Prediction of non-reassuring fetal status and umbilical artery acidosis by the maternal characteristic and ultrasound prior to induction of labor.

OBJECTIVE: To investigate the predictive value of pre-induction digital examination, sonographic measurements and parity for the prediction of non-reassuring fetal status and cord arterial pH < 7.2 prior to the induction of labor (IOL). METHOD: This was a prospective observational study, including 384 term pregnancies undergoing IOL. Before the IOL, the Bishop score (BS) by digital examination, sonographic Doppler parameters and the estimated fetal weight (EFW) was assessed. The fetal cord arterial was sampled to measure the pH at delivery. Multivariate logistic regression analysis was performed to identify independent predictors of non-reassuring fetal status and low cord arterial pH. RESULTS: Forty four cases (11.5%) had non-reassuring fetal status, and 76 cases (19.8%) had fetal cord arterial pH < 7.2. In the non-reassuring fetal status group, the incidence of cord arterial pH < 7.2 was significantly higher than that in the normal fetal heart rate group (χ2 = 6.401, p = 0.011). Multivariate analysis indicated that significant independent predictors of non-reassuring fetal status were nulliparity (adjusted odds ratio [AOR]: 3.746, p = 0.003), EFW < 10th percentile (AOR: 3.764, p = 0.003) and cerebroplacental ratio (CPR) < 10th centile (AOR:4.755, p < 0.001). In the prediction of non-reassuring fetal status, the performance of the combination of nulliparity and EFW < 10th percentile was improved by the addition of CPR < 10th percentile (AUC: 0.681, (95%CI: 0.636 to 0.742) vs 0.756, (95%CI:0.713 to 0.795)), but the difference was not significant (DeLong test: z = 1.039, p = 0.053).. None of the above variables were predictors of cord arterial pH < 7.2. CONCLUSION: The risk of fetal acidosis has increased in cases of non-reassuring fetal status. Nulliparity, small for gestational age and CPR < 10th centile are independent predictors for non-reassuring fetal status in term fetuses, though the addition of CPR < 10th centile could not significantly improve the screening accuracy.

Third-trimester growth diversity in small fetuses classified as appropriate-for-gestational age or small-for-gestational age at birth.

OBJECTIVE: We have shown previously that third-trimester growth in small fetuses (estimated fetal weight (EFW) < 10th percentile) with birth weight (BW) < 10th percentile is heterogeneous using individualized growth assessment (IGA). We aimed to test our hypothesis that individual growth patterns in small fetuses with BW > 10th percentile are also variable but in different ways. METHODS: This was a study of 191 cases with EFW < 10th percentile and BW > 10th percentile (appropriate-for-gestational-age (AGA) cohort), derived from the PORTO study. Composite size parameters were used to quantify growth pathology at individual third-trimester timepoints (individual composite prenatal growth assessment score (-icPGAS)). The fetal growth pathology score 1 (-FGPS1), calculated cumulatively from serial -icPGAS values, was used to characterize third-trimester growth patterns. Vascular-system evaluation included umbilical artery (UA) and middle cerebral artery (MCA) Doppler velocimetry. Outcome variables were birth age (preterm/term delivery) and BW (expressed as growth potential realization index for weight (GPRIWT ) and percentile). The findings from the AGA cohort were compared with those from small fetuses (EFW < 10th percentile) with BW < 10th percentile (small-for-gestational-age (SGA) cohort). RESULTS: The AGA cohort was found to have 134 fetuses (70%) with normal growth pattern and 57 (30%) with growth restriction based on IGA criteria. Seven growth-restriction -FGPS1 patterns were observed, including the previously defined progressive, late, adaptive and recovering types. The recovering type was the most common growth pattern in the AGA cohort (50.9%). About one-third of fetuses without any evidence of growth restriction had significant unexplained abnormalities in the UA (34%) and MCA (31%) and elevated mean GPRIWT values (113 ± 12.5%). Comparison of the AGA and SGA cohorts indicated a significant difference in the distribution of -FGPS1 growth patterns (P = 0.0001). Compared with the SGA cohort, the AGA cohort had more fetuses with a normal growth pattern (70% vs 38%) and fewer cases with growth restriction (30% vs 62%). While the recovering type was the most common growth-restriction pattern in the AGA cohort (51%), the progressive type was the primary growth-restriction pattern in the SGA cohort (44%). No difference in the incidence of MCA or UA abnormality was found between the SGA and AGA cohorts when comparing subgroups of more than 10 fetuses. CONCLUSIONS: Both normal-growth and growth-restriction patterns were observed in the AGA cohort using IGA, as seen previously in the SGA cohort. The seven types of growth restriction defined in the SGA cohort were also identified in AGA cases, but their distribution was significantly different. In one-third of cases without evidence of growth pathology in the AGA cohort, Doppler abnormalities in the UA and MCA were seen. This heterogeneity underscores the difficulty of accurate classification of fetal and neonatal growth status using conventional population-based methods. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

The effect of 75-g oral glucose tolerance test on maternal and foetal Doppler parameters in healthy pregnancies: a cross-sectional observational study.

Hyperglycaemia can alter placental resistance to blood flow and hyperglycaemia has adverse perinatal outcomes. Oral glucose tolerance testing (OGTT) increases the maternal plasma glucose levels temporarily and mimics metabolic hyperglycaemia. The blood flow of the uterine artery (UtA), umbilical artery (UA), middle cerebral artery (MCA) were assessed before, 1 and 2 h following the OGTT by using Doppler ultrasonography. Z-score of cerebroplacental ratio (CPR), pulsatility index (PI) for three vessels were evaluated separately. All measurements of the MCA, UA, UtA Doppler parameters were not statistically different for fasting, and 1 and 2 h following the 75 g OGTT in the 53 pregnant women with a singleton gestation in the low-risk group. This study results show that acute hyperglycaemia induced by OGTT has no effect on maternal and foetal Doppler parameters in healthy pregnancies.IMPACT STATEMENTWhat is already known on this subject? Foetal glucose is affected by maternal blood glucose concentrations and placental blood flow. Acute hyperglycaemia may have an effect on maternal, and foetal Doppler parameters among healthy pregnanciesWhat do the results of this study add? Our findings indicate that blood flow velocity metric measurements in the UA, MCA and UtA were not affected by the OGTT in healthy pregnant women.What are the implications of these findings for clinical practice and/or further research? Acute hyperglycaemia induced by OGTT does not have any effect on fetomaternal circulation, especially foetal brain blood flow. Other foetal vessels including ductus venosus, renal artery, etc. may be affected by maternal blood glucose levels during the OGTT or in diabetic patients. Future prospective studies consisting of diabetic patients are warranted to verify the exact effect of glucose levels on foetal and maternal circulation.

Fetal cerebrovascular impedance is reduced in left congenital diaphragmatic hernia.

OBJECTIVES: Congenital diaphragmatic hernia (CDH) can cause a significant mass effect in the fetal thorax, displacing the heart into the opposite hemithorax. In left-sided CDH (L-CDH), this is associated with smaller left-sided cardiac structures and reduced left-ventricular cardiac output (LVCO). The effect of these physiologic changes on cerebral blood flow is not well understood. We sought to describe the middle cerebral artery (MCA) pulsatility index (PI), a measure of cerebrovascular impedance, in fetuses with L-CDH and those with right-sided CDH (R-CDH) compared with unaffected fetuses, and the relationship between MCA-PI and LVCO. We hypothesized that MCA-PI would be lower in fetuses with L-CDH and similar in those with R-CDH compared to controls, and that MCA-PI would be correlated with LVCO. METHODS: We identified all fetuses with CDH evaluated at The University of California San Francisco, San Francisco, CA, USA from 2011 to 2018. Fetal echocardiograms and ultrasound scans were reviewed. Umbilical artery and MCA Doppler examinations were assessed to calculate pulsatility indices. Ventricular outputs were calculated using Doppler-derived stroke volume and fetal heart rate. Lung-to-head ratio (LHR), estimated fetal weight, biparietal diameter (BPD) and head circumference (HC) were obtained from fetal sonograms. Measurements in fetuses with CDH, according to the side of the defect, were compared with those in unaffected, gestational age-matched controls. A subset of CDH survivors had available data on neurodevelopmental outcome, as assessed using the Bayley Scales of Infant Development, 3rd edition. RESULTS: A total of 64 fetuses with CDH (L-CDH, n = 53; R-CDH, n = 11) comprised the study groups, with 27 unaffected fetuses serving as controls. Mean gestational age at evaluation was similar between the three groups. Compared to controls, fetuses with L-CDH had significantly lower LVCO expressed as a percentage of combined cardiac output (CCO) (32%; 95% CI, 29-35% vs 38%; 95% CI, 33-42%; P = 0.04) and lower MCA-PI Z-score (-1.3; 95% CI, -1.7 to -1.0 vs 0.08; 95% CI, -0.5 to 0.6; P < 0.001), while they did not differ between the R-CDH group and controls. There was a strong positive association between LVCO as a percentage of CCO and MCA-PI Z-score in the overall cohort of CDH and control fetuses (P = 0.01). BPD and HC were similar between the three groups. At neurodevelopmental follow-up, mean cognitive, motor and language scores in the CDH group were within 1 SD of those in the general population. CONCLUSION: MCA-PI values are significantly lower in fetuses with L-CDH as compared to controls, and lower LVCO was correlated with lower MCA vascular impedance. The neurodevelopmental effect of changes in MCA-PI in response to decreased LVCO is unknown, although, on average, CDH survivors had neurodevelopmental scores in the normal range. This may reflect a fetal compensatory mechanism in response to diminished antegrade cerebral blood flow. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Fetal cerebrovascular response to maternal hyperoxygenation in congenital heart disease: effect of cardiac physiology.

OBJECTIVE: Fetal cerebrovascular resistance is influenced by several factors in the setting of intact autoregulation to allow for normal cerebral blood flow and oxygenation. Maternal hyperoxygenation (MH) allows for acute alterations in fetal physiology and can be a tool to test cerebrovascular reactivity in late-gestation fetuses. In this study, we utilized MH to evaluate cerebrovascular reactivity in fetuses with specific congenital heart disease (CHD). METHODS: This was a cross-sectional study of fetuses with complex CHD compared to controls without CHD. CHD cases were grouped according to physiology into: left-sided obstructive lesion (LSOL), right-sided obstructive lesion (RSOL) or dextro-transposition of the great arteries (d-TGA). Subjects underwent MH testing during the third-trimester fetal echocardiogram. The pulsatility index (PI) was calculated for the fetal middle cerebral artery (MCA), umbilical artery (UA) and branch pulmonary artery (PA). The change in PI from baseline to during MH was compared between each CHD group and controls. RESULTS: Sixty pregnant women were enrolled (CHD, n = 43; control, n = 17). In the CHD group, there were 27 fetuses with LSOL, seven with RSOL and nine with d-TGA. Mean gestational age was 33.9 (95% CI, 33.6-34.2) weeks. At baseline, MCA-PI Z-score was lowest in the LSOL group (-1.8 (95% CI, -2.4 to -1.2)) compared with the control group (-0.8 (95% CI, -1.3 to -0.3)) (P = 0.01). In response to MH, MCA-PI Z-score increased significantly in the control and d-TGA groups but did not change significantly in the LSOL and RSOL groups. The change in MCA-PI Z-score was significantly higher in the control group than in the LSOL group (0.9 (95% CI, 0.42-1.4) vs 0.12 (95% CI, -0.21 to 0.45); P = 0.03). This difference was more pronounced in the LSOL subgroup with retrograde aortic arch flow. Branch PA-PI decreased significantly in response to MH in all groups, with no difference in the change from baseline to MH between the groups, while UA-PI was unchanged during MH compared with at baseline. CONCLUSIONS: The fetal cerebrovascular response to MH varies based on the underlying CHD diagnosis, suggesting that cardiovascular physiology may influence the autoregulatory capacity of the fetal brain. Further studies are needed to determine the clinical implications of these findings on long-term neurodevelopment in these at-risk children. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Diagnostic accuracy of first-trimester combined screening for early-onset and preterm pre-eclampsia at 8-10 compared with 11-13 weeks' gestation.

OBJECTIVES: To compare the ability of first-trimester combined screening for pre-eclampsia (PE) to predict early-onset and preterm PE when pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PlGF) were assessed before vs after 11 weeks' gestation. METHODS: This was a secondary analysis of a prospective cohort study of singleton pregnancies undergoing routine first-trimester screening conducted at Vall d'Hebron University Hospital, Barcelona, Spain, between October 2015 and September 2017. Demographic characteristics, obstetric history, maternal history and biophysical markers (mean uterine artery pulsatility index and mean arterial blood pressure (MAP)) were recorded at the first-trimester scan (at 11 + 0 to 13 + 6 weeks' gestation). Maternal serum concentrations of PAPP-A and PlGF were assessed from the routine first-trimester blood test (at 8 + 0 to 13 + 6 weeks). Women were classified into two groups depending on whether serum biomarkers were assessed at 8 + 0 to 10 + 6 weeks or at 11 + 0 to 13 + 6 weeks. Probability scores for early-onset and preterm PE were calculated by using two different algorithms: the multivariate Gaussian-distribution model and The Fetal Medicine Foundation (FMF) competing-risks model. Receiver-operating-characteristics (ROC) curves were produced and detection rates at fixed 5% and 10% false-positive rates were computed to compare the performance of these algorithms when PAPP-A and PlGF were assessed before vs after 11 weeks. RESULTS: Of the 2641 women included, serum biomarkers were assessed before 11 weeks in 1675 (63.4%) and at or after 11 weeks in 966 (36.6%). Of these, 90 (3.4%) women developed PE, including 11 (0.4%) cases of early-onset PE and 30 (1.1%) of preterm PE. Five (45.5%) cases of early-onset and 16 (53.3%) of preterm PE were identified in the group in which serum biomarkers were assessed at 8 + 0 to 10 + 6 weeks and six (54.5%) cases of early-onset and 14 (46.7%) of preterm PE in the group in which serum biomarkers were assessed at 11 + 0 to 13 + 6 weeks. In the prediction of early-onset and preterm PE using the Gaussian algorithm, no differences were observed between the areas under the ROC curves (AUCs) when PAPP-A and PlGF were measured before or after 11 weeks. In the prediction of early-onset and preterm PE using the FMF algorithm, no differences were observed between AUCs for any of the combinations used for risk calculation when the serum biomarkers were obtained before vs after 11 weeks, except for the combination of PAPP-A and MAP, which showed a greater AUC for the prediction of early-onset PE when PAPP-A was measured at or after 11 weeks. CONCLUSIONS: The prediction of early-onset and preterm PE is similar when serum biomarkers are measured before or after 11 weeks. This allows the use of a two-step approach for PE risk assessment that permits immediate risk calculation at the time of the first-trimester scan. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Determination of fetal heart rate short-term variation from umbilical artery Doppler waveforms.

OBJECTIVE: To evaluate the feasibility of using umbilical artery (UA) Doppler waveforms to measure fetal heart rate (FHR) short-term variation (STV) across gestation. METHODS: This was a prospective longitudinal study, conducted at two study sites, of 195 pregnancies considered low risk. Pulsed-wave Doppler of the UAs was performed at 4-weekly intervals, between 14 and 40 weeks of gestation, using a standardized imaging protocol. Up to 12 consecutive UA Doppler waveforms were analyzed using offline processing software. FHR STV was calculated using average R-R intervals extracted from the waveforms and baseline corrected for FHR. RESULTS: Baseline-corrected FHR STV increased significantly with gestational age (conditional R2 = 0.37; P < 0.0001) and was correlated inversely with FHR (conditional R2 = 0.54; P < 0.0001). The STV ranged (median (interquartile range)) from 3.5 (2.9-4.1) ms at 14-20 weeks' gestation to 6.3 (4.8-7.7) ms at 34-40 weeks' gestation. The change in heart rate STV did not differ between study sites or individual sonographers. CONCLUSIONS: UA Doppler waveforms offer a robust and feasible method to derive STV of the FHR. It should be emphasized that the UA Doppler-derived STV is not interchangeable with measurements derived with computerized cardiotocography. Accordingly, further investigations are needed to validate associations with outcome, in order to determine the value of concurrent fetal cardiovascular and heart rate evaluations that are possible with the technique described here. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Ten-year experience of protocol-based management of small-for-gestational-age fetuses: perinatal outcome in late-pregnancy cases diagnosed after 32 weeks.

OBJECTIVE: To report our 10-year experience of protocol-based management of small-for-gestational-age (SGA) fetuses, based on standardized clinical and Doppler criteria, in late-pregnancy cases. METHODS: A retrospective cohort was constructed of consecutive singleton pregnancies referred for late-onset (> 32 weeks) SGA (defined as estimated fetal weight (EFW) < 10th centile) that were classified as fetal growth restriction (FGR) or low-risk SGA, based on the severity of smallness (EFW < 3rd centile) and the presence of Doppler abnormalities (uterine artery pulsatility index (UtA-PI) ≥ 95th centile or cerebroplacental ratio (CPR) < 5th centile). Low-risk SGA pregnancies were followed at 2-week intervals and delivered electively at 40 weeks. FGR pregnancies were followed at 1-week intervals, or more frequently if there were signs of fetal deterioration, and were delivered electively after 37 + 0 weeks' gestation. The occurrence of stillbirth and composite adverse outcome (CAO; defined as neonatal death, metabolic acidosis, need for endotracheal intubation or need for admission to the neonatal intensive care unit) was analyzed in low-risk SGA and FGR pregnancies. RESULTS: A total of 1197 pregnancies with EFW < 10th centile were identified and classified at diagnosis as low-risk SGA (n = 619; 51.7%) or FGR (n = 578; 48.3%). Of these, 160 were delivered before 37 weeks' gestation; for obstetric reasons in 93 (58.1%) cases, severe pre-eclampsia in 33 (20.6%), FGR with severe hypoxia in 47 (29.4%) and stillbirth in four (2.5%) (indications are non-exclusive). During follow-up, 52/574 (9.1%) low-risk SGA pregnancies were reclassified as FGR, whereas 22/463 (4.8%) FGR pregnancies were reclassified as low-risk SGA. Overall, there were no stillbirths in the low-risk SGA group and four in the FGR group, all of which occurred before 37 weeks. There were no instances of neonatal death in pregnancies delivered ≥ 37 weeks. The risk of CAO was higher in those meeting antenatal criteria for FGR at 37 weeks than in those classified as low-risk SGA (32/493 (6.5%) vs 15/544 (2.8%); odds ratio, 2.5 (95% CI, 1.3-4.6)). In FGR pregnancies, the adjusted odds ratio (95% CI) for CAO was 6.3 (1.8-21.1) in those with EFW < 3rd centile, while it was 3.2 (1.5-6.8) and 4.2 (1.9-8.9) in those with UtA-PI ≥ 95th centile and CPR < 5th centile, respectively, as compared to FGR pregnancies without each of these criteria. CONCLUSION: Protocol-based risk stratification with different management and monitoring schemes for late pregnancy with a suspected SGA baby, based on clinical and Doppler criteria, enables identification and tailored assessment of high-risk FGR, while allowing expectant management with safe perinatal outcome for low-risk SGA fetuses. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Zone-specific reference ranges of fetal adrenal artery Doppler indices: a longitudinal study.

BACKGROUND: The fetal adrenal gland is a highly vascularized organs and develops two recognizable distinct zones in uetro, inner fetal zone (FZ) and outer definitive zone (DZ). Based on the region supplied, middle adrenal artery (MAA) mainly contribute to FZ while inferior adrenal artery (IAA) mainly to the inferior part of DZ. The purpose of this study was to establish reference ranges of adrenal artery Doppler indices of IAA and MAA, and assess zonal difference of blood supply to fetal adrenal gland. METHODS: The pulsatility index (PI), resistance index (RI), and systolic:diastolic ratio (S/D) of the IAA and MAA were obtained serially at 4-week intervals in normal fetuses. The MAA and IAA were referred based on the course and location in the gland: IAA referring the artery that mainly branches from the renal artery and walks along the renal upper pole, distributing the inferoposterior part of DZ in the adrenal gland while MAA as arterial blood flowing along the single central adrenal vein in the medial part of the gland. Multilevel modeling was performed to establish the gestational age-associated reference ranges for IAA and MAA. Differences in Doppler indices between the IAA and MAA were assessed. RESULTS: One hundred sixty-eight fetuses with 843 observations were included. The IAA had a higher detection rate than the MAA (100% vs 89.2%, p < 0.05). The resistance of IAA had a reduction around 35 weeks of gestation and that of MAA remained unchanged throughout the second half of pregnancy. Lower PI, RI and S/D were observed in the MAA than in the IAA (p < 0.05) from 752 paired measurements. CONCLUSION: There is a zonal difference in blood supply in favor of the fetal zone, which may correspond to its unique function. Reference ranges of Doppler parameters in adrenal artery maybe beneficial for further evaluation of fetal hemodynamics.

Fetal cerebral Doppler changes and outcome in late preterm fetal growth restriction: prospective cohort study.

OBJECTIVES: To explore the association between fetal umbilical and middle cerebral artery (MCA) Doppler abnormalities and outcome in late preterm pregnancies at risk of fetal growth restriction. METHODS: This was a prospective cohort study of singleton pregnancies at risk of fetal growth restriction at 32 + 0 to 36 + 6 weeks of gestation, enrolled in 33 European centers between 2017 and 2018, in which umbilical and fetal MCA Doppler velocimetry was performed. Pregnancies were considered at risk of fetal growth restriction if they had estimated fetal weight and/or abdominal circumference (AC) < 10th percentile, abnormal arterial Doppler and/or a fall in AC growth velocity of more than 40 percentile points from the 20-week scan. Composite adverse outcome comprised both immediate adverse birth outcome and major neonatal morbidity. Using a range of cut-off values, the association of MCA pulsatility index and umbilicocerebral ratio (UCR) with composite adverse outcome was explored. RESULTS: The study population comprised 856 women. There were two (0.2%) intrauterine deaths. Median gestational age at delivery was 38 (interquartile range (IQR), 37-39) weeks and birth weight was 2478 (IQR, 2140-2790) g. Compared with infants with normal outcome, those with composite adverse outcome (n = 93; 11%) were delivered at an earlier gestational age (36 vs 38 weeks) and had a lower birth weight (1900 vs 2540 g). The first Doppler observation of MCA pulsatility index < 5th percentile and UCR Z-score above gestational-age-specific thresholds (1.5 at 32-33 weeks and 1.0 at 34-36 weeks) had the highest relative risks (RR) for composite adverse outcome (RR 2.2 (95% CI, 1.5-3.2) and RR 2.0 (95% CI, 1.4-3.0), respectively). After adjustment for confounders, the association between UCR Z-score and composite adverse outcome remained significant, although gestational age at delivery and birth-weight Z-score had a stronger association. CONCLUSION: In this prospective multicenter study, signs of cerebral blood flow redistribution were found to be associated with adverse outcome in late preterm singleton pregnancies at risk of fetal growth restriction. Whether cerebral redistribution is a marker describing the severity of fetal growth restriction or an independent risk factor for adverse outcome remains unclear, and whether it is useful for clinical management can be answered only in a randomized trial. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Fetal Middle Cerebral Artery Pulsatility Index in No-Risk Pregnancies: Effects of Auditory Stimulation and Pregnancy Order.

Pulsatility index (PI) values in a fetal middle cerebral artery (MCA) were compared in no-risk pregnancies to examine the differences related to auditory stimulation test and pregnancy order. The study included 196 women with no-risk pregnancies selected from the database of more than 1000 pregnant women divided into two groups. Group 1 consisted of 98 nulliparous women (C1 = 98) and Group 2 consisted of 98 parous women (C2 = 98). All pregnant women were of comparable age and fetal gestational age (GA) when MCA-PI values were recorded. Measurements of PI values in fetal MCA were obtained before and immediately after the application of fetal auditory stimulation test. The MCA-PI measuring was conducted in the period between the 36th and the 41st week of GA. The results showed that PI baseline values and PI values after defined auditory stimulation were significantly different when measured in nulliparous women compared to parous women (p = 0.001; p = 0.003, respectively), while no group differences were observed in relative PI value changes due to auditory stimulation. These findings suggest that hemodynamic changes in fetal MCA caused by defined auditory stimulation measured by PI value changes may be valuable in the assessment of fetal auditory perception functionality and its development.

Cerebro-placental ratio as a prognostic factor of fetal outcome in pregnancy complicated by maternal sickle cell disease.

OBJECTIVES: To assess the role of the cerebro-placental ratio (CPR) in predicting adverse fetal outcomes among women with sickle cell disease (SCD). METHODS: A prospective cohort study at Korle-Bu Teaching Hospital, Accra, Ghana, between January and June 2016. Pregnant women with SCD at 34 gestational weeks or more underwent weekly fetal umbilical and middle cerebral artery Doppler assessment until delivery. Participants were categorized into two study arms based on CPR (<1.1 or ≥1.1). The primary outcome, a composite of adverse perinatal outcomes including intrauterine growth restriction, stillbirth, low birthweight, and neonatal intensive care unit admission, was compared between groups. RESULTS: Overall, 48 pregnant women with SCD were enrolled, and 5 had a fetus with CPR less than 1.1. Low CPR (<1.1) had a sensitivity and specificity of 29.4% and 100%, respectively, for predicting composite adverse perinatal outcomes. Sensitivity and specificity were, respectively, 100% and 93.5% for predicting stillbirth, and 40.2% and 97.4% for predicting low birthweight. Perinatal outcomes did not differ between the two major sickle cell genotypes (hemoglobin SS and hemoglobin SC). CONCLUSIONS: Among women with SCD, CPR less than 1.1 was associated with adverse perinatal outcomes, particularly low birthweight and stillbirth.

Prelabor screening at term using the cerebroplacental ratio and placental growth factor: a pragmatic randomized open-label phase 2 trial.

BACKGROUND AND OBJECTIVE: In some women placental function may not be adequate to meet fetal growth requirements in late pregnancy or the additional demands during labor, thus predisposing these infants to intrapartum fetal compromise and subsequent serious morbidity and mortality. The objective of this study was to determine if the introduction of a prelabor screening test at term combining the cerebroplacental ratio and maternal placental growth factor level would result in a reduction in a composite of adverse outcomes. STUDY DESIGN: Single-site, nonblinded, randomized controlled trial conducted at a tertiary hospital in Brisbane, Australia. Eligible women were randomized to either receive the screening test performed between 37-38 weeks or routine obstetric care. Screen-positive women were offered induction of labor. The primary outcome was a composite of emergency cesarean delivery for nonreassuring fetal status (fetal distress) or severe neonatal acidosis or low Apgar score or stillbirth or neonatal death. RESULTS: Women were recruited and randomized (n = 501) between April 2017 and January 2019. Sixty-three of 249 subjects (25.3%) in the screened group compared to 56 of 252 (22.2%) in the control group experienced the primary outcome (relative risk = 1.14 [95% confidence interval, 0.83-1.56]; P = .418). Women who screened positive were more likely to require operative delivery for fetal distress, have meconium-stained liquor, have pathologic fetal heart rate abnormalities, and have infants with lower birthweight compared to women that screened negative. CONCLUSION: The introduction of this test did not result in improvements in intrapartum intervention rates or neonatal outcomes. However, it did show discriminatory potential, and future research should focus on refining the thresholds used.

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.

Modified myocardial performance index and its prognostic significance for adverse perinatal outcome in early and late onset fetal growth restriction.

Objective: To compare the fetal modified myocardial performance index (Mod-MPI) in appropriately grown, early (EO) and late onset (LO) fetal growth restricted (FGR) fetuses and to assess its prognostic significance for adverse perinatal outcome.Study design: In a prospective case-control study, Mod-MPI was performed in 22 and 51 fetuses with EO and LO-FGR fetuses, respectively. Mod-MPI values of FGR fetuses were compared against gestation-matched controls (34 for EO-, and 32 for LO-FGR, respectively). Correlation testing related with poor perinatal outcomes were performed.Results: Incidences of pathologic uterine artery Doppler rate, cesarean section rate, 5-min Apgar score < 7, neonatal intensive care unit (NICU) admission and perinatal mortality were significantly higher in the EO-FGR group (p < .001). There was a decrease in Mod-MPI with gestational age in the normal (Pearson's r = 0.401, p < .001), and growth-restricted fetuses (Pearson's r = 0.248, p = .034). Mean Mod-MPI values were significantly higher in both EO- and LO-FGR group than gestation-matched controls (p < .001). There was no significant correlation between Mod-MPI values and perinatal deaths (Pearson's r = 0.004, p = .987) and 5-min Apgar score < 7 (Pearson's r = 0.391, p = .088) in the EO-FGR fetuses. There was a significant negative correlation between Mod-MPI values and cerebroplacental ratio (CPR) values (Pearson's r = -0.288, p = .041); however no significant correlation between Mod-MPI values and 5-min Apgar score< 7, and fetal distress during labor (Pearson's r = 0.149, p = 0.297) in the LO-FGR fetuses was noted.Conclusion: EO and LO-FGR fetuses have significantly higher Mod-MPI values, demonstrating prenatal cardiac dysfunction. Evaluating Mod-MPI is not so effective in predicting poor perinatal outcome in both EO and LO-FGR fetuses.

The use of actograph in the assessment of fetal well-being.

Purpose: Third trimester maternal perception of fetal movements is often used to assess fetal well-being. However, its true clinical value is unknown, primarily because of the variability in subjective quantification. The actograph, a technology available on most cardiotocograph machines, quantifies movements, but has never previously been investigated in relation to fetal health and existing monitoring devices. The objective of this study was to quantify actograph output in healthy third trimester pregnancies and investigate this in relation to other methods of assessing fetal well-being.Methods: Forty-two women between 24 and 34 weeks of gestation underwent ultrasound scan followed by a computerized cardiotocograph (CTG). Post capture analysis of the actograph recording was performed and expressed as a percentage of activity over time. The actograph output results were analyzed in relation to Doppler, ultrasound and CTG findings expressed as z-score normalized for gestation.Results: There was a significant association between actograph output recording and estimated fetal weight Z-score (R = 0.546, p ≤ .005). This activity was not related to estimated fetal weight. Increased actograph activity was negatively correlated with umbilical artery pulsatility index Z-score (R = -0.306, p = .049) and middle cerebral artery pulsatility index Z-score (R = -0.390, p = .011).Conclusion: Fetal movements assessed by the actograph are associated both with fetal size in relation to gestation and fetoplacental Doppler parameters. It is not the case that larger babies move more, however, as the relationship with actograph output related only to estimated fetal weight z-score. These findings suggest a plausible link between the frequency of fetal movements and established markers of fetal health.RATIONALEThe objective of this study was to quantify actograph output in healthy third trimester pregnancies and investigate this in relation to other methods of assessing fetal well-being. This is a widely available method of assessing fetal movements objectively, which has been shown to be an important marker of fetal health. This research is novel in the fact that actograph has never been truly investigated in relation to fetal well-being, despite being available on most cardiotocograph (CTG) machines.Our results show that fetal movements assessed by the actograph are associated both with fetal size in relation to gestation and fetoplacental Doppler parameters. If this proves to be true, smaller babies that move less maybe at particular perinatal risk.

Sex-specific reference ranges of cerebroplacental and umbilicocerebral ratios: longitudinal study.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Fetal echocardiographic assessment of cardiovascular impact of prolonged support on EXTrauterine Environment for Neonatal Development (EXTEND) system.

OBJECTIVE: EXTrauterine Environment for Neonatal Development (EXTEND) is a system to support ongoing fetal growth and organ development in an extrauterine environment, utilizing a pumpless low-resistance oxygenator circuit. The aim of this study was to evaluate hemodynamics and cardiac function in fetal sheep sustained on the EXTEND system. METHODS: This was a prospective study of fetal sheep supported for a minimum of 3 weeks on EXTEND. Hemodynamic parameters were assessed weekly and included heart rate, mean arterial pressure (MAP), Doppler-echocardiography-derived cardiac output (CO), pulsatility indices (PIs) of the fetal middle cerebral artery (MCA), umbilical artery (UA) and ductus venosus and cardiac function, as assessed by speckle-tracking-derived global longitudinal strain and strain rate in the right (RV) and left (LV) ventricles. Parameters were compared at 0 days and 1, 2 and 3 weeks following placement on EXTEND. RESULTS: Of 10 fetal sheep enrolled, seven survived for 3 weeks and were included in the analysis. Median gestational age at cannulation was 107 (range, 95-109) days. Heart rate decreased and MAP increased significantly, but within acceptable ranges, during the study period. The quantities and relative ratios of right and left CO remained stable within the anticipated physiological range throughout the study period. Vascular tracings and PIs appeared to be similar to those seen normally in the natural in-utero state, with MCA-PI being higher than UA-PI. UA tracings demonstrated maintained abundant diastolic flow despite the absence of placental circulation. In both the RV and LV, strain decreased significantly at 1 and 2 weeks relative to baseline but returned to baseline values by week 3. CONCLUSIONS: The EXTEND mechanical support system replicates natural physiology and creates a stable and sustainable cardiovascular construct that supports growth over a 3-week period. However, there is a period of depressed contractility within the first week with subsequent improvement by week 3. This may reflect a period of physiological accommodation that warrants further investigation. This study lays the foundation for further exploration as the EXTEND system moves towards human application. © 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.