Jointly modelling longitudinally measured urinary human chorionic gonadotrophin and early pregnancy outcomes

N B Ashra,L Marriott,S Johnson,M J Crowther,K R Abrams

doi:10.1038/s41598-020-61461-w

Abstract

Human chorionic gonadotrophin (hCG) is largely used to confirm pregnancy. Yet evidence shows that longitudinal hCG profiles are distinguishable between healthy and failing pregnancies. We retrospectively fitted a joint longitudinal-survival model to data from 127 (85 healthy and 42 failing pregnancies) US women, aged 18–45, who were attempting to conceive, to quantify the association between longitudinally measured urinary hCG and early miscarriage. Using subject-specific predictions, obtained uniquely from the joint model, we investigated the plausibility of adaptively monitoring early pregnancy outcomes based on updating hCG measurements. Volunteers collected daily early morning urine samples for their menstrual cycle and up to 28 days post day of missed period. The longitudinal submodel for log hCG included a random intercept and slope and fixed linear and quadratic time terms. The survival submodel included maternal age and cycle length covariates. Unit increases in log hCG corresponded to a 63.9% (HR 0.36, 95% CI 0.16, 0.47) decrease in the risk of miscarriage, confirming a strong association between hCG and miscarriage. Outputted conditional survival probabilities gave individualised risk estimates for the early pregnancy outcomes in the short term. However, longer term monitoring would require a larger sample size and prospectively followed up data, focusing on emerging extensions to the joint model, which allow assessment of the specificity and sensitivity.

Highlights

Human chorionic gonadotrophin is largely used to confirm pregnancy
Its use is more prevalent in tracking early pregnancy progress in an in vitro fertilisation (IVF) population and for identifying ectopic pregnancies[7]
Evidence suggests that longitudinal profiles of Human chorionic gonadotrophin (hCG) can be utilised to distinguish between viable and failing pregnancies, with similar patterns of hCG noted across maternal serum and urine[8]

Summary

Introduction

Human chorionic gonadotrophin (hCG) is largely used to confirm pregnancy. Yet evidence shows that longitudinal hCG profiles are distinguishable between healthy and failing pregnancies. We retrospectively fitted a joint longitudinal-survival model to data from 127 (85 healthy and 42 failing pregnancies) US women, aged 18–45, who were attempting to conceive, to quantify the association between longitudinally measured urinary hCG and early miscarriage. The repeated collection of a continuous biomarker, such as hCG, over time gives rise to intermittently observed longitudinal data which are subject to measurement error[9,10]. This data is analysed using linear mixed effects models, with time-to-event outcomes analysed using survival models[11,12]. Variables Age, years Ethnicity, n (%) White Black Asian Mixed Education, n (%) High School Graduate Postgraduate Occupation, n (%) Homemaker Student Skilled labourer Office admin Professional Other Cycle length Previous pregnancies Previous live births Time to conceive, months Previous miscarriage, n (%)

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