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

Richter, Anne; Salavati, Sahar; Kooi, Elisabeth M. W.; Heijer, Anne E den; Foreman, Anne B; Schoots, Mirthe H.; Bilardo, C. M.; Scherjon, Sicco A.; Tanis, Jozien C.; Bos, Arend F.

doi:10.3389/fped.2020.00225

Cited by 11 publications

(28 citation statements)

References 54 publications

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“…Finally, we reviewed the 12 studies that met the inclusion criteria. All of these were longitudinal studies: 11 prospective [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 36 , 37 , 38 ] and only one retrospective [ 35 ]. Two of the studies were secondary analyses of randomized clinical trials.…”

Section: Resultsmentioning

confidence: 99%

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Brain Sparing Effect on Neurodevelopment in Children with Intrauterine Growth Restriction: A Systematic Review

et al. 2021

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Background: Fetal growth restriction (FGR) is a pregnancy complication. Multiple studies have connected FGR to poor cognitive development, behavior disorders, and academic difficulties during childhood. Brain sparing has traditionally been defined as an adaptive phenomenon in which the brain obtains the blood flow that it needs. However, this adaptive phenomenon might not have a complete protective effect. This publication aims to systematically review the consequences of brain redistribution on neurodevelopment in children who presented with placental intrauterine growth restriction. Methods: We performed a systematic review according to PRISMA guidelines. It included studies on intrauterine growth restriction or small-for-gestational-age (SGA) fetuses, which middle cerebral artery was measured, and neurodevelopment assessed during childhood. PUBMED and EMBASE databases were searched for relevant published studies. Results: Of the 526 studies reviewed, only 12 were included. Brain sparing was associated with poor cognitive function and lower scores in IQ. Cerebral redistribution was related to better executive function and better behavior at 4 years old but not at 12 years old. Conclusions: We can assume that fetal brain sparing could not be a fully protective phenomenon. We could not find clinical differences in behavioral and executive functions because the results were heterogeneous. Some cognitive abilities could be affected in FGR brain sparing fetuses.

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Section: Resultsmentioning

confidence: 99%

“…This test analyzes communication, gross and fine motor skills, problem-solving and personal–social interaction. Weschler Intelligence Scale [ 29 , 31 , 35 ]. This test assesses intelligence, verbal comprehension, working memory, processing speed, and the perceptual reasoning index.…”

Section: Resultsmentioning

confidence: 99%

Brain Sparing Effect on Neurodevelopment in Children with Intrauterine Growth Restriction: A Systematic Review

et al. 2021

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“…Although an angiogenic dysbalance (lower circulating VEGF levels) has also been evidenced in patients with ASD, we have reported in our previous paper that both children also presented with impaired umbilical flow even if no signs of fetal brain-sparing were present. 5,51 Regardless of its origin, VEGFA hypermethylation does not seem to benefit neurodevelopmental outcome.…”

Section: Discussionmentioning

confidence: 97%

“…In a previous study, we found that preferential perfusion of the fetal brain in FGR was associated with better neurodevelopmental outcome at 4 years of age than FGR without fetal brain-sparing. 5 This seemed to be mediated through higher cerebral oxygen saturations as suggested by postnatal tissue oxygenation monitoring with nearinfrared spectroscopy. In the same cohort, we now find a trend toward hypermethylation at the autoregulatory HRE of the HIF1A promoter in the buccal DNA of these children.…”

Section: Discussionmentioning

confidence: 99%

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

Richter

Bekkering-Bauer

Verkaik-Schakel

et al. 2021

J Dev Orig Health Dis

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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.

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“…This hemodynamic redistribution remains visible after birth as altered cerebrorenal oxygenation, as demonstrated using near-infrared spectroscopy (NIRS) ( 3 , 4 ). Although an increase in cerebral oxygenation is intended as protective, it is debated whether this (fully) benefits neurodevelopmental outcome ( 5 , 6 ). Moreover, redistribution has been associated with impaired cerebral autoregulation ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

Prenatal Use of Sildenafil in Fetal Growth Restriction and Its Effect on Neonatal Tissue Oxygenation—A Retrospective Analysis of Hemodynamic Data From Participants of the Dutch STRIDER Trial

et al. 2020

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Objective: Sildenafil is under investigation as a potential agent to improve uteroplacental perfusion in fetal growth restriction (FGR). However, the STRIDER RCT was halted after interim analysis due to futility and higher rates of persistent pulmonary hypertension and mortality in sildenafil-exposed neonates. This hypothesis-generating study within the Dutch STRIDER trial sought to understand what happened to these neonates by studying their regional tissue oxygen saturation (rSO2) within the first 72 h after birth.Methods: Pregnant women with FGR received 25 mg placebo or sildenafil thrice daily within the Dutch STRIDER trial. We retrospectively analyzed the cerebral and renal rSO2 monitored with near-infrared spectroscopy (NIRS) in a subset of neonates admitted to two participating neonatal intensive care units, in which NIRS is part of standard care. Secondarily, blood pressure and heart rate were analyzed to aid interpretation. Differences in oxygenation levels and interaction with time (slope) between placebo- and sildenafil-exposed groups were tested using mixed effects analyses with multiple comparisons tests.Results: Cerebral rSO2 levels were not different between treatment groups (79 vs. 77%; both n = 14) with comparable slopes. Sildenafil-exposed infants (n = 5) showed lower renal rSO2 than placebo-exposed infants (n = 6) during several time intervals on day one and two. At 69–72 h, however, the sildenafil group showed higher renal rSO2 than the placebo group. Initially, diastolic blood pressure was higher and heart rate lower in the sildenafil than the placebo group, which changed during day two.Conclusions: Although limited by sample size, our data suggest that prenatal sildenafil alters renal but not cerebral oxygenation in FGR neonates during the first 72 post-natal hours. The observed changes in renal oxygenation could reflect a vasoconstrictive rebound from sildenafil. Similar changes observed in accompanying vital parameters support this hypothesis.

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

Cited by 11 publications

References 54 publications

Brain Sparing Effect on Neurodevelopment in Children with Intrauterine Growth Restriction: A Systematic Review

Brain Sparing Effect on Neurodevelopment in Children with Intrauterine Growth Restriction: A Systematic Review

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

Prenatal Use of Sildenafil in Fetal Growth Restriction and Its Effect on Neonatal Tissue Oxygenation—A Retrospective Analysis of Hemodynamic Data From Participants of the Dutch STRIDER Trial

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