Pregnancy Outcome Prediction study

Did You Know?

• The lab work using the biobank is led by Stephen Charnock-Jones.
• Other funding sources include the Medical Research Council, the British Heart Foundation, and Sands.

Background

The bulk of its first five years of funding supported the POP study. While screening for fetal abnormalities has advanced through ultrasound, biochemical screening, and molecular genetics, methods for screening low-risk populations for complications such as fetal growth restriction, pre-eclampsia, and stillbirth have remained largely unchanged for decades. The POP study focuses on improving screening for these conditions.

Design and aims

Nulliparous women with a viable singleton pregnancy were recruited at their dating ultrasound scan; multiple pregnancy was the only clinical exclusion criterion. Serial ultrasound scans and blood samples were obtained at recruitment, 20, 28, and 36 weeks of gestation. Partners provided DNA samples and height/weight measurements. After delivery, biopsies of the placenta, placental membranes, umbilical cord, and cord blood were collected. The resulting biobank includes approximately 230,000 blood and tissue samples stored at -80 °C, 24,000 formalin-fixed placental biopsies, and 4,000 paternal DNA samples. The study aims to understand mechanisms of placentally-related complications, study infectious agents in the placenta, evaluate known biomarkers and serial ultrasonography, and discover novel placentally-derived circulating biomarkers.

Key findings

Universal third-trimester ultrasound in nulliparous women roughly triples detection of small for gestational age infants; combining estimated fetal weight and growth velocity identifies small babies at increased risk of neonatal morbidity. Maternal serum DLK1 differentiates constitutionally small from pathologically small fetuses. Fetuses of mothers who develop gestational diabetes mellitus grow faster before diagnosis, suggesting earlier screening at 24 weeks. A predictive model using ultrasound estimated fetal weight at 36 weeks, maternal age, height, BMI, and weight gain identifies women at increased risk of emergency C-section. Third-trimester ultrasound increases detection of large for gestational age infants and, with growth velocity, identifies those at risk of adverse neonatal outcome. A screening test for pre-eclampsia and fetal growth restriction combines the sFLT1:PlGF ratio and ultrasonic fetal weight. The placenta shows sex-dependent differences in polyamine metabolism associated with X-chromosome escape by spermine synthase; maternal serum N1,N12-diacetylspermine levels increase pre-eclampsia risk but decrease fetal growth restriction risk. A novel biomarker, 4-hydroxyglutamate, improves first-trimester prediction of preterm pre-eclampsia.

Follow-up work

The Pregnancy Outcome Prediction study 2 (POPS2), funded by the Wellcome Trust and started in January 2020, aims to collect similar data and samples from approximately 4,500 unselected nulliparous women. Its goals are to assess whether the POP study's screening test (combining maternal risk factors, ultrasound, and sFlt-1:PlGF ratio) works in an independent cohort, to nest a randomised controlled trial of early induction of labour from 37 weeks in screen-positive women, and to develop new predictive tests. The POPStar follow-up study, funded by the NIHR Cambridge BRC and Action Medical Research, started in June 2020 when children were 8–12 years old. It links routinely-collected NHS and education data with POP study results to determine which pregnancy parameters predict later health or developmental problems in mothers and children.