Hemoglobin during pregnancy does not mediate the relationship between nutrition supplements and intrauterine growth: A secondary data analysis of Women First Preconception Nutrition Trial.

Background: Nutrition supplements such as multiple micronutrient-fortified small-quantity lipid-based nutrient supplementation (SQ-LNS) consumed either before or during pregnancy have been shown to improve intrauterine growth but the mechanisms through which the supplements improve intrauterine growth remain unclear.

Objective: We examined whether hemoglobin (Hb) during pregnancy could be a potential mechanism through which multiple micronutrient-fortified SQ-LNS improve intrauterine growth.

Methods: We used data collected from women and newborns in a randomized controlled trial conducted in Pakistan, India, the Democratic Republic of Congo, and Guatemala. Women were randomized to consume multiple micronutrient-fortified SQ-LNS from preconception until birth (Arm 1); consume the SQ-LNS from the second trimester of pregnancy until birth (Arm 2); or no supplement (Arm 3). Intrauterine growth, expressed as birth length, weight, and head circumference Z-scores, was the outcome. The mediator was Hb (g/dL) measured at 12 (n=2,075) and 32 weeks of gestation (n=2,157). Causal mediation analysis was employed to estimate direct and indirect effects.

Results: Hemoglobin levels at 12 or 32 weeks of gestation did not mediate the relation between the SQ-LNS and intrauterine growth. Indirect effects of preconception SQ-LNS (Arm 1) vs. Arm 3, mediated by Hb at 12 weeks of gestation, were 0.02 (95% CI: -0.02, 0.01), 0.01 (95% CI: -0.01, 0.02), and 0.01 (95% CI: -0.01, 0.02) for length, weight, and head circumference Z-scores, respectively. The corresponding direct effects (95% CIs), not mediated by Hb, were 0.18 (0.09, 0.33), 0.12 (0.03, 0.23), and 0.06 (-0.03, 0.20), respectively. Site-specific and gestational age-adjusted data analyses at 12 and 32 weeks of gestation confirmed the findings of no statistically significant mediated effects of Hb during pregnancy.

Conclusions: The observed main effect of multiple micronutrient-fortified SQ-LNS on intrauterine growth was not mediated by Hb levels at 12 or 32 weeks of gestation. The findings suggest exploring other pathways implicated in the association between the SQ-LNS and intrauterine growth. Background: ClinicalTrials.gov #NCT01883193; https://clinicaltrials.gov/ct2/show/NCT01883193?term=01883193&rank=1.