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ObjectiveTo investigate potential risk factors behind the increased incidence of necrotising enterocolitis (NEC) in Swedish extremely preterm infants.DesignRegistry data from two population-based national cohorts were studied. NEC diagnoses (Bell stage ≥II) were validated against hospital records.PatientsAll liveborn infants <27 weeks of gestation 2004–2007 (n=704) and 2014–2016 (n=895) in Sweden.Main outcome measuresNEC incidence.ResultsThe validation process resulted in a 28% reduction of NEC cases but still confirmed a higher NEC incidence in the later epoch compared with the earlier (73/895 (8.2%) vs 27/704 (3.8%), p=0.001), while the composite of NEC or death was lower (244/895 (27.3%) vs 229/704 (32.5%), p=0.022). In a multivariable Cox regression model, censored for mortality, there was no significant difference in early NEC (0–7 days of life) between epochs (HR=0.9 (95% CI 0.5 to 1.9), p=0.9), but being born in the later epoch remained an independent risk factor for late NEC (>7 days) (HR=2.7 (95% CI 1.5 to 5.0), p=0.001). In propensity score analysis, a significant epoch difference in NEC incidence (12% vs 2.8%, p<0.001) was observed only in the tertile of infants at highest risk of NEC, where the 28-day mortality was lower in the later epoch (35% vs 50%, p=0.001). More NEC cases were diagnosed with intramural gas in the later epoch (33/73 (45.2%) vs 6/26 (23.1%), p=0.047).ConclusionsThe increase in NEC incidence between epochs was limited to cases occurring after 7 days of life and was partly explained by increased survival in the most extremely preterm infants. Misclassification of NEC is common.

ObjectiveTo explore associations between perinatal activity and survival in infants born at 22 and 23 weeks of gestation in Sweden.Design/SettingData on all births at 22 and 23 weeks’ gestational age (GA) were prospectively collected in 2004–2007 (T1) or obtained from national registers in 2014–2016 (T2) and 2017–2019 (T3). Infants were assigned perinatal activity scores based on 3 key obstetric and 4 neonatal interventions.Main outcomeOne-year survival and survival without major neonatal morbidities (MNM): intraventricular haemorrhage grade 3–4, cystic periventricular leucomalacia, surgical necrotising enterocolitis, retinopathy of prematurity stage 3–5 or severe bronchopulmonary dysplasia. The association of GA-specific perinatal activity score and 1-year survival was also determined.Results977 infants (567 live births and 410 stillbirths) were included: 323 born in T1, 347 in T2 and 307 in T3. Among live-born infants, survival at 22 weeks was 5/49 (10%) in T1 and rose significantly to 29/74 (39%) in T2 and 31/80 (39%) in T3. Survival was not significantly different between epochs at 23 weeks (53%, 61% and 67%). Among survivors, the proportions without MNM in T1, T2 and T3 were 20%, 17% and 19% for 22 weeks and 17%, 25% and 25% for 23 weeks’ infants (p>0.05 for all comparisons). Each 5-point increment in GA-specific perinatal activity score increased the odds for survival in first 12 hours of life (adjusted OR (aOR) 1.4; 95% CI 1.3 to 1.6) in addition to 1-year survival (aOR 1.2; 95% CI 1.1 to 1.3), and among live-born infants it was associated with increased survival without MNM (aOR 1.3; 95% CI 1.1 to 1.4).ConclusionIncreased perinatal activity was associated with reduced mortality and increased chances of survival without MNM in infants born at 22 and 23 weeks of GA.

ObjectiveTo examine the association between gestational age at birth and risk of clinically diagnosed intellectual disability (ID) week by week to provide a detailed description of ID risk across the entire range of gestational ages and by severity of ID.MethodsAll individuals born alive in Sweden 1974–2017 were prospectively followed up from birth until 2017 using national registers. The HRs for ID according to weekly gestational age and gestational age categories were determined using Cox models. Sibling analyses were conducted to adjust for familial confounding.ResultsThe study included 3 572 845 live births. During the follow-up, 26 596 ID cases were registered. The adjusted weekly estimates showed a gradual increase in risk of ID from week 40 to week 24 (adjusted HR37weeks=1.80 (1.74 to 1.87), aHR32weeks=3.93 (3.73 to 4.13), aHR28weeks=7.53 (6.95 to 8.16), aHR24weeks=21.58 (18.62 to 25.00)) and from week 41 onwards (aHR42weeks=1.26 (1.19 to 1.32)), with statistically significantly higher risks across the range of gestational age compared with infants born at week 40. The associations were consistent in mild, moderate and severe/profound ID but most prominent for severe/profound ID.ConclusionThe risk of ID increased weekly as the date of delivery moved away from 40 weeks, both preterm and post-term. The results remained robust after detailed adjustment for confounding, including familial confounding.

IMPORTANCE: Active perinatal care increases the rate of survival of extremely preterm infants, but there are concerns that improved survival might increase the rate of disabled survivors. OBJECTIVE: To determine the neurodevelopmental outcomes of a national cohort of children 6.5 years of age who had been born extremely preterm (&lt;27 weeks’ gestational age) in Sweden. DESIGN, SETTING, AND PARTICIPANTS: Population-based prospective cohort study of consecutively born extremely preterm infants. All of these infants were born in Sweden during the period from April 1, 2004, to March 31, 2007. Of 707 live-born extremely preterm infants, 486 (68.7%) survived to 6.5 years of age. These children were assessed and compared with matched controls who had been born at term. Comparison estimates were adjusted for demographic differences. Assessments ended in February 2014, and analysis started thereafter. MAIN OUTCOMES AND MEASURES: Cognitive ability was measured with the fourth edition of the Wechsler Intelligence Scale for Children (WISC-IV), and the mean (SD) scores of the children who had been born extremely preterm were compared with those of the controls. Clinical examinations and parental questionnaires were used for diagnosis of cerebral palsy, hearing and vision impairments, and cognition for the children who were not assessed with the WISC-IV. RESULTS: Of 486 eligible infants who were born extremely preterm, 441 (90.7%) were assessed at 6.5 years of age (59 by medical record review only) alongside 371 controls. The adjusted mean (SD) full-scale WISC-IV score was 14.2 (95% CI, 12.1-16.3) points lower for children who had been born extremely preterm than for controls. Cognitive disability was moderate for 18.8% of extremely preterm children and 2.2% of controls (P &lt; .001), and it was severe for 11.1% of extremely preterm children and 0.3% of controls (P &lt; .001). Cerebral palsy was observed in 9.5% of extremely preterm children and 0.0% of controls (P &lt; .001), blindness was observed in 2.0% of extremely preterm children and 0.0% of controls (P &lt; .001), and hearing impairment was observed in 2.1% of extremely preterm children and 0.5% of controls (P = .07). Overall, 36.1% (95% CI, 31.7%-40.6%) of extremely preterm children had no disability, 30.4% (95% CI 26.3%-34.8%) had mild disability, 20.2% (95% CI, 16.6%-24.2%) had moderate disability, and 13.4% (95% CI, 10.5%-16.9%) had severe disability. For extremely preterm children, moderate or severe overall disability decreased with gestational age at birth (adjusted odds ratio per week, 0.65 [95% CI, 0.54-0.79]; P &lt; .001) and increased from 26.6% to 33.5% (P = .01) for children assessed both at 2.5 and 6.5 years. CONCLUSIONS AND RELEVANCE: Of the 441 extremely preterm infants who had received active perinatal care, 293 (66.4%) had no or mild disability at 6.5 years; of the 371 controls, 11 (3.0%) had moderate or severe disability. Disability rates at 6.5 years increased relative to the rates at 2.5 years. Results are relevant for health care professionals and planners, and for clinicians counseling families facing extremely preterm births.

Intraventricular hemorrhage (IVH) of the preterm neonate is a complex developmental disorder, with contributions from both the environment and the genome. IVH, or hemorrhage into the germinal matrix of the developing brain with secondary periventricular infarction, occurs in that critical period of time before the 32nd to 33rd wk postconception and has been attributed to changes in cerebral blood flow to the immature germinal matrix microvasculature. Emerging data suggest that genes subserving coagulation, inflammatory, and vascular pathways and their interactions with environmental triggers may influence both the incidence and severity of cerebral injury and are the subject of this review. Polymorphisms in the Factor V Leiden gene are associated with the atypical timing of IVH, suggesting an as yet unknown environmental trigger. The methylenetetrahydrofolate reductase (MTHFR) variants render neonates more vulnerable to cerebral injury in the presence of perinatal hypoxia. The present study demonstrates that the MTHFR 677C>T polymorphism and low 5-min Apgar score additively increase the risk of IVH. Finally, review of published preclinical data suggests the stressors of delivery result in hemorrhage in the presence of mutations in collagen 4A1, a major structural protein of the developing cerebral vasculature. Maternal genetics and fetal environment may also play a role.

Adenosine is an inhibitory modulator of neuronal activity and its possible involvement in seizures is of interest. We have examined changes in adenosine, its metabolites and receptors in brains of hipppocampus-kindled rats, a model of partial epilepsy. Purine levels were measured by in vivomicrodialysis and showed a small increase in adenosine and a dramatic increase in its metabolites after kindled seizures. Adenosine A1receptor binding using 3HDPCPX was unaltered after seizures, whereas A1agonist stimulated binding of GTP-35S and A1mRNA expression increased in the CA3 and other regions. Striatal adenosine A2AmRNA and receptor binding with 3HSCH-58261 decreased. These findings indicate that kindled seizures increase adenosine release and metabolism and induces adaptive changes in adenosine receptors.

The perinatal development of respiratory rhythm generation and its modulation by adenosinergic drugs have been examined in rats from embryonic d 18 (E18) to postnatal d 3 using an in vitro brain stem-spinal cord preparation. Generation of rhythmic respiratory activity in the medulla oblongata and inhibition of this activity by pontine structures were evident on E18. The adenosine A1-receptor agonist, N6-(2-phenylisopropyl) adenosine, R (−) isomer (R-PIA) (1 μM), induced an age-dependent reduction of respiratory frequency that could be reversed by the adenosine antagonist theophylline (55 μM). The effect of R-PIA was reduced 24 h after birth compared with E21 and 2 h postnatal age. In preparations from pups that had been exposed to a low dose of caffeine (0.3 g/L in drinking water to dams), pontine inhibition of respiratory rhythm generation in the medulla was more pronounced. When the pons was removed, the respiratory frequency was higher than in the control group. Adenosine A1-mRNA and A1-receptor development in pons and medulla were studied, and by E18, mRNA, receptor protein, and functional coupling to G-proteins were confirmed using guanylyl-5′-O-(γ-[35S]thio)-triphosphate binding. There were no major changes in receptor numbers or distribution of A1receptors or mRNA in rat pups subjected to caffeine exposure. We conclude that respiration is already modulated by adenosine A1receptors at the level of the medulla oblongata in the fetal period in an age-dependent manner. Furthermore, long-term maternal caffeine intake during gestation seems to increase the pontine inhibition of, and the activity of, respiratory rhythm-generating neuronal networks in medulla oblongata without detectable changes in expression of A1-receptor number or A1-receptor mRNA.

The perinatal development of respiratory rhythm generation and its modulation by adenosinergic drugs have been examined in rats from embryonic d 18 (E18) to postnatal d 3 using an in vitrobrain stem-spinal cord preparation. Generation of rhythmic respiratory activity in the medulla oblongata and inhibition of this activity by pontine structures were evident on E18. The adenosine A1-receptor agonist, N6-(2-phenylisopropyl) adenosine, R (-) isomer (R-PIA) (1 M), induced an age-dependent reduction of respiratory frequency that could be reversed by the adenosine antagonist theophylline (55 M). The effect of R-PIA was reduced 24 h after birth compared with E21 and 2 h postnatal age. In preparations from pups that had been exposed to a low dose of caffeine (0.3 g/L in drinking water to dams), pontine inhibition of respiratory rhythm generation in the medulla was more pronounced. When the pons was removed, the respiratory frequency was higher than in the control group. Adenosine A1-mRNA and A1-receptor development in pons and medulla were studied, and by E18, mRNA, receptor protein, and functional coupling to G-proteins were confirmed using guanylyl-5'-O-(-35Sthio)-triphosphate binding. There were no major changes in receptor numbers or distribution of A1receptors or mRNA in rat pups subjected to caffeine exposure. We conclude that respiration is already modulated by adenosine A1receptors at the level of the medulla oblongata in the fetal period in an age-dependent manner. Furthermore, long-term maternal caffeine intake during gestation seems to increase the pontine inhibition of, and the activity of, respiratory rhythm-generating neuronal networks in medulla oblongata without detectable changes in expression of A1-receptor number or A1-receptor mRNA.

This overview will focus on recent data from our laboratory. The four cloned human adenosine receptors stably transfected into Chinese hamster ovary cells were studied with respect to signaling via cyclic AMP and mitogen-activated protein (MAP) kinases. Adenosine acted as a full agonist at all the adenosine receptors when increases (A2A or A2B receptors) or decreases (A1 and A3 receptors) in cyclic AMP accumulation were studied. Adenosine was approximately equipotent at A1, A2A, and A3 receptors, but approximately 50 times higher concentrations were needed at A2B receptors. The potency of adenosine was such that levels encountered under basal physiological conditions (30–300 nM) were sufficient to activate all but the A2B receptors. Inosine was a low-efficacy agonist at A1 and A3 receptors but was inactive at A2A and A2B receptors. Thus, adenosine is the most important agonist and the only one at A2A and A2B receptors. When MAP kinase signaling was examined, adenosine was equipotent at all the four receptors, and significant activation was noted at 100 nM adenosine. The potency of adenosine is dependent not only on the type of receptor but also on receptor number. Thus, high potency of adenosine is seen only where the receptor is expressed abundantly. These and other results are reviewed and discussed in relation to agonist and antagonist effects in vivo. In particular, we summarize recent data that show that adenosine tonically activates A2A receptors in the basal ganglia. Some aspects of the use of adenosine A2A receptor antagonists in the treatment of Parkinson disease also are highlighted. Drug Dev. Res. 52:274–282, 2001. © 2001 Wiley-Liss, Inc.

This overview will focus on recent data from our laboratory. The four cloned human adenosine receptors stably transfected into Chinese hamster ovary cells were studied with respect to signaling via cyclic AMP and mitogen‐activated protein (MAP) kinases. Adenosine acted as a full agonist at all the adenosine receptors when increases (A2Aor A2Breceptors) or decreases (A1and A3receptors) in cyclic AMP accumulation were studied. Adenosine was approximately equipotent at A1, A2A, and A3receptors, but approximately 50 times higher concentrations were needed at A2Breceptors. The potency of adenosine was such that levels encountered under basal physiological conditions (30–300 nM) were sufficient to activate all but the A2Breceptors. Inosine was a low‐efficacy agonist at A1and A3receptors but was inactive at A2Aand A2Breceptors. Thus, adenosine is the most important agonist and the only one at A2Aand A2Breceptors. When MAP kinase signaling was examined, adenosine was equipotent at all the four receptors, and significant activation was noted at 100 nM adenosine. The potency of adenosine is dependent not only on the type of receptor but also on receptor number. Thus, high potency of adenosine is seen only where the receptor is expressed abundantly. These and other results are reviewed and discussed in relation to agonist and antagonist effects in vivo. In particular, we summarize recent data that show that adenosine tonically activates A2Areceptors in the basal ganglia. Some aspects of the use of adenosine A2Areceptor antagonists in the treatment of Parkinson disease also are highlighted. Drug Dev. Res. 52:274–282, 2001. © 2001 Wiley‐Liss, Inc.

Maternal caffeine intake has been suggested to influence the offspring. We have studied the effects of maternal caffeine intake on adenosine and GABA receptors, targets for caffeine, during development of the rat brain. Caffeine (0.3 g/L) was added to the drinking water of rat dams during pregnancy and early postnatal life. Adenosine A1and A2Aand GABAAreceptor development was studied using receptor autoradiography and in situ hybridization. Pups were examined on embryonic d 14 (E14), E18, E21, 2 h after birth (P2h), P24h, postnatal d 3 (P3), P7, P14, and P21. Adenosine A1receptor mRNA was detected at E14 and receptors at E18. A1mRNA levels increased from the level reached at E18 between P3 and P14 (maximally a doubling), whereas A1receptors, studied by [3H]-1,3-dipropyl-8-cyclopentyl xanthine binding, increased later and to a much larger extent (about 10-fold) postnatally. Caffeine treatment had no significant effect on adenosine A1receptors or on A1receptor mRNA. A2AmRNA had reached adult levels by E18, whereas receptor levels were low or undetectable before birth and increased dramatically until P14. Caffeine did not influence A2Areceptors or A2Areceptor mRNA at any stage during development. [3H]-flunitrazepam binding, representing GABAAreceptors, showed large regional variations during ontogeny, but there were no clear differences between the caffeine-exposed and the nonexposed pups. Thus, exposure to a low dose of caffeine during gestation and postnatal life had only minor effects on development of adenosine A1and A2Areceptors and GABAAreceptors in the rat brain.

Maternal caffeine intake has been suggested to influence the offspring. We have studied the effects of maternal caffeine intake on adenosine and GABA receptors, targets for caffeine, during development of the rat brain. Caffeine (0.3 g/L) was added to the drinking water of rat dams during pregnancy and early postnatal life. Adenosine A1and A2Aand GABAAreceptor development was studied using receptor autoradiography and in situhybridization. Pups were examined on embryonic d 14 (E14), E18, E21, 2 h after birth (P2h), P24h, postnatal d 3 (P3), P7, P14, and P21. Adenosine A1receptor mRNA was detected at E14 and receptors at E18. A1mRNA levels increased from the level reached at E18 between P3 and P14 (maximally a doubling), whereas A1receptors, studied by 3H-1,3-dipropyl-8-cyclopentyl xanthine binding, increased later and to a much larger extent (about 10-fold) postnatally. Caffeine treatment had no significant effect on adenosine A1receptors or on A1receptor mRNA. A2AmRNA had reached adult levels by E18, whereas receptor levels were low or undetectable before birth and increased dramatically until P14. Caffeine did not influence A2Areceptors or A2Areceptor mRNA at any stage during development. 3H-flunitrazepam binding, representing GABAAreceptors, showed large regional variations during ontogeny, but there were no clear differences between the caffeine-exposed and the nonexposed pups. Thus, exposure to a low dose of caffeine during gestation and postnatal life had only minor effects on development of adenosine A1and A2Areceptors and GABAAreceptors in the rat brain.

There is considerable concern over the widespread use of caffeine during and after pregnancy. We have therefore examined the effect of perinatal caffeine use on the vulnerability of the immature brain to hypoxic ischemia (HI). Rat pups were exposed to caffeine during the first 7 d after birth by addition of a low or a high dose (0.3 or 0.8 g/L) of caffeine to the drinking water of their dams. At 7 d the pups were exposed to unilateral carotid occlusion + exposure to 7.70 oxygen for 100 min. The extent of HI brain damage was evaluated 2 wk after the insult. The effects of caffeine on A1and A2areceptors, A1mRNA and A2amRNA, were examined by receptor autoradiography and in situhybridization. Caffeine, theobromine, theophylline, and paraxanthine were analyzed in plasma of separate animals. Exposure to caffeine reduced HI brain damage from 40.3 ± 3.2 in controls to 29.8 ± 4.0 (p< 0.05) in low dose and 33.7 ± 3.9 (NS) in the high dose group. The A1receptor density measured as [3H]-l,3-dipropyl-8-cyclopentyl xanthine ([3H]-DPCPX) binding was not significantly affected after low dose caffeine but increased in the brain of rat pups in the high dose group. The A2areceptor density measured as [3H]-2[p-(2-carbonylethyl)-phenethylamino]-5′-N-ethylcarboxamidoadenosine ([3H]-CGS 21680) binding and the expression of A1mRNA and A2amRNA were not altered by caffeine treatment. In conclusion, low dose caffeine exposure (plasma levels corresponding to umbilical cord plasma in newborns of coffee-consuming mothers) reduced HI brain damage by 30 in 7-d-old rats. This ameliorating effect could not be accounted for by up-regulation of adenosine receptors.

ABSTRACT: There is considerable concern over the widespread use of caffeine during and after pregnancy. We have therefore examined the effect of perinatal caffeine use on the vulnerability of the immature brain to hypoxic ischemia (HI). Rat pups were exposed to caffeine during the first 7 d after birth by addition of a low or a high dose (0.3 or 0.8 g/L) of caffeine to the drinking water of their dams. At 7 d the pups were exposed to unilateral carotid occlusion + exposure to 7.70% oxygen for 100 min. The extent of HI brain damage was evaluated 2 wk after the insult. The effects of caffeine on A1and A2areceptors, A1mRNA and A2amRNA, were examined by receptor autoradiography and in situ hybridization. Caffeine, theobromine, theophylline, and paraxanthine were analyzed in plasma of separate animals. Exposure to caffeine reduced HI brain damage from 40.3 ± 3.2% in controls to 29.8 ± 4.0% (p < 0.05) in low dose and 33.7 ± 3.9% (NS) in the high dose group. The A1receptor density measured as [3H]-l,3-dipropyl-8-cyclopentyl xanthine ([3H]-DPCPX) binding was not significantly affected after low dose caffeine but increased in the brain of rat pups in the high dose group. The A2areceptor density measured as [3H]-2[p-(2-carbonylethyl)-phenethylamino]-5'-N-ethylcarboxamidoadenosine ([3H]-CGS 21680) binding and the expression of A1mRNA and A2amRNA were not altered by caffeine treatment. In conclusion, low dose caffeine exposure (plasma levels corresponding to umbilical cord plasma in newborns of coffee-consuming mothers) reduced HI brain damage by 30% in 7-d-old rats. This ameliorating effect could not be accounted for by up-regulation of adenosine receptors.