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

Abstract

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 (p-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.

Keywords: inborn errors of metabolism; maternal age; newborn metabolites; newborn screening; precision medicine; public health.

Figure 1

Newborn metabolite levels and maternal age. To explore newborn metabolic differences in relation to maternal age (MA), we selected six newborn groups based on MA at delivery with the first group (1519 years, n = 19,528) being defined as a baseline for each metabolite. Effect size differences for the 46 metabolites between each of the five MA groups (2044 years) and the baseline group were calculated. Positive Cohen’s d (in red) indicates increased metabolite levels and negative Cohen’s d (in blue) indicates decreased levels compared to the baseline. Using hierarchical clustering, metabolites were grouped into two clusters of either increasing (at the top) or decreasing (at the bottom) levels compared with the baseline MA group. Seven markers in bold had significant differences between the five MA groups and the baseline group (absolute Cohen’s d > 0.2), including RUSP metabolic disease markers [19] (* label). Acylcarnitines (AC) were enriched in the top cluster of markers with increasing levels. (p-value = 0.0088). AA, Amino acid.

Figure 2

Maternal age and clinical variables. The association between maternal age at delivery (1544 years) and three representative metabolites (C16, C3DC, C5OH) (a–c) and the association between these metabolites, maternal age, and the covariates of infant sex (d–f), gestational age (g–i), and parent-reported ethnicity (j–l) are shown. For each metabolite, the relationship between different maternal ages is shown for male (n = 247,446) and female infants (n = 229,272) (d–f); preterm (n = 23,541) and term (n = 453,177) (g–i); Asian (n = 52,642), Black (n = 23,902), Hispanic (n = 184,595), and White infants (n = 120,362) (j–l). Solid smoothed lines are means estimated from generalized additive models with the shading showing the 95% confidence interval of the mean estimation.

Figure 2

Maternal age and clinical variables. The association between maternal age at delivery (1544 years) and three representative metabolites (C16, C3DC, C5OH) (a–c) and the association between these metabolites, maternal age, and the covariates of infant sex (d–f), gestational age (g–i), and parent-reported ethnicity (j–l) are shown. For each metabolite, the relationship between different maternal ages is shown for male (n = 247,446) and female infants (n = 229,272) (d–f); preterm (n = 23,541) and term (n = 453,177) (g–i); Asian (n = 52,642), Black (n = 23,902), Hispanic (n = 184,595), and White infants (n = 120,362) (j–l). Solid smoothed lines are means estimated from generalized additive models with the shading showing the 95% confidence interval of the mean estimation.

Figure 3

Newborn metabolic difference in relation to advanced maternal age (≥35 years). To identify metabolic differences related to advanced maternal age, 405,968 screen-negative term infants (3742 weeks) with birth weights from 2500 g to 4000 g were grouped into the advanced (≥35 years) and the baseline (1519 years) maternal age groups. Effect size differences (Cohen’s d) for each of the 46 metabolites were calculated between the advanced and the baseline MA group. Positive Cohen’s d values indicate elevated metabolite levels in the advanced MA group. Metabolites are ranked from top to bottom based on Cohen’s d values.