TABLE 1.
Summary of select studies of potential biochemical and physiological markers of FGR.
| Markers | Design | Subjects | Finding | Reference |
|---|---|---|---|---|
| Doppler ultrasound measures of UA, MCA, CPR | Systematic review and meta-analysis | 31 studies (mix of observational cohort studies and RCTs of early-onset FGR (diagnosed <34 weeks) | Increased risk of death for early-onset FGR fetuses with absent or reversed end-diastolic velocities in either the UA (OR 3.59 absent, 7.27 reversed) or DV (OR 11.6, absent or reversed) | Caradeux et al. (2018) |
| Systematic review and meta-analysis | 128 studies (mix of prospective, retrospective; mix of CPR alone, MCA Doppler alone and both CPR and MCA Doppler) | CPR-PI outperforms UA and MCA Doppler in prediction of composite adverse outcome (0.59 sensitivity, 0.91 specificity) and emergency delivery for fetal distress (0.58 sensitivity, 0.89 specificity) | Vollgraff Heidweiller-Schreurs et al. (2018) | |
| Cohort analysis of two European multicenter trials (GRIT and TRUFFLE) | 26–36 weeks gestation pregnant women, stratified by monitoring method for delivery | Early FGR monitoring with both cCTG and DV Doppler assessment was associated with a trend of improved survival without impairment at 2 years (84%), compared with only cCTG monitoring (80% GRIT; 77% TRUFFLE) or immediate delivery (70%) | Ganzevoort et al. (2020) | |
| Prospective RCT (TRUFFLE study) | 26–32 weeks gestation singleton early-onset FGR pregnancy | Using late changes in DV waveform to inform delivery may improve 2-year outcomes | Lees et al. (2015) | |
| Delphi consensus | 45 experienced clinical opinions | Early-onset FGR: UtA-PI and/or UA-PI >95th percentile | Gordijn et al. (2016) | |
| Late-onset FGR: CPR <5th percentile or UA-PI >95th percentile | ||||
| Maternal serum markers | Prospective case-control | 15 control, 15 FGR pregnancies | Maternal serum proteome profiling: Proapolipoprotein C-II, apolipoprotein C-III1, and apolipoprotein C-III2 constitute IUGR signature (sensitivity 0.73, specificity 0.87, AUC 0.86) | Wölter et al. (2016) |
| Pregnancy-associated plasma protein A | Prospective | First trimester screening study in 786 pregnant women (3.2% SGA) | <5th percentile PAPP-A group (0.37 MoM) during first trimester associated with SGA (sensitivity 0.10, specificity 0.97, PPV 0.16, NPV 0.95) | Genc et al. (2022) |
| Systematic review and meta-analysis | 32 studies of first trimester screening in 175,240 pregnancies | <5th percentile PAPP-A group associated with birth weight <10th centile OR 2.08, <5th centile OR 2.83. Birthweight <5th centile LR +ve 2.65, LR −ve 0.85 | Morris et al. (2017) | |
| Micro-RNAs | Retrospective case-control | 80 AGA, 80 FGR pregnancies | Combination of microRNA profile (miR-16-5p, miR-20a-5p, miR-145-5p, miR-146a-5p, miR-181a-5p, miR-342-3p, and miR-574-3p) during the first trimester detected FGR pregnancies (sensitivity 0.4268, specificity 0.95, cut off >0.6578 at 0.1 FPR) | Hromadnikova et al. (2022) |
| Placental growth factors | Prospective case-control | 32 uncomplicated, 49 SGA and 126 FGR pregnancies | High ratio of placental growth factors (sFIt-1/PIGF) was associated with severity of early-onset FGR <97.4 stage I, up to 523.7 stage II, ≥523.7 stage III (PPV 0.986, 0.429, 0.462 respectively) | Garcia-Manau et al. (2021) |
| Prospective observational | 138 singleton pregnancies with EFW <10th centile between 20 and 31 weeks of gestation | sFIt-1/PIGF ratio cut-off value of 38 predictive of delivery before 2 weeks (NPV 1) | Bonacina et al. (2022) | |
| Secondary analysis of two RCTs | Preeclampsia Intervention with Esomeprazole trial (22 AGA infants BW > 10th centile and 75 SGA infants BW < 10th centile) and Preeclampsia Intervention 2 trial (40 AGA infants BW > 10th centile and 95 SGA infants BW < 10th centile) | SPINT1 was decreased in pre-eclamptic pregnancies complicated by growth restriction. Ratios of sFlt-1/SPINT1 and sFlt1/PlGF were increased | Murphy et al. (2022) | |
| Secondary analysis of two RCTs | Maternal samples were assessed from the fetal longitudinal assessment of growth 2 study (152 AGA and 75 SGA) and the biomarker and ultrasound measures for preventable stillbirth study (198 SGA 198, 23 preeclampsia cases and 182 controls) | At 36 weeks of gestation, circulating SPINT2 concentration was increased in patients who developed preeclampsia or delivered a SGA infant | Murphy et al. (2021) | |
| Human chorionic gonadotropin | Retrospective | 1900 AGA and 146 FGR+PE pregnancies | Second trimester intact hCG (>3 MoM) associated with increased risk of developing FGR | Sharony et al. (2018) |
| Midkine | Prospective case-control | 72 AGA, 72 SGA pregnancies | High maternal serum Midkine at ∼36 weeks of gestation predictive of idiopathic FGR at term (sensitivity 0.63, specificity 0.64 at cut-off value 0.20) | Oluklu et al. (2022) |
| Maternal cardiovascular markers | Retrospective | 136 AGA, 16 FGR pregnancies | High maternal peripheral vascular resistance (>1355) at 22–24 weeks gestation is predictive of FGR (sensitivity 0.842, specificity 0.932, AUC 0.88) | Vasapollo et al. (2022) |
| Placental MRI | Observational | 12 AGA and 14 early-onset FGR pregnancies | FGR placenta have slow intervillous blood flow and patchy unperfused areas. Perfusion dynamics worsen with intermittent perturbations in flow | Brunelli et al. (2010) |
| Observational | 17 FGR and 36 normal pregnancies, between 28 and 38 weeks gestation | Placental perfusion fraction lower in FGR | Liu et al. (2021) | |
| Prospective observational | 79 control 35 FGR pregnancies between 18 and 39 weeks gestation | Placental volumes smaller in FGR vs. controls | Andescavage et al. (2017) | |
| Prospective observational | 94 control, 36 FGR/SGA pregnancies >18 weeks gestation | Microstructural alterations in FGR, particularly late-onset FGR | Andescavage et al. (2020) | |
| Prospective observational | 46 controls, 34 FGR pregnancies between 18 and39 weeks gestation | Proposed placental volume algorithm can identify FGR (0.86 accuracy, 0.77 precision, 0.86 recall, AUC 0.86) | Dahdouh et al. (2018) | |
| Retrospective case control | 1163 SGA (birthweight <3rd percentile) and 1163 sex and gestational age matched controls | LTV and STV in FHR have better predictive accuracy earlier (<34 weeks) in gestation. Marker values vary with fetal behavioral state | Stroux et al. (2017) | |
| Two separate prospective studies | singleton pregnancy; 31 SGA (EFW <10th percentile for gestational age) and 30 AGA controls | SGA does not show differences in Dawes and Redman parameter set between day and night; AGA does | Kapaya et al. (2018) | |
| Retrospective cross-sectional study | 9071 normal, 1986 SGA (birthweight <10th percentile), 543 extreme SGA (birthweight <3rd percentile) | SGA fetuses have lower baseline heart rate from 34 weeks, lower STV and LTV, fewer accelerations compared with AGA fetuses | Amorim-Costa et al. (2017a) | |
| Prospective case control | 66 SGA (abdominal circumference <5th percentile) and 79 uncomplicated pregnancies | Decrease of AC (OR 2.1) and DC (OR 0.5) in SGA fetuses from 25 weeks gestation compared with AGA; association is stronger in cases with brain-sparing (MCA-PI) | Stampalija et al. (2016) |
DV, ductus venosus; UA, umbilical artery; MCA, middle cerebral artery; CPR, cerebroplacental ratio; PI, pulsatility index; sFlt1, soluble fms-like tyrosine kinase-1; PlGF, placental growth factor; PE, pre-eclampsia; EFW, estimated fetal weight; cCTG, computerized cardiotocography; MoM, multiple of the median; AUC, area under the curve.