A critical review of placental function evaluation near term using Doppler ratios.

Pregnancies complicated by late-onset fetal growth restriction (FGR) are at increased risk of short- and long-term morbidities. Despite this, identification of cases at higher risk of adverse perinatal outcome, at the time of FGR diagnosis, is challenging. The aims of this study were to elucidate the strength of association between fetoplacental Doppler indices at the time of diagnosis of late-onset FGR and adverse perinatal outcome, and to determine their predictive accuracy. This was a prospective study of consecutive singleton pregnancies complicated by late-onset FGR. Late-onset FGR was defined as estimated fetal weight (EFW) or abdominal circumference (AC) < 3rd centile, or EFW or AC < 10th centile and umbilical artery (UA) pulsatility index (PI) > 95th centile or cerebroplacental ratio (CPR) < 5th centile, diagnosed after 32 weeks. EFW, uterine artery PI, UA-PI, fetal middle cerebral artery (MCA) PI, CPR and umbilical vein blood flow normalized for fetal abdominal circumference (UVBF/AC) were recorded at the time of the diagnosis of FGR. Doppler variables were expressed as Z-scores for gestational age. Composite adverse perinatal outcome was defined as the occurrence of at least one of emergency Cesarean section for fetal distress, 5-min Apgar score < 7, umbilical artery pH < 7.10 and neonatal admission to the special care unit. Logistic regression analysis was used to elucidate the strength of association between different ultrasound parameters and composite adverse perinatal outcome, and receiver-operating-characteristics (ROC)-curve analysis was used to determine their predictive accuracy. In total, 243 consecutive singleton pregnancies complicated by late-onset FGR were included. Composite adverse perinatal outcome occurred in 32.5% (95% CI, 26.7-38.8%) of cases. In pregnancies with composite adverse perinatal outcome, compared with those without, mean uterine artery PI Z-score (2.23 ± 1.34 vs 1.88 ± 0.89, P = 0.02) was higher, while Z-scores of UVBF/AC (-1.93 ± 0.88 vs -0.89 ± 0.94, P ≤ 0.0001), MCA-PI (-1.56 ± 0.93 vs -1.22 ± 0.84, P = 0.004) and CPR (-1.89 ± 1.12 vs -1.44 ± 1.02, P = 0.002) were lower. On multivariable logistic regression analysis, Z-scores of mean uterine artery PI (P = 0.04), CPR (P = 0.002) and UVBF/AC (P = 0.001) were associated independently with composite adverse perinatal outcome. UVBF/AC Z-score had an area under the ROC curve (AUC) of 0.723 (95% CI, 0.64-0.80) for composite adverse perinatal outcome, demonstrating better accuracy than that of mean uterine artery PI Z-score (AUC, 0.593; 95% CI, 0.50-0.69) and CPR Z-score (AUC, 0.615; 95% CI, 0.52-0.71). A multiparametric prediction model including Z-scores of MCA-PI, uterine artery PI and UVBF/AC had an AUC of 0.745 (95% CI, 0.66-0.83) for the prediction of composite adverse perinatal outcome. While CPR and uterine artery PI assessed at the time of diagnosis are associated independently with composite adverse perinatal outcome in pregnancies complicated by late-onset FGR, their diagnostic performance for composite adverse perinatal outcome is low. UVBF/AC showed better accuracy for prediction of composite adverse perinatal outcome, although its usefulness in clinical practice as a standalone predictor of adverse pregnancy outcome requires further research. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Guideline No. 442: Fetal Growth Restriction: Screening, Diagnosis, and Management in Singleton Pregnancies

ABSTRACTObjectivesFirst, to compare published Doppler reference charts of the ratios of flow in the fetal middle cerebral and umbilical arteries (i.e. the cerebroplacental ratio (CPR) and umbilicocerebral ratio (UCR)). Second, to assess the association of thresholds of CPR and UCR based on these charts with short‐term composite adverse perinatal outcome in a cohort of pregnancies considered to be at risk of late preterm fetal growth restriction.MethodsStudies presenting reference charts for CPR or UCR were searched for in PubMed. Formulae for plotting the median and the 10th percentile (for CPR) or the 90th percentile (for UCR) against gestational age were extracted from the publication or calculated from the published tables. Data from a prospective European multicenter observational cohort study of singleton pregnancies at risk of fetal growth restriction at 32 + 0 to 36 + 6 weeks' gestation, in which fetal arterial Doppler measurements were collected longitudinally, were used to compare the different charts. Specifically, the association of UCR and CPR thresholds (CPR < 10th percentile or UCR ≥ 90th percentile and multiples of the median (MoM) values) with composite adverse perinatal outcome was analyzed. The association was also compared between chart‐based thresholds and absolute thresholds. Composite adverse perinatal outcome comprised both abnormal condition at birth and major neonatal morbidity.ResultsTen studies presenting reference charts for CPR or UCR were retrieved. There were large differences between the charts in the 10th and 90th percentile values of CPR and UCR, respectively, while median values were more similar. In the gestational‐age range of 28–36 weeks, there was no relationship between UCR or CPR and gestational age. From the prospective observational study, 856 pregnancies at risk of late‐onset preterm fetal growth restriction were included in the analysis. The association of abnormal UCR or CPR with composite adverse perinatal outcome was similar for percentile thresholds or MoM values, as calculated from the charts, and for absolute thresholds, both on univariable analysis and after adjustment for gestational age at measurement, estimated fetal weight MoM and pre‐eclampsia. The adjusted odds ratio for composite adverse perinatal outcome was 3.3 (95% CI, 1.7–6.4) for an absolute UCR threshold of ≥ 0.9 or an absolute CPR threshold of < 1.11 (corresponding to ≥ 1.75 MoM), and 1.6 (95% CI, 0.9–2.9) for an absolute UCR threshold of ≥ 0.7 to < 0.9 or an absolute CPR threshold of ≥ 1.11 to < 1.43 (corresponding to ≥ 1.25 to < 1.75 MoM).ConclusionsIn the gestational‐age range of 32 to 36 weeks, adjustment of CPR or UCR for gestational age is not necessary when assessing the risk of adverse outcome in pregnancies at risk of fetal growth restriction. The adoption of absolute CPR or UCR thresholds, independent of reference charts, is feasible and makes clinical assessment simpler than if using percentiles or other gestational‐age normalized units. The high variability in percentile threshold values among the commonly used UCR and CPR reference charts hinders reliable diagnosis and clinical management of late preterm fetal growth restriction. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Fetal growth restriction (FGR) is defined as the failure of the fetus to meet its growth potential due to a pathological factor, most commonly placental dysfunction. Worldwide, FGR is a leading cause of stillbirth, neonatal mortality, and short- and long-term morbidity. Ongoing advances in clinical care, especially in definitions, diagnosis, and management of FGR, require efforts to effectively translate these changes to the wide range of obstetric care providers. This article highlights agreements based on current research in the diagnosis and management of FGR, and the areas that need more research to provide further clarification of recommendations. The purpose of this article is to provide a comprehensive summary of available evidence along with practical recommendations concerning the care of pregnancies at risk of or complicated by FGR, with the overall goal to decrease the risk of stillbirth and neonatal mortality and morbidity associated with this condition. To achieve these goals, FIGO (the International Federation of Gynecology and Obstetrics) brought together international experts to review and summarize current knowledge of FGR. This summary is directed at multiple stakeholders, including healthcare providers, healthcare delivery organizations and providers, FIGO member societies, and professional organizations. Recognizing the variation in the resources and expertise available for the management of FGR in different countries or regions, this article attempts to take into consideration the unique aspects of antenatal care in low-resource settings (labelled “LRS” in the recommendations). This was achieved by collaboration with authors and FIGO member societies from low-resource settings such as India, Sub-Saharan Africa, the Middle East, and Latin America.

Introduction: The role of cerebroplacental ratio (CPR) or umbilicocerebral ratio (UCR) to predict adverse intrapartum and perinatal outcomes in pregnancies complicated by late fetal growth restriction (FGR) remains controversial. Methods: This was a multicenter, retrospective cohort study involving 5 referral centers in Italy and Spain, including singleton pregnancies complicated by late FGR, as defined by Delphi consensus criteria, with a scan 1 week prior to delivery. The primary objective was to compare the diagnostic accuracy of the CPR and UCR for the prediction of a composite adverse outcome, defined as the presence of either an adverse intrapartum outcome (need for operative delivery/cesarean section for suspected fetal distress) or an adverse perinatal outcome (intrauterine death, Apgar score <7 at 5 min, arterial pH <7.1, base excess of >−11 mEq/mL, or neonatal intensive care unit admission). Results: Median CPR absolute values (1.11 vs. 1.22, p = 0.018) and centiles (3 vs. 4, p = 0.028) were lower in pregnancies with a composite adverse outcome than in those without it. Median UCR absolute values (0.89 vs. 0.82, p = 0.018) and centiles (97 vs. 96, p = 0.028) were higher. However, the area under the curve, 95% confidence interval for predicting the composite adverse outcome showed a poor predictive value: 0.580 (0.512–0.646) for the raw absolute values of CPR and UCR, and 0.575 (0.507–0.642) for CPR and UCR centiles adjusted for gestational age. The use of dichotomized values (CPR <1, UCR >1 or CPR <5th centile, UCR >95th centile) did not improve the diagnostic accuracy. Conclusion: The CPR and UCR measured in the week prior delivery are of low predictive value to assess adverse intrapartum and perinatal outcomes in pregnancies with late FGR.

Diagnosis and management of fetal growth restriction: the ISUOG guideline and comparison with the SMFM guideline.

Background:Doppler ultrasound of fetal vessels plays an important role in diagnosing fetal growth restriction (FGR). It also aids in early detection of fetal compromise and clinical decision making. Aim: To determine the efficacy of the pulsatility index (PI) of the fetal umbilical artery (UA) and middle cerebral artery (MCA) in the third trimester of pregnancy for predicting adverse perinatal outcomes in the growth restricted fetuses. To study the differences in Doppler profiles in early- and late FGR (EFGR and LFGR, respectively) and their association with adverse outcomes. Materials and methods:The study was approved by the Institute's Ethical Committee. Informed consent was taken from study participants. Eighty singleton pregnancies in the third trimester, which had been diagnosed with FGR, were studied. The UA and MCA Doppler PI and cerebroplacental ratio (CPR) (ratios of PI of MCA/UA) as well as perinatal outcomes were recorded. Adverse perinatal outcomes included perinatal death, hypoxia, seizures, respiratory distress, prolonged Neonatal Intensive Care Unit (NICU) stay, and low Apgar scores at one minute and five minutes. Statistical association of PI with adverse outcomes and differences in Doppler profiles of EFGR and LFGR were studied. Results:Abnormal pulsatility in fetal vessels was associated with adverse perinatal outcomes. The UA PI was the most sensitive (66%) and CPR the most specific parameter (80%) for predicting adverse perinatal outcomes. Absent or reversal of diastolic flow in UA was associated with adverse perinatal outcomes in 75% and 40% of cases, respectively. The UA PI was the most sensitive parameter in both EFGR (70%) and LFGR (66%) and specific Doppler parameter in EFGR (75%). However, CPR and MCA PI were the most specific (89%) and diagnostically accurate in LFGR (79%). Conclusion:The UA PI is the most sensitive Doppler parameter for predicting adverse perinatal outcomes. Cerebroplacental ratio has a high specificity and accuracy and is an important parameter in LFGR cases.

This study aimed to assess the predictive value of the Diastolic Deceleration Area (DDA), a novel Doppler ultrasound parameter, in detecting adverse neonatal outcomes in fetuses with late-onset fetal growth restriction (FGR). While Doppler parameters such as cerebroplacental ratio (CPR), umbilicocerebral ratio (UCR), and cerebralplacentaluterine ratio (CPUR) are commonly used for fetal monitoring, their predictive power varies. Given the importance of cerebral blood flow redistribution in fetal adaptation to hypoxia, we investigated whether DDA could serve as a reliable indicator of fetal distress and adverse perinatal outcomes. This prospective case-control study was conducted between January 2024 and July 2024, including 90 pregnant women: 45 diagnosed with late-onset FGR and 45 gestational age-matched healthy controls. Doppler ultrasound measurements, including umbilical artery, uterine artery, middle cerebral artery Doppler indices, CPR, UCR, CPUR, and DDA, were performed. The primary outcome was the prediction of adverse neonatal events, such as neonatal intensive care unit (NICU) admission, neonatal sepsis, respiratory distress, low APGAR scores, and low cord blood pH. Receiver Operating Characteristic (ROC) curve analysis was used to determine the predictive ability of the Doppler indices. DDA values were significantly higher in the FGR group compared to controls (p<0.001). At a cut-off value of >7.23, DDA demonstrated 50% sensitivity and 88% specificity, making it the most specific Doppler parameter for predicting adverse neonatal outcomes. In comparison, CPR (cut-off ≤2.11), UCR (cut-off >0.46) and CPUR (cut-off ≤1.36) had higher sensitivity (96%, 96%, 54%) but lower specificity (32%, 31% and 85% respectively). DDA is a promising Doppler parameter for identifying fetuses at risk in late-onset FGR. Its high specificity suggests it could be a valuable supplementary tool alongside traditional Doppler indices for better risk assessment and clinical decision-making. Further studies are needed to validate its role in perinatal care.

Objective The cerebroplacental ratio (CPR) has shown utility as a surrogate marker for fetal growth restriction and can be used to stratify the risk for adverse perinatal outcomes in affected pregnancies. However, recent studies suggest that its inverse, the umbilico-cerebral ratio (UCR), may be a better predictor of such outcomes. The aim of this study was to compare the prognostic accuracy of CPR to that of UCR Doppler in predicting short-term adverse perinatal outcomes in growth-restricted fetuses. Methods We conducted a secondary analysis using data from a prospective study on women referred for fetal growth ultrasounds between 26 and 36 weeks of gestation and with an EFW < 10th percentile by Hadlock standard. The CPR and UCR were converted into Z-scores adjusted for gestational age at ultrasound. Abnormal CPR was defined as Z-score below the 10th percentile for the gestational age and abnormal UCR as Z-score above the 90th percentile. We calculated sensitivity and specificity of the two Doppler parameters for predicting composite adverse perinatal outcome (APO) defined as the presence of any one of the following: umbilical cord arterial pH <7.10, Apgars at 5 min <7, NICU admission,grade III/IV intraventricular hemorrhage (IVH), neonatal seizure and death. Logistic regression analysis was performed, ROC curves plotted and the area under the ROC curve (AUC) were compared between CPR and UCR. Results Over the study period, there were 197 women meeting inclusion criteria, of which 27 (13.7%) had a composite adverse neonatal outcome. The sensitivity using CPR Z-score for predicting the composite APO was higher thanwas similar to using UCR Z-score (39.3% compared with 37%) for a similar specificity (94.7 versus 94.1), respectively. However, the positive predictive value (PPV) was higher for CPR (55% vs UCR 50%) and the negative predictive values (NPV) were similar. For a fixed false positive rate of 10%, the detection rates for adverse neonatal outcomes were 40% using either CPR or UCR. The AUC for CPR and UCR were 0.70 and 0.68, respectively. Conclusion This study did not find any advantage in utilizing the UCR over the CPR.

Introduction: Fetal growth restriction (FGR) is a major obstetric complication associated with an increased risk of adverse perinatal outcomes. Objectives: This study aimed to evaluate the relationship between Doppler parameters, including the cerebroplacental ratio (CPR), umbilicocerebral ratio (UCR), and cerebro-placental-uterine ratio (CPUR), with adverse perinatal outcomes in singleton pregnancies complicated by FGR. Patients and Methods: This was a prospective study of 100 women with a singleton pregnancy 28 and 36.8 weeks of gestation was complicated by FGR and mild abnormalities. Feto-maternal Doppler examinations were conducted by the CPR, UCR, and CPUR parameters. Adverse outcomes were defined as Apgar score &lt;7 at 5 minutes, preterm birth &lt;37-week, neonatal intensive care unit (NICU) admission, fetal distress, and emergency cesarean section. These outcome parameters were checked with the results of the last ultrasound which performed 1-2 weeks before delivery. Results: Mean umbilical artery pulsatility index (UA-PI) (1.18±0.31 versus 1.04±0.21, P=0.010) and mean uterine arteries (UtAs)-PI (1.18±0.45 versus 0.96±0.36, P=0.20) were significantly higher in pregnancies that experienced adverse perinatal outcomes than those that did not experience them. Mean CPUR (1.82±1.03 versus 2.25±0.83, P=0.039) was significantly lower in pregnancies that experienced adverse perinatal outcomes versus those that did not. In binary multivariate logistic regression analysis, CPR, UCR, and CPUR parameters were evaluated with adverse perinatal outcomes. Only CPUR had a significant relationship with adverse perinatal outcomes. CPUR had a substantial relationship with Apgar score &lt;7 at 5 minutes (OR: 0.13; 95% CI: 0.02-0.63; P=0.012). Conclusion: CPUR is a new Doppler ratio associated with adverse perinatal outcomes in FGR pregnancies with minimal abnormalities.

Reply

Observational studies have shown that low cerebroplacental ratio (CPR) values predict an increased risk of adverse perinatal outcome. The inverse ratio, i.e. the umbilicocerebral ratio (UCR), has been suggested to be a better predictor as it rises with increasing degree of fetal compromise. However, longitudinal reference ranges for UCR have not been established, and whether gestational-age-dependent changes in CPR or UCR differ between male and female fetuses has not been studied. Thus, the aims of this study were to investigate sex-specific, gestational-age-associated serial changes in CPR and UCR during the second half of pregnancy and to establish longitudinal reference ranges. This was a secondary analysis of prospectively collected data from a dual-center longitudinal observational cohort study of low-risk singleton pregnancies. Doppler blood-flow velocity waveforms were obtained serially from the umbilical artery (UA) and fetal middle cerebral artery (MCA) from 19-41 weeks' gestation, and pulsatility indices (PIs) were determined. CPR and UCR were calculated as the ratios MCA-PI/UA-PI and UA-PI/MCA-PI, respectively. The course and outcome of pregnancies were recorded, and the sex of the fetus was determined after delivery. Reference intervals for CPR and UCR were constructed using multilevel modeling, and gestational-age-specific Z-scores in male and female fetuses were compared. Of a total of 299 pregnancies enrolled, 284 (148 male and 136 female fetuses) were included in the final analysis, and 979 paired measurements of UA-PI and MCA-PI were used to construct sex-specific longitudinal reference intervals. The relationship of both CPR and UCR with gestational age was U-shaped, but in opposite directions. There was a small but significant difference in Z-scores of CPR and UCR between male and female fetuses throughout the second half of pregnancy (P = 0.007). We have established longitudinal reference ranges for CPR and UCR suitable for serial monitoring, with the possibility of refining assessment by using fetal sex-specific ranges and conditioning by a previous measurement. The clinical significance of such refinements needs further evaluation. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Background/Aim: Fetal growth restriction (FGR) causes a high risk of perinatal morbidity and mortality, and the timing of the correct delivery time decision remains controversial. Cerebroplacental ratio (CPR), umbilical artery, uterine artery (UA) and middle cerebral artery (MCA) Doppler studies are used to predict adverse perinatal outcomes in FGR. However, since there is insufficient reliability for each separately and together, the search for new methods continues. This retrospective study was conducted to determine the degree of neonatal morbidity in fetuses suspected of having FGR by evaluating the MCA to UA pulsatility index (PI) ratios together with frequently used Doppler examinations. Methods: This was a retrospective cohort study conducted in a single-center hospital with the approval of the Medical Institutional Ethics Committee. A total of 424 pregnant women admitted to a tertiary hospital and diagnosed with FGR between July 2020 and December 2021 who were informed and approved were included in the study. Gestational age was confirmed by first trimester sonographic measurements of pregnancy. All pregnant women were examined by Doppler USG and umbilical artery, mean UA, fetal MCA, ductus venosus, CPR (MCA/umbilical artery pulsatility index ratio) and cerebrouterine ratio (MCA/UA) PI values were measured. Negative perinatal outcomes were recorded as blood gas level of the newborn at 7.2 and below, Apgar score of 7 and below at the fifth minute, and needing neonatal intensive care (NICU). Adverse perinatal and postnatal outcomes were recorded and compared with Doppler findings. If there were no signs of a negative perinatal outcome, it was considered a positive outcome. If at least one of the symptoms of adverse perinatal outcomes was present, it was considered a negative outcome Results: Decreased CPR and decreased MCA to UA PI were significantly and positively associated with an increased likelihood of exhibiting negative perinatal outcomes in pregnancies with FGR (P &lt; 0.001, P &lt; 0.001, respectively). The receiver operating characteristic (ROC) curve analysis showed that the optimal cut-off value for MCA to uterine artery PI was 1.41 to predict FGR with 57.37% sensitivity and 62.50% specificity (AUC: 0.629; 95% CI: 0.581–0.675). When the CPR cut-off value was taken as 1.2069, the sensitivity was 42.86% and the specificity 83.93% in predicting negative perinatal outcomes in CPR values below this value (P &lt; 0.001). Conclusion: CPR is the most successful criterion in distinguishing between positive and negative perinatal outcomes. It has been demonstrated that the MCA to uterine artery PI ratio values after CPR can also be used for this distinction. MCA to UA PI ratio sensitivity was higher than CPR and umbilical artery. This situation shows that MCA to uterine artery PI ratio (alone or when evaluated together with PPV and NPV ratios) is a criterion that can be added to other Doppler examinations in predicting negative perinatal outcomes.

We thank Prof. Lees et al. for their comments regarding our study1 in which we endeavored to apply the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG)2 and Society for Maternal–Fetal Medicine (SMFM)3 definitions of fetal growth restriction (FGR) to a pre-existing cohort of patients with the aim to compare their performance in predicting neonatal small-for-gestational age (SGA) and composite adverse neonatal outcome. As outlined in the Discussion, our study has limitations. In table S1 of the study, we report that six of the 53 fetuses with late-onset FGR according to the ISUOG definition had estimated fetal weight (EFW) or fetal abdominal circumference (AC) crossing centiles of more than 2 quartiles on growth centiles. Our group has previously compared the ability of the Delphi criteria for FGR (including AC or EFW crossing > 2 quartiles) with that of EFW < 10th percentile for gestational age to predict neonatal SGA, and did not find the Delphi criteria to be a better predictor4. Furthermore, other studies have shown that the addition of fetal growth velocity between 20 and 36 weeks' gestation does not improve the ability of EFW at 35–37 weeks to predict delivery of a SGA neonate5. Lees et al. also questioned the utilization of neonatal SGA as a proxy for FGR. We agree with the authors that most fetuses with EFW or AC < 10th percentile but > 3rd percentile for gestational age and normal fetal surveillance (umbilical artery Doppler, non-stress test or biophysical profile) are less likely to have poor perinatal outcome. However, the optimal way to incorporate Doppler evaluation of the middle cerebral artery, uterine artery and ductus venosus, or the cerebroplacental ratio, in the management of early- and late-onset FGR is not yet clear6-8. We also agree that labeling more fetuses as being growth restricted may not reflect an increase in the detection of those fetuses that truly have placental pathology and would benefit from early intervention. Nevertheless, in our study, we aimed to compare the performance of the different diagnostic criteria for FGR of the two leading governing bodies in fetal medicine. Lastly, we agree that the prediction of adverse outcome in FGR pregnancies, especially those with late-onset FGR, is poor by both definitions of FGR. Unfortunately, the optimal definition and management protocol for FGR remains elusive and we acknowledge that some of the guidelines developed by both the SMFM and ISUOG for the diagnosis and management of FGR are not supported by high-level evidence. However, the simplicity of the SMFM diagnostic criteria, which are based on only AC and/or EFW, makes easier their implementation across the globe.

Considering evidence in the management of fetal growth restriction.