Early oxygen levels contribute to brain injury in extremely preterm infants.

BACKGROUND: Extremely low gestational age newborns (ELGANs) are at risk of neurodevelopmental impairments that may originate in early NICU care. We hypothesized that early oxygen saturations (SpO2), arterial pO2 levels, and supplemental oxygen (FiO2) would associate with later neuroanatomic changes. METHODS: SpO2, arterial blood gases, and FiO2 from 73 ELGANs (GA 26.4 ± 1.2; BW 867 ± 179 g) during the first 3 postnatal days were correlated with later white matter injury (WM, MRI, n = 69), secondary cortical somatosensory processing in magnetoencephalography (MEG-SII, n = 39), Hempel neurological examination (n = 66), and developmental quotients of Griffiths Mental Developmental Scales (GMDS, n = 58). RESULTS: The ELGANs with later WM abnormalities exhibited lower SpO2 and pO2 levels, and higher FiO2 need during the first 3 days than those with normal WM. They also had higher pCO2 values. The infants with abnormal MEG-SII showed opposite findings, i.e., displayed higher SpO2 and pO2 levels and lower FiO2 need, than those with better outcomes. Severe WM changes and abnormal MEG-SII were correlated with adverse neurodevelopment. CONCLUSIONS: Low oxygen levels and high FiO2 need during the NICU care associate with WM abnormalities, whereas higher oxygen levels correlate with abnormal MEG-SII. The results may indicate certain brain structures being more vulnerable to hypoxia and others to hyperoxia, thus emphasizing the role of strict saturation targets. IMPACT: This study indicates that both abnormally low and high oxygen levels during early NICU care are harmful for later neurodevelopmental outcomes in preterm neonates. Specific brain structures seem to be vulnerable to low and others to high oxygen levels. The findings may have clinical implications as oxygen is one of the most common therapies given in NICUs. The results emphasize the role of strict saturation targets during the early postnatal period in preterm infants.

Umbilical artery pH and base excess at birth are poor predictors of neurodevelopmental morbidity in early childhood.

AIM: We sought to evaluate the associations between umbilical artery pH and base excess and neurodevelopmental outcome at four years of age. METHODS: This study comprised 84 588 singleton children born alive at term in 2005-2011 in the hospital district of Helsinki and Uusimaa in Finland. Data from the maternity hospital information system were linked to the data from the Medical Birth Register and the Hospital Discharge Register. Neurodevelopmental morbidity included cerebral palsy, epilepsy, intellectual or sensorineural impairment. RESULTS: After adjustment for maternal and perinatal factors, a combination of pH <7.00 and base excess <-16.00 was associated with infant death (adjusted odds ratio 19.97; 95% confidence interval 5.38-74.17). Values of pH 7.00-7.10 were associated with cerebral palsy (adjusted odds ratio 2.40; 95% confidence interval 1.05-5.47). A combination of low five-minute Apgar score and umbilical artery base excess <-16.00 showed the highest positive predictive value (9.1%) for neurodevelopmental impairments. When umbilical artery pH <7.00 was included, a positive predictive value of 25.0% was observed for infant mortality. CONCLUSION: Low umbilical artery pH and base excess at birth were the poor predictors of long-term neurodevelopmental morbidity in an unselected population. However, these parameters might be useful in assessing the risk of infant mortality.

Amniotic fluid and umbilical cord serum erythropoietin in term and prolonged pregnancies.

OBJECTIVE: Erythropoietin - a hormone regulating erythropoiesis - is a biomarker of chronic fetal hypoxia. High erythropoietin levels in fetal plasma and amniotic fluid are associated with increased risk of adverse neonatal outcome. Since the risk of perinatal morbidity and mortality is increased in pregnancies beyond 41 gestational weeks, we evaluated erythropoietin levels in amniotic fluid and umbilical cord serum in apparently low-risk term (≥ 37 gestational weeks) and prolonged pregnancies (≥ 41 gestational weeks) with labor induction. STUDY DESIGN: This prospective cohort study comprised 93 singleton pregnancies at 37+0-42+1 gestational weeks, of which prolonged pregnancies numbered 63 (67.7%). Amniotic fluid samples were collected at time of labor induction by amniotomy. Umbilical cord blood samples for evaluation of pH, base excess, and umbilical cord serum erythropoietin were collected at birth. Erythropoietin levels were measured by immunochemiluminometric assay. Normal value of amniotic fluid erythropoietin level was defined as ≤ 3 IU/L, and abnormal value as ≥ 27 IU/L. Normal umbilical cord serum erythropoietin was defined as < 40 IU/L. Data on maternal pregnancy and delivery characteristics and short-term neonatal outcomes such as Apgar score were obtained from the hospital charts. Associations were calculated using Spearman's rank correlation coefficient. The Chi-square test, Fisher's exact test and the Mann-Whitney U test were utilized to determine differences in the study groups. RESULTS: Amniotic fluid erythropoietin levels correlated with gestational age (r = 0.261, p = 0.012) and were higher among prolonged pregnancies as compared to term pregnancies (p = 0.005). There were 78 (83.9%) vaginal deliveries, and among these erythropoietin levels in amniotic fluid correlated with the levels in umbilical cord serum (r = 0.513, p < 0.000). Umbilical cord serum erythropoietin levels correlated with gestational age among vaginal deliveries (r = 0.250, p = 0.027). Erythropoietin levels in amniotic fluid and umbilical cord serum did not correlate with umbilical artery pH or base excess, or other adverse pregnancy outcome. CONCLUSIONS: In vaginal deliveries erythropoietin levels in amniotic fluid correlated with the levels in umbilical cord serum. Erythropoietin levels correlated with gestational age, probably due to weakening placental function and relative hypoxemia occurring in advanced gestation. However, in this relatively low-risk study population erythropoietin was not related to adverse delivery outcome.

Low Apgar scores at both one and five minutes are associated with long-term neurological morbidity.

AIM: This study evaluated the associations between low Apgar scores at one and five minutes and long-term neurological impairments. METHODS: This study used population-based data on 399,815 singletons born in Finland in 2004-2010 and multivariable logistic regression to examine any associations between low (0-3) and intermediate (4-6) Apgar scores and cerebral palsy, epilepsy, intellectual disability and sensorineural defects by the age of four years. RESULTS: The odd ratios (OR) and 95% confidence intervals (95% CI) showed that low Apgar scores were associated with cerebral palsy at one and five minutes (ORs 2.08, 95% CI 1.32-3.26 and 5.19, 95% CI 3.06-8.80), epilepsy (ORs 1.62, 95% CI 1.13-2.33 and 4.79, 95% CI 3.03-7.56), and intellectual disability (ORs 2.46, 95% CI 1.45-4.16 and 6.21, 95% CI 3.33-11.58). Only a low five-minute Apgar score was associated with sensorineural defects (OR 3.13, 95% CI 1.95-5.02). Neurological impairment risks were increased by low Apgar scores at both one and five minutes (OR 11.1, 95% CI 8.6-14.5), but 90.3% of children with persistent low Apgar scores had no impairment. CONCLUSION: Low one-minute and five-minute Apgar scores were associated with long-term neurological morbidity, especially when both scores were low.

Comparison of Umbilical Serum Copeptin Relative to Erythropoietin and S100B as Asphyxia Biomarkers at Birth.

BACKGROUND: Birth asphyxia, estimated to account for a million neonatal deaths annually, can cause a wide variety of neurodevelopmental impairments. There is a need to develop new, swift methods to identify those neonates who would benefit from neuroprotective treatments such as hypothermia. OBJECTIVES: To examine the utility of cord serum copeptin, a stable byproduct of arginine vasopressin release, as a biomarker of birth asphyxia based on a comparison with 2 biomarkers of hypoxia and brain trauma: erythropoietin and S100B. METHODS: The study population consisted of 140 singleton, term neonates: 113 controls and 27 with birth asphyxia (2/3 criteria met: umbilical artery pH <7.10, base excess ≤12 mmol/L, and 5-min Apgar score <7). All deliveries were planned vaginal, but 51 neonates were born by emergency cesarean section. Copeptin, S100B, and erythropoietin levels in umbilical artery samples were measured by immunoassays. RESULTS: Copeptin correlated in the entire study population more strongly with umbilical artery base excess than S100B and erythropoietin, and only copeptin correlated with arterial pH. Furthermore, only copeptin levels were significantly higher in cases of birth asphyxia, and in vaginally born neonates they were found to increase as a function of labor duration. Copeptin was elevated in neonates born via vacuum extraction, whereas erythropoietin levels showed a slight increase after emergency cesarean section. CONCLUSIONS: In this study population, S100B and erythropoietin were not valid biomarkers of birth asphyxia. In contrast, our work suggests that copeptin has high potential to become a routinely used biomarker for acute birth asphyxia and neonatal distress.

Asphyxia, Neurologic Morbidity, and Perinatal Mortality in Early-Term and Postterm Birth.

BACKGROUND AND OBJECTIVES: Neonatal outcomes vary by gestational age. We evaluated the association of early-term, full-term, and postterm birth with asphyxia, neurologic morbidity, and perinatal mortality. METHODS: Our register-based study used retrospective data on 214 465 early-term (37(+0)-38(+6) gestational weeks), 859 827 full-term (39(+0)-41(+6)), and 55 189 postterm (≥42(+0)) live-born singletons during 1989-2008 in Finland. Asphyxia parameters were umbilical cord pH and Apgar score at 1 and 5 minutes. Neurologic morbidity outcome measures were cerebral palsy (CP), epilepsy, intellectual disability, and sensorineural defects diagnosed by the age of 4 years. Newborns with major congenital anomalies were excluded from perinatal deaths. RESULTS: Multivariate analysis showed that, compared with full-term pregnancies, early-term birth increased the risk for low Apgar score (<4) at 1 and 5 minutes (odds ratio 1.03, 95% confidence interval 1.03-1.04 and 1.24, 1.04-1.49, respectively), CP (1.40, 1.27-1.55), epilepsy (1.14, 1.06-1.23), intellectual disability (1.39, 1.27-1.53), sensorineural defects (1.24, 1.17-1.31), and perinatal mortality (2.40, 2.14-2.69), but risk for low umbilical artery pH ≤7.10 was decreased (0.83, 0.79-0.87). Postterm birth increased the risk for low Apgar score (<4) at 1 minute (1.26, 1.26-1.26) and 5 minutes (1.80, 1.43-2.34), low umbilical artery pH ≤7.10 (1.26, 1.19-1.34), and intellectual disability (1.19, 1.00-1.43), whereas risks for CP (1.03, 0.84-1.26), epilepsy (1.00, 0.87-1.15), sensorineural defects (0.96, 0.86-1.07), and perinatal mortality (0.91, 0.69-1.22) were not increased. CONCLUSIONS: Early-term birth was associated with low Apgar score, increased neurologic morbidity, and perinatal mortality. Asphyxia and intellectual disability were more common among postterm births, but general neurologic morbidity and perinatal mortality were not increased.

Atypical sensory processing is common in extremely low gestational age children.

AIM: Atypical sensory processing is common in children born extremely prematurely. We investigated sensory processing abilities in extremely low gestational age (ELGA) children and analysed associated neonatal risk factors, neuroanatomical findings and neurodevelopmental outcome. METHODS: We carried out a prospective study of 44 ELGA children, including 42 who had undergone brain magnetic resonance imaging (MRI) at term-equivalent age, when they were 2 years of corrected age. Their sensory processing abilities were assessed with the Infant/Toddler Sensory Profile questionnaire and their neurodevelopmental with a structured Hempel neurological examination, Griffiths Mental Developmental Scales and Bayley Scales of Infant and Toddler Development Third Edition. RESULTS: Sensory profiles were definitely or probably atypical (<-1 SD) in half of the ELGA children, and the most common behavioural pattern was low registration (23%). Sensation seeking was associated with abnormalities in grey and/or white matter in the brain MRI (p < 0.01). Atypical oral sensory processing was associated with surgical closure of the patent ductus arteriosus (p = 0.02, adjusted p < 0.01). CONCLUSION: Atypical sensory processing in ELGA children was common, and children with neonatal neuroanatomical lesions tended to present specific behavioural responses to sensory stimuli. Surgical closure of the patent ductus arteriosus may predispose infants to feeding problems due to atypical oral sensory processing.

Evaluation of somatosensory cortical processing in extremely preterm infants at term with MEG and EEG.

OBJECTIVE: Prior studies on extremely preterm infants have reported long-term prognostic value of absent secondary somatosensory cortex (SII) responses in magnetoencephalography (MEG) at term. The present work (i) further examines the potential added value of SII responses in neonatal neurological evaluation of preterm infants, and (ii) tests whether SII responses are detectable in routine neonatal electroencephalogram complemented with median nerve stimulation (EEG-SEP). METHODS: Altogether 29 infants born <28 gestational weeks underwent MEG, MRI, and neonatal neurological examination at term age, and Hempel neurological examination at 2-years corrected age. Term-age EEG-SEP was available for seven infants. RESULTS: While in neonatal neurological examination severely abnormal finding predicted unfavorable outcome in 2/2 infants, outcome was unfavorable also in 3/9 (33%) moderately abnormal and in 5/18 (28%) mildly abnormal/normal infants. Of these eight infants four had unilaterally absent SII responses in MEG, compared with only two of the 24 infants with favorable outcome. Furthermore, SII responses (when present in MEG) were also usually detectable in EEG-SEP. CONCLUSIONS: Complementing clinical EEG recording with SEP holds promise for valuable extension of neonatal neurophysiological assessment. SIGNIFICANCE: Multimodal study of EEG and sensory evoked responses is informative, safe, and cheap, and it can be readily performed at bedside.

Amniotic fluid erythropoietin and neonatal outcome in pregnancies complicated by intrauterine growth restriction before 34 gestational weeks.

OBJECTIVE: High amniotic fluid erythropoietin concentration reflects chronic fetal hypoxia. Our aim was to study amniotic fluid erythropoietin concentration in relation to neonatal outcome in pregnancies complicated by intrauterine growth restriction. DESIGN: Retrospective case series. SETTING: Helsinki University Hospital, Finland. SAMPLE: A total of 66 singleton pregnancies complicated by intrauterine growth restriction. METHODS: Amniocentesis or amniotic fluid sampling at cesarean section was performed between 24 and 34 gestational weeks. Values of amniotic fluid erythropoietin were quantitated with immunochemiluminometric assay. Normal amniotic fluid erythropoietin was defined as <3 IU/L, intermediate as 3-27 IU/L, and abnormal as >27 IU/L. MAIN OUTCOME MEASURES: Adverse neonatal outcome. RESULTS: Abnormal biophysical profile and reversed end-diastolic flow in umbilical artery were associated with abnormal amniotic fluid erythropoietin (p < 0.001 and p = 0.042, respectively). Abnormal amniotic fluid erythropoietin was not associated with absent end-diastolic flow in umbilical artery or with oligohydramnios (p = 0.404 and p = 0.080, respectively). Decreased umbilical artery pH and base excess values were associated with abnormal amniotic fluid erythropoietin (p = 0.027 and p = 0.007, respectively). Composite adverse neonatal outcome defined as intraventricular hemorrhage, periventricular leukomalacia, cerebral infarction and/or necrotizing enterocolitis was associated with abnormal amniotic fluid erythropoietin (p < 0.001). CONCLUSIONS: High amniotic fluid erythropoietin concentrations are associated with decreased umbilical artery pH and base excess and with adverse neonatal outcome in pregnancies complicated by intrauterine growth restriction before 34 gestational weeks. In selected pregnancies complicated by intrauterine growth restriction, determining amniotic fluid erythropoietin could be a useful additional tool in fetal surveillance and possibly in optimizing timing of delivery.

Mother-child interaction is associated with neurocognitive outcome in extremely low gestational age children.

Early mother-child interaction is one of the factors suggested to have an impact on neurocognitive development of extremely low gestational age (ELGA) children. Our aim was to examine associations of mother-child interaction with neurocognitive outcome, neurological impairments and neonatal brain injuries in ELGA children. A prospective study of 48 ELGA children, born before 28 gestational weeks (26.3 ± 1.2 weeks, birth weight 876 g ± 194 g), and 16 term controls. Brain MRI was performed at term-equivalent age. At two years of corrected age, the mother-child interaction was assessed in a structured play situation using the Erickson Scales and Mutually Responsive Orientation Scales. Neurocognitive outcome was assessed with Griffiths Mental Developmental Scales (GMDS) and Bayley Scales of Infant and Toddler Development - Third Edition (BSID-III) and with Hempel neurological examination. Among ELGA children, higher quality of dyadic relationship and maternal sensitivity, responsiveness, and supportiveness were associated with positive neurocognitive outcome measured both with GMDS and BSID-III (adjusted p < 0.05). This association remained after adjusting for mother's educational level. Neurological impairments at two years, white matter or gray matter abnormalities in MRI at term-equivalent age, and grade III-IV intraventricular hemorrhage during the neonatal period were not associated with mother-child interaction. This study emphasizes the importance of the quality of mother-child interaction after extremely preterm birth for neurocognitive development. Neonatal brain injury and neurological impairments were not associated with worse parent-child interaction after two years.

Cortical somatosensory processing measured by magnetoencephalography predicts neurodevelopment in extremely low-gestational-age infants.

BACKGROUND: Higher cortical function during sensory processing can be examined by recording specific somatosensory-evoked magnetic fields (SEFs) with magnetoencephalography (MEG). We evaluated whether, in extremely low-gestational-age (ELGA) infants, abnormalities in MEG-recorded SEFs at term age are associated with adverse neurodevelopment at 2 y of corrected age. METHODS: SEFs to tactile stimulation of the index finger were recorded at term age in 30 ELGA infants (26.5 ± 1.2 wk, birth weight: 884 g ± 181 g). Neurodevelopment was evaluated at 2 y of corrected age. Controls were 11 healthy term infants. RESULTS: In nine of the ELGA infants (30.0%), SEFs were categorized as abnormal on the basis of lack of response from secondary somatosensory cortex (SII). At 2 y, these infants had a significantly worse mean developmental quotient and locomotor subscale on the Griffiths Mental Development Scales than the ELGA infants with normal responses. Mild white matter abnormalities in magnetic resonance imaging at term age were detected in 21% of infants, but these abnormalities were not associated with adverse neurodevelopment. CONCLUSION: Abnormal SII responses at term predict adverse neuromotor development at 2 y of corrected age. This adverse development may not be foreseen with conventional neuroimaging methods, suggesting a role for evaluating SII responses in the developmental risk assessment of ELGA infants.