined as the proportion of participants who received the correct number of IPTp tablets and correctly repeated dosing instructions (ie, correctly recalled the instructions they received about self-administered dihydroartemisinin-piperaquine doses and the number of sulfadoxine-pyrimethamine tablets they had received) at their exit from the antenatal clinic. Individuals receiving treatment for malaria, visiting a clinic for registration only, or interviewed during IPTp drug stock-outs were excluded from analyses. We used generalised linear mixed models to compare endpoints among the IPTp with dihydroartemisinin-piperaquine groups. This trial was registered with ClinicalTrials.gov, NCT04160026, and is complete. FINDINGS: 15 facilities (five per group) completed the trial, with 1189 participants having exit interviews (377 in the IPTp with sulfadoxine-pyrimethamine group, 408 in the IPTp with dihydroartemisinin-piperaquine only group, and 404 in the IPTp with dihydroartemisinin-piperaquine plus targeted information transfer intervention group) and 586 participants having home visits (267 in the IPTp with dihydroartemisinin-piperaquine only group and 319 in the IPTp with dihydroartemisinin-piperaquine plus targeted information transfer intervention group) from Sept 8 to Dec 10, 2020. Relative to the IPTp with dihydroartemisinin-piperaquine only group, adherence was 16% higher in the IPTp with dihydroartemisinin-piperaquine plus targeted information transfer intervention group (266 [83%] of 319 participants vs 196 [73%] of 267 participants; adjusted relative risk [RR] 1·16, 95% CI 1·03-1·31; p=0·0140). Delivery effectiveness in the IPTp with dihydroartemisinin-piperaquine plus targeted information transfer intervention group was not significantly different from that in the IPTp with sulfadoxine-pyrimethamine group (352 [87%] of 403 participants vs 335 [89%] of 375 participants; adjusted RR 0·97, 95% CI 0·90-1·05; p=0·4810). However, delivery effectiveness in the IPTp with dihydroartemisinin-piperaquine only group was significantly lower than in the IPTp with sulfadoxine-pyrimethamine group (300 [74%] of 404 participants vs 335 [89%] of 375 participants; 0·84, 0·75-0·95; p=0·0030). INTERPRETATION: Targeted information transfer interventions to health-care providers and pregnant individuals boost antenatal care delivery adherence to a multiday regimen with dihydroartemisinin-piperaquine. FUNDING: European and Developing Countries Clinical Trials Partnership 2, UK Joint Global Health Trials Scheme of the Foreign, Commonwealth and Development Office, Medical Research Council, National Institute for Health and Care Research, and Wellcome Trust; and Swedish International Development Cooperation Agency.

Exploring the influence of postnatal depression on neonatal care practices among mothers in Western Kenya: A qualitative study.

BACKGROUND: Postnatal depression (PND) is associated with adverse infant neurodevelopmental outcomes. Evidence is limited on how PND influences neonatal (<28 days old) outcomes in low- and middle-income countries, such as Kenya, which bear the global burden of neonatal morbidity and mortality. OBJECTIVES: To explore how PND influences neonatal feeding and care practices among women in the early postnatal period in rural Western Kenya. DESIGN: A cross-sectional study. METHODS: Semi-structured interviews were conducted at 2-weeks postpartum among mothers of newborn infants identified <72 h old from the postnatal wards and clinics across five health facilities in Kisumu County of Western Kenya. They were all screened for features suggestive of postnatal depression using the Edinburgh Postnatal Depression Scale. RESULTS: Twenty-four mothers were interviewed, 13 of whom had features suggestive of PND. All mothers experienced health or socio-economic adversities in the perinatal period, including traumatic deliveries, financial constraints, and challenging relationships with partners/other family members. Feeding difficulties due to perceived insufficient breastmilk were a particular challenge for mothers with features of PND, who were more likely to introduce complementary feeds. Maternal health-seeking decisions were influenced by high financial cost, long waiting times and poor interactions with health care providers that induced stress and fear among mothers. Maternal caregiving capacity was influenced by her ability to juggle other household duties, which was difficult for mothers with features suggestive of PND. Support from friends and relatives positively impacted maternal mood and caregiving ability. CONCLUSION: Mothers experienced many stress-inducing events in the perinatal period which potentially exacerbated features of PND in the immediate postnatal period. Women with features of PND were particularly vulnerable to these stressors that influenced infant caregiving practices. Addressing the socio-economic challenges and health system gaps that include scale up of compassionate and respectful care for women during pregnancy and childbirth, as well as early screening and intervention of PND, through enhanced referral pathways between health facilities and community support structures, could mitigate against the impact of PND on neonatal caregiving.

Qualitative perspectives on COVID-19, interpersonal violence, and interventions to improve well-being from adolescent girls and young women in Kisumu, Kenya.

Introduction: Adolescent girls and young women (AGYW) face a high burden of gender-based violence (GBV) worldwide. The COVID-19 pandemic and associated policies led to global increases in GBV, decreased access to resources, and disruptions of pathways to care. We aimed to understand the effects of COVID-19 on AGYW affected by GBV in Kisumu, Kenya, as well as to identify possible interventions to mitigate those effects. Methods: Focus group discussions (FGDs) were conducted with AGYW aged 15-25 with a history of exposure to GBV. AGYW were split into age-matched groups; aged 15-19 for younger groups and 19-25 for older groups. Discussions focused on how COVID-19 affected experiences of GBV, access to care services, economic and social outcomes, and opportunities for interventions to mitigate negative impacts of COVID-19 and violence. Results: Five FGDs with 46 AGYW were completed in June-September 2021. AGYW described increases in all types of GBV, particularly sexual abuse and intimate partner violence. Early marriage and subsistence transactional sex also increased. AGYW described violence as both a cause and effect of poor economic, social and health consequences related to the pandemic. Notably, AGYW emphasized stress, lack of mental health support and increased substance use as risk factors for violence, and discussed the deleterious mental health effects of violence-particularly in the wake of disruption of mental health services. COVID-19 disrupted referrals to violence-related services, and reduced access to both medical services and psychosocial services. AGYW believed that interventions focused on improving mental health as well as economic empowerment would be the most feasible and acceptable in mitigating the negative effects of COVID-19 and related exacerbations in violence. Discussion: AGYW reported increases in almost all forms of GBV during the pandemic, with related exacerbation in mental health. Concurrently, AGYW endorsed decreased access to care services. As there is no evidence that violence and mental health challenges will quickly resolve, there is an urgent need to identify and implement interventions to mitigate these negative effects.

Design and implementation of a community-based mother-to-mother peer support programme for the follow-up of low birthweight infants in rural western Kenya.

Background: Globally, low birthweight (LBW) infants (<2,500 g) have the highest risk of mortality during the first year of life. Those who survive often have adverse health outcomes. Post-discharge outcomes of LBW infants in impoverished communities in Africa are largely unknown. This paper describes the design and implementation of a mother-to-mother peer training and mentoring programme for the follow-up of LBW infants in rural Kenya. Methods: Key informant interviews were conducted with 10 mothers of neonates (infants <28 days) from two rural communities in western Kenya. These data informed the identification of key characteristics required for mother-to-mother peer supporters (peer mothers) following up LBW infants post discharge. Forty potential peer mothers were invited to attend a 5-day training programme that focused on three main themes: supportive care using appropriate communication, identification of severe illness, and recommended care strategies for LBW infants. Sixteen peer mothers were mentored to conduct seven community follow-up visits to each mother-LBW infant pair with fifteen completing all the visits over a 6-month period. A mixed methods approach was used to evaluate the implementation of the programme. Quantitative data of peer mother socio-demographic characteristics, recruitment, and retention was collected. Two post-training focus group discussions were conducted with the peer mothers to explore their experiences of the programme. Descriptive statistics were generated from the quantitative data and the qualitative data was analysed using a thematic framework. Results: The median age of the peer mothers was 26 years (range 21-43). From March-August 2019, each peer mother conducted a median of 28 visits (range 7-77) with fourteen (88%) completing all their assigned follow-up visits. Post training, our interviews suggest that peer mothers felt empowered to promote appropriate infant feeding practices. They gave multiple examples of improved health seeking behaviours as a result of the peer mother training programme. Conclusion: Our peer mother training programme equipped peer mothers with the knowledge and skills for the post-discharge follow-up of LBW infants in this rural community in Kenya. Community-based interventions for LBW infants, delivered by appropriately trained peer mothers, have the potential to address the current gaps in post-discharge care for these infants.

Understanding ART Adherence among Adolescent Girls and Young Women in Western Kenya: A Cross-Sectional Study of Barriers and Facilitators.

BACKGROUND: HIV remains a leading cause of death for adolescent girls and young women (AGYW) in sub-Saharan Africa. This population has a high incidence of HIV and other comorbidities, such as experiencing violence, and low antiretroviral therapy (ART) adherence. To reach global HIV goals, data are needed on the specific adherence barriers for AGYW living with HIV, so interventions can be targeted effectively. METHODS: Cross-sectional data were collected at urban and rural health facilities in and around Kisumu County, western Kenya, from January to June 2022, from AGYW 15-24 years of age who were living with HIV. Surveys included questions on intimate partner violence, mental health issues, food security, and orphanhood. Adherence was categorized using viral load testing where available and the Center for Adherence Support Evaluation (CASE) adherence index otherwise. Logistic regression was used to assess associations between potential explanatory variables and adherence. FINDINGS: In total, 309 AGYW participated. AGYW with experiences of emotional violence (Odds Ratio [OR] = 1.94, 95% Confidence Interval [CI] = 1.03-3.66), moderate or severe depression (OR = 3.19, 95% CI = 1.47-6.94), and/or substance use (OR = 2.71, 95% CI = 1.24-5.92) had significantly higher odds of poor adherence when compared to AGYW without these respective experiences. Physical and sexual violence, food insecurity, and orphanhood were not associated with poor adherence in this cohort. INTERPRETATION: Elucidating the risk factors associated with poor adherence among AGYW living with HIV allows us to identify potential targets for future interventions to improve ART adherence and HIV care outcomes. Mental health and violence prevention interventions, including combination interventions, may prove to be promising approaches.

Fetal growth and birth weight are independently reduced by malaria infection and curable sexually transmitted and reproductive tract infections in Kenya, Tanzania, and Malawi: A pregnancy cohort study.

OBJECTIVES: Malaria and sexually transmitted and reproductive tract infections (STIs/RTIs) are highly prevalent in sub-Saharan Africa and associated with poor pregnancy outcomes. We investigated the individual and combined effects of malaria and curable STIs/RTIs on fetal growth in Kenya, Tanzania, and Malawi. METHODS: This study was nested within a randomized trial comparing monthly intermittent preventive treatment for malaria in pregnancy with sulfadoxine-pyrimethamine vs dihydroartemisinin-piperaquine, alone or combined with azithromycin. Fetal weight gain was assessed by serial prenatal ultrasound. Malaria was assessed monthly, and Treponema pallidum, Neisseria gonorrhoeae, Trichomonas vaginalis, Chlamydia trachomatis, and bacterial vaginosis at enrollment and in the third trimester. The effect of malaria and STIs/RTIs on fetal weight/birthweight Z-scores was evaluated using mixed-effects linear regression. RESULTS: In total, 1435 pregnant women had fetal/birth weight assessed 3950 times. Compared to women without malaria or STIs/RTIs (n = 399), malaria-only (n = 267), STIs/RTIs only (n = 410) or both (n = 353) were associated with reduced fetal growth (adjusted mean difference in fetal/birth weight Z-score [95% confidence interval]: malaria = -0.18 [-0.31,-0.04], P = 0.01; STIs/RTIs = -0.14 [-0.26,-0.03], P = 0.01; both = -0.20 [-0.33,-0.07], P = 0.003). Paucigravidae experienced the greatest impact. CONCLUSION: Malaria and STIs/RTIs are associated with poor fetal growth especially among paucigravidae women with dual infections. Integrated antenatal interventions are needed to reduce the burden of both malaria and STIs/RTIs.

Performance of a rapid antigen test for SARS-CoV-2 in Kenya.

Testing for SARS-CoV-2 in resource-poor settings remains a considerable challenge. Gold standard nucleic acid tests are expensive and depend on availability of expensive equipment and highly trained laboratory staff. More affordable and easier rapid antigen tests are an attractive alternative. This study assessed field performance of such a test in western Kenya. We conducted a prospective multi-facility field evaluation study of NowCheck COVID-19 Ag-RDT compared to gold standard PCR. Two pairs of oropharyngeal and nasopharyngeal swabs were collected for comparative analysis. With 997 enrolled participants the Ag-RDT had a sensitivity 71.5% (63.2-78.6) and specificity of 97.5% (96.2-98.5) at cycle threshold value <40. Highest sensitivity of 87.7% (77.2-94.5) was observed in samples with cycle threshold values ≤30. NowCheck COVID-19 Ag-RDT performed well at multiple healthcare facilities in an African field setting. Operational specificity and sensitivity were close to WHO-recommended thresholds.

Public-private partnership to rapidly strengthen and scale COVID-19 response in Western Kenya.

Introduction: In Africa almost half of healthcare services are delivered through private sector providers. These are often underused in national public health responses. To support and accelerate the public sector's COVID-19 response, we facilitated recruitment of additional private sector capacity by initiating a public-private partnership (PPP) in Kisumu County, Kenya. In this manuscript we demonstrate this PPP's performance. Methods: COVID-19 diagnostic testing formed the basis for a PPP between Kenyan Medical Research Institute (KEMRI), Department of Health Kisumu County, PharmAccess Foundation, and local faith-based and private healthcare facilities: COVID-Dx. First phase COVID-Dx was implemented from June 01, 2020, to March 31, 2021 in Kisumu County, Kenya. Trained laboratory technologists in participating healthcare facilities collected nasopharyngeal and oropharyngeal samples from patients meeting the Kenyan MoH COVID-19 case definition. Healthcare workers in participating facilities collected patient clinical data using a digitized MoH COVID-19 Case Identification Form. We shared aggregated results from these data via (semi-) live dashboards with all relevant stakeholders through their mobile phones and tablets. Statistical analyses were performed using Stata 16 to inform project processes. Results: Nine private facilities participated in the project. A patient trajectory was developed from case identification to result reporting, all steps supported by a semi-real time digital dashboard. A total of 4,324 PCR tests for SARS-CoV-2 were added to the public response, identifying 425 positives, accounting for 16% of all COVID-19 tests performed in the County over the given time-period. Geo-mapped and time-tagged information on incident cases was depicted on Google maps through PowerBI-dashboards and fed back to policymakers for informed rapid decision making. Preferential COVID-19 testing was performed on health workers at risk, with 1,009 tests performed (up to 43% of all County health workforce). Conclusion: We demonstrate feasibility of rapidly increasing the public health sector COVID-19 response through coordinated private sector efforts in an African setting. Our PPP intervention in Kisumu, Kenya was based on a joint testing strategy and demonstrated that semi-real time digitalization of patient trajectories can gain significant efficiencies, linking public and private healthcare efforts, increasing transparency, support better quality health services and informing policy makers to target interventions.

Association between fetal abdominal growth trajectories, maternal metabolite signatures early in pregnancy, and childhood growth and adiposity: prospective observational multinational INTERBIO-21st fetal study.

BACKGROUND: Obesity predominantly affects populations in high-income countries and those countries facing epidemiological transition. The risk of childhood obesity is increased among infants who had overweight or obesity at birth, but in low-resource settings one in five infants are born small for gestational age. We aimed to study the relationships between: (1) maternal metabolite signatures; (2) fetal abdominal growth; and (3) postnatal growth, adiposity, and neurodevelopment. METHODS: In the prospective, multinational, observational INTERBIO-21st fetal study, conducted in maternity units in Pelotas (Brazil), Nairobi (Kenya), Karachi (Pakistan), Soweto (South Africa), Mae Sot (Thailand), and Oxford (UK), we enrolled women (≥18 years, with a BMI of less than 35 kg/m2, natural conception, and a singleton pregnancy) who initiated antenatal care before 14 weeks' gestation. Ultrasound scans were performed every 5±1 weeks until delivery to measure fetal growth and feto-placental blood flow, and we used finite mixture models to derive growth trajectories of abdominal circumference. The infants' health, growth, and development were monitored from birth to age 2 years. Early pregnancy maternal blood and umbilical cord venous blood samples were collected for untargeted metabolomic analysis. FINDINGS: From Feb 8, 2012, to Nov 30, 2019, we enrolled 3598 pregnant women and followed up their infants to 2 years of age. We identified four ultrasound-derived trajectories of fetal abdominal circumference growth that accelerated or decelerated within a crucial 20-25 week gestational age window: faltering growth, early accelerating growth, late accelerating growth, and median growth tracking. These distinct phenotypes had matching feto-placental blood flow patterns throughout pregnancy, and different growth, adiposity, vision, and neurodevelopment outcomes in early childhood. There were 709 maternal metabolites with positive effect for the faltering growth phenotype and 54 for the early accelerating growth phenotype; 31 maternal metabolites had a negative effect for the faltering growth phenotype and 76 for the early accelerating growth phenotype. Metabolites associated with the faltering growth phenotype had statistically significant odds ratios close to 1·5 (ie, suggesting upregulation of metabolic pathways of impaired fetal growth). The metabolites had a reciprocal relationship with the early accelerating growth phenotype, with statistically significant odds ratios close to 0.6 (ie, suggesting downregulation of fetal growth acceleration). The maternal metabolite signatures included 5-hydroxy-eicosatetraenoic acid, and 11 phosphatidylcholines linked to oxylipin or saturated fatty acid sidechains. The fungicide, chlorothalonil, was highly abundant in the early accelerating growth phenotype group. INTERPRETATION: Early pregnancy lipid biology associated with fetal abdominal growth trajectories is an indicator of patterns of growth, adiposity, vision, and neurodevelopment up to the age of 2 years. Our findings could contribute to the earlier identification of infants at risk of obesity. FUNDING: Bill & Melinda Gates Foundation.

Preeclampsia prediction with blood pressure measurements: A global external validation of the ALSPAC models.

OBJECTIVE: The prediction of preeclampsia in pregnancy has resulted in a plethora of prognostic models. Yet, very few make it past the development stage and most fail to influence clinical practice. The timely identification of high-risk pregnant women could deliver a tailored antenatal care regimen, particularly in low-resource settings. This study externally validated and calibrated previously published models that predicted the risk of preeclampsia, based on blood pressure (BP) at multiple time points in pregnancy, in a geographically diverse population. METHODS: The prospective INTERBIO-21st Fetal Study included 3,391 singleton pregnancies from Brazil, Kenya, Pakistan, South Africa, Thailand and the UK, 2012-2018. Preeclampsia prediction was based on baseline characteristics, BP and deviation from the expected BP trajectory at multiple time points in pregnancy. The prediction rules from the Avon Longitudinal Study of Parents and Children (ALSPAC) were implemented in the INTERBIO-21st cohort. RESULTS: Model discrimination was similar to the development cohort. Performance was best with baseline characteristics and a BP measurement at 34 weeks' gestation (AUC 0.85, 95 % CI 0.80-0.90). The ALSPAC models largely overestimated the true risk of preeclampsia incidence in the INTERBIO-21st cohort. CONCLUSIONS: After recalibration, these prediction models could potentially serve as a risk stratifying tool to help identify women who might benefit from increased surveillance during pregnancy.

Caregiver experiences and healthcare worker perspectives of accessing healthcare for low-birthweight.

BACKGROUND: Low-birthweight (LBW) infants (<2500 g) are at greatest risk of mortality in the neonatal period, particularly in low- and middle-income countries. Timely access to quality healthcare averts adverse outcomes. AIM: To explore caregiver experiences and healthcare provider perspectives of accessing healthcare for LBW infants in rural Kenya. METHODS: This qualitative study was undertaken in Homa Bay County of in rural western Kenya in June 2019. In-depth interviews with eleven caregivers and four healthcare providers were conducted by a trained research assistant. All interviews were transcribed verbatim, and transcripts in the local languages were translated into English. A thematic framework was used to analyse the data. RESULTS: At the community and individual level,community misconceptions about LBW infants, inadequate infant care practices after discharge, lack of maternal support networks, long distances from healthcare facilities and lack of financial support were key challenges. In addition, long hospital waiting times, healthcare worker strikes and the apparent inadequate knowledge and skills of healthcare providers were disincentives among caregivers. Among healthcare providers, health system deficiencies (staff shortages and inadequate resources for optimal assessment and treatment of LBW infants) and maternal illiteracy were key challenges. Education by staff during antenatal visits and community support groups were enablers. CONCLUSION: Accessing healthcare for LBW infants in this community is fraught with challenges which have implications for their post-discharge outcome. There is an urgent need to develop and test strategies to address the barriers at the community and health system level to optimise outcome..

Fetal cranial growth trajectories are associated with growth and neurodevelopment at 2 years of age: INTERBIO-21st Fetal Study.

Many observational studies and some randomized trials demonstrate how fetal growth can be influenced by environmental insults (for example, maternal infections)1 and preventive interventions (for example, multiple-micronutrient supplementation)2 that can have a long-lasting effect on health, growth, neurodevelopment and even educational attainment and income in adulthood3. In a cohort of pregnant women (n = 3,598), followed-up between 2012 and 2019 at six sites worldwide4, we studied the associations between ultrasound-derived fetal cranial growth trajectories, measured longitudinally from <14 weeks' gestation, against international standards5,6, and growth and neurodevelopment up to 2 years of age7,8. We identified five trajectories associated with specific neurodevelopmental, behavioral, visual and growth outcomes, independent of fetal abdominal growth, postnatal morbidity and anthropometric measures at birth and age 2. The trajectories, which changed within a 20-25-week gestational age window, were associated with brain development at 2 years of age according to a mirror (positive/negative) pattern, mostly focused on maturation of cognitive, language and visual skills. Further research should explore the potential for preventive interventions in pregnancy to improve infant neurodevelopmental outcomes before the critical window of opportunity that precedes the divergence of growth at 20-25 weeks' gestation.

Association Between Preterm-Birth Phenotypes and Differential Morbidity, Growth, and Neurodevelopment at Age 2 Years: Results From the INTERBIO-21st Newborn Study.

Importance: The etiologic complexities of preterm birth remain inadequately understood, which may impede the development of better preventative and treatment measures. Objective: To examine the association between specific preterm-birth phenotypes and clinical, growth, and neurodevelopmental differences among preterm newborns compared with term newborns up to age 2 years. Design, Setting, and Participants: The INTERBIO-21st study included a cohort of preterm and term newborn singletons enrolled between March 2012 and June 2018 from maternity hospitals in 6 countries worldwide who were followed up from birth to age 2 years. All pregnancies were dated by ultrasonography. Data were analyzed from November 2019 to October 2020. Exposures/Interventions: Preterm-birth phenotypes. Main Outcomes and Measures: Infant size, health, nutrition, and World Health Organization motor development milestones assessed at ages 1 and 2 years; neurodevelopment evaluated at age 2 years using the INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA) tool. Results: A total of 6529 infants (3312 boys [50.7%]) were included in the analysis. Of those, 1381 were preterm births (mean [SD] gestational age at birth, 34.4 [0.1] weeks; 5148 were term births (mean [SD] gestational age at birth, 39.4 [0] weeks). Among 1381 preterm newborns, 8 phenotypes were identified: no main maternal, fetal, or placental condition detected (485 infants [35.1%]); infections (289 infants [20.9%]); preeclampsia (162 infants [11.7%]); fetal distress (131 infants [9.5%]); intrauterine growth restriction (110 infants [8.0%]); severe maternal disease (85 infants [6.2%]); bleeding (71 infants [5.1%]); and congenital anomaly (48 infants [3.5%]). For all phenotypes, a previous preterm birth was a risk factor for recurrence. Each phenotype displayed differences in neonatal morbidity and infant outcomes. For example, infants with the no main condition detected phenotype had low neonatal morbidity but increased morbidity and hospitalization incidence at age 1 year (odds ratio [OR], 2.2; 95% CI, 1.8-2.7). Compared with term newborns, the highest risk of scoring lower than the 10th centile of INTER-NDA normative values was observed in the fine motor development domain among newborns with the fetal distress (OR, 10.6; 95% CI, 5.1-22.2) phenotype. Conclusions and Relevance: Results of this study suggest that phenotypic classification may provide a better understanding of the etiologic factors and mechanisms associated with preterm birth than continuing to consider it an exclusively time-based entity.

Congenital microcephaly unrelated to flavivirus exposure in coastal Kenya.

Background: Zika virus (ZIKV) was first discovered in East Africa in 1947.  ZIKV has caused microcephaly in the Americas, but it is not known whether ZIKV is a cause of microcephaly in East Africa. Methods: We used surveillance data from 11,061 live births at Kilifi County Hospital in coastal Kenya between January 2012 and October 2016 to identify microcephaly cases and conducted a nested case-control study to determine risk factors for microcephaly. Gestational age at birth was estimated based on antenatal ultrasound scanning ('Scanned cohort') or last menstrual period ('LMP cohort', including births ≥37 weeks' gestation only). Controls were newborns with head circumference Z scores between >-2 and ≤2 SD that were compared to microcephaly cases in relation to ZIKV exposure and other maternal and newborn factors. Results: Of the 11,061 newborns, 214 (1.9%, 95%CI 1.69, 2.21) had microcephaly. Microcephaly prevalence was 1.0% (95%CI 0.64, 1.70, n=1529) and 2.1% (95%CI 1.81, 2.38, n=9532) in the scanned and LMP cohorts, respectively. After excluding babies <2500 g (n=1199) in the LMP cohort the prevalence was 1.1% (95%CI 0.93, 1.39). Microcephaly showed an association with being born small for gestational age (p<0.001) but not with ZIKV neutralising antibodies (p=0.6) or anti-ZIKV NS1 IgM response (p=0.9). No samples had a ZIKV neutralising antibody titre that was at least fourfold higher than the corresponding dengue virus (DENV) titre. No ZIKV or other flavivirus RNA was detected in cord blood from cases or controls. Conclusions: Microcephaly was prevalent in coastal Kenya, but does not appear to be related to ZIKV exposure; the ZIKV response observed in our study population was largely due to cross-reactive responses to DENV or other related flaviviruses. Further research into potential causes and the clinical consequences of microcephaly in this population is urgently needed.

Health disparities across the counties of Kenya and implications for policy makers, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.

BACKGROUND: The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 provided comprehensive estimates of health loss globally. Decision makers in Kenya can use GBD subnational data to target health interventions and address county-level variation in the burden of disease. METHODS: We used GBD 2016 estimates of life expectancy at birth, healthy life expectancy, all-cause and cause-specific mortality, years of life lost, years lived with disability, disability-adjusted life-years, and risk factors to analyse health by age and sex at the national and county levels in Kenya from 1990 to 2016. FINDINGS: The national all-cause mortality rate decreased from 850·3 (95% uncertainty interval [UI] 829·8-871·1) deaths per 100 000 in 1990 to 579·0 (562·1-596·0) deaths per 100 000 in 2016. Under-5 mortality declined from 95·4 (95% UI 90·1-101·3) deaths per 1000 livebirths in 1990 to 43·4 (36·9-51·2) deaths per 1000 livebirths in 2016, and maternal mortality fell from 315·7 (242·9-399·4) deaths per 100 000 in 1990 to 257·6 (195·1-335·3) deaths per 100 000 in 2016, with steeper declines after 2006 and heterogeneously across counties. Life expectancy at birth increased by 5·4 (95% UI 3·7-7·2) years, with higher gains in females than males in all but ten counties. Unsafe water, sanitation, and handwashing, unsafe sex, and malnutrition were the leading national risk factors in 2016. INTERPRETATION: Health outcomes have improved in Kenya since 2006. The burden of communicable diseases decreased but continues to predominate the total disease burden in 2016, whereas the non-communicable disease burden increased. Health gains varied strikingly across counties, indicating targeted approaches for health policy are necessary. FUNDING: Bill & Melinda Gates Foundation.