Neurological abnormalities in full-term asphyxiated newborns and salivary S100B testing: the “cooperative multitask against brain injury of neonates” (CoMBINe) international study

BACKGROUND: Perinatal asphyxia (PA) is a leading cause of mortality and morbidity in newborns: its prognosis depends both on the severity of the asphyxia and on the immediate resuscitation to restore oxygen supply and blood circulation. Therefore, we investigated whether measurement of S100B, a consolidated marker of brain injury, in salivary fluid of PA newborns may constitute a useful tool for the early detection of asphyxia-related brain injury. METHODS: We conducted a cross-sectional study in 292 full-term newborns admitted to our NICUs, of whom 48 suffered PA and 244 healthy controls admitted at our NICUs. Saliva S100B levels measurement longitudinally after birth; routine laboratory variables, neurological patterns, cerebral ultrasound and, magnetic resonance imaging were performed. The primary end-point was the presence of neurological abnormalities at 12-months after birth. RESULTS: S100B salivary levels were significantly (P3.25 MoM S100B achieved a sensitivity of 100% (CI5-95%: 89.3%-100%) and a specificity of 100% (CI5-95%: 98.6%-100%) as a single marker for predicting the occurrence of abnormal neurological outcome (area under the ROC curve: 1.000; CI5-95%: 0.987-1.0). CONCLUSIONS: S100B protein measurement in saliva, soon after birth, is a useful tool to identify which asphyxiated infants are at risk of neurological sequelae

Mean saliva S100B concentrations (µg/mL) expressed as MoM [lower and upper 95% Confidence Interval (CI)] at birth (T0) and at 4 (T1), 8 (T2), 12 (T3), 16 (T4), 20 (T5), 24 (T6), 48 (T7), 72 (T8) and 96 (T9) hours after birth in Reference Group (n = 244) and in asphyxiated full-term newborns with good (Group A) or severe (Group B) neurological outcome at 12-months follow-up.

<p>^*P<0.001 vs Healthy Group and asphyxiated full-term newborns with good neurological prognosis (Group A).^*P<0.001 vs Group B values at 48, 72 and, 96 hours</p><p>Salivary S100B concentrations were significantly higher in neonates belonging to Group B at all monitoring time-points (p<0.001, for all).</p><p>Statistical evaluation of differences among Groups at each time point was performed by using the Kruskal-Wallis test followed by the Dunn’s post test</p><p>Mean saliva S100B concentrations (µg/mL) expressed as MoM [lower and upper 95% Confidence Interval (CI)] at birth (T0) and at 4 (T1), 8 (T2), 12 (T3), 16 (T4), 20 (T5), 24 (T6), 48 (T7), 72 (T8) and 96 (T9) hours after birth in Reference Group (n = 244) and in asphyxiated full-term newborns with good (Group A) or severe (Group B) neurological outcome at 12-months follow-up.</p

Perinatal clinical characteristics and outcomes in asphyxiated newborns with normal (Group A) or abnormal (Group B) neurological outcome and in healthy subjects (Reference Group, R Group).

<p>Values are expressed as mean ± SD. n.p.: not performed.</p><p>^*P<0.01 vs controls.</p><p>Perinatal clinical characteristics and outcomes in asphyxiated newborns with normal (Group A) or abnormal (Group B) neurological outcome and in healthy subjects (Reference Group, R Group).</p

Saliva levels of S100B in neonates with normal, BG/W score 1–2 and BG/W score 3–4.

<p>The box plots represent the medians and interquartile ranges for each group. ^*^*P<0.001 global BG/W vs severe BG/W injury; ^*P<0.001 vs normal MRI group.</p

Laboratory parameters recorded at birth in asphyxiated newborns with normal (Group A) or abnormal (Group B) neurological outcome and in healthy subjects (Reference Group, R Group).

<p>Values are expressed as mean ± SD.</p><p>^*P<0.0001 vs controls.</p><p>Laboratory parameters recorded at birth in asphyxiated newborns with normal (Group A) or abnormal (Group B) neurological outcome and in healthy subjects (Reference Group, R Group).</p

Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude

BACKGROUND: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear. METHODS: We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N?=?9358) and in children aged 1-11 years (12 cohorts, N?=?3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points. RESULTS: We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values?&lt;?0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (=?50°N), lower (&lt;?50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (=?50°N). CONCLUSIONS: In this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNAm and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes

Genetics of early-life head circumference and genetic correlations with neurological, psychiatric and cognitive outcomes

Background: Head circumference is associated with intelligence and tracks from childhood into adulthood. Methods: We performed a genome-wide association study meta-analysis and follow-up of head circumference in a total of 29,192 participants between 6 and 30 months of age. Results: Seven loci reached genome-wide significance in the combined discovery and replication analysis of which three loci near ARFGEF2, MYCL1, and TOP1, were novel. We observed positive genetic correlations for early-life head circumference with adult intracranial volume, years of schooling, childhood and adult intelligence, but not with adult psychiatric, neurological, or personality-related phenotypes. Conclusions: The results of this study indicate that the biological processes underlying early-life head circumference overlap largely with those of adult head circumference. The associations of early-life head circumference with cognitive outcomes across the life course are partly explained by genetics

Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude.

BACKGROUND: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear. METHODS: We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11&nbsp;years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points. RESULTS: We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values &lt; 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (&lt; 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N). CONCLUSIONS: In this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNAm and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes

Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude

BACKGROUND: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear.METHODS: We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points.RESULTS: We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values &lt; 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (&lt; 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N).CONCLUSIONS: In this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNAm and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes.</p

Additional file 4 of Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude

Additional file 4. Table S2: “Models used in this meta-analysis study”. Inflation (lambda) and bias information of the models. Table S3: “Comparison of magnitude and direction of the FDR-significant DNA methylation signals identified in the at-birth and childhood meta-analyses”