From 1998 to 2008, more than 90,000 prospective mothers in Norway volunteered to join a nationwide investigation into the role of genes and environmental exposures in health and disease. We and other authors led the Autism Birth Cohort, the first and largest study in this effort.
We collected information on health, nutrition and environment from mothers of more than 114,000 children during the 17th and 30th week of pregnancy. We then tracked their children for an autism diagnosis with questionnaires at ages 3 and 7 years and by using a nationwide registry.
Blood was collected from mothers at their first prenatal visit in the 17th-21st week of pregnancy and on the day of birth. Cord blood was collected from the child on the day of birth. Our goal in collecting information and samples before autism diagnosis was to ensure that findings would be accurate and not influenced by retrospective bias.
What did we find? First, that blood samples from mothers of children who received an autism diagnosis had evidence of significant differences in levels of molecules associated with immune and brain function as early as the 17th week of pregnancy.
Second, women who have fever during the second trimester of pregnancy were at higher risk for having children with autism. And, that this risk was reduced when mothers with fever take paracetamol (acetaminophen). Fever was frequently accompanied by evidence in the mother’s blood of inflammation and infection with influenza virus or herpes viruses.
Third, folate supplements taken early in pregnancy — preferably prior to conception, in fact — reduced the risk of autism.
When we began the Autism Birth Cohort study, the reported frequency of autism was 1 in 150 children. By the time we published our final report in 2023, it had increased to 1 in 31. This statistic seems alarming and has been used to suggest a new environmental trigger. However, there was no dramatic increase in the number of children with severe disability. The increase was due to changes in the criteria for an autism diagnosis.
What, then, causes autism? Genes clearly play a part. Pairs of identical and fraternal twins both share the same wombs; however, when at least one twin has autism, identical twins are far more likely to share it than are fraternal twins. This does not exclude an environmental factor — it may be that some genes make some mothers or children more sensitive to their environment.
Researchers already have clues to follow up. For example, our results and others suggest that some mothers may need more folate in early pregnancy. Advanced paternal age is also a risk factor in autism, just as maternal age is a risk factor in Down syndrome. Some drugs, such as the seizure medication Valproate, are associated with increased risk.
What is clear is that the Measles, Mumps and Rubella Vaccine and the vaccine preservative thimerosal are not causal factors. One of us directed a trial in which the team that implicated MMR in autism in 1998 could not reproduce its own findings when given new unlabeled samples for analysis. There is another compelling reason: Even after thimerosal was eliminated from childhood vaccines in 2001, rates of autism diagnosis continued to climb. Thus, thimerosal cannot be implicated.
Although many people with autism can lead fulfilling lives, more than one in four with the diagnosis — over 1 million people in the U.S. — have what is called profound autism. These are intellectually impaired, cannot communicate and require constant, lifelong care. In addition to the personal toll this takes on them and their families, the annual cost to the economy of the U.S. alone is estimated at $450 billion.
One of the earliest theories about the causes of autism implicated emotionally distant “refrigerator mothers.” This has been conclusively disproven. Nonetheless, sadly, the notion that mothers are responsible has again come to the fore.
Paracetamol overdosing can cause liver damage. But eliminating this drug won’t eliminate autism. It will only eliminate one of the few medicines that prospective mothers can safely take during pregnancy and engender guilt in those who do.
If there is a silver lining to this controversy it is the welcome focus on autism research and treatment. We are eager to see that focus translate into resources to address this urgent challenge in medicine and public health.
W. Ian Lipkin, MD, is director of the Center for Infection and Immunity at Columbia University Mailman School of Public Health and the John Snow Professor of Epidemiology, Neurology, Pathology and Cell Biology. Ezra Susser, MD, is a professor of Epidemiology at Columbia University Mailman School of Public Health, director of the Psychiatric Epidemiology Training program and professor of Psychiatry at Columbia University’s Irving Medical Center.
Camilla Stoltenberg, MD, Ph.D., is director-general of the Norwegian Institute of Public Health.
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