Effect of fortified balanced energy-protein supplementation during pregnancy and lactation on infant neurodevelopment: a community-based randomized controlled trial in rural Nepal

Technical Summary: Effect of Fortified Balanced Energy-Protein Supplementation on Infant Neurodevelopment in Rural Nepal

Problem Statement
Infant neurodevelopment in low- and middle-income countries (LMICs) is significantly compromised by poverty, poor health, and malnutrition, with an estimated 250 million children under five failing to reach their full cognitive potential. While maternal nutrition is a modifiable factor linked to fetal brain development, evidence regarding the efficacy of balanced energy-protein (BEP) supplementation specifically on infant neurodevelopment remains limited. Previous systematic reviews indicate that BEP supplementation during pregnancy reduces risks of stillbirth and small-for-gestational-age (SGA) births and increases birth weight, but trials focusing on lactation have shown modest improvements in growth with no clear evidence of direct gains in neurodevelopment by standard early measures. Furthermore, gaps exist in understanding the combined effects of prenatal and postnatal macronutrient and micronutrient supplementation on early cognitive, language, and motor development.

Methodology
The study utilized data from the Maternal Infant Nutrition Trial (MINT), a 2x2 factorial, household-randomized, unblinded, efficacy trial conducted in Sarlahi District, rural Nepal, between November 2021 and September 2024.

• Participants: The trial enrolled 1,944 pregnant women. A neurodevelopment substudy was conducted on a subsample of 400 infants (100 per intervention arm) born to women in the first enrollment cohort who reached 6 months of age.
• Intervention: Women were randomized at the household level to receive daily fortified BEP supplementation (a lipid-based peanut paste providing ~400 kcal, 14.5g protein, 15 micronutrients, and 500mg calcium) or no supplementation during pregnancy. Those with a live birth were re-randomized postpartum to receive supplementation or not until 6 months postpartum. This created four groups: (1) control (no BEP in either period), (2) BEP in pregnancy only, (3) BEP in lactation only, and (4) BEP in both periods.
• Outcomes: The primary outcome for this substudy was infant neurodevelopment at 6 months of age, assessed using the Bayley Scales of Infant and Toddler Development, fourth edition (Bayley-4). Assessments covered four domains: cognition, motor (fine and gross), language (receptive and expressive), and socio-emotional. Additionally, WHO gross motor milestones were assessed.
• Analysis: Multivariable linear regression models were used to estimate mean differences (MD) and 95% confidence intervals (CI) for standard scores. Interaction effects between pregnancy and lactation supplementation were tested for each domain.

Key Results

• Baseline Characteristics: Baseline characteristics were similar across the four intervention groups, with high inter-rater reliability (ICC 0.98–0.99) for neurodevelopmental assessments.
• Interaction Effects: A significant interaction (p = 0.015) between pregnancy and lactation supplementation was observed exclusively in the language domain. No significant interactions were found for cognitive, motor, or socio-emotional domains.
• Marginal Effects:
  • Pregnancy Supplementation: Infants whose mothers received BEP during pregnancy showed no significant differences in standard scores for cognitive (MD: 2.0, 95% CI: -0.29, 4.29), motor (MD: 0.98, 95% CI: -1.41, 3.36), or socio-emotional (MD: -2.35, 95% CI: -5.27, 0.57) domains compared to the control group.
  • Lactation Supplementation: Similarly, no significant differences were observed in these three domains for infants whose mothers received BEP during lactation versus those who did not.
• Combined Effect (Language): Infants born to mothers who received BEP supplementation during both pregnancy and lactation had significantly higher mean language standard scores compared to the control group (MD: 2.12, 95% CI: 0.16, 4.08). This improvement was driven specifically by the expressive communication subtest.
• Gross Motor Milestones: At 6 months, approximately 21% of infants could sit without support, and less than 3% could crawl on hands and knees. These milestones did not vary significantly across the four groups.

Significance and Claims
The paper concludes that fortified BEP supplementation during pregnancy or lactation alone was not associated with improvements in cognitive, motor, or socio-emotional domains at 6 months of age. However, the study identifies a specific, significant benefit of combined supplementation (during both pregnancy and lactation) on infant language development, particularly expressive communication.

The authors emphasize that these findings are modest and require careful interpretation:

1. Timing of Assessment: The assessment at 6 months provides only a limited snapshot of development. The authors note that neurodevelopmental assessments in early childhood have low reliability and that longer follow-up (e.g., at 18 or 24 months) is necessary to determine if early language differences predict long-term cognitive trajectories.
2. Mechanism: The observed effect on expressive language may reflect early-stage developmental trajectories or indirect effects via improved maternal nutrition supporting breast milk quality, though the study did not measure home environment or caregiving quality, which are known confounders.
3. Future Directions: The paper explicitly states that evaluation at later ages is warranted to understand the sustained effects of BEP supplementation and to clarify whether early language gains translate to broader neurodevelopmental improvements.

The study does not claim that BEP supplementation is a definitive solution for neurodevelopmental delays but highlights the potential of combined prenatal and postnatal nutritional support for specific language outcomes in undernourished populations, warranting further longitudinal investigation.