Exome sequencing links the SUMO protease SENP7 with fatal arthrogryposis multiplex congenita, early respiratory failure and neutropenia.

BACKGROUND: SUMOylation involves the attachment of small ubiquitin-like modifier (SUMO) proteins to specific lysine residues on thousands of substrates with target-specific effects on protein function. Sentrin-specific proteases (SENPs) are proteins involved in the maturation and deconjugation of SUMO. Specifically, SENP7 is responsible for processing polySUMO chains on targeted substrates including the heterochromatin protein 1α (HP1α). METHODS: We performed exome sequencing and segregation studies in a family with several infants presenting with an unidentified syndrome. RNA and protein expression studies were performed in fibroblasts available from one subject. RESULTS: We identified a kindred with four affected subjects presenting with a spectrum of findings including congenital arthrogryposis, no achievement of developmental milestones, early respiratory failure, neutropenia and recurrent infections. All died within four months after birth. Exome sequencing identified a homozygous stop gain variant in SENP7 c.1474C>T; p.(Gln492*) as the probable aetiology. The proband's fibroblasts demonstrated decreased mRNA expression. Protein expression studies showed significant protein dysregulation in total cell lysates and in the chromatin fraction. We found that HP1α levels as well as different histones and H3K9me3 were reduced in patient fibroblasts. These results support previous studies showing interaction between SENP7 and HP1α, and suggest loss of SENP7 leads to reduced heterochromatin condensation and subsequent aberrant gene expression. CONCLUSION: Our results suggest a critical role for SENP7 in nervous system development, haematopoiesis and immune function in humans.

Two-Year Outcomes After Minimally Invasive Surfactant Therapy in Preterm Infants: Follow-Up of the OPTIMIST-A Randomized Clinical Trial.

Importance: The long-term effects of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome remain to be definitively clarified. Objective: To examine the effect of MIST on death or neurodevelopmental disability (NDD) at 2 years' corrected age. Design, Setting, and Participants: Follow-up study of a randomized clinical trial with blinding of clinicians and outcome assessors conducted in 33 tertiary-level neonatal intensive care units in 11 countries. The trial included 486 infants with a gestational age of 25 to 28 weeks supported with continuous positive airway pressure (CPAP). Collection of follow-up data at 2 years' corrected age was completed on December 9, 2022. Interventions: Infants assigned to MIST (n = 242) received exogenous surfactant (200 mg/kg poractant alfa) via a thin catheter; those assigned to the control group (n = 244) received sham treatment. Main Outcomes and Measures: The key secondary outcome of death or moderate to severe NDD was assessed at 2 years' corrected age. Other secondary outcomes included components of this composite outcome, as well as hospitalizations for respiratory illness and parent-reported wheezing or breathing difficulty in the first 2 years. Results: Among the 486 infants randomized, 453 had follow-up data available (median gestation, 27.3 weeks; 228 females [50.3%]); data on the key secondary outcome were available in 434 infants. Death or NDD occurred in 78 infants (36.3%) in the MIST group and 79 (36.1%) in the control group (risk difference, 0% [95% CI, -7.6% to 7.7%]; relative risk [RR], 1.0 [95% CI, 0.81-1.24]); components of this outcome did not differ significantly between groups. Secondary respiratory outcomes favored the MIST group. Hospitalization with respiratory illness occurred in 49 infants (25.1%) in the MIST group vs 78 (38.2%) in the control group (RR, 0.66 [95% CI, 0.54-0.81]) and parent-reported wheezing or breathing difficulty in 73 (40.6%) vs 104 (53.6%), respectively (RR, 0.76 [95% CI, 0.63-0.90]). Conclusions and Relevance: In this follow-up study of a randomized clinical trial of preterm infants with respiratory distress syndrome supported with CPAP, MIST compared with sham treatment did not reduce the incidence of death or NDD by 2 years of age. However, infants who received MIST had lower rates of adverse respiratory outcomes during their first 2 years of life. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

Long-Term Effects of Inhaled Budesonide for Bronchopulmonary Dysplasia.

BACKGROUND: The long-term effects on neurodevelopment of the use of inhaled glucocorticoids in extremely preterm infants for the prevention or treatment of bronchopulmonary dysplasia are uncertain. METHODS: We randomly assigned 863 infants (gestational age, 23 weeks 0 days to 27 weeks 6 days) to receive early (within 24 hours after birth) inhaled budesonide or placebo. The prespecified secondary long-term outcome was neurodevelopmental disability among survivors, defined as a composite of cerebral palsy, cognitive delay (a Mental Development Index score of <85 [1 SD below the mean of 100] on the Bayley Scales of Infant Development, Second Edition, with higher scores on the scale indicating better performance), deafness, or blindness at a corrected age of 18 to 22 months. RESULTS: Adequate data on the prespecified composite long-term outcome were available for 629 infants. Of these infants, 148 (48.1%) of 308 infants assigned to budesonide had neurodevelopmental disability, as compared with 165 (51.4%) of 321 infants assigned to placebo (relative risk, adjusted for gestational age, 0.93; 95% confidence interval [CI], 0.80 to 1.09; P=0.40). There was no significant difference in any of the individual components of the prespecified outcome. There were more deaths in the budesonide group than in the placebo group (82 [19.9%] of 413 infants vs. 58 [14.5%] of 400 infants for whom vital status was available; relative risk, 1.37; 95% CI, 1.01 to 1.86; P=0.04). CONCLUSIONS: Among surviving extremely preterm infants, the rate of neurodevelopmental disability at 2 years did not differ significantly between infants who received early inhaled budesonide for the prevention of bronchopulmonary dysplasia and those who received placebo, but the mortality rate was higher among those who received budesonide. (Funded by the European Union and Chiesi Farmaceutici; ClinicalTrials.gov number, NCT01035190 .).

Effect of Minimally Invasive Surfactant Therapy vs Sham Treatment on Death or Bronchopulmonary Dysplasia in Preterm Infants With Respiratory Distress Syndrome: The OPTIMIST-A Randomized Clinical Trial.

Importance: The benefits of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome are uncertain. Objective: To examine the effect of selective application of MIST at a low fraction of inspired oxygen threshold on survival without bronchopulmonary dysplasia (BPD). Design, Setting, and Participants: Randomized clinical trial including 485 preterm infants with a gestational age of 25 to 28 weeks who were supported with continuous positive airway pressure (CPAP) and required a fraction of inspired oxygen of 0.30 or greater within 6 hours of birth. The trial was conducted at 33 tertiary-level neonatal intensive care units around the world, with blinding of the clinicians and outcome assessors. Enrollment took place between December 16, 2011, and March 26, 2020; follow-up was completed on December 2, 2020. Interventions: Infants were randomized to the MIST group (n = 241) and received exogenous surfactant (200 mg/kg of poractant alfa) via a thin catheter or to the control group (n = 244) and received a sham (control) treatment; CPAP was continued thereafter in both groups unless specified intubation criteria were met. Main Outcomes and Measures: The primary outcome was the composite of death or physiological BPD assessed at 36 weeks' postmenstrual age. The components of the primary outcome (death prior to 36 weeks' postmenstrual age and BPD at 36 weeks' postmenstrual age) also were considered separately. Results: Among the 485 infants randomized (median gestational age, 27.3 weeks; 241 [49.7%] female), all completed follow-up. Death or BPD occurred in 105 infants (43.6%) in the MIST group and 121 (49.6%) in the control group (risk difference [RD], -6.3% [95% CI, -14.2% to 1.6%]; relative risk [RR], 0.87 [95% CI, 0.74 to 1.03]; P = .10). Incidence of death before 36 weeks' postmenstrual age did not differ significantly between groups (24 [10.0%] in MIST vs 19 [7.8%] in control; RD, 2.1% [95% CI, -3.6% to 7.8%]; RR, 1.27 [95% CI, 0.63 to 2.57]; P = .51), but incidence of BPD in survivors to 36 weeks' postmenstrual age was lower in the MIST group (81/217 [37.3%] vs 102/225 [45.3%] in the control group; RD, -7.8% [95% CI, -14.9% to -0.7%]; RR, 0.83 [95% CI, 0.70 to 0.98]; P = .03). Serious adverse events occurred in 10.3% of infants in the MIST group and 11.1% in the control group. Conclusions and Relevance: Among preterm infants with respiratory distress syndrome supported with CPAP, minimally invasive surfactant therapy compared with sham (control) treatment did not significantly reduce the incidence of the composite outcome of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age. However, given the statistical uncertainty reflected in the 95% CI, a clinically important effect cannot be excluded. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

Newborn screening for cerebrotendinous xanthomatosis is the solution for early identification and treatment.

Cerebrotendinous xanthomatosis (CTX) is a progressive metabolic leukodystrophy. Early identification and treatment from birth onward effectively provides a functional cure, but diagnosis is often delayed. We conducted a pilot study using a two-tier test for CTX to screen archived newborn dried bloodspots (DBSs) or samples collected prospectively from a high-risk Israeli newborn population. All DBS samples were analyzed with flow injection analysis (FIA)-MS/MS, and 5% of samples were analyzed with LC-MS/MS. Consecutively collected samples were analyzed to identify CTX-causing founder genetic variants common among Druze and Moroccan Jewish populations. First-tier analysis with FIA-MS/MS provided 100% sensitivity to detect CTX-positive newborn DBSs, with a low false-positive rate (0.1-0.5%). LC-MS/MS, as a second-tier test, provided 100% sensitivity to detect CTX-positive newborn DBSs with a false-positive rate of 0% (100% specificity). In addition, 5ß-cholestane-3α,7α,12α,25-tetrol-3-O-ß-D-glucuronide was identified as the predominant bile-alcohol disease marker present in CTX-positive newborn DBSs. In newborns identifying as Druze, a 1:30 carriership frequency was determined for the c.355delC CYP27A1 gene variant, providing an estimated disease prevalence of 1:3,600 in this population. These data support the feasibility of two-tier DBS screening for CTX in newborns and set the stage for large-scale prospective pilot studies.

Early Inhaled Budesonide for the Prevention of Bronchopulmonary Dysplasia.

BACKGROUND: Systemic glucocorticoids reduce the incidence of bronchopulmonary dysplasia among extremely preterm infants, but they may compromise brain development. The effects of inhaled glucocorticoids on outcomes in these infants are unclear. METHODS: We randomly assigned 863 infants (gestational age, 23 weeks 0 days to 27 weeks 6 days) to early (within 24 hours after birth) inhaled budesonide or placebo until they no longer required oxygen and positive-pressure support or until they reached a postmenstrual age of 32 weeks 0 days. The primary outcome was death or bronchopulmonary dysplasia, confirmed by means of standardized oxygen-saturation monitoring, at a postmenstrual age of 36 weeks. RESULTS: A total of 175 of 437 infants assigned to budesonide for whom adequate data were available (40.0%), as compared with 194 of 419 infants assigned to placebo for whom adequate data were available (46.3%), died or had bronchopulmonary dysplasia (relative risk, stratified according to gestational age, 0.86; 95% confidence interval [CI], 0.75 to 1.00; P=0.05). The incidence of bronchopulmonary dysplasia was 27.8% in the budesonide group versus 38.0% in the placebo group (relative risk, stratified according to gestational age, 0.74; 95% CI, 0.60 to 0.91; P=0.004); death occurred in 16.9% and 13.6% of the patients, respectively (relative risk, stratified according to gestational age, 1.24; 95% CI, 0.91 to 1.69; P=0.17). The proportion of infants who required surgical closure of a patent ductus arteriosus was lower in the budesonide group than in the placebo group (relative risk, stratified according to gestational age, 0.55; 95% CI, 0.36 to 0.83; P=0.004), as was the proportion of infants who required reintubation (relative risk, stratified according to gestational age, 0.58; 95% CI, 0.35 to 0.96; P=0.03). Rates of other neonatal illnesses and adverse events were similar in the two groups. CONCLUSIONS: Among extremely preterm infants, the incidence of bronchopulmonary dysplasia was lower among those who received early inhaled budesonide than among those who received placebo, but the advantage may have been gained at the expense of increased mortality. (Funded by the European Union and Chiesi Farmaceutici; ClinicalTrials.gov number, NCT01035190.).

Factors associated with iatrogenesis in neonatal intensive care units: an observational multicenter study.

The objective of our study was to assess factors associated with iatrogenic events in Neonatal Intensive Care Units (NICUs). This was a retrospective analysis based on a cohort of patients who participated in our previous prospective study (Pediatrics 122:550-555, 2008), conducted in four tertiary university-affiliated NICUs in Israel, that included all consecutive infants (n = 615) hospitalized during the study period. Ongoing monitoring of iatrogenic events was performed by designated "iatrogenesis advocates." The main outcome measures were the association of individual infant characteristics and NICUs' environmental characteristics with iatrogenic events assessed by univariate and multiple logistic regression analysis. We found that four infant characteristics were significantly (p < 0.001) associated with iatrogenic events in a univariate analysis: gestational age, birth weight, severity of initial illness as assessed by the Score for Neonatal Acute Physiology and Perinatal Extension (SNAPPE II), and length of stay (LOS). All four factors demonstrated a significant (p < 0.001) dose-response relationship with iatrogenic events. Univariate analysis for environmental characteristics showed that type of shift, but not nursing workload, was significantly associated with iatrogenic events (p < 0.001). In a multiple logistic regression analysis, only LOS (adjusted OR 1.02 [95 % CI, 1.01-1.03]) and type of shift, morning vs. evening (adjusted OR 3.44 [95 % CI, 2.33-5.08]) and morning vs. night (adjusted OR 6.07 [95 % CI, 3.86-9.56]), remained independently associated with iatrogenic events (p < 0.001). Prolonged LOS and morning shifts were found to be significantly associated with iatrogenic events. Further prospective research is warranted to identify the specific causes for iatrogenic events in order to target active interventions to prevent them.

Limitations of the risk factor based approach in early neonatal sepsis evaluations.

AIM: Guidelines for detection of early neonatal sepsis employ a risk factor approach combined with laboratory parameters. In an era of increasing intrapartum antibiotic prophylaxis (IAP), we re-assessed the approach as a whole and each of the risk factors individually. METHOD: This retrospective study included infants with risk factors for sepsis or those treated with antibiotics or who had documented early sepsis. Safety of the protocol was assessed by the number of cases of either missed or partially treated late sepsis or meningitis and the sepsis-related mortality rate. Predictive value of each clinical and laboratory factor was calculated. RESULTS: Of the 22,215 neonates, 2096 were assessed. IAP among infants with risk factors rose from 68% in 2005 to 78% in 2008 (p = 0.001). A total of 1662 asymptomatic infants had risk factors, 635 received antibiotics and one (0.06%) had sepsis. A total of 434 symptomatic infants were treated with antibiotics and of these 234 had risk factors and 20 (4.6%) had sepsis. No cases of partially treated or missed sepsis were detected. Poor predictive value was found for all risk factors except prematurity and leukopenia. CONCLUSION: The risk factor based approach in asymptomatic infants cannot be justified. In-hospital observation of asymptomatic infants for 2-3 days with antibiotic treatment being reserved only for symptomatic infants may be a reasonable alternative.

Current evidence for prenatal and postnatal corticosteroids in preterm infants.

Antenatal corticosteroids undoubtedly save many lives and improve the quality of many others. However, the currently accepted dosage schedule has been in place since 1972, and recent studies have suggested that beneficial effects may be seen with less. Most but not all studies of long-term outcome show no adverse effects. The use of antenatal corticosteroids in women with COVID-19 raises important questions regarding potential risks and benefits. However, currently, most authorities recommend continuing according to published guidelines. With regard to postnatal corticosteroids, alternatives to systemic dexamethasone, the somewhat tainted standard of care, show promise in preventing bronchopulmonary dysplasia without adverse effects. Systemic hydrocortisone and inhaled corticosteroids are of note. The mixture of surfactant and corticosteroids deserves particular attention in the coming years.

Minimally invasive surfactant therapy versus intubation for surfactant delivery in preterm infant with RDS: evaluation of safety and efficacy.

BACKGROUND: Minimally invasive surfactant therapy (MIST) is a promising mode of administration that offers the potential to limit barotrauma and prevent lung injury in preterm infants with respiratory distress syndrome (RDS). OBJECTIVE: This study assessed the effects of the implementation of MIST on safety and efficacy in infants who met criteria for surfactant administration and were treated by MIST as compared with a historical control group treated with surfactant via an endotracheal tube during mechanical ventilation. METHODS: This retrospective study included infants born between 2012 and 2017 who met the following inclusion criteria: gestational age 23-36 + 6 weeks, a diagnosis of RDS requiring at least 30% oxygen with or without nasal continuous positive airway pressure (nCPAP). MIST was introduced in 2014 and a comparison was made between the study group who received MIST and the control group who met similar criteria and received surfactant via an endotracheal tube during mechanical ventilation. RESULTS: No significant differences were found between the groups in baseline and demographic data. Severity of initial disease, assessed by the CRIB II score, was similar in the two groups (control 4.6 ± 2.8, MIST 4.4 ± 2.4, p=.995). The requirement for oxygen during the first 3 d of life was significantly lower (area under the curve [AUC]: p=.001) in the MIST group as assessed by the AUC. Likewise, the mean days of oxygen requirement were significantly lower in the MIST group (Control: 10.3 d, MIST: 5.9 d, p=.04). Only six infants in the MIST group (13%) subsequently required intubation for mechanical ventilation, only one of whom adjacent to the procedure. A modest reduction in duration of ventilation was also noted. Duration of admission was 32 ± 23 d in the control group and 26 ± 21 d in the MIST group, p=.061. No significant differences were found between the groups in the incidence of major morbidities or mortality. No major adverse events related to the procedure were observed. CONCLUSIONS: Transition to MIST was associated with significantly reduced need for oxygen, mechanical ventilation and surfactant, and a borderline shortened NICU admission.

Neonatal SARS-CoV-2 Infections in Breastfeeding Mothers.

OBJECTIVES: To assess infection rates predischarge and postdischarge in breast milk-fed newborns with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive mothers who were separated postdelivery from their mothers and discharged from the hospital. Also, we aim to evaluate breastfeeding rates predischarge and postdischarge. METHODS: Nasopharyngeal swabs for SARS-CoV-2 were obtained from symptomatic and high-risk women in the delivery room. Mothers with positive SARS-CoV-2 test results were separated from the newborns. Newborns were screened within 48 hours of delivery, and anti-infectious guidelines were imparted to the mothers before discharge. Rescreening took place ≥14 days postdischarge. Data regarding SARS-CoV-2-positive household members and breastfeeding were obtained by follow-up phone calls. RESULTS: A total of 73 newborns of SARS-CoV-2-positive mothers were born in Israel during the ∼3-month period under study. Overall, 55 participated in this study. All neonates tested negative for the virus postdelivery. A total 74.5% of the neonates were fed unpasteurized expressed breast milk during the postpartum separation until discharge. Eighty-nine percent of the neonates were discharged from the hospital after their mothers were instructed in anti-infection measures. In 40% of the households, there were additional SARS-CoV-2-positive residents. A total of 85% of the newborns were breastfed postdischarge. Results for all 60% of the newborns retested for SARS-CoV-2 postdischarge were negative. CONCLUSIONS: No viral infection was identified in neonates born to and separated from their SARS-CoV-2-positive mothers at birth and subsequently fed unpasteurized breast milk. All infants breastfed at home remained SARS-CoV-2 negative. These findings may provide insights regarding the redundancy of postpartum mother-newborn separation in SARS-CoV-2-positive women and, assuming precautions are adhered to, support the safety of breast milk.

The red reflex examination in neonates: an efficient tool for early diagnosis of congenital ocular diseases.

BACKGROUND: The American Academy of Pediatrics recently published recommendations for the red reflex assessment in the newborn period to detect and treat ocular disorders as early as possible, and to prevent lifelong visual impairment and even save lives. The test is technically simple to perform, non-invasive, requires minimal equipment and can detect a variety of ocular pathologies including cataracts and retinal abnormalities. No specific national guidelines exist on this issue. OBJECTIVES: To document the implementation of red reflex examination in routine neonatal care and present the findings. METHODS: Our clinical experience following inclusion of the red reflex test into the newborn physical examination in a single center was reviewed. In addition, an electronic mail questionnaire was sent to all neonatology departments in Israel regarding performance of the red reflex test. RESULTS: During 2007-2008, five infants were identified with congenital cataracts at days 2-6 of life prior to discharge from hospital. Surgery was performed in one infant at age 2 months and all infants underwent a thorough follow-up. The incidence of congenital cataract in our center was 1:2300. Less than half the neonatology departments have endorsed the AAP recommendation and perform the red reflex test routinely. CONCLUSIONS: Abnormal red reflex test after delivery enables a rapid ophthalmologic diagnosis, intervention and close followup. We recommend that red reflex screening be performed as part of the newborn physical examination; if abnormal, an urgent ophthalmologic referral should be made.

Reassessing vitamin D supplementation in preterm infants: a prospective study and review of the literature.

Objectives Recommendations for vitamin D (VitD) intake and target serum levels of 25(OH)D in preterm infants are diverse. We hypothesized that preterm infants with low birth weight (BW) have low dietary intake of VitD and therefore should be supplemented with higher amounts of VitD. Methods Infants with BW < 2 kg were supplemented with 600 units of VitD a day during the first 2-6 weeks of life, whereas infants with BW>2 kg continued with the routine supplementation of 400 units of VitD daily. Serum levels of 25(OH)D, calcium, phosphorous, alkaline phosphatase (AP) and parathyroid hormone (PTH) were assessed 24 h after birth and before discharge. The total daily intake of vitD was calculated in each infant. Results Sixty-two infants were enrolled, 49 with BW < 2 kg. After birth, only 24% had sufficient levels of 25(OH)D, whereas before discharge 45 of 54 infants (83%) available for analysis reached sufficient levels of 25(OH)D. All 54 infants demonstrated significant elevation in serum levels of calcium, phosphorous, AP and significant reduction in PTH levels. The total daily intake of VitD was lower than recommended (800-1000 IU/d) in 16 of 45 infants with BW < 2 kg (36%) and in all nine infants with BW>2 kg. Nevertheless, only 2 of 25 infants with insufficient intake of VitD demonstrated insufficient levels of serum 25(OH)D. No case of vitamin D excess was recorded. Conclusions Increased supplementation of VitD (600 IU/d) for premature newborns with BW < 2 kg is effective in increasing both total daily intake of VitD and serum levels of 25(OH)D.

Third trimester fetal intracranial hemorrhage owing to vitamin K deficiency associated with hyperemesis gravidarum.

In rare cases, severe fetal vitamin K deficiency bleeding may occur in utero as a result of insufficient vitamin K placental transfer. We present a case of a 32-week-preterm infant born with severe intracranial hemorrhage to a pregnant woman who suffered from hyperemesis gravidarum. Neonatal hematologic status was compatible with vitamin K deficiency whereas the maternal coagulation function was normal. This case emphasizes the potential risk of fetal bleeding owing to vitamin K deficiency in pregnancies complicated with hyperemesis gravidarum. These women should be closely monitored and vitamin K prophylaxis might be considered.

Microcephaly, lymphedema, chorioretinopathy and atrial septal defect: a case report and review of the literature.

BACKGROUND: The rare congenital combination of microcephaly, lymphedema and chorioretinopathy (MLCD) has been described. Recently, three cases with these clinical characteristics have been diagnosed as having, in addition, various congenital cardiac anomalies, which may be part of this genetic entity that presents with variable expression. CLINICAL OBSERVATION: Here we present a new case of a one-year-old infant who was born with microcephaly and lymphedema and atrial septal defect (ASD) and developed chorioretinopathy at the age of 6 months. This infant had normal neurodevelopment at one year of age. CONCLUSION: We recommend that cardiac evaluation and long-term ophthalmologic follow-up should be part of the evaluation in each child born with microcephaly and lymphedema. Family counseling should include the fact that normal to near-normal development may be possible, despite the presence of microcephaly.