Association Between Maternal Caffeine Consumption and Metabolism and Neonatal Anthropometry: A Secondary Analysis of the NICHD Fetal Growth Studies–Singletons

IMPORTANCE: Higher caffeine consumption during pregnancy has been associated with lower birth weight. However, associations of caffeine consumption, based on both plasma concentrations of caffeine and its metabolites, and self-reported caffeinated beverage intake, with multiple measures of neonatal anthropometry, have yet to be examined. OBJECTIVE: To evaluate the association between maternal caffeine intake and neonatal anthropometry, testing effect modification by fast or slow caffeine metabolism genotype. DESIGN, SETTING, AND PARTICIPANTS: A longitudinal cohort study, the National Institute of Child Health and Human Development Fetal Growth Studies–Singletons, enrolled 2055 nonsmoking women at low risk for fetal growth abnormalities with complete information on caffeine consumption from 12 US clinical sites between 2009 and 2013. Secondary analysis was completed in 2020. EXPOSURES: Caffeine was evaluated by both plasma concentrations of caffeine and paraxanthine and self-reported caffeinated beverage consumption measured/reported at 10-13 weeks gestation. Caffeine metabolism defined as fast or slow using genotype information from the single nucleotide variant rs762551 (CYP1A2*1F). MAIN OUTCOMES AND MEASURES: Neonatal anthropometric measures, including birth weight, length, and head, abdominal, arm, and thigh circumferences, skin fold and fat mass measures. The β coefficients represent the change in neonatal anthropometric measure per SD change in exposure. RESULTS: A total of 2055 participants had a mean (SD) age of 28.3 (5.5) years, mean (SD) body mass index of 23.6 (3.0), and 580 (28.2%) were Hispanic, 562 (27.4%) were White, 518 (25.2%) were Black, and 395 (19.2%) were Asian/Pacific Islander. Delivery occurred at a mean (SD) of 39.2 (1.7) gestational weeks. Compared with the first quartile of plasma caffeine level (≤28 ng/mL), neonates of women in the fourth quartile (>659 ng/mL) had lower birth weight (β = −84.3 g; 95% CI, −145.9 to −22.6 g; P = .04 for trend), length (β = −0.44 cm; 95% CI, −0.78 to −0.12 cm; P = .04 for trend), and head (β = −0.28 cm; 95% CI, −0.47 to −0.09 cm; P < .001 for trend), arm (β = −0.25 cm; 95% CI, −0.41 to −0.09 cm: P = .02 for trend), and thigh (β = −0.29 cm; 95% CI, −0.58 to −0.04 cm; P = .07 for trend) circumference. Similar reductions were observed for paraxanthine quartiles, and for continuous measures of caffeine and paraxanthine concentrations. Compared with women who reported drinking no caffeinated beverages, women who consumed approximately 50 mg per day (~ 1/2 cup of coffee) had neonates with lower birth weight (β = −66 g; 95% CI, −121 to −10 g), smaller arm (β = −0.17 cm; 95% CI, −0.31 to −0.02 cm) and thigh (β = −0.32 cm; 95% CI, −0.55 to −0.09 cm) circumference, and smaller anterior flank skin fold (β = −0.24 mm; 95% CI, −0.47 to −0.01 mm). Results did not differ by fast or slow caffeine metabolism genotype. CONCLUSIONS AND RELEVANCE: In this cohort study, small reductions in neonatal anthropometric measurements with increasing caffeine consumption were observed. Findings suggest that caffeine consumption during pregnancy, even at levels much lower than the recommended 200 mg per day of caffeine, are associated with decreased fetal growth.