Interatrial Communications: Prevalence and Subtypes in 12,385 Newborns-a Copenhagen Baby Heart Study.

The prevalence of interatrial communications in newborns, i.e., patent foramen ovale or atrial septal defect, was previously reported to be between 24 and 92%, but the area has been impeded by lack of a universal classification method. A recently published novel echocardiographic diagnostic algorithm for systematic classification of interatrial communications had inter-and intraobserver agreements superior to standard expert assessment. This study aimed to determine the prevalence of subtypes of interatrial communications on transthoracic echocardiography in newborns. Echocardiograms of newborns aged 0-30 days were prospectively collected in the population-based cohort study Copenhagen Baby Heart Study in 2017-2018 and analyzed according to the new diagnostic algorithm, classifying interatrial communications into three subtypes of patent foramen ovale and three subtypes of atrial septal defects. Echocardiograms from 15,801 newborns were analyzed; 3416 (21.6%) were excluded due to suboptimal image quality or severe structural heart disease (n = 3), leaving 12,385 newborns (aged 12 [interquartile range 8; 15] days, 48.2% female) included in the study. An interatrial communication was detected in 9766 (78.9%) newborns. According to the algorithm, 9029 (72.9%) had a patent foramen ovale, while 737 (6.0%) fulfilled criteria for an atrial septal defect, further divided into subtypes. An interatrial communication was seen on echocardiography in almost 80% of newborns aged 0-30 days. Patent foramen ovale was 12 times more frequent than atrial septal defects. The observed prevalence of atrial septal defects was higher than previously reported. Follow up studies could distinguish which interatrial communications require follow-up or intervention. ClinicalTrial.gov, NCT02753348, posted April 27, 2016, [ https://classic.clinicaltrials.gov/ct2/show/NCT02753348 ].

Left Ventricular Noncompaction in Childhood: Echocardiographic Follow-Up and Prevalence in First-Degree Relatives.

Background: Left ventricular noncompaction (LVNC) is characterized by excessive trabeculations of the left ventricular (LV) wall. Objectives: The authors aimed to examine changes in LV function and morphology in 2 to 4-year-old children with and without LVNC at birth and to describe the prevalence of LVNC in first-degree relatives. Methods: Echocardiograms in children with and without LVNC (matched 1:4) were performed at 2 to 4 years and in first-degree relatives. LVNC was blindly assessed and defined as a ratio of non-compact to compact myocardium of ≥2 in ≥1 LV segment. Trabeculations were expressed as a percentage of the number of segments with LVNC out of the total number of segments. Results: In total, 14 (median age 3 years, 71% male) of 16 children with LVNC at birth and 56 children without (median age 4 years, 71% male), 37 first-degree relatives of children with LVNC (median age 31 years, 46% male) and 146 first-degree relatives of children without (median age 33 years, 50% male) were included. In children with LVNC, trabeculation (8% vs 13%, P = 0.81) and LV ejection fraction (50% vs 49%, P = 0.91) were unchanged from birth to follow-up but LV ejection fraction was lower compared to children without LVNC (49% vs 60%, P < 0.001). In relatives of children with LVNC, 11 of 37 (30%) fulfilled LVNC criteria compared to no relatives to children without LVNC (P < 0.001). Conclusions: At 2 to 4 years, children with LVNC diagnosed at birth had reduced systolic function compared to children without but did not have progression of LV dysfunction or extent of trabeculations. In first-degree relatives to children with LVNC, 30% fulfilled criteria.

The Prevalence and Spontaneous Closure of Ventricular Septal Defects the First Year of Life.

INTRODUCTION: Ventricular septal defect (VSD) is one of the most common congenital heart defects. We aimed to determine the prevalence of VSD in a population-based cohort of newborns and assess the rate of spontaneous closure during the first 12 months of life. METHODS: The Copenhagen Baby Heart Study (CBHS) is a population-based cohort study, including more than 25,000 newborns born in the greater Copenhagen area. Newborns underwent echocardiography within 60 days of birth. Newborns with VSDs had echocardiographic follow-up after 3, 6, and 12 months. RESULTS: A total of 850 newborns (3.3% of 25.556) with a VSD were identified in the CBHS. Of these, 787 (92.6% [95% CI 90.1-94.2]) were muscular VSDs, 60 (7.0% [95% CI, 5.5-9.0]) were perimembranous, and 3 (0.4% [95% CI, 0.0-1.1]) were subarterial. After 1 year, 83.5% (607 of 727) of all VSDs had closed spontaneously, resulting in a decrease of prevalence from 3.3% at birth to 0.5% in 1-year old children. Muscular VSDs showed significantly higher rate of spontaneous closure compared with perimembranous VSDs (86.9% (582/670) vs. 46.9% (25/54), p < 0.001). Determinants associated with spontaneous closure were smaller size of the VSD (p < 0.001) and the absence of multiple VSDs (p < 0.0025). CONCLUSION: The prevalence of VSDs in unselected newborns was 3.3%. Almost 9/10 of all VSDs identified in newborns, close spontaneously during the first year of life, ultimately resulting in a prevalence of VSD in 1-year-old children of 0.5%. The identified factors associated with spontaneous closure were muscular type, small size, and absence of multiple VSDs.

The Impact of Maternal and Perinatal Factors on the Neonatal Electrocardiogram.

INTRODUCTION: Myocardial development is still transitioning by the time of birth making the cardiomyocyte vulnerable to maternal and perinatal factors. We aimed at investigating the impact of maternal and perinatal factors on the neonatal electrocardiogram. METHODS: In a prospective cohort study, neonates underwent cardiac evaluation with electrocardiograms and echocardiograms (age 0-30 days). Associations between medical and demographic data, pregnancy, and birth-related factors, and electrocardiographic parameters were assessed. RESULTS: A total of 15,928 singletons with normal echocardiograms were included (52% boys). Neonates were divided into groups by accumulated number of maternal/perinatal factors: 0, 1, 2, 3, 4, and ≥5, and between-group differences in electrocardiographic parameters were analysed. We observed an additive effect with a leftward shift of the QRS axis and QT prolongation (all p < 0.01). Comparing extreme groups (0 vs. ≥5 maternal/perinatal factors), we found a 4.3% more left-shifted QRS axis (117 vs. 112°, p < 0.001) and a 0.8% prolonged QTcFridericia (QTcF; 363 vs. 366 ms, p < 0.001); the effect on QTcF was most pronounced in neonates examined in the first week of life (360 vs. 368 ms, p < 0.0001). CONCLUSION: We observed a cumulative effect of maternal and perinatal factors on neonatal electrocardiographic parameters, including a more left-shifted QRS axis and increased QT duration, although the variation was within normal reference ranges. Our findings add to the knowledge on the neonatal cardiac transition and the cardiac effect of maternal/perinatal factors.

Electrocardiographic Characteristics in 438 Neonates with Atrial Septal Defects.

Arrhythmias and electrocardiographic (ECG) abnormalities are common among patients with atrial septal defects (ASDs). We studied a large cohort of neonates with ASDs to investigate whether ECG abnormalities are present at this early stage or develop later, secondary to hemodynamic changes. We analyzed the echocardiograms and ECGs from the Copenhagen Baby Heart Study, a population-based cohort study. We compared ECG characteristics of 438 neonates with secundum ASDs to 1314 matched controls. In subgroup analyses, we investigated whether electrocardiographic characteristics were associated with age at examination. Neonates with ASDs (median age, 11 days; males, 51%) had longer P-wave durations (58 vs. 56 ms, p < 0.001), PR intervals (100 vs. 96 ms, p < 0.001), and a more rightward-shifted QRS axis (116 vs. 114 degrees, p = 0.032) compared to controls (median age, 10 days; males, 51%). There were no differences between cases and controls in the P-wave area, amplitude, or axis. Subgroup analyses showed that the differences in P-wave duration and PR interval were present in neonates examined in the first week after birth. The difference in the QRS axis was not found in neonates examined this early but was found in neonates examined at age two to four weeks. In conclusion, ASDs are associated with ECG changes from the neonatal phase. The P-wave duration and PR interval are longer in neonates with ASDs when compared to controls as early as the first week after birth, indicating that these changes are not purely secondary, but that neonates with an ASD have altered cardiac electrical activity.ClinicalTrials.gov Identifier NCT02753348 (April 27, 2016).

The Neonatal QRS Complex and Its Association with Left Ventricular Mass.

To evaluate QRS complex features during the first month of life and the association with echocardiographic measurements of left ventricular mass in neonates. Prospective cohort study of neonates with electrocardiography (ECG) and echocardiography performed during the first month of life. Left ventricular mass index (LVMI) was determined by echocardiography and the correlation with electrocardiographic markers of LVMI outliers (≥ 98th percentile) were analyzed. We included 17,450 neonates (52% boys; median age at examination 11 days) and found an increase in median QRS duration and LVMI during the first month of life (54 vs. 56 ms and 24.7 vs. 28.6 g/m2 at days 0-4 and 25-30, respectively; both p < 0.001). All investigated ECG features (QRS duration, QRS area in V1/V6, maximum amplitudes of S-V1/R-V6, and the Sokolow-Lyon voltage product) showed no to low correlation with LVMI, resulting in low sensitivities (0-9.0%), but high specificities (97.2-98.1%), and area under the curve values close to the identity line (0.49-0.61) for identifying LVMI outliers. Adjustment of outlier definition for LVMI and threshold for QRS features had no significant effect on sensitivity. We present reference values for QRS complex features and their association with LVMI in neonates from a large, unselected, population-based cohort. The QRS complex gradually evolved during the first month of life but had a low correlation with LVMI. Our results indicate a poor diagnostic value of using ECG features to identify LVMI outliers in neonates.Trial Registry Copenhagen Baby Heart, NCT02753348, https://clinicaltri-als.gov/ct2/show/NCT02753348?cond=Copenhagen+Baby+Heart&draw=2&rank=1 , deidentified individual participant data will not be made available.

Impact of maternal age and body mass index on the structure and function of the heart in newborns: a Copenhagen Baby Heart Study.

BACKGROUND: Maternal obesity and advanced age have been associated with an increased risk of structural congenital heart defects in the offspring. Whether these factors may also cause abnormalities in infant cardiac dimension and function is unknown. This study investigates whether maternal body mass index (BMI) and maternal age are associated with changes in left ventricular (LV) dimensions and function in the newborn. METHODS: Infants enrolled in the Copenhagen Baby Heart Study (CBHS), who were born at term, and contributed with a transthoracic echocardiography (TTE) within 60 days of birth were included. The exposure variables were prepregnancy maternal BMI (kg/m2) < 18.5; 18.5-24.9 (reference); 25-29.9; 30-34.9 and ≥ 35 and maternal age (years) < 25; 25-29; 30-34 (reference); 35-39 and ≥ 40. Outcomes were LV parameters ascertained by 2D-echocardiography. Associations between each maternal factor and infant LV parameters were analysed with either a linear model adjusted for the child's weight and length at birth, gestational age, sex, age at TTE, and maternal smoking, or a linear mixed model, further adjusted for random effects of analyst and month of analysis. Analyses investigating impact of maternal BMI were adjusted for maternal age, and vice versa. RESULTS: The study cohort included 24,294 infants. Compared with infants in the BMI reference group, infants born to women with a BMI ≥ 25 kg/m2 generally had smaller measures of LV internal diameters in end-diastole, reaching statistical significance for BMI 30-34.9 kg/m2 [-0.11 ± 0.04 mm, p = 0.01]. All groups of infants born to women with a BMI ≥ 25 kg/m2 had significantly smaller LV internal diameters in end-systole: BMI 25-29.9 kg/m2 [-0.04 ± 0.02 mm, p = 0.04], BMI 30-34.9 kg/m2 [-0.12 ± 0.03 mm, p = 0.001] and BMI ≥ 35 kg/m2 [-0.11 ± 0.05 mm, p = 0.03]. Compared with infants in the age reference group, infants born to women ≥ 40 years had significantly smaller LV internal diameters in end-diastole [-0.15 ± 0.04 mm, p = 0.001] and end-systole [-0.09 ± 0.04 mm, p = 0.009]. CONCLUSIONS: Systematic population-based echocardiography of infants showed that a maternal prepregnancy BMI ≥ 25 kg/m2 and maternal age ≥ 40 years were associated with smaller systolic and diastolic LV diameters. The long-term effects are unknown. CLINICAL TRIAL REGISTRATION: April 2016, Copenhagen Baby Heart, NCT02753348 .

Electrocardiographic characteristics of newborns with ventricular septal defects: a Copenhagen Baby Heart Study.

Ventricular septal defects (VSD) represent the most common congenital heart defect in newborns. We assessed the electrocardiographic characteristics of newborns with VSDs in a general population sample. The Copenhagen Baby Heart Study is a prospective population-based cohort study offering cardiac evaluation of newborns. Echocardiograms and electrocardiograms were obtained within 30 days after birth and systematically analysed. A VSD was identified in 530 newborns (mean age 11 ± 7 days, 42% boys). Newborns with VSDs had a more left-shifted QRS axis (116 ± 34 vs. 120 ± 3°, p = 0.02), and a higher S-wave amplitude in V1 (721 ± 584 vs. 636 ± 549 µV, p = 0.001) than controls. The largest differences were found in newborns with large or perimembraneous VSDs with a higher frequency of left axis deviation, higher S-wave amplitudes in V1, and higher R- and S-wave amplitudes in V6 compared with controls. R-waves in V1 and V6 were significantly associated to left ventricular mass, whereas S-waves in V1 and V6 were dependent on left ventricular end-diastolic diameter on echocardiography.  Conclusion: Newborns with VSDs showed significant differences in QRS axis, and R- and S-wave precordial amplitudes compared to matched controls. Perimembranous and large VSDs had the greatest effect on the neonatal ECG. What is Known: • Ventricular septal defects in newborns are prevalent and may affect cardiac function and structure. What is New: • The Copenhagen Baby Heart Study is the largest study including a cohort of unselected newborns undergoing postnatal cardiac examination. • We found that newborns with VSD showed significant electrocardiographic differences depending on size and type of VSD compared with healthy newborns.

Significance of lipids, lipoproteins, and apolipoproteins during the first 14-16 months of life.

BACKGROUND AND AIMS: The aims of this study were to investigate lipid parameters during the first 14-16 months of life, to identify influential factors, and to test whether high concentrations at birth predict high concentrations at 2- and 14-16 months. METHODS: The Copenhagen Baby Heart Study, including 13,354 umbilical cord blood samples and parallel venous blood samples from children and parents at birth (n = 444), 2 months (n = 364), and 14-16 months (n = 168), was used. RESULTS: Concentrations of lipids, lipoproteins, and apolipoproteins in umbilical cord blood samples correlated highly with venous blood samples from newborns. Concentrations of low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein (HDL) cholesterol, apolipoprotein B, and lipoprotein(a) increased stepwise from birth to 2 months to 14-16 months. Linear mixed models showed that concentrations of LDL cholesterol, non-HDL cholesterol, and lipoprotein(a) above the 80th percentile at birth were associated with significantly higher concentrations at 2 and 14-16 months. Finally, lipid concentrations differed according to sex, gestational age, birth weight, breastfeeding, and parental lipid concentrations. CONCLUSIONS: Lipid parameters changed during the first 14-16 months of life, and sex, gestational age, birth weight, breastfeeding, and high parental concentrations influenced concentrations. Children with high concentrations of atherogenic lipid traits at birth had higher concentrations at 2 and 14-16 months. These findings increase our knowledge of how lipid traits develop over the first 14-16 months of life and may help in deciding the optimal child age for universal familial hypercholesterolaemia screening.

The Wolff-Parkinson-White pattern in neonates: results from a large population-based cohort study.

AIMS: Wolff-Parkinson-White (WPW) syndrome is a conduction disorder characterized by an accessory electrical pathway between the atria and ventricles, which may predispose to supraventricular tachycardia (SVT) and sudden cardiac death. It can be seen as an isolated finding or associated with structural heart disease. Our aims were to determine the prevalence of a WPW pattern in a large and unselected cohort of neonates and to describe the electro- and echocardiographic characteristics as well as the natural history during early childhood. METHODS AND RESULTS: Electrocardiograms and echocardiograms of neonates (aged 0-30 days) from a large, prospective, population-based cohort study were included. Neonates with a WPW pattern were identified and matched 1:4 to controls. Localization of the accessory pathway was assessed by different algorithms. Among 17 489 neonates, we identified 17 (76% boys) with a WPW pattern consistent with a prevalence of 0.1%. One neonate had moderate mitral regurgitation while other echocardiographic parameters were similar between cases and controls (all P > 0.05). The accessory pathways were primarily predicted to be left-sided. At follow-up (available in 14/17 children; mean age 3.2 years) the pre-excitation pattern persisted in only four of the children and none of the children had experienced any episodes of SVT. CONCLUSION: The prevalence of a WPW pattern in our cohort of unselected neonates was 0.1%. The WPW pattern was more frequent in boys and generally not associated with structural heart disease, and the accessory pathways were primarily left-sided. At follow-up, the WPW pattern had disappeared in most of the children suggesting either an intermittent nature or that normalization occurs. CLINICAL TRIAL REGISTRATION: Copenhagen Baby Heart, NCT02753348.

Age-Related Prevalence of Open Ductus Arteriosus in Full-Term Newborns.

BACKGROUND: The ductus arteriosus is part of the fetal circulation. Normally, the vessel closes during the cardiac transition. Delayed closure is associated with complications. The aim of this study was to evaluate the age-related prevalence of open ductus arteriosus in full-term neonates. METHODS: Echocardiograms were collected in the population study, the Copenhagen Baby Heart Study. The present study included full-term neonates with an echocardiogram performed within 28 days after birth. All echocardiograms were reviewed to assess ductus arteriosus patency. RESULTS: A total of 21,649 neonates were included. In neonates examined at day zero and day seven, an open ductus arteriosus was found in 36% and 0.6%, respectively. Beyond day seven, the prevalence remained stable at 0.6%. CONCLUSION: More than one-third of full-term neonates had an open ductus arteriosus on the first day of life, declining rapidly within the first week and stabilizing below 1% after day seven.

Atrial Septal Defect: Larger Right Ventricular Dimensions and Atrial Volumes as Early as in the First Month After Birth-a Case-Control Study Including 716 Neonates.

Atrial septal defect (ASD) is characterized by a left-to-right shunt causing dilatation of the right atrium and right ventricle as well as pulmonary hyperperfusion. The detection of ASDs often occurs late in childhood or adulthood. Little is known about cardiac structure and function in neonates with ASD.We analyzed neonatal echocardiograms from the Copenhagen Baby Heart Study, a multicenter, population-based cohort study of 27,595 neonates. We included 716 neonates with secundum-type ASDs and matched them 1:1 on sex and age at examination with neonates without ASD from the same birth cohort. Neonates with an ASD (median age 11 days, 52% female) had larger right ventricular (RV) dimensions than matched controls (RV longitudinal dimension end-diastole: 27.7 mm vs. 26.7 mm, p < 0.001; RV basal dimension end-diastole: 14.9 mm vs. 13.8 mm, p < 0.001; and RV outflow tract diameter 13.6 mm vs. 12.4 mm, p < 0.001). Atrial volumes were larger in neonates with ASD compared to controls (right atrial end-systolic volume: 2.9 ml vs. 2.1 ml, p < 0.001; and left atrial end-systolic volume 2.0 ml vs. 1.8 ml, p < 0.001). Tricuspid annular plane systolic excursion was larger in neonates with ASD than in controls (10.2 mm vs. 9.6 mm, p < 0.001). Left ventricular dimensions and function did not differ between neonates with ASD and controls. In conclusion, ASDs were associated with altered cardiac dimensions already in the neonatal period, with larger right ventricular dimensions and larger atrial volumes at echocardiography within the first 30 days after birth.ClinicalTrials.gov Identifier: NCT02753348 (April 27, 2016).

Normative Echocardiographic Left Ventricular Parameters and Reference Intervals in Infants.

BACKGROUND: In pediatric echocardiography, reference intervals are required to distinguish normal variation from pathology. Left ventricular (LV) parameters are particularly important predictors of clinical outcome. However, data from healthy newborns are limited, and current reference intervals provide an inadequate approximation of normal reference ranges. OBJECTIVES: Normative reference intervals and z-scores for 2-dimensional echocardiographic measurements of LV structure and function based on a large group of healthy newborns were developed. METHODS: The study population included 13,454 healthy newborns from the Copenhagen Baby Heart Study who were born at term to healthy mothers, had an echocardiogram performed within 30 days of birth, and did not have congenital heart disease. To develop normative reference intervals, this study modeled 10 LV parameters as a function of body surface area through joint modeling of 4 statistical components. RESULTS: Infants in the study population (48.5% were female) had a median body surface area of 0.23 m2 (IQR: 0.22-0.25 m2) and median age of 12.0 days (IQR: 8.0-15.0 days) at examination. All normative reference intervals performed well in both sexes without stratification on infant sex. In contrast, creation of separate reference models for infants examined at <7 days of age and those examined at 7-30 days of age was necessary to optimize the performance of the reference intervals. CONCLUSIONS: This study provides normative reference intervals and z-scores for 10 clinical, widely used echocardiographic measures of LV structure and function based on a large cohort of newborns. These results provide highly needed reference material for clinical application by pediatric cardiologists.

Red blood cell parameters in early childhood: a prospective cohort study.

OBJECTIVES: Red blood cell parameters are frequently used biomarkers when assessing clinical status in newborns and in early childhood. Cell counts, amounts, and concentrations of these parameters change through gestation and after birth. Robust age-specific reference intervals are needed to optimize clinical decision making. METHODS: The Copenhagen Baby Heart Study (CBHS) and the COMPARE study are prospective cohort studies including red blood cell parameters from 7,938 umbilical cord blood samples and 295 parallel venous blood samples from newborns with follow-up at two and at 14-16 months after birth. RESULTS: For venous blood at birth, reference intervals for hemoglobin, erythrocytes, and hematocrit were 145-224 g/L, 4.1-6.4 × 1012/L, and 0.44-0.64, respectively. Hemoglobin, erythrocytes, and hematocrit were lower at birth in children delivered by prelabor cesarean section compared to vaginal delivery. Conversion algorithms based on term newborns were: venous hemoglobin=(umbilical cord hemoglobin-86.4)/0.39; venous erythrocytes=(umbilical cord erythrocytes-2.20)/0.44; and venous hematocrit=(umbilical cord hematocrit-0.24)/0.45. CONCLUSIONS: This study presents new reference intervals for red blood cell parameters in early childhood, describes the impact of delivery mode, and provide exact functions for converting umbilical cord to venous blood measurements for term newborns. These findings may improve clinical decision making within neonatology and infancy and enhance our clinical understanding of red blood cell parameters for health and diseases in early life.

Cardiac findings in newborn twins.

AIMS: To evaluate cardiac findings in newborn twins from the general population and investigate if newborn twins may require systematic evaluation of cardiac parameters. METHODS: Prospective cohort study of newborns with cardiac evaluation performed during the first month of life. Cardiac findings were compared 1:3 with matched singletons. RESULTS: We included 412 newborn twins (16% monochorionic; 50% boys) and 1236 singletons. Comparing cardiac findings showed twins had an increased prevalence of non-severe structural heart disease (most common: ventricular septal defects in both groups), thinner left ventricular posterior wall in diastole (LVPWd; 1.82 vs. 1.87 mm, p = 0.02), smaller diameter of the left atrium (10.6 vs. 11.1 mm, p = 0.04), higher heart rate (148 vs. 144 bpm, p = 0.04), more left-shifted QRS axis (106 vs. 111°, p < 0.001), and lower maximum R-wave amplitude in V1 (927 vs. 1015 µV, p = 0.02) compared to singletons. After multifactorial adjustment for potential confounders, the effect of twinning on cardiac parameters persisted only for LVPWd (p < 0.05). CONCLUSION: Despite contemporary surveillance, we found an increased prevalence of non-severe structural heart disease in a population-based cohort of newborn twins. However, the effect of twinning on cardiac parameters was modest and generally did not persist after correction for likely confounding factors.

A novel algorithm for classification of interatrial communications within the oval fossa in the newborn.

BACKGROUND: An interatrial communication is present in most neonates. The majority are considered the "normal" patency of the oval foramen, while a minority are abnormal atrial septal defects. Differentiation between the two with transthoracic echocardiography may be challenging, and no generally accepted method of classification is presently available. We aimed to develop and determine the reliability of a new classification of interatrial communications in newborns. METHODS AND RESULTS: An algorithm was developed based on echocardiographic criteria from 495 newborns (median age 11[8;13] days, 51.5% females). The algorithm defines three main categories: patency of the oval foramen, atrial septal defect, and no interatrial communication as well as several subtypes. We found an interatrial communication in 414 (83.6%) newborns. Of these, 386 (93.2%) were categorised as patency of the oval foramen and 28 (6.8%) as atrial septal defects.Echocardiograms from another 50 newborns (median age 11[8;13] days, 36.0% female), reviewed by eight experts in paediatric echocardiography, were used to assess the inter- and intraobserver variation of classification of interatrial communications into patency of the oval foramen and atrial septal defect, with and without the use of the algorithm. Review with the algorithm gave a substantial interobserver agreement (kappa = 0.66), and an almost perfect intraobserver agreement (kappa = 0.82). Without the use of the algorithm, the interobserver agreement between experienced paediatric cardiologists was low (kappa = 0.20). CONCLUSION: A new algorithm for echocardiographic classification of interatrial communications in newborns produced almost perfect intraobserver and substantial interobserver agreement. The algorithm may prove useful in both research and clinical practice.

Markers of Kidney Function in Early Childhood and Association With Maternal Comorbidity.

Importance: Kidney functional capacity is low at birth but doubles during the first 2 weeks of life and reaches near-adult levels at age 1 to 2 years. Existing reference intervals for markers of kidney function in newborns are mostly based on preterm newborns, newborns with illness, or small cohorts of term newborns, and the consequences of maternal comorbidities for newborn kidney function are sparsely described. Objective: To establish robust reference intervals for creatinine and urea in healthy children in early childhood and to assess whether maternal comorbidity is associated with newborn creatinine and urea concentrations. Design, Setting, and Participants: This multicenter, prospective, population-based cohort study assessed data and umbilical cord blood samples from participants in the Copenhagen Baby Heart Study (CBHS) who were born between April 1, 2016, and October 31, 2018, and venous blood samples from a subsample of CBHS participants who were enrolled in the COMPARE study between May 3, 2017, and November 4, 2018. Cord blood samples of 13 354 newborns from the CBHS and corresponding venous blood samples of 444 of those newborns from the COMPARE study were included. Blood samples were collected at birth, age 2 months, and age 14 to 16 months, with follow-up completed on February 12, 2020. Healthy nonadmitted term newborns from maternity wards at 3 hospitals in the Capital Region of Denmark were included. Exposures: Maternal comorbidity. Main Outcomes and Measures: Creatinine and urea concentrations. Results: Among 13 354 newborns in the CBHS cohort, characteristics of 12 938 children were stratified by sex and gestational age (GA). Of those, 6567 children (50.8%) were male; 5259 children (40.6%) were born at 37 to 39 weeks' GA, and 7679 children (59.4%) were born at 40 to 42 weeks' GA. Compared with children born at 40 to 42 weeks' GA, those born at 37 to 39 weeks' GA had lower birth weight, Apgar scores at 5 minutes, placental weight, and placental-fetal weight ratio. Children born at 37 to 39 weeks' GA vs those born at 40 to 42 weeks' GA were more frequently small for GA at birth and more likely to have placental insufficiency and exposure to maternal preeclampsia, maternal diabetes, maternal kidney disease, and maternal hypertension. Among children born at 37 to 39 weeks' GA, reference intervals were 0.54 to 1.08 mg/dL for creatinine and 5.32 to 14.67 mg/dL for urea; among children born at 40 to 42 weeks' GA, reference intervals were 0.57 to 1.19 mg/dL for creatinine and 5.60 to 14.85 mg/dL for urea. At birth, multifactorially adjusted odds ratios among children exposed to preeclampsia were 9.40 (95% CI, 1.68-52.54) for a venous creatinine concentration higher than the upper reference limit, 4.29 (95% CI, 1.32-13.93) for a venous creatinine concentration higher than the 90th percentile, and 3.10 (95% CI, 1.14-8.46) for a venous creatinine concentration higher than the 80th percentile. Conclusions and Relevance: In this study, improved reference intervals for creatinine and urea concentrations were generated. Preeclampsia was associated with an increased risk of high newborn creatinine concentrations, suggesting that newborns of mothers with preeclampsia need closer observation of their kidney function.

Prevalence of Left Ventricular Noncompaction in Newborns.

BACKGROUND: Left ventricular noncompaction (LVNC) is characterized by excessive trabeculations of the LV and may be associated with reduced systolic function or severe adverse outcomes. Several aspects remain to be elucidated; there is controversy to whether LVNC cardiomyopathy is a distinct cardiomyopathy caused by failure of the spongy fetal myocardium to condense during fetal development or acquired later in life as a morphological trait associated with other types of cardiomyopathy; the prevalence in unselected populations is unknown and the distinction between normal variation and pathology remains to be defined. In this study, we aimed to determine the prevalence of LVNC and the association to LV systolic function in a large, population-based cohort of neonates. In addition, we assessed the normal ratio of noncompact to compact (NC:C) myocardium in 150 healthy neonates. METHODS: Echocardiographic data were prospectively collected in the population study Copenhagen Baby Heart Study. The ratio of NC:C was measured in 12 ventricular segments. LVNC was defined as NC:C ≥2 in at least one segment. Neonates with LVNC were matched 1:10 to controls on sex, gestational age, and weight and age at the examination day. RESULTS: In total, 25 590 neonates (52% males, median age 11 [interquartile range, 7-15] days) underwent echocardiography. Among 21 133 with satisfactory visualization of ventricular segments, we identified a prevalence of LVNC of 0.076% (95% CI, 0.047-0.123). LV ejection fraction was lower in neonates with LVNC compared with matched controls (median 49.5 versus 59.0%; P<0.0001). In neonates with otherwise healthy hearts, the median NC:C ratio ranged from 0.0 to 0.7 and the 99th percentiles from 1.0 to 1.9 for each of the 12 segments. CONCLUSIONS: The prevalence of LVNC based on neonatal echocardiography was 0.076%. LVNC was associated with lower LV systolic function. The findings in normal newborns support the cutoff NC:C ≥2 as an appropriate diagnostic criterion. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02753348.

Maternal Hypertensive Disorders of Pregnancy and Cardiac Structure and Function in the Newborn.

Background: Maternal hypertensive disorders of pregnancy (HDPs) are strongly associated with offspring congenital heart defects. Objectives: This study assessed whether infants exposed to maternal HDPs were also more likely to have subtle cardiac structural and functional abnormalities than unexposed infants. Methods: We used regression analyses to compare: 1) left ventricular parameters from conventional echocardiography performed in infants from the Copenhagen Baby Heart Study born to mothers with preeclampsia, gestational hypertension (GH), or no HDP; and 2) advanced echocardiographic parameters for 545 term infants born to mothers with preeclampsia and 545 matched infants not exposed to HDPs. Results: Compared with infants unexposed to HDPs (n = 17,384), infants exposed to preeclampsia (n = 754) had a thicker interventricular septum in end-diastole (adjusted mean difference [± SD] 0.05 [±0.02] mm; P = 0.004), thicker left ventricular posterior wall (0.04 [±0.02] mm; P = 0.009), larger left ventricular internal diameter (0.12 [±0.06] mm; P = 0.04), and larger left ventricular volume (0.21 [±0.10] mL; P = 0.03). Systolic function changes included increased fractional shortening (0.36% [±0.14%]; P = 0.01) and stroke volume (0.18 [±0.07] mL; P = 0.006), whereas diastolic function changes included lower transmitral early peak inflow velocity (-1.76 [±0.49] mL; P = 0.0003), lower mitral annulus lateral wall a' (-0.21 [±0.09] cm/s; P = 0.02), and smaller lateral E/e' (-1.06 [±0.38] cm/s; P = 0.005). Conversely, there was little evidence of any association between maternal GH (n = 469) and offspring left ventricular parameters. Conclusions: Maternal preeclampsia, but not GH, was associated with subtle newborn cardiac morphological and functional alterations, including thickening of the left ventricular myocardium and altered systolic and diastolic function.