Reference ranges for liver function tests in pregnancy controlling for maternal characteristics

Liver dysfunction complicates 3% of pregnancies, and prompt diagnosis reduces severe maternal and perinatal morbidity and mortality. Recognition of liver dysfunction relies on the creation of reference ranges. Outside pregnancy, factors such as age and sex have been shown to affect liver biomarkers. However, despite recommendations for age- and sex-adjusted reference ranges for liver function tests, these have not been widely adopted clinically. In pregnancy, only a few studies have examined changes of liver function tests with gestation, and none of them have controlled for maternal demographic characteristics.

This study aimed to (1) provide reference ranges for liver function tests in a large population of uncomplicated pregnancies after adjusting for the effect of gestational age and maternal demographic characteristics on the median and measures of dispersion and shape (skewness and kurtosis) of the distribution of these variables, and (2) create an online calculator of z-scores of maternal liver function tests using the above-mentioned methodology.

This was a cross-sectional study of healthy women undergoing routine antenatal ultrasound scans at 11⁺⁰ to 13⁺⁶ weeks' gestation (visit 1), 19⁺⁰ to 24⁺⁶ weeks (visit 2), 30⁺⁰ to 34⁺⁶ weeks (visit 3), and 35⁺⁰ to 37⁺⁶ weeks (visit 4). Women with a history of liver dysfunction or adverse pregnancy outcomes were excluded from the analysis. We measured the following variables: ALP (alkaline phosphatase), ALT (alanine aminotransferase), AST (aspartate aminotransferase), GGT (gamma-glutamyl transferase), total bilirubin, and ALB (albumin). The assessment of the distribution of liver function tests across gestational age (controlling for maternal characteristics) was performed using the generalized additive model for location, scale, and shape, with the gamlss R package, which allows the implementation of distributions other than the normal distribution.

There were 3451 women who agreed to participate in the study and had uncomplicated pregnancies. Women participated only once in the study, with 805, 860, 886, and 900 women attending visits 1, 2, 3, and 4, respectively. The location parameter of the distribution of the liver function test variables is independently predicted by gestational age and ethnicity for all variables, by maternal body mass index for all variables except ALB, by maternal age for all variables except ALT-AST ratio and GGT, by maternal parity for all variables except total bilirubin and ALP, by maternal smoking for total bilirubin and ALB, and by maternal weight for ALP. The scale parameter of the distribution is also independently predicted by gestational age for all variables except ALP, maternal body mass index for ALT, AST, GGT, and ALP, maternal age and ethnicity for GGT, and maternal parity for ALT and AST. In contrast, the skewness and kurtosis of liver function tests are influenced nonuniformly by gestational age, maternal ethnicity, body mass index, age, and parity. An online calculator of z-scores for the above-mentioned variables is given at https://fetalmedicinefoundation.shinyapps.io/life/.

Assessing whether a pregnant woman's liver function tests deviate from the expected normal values necessitates adjusting for gestational age and maternal demographic characteristics, both for the median and measures of dispersion and shape of the distribution.