Long-Term Pulmonary and Neurodevelopmental Outcomes of Meconium Aspiration Syndrome Affected Infants: A Retrospective National Population-Based Study in Taiwan.

INTRODUCTION: Meconium aspiration syndrome (MAS) may cause severe pulmonary and neurologic injuries in affected infants after birth, leading to long-term adverse pulmonary or neurodevelopmental outcomes. METHODS: This retrospective population-based cohort study enrolled 1,554,069 mother-child pairs between 2004 and 2014. A total of 8,049 infants were in the MAS-affected group, whereas 1,546,020 were in the healthy control group. Children were followed up for at least 3 years. According to respiratory support, MAS was classified as mild, moderate, and severe. With the healthy control group as the reference, the associations between MAS severity and adverse pulmonary outcomes (hospital admission, intensive care unit (ICU) admission, length of hospital stay, or invasive ventilator support during admission related to pulmonary problem) or adverse neurodevelopmental outcomes (cerebral palsy, needs for rehabilitation, visual impairment, or hearing impairment) were accessed. RESULTS: MAS-affected infants had a higher risk of hospital and ICU admission and longer length of hospital stay, regardless of severity. Infants with severe MAS had a higher risk of invasive ventilator support during re-admission (odds ratio: 17.50, 95% confidence interval [CI]: 7.70-39.75, p < 0.001). Moderate (hazard ratio [HR]: 1.66, 95% CI: 1.30-2.13, p < 0.001) and severe (HR: 4.94, 95% CI: 4.94-7.11, p < 0.001) MAS groups had a higher risk of adverse neurodevelopmental outcome, and the statistical significance remained remarkable in severe MAS group after adjusting for covariates (adjusted HR: 2.28, 95% CI: 1.54-3.38, p < 0.001) Conclusions: Adverse pulmonary or neurodevelopmental outcomes could occur in MAS-affected infants at birth. Close monitoring and follow-up of MAS-affected infants are warranted.

Neonatal jaundice is associated with increased risks of congenital anomalies of the kidney and urinary tract and concomitant urinary tract infection.

The link between neonatal jaundice and urinary tract infection (UTI) remains debated, with congenital kidney and urinary tract anomalies (CAKUT) potentially playing a role. This population-based study aimed to analyze the correlations between neonatal jaundice, CAKUT, and concomitant UTI. The study cohort consisted of 2,078,122 live births from 2004 to 2014. We linked several population-based datasets in Taiwan to identify infants with unexplained neonatal jaundice and their mothers. The primary outcome was the rate of CAKUT occurring within 3 years after delivery, and the presence of concomitant UTI during neonatal jaundice hospitalization. Infants with neonatal jaundice had a significantly higher risk of CAKUT (adjusted odds ratio [aOR] 1.24, 95% confidence interval [CI] 1.11-1.39) during early childhood. Among the subtypes of CAKUT, obstructive uropathy, vesicoureteral reflux and other CAKUT were associated with an increased risk of neonatal jaundice. Infants who underwent intensive phototherapy, had a late diagnosis (> 14 days of postnatal age) or underwent a prolonged duration of phototherapy (> 3 days) exhibited a higher risk of concomitant UTI compared to other infants with jaundice. Our findings indicate a notable association between neonatal jaundice and increased risks of UTIs in the context of CAKUT. This study underscore the importance of vigilant monitoring and timely interventions for neonates presenting with jaundice, while acknowledging the complexity and variability in the progression of CAKUT and its potential connection to UTIs.

Preterm birth increases cerebral palsy hazards in children of mothers with chronic hypertension in pregnancy.

BACKGROUND: Children of mothers with chronic-hypertension in pregnancy have high rates of preterm-birth (<37 weeks of gestation) and small-for-gestational-age (SGA), both of which are risk factors of cerebral palsy (CP). This study investigated the cumulative risks of CP in children exposed to maternal chronic-hypertension vs. other types of hypertensive-disorders-of-pregnancy (HDP), and whether preterm-birth and SGA potentiate the antenatal impact of chronic-hypertension to increase CP hazards. METHODS: This population-based cohort study enrolled 1,417,373 mother-child pairs with singleton live births between 2004 and 2011 from the Taiwan Maternal and Child Health Database. A total of 19,457 pairs with HDP were identified and propensity-score-matched with 97,285 normotensive controls. Children were followed up for CP outcome until age 6-13 years. HDP were classified into chronic-hypertension, gestational-hypertension, preeclampsia, and preeclampsia-with-chronic-hypertension. Using the normotensive group as the reference, the associations between chronic-hypertension and CP hazard were assessed with adjusted hazard ratios (HR) and 95% confidence intervals (CI) in Cox proportional hazards regression models, and the effects of preterm-birth and SGA on the associations were examined. RESULTS: The HDP group had higher rates of CP (0.8%) than the normotensive group (0.5%), particularly the subgroup of preeclampsia-with-chronic-hypertension (1.0%), followed by preeclampsia (0.9%), chronic-hypertension (0.7%) and gestational-hypertension (0.6%). Preterm-birth, but not SGA, exerted moderating effects to increase CP risks in children exposed to maternal chronic-hypertension. Before adjustments, chronic-hypertension alone had no substantial contribution to CP hazard (HR 1.35, 95% CI 1.00-1.83), while preeclampsia alone (1.64, 1.28-2.11) or with superimposed-chronic-hypertension (1.83, 1.16-2.89) had significant effects. After including preterm-birth in the multivariable model, the CP hazard for chronic-hypertension alone rather than other types of HDP was raised and became significant (1.56, 1.15-2.12), and the significance remained after stepwise adjustments in the final model (1.74, 1.16-2.60). CONCLUSIONS: Preterm-birth might potentiate CP hazards in children of mothers with chronic-hypertension in pregnancy.

Maternal hypertensive pregnancy disorders increase childhood intellectual disability hazards independently from preterm birth and small for gestational age.

BACKGROUND: Children of mothers with hypertensive-disorders-of-pregnancy (HDP) have high rates of preterm-birth (<37 weeks' gestation) and small-for-gestational-age (SGA), both of which are risk factors of intellectual disability (ID). AIMS: To test the multiple-hit hypothesis that preterm-birth and SGA in the neonatal period might potentiate the antenatal impact of HDP to increase childhood ID hazards, and HDP might not have independent effects. METHODS: This population-based cohort study enrolled 1,417,373 mother-child pairs between 2004 and 2011. A total of 19,457 pairs with HDP were identified and propensity-score-matched with 97,285 normotensive controls. Children were followed up for ID outcome until 6-13 years of age. HDP were classified into chronic-hypertension, gestational-hypertension, preeclampsia, and preeclampsia-with-chronic-hypertension. Using the normotensive group as the reference, the associations between HDP subgroups and ID hazards were assessed with adjusted hazard ratios (aHR) and 95 % confidence intervals (CI), and the effects of preterm-birth and SGA on the associations were examined. RESULTS: The HDP group had higher cumulative rates of ID (1.6 %) than the normotensive group (0.9 %), particularly the subgroup of preeclampsia-with-chronic-hypertension (2.4 %), followed by preeclampsia (1.7 %), chronic-hypertension (1.5 %) and gestational hypertension (1.0 %). Preterm-birth and SGA exerted aggravating effects on ID hazards in children exposed to any HDP. After adjustments, maternal chronic-hypertension (aHR 1.59, 95 % CI 1.28-1.97), preeclampsia (1.52, 1.26-1.83), and preeclampsia-with-chronic-hypertension (1.86, 1.38-2.51) independently contributed to ID outcome. CONCLUSIONS: Maternal HDP other than gestational hypertension increased offspring's ID hazards independently from the potentiating hits of preterm-birth and SGA, implicating long-lasting influence of in-utero HDP exposure on children's cognitive development.

Preterm birth and small for gestational age potentiate the association between maternal hypertensive pregnancy and childhood autism spectrum disorder.

Children of mothers with hypertensive disorders of pregnancy (HDP) have high rates of preterm-birth (gestational age < 37 weeks) and small-for-gestational-age (SGA), both of which are risk factors of autism spectrum disorder (ASD). This study tested the multiple-hit hypothesis that preterm-birth and SGA in the neonatal period might potentiate the antenatal impact of HDP to increase childhood ASD hazards, and HDP might not be a major contributor. The propensity-score-matched cohort enrolled 18,131 mother-child pairs with HDP and 90,655 normotensive controls between 2004 and 2011. Children with siblings born to the same mothers were excluded for analysis to reduce the potential familial-genetic influence. HDP were classified into chronic-hypertension, gestational-hypertension, preeclampsia, and preeclampsia-with-chronic-hypertension. Using the normotensive group as the reference, the associations between HDP subgroups and the cumulative ASD risks were assessed with hazard ratios, and the effects of preterm-birth and SGA on the associations were examined. The HDP group had a higher cumulative rate of ASD (1.5%) than the normotensive group (1.2%). Preterm-birth and SGA exerted moderating effects to aggravate ASD hazards in children exposed to chronic-hypertension or gestational-hypertension. None of HDP types significantly contributed to ASD after adjustments. In conclusion, antenatal HDP exposure might predispose to ASD outcome through susceptibility to the impact of preterm-birth and SGA.

Maternal and neonatal risk factors of asthma in children: Nationwide population based study.

BACKGROUND: Small population group-based cohorts have found that perinatal factors may contribute to the development of asthma in children. We aimed to investigate maternal and neonatal risk factors for the asthma phenotypes using two databases from the Taiwan's Maternal and Child Health Database (TMCHD) and the National Health Insurance Research Database (NHIRD). METHODS: Perinatal data was obtained from 2004 to 2008 in the TMCHD and linked the NHIRD to obtain relevant medical information regarding maternal and neonatal risk factors of three asthma phenotypes which were identified as transient early asthma, persistent asthma, and late-onset asthma. A multivariate logistic regression analysis was conducted to adjust for covariates. RESULTS: The percentage of non-asthmatic patients was 77.02% and asthmatic (transient early asthma, late onset asthma, and persistent asthma) patients were 8.96%, 11.64%, and 2.42%, respectively. Maternal risk factors-including Cesarean section, maternal asthma, maternal allergic rhinitis (AR), and premature rupture of membranes-and neonatal risk factors, such as male gender, gestational age 29-37 weeks, ventilator use, antibiotics use, AR, and atopic dermatitis, were associated with the development of these three asthma phenotypes. Twins and a gestational age of 28 weeks or less premature were associated with the development of transient early asthma and persistent asthma, but not late onset asthma. Triplets and above were associated with the development of transient early asthma, but not late onset or persistent asthma. CONCLUSION: Various asthma phenotypes have different risk factors; therefore, their distinct risk factors should be identified in order to early diagnosis and treatment.

Adjuvant probiotic Bifidobacterium animalis subsp. lactis CP-9 improve phototherapeutic treatment outcomes in neonatal jaundice among full-term newborns: A randomized double-blind clinical study.

BACKGROUND: Probiotics had been used to decreased bilirubin level in neonatal jaundice (NJ) without being further studied mechanism and stratification. The intestinal pathogen Escherichia coli produced ß-glucuronidase would increase enterohepatic circulation and elevate serum bilirubin levels (SBLs) which might worsen the disease process of NJ. STUDY OBJECTIVE: We hypothesized that some probiotics could decrease bilirubin level through inhibiting the growth of E. coli. It's assumed that adjuvant probiotic intervention might accelerate the phototherapy for NJ and alleviate the severity of the NJ. Besides, it's further study the efficacy of the probiotic intervention in NJ among the full-term and preterm newborns. MATERIALS AND METHODS: Firstly, the Bifidobacterium animalis subsp. lactis CP-9 was screened for its anti-E. coli activity. Then, it was orally administered to newborns with NJ in combination with conventional phototherapy (wavelength 425-457 nm) to determine its efficacy. 83 neonatal patients whose serum bilirubinemia was at a concentration of ≥ 15 mg/dL were participated the double-blind randomized trial and conducted in the neonatal ward of China Medical University Children's Hospital (CMUCH, Taichung, Taiwan). The test was conducted in 2 groups: experimental group: phototherapy + B. animalis subsp. lactis CP-9 (n = 43; 5 × 109 CFU/capsule) and control group: phototherapy + placebo (n = 40). The SBL and total phototherapy duration were measured. RESULTS: The experimental group showed improved serum bilirubin decline rate (-0.16 ±â€…0.02 mg/dL/h; P = .009, 95% CI -0.12 to -0.2), particularly in the first 24 hour of in-hospital care, and reduced total phototherapy duration (44.82 ±â€…3.23 h; P = .011, 95% CI: 51.3-38.2) compared with the control group. Especially, probiotics had a significant therapeutic effect (serum bilirubin decline rate: -0.18 ±â€…0.02 mg/dL/h, 95% CI -0.12 to -0.23, P = .014; phototherapy duration: 43.17 ±â€…22.72 h, 95% CI 51.9-34.3, P = .019) in the low-risk subgroup (full-term newborns). CONCLUSIONS: In conclusion, B. animalis subsp. lactis CP-9 synergistically improves treatment outcomes of NJ during in-hospital phototherapy including reduced total phototherapy duration and improved serum bilirubin decline rate, particularly in full-term newborns.

Epidemiological evolution of early-onset neonatal sepsis over 12 years: A single center, population-based study in central Taiwan.

BACKGROUND: We aimed to explore the epidemiology and evolution of pathogens, antibiotic susceptibility, and mortality rate in cases of neonatal early-onset sepsis (EOS) reported over a period of 12 years in a level III neonatal center in Central Taiwan. METHODS: Patients' medical records in a neonatal center from 2007 to 2018 were reviewed to obtain information on infants with culture-proven EOS, which included pathogens found in the blood or cerebrospinal fluid cultures. RESULTS: The incidence of neonatal EOS during this period was 2.11 cases/1,000 admissions. Group B streptococcal (GBS) and Escherichia coli were the most common pathogens. The overall rates of GBS and E. coli infections were 0.68/1,000 and 0.77/1,000 live births, respectively. The incidence of EOS in infants with a birth weight ≥1,500 g decreased significantly with decreasing incidence of GBS-related sepsis. The incidence of EOS remained high in very-low-birth-weight (VLBW) infants and increased over time. There was an increasing trend in of E. coli infection and emergence of drug-resistant strains. In addition, E. coli sepsis had high mortality in VLBW infants. CONCLUSION: Novel screening and prevention strategies against E. coli and reserving broad-spectrum antibiotics for the most critically ill or VLBW patients with maternal chorioamnionitis might help in early diagnosis and further improve the outcomes of EOS.

Evidence base multi-discipline critical strategies toward better tomorrow for very preterm infants.

Despite advances in neonatal intensive care in the recent decade, a large number of very preterm infants (VPIs) remain at risk for significant neurodevelopmental impairment (NDI). Given that there are many interventions need to be implemented during the critical perinatal period so that complications of these vulnerable VPIs could be minimized, it is urgent to develop multi-discipline strategies based on evidence to be carried out. The objective of this new term evidence-based perinatal critical strategies (EBPCS), is to provide beneficial intervention towards better neurodevelopmental outcomes, specifically for preterm infants below 28 weeks gestational age. EBPCS is defined as the management of the VPIs during the perinatal period which would include antenatal counseling with team briefing and share decision making, treat the chorioamnionitis, antenatal MgS04, antenatal steroid, delayed cord clamping/milking, neonatal resuscitation team preparation, prevention of hypothermia, immediate respiratory support with continuous positive airway pressure at delivery room, less invasive surfactant administration, early surfactant with budesonide therapy, support of cardiovascular system, early initiate of probiotics administration, early caffeine, early parenteral and enteral nutrition, promptly initiating antibiotics. These critical strategies will be discussed detail in the text; nonetheless, standardized protocols, technical skills and repeated training are the cornerstones of successful of EBPCS. Further experience from different NICU is needed to prove whether these very complicate and comprehensive perinatal critical strategies could translate into daily practice to mitigate the incidence of NDI in high-risk VPIs.

Therapeutic strategy of patent ductus arteriosus in extremely preterm infants.

The ductus arteriosus is likely to close without treatment in most infants born at gestational age (GA) > 28 weeks (73%), and those with birth weight > 1000 g (94%). However, the rates of spontaneous ductal closure among less mature or smaller infants with respiratory distress syndrome are not known. Extremely preterm infants born at GA < 28 weeks are associated with a high risk of severe intraventricular hemorrhage (IVH) or pulmonary hemorrhage, which usually occur within 72 h after birth and affect mortality and long-term neurological development. These serious hemorrhagic complications may be closely related to hemodynamic changes caused by a hemodynamically significant patent ductus arteriosus (hs-PDA). While prophylactic indomethacin has been shown to reduce the rates of PDA, PDA ligation, severe IVH and early pulmonary hemorrhage, the available evidence does not support its prophylactic use in preterm infants. Symptomatic or late treatment is associated with lower success rate, and increased complications of a hs-PDA. The issue of "to treat or not to treat a PDA" is controversial. Considering the relationship between the effectiveness and timing of pharmacological treatment, early targeted treatment may be an alternative approach for the early identification of a hs-PDA in specific high-risk patient population, especially infants <26 weeks GA who are at the highest risk of severe IVH or pulmonary hemorrhage. Serial echocardiographic studies can be used to select patients who are candidates for early targeted medical treatment of hs-PDA. Surgical ligation of PDA, and transcatheter closure if proven to be safe, can be used as back-up therapy for patients who fail medical treatment and continue to have cardiopulmonary compromise.

Circulatory Management Focusing on Preventing Intraventricular Hemorrhage and Pulmonary Hemorrhage in Preterm Infants.

The goal of modern neonatal care of extremely preterm infants is to reduce mortality and long-term neurological impairments. Preterm infants frequently experience cerebral intraventricular or pulmonary hemorrhage, which usually occurs within 72 hours after birth and can lead to long-term neurological sequelae and mortality. These serious hemorrhagic complications are closely related to perinatal hemodynamic changes, including an increase in the afterload on the left ventricle of the heart after the infant is separated from the placenta, and an increased preload from a left-to-right shunt caused by a hemodynamically significant patent ductus arteriosus (PDA). The left ventricle of a preterm myocardium has limited ability to respond to such an increase in afterload and preload, and this can result in cardiac dysfunction and hemodynamic deterioration. We suggest that delayed umbilical cord clamping or umbilical cord milking to maintain optimal blood pressure and systemic blood flow (SBF), careful assessment to keep the afterload at an acceptable level, and a strategy of early targeted treatment of significant PDA to improve perfusion during this critical time period may reduce or prevent these serious complications in preterm infants.

Early optimal nutrition improves neurodevelopmental outcomes for very preterm infants.

Recent advances in perinatal and neonatal intensive care have resulted in significant improvements in the survival of preterm extremely low-birthweight (PELBW) infants; however, extrauterine growth restriction (EUGR) and undernutrition occur frequently during hospitalization and are associated with adverse outcomes, including bronchopulmonary dysplasia, sepsis, and neurodevelopmental impairment. Early optimal parenteral nutrition with adequate amino acids and lipids, especially long-chain polyunsaturated fatty acids, has been shown to decrease the incidence of EUGR, bronchopulmonary dysplasia, necrotizing enterocolitis, sepsis, and retinopathy of prematurity in animal models and clinical trials. In PELBW infants, breast milk and probiotics have been shown to reduce the incidence of necrotizing enterocolitis, and lactoferrin has been demonstrated to prevent late-onset sepsis. Thus, early administration of optimal postnatal parenteral and enteral nutrients can help prevent neurodevelopmental impairment caused by EUGR, necrotizing enterocolitis, sepsis, bronchopulmonary dysplasia, and retinopathy of prematurity, and recent evidence indicates such treatment is feasible.

Prevalence and morbidity of late preterm infants: current status in a medical center of Northern Taiwan.

BACKGROUND: "Late preterm" defines infants born at 34(0/7) through 36(6/7) weeks' gestation, which comprise a majority of preterm births. These infants were treated clinically as "near-term" in the past, but recent studies have implied increased morbidities that differentiate late preterm and term infants. The purpose of this study was to examine the prevalence and clinical complications that could be associated with late preterm birth, as compared to term. METHODS: This was a retrospective cohort study that reviewed infants born in a medical center in Northern Taiwan during a 2-year period between 2008 and 2009. Maternal obstetrical factors, neonatal demographic distributions, and neonatal complications were compared between full-term and late preterm deliveries. RESULTS: During the study period, there were 7998 live births in the institute, including 6507 term and 1491 preterm infants. Of the latter, there were 914 (61.3%) born after 34 weeks' gestation. The Neonatal Intensive Care Unit (NICU) (including a special care nursery) admission rate was higher in late preterm infants when compared to term (36% vs. 2%), and was 74%, 43%, and 21% in infants born at 34, 35, and 36 weeks' gestation, respectively. Compared with term infants, late-preterm infants had longer hospital stay if admitted to NICU (including special care nursery) (17 days vs. 10 days), and they were associated with increased risk of neonatal morbidities, including respiratory distress syndrome (2.6% vs. 0.02%), respiratory distress of other etiologies (16% vs. 2%), culture-proven sepsis (0.7% vs. 0.2%), hypoglycemia (3% vs. 0.4%), temperature instability (0.4% vs. 0.05%), feeding difficulty (2% vs. 0.4%), and hyperbilirubinemia needing phototherapy (14% vs. 3%). Late-preterm infants also had higher hospital readmission rate (4.4% vs. 2.3%, p<0.001) and neonatal mortality rate (0.3% vs. 0.08%, p=0.03). CONCLUSION: Late-preterm infants have increased risk of neonatal morbidities associated with organ immaturity. The results of this study emphasize the importance of judicious obstetrical decision-making when considering late preterm delivery, and the need to set up anticipatory clinical guidelines for the care of late preterm infants.