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.

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.

Risks of nonchromosomal birth defects, small-for-gestational age birthweight, and prematurity with in vitro fertilization: effect of number of embryos transferred and plurality at conception versus at birth.

PURPOSE: Excess embryos transferred (ET) (> plurality at birth) and fetal heartbeats (FHB) at 6 weeks' gestation are associated with reductions in birthweight and gestation, but prior studies have been limited by small sample sizes and limited IVF data. This analysis evaluated associations between excess ET, excess FHB, and adverse perinatal outcomes, including the risk of nonchromosomal birth defects. METHODS: Live births conceived via IVF from Massachusetts, New York, North Carolina, and Texas included 138,435 children born 2004-2013 (Texas), 2004-2016 (Massachusetts and North Carolina), and 2004-2017 (New York) were classified by ET and FHB. Major birth defects were reported by statewide registries within the first year of life. Logistic regression was used to estimate adjusted odds ratios (AORs) and 95% CIs of the risks of a major nonchromosomal birth defect, small-for-gestational age birthweight (SGA), low birthweight (LBW), and preterm birth (≤36 weeks), by excess ET, and excess ET + excess FHB, by plurality at birth (singletons and twins). RESULTS: In singletons with [2 ET, FHB =1] and [≥3 ET, FHB=1], risks [AOR (95% CI)] were increased, respectively, for major nonchromosomal birth defects [1.13 (1.00-1.27) and 1.18 (1.00-1.38)], SGA [1.10 (1.03-1.17) and 1.15 (1.05-1.26)], LBW [1.09 (1.02-1.13) and 1.17 (1.07-1.27)], and preterm birth [1.06 (1.00-1.12) and 1.14 (1.06-1.23)]. With excess ET + excess FHB, risks of all adverse outcomes except major nonchromosomal birth defects increased further for both singletons and twins. CONCLUSION: Excess embryos transferred are associated with increased risks for nonchromosomal birth defects, reduced birthweight, and prematurity in IVF-conceived births.

In vitro fertilization and risk for hypertensive disorders of pregnancy: associations with treatment parameters.

BACKGROUND: Although in vitro fertilization has been associated with an increased risk for hypertensive disorders of pregnancy, the association of risk with in vitro fertilization treatment parameters is unclear. OBJECTIVE: To evaluate risk for hypertensive disorders of pregnancy by maternal fertility status and in vitro fertilization treatment parameters. MATERIALS AND METHODS: Women in 8 states who underwent in vitro fertilization resulting in a live birth during 2004-2013 were linked to their infant's birth certificates. A 10:1 sample of births from non-in vitro fertilization deliveries were selected for comparison. Those with an indication of infertility treatment on the birth certificate were categorized as subfertile and omitted from the study population; all others were categorized as fertile. The in vitro fertilization pregnancies were additionally categorized by oocyte source (autologous versus donor) and embryo state (fresh versus thawed). Both the fertile and in vitro fertilization births were limited to singletons only, and the in vitro fertilization pregnancies were limited to those using partner sperm. Hypertensive disorders of pregnancy (including gestational hypertension and preeclampsia) were identified from the birth certificate, modeled using logistic regression, and reported as adjusted odds ratios and 95% confidence intervals. For analyses of in vitro fertilization pregnancies from autologous oocytes-fresh embryos, the reference group was fertile women (subgroup analysis 1). For analyses within the in vitro fertilization group, the reference group was autologous oocytes-fresh embryos (subgroup analysis 2). RESULTS: The study population included 1,465,893 pregnancies (1,382,311 births to fertile women and 83,582 births to in vitro fertilization-treated women). Compared to fertile women, in vitro fertilization-treated women with autologous-fresh cycles were not at increased risk for hypertensive disorders of pregnancy (adjusted odds ratio, 1.04; 95% confidence interval, 0.99, 1.08). Among in vitro fertilization births (subgroup analysis 2), the risk for hypertensive disorders of pregnancy was increased for the autologous-thawed (adjusted odds ratio, 1.30; 95% confidence interval, 1.20, 1.40); donor-fresh (adjusted oddds ratio, 1.92; 95% confidence interval, 1.71, 2.15); and donor-thawed (adjusted odds ratio, 1.70; 95% confidence interval, 1.47, 1.96) groups. Excluding women with pregestational diabetes or chronic hypertension as well as adjusting for body mass index and infertility diagnoses did not substantially change the results. When stratified by <34 weeks (early-onset hypertensive disorders of pregnancy) versus ≥34 weeks (late-onset hypertensive disorders of pregnancy), only the donor-fresh group had an increased risk of early-onset hypertensive disorders of pregnancy, but the risks for all other oocyte source-embryo state groups compared to autologous-fresh were increased for late-onset hypertensive disorders of pregnancy. CONCLUSION: The risk for hypertensive disorders of pregnancy is increased for in vitro fertilization-treated women in pregnancies conceived via frozen embryo transfer (with both autologous or donor oocyte) and fresh donor oocyte embryo transfer. No increase in risk was seen with autologous oocyte-fresh embryo transfers in vitro fertilization cycles. Excluding women with pregestational diabetes or chronic hypertension as well as adjusting for body mass index and infertility diagnoses did not substantially change the results.

Defining critical factors in multi-country studies of assisted reproductive technologies (ART): data from the US and UK health systems.

As the worldwide use of assisted reproductive technologies (ART) continues to grow, there is a critical need to assess the safety of these treatment parameters and the potential adverse health effects of their use in adults and their offspring. While key elements remain similar across nations, geographic variations both in treatments and populations make generalizability challenging. We describe and compare the demographic factors between the USA and the UK related to ART use and discuss implications for research. The USA and the UK share some common elements of ART practice and in how data are collected regarding long-term outcomes. However, the monitoring of ART in these two countries each brings strengths that complement each other's limitations.

A child in shock: carotid blowout syndrome.

Paediatricians commonly encounter neck lumps during their routine clinical practice; vascular abnormalities, such as (pseudo)aneurysms, are a rare cause of these. Pseudoaneurysms of the carotid artery in children are usually the result of blunt or penetrating trauma, infection or vasculitis/connective tissue disorders. They can present with a variety of symptoms including neck pain, as a pulsatile neck mass or with compressive symptoms (for example, cranial nerve palsies or dyspnoea). Pseudoaneurysms carry a risk of rupture in which case they are fatal, unless immediate treatment is provided.We report a 17-month-old male child with idiopathic carotid artery blowout syndrome presenting with acute oropharyngeal haemorrhage leading to asystolic cardiac arrest. He was successfully resuscitated and emergency embolisation controlled the bleeding. Despite extensive left hemispheric infarct, he has survived.Carotid artery blowout syndrome needs to be recognised as a potential cause of major haemorrhage in childhood. The purpose of this case report is to remind readers of the differential diagnosis and work-up of a child presenting with a neck lump, to highlight important aspects of the acute management of major haemorrhage and massive blood transfusion in paediatrics, to describe the aetiology, presentation and management of carotid artery pseudoaneurysm in children and to discuss long term rehabilitation in patients with consequent neurological sequelae (including the need for input from multiple specialty teams).

A systematic review of sudden unexpected death in epilepsy (SUDEP) in childhood.

BACKGROUND: Sudden Unexpected Death in Epilepsy (SUDEP) is a significant cause of death in childhood epilepsy, and causes considerable concern to patients and their families. Despite this, the condition remains poorly understood. This systematic review investigates the risk factors, pathophysiology, and circumstances associated with childhood SUDEP. It aimed to explore the etiology of SUDEP and inform clinicians approaching SUDEP risk disclosure. METHODS: A structured electronic database search of MEDLINE, CENTRAL, EMBASE, and ISI web of science was conducted. Studies were included if they described clinical details of one or more patients, aged 18 years of age and below, who had SUDEP. Two reviewers independently reviewed each article for data extraction and quality assessment. RESULTS: Information on 108 cases of pediatric SUDEP was extracted from 22 included studies. These comprised five cohort studies, four retrospective case control studies, seven case series, and five case reports. Factors that appeared to be linked to pediatric SUDEP included those associated with severe epilepsy (early age of onset, high seizure frequency, intellectual impairment and developmental delay, multiple antiepileptic drug therapy, and structural abnormalities). The majority of included studies was noncomparative and had significant risk of bias. CONCLUSIONS: There is currently insufficient evidence to determine the etiology of pediatric SUDEP. Current best practice to prevent pediatric SUDEP is to optimize the management of epilepsy. A national SUDEP registry would provide invaluable high-quality data and insights into modifiable risk factors, genetic predispositions, and novel prevention strategies.

Cancer risk among children born after assisted conception.

BACKGROUND: Accurate population-based data are needed on the incidence of cancer in children born after assisted conception. METHODS: We linked data on all children born in Britain between 1992 and 2008 after assisted conception without donor involvement with data from the United Kingdom National Registry of Childhood Tumours to determine the number of children in whom cancer developed before 15 years of age. Cohort cancer rates were compared with population-based rates in Britain over the same period, with stratification for potential mediating and moderating factors, including sex, age at diagnosis, birth weight, singleton versus multiple birth, parity, parental age, type of assisted conception, and cause of parental infertility. RESULTS: The cohort consisted of 106,013 children born after assisted conception (700,705 person-years of observation). The average duration of follow-up was 6.6 years. Overall, 108 cancers were identified, as compared with 109.7 expected cancers (standardized incidence ratio, 0.98; 95% confidence interval [CI], 0.81 to 1.19; P=0.87). Assisted conception was not associated with an increased risk of leukemia, neuroblastoma, retinoblastoma, central nervous system tumors, or renal or germ-cell tumors. It was associated with an increased risk of hepatoblastoma (standardized incidence ratio, 3.64; 95% CI, 1.34 to 7.93; P=0.02; absolute excess risk, 6.21 cases per 1 million person-years) and rhabdomyosarcoma (standardized incidence ratio, 2.62; 95% CI, 1.26 to 4.82; P=0.02; absolute excess risk, 8.82 cases per 1 million person-years), with hepatoblastoma developing in 6 children and rhabdomyosarcoma in 10 children. The excess risk of hepatoblastoma was associated with low birth weight. CONCLUSIONS: There was no increase in the overall risk of cancer among British children born after assisted conception during the 17-year study period. Increased risks of hepatoblastoma and rhabdomyosarcoma were detected, but the absolute risks were small. (Funded by Cancer Research UK and others.).

The phenomenon of micronutrient deficiency among children in China: a systematic review of the literature.

OBJECTIVE: The present study aimed to review the literature on micronutrient deficiency and other factors influencing a deficiency status among children living in China. DESIGN: A systematic review was performed to analyse the literature. SETTING: Studies were identified through a search of PubMed and secondary references. SUBJECTS: Children living in China aged less than 18 years. RESULTS: Sixty-one articles were included. The prevalence of vitamin A deficiency decreased to approximately 10 % in 1995-2009. It increased with age but no significant difference was found between genders. The prevalence of thiamin and vitamin B12 deficiency was 10·5 % in Yunnan and 4·5 % in Chongqing provinces, respectively. Higher vitamin D deficiency rates were seen in spring and winter. The incidence of bleeding due to vitamin K deficiency was 3·3 % in 1998-2001 and more prevalent in rural areas. Both iodine deficiency and excess iodine intake were observed. Goitre rates were reported in Tibet, Jiangxi, Gansu and Hong Kong (3·5-46 %). Anaemia rates ranged from 20 % to 40 % in 2007-2011. High Se deficiency rates were found in Tibet, Shaanxi and Jiangsu. High Zn deficiency rates were also found (50-70 %) in 1995-2006. Few studies reported Ca deficiency rates (19·6-34·3 %). The degrees of deficiency for vitamin A, vitamin B12, Fe and Zn were more substantial in rural areas compared with urban areas. CONCLUSIONS: The prevalence of micronutrient deficiency rates varied. Socio-economic status, environmental factors and the Chinese diet may influence micronutrient deficiency. Public health policies should consider implementing programmes of supplementation, food fortification and nutrition education to address these deficiencies among Chinese children.

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.

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.

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.

Unlicensed use of metformin in children and adolescents in the UK.

AIM: Metformin is the most commonly prescribed oral anti-diabetic drug in young people. It is also prescribed for polycystic ovarian syndrome (PCOS) and obesity treatment in adults in an unlicensed fashion. Little is known as to the extent metformin has been used in young people. We investigated the use of metformin in children and adolescents aged 0-18 years in the UK. METHODS: Population-based prescribing data were obtained from the UK IMS Disease Analyzer between January 2000 and December 2010. RESULTS: A total of 2674 metformin prescriptions were issued to 337 patients (80% female) between 2000 and 2010. The prevalence of metformin prescribing increased from 0.03 per 1000 person-years [95% confidence interval (CI) 0.02, 0.05] to 0.16 per 1000 person-years (95% CI 0.12, 0.20) (P= 0.001). There was a steady increase in metformin prescribing in girls aged 16-18 years. There were 290 metformin treated patients (81% female; n= 235) who had at least one diagnosis of diabetes, PCOS or obesity. Among these patients, PCOS was the most common indication for metformin prescribing in girls (n= 120) followed by diabetes. There were 22 patients (7.6%) who received metformin for obesity treatment only. CONCLUSIONS: Prescribing of metformin increased between 2000 and 2010, in particular amongst girls aged 16-18 years. The main indication for metformin prescribing was PCOS. At present, metformin is not licensed for PCOS and obesity treatment in adults or children. As there is a steady increase in the prescribing of metformin in young people, further studies are required to investigate the efficacy and safety of these prescriptions.

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.

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.

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.

How are patients with rare diseases and their carers in the UK impacted by the way care is coordinated? An exploratory qualitative interview study.

BACKGROUND: Care coordination is considered important for patients with rare conditions, yet research addressing the impact of care coordination is limited. This study aimed to explore how care coordination (or lack of) impacts on patients and carers. Semi-structured interviews were conducted with 15 patients and carers/parents in the UK, representing a range of rare conditions (including undiagnosed conditions). Transcripts were analysed thematically in an iterative process. RESULTS: Participants described a range of experiences and views in relation to care coordination. Reports of uncoordinated care emerged: appointments were uncoordinated, communication between key stakeholders was ineffective, patients and carers were required to coordinate their own care, and care was not coordinated to meet the changing needs of patients in different scenarios. As a result, participants experienced an additional burden and barriers/delays to accessing care. The impacts described by patients and carers, either attributed to or exacerbated by uncoordinated care, included: impact on physical health (including fatigue), financial impact (including loss of earnings and travel costs), and psychosocial impact (including disruption to school, work and emotional burden). Overall data highlight the importance of flexible care, which meets individual needs throughout patients'/carers' journeys. Specifically, study participants suggested that the impacts may be addressed by: having support from a professional to coordinate care, changing the approach of clinics and appointments (where they take place, which professionals/services are available and how they are scheduled), and improving communication through the use of technology, care plans, accessible points of contact and multi-disciplinary team working. CONCLUSION: This study provides further evidence of impacts of uncoordinated care; these may be complex and influenced by a number of factors. Approaches to coordination which improve access to care and lessen the time and burden placed on patients and carers may be particularly beneficial. Findings should influence future service developments (and the evaluation of such developments). This will be achieved, in the first instance, by informing the CONCORD Study in the UK.