Treating very preterm European infants with inhaled nitric oxide increased in-hospital mortality but did not affect neurodevelopment at 5 years of age

Aim: We examined the outcomes of using inhaled nitric oxide (iNO) to treat very preterm born (VPT) infants across Europe. Methods: This was a sub-study of the Screening to Improve Health in Very Preterm Infants in Europe research. It focused on all infants born between 22 + 0 and 31 + 6 weeks/days of gestation from 2011 to 2012, in 19 regions in 11 European countries. We studied 7268 infants admitted to neonatal care and 5 years later, we followed up the outcomes of 103 who had received iNO treatment. They were compared with 3502 propensity score-matched controls of the same age who did not receive treatment. Results: All countries used iNO and 292/7268 (4.0%) infants received this treatment, ranging from 1.2% in the UK to 10.5% in France. There were also large regional variations within some countries. Infants treated with iNO faced higher in-hospital mortality than matched controls (odds ratio 2.03, 95% confidence interval 1.33–3.09). The 5-year follow-up analysis of 103 survivors showed no increased risk of neurodevelopmental impairment after iNO treatment. Conclusion: iNO was used for VPT patients in all 11 countries. In-hospital mortality was increased in infants treated with iNO, but long-term neurodevelopmental outcomes were not affected in 103 5-year-old survivors

Aggravated brain injury after neonatal hypoxic ischemia in microglia-depleted mice.

BACKGROUND:Neuroinflammation plays an important role in neonatal hypoxic-ischemic encephalopathy (HIE). Although microglia are largely responsible for injury-induced inflammatory response, they play beneficial roles in both normal and disease states. However, the effects of microglial depletion on neonatal HIE remain unclear.METHODS:Tamoxifen was administered to Cx3cr1CreER/+Rosa26DTA/+ (microglia-depleted model) and Cx3cr1CreER/+Rosa26DTA/- (control) mice at P8 and P9 to assess the effect of microglial depletion. The density of microglia was quantified using Iba-1 staining. Moreover, the proportion of resident microglia after the HI insult was analyzed using flow cytometric analysis. At P10, the HI insult was conducted using the Rice-Vannucci procedure at P10. The infarct size and apoptotic cells were analyzed at P13. Cytokine analyses were performed using quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA) at P13.RESULTS:At P10, tamoxifen administration induced > 99% microglial depletion in DTA+ mice. Following HI insult, there was persisted microglial depletion over 97% at P13. Compared to male DTA- mice, male DTA+ mice exhibited significantly larger infarct volumes; however, there were no significant differences among females. Moreover, compared to male DTA- mice, male DTA+ mice had a significantly higher density of TUNEL+ cells in the caudoputamen, cerebral cortex, and thalamus. Moreover, compared to female DTA- mice, female DTA+ mice showed a significantly greater number of TUNEL+ cells in the hippocampus and thalamus. Compared to DTA- mice, ELISA revealed significantly lower IL-10 and TGF-β levels in both male and female DTA+ mice under both normal conditions and after HI (more pronounced).CONCLUSION:We established a microglial depletion model that aggravated neuronal damage and apoptosis after the HI insult, which was predominantly observed in males

Breakdown of whole-brain dynamics in preterm-born children

The brain operates at a critical point that is balanced between order and disorder. Even during rest, unstable periods of random behavior are interspersed with stable periods of balanced activity patterns that support optimal information processing. Being born preterm may cause deviations from this normal pattern of development. We compared 33 extremely preterm (EPT) children born at < 27 weeks of gestation and 28 full-term controls. Two approaches were adopted in both groups, when they were 10 years of age, using structural and functional brain magnetic resonance imaging data. The first was using a novel intrinsic ignition analysis to study the ability of the areas of the brain to propagate neural activity. The second was a whole-brain Hopf model, to define the level of stability, desynchronization, or criticality of the brain. EPT-born children exhibited fewer intrinsic ignition events than controls; nodes were related to less sophisticated aspects of cognitive control, and there was a different hierarchy pattern in the propagation of information and suboptimal synchronicity and criticality. The largest differences were found in brain nodes belonging to the rich-club architecture. These results provide important insights into the neural substrates underlying brain reorganization and neurodevelopmental impairments related to prematurity.Swedish Medical Research Council (grant numbers 523-2011-3981, 2017-03043); the regional agreement on medical training and clinical research (grant number, ALF SLL 20170243) between Stockholm County Council and the Karolinska Institutet; European Union Seventh Framework Project (grant number 223767); Swedish Order of Freemasons in Stockholm; Swedish Medical Society; Swedish Brain Foundation (grant number FO2017-0131); Sällskapet Barnavård; Linnèa och Josef Carlssons Stifelse’ Erik and Edith Fernström Stiftelse; Ishizu Matsumura Foundation

Association between parental psychiatric disorders and risk of offspring autism spectrum disorder: a Swedish and Finnish population-based cohort studyResearch in context

Summary: Background: Roughly more than one in six adults worldwide suffer from psychiatric conditions. Sporadic studies have associated parental psychiatric disorders with autism spectrum disorder in offspring. Comprehensively examining the association between parental psychiatric disorders and offspring autism spectrum disorder is needed to guide health policies, and to inform etiologic studies. Methods: We included all children born in Sweden and Finland 1997–2016. Diagnoses were clinically ascertained from National Registers through 2017. We calculated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for autism spectrum disorder in offspring of fathers and mothers with psychiatric disorders, in both parents jointly and across co-occurring conditions. Findings: Among 2,505,842 children, 33,612 were diagnosed with autism spectrum disorder, of which 20% had a parent with psychiatric disorders. The risk of autism spectrum disorder was increased across all psychiatric disorders in fathers (Sweden: aHR = 2.02, 95% CI = 1.92–2.12; Finland: aHR = 1.63, 95% CI = 1.50–1.77), mothers (Sweden: aHR = 2.34, 95% CI = 2.24–2.43; Finland aHR = 2.12, 95% CI = 1.92–2.28), or both parents (Sweden: aHR = 3.76, 95% CI = 3.48–4.07; Finland aHR = 3.61, 95% CI = 3.20–4.07), compared to neither parents. Co-occurrence of parental psychiatric disorders further increased risk (e.g., Sweden: for one, two or ≥three different diagnostic categories compared to no diagnosis, in fathers aHR = 1.81, 2.07, 2.52; in mothers aHR = 2.05, 2.63, 3.57). Interpretation: Psychiatric disorders in both parents conveyed the highest risk of offspring autism spectrum disorder, followed by mothers and then fathers. The risk increased with number of co-occurring disorders. All parental psychiatric disorders were associated with increased the risk of autism spectrum disorder. To reliably assess the risk of autism spectrum disorder in children, a comprehensive history incorporating the full range of parental psychiatric disorders is needed beyond solely focusing on familial autism spectrum disorder. Funding: Swedish-Research-Council-2021-0214

Analysis plan.

BackgroundWomen with psychiatric diagnoses are at increased risk of preterm birth (PTB), with potential life-long impact on offspring health. Less is known about the risk of PTB in offspring of fathers with psychiatric diagnoses, and for couples where both parents were diagnosed. In a nationwide birth cohort, we examined the association between psychiatric history in fathers, mothers, and both parents and gestational age.Methods and findingsWe included all infants live-born to Nordic parents in 1997 to 2016 in Sweden. Psychiatric diagnoses were obtained from the National Patient Register. Data on gestational age were retrieved from the Medical Birth Register. Associations between parental psychiatric history and PTB were quantified by relative risk (RR) and two-sided 95% confidence intervals (CIs) from log-binomial regressions, by psychiatric disorders overall and by diagnostic categories. We extended the analysis beyond PTB by calculating risks over the whole distribution of gestational age, including “early term” (37 to 38 weeks).Among the 1,488,920 infants born throughout the study period, 1,268,507 were born to parents without a psychiatric diagnosis, of whom 73,094 (5.8%) were born preterm. 4,597 of 73,500 (6.3%) infants were born preterm to fathers with a psychiatric diagnosis, 8,917 of 122,611 (7.3%) infants were born preterm to mothers with a pscyhiatric diagnosis, and 2,026 of 24,302 (8.3%) infants were born preterm to both parents with a pscyhiatric diagnosis. We observed a shift towards earlier gestational age in offspring of parents with psychiatric history. The risks of PTB associated with paternal and maternal psychiatric diagnoses were similar for different psychiatric disorders. The risks for PTB were estimated at RR 1.12 (95% CI [1.08, 1.15] p p p p p p p p p p p p ConclusionsPaternal and maternal psychiatric history were associated with a shift to earlier gestational age and increased risk of births before full term. The risk consistently increased when fathers had a positive history of different psychiatric disorders, increased further when mothers were diagnosed and was highest when both parents were diagnosed.</div

Supplementary Tables and Figures.

Table A. ICD codes for psychiatric disorders. Table B. Percentiles of gestational age in days by parental psychiatric history. Table C. Parental psychiatric history and relative risk of preterm birth, adjusting for maternal smoking and BMI. Table D. Parental psychiatric history before delivery and relative risk of very preterm birth (Table E. Number of co-occurring psychiatric disorders in fathers and mothers and relative risk of preterm birth. Table F. Parental psychiatric history and relative risk of preterm birth pairwise comparisons between exposure groups—father only, mother only, and both parents. Table G. Parental psychiatric history before delivery and relative risk of preterm birth, by spontaneous delivery and non-spontaneous delivery. Table H. Parental psychiatric history before delivery and relative risk of preterm birth, by offspring sex. Table I. Parental psychiatric history before delivery and relative risk of preterm birth in singletons. Table J. Parental psychiatric history before delivery and relative risk of preterm birth, restricting to psychiatric disorders first being diagnosed 2 years before conception. Table K. Parental psychiatric history before delivery and relative risk of preterm birth, requiring at least 2 diagnoses over 30 days. Table L. Parental psychiatric history before delivery and relative risk of preterm birth, restricting to births from 2005 onwards. Fig A. Flow diagram illustrating the identification of the study cohort. Fig B. Density curve of gestational age (GA) distributions by parental psychiatric history. Fig C. Cumulative distribution of years between birth of the child and last previous diagnosis in fathers and mothers. (PDF)</p

Parental psychiatric history and risk of preterm birth, by gestational age categories and by co-occurring different psychiatric disorders.

Part A: Parental psychiatric history and risk of very preterm birth, moderate/late preterm birth, and early term birth versus full term birth. ORs of GA Part B: Number of co-occurring psychiatric disorders from different diagnostic categories in fathers and mothers and risk of preterm birth. RRs of preterm birth with 95% CIs were calculated using log-binomial regression models, adjusted for birth year by cubic natural splines with 5 knots and any psychiatric diagnosis of the other parent. The dots in the figure represent RRs and lines represent 95% CIs. Diagnostic categories of psychiatric diagnoses: psychoactive substance use, schizophrenia and other non-mood psychotic disorder, mood disorders, neurotic/behavioral disorders, neurodevelopmental disorders, emotional and behavioral disorders of childhood origin and intellectual disability, and other psychiatric disorder (not otherwise specified). CI, confidence interval; GA, gestational age; OR, odds ratio; RR, relative risk.</p

Parental psychiatric history before delivery and RR of preterm birth.

RRs with 95% CIs were calculated using log-binomial regression models, adjusted for birth year by cubic natural splines with 5 knots. The dots in the figure represent RRs and lines represent 95% CIs. For psychiatric category “other,” upper 95% CI = 5.48. CI, confidence interval; P.hist, psychiatric history; RR, relative risk.</p

Parental psychiatric diagnosis before delivery and RR of preterm birth.

Parental psychiatric diagnosis before delivery and RR of preterm birth.</p