Changes in Lung Function Among Infants Born Extremely Preterm over a 20-Year Period in the Post-Surfactant Era: A Retrospective Study.

Lung function was assessed at 8 years in 308 infants born extremely preterm between 1994 and 2013. Although lung function of those infants born at 22 through 25 weeks remained unchanged, those who were born at 26-27 weeks showed a significant improvement over the past 2 decades.

Postneonatal mortality of severely small for gestational age extremely low birth weight infants.

BACKGROUND: Infants born with weights below the 10th percentile of the expected birth weight for gestational age, defined as small for gestational age (SGA), have an increased risk of neonatal mortality and prematurity-related complications. However, the relationship between SGA and postneonatal (28 days to <1 year) mortality among extremely low birth weight infants (ELBWIs) remains uncertain. Hence, this study aimed to investigate the association between birth weight percentiles and postneonatal mortality in ELBWIs. METHODS: A cohort of ELBWIs with a gestational age greater than 23 weeks who were admitted to Osaka Women's and Children's Hospital between 2008 and 2019 were considered eligible. Infants with major congenital anomalies, those large for their gestational age, or those who died within 28 days of birth were excluded. Baseline characteristics and outcomes of the three groups of ELBWIs-severe SGA (sSGA; birth weight, <3rd percentile), moderate SGA (mSGA; birth weight, 3rd to <10th percentile), and appropriate for gestational age (AGA; birth weight, 10th to <90th percentile)-were compared. Logistic regression analysis was used to identify perinatal factors associated with postneonatal mortality in sSGA infants. RESULTS: sSGA ELBWIs demonstrated higher incidence of meconium obstruction (25% vs. 8.3% vs. 7.6%, P < 0.001), cholestasis (21% vs. 4.2% vs. 9.7%, P < 0.003), and postneonatal mortality (7.3% vs. 0% vs. 0.7%, P < 0.004) than mSGA and AGA ELBWIs. In the logistic regression analysis, cholestasis (odds ratio, 30.1; 95% confidence interval, 2.98-304) and sepsis (odds ratio, 13.5; 95% confidence interval, 1.06-173) were significantly related to postneonatal mortality among ELBWIs with sSGA. The leading cause of postneonatal mortality in sSGA ELBWIs was liver failure (55.5%). CONCLUSION: sSGA ELBWIs exhibited a higher rate of postneonatal mortality compared to mSGA and AGA ELBWIs. Therefore, strategies aimed at preventing liver dysfunction in severely cholestatic ELBWIs with sSGA are necessary.

The Association between Early Gram-Negative Bacteria in Tracheal Aspirate Cultures and Severe Bronchopulmonary Dysplasia among Extremely Preterm Infants Requiring Prolonged Ventilation.

OBJECTIVE: The study aimed to evaluate the association between bronchopulmonary dysplasia (BPD) development at 36 weeks' postmenstrual age (PMA) and Gram-negative bacteria in tracheal aspirate cultures among extremely preterm infants. STUDY DESIGN: This study has a retrospective cohort. Patients were 155 infants aged less than or equal to 26 gestational weeks who were admitted to the neonatal intensive care unit of Osaka Women's and Children's Hospital from 2009 to 2018. Primary outcome was respiratory outcomes expressed as BPD development.Multivariable logistic regression analysis was used to identify neonatal and bacterial factors associated with BPD. RESULTS: After adjusting for gestational age, birth weight, sex, chorioamnionitis, Gram-positive cocci (GPC) and Gram-negative rods (GNRs) in tracheal aspirate cultures within 28 days after birth, GNRs were significantly associated with BPD development (odds ratio [OR]: 3.88, 95% confidence interval [CI]: 1.68-8.94). In contrast, GPCs were not associated with BPD development (OR: 0.47, 95% CI: 0.05-1.61). CONCLUSION: Gram-negative bacteria in tracheal cultures within 28 days of birth are associated with BPD development in infants aged less than or equal to 26 gestational weeks. KEY POINTS: · BPD is a factor for morbidity in extremely preterm infants.. · Respiratory infection is an adverse outcome of BPD.. · GNRs in tracheal cultures soon after birth disturb BPD development.. · GPC was not associated with BPD development..

Feasibility of portable capnometer for mechanically ventilated preterm infants in the delivery room.

This study aimed to determine whether a specific portable capnometer (EMMA™) can facilitate the maintenance of an appropriate partial pressure of arterial carbon dioxide (PaCO2) in intubated preterm infants in the delivery room. This study included preterm infants with a gestational age of 26 + 0 to 31 + 6 weeks who required intubation in the delivery room. We prospectively identified 40 infants who underwent the EMMA™ monitoring intervention group and 43 infants who did not undergo monitoring (historical control group). PaCO2 was evaluated either at admission in the neonatal intensive care unit or at 2 h after birth. The proportion of infants with an appropriate PaCO2 (35-60 mmHg) was greater in the intervention group than in the control group (80% vs. 42%; p = 0.001). There were no significant differences in the rate of accidental extubation (5.0% vs. 7.0%, p = 1.00) or in the proportion of infants with an appropriate PaCO2 among infants whose birth weight was < 1000 g (54% vs. 40%, p = 0.49). However, among infants whose birth weight was ≥ 1000 g, the PaCO2 tended to be more appropriate in the intervention group than in the control group (93% vs. 44%; p < 0.001).Conclusion: The EMMA™ facilitated the maintenance of an appropriate PaCO2 for mechanically ventilated preterm infants, especially infants with birth weight ≥1000 g, in the delivery room. What is Known: • An inappropriate partial pressure of arterial carbon dioxide has been associated with intraventricular hemorrhage in preterm infants. • There is a need to appropriately control the partial pressure of arterial carbon dioxide in preterm infants. What is New: • This is the first report regarding the feasibility of a portable capnometer, the EMMA™, in the delivery room. • The EMMA™ may be considered a feasible monitoring device in the delivery room for intubated preterm infants, especially infants with birth weight ≥1000 g.

Long-term outcome of urea cycle disorders: Report from a nationwide study in Japan.

Urea cycle disorders (UCDs) are inherited metabolic disorders with impaired nitrogen detoxification caused by defects in urea cycle enzymes. They often manifest with hyperammonemic attacks resulting in significant morbidity or death. We performed a nationwide questionnaire-based study between January 2000 and March 2018 to document all UCDs in Japan, including diagnoses, treatments, and outcomes. A total of 229 patients with UCDs were enrolled in this study: 73 males and 53 females with ornithine transcarbamylase deficiency (OTCD), 33 patients with carbamoylphosphate synthetase 1 deficiency, 48 with argininosuccinate synthetase deficiency, 14 with argininosuccinate lyase deficiency, and 8 with arginase deficiency. Survival rates at 20 years of age of male and female patients with late-onset OTCD were 100% and 97.7%, respectively. Blood ammonia levels and time of onset had a significant impact on the neurodevelopmental outcome (P < .001 and P = .028, respectively). Hemodialysis and liver transplantation did not prevent poor neurodevelopmental outcomes. While treatment including medication, hemodialysis, and liver transplantation may aid in decreasing blood ammonia and/or preventing severe hyperammonemia, a blood ammonia level ≥ 360 µmol/L was found to be a significant indicator for a poor neurodevelopmental outcome. In conclusion, although current therapy for UCDs has advanced and helped saving lives, patients with blood ammonia levels ≥ 360 µmol/L at onset often have impaired neurodevelopmental outcomes. Novel neuroprotective measures should therefore be developed to achieve better neurodevelopmental outcomes in these patients.

Availability of portable capnometers in children with tracheostomy.

BACKGROUND: A capnometer is a noninvasive monitor that is used to assess patients' respiratory status. This study was performed to evaluate the availability of a portable capnometer in children with tracheostomy. METHODS: This retrospective study included children with tracheostomy who were treated at the Osaka Women's and Children's Hospital Osaka, Japan, from 1 September 2018 to 31 October 2019. We assessed the correlation between the partial pressure of venous carbon dioxide (PvCO2 ) and end-tidal carbon dioxide tension (EtCO2 ) using a portable capnometer (EMMA; Masimo, Irvine, CA, USA). RESULTS: Nine infants and 43 simultaneous PvCO2 -EtCO2 pairs were analyzed. The correlation coefficient of these pairs was 0.87 (95% confidence interval, 0.77-0.93; P < 0.001). The Bland-Altman plot showed that EtCO2 was on average 10.0 mmHg lower than its paired PvCO2 value (95% limits of agreement, 1.0-19.1). The difference between PvCO2 and EtCO2 was significantly greater in patients on ventilators. CONCLUSIONS: The portable capnometer evaluated in this study (EMMA) was readily available and useful for assessment of the respiratory condition in children with tracheostomy.

Association between amount of dopamine and infections in extremely preterm infants.

This study aimed to assess the effect of dopamine on the development of infections after birth in extremely preterm infants. We retrospectively identified 258 extremely preterm infants (born at < 28 gestational weeks) between July 2009 and December 2018 in a tertiary neonatal intensive care unit (NICU). We extracted data on potential risk factors for infection, total amount of dopamine, and infection history during NICU stay for each infant. We compared the infection group with the non-infection group, and used the Cox proportional hazard regression analysis to identify risk factors for infection during NICU stay. After adjustment for all potential risk factors, factors that significantly affected development of infection were gestational age (hazard ratio [HR], 0.70; 95% confidence interval [CI] 0.55-0.89; p = 0.004) and total amount of dopamine (HR, 1.04; 95% CI 1.02-1.07; p = 0.002). The receiver operating characteristic curve of total amount of dopamine for infection suggested that total amount of dopamine greater than 7.271 mg/kg predicted infection development with 80.4% sensitivity and 41.7% specificity.Conclusion: A large amount of dopamine can increase infections in extremely preterm infants. We should avoid using a large amount of dopamine and remain aware of the potential development of infections in extremely preterm infants. What is Known: • Inotropes are often used for extremely preterm infants and dopamine is the most commonly used inotrope. • However, it is suggested that dopamine affects the immune system and related infections. What is New: • This is the first study of the association between the amount of dopamine and infection in extremely preterm infants. • We should avoid using a large amount of dopamine in extremely preterm infants.

Postnatal physiological changes in electrical activity of the diaphragm in extremely preterm infants.

OBJECTIVES: This study aimed to describe postnatal physiological changes in maximum values of peak electrical activity of the diaphragm (Edi) in extremely preterm infants during the preterm period. WORKING HYPOTHESIS: The amplitude and frequency of neural sigh are different at each postmenstrual age in extremely preterm infants. STUDY DESIGN: A retrospective, observational study. PATIENT-SUBJECT SELECTION: Edi values were evaluated in 14 extremely preterm infants with neurally-adjusted ventilatory assist. METHODOLOGY: Data of Edi peak and Edi minimum were collected from a ventilator. Edi-sigh was defined as the Edi peak value that was more than twice as large as the median Edi peak at each postmenstrual week in each patient. The frequency of Edi-sigh, and median values of Edi-sigh, Edi peak, and Edi minimum were evaluated at each postmenstrual week. The Jonckheere-Terpstra test was used to analyze the trend between postmenstrual weeks and Edi values. RESULTS: From 26 to 35 postmenstrual weeks, the number of Edi-sighs per hour significantly increased as postmenstrual weeks increased (P < .001). Furthermore, the median values of Edi-sigh significantly increased as postmenstrual weeks increased (16.9 µV at 26 weeks to 25.4 µV at 35 weeks, P < .001). There were no significant changes in the median values of Edi peak and Edi minimum at each week. CONCLUSIONS: The amplitude and frequency of neural sigh in extremely preterm infants increase with the number of postmenstrual weeks.

Effect of fluctuation of oxygenation on the development of severe retinopathy of prematurity in extremely preterm infants.

OBJECTIVE: To investigate factors associated with development of severe retinopathy of prematurity (ROP) in extremely preterm (EP) infants. STUDY DESIGN: This retrospective cohort study included 213 EP infants (22 + 0 to 27 + 6 weeks gestation) who were admitted to the neonatal intensive care unit of Osaka Women's and Children's Hospital between 2009 and 2017. Multivariable logistic regression analysis was used to identify neonatal factors associated with severe ROP requiring treatment. RESULT: After adjustments for gestational age (GA), birth weight, sex, red blood cell transfusion, average SpO2, and fluctuations of SpO2 from birth to 32 weeks postmenstrual age, fluctuations of SpO2 (odds ratio [OR]: 2.10, 95% confidence interval [CI]: 1.03-4.27), and low GA (OR: 0.95, 95% CI: 0.91-0.98) were significantly associated with severe ROP. CONCLUSIONS: Fluctuations of SpO2 from birth to 32 weeks postmenstrual age and low GA were significantly associated with development of severe ROP requiring treatment in EP infants.

Clinical outcomes and protocol for the management of isolated congenital diaphragmatic hernia based on our prenatal risk stratification system.

BACKGROUND/PURPOSE: The aim of this study was to evaluate our prenatal risk stratification system for risk-adjusted management in fetuses with isolated congenital diaphragmatic hernia (CDH). METHODS: Ninety-four infants prenatally diagnosed with isolated CDH treated between 1998 and 2017 at our institution were included in this retrospective single-center cohort study. RESULTS: The patients were prenatally classified into four risk groups: Group A (n = 54), which consisted of infants with neither liver-up nor a contralateral lung-to-thorax transverse area (L/T) ratio <0.08. The infants in group A were divided into two subgroups: Group A-1 (n = 24) consisted of mild conditions; and Group A-2 (n = 30) consisted of severe conditions; Group B (n = 23), which consisted of infants with either liver-up or L/T ratio <0.08; and Group C (n = 17), which consisted of infants with both liver-up and L/T ratio <0.08. The rates of survival to discharge in Groups A-1, A-2, B, and C were 100.0%, 100.0%, 87.0%, and 58.8%, respectively. The rates of intact discharge were 91.7%, 90.0%, 52.1%, and 23.5%, respectively. CONCLUSIONS: Our prenatal risk stratification system demonstrated a significant difference in the severity of postnatal status and clinical outcomes between the groups. STUDY TYPE: Case Series, Retrospective Review. LEVELS OF EVIDENCE: LEVEL IV.

Impact of Time to Neonatal Transport on Outcomes of Transient Tachypnea of the Newborn.

OBJECTIVE: To assess effects of neonatal transport on transient tachypnea of the newborn (TTN) in outborn term neonates. STUDY DESIGN: This retrospective cohort study included 66 term neonates diagnosed with TTN and transported to the Osaka Women's and Children's Hospital neonatal intensive care unit between January 2003 and March 2018. A multivariate logistic regression analysis identified perinatal and neonatal transport factors associated with adverse short-term outcomes defined as mechanical ventilation >48 hours, continuous positive airway pressure >72 hours, pulmonary hemorrhage, and requirement for inhaled nitric oxide, thoracentesis, or surfactant replacement therapy. RESULTS: A lower gestational age (GA) (37.7 [37.2, 38.3] vs. 39.6 [37.8, 40.3] weeks, p = 0.002), longer time to neonatal transport (10.0 [4.3, 25.5] vs. 5.5 [2.7, 9.7] hours, p = 0.01), and higher respiratory rates during transport (70 [60, 85] vs. 60 [55, 78.8] breaths/min, p = 0.04) were significantly associated with adverse short-term outcomes. After adjusting for GA, sex, cesarean section, and time to neonatal transport, GA (odds ratio [OR], 0.37; 95% confidence interval [CI], 0.24-0.87) and time to neonatal transport (OR, 1.07; 95% CI, 1.01-1.13) were significantly associated with adverse outcomes. CONCLUSION: Short-term adverse prognosis of TTN is strongly associated with a lower GA and longer time between birth and neonatal transport.

Lethal hypophosphatasia successfully treated with enzyme replacement from day 1 after birth.

UNLABELLED: Hypophosphatasia (HPP) is a rare metabolic bone disease caused by loss-of-function mutations in the gene ALPL encoding the tissue nonspecific alkaline phosphatase (TNSALP). There is a broad range of severity in the phenotype of HPP, and the most severe form exhibits perinatal lethality without mineralization of the skeleton. Here, we describe a female infant with perinatal lethal HPP diagnosed in utero. She was treated with a recombinant ALP (asfotase alfa) as an enzyme replacement therapy (ERT), which started from 1 day after birth. She required invasive ventilation immediately upon birth and demonstrated severe hypomineralization of whole body bone. Severe respiratory insufficiency was controlled by intensive respiratory care with high-frequency oscillation ventilation and nitric oxide inhalation and deep sedation just after birth. Bone mineralization improved with treatment; improvements were visible by 3 weeks of age and continued with treatment. Serum calcium levels decreased following treatment, resulting in hypocalcemia and convulsion, and calcium supplementation was required until 3 months of treatment. She was weaned from mechanical ventilation and has now survived more than 1 year. CONCLUSION: This case demonstrates the success of ERT in treating the severest HPP and highlights the importance of early diagnosis and intervention for these patients.

Parenteral-nutrition-associated liver disease after intestinal perforation in extremely low-birthweight infants: consequent lethal portal hypertension.

BACKGROUND: Parenteral nutrition (PN)-associated liver dysfunction (PNALD) in term infants usually manifests as intrahepatic cholestasis, which recovers with enteral nutrition (EN) in most cases; however, as the number of extremely low-birthweight infants (ELBWI) has been increasing, and consequently intestinal diseases associated with ELBWI have been increasing, more intractable PNALD has been encountered after surgical treatment in ELBWI, which does not resolve or rather worsens with EN. METHODS: Three cases of ELBWI with intestinal perforation, which developed PNALD and eventually died of hepatic failure with intractable portal hypertension, were reviewed. Their gestational age and birthweight ranged from 23 to 26 weeks, and from 434 to 968 g, respectively. The intestinal diseases included necrotizing enteritis in two and meconium-related ileus with focal intestinal perforation in one. RESULTS: The duration of total PN without EN in the three cases was 17, 24 and 24 days, respectively. The interval between the introduction of PN and the onset of PNALD was 14, 4 and 18 days, respectively. A marked elevation of serum endotoxin level was detected in both cases of necrotizing enteritis. Histopathological study of the liver revealed marked cholestasis, significant hepatic necrosis with fibrosis, and proliferation of ductules in all these cases, which was responsible for portal hypertension. CONCLUSIONS: PN after gastrointestinal disorders in ELBWI may cause refractory PNALD, which does not resolve, or rather worsens with the resumption of EN. Portal hypertension secondary to hepatic necrosis may be responsible for the exacerbation with the resumption of EN.

Inheritance of polyalanine expansion mutation of PHOX2B in congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS; MIM 209880) is caused mostly by dominant alanine expansion (most prevalent is 7-alanine expansion) mutations in PHOX2B. More than 90% of the alanine expansion mutations had been considered to be de novo due to unequal crossover during gametogenesis. However, a recent report stated that 25% of patients inherited the alanine-expanded allele from their parents with somatic mosaicism or constitutive mutation. We studied inheritance in 45 unrelated families, and found that one patient (2%) inherited 5-alanine expansion mutation from a parent with late-onset central hypoventilation syndrome and nine patients (20%) inherited 5- to 7-alanine expansion mutation from apparently asymptomatic parents with somatic mosaicism. Analysis using a sensitive method would be recommended to all parents of CCHS proband due to high incidence of somatic mosaicism. The absence of an alanine-contracted allele (expected counterpart allele in unequal crossover) and the highest prevalence of 6-alanine expansion mutation in somatic mosaicism suggest that the somatic mosaicism is likely caused by a mechanism other than an unequal crossover, such as a replication mechanism.