Second-Tier Next Generation Sequencing Integrated in Nationwide Newborn Screening Provides Rapid Molecular Diagnostics of Severe Combined Immunodeficiency.

Severe combined immunodeficiency (SCID) and other T cell lymphopenias can be detected during newborn screening (NBS) by measuring T cell receptor excision circles (TRECs) in dried blood spot (DBS) DNA. Second tier next generation sequencing (NGS) with an amplicon based targeted gene panel using the same DBS DNA was introduced as part of our prospective pilot research project in 2015. With written parental consent, 21 000 newborns were TREC-tested in the pilot. Three newborns were identified with SCID, and disease-causing variants in IL2RG, RAG2, and RMRP were confirmed by NGS on the initial DBS DNA. The molecular findings directed follow-up and therapy: the IL2RG-SCID underwent early hematopoietic stem cell transplantation (HSCT) without any complications; the leaky RAG2-SCID received prophylactic antibiotics, antifungals, and immunoglobulin infusions, and underwent HSCT at 1 year of age. The child with RMRP-SCID had complete Hirschsprung disease and died at 1 month of age. Since January 2018, all newborns in Norway have been offered NBS for SCID using 1st tier TRECs and 2nd tier gene panel NGS on DBS DNA. During the first 20 months of nationwide SCID screening an additional 88 000 newborns were TREC tested, and four new SCID cases were identified. Disease-causing variants in DCLRE1C, JAK3, NBN, and IL2RG were molecularly confirmed on day 8, 15, 8 and 6, respectively after birth, using the initial NBS blood spot. Targeted gene panel NGS integrated into the NBS algorithm rapidly delineated the specific molecular diagnoses and provided information useful for management, targeted therapy and follow-up i.e., X rays and CT scans were avoided in the radiosensitive SCID. Second tier targeted NGS on the same DBS DNA as the TREC test provided instant confirmation or exclusion of SCID, and made it possible to use a less stringent TREC cut-off value. This allowed for the detection of leaky SCIDs, and simultaneously reduced the number of control samples, recalls and false positives. Mothers were instructed to stop breastfeeding until maternal cytomegalovirus (CMV) status was determined. Our limited data suggest that shorter time-interval from birth to intervention, may prevent breast milk transmitted CMV infection in classical SCID.

Strictly controlled glucose infusion rates are associated with a reduced risk of hyperglycaemia in extremely low birth weight preterm infants.

AIM: We evaluated a strict strategy that aimed to avoid fluctuations in glucose infusion rates (GIRs) and assessed the independent effects of maximal daily GIRs on the hyperglycaemia risk among extremely low birth weight (ELBW) infants receiving early enhanced parenteral nutrition. METHODS: This study comprised all ELBW infants admitted to the neonatal intensive care unit of Oslo University Hospital Rikshospitalet, Norway, before (2007-2009) and after (2012-2013) implementing a strict GIR strategy. Severe hyperglycaemia was defined as two consecutive blood glucose values over 12 mmol/L. Maximum daily GIRs (mg/kg/min) were categorised into low (<5.1), intermediate (5.1-7.0) or high (>7.0). Mixed effects logistic regression modelling for repeated measurements was applied to investigate independent determinants of hyperglycaemia. RESULTS: We included 1293 treatment days for 195 infants. The maximum daily GIR decreased (6.3 versus 5.8 mg/kg/min), while mean daily glucose and energy intakes were maintained in the post-strategy period. The prevalence of severe hyperglycaemia (48% versus 23%), insulin use (39% versus 16%) and mortality (26% versus 10%) fell. Intermediate GIR (odds ratio 2.11) and high GIR (odds ratio 2.85) were significant independent predictors of severe hyperglycaemia compared to low GIR. CONCLUSION: A strict GIR strategy reduced the risk of severe hyperglycaemia and adverse outcomes.

Emotional and behavioral problems in late preterm and early term births: outcomes at child age 36 months.

BACKGROUND: Recent findings has shown that late preterm births (gestational weeks 34-36) and early term births (gestational weeks 37-38) is associated with an increased risk of several psychological and developmental morbidities. In this article we investigate whether late preterm and early term births is associated with an increased risk of emotional and behavioral problems at 36 months of age and whether there are gender differences in risk of these outcomes. METHODS: Forty-three thousand, two hundred ninety-seven children and their mothers participating in the Norwegian Mother and Child Cohort Study (MoBa). One thousand, eight hundred fifty-three (4.3%) of the children in the sample were born late preterm and 7,835 (18.1%) were born early term. Information on gestational age and on prenatal and postnatal risk factors was retrieved from the Medical Birth Registry of Norway. Information on emotional and behavioral problems was assessed by standardized questionnaires (CBCL/ITSEA) filled out by the mothers. Gender-stratified logistic regression analyses were used to explore the association between late preterm / early term and emotional and behavioral problems at 36 months of age. RESULTS: We found a gender-specific increased risk of emotional problems in girls born late preterm (OR 1.47 95%CI 1.11-1.95) and in girls born early term (OR 1.21 95%CI 1.04-1.42). We did not find an increased risk of emotional problems in boys born late preterm (OR 1.09 95%CI 0.82-1.45) or early term (OR 0.93 95%CI 0.79-1.10). Behavioral problems were not increased in children born late preterm or early term. CONCLUSION: Girls born late preterm and early term show an increased risk of emotional problems at 36 months of age. This finding suggests that gender should be taken into account when evaluating children born at these gestational ages.

Early Enhanced Parenteral Nutrition, Hyperglycemia, and Death Among Extremely Low-Birth-Weight Infants.

IMPORTANCE: Efforts to optimize early parenteral nutrition (PN) in extremely low-birth-weight (ELBW) infants to promote growth and development may increase hyperglycemia risk. Recent studies have identified an association between early hyperglycemia and adverse outcomes in ELBW infants. OBJECTIVES: To examine the prevalence of early hyperglycemia and clinical outcomes among ELBW infants before (2002-2005) and after (2006-2011) the implementation of an early enhanced PN protocol and to assess the independent effects of early enhanced PN and early hyperglycemia on mortality. DESIGN, SETTING, AND PARTICIPANTS: Observational cohort study in a level III neonatal intensive care unit. Prospectively collected clinical data in the neonatal intensive care unit's medical database, nutritional information, and blood glucose levels were merged for analysis. All ELBW infants born between January 1, 2002, and December 31, 2011, without lethal malformations and still alive at 12 hours of life were eligible for inclusion in the study. MAIN OUTCOMES AND MEASURES: Mortality was the main outcome measure. Severe hyperglycemia was defined as 2 consecutive blood glucose levels exceeding 216 mg/dL at least 3 hours apart. A multivariable logistic regression model was applied to determine the independent effects of early enhanced PN and hyperglycemia on mortality. RESULTS: In total, 343 infants were included in the study, 129 in a historical comparison group before the enhanced PN protocol and 214 in the early enhanced PN group. Baseline characteristics were similar between the study groups. After the introduction of early enhanced PN, the prevalence of severe hyperglycemia during the first week of life was higher in the early enhanced PN group (11.6% [15 of 129] vs 41.6% [89 of 214], P < .001), as was the mortality (10.9% [14 of 129] vs 24.3% [52 of 214], P = .003). When adjusting for background characteristics, treatment, and nutritional data, early severe hyperglycemia remained a strong independent risk factor for death (odds ratio, 4.68; 95% CI, 1.82-12.03), together with gestational age (odds ratio, 0.62; 95% CI, 0.49-0.79). CONCLUSIONS AND RELEVANCE: The implementation of an enhanced PN protocol was correlated with an increased prevalence of severe hyperglycemia and higher mortality. In the multivariable analysis, an enhanced PN regimen per se was not predictive of mortality, whereas early severe hyperglycemia remained strongly predictive of death. To avoid detrimental effects on outcomes in ELBW infants, the optimal composition of early PN to avoid postnatal growth failure must be carefully balanced against hyperglycemia risk.

Communication impairments in early term and late preterm children: a prospective cohort study following children to age 36 months.

OBJECTIVE: To investigate the risk of communication impairments at age 18 and 36 months in children born early term (gestational weeks 37-38) and late preterm (gestational weeks 34-36). STUDY DESIGN: A total of 39 423 children and their mothers participated in the Norwegian Mother and Child Cohort Study. The sample included 7109 children (18%) born early term and 1673 (4.2%) born late preterm. Information on gestational age and prenatal and postnatal risk factors was obtained from the Medical Birth Registry of Norway. Information on communication impairments was assessed using standardized questionnaires filled out by the mothers. Stepwise logistic regression analysis was applied to explore the associations between early term/late preterm birth and communication impairments at age 18 and 36 months. RESULTS: Compared with children born at term, children born early term and late preterm had an increased risk of communication impairments at age 18 and 36 months. In early term, the aOR was 1.27 (95% CI, 1.12-1.44) at 18 months for communication impairments and 1.22 (95% CI, 1.07-1.39) at 36 months for expressive language impairments. In late preterm, the aOR was 1.74 (95% CI, 1.41-2.14) at 18 months and 1.37 (95% CI, 1.09-1.73) at 36 months. CONCLUSION: Not only children born late preterm, but also those born early term, are at increased risk for communication impairments. Given the large number of children potentially affected, this may result in significant health care costs.