Children born to subfertile couples, how are they doing? Evidence from research.

More than 10 million children have been born with assisted reproductive technology (ART) as we begin to enter the third generation of individuals conceived by ART. Here we summarise key messages from an enlarging body of literature regarding their health. Earlier research had pointed towards increases in perinatal, neonatal and neurological risks, such as preterm birth, low birth weight, congenital malformations and cerebral palsy. Many of these risks have continued to persist in most recent work but have shown reduction. Newer research proposes long-term cardiometabolic and endocrine concerns. Fortunately, most reports conclude there is little or no risk of increased childhood malignancy or abnormal neurodevelopment. Moving forward, new research may benefit from changes in comparator groups and a better understanding of infertility per se in ART, and the confounding role it probably plays in many of the known risk associations, to reliably scan the horizon for health threats for individuals born after ART.

Clinical and cost-effectiveness of an adapted intervention for preschoolers with moderate to severe intellectual disabilities displaying behaviours that challenge: the EPICC-ID RCT.

Background: Stepping Stones Triple P is an adapted intervention for parents of young children with developmental disabilities who display behaviours that challenge, aiming at teaching positive parenting techniques and promoting a positive parent-child relationship. Objective: To evaluate the clinical and cost-effectiveness of level 4 Stepping Stones Triple P in reducing behaviours that challenge in children with moderate to severe intellectual disabilities. Design, setting, participants: A parallel two-arm pragmatic multisite single-blind randomised controlled trial recruited a total of 261 dyads (parent and child). The children were aged 30-59 months and had moderate to severe intellectual disabilities. Participants were randomised, using a 3 : 2 allocation ratio, into the intervention arm (Stepping Stones Triple P; n = 155) or treatment as usual arm (n = 106). Participants were recruited from four study sites in Blackpool, North and South London and Newcastle. Intervention: Level 4 Stepping Stones Triple P consists of six group sessions and three individual phone or face-to-face contacts over 9 weeks. These were changed to remote sessions after 16 March 2020 due to the coronavirus disease 2019 pandemic. Main outcome measure: The primary outcome measure was the parent-reported Child Behaviour Checklist, which assesses the severity of behaviours that challenge. Results: We found a small non-significant difference in the mean Child Behaviour Checklist scores (-4.23, 95% CI -9.98 to 1.52, p = 0.146) in the intervention arm compared to treatment as usual at 12 months. Per protocol and complier average causal effect sensitivity analyses, which took into consideration the number of sessions attended, showed the Child Behaviour Checklist mean score difference at 12 months was lower in the intervention arm by -10.77 (95% CI -19.12 to -2.42, p = 0.014) and -11.53 (95% CI -26.97 to 3.91, p = 0.143), respectively. The Child Behaviour Checklist mean score difference between participants who were recruited before and after the coronavirus disease 2019 pandemic was estimated as -7.12 (95% CI -13.44 to -0.81) and 7.61 (95% CI -5.43 to 20.64), respectively (p = 0.046), suggesting that any effect pre-pandemic may have reversed during the pandemic. There were no differences in all secondary measures. Stepping Stones Triple P is probably value for money to deliver (-£1057.88; 95% CI -£3218.6 to -£46.67), but decisions to roll this out as an alternative to existing parenting interventions or treatment as usual may be dependent on policymaker willingness to invest in early interventions to reduce behaviours that challenge. Parents reported the intervention boosted their confidence and skills, and the group format enabled them to learn from others and benefit from peer support. There were 20 serious adverse events reported during the study, but none were associated with the intervention. Limitations: There were low attendance rates in the Stepping Stones Triple P arm, as well as the coronavirus disease 2019-related challenges with recruitment and delivery of the intervention. Conclusions: Level 4 Stepping Stones Triple P did not reduce early onset behaviours that challenge in very young children with moderate to severe intellectual disabilities. However, there was an effect on child behaviours for those who received a sufficient dose of the intervention. There is a high probability of Stepping Stones Triple P being at least cost neutral and therefore worth considering as an early therapeutic option given the long-term consequences of behaviours that challenge on people and their social networks. Future work: Further research should investigate the implementation of parenting groups for behaviours that challenge in this population, as well as the optimal mode of delivery to maximise engagement and subsequent outcomes. Study registration: This study is registered as NCT03086876 (https://www.clinicaltrials.gov/ct2/show/NCT03086876?term=Hassiotis±Angela&draw=1&rank=1). Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: HTA 15/162/02) and is published in full in Health Technology Assessment; Vol. 28, No. 6. See the NIHR Funding and Awards website for further award information.

Research shows that in children without learning disabilities, parenting groups which support parents to develop skills to manage behaviours that challenge in their child can be helpful. The National Institute of Health and Care Excellence recommended that more research was needed to strengthen the evidence for such interventions for children with moderate to severe learning disability who are more likely to display behaviours that challenge in England. In this study, we tested in real-world conditions a programme called level 4 Stepping Stones Triple P, which has shown positive results in trials outside of the United Kingdom. Trained therapists delivered six groups and three individual sessions over 9 weeks to parents of children aged 30­59 months with moderate to severe learning disabilities. Two hundred and sixty-one parents were allocated to one of two arms by chance (randomisation): one received Stepping Stones Triple P and treatment as usual and the other treatment as usual only. Treatment as usual included support and advice by general practitioners or community child development teams. Our primary outcome was parent-reported child behaviour at 12 months after randomisation. We also collected data on other outcomes and carried out interviews with parents, service managers and therapists to find out their views about Stepping Stones Triple P. We did not find that Stepping Stones Triple P reduces behaviours that challenge in the child more than treatment as usual at 12 months. However, when we looked at people who received more than half of the sessions, there was a larger reduction in behaviours which suggests that Stepping Stones Triple P works for families if they attend the full programme. Stepping Stones Triple P seems to be good value for money, as we found that at 12 months (covering 10 months of costs), the Stepping Stones Triple P cost £1058 less than treatment as usual from a health and social care perspective. As such, Stepping Stones Triple P is fairly cheap to deliver and a suitable early intervention for behaviours that challenge especially because of positive feedback from parents. Throughout the trial, we included a Parent Advisory Group that oversaw study materials, interview topic guides and promotion of the study.

Childhood outcomes after low-grade intraventricular haemorrhage: A systematic review and meta-analysis.

AIM: To undertake a systematic review and meta-analysis exploring school-age neurodevelopmental outcomes of children after low-grade intraventricular haemorrhage (IVH). METHOD: The published and grey literature was extensively searched to identify observational comparative studies exploring neurodevelopmental outcomes after IVH grades 1 and 2. Our primary outcome was neurodevelopmental impairment after 5 years of age, which included cognitive, motor, speech and language, behavioural, hearing, or visual impairments. RESULTS: This review included 12 studies and over 2036 infants born preterm with low grade IVH. Studies used 30 different neurodevelopmental tools to determine outcomes. There was conflicting evidence of the composite risk of neurodevelopmental impairment after low-grade IVH. There was evidence of an association between low-grade IVH and lower IQ at school age (-4.23, 95% confidence interval [CI] -7.53, -0.92, I2 = 0%) but impact on school performance was unclear. Studies reported an increased crude risk of cerebral palsy after low-grade IVH (odds ratio [OR] 2.92, 95% CI 1.95, 4.37, I2 = 41%). No increased risk of speech and language impairment or behavioural impairment was found. Few studies addressed hearing and visual impairment. INTERPRETATION: This systematic review presents evidence that low-grade IVH is associated with specific neurodevelopmental impairments at school age, lending support to the theory that low-grade IVH is not a benign condition. WHAT THIS PAPER ADDS: The functional impact of low-grade intraventricular haemorrhage (IVH) at school age is unknown. Low-grade IVH is associated with a lower IQ at school age. The risk of cerebral palsy is increased after low-grade IVH. Low-grade IVH is not associated with speech and language impairment.

Quantitative impact of frenotomy on breastfeeding: a systematic review and meta-analysis.

BACKGROUND: Symptoms related to infant ankyloglossia/tongue-tie may deter mothers from breastfeeding, yet frenotomy is controversial. METHODS: Databases included PubMed, Embase, CINAHL, PsycINFO, Web of Science, and Google Scholar from 1961-2023. Controlled trials and cohort studies with validated measures of surgical efficacy for breastfeeding outcomes were eligible. Meta-analyses synthesized data with inverse-variance weighting to determine standardized mean differences (SMD) between pre-/postoperative scores. RESULTS: Twenty-one of 1568 screened studies were included. Breastfeeding self-efficacy improved significantly post-frenotomy: medium effect after 5-10 days (SMD 0.60 [95% CI: 0.48, 0.71; P < 0.001]), large effect after 1 month (SMD 0.91 [CI: 0.79, 1.04; P < 0.001]). Nipple pain decreased significantly post-frenotomy: large effect after 5-15 days (SMD -1.10 [CI: -1.49, -0.70; P < 0.001]) and 1 month (SMD -1.23 [CI: -1.79, -0.67; P = 0.002]). Frenotomy had a medium effect on infant gastroesophageal reflux severity at 1-week follow-up (SMD -0.63 [CI: -0.95, -0.31; P = 0.008]), with continued improvement at 1 month (SMD -0.41 [CI: -0.78, -0.05; P = 0.04]). From LATCH scores, breastfeeding quality improved after 5-7 days by a large SMD of 1.28 (CI: 0.56, 2.00; P = 0.01). CONCLUSIONS: Providers should offer frenotomy to improve outcomes in dyads with ankyloglossia-associated breastfeeding difficulties. PROTOCOL REGISTRATION: PROSPERO identifier CRD42022303838 . IMPACT: This systematic review and meta-analysis showed that breastfeeding self-efficacy, maternal pain, infant latch, and infant gastroesophageal reflux significantly improve after frenotomy in mother-infant dyads with breastfeeding difficulties and ankyloglossia. Providers should offer frenotomy to improve breastfeeding outcomes in symptomatic mother-infant dyads who face challenges associated with ankyloglossia.

Experiences of coordinated care for people in the UK affected by rare diseases: cross-sectional survey of patients, carers, and healthcare professionals.

BACKGROUND: Poorly coordinated care can have major impacts on patients and families affected by rare conditions, with negative physical health, psychosocial and financial consequences. This study aimed to understand how care is coordinated for rare diseases in the United Kingdom. METHODS: We undertook a national survey in the UK involving 760 adults affected by rare diseases, 446 parents/carers of people affected by rare diseases, and 251 healthcare professionals who care for people affected by rare diseases. RESULTS: Findings suggested that a wide range of patients, parents and carers do not have coordinated care. For example, few participants reported having a care coordinator (12% patients, 14% parents/carers), attending a specialist centre (32% patients, 33% parents/carers) or having a care plan (10% patients, 44% parents/carers). A very small number of patients (2%) and parents/carers (5%) had access to all three-a care coordinator, specialist centre and care plan. Fifty four percent of patients and 33% of parents/carers reported access to none of these. On the other hand, a higher proportion of healthcare professionals reported that families with rare conditions had access to care coordinators (35%), specialist centres (60%) and care plans (40%). CONCLUSIONS: Care for families with rare conditions is generally not well coordinated in the UK, with findings indicating limited access to care coordinators, specialist centres and care plans. Better understanding of these issues can inform how care coordination might be improved and embrace the needs and preferences of patients and families affected by rare conditions.

National Trends in Preterm Infant Mortality in the United States by Race and Socioeconomic Status, 1995-2020.

Importance: Inequalities in preterm infant mortality exist between population subgroups within the United States. Objective: To characterize trends in preterm infant mortality by maternal race and socioeconomic status to assess how inequalities in preterm mortality rates have changed over time. Design, Setting, and Participants: This was a retrospective longitudinal descriptive study using the US National Center for Health Statistics birth infant/death data set for 12 256 303 preterm infant births over 26 years, between 1995 and 2020. Data were analyzed from December 2022 to March 2023. Exposures: Maternal characteristics including race, smoking status, educational attainment, antenatal care, and insurance status were used as reported on an infant's US birth certificate. Main Outcomes and Measures: Preterm infant mortality rate was calculated for each year from 1995 to 2020 for all subgroups, with a trend regression coefficient calculated to describe the rate of change in preterm mortality. Results: The average US preterm infant mortality rate (IMR) decreased from 33.71 (95% CI, 33.71 to 34.04) per 1000 preterm births per year between 1995-1997, to 23.32 (95% CI, 23.05 to 23.58) between 2018-2020. Black non-Hispanic infants were more likely to die following preterm births than White non-Hispanic infants (IMR, 31.09; 95% CI, 30.44 to 31.74, vs 21.81; 95% CI, 21.43 to 22.18, in 2018-2020); however, once born, extremely prematurely Black and Hispanic infants had a narrow survival advantage (IMR rate ratio, 0.87; 95% CI, 0.84 to 0.91, in 2018-2020). The rate of decrease in preterm IMR was higher in Black infants (-0.015) than in White (-0.013) and Hispanic infants (-0.010); however, the relative risk of preterm IMR among Black infants compared with White infants remained the same between 1995-1997 vs 2018-2020 (relative risk, 1.40; 95% CI, 1.38 to 1.44, vs 1.43; 95% CI, 1.39 to 1.46). The rate of decrease in preterm IMR was higher in nonsmokers compared with smokers (-0.015 vs -0.010, respectively), in those with high levels of education compared with those with intermediate or low (-0.016 vs - 0.010 or -0.011, respectively), and in those who had received adequate antenatal care compared with those who did not (-0.014 vs -0.012 for intermediate and -0.013 for inadequate antenatal care). Over time, the relative risk of preterm mortality widened within each of these subgroups. Conclusions and Relevance: This study found that between 1995 and 2020, US preterm infant mortality improved among all categories of prematurity. Inequalities in preterm infant mortality based on maternal race and ethnicity have remained constant while socioeconomic disparities have widened over time.

School-age outcomes of children after perinatal brain injury: a systematic review and meta-analysis.

BACKGROUND: Over 3000 children suffer a perinatal brain injury in England every year according to national surveillance. The childhood outcomes of infants with perinatal brain injury are however unknown. METHODS: A systematic review and meta-analyses were undertaken of studies published between 2000 and September 2021 exploring school-aged neurodevelopmental outcomes of children after perinatal brain injury compared with those without perinatal brain injury. The primary outcome was neurodevelopmental impairment, which included cognitive, motor, speech and language, behavioural, hearing or visual impairment after 5 years of age. RESULTS: This review included 42 studies. Preterm infants with intraventricular haemorrhage (IVH) grades 3-4 were found to have a threefold greater risk of moderate-to-severe neurodevelopmental impairment at school age OR 3.69 (95% CI 1.7 to 7.98) compared with preterm infants without IVH. Infants with perinatal stroke had an increased incidence of hemiplegia 61% (95% CI 39.2% to 82.9%) and an increased risk of cognitive impairment (difference in full scale IQ -24.2 (95% CI -30.73 to -17.67) . Perinatal stroke was also associated with poorer academic performance; and lower mean receptive -20.88 (95% CI -36.66 to -5.11) and expressive language scores -20.25 (95% CI -34.36 to -6.13) on the Clinical Evaluation of Language Fundamentals (CELF) assessment. Studies reported an increased risk of persisting neurodevelopmental impairment at school age after neonatal meningitis. Cognitive impairment and special educational needs were highlighted after moderate-to-severe hypoxic-ischaemic encephalopathy. However, there were limited comparative studies providing school-aged outcome data across neurodevelopmental domains and few provided adjusted data. Findings were further limited by the heterogeneity of studies. CONCLUSIONS: Longitudinal population studies exploring childhood outcomes after perinatal brain injury are urgently needed to better enable clinicians to prepare affected families, and to facilitate targeted developmental support to help affected children reach their full potential.

Population-based screening methods in biliary atresia: a systematic review and meta-analysis.

OBJECTIVE: The aim of this study was to investigate tested methods of population-based biliary atresia (BA) screening. DESIGN: We searched 11 databases between 1 January 1975 and 12 September 2022. Data extraction was independently done by two investigators. MAIN OUTCOME MEASURES: Our primary outcomes were: sensitivity and specificity of screening method in BA detection, age at Kasai, BA associated morbidity and mortality, cost-effectiveness of screening. RESULTS: Six methods of BA screening were evaluated: stool colour charts (SCCs), conjugated bilirubin measurements, stool colour saturations (SCSs), measurements of urinary sulfated bile acids (USBAs), assessments of blood spot bile acids and blood carnitine measurements.In a meta-analysis, USBA was the most sensitive and specific, with a pooled sensitivity and specificity of 100.0% (95% CI 2.5% to 100.0%) and 99.5% (95% CI 98.9% to 99.8%) (based on one study). This was followed by conjugated bilirubin measurements: 100.0% (95% CI 0.0% to 100.0%) and 99.3% (95% CI 91.9% to 99.9%), SCS: 100.0% (95% CI 0.00% to 100.0%) and 92.4% (95% CI 83.4% to 96.7%), and SCC: 87.9% (95% CI 80.4% to 92.8%) and 99.9% (95% CI 99.9% to 99.9%).SCC reduced the age of Kasai to ~60 days, compared with 36 days for conjugated bilirubin. Both SCC and conjugated bilirubin improved overall and transplant-free survival. The use of SCC was considerably more cost-effective than conjugated bilirubin measurements. CONCLUSION: Conjugated bilirubin measurements and SCC are the most researched and demonstrate improved sensitivity and specificity in detecting BA. However, their use is expensive. Further research into conjugated bilirubin measurements, as well as alternative methods of population-based BA screening, is required. PROSPERO REGISTRATION NUMBER: CRD42021235133.

Reduced Presentation of Biliary Atresia During the COVID-19 Lockdown: A Population Based Observational Study.

OBJECTIVE: The aim of this study was to assess whether there has been a change in presentations of biliary atresia (BA) in England and Wales during the first and second coronavirus disease 2019 (COVID-19) lockdowns (January-June 2020 and 2021). DESIGN: This population study assessed all confirmed cases of BA, from January 2020 to December 2021 across the 3 UK pediatric liver centers originating from England and Wales. Data was then compared to the incidence of confirmed BA cases from January to December 2017, 2018, and 2019. RESULTS: During January-June 2020 and 2021, there were only 8 and 12 presenting cases of BA in England and Wales, compared to 16, 13, and 18 for the same time periods in 2017, 2018, and 2019, respectively. This difference was significant in a two-sided t test for 2020 ( P = 0.035) but not for 2021 ( P = 0.385). There was no difference in the mean days to Kasai procedure in January-June 2020 and 2021 compared to 2017-2019; however average time to Kasai after the lockdown periods was significantly higher. CONCLUSIONS: There was a significant reduction in the presenting cases of BA during the first COVID-19 lockdown, with an increased time for BA referrals after the pandemic lockdowns were lifted in England and Wales.

Severity and prevalence of ankyloglossia-associated breastfeeding symptoms: A systematic review and meta-analysis.

AIM: To evaluate breastfeeding symptoms associated with ankyloglossia/tongue-tie. METHODS: Databases included PubMed, Embase, CINAHL, PsycINFO, Web of Science, and Google Scholar. Eligible studies reported baseline breastfeeding symptoms/severity from tongue-tied infants. Two reviewers independently screened studies, extracted data, and assessed quality. Low-quality studies were excluded. Main outcomes were weighted mean severity scores for dyads with ankyloglossia relative to reference values for successful breastfeeding. Meta-analyses used inverse-variance-weighted random-effects models. RESULTS: Of 1328 screened studies, 39 were included (5730 infants with ankyloglossia). The mean LATCH score for patients with untreated ankyloglossia, 7.1 (95% CI: 6.7-7.4), was significantly below the good-breastfeeding threshold. The mean Infant Breastfeeding Assessment Tool score, 10.0 (8.2-11.7), was not significantly below the good-breastfeeding threshold. The mean Infant-Gastroesophageal Reflux Questionnaire-Revised score, 18.2 (10.5-26.0), was consistent with gastroesophageal reflux disease. The mean Breastfeeding Self-Efficacy Scale-Short Form score, 43.7 (39.3-48.1), indicated significant risk of cessation of exclusive breastfeeding within 1-3 months. Mean nipple pain was 4.9 (4.1-5.7) on a 0-10 scale, greater than typical scores for breastfeeding mothers without nipple damage. Total prevalence of breastfeeding difficulties was 49.3% (95% CI: 47.3-51.4%). Early, undesired weaning occurred in 20.3% (18.5-22.2%) of cases before intervention. CONCLUSION: Ankyloglossia is adversely associated with breastfeeding success and maternal well-being.

General health in a cohort of children conceived after assisted reproductive technology in the United Kingdom: a population-based record-linkage study.

BACKGROUND: Assisted reproductive technology use is increasing annually; however, data on long-term child health outcomes including hospital admissions are limited. OBJECTIVE: This study aimed to examine the potential effects of assisted reproductive technology on any and cause-specific hospital admissions unrelated to perinatal diagnoses. STUDY DESIGN: This was a population-based record-linkage study that included a previously established cohort of children born after assisted reproductive technology in the United Kingdom between 1997 and 2009 (n=63,877), their naturally conceived siblings (n=11,343), and matched naturally conceived population controls (n=127,544) linked to their postnatal health outcomes up to March 31, 2016 to provide robust risk estimates of the potential effects of assisted reproductive technology on any and cause-specific hospital admissions unrelated to perinatal diagnoses. In addition, comparison of hospital admissions by type of treatment was made. Cox regression was used to estimate the risk of hospital admission, and negative binomial regression was used to compare the number of hospital admissions per year. RESULTS: This study had 1.6 million person-years of follow-up (mean, 12.9 years; range, 0-19 years), and the mean age at the time of first hospital admission was 6.5 years (range, 0-19 years). Singletons born after assisted reproductive technology had increased risk of any hospital admission compared with naturally conceived population controls (hazard ratio, 1.08; 95% confidence interval, 1.05-1.10) but not naturally conceived siblings (hazard ratio, 1.01; 95% confidence interval, 0.94-1.09). We observed increased risk of diagnoses related to neoplasms and diseases of the respiratory, musculoskeletal, digestive, and genitourinary systems, and lower risk of injury, poisoning, and consequences of external causes compared with naturally conceived population controls. Children born after intracytoplasmic sperm injection had a lower risk of hospital admission compared with those born after in vitro fertilization, although no such differences were observed between children born after fresh embryo transfers and those born after frozen embryo transfers. CONCLUSION: Children born after assisted reproductive technology had greater numbers of hospital admissions compared with naturally conceived population controls. Attenuation of these differences in relation to their naturally conceived siblings suggested that this could be partially attributed to the influence of parental subfertility on child health, increased parental concerns, and an actual increase in morbidity in children born after assisted conception.

Preterm Brain Injury and Neurodevelopmental Outcomes: A Meta-analysis.

CONTEXT: Preterm brain injuries are common; neurodevelopmental outcomes following contemporary neonatal care are continually evolving. OBJECTIVE: To systematically review and meta-analyze neurodevelopmental outcomes among preterm infants after intraventricular hemorrhage (IVH) and white matter injury (WMI). DATA SOURCES: Published and grey literature were searched across 10 databases between 2000 and 2021. STUDY SELECTION: Observational studies reporting 3-year neurodevelopmental outcomes for preterm infants with IVH or WMI compared with preterm infants without injury. DATA EXTRACTION: Study characteristics, population characteristics, and outcome data were extracted. RESULTS: Thirty eight studies were included. There was an increased adjusted risk of moderate-severe neurodevelopmental impairment after IVH grade 1 to 2 (adjusted odds ratio 1.35 [95% confidence interval 1.05-1.75]) and IVH grade 3 to 4 (adjusted odds ratio 4.26 [3.25-5.59]). Children with IVH grade 1 to 2 had higher risks of cerebral palsy (odds ratio [OR] 1.76 [1.39-2.24]), cognitive (OR 1.79 [1.09-2.95]), hearing (OR 1.83 [1.03-3.24]), and visual impairment (OR 1.77 [1.08-2.9]). Children with IVH grade 3 to 4 had markedly higher risks of cerebral palsy (OR 4.98 [4.13-6.00]), motor (OR 2.7 [1.52-4.8]), cognitive (OR 2.3 [1.67-3.15]), hearing (OR 2.44 [1.42-4.2]), and visual impairment (OR 5.42 [2.77-10.58]). Children with WMI had much higher risks of cerebral palsy (OR 14.91 [7.3-30.46]), motor (OR 5.3 [3-9.36]), and cognitive impairment (OR 3.48 [2.18-5.53]). LIMITATIONS: Heterogeneity of outcome data. CONCLUSIONS: Mild IVH, severe IVH, and WMI are associated with adverse neurodevelopmental outcomes. Utilization of core outcome sets and availability of open-access study data would improve our understanding of the nuances of these outcomes.

The risks of birth defects and childhood cancer with conception by assisted reproductive technology.

STUDY QUESTION: Is there an association between fertility status, method of conception and the risks of birth defects and childhood cancer? SUMMARY ANSWER: The risk of childhood cancer had two independent components: (i) method of conception and (ii) presence, type and number of birth defects. WHAT IS KNOWN ALREADY: The rarity of the co-occurrence of birth defects, cancer and ART makes studying their association challenging. Prior studies have indicated that infertility and ART are associated with an increased risk of birth defects or cancer but have been limited by small sample size and inadequate statistical power, failure to adjust for or include plurality, differences in definitions and/or methods of ascertainment, lack of information on ART treatment parameters or study periods spanning decades resulting in a substantial historical bias as ART techniques have improved. STUDY DESIGN, SIZE, DURATION: This was a population-based cohort study linking ART cycles reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) from 1 January 2004 to 31 December 2017 that resulted in live births in 2004-2018 in Massachusetts and North Carolina and live births in 2004-2017 in Texas and New York. A 10:1 sample of non-ART births were chosen within the same time period as the ART birth. Non-ART siblings were identified through the ART mother's information. Children from non-ART births were classified as being born to women who conceived with ovulation induction or IUI (OI/IUI) when there was an indication of infertility treatment on the birth certificate, and the woman did not link to the SART CORS; all others were classified as being naturally conceived. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study population included 165 125 ART children, 31 524 non-ART siblings, 12 451 children born to OI/IUI-treated women and 1 353 440 naturally conceived children. All study children were linked to their respective State birth defect registries to identify major defects diagnosed within the first year of life. We classified children with major defects as either chromosomal (i.e. presence of a chromosomal defect with or without any other major defect) or nonchromosomal (i.e. presence of a major defect but having no chromosomal defect), or all major defects (chromosomal and nonchromosomal), and calculated rates per 1000 children. Logistic regression models were used to generate adjusted odds ratios (AORs) and 95% CIs of the risk of birth defects by conception group (OI/IUI, non-ART sibling and ART by oocyte source and embryo state) with naturally conceived children as the reference, adjusted for paternal and maternal ages; maternal race and ethnicity, education, BMI, parity, diabetes, hypertension; and for plurality, infant sex and State and year of birth. All study children were also linked to their respective State cancer registries. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs of cancer by birth defect status (including presence of a defect, type and number of defects), and conception group. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 29 571 singleton children (2.0%) and 3753 twin children (3.5%) had a major birth defect (chromosomal or nonchromosomal). Children conceived with ART from autologous oocytes had increased risks for nonchromosomal defects, including blastogenesis, cardiovascular, gastrointestinal and, for males only, genitourinary defects, with AORs ranging from 1.22 to 1.85; children in the autologous-fresh group also had increased risks for musculoskeletal (AOR 1.28, 95% CI 1.13, 1.45) and orofacial defects (AOR 1.40, 95% CI 1.17, 1.68). Within the donor oocyte group, the children conceived from fresh embryos did not have increased risks in any birth defect category, whereas children conceived from thawed embryos had increased risks for nonchromosomal defects (AOR 1.20, 95% CI 1.03, 1.40) and blastogenesis defects (AOR 1.74, 95% CI 1.14, 2.65). The risk of cancer was increased among ART children in the autologous-fresh group (HR 1.31, 95% CI 1.08, 1.59) and non-ART siblings (1.34, 95% CI 1.02, 1.76). The risk of leukemia was increased among children in the OI/IUI group (HR 2.15, 95% CI 1.04, 4.47) and non-ART siblings (HR 1.63, 95% CI 1.02, 2.61). The risk of central nervous system tumors was increased among ART children in the autologous-fresh group (HR 1.68, 95% CI 1.14, 2.48), donor-fresh group (HR 2.57, 95% CI 1.04, 6.32) and non-ART siblings (HR 1.84, 95% CI 1.12, 3.03). ART children in the autologous-fresh group were also at increased risk for solid tumors (HR 1.39, 95% CI 1.09, 1.77). A total of 127 children had both major birth defects and cancer, of which 53 children (42%) had leukemia. The risk of cancer had two independent components: (i) method of conception (described above) and (ii) presence, type and number of birth defects. The presence of nonchromosomal defects increased the cancer risk, greater for two or more defects versus one defect, for all cancers and each type evaluated. The presence of chromosomal defects was strongly associated with cancer risk (HR 8.70 for all cancers and HR 21.90 for leukemia), further elevated in the presence of both chromosomal and nonchromosomal defects (HR 21.29 for all cancers, HR 64.83 for leukemia and HR 4.71 for embryonal tumors). Among the 83 946 children born from ART in the USA in 2019 compared to their naturally conceived counterparts, these risks translate into an estimated excess of 761 children with major birth defects, 31 children with cancer and 11 children with both major birth defects and cancer. LIMITATIONS, REASONS FOR CAUTION: In the SART CORS database, it was not possible to differentiate method of embryo freezing (slow freezing versus vitrification), and data on ICSI were only available in the fresh embryo ART group. In the OI/IUI group, it was not possible to differentiate type of non-ART treatment utilized, and in both the ART and OI/IUI groups, data were unavailable on duration of infertility. Since OI/IUI is underreported on the birth certificate, some OI/IUI children were likely included among the naturally conceived children, which will decrease the difference between all the groups and the naturally conceived children. WIDER IMPLICATIONS OF THE FINDINGS: The use of ART is associated with increased risks of major nonchromosomal birth defects. The presence of birth defects is associated with greater risks for cancer, which adds to the baseline risk in the ART group. Although this study does not show causality, these findings indicate that children conceived with ART, non-ART siblings, and all children with birth defects should be monitored more closely for the subsequent development of cancer. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by grant R01 HD084377 from the National Institute of Child Health and Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Child Health and Human Development, or the National Institutes of Health, nor any of the State Departments of Health which contributed data. M.L.E. reports consultancy for Ro, Hannah, Dadi, Sandstone and Underdog; presidency of SSMR; and SMRU board member. The remaining authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Developing a taxonomy of care coordination for people living with rare conditions: a qualitative study.

BACKGROUND: Improving care coordination is particularly important for individuals with rare conditions (who may experience multiple inputs into their care, across different providers and settings). To develop and evaluate strategies to potentially improve care coordination, it is necessary to develop a method for organising different ways of coordinating care for rare conditions. Developing a taxonomy would help to describe different ways of coordinating care and in turn facilitate development and evaluation of pre-existing and new models of care coordination for rare conditions. To the authors' knowledge, no studies have previously developed taxonomies of care coordination for rare conditions. This research aimed to develop and refine a care coordination taxonomy for people with rare conditions. METHODS: This study had a qualitative design and was conducted in the United Kingdom. To develop a taxonomy, six stages of taxonomy development were followed. We conducted interviews (n = 30 health care professionals/charity representatives/commissioners) and focus groups (n = 4 focus groups, 22 patients/carers with rare/ultra-rare/undiagnosed conditions). Interviews and focus groups were audio-recorded with consent, and professionally transcribed. Findings were analysed using thematic analysis. Themes were used to develop a taxonomy, and to identify which types of coordination may work best in which situations. To refine the taxonomy, we conducted two workshops (n = 12 patients and carers group; n = 15 professional stakeholder group). RESULTS: Our taxonomy has six domains, each with different options. The six domains are: (1) Ways of organising care (local, hybrid, national), (2) Ways of organising those involved in care (collaboration between many or all individuals, collaboration between some individuals, a lack of collaborative approach), (3) Responsibility for coordination (administrative support, formal roles and responsibilities, supportive roles and no responsibility), (4) How often appointments and coordination take place (regular, on demand, hybrid), (5) Access to records (full or filtered access), and (6) Mode of care coordination (face-to-face, digital, telephone). CONCLUSIONS: Findings indicate that there are different ways of coordinating care across the six domains outlined in our taxonomy. This may help to facilitate the development and evaluation of existing and new models of care coordination for people living with rare conditions.

Development of models of care coordination for rare conditions: a qualitative study.

INTRODUCTION: Improving care coordination for people with rare conditions may help to reduce burden on patients and carers and improve the care that patients receive. We recently developed a taxonomy of different ways of coordinating care for rare conditions. It is not yet known which models of care coordination are appropriate in different situations. This study aimed to: (1) explore what types of care coordination may be appropriate in different situations, and (2) use these findings to develop hypothetical models of care coordination for rare conditions. METHODS: To explore appropriateness of different types of care coordination, we conducted interviews (n = 30), four focus groups (n = 22) and two workshops (n = 27) with patients, carers, healthcare professionals, commissioners, and charity representatives. Participants were asked about preferences, benefits and challenges, and the factors influencing coordination. Thematic analysis was used to develop hypothetical models of care coordination. Models were refined following feedback from workshop participants. RESULTS: Stakeholders prefer models of care that: are nationally centralised or a hybrid of national and local care, involve professionals collaborating to deliver care, have clear roles and responsibilities outlined (including administrative, coordinator, clinical and charity roles), provide access to records and offer flexible appointments (in terms of timing and mode). Many factors influenced coordination, including those relating to the patient (e.g., condition complexity, patient's location and ability to coordinate their own care), the healthcare professional (e.g., knowledge and time), the healthcare environment (e.g., resources) and societal factors (e.g., availability of funding). We developed and refined ten illustrative hypothetical models of care coordination for rare conditions. CONCLUSION: Findings underline that different models of care coordination may be appropriate in different situations. It is possible to develop models of care coordination which are tailored to the individual in context. Findings may be used to facilitate planning around which models of care coordination may be appropriate in different services or circumstances. Findings may also be used by key stakeholders (e.g. patient organisations, clinicians and service planners) as a decision-making tool.

Priorities for child health research across the UK and Ireland.

BACKGROUND: The General and Adolescent Paediatric Research Network in the UK and Ireland (GAPRUKI) was established in 2016. The aims of GAPRUKI are to unite general paediatricians around the UK and Ireland, to develop research ideas and protocols, and facilitate delivery of multicentre research. OBJECTIVES: To undertake a research prioritisation exercise among UK and Ireland general paediatricians. METHODS: This was a four-phase study using a modified Delphi survey. The first phase asked for suggested research priorities. The second phase developed ideas and ranked them in priority. In the third phase, priorities were refined; and the final stage used the Hanlon Prioritisation Process to agree on the highest priorities. RESULTS: In phase one, there were 250 questions submitted by 61 GAPRUKI members (66% of the whole membership). For phase two, 92 priorities were scored by 62 members and the mean Likert scale (1-7) scores ranged from 3.13 to 5.77. In a face-to-face meeting (phases three and four), 17 research questions were identified and ultimately 14 priorities were identified and ranked. The four priorities with the highest ranking focused on these three respiratory conditions: asthma, bronchiolitis and acute wheeze. Other priorities were in the diagnosis or management of constipation, urinary tract infection, fever, gastro-oesophageal reflux and also new models of care for scheduled general paediatric clinics. CONCLUSION: Research priorities for child health in the UK and Ireland have been identified using a robust methodology. The next steps are for studies to be designed and funded to address these priorities.

Cohort profile: a national, population-based cohort of children born after assisted conception in the UK (1992-2009): methodology and birthweight analysis.

PURPOSE: To generate a large cohort of children born after assisted reproductive technology (ART) in the UK between 1992 and 2009, their naturally conceived siblings (NCS) and matched naturally conceived population (NCP) controls and linking this with health outcome data to allow exploration of the effects of ART. The effects of fresh and frozen embryo transfer on birth weight (BW) were analysed to test the validity of the cohort. PARTICIPANTS: Children recorded on the Human Fertilisation and Embryology Authority (HFEA) register as being born after ART between 1992 and 2009, their NCS and matched NCP controls linked to Office for National Statistics birth registration dataset (HFEA-ONS cohort). This cohort was further linked to the UK Hospital Episode Statistics database to allow monitoring of the child's post-natal health outcomes up to 2015 (HFEA-ONS-HES subcohort). FINDINGS TO DATE: The HFEA-ONS cohort consisted of 75 348 children born after non-donor ART carried out in the UK between 1 April 1992 and 31 July 2009 and successfully linked to birth registration records, 14 763 NCS and 164 823 matched NCP controls. The HFEA-ONS-HES subcohort included 63 877 ART, 11 343 NCS and 127 544 matched NCP controls further linked to health outcome data. The exemplar analysis showed that children born after fresh embryo transfers were lighter (BW difference: -131 g, 95% CI: -140 to -123) and those born after frozen embryo transfers were heavier (BW difference: 35 g, 95% CI: 19 to 52) than the NCP controls. The within-sibling analyses were directionally consistent with the population control analyses, but attenuated markedly for the fresh versus natural conception (BW difference: -54 g; 95% CI: -72 to -36) and increased markedly for the frozen versus natural conception (BW difference: 152 g; 95% CI: 113 to 190) analyses. FUTURE PLANS: To use this cohort to explore the relationship between ART conception and short-term and long-term health outcomes in offspring.

Consensus statements on the information to deliver after a febrile seizure.

Febrile seizures (FS) are usually self-limiting and cause no morbidity. Nevertheless they represent very traumatic events for families. There is a need to identify key messages that reassure carers and help to prevent inappropriate, anxiety-driven behaviors associated with "fever phobia." No recommendations have been proposed to date regarding the content of such messages. Using a Delphi process, we have established a consensus regarding the information to be shared with families following a FS. Twenty physicians (child neurologists and pediatricians) from five European countries participated in a three-step Delphi process between May 2018 and October 2019. In the first step, each expert was asked to give 10 to 15 free statements about FS. In the second and third steps, statements were scored and selected according to the expert ranking of importance. A list of key messages for families has emerged from this process, which offer reassurance about FS based on epidemiology, underlying mechanisms, and the emergency management of FS should they recur. Interestingly, there was a high level of agreement between child neurologists and general pediatricians.Conclusion: We propose key messages to be communicated with families in the post-FS clinic setting. What is Known: • Febrile seizures (FS) are traumatic events for families. • No guidelines exist on what information to share with parents following a FS. What is New: • A Delphi process involving child neurologists and pediatricians provides consensual statement about information to deliver after a febrile seizure. • We propose key messages to be communicated with families in the post-FS clinic setting.

Cost of neonatal abstinence syndrome: an economic analysis of English national data held in the National Neonatal Research Database.

OBJECTIVE: To determine the incidence of neonatal abstinence syndrome (NAS) across neonatal units, explore healthcare utilisation and estimate the direct cost to the NHS. DESIGN: Population cohort study. SETTING: NHS neonatal units, using data held in the National Neonatal Research Database. PARTICIPANTS: Infants born between 2012 and 2017, admitted to a neonatal unit in England, receiving a diagnosis of NAS (n=6411). MAIN OUTCOME MEASURES: Incidence, direct annual cost of care (£, 2016-2017 prices), duration of neonatal unit stay (discharge HR), predicted additional cost of care, and odds of receiving pharmacotherapy. RESULTS: Of 524 334 infants admitted during the study period, 6411 had NAS. The incidence (1.6/1000 live births) increased between 2012 and 2017 (ß=0.07, 95% CI (0 to 0.14)) accounting for 12/1000 admissions and 23/1000 cot days nationally. The direct cost of care was £62 646 661 over the study period. Almost half of infants received pharmacotherapy (n=2631; 49%) and their time-to-discharge was significantly longer (median 18.2 vs 5.1 days; adjusted HR (aHR) 0.16, 95% CI (0.15 to 0.17)). Time-to-discharge was longer for formula-fed infants (aHR 0.73 (0.66 to 0.81)) and those discharged to foster care (aHR 0.77 (0.72 to 0.82)). The greatest predictor of additional care costs was receipt of pharmacotherapy (additional mean adjusted cost of £8420 per infant). CONCLUSIONS: This population study highlights the substantial cot usage and economic costs of caring for infants with NAS on neonatal units. A shift in how healthcare systems provide routine care for NAS could benefit infants and families while alleviating the burden on services.