Association Between Abnormal Fetal Head Growth and Autism Spectrum Disorder

Regev, Ohad; Cohen, Gal; Hadar, Amnon; Schuster, Jenny; Flusser, Hagit; Michaelovski, Analya; Meiri, Gal; Dinstein, Ilan; Hershkovitch, Reli; Menashe, Idan

doi:10.1016/j.jaac.2020.11.019

Cited by 7 publications

(19 citation statements)

References 60 publications

(110 reference statements)

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“…7,56,70 Abnormalities in the CSF circulation in the extra-axial space may lead to an accumulation of CSF above the frontal lobes, [66][67][68][69] resulting in an abnormal and elongated (dolichocephalic) head shape, as revealed in this analysis and our previous smaller study. 20 In addition, ASD fetuses had relatively wider set eyes vs. the other fetuses in the cohort. This finding is in line with evidence from postnatal head image analysis demonstrating wide-set eyes in a subgroup of children with ASD.…”

Section: Discussionmentioning

confidence: 94%

“…This study is the first to systematically examine organogenesis in fetuses later developing into children with ASD by exploiting retrospectively the fetal ultrasound anatomic survey. The use of two distinct control groups, TDS and TDP, enabled us to adjust our findings to multiple familial and prenatal confounders that are known to have a considerable effect on both ASD risk and fetal growth (e.g., sex 2,20 and shared genetics among siblings 1,76,77 ), making our findings more compelling.…”

Section: Discussionmentioning

confidence: 99%

“…16 A growing body of evidence suggests that the initial signs of ASD emerge during early childhood [17][18][19] and possibly even before birth. [20][21][22][23][24][25] Indeed, recent postnatal studies have found indications of the prenatal onset of abnormal neurodevelopment in children with ASD, 21 and some prenatal studies have provided preliminary indications for higher rates of structural anomalies both in the renal system of fetuses later developing into children with ASD and in children with specific genetic syndromes associated with ASD. [26][27][28][29][30][31] Taken together, these findings suggest that ASD may be associated with abnormal embryonic organogenesis of different body parts, which consequently leads to postnatal malformations in some children with ASD.…”

Section: Introductionmentioning

confidence: 99%

“…8,21,32,33 Accordingly, there is emerging interest in examining the prenatal organ development of fetuses later developing into children diagnosed with ASD. 20,22,25 The tool of choice for this task is prenatal ultrasound, a commonly used pregnancy monitoring tool that allows physicians to survey fetal growth and organ development and may hence reveal anomalies suggesting genetic and developmental problems that require further testing and follow-up. In prenatal monitoring protocols, one of the primary ultrasound screenings is the fetal anatomical survey, which is considered standard of care for examining fetal organ development and detecting fetal organ anomalies.…”

Section: Introductionmentioning

confidence: 99%

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Association Between Ultrasonography Fetal Anomalies and Autism Spectrum Disorder

Regev

Hadar

Meiri

et al. 2021

Preprint

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BackgroundPrenatal ultrasound is frequently used to monitor fetal growth and identify fetal anomalies that may suggest genetic or developmental abnormalities which may develop into congenital anomalies and diseases. Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder, associated with a wide range of congenital anomalies. Nevertheless, very little has been done to investigate organ development using prenatal ultrasound as a means to identify fetuses with ASD susceptibility.MethodsA retrospective matched case-sibling-control study. ASD cases were matched to two control groups: typically developing sibling (TDS) closest in age to ASD child; and typically developing population (TDP), matched for age, sex, and ethnicity. The study comprised 659 children: 229 ASD, 201 TDS, and 229 TDP; 471 (71.5%) males.ResultsUltrasonography fetal anomalies (UFAs) were found in 29.3% of ASD cases vs. only 15.9% and 9.6% in the TDS and TDP groups (aOR=2.23, 95%CI=1.32-3.78, and OR=3.50, 95%CI=2.07-5.91, respectively). Also, multiple co-occurring UFAs were significantly more prevalent among ASD cases. UFAs in the urinary system, heart, and head&brain were the most significantly associated with ASD diagnosis (aORUrinary =2.08, 95%CI=0.96-4.50 and ORUrinary=2.90, 95%CI=1.41-5.95; aORHeart=3.72, 95%CI=1.50-9.24 and ORHeart=8.67, 95%CI=2.62-28.63; and aORHead&Brain=1.77, 95%CI=0.68-4.64 and ORHead&Brain=6.50, 95%CI=1.47-28.80; vs. TDS and TDP, respectively). ASD fetuses were characterized by a narrower head and a relatively wider ocular-distance vs. TDP fetuses (ORBPD=0.81, 95%CI=0.70-0.94, and aOROcular-Distance=1.29, 95%CI=1.06-1.57). Finally, UFAs were associated with more severe ASD symptoms.ConclusionsOur findings shed important light on the abnormal multiorgan embryonic development of ASD and suggest fetal ultrasonography biomarkers for ASD.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Association Between Ultrasonography Fetal Anomalies and Autism Spectrum Disorder

Regev

Hadar

Meiri

et al. 2021

Preprint

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“…Derangements in maternal one-carbon metabolism are associated with childhood behaviour and cognition problems and to psychosis and ASD later in life [22]. Atypical foetal brain growth patterns are considered an early biomarker for learning or behaviour difficulties, as children with ASD and language impairment exhibit reduced HC growth patterns prenatally followed by catch-up growth postnatally [60][61][62][63]. Currently, the most common measurement of foetal brain growth is HC at birth, which is acknowledged as a non-invasive marker for brain volume and growth in a clinical setting [64].…”

Section: Discussionmentioning

confidence: 99%

Maternal One-Carbon Metabolism during the Periconceptional Period and Human Foetal Brain Growth: A Systematic Review

Rubini

Baijens

Horánszky

et al. 2021

Genes

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The maternal environment during the periconceptional period influences foetal growth and development, in part, via epigenetic mechanisms moderated by one-carbon metabolic pathways. During embryonic development, one-carbon metabolism is involved in brain development and neural programming. Derangements in one-carbon metabolism increase (i) the short-term risk of embryonic neural tube-related defects and (ii) long-term childhood behaviour, cognition, and autism spectrum disorders. Here we investigate the association between maternal one-carbon metabolism and foetal and neonatal brain growth and development. Database searching resulted in 26 articles eligible for inclusion. Maternal vitamin B6, vitamin B12, homocysteine, and choline were not associated with foetal and/or neonatal head growth. First-trimester maternal plasma folate within the normal range (> 17 nmol/L) associated with increased foetal head size and head growth, and high erythrocyte folate (1538–1813 nmol/L) with increased cerebellar growth, whereas folate deficiency (< 7 nmol/L) associated with a reduced foetal brain volume. Preconceptional folic acid supplement use and specific dietary patterns (associated with increased B vitamins and low homocysteine) increased foetal head size. Although early pregnancy maternal folate appears to be the most independent predictor of foetal brain growth, there is insufficient data to confirm the link between maternal folate and offspring risks for neurodevelopmental diseases.

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Association between ultrasonography foetal anomalies and autism spectrum disorder

Regev

Hadar

Meiri

et al. 2022

Brain

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Multiple evidence support the prenatal predisposition of autism spectrum disorder (ASD). Nevertheless, robust data about abnormalities in fetuses later developing into children diagnosed with ASD are lacking. Prenatal ultrasound is an excellent tool to study abnormal fetal development as it frequently used to monitor fetal growth and identify fetal anomalies throughout pregnancy. We conducted a retrospective case-sibling-control study of children diagnosed with ASD (cases); their own typically developing, closest-in-age siblings (TDS); and typically developing children from the general population (TDP), matched by year of birth, sex and ethnicity to investigate the association between ultrasonography fetal anomalies (UFAs) and ASD. The case group was drawn from all children diagnosed with ASD enrolled at the Azrieli National Center of Autism and Neurodevelopment Research. Fetal ultrasound data from the fetal anatomy survey were obtained from prenatal ultrasound clinics of Clalit Health Services (CHS) in southern Israel. The study comprised 659 children: 229 ASD, 201 TDS, and 229 TDP. UFAs were found in 29.3% of ASD cases vs. only 15.9% and 9.6% in the TDS and TDP groups (aOR = 2.23, 95%CI = 1.32-3.78, and aOR = 3.50, 95%CI = 2.07-5.91, respectively). Multiple co-occurring UFAs were significantly more prevalent among ASD cases. UFAs in the urinary system, heart, and head&brain were the most significantly associated with ASD diagnosis (aORUrinary =2.08, 95%CI = 0.96-4.50 and aORUrinary = 2.90, 95%CI = 1.41-5.95; aORHeart = 3.72, 95%CI = 1.50-9.24 and aORHeart = 8.67, 95%CI = 2.62-28.63; and aORHead&Brain = 1.96, 95%CI = 0.72-5.30 and aORHead&Brain = 4.67, 95%CI = 1.34-16.24; vs. TDS and TDP, respectively). ASD females had significantly more UFAs than ASD males (43.1% vs. 25.3%, p = 0.013) and a higher prevalence of multiple co-occurring UFAs (15.7% vs. 4.5%, p = 0.011). No sex differences were seen among TDS and TDP controls. ASD fetuses were characterized by a narrower head and a relatively wider ocular-distance vs. TDP fetuses (ORBPD = 0.81, 95%CI = 0.70-0.94, and aOROcular-Distance = 1.29, 95%CI = 1.06-1.57). UFAs were associated with more severe ASD symptoms. Our findings shed important light on the abnormal multiorgan embryonic development of ASD and suggest fetal ultrasonography biomarkers for ASD.

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Association Between Abnormal Fetal Head Growth and Autism Spectrum Disorder

Cited by 7 publications

References 60 publications

Association Between Ultrasonography Fetal Anomalies and Autism Spectrum Disorder

Association Between Ultrasonography Fetal Anomalies and Autism Spectrum Disorder

Maternal One-Carbon Metabolism during the Periconceptional Period and Human Foetal Brain Growth: A Systematic Review

Association between ultrasonography foetal anomalies and autism spectrum disorder

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