We evaluated differences in growth between fetuses with and without congenital heart disease (CHD) and tested associations between growth and early childhood neurodevelopment (ND). In this ...prospective cohort study, fetuses with hypoplastic left heart syndrome (HLHS), transposition of the great arteries (TGA), and tetralogy of Fallot (TOF) and controls had biparietal diameter (BPD), head (HC) and abdominal circumference (AC), femur length (FL), and estimated fetal weight (EFW) recorded serially during pregnancy at 18–26 weeks GA (F1), at 27–33 weeks GA (F2), and at 34–40 weeks GA (F3). CHD subjects underwent Bayley Scales of Infant Development-III ND testing at 18 months. Differences between CHD fetuses and controls were assessed using
t
tests and generalized linear modeling. Correlations between biometry and ND informed regression modeling. We enrolled 41 controls and 68 fetuses with CHD (
N
= 24 HLHS,
N
= 21 TGA,
N
= 23 TOF), 46 of whom had ND scores available. At 18–26 weeks, CHD fetuses were smaller than controls in all biometric parameters. Differences in growth rates were observed for HC, BPD, and AC, but not for FL or EFW. Cognitive score correlated with HC/AC at F2 (
r
= −0.33,
P
= 0.04) and mean HC/AC across gestation (
r
= −0.35,
P
= 0.03). Language correlated with FL/BPD at F2 (
r
= 0.34,
P
= 0.04). In stepwise linear regression, mean HC/AC predicted Cognition (
B
= −102,
P
= 0.026,
R
2
= 0.13) and FL/BPD at F2 predicted Language score (
B
= 127,
P
= 0.03,
R
2
= 0.12). Differences in growth between CHD fetuses and controls can be measured early in pregnancy. In CHD fetuses, larger abdominal relative to head circumference is associated with better 18-month neurodevelopment.
Abstract
OBJECTIVES
Neurodevelopmental disability is the most common complication among congenital heart surgery survivors. The Bayley scales are standardized instruments to assess neurodevelopment. ...The most recent edition (Bayley Scales of Infant and Toddler Development 3rd Edition, Bayley-III) yields better-than-expected scores in typically developing and high-risk infants than the second edition (Bayley Scales of Infant Development 2nd Edition, BSID-II). We compared BSID-II and Bayley-III scores in infants undergoing cardiac surgery.
METHODS
We evaluated 2198 infants who underwent operations with cardiopulmonary bypass between 1996 and 2009 at 26 institutions. We used propensity score matching to limit confounding by indication in a subset of patients (n = 705).
RESULTS
Overall, unadjusted Bayley-III motor scores were higher than BSID-II Psychomotor Development Index scores (90.7 ± 17.2 vs 77.6 ± 18.8, P < 0.001), and unadjusted Bayley-III composite cognitive and language scores were higher than BSID-II Mental Development Index scores (92.0 ± 15.4 vs 88.2 ± 16.7, P < 0.001). In the propensity-matched analysis, Bayley-III motor scores were higher than BSID-II Psychomotor Development Index scores absolute difference 14.1, 95% confidence interval (CI) 11.7–17.6; P < 0.001 and the Bayley-III classified fewer children as having severe odds ratio (OR) 0.24; 95% CI 0.14–0.42 or mild-to-moderate impairment (OR 0.21; 95% CI 0.14–0.32). The composite of Bayley-III cognitive and language scores was higher than BSID-II Mental Development Index scores (absolute difference 4.0, 95% CI 1.4–6.7; P = 0.003), but there was no difference between Bayley editions in the proportion of children classified as having severe cognitive and language impairment.
CONCLUSIONS
The Bayley-III yielded higher scores than the BSID-II and classified fewer children as severely impaired. The systematic bias towards higher scores with the Bayley-III precludes valid comparisons between early and contemporary cardiac surgery cohorts.
Background Optimal timing for total repair in tetralogy of Fallot (TOF) is controversial. We aimed to determine if weight at 1 year differs between patients who undergo neonatal total repair versus ...those who undergo nonneonatal total repair later in the first year of life. Methods A retrospective review of infants admitted with TOF between January 2004 and June 2011 was conducted. Patient data, including weight, were collected throughout the first year of life, and neonatal total repair versus nonneonatal total repair groups were compared. Results Of 163 infants, neonatal total repair was undertaken in 36 (22%) of them, whereas 127 (78%) infants had nonneonatal total repair at greater than 28 days of life. The median neonatal intensive care unit length of stay (LOS) was longer for the neonatal total repair group than for the nonneonatal total repair group (17.5 11–24 versus 7 0–15 days; p < 0.001). Patients in the neonatal total repair group were more likely to have a transannular patch (TAP) ( p < 0.001) than were those in the nonneonatal total repair group, whereas patients in the nonneonatal total repair group were more likely to have undergone a valve-sparing operation ( p = 0.002). The mean weight-for-age z score was 0.7 higher in the neonatal total repair group compared with the nonneonatal total repair group ( p = 0.03) controlling for birth weight (BW), diagnostic subgroup, and gestational age (GA). Conclusions Patients with TOF who underwent neonatal total repair were more likely to receive a TAP but had higher weight-for-age scores at 1 year compared with patients who underwent full repair later in the first year of life.
Abstract Background Exposure to antenatal stressors affects autonomic regulation in fetuses. Whether the presence of congenital heart disease (CHD) alters the developmental trajectory of autonomic ...regulation is not known. Aims/Study Design This prospective observational cohort study aimed to further characterize autonomic regulation in fetuses with CHD; specifically hypoplastic left heart syndrome (HLHS), transposition of the great arteries (TGA), and tetralogy of Fallot (TOF). Subjects From 11/2010 to 11/2012, 92 fetuses were enrolled: 41 controls and 51 with CHD consisting of 19 with HLHS, 12 with TGA, and 20 with TOF. Maternal abdominal fetal electrocardiogram (ECG) recordings were obtained at 3 gestational ages: 19–27 weeks (F1), 28–33 weeks (F2), and 34–38 weeks (F3). Outcome measures Fetal ECG was analyzed for mean heart rate along with 3 measures of autonomic variability of the fetal heart rate: interquartile range, standard deviation, and root mean square of the standard deviation of the heart rate (RMSSD), a measure of parasympathetic activity. Results During F1 and F2 periods, HLHS fetuses demonstrated significantly lower mean HR than controls ( p < 0.05). Heart rate variability at F3, as measured by standard deviation, interquartile range, and RMSSD was lower in HLHS than controls ( p < 0.05). Other CHD subgroups showed a similar, though non-significant trend towards lower variability. Conclusions Autonomic regulation in CHD fetuses differs from controls, with HLHS fetuses most markedly affected.
Background
This study aimed to evaluate fetal echocardiographic measurements at the time of the first fetal echocardiogram as predictors of neonatal outcome for tetralogy of Fallot (TOF).
Methods
The ...study reviewed all infants with a prenatal diagnosis of TOF from January 2004 to June 2011. Aortic valve (AoV), pulmonary valve (PV), main pulmonary artery (MPA), left and right pulmonary artery diameters, and ductus arteriosus flow were evaluated on fetal echocardiograms, and associations between the fetal echocardiogram and the neonatal echocardiogram measurements and outcomes were assessed.
Results
The study identified 67 TOF patients who had an initial fetal echocardiogram at a mean gestational age of 25.0 ± 5.2 weeks. Patients with absent PV syndrome or major aortopulmonary collaterals were excluded from the study, as were those without anterograde pulmonary blood flow at the first fetal echocardiogram. Of the remaining 44 patients, 10 were ductal dependent and required neonatal surgery. Infants who were ductal dependent had lower fetal PV (−5.38 ± 2.95 vs. −3.51 ± 1.66;
p
< 0.05) and MPA (−3.94 ± 1.66 vs. −2.87 ± 1.04;
p
< 0.05)
z
-scores. A fetal PV
z
-score of −5 predicted ductal dependence with 78 % sensitivity and 87 % specificity, and a PV
z
-score of −3 showed 100 % sensitivity and 34 % specificity (
p
< 0.001). Fetuses with a reversed left-to-right flow across the ductus arteriosus (DA) were more likely to be ductal dependent (odds ratio, 25;
p
< 0.001) than those who had normal ductal flow.
Conclusions
In TOF, fetal PV and MPA
z
-scores and direction of the DA blood flow predict neonatal ductal dependence. Patients with fetal PV
z
-scores lower than −3 or any left-to-right flow at the level of the DA should be admitted to a center where prostaglandin is available.
To assess foetal electrocardiographic intervals across gestational age among foetuses with and without congenital heart disease, and to investigate differences between groups.
A prospective ...observational cohort study.
Center for Prenatal Pediatrics, Morgan Stanley Children's Hospital of New York-Presbyterian. Population or sample A total of 92 participants with singleton pregnancies, 41 with normal anatomy and 51 with congenital heart disease were included in this study.
Using a maternal abdominal monitor, foetal electrocardiogram was obtained serially from foetuses with and without congenital heart disease at 20-24 weeks (F1), 28-32 weeks (F2), and 34-38 weeks (F3) of gestation. A signal-averaged waveform was calculated, and PR, QRS, and QT intervals were measured. Intervals from controls were compared with gestational age norms. Using Pearson's correlation coefficient, we analysed the relationship between gestational age and foetal electrocardiographic intervals. Intervals from control and congenital heart disease foetuses were compared by Student's t-test.
PR (r=0.333, p=0.02) and QRS (r=0.248, p=0.05) intervals correlated with gestational age only among controls. QRS intervals in foetuses with congenital heart disease were significantly longer than controls at F1 (63 ± 6 versus 52 ± 5 ms, p<0.001), F2 (61 ± 8 versus 56 ± 7 ms, p=0.02), and F3 (64 ± 10 versus 56 ± 9 ms, p=0.007).
PR and QRS intervals lengthen across gestational age among foetuses with normal cardiac anatomy but not in foetuses with congenital heart diseases. As early as 20 weeks of gestation, differences between foetuses with and without congenital heart disease are discernible, with congenital heart disease foetuses demonstrating longer QRS intervals compared with controls.
BACKGROUND:In the SVR trial (Single Ventricle Reconstruction), 1-year transplant-free survival was better for the Norwood procedure with right ventricle-to-pulmonary artery shunt (RVPAS) compared ...with a modified Blalock–Taussig shunt in patients with hypoplastic left heart and related syndromes. At 6 years, we compared transplant-free survival and other outcomes between the groups.
METHODS:Medical history was collected annually using medical record review, telephone interviews, and the death index. The cohort included 549 patients randomized and treated in the SVR trial.
RESULTS:Transplant-free survival for the RVPAS versus modified Blalock–Taussig shunt groups did not differ at 6 years (64% versus 59%, P=0.25) or with all available follow-up of 7.1±1.6 years (log-rank P=0.13). The RVPAS versus modified Blalock–Taussig shunt treatment effect had nonproportional hazards (P=0.009); the hazard ratio (HR) for death or transplant favored the RVPAS before stage II surgery (HR, 0.66; 95% confidence interval, 0.48–0.92). The effect of shunt type on death or transplant was not statistically significant between stage II to Fontan surgery (HR, 1.36; 95% confidence interval, 0.86–2.17; P=0.17) or after the Fontan procedure (HR, 0.76; 95% confidence interval, 0.33–1.74; P=0.52). By 6 years, patients with RVPAS had a higher incidence of catheter interventions (0.38 versus 0.23/patient-year, P<0.001), primarily because of more interventions between the stage II and Fontan procedures (HR, 1.72; 95% confidence interval, 1.00–3.03). Complications did not differ by shunt type; by 6 years, 1 in 5 patients had had a thrombotic event, and 1 in 6 had had seizures.
CONCLUSIONS:By 6 years, the hazards of death or transplant and catheter interventions were not different between the RVPAS versus modified Blalock–Taussig shunt groups. Children assigned to the RVPAS group had 5% higher transplant-free survival, but the difference did not reach statistical significance, and they required more catheter interventions. Both treatment groups have accrued important complications.
CLINICAL TRIAL REGISTRATION:URLhttps://www.clinicaltrials.gov. Unique identifierNCT00115934.
BACKGROUND—In the Single Ventricle Reconstruction (SVR) trial, 1-year transplantation-free survival was better for the Norwood procedure with right ventricle–to–pulmonary artery shunt (RVPAS) ...compared with a modified Blalock-Taussig shunt (MBTS). At 3 years, we compared transplantation-free survival, echocardiographic right ventricular ejection fraction, and unplanned interventions in the treatment groups.
METHODS AND RESULTS—Vital status and medical history were ascertained from annual medical records, death indexes, and phone interviews. The cohort included 549 patients randomized and treated in the SVR trial. Transplantation-free survival for the RVPAS versus MBTS groups did not differ at 3 years (67% versus 61%; P=0.15) or with all available follow-up of 4.8±1.1 years (log-rank P=0.14). Pre-Fontan right ventricular ejection fraction was lower in the RVPAS group than in the MBTS group (41.7±5.1% versus 44.7±6.0%; P=0.007), and right ventricular ejection fraction deteriorated in RVPAS (P=0.004) but not MBTS (P=0.40) subjects (pre-Fontan minus 14-month mean, −3.25±8.24% versus 0.99±8.80%; P=0.009). The RVPAS versus MBTS treatment effect had nonproportional hazards (P=0.004); the hazard ratio favored the RVPAS before 5 months (hazard ratio=0.63; 95% confidence interval, 0.45–0.88) but the MBTS beyond 1 year (hazard ratio=2.22; 95% confidence interval, 1.07–4.62). By 3 years, RVPAS subjects had a higher incidence of catheter interventions (P<0.001) with an increasing HR over time (P=0.005)<5 months, 1.14 (95% confidence interval, 0.81–1.60); from 5 months to 1 year, 1.94 (95% confidence interval, 1.02–3.69); and >1 year, 2.48 (95% confidence interval, 1.28–4.80).
CONCLUSIONS—By 3 years, the Norwood procedure with RVPAS compared with MBTS was no longer associated with superior transplantation-free survival. Moreover, RVPAS subjects had slightly worse right ventricular ejection fraction and underwent more catheter interventions with increasing hazard ratio over time.
CLINICAL TRIAL REGISTRATION—URLhttp://www.clinicaltrials.gov. Unique identifierNCT00115934.
Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo ...mutations. Here we compare the incidence of de novo mutations in 362 severe CHD cases and 264 controls by analysing exome sequencing of parent-offspring trios. CHD cases show a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging (premature termination, frameshift, splice site) mutations. Similar odds ratios are seen across the main classes of severe CHD. We find a marked excess of de novo mutations in genes involved in the production, removal or reading of histone 3 lysine 4 (H3K4) methylation, or ubiquitination of H2BK120, which is required for H3K4 methylation. There are also two de novo mutations in SMAD2, which regulates H3K27 methylation in the embryonic left-right organizer. The combination of both activating (H3K4 methylation) and inactivating (H3K27 methylation) chromatin marks characterizes 'poised' promoters and enhancers, which regulate expression of key developmental genes. These findings implicate de novo point mutations in several hundreds of genes that collectively contribute to approximately 10% of severe CHD.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives To describe neurodevelopmental outcomes in infants with single ventricle (SV) physiology and determine factors associated with worse outcomes. Study design Neurodevelopmental outcomes for ...infants with SV enrolled in a multicenter drug trial were assessed at 14 months of age using the Bayley Scales of Infant Development-II . Multivariable regression analysis was used to identify factors associated with worse outcomes. Results Neurodevelopmental testing was performed at 14 ± 1 months in 170/185 subjects in the trial. Hypoplastic left heart syndrome was present in 59% and 75% had undergone the Norwood operation. Mean Psychomotor Developmental Index (PDI) and mental developmental index (MDI) were 80 ± 18 and 96 ± 14, respectively, (normal 100 ± 15, P < .001 for each). Group-based trajectory analysis provided a 2-group model (“high” and “low”) for height z-score trajectory and brain type natriuretic peptide (BNP) trajectory. The predicted PDI scores were 15 points higher in the “high” height z-score trajectory compared with the “low” cluster ( P < .001). A higher number of serious adverse events during the trial was associated with lower PDI scores ( P = .02). The predicted MDI scores were 13-17 points lower in “low height trajectory-high BNP trajectory” group compared with the other 3 groups ( P < .001). MDI scores were also lower in subjects who required extracorporeal membrane oxygenation during the neonatal hospitalization ( P = .01) or supplemental oxygen at discharge ( P = .01). Conclusions Neurodevelopmental outcome at 14 months of age is impaired in infants with SV physiology. Low height trajectory and high BNP trajectory were associated with worse neurodevelopmental outcomes. Efforts to improve nutritional status alone may not improve neurodevelopmental outcomes.
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