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Background Poor representation of pregnant and lactating women and people in clinical trials has marginalised their health concerns and denied the maternal-fetal/infant dyad benefits of innovation in therapeutic research and development. This mixed-methods systematic review synthesised factors affecting the participation of pregnant and lactating women in clinical trials, across all levels of the research ecosystem. Methods and findings We searched 8 databases from inception to 14 February 2024 to identify qualitative, quantitative, and mixed-methods studies that described factors affecting participation of pregnant and lactating women in vaccine and therapeutic clinical trials in any setting. We used thematic synthesis to analyse the qualitative literature and assessed confidence in each qualitative review finding using the GRADE-CERQual approach. We compared quantitative data against the thematic synthesis findings to assess areas of convergence or divergence. We mapped review findings to the Theoretical Domains Framework (TDF) and Capability, Opportunity, and Motivation Model of Behaviour (COM-B) to inform future development of behaviour change strategies. We included 60 papers from 27 countries. We grouped 24 review findings under 5 overarching themes: (a) interplay between perceived risks and benefits of participation in women's decision-making; (b) engagement between women and the medical and research ecosystems; (c) gender norms and decision-making autonomy; (d) factors affecting clinical trial recruitment; and (e) upstream factors in the research ecosystem. Women's willingness to participate in trials was affected by: perceived risk of the health condition weighed against an intervention's risks and benefits, therapeutic optimism, intervention acceptability, expectations of receiving higher quality care in a trial, altruistic motivations, intimate relationship dynamics, and power and trust in medicine and research. Health workers supported women's participation in trials when they perceived clinical equipoise, had hope for novel therapeutic applications, and were convinced an intervention was safe. For research staff, developing reciprocal relationships with health workers, having access to resources for trial implementation, ensuring the trial was visible to potential participants and health workers, implementing a woman-centred approach when communicating with potential participants, and emotional orientations towards the trial were factors perceived to affect recruitment. For study investigators and ethics committees, the complexities and subjectivities in risk assessments and trial design, and limited funding of such trials contributed to their reluctance in leading and approving such trials. All included studies focused on factors affecting participation of cisgender pregnant women in clinical trials; future research should consider other pregnancy-capable populations, including transgender and nonbinary people. Conclusions This systematic review highlights diverse factors across multiple levels and stakeholders affecting the participation of pregnant and lactating women in clinical trials. By linking identified factors to frameworks of behaviour change, we have developed theoretically informed strategies that can help optimise pregnant and lactating women's engagement, participation, and trust in such trials., Author(s): Mridula Shankar 1,*, Alya Hazfiarini 1, Rana Islamiah Zahroh 1, Joshua P. Vogel 2, Annie R. A. McDougall 2, Patrick Condron 3, Shivaprasad S. Goudar 4, Yeshita V. Pujar [...]

Introduction: Optimal human milk (HM) B-vitamin concentrations remain undefined, especially in areas where undernutrition is prevalent. The impact of supplementation pre-conception through pregnancy on HM B-vitamin composition remains unknown. Methods: Human milk (HM) was collected at 2-weeks postpartum from 200 women in Guatemala, India, and Pakistan (the Women First Trial). The women were randomized to start a lipid-based nutrient supplement before conception, at end of the first trimester, or not at all; intervention continued until delivery. HM concentrations of eight B-vitamins and choline were assessed via ultra-performance liquid chromatography-tandem mass spectrometry. Maternal diet was assessed in early pregnancy, and infant growth followed through 6 months post-delivery. Results: Despite supplement exposure averaging 15.7 (pre-conception arm) and 6.0 months (prenatal arm), HM B-vitamins did not differ between arms, but site differences were evident. Guatemala had higher HM concentrations of vitamin B3 than Pakistan and India. Pakistan had higher HM concentrations of thiamin and vitamin B6 than India and Guatemala. Cohort average HM vitamin B2 (162 ± 79 μg/L) and B6 (31.8 ± 24.6 μg/L) fell below values defined as deficient in 81.5 and 85.5% of samples, potentially reflecting sampling procedures and timing. Maternal dietary intakes of only vitamin B6 and choline were associated with the corresponding concentrations in HM (p < 0.005). No HM B-vitamin concentrations were associated with infant growth. Conclusion: Prenatal supplementation for at least 6 months had no impact on HM B-vitamin concentrations at 2-weeks postpartum. Results suggest that the adequacy of HM composition was generally maintained, with potential exceptions of vitamin B2 and B6.

Background: Hypertensive disorders of pregnancy (HDP) remain a primary contributor for maternal and perinatal death and results in long-term health risks for both the mother and child. Heterogeneous studies have evaluated the possible benefit of low dose aspirin (50 to 150 mg per day) in pregnancy to minimize the risk of HDP. Objective: To assess the impact of low-dose Aspirin (LDA) starting in early pregnancy on delaying preterm hypertensive disorders of pregnancy. Methodology: This was a non-prespecified secondary analysis of a randomized masked trial of Low-dose Aspirin (LDA). Nulliparous singleton pregnancies between 6 weeks and 0 days and 13 weeks 6 days in 6 low- middle income countries (Democratic Republic of Congo, Guatemala, India, Kenya, Pakistan, Zambia) enrolled in the ASPIRIN Trial were included. The incidence of HDP at delivery at three gestational age periods (< 37 weeks) between women who were randomized to Aspirin or Placebo. Women were included if they were randomized and had an outcome at or beyond 20 weeks (Modified Intent to Treat). Results: Amongst the 11,976 pregnancies, LDA did not significantly lower HDP at delivery. Conclusion: In low-risk nulliparous singleton pregnancies, early administration of LDA resulted in lower rates of preterm HDP and delivery before 34 and 37 weeks. LDA works in part by delaying HDP.

Feeding practices over the first several years of a child's life can critically influence development. The purpose of this study was to examine associations between feeding practices and growth and neurodevelopmental outcomes at 36 months of age among children from low- and low-middle-income countries (LMIC). We conducted a secondary analysis using data collected from children in India, Pakistan, and Zambia who were enrolled in a randomized controlled trial of a home-based early development intervention program called Brain Research to Ameliorate Impaired Neurodevelopment Home-based Intervention Trial. Qualitative dietary data collected at 36 months was used to assess the modified Minimum Acceptable Diet (mMAD), a measure based on a core indicator developed by the World Health Organization to measure whether young children receive the minimum number of meals recommended and adequate diversity of major food groups in their diet. Regression models were used to assess cross-sectional associations between diet and growth indices, including Z-scores for height-for-age (HAZ), weight-for-age (WAZ), weight-for-height (WHZ), head circumference (HCZ), and Bayley Scales of Infant Development II mental and psychomotor developmental measures at 36 months of age. Of 371 children, 174 (47%) consumed the mMAD, with significantly higher mean adjusted WHZ than those who did not meet mMAD (0.20 vs - 0.08, p = 0.05). Egg consumption was found to be significantly associated with a decreased risk of wasting [adjusted RR (95% CI): 0.37 (0.15, 0.89), p = 0.03]. HCZ at 36 months did not differ significantly for children who did and did not receive the mMAD. Meeting the mMAD was associated with better weight-for-height outcomes at 36 months in children in these three LMIC, highlighting the importance of adequate food quantity and quality. registered on March 20, 2008.

ObjectiveTo investigate whether early developmental intervention (EDI) can positively affect the trajectories of cognitive development among children from low-resource families.MethodsLongitudinal analyses were conducted of data from 293 children in the Brain Research to Ameliorate Impaired Neurodevelopment Home-based Intervention Trial, a randomized controlled trial of a home-based EDI program, to examine trajectories of Bayley Scales of Infant Development-Second Edition Mental Development Index (MDI) scores from 12 to 36 months of age among young children from high- and low-resource families in 3 low- to middle-resource countries.ResultsA 3-way interaction among family resources, intervention group, and age was statistically significant after controlling for maternal, child, and birth characteristics (Wald χ(2)(1) = 9.41, P = .002). Among children of families with high resources, both the intervention and control groups had significant increases in MDI scores over time (P < .001 and P = .002, respectively), and 36-month MDI scores for these 2 groups did not differ significantly (P = .602). However, in families with low resources, the EDI group displayed greater improvement, resulting in significantly higher 36-month MDI scores than the control group (P < .001). In addition, the 36-month MDI scores for children in families with low resources receiving EDI did not differ significantly from children from high-resource families in either the EDI (P = .509) or control (P = .882) groups.ConclusionsA home-based EDI during the first 3 years of life can substantially decrease the developmental gap between children from families with lower versus higher resources, even among children in low- to middle-resource countries.

Objective To estimate the prevalence and prognosis of proteinuria at enrolment in the 27 intervention clusters of the Community-Level Interventions for Pre-eclampsia cluster randomized trials. Methods We identified pregnant women eligible for inclusion in the trials in their communities in four countries (2013-2017). We included women who delivered by trial end and received an intervention antenatal care visit. The intervention was a community health worker providing supplementary hypertension-oriented care, including proteinuria assessment by visual assessment of urinary dipstick at the first visit and all subsequent visits when hypertension was detected. In a multilevel regression model, we compared baseline prevalence of proteinuria ([greater than or equal to] 1 + or [greater than or equal to] 2+) across countries. We compared the incidence of subsequent complications by baseline proteinuria. Findings Baseline proteinuria was detected in less than 5% of eligible pregnancies in each country (India: 234/6120; Mozambique: 94/4234; Nigeria: 286/7004; Pakistan: 315/10 885), almost always with normotension (India: 225/234; Mozambique: 93/94; Nigeria: 241/286; Pakistan: 264/315). There was no consistent relationship between baseline proteinuria (either [greater than or equal to] 1+ or [greater than or equal to] 2+) and progression to hypertension, maternal mortality or morbidity, birth at < 37 weeks, caesarean section delivery or perinatal mortality or morbidity. If proteinuria testing were restricted to women with hypertension, we projected annual cost savings of 153 223 981 United States dollars (US$) in India, US$ 9 055 286 in Mozambique, US$ 53 181 933 in Nigeria and US$ 38 828 746 in Pakistan. Conclusion Our findings question the recommendations to routinely evaluate proteinuria at first assessment in pregnancy. Restricting proteinuria testing to pregnant women with hypertension has the potential to save resources. [phrase omitted] [phrase omitted] Metodos Se identificaron mujeres embarazadas que cumplian los requisitos para participar en los ensayos en sus comunidades en cuatro paises (2013-2017). Se incluyeron las mujeres que tuvieron un parto al final del ensayo y recibieron una visita de atencion prenatal de intervencion. Esta intervencion consistio en un profesional sanitario de la comunidad quien presto atencion suplementaria centrada en la hipertension, incluida la evaluacion de la proteinuria a traves del analisis visual de la tira reactiva de orina en la primera visita y en todas las visitas posteriores si se presentaba hipertension. En un modelo de regresion multinivel, se comparo la prevalencia del valor basal de la proteinuria ([greater than or equal to] 1 + o [greater than or equal to] 2+) en todos los paises. Luego, se comparo la incidencia de las complicaciones posteriores en funcion del valor basal de la proteinuria. Resultados El valor basal de la proteinuria se detecto en menos del 5 % de los embarazos que cumplian los requisitos en cada pais (India: 234/6120; Mozambique: 94/4234; Nigeria: 286/7004, Pakistan: 315/10 885), la mayoria de las veces con una tension arterial normal (India: 225/234; Mozambique: 93/94; Nigeria: 241/286; Pakistan: 264/315). No se observo una relacion coherente entre el valor basal de la proteinuria (ya sea [greater than or equal to] 1 + o [greater than or equal to] 2+) y la progresion a la hipertension, la mortalidad o morbilidad materna, el nacimiento a las < 37 semanas, el parto por cesarea o la mortalidad o morbilidad perinatal. Si la prueba de proteinuria se limitara a las mujeres con hipertension, se calcularian ahorros anuales de 153 223 981 dolares estadounidenses (USD) en la India, 9 055 286 USD en Mozambique, 53 181 933 USD en Nigeria y 38 828 746 USD en Pakistan. Conclusion Los resultados cuestionan las recomendaciones de evaluar la proteinuria de forma rutinaria en la primera evaluacion durante el embarazo. Limitar la prueba de proteinuria a las mujeres embarazadas con hipertension podria suponer un ahorro de recursos. [phrase omitted] Objectif Estimer la prevalence et le pronostlc de la proteinurie au moment de l'inscription dans l'un des 27 groupes repris dans les essais randomises en grappes sur les interventions communautaires liees a la preeclampsie. Methodes Nous avons selectionne des femmes enceintes remplissant les conditions requises pour les essais menes au sein de leur communaute dans quatre pays (2013-2017). Nous avons inclus des femmes ayant accouche au terme de l'essai et ayant fait l'objet d'une consultation prenatale avec intervention. Lintervention etait menee par un professionnel de sante communautaire prodiguant des soins complementaires en lien avec l'hypertension, dont un controle de la proteinurie par examen visuel d'une bandelette reactive trempee dans les urines lors de la premiere visite, ainsi que lors des visites qui suivent tout diagnostic d'hypertension. Nous avons employe un modele de regression multiniveaux pour analyser la prevalence initiale de la proteinurie ([greater than or equal to] 1+ ou [greater than or equal to] 2+) dans les differents pays. Enfin, nous avons compare l'incidence des complications ulterieures en fonction de la proteinurie initiale. Resultats La proteinurie initiale a ete detectee chez moins de 5% des grossesses etudiees dans chaque pays (Inde: 234/6120; Mozambique: 94/4234; Nigeria: 286/7004, Pakistan: 315/10 885), et allait presque toujours de pair avec une tension arterielle normale (Inde: 225/234; Mozambique: 93/94; Nigeria: 241/286; Pakistan: 264/315). Nous n'avons identifie aucun lien concluant entre la proteinurie initiale (qu'elle soit [greater than or equal to] 1+ ou [greater than or equal to] 2+) et une progression vers de l'hypertension, une mortalite ou morbidite maternelle, une naissance avant 37 semaines, un accouchement par cesarienne, ou encore une mortalite ou morbidite perinatale. Si les tests de depistage de proteinurie etaient reserves aux femmes souffrant d'hypertension, les economies realisees chaque annee representeraient 153 223 981 dollars americains en Inde, 9 055 286 dollars americains au Mozambique, 53 181 933 dollars americains au Nigeria et 38 828 746 dollars americains au Pakistan. Conclusion Nos resultats remettent en question les recommandations selon lesquelles il convient de controler regulierement la proteinurie des le premier bilan de grossesse. Limiter les tests aux femmes enceintes souffrant d'hypertension pourrait potentiellement permettre de menager les ressources. Objetivo Estimar la prevalencia y el pronostico de la proteinuria al momento de la inscripcion en los 27 grupos de intervencion de los ensayos aleatorizados del grupo de intervenciones a nivel comunitario para la preeclampsia., Introduction Hypertensive disorders of pregnancy are a leading cause of maternal and perinatal death and disability worldwide. As such, antenatal care is devoted in large part to the detection of [...]

BackgroundThe positive effects of early developmental intervention (EDI) on early child development have been reported in numerous controlled trials in a variety of countries. An important aspect to determining the efficacy of EDI is the degree to which dosage is linked to outcomes. However, few studies of EDI have conducted such analyses. This observational cohort study examined the association between treatment dose and children's development when EDI was implemented in three low and low-middle income countries as well as demographic and child health factors associated with treatment dose.MethodsInfants (78 males, 67 females) born in rural communities in India, Pakistan, and Zambia received a parent-implemented EDI delivered through biweekly home visits by trainers during the first 36 months of life. Outcome was measured at age 36 months with the Mental (MDI) and Psychomotor (PDI) Development Indices of the Bayley Scales of Infant Development-II. Treatment dose was measured by number of home visits completed and parent-reported implementation of assigned developmental stimulation activities between visits. Sociodemographic, prenatal, perinatal, and child health variables were measures as correlates.ResultsAverage home visits dose exceeded 91% and mothers engaged the children in activities on average 62.5% of days. Higher home visits dose was significantly associated with higher MDI (mean for dose quintiles 1-2 combined = 97.8, quintiles 3-5 combined = 103.4, p = 0.0017). Higher treatment dose was also generally associated with greater mean PDI, but the relationships were non-linear. Location, sociodemographic, and child health variables were associated with treatment dose.ConclusionsReceiving a higher dose of EDI during the first 36 months of life is generally associated with better developmental outcomes. The higher benefit appears when receiving ≥91% of biweekly home visits and program activities on ≥67% of days over 3 years. It is important to ensure that EDI is implemented with a sufficiently high dose to achieve desired effect. To this end groups at risk for receiving lower dose can be identified and may require special attention to ensure adequate effect.

BackgroundPrevious research has indicated positive effects of early developmental intervention (EDI) on the development of children in developing countries. Few studies, however, have examined longitudinally when differential treatment effects may be observed and whether differential outcomes are associated with exposure to different risk factors and country of implementation. Also, birth asphyxia as a risk condition has not been well studied. To address these limitations, we conducted a randomized controlled trial to test the hypothesis that there will be differential developmental trajectories favoring those who receive EDI versus a health education intervention in children in rural areas of India, Pakistan, and Zambia.MethodsChildren with and without birth asphyxia were randomized to EDI or control intervention, which was implemented by parents who received training in biweekly home visits initiated before child age 1 month and continuing until 36 months. Development was assessed in 376 children at ages 12, 24, and 36 months using the Bayley Scales of Infant Development and Ages & Stages Questionnaire administered by evaluators blind to intervention assignment and risk condition.ResultsLongitudinal mixed model analysis indicated that EDI resulted in better development over 36 months in cognitive abilities, regardless of risk condition, maternal resources, child gender, or country. Psychomotor development and parent-reported general development showed similar trends as for cognitive abilities, but were not statistically different between intervention conditions. Developmental differences were observed first at 36 months of age.ConclusionEarly developmental intervention has promise for improving development in children across developing countries when exposed to various risk conditions. EDI should be one prominent approach used to begin to address long-term outcomes and intergenerational transmission of poverty.

BackgroundResuscitation following birth asphyxia reduces mortality, but may be argued to increase risk for neurodevelopmental disability in survivors.AimsTo test the hypothesis that development of infants who received resuscitation following birth asphyxia is not significantly different through 36months of age from infants who had healthy births.Study designProspective observational cohort design comparing infants exposed to birth asphyxia with resuscitation or healthy birth.SubjectsA random sample of infants with birth asphyxia who received bag-and-mask resuscitation was selected from birth records in selected communities in 3 countries.Exclusion criteriabirth weight

BackgroundResuscitation following birth asphyxia reduces mortality, but may be argued to increase risk for neurodevelopmental disability in survivors.AimsTo test the hypothesis that development of infants who received resuscitation following birth asphyxia is not significantly different through 36months of age from infants who had healthy births.Study designProspective observational cohort design comparing infants exposed to birth asphyxia with resuscitation or healthy birth.SubjectsA random sample of infants with birth asphyxia who received bag-and-mask resuscitation was selected from birth records in selected communities in 3 countries.Exclusion criteriabirth weight