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Objective: To construct nomograms for fetal cardiac, ventricular and atrial relative size and geometry parameters from 18 to 41 weeks' gestation using a low-risk population of singleton pregnancies., Methods: This was a prospective cohort study of 602 low-risk singleton pregnancies undergoing comprehensive fetal echocardiography, from 18 to 41 weeks of gestation, to assess fetal cardiac, atrial and ventricular relative size and sphericity, ventricular dominance, wall asymmetry and relative wall thickness. Intra- and interobserver measurement reproducibility was evaluated using intraclass correlation coefficients (ICC). In order to construct reference ranges across pregnancy, parametric regressions were tested to model each measurement against gestational age and estimated fetal weight. The measurements evaluated were: cardiothoracic ratio; atrial-to-heart area ratios; ventricular-to-heart area ratios; cardiac, ventricular and atrial sphericity indices; right-to-left basal and midventricular ratios; septal-to-free wall thickness ratios; and relative wall thickness., Results: Fetal cardiac, ventricular and atrial morphometry for assessing relative size and geometry could be successfully performed in > 95% of the population, with moderate-to-excellent interobserver reproducibility (ICC, 0.623-0.907) and good-to-excellent intraobserver reproducibility (ICC, 0.787-0.938). Cardiothoracic ratio and ventricular right-to-left ratio showed a modest increase throughout gestation. Atrial-to-heart and ventricular-to-heart area ratios, atrial sphericity indices and septal-to-free wall thickness ratios were constant with gestational age. Left and right ventricular basal sphericity indices showed a tendency to decrease at the end of gestation, while left and right midventricular sphericity indices tended to decrease in the second trimester. The cardiac sphericity index and left and right relative wall thickness showed a modest decrease with gestational age. Nomograms across gestation were constructed for all echocardiographic parameters described., Conclusions: The assessment of cardiac, ventricular and atrial relative size and geometry is feasible and reproducible in the fetus. We provide standardized reference ranges for these parameters throughout gestation, enabling the accurate assessment of cardiac remodeling patterns during fetal life. © 2020 International Society of Ultrasound in Obstetrics and Gynecology., (© 2020 International Society of Ultrasound in Obstetrics and Gynecology.)

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., (© 2020 International Society of Ultrasound in Obstetrics and Gynecology.)

Objectives: Coarctation of the aorta (CoA) is associated with left ventricular (LV) dysfunction in neonates and adults. Cardiac structure and function in fetal CoA and cardiac adaptation to early neonatal life have not been described. We aimed to investigate the presence of cardiovascular structural remodeling and dysfunction in fetuses with CoA and their early postnatal cardiac adaptation., Methods: This was a prospective observational case-control study, conducted between 2011 and 2018 in a single tertiary referral center, of fetuses with CoA and gestational age-matched normal controls. All fetuses/neonates underwent comprehensive echocardiographic evaluation in the third trimester of pregnancy and after birth. Additionally, myocardial microstructure was assessed in one fetal and one neonatal CoA-affected heart specimen, using synchrotron radiation-based X-ray phase-contrast microcomputed tomography and histology, respectively., Results: We included 30 fetuses with CoA and 60 gestational age-matched controls. Of these, 20 CoA neonates and 44 controls were also evaluated postnatally. Fetuses with CoA showed significant left-to-right volume redistribution, with right ventricular (RV) size and output dominance and significant geometry alterations with an abnormally elongated LV, compared with controls (LV midventricular sphericity index (median (interquartile range; IQR), 2.4 (2.0-2.7) vs 1.8 (1.7-2.0); P < 0.001). Biventricular function was preserved and no ventricular hypertrophy was observed. Synchrotron tomography and histological assessment revealed normal myocyte organization in the fetal and neonatal specimens, respectively. Postnatally, the LV in CoA cases showed prompt remodeling, becoming more globular (LV midventricular sphericity index (mean ± SD), 1.5 ± 0.3 in CoA vs 1.8 ± 0.2 in controls; P < 0.001) with preserved systolic and normalized output, but altered diastolic, parameters compared with controls (LV inflow peak velocity in early diastole (mean ± SD), 97.8 ± 14.5 vs 56.5 ± 12.9 cm/s; LV inflow peak velocity in atrial contraction (median (IQR), 70.5 (60.1-84.9) vs 47.0 (43.0-55.0) cm/s; LV peak myocardial velocity in atrial contraction (mean ± SD), 5.1 ± 2.6 vs 6.3 ± 2.2 cm/s; P < 0.05). The neonatal RV showed increased longitudinal function in the presence of a patent arterial duct., Conclusions: Our results suggest unique fetal cardiac remodeling in CoA, in which the LV stays smaller from the decreased growth stimulus of reduced volume load. Postnatally, the LV is acutely volume-loaded, resulting in an overall geometry change with higher filling velocities and preserved systolic function. These findings improve our understanding of the evolution of CoA from fetal to neonatal life. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.)

The heart is a central organ in the fetal adaptation to an adverse environment. Fetal cardiac changes may persist postnatally and increase the risk of cardiovascular disease in adulthood. Knowledge about fetal cardiac structural as well as functional remodeling has radically improved over the last few years. As it occurs in postnatal life, the fetal heart remodels - changing its structure and shape - to adapt to an insult. Several conditions have been reported to be associated with fetal cardiac remodeling including intrauterine growth restriction, diabetes, exposure to antiretroviral drugs, conception by assisted reproductive technologies, pulmonary stenosis, and other congenital heart diseases. Here we summarized the main observable patterns of cardiac remodeling, i.e., globular shape, hypertrophy without dilation, and hypertrophy with cardiomegaly. We discuss the potential pathophysiology behind different types of remodeling. Defining precisely the distinct patterns of fetal cardiac remodeling is critical for advancing in the understanding of fetal cardiovascular programming and its consequences on adult health, and potentially for the design of preventive strategies that might have an impact on long-term cardiovascular health., (© 2020 S. Karger AG, Basel.)

Objective: There is a need for standardized reference values for cardiac dimensions in prenatal life. The objective of the present study was to construct nomograms for fetal cardiac dimensions using a well-defined echocardiographic methodology in a low-risk population., Methods: This is a prospective cohort study including 602 low-risk singleton pregnancies undergoing a standardized fetal echocardiography to accurately assess fetal cardiac, ventricular, and atrial dimensions. Parametric regressions were tested to model each measurement against gestational age from 18 to 41 weeks of gestation., Results: Nomograms were constructed for fetal cardiac dimensions (transverse and longitudinal diameters and areas) of the whole heart, atria, and ventricles, as well as myocardial wall thicknesses. All dimensions showed a progressive increase with gestational age. The best model for most parameters was a second-degree linear polynomial. Fetal cardiac, ventricular, and atrial diameters and areas were successfully obtained in 98.6% of the fetuses, while myocardial wall thicknesses could be obtained in 96.5% of the population. The results showed excellent interobserver and intraobserver reproducibility (intraclass correlation coefficient, ICC > 0.811 and ICC > 0.957, respectively)., Conclusions: We provide standardized and comprehensively evaluated reference values for fetal cardiac morphometric parameters across gestation in a low-risk population. These no mograms would enable the early identification of different patterns of fetal cardiac remodeling., (© 2019 S. Karger AG, Basel.)

Background: Preeclampsia and fetal growth restriction share some pathophysiologic features and are both associated with placental insufficiency. Fetal cardiac remodeling has been described extensively in fetal growth restriction, whereas little is known about preeclampsia with a normally grown fetus., Objective: To describe fetal cardiac structure and function in pregnancies complicated by preeclampsia and/or fetal growth restriction as compared with uncomplicated pregnancies., Study Design: This was a prospective, observational study including pregnancies complicated by normotensive fetal growth restriction (n=36), preeclampsia with a normally grown fetus (n=35), preeclampsia with fetal growth restriction (preeclampsia with a normally grown fetus-fetal growth restriction, n=42), and 111 uncomplicated pregnancies matched by gestational age at ultrasound. Fetal echocardiography was performed at diagnosis for cases and recruitment for uncomplicated pregnancies. Cord blood concentrations of B-type natriuretic peptide and troponin I were measured at delivery. Univariate and multiple regression analysis were conducted., Results: Pregnancies complicated by preeclampsia and/or fetal growth restriction showed similar patterns of fetal cardiac remodeling with larger hearts (cardiothoracic ratio, median [interquartile range]: uncomplicated pregnancies 0.27 [0.23-0.29], fetal growth restriction 0.31 [0.26-0.34], preeclampsia with a normally grown fetus 0.31 [0.29-0.33), and preeclampsia with fetal growth restriction 0.28 [0.26-0.33]; P<.001) and more spherical right ventricles (right ventricular sphericity index: uncomplicated pregnancies 1.42 [1.25-1.72], fetal growth restriction 1.29 [1.22-1.72], preeclampsia with a normally grown fetus 1.30 [1.33-1.51], and preeclampsia with fetal growth restriction 1.35 [1.27-1.46]; P=.04) and hypertrophic ventricles (relative wall thickness: uncomplicated pregnancies 0.55 [0.48-0.61], fetal growth restriction 0.67 [0.58-0.8], preeclampsia with a normally grown fetus 0.68 [0.61-0.76], and preeclampsia with fetal growth restriction 0.66 [0.58-0.77]; P<.001). Signs of myocardial dysfunction also were observed, with increased myocardial performance index (uncomplicated pregnancies 0.78 z scores [0.32-1.41], fetal growth restriction 1.48 [0.97-2.08], preeclampsia with a normally grown fetus 1.15 [0.75-2.17], and preeclampsia with fetal growth restriction 0.45 [0.54-1.94]; P<.001) and greater cord blood B-type natriuretic peptide (uncomplicated pregnancies 14.2 [8.4-30.9] pg/mL, fetal growth restriction 20.8 [13.1-33.5] pg/mL, preeclampsia with a normally grown fetus 31.8 [16.4-45.8] pg/mL and preeclampsia with fetal growth restriction 37.9 [15.7-105.4] pg/mL; P<.001) and troponin I as compared with uncomplicated pregnancies., Conclusion: Fetuses of preeclamptic mothers, independently of their growth patterns, presented cardiovascular remodeling and dysfunction in a similar fashion to what has been previously described for fetal growth restriction. Future research is warranted to better elucidate the mechanism(s) underlying fetal cardiac adaptation in these conditions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: Fetal right ventricular (RV) function assessment is challenging due to the RV geometry and limitations of in utero assessment. Postnatally, 2D echocardiographic RV fractional area change (FAC) is used to assess RV global systolic function by calculating the percentage of change in RV area from systole to diastole. Reports on FAC are scarce in prenatal life, and nomograms throughout pregnancy are not available. Our aims were (1) to study prenatal RV FAC feasibility and reproducibility and (2) to construct nomograms for RV FAC and end-diastolic (ED) and end-systolic (ES) RV areas from 18 to 41 weeks of gestation., Methods: Prospective cohort study including 602 low-risk singleton pregnancies undergoing a fetal echocardiography from 18 to 41 weeks of gestation. RV ED and ES areas were measured following standard recommendations for ventricular dimensions and establishing strict landmarks to identify the different phases of the cardiac cycle. RV FAC was calculated as: ([ED area - ES area]/ED area) × 100. RV FAC intra- and inter-observer reproducibility was evaluated in 45 fetuses by calculating the intraclass correlation coefficient (ICC). Parametric regressions were tested to model each parameter against gestational age (GA) and estimated fetal weight (EFW)., Results: RV areas and FAC were successfully obtained in ∼99% of fetuses with acceptable reproducibility throughout gestation (RV ED area inter-observer ICC [95% CI] 0.96 [0.93-0.98], RV ES area 0.97 [0.94-0.98], and FAC 0.69 [0.44-0.83]). Nomograms were constructed for RV ED and ES areas and FAC. RV areas showed a quadratic and logarithmic increase with GA and EFW, respectively. In contrast, RV FAC showed a slight quadratic decrease throughout gestation (mean RV FAC ranged from 36% at 18 weeks of gestation [10-90th centiles: 25-47%, respectively] to 29% at 41 weeks [10-90th centiles: 18-40%, respectively]). The best models for RV areas and FAC were a second-degree polynomial., Conclusions: RV FAC is a feasible and reproducible parameter to assess RV global systolic function in fetal life. We provide reference ranges adjusted by GA and EFW that can be used as normal references for the assessment of RV function in prenatal conditions., (© 2019 S. Karger AG, Basel.)

Background: We have used a previously reported rabbit model of fetal growth restriction (FGR), reproducing perinatal neurodevelopmental and cardiovascular impairments, to investigate the main relative changes in cerebral and cardiac metabolism of term FGR fetuses during nutrient infusion., Methods: FGR was induced in 9 pregnant New Zealand rabbits at 25 days of gestation: one horn used as FGR, by partial ligation of uteroplacental vessels, and the contralateral as control (appropriate for gestation age, AGA). At 30 days of gestation, fasted mothers under anesthesia were infused i.v. with 1-13C-glucose (4 mothers), 2-13C-acetate (3 mothers), or not infused (2 mothers). Fetal brain and heart samples were quickly harvested and frozen down. Brain cortex and heart apex regions from 30 fetuses were studied ex vivo by HRMAS at 4°C, acquiring multinuclear 1D and 2D spectra. The data were processed, quantified by peak deconvolution or integration, and normalized to sample weight., Results: Most of the total 13C-labeling reaching the fetal brains/hearts (80-90%) was incorporated to alanine and lactate (cytosol), and to the glutamine-glutamate pool (mitochondria). Acetate-derived lactate (Lac C2C3) had a slower turnover in FGR brains (~ -20%). In FGR hearts, mitochondrial turnover of acetate-derived glutamine (Gln C4) was slower (-23%) and there was a stronger accumulation of phospholipid breakdown products (glycerophosphoethanolamine and glycerophosphocholine, +50%), resembling the profile of non-infused control hearts., Conclusions: Our results indicate specific functional changes in cerebral and cardiac metabolism of FGR fetuses under nutrient infusion, suggesting glial impairment and restricted mitochondrial metabolism concomitant with slower cell membrane turnover in cardiomyocytes, respectively. These prenatal metabolic changes underlie neurodevelopmental and cardiovascular problems observed in this FGR model and in clinical patients, paving the way for future studies aimed at evaluating metabolic function postnatally and in response to stress and/or treatment., Competing Interests: The authors have declared that no competing interests exist.

Objective: To evaluate cardiac function by conventional echocardiography and tissue Doppler imaging in fetuses with left congenital diaphragmatic hernia (CDH)., Methods: Conventional echocardiography (myocardial performance index, ventricular filling velocities, and E/A ratios) and tissue Doppler imaging (annular myocardial peak velocities, E/E' and E'/A' ratios) in mitral, septal, and tricuspid annulus were evaluated in a cohort of 31 left-sided CDH fetuses and compared with 75 controls matched for gestational age 2:1., Results: In comparison to controls, CDH fetuses had prolonged isovolumetric time periods (isovolumetric contraction time 35 ms vs 28 ms, P < .001), with higher myocardial performance index (0.49 vs 0.42, P < .001) and tricuspid E/A ratios (0.77 vs 0.72, P = .033). Longitudinal function assessed by tissue Doppler showed signs of impaired relaxation (mitral lateral A' 8.0 vs 10.1 cm/s, P < .001 and an increased mitral lateral E'/A' ratio 0.93 vs 0.78, P < .001) in the CDH fetuses as compared with controls, with preserved systolic function., Conclusion: Left CDH fetuses show echocardiographic signs of diastolic dysfunction, probably secondary to fetal heart compression, maintaining a preserved systolic function., (© 2018 John Wiley & Sons, Ltd.)

Objective: Recent data suggest that singleton fetuses conceived by assisted reproductive technology (ART) present cardiovascular remodeling that may persist postnatally. Twin pregnancies are more frequent in the ART population and are associated with increased adverse perinatal outcomes, such as hypertensive disorders, gestational diabetes and preterm birth. However, it is unknown whether cardiac remodeling is also present in twin pregnancies conceived by ART. Our aim was to assess the presence of fetal cardiac remodeling and dysfunction in twin pregnancies conceived by ART as compared with those conceived spontaneously (SC)., Methods: This was a prospective cohort study including 50 dichorionic twin fetuses conceived by ART and 50 SC twin fetuses. The study protocol included collection of baseline/perinatal data and a fetal ultrasound examination at 28-30 weeks' gestation, including assessment of estimated fetal weight, fetoplacental Doppler and fetal echocardiography. Measurements of atrial area, atrial/heart ratio, ventricular sphericity index, free wall thickness, mitral and tricuspid annular plane systolic excursions, and systolic and early diastolic peak velocities were assessed. Multilevel analyses were used to compare perinatal and ultrasonographic parameters. Comparisons of echocardiographic variables were adjusted for parental age, paternal body mass index and incidence of pre-eclampsia., Results: Compared with SC twins, ART twin fetuses showed significant cardiac changes, predominantly affecting the right heart, such as dilated atria (right atrial/heart area: 15.7 ± 3.1 vs 18.4 ± 3.2, P < 0.001), more globular ventricles (right ventricular sphericity index: 1.57 ± 0.25 vs 1.41 ± 0.23, P = 0.001) and thicker myocardial walls (septal wall thickness: 2.57 ± 0.45 mm vs 2.84 ± 0.41 mm, P = 0.034) together with reduced longitudinal motion (tricuspid annular plane systolic excursion: 6.36 ± 0.89 mm vs 5.18 ± 0.93 mm, P < 0.001)., Conclusions: ART twin fetuses present signs of cardiac remodeling and dysfunction. These changes are similar to those observed in ART singletons and reinforce the concept of fetal cardiac programing in ART. These results open opportunities for early detection and intervention in infants conceived by ART. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: Fetuses conceived by assisted reproductive technology (ART) and those that are small-for-gestational age (SGA) show cardiovascular remodeling in utero; however, these two conditions are often associated. We aimed to evaluate the differential effect of ART and SGA on fetal cardiac remodeling., Methods: This was a prospective cohort study of term singleton pregnancies seen at our department between April 2011 and September 2013. The cohort was divided according to fetal growth and mode of conception into the following four groups: 102 appropriate-for-gestational-age (AGA) fetuses conceived spontaneously (controls), 72 AGA fetuses conceived by ART (ART-AGA), 31 SGA fetuses conceived by ART (ART-SGA) and 28 SGA fetuses conceived naturally (Spont-SGA). SGA was defined as birth weight < 10 th centile. Fetal echocardiography was performed at 28-32 weeks to assess cardiac dimensions, geometry and function., Results: ART fetuses had dilated atria (mean left atrium-to-heart area ratio: controls, 15 ± 2.7%; ART-AGA, 18 ± 4.1%; Spont-SGA, 14 ± 3.7%) and more globular ventricles (left ventricular sphericity index: controls, 1.77 ± 0.2; ART-AGA, 1.68 ± 0.2; Spont-SGA, 1.72 ± 0.2), with normally sized hearts. In contrast, SGA fetuses had enlarged hearts (cardiothoracic ratio: controls, 24 ± 3%; ART-AGA, 24 ± 4%; Spont-SGA, 29 ± 6%), preserved atrial size, more globular and concentric hypertrophic ventricles (left ventricle relative wall thickness: controls, 0.48 ± 0.17; ART-AGA, 0.54 ± 0.13; Spont-SGA, 0.63 ± 0.23). Both ART and SGA fetuses had decreased longitudinal motion (tricuspid annular ring displacement: controls, 6.5 ± 0.8 mm; ART-AGA, 5.5 ± 0.7 mm; Spont-SGA, 5.9 ± 0.6 mm) and impaired relaxation (left isovolumetric relaxation time: controls, 47.0 ± 7.3 ms; ART-AGA, 50.0 ± 7.9 ms; Spont-SGA, 49.5 ± 9.3 ms). ART-SGA fetuses presented a combination of features from both ART and SGA groups., Conclusion: SGA and conception with ART were associated with distinct patterns of fetal cardiac remodeling, supporting the concept that they are independent causes of cardiac programming. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: This study investigated the role of oxidative damage and nitric oxide (NO) synthases in the fetal heart using a model of intrauterine growth restriction induced by uteroplacental circulation restriction (UCR)., Methods: New Zealand white rabbits kept under 12-h light cycles, with food and water provided ad libitum, were subjected at day 25 of pregnancy to 40-50% uteroplacental artery ligation. We analyzed the gene expression of enzymes linked to nitric oxide synthesis (iNOS, eNOS, HO-1, and ARG-2), hypoxia inducible factor 1 alpha (HIF-1α), and the state of oxidative stress (protein carbonyl levels) in fetal heart homogenates. Additionally, we studied the histological morphology of the fetal heart., Results: We found that fetal growth restriction was associated with a significant reduction in heart weight but a normal heart/body weight ratio in UCR animals. Hematoxylin and eosin staining showed normal left and right ventricular thickness but increased vessel dilatation with hyperemia in the hearts of the UCR group. We observed HIF-1α, eNOS, p-eNOS, and iNOS induction concomitant with intensified protein carbonyl levels but observed no changes in HO-1 or ARG-2 expression, suggesting increased NO and oxidative stress in the hearts of UCR animals., Conclusion: Uteroplacental circulation restriction increased NO-linked enzymes, oxidative damage, and dilated coronary vessels in fetal hearts. © 2017 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd., (© 2017 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.)

Objective: To evaluate mitral and tricuspid annular plane systolic excursion (MAPSE and TAPSE) in fetuses with twin-to-twin transfusion syndrome (TTTS) before and after laser therapy., Methods: A prospective study in 24 fetal pairs with TTTS evaluated 24 h before and within 48 h after fetoscopy and 13 gestational age-matched normal monochorionic fetal pairs. MAPSE and TAPSE were measured in an apical or basal four-chamber view by placing the M-mode cursor at the lateral valve ring., Results: Mean preoperative MAPSE (controls 3.6 ± 1.3 mm vs. donors 2.7 ± 0.8 mm vs. recipients 2.8 mm ± 0.9; P < 0.001) and TAPSE (controls 4.4 ± 1.5 mm vs. donors 3.3 ± 1 mm vs. recipients 3.6  ± 1.1 mm; P < 0.001) values were significantly reduced in both TTTS fetuses. When subdividing according to TTTS stages, changes were significant in both stage I-II and III-IV subgroups, although differences were more pronounced in the latter. All observations remained unchanged 48 h post-fetoscopy., Conclusion: Both recipient and donor fetuses had decreased global longitudinal motion, even in early TTTS stages., (© 2015 John Wiley & Sons, Ltd.)

Objective: Among late-onset small fetuses, a combination of estimated fetal weight (EFW), cerebroplacental ratio (CPR) and mean uterine artery (UtA) pulsatility index (PI) can predict a subgroup of fetuses with poor perinatal outcome; however, the association of these criteria with fetal cardiac structure and function is unknown. Our aim was to determine the presence and severity of signs indicating cardiac dysfunction in small fetuses, classified as intrauterine growth-restricted (IUGR) or small-for-gestational age (SGA), according to EFW, CPR and UtA-PI., Methods: A cohort of 209 late-onset small fetuses that were delivered > 34 weeks of gestation was divided in two categories: SGA (n = 59) if EFW was between the 3(rd) and 9(th) centiles with normal CPR and UtA-PI; and IUGR (n = 150) if EFW was < 3(rd) centile, or < 10(th) centile with a CPR < 5(th) centile and/or UtA-PI > 95(th) centile. The small population was compared with 150 appropriately grown fetuses (controls). Fetal cardiac morphometry and function were assessed by echocardiography using two-dimensional M-mode, conventional and tissue Doppler., Results: Compared with controls, both IUGR and SGA fetuses showed larger and more globular hearts (mean left sphericity index ± SD: controls, 1.8 ± 0.3; SGA, 1.5 ± 0.2; and IUGR, 1.6 ± 0.3; P < 0.01) and showed signs of systolic and diastolic dysfunction, including decreased tricuspid annular plane systolic excursion (mean ± SD: controls, 8.2 ± 1.1; SGA, 7.4 ± 1.2; and IUGR, 6.9 ± 1.1; P < 0.001) and increased left myocardial performance index (mean ± SD: controls, 0.45 ± 0.14; SGA, 0.51 ± 0.08; and IUGR, 0.57 ± 0.1; P < 0.001)., Conclusions: Despite a perinatal outcome comparable to that of normal fetuses, the population of so-defined SGA fetuses showed signs of prenatal cardiac dysfunction. This supports the concept that at least a proportion of them are not 'constitutionally small' and that further research is needed., (Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.)

Background: Intrauterine growth restriction (IUGR) induces fetal cardiac remodelling and dysfunction, which persists postnatally and may explain the link between low birth weight and increased cardiovascular mortality in adulthood. However, the cellular and molecular bases for these changes are still not well understood. We tested the hypothesis that IUGR is associated with structural and functional gene expression changes in the fetal sarcomere cytoarchitecture, which remain present in adulthood., Methods and Results: IUGR was induced in New Zealand pregnant rabbits by selective ligation of the utero-placental vessels. Fetal echocardiography demonstrated more globular hearts and signs of cardiac dysfunction in IUGR. Second harmonic generation microscopy (SHGM) showed shorter sarcomere length and shorter A-band and thick-thin filament interaction lengths, that were already present in utero and persisted at 70 postnatal days (adulthood). Sarcomeric M-band (GO: 0031430) functional term was over-represented in IUGR fetal hearts., Conclusion: The results suggest that IUGR induces cardiac dysfunction and permanent changes on the sarcomere.

Background: Fetal growth restriction (FGR) is associated with global adverse cardiac remodeling in utero and increased cardiovascular mortality in adulthood. Prenatal myocardial deformation has not been evaluated in FGR to date. We aimed to evaluate prenatal cardiac remodeling comprehensively in FGR including myocardial deformation imaging., Methods and Results: Echocardiography was performed in 37 consecutive FGR (defined as birthweight <10th centile) and 37 normally grown fetuses. A comprehensive fetal echocardiography was performed including tissue Doppler and 2-dimensional-derived strain and strain rate. Postnatal blood pressure measurement at 6 months of age was also performed. FGR cases showed signs of more globular hearts with decreased longitudinal motion (left systolic annular peak velocity: controls mean 6 cm/s [SD 1.2] versus FGR 5.3 [1]) and diastolic dysfunction (isovolumic relaxation time: controls 44 ms [6] versus FGR 52 [9]). Peak strain and strain rate values of the left ventricle were not significantly different; however, a postsystolic shortening in the basal segment of the septal ventricular wall was observed in 57% of the FGR cases and in none of controls (P<0.001). FGR cases with postsystolic shortening had absence of a hypertrophic response, a poorer perinatal outcome (lower gestational age and birthweight, containing all cases of perinatal mortality [8%]), and higher values of blood pressure., Conclusions: Myocardial deformation imaging revealed a postsystolic shortening in 57% of FGR, which supports increased pressure overload as a mechanism for cardiovascular programming in FGR. Postsystolic shortening was associated with severity and with higher blood pressure postnatally., (© 2014 American Heart Association, Inc.)

Background: Assisted reproductive technologies (ARTs) have been shown to be associated with general vascular dysfunction in late childhood. However, it is unknown whether cardiac remodeling is also present and if these changes already manifest in prenatal life. Our aim was to assess fetal and infant (6 months of age) cardiovascular function in ART pregnancies., Methods and Results: This prospective cohort study included 100 fetuses conceived by ART and 100 control pregnancies. ART fetuses showed signs of cardiovascular remodeling, including a more globular heart with thicker myocardial walls, decreased longitudinal function (tricuspid ring displacement in controls: median, 6.5 mm [interquartile range, 6.1-7.1 mm]; tricuspid ring displacement in ART: 5.5 mm [interquartile range, 5.1-6.1]; P<0.001), impaired relaxation, and dilated atria (atrial area in controls, 1.46 cm(2) [interquartile range, 1.2-1.5 cm(2)]; atrial area in ART, 1.6 cm(2) [interquartile range, 1.3-1.8 cm(2)]; P<0.001). Additionally, ART infants showed persistence of most cardiac changes and a significant increase in blood pressure and aortic intima-media thickness (systolic blood pressure in controls, 74 mm Hg [interquartile range, 67-83 mm Hg]; systolic blood pressure in ART, 83 mm Hg [interquartile range, 75-94 mm Hg]; P<0.001; aortic intima-media thickness in controls, 0.52 mm [interquartile range, 0.45-0.56 mm]; aortic intima-media thickness in ART, 0.64 mm [interquartile range, 0.62-0.67]; P<0.001). We could not demonstrate that our findings were directly caused by ART because of their association with various confounding factors, including intrauterine growth restriction or factors related to the cause of infertility., Conclusions: Children conceived by ART manifest cardiac and vascular remodeling that is present in fetal life and persists in postnatal life, suggesting opportunities for early detection and potential intervention. The underlying mechanisms and the effect of potential confounders such as growth restriction or prematurity remain to be elucidated.

Objective: To compare the ability of two different methods for longitudinal annular motion measurement, M-mode and tissue Doppler imaging (TDI), to demonstrate cardiac dysfunction in intrauterine-growth-restricted (IUGR) fetuses., Methods: Cardiac longitudinal annular motion in the basal free wall of the left ventricle (mitral annulus), interventricular septum and tricuspid annulus was assessed in 23 early-onset IUGR cases and 43 controls by TDI (annular peak velocities) and M-mode (displacement)., Results: All annular parameters were significantly decreased in the IUGR group with respect to controls using both methods. M-mode showed a trend towards equal performance as classifier between cases and controls, as compared to TDI, mainly in the tricuspid annulus., Conclusions: Both M-mode and TDI demonstrate annular motion changes and consequently cardiac dysfunction in IUGR fetuses. M-mode imaging is simpler to perform and could be as sensitive as TDI for detecting subtle changes., (Copyright © 2012 ISUOG. Published by John Wiley & Sons Ltd.)

Objectives: To construct gestational age (GA)- and estimated fetal weight (EFW)-adjusted reference ranges for tissue Doppler cardiac function parameters from 24 to 41 weeks' gestation., Methods: This was a prospective cross-sectional observational study involving 213 singleton pregnancies between 24 and 41 weeks' gestation. Myocardial peak velocities and myocardial performance index (MPI') were measured by tissue Doppler ultrasonography (values indicated by 'prime') in the left and right annulus and interventricular septum. Left and right atrioventricular parameters were also measured by conventional Doppler and ratios between the values found by the two methods calculated. Regression analysis was used to determine GA- and EFW-adjusted reference ranges and to construct nomograms for tissue Doppler parameters., Results: All myocardial peak velocities, left and right E'/A' and left MPI' showed a progressive increase with GA. In contrast, left and right E/E' showed a progressive decline. Septal E'/A', and right and septal MPI' remained constant. Myocardial peak velocities showed a progressive increase with increasing fetal weight., Conclusions: Normal data of fetal myocardial peak velocities, their ratios and MPI' by tissue Doppler adjusted by GA and EFW are provided. The reported reference values may be useful in research or clinical studies and can be used in fetuses with intrauterine growth restriction.

Objective: To evaluate the accuracy of four-dimensional (4D) spatiotemporal image correlation (STIC) echocardiography for the diagnosis of fetal congenital heart disease (CHD) in a selected high-risk population., Methods: Three hundred and sixty-three pregnant women referred for suspected CHD on screening ultrasound were evaluated by means of conventional echocardiography between 14 and 41 weeks' gestation and 4D-STIC volumes were obtained (including gray-scale and color Doppler information). Stored volumes were analyzed, at least 1 year after they had been acquired, by examiners blinded to the patients' identities and outcomes. The STIC diagnoses were compared to those made on conventional two-dimensional echocardiography and the accuracy of diagnosis was assessed with respect to postnatal examination, or autopsy in cases of termination of pregnancy or perinatal death., Results: The mean gestational age at volume acquisition was 24 + 5 weeks. STIC evaluation was possible in 98% of cases. Twenty-one cases were lost to follow-up, with a total of 167 normal hearts and 175 cases of CHD diagnosed at postnatal evaluation. The overall accuracy, sensitivity, specificity and positive and negative predictive values of STIC in determining the presence or absence of CHD were 91.6, 94.9, 88.1, 89.7 and 94.0%, respectively. Absolute concordance with the final specific diagnosis among cases with confirmed CHD was 74.3% for STIC echocardiography, compared with 81.7% for real-time evaluation., Conclusion: 4D-STIC echocardiography performed by experienced operators can be used in fetuses at risk for cardiac anomalies in order to reliably provide reassurance of normality or to accurately diagnose major structural heart defects., (Copyright © 2010 ISUOG. Published by John Wiley & Sons, Ltd.)

Objective: To evaluate the independent contribution of ductus venosus (DV) blood flow assessment at 11-14 weeks' gestation to the prediction of congenital heart defects (CHD) in chromosomally normal fetuses, irrespective of the value of the nuchal translucency thickness (NT)., Methods: During a 4-year period, all singleton pregnancies from 11 + 0 to 13 + 6 weeks' gestation were scanned for NT and DV blood flow in a tertiary center. Abnormal DV blood flow was defined as either absent or reversed flow during atrial contraction (AR-DV). Fetal echocardiography was performed in all cases with either NT > 99(th) percentile or AR-DV. Follow-up was assessed by postnatal examination or autopsy in cases of termination of pregnancy or perinatal death., Results: A total of 6120 pregnancies were scanned at a median gestational age of 12 weeks, and 45 cases of CHD were detected. AR-DV was found in 206 fetuses, of which 145 (70.4%) had a normal karyotype. Among fetuses with AR-DV and normal karyotype, 11 cases of CHD were diagnosed, giving a sensitivity of 24.4%, a positive predictive value of 7.6% and an odds ratio of 9.8. Increased NT (> 99(th) centile) was present in 55 of the 145 (37.9%) cases with AR-DV and normal karyotype, and in 6/11 (54.5%) of those with CHD. Thus, the group of 90 fetuses with abnormal DV blood flow and normal NT contained five cases of CHD, for a sensitivity of 11.1%, a positive predictive value of 5.5% and an odds ratio of 8.5. Right-heart anomalies were predominant in those cases with isolated AR-DV (4/5), but no specific CHD pattern was found in those with increased NT. The detection rate of CHD by the combined use of increased NT and/or AR-DV in the first trimester improved from 28.9% (13/45) to 40.0% (18/45)., Conclusions: In experienced hands, abnormal DV blood flow in the first trimester is an independent predictor of CHD and should constitute an indication for early echocardiography. In this study, the use of DV blood flow assessment increased early detection of CHD by 11% with respect to the use of NT measurement alone., ((c) 2010 ISUOG. Published by John Wiley & Sons, Ltd.)

Objective: To assess the intra- and interobserver repeatability of the evaluation of fetal cardiac structures and measurements using spatiotemporal image correlation (STIC) technology in each trimester of pregnancy., Methods: Four-dimensional (4D)-STIC volumes from 150 low-risk pregnancies were acquired at first-, second- or third-trimester scan for later analysis by two different reviewers. A total of 19 items, including the evaluation of 14 structures as well as five measurements of the fetal heart, were evaluated. The reliability of qualitative variables was evaluated using Cohen's kappa and absolute agreement analysis while that of quantitative parameters was assessed using the intraclass correlation coefficient (ICC)., Results: Forty-five, 47 and 47 STIC volumes were included in the final analysis from the first, second and third trimesters, respectively. For the evaluation of cardiac structures, good or excellent intra- and interobserver agreement (kappa > 0.6) was obtained in 12/14 and 9/14, respectively, while absolute agreement was > 90% for most structures evaluated. Regarding the quantitative cardiac measurements, ICC values were above 0.90 for all but cardiac axis (intraobserver ICC, 0.81 and interobserver ICC, 0.61). There were no significant differences in the repeatability values observed for qualitative or quantitative parameters among the trimesters of pregnancy., Conclusion: Cardiac examination from 4D-STIC volumes showed a high repeatability between and within observers in each trimester of pregnancy., ((c) 2010 ISUOG. Published by John Wiley & Sons, Ltd.)

Objectives: Increasing evidence shows that intrauterine growth restriction (IUGR) is associated with fetal cardiac dysfunction. Most studies group IUGR with and without pre-eclampsia (PE) altogether. Our objective was to evaluate whether the association with PE has any impact on cardiac function in IUGR fetuses, Methods: Thirty-one normotensive IUGR cases and 31 IUGR cases with pre-eclampsia (PE + IUGR) below 34 weeks of gestation were included. IUGR was defined as a birth weight below the 10(th) centile together with an umbilical artery pulsatility index above 2 SD. Fetal cardiac function was assessed by measuring ductus venosus pulsatility index, modified myocardial performance index, aortic isthmus blood flow, E/A ratios and cardiac output. The presence of fetal cardiac dysfunction was also assessed by measuring cord blood B-type natriuretic peptide (BNP) levels collected at birth. Echocardiographic data were compared with those in 80 term appropriate-for-gestational age (AGA) fetuses from normotensive mothers. Cord blood BNP levels were compared with those in 40 AGA cases that delivered preterm., Results: All IUGR cases (with or without PE) showed echocardiographic and biochemical signs of cardiac dysfunction compared with AGA cases. However, no differences were observed between IUGR and PE + IUGR cases either in echocardiographic or in biochemical parameters. IUGR cases with or without PE had similar perinatal results., Conclusions: IUGR fetuses showed echocardiographic and biochemical signs of cardiac dysfunction. Pre-eclampsia per se does not influence cardiac function in IUGR fetuses., (Copyright 2009 ISUOG. Published by John Wiley & Sons, Ltd.)

Objectives: To evaluate the potential value of early fetal echocardiography (EFE) by means of four-dimensional (4D) spatiotemporal image correlation (STIC) technology for either reassurance of normality or prenatal diagnosis of major congenital heart defects (CHDs)., Methods: Sixty-nine pregnant women from 11 to 15 weeks' gestation underwent EFE. 4D-STIC volumes were acquired by the transvaginal approach for later review by two different examiners. STIC evaluation was considered complete when the four-chamber view, and the origin and double-crossing of the great arteries were identified correctly. Color Doppler imaging was used to detect either septal shunts or transvalvular regurgitation/aliasing suggesting abnormalities. STIC diagnoses were compared with those of conventional EFE. Reliability was assessed by postnatal examination, or autopsy in cases of termination of pregnancy or perinatal death., Results: The median gestational age at volume acquisition was 13 + 3 weeks. Eleven (15.9%) cases of CHD were diagnosed. A complete EFE was possible in 64 cases. We were able to provide reassurance of normality in 51 of the 53 confirmed normal hearts, with no false-positive results for major defects, although two minor defects (one ventricular septal defect (VSD) and one persistent left superior vena cava) were falsely suspected. The only false negative was a significant VSD at birth overlooked by both observers. Therefore, the total accuracy of STIC-EFE was 95.3% (61/64), with sensitivity, specificity, and positive and negative predictive values of 90.9%, 96.2%, 83.3% and 98.1%. The accuracy of conventional EFE (98.4%, 63/64) was slightly better than that of STIC, with no false-positive results recorded., Conclusions: Offline evaluation of 4D-STIC acquired volumes of the fetal heart in the first and early second trimester of pregnancy is reliable not only for early reassurance of normal cardiac anatomy but also to diagnose most major structural heart defects., ((c) 2009 ISUOG.)

Objective: It has been shown that the modified myocardial performance index (Mod-MPI) is associated with higher reproducibility than conventional MPI because it uses mitral and aortic valve 'clicks' to calculate each time period. We aimed to construct normal reference values for the Mod-MPI after 19 weeks' gestation., Methods: The Mod-MPI was calculated in the left ventricle of 557 normal fetuses at 19-39 weeks' gestation. The isovolumetric contraction time (ICT), isovolumetric relaxation time (IRT) and ejection time (ET) were measured using the Doppler signals (clicks) of the opening and closing of the mitral and aortic valves as landmarks. Mod-MPI was calculated as (ICT + IRT)/ET., Results: Throughout gestation, there was a small increase in the Mod-MPI (at 19 weeks it was 0.35 +/- 0.027 (mean +/- SD); at 39 weeks, 0.37 +/- 0.029; Mod-MPI = 0.33 + 0.001x gestational age (GA) (weeks), r(2) = 0.017). Of the three components, ICT remained constant, IRT increased (IRT = 0.028 + 2.52 x GA (weeks)), and ET slightly decreased (ET = 0.184 - 3.65 x GA (weeks)). Fetal heart rate (FHR) had no effect on the Mod-MPI, but the duration of IRT, ICT and ET decreased by 13-15% when FHR increased from 130 to 160 beats per minute., Conclusion: The GA-adjusted reference values for the Mod-MPI and the three time periods used for its calculation can be applied to fetal cardiac evaluation in the presence of pregnancy-associated complications.

STUDY QUESTION Do spontaneously conceived (SC) fetuses from subfertile couples show the same signs of cardiac remodeling as those observed after IVF treatments? SUMMARY ANSWER As opposed to fetuses from IVF, SC fetuses from subfertile couples do not show cardiac remodeling and present a similar cardiac structure and function to those of SC fetuses from fertile couples. WHAT IS KNOWN ALREADY Subjects conceived by IVF present signs of cardiac remodeling and suboptimal function in utero and during childhood, including larger atria, more globular and thicker ventricles, reduced longitudinal motion, and impaired relaxation as compared to SC individuals from fertile couples. There are no previous publications investigating the independent cardiac programming effects of infertility in SC fetuses from subfertile couples (with time-to-pregnancy (TTP) over 12 months). STUDY DESIGN, SIZE, DURATION A prospective cohort study of 289 singleton pregnancies exposed and not exposed to subfertility recruited from 2019 to 2021, including 96 SC pregnancies from fertile couples (TTP under 12 months), 97 SC from subfertile couples (TTP over 12 months), and 96 from IVF after fresh embryo transfer. Fetal echocardiography was performed in all pregnancies. Epidemiological data and perinatal outcomes were collected in all pregnancies. The overall attrition rate was 15.7%. PARTICIPANTS/MATERIALS, SETTING, METHODS SC from subfertile couples and IVF pregnancies were identified as eligible at pregnancy diagnosis, and eligible SC pregnancies from fertile couples who attended our maternal-fetal unit were invited to participate at third trimester, being matched to the other groups by maternal age. Fetal echocardiography was performed at 29–34 weeks of pregnancy to assess cardiac structure and function, and results were adjusted by parental age, maternal smoking status, child's birth order, birthweight centile, gestational age, and estimated fetal weight at scan. MAIN RESULTS AND THE ROLE OF CHANCE Parental age, ethnicity, BMI, and smoking exposure, median gestational age and estimated fetal weight were similar in all study groups. There were no significant differences in infertility duration or etiology between the subfertile and the IVF populations (TTP: subfertile median 35 months (interquartile range 20–48) versus IVF: 47 (25–61); P -value = 0.051). While both fertile and subfertile SC groups presented similar fetal cardiac results, IVF fetuses showed larger atria (right atria-to-heart ratio: IVF mean 18.9% (SD 3.4) versus subfertile 17.8% (3.5) versus fertile 17.6% (3.3); adjusted P -value < 0.001), more globular ventricles (right ventricular sphericity index: IVF 1.56 (0.25) versus subfertile 1.72 (0.26) versus fertile 1.72 (0.26); <0.001), and thicker myocardial walls (relative wall thickness: IVF 0.86 (0.22) versus subfertile 0.64 (0.13) versus fertile 0.64 (0.18); <0.001). Whereas SC fetuses from fertile and subfertile couples had preserved cardiac function, IVF fetuses showed signs of suboptimal systolic and diastolic function, with reduced tricuspid ring displacement (IVF 7.26 mm (1.07) versus subfertile 8.04 mm (1.18) versus fertile 7.89 mm (1.51); <0.001) and increased left myocardial performance index (IVF 0.49 (0.08) versus subfertile 0.45 (0.09) versus fertile 0.45 (0.10); <0.001). A sub-analysis including only unexplained infertility cases in subfertile SC and IVF groups showed similar results. LIMITATIONS, REASONS FOR CAUTION The fetal cardiac changes reported here are subclinical, and most of the cardiovascular parameters were within normal ranges. Although echocardiographic changes are recognized as potential cardiovascular risk factors, their association with long-term cardiovascular disease remains to be demonstrated. WIDER IMPLICATIONS OF THE FINDINGS Subfertility per se does not seem to be associated to fetal cardiac remodeling, which has been previously described in IVF fetuses. Future studies are warranted to further investigate other factors related to the observed fetal cardiac changes associated with ART. STUDY FUNDING/COMPETING INTEREST(S) This project has been partially funded with support from the Erasmus + Programme of the European Union (Framework Agreement number: 2013-0040). This publication reflects the views only of the author, and the Commission cannot be held responsible for any use, which may be made of the information contained therein. Additionally, the research leading to these results has received funding from 'la Caixa' Foundation under grant agreement LCF/PR/GN18/10310003, the Instituto de Salud Carlos III (PI15/00130, PI16/00861, PI17/00675, PI18/00073, INT21/00027)—co-funded by the European Union, Cerebra Foundation for the Brain Injured Child (Carmarthen, Wales, UK) and AGAUR 2017 SGR grant no 1531. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Study Question: Do fetuses from frozen embryo transfer (FET) present signs of cardiac remodeling and suboptimal function similar to those observed in fetuses from fresh embryo transfer (ET)?Summary Answer: Fetuses from both fresh ET and FET present signs of fetal cardiac remodeling and suboptimal function, with more pronounced changes after fresh ET as compared to FET.What Is Known Already: Our group and others have previously demonstrated that fetuses and children conceived by ARTs present cardiac remodeling and suboptimal function. These fetuses show dilated atria, more globular and thicker ventricles, reduced longitudinal motion, and impaired relaxation. Cardiac changes were already present in utero and persisted after birth. Most of the ART fetuses included in previous publications were from fresh ET. However, singletons from FET have different perinatal outcomes compared to those from fresh ET. There are no previous studies comparing cardiac morphology and function between fetuses following fresh and FET.Study Design, Size, Duration: This is a prospective cohort study of 300 singleton pregnancies recruited from 2017 to 2020, including 100 spontaneously conceived (SC) pregnancies, 100 fetuses conceived by IVF with FET, and 100 fetuses conceived by IVF with fresh ET. Fetal structural and functional echocardiography was performed in all pregnancies.Participants/materials, Setting, Methods: Pregnancies conceived by IVF were recruited from a single assisted reproduction center, ensuring homogeneity in IVF stimulation protocols, endometrial preparation for FET, laboratory procedures, and embryo culture conditions. SC pregnancies from fertile couples were selected from the general population and matched to IVF pregnancies by maternal age. Epidemiological and perinatal outcomes were collected in all cases. Fetal echocardiography was performed at 28-33 weeks of pregnancy to assess cardiac structure and function in all pregnancies. All echocardiographic comparisons were adjusted by maternal age, nulliparity, birthweight centile, preeclampsia, and prematurity.Main Results and the Role Of Chance: Parental age, ethnicity, body mass index and smoking were similar among the study groups. Median gestational age at echocardiography and estimated fetal weight were similar in all study groups. Both fresh ET and FET groups showed similar fetal echocardiographic changes, with more pronounced features in the fresh ET as compared to FET pregnancies. Fetuses conceived by IVF showed larger atria (right atria-to-heart ratio: fresh ET mean 18.1% (SD 3.2) vs FET 18.0% (3.9) vs SC 17.3% (3.2); linear tendency P-value <0.001), more globular ventricles (right ventricular sphericity index: fresh ET 1.62 (0.29) vs FET 1.61 (0.25) vs SC 1.68 (0.26); <0.001) and thicker myocardial walls (relative wall thickness: fresh ET 0.79 (0.21) vs FET 0.74 (0.22) vs SC 0.65 (0.25); <0.001) as compared to SC pregnancies. Both fresh ET and FET groups also had signs of suboptimal systolic and diastolic function, with reduced tricuspid annular systolic peak velocity (fresh ET 7.17 cm/s (1.22) vs FET 7.41 cm/s (1.19) vs SC 7.58 cm/s (1.32); <0.001) and increased left myocardial performance index (fresh ET 0.53 (0.08) vs FET 0.53 (0.08) vs SC 0.50 (0.09); <0.001) as compared to SC pregnancies.Limitations, Reasons For Caution: The cardiac changes reported here are subclinical, with most cardiovascular indexes lying within normal ranges. Although echocardiographic changes are recognized as potential cardiovascular risk factors, their association with the long-term cardiovascular disease remains to be proven. The observed milder fetal cardiac features in FET fetuses cannot condition the choice of this technique and must be considered together with the global perinatal results related to these gestations.Wider Implications Of the Findings: The identification of cardiac remodeling in fetuses conceived by IVF with fresh ET and FET represents an opportunity for early detection. Future studies are warranted to study the potential long-term consequences of these findings.Study Funding/competing Interest(s): This project has been partially funded with support from the Erasmus + Programme of the European Union (Framework Agreement number: 2013-0040). This publication reflects the views only of the author, and the Commission cannot be held responsible for any use, which may be made of the information contained therein. Additionally, the research leading to these results has received funding from 'la Caixa' Foundation under grant agreement LCF/PR/GN18/10310003, the Instituto de Salud Carlos III (PI15/00130, PI17/00675, PI18/00073) integrated into the Plan Nacional de I + D+I and cofinanced by ISCIII-Subdirección General de Evaluación and Fondo Europeo de Desarrollo Regional (FEDER) 'Una manera de hacer Europa', Cerebra Foundation for the Brain Injured Child (Carmarthen, Wales, UK) and AGAUR 2017 SGR grant n° 1531. The authors declare no conflicts of interest.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Objective: To assess the postnatal persistence of fetal cardiovascular remodelling associated with assisted reproductive technologies (ART) in children at 3 years of age.Design: A cohort study of children conceived by ART.Setting: Maternal-Fetal Medicine Unit, Hospital Clinic Barcelona, Spain.Population Sample: Eighty singleton pregnancies conceived by ART and 80 spontaneously conceived (controls) followed from fetal life up to childhood.Methods: Cardiovascular evaluation was performed at 3 years of corrected age, including echocardiography, carotid intima-media (cIMT) by ultrasound, and blood pressure.Main Outcome Measures: Postnatal persistence of cardiovascular changes in children conceived by ART.Results: Compared with controls, children conceived by ART showed larger atria (right atrial area: control 4.9 cm2 (0.9) versus ART 5.5 cm2 (0.9), P < 0.001), more globular ventricles (right ventricular sphericity index: control mean 1.8 (SD 0.5) versus ART 1.6 (0.2), P < 0.001), and signs of systolic (tricuspid annular plane systolic excursion: control 18 mm (2) versus ART 16 mm (3), P < 0.001) and diastolic dysfunction (isovolumic relaxation time: control 68 ms (12) versus ART 79 ms (12), P < 0.001). ART children also presented increased systolic blood pressure (control 90 mmHg (6) versus ART 94 mmHg (5), P < 0.003) and cIMT (control 0.52 μm (0.14) versus ART 0.60 μm (0.16), P < 0.001) as compared with those spontaneously conceived.Conclusions: Cardiovascular changes previously reported in ART fetuses persist postnatally at 3 years of age. These results underscore the importance of future studies for assessing the long-term cardiovascular health associated with ART.Tweetable Abstract: Cardiovascular changes described in fetuses conceived by ART, persist in children at 3 years of age. [ABSTRACT FROM AUTHOR]

An abstract of the article "Cardiac dysfunction in small-for-gestational age and growth-restricted fetuses born at tern," by M. Pérez Cruz and colleagues is presented.

An abstract of the article "Fetal cardiovascular programming in growth restricted 6 month-old infants with and without catch-up growth" by M. Cruz-Lemini and colleagues is presented.

An abstract of the research paper "Comparison of Simpson vs Teicholz methods for the evaluation of ejection fraction in the fetal heart" by F. Crispi and others, presented at the 24th World Congress on Ultrasound in Obstetrics and Gynecology held in Spain from September 14-17, 2014, is presented.

An abstract of the article "Cardiovascular characteristics at 6 months of life in infants suffering intrauterine growth restriction," by M. C. Cruz Lemini, F. Crispi, F. Figueras, J. Domínguez, I. Stergiotou, M. Sitges, B. Bijnens and E. Gratacós is presented.

An abstract of the article "Fetal echocardiography for prediction of postnatal cardiovascular programming due to intrauterine growth restriction," by M. C. Cruz Lemini, F. Crispi, B. Bijnen, M. Sitges, F. Figueras and E. Gratacós is presented.

An abstract of the article "Reproducibility of cardiothoracic ratio and ventricular sphericity indices in the evaluation of fetal cardiac remodeling," by M. C. Cruz Lemini, B. Valenzuela-Alcaraz, F. Crispi and E. Gratacós is presented.