Genome-wide association study identifies WWC2 as a possible locus associated with persistent pulmonary hypertension of the newborn in the Thai population.

Background: There is known to be significant genetic involvement in persistent pulmonary hypertension of the newborn (PPHN), but to date there is not a clear understanding of this situation, and clarifying that involvement would be of considerable assistance in devising effective treatments for the disease. This case-control study was undertaken to search for genetic variants associated with PPHN in the Thai population using a genome-wide association study (GWAS). Methods: A 659,184 single nucleotide polymorphisms from 387 participants (54 PPHN cases and 333 healthy participants) were genotyped across the human genome using an Illumina Asian Screening Array-24 v1.0 BeadChip Array. After quality control, we obtained 443,063 autosomal SNPs for the GWAS analysis. The FaST-LMM and R packages were used for all statistical analyses. Results: For the case-control analysis, the genomic inflation factor (λ) was 1.016, rs149768622 T>C in the first intron of WWC2 gene showed the strongest association with a P value of 3.76E-08 and odds ratio (OR) of 13.24 (95% CI: 3.91-44.78). The variants at the LOC102723906/LOC105377599, CADM4, GPM6A, CIT, RIMBP2, LOC105374510, LOC105375193, PTPRN2, CDK14, and LCORL loci showed suggestive evidence of associations with PPHN (P<1E-05). Conclusions: This GWAS found that rs149768622 T>C in the WWC2 gene was possibly associated with PPHN. However, replication and functional studies are needed to validate this association and further explore the role(s) of the WWC2 gene in PPHN.

Possible association between a polymorphism of EPAS1 gene and persistent pulmonary hypertension of the newborn: a case-control study

Abstract Objective: To explore possible genes related to the development of persistent pulmonary hypertension of the newborn (PPHN). Methods: The authors identified 285 single nucleotide polymorphisms (SNPs) of 11 candidate genes (BMPR2, EPAS1, PDE3A, VEGFA, ENG, NOTCH3, SOD3, CPS1, ABCA3, ACVRL1, and SMAD9), using an Illumina Asian Screening Array-24 v1.0 BeadChip Array. The FastLmmC and R package was used for statistical analyses. The chi-square test and Cochrane-Armitage trend test were used to compare the allele and genotype frequencies between the groups and to test the genetic models, respectively. Results: A total of 45 PPHN infants and 294 control subjects were analyzed. The most common cause of PPHN was meconium aspiration syndrome. Among the 285 SNPs, 17 SNPs from 6 candidate genes (BMPR2, EPAS1, PDE3A, VEGFA, ENG, and NOTCH3) were significantly associated with PPHN (P < 0.05). After using the Bonferroni correction (P < 0.00018), only the rs17034984 SNP located in intron 1 of the EPAS1 gene remained significantly different between the PPHN and control subjects (P = 0.00014). The frequency of the TC/TT genotype of rs17034984 in the gene with the dominant model was significant in the patients with PPHN (OR = 5.38, 95% CI: 2.15-13.49). The T allele frequency of rs17034984 in the gene showed a significant difference compared with the control subjects (OR = 4.89, 95% CI: 2.03-11.82). Conclusions: The present study suggests that the rs17034984 variant of EPAS1 gene is associated with PPHN.

Possible association between a polymorphism of EPAS1 gene and persistent pulmonary hypertension of the newborn: a case-control study.

OBJECTIVE: To explore possible genes related to the development of persistent pulmonary hypertension of the newborn (PPHN). METHODS: The authors identified 285 single nucleotide polymorphisms (SNPs) of 11 candidate genes (BMPR2, EPAS1, PDE3A, VEGFA, ENG, NOTCH3, SOD3, CPS1, ABCA3, ACVRL1, and SMAD9), using an Illumina Asian Screening Array-24 v1.0 BeadChip Array. The FastLmmC and R package was used for statistical analyses. The chi-square test and Cochrane-Armitage trend test were used to compare the allele and genotype frequencies between the groups and to test the genetic models, respectively. RESULTS: A total of 45 PPHN infants and 294 control subjects were analyzed. The most common cause of PPHN was meconium aspiration syndrome. Among the 285 SNPs, 17 SNPs from 6 candidate genes (BMPR2, EPAS1, PDE3A, VEGFA, ENG, and NOTCH3) were significantly associated with PPHN (P < 0.05). After using the Bonferroni correction (P < 0.00018), only the rs17034984 SNP located in intron 1 of the EPAS1 gene remained significantly different between the PPHN and control subjects (P = 0.00014). The frequency of the TC/TT genotype of rs17034984 in the gene with the dominant model was significant in the patients with PPHN (OR = 5.38, 95% CI: 2.15-13.49). The T allele frequency of rs17034984 in the gene showed a significant difference compared with the control subjects (OR = 4.89, 95% CI: 2.03-11.82). CONCLUSIONS: The present study suggests that the rs17034984 variant of EPAS1 gene is associated with PPHN.

Risk factor analysis of pneumothorax associated with persistent pulmonary hypertension of the newborn in Thai neonates.

Objective: To determine the risk factors and outcomes of persistent pulmonary hypertension of the newborn (PPHN)-associated pneumothorax (PTX).Study design: The medical records of infants diagnosed with PPHN with or without PTX from January 2012 to July 2017 were retrospectively reviewed.Results: Of the 102 included PPHN infants, PTX was found in 32 (31.4%) infants with 43.8% (14/32) mortality. PTX was significantly associated with increased mortality with an odds ratio (OR) of 5.27 (95% confidence interval [CI] 1.96-14.17). Unilateral PTX was more common than bilateral PTX (53.1 versus 46.9%, respectively). Multivariate logistic regression analysis indicated that a 1-minute Apgar score of ≤7 was associated with an increased risk for PTX (adjusted OR = 2.67 [95% CI 1.14-6.25]). In subgroup analysis, each increase of maximum peak inspiratory pressure (PIP) of 1 cmH2O significantly increased the odds of PTX by 1.46 (95% CI 1.02-2.07), while each 1 mmHg increase in arterial partial pressure of oxygen (PaO2) decreased the odds of PTX (adjusted OR = by 0.98 [95% CI 0.97-0.99]).Conclusions: PTX was significantly associated with higher mortality in PPHN infants. Lower Apgar score and increasing PIP in conventional mechanical ventilation were risk factors for PTX. Higher PaO2 was associated with a decreased rate of PTX.

An Asian multicenter retrospective study on persistent pulmonary hypertension of the newborn: incidence, etiology, diagnosis, treatment and outcome.

Objectives: To explore the incidence, etiologies, diagnostic methods, treatment options and outcomes in neonates with persistent pulmonary hypertension of the newborn (PPHN) and to identify mortality risk factors in a study from six Asian countries.Methods: A retrospective chart review of patients with documented PPHN from seven centers in six Asian countries (Japan, Kuwait, India, Pakistan, Singapore, and Thailand) between 1 January, 2014 and 31 December, 2016, was performed.Results: A total of 369 PPHN infants were identified. The incidence of PPHN ranged from 1.2 to 4.6 per 1000 live births. The all-cause mortality rate was 20.6% (76 of 369). Meconium aspiration syndrome was the primary cause of PPHN (24.1%). In most cases (84.8%) echocardiography was used to establish the diagnosis of PPHN. Sildenafil was the most commonly used pulmonary vasodilator (51.2%). Multivariate multiple regression analysis indicated gestational age <34 weeks (adjusted odds ratio (OR) = 3.27; 95% CI 1.56-6.74), congenital diaphragmatic hernia (CDH)/lung hypoplasia (LH) (adjusted OR = 6.13 (95% CI 2.28-16.42)), treatment with high frequency oscillation ventilation (HFOV) with or without inhaled nitric oxide (iNO) (adjusted OR = 3.11 (95% CI 1.52-6.34)), and inotropic agents (adjusted OR = 9.43 (95% CI 2.71-32.83)) were independently associated with increased risk of death.Conclusions: The incidence of PPHN in the current study was higher than in western settings. Birth weight, gestational age, CDH/LH, HFOV/iNO, and inotropic agents were significant mortality risk factors.

The Use of Colistin for the Treatment of Multidrug-resistant Gram-negative Infections in Neonates and Infants: A Review of the Literature.

In this review, we report the available data regarding efficacy, safety and pharmacokinetics of colistin in the treatment of multidrug-resistant Gram-negative bacteria in neonates and infants. Seventeen clinical studies, involving 312 patients, and 3 pharmacokinetics studies were identified. Blood stream infection was the most common source of infection, followed by pneumonia and meningitis/ventriculitis. In most cases, colistin was administered in association with other antibiotics. The most common route of administration was intravenous, with colistimethate doses ranging from 25,000 to 225,000 IU/kg/day divided into 2 or 3 doses. A recent pharmacokinetic study suggested that the appropriate intravenous dose should be >150,000 IU/kg/day. Microbiologic cure was obtained in 94.2% of patients and survival was 76.6%. The combination of intraventricular and intravenous colistin should be used in meningitis/ventriculitis. Nebulized colistin should be used as adjunctive treatment, but not as monotherapy. Nephrotoxicity and apnea were reported in 5.8% and 3.9% of patients respectively.The use of colistin for multidrug-resistant Gram-negative infections in neonates and infants is effective and safe, but the quality of studies is moderate. The optimal intravenous dose should be higher than that indicated in most reports.

The Practical Challenges of Diagnosis and Treatment Options in Persistent Pulmonary Hypertension of the Newborn: A Developing Country's Perspective.

Persistent pulmonary hypertension of the newborn (PPHN) is a complication of several respiratory diseases characterized by an elevation in pulmonary vascular resistance with resultant right-to-left shunting of blood and severe hypoxemia in the neonatal period. PPHN carries a high rate of morbidity and mortality, particularly in limited-resource settings (low-income and/or developing country). Echocardiography remains the gold standard for diagnosis of PPHN. Modern therapies such as inhaled nitric oxide, high-frequency oscillatory ventilation, extracorporeal membrane oxygenation, and/or other pulmonary vasodilators agents can reduce the mortality rate of PPHN. Unfortunately, echocardiography and the use of these modern therapies are often difficult for a medical institution to provide for patients in developing countries, even when a timely diagnosis of PPHN has been made. In this review, the practical challenges of timely diagnosis of PPHN and efficient use of available treatment options faced by pediatricians or neonatologists in limited-resource settings are discussed.

Factors and Outcomes of Persistent Pulmonary Hypertension of the Newborn Associated with Acute Kidney Injury in Thai Neonates.

OBJECTIVE: This study aims to determine the risk factors and outcome of persistent pulmonary hypertension of the newborn (PPHN)-associated acute kidney injury (AKI). STUDY DESIGN: Infants diagnosed with PPHN at Hat Yai Hospital from January 2012 to December 2016 were retrospectively reviewed. RESULTS: Of the 109 included PPHN infants, 28.4% (31/109) died, and AKI was found in 28.4% following neonatal KDIGO classification. Of the 31, 19 who died (61.3%) reached stage 1, 3 (9.7%) reached stage 2, and 9 (29.0%) reached stage 3. AKI (all stages combined) was significantly associated with increased mortality with an odds ratio (OR) of 8.71 (95% confidence interval [CI], 3.37-22.49). Multivariate logistic regression analysis indicated that male gender (adjusted OR = 8.56; 95% CI = 0.84-85.09) and urine output of < 1 mL/kg/h in 12 hours of admission (adjusted OR = 15.57; 95% CI = 2.58-93.98) were the main factors associated with an increased risk for AKI, while birth by cesarean delivery was associated with reduced risk of AKI (adjusted OR = 0.10; 95% CI = 0.16-0.68). CONCLUSION: The incidence of AKI in PPHN was high in this study, and this complication was also significantly associated with higher mortality. In PPHN neonates, AKI should be especially closely monitored in males and infants who have a urine output of < 1 mL/kg/h in the first 12 hours of admission.

Fatal Vernix Caseosa Aspiration Associated With Persistent Pulmonary Hypertension of the Newborn.

Vernix caseosa aspiration is an extremely rare condition resulting in high mortality if complicated by persistent hypertension of the newborn (PPHN). Herein we offer the first case report of PPHN due to massive vernix caseosa aspiration documented by histopathological examination. This case report is presented to provide a synopsis of the pathoetiology of PPHN related to vernix caseosa aspiration syndrome as likely to be encountered by neonatologists and general pediatricians involved with neonatal care.

Pharmacokinetics of Colistin Following a Single Dose of Intravenous Colistimethate Sodium in Critically Ill Neonates.

In this study, we sought to evaluate the pharmacokinetics of colistin after intravenous administration of colistimethate sodium (CMS) in the critically ill neonates with Gram-negative bacterial infections. A single intravenous dose of CMS [approximately 150,000 IU/kg, equivalent to 5 mg/kg colistin base activity (CBA)] was administered to 7 critically ill neonates. Mean (±SD) maximum plasma colistin concentration and area under the time-concentration curve from 0 to infinity were 3.0 ± 0.7 µg/mL and 25.3 ± 10.4 µg·h/mL, respectively. Time to maximum concentration, half-life, apparent volume of distribution and clearance were 1.3 ± 0.9 hours, 9.0 ± 6.5 hours, 7.7 ± 9.3 L/kg and 0.6 ± 0.3 L/h/kg, respectively. After a dose regimen of 5 mg/kg CBA every 24 hours, the average concentration expected at steady state is 1.1 ± 0.4 µg/mL. In critically ill neonates, a single intravenous dose of 5 mg CBA/kg (approximately 150,000 IU/kg of CMS) resulted in suboptimal plasma concentrations of colistin. According to our pharmacokinetics data, the dosage of CMS currently used in critically ill neonates is insufficient.

Acute kidney injury and pneumothorax are risk factors for mortality in persistent pulmonary hypertension of the newborn in Thai neonates.

OBJECTIVES: To describe the clinical characteristics, diagnostic methods, treatment modalities, and complications, and identify the mortality risk factors, of infants with short-term persistent pulmonary hypertension of the newborn (PPHN). METHODS: The clinical data of infants diagnosed with PPHN at Hat Yai Hospital from January 2010 to February 2014 were retrospectively reviewed. Cox proportional hazard regression analysis was performed to assess factors associated with mortality. RESULTS: The records of 119 infants were analyzed. Of these, 47 died giving an in-hospital mortality rate of 39.5%. The prevalence of PPHN (based on inborn births) was 2.8 per 1000 live births. The mean gestational age and birth weight were 39.1 ± 1.6 weeks and 3044 ± 563 g, respectively. Multivariate Cox regression analysis indicated that pneumothorax [adjusted hazard ratio (HR) = 2.07 (95% CI 1.09-3.93)] and acute kidney injury [adjusted HR = 2.99 (95% CI 1.59-5.61)] were factors associated independently with an increased risk for death, while infants who received total parenteral nutrition [adjusted HR = 0.22 (95% CI 0.10-0.50)] had lower mortality. CONCLUSION: A high mortality rate of PPHN was observed in this study. Significantly higher mortality was noted in infants complicated with pneumothorax and acute kidney injury.

Pulmonary and Systemic Pharmacokinetics of Colistin Following a Single Dose of Nebulized Colistimethate in Mechanically Ventilated Neonates.

The purpose of this study was to evaluate the pulmonary and systemic pharmacokinetics of colistin following a single dose of nebulized colistimethate sodium (CMS) in mechanically ventilated neonates. We administered a single dose of nebulized CMS (approximately 120,000 IU/kg of CMS, equivalent to 4 mg/kg colistin base activity) to 6 ventilated neonates with ventilator-associated pneumonia. The median gestational age was 39 weeks (range, 32-39 weeks). Mean (± SD) tracheal aspirate colistin maximum concentration (Cmax), area under the concentration-time curve (AUC 0-24) and t1/2 were 24.0 ± 8.2 µg/mL, 147.6 ± 53.5 µg · hours/mL and 9.8 ± 5.5 hours, respectively. The plasma concentrations of colistin were low. In neonates, a single nebulized dose of CMS (120,000 IU) resulted in high local concentrations for at least 12 hours and low systemic concentrations of colistin. Twice daily nebulization might be more appropriate.

Neonatal infections in China, Malaysia, Hong Kong and Thailand.

OBJECTIVE: Neonatal sepsis is a major cause of neonatal deaths in Asia but data remain scarce. We aimed to investigate the causative organisms and antibiotic resistance in neonatal care units in China, Malaysia, Hong Kong and Thailand. METHODS: Prospective cohort study of neonatal sepsis defined as positive culture of a single potentially pathogenic organism from blood or cerebrospinal fluid differentiated into early-onset sepsis (EOS) occurring <3 days of birth and late-onset sepsis (LOS) ≥3 days after birth. RESULTS: During the study period, there were 963 episodes of neonatal sepsis. The incidence of EOS was 0.62 (95% CI 0.45 to 0.82) per 1000 live births or 4.91 (95% CI 4.22 to 5.68) per 1000 admissions while the incidence of LOS was 5.00 (95% CI 4.51 to 5.53) per 1000 live births or 21.22 (95% CI 19.79 to 22.77) per 1000 admissions. The incidence of Group B Streptococcus (GBS) sepsis was low but remained the most common single pathogen for EOS among inborn babies. Klebsiella spp. was the most common Gram-negative organism causing most deaths. The case-fatality was 7.0% (95% CI 3.9% to 12.0%) for EOS and 16.0% (95% CI 13.7% to 19.0%) for LOS, and was significantly different between participating units after adjusting for potential confounders. Of all Gram-negative organisms, 47%, 37% and 32% were resistant to third-generation cephalosporins, gentamicin or both, respectively. CONCLUSIONS: The pattern of EOS in Asian settings is similar to that in industrialised countries with low incidence of GBS sepsis. The important features of neonatal sepsis in Asia are the burden of Klebsiella spp. and high level of antibiotic resistance. These should be addressed while developing measures to reduce neonatal mortality due to infection.

Predicting mortality in infants with persistent pulmonary hypertension of the newborn with the Score for Neonatal Acute Physiology-Version II (SNAP-II) in Thai neonates.

AIM: To evaluate the ability of the Score for Neonatal Acute Physiology-Version II (SNAP-II) to predict mortality in infants with persistent pulmonary hypertension of the newborn (PPHN). METHODS: A prospective cohort study of 41 infants with PPHN admitted to our neonatal intensive care unit between June 2008 and March 2010, who underwent a SNAP-II test within 12 h of admission. RESULTS: Of the 41 infants, 14 died (34.1%) and 27 survived (65.9%). The SNAP-II scores were significantly higher in infants who died (50.1 ± 18.5 vs. 35.7 ± 16.8, P=0.02). Each point increase in the SNAP score increased the odds of mortality by 1.04 [95% confidence interval (CI) 1.01-1.07, P<0.01]. Infants who had a SNAP-II score of ≥ 43 had the greatest mortality risk with an odds ratio (OR) of 10.00 (95% CI 1.03-97.50). The SNAP-II model showed moderate discrimination in predicting mortality with a result of 0.72 (95% CI 0.56-0.88) under the receiver operating characteristic curve. The lowest blood pressure, lowest PaO(2)/FIO(2) ratio, and urine output within the first 12 h of admission were also independently found to be good predictors of an increased risk for death. CONCLUSION: The SNAP-II scoring system significantly predicted mortality. PPHN infants with a SNAP-II score of ≥ 43 had the greatest mortality risk.

Septicemia, meningitis, and skull osteomyelitis complicating infected cephalhematoma caused by ESBL-producing Escherichia coli.

An infected cephalhematoma is a rare condition in neonates. We report a case of an 18-day-old neonate who was diagnosed with an infected cephalhematoma caused by an extended spectrum beta-lactamase (ESBL)-producing Escherichia coli complicated with septicemia, meningitis, and skull osteomyelitis. He was successfully treated with meropenem and surgical incision and drainage. ESBL-producing E. coli may cause infection of a cephalhematoma in neonates.

Persistent pulmonary hypertension of the newborn successfully treated with beraprost sodium: a retrospective chart review.

BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) is one of the most serious conditions in neonates resulting in a high mortality and morbidity. New alternative therapies for PPHN have been sought to improve survival and reduce morbidity. OBJECTIVES: To report an initial experience of using beraprost sodium (BPS) to treat infants with PPHN and to assess its effect on oxygenation and hemodynamic stability over a 72-hour study period. METHODS: The clinical data of neonates who received BPS as an adjunctive therapy for PPHN in our hospital between July 2007 and June 2008 were retrospectively reviewed. RESULTS: During the study period, 7 infants with PPHN were successfully treated with BPS. The mean gestational age and birth weight were 39.3 ± 1.5 weeks and 3,365.7 ± 569.8 g, respectively. BPS was initiated at a median age of 42.7 h after birth (range: 2.1-166.5 h) with a baseline mean oxygen index (OI) of 33.9 ± 15.7 and a baseline mean systolic blood pressure (SBP) of 79.4 ± 9.9 mm Hg. The mean difference of OI at 24, 48 and 72 h following the treatment was -15.7 ± 14.8 (p = 0.043), -18.2 ± 12.3 (p = 0.018) and -16.7 ± 17.5 (p = 0.042), respectively. The mean SBP was significantly reduced as early as 6 h after initiation of treatment (-11.1 ± 11.5 mm Hg, p = 0.034) without changes in heart rate. Three cases were complicated with chronic lung disease, and the remaining 4 cases were normal at hospital discharge. No neurodevelopmental and cardiopulmonary disorders were observed in all cases at 1 year of age. CONCLUSIONS: BPS may be used as an alternative treatment for infants with PPHN giving a significant improvement in oxygenation.