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Purpose Newborn genomic sequencing (nGS) has great potential to improve pediatric care. Parental interest and concerns about genomics are relatively unexplored. Understanding why parents decline research consent for nGS may reveal implementation barriers. Methods We evaluated parental interest in a randomized trial of nGS in well-baby and intensive care unit nursery settings. Interested families attended an informational enrollment session (ES) with a genetic counselor prior to consenting. Reason(s) for declining participation and sociodemographic associations were analyzed. Results Of 3860 eligible approached families, 10% attended ES, 67% of whom enrolled. Of 1760 families queried for decline reasons, 58% were uninterested in research. Among 499 families considering research, principal reasons for decline prior to ES included burdensome study logistics (48%), feeling overwhelmed postpartum (17%), and lack of interest/discomfort with genetic testing (17%). Decliners after ES more often cited concerns about privacy/insurability (41%) and uncertain/unfavorable results (23%). Conclusion Low interest in research and study logistics were major initial barriers to postpartum enrollment and are likely generic to many postpartum research efforts. Concerns over privacy and result implications were most commonly cited in decliners after ES. Understanding parental concerns around research nGS may inform future integration of nGS into newborn screening, predictive testing, and pediatric diagnostics.

Background The greatest opportunity for lifelong impact of genomic sequencing is during the newborn period. The “BabySeq Project” is a randomized trial that explores the medical, behavioral, and economic impacts of integrating genomic sequencing into the care of healthy and sick newborns. Methods Families of newborns are enrolled from Boston Children’s Hospital and Brigham and Women’s Hospital nurseries, and half are randomized to receive genomic sequencing and a report that includes monogenic disease variants, recessive carrier variants for childhood onset or actionable disorders, and pharmacogenomic variants. All families participate in a disclosure session, which includes the return of results for those in the sequencing arm. Outcomes are collected through review of medical records and surveys of parents and health care providers and include the rationale for choice of genes and variants to report; what genomic data adds to the medical management of sick and healthy babies; and the medical, behavioral, and economic impacts of integrating genomic sequencing into the care of healthy and sick newborns. Discussion The BabySeq Project will provide empirical data about the risks, benefits and costs of newborn genomic sequencing and will inform policy decisions related to universal genomic screening of newborns. Trial registration The study is registered in ClinicalTrials.gov Identifier: NCT02422511 . Registration date: 10 April 2015.

Background: In spinal muscular atrophy, clinical trial results indicated that disease-modifying treatments are highly effective when given prior to symptom onset, which has prompted newborn screening programs in growing number of countries. However, prognosis of those patients cannot be inferred from clinical trials conducted in presymptomatic individuals, as in some cases disease presents very early. Methods: we conducted a systematic review of articles published up to January 2023. Results: Among 35 patients with three SMN2 copies treated before 42 days of age and followed-up for at least 18 months, all but one achieved autonomous ambulation. Of 41 patients with two SMN2 copies, who were non-symptomatic at treatment initiation, all achieved a sitting position independently and 31 were able to walk. Of 16 patients with two SMN2 copies followed-up for at least 18 months who presented with symptoms at treatment onset, 3 achieved the walking milestone and all but one were able to sit without support. Conclusions: evaluation of data from 18 publications indicates that the results of early treatment depend on the number of SMN2 copies and the initial neurological status of the patient.

Newborn screening for cystic fibrosis (CF-NBS) using an IRT-DNA algorithm with a 12 CFTR-variant panel and an IRT/IRT failsafe was officially implemented in the French-speaking Community of Belgium in January 2020. This screening protocol was evaluated after 4 years according to the criteria defined by the European Cystic Fibrosis Society’s working group on neonatal screening. Immunoreactive trypsinogen concentration (IRT) was measured on dried blood spots collected between the second and the fourth day of life. CFTR variants genotyping was initiated when IRT ≥ 99th percentile (P99). If at least 1 variant was identified, the child was referred to a CF center for a sweat test (ST). If IRT ≥ 99.9th percentile with no variant identified, a failsafe was provided with IRT repeated on day 21 and subsequent ST in case of persistent IRT > P99. Extensive Gene Analysis was initiated if sweat chloride level was ≥ 30 mmol/L. Over a period of 4 years, 212.979 newborns were screened. Forty-two were diagnosed with CF: 34 by CF-NBS, 3 following a meconium ileus, 3 by family history and 2 missed cases. Additionally, 112 healthy carriers and 14 CFSPID were identified. The median age at the first consultation was 23 days. The sensitivity of our CF-NBS is 95% (target ≥ 95%), the positive predictive value 18% (target ≥ 30%) and CF/CFSPID ratio 2.8. Conclusion : Although follow-up is limited, this first evaluation demonstrates encouraging sensitivity and early management before one month of age. What is Known: • Newborn screening for cystic fibrosis improves the prognosis of patients. What is New: • This article presents an initial assessment of our screening after 4 years.

To report the 5-year results of the Stanford University Network for Diagnosis of Retinopathy of Prematurity (SUNDROP) telemedicine initiative. Infants requiring retinopathy of prematurity (ROP) screening at six neonatal intensive care units from December 1, 2005, to November 30, 2010, were evaluated with remote retinal photography by an ROP specialist. Every infant received outpatient binocular indirect ophthalmoscope examinations until termination criteria were achieved or until treatment. Outcomes were treatment-warranted ROP (TW-ROP, ETROP type 1) and adverse anatomical events. Five hundred eleven infants (1,022 eyes) were screened. Fifteen infants had TW-ROP and underwent laser photocoagulation. The TW-ROP cohort had significantly lower birth weight and gestational age (both P < .001). No patient progressed to adverse anatomical outcomes and no case of TW-ROP was missed. Tele-medicine had 100% sensitivity, 99.8% specificity, 93.8% positive predictive value, and 100% negative predictive value for detection of TW-ROP. Telemedicine demonstrates high diagnostic accuracy for detection of TW-ROP and can complement ROP screening.

IntroductionJaundice caused by hyperbilirubinaemia is a physiological phenomenon in the neonatal period. However, severe hyperbilirubinaemia, when left untreated, may cause kernicterus, a severe condition resulting in lifelong neurological disabilities. Although commonly applied, visual inspection is ineffective in identifying severe hyperbilirubinaemia. We aim to investigate whether among babies cared for in primary care: (1) transcutaneous bilirubin (TcB) screening can help reduce severe hyperbilirubinaemia and (2) primary care-based (versus hospital-based) phototherapy can help reduce hospital admissions.Methods and analysisA factorial stepped-wedge cluster randomised controlled trial will be conducted in seven Dutch primary care birth centres (PCBC). Neonates born after 35 weeks of gestation and cared for at a participating PCBC for at least 2 days within the first week of life are eligible, provided they have not received phototherapy before. According to the stepped-wedge design, following a phase of ‘usual care’ (visual assessment and selective total serum bilirubin (TSB) quantification), either daily TcB measurement or, if indicated, phototherapy in the PCBC will be implemented (phase II). In phase III, both interventions will be evaluated in each PCBC. We aim to include 5500 neonates over 3 years.Primary outcomes are assessed at 14 days of life: (1) the proportion of neonates having experienced severe hyperbilirubinaemia (for the TcB screening intervention), defined as a TSB above the mean of the phototherapy and the exchange transfusion threshold and (2) the proportion of neonates having required hospital admission for hyperbilirubinaemia treatment (for the phototherapy intervention in primary care).Ethics and disseminationThis study has been approved by the Medical Research Ethics Committee of the Erasmus MC Rotterdam, the Netherlands (MEC-2017-473). Written parental informed consent will be obtained. Results from this study will be published in peer-reviewed journals and presented at (inter)national meetings.Trial registration numberNTR7187.

Background and aim To describe current diagnostic and therapeutic strategies in organic acidurias (OADs) and to evaluate their impact on the disease course allowing harmonisation. Methods Datasets of 567 OAD patients from the E-IMD registry were analysed. The sample includes patients with methylmalonic (MMA, n  = 164), propionic (PA, n  = 144) and isovaleric aciduria (IVA, n  = 83), and glutaric aciduria type 1 (GA1, n  = 176). Statistical analysis included description and recursive partitioning of diagnostic and therapeutic strategies, and odds ratios (OR) for health outcome parameters. For some analyses, symptomatic patients were divided into those presenting with first symptoms during (i.e. early onset, EO) or after the newborn period (i.e. late onset, LO). Results Patients identified by newborn screening (NBS) had a significantly lower median age of diagnosis (8 days) compared to the LO group (363 days, p  < 0.001], but not compared to the EO group. Of all OAD patients 71 % remained asymptomatic until day 8. Patients with cobalamin-nonresponsive MMA (MMA-Cbl − ) and GA1 identified by NBS were less likely to have movement disorders than those diagnosed by selective screening (MMA-Cbl − : 10 % versus 39 %, p  = 0.002; GA1: 26 % versus 73 %, p  < 0.001). For other OADs, the clinical benefit of NBS was less clear. Reported age-adjusted intake of natural protein and calories was significantly higher in LO patients than in EO patients reflecting different disease severities. Variable drug combinations, ranging from 12 in MMA-Cbl − to two in isovaleric aciduria, were used for maintenance treatment. The effects of specific metabolic treatment strategies on the health outcomes remain unclear because of the strong influences of age at onset (EO versus LO), diagnostic mode (NBS versus selective screening), and the various treatment combinations used. Conclusions NBS is an effective intervention to reduce time until diagnosis especially for LO patients and to prevent irreversible cerebral damage in GA1 and MMA-Cbl − . Huge diversity of therapeutic interventions hampers our understanding of optimal treatment.

Background Using next-generation sequencing (NGS) in newborn screening (NBS) could expand the number of genetic conditions detected pre-symptomatically, simultaneously challenging current precedents, raising ethical concerns, and extending the role of parental decision-making in NBS. The NC NEXUS (Newborn Exome Sequencing for Universal Screening) study seeks to assess the technical possibilities and limitations of NGS-NBS, devise and evaluate a framework to convey various types of genetic information, and develop best practices for incorporating NGS-NBS into clinical care. The study is enrolling both a healthy cohort and a cohort diagnosed with known disorders identified through recent routine NBS. It uses a novel age-based metric to categorize a priori the large amount of data generated by NGS-NBS and interactive online decision aids to guide parental decision-making. Primary outcomes include: (1) assessment of NGS-NBS sensitivity, (2) decision regret, and (3) parental decision-making about NGS-NBS, and, for parents randomized to have the option of requesting them, additional findings (diagnosed and healthy cohorts). Secondary outcomes assess parents’ reactions to the study and to decision-making. Methods/design Participants are parents and children in a well-child cohort recruited from a prenatal clinic and a diagnosed cohort recruited from pediatric clinics that treat children with disorders diagnosed through traditional NBS (goal of 200 children in each cohort). In phase 1, all parent participants use an online decision aid to decide whether to accept NGS-NBS for their child and provide consent for NGS-NBS. In phase 2, parents who consent to NGS-NBS are randomized to a decision arm or control arm (2:1 allocation) and learn their child’s NGS-NBS results, which include conditions from standard (non-NGS) NBS plus other highly actionable childhood-onset conditions. Parents in the decision arm use a second decision aid to make decisions about additional results from their child’s sequencing. In phase 3, decision arm participants learn additional results they have requested. Online questionnaires are administered at up to five time points. Discussion NC NEXUS will use a rigorous interdisciplinary approach designed to collect rich data to inform policy, practice, and future research. Trial registration clinicaltrials.gov, NCT02826694 . Registered on 11 July, 2016.

Objective: To assess the efficacy of the heme oxygenase inhibitor, tin mesoporphyrin (SnMP), to reduce total bilirubin (TB) levels. Study Design: Masked, SnMP (4.5 mg kg −1 ), placebo-controlled, multicenter trial of single intramuscular injection to newborns ⩾35 weeks gestational age whose predischarge screening transcutaneous bilirubin (TcB) was >75th percentile. Results: Two hundred and thirteen newborns (median age 30 h) were randomized to treatment with SnMP ( n =87) or ‘sham’ ( n =89). We found that the duration of phototherapy was halved. Within 12 h of SnMP administration, the natural TB trajectory was reversed. At age 3 to 5 days, TB in the SnMP-treated group was +8% but sixfold lower than the 47% increase in the sham-treated group ( P <0.001). At age 7 to 10 days, mean TB declined 18% ( P <0.001) compared with a 7.1% increase among controls. No short-term adverse events from SnMP treatment were noted other than photoreactivity due to inadvertent exposure to white light phototherapy. Conclusion: Early, predischarge SnMP administration decreased the duration of phototherapy, reversed TB trajectory and reduced the severity of subsequent hyperbilirubinemia.

Background Extreme hyperbilirubinemia leading to neurologic disability and death is disproportionately higher in low- and middle-income countries (LMIC) such as Bangladesh, and is largely preventable through timely treatment. In LMICs, an estimated half of all newborns are born at home and few receive screening or treatment for hyperbilirubinemia, leading to 6 million newborns per year who need phototherapy treatment for hyperbilirubinemia but are untreated. Household screening and treatment for neonatal hyperbilirubinemia with phototherapy administered by a trained community health worker (CHW) may increase indicated treatment for neonatal hyperbilirubinemia in comparison to the existing care system in Bangladesh. Methods 530 Bangladeshi women in their second or third trimester of pregnancy from the rural community of Sakhipur, Bangladesh will be recruited for a cluster randomized trial and randomized to the intervention arm — home screening and treatment for neonatal hyperbilirubinemia — or the comparison arm to receive usual care. In the intervention arm, CHWs will provide mothers with two prenatal visits, visit newborns by 2 days of age and then daily for 3 days to measure transcutaneous bilirubin (TcB) and monitor for clinical danger signs. Newborns without danger signs but with a TcB above the treatment threshold, but >15 mg/dL will be treated with light-emitting diode (LED) phototherapy at home. Newborns with danger signs or TcB ≥15 mg/dL will be referred to a hospital for treatment. Treatment rates for neonatal hyperbilirubinemia in each arm will be compared. Conclusion This study will evaluate the effectiveness of CHW-led home phototherapy to increase neonatal hyperbilirubinemia treatment rates in rural Bangladesh. LMICs are expanding access to postnatal care by using CHWs, and our work will give CHWs a curative treatment option for neonatal hyperbilirubinemia. Similar projects in other LMICs can be pursued to dramatically extend healthcare access to vulnerable newborns with hyperbilirubinemia.