BACKGROUND: Maternal diabetes adversely affects fetal cardiovascular system development. Previous studies have reported that the fetuses of mothers with diabetes exhibit both structural and functional changes; nevertheless, prior studies have not examined the association between glucose control and fetal cardiac morphology and performance. Thus, the objective was to determine the association between fetal cardiac morphology and function and maternal glucose control in type 1 diabetes and to compare the differences in measured cardiac parameters between the fetuses of mothers with diabetes and healthy controls.
METHODS: In this prospective, longitudinal case-control study - including 62 pregnant women with type 1 diabetes mellitus and 30 healthy pregnant women - fetal cardiac assessment using B-mode, M-mode, and spectral pulsed-wave Doppler was performed in the second and third trimesters. In women with T1DM, glycated hemoglobin and data obtained from glucose sensors - including the percentage of time in, below, and above the range (TIR, TBR, and TAR, respectively), and coefficient of variation (CV) - were analyzed across three time periods: the last menstrual period to 13 (V1), 14-22 (V2), and 23-32 weeks (V3) of gestation. Fetal cardiac indices were compared between groups, and the correlation between glucose control and fetal cardiac indices was assessed.
RESULTS: At 28-32 weeks, the fetuses of women with T1DM exhibited increased left ventricular end-diastolic length, relative interventricular septum thickness, right ventricular cardiac output, and pulmonary valve peak systolic velocity compared with healthy controls. At 18-22 weeks, pulmonary and aortic valve diameters, left and right ventricular stroke volumes, and left cardiac output inversely correlated with the CV and glycated hemoglobin levels at V1 and V2. Furthermore, at 28-32 weeks, pulmonary and aortic valve diameters, left ventricular stroke volume, cardiac output, and right/left atrioventricular valve ratio inversely correlated with the TBR at V1, V2, and V3. Moreover, diastolic functional parameters correlated with the TAR and glycated hemoglobin levels, particularly after the first trimester.
CONCLUSIONS: In women with T1DM, maternal hyperglycemia during pregnancy correlates with fetal diastolic function, whereas glucose variability and hypoglycemia inversely correlate with fetal left ventricular systolic function in the second and third trimesters.

UNASSIGNED: To explore the Shunt rate of ductus arteriosus (DA) and ductus venosus (DV) in middle and late fetuses and their application value in the evaluation of fetal growth restriction (FGR).
UNASSIGNED: In this retrospective observational study, we reviewed the clinical data of the patients who admitted to the Second Affiliated Hospital of Wenzhou Medical University from September 10, 2017 to November 27, 2018, and finally included 44 normal women at 28-31 weeks of pregnancy (Normal group) and 15 pregnant women with fetal growth restriction (FGR) within 28-31 weeks of gestation (FGR group). We measured blood flows of the DA (QDA), pulmonary artery (QPA), DV (QDV), and umbilical vein (QUV) and the shunt rates of the DA and DV (QDA/QPA and QDV/QUV, respectively) in all fetuses. We compared the mean variables between groups using the Normal group means as the normal reference values for analysis.
UNASSIGNED: DA shunt rate was linearly and positively correlated with gestational age (Y=1.455X+2.787; r=0.767, P<0.01), while the DV shunt rate was linearly and negatively correlated with gestational age (Y=-2.791X+126.885; r=0.761, P<0.01). The DA shunt rates (QDA/QPA) of fetuses in the normal were higher than those in the FGR groups, but the differences between the two groups were not statistically significant (P > 0.05). The DV shunt rates (QDV/QUV) of fetuses in the normal were significantly lower than those in the FGR groups (P < 0.05). The DV shunt rates in the FGR group were significantly higher than those in the normal group with differences being statistically significant at 30-30+6 and 31-31+6 gestational weeks (P < 0.05) The receiver operating characteristic curve (ROC curve) showed that the higher the shunt rate, the worse the birth outcome of a fetus with FGR.
UNASSIGNED: The DV shunt rate in middle- and late-stage fetuses can predict the fetal birth outcome, and the higher the shunt ratio, the worse the birth outcome of FGR fetuses.

Introduction: In the fetus, a large proportion of the superior vena cava blood flow (QSVC) comes from the brain. To provide the possibility of using this blood flow as a representation of fetal brain circulation, we aimed to determine the fetal QSVC and its fraction of cardiac output during the second half of physiological pregnancies. Materials and Methods: This was a prospective longitudinal study specifically designed for studying fetal hemodynamic development. Healthy women with singleton low-risk pregnancies were included. Ultrasonography was performed at 4-weekly intervals from 20+0 gestational weeks to term. Doppler velocity recordings of the superior vena cava (SVC) and cardiac ventricular outflow tracts were used to obtain the time-averaged maximum velocities (TAMxV). Vessel diameters were measured to calculate their cross-sectional areas (CSA): π(diameter/2)2. Blood flow (Q) was computed as: h *TAMxV*CSA, h being the spatial blood velocity profile, to obtain QSVC and cardiac outputs. The sum of left and right ventricular cardiac outputs constituted the combined cardiac output (CCO). Ultrasound biometry based estimated fetal weight and brain weight were used to normalize the flow. QSVC was also expressed as the fraction (%) of CCO. Gestational age specific percentiles were established for each blood flow parameter using multilevel modeling. Results: Totally, 134 of the 142 included women were eligible for the study with 575 sets of observations. The SVC mean diameter (19-52 mm), mean TAMxV (8.83-16.14 cm/s), and QSVC (15.4-192.0 ml/min) increased significantly during the second half of pregnancy (p < 0.001) while the mean QSVC normalized by estimated fetal weight (49 ml/min/kg) and by estimated brain weight (50 ml/min/100 g) were relatively stable. Similarly, the mean CCO increased (156-1,776 ml/min; p < 0.001) while the normalized CCO (509 ± 13 ml/min/kg) and QSVC as a fraction of CCO (10 ± 0.92%) did not change significantly with gestational age. Conclusion: We provide reference values for fetal QSVC which increases significantly with gestation, and constitutes roughly 10% of the fetal CCO at any time during the second half of pregnancy.

Overproduction of reactive oxygen species (ROS) and, as a result, uncontrolled oxidative stress (OS) can play a central role in disorders of fetal hemodynamics and subsequent development of adverse perinatal outcomes in newborns with fetal growth restriction (FGR). Given the epigenetic nature of such disorders, the aim of our study was to evaluate the expression of miRNAs associated with OS and endothelial dysfunction (miR-27a-3p, miR-30b-5p, miR-125b-5p, miR-221-3p, miR-451a and miR-574-3p) in umbilical cord blood using real-time quantitative RT-PCR. ΜiRNA expression was evaluated in patients with FGR delivery before (n = 9 pregnant) and after 34 weeks of gestation (n = 13 pregnant), and the control groups corresponding to the main groups by gestational age (13 pregnant women in each group, respectively). A significant increase in miR-451a expression was detected in late-onset FGR and correlations with fetoplacental and cerebral circulation were established (increase of resistance in the umbilical artery (pulsatility index, PI UA (umbilical artery): r = -0.59, p = 0.001) and a decrease in cerebral blood flow (CPR: r = 0.48, p = 0.009)). The change in miR-125b-5p expression in the placenta is associated with reduced Doppler of cerebral hemodynamics (CPR: r = 0.73, p = 0.003; PI MCA (middle cerebral artery) : r = 0.79, p = 0.0007), and newborn weight (r = 0.56, p = 0.04) in early-onset FGR. In addition, significant changes in miR-125b-5p and miR-451a expression in umbilical cord blood plasma were found in newborns with neonatal respiratory distress syndrome (NRDS) (in early-onset FGR) and very low birth weight (VLBW) (in late-onset FGR). A number of key signaling pathways have been identified in which the regulation of the studied miRNAs is involved, including angiogenesis, neurotrophin signaling pathway and oxidative stress response. In general, our study showed that changes of the redox homeostasis in the mother-placenta-fetus system in FGR and subsequent perinatal outcomes may be due to differential expression of oxidative stress-associated miRNAs.

Human fetal circulatory physiology has been investigated extensively using grey-scale ultrasound, which provides excellent visualization of cardiac anatomy and function, while velocity profiles in the heart and vessels can be interrogated using Doppler. Measures of cerebral and placental vascular resistance, as well as indirect measures of intracardiac pressure obtained from the velocity waveform in the ductus venosus are routinely used to guide the management of fetal cardiovascular and placental disease. However, the characterization of some key elements of cardiovascular physiology such as vessel blood flow and the oxygen content of blood in the arteries and veins, as well as fetal oxygen delivery and consumption are not readily measured using ultrasound. To study these parameters, we have historically relied on data obtained using invasive measurements made in animal models, which are not equivalent to the human in every respect. Over recent years, a number of technical advances have been made that have allowed us to examine the human fetal circulatory system using cardiovascular magnetic resonance (CMR). The combination of vessel blood flow measurements made using cine phase contrast magnetic resonance imaging and vessel blood oxygen saturation and hematocrit measurements made using T1 and T2 mapping have enabled us to emulate those classic fetal sheep experiments defining the distribution of blood flow and oxygen transport across the fetal circulation in the human fetus. In addition, we have applied these techniques to study the relationship between abnormal fetal cardiovascular physiology and fetal development in the setting of congenital heart disease and placental insufficiency. CMR has become an important diagnostic tool in the assessment of cardiovascular physiology in the setting of postnatal cardiovascular disease, and is now being applied to the fetus to enhance our understanding of normal and abnormal fetal circulatory physiology and its impact on fetal well-being.

UNASSIGNED: To evaluate the progression of Doppler abnormalities in fetuses with late-onset fetal smallness (SGA) that become growth restricted (FGR).
UNASSIGNED: 524 Doppler examinations of the umbilical and cerebral arteries systems, belonging to 442 late-onset SGA fetuses after week 34, were studied, evaluating by means of the statistical difference with the respective abnormal centiles, the pattern of progression into abnormal Doppler values and the distribution and cumulative sum of Doppler anomalies according to the interval to delivery.
UNASSIGNED: Only one third (33.5%, N = 148) of late-onset SGA fetuses presented Doppler anomalies, suggesting that most were of constitutional origin. The most frequent progression pattern into abnormal Doppler (N = 127, 85.81%) was that in which only one system (umbilical or cerebral) became abnormal. Half of fetuses debuted with abnormal umbilical flow (52%, N = 77) and half with cerebral anomalies (47.97%, N = 71), which were more likely to appear later and at shorter intervals to delivery (p = .007). These progression patters defined two varieties of late-onset FGR (type I and II) with similar outcome but different birth weight centiles (BW centile = 2.51, SD 2.91 versus 3.97, SD 3.17, p < .01).
UNASSIGNED: Two thirds of late-onset fetal smallness occurs without hemodynamic changes. In half of the remaining cases an initial cerebral vasodilation defines a group of fetuses with similar outcome but higher BW centile.

Birth weight (BW) is crucial for surgical outcome in children with left heart obstruction (LHO). Head circumference (HC) is believed to correlate with the neurocognitive outcome in LHO. Our aim was to investigate the application of international standardized growth charts from the INTERGROWTH-21st project in comparison to customized growth charts in fetal LHO.
This is a retrospective cohort study consisting of 60 singleton pregnancies complicated by fetal LHO. For the z score calculation of estimated fetal weight (EFW) and biometric parameters, the INTERGROWTH-21st calculator was used as well as algorithms of customized growth charts. Antenatal measurements were compared to newborn biometry and the association with fetal Doppler results (MCA PI: middle cerebral artery pulsatility index and CPR: cerebroplacental ratio) was examined. Furthermore, the ability of each antenatal chart to predict adverse perinatal outcome was evaluated.
At a mean gestational age of 37 weeks, all assessment charts showed significantly smaller mean values for antenatal head circumference (HC) z scores. Highest detection rate for restricted HC growth antenatally was achieved with Hadlock charts. MCA PI and CPR were not associated with neonatal HC. A significant association was observed between EFW and 1-year survival, independent of the considered growth chart.
Growth chart independently, antenatal HC did tend to be smaller in LHO fetuses. A significant association was observed between EFW and 1-year survival rate. Prospective investigations in CHD fetuses should be carried out with internationally standardized growth charts to better examine their prognostic value in this high-risk population.

Objective: To examine the potential value of fetal ultrasound and maternal characteristics in the prediction of antepartum stillbirth after 32 weeks\' gestation.Methods: This was a retrospective multicenter study in Spain. In 29 pregnancies, umbilical artery pulsatility index (UA PI), middle cerebral artery pulsatility index (MCA PI), cerebroplacental ratio (CPR), estimated fetal weight (EFW), and maternal characteristics were recorded within 15 days prior to a stillbirth. The values of UA PI, MCA PI, and CPR were converted into multiples of the normal median (MoM) for gestational age and the EFW was expressed as percentile according to a Spanish reference range for gestational age. Data from the 29 pregnancies with stillbirths and 2298 control pregnancies resulting in livebirths were compared and multivariate logistic regression analysis was used to determine significant predictors of stillbirth.Results: The only significant predictor of stillbirth was CPR (OR = 0.161, 95% confidence interval [CI] 0.035, 0.654; p = .014); the area under the receiver operating characteristics curve was 0.663 (95% CI 0.545, 0.782) and the detection rate (DR) was 32.14% at a 10% false-positive rate (FPR). In addition, when we included MCA and UA PI MoM instead of CPR, only MCA PI MoM was significant (OR = 0.104, 95% confidence interval [CI] 0.013, 0.735; p = .029), with similar prediction abilities (area under the curve (AUC) 0.645, DR 28.6%, FPR 10%).Conclusions: The CPR and MCA PI are predictors of late stillbirth but the performance of prediction is poor.

OBJECTIVE: To evaluate the progression of Doppler abnormalities in early-onset fetal smallness (SGA).
METHODS: A total of 948 Doppler examinations of the umbilical artery (UA), middle cerebral artery (MCA) and ductus venosus (DV), belonging to 405 early-onset SGA fetuses, were studied, evaluating the sequences of Doppler progression, the interval examination-labor at which Doppler became abnormal and the cumulative sum of Doppler anomalies in relation with labor proximity.
RESULTS: The most frequent sequences were that in which only the UA pulsatility index (PI) became abnormal (42.1%) and that in which an abnormal UA PI appeared first, followed by an abnormal MCA PI (24.2%). In general, 71.3% of the fetuses followed the classical progression sequence UA→MCA→DV, mostly in the early stages of growth restriction (84.1%). In addition, the UA PI was the first parameter to be affected (9 weeks before delivery), followed by the MCA PI and the DV PIV (1 and 0 weeks). Finally, the UA PI began to sum anomalies 5 weeks before delivery, while the MCA and DV did it at 3 and 1 weeks before the pregnancy ended.
CONCLUSIONS: In early-onset SGA fetuses, Doppler progression tends to follow a predictable order, with sequential changes in the umbilical, cerebral and DV impedances.

OBJECTIVE: Decreased middle cerebral artery (MCA) pulsatility index (PI) is a marker of fetal brain-sparing in placental insufficiency and it is also found in fetuses with severe congenital heart disease. This study sought to explore the impact of anatomical subtypes in fetal heart disease on MCA-PI and head growth.
METHODS: We retrospectively reviewed fetal echocardiograms of pregnancies complicated by fetal hypoplastic left heart syndrome (HLHS; n = 42) with and without anatomic coarctation (n = 28 and n = 10, respectively), isolated severe aortic coarctation (n = 21), D-transposition of the great arteries (TGA; n = 11) and pulmonary outflow tract obstruction without forward flow across the pulmonary valve (POTO; n = 15), comparing observations with gestational age-matched controls (n = 89). No fetus had major extracardiac pathology or aneuploidy. MCA and umbilical artery (UA) PI, the cerebral placental ratio (CPR  =  MCA-PI/ UA-PI) and neonatal head circumference were obtained and expressed as Z-scores.
RESULTS: Lower MCA-PI, higher UA-PI and lower CPR were observed in fetal HLHS and isolated coarctation with reversed arch flow (n = 6) (P < 0.001) but not TGA, POTO or isolated coarctation with antegrade arch flow (n = 15) compared with controls. No difference was found between HLHS with anatomical coarctation and those without; however, MCA-PI correlated positively with neonatal head circumference in HLHS with reversed distal arch flow (r = 0.33, P < 0.05).
CONCLUSIONS: Severe left heart obstruction with reversed aortic arch flow is associated with altered fetal cerebral blood flow, and in these conditions, MCA-PI positively correlates with head growth. Anatomical arch obstruction itself may not be a contributing factor to altered MCA flow in fetal HLHS.