Neonatal Hemoglobin Levels in Preterm Infants Are Associated with Early Neurological Functioning

Background: Neonatal anemia may compromise oxygen transport to the brain. The effects of anemia and cerebral oxygenation on neurological functioning in the early neonatal period are largely unknown. Objective: This study aimed to determine the association between initial hemoglobin levels (Hb) and early neurological functioning in preterm infants by assessing their general movements (GMs). Methods: A retrospective analysis of prospectively collected data on preterm infants born before 32 weeks of gestation was conducted. We excluded infants with intraventricular hemorrhage > grade II. On day 8, we assessed infants' GMs, both generally as normal/abnormal and in detail using the general movement optimality score (GMOS). We measured cerebral tissue oxygen saturation (r(c)SO(2)) on day 1 using near-infrared spectroscopy. Results: We included 65 infants (median gestational age 29.9 weeks [IQR 28.2-31.0]; median birth weight 1,180 g [IQR 930-1,400]). Median Hb on day 1 was 10.3 mmol/L (range 4.2-13.7). Lower Hb on day 1 was associated with a higher risk of abnormal GMs (OR = 2.3, 95% CI: 1.3-4.1) and poorer GMOSs (B = 0.9, 95% CI: 0.2-1.7). Hemoglobin strongly correlated with r(c)SO(2) (rho = 0.62, p < 0.01). Infants with lower r(c)SO(2) values tended to have a higher risk of abnormal GMs (p = 0.06). After adjusting for confounders, Hb on day 1 explained 44% of the variance of normal/abnormal GMs and r(c)SO(2) explained 17%. Regarding the explained variance of the GMOS, this was 25% and 16%, respectively. Conclusions: In preterm infants, low Hb on day 1 is associated with impaired neurological functioning on day 8, which is partly explained by low cerebral oxygenation

Altered neurodevelopmental DNA methylation status after fetal growth restriction with brain-sparing

It is under debate how preferential perfusion of the brain (brain-sparing) in fetal growth restriction (FGR) relates to long-term neurodevelopmental outcome. Epigenetic modification of neurotrophic genes by altered fetal oxygenation may be involved. To explore this theory, we performed a follow-up study of 21 FGR children, in whom we prospectively measured the prenatal cerebroplacental ratio (CPR) with Doppler sonography. At 4 years of age, we tested their neurodevelopmental outcome using the Wechsler Preschool and Primary Scale of Intelligence, the Child Behavior Checklist, and the Behavior Rating Inventory of Executive Function. In addition, we collected their buccal DNA to determine the methylation status at predefined genetic regions within the genes hypoxia-inducible factor-1 alpha (HIF1A), vascular endothelial growth factor A (VEGFA), erythropoietin (EPO), EPO-receptor (EPOR), brain-derived neurotrophic factor (BDNF), and neurotrophic tyrosine kinase, receptor, type 2 (NTRK2) by pyrosequencing. We found that FGR children with fetal brain-sparing (CPR <1, n = 8) demonstrated a trend (0.05 < p < 0.1) toward hypermethylation of HIF1A and VEGFA at their hypoxia-response element (HRE) compared with FGR children without fetal brain-sparing. Moreover, in cases with fetal brain-sparing, we observed statistically significant hypermethylation at a binding site for cyclic adenosine monophophate response element binding protein (CREB) of BDNF promoter exon 4 and hypomethylation at an HRE located within the NTRK2 promoter (both p <0.05). Hypermethylation of VEGFA was associated with a poorer Performance Intelligence Quotient, while hypermethylation of BDNF was associated with better inhibitory self-control (both p <0.05). These results led us to formulate the hypothesis that early oxygen-dependent epigenetic alterations due to hemodynamic alterations in FGR may be associated with altered neurodevelopmental outcome in later life. We recommend further studies to test this hypothesis

Fetal Brain-Sparing, Postnatal Cerebral Oxygenation, and Neurodevelopment at 4 Years of Age Following Fetal Growth Restriction

Objectives: To assess the role of fetal brain-sparing and postnatal cerebral oxygen saturation (r cSO 2) as determinants of long-term neurodevelopmental outcome following fetal growth restriction (FGR). Methods: This was a prospective follow-up study of an FGR cohort of 41 children. Prenatally, the presence of fetal brain-sparing (cerebroplacental ratio < 1) was assessed by Doppler ultrasound. During the first two days after birth, r cSO 2 was measured with near-infrared spectroscopy. At 4 years of age, intelligence (IQ points), behavior (T-scores), and executive function (T-scores) were assessed using the Wechsler Preschool and Primary Scale of Intelligence, Child Behavior Checklist, and Behavior Rating Inventory of Executive Function—Preschool Version, respectively. Using linear regression analyses, we tested the association (p < 0.05) between brain-sparing/r cSO 2 and normed neurodevelopmental scores. Results: Twenty-six children (gestational age ranging from 28.0 to 39.9 weeks) participated in the follow-up at a median age of 4.3 (range: 3.6 to 4.4) years. Autism spectrum disorder was reported in three children (11.5%). Fetal brain-sparing was associated with better total and externalizing behavior (betas: −0.519 and −0.494, respectively). R cSO 2 levels above the lowest quartile, particularly on postnatal day 2 (≥ 77%), were associated with better total and internalizing behavior and executive functioning (betas: −0.582, −0.489, and −0.467, respectively), but also lower performance IQ (beta: −0.530). Brain-sparing mediated some but not all of these associations. Conclusions: In this FGR cohort, fetal brain-sparing and high postnatal r cSO 2 were—independently, but also as a reflection of the same mechanism—associated with better behavior and executive function. Postnatal cerebral hyperoxia, however, was negatively associated with brain functions responsible for performance IQ

Online versus offline spatiotemporal image correlation (STIC) M-mode for the evaluation of cardiac longitudinal annular displacement in fetal growth restriction

Purpose: Our first aim was to compare online M-mode with offline spatiotemporal image correlation (STIC) M-mode for assessing longitudinal annular displacement (LAD) in growth-restricted fetuses (FGR). Our second aim was to compare LAD measures of FGR cases with controls. Materials and methods: Prospective study including 40 FGR cases (defined estimated fetal weight and birth weight <10th centile) and 72 normally grown fetuses matched to cases by gestational age at scan. LAD was measured with online M-mode and offline STIC M-mode at the left and right ventricular free walls and septum in all fetuses. Results: FGR cases had a significant decrease in LAD by STIC in all sites as compared to controls (e.g. right LAD in FGR mean 6.7 mm (SD 1.2) versus controls 7.2 mm (1.2), p = .033). There was a non-significant trend for lower values in FGR when using online M-mode (e.g. right LAD in FGR 6.9 mm (1.5) versus controls 7.4 mm (1.5), p = .084). Conclusions: STIC M-mode seems a better method than online M-mode for detecting subtle changes in myocardial motion. STIC presents more precise results and allows an ideal placement of the M-mode arrow. These results confirm previous data suggesting decreased longitudinal motion in FGR.This study was supported by grants from the Graduate School of Medical Sciences of the University of Groningen, the research institute BCN-BRAIN, the Ministerio de Economia y Competitividad (ref. SAF2012–37196), the Instituto de Salud Carlos III (ref. PI11/00051, PI11/01709, PI12/02230) integrado en el Plan Nacional de I + D + I y cofinanciado por el ISCIII-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER) “Otra manera de hacer Europa”, the Cerebra Foundation for the Brain Injured Child (Carmarthen, Wales, UK), Obra Social “la Caixa”, the Fundación Mutua Madrileña, and AGAUR 2014 SGR grant no. 928

Functional Outcomes at Age 7 Years of Moderate Preterm and Full Term Children Born Small for Gestational Age

OBJECTIVE: To compare functional outcomes of 7-year-old (school-age) children born small for gestational age (SGA; ie, a birth weight z score ≤ -1 SD), with appropriate for gestational age (AGA) peers, born moderately preterm or full term. STUDY DESIGN: Data were collected as part of the Longitudinal Preterm Outcome Project study, a community-based, prospective cohort study of 336 AGA and 42 SGA born children (median gestational age 35 weeks, range 31-41). Of the SGA children, 32 were moderately preterm, 10 were full term; of the AGA, these numbers were 216 and 120, respectively. At 6.9 years, we assessed intelligence, verbal memory, attention, visuomotor integration, and motor skills and we collected the parent-reported executive functioning. We compared the outcomes of the SGA children with those of their AGA peers. RESULTS: The performance of SGA children was similar to that of their AGA peers, except for attention control which was abnormal more often in SGA children (OR 3.99, 95% CI 1.32-12.12). The IQ of SGA children was 3 points lower, but this difference failed to reach significance. CONCLUSIONS: At school age, children born SGA have a greater risk of abnormal test scores on attention control than children born AGA, independent of gestational age. Their motor and many other cognitive functions are similar. The impact of these outcomes seems limited. Nevertheless, the consequences for school performance deserve attention

Differential placental DNA methylation of VEGFA and LEP in small-for-gestational age fetuses with an abnormal cerebroplacental ratio

BACKGROUND: In Fetal Growth Restriction 'fetal programming' may take place via DNA methylation, which has implications for short-term and long-term health outcomes. Small-for-gestational age fetuses are considered fetal growth restricted, characterized by brain-sparing when fetal Doppler hemodynamics are abnormal, expressed as a cerebroplacental ratio (CPR) <1. We aimed to determine whether brain-sparing is associated with altered DNA methylation of selected genes. METHODS: We compared DNA methylation of six genes in 41 small-for-gestational age placentas with a normal or abnormal CPR. We selected EPO, HIF1A, VEGFA, LEP, PHLDA2, and DHCR24 for their role in angiogenesis, immunomodulation, and placental and fetal growth. DNA methylation was analyzed by pyrosequencing. RESULTS: Growth restricted fetuses with an abnormal CPR showed hypermethylation of the VEGFA gene at one CpG (VEGFA-309, p = .001) and an overall hypomethylation of the LEP gene, being significant at two CpGs (LEP-123, p = .049; LEP-51, p = .020). No differences in methylation were observed for the other genes. CONCLUSIONS: VEGFA and LEP genes are differentially methylated in placentas of small-for-gestational age fetuses with brain-sparing. Hypermethylation of VEGFA-309 in abnormal CPR-placentas could indicate successful compensatory mechanisms. Methylation of LEP-51 is known to suppress LEP expression. Hypomethylation in small-for-gestational age placentas with abnormal CPR may result in hyperleptinemia and predispose to leptin-resistance later in life

A Hemodynamically Significant Patent Ductus Arteriosus Does Not Affect Cerebral or Renal Tissue Oxygenation in Preterm Infants

BACKGROUND: Patent ductus arteriosus (PDA) is common in preterm infants and is associated with significant morbidity. To determine whether the PDA is hemodynamically significant (HSDA), several echocardiographic parameters have been suggested, including retrograde diastolic blood flow in the descending aorta (Dao). OBJECTIVE: To assess the impact of an HSDA, including retrograde diastolic flow in the Dao, on regional tissue oxygen saturation (rSO2) and extraction measured by near-infrared spectroscopy (NIRS). METHODS: This is a prospective observational cohort study in which we included preterm infants (GA 1.4 and/or left pulmonary artery end-diastolic flow velocity >0.2 m/s and/or retrograde diastolic blood flow in the Dao. RESULTS: Forty-nine infants were included, with a median GA of 27.6 weeks (IQR: 26.1-29.0), birth weight of 980 g (IQR: 800-1,200), and postnatal age of 77 h (IQR: 70-107). Infants with a closed duct (n = 11), a non-HSDA (n = 18), and an HSDA (n = 20) had similar cerebral and renal NIRS measurements. Retrograde diastolic blood flow in the Dao, present in 11 infants with PDA, also did not affect cerebral and renal NIRS measurements. CONCLUSION: In preterm infants with clinical signs of an HSDA within 2 weeks after birth, cerebral and renal oxygen saturation and extraction are not affected by an HSDA or by retrograde diastolic blood flow in the Dao

Supplementary Material for: Neonatal Hemoglobin Levels in Preterm Infants Are Associated with Early Neurological Functioning

Background: Neonatal anemia may compromise oxygen transport to the brain. The effects of anemia and cerebral oxygenation on neurological functioning in the early neonatal period are largely unknown. Objective: This study aimed to determine the association between initial hemoglobin levels (Hb) and early neurological functioning in preterm infants by assessing their general movements (GMs). Methods: A retrospective analysis of prospectively collected data on preterm infants born before 32 weeks of gestation was conducted. We excluded infants with intraventricular hemorrhage &gt; grade II. On day 8, we assessed infants’ GMs, both generally as normal/abnormal and in detail using the general movement optimality score (GMOS). We measured cerebral tissue oxygen saturation (rcSO2) on day 1 using near-infrared spectroscopy. Results: We included 65 infants (median gestational age 29.9 weeks [IQR 28.2–31.0]; median birth weight 1,180 g [IQR 930–1,400]). Median Hb on day 1 was 10.3 mmol/L (range 4.2–13.7). Lower Hb on day 1 was associated with a higher risk of abnormal GMs (OR = 2.3, 95% CI: 1.3–4.1) and poorer GMOSs (B = 0.9, 95% CI: 0.2–1.7). Hemoglobin strongly correlated with rcSO2 (rho = 0.62, p &lt; 0.01). Infants with lower rcSO2 values tended to have a higher risk of abnormal GMs (p = 0.06). After adjusting for confounders, Hb on day 1 explained 44% of the variance of normal/abnormal GMs and rcSO2 explained 17%. Regarding the explained variance of the GMOS, this was 25% and 16%, respectively. Conclusions: In preterm infants, low Hb on day 1 is associated with impaired neurological functioning on day 8, which is partly explained by low cerebral oxygenation