Association of Maternal Age and Blood Markers for Metabolic Disease in Newborns

Pregnancy at an advanced maternal age is considered a risk factor for adverse maternal, fetal, and neonatal outcomes. Here we investigated whether maternal age could be associated with differences in the blood levels of newborn screening (NBS) markers for inborn metabolic disorders on the Recommended Universal Screening Panel (RUSP). Population-level NBS data from screen-negative singleton infants were examined, which included blood metabolic markers and covariates such as age at blood collection, birth weight, gestational age, infant sex, parent-reported ethnicity, and maternal age at delivery. Marker levels were compared between maternal age groups (age range: 1544 years) using effect size analyses, which controlled for differences in group sizes and potential confounding from other covariates. We found that 13% of the markers had maternal age-related differences, including newborn metabolites with either increased (Tetradecanoylcarnitine [C14], Palmitoylcarnitine [C16], Stearoylcarnitine [C18], Oleoylcarnitine [C18:1], Malonylcarnitine [C3DC]) or decreased (3-Hydroxyisovalerylcarnitine [C5OH]) levels at an advanced maternal age (≥35 years, absolute Cohen's d > 0.2). The increased C3DC levels in this group correlated with a higher false-positive rate in newborn screening for malonic acidemia ( -value < 0.001), while no significant difference in screening performance was seen for the other markers. Maternal age is associated with inborn metabolic differences and should be considered together with other clinical variables in genetic disease screening.