Quantification of metabolites of progesterone in maternal blood by high performance liquid chromatography tandem mass spectrometry, and application in identifying risk of poor outcomes in pregnancy

Abstract

Stillbirth affects 2.6 million pregnancies worldwide each year, with rates in the UK higher than other comparable high-income countries. Fetal growth restriction (FGR) resulting in small for gestational age (SGA) infants is the most significant risk factor for stillbirth, and is strongly associated with placental dysfunction (Brosens et al, 2011).

Current antenatal screening tests for SGA infants include ultrasound scanning, and obtaining a medical and obstetric history in early pregnancy to identify women at higher-risk. Whilst early identification of SGA infants is associated with reduction in perinatal mortality rates, these current screening tests lack both specificity and sensitivity, there is therefore a need to improve screening for FGR (Heazell et al, 2015). Ideally a simple biochemical blood based screening test could be used either alone, or in combination with other tests such as ultrasound, to improve risk stratification and identify asymptomatic women in the early stages of pregnancy, enabling earlier intervention and improved clinical outcomes.

Metabolomic approaches have been used to characterise maternal blood biomarker profiles differing between women with normal pregnancies, and those with poor outcomes including SGA and stillbirth. One such study identified significantly decreased expression of progesterone metabolites, including 17-hydroxypregnenolone sulphate, in women with poor pregnancy outcomes (Heazell et al, 2012). Progesterone is known to play a crucial role in the initiation and maintenance of pregnancy, with the placenta considered an endocrine organ, which is itself capable of progesterone synthesis (Costa, 2016). It has been hypothesized that there may be downregulation of the entire progesterone steroid pathway in pregnancies ending in poor pregnancy outcome (Heazell et al, 2012).

The aim of this research is to identify if levels of progesterone, and metabolites of progesterone, may serve as a proxy test for placental dysfunction. These metabolites will be quantified in cultured medium obtained from an established in-vitro model of the human placenta, and in blood samples taken from a cohort of women with poor pregnancy outcome. We will determine if any combination of progesterone metabolites could function as an early indicator of placental dysfunction, thus providing a reliable and improved screening test for SGA infants.

Outputs

n/a project not yet completed.