The relationship between caffeine consumption and small-for-gestational-age (SGA) birth remains uncertain. However, factors that can influence caffeine metabolism, such as genetic polymorphisms, have not been considered, while other similar factors such as smoking and ethnicity have not always been fully accounted for in the interpretation of results. A case–control study was carried out comprising 493 cases and 472 controls. Cases were newborns whose birthweight was below the 10th percentile according to gestational age and sex, based on national norms, and controls were at or above the 10th percentile. Caffeine consumption from beverages was estimated for each pregnancy trimester. Maternal and newborn variants in the CYP1A2 and CYP2E1 genes involved in the metabolism of caffeine were determined.
Contrasting consumption ≥300 mg/day with a lower level, or using caffeiwne as a continuous measure, while adjusting for smoking and nausea, showed no increased risk for SGA. However, when stratifying for cigarette smoking, caffeine odds ratios (for the continuous and dichotomous measures) in the first trimester were statistically heterogeneous, suggesting a greater risk among non-smokers. Using birthweight as the outcome and caffeine as a continuous measure, a small 38 g [95% confidence interval −68, −8] decrement for every 100 mg of daily caffeine was observed in the third trimester. The studied polymorphisms did not modify the effect of caffeine. Caffeine consumption is unlikely to be a major risk factor for SGA or low birthweight in pregnant women.