Is There a Causal Relation between Maternal Acetaminophen Administration and ADHD?
OBJECTIVE
Recent epidemiological studies reported an association between maternal intake of acetaminophen (APAP) and attention deficit hyperactivity disorder (ADHD) in their children. However, none of these studies demonstrated causality. Our objective was to determine whether exposure to APAP during pregnancy result in hyperkinetic dysfunctions in offspring, using a murine model.


METHODS
Pregnant CD1 mice (N = 8/group) were allocated to receive by gavage either APAP (150 mg/kg/day, equivalent to the FDA-approved maximum human clinical dose), or 0.5% carboxymethylcellulose (control group), starting on embryonic day 7 until delivery. Maternal serum APAP and alanine transaminase (ALT) concentrations were determined by ELISA and kinetic colorimetric assays, respectively. Open field locomotor activity (LMA) in the 30-day old mouse offspring was quantified using Photobeam Activity System. Mouse offspring were then sacrificed, whole brains processed for magnetic resonance imaging (MRI; 11.7 Tesla magnet) and for neuronal quantification using Nissl stain. The association between APAP exposure and LMA in mouse offspring was analyzed using a mixed effects Poisson regression model that accounted for mouse offspring weight, gender, random selection, and testing time and day. We corrected for multiple comparisons and considered P<0.008 as statistically significant.


RESULTS
Maternal serum APAP concentration peaked 30 minutes after gavage, reaching the expected mean of 117 μg/ml. Serum ALT concentrations were not different between groups. There were no significant differences in vertical (rearing), horizontal, or total locomotor activity between the two rodent offspring groups at the P level fixed to adjust for multiple testing. In addition, no differences were found in volumes of 29 brain areas of interest on MRI or in neuronal quantifications between the two groups.


CONCLUSIONS
This study refutes that hypothesis that prenatal exposure to APAP causes hyperkinetic dysfunction in mouse offspring. Due to lack of accurate assessment of ADHD in murine models, our results should be taken with caution when compared to the reported clinical data.
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Antonio
A
Saad
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Shruti
S
Hegde
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Talar
T
Kechichian
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Phyllis
P
Gamble
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Mahbubur
M
Rahman
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Sonja J
SJ
Stutz
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Noelle C
NC
Anastasio
The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland, United States of America.
Wael
W
Alshehri
Integrated Research Center for Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University, Baltimore, Maryland, United States of America.
Jun
J
Lei
The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland, United States of America.
Susumu
S
Mori
Integrated Research Center for Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University, Baltimore, Maryland, United States of America.
Bridget
B
Kajs
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Kathryn A
KA
Cunningham
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas, United States of America.
George
G
Saade
Integrated Research Center for Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University, Baltimore, Maryland, United States of America.
Irina
I
Burd
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Maged
M
Costantine
D000082:Acetaminophen / Q000009:adverse effects*; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects*; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000503:physiopathology; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000503:physiopathology
D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen