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. 2024 Feb 10:36:100739.
doi: 10.1016/j.bbih.2024.100739. eCollection 2024 Mar.

Maternal pre-pregnancy and prenatal penicillin, neonatal inflammation and growth factors are associated to ADHD in the offspring

Solveig Holmgaard  1 , Pia Kiilerich  1 , Nis Borbye-Lorenzen  1 , Kristin Skogstrand  1
Affiliations

Maternal pre-pregnancy and prenatal penicillin, neonatal inflammation and growth factors are associated to ADHD in the offspring

Solveig Holmgaard et al. Brain Behav Immun Health. .

Abstract

Background: The etiology for Attention Deficit Hyperactivity Disorder (ADHD) is generally unknown, but both genetics, biology and environment have been shown to increase the risk. The purpose of this study was to explore the prenatal risk factors, especially maternal antibiotics consumed before and during pregnancy, for the offspring for later being diagnosed with ADHD, and to find associations with neonatal biomarkers.

Methods: We included new-borns from the CODIBINE study, 465 children were ADHD cases and 10 954 children were controls. Ten biomarkers reflecting inflammation, neonatal stress, and/or neurologic development or damage were measured in dried blood spot samples drawn 2-3 days after birth. Maternal and child prescriptions of medication, birth data, and disorder codes were included in the statistical analyses.

Results: We found that maternal penicillin prescriptions until 2 years before birth increased the risk for offspring ADHD. The risk was higher with multiple prescriptions, both before and during pregnancy. Cases with maternal penicillin prescriptions had lower neonatal levels of epidermal growth factor (EGF) and soluble Tumor Necrosis Factor Receptor I (sTNF RI). Maternal prescriptions for psychotropic medication have, as expected, the highest correlation to offspring ADHD, but we found no differences in biomarkers in this group.

Conclusion: The fact that the offspring risk for ADHD was increased also with pre-pregnancy prescriptions of penicillin, indicates that it is not the penicillin that is the direct cause of the adverse effects. The significant differences in biomarkers strengthens the findings, as these could not be associated to other factors than maternal penicillin and offspring ADHD.

Keywords: ADHD; CODIBINE; Dried blood spot samples; Inflammation; Penicillin; Prenatal.

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Conflict of interest statement

Solveig Holmgaard: Declarations of interest: none. Pia Kiilerich: Declarations of interest: none. Nis Borbye-Lorenzen: Declarations of interest: none. Kristin Skogstrand: Declarations of interest: none.

Figures

Fig. 1
Fig. 1
An overview of all statistical analyses.
Fig. 2
Fig. 2
The mean probability of ADHD in the offspring for different maternal penicillin prescription groups The error-bars indicate the SE of the mean, the stars indicate significant (p-value<0.05) difference between the group and no maternal penicillin prescribed. The overall p-value describes the overall association between the grouped maternal penicillin prescriptions and ADHD in the child found by the ANCOVA. A: The adjusted mean probability of ADHD in the offspring compared to no maternal penicillin prescriptions, maternal penicillin prescriptions grouped by time relative to pregnancy: Before, during, or both before and during pregnancy. B: The adjusted mean probability of ADHD in the offspring compared to no maternal penicillin prescriptions, maternal penicillin prescriptions grouped by time relative to pregnancy. C: The adjusted mean probability of ADHD in the offspring compared to no maternal penicillin prescriptions.
Fig. 3
Fig. 3
Biomarker levels divided into maternal penicillin prescriptions Adjusted means of the biomarkers for the interaction between ADHD in the offspring and maternal penicillin prescriptions. The error-bars indicate the SE of the mean, the stars indicate significant (p-value<0.05) difference between the ADHD group and the control group within the indicated maternal penicillin prescription group. The interaction p-values describe the overall association between the specific biomarker and the interaction between maternal penicillin prescriptions and ADHD in the offspring.
Fig. 4
Fig. 4
Biomarker levels divided into the number of maternal penicillin prescriptions Adjusted means of the biomarkers for the interaction between ADHD in the child and maternal penicillin prescriptions, prescriptions grouped by the amount of treatments. The error-bars indicate the SE of the mean, the stars indicate significant (p-value<0.05) difference between the ADHD group and the control group within the indicated maternal penicillin prescription group. The interaction p-values describe the overall association between the specific biomarker and the interaction between maternal penicillin prescriptions and ADHD in the offspring.
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