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Association Between Abnormal Fetal Head Growth and Autism Spectrum Disorder

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Objective

Despite evidence for the prenatal onset of abnormal head growth in children with autism spectrum disorder (ASD), studies on fetal ultrasound data in ASD are limited and controversial.

Method

We conducted a longitudinal matched case-sibling−control study on prenatal ultrasound biometric measures of children with ASD, and 2 control groups: (1) their own typically developed sibling (TDS) and (2) typically developed population (TDP). The cohort comprised 528 children (72.7% male), 174 with ASD, 178 TDS, and 176 TDP.

Results

During the second trimester, ASD and TDS fetuses had significantly smaller biparietal diameter (BPD) than TDP fetuses (adjusted odds ratio for the z score of BPD [aORzBPD] = 0.685, 95% CI = 0.527−0.890, and aORzBPD = 0.587, 95% CI = 0.459−0.751, respectively). However, these differences became statistically indistinguishable in the third trimester. Interestingly, head biometric measures varied by sex, with male fetuses having larger heads than female fetuses within and across groups. A linear mixed-effect model assessing the effects of sex and group assignment on fetal longitudinal head growth indicated faster BPD growth in TDS versus both ASD and TDP in male fetuses (β = 0.084 and β = 0.100 respectively; p < .001) but not in female fetuses, suggesting an ASD–sex interaction in head growth during gestation. Finally, fetal head growth showed conflicting correlations with ASD severity in male and female children across different gestation periods, thus further supporting the sex effect on the association between fetal head growth and ASD.

Conclusion

Our findings suggest that abnormal fetal head growth is a familial trait of ASD, which is modulated by sex and is associated with the severity of the disorder. Thus, it could serve as an early biomarker for ASD.

Section snippets

Study Sample

The participants in this case/control study were singletons whose families were members of Clalit Health Services (CHS), Israel’s largest health maintenance organization, serving about 75% of the approximately 700,000 residents of southern Israel, composed of Jews and Bedouins, 2 ethnic groups that differ in their genetic background and environmental exposures. Members of CHS in this region receive most of their hospital-related services (including ASD diagnosis) at the Soroka University

Sociodemographic and Clinical Characteristics

Clinical and sociodemographic characteristics of the study sample are shown in Table 1. As expected, the sex ratio for the TDS group was significantly different from that for the ASD group, close to 1:1 versus 4:1 male/female, respectively (p < .001). In addition, for the TDP group, US scans were performed earlier in the second trimester compared to those for cases (21.4 ± 2.8 versus 22.3 ± 1.8 weeks, respectively; p = .006). No other statistically significant differences were seen between

Discussion

This is the largest and most comprehensive study to date to examine the association between fetal growth parameters and ASD. Three main findings (discussed in detail below) emerged from this study. First, fetuses later diagnosed with ASD and their TDS have narrower heads during mid-gestation compared to TDP, thus suggesting that such fetal head growth abnormality is a familial trait of ASD. Second, ASD-related head growth abnormalities are modulated by the sex of the fetus, with male and female

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  • This study was supported by an Israel Science Foundation grant, 527/15, to Prof. Idan Menashe. This study was conducted as part of the requirements to obtain a degree in medicine from the Joyce and Irving Goldman Medical School, Faculty of Health Sciences, Ben-Gurion University of the Negev.

    This work has been previously posted on a preprint server: https://doi.org/10.1101/2020.08.09.20170811.

    Prof. Menashe and Prof. Norm O'Rourke, PhD, of Ben-Gurion University of the Negev, served as the statistical experts for this research.

    Author Contributions

    Conceptualization: Menashe

    Data curation: Regev, Cohen, Schuster

    Formal analysis: Regev, Cohen, Flusser, Michaelovski, Meiri

    Funding acquisition: Meiri, Menashe

    Investigation: Regev, Cohen, Hadar, Menashe

    Methodology: Regev, Hershkovitch, Menashe

    Project administration: Hadar, Hershkovitch, Menashe

    Resources: Hadar, Schuster, Flusser, Michaelovski, Meiri, Dinstein

    Supervision: Flusser, Michaelovski, Meiri, Dinstein, Hershkovitch, Menashe

    Validation: Regev, Hadar, Flusser, Michaelovski, Meiri, Dinstein, Hershkovitch, Menashe

    Visualization: Regev, Cohen, Hadar, Schuster, Dinstein

    Writing – original draft: Regev

    Writing – review and editing: Menashe

    The authors thank Inez Mureinik, BSc, and Prof. O'Rourke, of Ben-Gurion University of the Negev, for critical reviewing and editing of the manuscript.

    Disclosure: Drs. Hadar, Flusser, Michaelovski, Meiri, Profs. Dinstein, Hershkovitch, and Menashe, Mr. Regev, and Mss. Cohen and Schuster have reported no biomedical financial interests or potential conflicts of interest.

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