Divergent neurodevelopmental profiles of very-low-birth-weight infants.

BACKGROUND: Advanced perinatal medicine has decreased the mortality rate of preterm infants. Long-term neurodevelopmental outcomes of very-low-birth-weight infants (VLBWIs) remain to be investigated. METHODS: Participants were 124 VLBWIs who had in-hospital birth from 2007 to 2015. Perinatal information, developmental or intelligence quotient (DQ/IQ), and neurological comorbidities at ages 3 and 6 years were analyzed. RESULTS: Fifty-eight (47%) VLBWIs received neurodevelopmental assessments at ages 3 and 6 years. Among them, 15 (26%) showed DQ/IQ <75 at age 6 years. From age 3 to 6 years, 21 (36%) patients showed a decrease (≤-10), while 5 (9%) showed an increase (≥+10) in DQ/IQ scores. Eight (17%) with autism spectrum disorder or attention-deficit hyperactivity disorder (ASD/ADHD) showed split courses of DQ/IQ, including two with ≤-10 and one with +31 to their scores. On the other hand, all 7 VLBWIs with cerebral palsy showed DQ ≤35 at these ages. Magnetic resonance imaging detected severe brain lesions in 7 (47%) of those with DQ <75 and 1 (18%) with ASD/ADHD. CONCLUSIONS: VLBWIs show a broad spectrum of neurodevelopmental outcomes after 6 years. These divergent profiles also indicate that different risks contribute to the development of ASD/ADHD from those of cerebral palsy and epilepsy in VLBWIs. IMPACT: Very-low-birth-weight infants (VLBWIs) show divergent neurodevelopmental outcomes from age 3 to 6 years. A deep longitudinal study depicts the dynamic change in neurodevelopmental profiles of VLBWIs from age 3 to 6 years. Perinatal brain injury is associated with developmental delay, cerebral palsy and epilepsy, but not with ASD or ADHD at age 6 years.

Loss of imprinting of the human-specific imprinted gene ZNF597 causes prenatal growth retardation and dysmorphic features: implications for phenotypic overlap with Silver-Russell syndrome.

BACKGROUND: ZNF597, encoding a zinc-finger protein, is the human-specific maternally expressed imprinted gene located on 16p13.3. The parent-of-origin expression of ZNF597 is regulated by the ZNF597:TSS-DMR, of which only the paternal allele acquires methylation during postimplantation period. Overexpression of ZNF597 may contribute to some of the phenotypes associated with maternal uniparental disomy of chromosome 16 (UPD(16)mat), and some patients with UPD(16)mat presenting with Silver-Russell syndrome (SRS) phenotype have recently been reported. METHODS: A 6-year-old boy presented with prenatal growth restriction, macrocephaly at birth, forehead protrusion in infancy and clinodactyly of the fifth finger. Methylation, expression, microsatellite marker, single nucleotide polymorphism array and trio whole-exome sequencing analyses were conducted. RESULTS: Isolated hypomethylation of the ZNF597:TSS-DMR and subsequent loss of imprinting and overexpression of ZNF597 were confirmed in the patient. Epigenetic alterations, such as UPD including UPD(16)mat and other methylation defects, were excluded. Pathogenic sequence or copy number variants affecting his phenotypes were not identified, indicating that primary epimutation occurred postzygotically. CONCLUSION: We report the first case of isolated ZNF597 imprinting defect, showing phenotypic overlap with SRS despite not satisfying the clinical SRS criteria. A novel imprinting disorder entity involving the ZNF597 imprinted domain can be speculated.

Trends in Bronchopulmonary Dysplasia Among Extremely Preterm Infants in Japan, 2003-2016.

OBJECTIVE: To investigate recent trends in bronchopulmonary dysplasia (BPD) and its risk factors among extremely preterm infants. STUDY DESIGN: Demographic and clinical data were reviewed for 19 370 infants born at 22-27 weeks of gestation registered in the affiliated hospitals of the Neonatal Research Network of Japan between 2003 and 2016. We investigated the overall survival and prevalence of bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age and risk factors for developing BPD among the survivors. RESULTS: Among 19 370 infants, 2244 (11.6%) died by 36 weeks' postmenstrual age. The mortality rate decreased from 19.0% (99% CI, 15.7%-22.8%) in 2003 to 8.0% (99% CI, 6.2%-10.3%) in 2016. Among 17 126 survivors, BPD developed in 7792 (45.5%) infants, and its proportion significantly increased from 41.4% (99% CI, 36.5%-46.4%) in 2003 to 52.0% (99% CI, 48.2%-55.9%) in 2016. A multivariable analysis of the survivors showed a positive association of BPD with ≥4 weeks' supplemental oxygen or invasive ventilation, birth weight <750 g, small for gestational age, ≥4 weeks' noninvasive positive pressure ventilation, chorioamnionitis, <26 weeks' gestational age, <20 cases per year of center patient volume, or treated patent ductus arteriosus. Although the median duration of invasive ventilation was shortened, the proportions of factors associated adversely with BPD generally showed increasing trends over time. CONCLUSIONS: The mortality rate of extremely preterm infants has decreased, but the rate of BPD has increased in survivors between 2003 and 2016. Despite the decreasing duration of invasive ventilation over time, increasing rates of BPD suggest that differences in the patient population or other management strategies influence the development of BPD.

Longitudinal analysis of serum cystatin C for estimating the glomerular filtration rate in preterm infants.

BACKGROUND: Cystatin C (Cys-C) is a more sensitive marker of renal function than creatinine (Cre) in pediatric and adult populations. However, the reference values of serum Cys-C for estimating glomerular filtration rates (eGFRs) in premature infants during the first year of life have not been sufficiently studied. METHODS: In this prospective study, 481 blood samples were collected from 261 preterm infants with uncomplicated clinical courses during their first year of life. Infants were divided into three groups according to gestational age at birth: 27-30 weeks, 31-33 weeks, and 34-36 weeks. Serum Cys-C and Cre levels were measured at 6-30 days, 3-5 months, 7-9 months, and 12-14 months after birth and the eGFR was calculated using two previously published equations. RESULTS: The median serum Cys-C levels were 1.776, 1.248, 1.037, and 0.960 mg/L at the first, second, third, and fourth measurement time-point, respectively, with the value significantly decreasing with age up to 12-14 months. Cys-C levels were independent of gestational age and gender. In contrast to Cys-C, serum Cre values declined rapidly up to 3-5 months, then remained constant up to 12-14 months. Using the Cys-C-based equation, the eGFR significantly increased with increasing age until approximately 1 year after birth; however, no such trend was noted using the equation based on Cys-C + Cre. CONCLUSIONS: Reference ranges for Cys-C in premature infants decline gradually over the first year after birth. Cys-C appears to be a more reliable marker than Cre for estimating GFR in preterm infants.

Inhaled nitric oxide therapy for preterm infants after 7 days of age: a scoping review protocol.

INTRODUCTION: Inhaled nitric oxide (iNO) use is recommended for persistent pulmonary hypertension of the newborn in term and late preterm infants. Recently, iNO therapy to prevent bronchopulmonary dysplasia (BPD) or rescue for hypoxic respiratory failure and pulmonary hypertension secondary to BPD has increasingly been used in preterm infants after 7 days of postnatal age (in the postacute phase), despite its off-label use. However, the initiation criteria of iNO therapy for preterm infants in the postacute phase are varied. The aim of this scoping review is to identify the clinical and/or echo findings at the initiation of iNO therapy in preterm infants in the postacute phase. METHODS AND ANALYSIS: We will search PubMed, Embase and the Japanese database 'Ichushi.' The following studies will be included in the review: randomised controlled trials, prospective/retrospective cohort studies, case-control studies and case series on iNO therapy for preterm infants in the postacute phase; studies published between January 2003 and August 2023; studies conducted in developed countries and studies written in English or Japanese. We will independently screen, extract and chart data using the population-concept-context framework following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. We will summarise the characteristics and findings of the included studies. ETHICS AND DISSEMINATION: Obtaining an institutional review board approval is not required because of the nature of this review. A final report of review findings will be published and disseminated through a peer-reviewed journal and presentation at relevant conferences. TRIAL REGISTRATION NUMBER: UMIN000051498.

Effectiveness of umbilical culture for surveillance of methicillin-resistant Staphylococcus aureus among neonates admitted to neonatal intensive care units.

To compare the culture sensitivities of MRSA detection, we collected 988 paired umbilical and nasal cultures from screened neonates. MRSA positivity rates were 79.1% from umbilicus and 41.9% from nares (P = .01). The umbilicus was a more useful culture site than the nares for surveillance of MRSA among neonates upon admission.

Low placental weight may be involved in the etiology of congenital cryptorchidism in neonatal boys.

INTRODUCTION: Several factors have been reported to be associated with the etiology of cryptorchidism; however, clear evidence regarding the risk factors for cryptorchidism is elusive. In the present study, we evaluated the clinical characteristics of cryptorchidism using the common neonatal intensive-care unit (NICU) database of the National Hospital Organization and explored one of possible factors associated with the development of cryptorchidism. METHODS: A total of 7882 male neonates were included in this study. We separated them into two groups: those without cryptorchidism (n = 7852) and those with cryptorchidism (n = 30) at the time of discharge from the NICU. Cryptorchidism was defined as a condition in which the testis was located out of the scrotum on the route of descent at the time of NICU discharge. The associations between cryptorchidism and the maternal, placental, and neonatal information were analyzed. Analyses were performed statistically to compare nominal variables between the groups using Fisher's direct establishment calculation method and logistic regression analyses. RESULTS: Univariate analyses showed the placental weight <10% tile (odds ratio 3.31, 95% confidence interval [CI] 1.18-8.64), birth height <-2 standard deviations (SD) (odds ratio 3.65, 95% CI 0.92-10.6), birth weight <-2SD (odds ratio 4.06, 95% CI 1.55-9.51), and small for gestational age (odds ratio 3.82, 95% CI 1.46-8.97) were significantly associated with the development of cryptorchidism. Multivariate analyses showed that placental weight <10th percentile (odds ratio 2.86, 95% CI 1.11-7.44) was significantly associated with the development of cryptorchidism. DISCUSSION: Although, this study population was limited to infants admitted to the ICU, the data indicated a possible association between low placental weight and the development of cryptorchidism in neonatal boys.

Changing risk factors for postpartum depression in mothers admitted to a perinatal center.

BACKGROUND: The Edinburgh postnatal depression scale (EPDS) is commonly used in screening for major postpartum depression (PPD). We explored the clinical factors associated with score changes. METHODS: Mothers (n=1,287) who delivered a single live-born infant in Kokura Medical Center in Japan during 2018-2019 were analyzed. The EPDS-Japanese version was conducted at the first and fourth weeks after childbirth. Scores of ≥9 were considered to indicate an increased risk of PPD. RESULTS: The scores improved during the four-week period (5.03±0.12 to 3.79±0.10). Primiparity, Cesarean section (CS), and a low Apgar score were identified as initial risk factors, however, primiparity remained in the multivariate analysis (aOR 2.02, 95% CI 1.37-2.97). Age ≥35 years was associated with worsened scores (aOR 1.88, 95%CI 1.01-3.51), but CS improved (aOR 0.38, 95%CI 0.21-0.70). Primiparity, CS, and neonatal respiratory support were the initial risk factors, while infant anomaly was a late risk factor in mothers whose infants were admitted to the neonatal intensive care unit (NICU) (aOR 3.35, 95%CI 1.31-8.56). In mothers of infants with an NICU stay of ≥4 weeks, infant anomaly was associated with worsened scores (aOR 6.61, 95%CI 1.11-39.3), while respiratory support was associated with improved scores (aOR 0.09, 95%CI 0.01-0.65). Twenty-six mothrs with worsened scores received psychiatric support; three developed PPD. Two of the three were ≥35 years of age, neither of their infants had anomalies. CONCLUSION: Maternal aging and infant anomaly were risk factors for PPD. PPD occurred in mothers with worsened EPDS scores after mental care. Puerperants with worsening risk factors should be targeted to control PPD.

Abnormal placental cord insertion, hypertensive disorders of pregnancy and birth length may be involved in development of hypospadias in male fetuses.

OBJECTIVES: Hypospadias is a congenital disease characterized by morphological abnormalities of the penis, including abnormal urethral opening and penile flexion, which cause urination disorders and/or sexual intercourse difficulty. Various factors have been suggested to cause this anomaly, but evidence concerning risk factors causing this anomaly is insufficient. We evaluated the etiology of hypospadias in Japan using the Common Database of the National Hospitals' Neonatal study group. STUDY DESIGN: We retrospectively evaluated 7,865 male neonates registered in the NICU Common Database of the National Hospitals' Neonatal study group. The subjects were divided into two groups by the presence (n = 43) or absence (n = 7,822) of hypospadias. Statistical analyses were performed to compare nominal variables between the groups by Fisher's direct establishment calculation method and logistic regression analyses. RESULTS: A univariate analysis showed significant between-group differences in hypertensive disorders in pregnancy (odds ratio [OR]: 4.02, 95% confidence interval [CI]: 1.95-7.90), placental weight <-1.28 standard deviation (SD; OR: 5.06, 95% CI: 2.45-10.32), abnormal placental cord insertion (OR: 4.7, 95% CI: 2.62-9.76), birth length <-2SD (OR: 10.56, 95% CI: 5.00-21.1) and birth weight <-2SD (OR: 8.17, 95% CI: 4.17-15.68). A multivariate analysis showed a significant between-group difference in hypertensive disorders of pregnancy (adjusted OR [AOR]: 2.30, 95% CI: 1.09-4.85), abnormal placental cord insertion (AOR: 3.69, 95% CI: 1.83-7.44) and birth length <-2SD (AOR: 3.44, 95% CI: 1.26-9.42). CONCLUSION: Abnormal placental cord insertion, hypertensive disorders of pregnancy and birth length may be involved in hypospadias development in male neonates in conjunction with placental dysfunction in early pregnancy.

Long-term outcome of infants with twin-to-twin transfusion syndrome.

OBJECTIVE: To clarify the long-term neurodevelopmental outcome of twin-to-twin transfusion syndrome (TTTS) survivors. METHODS: From January 1994 to December 2003, 33 newborns with TTTS who were derived from 18 monochorionic twin gestations were enrolled for the study. The development and growth at 3 or 6 years of age were compared between TTTS survivors and weight-matched singleton controls. RESULTS: The mortality in TTTS (8/33: 24%) was significantly higher than that of the controls (7/80: 9%). Of all 12 TTTS patients who were diagnosed before 25 weeks and born before 28 weeks of gestation, in 10 (83%) it led to neonatal or intrauterine death. The morbidity of cerebral palsy, epilepsy, and mental retardation did not differ between TTTS and control patients. The morbidity and severity of neurological deficits at school age were similar in both groups. No growth parameters at 3 or 6 years of age differed between TTTS and controls. CONCLUSIONS: Morbidity, growth and development of TTTS survivors attained comparable levels of weight-matched controls, despite the higher neonatal mortality. These results suggest that the early management of TTTS is critical for refining the total outcome of the affected twins.