Expectant Management or Early Ibuprofen for Patent Ductus Arteriosus.

BACKGROUND: Cyclooxygenase inhibitors are commonly used in infants with patent ductus arteriosus (PDA), but the benefit of these drugs is uncertain. METHODS: In this multicenter, noninferiority trial, we randomly assigned infants with echocardiographically confirmed PDA (diameter, >1.5 mm, with left-to-right shunting) who were extremely preterm (<28 weeks' gestational age) to receive either expectant management or early ibuprofen treatment. The composite primary outcome included necrotizing enterocolitis (Bell's stage IIa or higher), moderate to severe bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. The noninferiority of expectant management as compared with early ibuprofen treatment was defined as an absolute risk difference with an upper boundary of the one-sided 95% confidence interval of less than 10 percentage points. RESULTS: A total of 273 infants underwent randomization. The median gestational age was 26 weeks, and the median birth weight was 845 g. A primary-outcome event occurred in 63 of 136 infants (46.3%) in the expectant-management group and in 87 of 137 (63.5%) in the early-ibuprofen group (absolute risk difference, -17.2 percentage points; upper boundary of the one-sided 95% confidence interval [CI], -7.4; P<0.001 for noninferiority). Necrotizing enterocolitis occurred in 24 of 136 infants (17.6%) in the expectant-management group and in 21 of 137 (15.3%) in the early-ibuprofen group (absolute risk difference, 2.3 percentage points; two-sided 95% CI, -6.5 to 11.1); bronchopulmonary dysplasia occurred in 39 of 117 infants (33.3%) and in 57 of 112 (50.9%), respectively (absolute risk difference, -17.6 percentage points; two-sided 95% CI, -30.2 to -5.0). Death occurred in 19 of 136 infants (14.0%) and in 25 of 137 (18.2%), respectively (absolute risk difference, -4.3 percentage points; two-sided 95% CI, -13.0 to 4.4). Rates of other adverse outcomes were similar in the two groups. CONCLUSIONS: Expectant management for PDA in extremely premature infants was noninferior to early ibuprofen treatment with respect to necrotizing enterocolitis, bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. (Funded by the Netherlands Organization for Health Research and Development and the Belgian Health Care Knowledge Center; BeNeDuctus ClinicalTrials.gov number, NCT02884219; EudraCT number, 2017-001376-28.).

Global cross-sectional survey on neonatal pharmacologic sedation and analgesia practices and pain assessment tools: impact of the sociodemographic index (SDI).

BACKGROUND: There is variability in the use of sedatives and analgesics in neonatal intensive care units (NICUs). We aimed to investigate the use of analgesics and sedatives and the management of neonatal pain and distress. METHODS: This was a global, prospective, cross-sectional study. A survey was distributed May-November 2022. The primary outcome of this research was to compare results between countries depending on their socio-sanitary level using the sociodemographic index (SDI). We organized results based on geographical location. RESULTS: The survey collected 1304 responses, but we analyzed 924 responses after database cleaning. Responses from 98 different countries were analyzed. More than 60% of NICUs reported having an analgosedation guideline, and one-third of respondents used neonatal pain scales in more than 80% of neonates. We found differences in the management of sedation and analgesia between NICUs on different continents, but especially between countries with different SDIs. Countries with a higher SDI had greater availability of and adherence to analgosedation guidelines, as well as higher rates of analgosedation for painful or distressing procedures. Countries with different SDIs reported differences in analgosedation for neonatal intubation, invasive ventilation, and therapeutic hypothermia, among others. CONCLUSIONS: Socio-economic status of countries impacts on neonatal analgosedation management. IMPACT: There is significant variability in the pain management practices in neonates. There is a lack of knowledge related to how neonatal pain management practices differ between regions. Sociodemographic index is a key factor associated with differences in neonatal pain management practices across global regions.

Hyperbilirubinemia and retinopathy of prematurity: a retrospective cohort study.

Retinopathy of prematurity (ROP) is a vasoproliferative retinal disease in preterm infants. Oxidative stress plays a key role in the pathogenesis of ROP. Due to its antioxidant effects, bilirubin has been proposed to be protective against ROP. This study explored the association between hyperbilirubinemia and ROP. We analyzed a 10-year cohort from a neonatal intensive care unit in Milan, Italy, including 1606 infants born under 32 weeks and/or < 1500 g. Data from 1606 infants meeting specific inclusion criteria were reviewed. Eighty infants were excluded due to lack of data, 1526 were deemed eligible for analysis, and 1269 had hyperbilirubinemia requiring phototherapy. There was a higher incidence of ROP among infants with hyperbilirubinemia (13.8%) versus those without (7.8%, p<0.01). Infants with any ROP, non-severe or severe ROP, were exposed to hyperbilirubinemia for a significantly higher number of days compared with those without ROP. Each additional day of exposure increases the risk of developing any ROP by 5%, non-severe ROP by 4%, and severe ROP by 6%. However, this correlation was not observed in infants with gestational age less than 27 weeks and/or body weight less than 1000 g.    Conclusion: Our data show that hyperbilirubinemia requiring phototherapy is associated with an increased risk of developing ROP. However, severe hyperbilirubinemia and ROP share many of their risk factors. Therefore, rather than being a risk factor itself, hyperbilirubinemia may be a surrogate for other risk factors for ROP.    Clinical Trial Registration: NCT05806684. What is Known: • The development of retinopathy of prematurity (ROP) is influenced by several critical risk factors, including low gestational age, low birth weight, supplemental oxygen use, and increased oxidative stress. • In vitro, unconjugated bilirubin is an effective scavenger of harmful oxygen species and a reducing agent, highlighting its potential protective role against oxidative stress. What is New: • Hyperbilirubinemia requiring phototherapy was associated with an increased risk of developing ROP, but this association was not observed in the most vulnerable population of extremely preterm infants. • Every additional day of phototherapy for hyperbilirubinemia increases the risk of ROP by 5% for any ROP, 4% for non-severe ROP, and 6% for severe ROP.

Grandmaternal body mass index in early pregnancy and risk of grandoffspring stillbirth: A nationwide, three-generation cohort study.

We investigated the association between maternal grandmaternal early pregnancy body mass index (BMI) and grandoffspring stillbirth risk in a Swedish population-based three-generation cohort of 176,908 grandmothers (F0), 197,579 mothers (F1), and 316,459 grandoffspring (F2) born 1997-2016. There were 998 stillbirths (risk, 3.2 per 1000 births). Compared with grandmaternal BMI 18.5-24.9, adjusted relative risks [RR (95% CI)] of grandoffspring stillbirth for BMI 25.0-29.9 and ≥30 were, respectively, 1.41 (1.15, 1.72) and 1.62 (1.14, 2.30). RR (95% CI) for corresponding maternal (F1) BMI categories were, respectively, 1.32 (1.06, 1.65) and 1.77 (1.39, 2.25). Maternal BMI mediated only 19% of this relation. Grandmaternal preeclampsia and maternal small-for-gestational age (SGA) birth were related to increased F2 stillbirth risk but did not mediate the association between grandmaternal BMI and grandoffspring stillbirth risk. To explore whether this association was explained by factors shared within families, we studied the relation of maternal full sisters' BMI and stillbirth risk in 101,368 pregnancies. Stillbirth RR (95% CI) for full sisters' BMI 25.0-29.9 and ≥30 compared with 18.5-24.9 were, respectively, 0.76 (0.51, 1.13) and 0.88 (0.55, 1.40). In conclusion, grandmaternal overweight and obesity are associated with grandoffspring stillbirth. This association is not fully explained by shared familial factors.

Increased Serum Total and Free 25-Hydroxyvitamin D with Daily Intake of Cholecalciferol-Fortified Skim Milk: A Randomized Controlled Trial in Colombian Adolescents.

BACKGROUND: The efficacy of cholecalciferol (vitamin D3) food fortification in low- and middle-income countries near the Equator is unknown. OBJECTIVES: We examined the effects of providing cholecalciferol-fortified skim milk to adolescents and their mothers on serum total 25(OH)D, free 25(OH)D, and vitamin D-binding protein (DBP) concentrations in a randomized controlled trial. METHODS: We randomly assigned 80 Colombian families each with a child aged 12-14.5 y and their mother 1 L of skim milk daily, either fortified with 2400 IU (60 µg) cholecalciferol or unfortified, for 6 wk. We prescribed 500 mL of milk daily to adolescents; mothers consumed the remainder ad libitum. We estimated intent-to-treat effects as the between-arm difference in the change in serum total and free 25(OH)D and DBP concentrations from baseline to the end of follow-up. Secondary analyses included stratification by baseline characteristics and per-protocol comparisons. RESULTS: Among adolescents, fortification effects (95% CI) on serum total 25(OH)D, free 25(OH)D, and DBP concentrations were 5.4 nmol/L (2.1, 8.8 nmol/L), 0.6 pmol/L (-0.2, 1.4 pmol/L), and -416 nmol/L (-944, 112 nmol/L), respectively. Effects on total 25(OH)D were stronger in adolescents with lower DBP concentrations, darker skin, less sunlight exposure, and higher compliance than in their respective counterparts. Fortification increased free 25(OH)D concentrations in high compliers. Among mothers, the effects (95% CI) on total 25(OH)D and DBP concentrations were 4.0 nmol/L (0.6, 7.5 nmol/L) and -128 nmol/L (-637, 381 nmol/L), respectively. There were no adverse events. CONCLUSIONS: Provision of cholecalciferol-fortified skim milk increases serum total 25(OH)D concentrations in Colombian adolescents and adult women.

Associations of pregnancy complications and neonatal characteristics with bipolar disorder in the offspring: Nationwide cohort and sibling-controlled studies.

OBJECTIVES: To investigate associations of neonatal characteristics and pregnancy complications with bipolar disorder (BPD) in offspring. METHODS: We conducted a nationwide cohort study among 2,059,578 non-malformed singleton live-births in Sweden born 1983-2004. Using national registries with prospectively recorded information, we followed participants for a BPD diagnosis from 13 up to 34 years of age. We compared BPD risks between exposure categories using hazard ratios (HR) with 95% confidence intervals (CI) from adjusted Cox models. We also conducted sibling-controlled analyses among 1,467,819 full siblings. RESULTS: There were 14,998 BPD diagnoses. Risk of BPD was 0.74% through 25 years of age. Very/extremely preterm birth (22 to 31 weeks) was related to increased BPD HRs in sibling-controlled analyses; compared with a gestational age of 37 weeks, adjusted HR (95% CI) for 31, 28, and 22 weeks were, respectively, 1.31 (0.99, 1.74), 2.09 (1.15, 3.79), and 5.74 (1.15, 28.63). Spontaneous but not medically indicated very/extremely preterm birth was associated with increased risk. Compared with vaginal birth, caesarean section birth was associated with 1.20 (1.08, 1.33) and 1.58 (1.06, 2.36) times higher BPD risk in general and sibling cohorts, respectively. Small-for-gestational age (SGA) birth was related to increased BPD HRs in general cohort and sibling analyses (HRs [95% CI] were 1.22 [1.06, 1.39] and 1.68 [1.13, 2.50], respectively); only term SGA was associated with increased risk. Head circumference-for-gestational age, gestational diabetes, preeclampsia, and placental abruption were not associated with BPD. CONCLUSIONS: Very/extremely preterm birth, caesarean birth, and SGA are related to BPD incidence.

Maternal early pregnancy body mass index and bipolar disorder in the offspring.

OBJECTIVES: To investigate the association between maternal early pregnancy body mass index (BMI) and offspring bipolar disorder (BPD). METHODS: We conducted a nationwide cohort study among 1,507,056 non-malformed singleton live-births in Sweden born 1983-2004. Using national registries with prospectively recorded information, we followed participants for a BPD diagnosis from ages 13 to up to 35 years. We compared BPD risks by early pregnancy BMI using hazard ratios (HR) with 95% confidence intervals (CI) from adjusted Cox models. We also conducted sibling-controlled analyses among 874,047 full siblings. RESULTS: There were 9970 BPD diagnoses. Risk of BPD was 0.72% through 25 years of age. Maternal early pregnancy BMI was positively associated with offspring BPD risk. Compared with normal BMI (18.5-24.9), adjusted HR (95% CI) for overweight (BMI 25-29.9), obesity grade 1 (BMI 30-34.9), and obesity grades 2-3 (BMI ≥35) were 1.08 (1.02, 1.15), 1.26 (1.14, 1.40), and 1.31 (1.07, 1.60), respectively. Adjusted HR per unit BMI was 1.015 (95% CI 1.009, 1.021). A similar trend was observed among siblings. Pregnancy and neonatal complications did not substantially mediate the association between maternal obesity (BMI ≥30) and offspring BPD. CONCLUSIONS: Maternal BMI ≥25 is associated with offspring BPD risk in a dose-response manner.

Associations of the digit ratio with adolescent behavior problems are inconsistent with an intrauterine androgenic origin.

A low second-to-fourth digit ratio (2D:4D) is a purported biomarker of increased intrauterine androgenic exposure, presumably linked to postnatal behavior. We aimed to examine the associations between 2D:4D and adolescence behavior problems expected from high (externalizing and attention problems) or low (internalizing problems) prenatal androgen exposure. We conducted a cross-sectional study of 1042 Colombian schoolchildren aged 11-18 y. We examined whether caliper-assessed 2D:4D was associated with behavior problems per the Youth Self-Report questionnaire. Mean problem standardized score point differences were estimated between hand- and sex-specific quintiles of 2D:4D with use of multivariable linear regression. Lower right-hand 2D:4D was associated with decreased externalizing and internalizing behavior problem scores. Corresponding lowest-to-median quintile adjusted mean differences (95% CI) were -4.6 (-7.5, -1.7) and -3.5 (-6.4, -0.6) points in boys; and -3.4 (-5.9, -0.9) and -3.5 (-6.2, -0.8) points in girls. Lower right-hand 2D:4D was also related to less attention and thought problems in boys, and to less social problems among girls. Associations were nonlinear, apparent only below 2D:4D medians, and stronger with the right than the left hand. In conclusion, right-hand 2D:4D is related to behavior problems in adolescence in directions that are not fully consistent with an androgenic exposure origin.

Common infectious morbidity and white blood cell count in middle childhood predict behavior problems in adolescence.

We examined the associations of middle childhood infectious morbidity and inflammatory biomarkers with adolescent internalizing and externalizing behavior problems. We recruited 1018 Colombian schoolchildren aged 5-12 years into a cohort. We quantified white blood cell (WBC) counts and C-reactive protein at enrollment and prospectively recorded incidence of gastrointestinal, respiratory, and fever-associated morbidity during the first follow-up year. After a median 6 years, we assessed adolescent internalizing and externalizing behavior problems using child behavior checklist (CBCL) and youth self-report (YSR) questionnaires. Behavior problem scores were compared over biomarker and morbidity categories using mean differences and 95% confidence intervals (CI) from multivariable linear regression. Compared with children without symptoms, CBCL internalizing problem scores were an adjusted 2.5 (95% CI: 0.1, 4.9; p = .04) and 3.1 (95% CI: 1.1, 5.2; p = .003) units higher among children with moderate diarrhea with vomiting and high cough with fever rates, respectively. High cough with fever and high fever rates were associated with increased CBCL somatic complaints and anxious/depressed scores, respectively. WBC >10,000/mm3 was associated with both internalizing problem and YSR withdrawn/depressed scores. There were no associations with externalizing behavior problems. Whether or not decreasing the burden of common infections results in improved neurobehavioral outcomes warrants further investigation.

Leukocyte telomere length predicts subsequent infectious morbidity among Colombian schoolchildren.

OBJECTIVE: Telomere length (TL) attrition is related to chronic disease risk. However, less is known on whether TL predicts infectious outcomes, especially in childhood. We examined whether leukocyte TL (LTL) was associated with subsequent infectious morbidity in schoolchildren. METHODS: We assessed LTL in 717 Colombian children 5-12 years-old at the beginning of a school year and followed them through the year for daily occurrence of common infection symptoms and doctor visits. We estimated adjusted incidence rate ratios (IRR) with 95% confidence intervals (CI) of gastrointestinal and respiratory syndromes for quartiles of standardized LTL Z score and per unit LTL Z score. RESULTS: A longer LTL was associated with increased incidence of all infectious morbidity syndromes considered. Adjusted IRR (95% CI) per unit LTL Z score were 1.55 (1.20, 2.00) for diarrhea with vomiting, 1.34 (1.13, 1.60) for cough with fever, 1.70 (1.28, 2.28) for ear infection, and 1.66 (1.36, 2.02) for doctor visits with symptoms. CONCLUSIONS: Longer LTL is related to increased incidence of common infectious morbidities in middle childhood.

Gestational weight gain and breastfeeding practices in relation to offspring body mass index among Amazonian young children.

OBJECTIVE: Excessive weight gain during childhood has been considered an early life risk factor for chronic disease in the long term. We examined the role of excessive gestational weight gain (GWG) and breastfeeding (BF) practices with the offspring's body mass index-for-age z-score (zBMI) at 2 years. METHODS: Data from 743 Amazonian young children of the MINA-Brazil population-based birth cohort study were used. Linear regression models were run to estimate the associations between excessive GWG and BF practices (exclusive breastfeeding, EBF <3 months of age and BF <1 year) with zBMI. RESULTS: Excessive GWG and BF <1 year were associated with an adjusted 0.24 units (95% CI: 0.08, 0.41) and 0.28 units (95% CI: 0.12, 0.44) higher zBMI at age 2 years, respectively. CONCLUSIONS: Gain excessive weight during pregnancy and shorter BF duration (<1y) were associated with a higher body mass index at 2 years of age among Brazilian Amazonian children.

Sleep duration in middle childhood and age at menarche.

OBJECTIVE: Puberty affects sleep phasing. However, it is unclear if sleep duration earlier in childhood could influence the timing of pubertal events. We aimed to assess the association between middle childhood nighttime sleep duration and age at menarche (AAM). METHODS: In a cohort of 819 premenarcheal Colombian girls who were followed annually for the occurrence of menarche, we estimated adjusted hazard ratios (HR) with 95% confidence intervals (CI) for menarche by categories of recommended sleep duration in middle childhood using Cox models. Analyses were stratified by age at sleep assessment. RESULTS: Among girls aged 9 to <11 years, compared with girls who slept within recommendations, sleeping above recommendations was related to an adjusted 76% (95% CI: 4%, 198%; p = .04) higher probability of experiencing menarche during follow up. In girls aged ≥11 years, compared with girls who slept within recommendations, sleeping under recommendations was related to an adjusted 42% (95% CI: 5%, 93%; p = .03) higher probability of experiencing menarche during follow-up. Sleep duration was not associated with AAM in girls aged <9 years at the time of sleep assessment. CONCLUSIONS: Sleeping above recommendations in girls 9 to <11 years-old and sleeping under recommendations in girls ≥11 years-old is associated with earlier menarche.

Defective Placentation Syndromes and Intellectual Disability in the Offspring: Nationwide Cohort and Sibling-Controlled Studies.

We investigated the relationships between syndromic manifestations of defective placentation and the incidence of intellectual disability (ID) in offspring by conducting a population-based cohort study of 1,581,200 nonmalformed, live singleton infants born in Sweden between 1998 and 2014. Exposures were: 1) placental abruption, 2) preterm preeclampsia (<34 weeks of gestation), 3) preeclampsia combined with infant being small for gestational age (SGA) at birth, and 4) spontaneous preterm birth. The outcome was an ID diagnosis after 3 years of age. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for each syndrome using Cox regression and robust variances. There were 9,451 children with ID (5.5 per 10,000 child-years). ID incidence rates increased with placental abruption (HR = 2.8, 95% CI: 2.3, 3.5), preterm preeclampsia (HR = 3.7, 95% CI: 2.9, 4.7), preeclampsia combined with SGA (HR = 3.3, 95% CI: 2.6, 4.1), and spontaneous preterm birth (for 32-36 and 22-31 weeks, respectively, HR = 1.6 (95% CI: 1.4, 1.8) and 5.2 (95% CI: 4.3, 6.2)). The same pattern of results was evident in sibling-controlled analyses among 1,043,158 full siblings. The strength of associations increased with ID severity. Preterm birth only partly explained the associations of placental abruption, preeclampsia, or SGA with ID. We conclude that defective placentation is related to increased incidence of ID in the offspring.

Association of the dysfunctional placentation endotype of prematurity with bronchopulmonary dysplasia: a systematic review, meta-analysis and meta-regression.

BACKGROUND: Antenatal pathological conditions are key in the pathogenesis of bronchopulmonary dysplasia (BPD). Pathophysiological pathways or endotypes leading to prematurity and perinatal lung injury can be clustered into two groups: infection and dysfunctional placentation, which include hypertensive disorders of pregnancy (HDP) and intrauterine growth restriction (IUGR). We conducted a systematic review of observational studies exploring the association between the dysfunctional placentation endotype and BPD. METHODS: MEDLINE, Embase and Web of Science databases were searched up to February 2020 for studies reporting data on the diagnosis of HDP, IUGR or small for gestational age (SGA) and BPD risk. BPD was classified as BPD28 (supplemental oxygen on day 28), BPD36 (oxygen at 36 weeks postmenstrual age), severe BPD (≥ 30% oxygen or mechanical ventilation), BPD36/death and BPD-associated pulmonary hypertension. RESULTS: Of 6319 studies screened, 211 (347 963 infants) were included. Meta-analysis showed an association between SGA/IUGR and BPD36 (OR 1.56, 95% CI 1.37 to 1.79), severe BPD (OR 1.82, 95% CI 1.36 to 2.29) and BPD/death (OR 1.91, 95% CI 1.55 to 2.37). Exposure to HDP was not associated with BPD but was associated with decreased odds of BPD/death (OR 0.77, 95% CI 0.64 to 0.94). Both HDP (OR 1.41, 95% CI 1.10 to 1.80) and SGA/IUGR (OR 2.37, 95% CI 1.86 to 3.02) were associated with BPD-associated pulmonary hypertension. CONCLUSION: When placental vascular dysfunction is accompanied by fetal growth restriction or being born SGA, it is associated with an increased risk of developing BPD and pulmonary hypertension. The placental dysfunction endotype of prematurity is strongly associated with the vascular phenotype of BPD. PROSPERO REGISTRATION NUMBER: Review protocol was registered in PROSPERO database (ID=CRD42018086877).

Maternal melatonin: Effective intervention against developmental programming of cardiovascular dysfunction in adult offspring of complicated pregnancy.

Adopting an integrative approach, by combining studies of cardiovascular function with those at cellular and molecular levels, this study investigated whether maternal treatment with melatonin protects against programmed cardiovascular dysfunction in the offspring using an established rodent model of hypoxic pregnancy. Wistar rats were divided into normoxic (N) or hypoxic (H, 10% O2 ) pregnancy ± melatonin (M) treatment (5 µg·ml-1 .day-1 ) in the maternal drinking water. Hypoxia ± melatonin treatment was from day 15-20 of gestation (term is ca. 22 days). To control for possible effects of maternal hypoxia-induced reductions in maternal food intake, additional dams underwent pregnancy under normoxic conditions but were pair-fed (PF) to the daily amount consumed by hypoxic dams from day 15 of gestation. In one cohort of animals from each experimental group (N, NM, H, HM, PF, PFM), measurements were made at the end of gestation. In another, following delivery of the offspring, investigations were made at adulthood. In both fetal and adult offspring, fixed aorta and hearts were studied stereologically and frozen hearts were processed for molecular studies. In adult offspring, mesenteric vessels were isolated and vascular reactivity determined by in-vitro wire myography. Melatonin treatment during normoxic, hypoxic or pair-fed pregnancy elevated circulating plasma melatonin in the pregnant dam and fetus. Relative to normoxic pregnancy, hypoxic pregnancy increased fetal haematocrit, promoted asymmetric fetal growth restriction and resulted in accelerated postnatal catch-up growth. Whilst fetal offspring of hypoxic pregnancy showed aortic wall thickening, adult offspring of hypoxic pregnancy showed dilated cardiomyopathy. Similarly, whilst cardiac protein expression of eNOS was downregulated in the fetal heart, eNOS protein expression was elevated in the heart of adult offspring of hypoxic pregnancy. Adult offspring of hypoxic pregnancy further showed enhanced mesenteric vasoconstrictor reactivity to phenylephrine and the thromboxane mimetic U46619. The effects of hypoxic pregnancy on cardiovascular remodelling and function in the fetal and adult offspring were independent of hypoxia-induced reductions in maternal food intake. Conversely, the effects of hypoxic pregnancy on fetal and postanal growth were similar in pair-fed pregnancies. Whilst maternal treatment of normoxic or pair-fed pregnancies with melatonin on the offspring cardiovascular system was unremarkable, treatment of hypoxic pregnancies with melatonin in doses lower than those recommended for overcoming jet lag in humans enhanced fetal cardiac eNOS expression and prevented all alterations in cardiovascular structure and function in fetal and adult offspring. Therefore, the data support that melatonin is a potential therapeutic target for clinical intervention against developmental origins of cardiovascular dysfunction in pregnancy complicated by chronic fetal hypoxia.

Defective placentation syndromes and autism spectrum disorder in the offspring: population-based cohort and sibling-controlled studies.

Defective placentation underlies diverse syndromic manifestations that could affect brain development including: (1) placental abruption, (2) term preeclampsia with a small-for-gestational age (SGA) infant, (3) preterm preeclampsia, and (4) spontaneous preterm birth. We investigated the relations between these defective placentation syndromes and the incidence of Autism Spectrum Disorder (ASD) in offspring. We conducted a population-based cohort study of 1,645,455 non-malformed singleton infants born in Sweden 2000-2016 who were followed for up to 17 years using national registers. We compared ASD rates for children prenatally exposed and unexposed to defective placentation syndromes with use of adjusted hazard ratios (HR) with 95% confidence intervals (CI) from Cox regression. We also conducted sibling-controlled analyses among 1,092,132 full siblings. The association of the syndromes with ASD independent of preterm birth was estimated in mediation analyses. There were 23,810 cases of ASD. In both general cohort and sibling analyses, adjusted HRs (95% CI) of ASD were increased in children of mothers with term preeclampsia combined with SGA [1.5 (1.3, 1.9) and 1.9 (1.1, 3.3), respectively], preterm preeclampsia < 34 weeks [1.8 (1.4, 2.2) and 4.2 (2.1, 8.5), respectively], and spontaneous very or extremely preterm birth (≤ 31 weeks) [2.6 (2.2, 3.0) and 2.4 (1.5, 3.8), respectively]. Placental abruption was associated with increased HR of ASD in general cohort analysis only. The association between preeclampsia and ASD was not fully explained by preterm birth. In conclusion, syndromes linked to defective placentation are associated with increased incidence of ASD in the offspring.

The role of magnetic resonance imaging in the diagnosis and prognostic evaluation of fetuses with congenital diaphragmatic hernia.

In recent years, magnetic resonance imaging (MRI) has largely increased our knowledge and predictive accuracy of congenital diaphragmatic hernia (CDH) in the fetus. Thanks to its technical advantages, better anatomical definition, and superiority in fetal lung volume estimation, fetal MRI has been demonstrated to be superior to 2D and 3D ultrasound alone in CDH diagnosis and outcome prediction. This is of crucial importance for prenatal counseling, risk stratification, and decision-making approach. Furthermore, several quantitative and qualitative parameters can be evaluated simultaneously, which have been associated with survival, postnatal course severity, and long-term morbidity. CONCLUSION: Fetal MRI will further strengthen its role in the near future, but it is necessary to reach a consensus on indications, methodology, and data interpretation. In addition, it is required data integration from different imaging modalities and clinical courses, especially for predicting postnatal pulmonary hypertension. This would lead to a comprehensive prognostic assessment. WHAT IS KNOWN: • MRI plays a key role in evaluating the fetal lung in patients with CDH. • Prognostic assessment of CDH is challenging, and advanced imaging is crucial for a complete prenatal assessment and counseling. WHAT IS NEW: • Fetal MRI has strengthened its role over ultrasound due to its technical advantages, better anatomical definition, superior fetal lung volume estimation, and outcome prediction. • Imaging and clinical data integration is the most desirable strategy and may provide new MRI applications and future research opportunities.

Middle childhood and adolescence sleep duration and behavior problems in adolescence.

We examined the associations of middle childhood and adolescence nighttime sleep duration with adolescence internalizing and externalizing behavior problems per the Youth Self-Report (YSR) and the Child Behavior Checklist (CBCL) questionnaires, in a cohort of 889 Colombian schoolchildren. We estimated adjusted differences with 95% confidence intervals (CI) in mean behavior problem t-scores in standardized units between recommended sleep duration categories and as a continuous exposure using multiple linear regression and restricted cubic spline models, respectively. Compared with sleep duration within recommendations, middle childhood sleep above recommendations was related to 4.6 (95% CI: 1.6, 7.6; p = .004) and 5.4 (95% CI: 1.2, 9.7; p = .01) adjusted units higher YSR and CBCL externalizing problem scores, respectively. In continuous exposure analyses, this association seemed restricted to children aged ≥11 years. Longer sleep, both in categories and as a continuous exposure, was also associated with increased CBCL internalizing problems. Results did not differ by sex or weekend/weekday sleep. Sleeping under recommendations in middle childhood was not significantly related to behavior problems; nevertheless, shorter sleep in adolescence, in both categorical and continuous scales, was significantly related to behavior problems. In conclusion, behavior problems in adolescence are associated with longer sleep in middle childhood and shorter sleep in adolescence.

Leukocyte telomere length is inversely associated with a metabolic risk score in Mesoamerican children.

OBJECTIVE: Leukocyte telomere length (LTL) may be involved in the etiology of the metabolic syndrome (MetS). We examined the associations of LTL with MetS and its components among Mesoamerican children and their adult parents, in a region where MetS prevalence is high. METHODS: We conducted a cross-sectional study of 151 children aged 7-12 years and 346 parents from the capitals of Belize, Honduras, Nicaragua, Costa Rica, Panama, and Chiapas State, Mexico. We quantified LTL by qPCR on DNA extracted from whole blood. In children, we created an age- and sex-standardized metabolic risk score using waist circumference (WC), the homeostasis model of insulin resistance (HOMA-IR), blood pressure, serum high-density lipoprotein (HDL) cholesterol, and serum triglycerides. In adults, MetS was defined according to the National Cholesterol Education Program's Adult Treatment Panel III definition. We estimated mean differences in metabolic risk score and prevalence ratios of MetS across quartiles of LTL using multivariable-adjusted linear and Poisson regression models, respectively. RESULTS: In children, every 1 LTL z-score was related to an adjusted 0.05 units lower (95% CI: -0.09, -0.02, P = 0.005) MetS risk score, through WC, HOMA-IR, and HDL. Among adults, LTL was not associated with MetS prevalence; however, every 1 LTL z-score was associated with an adjusted 34% lower prevalence of high fasting glucose (95% CI: 3%, 55%, p = .03). CONCLUSIONS: Among Mesoamerican children, LTL is associated with an improved metabolic profile; among adults, LTL is inversely associated with the prevalence of high fasting glucose.

Associations of preterm birth, small-for-gestational age, preeclampsia and placental abruption with attention-deficit/hyperactivity disorder in the offspring: Nationwide cohort and sibling-controlled studies.

AIM: The aim of this study was to investigate preterm birth, small-for-gestational age (SGA), preeclampsia and placental abruption in relation to attention-deficit/hyperactivity disorder (ADHD) in offspring. METHODS: We conducted a population-based cohort study among non-malformed live-born singleton children in Sweden born during 2002-2014. Using national registries with recorded information, we followed 1,212,201 children for an ADHD diagnosis from 3 to 15 years. We compared ADHD rates between exposure categories using adjusted hazard ratios (HR) with 95% confidence intervals (CI) from Cox proportional hazards models. We also conducted sibling-controlled analyses among 751,464 full siblings. RESULTS: There were 27,665 ADHD diagnoses in the cohort. Compared with term birth (≥37 weeks), adjusted HR (95% CI) for ADHD increased with decreasing gestational age: 1.18 (1.11, 1.25), 1.61 (1.37, 1.89) and 2.79 (2.23, 3.49) for 32-36 weeks, 28-31 weeks and 22-27 weeks. Both spontaneous and medically indicated preterm birth were associated with ADHD. SGA was related to 1.62 (1.49, 1.77) times higher ADHD incidence. Preeclampsia, but not placental abruption, was associated with ADHD. Sibling-controlled analyses showed similar results. Preterm birth did not fully explain the associations of SGA or preeclampsia with ADHD. CONCLUSION: Preterm birth, SGA and preeclampsia are related to ADHD incidence in offspring.