Intra-amniotic infection and/or inflammation is associated with fetal cardiac concentric hypertrophy and diastolic dysfunction in preterm labor and preterm prelabor rupture of membranes.

BACKGROUND: Preterm delivery is associated with cardiovascular remodeling and dysfunction in children and adults. However, it is unknown whether these effects are caused by the neonatal consequences of preterm birth or if these are already present in utero. OBJECTIVE: We evaluated fetal cardiac morphology and function in fetuses of mothers admitted for preterm labor or preterm prelabor rupture of membranes and the association of these changes with the presence of intra-amniotic infection and/or inflammation. STUDY DESIGN: In this prospective cohort study, fetal echocardiography and amniocentesis were performed at admission in singleton pregnant women with preterm labor and/or preterm prelabor rupture of membranes between 24.0 and 34.0 weeks' gestation with (intra-amniotic infection and/or inflammation group, n=41) and without intra-amniotic infection and/or inflammation (non-intra-amniotic infection and/or inflammation, n=54). Controls (n=48) were outpatient pregnant women without preterm labor or preterm prelabor rupture of membranes. Intra-amniotic infection was defined by a positive amniotic fluid culture or positive 16S ribosomal RNA gene. Intra-amniotic inflammation was defined by using the amniotic fluid interleukin-6 cutoff levels previously reported by our group being >1.43 ng/mL in preterm prelabor rupture of membranes and >13.4 ng/mL in preterm labor. Fetal cardiac morphology and function was evaluated using echocardiography, and troponin-I and N-terminal pro-brain natriuretic peptide concentrations were measured in amniotic fluid from women with preterm labor or preterm prelabor rupture of membranes and compared with 20 amniotic fluid Biobank samples obtained for reasons other than preterm labor or preterm prelabor rupture of membranes or cardiac pathology. The data were adjusted for the estimated fetal weight below the 10th percentile and for preterm prelabor rupture of membranes at admission and also for gestational age at amniocentesis when amniotic fluid biomarkers were compared. RESULTS: From 2018 to 2021, 143 fetuses were included; 95 fetuses were from mothers admitted with a diagnosis of preterm labor or preterm prelabor rupture of membranes, and among those, 41 (28.7%) were in the intra-amniotic infection and/or inflammation group and 54 (37.8%) were in the non-intra-amniotic infection and/or inflammation group. A total of 48 (33.6%) fetuses were included in the control group. Fetuses with preterm labor and/or preterm prelabor rupture of membranes had signs of subclinical cardiac concentric hypertrophy (median left wall thickness of 0.93 [interquartile range, 0.72-1.16] in the intra-amniotic infection and/or inflammation group; 0.79 [0.66-0.92] in the non-intra-amniotic infection and/or inflammation group; and 0.69 [0.56-0.83] in controls; P<.001) and diastolic dysfunction (tricuspid A duration 0.23 seconds [0.21-0.25], 0.24 [0.22-0.25], and 0.21 [0.2-0.23]; P=.007). Systolic function was similar among groups. Higher values of amniotic fluid troponin I (1413 pg/mL [927-2334], 1190 [829-1636], and 841 [671-959]; P<.001) and N-terminal pro-brain natriuretic peptide were detected (35.0%, 17%, and 0%; P=.005) in fetuses with preterm labor or preterm prelabor rupture of membranes when compared with the control group. The highest N-terminal pro-brain natriuretic peptide concentrations were found in the intra-amniotic infection and/or inflammation group. CONCLUSION: Fetuses with preterm labor or preterm prelabor rupture of membranes showed signs of cardiac remodeling and subclinical dysfunction, which were more pronounced in those exposed to intra-amniotic infection and/or inflammation. These findings support that the cardiovascular effects observed in children and adults born preterm have, at least in part, a prenatal origin.

Impact of maternal bariatric surgery on offspring perinatal cardiac function: A prospective study.

OBJECTIVE: To assess perinatal cardiac function in offspring of women with previous bariatric surgery and examine its association with maternal glucose control. DESIGN: Prospective study. SETTING: Maternity unit, UK. POPULATION: Fifty-four fetuses/neonates; 29 of post-bariatric surgery women and 25 of women without surgery. METHODS: Prospective, longitudinal observational study of pregnant women with and without previous bariatric surgery, matched for early pregnancy body mass index. Cardiac function of all offspring was assessed by two-dimensional conventional, spectral tissue Doppler and speckle-tracking echocardiography at 35-37 weeks of gestation and at 5-7 weeks of age. Maternal glycated haemoglobin (HbA1c) was measured at 27-30 weeks of gestation. Maternal demographics and fetal/infant cardiac function indices were compared between the groups. Correlation coefficient (r) is reported. MAIN OUTCOME MEASURES: Fetal/infant cardiac function indices. RESULTS: Compared with no-bariatric neonates, offspring of post-bariatric women were smaller at birth (birthweight centiles: 64.96 ± 36.41 versus 40.17 ± 27.99; p = 0.007). There were no significant differences in fetal/infant cardiac function indices and perinatal cardiac changes, between groups. There was a positive correlation between maternal HbA1c and fetal left ventricular (LV) longitudinal strain (r = 0.33) and LV longitudinal strain rate (r = 0.29), suggesting an inverse relation between HbA1c and fetal LV systolic function, but this was mainly seen in offspring of women with no previous bariatric surgery (r = 0.56 and r = 0.50, respectively). CONCLUSIONS: Maternal bariatric surgery does not appear to inadvertently affect the offspring cardiac performance. We found an inverse correlation between maternal HbA1c levels and fetal LV systolic function but this was mainly seen in the no-bariatric pregnancies.

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 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.

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.

Noninvasive Fetal Electrocardiography in the Diagnosis of Long QT Syndrome: A Case Series.

INTRODUCTION: Early detection and monitoring for malignant arrhythmias is fundamental to prenatal care in long QT syndrome (LQTS). Recently, we studied the feasibility of isolating the fetal electrocardiogram (fECG) and measuring electrocardiographic intervals with a noninvasive fECG device using blind source separation with reference signal. Our aim was to evaluate the ability of fECG to diagnose LQTS. CASE PRESENTATIONS: We identified 3 cases of clinically suspected LQTS based on fetal echocardiogram (2 had sinus bradycardia, 1 had second-degree atrioventricular block with negative maternal anti-SSA/SSB antibody titers). With institutional review board approval, these patients were prospectively enrolled for fECG acquisition. Offline post-processing generated fECG waveforms and calculated QT intervals. Case 1 and 3 had a maternal history of LQTS. Two of the three fetuses with suspected LQTS had confirmed LQTS by postnatal ECG and genetic testing. FECG was able to identify a prolonged corrected QT interval in both cases. One of these also had fetal magnetocardiography (fMCG), which yielded similar findings to the fECG. The third fetus had a normal fECG; fMCG and postnatal ECG were also normal. CONCLUSIONS: In 3 cases, fECG findings corroborated the diagnosis of LQTS. Noninvasive fECG may offer a novel method for fECG that is portable and more clinically accessible.

Complex and Novel Arrhythmias Precede Stillbirth in Fetuses With De Novo Long QT Syndrome.

BACKGROUND: Long QT syndrome (LQTS) is a leading cause of sudden cardiac death in early life and has been implicated in ≈10% of sudden infant deaths and unexplained stillbirths. The purpose of our study was to use fetal magnetocardiography to characterize the electrophysiology and rhythm phenotypes of fetuses with de novo and inherited LQTS variants and identify risk factors for sudden death before birth. METHODS: We reviewed the fetal magnetocardiography database from the University of Wisconsin Biomagnetism Laboratory for fetuses with confirmed LQTS. We assessed waveform intervals, heart rate, and rhythm, including the signature LQTS rhythms: functional 2° atrioventricular block, T-wave alternans, and torsade de pointes (TdP). RESULTS: Thirty-nine fetuses had pathogenic variants in LQTS genes: 27 carried the family variant, 11 had de novo variants, and 1 was indeterminate. De novo variants, especially de novo SCN5A variants, were strongly associated with a severe rhythm phenotype and perinatal death: 9 (82%) showed signature LQTS rhythms, 6 (55%) showed TdP, 5 (45%) were stillborn, and 1 (9%) died in infancy. Those that died exhibited novel fetal rhythms, including atrioventricular block with 3:1 conduction ratio, QRS alternans in 2:1 atrioventricular block, long-cycle length TdP, and slow monomorphic ventricular tachycardia. Premature ventricular contractions were also strongly associated with TdP and perinatal death. Fetuses with familial variants showed a lower incidence of signature LQTS rhythm (6/27=22%), including TdP (3/27=11%). All were live born. CONCLUSIONS: The malignancy of de novo LQTS variants was remarkably high and demonstrate that these mutations are a significant cause of stillbirth. Their ability to manifest rhythms not known to be associated with LQTS increases the difficulty of echocardiographic diagnosis and decreases the likelihood that a resultant fetal loss is attributed to LQTS. Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03047161.

Maternal azithromycin therapy for Ureaplasma parvum intraamniotic infection improves fetal hemodynamics in a nonhuman primate model.

BACKGROUND: Ureaplasma parvum infection is a prevalent cause of intrauterine infection associated with preterm birth, preterm premature rupture of membranes, fetal inflammatory response syndrome, and adverse postnatal sequelae. Elucidation of diagnostic and treatment strategies for infection-associated preterm labor may improve perinatal and long-term outcomes for these cases. OBJECTIVE: This study assessed the effect of intraamniotic Ureaplasma infection on fetal hemodynamic and cardiac function and the effect of maternal antibiotic treatment on these outcomes. STUDY DESIGN: Chronically catheterized pregnant rhesus monkeys were assigned to control (n=6), intraamniotic inoculation with Ureaplasma parvum (107 colony-forming units/mL, n=15), and intraamniotic infection plus azithromycin treatment (12.5 mg/kg twice a day intravenously, n=8) groups. At approximately 135 days' gestation (term=165 days), pulsed and color Doppler ultrasonography was used to obtain measurements of fetal hemodynamics (pulsatility index of umbilical artery, ductus venosus, descending aorta, ductus arteriosus, aortic isthmus, right pulmonary artery, middle cerebral artery and cerebroplacental ratio, and left and right ventricular cardiac outputs) and cardiac function (ratio of peak early vs late transmitral flow velocity [marker of ventricular function], Tei index [myocardial performance index]). These indices were stratified by amniotic fluid proinflammatory mediator levels and cardiac histology. RESULTS: Umbilical and fetal pulmonary artery vascular impedances were significantly increased in animals from the intraamniotic inoculation with Ureaplasma parvum group (P<.05). Azithromycin treatment restored values to control levels. Amniotic fluid prostaglandin F2 alpha levels were significantly higher in animals with abnormal umbilical artery pulsatility index (>1.1) than in those with normal blood flow (P<.05; Spearman ρ=0.6, P<.05). In the intraamniotic inoculation with Ureaplasma parvum group, left ventricular cardiac output was significantly decreased (P<.001), and more animals had abnormal right-to-left ventricular cardiac output ratios (defined as >1.6, P<.05). Amniotic fluid interleukin-6 concentrations were elevated in cases of abnormal right-to-left ventricular cardiac output ratios compared with those in normal cases (P<.05). CONCLUSION: Fetal hemodynamic alterations were associated with intraamniotic Ureaplasma infection and ameliorated after maternal antibiotic treatment. Doppler ultrasonographic measurements merit continuing investigation as a diagnostic method to identify fetal cardiovascular and hemodynamic compromise associated with intrauterine infection or inflammation and in the evaluation of therapeutic interventions or clinical management of preterm labor.

The correlation of fetal cardiac function with gestational diabetes mellitus (GDM) and oxidative stress levels.

Background The primary objective of this study was to compare the fetal cardiac performance index (Tei index) between the fetuses of gestational diabetes mellitus (GDM) mothers and non-GDM mothers; and the secondary objective was to compare various other parameters of fetal cardiac function as well as maternal oxidative stress levels between the groups of GDM and non-GDM mothers. Methods A cross-sectional study was conducted on pregnant women at 24-28 weeks of gestation. All of the participants underwent 100 g, 3-h oral glucose tolerance test (OGTT) as a diagnostic test for GDM and were categorized as non-GDM and GDM group. All participants had fetal echocardiography performed for cardiac function, and then maternal blood samples were collected for biomarker measurements. Results A total of 80 pregnant women, including 43 in the GDM group and 37 in the non-GDM group, were included in the study. The maternal serum 8-isoprostane (8IsoP), tumor necrosis factor-α (TNF-α) and interleukin (IL)-10 levels were significantly higher in the GDM group than those in the non-GDM group (P: 0.028, P: 0.019 and P: 0.031, respectively). The fetal cardiac function parameters were not significantly different between the two groups. Regardless of the GDM status, the fetuses with high levels of oxidative stress (8Isop ≥1000 pg/mg protein) had a significantly higher rate of impaired shortening fraction (SF) of the left ventricle (P: 0.001). Conclusion GDM is significantly associated with an increase in the oxidative stress process, and a high level of oxidative stress was significantly associated with left ventricular (LV) function impairment. Though a correlation between GDM and fetal cardiac function impairment was not clearly demonstrated in this study, this study suggests that GDM patients with a high level of oxidative stress should be evaluated for fetal cardiac function.

Differential gene responses 3 days following infarction in the fetal and adolescent sheep heart.

There are critical molecular mechanisms that can be activated to induce myocardial repair, and in humans this is most efficient during fetal development. The timing of heart development in relation to birth and the size/electrophysiology of the heart are similar in humans and sheep, providing a model to investigate the repair capacity of the mammalian heart and how this can be applied to adult heart repair. Myocardial infarction was induced by ligation of the left anterior descending coronary artery in fetal (105 days gestation when cardiomyocytes are proliferative) and adolescent sheep (6 mo of age when all cardiomyocytes have switched to an adult phenotype). An ovine gene microarray was used to compare gene expression in sham and infarcted (remote, border and infarct areas) cardiac tissue from fetal and adolescent hearts. The gene response to myocardial infarction was less pronounced in fetal compared with adolescent sheep hearts and there were unique gene responses at each age. There were also region-specific changes in gene expression between each age, in the infarct tissue, tissue bordering the infarct, and tissue remote from the infarction. In total, there were 880 genes that responded to MI uniquely in the adolescent samples compared with 170 genes in the fetal response, as well as 742 overlap genes that showed concordant direction of change responses to infarction at both ages. In response to myocardial infarction, there were specific changes in genes within pathways of mitochondrial oxidation, muscle contraction, and hematopoietic cell lineages, suggesting that the control of energy utilization and immune function are critical for effective heart repair. The more restricted gene response in the fetus may be an important factor in its enhanced capacity for cardiac repair.

Diagnosis of major heart defects by routine first-trimester ultrasound examination: association with increased nuchal translucency, tricuspid regurgitation and abnormal flow in ductus venosus.

OBJECTIVE: To examine the association between fetal major heart defects and increased nuchal translucency thickness (NT), tricuspid regurgitation and abnormal flow in the ductus venosus in a large population of singleton pregnancies undergoing routine ultrasound examination at 11-13 weeks' gestation. METHODS: This was a retrospective study of prospectively collected data from singleton pregnancies attending for a routine ultrasound scan at 11-13 weeks' gestation, which included examination of fetal anatomy, measurement of NT and assessment of blood flow across the tricuspid valve and in the ductus venosus, according to a standardized protocol. The incidence of fetal NT ≥ 95th and ≥ 99th percentiles, tricuspid regurgitation and reversed a-wave in the ductus venosus in fetuses with and those without a major heart defect was determined and the performance of each marker and their combination in the detection of major heart defects was calculated. RESULTS: The study population of 93 209 pregnancies with no apparent chromosomal abnormality included 211 (0.23%) with a fetal major heart defect and 92 998 morphologically normal neonates. In 113 (53.6%) cases with a major heart defect, the diagnosis was made at the 11-13-week scan, in 82 (38.9%) at the 18-24-week scan, in 10 (4.7%) at the third-trimester scan and in six (2.8%) postnatally. At the 11-13-week scan, we diagnosed all cases of tricuspid or pulmonary atresia and polyvalvular dysplasia, > 90% of cases of hypoplastic left heart syndrome or atrioventricular septal defect, about 60% of complex heart defects and cases of left atrial isomerism (interrupted inferior vena cava with normal intracardiac anatomy), 30-40% of cases of tetralogy of Fallot and arch abnormalities, 25% of tricuspid valve abnormalities and about 15% of cases of transposition of the great arteries, but none of aortic or pulmonary stenosis or common arterial trunk. Fetal NT ≥ 95th or ≥ 99th percentile, tricuspid regurgitation or abnormal ductus venosus flow was observed in 77 (36.5%), 45 (21.3%), 61 (28.9%) and 58 (27.5%) fetuses with a major heart defect, respectively, and in 5678 (6.1%), 857 (0.9%), 1136 (1.2%) and 1644 (1.8%) of those without a heart defect. Any one of NT ≥ 95th percentile, tricuspid regurgitation or abnormal flow in the ductus venosus was found in 117 (55.5%; 95% CI, 48.5-62.3%) fetuses with a heart defect and in 8166 (8.8%; 95% CI, 8.6-9.0%) of those without a heart defect. Any one of NT ≥ 99th percentile or the other two markers was found in 99 (46.9%; 95% CI, 40.0-53.9%) fetuses with a heart defect and in 3517 (3.8%; 95% CI, 3.7-3.9%) of those without a heart defect. CONCLUSION: At 11-13 weeks' gestation, measurement of fetal NT and assessment of flow across the tricuspid valve and in the ductus venosus can lead to early diagnosis of major heart defect. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Coração fetal: por que e quando investigar? / Fetal ultrasound: why explore the heart?

O incremento do arsenal diagnóstico do pré-natal, por meio de exames de ultrassom, com tecnologias de imagens cada vez mais perfeitas, proporciona o estudo detalhado da anatomia fetal. A mortalidade infantil está diretamente relacionada com as malformações congênitas fetais, especialmente com as alterações anatômicas do coração. Aproximadamente 90% das gestantes não apresentam nenhum fator de risco para malformações cardíacas congênitas (MCCs), portanto o rastreamento pré-natal deve ser realizado em todas as gestações, conforme sugestão da primeira Diretriz Brasileira de Cardiologia Fetal. A revisão bibliográfica da literatura sugere que o diagnóstico pré-natal das MCCs permite intervenções fetais durante o pré-natal e adequado planejamento do parto. Essas ações interferem na morbiletalidade perinatal e no prognóstico dos fetos portadores de cardiopatias, além de auxiliarem a equacionar as vagas nos hospitais de referência e estimarem os gastos na saúde pública e privada.(AU)

The improvement of the ultrasound scan used in the prenatal evaluations provides better images data for the study of the fetal heart. Congenital heart malformations are one of the most leading causes of infant death in the world. Ninety percent of pregnant women do not present any risk factors for Congenital Heart Malformations, so prenatal screening should be performed in all pregnancies, as suggested by the first Brazilian Guideline on Fetal Cardiology. The literature review propose that prenatal diagnosis of congenital heart malformations supports fetal care satisfactory delivery planning and interventions during prenatal. These kindness influences the prognosis of the cardiopathies, perinatal morbidity and mortality and help to reorganize hospital admission and public health care.(AU)

Fetal iGRASP cine CMR assisting in prenatal diagnosis of complicated cardiac malformation with impact on delivery planning.

Limited visualization of the fetal heart and vessels by fetal ultrasound due to suboptimal fetal position, patient habitus and skeletal calcification may lead to missed diagnosis, overdiagnosis and parental uncertainty. Counselling and delivery planning may in those cases also be tentative. The recent fetal cardiac magnetic resonance (CMR) reconstruction method utilizing tiny golden-angle iGRASP (iterative Golden-angle RAdial Sparse Parallel MRI) allows for cine imaging of the fetal heart for use in clinical practice. This case describes an unbalanced common atrioventricular canal where limited ultrasound image quality and visibility of the aortic arch precluded confirming or ruling out presence of a ventricular septal defect. Need of prostaglandins or neonatal intervention was thus uncertain. Cardiovascular magnetic resonance imaging confirmed ultrasound findings and added value by ruling out a significant ventricular septal defect and diagnosing arch hypoplasia. This confirmed the need of patient relocation for delivery at a paediatric cardiothoracic surgery centre and prostaglandins could be initiated before the standard postnatal ultrasound. The applied CMR method can thus improve diagnosis of complicated fetal cardiac malformation and has direct clinical impact.

Maternal biomarkers for fetal heart failure in fetuses with congenital heart defects or arrhythmias.

BACKGROUND: Diagnosis of fetal heart failure depends primarily on fetal ultrasonography assessment. Our recent study demonstrated that plasma natriuretic peptide levels in umbilical cord blood were correlated with the severity of heart failure in fetuses with congenital heart defects or arrhythmias. However, percutaneous umbilical blood sampling is an invasive procedure, and therefore, less or noninvasive biomarkers reflecting fetal heart failure are required. OBJECTIVE: The aim of this study was to investigate the possibility of whether maternal serum biomarkers can diagnose fetal heart failure in fetuses with congenital heart defects or arrhythmias. STUDY DESIGN: This exploratory cross-sectional study was conducted at a tertiary pediatric cardiac center. A total of 50 singletons with fetal congenital heart defects or arrhythmias and 50 controls who were registered in the National Cerebral and Cardiovascular Center Biobank from 2013 to 2016 were included. Maternal serum samples obtained during the third trimester were analyzed for 2 hormones and 36 cytokines using the Bio-Plex Pro Human Cancer Biomarker panels 1 and 2. We comprehensively analyzed the association between maternal serum biomarkers and ultrasonography findings or fetal arrhythmia status. Fetal heart failure was defined as a cardiovascular profile score ≤7. RESULTS: Of 37 fetuses with congenital heart defects, heart failure was found in 1 case of tricuspid valve dysplasia with moderate tricuspid regurgitation. Of 13 fetuses with arrhythmias, 5 had heart failure at 28-33 weeks of gestation. Maternal serum cytokine and hormone concentrations were compared between patients with and without fetal heart failure at 28-33 weeks of gestation (n = 6 and n = 61, respectively). Sixty-one fetuses without heart failure consisted of 10 with congenital heart defect, 6 with arrhythmia, and 45 controls. Maternal serum concentrations of tumor necrosis factor-α, interleukin-6, soluble Fas ligand, transforming growth factor-α, and vascular endothelial growth factor-D were significantly higher when fetuses had heart failure than when they did not (P < .05), whereas maternal serum concentrations of heparin-binding epidermal growth factor-like growth factor were significantly lower when fetuses had heart failure than when they did not (P < .05). Multivariate analysis showed that maternal serum concentrations of tumor necrosis factor-α, vascular endothelial growth factor-D, and heparin-binding epidermal growth factor-like growth factor were independently associated with fetal heart failure. The cutoff values were as follows: tumor necrosis factor-α, 68 pg/mL (sensitivity of 50.0%, specificity of 93.4%, positive likelihood ratio of 7.6, negative likelihood ratio of 0.5); vascular endothelial growth factor-D, 1156 pg/mL (sensitivity of 50.0%, specificity of 93.4%, positive likelihood ratio of 7.6, negative likelihood ratio of 0.5); and heparin-binding epidermal growth factor-like growth factor, 90 pg/mL (sensitivity of 83.3%, specificity of 83.6%, positive likelihood ratio of 5.1, negative likelihood ratio of 0.2). The combination of these 3 cytokines showed sensitivity of 100%, specificity of 80.3%, positive likelihood ratio of 5.1, and negative likelihood ratio of 0. In the absence of fetal heart failure, concentrations of all maternal serum cytokines and hormones were similar in cases of fetal congenital heart defects and controls, while maternal serum soluble CD40 ligand concentrations were increased only in fetal arrhythmias. CONCLUSION: Maternal serum concentrations of tumor necrosis factor-α, vascular endothelial growth factor-D, and heparin-binding epidermal growth factor-like growth factor were associated with fetal heart failure.

Complex Congenital Heart Disease Associated With Disordered Myocardial Architecture in a Midtrimester Human Fetus.

BACKGROUND: In the era of increasingly successful corrective interventions in patients with congenital heart disease (CHD), global and regional myocardial remodeling are emerging as important sources of long-term morbidity/mortality. Changes in organization of the myocardium in CHD, and in its mechanical properties, conduction, and blood supply, result in altered myocardial function both before and after surgery. To gain a better understanding and develop appropriate and individualized treatment strategies, the microscopic organization of cardiomyocytes, and their integration at a macroscopic level, needs to be completely understood. The aim of this study is to describe, for the first time, in 3 dimensions and nondestructively the detailed remodeling of cardiac microstructure present in a human fetal heart with complex CHD. METHODS AND RESULTS: Synchrotron X-ray phase-contrast imaging was used to image an archival midgestation formalin-fixed fetal heart with right isomerism and complex CHD and compare with a control fetal heart. Analysis of myocyte aggregates, at detail not accessible with other techniques, was performed. Macroanatomic and conduction system changes specific to the disease were clearly observable, together with disordered myocyte organization in the morphologically right ventricle myocardium. Electrical activation simulations suggested altered synchronicity of the morphologically right ventricle. CONCLUSIONS: We have shown the potential of X-ray phase-contrast imaging for studying cardiac microstructure in the developing human fetal heart at high resolution providing novel insight while preserving valuable archival material for future study. This is the first study to show myocardial alterations occur in complex CHD as early as midgestation.

G-protein receptor kinases 2, 5 and 6 redundantly modulate Smoothened-GATA transcriptional crosstalk in fetal mouse hearts.

G-protein receptor kinases (GRKs) regulate adult hearts by modulating inotropic, chronotropic and hypertrophic signaling of 7-transmembrane spanning neurohormone receptors. GRK-mediated desensitization and downregulation of ß-adrenergic receptors has been implicated in adult heart failure; GRKs are therefore a promising therapeutic target. However, germ-line (but not cardiomyocyte-specific) GRK2 deletion provoked lethal fetal heart defects, suggesting an unexplained role for GRKs in heart development. Here we undertook to better understand the consequences of GRK deficiency on fetal heart development by creating mice and cultured murine embryonic fibroblasts (MEFs) having floxed GRK2 and GRK5 alleles on the GRK6 null background; simultaneous conditional deletion of these 3 GRK genes was achieved using Nkx2-5 Cre or adenoviral Cre, respectively. Phenotypes were related to GRK-modulated gene expression using whole-transcriptome RNA sequencing, RT-qPCR, and luciferase reporter assays. In cultured MEFs the atypical 7-transmembrane spanning protein and GRK2 substrate Smoothened (Smo) stimulated Gli-mediated transcriptional activity, which was interrupted by deleting GRK2/5/6. Mice with Nkx2-5 Cre mediated GRK2/5/6 ablation died between E15.5 and E16.5, whereas mice expressing any one of these 3 GRKs (i.e. GRK2/5, GRK2/6 or GRK5/6 deleted) were developmentally normal. GRK2/5/6 triple null mice at E14.5 exhibited left and right heart blood intermixing through single atrioventricular valves or large membranous ventricular septal defects. Hedgehog and GATA pathway gene expression promoted by Smo/Gli was suppressed in GRK2/5/6 deficient fetal hearts and MEFs. These data indicate that GRK2, GRK5 and GRK6 redundantly modulate Smo-GATA crosstalk in fetal mouse hearts, orchestrating transcriptional pathways previously linked to clinical and experimental atrioventricular canal defects. GRK modulation of Smo reflects convergence of conventional neurohormonal signaling and transcriptional regulation pathways, comprising an unanticipated mechanism for spatiotemporal orchestration of developmental gene expression in the heart.

Fetal modified left myocardial performance index monitoring during open surgery for myelomeningocele repair.

OBJECTIVE: Fetal hemodynamic changes have already been described during open myelomeningocele repair. This study aimed to access fetal myocardial performance index (MPI) during this high-complexity surgery. METHODS: Open myelomeningocele repair was performed in 37 fetuses between the 24th and 27th week of gestation. MPI was calculated at specific periods: pre-anesthesia, postanesthesia, neurosurgery (early skin manipulation, spinal cord releasing, and sintesis), and end of surgery. Mean ± standard deviation (SD) of MPI and its related times-isovolumetric contraction time (ICT), isovolumetric relaxation time (IRT), and ejection time (ET)-was determined for each period. Analysis of variance (ANOVA) with repeated measures was used to assess differences among these periods. Tukey multiple comparison times test compared global surgery stages. RESULTS: The mean of MPI in the specific time points was 0.32, 0.32, 0.34, 0.48, 0.36, and 0.32, respectively (P < .001). In the two-tailed comparison times, neurosurgery stage presents MPI highest levels, especially on stage 3b (early skin manipulation and spinal cord releasing) related to ICT and IRT rising and ET decreased levels. CONCLUSION: Fetal global cardiac function is altered during the open myelomeningocele repair. The neurosurgery stage represents the critical phase of the procedure.

Dynamic fetal cardiovascular magnetic resonance imaging using Doppler ultrasound gating.

BACKGROUND: Fetal cardiovascular magnetic resonance (CMR) imaging may provide a valuable adjunct to fetal echocardiography in the evaluation of congenital cardiovascular pathologies. However, dynamic fetal CMR is difficult due to the lack of direct in-utero cardiac gating. The aim of this study was to investigate the effectiveness of a newly developed Doppler ultrasound (DUS) device in humans for fetal CMR gating. METHODS: Fifteen fetuses (gestational age 30-39 weeks) were examined using 1.5 T CMR scanners at three different imaging sites. A newly developed CMR-compatible DUS device was used to generate gating signals from fetal cardiac motion. Gated dynamic balanced steady-state free precession images were acquired in 4-chamber and short-axis cardiac views. Gating signals during data acquisition were analyzed with respect to trigger variability and sensitivity. Image quality was assessed by measuring endocardial blurring (EB) and by image evaluation using a 4-point scale. Left ventricular (LV) volumetry was performed using the single-plane ellipsoid model. RESULTS: Gating signals from the fetal heart were detected with a variability of 26 ± 22 ms and a sensitivity of trigger detection of 96 ± 4%. EB was 2.9 ± 0.6 pixels (4-chamber) and 2.5 ± 0.1 pixels (short axis). Image quality scores were 3.6 ± 0.6 (overall), 3.4 ± 0.7 (mitral valve), 3.4 ± 0.7 (foramen ovale), 3.6 ± 0.7 (atrial septum), 3.7 ± 0.5 (papillary muscles), 3.8 ± 0.4 (differentiation myocardium/lumen), 3.7 ± 0.5 (differentiation myocardium/lung), and 3.9 ± 0.4 (systolic myocardial thickening). Inter-observer agreement for the scores was moderate to very good (kappa 0.57-0.84) for all structures. LV volumetry revealed mean values of 2.8 ± 1.2 ml (end-diastolic volume), 0.9 ± 0.4 ml (end systolic volume), 1.9 ± 0.8 ml (stroke volume), and 69.1 ± 8.4% (ejection fraction). CONCLUSION: High-quality dynamic fetal CMR was successfully performed using a newly developed DUS device for direct fetal cardiac gating. This technique has the potential to improve the utility of fetal CMR in the evaluation of congenital pathologies.

Feasibility of detecting myocardial infarction in the sheep fetus using late gadolinium enhancement CMR imaging.

BACKGROUND: Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging has enabled the accurate assessment of myocardial infarction (MI). However, LGE CMR has not been performed successfully in the fetus, where it could be useful for animal studies of interventions to promote cardiac regeneration. We believe that LGE imaging could allow us to document the presence, extent and effect of MI in utero and would thereby expand our capacity for conducting fetal sheep MI research. We therefore aimed to investigate the feasibility of using LGE to detect MI in sheep fetuses. METHODS: Six sheep fetuses underwent a thoracotomy and ligation of a left anterior descending (LAD) coronary artery branch; while two fetuses underwent a sham surgery. LGE CMR was performed in a subset of fetuses immediately after the surgery and three days later. Early gadolinium enhancement (EGE) CMR was also performed in a subset of fetuses on both days. Cine imaging of the heart was performed to measure ventricular function. RESULTS: The imaging performed immediately after LAD ligation revealed no evidence of infarct on LGE (n=3). Two of four infarcted fetuses (50%) showed hypoenhancement at the infarct site on the EGE images. Three days after the ligation, LGE images revealed a clear, hyper-enhanced infarct zone in four of the five infarcted fetuses (80%). No hyper-enhanced infarct zone was seen on the one sham fetus that underwent LGE CMR. No hypoenhancement could be seen in the EGE images in either the sham (n=1) or the infarcted fetus (n=1). No regional wall motion abnormalities were apparent in two of the five infarcted fetuses. CONCLUSION: LGE CMR detected the MI three days after LAD ligation, but not immediately after. Using available methods, EGE imaging was less useful for detecting deficits in perfusion. Our study provides evidence for the ability of a non-invasive tool to monitor the progression of cardiac repair and damage in fetuses with MI. However, further investigation into the optimal timing of LGE and EGE scans and improvement of the sequences should be pursued with the aim of expanding our capacity to monitor cardiac regeneration after MI in fetal sheep.