Pre- and Post-Natal Small-Quantity Lipid-Based Nutrient Supplements Exposure on Children’s Pubertal Development and Hair Cortisol at Age 9-11 and 11-13 Years

Abstract

Background: Both early and delayed onset of puberty are linked to negative health and psychosocial outcomes. The impact of early nutrition on regulating the hypothalamic pituitary-adrenal (HPA) axis and stress responses, as reflected by changes in hair cortisol concentration (HCC), is not yet fully understood. Investigating the relationship between anthropometric status, body composition, and pubertal development in children can provide valuable insights into growth patterns and their potential long-term health risks. This dissertation examines the effects of early-life nutritional exposure on children’s growth patterns and pubertal development, with a focus on the International Lipid-Based Nutrient Supplement (iLiNS)-DYAD-Ghana birth cohort. The dissertation first summarizes the literature on the association of children’s anthropometric status and body composition with pubertal development in Sub-Saharan Africa. Next, it explores the longer-term impact of small-quantity lipid-based nutrient supplements (SQ-LNS) used in the iLiNS-DYAD-Ghana trial on children’s pubertal status and hair cortisol at 9-11 and 11-13 years (y) of age. Lastly, it evaluates the associations of anthropometric and body composition indices measured at birth, preschool age (4-6 y), and pubescence (9-11 and 11-13 y of age) with pubertal development by 9-11 and 11-13 y of age. Method: A search was conducted in PubMed and Scopus on April 1, 2023, in a systematic review examining the relationship between nutritional status and pubertal milestones from infancy to 22 y in Sub-Saharan Africa. The risk of bias in the retrieved studies was assessed using the Newcastle-Ottawa Scale (NOS); the results were presented following PRISMA guidelines. The iLiNS-DYAD-Ghana cohort included children born to mothers who were 18 y or older and no more than 20 weeks pregnant at enrolment. These mothers were randomly assigned to one of three daily supplementation regimens during pregnancy and postpartum: (i) a regimen with 60 mg iron and 400 µg folic acid during pregnancy and 200 mg calcium as a placebo during the first 6 months (mo) postpartum, with no supplementation provided to their children (IFA group); (ii) a multiple micronutrient (MMN) regimen, supplying 1-2 times the Recommended Dietary Allowance (RDA) for 18 micronutrients, including 30 mg iron during pregnancy and the first 6 mo postpartum, with no supplementation for their children; or (iii) a small-quantity lipid-based nutrient supplement (SQ-LNS) containing the same micronutrients as the MMN, along with calcium, phosphorus, potassium, magnesium, essential fatty acids, 118 kcal energy, and 2.6 g protein during pregnancy and the first 6 mo postpartum, with the children receiving SQ-LNS designed for infants from 6 to 18 mo of age. At ages 9-11 y and 11-13 y, 966 and 919 children, respectively, were re-enrolled. Pubertal status scores were calculated using the Petersen Pubertal Development Scale (PDS) to evaluate growth spurt, skin changes, body hair, facial hair, voice break, breast development, and menstruation. The PDS score was regressed on the child's age to generate age-adjusted PDS z-scores (aPDSZ). Hair samples were collected from 686 children at ages 9-11 y, from which hair cortisol concentration (HCC) was determined. Analysis of Covariance models assessed group differences, intervention effect modifiers, and mediators. Regression models were used to examine the relationships of anthropometric and body composition z-scores with age adjusted PDS score z-scores (aPDSZ), while also evaluating potential interactions by sex. Results: The systematic review included 23 papers published between 1992 to 2021, covering nine countries and 21,853 children. In several countries, higher height-for-age and BMI z-scores were positively associated with pubertal development, including breast, pubic hair, and genital development; stunting and underweight were linked to delayed pubertal milestones, such as voice break in boys. Early life exposure to SQ-LNS had a positive effect on children’s pubertal development at 11-13 y when pubertal development was underway, but not at 9-11 y when puberty had barely begun. Children in the MMN group had slightly higher HCC, an indicator of HPA axis activity, compared to the IFA and SQ-LNS groups, with significant effects in females only, suggesting a potential link between nutritional supplementation and physiological stress responses. Additionally, significant positive associations were observed between most of the anthropometric and body composition indices (except for negative association for fat-free mass) and pubertal development, particularly in females compared to males. Conclusions: In Sub-Saharan Africa, greater nutritional measures are significantly linked to earlier and more advanced pubertal development. These results underscore the importance of early growth patterns in achieving healthy pubertal outcomes and promoting long-term health. The findings from the dissertation highlight the role of early nutritional interventions in supporting pubertal development and suggest that SQ-LNS may be an effective strategy for promoting healthy pubertal progression. Further research is needed to investigate the long-term effects of SQ-LNS supplementation on stress regulation as well as the sex-specific impacts of early-life nutritional interventions and growth patterns.