BackgroundWhile being small-for-gestational-age due to placental insufficiency is a major risk factor for stillbirth, 50% of stillbirths occur in appropriate-for-gestational-age (AGA, > 10th centile) fetuses. AGA fetuses are plausibly also at risk of stillbirth if placental insufficiency is present. Such fetuses may be expected to demonstrate declining growth trajectory across pregnancy, although they do not fall below the 10th centile before birth. We investigated whether reduced growth velocity in AGA fetuses is associated with antenatal, intrapartum and neonatal indicators of placental insufficiency.MethodsWe performed a prospective cohort study of 308 nulliparous women who subsequently gave birth to AGA infants. Ultrasound was utilised at 28 and 36 weeks’ gestation to determine estimated fetal weight (EFW) and abdominal circumference (AC). We correlated relative EFW and AC growth velocities with three clinical indicators of placental insufficiency, namely (1) fetal cerebroplacental ratio (CPR; CPR < 5th centile reflects placental resistance, and blood flow redistribution to the brain – a fetal response to hypoxia); (2) neonatal acidosis after the hypoxic challenge of labour (umbilical artery (UA) pH < 7.15 at birth); and (3) low neonatal body fat percentage (BF%, measured by air displacement plethysmography) reflecting reduced nutritional reserve in utero.ResultsFor each one centile reduction in EFW growth velocity between 28 and 36 weeks’ gestation, there was a 2.4% increase in the odds of cerebral redistribution (CPR < 5th centile, odds ratio (OR) (95% confidence interval) = 1.024 (1.005–1.042), P = 0.012) and neonatal acidosis (UA pH < 7.15, OR = 1.024 (1.003–1.046), P = 0.023), and a 3.3% increase in the odds of low BF% (OR = 1.033 (1.001–1.067), P = 0.047). A decline in EFW of > 30 centiles between 28 and 36 weeks (compared to greater relative growth) was associated with cerebral redistribution (CPR < 5th centile relative risk (RR) = 2.80 (1.25–6.25), P = 0.026), and a decline of > 35 centiles was associated with neonatal acidosis (UA pH < 7.15 RR = 3.51 (1.40–8.77), P = 0.030). Similar associations were identified between low AC growth velocity and clinical indicators of placental insufficiency.ConclusionsReduced growth velocity between 28 and 36 weeks’ gestation among fetuses born AGA is associated with antenatal, intrapartum and neonatal indicators of placental insufficiency. These fetuses potentially represent an important unrecognised cohort at increased risk of stillbirth and may warrant more intensive antenatal surveillance.

Placental insufficiency can cause fetal growth restriction and stillbirth. There are no reliable screening tests for placental insufficiency, especially near-term gestation when the risk of stillbirth rises. Here we show a strong association between low circulating plasma serine peptidase inhibitor Kunitz type-1 (SPINT1) concentrations at 36 weeks' gestation and low birthweight, an indicator of placental insufficiency. We generate a 4-tier risk model based on SPINT1 concentrations, where the highest risk tier has approximately a 2-5 fold risk of birthing neonates with birthweights under the 3 rd , 5 th , 10 th and 20 th centiles, whereas the lowest risk tier has a 0-0.3 fold risk. Low SPINT1 is associated with antenatal ultrasound and neonatal anthropomorphic indicators of placental insufficiency. We validate the association between low circulating SPINT1 and placental insufficiency in two other cohorts. Low circulating SPINT1 is a marker of placental insufficiency and may identify pregnancies with an elevated risk of stillbirth.

Background We investigated the biomarker potential of growth differentiation factor 15 (GDF‐15), a stress response protein highly expressed in placenta, to predict preeclampsia. Methods and Results In 2 prospective cohorts (cohort 1: 960 controls, 39 women who developed preeclampsia; cohort 2: 950 controls, 41 developed preeclampsia), plasma concentrations of GDF‐15 at 36 weeks' gestation were significantly increased among those who developed preeclampsia ( P <0.001), area under the receiver operating characteristic curves (AUC) of 0.66 and 0.71, respectively. In cohort 2 a ratio of sFlt‐1/PlGF (a clinical biomarker for preeclampsia) had a sensitivity of 61.0% at 83.2% specificity to predict those who will develop preeclampsia (AUC of 0.79). A ratio of GDF‐15×sFlt‐1/PlGF yielded a sensitivity of 68.3% at 83.2% specificity (AUC of 0.82). GDF‐15 was consistently elevated across a number of international cohorts: levels were higher in placenta and blood from women delivering <34 weeks' gestation due to preterm preeclampsia in Melbourne, Australia; and in the blood at 26 to 32 weeks' gestation among 57 women attending the Manchester Antenatal Vascular Service (MAViS, UK) who developed preeclampsia ( P =0.0002), compared with 176 controls. In the Preeclampsia Obstetric adVerse Events biobank (PROVE, South Africa), plasma GDF‐15 was significantly increased in women with preeclampsia with severe features ( P =0.02; n=14) compared to controls (n=14). Conclusions We conclude circulating GDF‐15 is elevated among women more likely to develop preeclampsia or diagnosed with the condition. It may have value as a clinical biomarker, including the potential to improve the sensitivity of sFlt‐1/PlGF ratio.

BackgroundFetal growth restriction is a disorder of placental dysfunction with three to four-fold increased risk of stillbirth. Fetal growth restriction has pathophysiological features in common with preeclampsia. We hypothesised that angiogenesis-related factors in maternal plasma, known to predict preeclampsia, may also detect fetal growth restriction at 36 weeks’ gestation. We therefore set out to determine the diagnostic performance of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), and the sFlt-1:PlGF ratio, measured at 36 weeks’ gestation, in identifying women who subsequently give birth to small-for-gestational-age (SGA; birthweight <10th centile) infants. We also aimed to validate the predictive performance of the analytes for late-onset preeclampsia in a large independent, prospective cohort.MethodsA nested 1:2 case-control study was performed including 102 cases of SGA infants and a matched group of 207 controls; and 39 cases of preeclampsia. We determined the diagnostic performance of each angiogenesis-related factor, and of their ratio, to detect SGA infants or preeclampsia, for a predetermined 10% false positive rate.ResultsMedian plasma levels of PlGF at 36 weeks’ gestation were significantly lower in women who subsequently had SGA newborns (178.5 pg/ml) compared to normal birthweight controls (326.7 pg/ml, p < 0.0001). sFlt-1 was also higher among SGA cases, but this was not significant after women with concurrent preeclampsia were excluded. The sensitivity of PlGF to predict SGA infants was 28.8% for a 10% false positive rate. The sFlt-1:PlGF ratio demonstrated better sensitivity for preeclampsia than either analyte alone, detecting 69.2% of cases for a 10% false positive rate.ConclusionsPlasma PlGF at 36 weeks’ gestation is significantly lower in women who subsequently deliver a SGA infant. While the sensitivity and specificity of PlGF currently limit clinical translation, our findings support a blood-based biomarker approach to detect late-onset fetal growth restriction. Thirty-six week sFlt-1:PlGF ratio predicts 69.2% of preeclampsia cases, and could be a useful screening test to triage antenatal surveillance.Electronic supplementary materialThe online version of this article (10.1186/s12884-018-1992-x) contains supplementary material, which is available to authorized users.

Background Fetal growth restriction (FGR) due to placental insufficiency is a major risk factor for stillbirth. While small-for-gestational-age (SGA; weight < 10th centile) is a commonly used proxy for FGR, detection of FGR among appropriate-for-gestational-age (AGA; weight ≥ 10th centile) fetuses remains an unmet need in clinical care. We aimed to determine whether reduced antenatal growth velocity from the time of routine mid-trimester ultrasound is associated with antenatal, intrapartum and postnatal indicators of placental insufficiency among term AGA infants. Methods Three hundred and five women had biometry measurements recorded from their routine mid-trimester (20-week) ultrasound, at 28 and 36 weeks’ gestation, and delivered an AGA infant. Mid-trimester, 28- and 36-week estimated fetal weight (EFW) and abdominal circumference (AC) centiles were calculated. The EFW and AC growth velocities between 20 and 28 weeks, and 20–36 weeks, were examined as predictors of four clinical indicators of placental insufficiency: (i) low 36-week cerebroplacental ratio (CPR; CPR < 5th centile reflects cerebral redistribution—a fetal adaptation to hypoxia), (ii) neonatal acidosis (umbilical artery pH < 7.15) after the hypoxic challenge of labour, (iii) low neonatal body fat percentage (BF%) reflecting reduced nutritional reserve and (iv) placental weight < 10th centile. Results Declining 20–36-week fetal growth velocity was associated with all indicators of placental insufficiency. Each one centile reduction in EFW between 20 and 36 weeks increased the odds of cerebral redistribution by 2.5% (odds ratio (OR) = 1.025, P = 0.001), the odds of neonatal acidosis by 2.7% (OR = 1.027, P = 0.002) and the odds of a < 10th centile placenta by 3.0% (OR = 1.030, P < 0.0001). Each one centile reduction in AC between 20 and 36 weeks increased the odds of neonatal acidosis by 3.1% (OR = 1.031, P = 0.0005), the odds of low neonatal BF% by 2.8% (OR = 1.028, P = 0.04) and the odds of placenta < 10th centile by 2.1% (OR = 1.021, P = 0.0004). Falls in EFW or AC of > 30 centiles between 20 and 36 weeks were associated with two–threefold increased relative risks of these indicators of placental insufficiency, while low 20–28-week growth velocities were not. Conclusions Reduced growth velocity between 20 and 36 weeks among AGA fetuses is associated with antenatal, intrapartum and postnatal indicators of placental insufficiency. These fetuses potentially represent an important, under-recognised cohort at increased risk of stillbirth. Encouragingly, this novel fetal assessment would require only one additional ultrasound to current routine care, and adds to the potential benefits of routine 36-week ultrasound.