Screening for fetal growth restriction using fetal biometry combined with maternal biomarkers

Am J Obstet Gynecol. 2018 Feb;218(2S):S725-S737. doi: 10.1016/j.ajog.2017.12.002. Epub 2017 Dec 22.

Abstract

Fetal growth restriction is a major determinant of perinatal morbidity and mortality. Screening for fetal growth restriction is a key element of prenatal care but it is recognized to be problematic. Screening using clinical risk assessment and targeting ultrasound to high-risk women is the standard of care in the United States and United Kingdom, but the approach is known to have low sensitivity. Systematic reviews of randomized controlled trials do not demonstrate any benefit from universal ultrasound screening for fetal growth restriction in the third trimester, but the evidence base is not strong. Implementation of universal ultrasound screening in low-risk women in France failed to reduce the risk of complications among small-for-gestational-age infants but did appear to cause iatrogenic harm to false positives. One strategy to making progress is to improve screening by developing more sensitive and specific tests with the key goal of differentiating between healthy small fetuses and those that are small through fetal growth restriction. As abnormal placentation is thought to be the major cause of fetal growth restriction, one approach is to combine fetal biometry with an indicator of placental dysfunction. In the past, these indicators were generally ultrasonic measurements, such as Doppler flow velocimetry of the uteroplacental circulation. However, another promising approach is to combine ultrasonic suspicion of small-for-gestational-age infant with a blood test indicating placental dysfunction. Thus far, much of the research on maternal serum biomarkers for fetal growth restriction has involved the secondary analysis of tests performed for other indications, such as fetal aneuploidies. An exemplar of this is pregnancy-associated plasma protein A. This blood test is performed primarily to assess the risk of Down syndrome, but women with low first-trimester levels are now serially scanned in later pregnancy due to associations with placental causes of stillbirth, including fetal growth restriction. The development of "omic" technologies presents a huge opportunity to identify novel biomarkers for fetal growth restriction. The hope is that when such markers are measured alongside ultrasonic fetal biometry, the combination would have strong predictive power for fetal growth restriction and its related complications. However, a series of important methodological considerations in assessing the diagnostic effectiveness of new tests will have to be addressed. The challenge thereafter will be to identify novel disease-modifying interventions, which are the essential partner to an effective screening test to achieve clinically effective population-based screening.

Keywords: A-disintegrin and metalloprotease 12; alpha fetoprotein; biomarker; fetal biometry; fetal death; human chorionic gonadotropin; human placental lactogen; inhibin; models; placenta; placental growth factor; placental protein 13; prediction; pregnancy-associated plasma protein-A; randomized controlled trial; review; screening; small for gestational age; soluble endoglin; soluble fms-like tyrosine kinase-1; stillbirth; study design; ultrasound.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • ADAM12 Protein / metabolism
  • Biomarkers / metabolism*
  • Biometry*
  • Calcium-Binding Proteins
  • Chorionic Gonadotropin / metabolism
  • Endoglin / metabolism
  • Estriol / metabolism
  • Female
  • Fetal Growth Retardation / diagnosis
  • Fetal Growth Retardation / diagnostic imaging*
  • Fetal Growth Retardation / metabolism
  • Galectins / metabolism
  • Humans
  • Inhibins / metabolism
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Laser-Doppler Flowmetry
  • Membrane Proteins / metabolism
  • Placenta Growth Factor / metabolism
  • Placental Circulation
  • Placental Lactogen / metabolism
  • Pregnancy
  • Pregnancy Proteins / metabolism
  • Pregnancy-Associated Plasma Protein-A / metabolism
  • Prenatal Diagnosis
  • Ultrasonography, Prenatal
  • Vascular Endothelial Growth Factor Receptor-1 / metabolism
  • alpha-Fetoproteins / metabolism

Substances

  • Biomarkers
  • Calcium-Binding Proteins
  • Chorionic Gonadotropin
  • DLK1 protein, human
  • ENG protein, human
  • Endoglin
  • Galectins
  • Intercellular Signaling Peptides and Proteins
  • LGALS13 protein, human
  • Membrane Proteins
  • Pregnancy Proteins
  • alpha-Fetoproteins
  • inhibin A
  • Placenta Growth Factor
  • Inhibins
  • Placental Lactogen
  • FLT1 protein, human
  • Vascular Endothelial Growth Factor Receptor-1
  • ADAM12 Protein
  • ADAM12 protein, human
  • Pregnancy-Associated Plasma Protein-A
  • PAPPA protein, human
  • Estriol