The association of early unexplained elevated alanine aminotransferase with large-for-gestational-age birthweight

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Abstract

Background

Nonalcoholic fatty liver disease causes hepatic insulin resistance and is associated with metabolic syndrome. Elevated levels of alanine aminotransferase are associated with nonalcoholic fatty liver disease. The effect of hepatic insulin resistance is not only increased glycogen breakdown but also liberation of free fatty acids due to increased lipolysis. Both of these fuel sources are associated with macrosomia. There is little known about the impact of maternal nonalcoholic fatty liver disease on excessive fetal growth.

Objective

The purpose of this study was to investigate the association of early elevated alanine aminotransferase with large-for-gestational-age birthweight.

Study Design

This is a secondary analysis from a nested case-control study of maternal alanine aminotransferase values measured between 8–18 weeks and subsequent gestational diabetes. We included women with singleton gestations with complete delivery information and without known diabetes, liver disease, or moderate self-reported alcohol use during pregnancy. We used inverse probability weighting to standardize the population and minimize selection bias. We calculated population-based birthweight z scores and defined large for gestational age as ≥90th percentile for gestational age. We compared maternal baseline characteristics with analysis of variance, Fisher exact test, or Wilcoxon rank sum. We then performed conditional logistic regression to evaluate the relationship between alanine aminotransferase and large for gestational age adjusting for maternal age, body mass index, parity, gestational diabetes, smoking, and maternal weight gain.

Results

We identified 26 cases of large for gestational age out of 323 mother-infant dyads. The mean maternal body mass index was higher in the large-for-gestational-age group compared to controls (33.7 [SD 4.3] vs 28.9 [SD 6.5], P = .002). Large-for-gestational-age babies were less likely to be male (8 [31%] vs 172 [58%], P = .01) and had a higher mean gestational age (39.5 [SD 0.9] vs 38.4 [SD 2.3] weeks, P = .01). Maternal and infant characteristics were otherwise similar. The mean alanine aminotransferase among the large-for-gestational-age cases was 28 (SD 37) U/L compared to 16 (SD 8) U/L for controls. Each unit increase in log-transformed alanine aminotransferase was associated with a 3-fold odds of large for gestational age (adjusted odds ratio, 3.05; 95% confidence interval, 2.27–4.10; P < .0001), and alanine aminotransferase ≥90th percentile (26 U/L) was associated with a 4-fold increased odds of large for gestational age (adjusted odds ratio, 4.03; 95% confidence interval, 2.84–5.70; P < .0001). This association was unchanged when analysis was restricted only to women without gestational diabetes with a glucose loading test <120 mg/dL (log-transformed alanine aminotransferase: adjusted odds ratio, 3.05; 95% confidence interval, 1.04–8.96; P = .04, and alanine aminotransferase ≥90th percentile: adjusted odds ratio, 4.21; 95% confidence interval, 1.20–14.82; P = .03).

Conclusion

Unexplained elevated alanine aminotransferase in the first trimester was associated with a 4-fold increase in the odds of large-for-gestational-age birthweight even in the absence of clinical glucose intolerance. This may represent the impact of maternal nonalcoholic fatty liver on the fetal developmental milieu.

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