Association between the fetal cerebroplacental ratio and biomarkers of hypoxia and angiogenesis in the maternal circulation at term.

OBJECTIVES: A low fetal cerebroplacental ratio (CPR) in late pregnancy is a marker of a fetus that has failed to reach its growth potential and is associated with a variety of perinatal and pregnancy complications. It is not known if it is also correlated with aberrations in angiogenic, hypoxia-responsive or inflammatory cytokine levels in the maternal circulation. We investigated if there were any differences in levels of biomarkers of angiogenesis, endothelial cell dysfunction, hypoxia and/or inflammation in term pregnancies with a low fetal CPR compared to controls. We hypothesized that as the CPR is a marker of suboptimal growth, this would be reflected in a shift towards upregulation of hypoxia-responsive factors even in non-small for gestational age fetuses. STUDY DESIGN: We used Multiplex ELISA to measure a panel of 28 candidate biomarkers of angiogenesis and/or hypoxia in pre-labour maternal plasma from 113 women at term, stratified for CPR <10th centile vs. CPR >10th centile. Plasma levels of the biomarkers were measured using 2 multiplex Luminex assays - a commercially available human angiogenesis/growth factor panel (R&D Systems®), comprising 15 analytes and an in-house custom panel of a further 13 candidate biomarkers. RESULTS: Of the 28 candidate biomarkers investigated, we found significantly elevated levels of Carbonic Anhydrase 9 and soluble Fms-like tyrosine kinase (Vascular Endothelial Growth Factor Receptor 1), and lower levels of Placental Growth Factor in plasma from women with a low fetal CPR. The soluble Fms-like tyrosine kinase-1/Placental Growth Factor ratio was also markedly elevated in this cohort. We also demonstrated significant inverse correlations between the fetal CPR and Carbonic Anydrase 9, soluble Fms-like tyrosine kinase and Hepatocyte Growth Factor. CONCLUSIONS: A low fetal CPR is associated with changes in some hypoxia-responsive and angiogenesis factors in the maternal circulation in pregnancies with normally grown fetuses.

Reduced growth velocity at term is associated with adverse neonatal outcomes in non-small for gestational age infants.

OBJECTIVES: To investigate the association between decreased growth velocity at term, measured by estimated fetal weight z-score change, and adverse neonatal outcome and operative birth for intrapartum fetal compromise in a cohort of non-small for gestational age infants. STUDY DESIGN: A prospective observational study was conducted at Mater Mothers' Hospital, Brisbane, Australia. Serial ultrasound assessment was undertaken every two weeks from 36 weeks gestation until delivery to determine estimated fetal weight on 436 women with uncomplicated pregnancies. Intrapartum and neonatal outcomes were recorded. The outcome measures were adverse neonatal outcome [severe acidosis (cord pH < 7.0, base deficit ≤-12 mmol/L and/or lactate >6 mmol/L), low Apgar score (<7 at 5 min) or neonatal intensive care unit admission] and operative delivery for intrapartum fetal compromise. Estimated fetal weight z-score change was compared between those with and without adverse neonatal outcome and operative delivery for intrapartum fetal compromise using Generalised Linear Mixed Models. RESULTS: The estimated fetal weight z-score per week declined for infants with the adverse neonatal outcome whilst those without demonstrated an increase [-0.04 (0.18) vs. 0.02 (0.21), p = 0.02]. There was no difference in estimated fetal weight z-score change per week in those with and without operative delivery for intrapartum fetal compromise. CONCLUSION: Reduced growth velocity in non-small for gestational age fetuses at term is associated with an increased risk of adverse neonatal outcomes.

Assessment of left ventricular function using the Myocardial Performance Index in term fetuses that develop intrapartum compromise.

OBJECTIVE: To investigate the relationship between the prelabour left ventricular Myocardial Performance Index (LVMPI) and intrapartum fetal compromise (IFC) in low-risk term pregnancies. METHODS: A blinded, prospective observational cohort study at the Mater Mother's Hospital, Brisbane, Australia. A cohort of 284 women with uncomplicated singleton pregnancies underwent fortnightly ultrasound from 36 weeks until delivery. The LVMPI was assessed by conventional Doppler ultrasound and correlated with intrapartum outcomes. The LVMPI was also correlated with other Doppler indices of fetal wellbeing. RESULTS: Two hundred and seventy-three women were included in the final analysis, the median LVMPI was higher in fetuses that required any emergency operative delivery for IFC (0.56, 0.52-0.60 versus 0.54, 0.50-0.58, p = .007). The left ventricular cardiac output (LVCO) and cerebroplacental ratio (CPR) were lower in fetuses that required any emergency operative delivery for IFC compared to those that did not (164 ± 19 ml/min/kg versus 181 ± 30 ml/min/kg, p < .001) (1.63 + 0.30 versus 1.90 + 0.50, p < .001), respectively. The LVMPI was inversely correlated with the CPR (r = -0.20, p < .01), MCA PI (r = -0.29, p < .01), and LVCO (r = -0.22, p < .01). CONCLUSIONS: Higher global LVMPI is associated with a higher risk for IFC and poorer condition of the newborn.

Prelabour myocardial deformation and cardiac output in fetuses that develop intrapartum compromise at term: a prospective observational study.

Objective: Redistribution of cardiac output is responsible for the "brain sparing" effect seen during periods of acute or chronic fetal stress. We investigated the relationship between prelabour cardiac function in fetuses that subsequently developed intrapartum fetal compromise (IFC). Methods: A blinded, prospective, observational, cohort study, at Mater Mother's Hospital, Brisbane, Australia. A cohort of 284 women with uncomplicated singleton pregnancies underwent ultrasound every 2 weeks from 36 weeks until delivery. Fetal cardiac output was assessed by conventional Doppler ultrasound and myocardial deformation was measured using velocity vector imaging. Results: Two hundred and seventy three women were included in the final analysis, of which 19% had an emergency operative delivery for intrapartum fetal compromise (IFC). Global left ventricular strain (-12.1%, interquartile ranges (IQR) - 10.3 to -14% versus 13%, IQR -11.3 to -14.2%, p = .01) and strain rate (-1.00, IQR 0.85-1.16 s-1 versus -1.11, IQR -1.00 to -1.21 s-1, p < .001) were lower in fetuses that required any emergency operative delivery for IFC compared to those that did not. Global longitudinal right ventricular strain rate was lower in fetuses that developed IFC (-1.04 ± 0.22 s-1 versus 1.13 ± 0.22 s-1, p < .001), whereas global right ventricular strain did not show any significance differences between the two groups. Additionally, left ventricular cardiac output was lower in fetuses that developed IFC or had a composite neonatal morbidity (560 ± 44 mL/min versus 617 ± 72 mL/min, p < .001) or (581 ± 44 mL/min versus 612 ± 72 mL/min, p < .01), respectively. Conclusion: Lower global left ventricular strain and strain rate and cardiac output are associated with IFC and poorer condition of the newborn. Assessment of fetal cardiac function may be useful for risk stratification for intrapartum fetal compromise in apparently "low risk" term pregnancies.

Screening for adverse perinatal outcomes: uterine artery Doppler, cerebroplacental ratio and estimated fetal weight in low-risk women at term.

OBJECTIVE: To stratify apparently low-risk pregnant women into those who are at risk of adverse perinatal outcomes. Appropriate stratification would allow targeted prenatal and intrapartum management. METHODS: This prospective, observational study included normotensive women with appropriately grown, non-anomalous, singleton pregnancies. Participants underwent fortnightly ultrasounds from 36 weeks' gestation and intrapartum and neonatal outcomes were recorded. The association between uterine artery pulsatility index (UtA-PI), the cerebroplacental ratio (CPR) and estimated fetal weight (EFW) were explored along with their screening performance for CS-IFC and CNM. RESULTS: The final cohort included 429 women. As continuous variables, UtA-PI and the CPR were not correlated (rho = -0.05, p = .33). UtA-PI >95th centile and the CPR <10th centile were predictive of CS-IFC and CNM, with the highest sensitivity achieved by their combination (33.3%, 95% CI 11.6-55.1) for a false positive rate (FPR) of 15.8% (12.3-19.3). For CNM, the highest sensitivity (28.4%, 95% CI 18.6-38.2) and corresponding FPR (17.0%, 95% CI 13.0-20.9) was achieved by combining UtA-PI 95th centile, the CPR 10th centile and EFW 10th centile. EFW was the weakest of the three predictors. CONCLUSION: In this population, UtA-PI 95th centile and the CPR 10th centile have modest screening performance for CS-IFC and CNM.

Diagnostic Performance of Cerebroplacental Ratio Thresholds at Term for Prediction of Low Birthweight and Adverse Intrapartum and Neonatal Outcomes in a Term, Low-Risk Population.

OBJECTIVES: To investigate the screening performance and best threshold centile (5th vs. 10th) of the cerebroplacental ratio (CPR) in low-risk, term pregnancies to predict low birthweight and adverse intrapartum and neonatal outcomes in a term, low-risk population. METHODS: This was a blinded, prospective, cross-sectional study of low-risk singleton pregnancies at term. Women attended fortnightly from 36 weeks for CPR and estimated fetal weight assessment. Intrapartum and neonatal outcomes were recorded. Primary outcomes assessed were low birthweight, cesarean section for intrapartum fetal compromise, and composite adverse neonatal outcome. RESULTS: A total of 483 women participated in the study. The CPR 10th centile (1.48) threshold resulted in the best screening performance. Sensitivities for low birthweight, cesarean section for intrapartum fetal compromise, and composite adverse neonatal outcome of 41.9, 61.1, and 38.3% were achieved for false-positive rates of 17.7, 17.7, and 15.2%, respectively. The corresponding areas under the receiver operating characteristic curves were 0.62, 0.72, and 0.62. CONCLUSION: The CPR 10th centile resulted in the best screening performance, although this would be considered fair at best. The CPR 10th centile may be useful as part of a risk stratification tool for prediction of low birthweight and adverse intrapartum and neonatal outcomes.

Screening Performance of Placental Growth Factor for the Prediction of Low Birth Weight and Adverse Intrapartum and Neonatal Outcomes in a Term Low-Risk Population.

INTRODUCTION: Fetuses who fail to reach their genetic growth potential are thought to have sub-optimal placental function. Low placental growth factor (PlGF) levels have been shown to be predictive of placentally mediated conditions, such as pre-eclampsia or fetal growth restriction. We investigated the screening performance of PlGF for the prediction of low birth weight (<10th centile for gestation) and adverse intrapartum and neonatal outcomes in apparently low-risk term pregnancies. MATERIALS AND METHODS: Maternal PlGF levels were measured fortnightly in a blinded, prospective, observational study from 36 weeks of pregnancy. Women and clinicians were blinded to PlGF results, and pregnancies were managed according to local policies and guidelines. Intrapartum and neonatal outcomes were recorded. PlGF was analysed for association with, and predictive capacity for, low birth weight, caesarean section for intrapartum fetal compromise (CS-IFC) and adverse neonatal outcomes. RESULTS: A total of 438 women were included in the final analysis. Lower PlGF levels were associated with low birth weight, CS-IFC and adverse neonatal outcome. For a false-positive rate of 10 and 20%, respectively, the corresponding sensitivities were 9.7-11.1% and 22.2-26.8%. CONCLUSION: As a sole predictor for low birth weight, CS-IFC and adverse neonatal outcome, PlGF was poor as a test.

The relationship between maternal placental growth factor levels and intrapartum fetal compromise.

INTRODUCTION: Whilst some cases of intrapartum fetal compromise are the result of unpredictable catastrophic events, the majority arise from an unrecognised reduction in feto-placental reserve in otherwise healthy pregnancies. There is currently no reliable technique prior to labour that identifies the at-risk fetus. We aimed to investigate the relationship between maternal levels of serum placental growth factor (PlGF) and intrapartum fetal compromise in term pregnancies prior to labour. Secondary outcomes were caesarean delivery for intrapartum fetal compromise and adverse neonatal outcomes. METHODS: A blinded, prospective, cross sectional study set at Mater Mother's Hospital, Brisbane, Australia. Maternal PlGF concentration was assessed fortnightly from 36 weeks until delivery in 378 low-risk pregnant women. Antenatal and intrapartum care was managed according to local protocols and guidelines, and intrapartum and neonatal outcomes were recorded. RESULTS: Pregnancies that developed intrapartum fetal compromise had lower PlGF than those that did not. PlGF concentration was also lower amongst pregnancies that developed intrapartum fetal heart rate abnormalities, were delivered with abnormal cord gases or Apgar ≤7 at 5 min. Additionally, PlGF levels were lower in pregnancies with an adverse composite neonatal outcome. DISCUSSION: Lower maternal PlGF concentration is associated with intrapartum fetal compromise and poorer condition of the newborn. Maternal PlGF levels may be useful as a component of a risk stratification tool for intrapartum fetal compromise in apparently 'low risk' term pregnancies prior to labour.