Background: Graves\' disease has been associated with adverse pregnancy, labor and delivery, and neonatal outcomes. Thyroid function levels, assessed during newborn screening (NBS), can serve as indicators of the adaptation in the hypothalamic-pituitary-thyroid axis. We utilized data from the national thyroid NBS program to investigate the characteristics of the mother-infant dyad of term infants born to mothers with past or active Graves\' disease. Methods: The dataset of the Israeli NBS for thyroid function was linked with the electronic records of a tertiary medical center to generate a unified database of mothers and their term infants born between 2011 and 2021. The MDClone big data platform extracted maternal, pregnancy, disease course, labor and delivery, and neonatal characteristics of the mother-infant dyads. Results: Out of 103,899 registered mother-infant dyads, 292 (0.3%) mothers had past or active Graves\' disease. A forward multivariate linear regression demonstrated that Graves\' disease did not significantly affect NBS total thyroxine (tT4) levels (p = 0.252). NBS tT4 levels in infants born to mothers with active Graves\' disease were higher than those observed in the general Israeli population (p < 0.001). Mothers with Graves\' disease more frequently used assisted reproductive technology (12.7% vs. 9.0%, respectively, p = 0.012; odds ratio [OR] = 1.46 [CI 1.03-2.07], p = 0.031), and had more gestational hypertension (3.9% vs. 1.1%, p < 0.001; OR = 3.53 [CI 1.92-6.47], p < 0.001), proteinuria (2.5% vs. 0.9%, p < 0.001; OR = 3.03 [CI 1.43-6.45], p = 0.004), cesarean sections (26.4% vs. 19.7%, p = 0.029; OR = 1.46 [CI 1.13-1.90], p = 0.004), prelabor rupture of membranes (15.4% vs. 4.1%, p < 0.001; OR = 4.3 [CI 3.13-5.91], p < 0.001), and placental abnormalities (5.1% vs. 2.0%, p < 0.001; OR = 2.64 [CI 1.57-4.44]; p < 0.001). Their infants had lower adjusted birthweight z-scores (-0.18 ± 0.94 vs. -0.03 ± 0.90, p = 0.007) and were more likely to be small for gestational age (12.0% vs. 8.1%, p = 0.005; OR = 1.54 [CI 1.08-2.19], p = 0.018). Conclusions: Neonatal thyroid function levels were affected by maternal Graves\' disease only when the disease was active during gestation. Moreover, maternal Graves\' disease was also associated with an increased risk of adverse outcomes for the mother-infant dyad.

BACKGROUND: The Portuguese Neonatal Screening Programme (PNSP) identifies patients with rare diseases through nationwide screening. Currently, 27 diseases are diagnosed, amongst which are 24 Inborn Errors of Metabolism (IEM), covering approximately 100% of neonates (1). In 2004, the national laboratory implemented a new screening method, tandem mass spectrometry (MS/MS) to test for amino acids and acylcarnitines. This new protocol revolutionized the PNSP and allowed for the analysis of an increased number of IEM, with clear improvements in treatment timings and clinical outcomes (2).
METHODS: From 2004 to 2022, 1 764 830 neonates were screened with MS/MS technology. Those who displayed biochemical profiles indicating an IEM were subjected to molecular characterization via genomic DNA extraction, PCR amplification, and direct Sanger sequencing method of dried blood spot samples.
RESULTS: A cohort of 681 newborns were diagnosed with an IEM. MCAD deficiency is the most frequent, with 233 confirmed diagnoses, showing predominantly c.985A>G (p.K329E) mutation of the ACADM gene in homozygosity. Approximately 1/3 of the 33 confirmed cases of Glutaric Aciduria type I present homozygous for the c.1204C>T (p.Arg402Trp) mutation in GCDH. Around 60% of cases of MAT II/III deficiency display the dominant mutation of the MAT1A gene, c.791G>A (p.Arg264His). These genetic profiles and others were determined as diagnostic confirmation for 24 of the IEM screened.
CONCLUSIONS: This data shows the molecular epidemiology of patients with confirmed IEM diagnosis identified by neonatal screening. Some diseases out of the scope of the PNSP were also detected as a differential diagnosis after biochemical suspicion in the dried blood spot sample. The retrospective analysis of the PNSP allows for an overview of 18 years of achievements accomplished by the national screening for IEM since MS/MS was implemented. For some pathologies with low incidence, it\'s difficult to trace a discernible pattern. However, presenting de novo mutations for these diseases might provide insights on how to approach different phenotypes. The aim of this work is to establish the molecular epidemiology of metabolic diseases screened.

Assessing the association of the newborn metabolic state with severity of subsequent respiratory tract infection may provide important insights on infection pathogenesis. In this multi-site birth cohort study, we identified newborn metabolites associated with lower respiratory tract infection (LRTI) in the first year of life in a discovery cohort and assessed for replication in two independent cohorts. Increased citrulline concentration was associated with decreased odds of LRTI (discovery cohort: aOR 0.83 [95% CI 0.70-0.99], p = 0.04; replication cohorts: aOR 0.58 [95% CI 0.28-1.22], p = 0.15). While our findings require further replication and investigation of mechanisms of action, they identify a novel target for LRTI prevention and treatment.

Introduction: With increasing utility and decreasing cost of genomic sequencing, augmentation of standard newborn screening (NBS) programs with newborn genomic sequencing (nGS) has been proposed. Before nGS can be integrated into newborn screening, parents\' perspectives must be better understood. Objective: Using data from surveys administered to parents of healthy newborns who were enrolled in the BabySeq Project, a randomized clinical trial of nGS alongside NBS, this paper reports parents\' attitudes regarding population-based NBS and nGS assessed 3 months after results disclosure. Methods: Parental attitudes regarding whether all newborns should receive, and whether informed consent should be required for, NBS and nGS, as well as whether nGS should be mandated were assessed using 5-point scales from strongly disagree (=1) to strongly agree (=5). Parents\' interest in receiving types of results from nGS was assessed on a 5-point scale from not at all interested (=1) to very interested (=5). Survey responses were analyzed using Fisher\'s exact tests, paired t-tests, and repeated measures ANOVA. Results: At 3 months post-disclosure, 248 parents of 174 healthy newborns submitted a survey. Support for every newborn receiving standard NBS (mean 4.67) was higher than that for every newborn receiving nGS (mean 3.60; p < 0.001). Support for required informed consent for NBS (mean 3.44) was lower than that for nGS (mean 4.27, p < 0.001). Parents\' attitudes toward NBS and nGS were not significantly associated with self-reported political orientation. If hypothetically receiving nGS outside of the BabySeq Project, most parents reported being very interested in receiving information on their baby\'s risk of developing a disease in childhood that can be prevented, treated, or cured (86.8%) and their risk of developing a disease during adulthood that can be prevented, treated, or cured (84.6%). Discussion: Parents\' opinions are crucial to inform design and delivery of public health programs, as the success of the program hinges on parents\' trust and participation. To accommodate parents\' preferences without affecting the current high participation rates in NBS, an optional add-on consent to nGS in addition to NBS may be a feasible approach. Trial Registration ClinicalTrials.gov Identifier: NCT02422511.

BACKGROUND: Previous studies suggest that PAP-based CF protocols are suitable for newborn screening (NBS) for cystic fibrosis (CF) when newborns designated as CFSPID should not be detected. However, there are still discussions about the performance of IRT/PAP algorithms. We present the final results of a pilot study evaluating a IRT/PAP protocol with an IRT-dependent safety net (SN) conducted from 2008 to 2016 in southwestern Germany on nearly 500,000 newborns.
METHODS: To achieve reliable data, all newborns were screened using both the PAP-based and a DNA-based CFNBS algorithm. PAP quantification and genetic analysis of the four most common CFTR mutations in Germany were performed in all newborns with IRT≥99.0 percentile. NBS was rated positive if either PAP was ≥1.6 µg/l and/or at least one CFTR mutation was detected. In addition, an IRT-dependent SN resulted in positive rating for both protocols if IRT was ≥99.9 percentile. To evaluate the IRT/PAP protocol, its performance was compared to that of the IRT/DNA protocol.
RESULTS: The IRT/PAP protocol with IRT-based SN used in the study achieved a sensitivity of 94%, if false-negative detected neonates with meconium ileus and those designated as CFSPID were excluded from analysis. CF/CFSPID ratio was 92. However, PPV of the IRT/PAP+SN protocol was with 10.3% very low.
CONCLUSIONS: PAP-based CFNBS protocols can be used, if less detection of CFSPID is desired. The IRT/PAP protocol with IRT-dependent SN evaluated here achieved adequate sensitivity but should probably be used in combination with a third-tier test to also achieve an acceptable PPV.

Knowledge about newborn screening (NBS) is an important factor for parents to make an informed decision about participation. In Europe, countries inform parents differently about their NBS program, potentially including different knowledge aspects in their information. The aim of this study was to assess twenty-six European parental information products and to analyze their knowledge aspects through a content analysis. The analyzed aspects were compared to a list of eight knowledge aspects from scientific literature. The list includes aspects important for parents\' decision-making, such as the purpose of screening. The study showed that most of the eight knowledge aspects are included in NBS information products of the majority of countries. However, there were differences between countries, for example in the amount of detail and phrasing of the information. Additional relevant knowledge aspects have also been identified and are recommended to optimize information products, such as the handling of residual bloodspot samples. This study only assessed knowledge aspects in information products meant for printing, but many countries also use other communication methods, and the impact on knowledge of the delivery of the information needs further study. Preferences of parents on alternative communication methods need to be considered and evaluated on their effectiveness.