Brain metabolism in fetal intrauterine growth restriction: a proton magnetic resonance spectroscopy study

doi:10.1016/j.ajog.2011.06.032

American Journal of Obstetrics and Gynecology

Volume 205, Issue 5, November 2011, Pages 483.e1-483.e8

https://doi.org/10.1016/j.ajog.2011.06.032 Get rights and content

Objective

The purpose of this study was to investigate alterations in brain metabolism in fetuses with intrauterine growth restriction (IUGR) and evidence of cerebral redistribution of blood flow.

Study Design

Biometry and Doppler assessment of blood flow was assessed with ultrasound in 28 fetuses with IUGR and cerebral redistribution and in 41 appropriately grown control subjects. Proton magnetic resonance spectroscopy of the fetal brain was then performed to determine the presence of choline (Cho), creatine (Cr), N-acetylaspartate (NAA), and lactate and to generate ratios for NAA:Cho, NAA:Cr, and Cho:Cr.

Results

Sixty-five percent of spectra were interpretable: N-acetylaspartate, choline, and creatine peaks were identified in all these spectra; lactate was present in 5 IUGR fetuses and in 3 appropriately grown fetuses. NAA:Cr and NAA:Cho ratios were significantly lower in IUGR fetuses with cerebral redistribution.

Conclusion

Cerebral redistribution is associated with altered brain metabolism that is evidenced by a reduction in NAA:Cho and NAA:Cr ratios.

Section snippets

Materials and Methods

Pregnant women were recruited between June 2007 and January 2010 from Queen Charlotte's and Chelsea Hospital London; the study included appropriately grown fetuses after a normal anatomy ultrasound scan and with no associated pregnancy complications and IUGR fetuses from the Centre for Fetal Care. All fetuses were dated with a first trimester dating scan. Inclusion criteria for IUGR fetuses were an estimated fetal weight <10th percentile, abnormal Doppler velocimetry in the umbilical artery

Results

Twenty-eight fetuses with IUGR (gestational age, 20⁺³–35⁺⁰ weeks; median, 27⁺⁶ weeks) and 41 appropriately grown fetuses (gestational age, 22⁺⁰–38⁺⁶ weeks; median, 29⁺⁵ weeks) were included. Two appropriately grown fetuses and 2 IUGR fetuses were scanned twice during gestation. One fetus with an intracerebral cyst that was detected on magnetic resonance imaging was excluded from the study. No other structural abnormalities were identified in any fetus.

At the time of imaging, all

Comment

In this study, 50 interpretable magnetic resonance brain spectra were obtained that identified peaks for NAA, choline, and creatine across the gestational range of 22⁺⁰ to 37⁺⁵ weeks. Brain metabolism was altered in IUGR fetuses, who demonstrated reduced NAA:Cho and NAA:Cr ratios in comparison with the control group (P = .001 and .003, respectively). Lactate was identified in 5 IUGR fetuses and 3 appropriately grown fetuses.

In accordance with previous studies, we have demonstrated that, in a

Acknowledgments

We thank the clinical support staff at the Imaging Sciences Department, Imperial College London; the staff at the Centre for Fetal Care, Queen Charlotte's and Chelsea Hospital London; and the Phillips Medical Systems and Bernard North at the Statistics Advisory Service Imperial College London.

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Placental dysfunction is a major cause of fetal demise, fetal growth restriction, and preterm birth, as well as significant maternal morbidity and mortality. Infant survivors of placental dysfunction are at elevatedrisk for lifelong neuropsychiatric morbidity. However, despite the significant consequences of placental disease, there are no clinical tools to directly and non-invasively assess and measure placental function in pregnancy. In this work, we will review advanced MRI techniques applied to the study of the in vivo human placenta in order to better detail placental structure, architecture, and function. We will discuss the potential of these measures to serve as optimal biomarkers of placental dysfunction and review the evidence of these tools in the discrimination of health and disease in pregnancy. Efforts to advance our understanding of in vivo placental development are necessary if we are to optimize healthy pregnancy outcomes and prevent brain injury in successive generations. Current management of many high-risk pregnancies cannot address placental maldevelopment or injury, given the standard tools available to clinicians. Once accurate biomarkers of placental development and function are constructed, the subsequent steps will be to introduce maternal and fetal therapeutics targeting at optimizing placental function. Applying these biomarkers in future studies will allow for real-time assessments of safety and efficacy of novel interventions aimed at improving maternal-fetal well-being.
Society for Maternal-Fetal Medicine Consult Series #52: Diagnosis and management of fetal growth restriction: (Replaces Clinical Guideline Number 3, April 2012)
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Citation Excerpt :
It also can contribute to cardiac remodeling, leading to cardiovascular dysfunction that can persist into childhood and adolescence.13,14 In addition, studies have shown an association between FGR and long-term neurologic impairment,15–20 with rates of cognitive and learning disabilities as high as 20%–40% by school age.21 FGR remains a complex obstetrical problem with disparate published diagnostic criteria, relatively low detection rates, and limited preventative and treatment options.22–25
Fetal growth restriction can result from a variety of maternal, fetal, and placental conditions. It occurs in up to 10% of pregnancies and is a leading cause of infant morbidity and mortality. This complex obstetrical problem has disparate published diagnostic criteria, relatively low detection rates, and limited preventative and treatment options. The purpose of this Consult is to outline an evidence-based, standardized approach for the prenatal diagnosis and management of fetal growth restriction. The recommendations of the Society for Maternal-Fetal Medicine are as follows: (1) we recommend that fetal growth restriction be defined as an ultrasonographic estimated fetal weight or abdominal circumference below the 10th percentile for gestational age (GRADE 1B); (2) we recommend the use of population-based fetal growth references (such as Hadlock) in determining fetal weight percentiles (GRADE 1B); (3) we recommend against the use of low-molecular-weight heparin for the sole indication of prevention of recurrent fetal growth restriction (GRADE 1B); (4) we recommend against the use of sildenafil or activity restriction for in utero treatment of fetal growth restriction (GRADE 1B); (5) we recommend that a detailed obstetrical ultrasound examination (current procedural terminology code 76811) be performed with early-onset fetal growth restriction (<32 weeks of gestation) (GRADE 1B); (6) we recommend that women be offered fetal diagnostic testing, including chromosomal microarray analysis, when fetal growth restriction is detected and a fetal malformation, polyhydramnios, or both are also present regardless of gestational age (GRADE 1B); (7) we recommend that pregnant women be offered prenatal diagnostic testing with chromosomal microarray analysis when unexplained isolated fetal growth restriction is diagnosed at <32 weeks of gestation (GRADE 1C); (8) we recommend against screening for toxoplasmosis, rubella, or herpes in pregnancies with fetal growth restriction in the absence of other risk factors and recommend polymerase chain reaction for cytomegalovirus in women with unexplained fetal growth restriction who elect diagnostic testing with amniocentesis (GRADE 1C); (9) we recommend that once fetal growth restriction is diagnosed, serial umbilical artery Doppler assessment should be performed to assess for deterioration (GRADE 1C); (10) with decreased end-diastolic velocity (ie, flow ratios greater than the 95th percentile) or in pregnancies with severe fetal growth restriction (estimated fetal weight less than the third percentile), we suggest weekly umbilical artery Doppler evaluation (GRADE 2C); (11) we recommend Doppler assessment up to 2–3 times per week when umbilical artery absent end-diastolic velocity is detected (GRADE 1C); (12) in the setting of reversed end-diastolic velocity, we suggest hospitalization, administration of antenatal corticosteroids, heightened surveillance with cardiotocography at least 1–2 times per day, and consideration of delivery depending on the entire clinical picture and results of additional evaluation of fetal well-being (GRADE 2C); (13) we suggest that Doppler assessment of the ductus venosus, middle cerebral artery, or uterine artery not be used for routine clinical management of early- or late-onset fetal growth restriction (GRADE 2B); (14) we suggest weekly cardiotocography testing after viability for fetal growth restriction without absent/reversed end-diastolic velocity and that the frequency be increased when fetal growth restriction is complicated by absent/reversed end-diastolic velocity or other comorbidities or risk factors (GRADE 2C); (15) we recommend delivery at 37 weeks of gestation in pregnancies with fetal growth restriction and an umbilical artery Doppler waveform with decreased diastolic flow but without absent/reversed end-diastolic velocity or with severe fetal growth restriction with estimated fetal weight less than the third percentile (GRADE 1B); (16) we recommend delivery at 33–34 weeks of gestation for pregnancies with fetal growth restriction and absent end-diastolic velocity (GRADE 1B); (17) we recommend delivery at 30–32 weeks of gestation for pregnancies with fetal growth restriction and reversed end-diastolic velocity (GRADE 1B); (18) we suggest delivery at 38–39 weeks of gestation with fetal growth restriction when the estimated fetal weight is between the 3rd and 10th percentile and the umbilical artery Doppler is normal (GRADE 2C); (19) we suggest that for pregnancies with fetal growth restriction complicated by absent/reversed end-diastolic velocity, cesarean delivery should be considered based on the entire clinical scenario (GRADE 2C); (20) we recommend the use of antenatal corticosteroids if delivery is anticipated before 33 6/7 weeks of gestation or for pregnancies between 34 0/7 and 36 6/7 weeks of gestation in women without contraindications who are at risk of preterm delivery within 7 days and who have not received a prior course of antenatal corticosteroids (GRADE 1A); and (21) we recommend intrapartum magnesium sulfate for fetal and neonatal neuroprotection for women with pregnancies that are <32 weeks of gestation (GRADE 1A).
Advanced MRI analysis to detect white matter brain injury in growth restricted newborn lambs
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Citation Excerpt :
Brain metabolite concentrations were altered in a preclinical study in newborn FGR rabbits, with lower levels of aspartate and n-acetylaspartate in cortical and hippocampal regions, and increased glycine in the striatum (Simoes et al., 2015). MRS undertaken during pregnancy shows that growth restricted fetuses with brain sparing have lower NAA:Cr and NAA:Cho ratios compared to AGA fetuses, indicative of reduced neuronal number and/or function (Story et al., 2011). In contrast, a study on small for gestational age infants studied at two time points early in the neonatal period found no differences in cerebral metabolism (Roelants-van Rijn et al., 2004).
Fetal growth restriction (FGR) is a serious pregnancy complication associated with increased risk of adverse neurodevelopment and neuromorbidity. Current imaging techniques, including conventional magnetic resonance imaging (MRI), are not sensitive enough to detect subtle structural abnormalities in the FGR brain. We examined whether advanced MRI analysis techniques have the capacity to detect brain injury (particularly white matter injury) caused by chronic hypoxia-induced fetal growth restriction in newborn preterm lambs.
Surgery was undertaken in twin bearing pregnant ewes at 88–90 days gestation (term = 150 days) to induce FGR in one fetus. At 127 days gestation (~32 weeks human brain development), FGR and control (appropriate for gestational age, AGA) lambs were delivered by caesarean section, intubated and ventilated. Conventional and advanced brain imaging was conducted within the first two hours of life using a 3T MRI scanner. T1-weighted (T1w) and T2-weighted (T2w) structural imaging, magnetic resonance spectroscopy (MRS), and diffusion MRI (dMRI) data were acquired. Diffusion tensor imaging (DTI) modelling and analysis of dMRI data included the following regions of interest (ROIs): subcortical white matter, periventricular white matter, cerebellum, hippocampus, corpus callosum and thalamus. Fixel-based analysis of 3-tissue constrained spherical deconvolution (CSD) of the dMRI data was performed and compared between FGR and AGA lambs. Lambs were euthanised immediately after the scans and brain histology performed in the regions of interest to correlate with imaging.
FGR and AGA lamb (body weight, mean (SD): 2.2(0.5) vs. 3.3(0.3) kg, p = .002) MRI brain scans were analysed. There were no statistically significant differences observed between the groups in conventional T1w, T2w or MRS brain data. Mean, axial and radial diffusivity, and fractional anisotropy indices obtained from DTI modelling also did not show any statistically significant differences between groups in the ROIs. Fixel-based analysis of 3-tissue CSD, however, did reveal a decrease in fibre cross-section (FC, p < .05) but not in fibre density (FD) or combined fibre density and cross-section (FDC) in FGR vs. AGA lamb brains. The specific tracts that showed a decrease in FC were in the regions of the periventricular white matter, hippocampus and cerebellar white matter, and were supported by histological evidence of white matter hypomyelination and disorganisation in corresponding FGR lamb brain regions.
The neuropathology associated with FGR in neonatal preterm lambs is subtle and imaging detection may require advanced MRI and tract-based analysis techniques. Fixel-based analysis of 3-tissue CSD demonstrates that the preterm neonatal FGR brain shows evidence of macrostructural (cross-sectional) deficits in white matter subsequent to altered antenatal development. These findings can inform analysis of similar brain pathology in neonatal infants.
The use of antenatal fetal magnetic resonance imaging in the assessment of patients at high risk of preterm birth
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Citation Excerpt :
The development of advanced MRI techniques has now enabled assessment of cortical folding [20], subtle white matter injury and haemorrhage in the fetus: information not previously obtainable using conventional ultrasound imaging techniques. Volumetry of cerebral structures MRS [32], and diffusion imaging can now also be obtained from a fetal MRI. Such information about brain development may be useful with respect to counselling of parents with regards to longer-term outcomes as well as helping clinical decision making with regards to the timing of delivery or therapeutic interventions.
Preterm birth, defined as birth occurring prior to 37 weeks gestation is a common obstetric complication affecting 8% of pregnancies and is associated with significant morbidity and mortality. Infection/inflammation has been implicated in both the aetiology of preterm birth itself and associated neonatal pulmonary and neurological morbidity. Treatment options are currently limited to prolongation of the pregnancy using cervical cerclage, pessaries or progesterone or administration of drugs including steroids to promote lung maturity and neuroprotective agents such as magnesium sulphate, the timing of which are highly critical. Although delivery is expedited in cases of overt infection, decisions regarding timing and mode of delivery in subclinical infection are not clear-cut. This review aims to explore the use of magnetic resonance imaging (MRI) in the antenatal assessment of pregnancies at high risk of preterm birth and its potential to guide management decisions in the future.
Brain metabolite alterations in infants born preterm with intrauterine growth restriction: association with structural changes and neurodevelopmental outcome
2017, American Journal of Obstetrics and Gynecology
Intrauterine growth restriction and premature birth represent 2 independent problems that may occur simultaneously and contribute to impaired neurodevelopment.
The objective of the study was to assess changes in the frontal lobe metabolic profiles of 1 year old intrauterine growth restriction infants born prematurely and adequate-for-gestational-age controls, both premature and term adequate for gestational age and their association with brain structural and biophysical parameters and neurodevelopmental outcome at 2 years.
A total of 26 prematurely born intrauterine growth restriction infants (birthweight <10th centile for gestational age), 22 prematurely born but adequate for gestational age controls, and 26 term adequate-for-gestational-age infants underwent brain magnetic resonance imaging and magnetic resonance spectroscopy at 1 year of age during natural sleep, on a 3 Tesla scanner. All brain T1-weighted and diffusion-weighted images were acquired along with short echo time single-voxel proton spectra from the frontal lobe. Magnetic resonance imaging/magnetic resonance spectroscopy data were processed to derive structural, biophysical, and metabolic information, respectively. Neurodevelopment was evaluated at 2 years of age using the Bayley Scales 3rd edition, assessing cognitive, language, motor, socioemotional, and adaptive behavior.
Prematurely born intrauterine growth restriction infants had slightly smaller brain volumes and increased frontal lobe white matter mean diffusivity compared with both prematurely born but adequate for gestational age and term adequate for gestational age controls. Frontal lobe N-acetylaspartate levels were significantly lower in prematurely born intrauterine growth restriction than in prematurely born but adequate for gestational age infants but increased in prematurely born but adequate for gestational age compared with term adequate-for-gestational-age infants. The prematurely born intrauterine growth restriction group also showed slightly lower choline compounds, borderline decrements of estimated glutathione levels, and increased myoinositol to choline ratios, compared with prematurely born but adequate for gestational age controls. These specific metabolite changes were locally correlated to lower gray matter content and increased mean diffusivity and reduced white matter fraction and fractional anisotropy. Prematurely born intrauterine growth restriction infants also showed a tendency for poorer neurodevelopmental outcome at 2 years, associated with lower levels of frontal lobe N-acetylaspartate at 1 year within the preterm subset.
Preterm intrauterine growth restriction infants showed altered brain metabolite profiles during a critical stage of brain maturation, which correlate with brain structural and biophysical parameters and neurodevelopmental outcome. Our results suggest altered neurodevelopmental trajectories in preterm intrauterine growth restriction and adequate-for-gestational-age infants, compared with term adequate-for-gestational-age infants, which require further characterization.

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: Supported by the Moonbeam Trust, Action Medical Research, Medical Research Council.

: The authors report no conflicts of interest.

: Cite this article as: Story L, Damodaram MS, Allsop JM, et al. Brain metabolism in fetal intrauterine growth restriction: a proton magnetic resonance spectroscopy study. Am J Obstet Gynecol 2011;205:483.e1-8.

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ResearchImagingBrain metabolism in fetal intrauterine growth restriction: a proton magnetic resonance spectroscopy study

Objective

Study Design

Results

Conclusion

Section snippets

Materials and Methods

Results

Comment

Acknowledgments

Brain Res

Semin Neonatol

Eur J Radiol

J Biol Chem

Prog Neurobiol

Biochem Biophys Res Commun

Int J Dev Neurosci

J Biol Chem

Am J Obstet Gynecol

Brain Res

Neurosci Res

ACOG practice bulletin no. 12

Perinatal outcome and later implications of intrauterine growth restriction

Clin Obstet Gynecol

Intrauterine growth restriction: how to manage and when to deliver

Clin Obstet Gynecol

Altered expression and function of mitochondrial beta-oxidation enzymes in juvenile intrauterine-growth-retarded rat skeletal muscle

Pediatr Res

Impaired oxidative phosphorylation in hepatic mitochondria in growth-retarded rats

Am J Physiol Endocrinol Metab

Uteroplacental insufficiency alters cerebral mitochondrial gene expression and DNA in fetal and juvenile rats

Pediatr Res

Subfield-specific loss of hippocampal N-acetyl aspartate in temporal lobe epilepsy

Epilepsia

Maturation of the human fetal brain as observed by 1H MR spectroscopy

Magn Reson Med

Assessment of normal fetal brain maturation in utero by proton magnetic resonance spectroscopy

Magn Reson Med

Quantitative proton spectroscopy of canine brain: in vivo and in vitro correlations

Magn Reson Med

Brain metabolite composition during early human brain development as measured by quantitative in vivo 1H magnetic resonance spectroscopy

Magn Reson Med

Research
Imaging
Brain metabolism in fetal intrauterine growth restriction: a proton magnetic resonance spectroscopy study