Fetal growth restriction and stillbirth: Biomarkers for identifying at risk fetuses

Abstract

Fetal growth restriction (FGR) is a major cause of stillbirth, prematurity and impaired neurodevelopment. Its etiology is multifactorial, but many cases are related to impaired placental development and dysfunction, with reduced nutrient and oxygen supply. The fetus has a remarkable ability to respond to hypoxic challenges and mounts protective adaptations to match growth to reduced nutrient availability. However, with progressive placental dysfunction, chronic hypoxia may progress to a level where fetus can no longer adapt, or there may be superimposed acute hypoxic events. Improving detection and effective monitoring of progression is critical for the management of complicated pregnancies to balance the risk of worsening fetal oxygen deprivation in utero, against the consequences of iatrogenic preterm birth. Current surveillance modalities include frequent fetal Doppler ultrasound, and fetal heart rate monitoring. However, nearly half of FGR cases are not detected in utero, and conventional surveillance does not prevent a high proportion of stillbirths. We review diagnostic challenges and limitations in current screening and monitoring practices and discuss potential ways to better identify FGR, and, critically, to identify the "tipping point" when a chronically hypoxic fetus is at risk of progressive acidosis and stillbirth.

Keywords: biomarkers; fetal growth restriction (FGR); fetal heart rate variability (fHRV); fetal hypoxia; preterm brain injury; stillbirth.

FIGURE 1

Schematic showing current FGR detection and monitoring techniques and modalities, with potential avenues for improvement. aFECG, abdominal fetal electrocardiogram; CTG, cardiotocogram; MRI, magnetic resonance imaging; UA, umbilical artery; MCA, middle cerebral artery; DV, ductus venosus; PI, pulsatility index; STV, short term variability; LTV, long term variability; PlGF, placental growth factor; sFlt1, soluble fms-like tyrosine kinase-1; PAPP-A, pregnancy associated plasma protein A; β-HCG, beta human chorionic gonadotropin; SPINT, serine protease inhibitor.

FIGURE 2

Example of placental MRI modalities. Comparing central slices through the placenta, (A) is a normal pregnancy (fetal abdominal diameter 96.5 mm) at 37 weeks gestation, with placental thickness of 41.2 mm. (B) is FGR (fetal abdominal diameter 79.2 mm, birthweight 1.4 centile) at 37 weeks gestation, with placental thickness of 21.8 mm. Placentae in FGR pregnancies are typically described as smaller and appearing darker and more heterogenous in MRI. (C) shows identification of a placental region of interest. (D) shows a parameter map of apparent diffusion coefficient, a parameter that relates to blood movement, and is typically extracted from MRI studies.