Development, Implementation, and Process Evaluation of Bukhali: An Intervention from Preconception to Early Childhood.

The Healthy Life Trajectories Initiative, an international consortium developed in partnership with the World Health Organization, is addressing childhood obesity from a life-course perspective. It hypothesises that an integrated complex intervention from preconception, through pregnancy, infancy and early childhood, will reduce childhood adiposity and non-communicable disease risk, and improve child development. As part of the Healthy Life Trajectories Initiative in South Africa, the Bukhali randomised controlled trial is being conducted with 18-28-year-old women in Soweto, where young women face numerous challenges to their physical and mental health. The aims of this paper were to describe the intervention development process (including adaptations), intervention components, and process evaluation; and to highlight key lessons learned. Intervention materials have been developed according to the life-course stages: preconception (Bukhali), pregnancy (Bukhali Baby), infancy (Bukhali Nana; birth-2 years), and early childhood (Bukhali Mntwana, 2-5 years). The intervention is delivered by community health workers, and includes the provision of health literacy resources, multi-micronutrient supplementation, in-person health screening, services and referral, nutrition risk support, SMS-reminders and telephonic contacts to assist with behaviour change goals. A key adaption is the incorporation of principles of trauma-information care, given the mental health challenges faced by participants. The Bukhali process evaluation is focussing on context, implementation and mechanisms of impact, using a mixed methods approach. Although the completion of the trial is still a number of years away, the documentation of the intervention development process and process evaluation of the trial can provide lessons for the development, implementation, and evaluation of such complex life-course trials. Supplementary Information: The online version contains supplementary material available at 10.1007/s43477-023-00073-8.

Comparative effectiveness of prophylactic strategies for preeclampsia: a network meta-analysis of randomized controlled trials.

OBJECTIVE: Preeclampsia is a common disease during pregnancy that leads to fetal and maternal adverse events. Few head-to-head clinical trials are currently comparing the effectiveness of prophylactic strategies for preeclampsia. In this network meta-analysis, we aimed to compare the efficacy of prophylactic strategies for preventing preeclampsia in pregnant women at risk. DATA SOURCES: Articles published in or before September 2021 from PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov, references of key articles, and previous meta-analyses were manually searched. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials comparing prophylactic strategies preventing preeclampsia with each other or with negative controls were included. METHODS: Two reviewers independently extracted data, assessed the risk of bias, and assessed evidence certainty. The efficacy of prophylactic strategies was estimated by frequentist and Bayesian network meta-analysis models. The primary composite outcome was preeclampsia/ pregnancy-induced hypertension. RESULTS: In total, 130 trials with a total of 112,916 patients were included to assess 13 prophylactic strategies. Low-molecular-weight heparin (0.60; 95% confidence interval, 0.42-0.87), vitamin D supplementation (0.65; 95% confidence interval, 0.45-0.95), and exercise (0.68; 95% confidence interval, 0.50-0.92) were as efficacious as calcium supplementation (0.71; 95% confidence interval, 0.62-0.82) and aspirin (0.79; 95% confidence interval, 0.72-0.86) in preventing preeclampsia/pregnancy-induced hypertension, with a P score ranking of 85%, 79%, 76%, 74%, and 61%, respectively. In the head-to-head comparison, no differences were found between these effective prophylactic strategies for preventing preeclampsia and pregnancy-induced hypertension, except with regard to exercise, which tended to be superior to aspirin and calcium supplementation in preventing pregnancy-induced hypertension. Furthermore, the prophylactic effects of aspirin and calcium supplementation were robust across subgroups. However, the prophylactic effects of low-molecular-weight heparin, exercise, and vitamin D supplementation on preeclampsia and pregnancy-induced hypertension varied with different risk populations, dosages, areas, etc. The certainty of the evidence was moderate to very low. CONCLUSION: Low-molecular-weight heparin, vitamin D supplementation, exercise, calcium supplementation, and aspirin reduce the risk of preeclampsia/pregnancy-induced hypertension. No significant differences between effective prophylactic strategies were found in preventing preeclampsia. These findings raise the necessity to reevaluate the prophylactic effects of low-molecular-weight heparin, vitamin D supplementation, and exercise on preeclampsia.

Maternal prenatal psychological distress and vitamin intake with children's neurocognitive development.

BACKGROUND: Maternal prenatal psychological distress (PPD) is increasingly linked to sub-optimal child neurodevelopment. Daily intake of prenatal vitamin during pre-conception and early pregnancy may ameliorate the effects of PPD on cognition in the offspring. METHODS: PPD was assessed in early (12-16 weeks) and late (28-32 weeks) gestation in the Ontario Birth Study. Prenatal vitamin supplement intake information was collected in early gestation. Child cognition at 4 years was assessed using the NIH Toolbox. Poisson regression was used to investigate associations between PPD and/or prenatal vitamin intake and child cognition. RESULTS: Four hundred and eighteen mother-child dyads were assessed. Moderate-severe PPD experienced during early gestation was associated with reduced cognition (adjusted incidence rate ratio (IRRadj) = 3.71, 95% confidence interval (CI): 1.57-8.77, P = 0.003). Daily intake of prenatal vitamins was not associated with cognition (IRRadj = 1.34, 95% CI: 0.73-2.46, P = 0.34). Upon stratification, the experience of mild-severe PPD with daily intake of prenatal vitamins was associated with higher incident rates of suboptimal cognition compared to children of women with daily prenatal vitamin intake without any episode of PPD (IRRadj = 2.88, 95% CI: 1.1-7.4). CONCLUSIONS: Moderate-severe PPD in early pregnancy is associated with poor cognition in children and daily intake of prenatal vitamin did not ameliorate this association. IMPACT: Our findings expand on existing literature by highlighting that exposure to prenatal psychological distress (PPD), in moderate-to-severe form, in the early stages of pregnancy, can have detrimental effects on the offspring's cognitive development at 4 years. Overall, prenatal vitamin intake did not ameliorate the effects of PPD. Early screening and treatment of prenatal maternal mental illness is crucial.

Probiotic Lactobacillus rhamnosus GR-1 is a unique prophylactic agent that suppresses infection-induced myometrial cell responses.

Preterm birth (PTB) is a multifactorial syndrome affecting millions of neonates worldwide. Intrauterine infection can induce PTB through the secretion of pro-inflammatory cytokines and untimely activation of uterine contractions. In pregnant mice, prophylactic administration of probiotic Lactobacillus rhamnosus GR-1 supernatant (GR1SN) prevented lipopolysaccharide (LPS)-induced PTB and reduced cytokine expression in the uterine muscle (myometrium). In this study we sought to delineate the mechanisms by which GR1SN suppressed cytokine secretion in the myometrium. We observed that L. rhamnosus GR-1 uniquely secretes heat-resistant but trypsin-sensitive factors, which significantly suppressed LPS-induced secretion of pro-inflammatory cytokines IL-6, IL-8, and MCP-1 in the human myometrial cell line, hTERT-HM. This effect was unique to GR1SN and could not be replicated using supernatant derived from non-GR-1 commensal lactobacilli species: L. rhamnosus GG, L. lactis, L. casei, or L. reuteri RC-14. Furthermore, pre-incubation of hTERT-HM cells with low-dose Pam3CSK (a TLR1/2 synthetic agonist which mimics LPS action) prior to LPS administration also significantly decreased LPS-induced cytokine secretion. This study highlights the distinct capacity of protein-like moieties secreted by L. rhamnosus GR-1 to inhibit pro-inflammatory cytokine production by human myometrial cells, potentially through a TLR1/2-mediated mechanism.

Prioritizing research for integrated implementation of early childhood development and maternal, newborn, child and adolescent health and nutrition platforms.

BACKGROUND: Existing health and nutrition services present potential platforms for scaling up delivery of early childhood development (ECD) interventions within sensitive windows across the life course, especially in the first 1000 days from conception to age 2 years. However, there is insufficient knowledge on how to optimize implementation for such strategies in an integrated manner. In light of this knowledge gap, we aimed to systematically identify a set of integrated implementation research priorities for health, nutrition and early child development within the 2015 to 2030 timeframe of the Sustainable Development Goals (SDGs). METHODS: We applied the Child Health and Nutrition Research Initiative method, and consulted a diverse group of global health experts to develop and score 57 research questions against five criteria: answerability, effectiveness, deliverability, impact, and effect on equity. These questions were ranked using a research priority score, and the average expert agreement score was calculated for each question. FINDINGS: The research priority scores ranged from 61.01 to 93.52, with a median of 82.87. The average expert agreement scores ranged from 0.50 to 0.90, with a median of 0.75. The top-ranked research question were: i) "How can interventions and packages to reduce neonatal mortality be expanded to include ECD and stimulation interventions?"; ii) "How does the integration of ECD and MNCAH&N interventions affect human resource requirements and capacity development in resource-poor settings?"; and iii) "How can integrated interventions be tailored to vulnerable refugee and migrant populations to protect against poor ECD and MNCAH&N outcomes?". Most highly-ranked research priorities varied across the life course and highlighted key aspects of scaling up coverage of integrated interventions in resource-limited settings, including: workforce and capacity development, cost-effectiveness and strategies to reduce financial barriers, and quality assessment of programs. CONCLUSIONS: Investing in ECD is critical to achieving several of the SDGs, including SDG 2 on ending all forms of malnutrition, SDG 3 on ensuring health and well-being for all, and SDG 4 on ensuring inclusive and equitable quality education and promotion of life-long learning opportunities for all. The generated research agenda is expected to drive action and investment on priority approaches to integrating ECD interventions within existing health and nutrition services.

DREAM mediated regulation of GCM1 in the human placental trophoblast.

The trophoblast transcription factor glial cell missing-1 (GCM1) regulates differentiation of placental cytotrophoblasts into the syncytiotrophoblast layer in contact with maternal blood. Reduced placental expression of GCM1 and abnormal syncytiotrophoblast structure are features of hypertensive disorder of pregnancy--preeclampsia. In-silico techniques identified the calcium-regulated transcriptional repressor--DREAM (Downstream Regulatory Element Antagonist Modulator)--as a candidate for GCM1 gene expression. Our objective was to determine if DREAM represses GCM1 regulated syncytiotrophoblast formation. EMSA and ChIP assays revealed a direct interaction between DREAM and the GCM1 promoter. siRNA-mediated DREAM silencing in cell culture and placental explant models significantly up-regulated GCM1 expression and reduced cytotrophoblast proliferation. DREAM calcium dependency was verified using ionomycin. Furthermore, the increased DREAM protein expression in preeclamptic placental villi was predominantly nuclear, coinciding with an overall increase in sumolylated DREAM and correlating inversely with GCM1 levels. In conclusion, our data reveal a calcium-regulated pathway whereby GCM1-directed villous trophoblast differentiation is repressed by DREAM. This pathway may be relevant to disease prevention via calcium-supplementation.