An analysis of studies found that women who used the common pain reliever acetaminophen when pregnant were about 20% more likely to have kids who developed symptoms of attention deficit hyperactivity disorder or autism spectrum conditions.
Researchers, who published their results Thursday in the European Journal of Epidemiology, analyzed 73,881 mother-child pairs from six European studies. The findings are in line with other meta-analyses that found prenatal exposure to acetaminophen was associated with ADHD or autism symptoms, but the new meta-analysis collated data from studies with similar methodology to gain a clearer picture of the link between neurological conditions in both girls and boys and prenatal and postnatal exposure to this pain reliever.
"They share some features, although each disorder has its own features," said Silvia Alemany, lead author of the study and a postdoctoral researcher at Vall d'Hebron Research Institute, who did this work at the Barcelona Institute for Global Health. "Autism or autism spectrum conditions are characterized by difficulties in communication and social interaction and also by repetitive behaviors and restricted range of interests, while attention deficit hyperactivity disorder is characterized by difficulties in maintaining attention and also issues with control of impulsivity."
Exactly what causes these neurological conditions is not entirely clear, but Alemany said that there is a strong genetic component. Research also suggests maternal factors during pregnancy — such as diabetes, obesity, hypertension and stress — are risk factors for these conditions. Exposure to certain chemicals or drugs during pregnancy has also been linked with the development of autism in children.
Acetaminophen, also called paracetamol, is a widely used analgesic for the treatment of headaches, fever and other aches and pains. With brand names such as Tylenol and Panadol, this over-the-counter drug is considered to be one of the safest pain relievers for pregnant women, but several studies and two recent meta-analyses found links between prenatal exposure to acetaminophen and the development of ADHD and autism.
However, according to Alemany, other researchers criticized these meta-analyses because they pulled together results from studies that used different ways of measuring exposure to acetaminophen and different definitions of ADHD and autism traits, potentially muddying the results.
With the goal of overcoming these limitations, Alemany and her colleagues analyzed studies with similar methodologies. They gathered data from six birth cohort studies from England, Italy, Spain, Denmark, Greece and the Netherlands, which followed thousands of mothers and children from before birth until childhood or later.
The studies assessed exposure to acetaminophen through questionnaires or interviews with the mothers. The researchers defined prenatal exposure as the result of moms taking any dose of acetaminophen at any point of pregnancy, while postnatal exposure referred to kids being given the drug during the first 18 months of life.
The studies used validated questionnaires to screen children for ADHD and autism on a numerical scale. Because both conditions exist on a spectrum, Alemany and her colleagues defined ADHD and autism symptoms as values that met the cutoff for a clinical diagnosis as well as those that fell near the borderline of this cutoff.
The analysis showed that children who were exposed to acetaminophen in the womb were 19% more likely to develop autism symptoms and 21% more likely to develop ADHD symptoms compared with youngsters whose moms didn't take the drug while pregnant.
Research suggests that the brains of male and female autistic children differ, highlighting the importance of considering sex and gender in autism research. The new meta-analysis found that prenatal exposure to acetaminophen was associated with the development of autism or ADHD symptoms in both girls and boys, although the link was slightly stronger for boys.
The researchers noted that their findings were consistent across the different cohort studies included in the analysis, which they said supports the conclusion that acetaminophen is a risk factor for autism and ADHD.
Exactly how the pain reliever could impact a child's brain development is not established, but Alemany says that there are plausible hypotheses.
"We have evidence that acetaminophen can make changes in some proteins that are relevant for neurological development, such as a brain-derived neurotrophic factor, which is a really important protein for neurodevelopment," Alemany told The Academic Times.
Other hypotheses are that acetaminophen alters neurotransmission or endocrine pathways or causes oxidative stress by modulating inflammation processes, she added.
There was no difference in the likelihood of developing either neurological condition between children who took acetaminophen during their first 18 months of life and those who did not, suggesting that postnatal exposure is not a risk factor for ADHD and autism.
The researchers stopped short of recommending that pregnant women avoid acetaminophen if they need it.
"It's important to take paracetamol if a health professional is recommending that," Alemany said. "But maybe it should be revised in the way it is being used." For example, it may be important to understand how people are using this drug and establish when it's necessary to take.
"We are not saying that people are not using it correctly or anyone can develop the disorder just because the mother takes it," she continued.
Autism and ADHD are complex, with multiple factors that likely contribute to the development of the conditions.
"There are genetic factors, there are environmental factors, and probably these factors interact with each other, so exposure to paracetamol may be only a risk factor in certain circumstances, and it's not likely to be an explanation for the occurrence of the symptoms by itself," Alemany said.
More research is needed to establish whether the dose or timing of acetaminophen use during pregnancy makes a difference to the risk of developing ADHD or autism. The researchers considered only whether the mother took the drug — yes or no — at any time while pregnant.
"We are not addressing the timing of exposure, so we can't tell whether exposure during the first trimester or the second or the third may have a stronger association," she said. "We are also not addressing dose-response relationships, so that's also a limitation of our study."
The study, "Prenatal and postnatal exposure to acetaminophen in relation to autism spectrum and attention‑deficit and hyperactivity symptoms in childhood: meta‑analysis in six European population‑based cohorts," published May 27 in European Journal of Epidemiology, was authored by Silvia Alemany, Raquel García‑Esteban and Maribel Casas, ISGlobal, Barcelona Institute for Global Health, Universitat Pompeu Fabra (UPF) and CIBER Epidemiology and Public Health (CIBERESP); Claudia Avella‑García, ISGlobal, Barcelona Institute for Global Health, Universitat Pompeu Fabra (UPF), CIBER Epidemiology and Public Health (CIBERESP) and Hospital Sagrat Cor, Martorell; Zeyan Liew, Yale School of Public Health; Kosuke Inoue, University of California, Los Angeles; Tim Cadman, University of Bristol and Bristol Medical School; Mònica López‑Vicente, Erasmus MC–Sophia; Llúcia González, CIBER Epidemiology and Public Health (CIBERESP) and FISABIO-Universitat Jaume I-Universitat de Valencia; Isolina Riaño Galán, CIBER Epidemiology and Public Health (CIBERESP) and University of Oviedo and ISPA; Ainara Andiarena, University of the Basque Country and Health Research Institute, Biodonostia; Katerina Margetaki, University of Crete; Katrine Strandberg‑Larsen, University of Copenhagen; Deborah A. Lawlor, University of Bristol, Bristol Medical School and Bristol NIHR Biomedical Research Centre; Hanan El Marroun, Erasmus MC–Sophia, University Medical Center Rotterdam and Erasmus University Rotterdam; Henning Tiemeier, Erasmus MC–Sophia and Harvard TH Chan School of Public Health; Carmen Iñiguez, Universitat de Valencia, CIBER Epidemiology and Public Health (CIBERESP) and FISABIO-Universitat Jaume I-Universitat de Valencia; Adonina Tardón, CIBER Epidemiology and Public Health (CIBERESP) and University of Oviedo; Loreto Santa‑Marina, CIBER Epidemiology and Public Health (CIBERESP), Health Research Institute, Biodonostia and Basque Government; Jordi Júlvez, ISGlobal, Barcelona Institute for Global Health, Universitat Pompeu Fabra (UPF), CIBER Epidemiology and Public Health (CIBERESP) and Hospital Universitari Sant Joan de Reus; Daniela Porta, Lazio Regional Health Service; Leda Chatzi, University of Southern California; and Jordi Sunyer, ISGlobal, Barcelona Institute for Global Health, Universitat Pompeu Fabra (UPF), CIBER Epidemiology and Public Health (CIBERESP) and IMIM (Hospital del Mar Medical Research Institute).