Sodium dichloroacetate stimulates cardiac mitochondrial metabolism and improves cardiac conduction in the ovine fetus during labor.

Previous studies in our laboratory have suggested that the increase in stillbirth in pregnancies complicated by chronic maternal stress or hypercortisolemia is associated with cardiac dysfunction in late stages of labor and delivery. Transcriptomics analysis of the overly represented differentially expressed genes in the fetal heart of hypercortisolemic ewes indicated involvement of mitochondrial function. Sodium dichloroacetate (DCA) has been used to improve mitochondrial function in several disease states. We hypothesized that administration of DCA to laboring ewes would improve both cardiac mitochondrial activity and cardiac function in their fetuses. Four groups of ewes and their fetuses were studied: control, cortisol-infused (1 g/kg/day from 115 to term; CORT), DCA-treated (over 24 h), and DCA + CORT-treated; oxytocin was delivered starting 48 h before the DCA treatment. DCA significantly decreased cardiac lactate, alanine, and glucose/glucose-6-phosphate and increased acetylcarnitine/isobutyryl-carnitine. DCA increased mitochondrial activity, increasing oxidative phosphorylation (PCI, PCI + II) per tissue weight or per unit of citrate synthase. DCA also decreased the duration of the QRS, attenuating the prolongation of the QRS observed in CORT fetuses. The effect to reduce QRS duration with DCA treatment correlated with increased glycerophosphocholine and serine and decreased phosphorylcholine after DCA treatment. There were negative correlations of acetylcarnitine/isobutyryl-carnitine to both heart rate (HR) and mean arterial pressure (MAP). These results suggest that improvements in mitochondrial respiration with DCA produced changes in the cardiac lipid metabolism that favor improved conduction in the heart. DCA may therefore be an effective treatment of fetal cardiac metabolic disturbances in labor that can contribute to impairments of fetal cardiac conduction.

Cardiotocographic features in COVID-19 infected pregnant women.

OBJECTIVES: We aimed to evaluate the cardiotocograph (CTG) traces of 224 women infected with novel coronavirus 2019 (COVID-19) and analyze whether changes in the CTG traces are related to the severity of COVID-19. METHODS: We designed a prospective cohort study. Two-hundred and twenty-four women who had a single pregnancy of 32 weeks or more, and tested positive for SARS-CoV-2 were included. Clinical diagnosis and classifications were made according to the Chinese management guideline for COVID-19 (version 6.0). Patients were classified into categories as mild, moderate, severe and the CTG traces were observed comparing the hospital admission with the third day of positivity. RESULTS: There was no statistically significant relationship between COVID-19 severity and CTG category, variability, tachycardia, bradycardia, acceleration, deceleration, and uterine contractility, Apgar 1st and 5th min. CONCLUSIONS: Maternal COVID-19 infection can cause changes that can be observed in CTG. Regardless of the severity of the disease, COVID-19 infection is associated with changes in CTG. The increase in the baseline is the most obvious change.

Foetal cardiac function in third trimester pregnancies with reduced fetal movements.

The objective of our study was to investigate the possible relationship between poor perinatal outcome and foetal cardiac functions in pregnant women with reduced foetal movements (RFM). This cross-sectional study included 126 pregnant women with normal foetal movements (Group 1, Controls) and 42 pregnant women over 32 weeks gestation with RFM (Group 2). Group 2 was further divided into two subgroups according to their perinatal outcome: normal perinatal outcome (Group 2a) and poor perinatal outcome (Group 2b). Cardiotocography, the E/A ratio in both atrioventricular valves, myocardial performance index (MPI) and foetal tricuspid annular plane systolic excursion (f-TAPSE) were evaluated. Foetuses with poor perinatal outcome had a higher MPI (p = .003), higher tricuspid and mitral E/A (p < .001), and lower f-TAPSE values (p < .001). In regression analysis, f-TAPSE was the only parameter (p = .04) independently associated with poor perinatal outcome. In conclusion, examining f-TAPSE may predict adverse perinatal outcome in pregnancies with RFM.IMPACT STATEMENTWhat is already known on this subject? Reduced foetal movement (RFM) is associated with adverse pregnancy outcome. Cardiotocography, amniotic fluid assessment, estimated birthweight, foetal Doppler and formal foetal movement count (kick chart) are generally used in the clinical assessment of pregnancies with reduced foetal movements. These tests, we currently use to assess foetal wellbeing in women with reduced foetal movements, have limited sensitivity in predicting foetal compromise.What do the results of this study add? Foetal cardiac Doppler may potentially be used as an important adjunct to the conventional management of women with a perception of reduced foetal movements.What are the implications of these findings for clinical practice and/or further research? Foetal echocardiographic evaluation, such as f-TAPSE, may influence clinical practice by enabling improved risk stratification for poor perinatal outcome, thus allowing more timely definitive intervention. This could help to decrease the rate of stillbirth related to reduced foetal movements. The few established echocardiographically derived parameters, which can asses global right ventricle function, are not always easy to obtain, however, f-TAPSE is easily obtainable using ultrasound and it appears to be a clinically useful echocardiographic measurement of right ventricular function.

Evaluation of right side foetal myocardial performance index in pregestational and gestational diabetes mellitus.

The aim of our study is to investigate the myocardial performance index (MPI) of the right side of the foetal heart in pregestational and gestational diabetes mellitus and to compare it with non-diabetic pregnancies. This prospective cross-sectional study was conducted between August 2018 and March 2019 at Kanuni Sultan Suleyman Research and Training Hospital. Women with pregestational or gestational diabetes mellitus at 24-34 weeks of gestation were included in the study and non-diabetic pregnant women were included as the control group. MPI of the right side of the foetal heart were evaluated and compared between the groups. A total of 65 pregestational or gestational diabetic patients and 65 non-diabetic patients were included in the study. Isovolumetric contraction time and isovolumetric relaxation time values were significantly longer in the diabetic group (p < .001). Ejection time values were significantly shorter in the diabetic group (p < .001). MPI values were significantly higher in the diabetic group than the non-diabetic group (p < .001). In conclusion, MPI of the right side of the foetal heart is significantly higher in pregestational and gestational diabetes than in the non-diabetic group.IMPACT STATEMENTWhat is already known on this subject? Gestational diabetes mellitus causes foetal cardiomyopathy and foetal diastolic dysfunction. Myocardial performance index (MPI) is a non-invasive, Doppler-derived myocardial performance assessment that is independent of both heart rate and ventricular anatomy.What do the results of this study add? MPI of the right side of the foetal heart was significantly higher in pregestational and gestational diabetes than in the non-diabetic group. There was no difference in right ventricular MPI between pregestational and gestational groups in diabetic pregnancies, and between insulin using and not insulin using groups.What are the implications of these findings for clinical practice and/or further research? Our study results are promising. MPI of the right side of the foetal heart is significantly higher in pregestational and gestational diabetes than in the non-diabetic group. Prospective cohort studies evaluating serial MPI and evaluating by postpartum foetal echocardiography are needed to evaluate possible adverse effects of diabetes on foetal cardiac functions.

Nomograms of fetal cardiothoracic ratio from 17 to 37 weeks' gestation as assessed by three different measurement techniques and their correlation with gestational age.

OBJECTIVE: To create nomograms for fetal cardiothoracic (CT) ratio as assessed by three different 2-dimensional sonographic measurements, including CT diameter, circumference, and area ratios, in Thai fetuses with a gestational age (GA) of 17-37 weeks, and to evaluate both their correlation with GA or biparietal diameter (BPD) and variability among the three measurement methods. METHODS: Two-dimensional sonographic measurements of fetal CT ratio in 4-chamber view were assessed by three different measurement techniques. The 95% reference intervals and Z-scores of all measurement methods based on GA or BPD were constructed. Intraclass correlation coefficients (ICC) for the reproducibility of each technique were compared. RESULTS: A total of 511 uncomplicated singleton pregnancies were included. The fetal CT ratio values by all measurement techniques gradually and smoothly increased with increasing GA and BPD. The fetal CT circumference ratio showed the least correlation with both GA and BPD. The intraobserver and interobserver reliability coefficients of all techniques demonstrated almost excellent agreement (all ICCs at least 0.87). CONCLUSION: Reference intervals and Z-score reference ranges were developed using three different techniques for fetal CT ratio with a GA of 17-37 weeks. These nomograms are a simple and reliable screening tool for identifying abnormal fetal heart size.

Analysis of 3-Dimensional Arch Anatomy, Vascular Flow, and Postnatal Outcome in Cases of Suspected Coarctation of the Aorta Using Fetal Cardiac Magnetic Resonance Imaging.

BACKGROUND: Identifying fetuses at risk of severe neonatal coarctation of the aorta (CoA) can be lifesaving but is notoriously challenging in clinical practice with a high rate of false positives. Novel fetal 3-dimensional and phase-contrast magnetic resonance imaging (MRI) offers an unprecedented means of assessing the human fetal cardiovascular system before birth. We performed detailed MRI assessment of fetal vascular morphology and flows in a cohort of fetuses with suspected CoA, correlated with the need for postnatal intervention. METHODS: Women carrying a fetus with suspected CoA on echocardiography were referred for MRI assessment between 26 and 36 weeks of gestation, including high-resolution motion-corrected 3-dimensional volumes of the fetal heart and phase-contrast flow sequences gated with metric optimized gating. The relationship between aortic geometry and vascular flows was then analyzed and compared with postnatal outcome. RESULTS: Seventy-two patients (51 with suspected fetal CoA and 21 healthy controls) underwent fetal MRI with motion-corrected 3-dimensional vascular reconstructions. Vascular flow measurements from phase-contrast sequences were available in 53 patients. In the CoA group, 25 of 51 (49%) required surgical repair of coarctation after birth; the remaining 26 of 51 (51%) were discharged without neonatal intervention. Reduced blood flow in the fetal ascending aorta and at the aortic isthmus was associated with increasing angulation (P=0.005) and proximal displacement (P=0.006) of the isthmus and was seen in both true positive and false positive cases. A multivariate logistic regression model including aortic flow and isthmal displacement explained 78% of the variation in outcome and correctly predicted the need for intervention in 93% of cases. CONCLUSIONS: Reduced blood flow though the left heart is associated with important configurational changes at the aortic isthmus in fetal life, predisposing to CoA when the arterial duct closes after birth. Novel fetal MRI techniques may have a role in both understanding and accurately predicting severe neonatal CoA.

Contemporary Outcomes in Tetralogy of Fallot With Absent Pulmonary Valve After Fetal Diagnosis.

Background Tetralogy of Fallot with absent pulmonary valve is associated with high mortality, but it remains difficult to predict outcomes prenatally. We aimed to identify risk factors for mortality in a large multicenter cohort. Methods and Results Fetal echocardiograms and clinical data from 19 centers over a 10-year period were collected. Primary outcome measures included fetal demise and overall mortality. Of 100 fetuses, pregnancy termination/postnatal nonintervention was elected in 22. Of 78 with intention to treat, 7 (9%) died in utero and 21 (27%) died postnatally. With median follow-up of 32.9 months, no deaths occurred after 13 months. Of 80 fetuses with genetic testing, 46% had chromosomal abnormalities, with 22q11.2 deletion in 35%. On last fetal echocardiogram, at a median of 34.6 weeks, left ventricular dysfunction independently predicted fetal demise (odds ratio [OR], 7.4; 95% CI 1.3, 43.0; P=0.026). Right ventricular dysfunction independently predicted overall mortality in multivariate analysis (OR, 7.9; 95% CI 2.1-30.0; P=0.002). Earlier gestational age at delivery, mediastinal shift, left ventricular/right ventricular dilation, left ventricular dysfunction, tricuspid regurgitation, and Doppler abnormalities were associated with fetal and postnatal mortality, although few tended to progress throughout gestation on serial evaluation. Pulmonary artery diameters did not correlate with outcomes. Conclusions Perinatal mortality in tetralogy of Fallot with absent pulmonary valve remains high, with overall survival of 64% in fetuses with intention to treat. Right ventricular dysfunction independently predicts overall mortality. Left ventricular dysfunction predicts fetal mortality and may influence prenatal management and delivery planning. Mediastinal shift may reflect secondary effects of airway obstruction and abnormal lung development and is associated with increased mortality.

Prenatal cardiac biometry and flow assessment in fetuses with bicuspid aortic valve at 20 weeks' gestation: multicenter cohort study.

OBJECTIVE: To investigate prenatal changes in cardiac biometric and flow parameters in fetuses with bicuspid aortic valve (BAV) diagnosed neonatally compared with controls with normal cardiac anatomy. METHODS: This analysis was conducted as part of the Copenhagen Baby Heart Study, a multicenter cohort study of 25 556 neonates that underwent second-trimester anomaly scan at 18 + 0 to 22 + 6 weeks' gestation and neonatal echocardiography within 4 weeks after birth, in Copenhagen University Hospital Herlev, Hvidovre Hospital and Rigshospitalet in greater Copenhagen, between April 2016 and October 2018. From February 2017 (Rigshospitalet) and September 2017 (Herlev and Hvidovre hospitals), the protocol for second-trimester screening of the heart was extended to include evaluation of the four-chamber view, with assessment of flow across the atrioventricular valves, sagittal view of the aortic arch and midumbilical artery and ductus venosus pulsatility indices. All images were evaluated by two investigators, and cardiac biometric and flow parameters were measured and compared between cases with BAV and controls. All cases with neonatal BAV were assessed by a specialist. Maternal characteristics and first- and second-trimester biomarkers were also compared between the two groups. RESULTS: Fifty-five infants with BAV and 8316 controls with normal cardiac anatomy were identified during the study period and assessed using the extended prenatal cardiac imaging protocol. There were three times as many mothers who smoked before pregnancy in the group with BAV as in the control group (9.1% vs 2.7%; P = 0.003). All other baseline characteristics were similar between the two groups. Fetuses with BAV, compared with controls, had a significantly larger diameter of the aorta at the level of the aortic valve (3.1 mm vs 3.0 mm (mean difference, 0.12 mm (95% CI, 0.03-0.21 mm))) and the pulmonary artery at the level of the pulmonary valve (4.1 mm vs 3.9 mm (mean difference, 0.15 mm (95% CI, 0.03-0.28 mm))). Following conversion of the diameter measurements of the aorta and pulmonary artery to Z-scores and Bonferroni correction, the differences between the two groups were no longer statistically significant. Pregnancy-associated plasma protein-A (PAPP-A) multiples of the median (MoM) was significantly lower in the BAV group than in the control group (0.85 vs 1.03; P = 0.04). CONCLUSIONS: Our findings suggest that fetuses with BAV may have a larger aortic diameter at the level of the aortic valve, measured in the left-ventricular-outflow-tract view, and a larger pulmonary artery diameter at the level of the pulmonary valve, measured in the three-vessel view, at 20 weeks' gestation. Moreover, we found an association of maternal smoking and low PAPP-A MoM with BAV. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Fetal Heart Rate Decelerations in Women with Sleep-Disordered Breathing.

Emerging literature has shown that women with sleep-disordered breathing (SDB) have increased risk for gestational hypertension/preeclampsia and gestational diabetes. Case reports suggest an association between maternal apnea and fetal heart rate deceleration but data are lacking on how maternal sleep impacts fetal health. Since decelerations may be associated with adverse outcomes, we sought to determine whether fetal heart rate decelerations were associated with SDB. A cohort study of third trimester pregnant women with a singleton fetus was conducted. Participants underwent a home sleep test with continuous portable electronic fetal monitoring. SDB was defined as a respiratory disturbance index (RDI)≥10 events/hour. The temporality between a respiratory event and fetal heart rate decelerations was determined to be present if a deceleration occurred < 30 s after a respiratory event. Forty women were included with mean (±SD) age, BMI, and gestational age of 32.0±5.5 years, 37.1±8.0 kg/m2, and 34.6±2.4 weeks respectively. Overall, n=23 (57.5%) women had SDB. Thirty-seven late decelerations were observed in 18 women; of these, 84% were temporally associated with a respiratory event. Nine of the 18 women (50%) had SDB. Ten prolonged decelerations were observed in 6 women of which nine (90%) were temporally associated with a respiratory event. Five of the six women (83%) had an RDI≥10. These initial data suggest that, in this population, the majority of both late and prolonged fetal heart rate decelerations occur with a maternal respiratory event. Since respiratory events are characteristic of maternal SDB, this raises the possibility that SDB may influence fetal well-being.

Antenatal betamethasone redistributes central blood flows and preferentially augments right ventricular output and pump function in preterm fetal lambs.

The glucocorticosteroid betamethasone, which is routinely administered prior to anticipated preterm birth to enhance maturation of the lungs and the cardiovascular system, has diverse fetal regional blood flow effects ranging from increased pulmonary flow to decreased cerebral flow. The aim of this study was to test the hypothesis that these diverse effects reflect alterations in major central flow patterns that are associated with complementary shifts in left ventricular (LV) and right ventricular (RV) pumping performance. Studies were performed in anesthetized preterm fetal lambs (gestation = 127 ± 1 days, term = 147 days) with (n = 14) or without (n = 12) preceding betamethasone treatment via maternal intramuscular injection. High-fidelity central arterial blood pressure and flow signals were obtained to calculate LV and RV outputs and total hydraulic power. Betamethasone therapy was accompanied by 1) increased RV, but not LV, output; 2) a greater RV than LV increase in total power; 3) a redistribution of LV output away from the fetal upper body region and toward the lower body and placenta; 4) a greater proportion of RV output passing to the lungs, and a lesser proportion to the lower body and placenta; and 5) a change in the relative contribution of venous streams to ventricular filling, with the LV having increased pulmonary venous and decreased foramen ovale components, and the RV having lesser superior vena caval and greater inferior vena caval portions. Taken together, these findings suggest that antenatal betamethasone produces a widespread redistribution of central arterial and venous flows in the fetus, accompanied by a preferential rise in RV pumping performance.

Maternal obesity increases the risk of fetal cardiac dysfunction via visceral adipose tissue derived exosomes.

INTRODUCTION: There is a strong association between gestational obesity and fetal cardiac dysfunction, while the exact mechanisms remain largely unknown. The purpose of this study was to investigate the role of exosomes from maternal visceral adipose tissue in abnormal embryonic development in obese pregnancy. METHODS: Female C57BL/6J obese mice were induced by a high-fat diet (containing 60% fat). Fetal cardiac function and morphology were examined by echocardiography and histology. The placenta was extracted for histological examination. miRNA expression in exosomes from the visceral adipose tissue was profiled by RNA-seq. Gene expression of inflammatory factors was analyzed by qPCR. RESULTS: In the obese pregnant mice, there were obvious inflammation and lipid droplets in the placenta. And the fetal cardiac function in obese pregnancy was also compromised. Moreover, injection of the visceral adipose tissue exosomes from the obese mice significantly decreased the fetal cardiac function in the normal lean pregnant mice. Mechanistically, the decreased expression of miR-19b might be responsible for the enhanced inflammation in the placenta. DISCUSSION: Exosomes derived from visceral adipose tissue in obese mice contribute to fetal heart dysfunction, at least partially via affecting the function of the placenta.

Congenital right ventricular diverticulum formed by pulmonary regurgitative jet flow in a fetus with tetralogy of Fallot and absent pulmonary valve.

Congenital ventricular diverticulum is a rare anomaly with an unclear pathology. Here, we report a male fetus at 24 weeks of gestation, diagnosed with right ventricular diverticulum associated with tetralogy of Fallot and absent pulmonary valve. The diverticulum was located at the anterosuperior wall of the right ventricle and faced into the massive pulmonary regurgitation flow jet. Intrauterine fetal death from heart failure resulted at 26 weeks of gestation. An autopsy revealed significant subendocardial fibrosis in the diverticular wall without inflammatory cell infiltration. Clinical and pathologic features suggested that the regurgitative blood flow contributed to the formation of the right ventricular diverticulum.

Use of the modified myocardial performance index for evaluating fetal cardiac functions in pregestational diabetic pregnancy babies.

The aim of this study is assessment of importance of use of the modified myocardial performance index (Mod-MPI) for the evaluation of foetal cardiac function in foetuses of women with pregestational diabetes mellitus (PDM). In this study, data of 30 pregnant patients aged 18-45 years diagnosed with PDM and 30 pregnant women aged 18-45 years with normal pregnancy and their babies were evaluated. Foetal echocardiographic and doppler measurements, foetal biometric measurements, umbilical artery and ductus venosus pulsatility indexes were measured in both PDM and control groups. The Mod-MPI was significantly higher in foetuses of PDM women. Many influences especially cardiac and postpartum complications are observed in infants of PDM women. The Mod-MPI is a simple and useful method for assessing foetal ventricular function. Our study has shown that PDM is associated with foetal ventricular dysfunction.Impact statementWhat is already known on this subject? Although MPI is frequently used in routine clinical assessment of neonates, it is not used adequately in foetuses. Many influences especially cardiac and postpartum complications are observed in infants of PDM women. However, there are few studies focussed specifically on the assessment of foetal cardiac function in PDM.What do the results of this study add? MPI, which shows both diastolic and systolic functions is independent of ventricular anatomy and foetal heart rate, was found significantly higher in diabetic mother foetuses, can be said to be a valuable parameter in evaluating foetal cardiac functions globally.What are the implications of these findings for clinical practice and/or further research? Our study has shown that foetuses PDM are associated with foetal ventricular dysfunction. For this MPI measurement can be routinely performed at foetal cardiac measurements in foetuses of PDM mothers.

Fetal cardiac function at 35-37 weeks' gestation in pregnancies that subsequently develop pre-eclampsia.

OBJECTIVE: To compare fetal cardiac morphology and function between pregnancies that subsequently developed pre-eclampsia (PE) and those that remained normotensive. METHODS: This was a prospective observational study in 1574 pregnancies at 35-37 weeks' gestation, including 76 that subsequently developed PE. We carried out comprehensive assessment of fetal cardiac morphology and function including novel imaging modalities, such as speckle-tracking echocardiography, and measured uterine artery pulsatility index, mean arterial pressure (MAP), serum placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and cerebroplacental ratio (CPR). The findings in the group that subsequently developed PE were compared to those in pregnancies that remained normotensive. RESULTS: In fetuses of mothers who subsequently developed PE, compared to those from normotensive pregnancies, there was a more globular right ventricle, as shown by reduced right ventricular sphericity index, reduced right ventricular systolic contractility, as shown by reduced global longitudinal strain, and reduced left ventricular diastolic function, as shown by increased E/A ratio. On multivariable regression analysis, these indices demonstrated an association with PE, independent of maternal characteristics and fetal size. In pregnancies that subsequently developed PE, compared to those that remained normotensive, MAP, sFlt-1 and the incidence of low birth weight were higher, whereas serum PlGF, CPR and the interval between assessment and delivery were lower. These findings demonstrate that, in pregnancies that develop PE, there is evidence of impaired placentation, reflected in low PlGF and reduced birth weight, placental ischemia, evidenced by increased sFlt-1 which becomes apparent in the interval of 2-4 weeks preceding the clinical onset of PE, and consequent fetal hypoxia-induced redistribution in the fetal circulation, reflected in the low CPR. CONCLUSION: Although the etiology of the observed fetal cardiac changes in pregnancies that subsequently develop PE remains unclear, it is possible that the reduction in right-heart systolic function is the consequence of high afterload due to increased placental resistance, whilst the early left ventricular diastolic changes could be due to fetal hypoxia-induced redistribution in the fetal circulation. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Cardiac function in gestational diabetes mellitus: A longitudinal study from fetal life to infancy.

OBJECTIVE: To determine whether cardiac functional and structural changes in fetuses of mothers with gestational diabetes mellitus (GDM) persist in the offspring beyond the neonatal period. DESIGN: Longitudinal study. SETTING: Fetal Medicine Unit in a UK teaching hospital. METHODS: 73 women with GDM and 73 women with uncomplicated pregnancy were recruited and fetal cardiac scans were performed at 35-36 weeks' gestation. Repeat echocardiogram was performed in their offspring during infancy. MAIN OUTCOME MEASURES: Fetal and infant cardiac functional and structural changes. RESULTS: Fetuses of mothers with GDM, compared with controls, had more globular right ventricles (sphericity index 0.7, interquartile range [IQR] 0.6/0.7 versus 0.6, IQR 0.5/0.6, P < 0.001) and reduced right global longitudinal systolic strain (-16.4, IQR -18.9/-15.3 versus -18.5, IQR -20.6/-16.8, P = 0.001) and left global longitudinal systolic strain (-20.1, IQR -22.5/-16.9 versus -21.3, IQR -23.5/-19.5), P = 0.021). In the GDM group, compared with controls, in infancy there was higher left ventricular E/e' (8.7, IQR 7.3/9.7 versus 7.9 IQR, 6.8/8.9 P = 0.011) and lower left ventricular global longitudinal systolic strain (-21.0, IQR -22.5/-19.4 versus -22.3, IQR -23.5/-20.7, P = 0.001) and tricuspid annular plane systolic excursion (13.8, IQR 12.7/16.1 versus 15.2, IQR 13.8/16.8, P = 0.003). These differences remained following multivariable analysis. CONCLUSION: Gestational diabetes mellitus is associated with alterations in fetal cardiac function and structure compared with controls and persistent cardiac changes in infancy. TWEETABLE ABSTRACT: Gestational diabetes mellitus, even when well controlled, is associated with fetal cardiac changes and these persist in infancy.

Effect of maternal diabetes on fetal heart function on echocardiography: systematic review and meta-analysis.

OBJECTIVE: Maternal diabetes in pregnancy is associated with structural anomalies of the fetal heart, as well as hypertrophy and functional impairment. This systematic review and meta-analysis aimed to estimate the effect of maternal diabetes on fetal cardiac function as measured by prenatal echocardiography. METHODS: We performed a search of the EMBASE, PubMed and The Cochrane Library databases, from inception to 4 July 2019, for studies evaluating fetal cardiac function using echocardiography in pregnancies affected by diabetes compared with uncomplicated pregnancies. Outcome measures were cardiac hypertrophy and diastolic, systolic and overall cardiac function as assessed by various ultrasound parameters. The quality of the studies was assessed using the Newcastle-Ottawa Scale. Data on interventricular septal (IVS) thickness, myocardial performance index (MPI) and E/A ratio were pooled for the meta-analysis using random-effects models. For pregnancies with diabetes, results were reported overall and according to whether diabetes was pregestational (PDM) or gestational (GDM). Results were also stratified according to the trimester in which fetal cardiac assessment was performed. RESULTS: Thirty-nine studies were included, comprising data for 2276 controls and 1925 women with pregnancy affected by diabetes mellitus (DM). Of these, 1120 had GDM, 671 had PDM and in 134 cases diabetes type was not specified. Fetal cardiac hypertrophy was more prevalent in diabetic pregnancies than in non-diabetic controls in 21/26 studies, and impaired diastolic function was observed in diabetic pregnancies in 22/28 studies. The association between DM and systolic function was inconsistent, with 10/25 studies reporting no difference between cases and controls, although more recent studies measuring cardiac deformation, i.e. strain, did show decreased systolic function in diabetic pregnancies. Of the studies measuring overall fetal cardiac function, the majority (14/21) found significant impairment in diabetic pregnancies. Results were similar when stratified according to GDM or PDM. These effects were already present in the first trimester, but were most profound in the third trimester. Meta-analysis of studies performed in the third trimester showed, compared with controls, increased IVS thickness in both PDM (mean difference, 0.75 mm (95% CI, 0.56-0.94 mm)) and GDM (mean difference, 0.65 mm (95% CI, 0.39-0.91 mm)) pregnancies, decreased E/A ratio in PDM pregnancies (mean difference, -0.09 (95% CI, -0.15 to -0.03)), no difference in E/A ratio in GDM pregnancies (mean difference, -0.01 (95% CI, -0.02 to 0.01)) and no difference in MPI in either PDM (mean difference, 0.04 (95% CI, -0.01 to 0.09)) or GDM (mean difference, 0.03 (95% CI, -0.01 to 0.06)) pregnancies. CONCLUSIONS: The findings of this review show that maternal diabetes is associated with fetal cardiac hypertrophy, diastolic dysfunction and overall impaired myocardial performance on prenatal ultrasound, irrespective of whether diabetes is pregestational or gestational. Further studies are needed to demonstrate the relationship with long-term outcomes. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Urgent neonatal balloon atrial septostomy in simple transposition of the great arteries: predictive value of fetal cardiac parameters.

OBJECTIVES: To investigate the impact of abnormal perinatal loading conditions on cardiac geometry and function in term fetuses and neonates with transposition of the great arteries with intact interventricular septum (simple TGA), and to explore the predictive value of fetal cardiac parameters for an urgent balloon atrial septostomy (BAS) after birth. METHODS: This was a prospective longitudinal follow-up study of women delivering at term, including both uncomplicated pregnancies with normal outcome and pregnancies affected by fetal simple TGA. Conventional, spectral-tissue Doppler and speckle-tracking echocardiographic parameters were obtained within 1 week before delivery and within the first few hours after delivery. Neonates with simple TGA that required urgent BAS were assessed after the procedure and before corrective arterial switch surgery. Cardiac parameters were normalized by cardiac cycle length, ventricular end-diastolic length or end-diastolic dimension, as appropriate. Fetal and neonatal cardiac parameters were compared between simple-TGA cases and controls, and perinatal changes in the simple-TGA group were assessed. Receiver-operating-characteristics (ROC)-curve analysis was used to assess the predictive value of fetal cardiac parameters for urgent BAS after birth in the simple-TGA group. RESULTS: A total of 67 pregnant women delivering at term were included in the study (54 normal pregnancies and 13 with a diagnosis of fetal simple TGA). Compared with normal term fetuses, term fetuses with simple TGA exhibited more globular hypertrophied ventricles, increased biventricular systolic function and diastolic dysfunction (right ventricular (RV) sphericity index (SI), 0.58 vs 0.54; left ventricular (LV)-SI, 0.55 vs 0.49; combined cardiac output (CCO), 483 vs 406 mL/min/kg; LV torsion, 4.3 vs 3.0 deg/cm; RV isovolumetric relaxation time (IVRT'), 127 vs 102 ms; P < 0.01 for all). Compared with normal neonates, neonates with simple TGA demonstrated biventricular hypertrophy, a more spherical right ventricle and altered systolic and diastolic functional parameters (RV-SI, 0.61 vs 0.43; RV myocardial performance index, 0.47 vs 0.34; CCO, 697 vs 486 mL/min/kg; LV-IVRT', 100 vs 79 ms; RV-IVRT', 106 vs 71 ms; P < 0.001 for all). Paired comparison of neonatal and fetal cardiac indices in the simple-TGA group showed persistence of the fetal phenotype, increased biventricular systolic myocardial contractility and CCO, and diastolic dysfunction (RV systolic myocardial velocity (S'), 0.31 vs 0.24 cm/s; LV-S', 0.23 vs 0.18 cm/s; CCO, 697 vs 483 mL/min/kg; LV torsion, 1.1 vs 4.3 deg/cm; P < 0.001 for all). Several fetal cardiac parameters in term fetuses with simple TGA demonstrated high predictive value for an urgent BAS procedure after birth. Our proposed novel fetal cardiac index, LV rotation-to-shortening ratio, as a potential marker of subendocardial dysfunction, for a cut-off value of ≥ 0.23, had an area under the ROC curve (AUC) of 0.94, sensitivity of 100% and specificity of 83%. For RV/LV end-diastolic area ratio ≥ 1.33, pulmonary-valve-to-aortic-valve-dimension ratio ≤ 0.89, RV/LV cardiac output ratio ≥ 1.38 and foramen-ovale-dimension-to-total-interatrial-septal-length ratio ≤ 0.27, AUC was 0.93-0.98, sensitivity was 86% and specificity was 83-100% for all. CONCLUSIONS: Simple-TGA fetuses exhibited cardiac remodeling at term with more profound alterations in these cardiac parameters after birth, suggestive of adaptation to abnormal loading conditions and possible adaptive responses to hypoxemia. Perinatal adaptation in simple TGA might reflect persistence of the abnormal parallel arrangement of cardiovascular circulation and the presence of widely patent fetal shunts imposing volume load on the neonatal heart. The fetal cardiac parameters that showed high predictive value for urgent BAS after birth might reflect the impact of late-gestation pathophysiology and progressive hypoxemia on fetal cardiac geometry and function in simple TGA. If these findings are validated in larger prospective studies, detailed cardiac assessment of fetuses with simple TGA near term could facilitate improvements in perinatal management and refinement of the timing of postnatal intervention strategies to prevent adverse pregnancy outcomes. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Fetal cardiac filling and ejection time fractions by pulsed-wave Doppler: reference ranges and potential clinical application.

OBJECTIVES: Fetal cardiac function can be evaluated using a variety of parameters. Among these, cardiac cycle time-related parameters, such as filling time fraction (FTF) and ejection time fraction (ETF), are promising but rarely studied. We aimed to report the feasibility and reproducibility of fetal FTF and ETF measurements using pulsed-wave Doppler, to provide reference ranges for fetal FTF and ETF, after evaluating their relationship with heart rate (HR), gestational age (GA) and estimated fetal weight (EFW), and to evaluate their potential clinical utility in selected fetal conditions. METHODS: This study included a low-risk prospective cohort of singleton pregnancies and a high-risk population of fetuses with severe twin-twin transfusion syndrome (TTTS), aortic stenosis (AoS) or aortic coarctation (CoA), from 18 to 41 weeks' gestation. Left ventricular (LV) and right ventricular inflow and outflow pulsed-wave Doppler signals were analyzed, using valve clicks as landmarks. FTF was calculated as: (filling time/cycle time) × 100. ETF was calculated as: (ejection time/cycle time) × 100. Intraclass correlation coefficients (ICC) were used to evaluate the intra- and interobserver reproducibility of FTF and ETF measurements in low-risk fetuses. The relationships of FTF and ETF with HR, GA and EFW were evaluated using multivariate regression analysis. Reference ranges for FTF and ETF were then constructed using the low-risk population. Z-scores of FTF and ETF in the high-risk fetuses were calculated and analyzed. RESULTS: In total, 602 low-risk singleton pregnancies and 54 high-risk fetuses (nine pairs of monochorionic twins with severe TTTS, 16 fetuses with AoS and 20 fetuses with CoA) were included. Adequate Doppler traces for FTF and ETF could be obtained in 95% of low-risk cases. Intraobserver reproducibility was good to excellent (ICC, 0.831-0.905) and interobserver reproducibility was good (ICC, 0.801-0.837) for measurements of all timing parameters analyzed. Multivariate analysis of FTF and ETF in relation to HR, GA and EFW in low-risk fetuses identified HR as the only variable predictive of FTF, while ETF was dependent on both HR and GA. FTF increased with decreasing HR in low-risk fetuses, while ETF showed the opposite behavior, decreasing with decreasing HR. Most recipient twins with severe TTTS showed reduced FTF and preserved ETF. AoS was associated with decreased FTF and increased ETF in the LV, with seemingly different patterns associated with univentricular vs biventricular postnatal outcome. The majority of fetuses with CoA had FTF and ETF within the normal range in both ventricles. CONCLUSIONS: Measurement of FTF and ETF using pulsed-wave Doppler is feasible and reproducible in the fetus. The presented reference ranges account for associations of FTF with HR and of ETF with HR and GA. These time fractions are potentially useful for clinical monitoring of cardiac function in severe TTTS, AoS and other fetal conditions overloading the heart. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Impact of gestational diabetes mellitus on fetal cardiac morphology and function: cohort comparison of second- and third-trimester fetuses.

OBJECTIVES: To assess differences in cardiac morphology and function in fetuses of mothers with gestational diabetes mellitus (GDM) compared to controls, and to assess whether, in women with GDM, fetal cardiac changes are accentuated with advancing gestational age. METHODS: We studied 112 women with GDM and 224 women with uncomplicated pregnancy at 24-40 weeks' gestation. In all fetuses, a standard four-chamber oblique view was obtained and offline speckle-tracking analysis was performed to measure right and left endocardial global longitudinal strain (GLS) and tricuspid and mitral annular plane systolic excursion. Global sphericity index was also calculated. Echocardiographic parameters were compared between GDM fetuses and controls at two gestational time periods of 24 + 0 to 32 + 0 weeks and 32 + 1 to 40 + 1 weeks. RESULTS: At 24 + 0 to 32 + 0 weeks, we phenotyped 43 fetuses from mothers with GDM and 71 from uncomplicated pregnancies, and, at 32 + 1 to 40 + 1 weeks, we phenotyped 69 fetuses from mothers with GDM and 153 from women with uncomplicated pregnancy. In fetuses of mothers with GDM, compared to controls, right ventricular functional indices were consistently lower both at 24 + 0 to 32 + 0 weeks and at 32 + 1 to 40 + 1 weeks. Right ventricular GLS was reduced in the GDM group at 24 + 0 to 32 + 0 weeks (adjusted mean difference, 0.7%; 95% CI, 0.3-1.1%) and at 32 + 1 to 40 + 1 weeks (adjusted mean difference, 0.9%; 95% CI, 0.6-1.1%). Fetal left ventricular global longitudinal function was similar in GDM pregnancies compared with controls, with the exception of the contractility of the left ventricular basal segment, which was reduced. Global sphericity index was reduced in GDM pregnancies only at 32 + 1 to 40 + 1 weeks (adjusted mean difference, -0.4; 95% CI, -0.7 to 0.1). CONCLUSIONS: The offspring of women with GDM are at high risk for development of cardiovascular disease in childhood and early adulthood. Our study demonstrates that GDM is associated with a reduction mainly in fetal right ventricular function, compared to controls, and this response is not exaggerated with increasing gestational age. Further studies are needed to determine whether fetuses with the observed alterations in cardiac function are those at highest risk for subsequent development of cardiovascular disease. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.