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. 2022 Apr 7;12(1):148.
doi: 10.1038/s41398-022-01907-z.

Maternal levels of acute phase proteins in early pregnancy and risk of autism spectrum disorders in offspring

Martin Brynge  1 , Renee Gardner  2 , Hugo Sjöqvist  2 , Håkan Karlsson #  3 , Christina Dalman #  2   4
Affiliations

Maternal levels of acute phase proteins in early pregnancy and risk of autism spectrum disorders in offspring

Martin Brynge et al. Transl Psychiatry. .

Abstract

Previous research supports a contribution of early-life immune disturbances in the etiology of autism spectrum disorders (ASD). Biomarker studies of the maternal innate (non-adaptive) immune status related to ASD risk have focused on one of the acute phase proteins (APP), C-reactive protein (CRP), with conflicting results. We evaluated levels of eight different APP in first-trimester maternal serum samples, from 318 mothers to ASD cases and 429 mothers to ASD-unaffected controls, nested within the register-based Stockholm Youth Cohort. While no overall associations between high levels of APP and ASD were observed, associations varied across diagnostic sub-groups based on co-occurring conditions. Maternal levels of CRP in the lowest compared to the middle tertile were associated with increased risk of ASD without ID or ADHD in offspring (OR = 1.92, 95% CI 1.08-3.42). Further, levels of maternal ferritin in the lowest (OR = 1.78, 95% CI 1.18-2.69) and highest (OR = 1.64, 95% CI 1.11-2.43) tertiles were associated with increased risk of any ASD diagnosis in offspring, with stronger associations still between the lowest (OR = 3.81, 95% CI 1.91-7.58) and highest (OR = 3.36, 95% CI 1.73-6.53) tertiles of ferritin and risk of ASD with ID. The biological interpretation of lower CRP levels among mothers to ASD cases is not clear but might be related to the function of the maternal innate immune system. The finding of aberrant levels of ferritin conferring risk of ASD-phenotypes indicates a plausibly important role of iron during neurodevelopment.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Heat map showing the mean maternal APP z-score by categories of the covariates, among mothers to 429 unaffected individuals in the cohort.
Solid boxes indicate that the APP is associated with the covariate at p < 0.05. Dashed boxes indicate that the APP is associated with the covariate at p < 0.20. Abbreviations: A2M α-2 macroglobulin, CRP C-reactive protein, FER ferritin, FIB fibrinogen, PCT procalcitonin, SAA serum amyloid A, SAP serum amyloid P, tPA tissue plasminogen activator, Psych Psychiatric, BMI body mass index, Income Q income quintile.
Fig. 2
Fig. 2. The relationship between maternal APP measured prenatally and odds of ASD, stratified by co-occurrence of ID and ADHD, when comparing mothers of 318 ASD cases to mothers of 429 unaffected individuals selected from the cohort.
Tertiles of each APP were created using the distribution of z-scores among unaffected individuals to set the cut-offs, and the middle quintile was used as the referent category. Models were adjusted for sex, birth order, maternal BMI, maternal psychiatric history, maternal region of origin, maternal age and family income quintile. Error bars represent the 95% confidence interval for the fully adjusted model. P values are shown for a Wald test with a null hypothesis that all APP categorical terms were jointly equal to zero, as a test of whether each APP was generally associated with the outcome. Abbreviations: A2M α-2 macroglobulin, CRP C-reactive protein, FER ferritin, FIB fibrinogen, PCT procalcitonin, SAA serum amyloid A, SAP serum amyloid P, tPA tissue plasminogen activator.
Fig. 3
Fig. 3. The relationship between maternal APP measured prenatally and odds of ASD with ID when comparing mothers of 101 individuals affected by ASD with ID to mothers of 429 unaffected individuals selected from the cohort.
Each panel displays the odds of ASD with ID according to APP z-score, flexibly fit using restricted cubic spline models with three knots and a z-score = 0 as the referent. The dashed line represents the unadjusted estimate of the relationship between each APP and odds of ASD with ID. The solid line represents the fully adjusted model, adjusted for sex, birth order, maternal BMI, maternal psychiatric history, maternal region of origin, maternal age and family income quintile. The gray bands represent the 95% confidence interval for the fully adjusted model. P values are shown for a Wald test with a null hypothesis that all APP spline terms were jointly equal to zero, as a test of whether each APP was generally associated with the outcome. Abbreviations: A2M α-2 macroglobulin, CRP C-reactive protein, FER ferritin, FIB fibrinogen, PCT procalcitonin, SAA serum amyloid A, SAP serum amyloid P, tPA tissue plasminogen activator.
Fig. 4
Fig. 4. The relationship between maternal APP and odds of ASD without co-occurring ID or ADHD when comparing mothers of 100 individuals affected by ASD without co-occurring ID or ADHD to mothers of 429 unaffected individuals selected from the cohort.
Each panel displays the odds of ASD without co-occurring ID or ADHD according to APP z-score, flexibly fit using restricted cubic spline models with three knots and a z-score = 0 as the referent. The dashed line represents the unadjusted estimate of the relationship between each APP and odds of ASD without co-occurring ID or ADHD. The solid line represents the fully adjusted model, adjusted for sex, birth order, maternal BMI, maternal psychiatric history, maternal region of origin, maternal age and family income quintile. The gray bands represent the 95% confidence interval for the fully adjusted model. P values are shown for a Wald test with a null hypothesis that all APP spline terms were jointly equal to zero, as a test of whether each APP was generally associated with the outcome. Abbreviations: A2M α-2 macroglobulin, CRP C-reactive protein, FER ferritin, FIB fibrinogen, PCT procalcitonin, SAA serum amyloid A, SAP serum amyloid P, and tPA tissue plasminogen activator.
Fig. 5
Fig. 5. The relationship between maternal APP and odds of ASD with co-occurring ADHD when comparing mothers of 117 individuals affected by ASD with co-occurring ADHD to mothers of 429 unaffected individuals selected from the cohort.
Each panel displays the odds of ASD with co-occurring ADHD according to APP z-score, flexibly fit using restricted cubic spline models with three knots and a z-score = 0 as the referent. The dashed line represents the unadjusted estimate of the relationship between each APP and odds of ASD with co-occurring ADHD. The solid line represents the fully adjusted model, adjusted for sex, birth order, maternal BMI, maternal psychiatric history, maternal region of origin, maternal age and family income quintile. The gray bands represent the 95% confidence interval for the fully adjusted model. P values are shown for a Wald test with a null hypothesis that all APP spline terms were jointly equal to zero, as a test of whether each APP was generally associated with the outcome. Abbreviations: A2M α-2 macroglobulin, CRP C-reactive protein, FER ferritin, FIB fibrinogen, PCT procalcitonin, SAA serum amyloid A, SAP serum amyloid P, tPA tissue plasminogen activator.
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References

    1. Lyall K, Croen L, Daniels J, Fallin MD, Ladd-Acosta C, Lee BK, et al. The changing epidemiology of autism spectrum disorders. Annu Rev Public Health. 2017;38:81–102. - PMC - PubMed
    1. Lord C, Elsabbagh M, Baird G, Veenstra-Vanderweele J. Autism spectrum disorder. Lancet. 2018;392:508–20. - PMC - PubMed
    1. Lai MC, Kassee C, Besney R, Bonato S, Hull L, Mandy W, et al. Prevalence of co-occurring mental health diagnoses in the autism population: a systematic review and meta-analysis. Lancet Psychiatry. 2019;6:819–29. - PubMed
    1. Xie S, Karlsson H, Dalman C, Widman L, Rai D, Gardner RM, et al. The familial risk of autism spectrum disorder with and without intellectual disability. Autism Res. 2020;13:2242-2250. - PMC - PubMed
    1. LaBianca S, Brikell I, Helenius D, Loughnan R, Mefford J, Palmer CE, et al. Polygenic profiles define aspects of clinical heterogeneity in ADHD. 2021. https://www.medrxiv.org/content/10.1101/2021.07.13.21260299v1. - DOI - PubMed

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