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

Abstract

Background: 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 gender have been shown to affect liver biomarkers but despite recommendations for age and gender-adjusted reference ranges for liver function tests, these have not been widely adopted clinically. In pregnancy, there are only a few studies that have examined changes of liver function tests (LFTs) with gestation, and none of them have controlled for maternal demographic characteristics.

Objectives: The aims of this study are first, to provide reference ranges of LFTs 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 second, to create an on-line calculator of z-scores of maternal LFTs using the above-mentioned methodology.

Study design: This was a cross-sectional study of healthy women attending for 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 outcome were excluded from the analysis. We measured the following variables: alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), total bilirubin (TBIL) and albumin (ALB). The assessment of the distribution of LFTs across gestational age, (controlling for maternal characteristics) was performed with Generalized Additive Models for Location, Scale, and Shape (GAMLSS), using the GAMLSS R package, which allows the implementation of distributions other than normal distribution.

Results: 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 in visits 1, 2, 3 and 4, respectively. The location parameter of the distribution of the LFT variables is independently predicted by gestational age and ethnicity for all variables, by maternal body mass index (BMI) for all variables except ALB, by maternal age for all variables except ALT/AST ratio and GGT, by maternal parity for all variables except TBIL and ALP, by maternal smoking for TBIL and ALB, and by maternal weight for ALP. The scale parameter of the distribution is also independently predicted by gestational age for all variables apart from ALP, maternal BMI 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 LFTs have a non-uniform influence by gestational age, and maternal ethnicity, BMI, age and parity. An on-line calculator of z-scores for the above-mentioned variables is given at https://fetalmedicinefoundation.shinyapps.io/life/ CONCLUSION: Assessing if a pregnant woman's LFTs 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.