The type and timing of patent ductus arteriosus treatment was associated with neurodevelopment when extremely preterm infants reached 6.5 years.

AIM: This study investigated patent ductus arteriosus (PDA) treatment and neurodevelopmental outcomes when extremely preterm born children reached 6.5 years. METHOD: Our cohort was 435 children with neonatal PDA treatment data and neurodevelopmental follow-up data, born in 2004-2007, who participated in the Extremely Preterm Infants in Sweden Study. Pharmacological or surgical PDA treatment and the age at PDA treatment, were investigated in relation to the risks of moderate to severe neurodevelopmental impairment (NDI) and full-scale intelligence quotient (FSIQ) at 6.5 years. RESULTS: The children who received PDA drug treatment, including those who also had surgery, had the same risk of moderate to severe NDI or lower FSIQ as untreated children. However, children who had primary PDA surgery faced increased risks of NDI, with an adjusted incidence rate ratio of 1.62 (95% confidence interval [CI] 1.28-2.06) and a lower adjusted mean difference FSIQ of -7.1 (95% CI -11 to -3.2). Surgery at less than 10 days of life was associated with a significantly increased risk of moderate to severe NDI and lower FSIQ than surgery after 20 days. CONCLUSION: Drug treatment followed by deferred surgery appeared to be a safer option for extremely preterm infants severely affected by PDA.

Cardiac Troponin T in Healthy Full-Term Infants.

In this prospective cohort study of healthy full-term infants, we hypothesized that high-sensitivity cardiac troponin T (hs-cTnT) would be elevated in cord blood, compared with adult reference values, and that it would further increase over the first days of age. Cardiac troponin T has been shown to be significantly increased in healthy full-term newborns compared with adult reference values, but there is no established reference range. Most studies of cTnT in newborns have been performed before the introduction of high-sensitivity cTnT (hs-cTnT) assay. We conducted a study including 158 full-term newborns, at Stockholm South General Hospital. High-sensitivity cTnT was analyzed in umbilical cord blood and at 2-5 days of age. Median hs-cTnT (interquartile range) in cord blood was 34(26-44) ng/L; 99th percentile 88 ng/L. Median hs-cTnT at 2-5 days of age was 92(54-158) ng/L; 99th percentile 664 ng/L. We conclude that hs-cTnT is elevated in cord blood in healthy, full-term newborn infants compared with adult reference values, and that it increases significantly during the first days of life. Our findings further underline the need of caution when using hs-cTnT as a measurement of cardiac impact in newborns.

Low breastfeeding continuation to 6 months for very preterm infants: A European multiregional cohort study.

Breastfeeding confers multiple benefits for the health and development of very preterm infants, but there is scarce information on the duration of breastfeeding after discharge from the neonatal intensive care unit (NICU). We used data from the Effective Perinatal Intensive Care in Europe population-based cohort of births below 32 weeks of gestation in 11 European countries in 2011-2012 to investigate breastfeeding continuation until 6 months. Clinical and sociodemographic characteristics were collected from obstetric and neonatal medical records as well as parental questionnaires at 2 years of corrected age. Among 3,217 ever-breastfed infants, 34% were breastfeeding at 6 months of age (range across countries from 25% to 56%); younger and less educated mothers were more likely to stop before 6 months (adjusted relative risk [aRR] <25 years: 0.68, 95% CI [0.53, 0.88], vs. 25-34 years; lower secondary: 0.58, 95% CI [0.45, 0.76] vs. postgraduate education). Multiple birth, bronchopulmonary dysplasia (BPD), and several neonatal transfers reduced the probability of continuation but not low gestational age, fetal growth restriction, congenital anomalies, or severe neonatal morbidities. Among infants breastfeeding at discharge, mixed versus exclusive breast milk feeding at discharge was associated with stopping before 6 months: aRR = 0.60, 95% CI [0.48, 0.74]. Low breastfeeding continuation rates in this high-risk population call for more support to breastfeeding mothers during and after the neonatal hospitalization, especially for families with low socio-economic status, multiples, and infants with BPD. Promotion of exclusive breastfeeding in the NICU may constitute a lever for improving breastfeeding continuation after discharge.

Variation in term birthweight across European countries affects the prevalence of small for gestational age among very preterm infants.

AIM: This study assessed the prevalence of small for gestational age (SGA) among very preterm (VPT) infants using national and European intrauterine references. METHODS: We generated country-specific and common European intrauterine growth references for 11 European countries, according to Gardosi's approach and Hadlock's foetal growth model, using national data on birthweights by sex. These references were applied to the Effective Perinatal Intensive Care in Europe (EPICE) cohort, which comprised 7766 live VPT births without severe congenital anomalies under 32 weeks of gestation in 2011-2012, to estimate the prevalence of infants with SGA birthweights, namely those below the 10th percentile. RESULTS: The SGA prevalence was 31.8% with country-specific references and 34.0% with common European references. The European references yielded a 10-point difference in the SGA prevalence between countries with lower term birthweights (39.9%) - Portugal, Italy and France - and higher term birthweights, namely Denmark, the Netherlands, Sweden (28.9%; p < 0.001). This was not observed with country-specific references, where the respective figures were 32.4% and 33.9% (p = 0.34), respectively. CONCLUSION: One-third of VPT infants were SGA according to intrauterine references. Common European references showed significant differences in SGA prevalence between countries with high and low-term birthweights.

Registers of the Swedish total population and their use in medical research.

The primary aim of the Swedish national population registration system is to obtain data that (1) reflect the composition, relationship and identities of the Swedish population and (2) can be used as the basis for correct decisions and measures by government and other regulatory authorities. For this purpose, Sweden has established two population registers: (1) The Population Register, maintained by the Swedish National Tax Agency ("Folkbokföringsregistret"); and (2) The Total Population Register (TPR) maintained by the government agency Statistics Sweden ("Registret över totalbefolkningen"). The registers contain data on life events including birth, death, name change, marital status, family relationships and migration within Sweden as well as to and from other countries. Updates are transmitted daily from the Tax Agency to the TPR. In this paper we describe the two population registers and analyse their strengths and weaknesses. Virtually 100 % of births and deaths, 95 % of immigrations and 91 % of emigrations are reported to the Population Registers within 30 days and with a higher proportion over time. The over-coverage of the TPR, which is primarily due to underreported emigration data, has been estimated at up to 0.5 % of the Swedish population. Through the personal identity number, assigned to all residents staying at least 1 year in Sweden, data from the TPR can be used for medical research purposes, including family design studies since each individual can be linked to his or her parents, siblings and offspring. The TPR also allows for identification of general population controls, participants in cohort studies, as well as calculation of follow-up time.

Hospital-assisted home care after early discharge from a Swedish neonatal intensive care unit was safe and readmissions were rare.

AIM: It is common in Sweden to discharge infants early from a neonatal intensive care unit (NICU) and provide hospital-assisted neonatal home care (HANHC), as an alternative to hospital care, for infants with a persisting need for specialised care. This study assessed the safety of HANHC by reviewing hospital readmissions. METHODS: We retrospectively reviewed the files of all 1410 infants enrolled in HANHC at the NICU at Sachs' Children's Hospital, Stockholm, from 2002 to 2011 up until hospital readmission or their discharge from HANHC. Each readmitted infant was matched to the next HANHC infant who was not readmitted. Predictors and reasons for readmission were investigated in a retrospective nested case-control study. RESULTS: We readmitted 74 (5.2%) of the 1410 infants in HANHC. Extremely preterm infants, born at less than 28 weeks, were readmitted more frequently than other infants, with an odds ratio of 6.07 (range 2.06-17.8). The most common symptoms were respiratory symptoms (55%), and viral respiratory tract infections were the most common reason (28%) for readmission. CONCLUSION: HANHC was safe for the vast majority of infants (94.8%). Extremely preterm birth was identified as a predictor for hospital readmission. Further studies investigating the safety of HANHC in other settings would be valuable.

Cerebrovascular and ischemic heart disease in young adults born preterm: a population-based Swedish cohort study.

Preterm birth is associated with overall cardiovascular mortality in young adulthood, but which specific conditions that underlie this association is unknown. We studied mortality and morbidity from cerebrovascular and ischemic heart disease in individuals born preterm. In a nationwide Swedish study, we included 1,306,943 individuals without congenital malformations born between 1983 and 1995, followed from 15 years of age to December 31st, 2010. Of these, 73,489 (5.6 %) were born preterm (<37 weeks of gestation). Cox proportional hazards regression analysis was used to calculate hazard ratios (HR) with 95 % confidence intervals (CI), after adjusting for maternal characteristics and birth weight for gestational age. Of 955 incident cases of cerebrovascular disease, 58 (6.1 %) occurred in preterm born subjects. The corresponding numbers of ischemic heart disease cases were 180 and 13 (7.2 %), respectively. Birth before 32 weeks was associated with a nearly twofold increased risk of cerebrovascular disease; adjusted HR, (95 % CI) = 1.89 (1.01-3.54) compared to term born individuals, whereas individuals born at 32-36 weeks were not at increased risk. Preterm birth was not associated with later ischemic heart disease; no cases of ischemic heart disease were recorded among those born before 32 weeks and the HR (95 % CI) for those born at 32-36 weeks of gestation was 1.45 (0.81-2.57), compared to term-born individuals. Birth before 32 weeks is associated with increased risk of cerebrovascular disease in young adulthood. Our data suggest that cardiovascular health promotion in follow-up programs after very preterm birth may be beneficial.

Relative intima-media thickening after preterm birth.

AIM: Preterm infants are at increased risk of early arterial growth arrest and cardiovascular mortality. We assessed intima-media thickness (IMT) - an early marker of accelerated vascular ageing - in very preterm infants. METHODS: Longitudinal cohort study of 21 very preterm and 29 term infants, all with appropriate birthweights. Intima-media thickness was assessed by M-Mode ultrasound of the aorta and carotid arteries at three occasions during a 6-month period corresponding to the third trimester of pregnancy and ending 3 months after term equivalent age. RESULTS: No differences in absolute aortic or carotid IMT were found. However, in relation to vessel lumen diameter, the IMT switched from being narrower in preterm infants, compared with foetuses at 28 weeks of gestation, to being significantly thicker in both the aorta and carotid artery in older infants born preterm, compared with term controls of equivalent postmenstrual age. Although the aortic and carotid artery diameters increased significantly with postnatal age, IMT did not. CONCLUSION: In relation to vessel diameter, subjects born preterm show thicker intima-media in the great arteries than infants born at term. It remains to be established whether this relative intima-media thickening persists and may be a risk marker for future cardiovascular disease.

Birth characteristics and subsequent risks of maternal cardiovascular disease: effects of gestational age and fetal growth.

BACKGROUND: Prior studies showing an inverse relationship between low birth weight in offspring and maternal risks of cardiovascular diseases (CVD) are limited by lack of information on gestational age and/or insufficient adjustment for confounders. METHODS AND RESULTS: In a nationwide Swedish study, we included information on 923 686 women and their first singleton births between 1983 and 2005. Cox proportional hazards models were used to study associations between gestational length, fetal growth, and maternal incident hospitalization or death from CVD (coronary heart disease, cerebrovascular events, and heart failure). Multivariable adjusted models accounted for birth year, income, education, country of birth, smoking, diabetes mellitus, hypertension, and preeclampsia. The risk of maternal CVD increased with decreasing gestational age whereas the risk increase related to fetal growth appeared to be restricted to very small-for-gestational-age (SGA) infants. Compared with mothers of non-SGA infants born at term, the hazard ratio of CVD ranged from 1.39 (95% confidence interval 1.22-1.58) to 2.57 (95% confidence interval 1.97-3.34) among mothers to moderately and very preterm infants, respectively. There was a significant interaction between preterm birth and fetal growth with respect to mothers' risk of CVD (P<0.001). Among mothers to very SGA infants, the hazard ratio of CVD ranged from 1.38 (95% confidence interval 1.15-1.65) to 3.40 (95% confidence interval 2.26-5.11) in mothers to term and very preterm infants, respectively. CONCLUSIONS: Delivery of a preterm or SGA infant is associated with later life maternal hospitalization or death from CVD even after accounting for socioeconomic factors, smoking, and pregnancy-related complications.

Association of Maternal Preeclampsia With Offspring Risks of Ischemic Heart Disease and Stroke in Nordic Countries.

Importance: An association between maternal preeclampsia and an increased risk of cardiovascular disease in the offspring is plausible, but evidence in this area is limited. Objective: To investigate (1) the association between maternal preeclampsia and risks of ischemic heart disease (IHD) and stroke in the offspring, (2) whether the association varies by severity or timing of onset of preeclampsia, and (3) the role of preterm birth and small for gestational age (SGA) birth, both of which are related to preeclampsia and cardiovascular diseases, in this association. Design, Setting, and Participants: This multinational population-based cohort study obtained data from Danish, Finnish, and Swedish national registries. Live singleton births from Denmark (1973-2016), Finland (1987-2014), and Sweden (1973-2014) were followed up until December 31, 2016, in Denmark and December 31, 2014, in Finland and Sweden. Data analyses were performed between September 2020 and September 2022. Exposures: Preeclampsia and its subtypes, including early onset (<34 gestational weeks) and late onset (≥34 gestational weeks), severe and mild or moderate, and with and without SGA birth. Main Outcomes and Measures: Diagnoses of IHD and stroke were extracted from patient and cause-of-death registers. Cox proportional hazards regression models and flexible parametric survival models were used to analyze the associations. Sibling analyses were conducted to control for unmeasured familial factors. Results: The cohort included of 8 475 819 births (2 668 697 [31.5%] from Denmark, 1 636 116 [19.3%] from Finland, and 4 171 006 [49.2%] from Sweden, comprising 4 350 546 boys [51.3%]). Of these offspring, 188 670 (2.2%) were exposed to maternal preeclampsia, 7446 (0.1%) were diagnosed with IHD, and 10 918 (0.1%) were diagnosed with stroke during the median (IQR) follow-up of 19.3 (9.0-28.1) years. Offspring of individuals with preeclampsia had increased risks of IHD (adjusted hazard ratio [HR], 1.33; 95% CI, 1.12-1.58) and stroke (adjusted HR, 1.34; 95% CI, 1.17-1.52). These associations were largely independent of preterm or SGA birth. Severe forms of preeclampsia were associated with a higher stroke risk than less severe forms (severe vs mild or moderate: adjusted HR, 1.81 [95% CI, 1.41-2.32] vs 1.22 [95% CI, 1.05-1.42]; early vs late onset: adjusted HR, 2.55 [95% CI, 1.97-3.28] vs 1.18 [95% CI, 1.01-1.39]; with vs without SGA birth: adjusted HR, 1.84 [95% CI, 1.44-2.34] vs 1.25 [95% CI, 1.07-1.48]). Sibling analyses suggested that the associations were partially explained by unmeasured familial factors. Conclusions and Relevance: Results of this study suggest that offspring born to individuals with preeclampsia had increased IHD and stroke risk that were not fully explained by preterm or SGA birth, and that the associated risks for stroke were higher for severe forms of preeclampsia.

Human- Versus Machine Learning-Based Triage Using Digitalized Patient Histories in Primary Care: Comparative Study.

BACKGROUND: Smartphones have made it possible for patients to digitally report symptoms before physical primary care visits. Using machine learning (ML), these data offer an opportunity to support decisions about the appropriate level of care (triage). OBJECTIVE: The purpose of this study was to explore the interrater reliability between human physicians and an automated ML-based triage method. METHODS: After testing several models, a naïve Bayes triage model was created using data from digital medical histories, capable of classifying digital medical history reports as either in need of urgent physical examination or not in need of urgent physical examination. The model was tested on 300 digital medical history reports and classification was compared with the majority vote of an expert panel of 5 primary care physicians (PCPs). Reliability between raters was measured using both Cohen κ (adjusted for chance agreement) and percentage agreement (not adjusted for chance agreement). RESULTS: Interrater reliability as measured by Cohen κ was 0.17 when comparing the majority vote of the reference group with the model. Agreement was 74% (138/186) for cases judged not in need of urgent physical examination and 42% (38/90) for cases judged to be in need of urgent physical examination. No specific features linked to the model's triage decision could be identified. Between physicians within the panel, Cohen κ was 0.2. Intrarater reliability when 1 physician retriaged 50 reports resulted in Cohen κ of 0.55. CONCLUSIONS: Low interrater and intrarater agreement in triage decisions among PCPs limits the possibility to use human decisions as a reference for ML to automate triage in primary care.

Maternal obesity and risk of cardiovascular diseases in offspring: a population-based cohort and sibling-controlled study.

BACKGROUND: Maternal overweight and obesity might increase risks of adiposity and cardiovascular and metabolic diseases in offspring. We examined associations between maternal overweight and obesity severity and risk of cardiovascular diseases in young offspring. METHODS: In this population-based cohort study, we used data from live singleton births recorded in the Swedish Medical Birth Register. We calculated maternal BMI in early pregnancy from self-reported height and weight measurements at the first prenatal visit. We used multivariable Cox proportional hazards regression to estimate adjusted hazard ratios (HRs) and 95% CIs. We calculated the proportion of the associations mediated through known consequences of obesity that also predicted cardiovascular diseases and did family case-control analyses. FINDINGS: We identified 2 230 115 live singleton infants (without congenital malformations) in Sweden registered between Jan 1, 1992, and Dec 31, 2016. Overall, 1741 (0·08%) offspring were diagnosed with a cardiovascular disease between ages 1 and 25 years. Cardiovascular disease rates by maternal BMI categories were 0·57 per 10 000 child-years (BMI 18·5-24·9 kg/m2; normal weight), 0·61 per 10 000 child-years (25·0-29·9 kg/m2; overweight), 0·67 per 10 000 child-years (30·0-34·9 kg/m2; obesity grade I), 1·02 per 10 000 child-years (35·0-39·9 kg/m2; obesity grade II), and 1·38 per 10 000 child-years (≥40·0 kg/m2; obesity grade III). Compared with offspring of mothers with normal BMI, HRs of cardiovascular diseases were 1·10 (95% CI 0·97-1·25) for overweight, 1·16 (0·95-1·43) for obesity grade I, 1·84 (1·36-2·49) for obesity grade II, and 2·51 (1·60-3·92) for obesity grade III. Risks of cerebrovascular diseases increased with maternal obesity severity and were partly mediated through asphyxia-related neonatal complications. The sibling-cohort analysis also indicated a positive trend between maternal BMI and cardiovascular disease rates. INTERPRETATIONS: Our findings indicate that maternal obesity might be a risk factor for cardiovascular diseases in childhood and early adulthood. These results need to be replicated and possible underlying mechanisms identified. FUNDING: Swedish Research Council for Health, Working Life and Welfare.

Perinatal risk factors for ischemic heart disease: disentangling the roles of birth weight and preterm birth.

BACKGROUND: Several studies have reported an association between low birth weight and ischemic heart disease, but it remains unclear whether the association is mediated through poor fetal growth or short gestational duration. METHODS AND RESULTS: In a cohort study, we have identified all subjects born preterm or with a low birth weight at 4 major delivery units in Sweden from 1925 through 1949. For comparison, an equal number of subjects with none of these criteria were identified within the same source population. The study population consists of 6425 subjects, of whom 2931 were born before 37 weeks of gestation and 2176 had a birth weight < 2500 g. Fetal growth was estimated through birth weight for gestational age. The cohort was followed up for occurrence of ischemic heart disease through the nationwide Hospital Discharge and Cause of Death Registries during the period of 1987 through 2002. In the cohort, 617 cases of ischemic heart disease occurred. Compared with subjects with a normal fetal growth, those born small for gestational age (birth weight < or = -2 SD below the mean) were at increased risk of ischemic heart disease (adjusted hazard ratio, 1.64; 95% confidence interval, 1.23 to 2.18). The negative association between fetal growth and risk of ischemic heart disease was independent of gestational duration. CONCLUSIONS: The association between low birth weight and adult risk of ischemic heart disease appears to be mediated entirely by poor fetal growth.

Association of Short Antenatal Corticosteroid Administration-to-Birth Intervals With Survival and Morbidity Among Very Preterm Infants: Results From the EPICE Cohort.

Importance: Administration-to-birth intervals of antenatal corticosteroids (ANS) vary. The significance of this variation is unclear. Specifically, to our knowledge, the shortest effective administration-to-birth interval is unknown. Objective: To explore the associations between ANS administration-to-birth interval and survival and morbidity among very preterm infants. Design, Setting, and Participants: The Effective Perinatal Intensive Care in Europe (EPICE) study, a population-based prospective cohort study, gathered data from 19 regions in 11 European countries in 2011 and 2012 on 4594 singleton infants with gestational ages between 24 and 31 weeks, without severe anomalies and unexposed to repeated courses of ANS. Data were analyzed November 2016. Exposure: Time from first injection of ANS to delivery in hours and days. Main Outcomes and Measures: Three outcomes were studied: in-hospital mortality; a composite of mortality or severe neonatal morbidity, defined as an intraventricular hemorrhage grade of 3 or greater, cystic periventricular leukomalacia, surgical necrotizing enterocolitis, or stage 3 or greater retinopathy of prematurity; and severe neonatal brain injury, defined as an intraventricular hemorrhage grade of 3 or greater or cystic periventricular leukomalacia. Results: Of the 4594 infants included in the cohort, 2496 infants (54.3%) were boys, and the mean (SD) gestational age was 28.5 (2.2) weeks and mean (SD) birth weight was 1213 (400) g. Mortality for the 662 infants (14.4%) unexposed to ANS was 20.6% (136 of 661). Administration of ANS was associated with an immediate and rapid decline in mortality, reaching a plateau with more than 50% risk reduction after an administration-to-birth interval of 18 to 36 hours. A similar pattern for timing was seen for the composite mortality or morbidity outcome, whereas a significant risk reduction of severe neonatal brain injury was associated with longer administration-to-birth intervals (greater than 48 hours). For all outcomes, the risk reduction associated with ANS was transient, with increasing mortality and risk for severe neonatal brain injury associated with administration-to-birth intervals exceeding 1 week. Under the assumption of a causal relationship between timing of ANS and mortality, a simulation of ANS administered 3 hours before delivery to infants who did not receive ANS showed that their estimated decline in mortality would be 26%. Conclusions and Relevance: Antenatal corticosteroids may be effective even if given only hours before delivery. Therefore, the infants of pregnant women at risk of imminent preterm delivery may benefit from its use.

Trends in Congenital Heart Defects in Infants With Down Syndrome.

BACKGROUND: As a result of antenatal screening, abortion of fetuses with Down syndrome has become increasingly common. Little is known about the cardiovascular phenotype in infants with Down syndrome born today. METHODS: Population-based cohort study based on national health registers including 2588 infants with Down syndrome, live-born in Sweden from 1992 to 2012. Risk ratios for congenital heart defects were calculated per 3-year period, adjusted for maternal age, parity, BMI, smoking, diabetes and hypertensive disease, and infant gender. RESULTS: Any congenital heart defect was diagnosed in 54% of infants with Down syndrome. Overall, year of birth was not associated with risk of any congenital heart defect. However, the risk of complex congenital heart defects decreased over time. Compared with 1992 to 1994, the risk in 2010 to 2012 was reduced by almost 40% (adjusted risk ratio 0.62, 95% confidence interval 0.48-0.79). In contrast, risks for isolated ventricular septal defect (VSD) or atrial septal defect showed significant increases during latter years. Overall, the 3 most common diagnoses were atrioventricular septal defect, VSD, or atrial septal defect, accounting for 42%, 22%, and 16% of congenital heart defects, respectively. Although atrioventricular septal defect was far more common than VSD in 1992 to 1994, they were equally common in 2010 to 2012. CONCLUSIONS: Complex congenital heart defects have become less common in infants diagnosed with Down syndrome. This phenotypic shift could be a result of selective abortion of fetuses with Down syndrome, or due to general improvements in antenatal diagnostics of complex congenital heart defects.