Angiogenic imbalance in maternal and cord blood is associated with neonatal birth weight and head circumference in pregnancies with major fetal congenital heart defect.

OBJECTIVES: To ascertain whether abnormalities in neonatal head circumference and/or body weight are associated with levels of angiogenic/antiangiogenic factors in the maternal and cord blood of pregnancies with a congenital heart defect (CHD) and to assess whether the specific type of CHD influences this association. METHODS: This was a multicenter case-control study of women carrying a fetus with major CHD. Recruitment was carried out between June 2010 and July 2018 at four tertiary care hospitals in Spain. Maternal venous blood was drawn at study inclusion and at delivery. Cord blood samples were obtained at birth when possible. Placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) were measured in maternal and cord blood. Biomarker concentrations in the maternal blood were expressed as multiples of the median (MoM). RESULTS: PlGF, sFlt-1 and sEng levels were measured in the maternal blood in 237 cases with CHD and 260 healthy controls, and in the cord blood in 150 cases and 56 controls. Compared with controls, median PlGF MoM in maternal blood was significantly lower in the CHD group (0.959 vs 1.022; P < 0.0001), while median sFlt-1/PlGF ratio MoM was significantly higher (1.032 vs 0.974; P = 0.0085) and no difference was observed in sEng MoM (0.981 vs 1.011; P = 0.4673). Levels of sFlt-1 and sEng were significantly higher in cord blood obtained from fetuses with CHD compared to controls (mean ± standard error of the mean, 447 ± 51 vs 264 ± 20 pg/mL; P = 0.0470 and 8.30 ± 0.92 vs 5.69 ± 0.34 ng/mL; P = 0.0430, respectively). Concentrations of sFlt-1 and the sFlt-1/PlGF ratio in the maternal blood at study inclusion were associated negatively with birth weight and head circumference in the CHD group. The type of CHD anomaly (valvular, conotruncal or left ventricular outflow tract obstruction) did not appear to alter these findings. CONCLUSIONS: Pregnancies with fetal CHD have an antiangiogenic profile in maternal and cord blood. This imbalance is adversely associated with neonatal head circumference and birth weight. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Multicenter prospective clinical study to evaluate children short-term neurodevelopmental outcome in congenital heart disease (children NEURO-HEART): study protocol.

BACKGROUND: Congenital heart disease (CHD) is the most prevalent congenital malformation affecting 1 in 100 newborns. While advances in early diagnosis and postnatal management have increased survival in CHD children, worrying long-term outcomes, particularly neurodevelopmental disability, have emerged as a key prognostic factor in the counseling of these pregnancies. METHODS: Eligible participants are women presenting at 20 to < 37 weeks of gestation carrying a fetus with CHD. Maternal/neonatal recordings are performed at regular intervals, from the fetal period to 24 months of age, and include: placental and fetal hemodynamics, fetal brain magnetic resonance imaging (MRI), functional echocardiography, cerebral oxymetry, electroencephalography and serum neurological and cardiac biomarkers. Neurodevelopmental assessment is planned at 12 months of age using the ages and stages questionnaire (ASQ) and at 24 months of age with the Bayley-III test. Target recruitment is at least 150 cases classified in three groups according to three main severe CHD groups: transposition of great arteries (TGA), Tetralogy of Fallot (TOF) and Left Ventricular Outflow Tract Obstruction (LVOTO). DISCUSSION: The results of NEURO-HEART study will provide the most comprehensive knowledge until date of children's neurologic prognosis in CHD and will have the potential for developing future clinical decisive tools and improving preventive strategies in CHD. TRIAL REGISTRATION: NCT02996630 , on 4th December 2016 (retrospectively registered).

Brain angiogenic gene expression in fetuses with congenital heart disease.

OBJECTIVE: To assess potential differences in the expression of antiangiogenic and angiogenic factors and of genes associated with chronic hypoxia in cerebral tissue of euploid fetuses with congenital heart disease (CHD) vs those without. METHODS: Cerebral tissue was obtained from 15 fetuses with CHD and 12 control fetuses that had undergone termination of pregnancy. Expression profiles of the antiangiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1), the angiogenic vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF), and of genes associated with chronic hypoxia were determined by real-time polymerase chain reaction in tissue from the frontal cortex and the basal ganglia of the fetuses. RESULTS: Expression of sFlt-1 was 48% higher in the frontal cortex (P = 0.0431) and 72% higher in the basal ganglia (P = 0.0369) of CHD fetuses compared with controls. The expression of VEGF-A was 60% higher (P = 0.0432) and that of hypoxia-inducible factor 2-alpha was 98% higher (P = 0.0456) in the basal ganglia of CHD fetuses compared with controls. No significant differences were observed between the two groups in the expression of PlGF and hypoxia-inducible factor 1-alpha. CONCLUSION: An overall dysregulation of angiogenesis with a net balance towards an antiangiogenic environment was observed in the cerebral tissue of fetuses with CHD, suggesting that these fetuses may have an intrinsic angiogenic impairment that could contribute to impaired brain perfusion and abnormal neurological development later in life. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Longitudinal changes in fetal biometry and cerebroplacental hemodynamics in fetuses with congenital heart disease.

OBJECTIVES: To determine the longitudinal behavior of fetal biometric measures and cerebroplacental hemodynamics throughout gestation in fetuses with congenital heart disease (CHD). METHODS: Fetal biometry and Doppler hemodynamics (uterine artery (UtA), umbilical artery (UA) and fetal middle cerebral artery (MCA)) were measured serially in a cohort of consecutive fetuses diagnosed with CHD. Evaluations were made at various time points, from diagnosis (20-25 weeks) to delivery, with at least two measurements per fetus that were at least 2 weeks apart. Fetuses were classified into three groups according to the pattern of blood supply to the brain (placental vs systemic) that would be expected on the basis of the type of CHD. All parameters were transformed into Z-scores. A linear mixed model to analyze repeated measurements was constructed for each parameter to assess its behavior throughout gestation. RESULTS: Four hundred and forty-four ultrasound examinations were performed in 119 CHD fetuses, with a median of two measurements per fetus. The fetuses presented a small head at diagnosis (biparietal diameter (BPD) Z-score, -1.32 ± 0.99; head circumference (HC) Z-score, -0.79 ± 1.02), which remained small throughout gestation. UtA and UA pulsatility indices (PI) showed a significant increase towards the end of pregnancy, whereas no significant changes were observed in MCA-PI or cerebroplacental ratio (CPR) with gestational age. Both MCA and CPR presented significant differences in longitudinal behavior between CHD groups, while BPD and HC did not. CONCLUSIONS: CHD fetuses have a relatively small head from the second trimester of pregnancy, regardless of the type of CHD anomaly, and increasing resistance in the UtA and UA as pregnancy progresses, suggestive of increasing degree of placental impairment. Our findings indicate the early onset of mechanisms that could lead to poorer neurodevelopment later in life. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Hypertrophic cardiomyopathy-like changes in monochorionic twin pregnancies with selective intrauterine growth restriction and intermittent absent/reversed end-diastolic flow in the umbilical artery.

OBJECTIVE: To evaluate the prevalence of hypertrophic cardiomyopathy-like (HCL) changes in monochorionic twins with selective intrauterine growth restriction (sIUGR) and intermittent absent/reversed end-diastolic flow (iAREDF), also defined as Type III sIUGR, and the clinical relevance of this condition. METHODS: A total of 80 pregnancies with sIUGR were studied, 40 with, and 40 without iAREDF. HCL changes were defined as an increased thickness of either left or right ventricular wall (mean > 2 SD) estimated with M-mode ultrasonography. Data were plotted on normal reference values constructed from 75 uncomplicated monochorionic twin pregnancies (150 fetuses) at 22-34 weeks' gestation. Perinatal outcomes in pregnancies with and without HCL changes were compared. RESULTS: In the group with iAREDF, 8/40 of the larger twins (20%) had HCL changes (five bilaterally, two in the right, and one in the left ventricle) as compared with 1/40 (2.5%) in fetuses without iAREDF (P = 0.03). No differences were observed in the smaller twin (1/40 in both groups). HCL changes were not associated with a significant increment in perinatal mortality as only one large fetus from the group with iAREDF died in utero. In the remaining 10 cases, no differences in the intertwin weight discordance, placental surface discordance, or rate of neonatal neurological damage were observed. However, all 10 presented mildly abnormal neonatal cardiac findings that resolved over time with no apparent short-term impact on cardiac function. CONCLUSIONS: HCL changes in the larger twin should be regarded as part of the spectrum of findings in Type III monochorionic-sIUGR (presenting iAREDF). This finding does not seem to be associated with an increased rate of short-term neurological or cardiac complications.