Genetic architecture in neonatal intensive care unit patients with congenital heart defects: a retrospective study from the China Neonatal Genomes Project.

BACKGROUND: Congenital heart defects (CHDs) are the most common type of birth defects. The genetic aetiology of CHD is complex and incompletely understood. The overall distribution of genetic causes in patients with CHD from neonatal intensive care units (NICUs) needs to be studied. METHODS: CHD cases were extracted from the China Neonatal Genomes Project (2016-2021). Next-generation sequencing results and medical records were retrospectively evaluated to note the frequency of genetic diagnosis and the respective patient outcomes. RESULTS: In total, 1795 patients were included. The human phenotype ontology term of atrial septal defect, patent ductus arteriosus and ventricular septal defect account for a large portion of the CHD subtype. Co-occurring extracardiac anomalies were observed in 35.1% of patients. 269 of the cases received genetic diagnoses that could explain the phenotype of CHDs, including 172 copy number variations and 97 pathogenic variants. The detection rate of trio-whole-exome sequencing was higher than clinical exome sequencing (21.8% vs 14.5%, p<0.05). Further follow-up analysis showed the genetic diagnostic rate was higher in the deceased group than in the surviving group (29.0% vs 11.9%, p<0.05). CONCLUSION: This is the largest cohort study to explore the genetic spectrum of patients with CHD in the NICU in China. Our findings may benefit future work on improving genetic screening and counselling for NICU patients with CHD.

Genetic spectrums and clinical profiles of critically ill neonates with congenital auricular deformity in the China Neonatal Genomes Project.

Congenital auricular deformity (CAD) is a complex phenotype that may occur as a single malformation or part of a congenital syndrome. The genetic architecture and utility of next-generation sequencing (NGS) in a sizable cross-sectional study of critically ill neonates with CAD have not yet been systematically investigated. This cross-sectional study investigated the genetic spectrum in critically ill neonates with CADs. Critically ill neonates with CADs (n = 251) were enrolled between August 8, 2016 and October 1, 2022. All neonates underwent NGS. The outcomes were molecular diagnostic yield, spectrum of genetic events, and clinical findings. Genetic findings were obtained in 107 neonates (42.6%), of which 67.3% (72/107) had pathogenic/likely pathogenic/variants of uncertain significance (P/LP/VUS) gene variations and 32.7% (35/107) had P/LP/VUS copy number variations (CNVs). The diagnostic rates of clinical exome sequencing were similar to those of exome sequencing. The logistic regression model revealed that CAD neonates with craniofacial abnormalities (OR = 4.15, 95% CI 2.29-7.53) or cardiovascular malformation (OR = 2.09, 95% CI 1.14-3.84) are more likely to be attributed to genetic causes. Follow-up analysis revealed that, compared to those in the undiagnosed group, the number of neonates whose care was withdrawn or who died was higher in the genetically diagnosed group (P < 0.05). This study identified a high incidence of genetic causes in critically ill neonates with CADs, with a combination of single-nucleotide variations and CNVs among the genetic causes of CAD. These findings highlight potential of NGS in the genetic testing of critically ill neonates with CADs.

Diagnostic and clinical utility of next-generation sequencing in children born with multiple congenital anomalies in the China neonatal genomes project.

Multiple congenital anomalies (MCAs) at birth have emerged as an important cause of neonatal morbidity and mortality. This study aimed to investigate the genetic causes and characteristics of clinical outcomes in a large cohort of neonates with MCAs. Clinical exome sequencing/exome sequencing/genome sequencing were undertaken from December 1, 2016 to December 1, 2019 to detect single nucleotide variations (SNVs) and copy number variations (CNVs) simultaneously in individuals who met the inclusion criteria. A total of 588 neonates with MCAs were enrolled. One hundred sixty-one patients received diagnosis, with 71 CNVs and 90 SNVs detected, the overall diagnostic rate being 27.38%. Cardiovascular malformation was the most common anomaly (60%) and accounted for the top symptomatic proportion in both CNVs and SNVs. As the number of involved system increased from 2 to 3-4, and then to ≥5, the overall diagnostic rate increased gradually from 23.1% to 30.5%, and then to 52.2%, respectively. Patients who received genetic diagnoses were offered better clinical management or were referred to the specific disease clinic. In conclusion, this large cohort study demonstrates that both CNVs and SNVs contribute to the genetic causes of MCAs, and earlier genetic assertion may lead to better clinical management for patients.

Application of Full-Spectrum Rapid Clinical Genome Sequencing Improves Diagnostic Rate and Clinical Outcomes in Critically Ill Infants in the China Neonatal Genomes Project.

OBJECTIVES: To determine the diagnostic and clinical utility of trio-rapid genome sequencing in critically ill infants. DESIGN: In this prospective study, samples from critically ill infants were analyzed using both proband-only clinical exome sequencing and trio-rapid genome sequencing (proband and biological parents). The study occurred between April 2019 and December 2019. SETTING: Thirteen member hospitals of the China Neonatal Genomes Project spanning 10 provinces were involved. PARTICIPANTS: Critically ill infants (n = 202), from birth up until 13 months of life were enrolled based on eligibility criteria (e.g., CNS anomaly, complex congenital heart disease, evidence of metabolic disease, recurrent severe infection, suspected immune deficiency, and multiple malformations). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 202 participants, neuromuscular (45%), respiratory (22%), and immunologic/infectious (18%) were the most commonly observed phenotypes. The diagnostic yield of trio-rapid genome sequencing was higher than that of proband-only clinical exome sequencing (36.6% [95% CI, 30.1-43.7%] vs 20.3% [95% CI, 15.1-26.6%], respectively; p = 0.0004), and the average turnaround time for trio-rapid genome sequencing (median: 7 d) was faster than that of proband-only clinical exome sequencing (median: 20 d) (p < 2.2 × 10-16). The metagenomic analysis identified pathogenic or likely pathogenic microbes in six infants with symptoms of sepsis, and these results guided the antibiotic treatment strategy. Sixteen infants (21.6%) experienced a change in clinical management following trio-rapid genome sequencing diagnosis, and 24 infants (32.4%) were referred to a new subspecialist. CONCLUSIONS: Trio-rapid genome sequencing provided higher diagnostic yield in a shorter period of time in this cohort of critically ill infants compared with proband-only clinical exome sequencing. Precise and fast molecular diagnosis can alter medical management and positively impact patient outcomes.

[Follow-up observation of catch-up growth of preterm infants after discharge and risk factors for extrauterine growth retardation].

OBJECTIVE: To investigate the catch-up growth of preterm infants within a corrected age of 6 months and the risk factors for extrauterine growth retardation (EUGR). METHODS: A total of 321 preterm infants who were discharged after treatment in the neonatal intensive care unit and had regular follow-up documents with complete follow-up records were enrolled. According to the Prenatal Health Care Norms in 2015, these infants were divided into low-risk group with 69 infants and high-risk group with 252 infants. The Z-score method was used to evaluate body weight, body length, and head circumference, and the catch-up growth of the preterm infants within a corrected age of 6 months was analyzed. A multivariate logistic regression analysis was performed to identify the risk factors for EUGR at the corrected age of 6 months. RESULTS: The percentage of preterm infants with Z scores of body weight, body length, and head circumference of < -2 (not reach the standard for catch-up growth) in both groups decreased gradually with increasing corrected age. At the corrected age of 6 months, the percentages of preterm infants whose body weight, body length, and head circumference did not reach the standard for catch-up growth in the low-risk group were reduced to 1.4% (1/69), 2.9% (2/69), and 1.4% (1/69) respectively, while in the high-risk group, these percentages were reduced to 1.2% (3/252), 1.6% (4/252), and 3.6% (9/252) respectively. The high-risk group had a significantly higher incidence rate of EUGR at the corrected age of 6 months than the low-risk group (28.2% vs 15.9%, P=0.039). The multivariate logistic regression analysis showed that multiple birth (OR=2.68, P=0.010), low birth weight (<1 000 g: OR=14.84, P<0.001; 1 000-1 499 g: OR=2.85, P=0.005), and intrauterine growth retardation (IUGR) (OR=11.41, P<0.001) were risk factors for EUGR at the corrected age of 6 months, while nutritional enhancement after birth (OR=0.25, P<0.001) reduced the risk of EUGR. CONCLUSIONS: Most preterm infants can achieve catch-up growth at the corrected age of 6 months. High-risk preterm infants have a high incidence rate of EUGR at the corrected age of 6 months. Multiple birth, low birth weight, and IUGR are risk factors for EUGR, while rational nutritional enhancement after birth can reduce the incidence rate of EUGR in preterm infants.

[Application of humidified high-flow nasal cannula in neonates with meconium aspiration syndrome and pulmonary hypertension after extubation].

OBJECTIVE: To investigate the clinical value of humidified high-flow nasal cannula (HHFNC) as a respiratory support after extubation by comparing it with nasal continuous positive airway pressure (NCPAP) in neonates with meconium aspiration syndrome (MAS) and persistent pulmonary hypertension of the newborn (PPHN). METHODS: A total of 78 neonates with MAS and PPHN were randomly administered with HHFNC or NCPAP immediately after extubation. The following indices were compared between the two groups: blood gas parameters, duration of noninvasive ventilation, rate of extubation failure, and incidence of complications, such as nasal damage, abdominal distension, and intraventricular hemorrhage. RESULTS: There were no significant differences in the rate of extubation failure, PaO2, PCO2, and PaO2/FiO2 ratio at one hour after NCPAP or HHFNC, duration of noninvasive ventilation, time to full enteral feeding, length of hospital stay, and incidence of intraventricular hemorrhage between the two groups (P>0.05). The HHFNC group had significantly lower incidence of nasal damage (5.0% vs 31.6%; P<0.05) and incidence of abdominal distension (7.5% vs 34.2%; P<0.05) than the NCPAP group. CONCLUSIONS: Both NCPAP and HHFNC can be used as the sequential therapy for neonates with MSA and PPHN after extubation, and they both have a definite effect. As a new strategy of respiratory support, HHFNC is better tolerated, and has fewer side effects than NCPAP.

[Influencing factors for severity of bronchopulmonary dysplasia in preterm infants].

OBJECTIVE: To explore the influencing factors for the severity of bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: The clinical data of 110 preterm infants who were diagnosed with BPD and had a hospital stay of over 28 days between January 2011 and December 2013 were analyzed. These BPD infants were divided into 3 groups according to the clinical criteria: mild group (n=52), moderate group (n=44), and severe group (n=14). The relationship between the severity of BPD and the gestational age, birth weight, asphyxia, oxygen therapy, pregnancy complications, intrauterine pneumonia and mechanical ventilation was analyzed. RESULTS: The severity of BPD was correlated with the following factors: gestational age, birth weight, prenatal infection, duration of oxygen inhalation with a concentration of >40%, use of mechanical ventilation, parameters and duration of mechanical ventilation, duration of continuous positive airway pressure, adoption of intubation surfactant extubation (INSURE) approach, Ureaplasma urealyticum infection, intrauterine pneumonia and patent ductus arteriosus. Logistic regression analysis indicated that the mechanical ventilator parameter peak inspiratory pressure (OR=1.260, 95%CI: 1.096-1.448) and duration of mechanical ventilation (OR=1.010, 95%CI: 1.005-1.016) were independent risk factors for the severity of BPD, while the INSURE approach was a protective factor (OR=0.208, 95%CI: 0.060-0.923). CONCLUSIONS: The severity of BPD is associated with various factors in preterm infants. The important measures for preventing BPD include avoiding the birth of preterm infants with a very low birth weight, shortening the duration of mechanical ventilation, preventing and reducing pulmonary infections, and applying the INSURE approach.

[Cellular and humoral immunity in preterm infants of different gestational ages].

OBJECTIVE: To investigate the characteristics of immune function in newborn infants of different gestational ages. METHODS: A total of 115 premature infants free of infection between June 1, 2012 and June 1, 2013 were divided into two groups according to their gestational age at birth: early preterm infant group (28-33+6 weeks, n=57) and late preterm infant group (34-36+6 weeks, n=58). Meanwhile, 88 full-term infants (37-41+6 week) were recruited to the control group. Venous blood samples were collected within 24 hours after birth. The percentages of lymphocyte subsets, such as CD3+, CD4+, CD8+, and CD19+ T cells and natural killer (NK) cells were measured by flow cytometry, and the absolute count of each population was calculated using the results from routine blood work. Concentrations of serum IgG, IgA, and IgM were measured by immunoturbidimetry. RESULTS: Both preterm infant groups had significantly higher percentages of CD3+ and CD4+ T cells and CD4+/CD8+ ratio (P<0.05) and significantly lower percentages of CD8+ and CD19+ T cells and NK cells (P<0.05), as compared with the full-term infant group. The absolute counts of total lymphocytes, CD3+, CD4+, CD8+, and CD19+ T cells, and NK cells in both preterm infant groups were significantly lower than those in the full-term infant group (P<0.05), and the above parameters in the late preterm infant group were significantly higher than those in the early preterm infant group (P<0.05). Both preterm infant groups showed significantly lower concentrations of serum IgG than the full-term infant group (P<0.05), while no significant differences in concentrations of serum IgA and IgM were observed between the three groups (P>0.05). CONCLUSIONS: Neonatal gestational age has an effect on cellular and humoral immunity. The immune function gradually improves with increasing gestational age.

[Efficacy of inhaled nitric oxide in premature infants with hypoxic respiratory failure].

OBJECTIVE: To investigate the safety and efficacy of low-concentration inhaled nitric oxide (NO) in the treatment of hypoxic respiratory failure (HRF) among premature infants. METHODS: Sixty premature infants (gestational age ≤ 34 weeks) with HRF were randomized into NO and control groups between 2012 and 2013, with 30 cases in each group. Both groups received nasal continuous positive airway pressure (nCPAP) or mechanical ventilation. NO inhalation was continued for at least 7 days or until weaning in the NO group. The general conditions, blood gas results, complications, and clinical outcomes of the two groups were analyzed. RESULTS: The NO group showed significantly more improvement in blood gas results than the control group after 12 hours of treatment (P<0.05). After that, the change in oxygenation status over time showed no significant difference between the two groups (P>0.05). There were no significant differences in total time of assisted ventilation and duration of oxygen therapy between the two groups (P>0.05). The incidence of bronchopulmonary dysplasia (BPD), patent ductus arteriosus, necrotizing enterocolitis, retinopathy of prematurity, and pneumothorax in infants showed no significant differences between the NO and control groups (P>0.05), but the incidence of IVH and mortality were significantly lower in the NO group than in the control group (7% vs 17%, P<0.05; 3% vs 13%, P<0.05). CONCLUSIONS: NO inhalation may improve oxygenation status and reduce the mortality in premature infants with HRF, but it cannot reduce the incidence of BPD and the total time of mechanical ventilation or nCPAP and duration of oxygen therapy. NO therapy may have a brain-protective effect for premature infants with HRF and does not increase clinical complications.

Incidence of Neonatal Seizures in China Based on Electroencephalogram Monitoring in Neonatal Neurocritical Care Units.

Importance: Neonatal seizures pose a significant challenge in critical care, and continuous video electroencephalography (cEEG) monitoring holds promise for early detection of seizures. However, large-scale data on the incidence of neonatal seizures and monitoring systems in China are lacking. Objectives: To determine the incidence of neonatal seizures in infants with high risk in China. Design, Setting, and Participants: A large, cross-sectional multicenter study was conducted from January 2017 to December 2018 in the neonatal intensive care units (NICUs) of 7 tertiary medical centers in China. Neonates with high risk were included, and cEEG monitoring was conducted. Data were collected between January 1, 2017, and January 31, 2020. The data were analyzed between January 2021 and January 2022. Main Outcomes and Measures: The incidence of neonatal seizures, categorized by etiology, and seizure burden. Results: A total of 20 310 neonates with high risk were included (10 495 [51.7%] male; mean [SD] postmenstrual age, 37.7 [3.7] weeks), and seizures were observed in 3423 infants (16.9%). The highest proportion of seizures was attributed to acute neonatal encephalopathy (1448 [42.3%]). The incidence of seizures decreased with postmenstrual age and birth weight, with the highest occurrence observed in neonates with postmenstrual age of less than 28 weeks (237 of 879 [27.0%]) or birth weight of less than 1.0 kg (269 of 914 [29.4%]). Preterm infants had a higher proportion of moderate and severe seizure burdens compared with full-term infants (moderate severity: 248 of 1199 [20.7%] vs 454 of 2224 [20.4%]), but no significant differences were observed in etiology. Seizure burden was highest with genetic syndromes (49 of 188 [26.1%]), central nervous system malformations (33 of 127 [26.0%]), and inborn errors of metabolism (27 of 113 [23.9%]). During hospitalization, 7.8% of neonates with seizures died (267 neonates), with 81.3% of these cases having a moderate or severe seizure burden (217 neonates). Mortality was generally higher in preterm vs full-term infants (98 of 1199 [8.2%] vs 169 of 2224 [7.6%]) and increased with the severity of seizure burden (217 of 267 neonates with moderate or severe burden [81.3%]). Conclusions and Relevance: This cross-sectional study of neonatal seizures underscores the substantial burden seizures pose to high-risk infants with brain injury in China, particularly those who are born prematurely or who have congenital conditions.

Genetic Spectrum of Congenital Anomalies of the Kidney and Urinary Tract in Chinese Newborn Genome Project.

Introduction: Congenital anomalies of the kidney and urinary tract (CAKUT) corresponds to a spectrum of defects. Several large-cohort studies have used high-throughput sequencing to investigate the genetic risk of CAKUT during antenatal, childhood, and adulthood period. However, our knowledge of newborns with CAKUT is limited. Methods: This multicenter retrospective cohort study explored the genetic spectrum of CAKUT in a Chinese neonatal cohort. Clinical data and whole exome sequencing (WES) data of 330 newborns clinically diagnosed with CAKUT were collected. WES data were analyzed for putative deleterious single nucleotide variants (SNVs) and potential disease-associated copy number variants (CNVs). Results: In this study, pathogenic variants were identified in 61 newborns (18.5%, 61/330), including 35 patients (57.4%) with SNVs, 25 patients (41%) with CNVs, and 1 patient with both an SNV and a CNV. Genetic diagnosis rates were significantly higher in patients with extrarenal manifestations (P＜0.001), especially in those with cardiovascular malformations (P＜0.05). SNVs in genes related to syndromic disorders (CAKUT with extrarenal manifestations) were common, affecting 20 patients (57.1%, 20/35). KMT2D was the most common gene (5 patients) and 17q12 deletion was the most common CNV (4 patients). Patient 110 was detected with both a CNV (17q12 deletion) and an SNV (a homozygous variant of SLC25A13). Among the newborns with positive genetic results, 22 (36.1%, 22/61) patients may benefit from a molecular diagnosis and change in clinical management (including early multidisciplinary treatment, disease-specific follow-up, and familial genetic counseling). Conclusion: This study shows the heterogeneous genetic etiologies in a Chinese CAKUT neonatal cohort by using WES. Patients with CAKUT who have extrarenal manifestations are more likely to harbor genetic diagnoses. Kabuki syndrome and 17q12 deletion syndrome were the most common genetic findings. Approximately 36.1% of the patients may benefit from molecular diagnoses and a change in clinical management.

The long-term outcomes of preterm infants receiving non-invasive high-frequency oscillatory ventilation.

Objective: To investigate the clinical outcomes of preterm infants who received non-invasive high-frequency oscillatory ventilation following extubation in a neonatal intensive care unit. Methods: Infants born between 25 and 34 weeks of gestation with a birth weight of <1,500 g, who were admitted into the neonatal intensive care unit of Guangxi Maternal and Child Health Hospital, Nanning, Guangxi, China, requiring mechanical ventilation on admission were randomized to the non-invasive high-frequency ventilation group, nasal intermittent positive pressure ventilation group, or nasal continuous positive airway pressure group following extubation. Their respiratory and neurodevelopmental outcomes were assessed at 12 and 24 months of corrected age. Results: Among 149 preterm infants who underwent randomization, 139 completed their treatment in the neonatal intensive care unit (45, 47, 47 in the non-invasive high-frequency ventilation group, nasal intermittent positive pressure ventilation group, or nasal continuous positive airway pressure group, respectively), 113 were assessed at 12-month corrected age, and 110 of 113 were assessed again at 24-month corrected age. There were no differences in the number of times bronchitis, pneumonia, wheezing episodes, and re-hospitalization rates appeared due to respiratory diseases among the three groups (P > 0.05); the pulmonary function tests at 12-month corrected age showed respiratory rate, tidal volume, inspiratory time/expiratory time, time to peak expiratory flow/expiratory time, volume at peak expiratory flow/expiratory volume, expiratory flow at 25, 50, and 75% tidal volume were all similar among infants from the 3 groups (P > 0.05). There were no differences in the rates of neurodevelopmental impairment among the three groups at 24-month corrected age (P > 0.05). Conclusion: As post-extubation respiratory support in preterm infants, non-invasive high-frequency ventilation did not increase the rates of long-term respiratory morbidities and neurodevelopmental impairment compared with nasal intermittent positive pressure ventilation and nasal continuous positive airway pressure.

Aetiology and outcomes of prolonged neonatal jaundice in tertiary centres: data from the China Neonatal Genome Project.

OBJECTIVE: To investigate the distribution of aetiologies and outcomes in neonates with prolonged neonatal jaundice. DESIGN: An observational study. SETTING: Multiple tertiary centres from the China Neonatal Genome Project. PATIENTS: Term infants with jaundice lasting more than 14 days or preterm infants with jaundice lasting more than 21 days were recruited between 1 June 2016 and 30 June 2020. MAIN OUTCOME MEASURES: Aetiology and outcomes were recorded from neonates with prolonged unconjugated hyperbilirubinaemia (PUCHB) and prolonged conjugated hyperbilirubinaemia (PCHB). RESULTS: A total of 939 neonates were enrolled, and known aetiologies were identified in 84.1% of neonates (790 of 939). Among 411 neonates with PCHB, genetic disorders (27.2%, 112 of 411) were the leading aetiologies. There were 8 deceased neonates, 19 neonates with liver failure and 12 with neurodevelopmental delay. Among 528 neonates with PUCHB, a genetic aetiology was identified in 2 of 219 neonates (0.9%) who showed disappearance of jaundice within 4 weeks of age and in 32 of 309 neonates (10.4%) with persistent jaundice after 4 weeks of age. A total of 96 of 181 neonates (53.0%) who received genetic diagnoses had their clinical diagnosis modified as a result of the genetic diagnoses. CONCLUSION: Known aetiologies were identified in approximately 80% of neonates in our cohort, and their overall outcomes were favourable. Genetic aetiology should be considered a priority in neonates with PCHB or the persistence of jaundice after 4 weeks of age. Moreover, genetic data can modify the clinical diagnosis and guide disease management, potentially improving outcomes.

Non-invasive high-frequency oscillatory ventilation in preterm infants after extubation: a randomized, controlled trial.

OBJECTIVE: To investigate the effectiveness and safety of non-invasive high-frequency oscillatory ventilation (NHFOV) in post-extubation preterm infants. METHODS: This was a randomized, controlled trial. A total of 149 preterm infants aged between 25 to 34 weeks' gestational age with a birth weight of <1500 g who required invasive mechanical ventilation on admission were included. After extubation, they were randomized to the NHFOV group (n = 47), nasal intermittent positive pressure ventilation (NIPPV) group (n = 51), or nasal continuous positive airway pressure (NCPAP) group (n = 51). We compared the effectiveness and safety among these three groups. RESULTS: A total of 139 preterm infants finally completed the study. The reintubation rate was significantly lower in the NHFOV group than in the other groups. The duration of non-invasive ventilation and the length of hospital stay in the NHFOV and NIPPV groups were significantly shorter than those in the NCPAP group. The incidence of bronchopulmonary dysplasia in the NHFOV and NIPPV groups was significantly lower than that in the NCPAP group. The NHFOV group had significantly less nasal injury than the NCPAP group. CONCLUSION: As post-extubation respiratory support in preterm infants, NHFOV has a lower reintubation rate compared with NCPAP and NIPPV, without increasing the rate of complications.

Clinical exome sequencing revealed that FLNC variants contribute to the early diagnosis of cardiomyopathies in infant patients.

BACKGROUND: FLNC encodes actin-binding protein and is mainly concentrated in skeletal and cardiac muscle. Mutations in FLNC were found in cardiomyopathies. To date, studies on FLNC-cardiomyopathies have mainly been reported in adults. There are limited studies that have investigated FLNC variants in pediatric patients with cardiomyopathies. METHODS: We summarized the patients who carried rare variants of FLNC from May 2016 to May 2019 in the Center for Molecular Medicine, Children's Hospital of Fudan University, from clinical exome sequencing data. RESULTS: A total of 5 patients with FLNC rare variants were included. Of them, 3 were male and 2 were female. The median age was 3 months (range from 19 days to 30 months). A1186V was a known pathogenic variant reported in pediatric patients with cardiomyopathy (PMID: 29858533), and the other four variants were novel. In the four novel variants, there are one splicing (c.2265+4del) and three missense (p.R441I, p.C1639Y, and p.A2648S). Two patients (patients 1 and 3) were diagnosed with restrictive cardiomyopathy, two patients (patients 2 and 5) were diagnosed with dilated cardiomyopathy, and one patient (patient 4) was diagnosed with arrhythmia. CONCLUSIONS: All five patients have survived to date. In summary, FLNC rare variants identified by clinical exome sequencing provide genetic evidence to make early diagnosis of cardiomyopathy in infant patients.

A randomized controlled trial protocol comparing the feeds of fresh versus frozen mother's own milk for preterm infants in the NICU.

BACKGROUND: Necrotizing enterocolitis (NEC) is the leading cause of death among preterm infants born at < 30 weeks' gestation. The incidence of NEC is reduced when infants are fed human milk. However, in many neonatal intensive care units (NICUs), it is standard practice to freeze and/or pasteurize human milk, which deactivates bioactive components that may offer additional protective benefits. Indeed, our pilot study showed that one feed of fresh mother's own milk per day was safe, feasible, and can reduce morbidity in preterm infants. To further evaluate the benefits of fresh human milk in the NICU, a randomized controlled trial is needed. METHODS: Our prospective multicenter, double-blinded, randomized, controlled trial will include infants born at < 30 weeks' gestation and admitted to one of 29 tertiary NICUs in China. Infants in the intervention (fresh human milk) group (n = 1549) will receive at least two feeds of fresh human milk (i.e., within 4 h of expression) per day from the time of enrollment until 32 weeks' corrected age or discharge to home. Infants in the control group (n = 1549) will receive previously frozen human milk following the current standard protocols. Following informed consent, enrolled infants will be randomly allocated to the control or fresh human milk groups. The primary outcome is the composite outcome mortality or NEC ≥ stage 2 at 32 weeks' corrected age, and the secondary outcomes are mortality, NEC ≥ stage 2, NEC needing surgery, late-onset sepsis, retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), weight gain, change in weight, increase in length, increase in head circumference, time to full enteral feeds, and finally, the number and type of critical incident reports, including feeding errors. DISCUSSION: Our double-blinded, randomized, controlled trial aims to examine whether fresh human milk can improve infant outcomes. The results of this study will impact both Chinese and international medical practice and feeding policy for preterm infants. In addition, data from our study will inform changes in health policy in NICUs across China, such that mothers are encouraged to enter the NICU and express fresh milk for their infants. TRIAL REGISTRATION: Chinese Clinical Trial Registry; #ChiCTR1900020577; registered January 1, 2019; http://www.chictr.org.cn/showprojen.aspx?proj=34276.

Neurodevelopmental outcomes of extremely preterm infants in southern China: A multicenter study.

OBJECTIVE: To assess treatment outcomes and associated factors of extremely preterm infants (EPIs) in GuangXi, China. METHODS: This was a retrospective study consisting of 131 eligible cases with gestational age (GA) between 22 and 28 weeks, and infants were followed until 18-24 months. Data including clinical characteristics, perinatal factors and after-birth conditions were collected from the neonatal intensive care unit in 10 hospitals in Guangxi from January 1st 2010 until May 31st 2016. RESULTS: During that period, 307 EPIs were born in the hospitals. 137 infants died in hospital after their parents decided to withdraw clinical treatment, and 11 infants died despite full resuscitation was provided. Of the 159 surviving infants, 28 infants were lost to follow-up. In total, 131 infants who survived and were presented to follow-up at 18-24 months of age were enrolled into this study. Of the 131 infants evaluated at 18-24 months follow-up, 47 (35.9%) were diagnosed with neurodevelopmental disability (ND), and 84 (64%) demonstrated on tract motor and language skills. The incidence of chorioamnionitis, early onset sepsis (EOS), bronchopulmonary dysplasia (BPD) were all higher in the group of infants who were diagnosed with ND compared to those with normal motor language development (NML), the duration of mechanical ventilation (MV) was longer in ND group, and the higher incidence of ND was seen in the smaller GA babies (p < 0.05). Adjusted the BPD severity, GA was a protective factor of neurodevelopmental outcome (combined OR = 0.338, 95% CI: 0.145-0.791). In EPIs with moderate BPD and severe BPD, chorioamnionitis was a risk factor of ND (OR = 10.313 and 5.778，respectively, 95% CI: 1.389-6.486 and 1.444-23.119, respectively). The Logistic regression analysis showed that GA (OR = 0.207, 95%CI = 0.047-0.917) was a protective factor for ND, and chorioamnionitis (OR = 6.010, 95%CI: 1.331-27.138), moderate-to-severe BPD (OR = 4.285, 95%CI: 1.495-12.287), the duration of MV (OR = 3.508, 95%CI: 2.077-5.926) were independent risk factors for ND in EPIs. CONCLUSIONS: Chorioamnionitis, moderate-to-severe BPD, and the duration of MV were associated with neurodevelopmental disability in EPIs. The smaller the GA, the higher incidence of neurodevelopmental disability.

Treatment outcomes and associated factors among extremely preterm infants in a major children hospital in Guangxi, China.

BACKGROUND: In developing countries, infant survival rate and long-term outcomes of extremely preterm infants(EPIs) have significantly improved due to advances in perinatal care. The striking gap in the treatment outcome of EPIs between China and the other developed countries was a major concern. To assess treatment outcomes and associated factors among EPIs in Nanning, China. METHODS: This was a perspective study consisting of eligible cases with gestational age between 22 and 28 weeks and infants were followed to 18-24 months of age. Data including clinical characteristics, perinatal factors and after-birth conditions were collected from the neonatal intensive care unit (NICU) in a major women's and children's health hospital in Guangxi Province from January 1st 2010 to February 1st 2015. RESULTS: During that period 79 EPIs were born in the hospital. Twenty-eight infants died in hospital after their parents decided to withdraw clinical treatment. Of the 51 surviving infants, 5 infants were lost to follow-up. Eleven of the 46 infants were evaluated at 18-24 months of age and were diagnosed with neurodevelopmental disability and 35 infants showed normal motor language development. The incidence of intrauterine infection and intraventricular hemorrhage (IVH) grade III were both higher in the group of infants who were diagnosed neurodevelopmental disability than in the group of infants with normal motor language development (p < 0.05). Logistic regression analysis showed that intrauterine infection (OR = 33.290, 95%CI = 2.180-508.351) and IVH grade III (OR = 26.814, 95%CI = 3.631-197.989) were the major risk factors for neurodevelopmental disability in EPIs. CONCLUSIONS: Intrauterine infection and IVH grade III were associated with the neurodevelopmental disability in EPIs.

Analysis of In-hospital Neonatal Death in the Tertiary Neonatal Intensive Care Unit in China: A Multicenter Retrospective Study.

BACKGROUND: Globally, the proportion of child deaths that occur in the neonatal period remains a high level of 37-41%. Differences of cause in neonate death exist in different regions as well as in different economic development countries. The specific aim of this study was to investigate the causes, characteristics, and differences of death in neonates during hospitalization in the tertiary Neonatal Intensive Care Unit (NICU) of China. METHODS: All the dead neonates admitted to 26 NICUs were included between January l, 2011, and December 31, 2011. All the data were collected retrospectively from clinical records by a designed questionnaire. Data collected from each NICU were delivered to the leading institution where the results were analyzed. RESULTS: A total of 744 newborns died during the 1-year survey, accounting for 1.2% of all the neonates admitted to 26 NICUs and 37.6% of all the deaths in children under 5 years of age in these hospitals. Preterm neonate death accounted for 59.3% of all the death. The leading causes of death in preterm and term infants were pulmonary disease and infection, respectively. In early neonate period, pulmonary diseases (56.5%) occupied the largest proportion of preterm deaths while infection (27%) and neurologic diseases (22%) were the two main causes of term deaths. In late neonate period, infection was the leading cause of both preterm and term neonate deaths. About two-thirds of neonate death occurred after medical care withdrawal. Of the cases who might survive if receiving continuing treatment, parents' concern about the long-term outcomes was the main reason of medical care withdrawal. CONCLUSIONS: Neonate death still accounts for a high proportion of all the deaths in children under 5 years of age. Our study showed the majority of neonate death occurred in preterm infants. Cause of death varied with the age of death and gestational age. Accurate and prompt evaluation of the long-term outcomes should be carried out to guide the critical decision.

Validation of transcutaneous bilirubin nomogram for identifying neonatal hyperbilirubinemia in healthy Chinese term and late-preterm infants: a multicenter study.

OBJECTIVE: to prospectively validate a previously constructed transcutaneous bilirubin (TcB) nomogram for identifying severe hyperbilirubinemia in healthy Chinese term and late-preterm infants. METHODS: this was a multicenter study that included 9,174 healthy term and late-preterm infants in eight hospitals of China. TcB measurements were performed using a JM-103 bilirubinometer. TcB values were plotted on a previously developed TcB nomogram, to identify the predictive ability for subsequent significant hyperbilirubinemia. RESULTS: in the present study, 972 neonates (10.6%) developed significant hyperbilirubinemia. The 40(th) percentile of the nomogram could identify all neonates who were at risk of significant hyperbilirubinemia, but with a low positive predictive value (PPV) (18.9%). Of the 453 neonates above the 95(th) percentile, 275 subsequently developed significant hyperbilirubinemia, with a high PPV (60.7%), but with low sensitivity (28.3%). The 75(th) percentile was highly specific (81.9%) and moderately sensitive (79.8%). The area under the curve (AUC) for the TcB nomogram was 0.875. CONCLUSIONS: this study validated the previously developed TcB nomogram, which could be used to predict subsequent significant hyperbilirubinemia in healthy Chinese term and late-preterm infants. However, combining TcB nomogram and clinical risk factors could improve the predictive accuracy for severe hyperbilirubinemia, which was not assessed in the study. Further studies are necessary to confirm this combination.