Early Detection of Isolated Severe Congenital Heart Defects Is Associated with a Lower Threshold to Terminate the Pregnancy.

INTRODUCTION: Early detection of isolated severe congenital heart defects (CHDs) allows extra time for chromosomal analysis and informed decision making, resulting in improved perinatal management and patient satisfaction. Therefore, the aim of this study was to assess the value of an additional first-trimester screening scan compared to only a second-trimester scan in fetuses diagnosed with isolated severe CHDs. Prenatal detection rate, time of prenatal diagnosis, and pregnancy outcome were evaluated in the Netherlands after implementation of a national screening program. MATERIALS AND METHODS: We performed a retrospective geographical cohort study and included 264 pre- and postnatally diagnosed isolated severe CHD cases between January 1, 2007, and December 31, 2015, in the Amsterdam region. Severe CHD was defined as potentially life threatening if intervention within the first year of life was required. Two groups were defined: those with a first- and second-trimester anomaly scan (group 1) and those with a second-trimester anomaly scan only (group 2). A first-trimester scan was defined as a scan between 11 + 0 and 13 + 6 weeks of gestation. RESULTS: Overall, the prenatal detection rate for isolated severe CHDs was 65%; 63% were detected before 24 weeks of gestation (97% of all prenatally detected CHDs). Prenatal detection rate was 70.2% in the group with a first- and second-trimester scan (group 1) and 58% in the group with a second-trimester scan only (group 2) (p < 0.05). Median gestational age at detection was 19 + 6 (interquartile range [IQR] 15 + 4 - 20 + 5) in group 1 versus 20 + 3 (IQR: 20 + 0 - 21 + 1) in group 2 (p < 0.001). In group 1, 22% were diagnosed before 18 weeks of gestation. Termination of pregnancy rate in group 1 and group 2 were 48% and 27%, respectively (p < 0.01). Median gestational age at termination did not differ between the two groups. CONCLUSION: Prenatal detection rate of isolated severe CHDs and termination of pregnancy rate was higher in the group with both a first- and second-trimester scan. We found no differences between timing of terminations. The additional time after diagnosis allows for additional genetic testing and optimal counseling of expectant parents regarding prognosis and perinatal management, so that well-informed decisions can be made.

Factors related to fetal demise in cases with congenital heart defects.

BACKGROUND: Congenital heart defects are the most common congenital anomaly. Despite the increasing survival of these children, there is still an increased incidence of fetal demise, frequently attributed to cardiac failure. Considering that abnormal placental development has been described in congenital heart disease, our hypothesis is that placental insufficiency may contribute to fetal death in congenital heart disease. OBJECTIVE: This study aimed to assess cases with fetal congenital heart disease and intrauterine demise, and analyze factors that are related to the demise. STUDY DESIGN: All congenital heart disease cases diagnosed prenatally during the period January 2002 to January 2021 were selected from the regional prospective congenital heart disease registry, PRECOR. Multiple pregnancies and pregnancies with fetal trisomy 13 or 18, triploidy, and Turner's syndrome were excluded from the analysis, because fetal demise is attributed to the chromosomal abnormality in these cases. Cases were categorized into 4 groups based on the possible cause of fetal death as follows: cardiac failure, additional (genetic) diagnosis, placental insufficiency, and a group in which no cause was found. A separate analysis was performed for isolated congenital heart disease cases. RESULTS: Of the 4806 cases in the PRECOR registry, 112 had fetal demise, of which 43 were excluded from the analysis (13 multiple pregnancies, 30 genetic). Of these, 47.8% were most likely related to cardiac failure, 42.0% to another (genetic) diagnosis, and 10.1% to placental insufficiency. No cases were allocated to the group with an unknown cause. Only 47.8% of the cases had isolated congenital heart disease, and in this group 21.2% was most likely related to placental insufficiency. CONCLUSION: This study shows that in addition to cardiac failure and other (genetic) diagnoses, placental factors play an important role in fetal demise in congenital heart disease, especially in cases of isolated heart defects. Therefore, these findings support the importance of regular ultrasonographic assessment of fetal growth and placental function in fetal congenital heart disease.

Short-term outcome after the prenatal diagnosis of right aortic arch.

OBJECTIVES: To determine the proportion of children that require surgery in the first year of life and thereafter in order to improve the counseling of parents with a fetus with a right aortic arch (RAA). METHODS: Fetuses diagnosed with isolated RAA, defined as the absence of intra- or extracardiac anomalies, between 2007 and 2021 were extracted from the prospective registry PRECOR. RESULTS: In total, 110 fetuses were included, 92 with a prenatal diagnosis of RAA and 18 with double aortic arch (DAA). The prevalence of 22q11 deletion syndrome was 5.5%. Six pregnancies were terminated and five cases were false-positive; therefore, the follow-up consisted of 99 neonates. Surgery was performed in 10 infants (10%) in the first year of life. In total, 25 (25%) children had surgery at a mean age of 17 months. Eight of these 25 (32%) had a DAA. Only one child, with a DAA, required surgery in the first week of life due to obstructive stridor. CONCLUSIONS: Children with a prenatally diagnosed RAA are at a low risk of acute respiratory postnatal problems. Delivery in a hospital with neonatal intensive care and pediatric cardiothoracic facilities seems only indicated in cases with suspected DAA. Expectant parents should be informed that presently 25% of the children need elective surgery and only incidentally due to acute respiratory distress.

Serial neurosonography in fetuses with congenital heart defects shows mild delays in cortical development.

INTRODUCTION: Neurodevelopmental delay is more common in children born with congenital heart defects (CHD), even with optimal perinatal and peri-operative care. It is hypothesized that fetuses with CHD are prone to neurological impairment in utero due to their cardiac defect, possibly leading to delayed cortical development. METHODS: Cerebral cortical maturation was assessed with advanced neurosonographic examinations every 4 weeks in fetuses with CHD and compared to control fetuses. Five different primary fissures and four areas were scored (ranging 0-5) by blinded examiners using a cortical maturation scheme. RESULTS: Cortical staging was assessed in 574 ultrasound examinations in 85 CHD fetuses and 61 controls. Small differences in grading were seen in Sylvian and cingulate fissures. (Sylvian fissure: -0.12 grade, 95% CI (-0.23; -0.01) p = 0.05, cingulate fissure: -0.24 grade, 95% CI (-0.38; -0.10) p = <0.001. Other cortical areas showed normal maturation as compared to control fetuses. CONCLUSION: Small differences were seen in three of the nine analyzed cortical areas in CHD fetuses, in contrast to previous reports on progressive third-trimester delay. The clinical implications of the small differences however, remain unknown.

The association between flow and oxygenation and cortical development in fetuses with congenital heart defects using a brain-age prediction algorithm.

OBJECTIVES: Presumably, changes in fetal circulation contribute to the delay in maturation of the cortex in fetuses with congenital heart defect (CHD). The aim of the current study is to analyze fetal brain development based on hemodynamic differences, using novel brain-age prediction software. METHODS: We have performed detailed neurosonography, including acquiring 3D volumes, prospectively in cases with isolated CHD from 20 weeks onwards. An algorithm that assesses the degree of fetal brain-age automatically was used to compare CHD cases to controls. We stratified CHD cases according to flow and oxygenation profiles by lesion physiology and performed subgroup analyses. RESULTS: A total of 616 ultrasound volumes of 162 CHD cases and 75 controls were analyzed. Significant differences in maturation of the cortex were observed in cases with normal blood flow toward the brain (-3.8 days, 95%CI [-5.5; -2.0], P = <.001) and low (-4.0 days, 95% CI [-6.7; -1.2] P = <.05; hypoplastic left heart syndrome[HLHS]) and mixed (-4.4 days, 95%CI [-6.4; -2.5] p = <.001) oxygen saturation in the ascending aorta (TGA) and in cardiac mixing (eg, Fallot) cases. CONCLUSION: The current study shows significant delay in brain-age in TGA and Fallot cases as compared to control cases. However, the small differences found in this study questions the clinical relevance.

Rhinovirus Detection in the Nasopharynx of Children Undergoing Cardiac Surgery Is Not Associated With Longer PICU Length of Stay: Results of the Impact of Rhinovirus Infection After Cardiac Surgery in Kids (RISK) Study.

OBJECTIVES: To determine whether children with asymptomatic carriage of rhinovirus in the nasopharynx before elective cardiac surgery have an increased risk of prolonged PICU length of stay. STUDY DESIGN: Prospective, single-center, blinded observational cohort study. SETTING: PICU in a tertiary hospital in The Netherlands. PATIENTS: Children under 12 years old undergoing elective cardiac surgery were enrolled in the study after informed consent of the parents/guardians. INTERVENTIONS: The parents/guardians filled out a questionnaire regarding respiratory symptoms. On the day of the operation, a nasopharyngeal swab was obtained. Clinical data were collected during PICU admission, and PICU/hospital length of stay were reported. If a patient was still intubated 3 days after operation, an additional nasopharyngeal swab was collected. Nasopharyngeal swabs were tested for rhinovirus and other respiratory viruses with polymerase chain reaction. MEASUREMENTS AND MAIN RESULTS: Of the 163 included children, 74 (45%) tested rhinovirus positive. Rhinovirus-positive patients did not have a prolonged PICU length of stay (median 2 d each; p = 0.257). Rhinovirus-positive patients had a significantly shorter median hospital length of stay compared with rhinovirus-negative patients (8 vs 9 d, respectively; p = 0.006). Overall, 97 of the patients (60%) tested positive for one or more respiratory virus. Virus-positive patients had significantly shorter PICU and hospital length of stay, ventilatory support, and nonmechanical ventilation. Virus-negative patients had respiratory symptoms suspected for a respiratory infection more often. In 31% of the children, the parents reported mild upper respiratory complaints a day prior to the cardiac surgery, this was associated with postextubation stridor, but no other clinical outcome measures. CONCLUSIONS: Preoperative rhinovirus polymerase chain reaction positivity is not associated with prolonged PICU length of stay. Our findings do not support the use of routine polymerase chain reaction testing for respiratory viruses in asymptomatic children admitted for elective cardiac surgery.

The prevalence of genetic diagnoses in fetuses with severe congenital heart defects.

PURPOSE: Congenital heart defects (CHD) are associated with genetic syndromes. Rapid aneuploidy testing and chromosome microarray analysis (CMA) are standard care in fetal CHD. Many genetic syndromes remain undetected with these tests. This cohort study aims to estimate the frequency of causal genetic variants, in particular structural chromosome abnormalities and sequence variants, in fetuses with severe CHD at mid-gestation, to aid prenatal counselling. METHODS: Fetuses with severe CHD were extracted from the PRECOR registry (2012-2016). We evaluated pre- and postnatal genetic testing results retrospectively to estimate the frequency of genetic diagnoses in general, as well as for specific CHDs. RESULTS: 919 fetuses with severe CHD were identified. After exclusion of 211 cases with aneuploidy, a genetic diagnosis was found in 15.7% (111/708). These comprised copy number variants in 9.9% (70/708). In 4.5% (41/708) sequence variants were found that would have remained undetected with CMA. Interrupted aortic arch, pulmonary atresia with ventricular septal defect and atrioventricular septal defect were most commonly associated with a genetic diagnosis. CONCLUSION: In case of normal CMA results, parents should be offered exome sequencing sequentially, if time allows for it, especially if the CHD is accompanied by other structural malformations due to the large variety in genetic syndromes.

Cortical development in fetuses with congenital heart defects using an automated brain-age prediction algorithm.

INTRODUCTION: Congenital heart defects are associated with neurodevelopmental delay. It is hypothesized that fetuses affected by congenital heart defect have altered cerebral oxygen perfusion and are therefore prone to delay in cortical maturation. The aim of this study was to determine the difference in fetal brain age between consecutive congenital heart defect cases and controls in the second and third trimester using ultrasound. MATERIAL AND METHODS: Since 2014, we have included 90 isolated severe congenital heart defect cases in the Heart And Neurodevelopment (HAND)-study. Every 4 weeks, detailed neurosonography was performed in these fetuses, including the recording of a 3D volume of the fetal brain, from 20 weeks onwards. In all, 75 healthy fetuses underwent the same protocol to serve as a control group. The volumes were analyzed by automated age prediction software which determines gestational age by the assessment of cortical maturation. RESULTS: In total, 477 volumes were analyzed using the age prediction software (199 volumes of 90 congenital heart defect cases; 278 volumes of 75 controls). Of these, 16 (3.2%) volume recordings were excluded because of imaging quality. The age distribution was 19-33 weeks. Mixed model analysis showed that the age predicted by brain maturation was 3 days delayed compared with the control group (P = .002). CONCLUSIONS: This study shows that fetuses with isolated cases of congenital heart defects show some delay in cortical maturation as compared with healthy control cases. The clinical relevance of this small difference is debatable. This finding was consistent throughout pregnancy and did not progress during the third trimester.

The effect of the introduction of the three-vessel view on the detection rate of transposition of the great arteries and tetralogy of Fallot.

OBJECTIVES: The aim of this study was to analyze the annual detection rate (DR) of transposition of the great arteries (TGA) and tetrology of Fallot (ToF), after the introduction of the three-vessel view as a mandatory plane in 2012. METHODS: All registered TGA and ToF cases were retrospectively extracted from our registry between 2007 and 2016. We compared the DR in a 10-year period, before 2011, with the DR of TGA and ToF after 2012. RESULTS: In the period before 2012, 23 of the 52 TGA cases were prenatally detected (44.2%), compared with 42 of the 51 cases (82.4%) after 2012. For ToF, the DRs increased from 28 of 64 cases (43.8%) to 42 of 62 cases (67.7%) in the aforementioned periods. The increase in DRs for both defects was statistically significant (P ≤ 0.001 and P ≤ 0.05). CONCLUSIONS: In this nationally organized prenatal screening program with a quality monitoring system and a uniform protocol, DRs of 82.4% for TGA and 67.7% for ToF were reached after the introduction of the three-vessel view as a mandatory item. The three-vessel view significantly contributes to the detection of these conotruncal anomalies.

Paediatric Ebstein's anomaly: how clinical presentation predicts mortality.

BACKGROUND: Forecasting the prognosis of a child when diagnosed with Ebstein's anomaly is difficult. We, therefore, studied which factors at the time of diagnosis are associated with death during childhood. METHODS: All consecutive patients (0-18 years) diagnosed with Ebstein's anomaly in the Netherlands between 1980 and 2014 were included. Survival curves were obtained using the Kaplan-Meier method. By using the Cox proportional hazard model, we analysed the factors (at diagnosis) that were associated with death. RESULTS: We included 176 patients. Thirty-one patients (18%) died before the age of 18 years. The 1-year survival was 84% and remained stable at 82% from 35 months after diagnosis and onwards. Modified Ross Heart Failure Class 4 at the time of diagnosis was the most important risk factor for death during childhood (HR 12.5, 95% CI 4.4 to 35.9). Furthermore, diagnosis in the neonatal period (HR 4.2, 95% CI 1.5 to 12.0), severe tricuspid valve regurgitation (HR 2.4, 95% CI 1.2 to 5.0), severe right ventricular outflow tract obstruction (HR 3.7, 95% CI 1.8 to 7.7) and a patent ductus arteriosus (HR 2.8, 95% CI 1.3 to 6.0) at the time of diagnosis were univariately associated with death. Multivariable analysis showed that presentation with Heart Failure Class 4 and a ventricular septal defect is the strongest predictor of death in childhood and adolescence. CONCLUSION: Patients with Ebstein's anomaly presenting with Heart Failure Class 4 and a ventricular septal defect have a high risk of death during childhood.

Surgical outcome in pediatric patients with Ebstein's anomaly: A multicenter, long-term study.

OBJECTIVE: Surgical outcomes of pediatric patients with Ebstein's anomaly are often described as part of all-age-inclusive series. Our objective is to focus on patients treated surgically in childhood (0-18 y). We study the intended treatment (biventricular or 1.5 ventricle repair or univentricular palliation), freedom from unplanned reoperation and survival of this specific age group, in a nationwide study. DESIGN: Records of all Ebstein's anomaly patients born between 1980 and 2013 were reviewed. Demographic variables, intraoperative procedures and postoperative outcomes were analyzed. RESULTS: Sixty-three patients underwent 109 operations. Median follow-up after diagnosis was 121 months (range 0-216 months). Twenty-nine (46%) patients required surgery in the first year of life, including 21 who required neonatal surgery. The intended treatment was biventricular (n = 37, 59%) and 1.5 ventricle (n = 5, 8%) repair or univentricular (n = 21, 33%) palliation. The one-, five-, and 10-year freedom from unplanned reoperation was 89%, 79%, and 75% respectively. There were nine (14%) in hospital deaths (within 30 d after surgery). Causes of death were low cardiac output syndrome, cardiac failure, hypoxemia, pulmonary hypertension or an unknown cause. There were no late deaths. CONCLUSIONS: Surgery in childhood represents the worse spectrum of disease, biventricular repair is often not applied. Patients often face revision surgery. Mortality is limited to the immediate postsurgical period.

Perinatal management and long-term cardiac outcome in fetal arrhythmia.

BACKGROUND: cardiac arrhythmias are commonly observed in the fetus, however, may have major consequences for fetal development and post natal life. AIMS: to evaluate the perinatal management and cardiac outcome of fetuses with tachy- or bradyarrhythmia. STUDY DESIGN: perinatal management, outcome and long-term cardiac follow-up were evaluated retrospectively in consecutive fetuses with cardiac arrhythmias. RESULTS: forty-four fetuses were diagnosed: supraventricular tachycardia (SVT, n=28), atrial flutter (AF, n=7) and atrioventricular block (AVB, n=9). The overall incidence of cardiac anomalies was 18% mainly in the AVB group; hydrops was present in 34%. Direct or transplacental fetal anti-arrhythmic medication was given in 76%. Mortality was 6% in SVT/AF and 78% in the AVB group, respectively. AF resolved in all patients. In the SVT group, Wolff-Parkinson-White (WPW) syndrome was present in 21%, diagnosed at birth or later in life. After the age of one year about 90% of patients in the SVT group remained asymptomatic and free of drugs (median follow-up 76months). CONCLUSIONS: mortality rate is low in patients with fetal SVT and AF but high in patients with AVB. Related morbidity includes WPW-syndrome and congenital cardiac anomalies. Electrocardiographic screening is recommended in all fetal SVT cases before adolescence since WPW-syndrome may occur later in life.

Long-term neurodevelopmental outcome after fetal arrhythmia.

OBJECTIVE: The purpose of this study was to determine the long-term neurodevelopmental outcome in fetuses with severe tachy- or bradyarrhythmia. STUDY DESIGN: This was a follow-up study to assess the neurologic, mental, and psychomotor development in cases with fetal cardiac arrhythmia. RESULTS: A total of 44 fetuses were diagnosed with fetal tachy- or bradyarrhythmia: 28 fetuses had supraventricular tachycardia (SVT); 7 fetuses had atrial flutter (AF), and 9 fetuses had atrioventricular block (AVB). The mortality rate was low (6%; 2/35 fetuses) in the SVT and AF groups and high in the AVB group (78%; 7/9 fetuses). Six patients were lost to follow-up evaluation (14%). Neurodevelopmental outcome was normal in all survivors in the SVT and AF groups, except for 1 patient who experienced plexus brachialis injury because of shoulder dystocia. Two of the 3 survivors in the AVB group had severe developmental delay. CONCLUSION: The mortality rate and neurodevelopmental impairment in infants with SVT and AF are low, but the mortality rate in infants with AVB is elevated.

Cardiac arrhythmias associated with umbilical venous catheterisation in neonates.

Umbilical venous catheters (UVCs) are commonly used in the management of severely ill neonates. Several life-threatening complications have been described, including catheter-related infections, myocardial perforation, pericardial effusion and cardiac arrhythmias. This report describe two neonates with cardiac arrhythmias due to umbilical venous catheterisation. One neonate had a supraventricular tachycardia requiring treatment with intravenous adenosine administration. Another neonate had an atrial flutter and was managed successfully with synchronised cardioversion. The primary cause of cardiac arrhythmias after umbilical venous catheterisation is inappropriate position of the UVC within the heart and the first step to treat them should be to pull back or even remove the catheter. Cardiac arrhythmia is a rare but potentially severe complication of umbilical venous catheterisation in neonates.

Hb Oegstgeest [alpha104(G11)Cys-->Ser (alpha1)]. A new hemoglobin variant associated with a mild alpha-thalassemia phenotype.

A microcytic hypochromic anemic state was observed in an 8-year old Black female of Surinam origin during pre-operative Hb S [beta6(A3)Glu-->Val] screening. Her high zinc protoporphyrin (ZPP) level suggested a chronic iron depletion but, in contrast, the high red blood cell (RBC) count (5.85 x 10(12)/L) was indicative of a possible coexisting thalassemia. No abnormal hemoglobin (Hb) bands were present on high performance liquid chromatography (HPLC) or alkaline electrophoresis and the Hb A2 level was normal. Break point polymerase chain reaction (PCR) failed to reveal any of the common alpha-thalassemia (thal) mutations but selective DNA sequencing of both alpha-globin genes disclosed a TGC-->AGC transversion at codon 104 of the alpha1 gene. Cystine at codon 104 is involved in alpha/beta globin contact and has been described to be a critical amino acid of the alpha2 chain when substituted by a tyrosine (Hb Sallanches), inducing Hb H (beta4) disease in the homozygous state. Our heterozygous patient had a moderate anemia of 12.2 g/dL and a borderline haptoglobin suggesting some degree of hemolysis.

Midface hypoplasia, obesity, developmental delay and neonatal hypotonia in two brothers.

We describe two brothers born to consanguineous parents, who presented with hypotonia and hypoglycaemia in the neonatal period and later developed obesity and developmental delay. They had brachydactyly and similar facial features including a prominent forehead, low nasal bridge, midface hypoplasia, full lips, a small mouth, and small, low set ears with overfolded helices. Their sister had mild learning disabilities. No additional anomalies were found, and metabolic investigations including peroxisomal functions gave normal results. We suggest the patients have a hitherto unreported condition, with an autosomal or X-linked mode of inheritance.