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Statistical analysis plan of the maternal nutrition, inflammation, estriol, and stress biomarkers measured during pregnancy and child stress outcomes in the WASH Benefits Bangladesh trial

This is the WASH Benefits Bangladesh trial's registered, pre-specified analysis plan to evaluate the association between stress biomarkers and growth outcomes.

WASH Benefits Bangladesh: Nutritional Status, Inflammation, Stress, and Estriol During Pregnancy and Child Inflammation Analysis Plan Date updated: 31 January 2021

WASH Benefits Bangladesh Immune Status and Child Development Analysis Plan

This statistical analysis plan specifies the methods that we will use to evaluate individualized optimal treatment regimes of interventions' impact on child growth by environmental enteric dysfunction biomarker and pathogen status in the WASH Benefits Bangladesh study.

Preprint and final manuscripts associated with the analysis

This is an archive of the primary analysis materials for the WASH Benefits Kenya trial (NCT01704105).

Open data and script repository for Environmental Health Perspectives paper: Associations between high temperature, heavy rainfall, and diarrhea among young children in rural Tamil Nadu, India: A prospective cohort study

This OSF registration includes the statistical analysis plan of the intimate partner violence, depression, perceived stress, and child immune status outcomes of the WASH Benefits Bangladesh trial (NCT01590095).

WASH Benefits Bangladesh: Nutritional Status, Inflammation, Stress, and Estriol During Pregnancy and Child Telomeres Analysis Plan

WASH Benefits Bangladesh immune status and growth analysis plan update

WASH Benefits Bangladesh Immune Status and Child Development Analysis Plan

WASH Benefits Environmental Enteric Dysfunction and Early Child Development Analysis Plan

WASH Benefits Bangladesh Child Immune Status and Child Development Analysis Plan

WASH Benefits Nutrition, Inflammation, Estriol, and Stress and Telomere Outcomes Analysis Plan

This registration contains the analysis plan for the WASH Benefits Bangladesh immune status and growth analysis.

WASH Benefits Bangladesh: maternal exposure to intimate partner violence, maternal depression, parental perceived stress and child telomere length analysis plan

WASH Benefits Bangladesh Telomere Length and Early Child Development Analysis Plan Update. Date updated: January 28, 2021

WASH Benefits Bangladesh: Nutritional Status, Inflammation, Stress, and Estriol During Pregnancy and Child Telomeres Analysis Plan. Date updated: 28 January 2021

WASH Benefits Bangladesh: Maternal Exposure to Intimate Partner Violence, Maternal Depression, Parental Stress and Child Stress Biomarkers Analysis Plan Date updated: 29 January 2021

Summary Growth faltering (low length-for-age or weight-for length) in the first 1000 days — from conception to two years of age — influences both short and long-term health and survival. Evidence for interventions to prevent growth faltering such as nutritional supplementation during pregnancy and the postnatal period has increasingly accumulated, but programmatic action has been insufficient to eliminate the high burden of stunting and wasting in low- and middle-income countries. In addition, there is need to better understand age-windows and population subgroups in which to focus future preventive efforts. Here, we show using a population intervention effects analysis of 33 longitudinal cohorts (83,671 children) and 30 separate exposures that improving maternal anthropometry and child condition at birth, in particular child length-at-birth, accounted for population increases by age 24 months in length-for-age Z of 0.04 to 0.40 and weight-for-length Z by 0.02 to 0.15. Boys had consistently higher risk of all forms of growth faltering than girls, and early growth faltering predisposed children to subsequent and persistent growth faltering. Children with multiple growth deficits had higher mortality rates from birth to two years than those without deficits (hazard ratios 1.9 to 8.7). The importance of prenatal causes, and severe consequences for children who experienced early growth faltering, support a focus on pre-conception and pregnancy as key opportunities for new preventive interventions.

Globally 149 million children under five are estimated to be stunted (length more than 2 standard deviations below international growth standards). Stunting, a form of linear growth faltering, increases risk of illness, impaired cognitive development, and mortality. Global stunting estimates rely on cross-sectional surveys, which cannot provide direct information about the timing of onset or persistence of growth faltering- a key consideration for defining critical windows to deliver preventive interventions. We performed the largest pooled analysis of longitudinal studies in low- and middle-income countries to date (n=32 cohorts, 52,640 children, ages 0-24 months), allowing us to identify the typical age of linear growth faltering onset and to investigate recurrent faltering in early life. The highest incidence of stunting onset occurred from birth to age 3 months. From 0 to 15 months, less than 5% of children per month reversed their stunting status, and among those who did, stunting relapse was common. Early timing and low reversal rates emphasize the importance of preventive intervention delivery within the prenatal and early postnatal phases coupled with continued delivery of postnatal interventions through the first 1000 days of life.

Background: Shorter childhood telomere length (TL) and more rapid TL attrition are widely regarded as manifestations of stress. However, the potential effects of health interventions on child TL are unknown. We hypothesized that a water, sanitation, handwashing (WSH), and nutritional intervention would slow TL attrition during the first two years of life. Methods: In a trial in rural Bangladesh (ClinicalTrials.gov, NCT01590095), we randomized geographical clusters of pregnant women into individual water treatment, sanitation, handwashing, nutrition, combined WSH, combined nutrition plus WSH (N + WSH), or control arms. We conducted a substudy enrolling children from the control arm and the N + WSH intervention arm. Participants and outcome assessors were not masked; analyses were masked. Relative TL was measured at 1 and 2 years after intervention, and the change in relative TL was reported. Analysis was intention-to-treat. Findings: Between May 2012 and July 2013, in the overall trial, we randomized 720 geographical clusters of 5551 pregnant women to a control or an intervention arm. In this substudy, after 1 year of intervention, we assessed a total of 662 children (341 intervention and 321 control) and 713 children after 2 years of intervention (383 intervention and 330 control). Children in the intervention arm had significantly shorter relative TL compared with controls after 1 year of intervention (difference −163 base pairs (bp), p=0.001). Between years 1 and 2, TL increased in the intervention arm (+76 bp) and decreased in the controls (−23 bp) (p=0.050). After 2 years, there was no difference between the arms (p=0.305). Interpretation: Our unexpected finding of increased telomere attrition during the first year of life in the intervention group suggests that rapid telomere attrition during this critical period could reflect the improved growth in the intervention group, rather than accumulated stress. Funding: The Bill and Melinda Gates Foundation, eLife digest Stress negatively affects health by causing changes in cells. As a result, excess stress may predispose people to fall ill more often or age faster. It is difficult to measure stress. Some studies suggest that measuring the ends of chromosomes, known as telomeres, may be one way to measure stress. Like the plastic tips on shoelaces, telomeres protect chromosomes from fraying. All peoples’ telomeres shorten over their lifetime with each cell division. Many studies show that telomeres shorten faster in people who experience more stress. When telomeres become too short, cells die faster without being replaced, and the body ages. Most studies on telomere length have looked at adults. Few studies have looked at children early in life or asked whether there are ways to intervene to stop or reverse stress-related telomere shortening. The first two years of life are a crucial period for the developing brain and immune system, which could set children on a lifelong course toward health or disease. Young children living in low-resource settings often encounter many sources of stress, like poor nutrition, infectious diseases or violence. Studies are needed to determine if interventions in early childhood aimed at reducing some sources of stress improve telomere length or long-term health. Now, Lin et al. show that interventions to provide safe water, sanitation, handwashing facilities, and better nutrition to children in rural Bangladesh unexpectedly shortened telomeres. As part of a larger study, pregnant women in rural Bangladesh were divided, at random, into groups. One group received a suite of interventions, which included more sanitary toilets, handwashing facilities, and nutritional supplements for their infants. Another group served as a control and did not receive this extra help. Lin et al. looked at telomere length, growth, and infections in a subset of 713 children whose mothers participated in the study. Children who got the extra help grew faster and were less likely to get diarrhea or parasitic infections than the children in the control group. Unexpectedly, children in the intervention group had shorter telomeres at 14 months of age than the children in the control group. Lin et al. suggest that the telomere shortening in the intervention group might be a consequence of rapid growth and immune system development in the first year of life rather than resulting from biological stress. More studies are needed to ask whether telomere shortening is indeed linked to faster growth and development early in life. The strong and unexpected findings highlight how little is known about how the length of telomeres can be used to predict future health or disease. Interpreting the length of telomeres over a person’s lifetime could prove more nuanced than originally thought.