Prenatal Exposure to Acetaminophen Linked to Childhood Wheezing

Becky McCall

December 16, 2010

December 16, 2010 (Dubai, United Arab Emirates) — The exposure of pregnant women to certain environmental factors is associated with wheezing and asthma in their children.

Speaking here at the World Allergy Organization (WAO) 2010 International Scientific Conference, Harold Nelson, MD, professor of medicine at National Jewish Health in Denver, Colorado, discussed the environmental factors that trigger epigenetic changes in the fetus, but which might not manifest until the children are 3 to 5 years of age, or even older.

"The children's genotypes are changed so that if they run into the appropriate environmental factors when they are older, they may be susceptible to wheezing or asthma," he told Medscape Medical News.

Factors that might present a risk to the developing fetus include acetaminophen, maternal vitamin D deficiency, domestic spray chemicals, tobacco smoke, and maternal use of antibiotics.

"How can something that happens in the uterus have an impact on asthma in the child aged 6, 7, or 8? The explanation, if it is causal, is in epigenetic mechanisms," Dr. Nelson explained. "Early environmental exposure in utero plays a key role in activating and altering genes through histone methylation and acetylation of DNA, and alteration of chromatin structure. Once these have occurred in the fetus, they will be replicated throughout the infant's life, and may even be passed to subsequent generations."

Low intake of vitamin D by the mother might be associated with epigenetic changes in the fetus. Dr. Nelson added that low levels of vitamin D are a major problem in people in temperate regions of the globe. "By contrast, the Mediterranean diet, which is rich in oily fish, dairy, and produce, has been reported to be protective against asthma during pregnancy."

"This isn't the severe rickets-causing deficiency, but rather insufficient levels of the vitamin," Dr. Nelson pointed out. He said that insufficient vitamin D is linked to dysfunctional T cell regulation, with a lack of downregulation of Th1 and Th2. Vitamin D also interferes with the toll-like receptor signaling associated with bacterial and viral infections, which predisposes the infant to increased respiratory tract infections."

Domestic spray cleaning products have also been associated with epigenetic changes. Dr. Nelson cited European data from adults supporting an association between maternal use of domestic chemicals during pregnancy and wheezing and impaired lung function in children up to 8.5 years of age.

"They showed that exposure was associated with the early onset of persistent asthma, intermediate onset of persistent asthma, and late onset of wheezing. These were only found in nonatopic children," Dr. Nelson reported.

"There were also detriments in pulmonary function. Risk of wheezing at 8.5 years is linked to exposure to domestic chemicals prenatally. We see no relation with intermittent wheezing, which is more related to viral infections," he added.

An increasing number of longitudinal and observational studies have related exposure to acetaminophen in utero to asthma in later childhood.

In the United States, acetaminophen use by pregnant women has increased substantially since the early 1980s, so that the majority of women in the United States take acetaminophen during pregnancy. "Over a similar time period, 1980 to 1995, asthma prevalence among children in the United States doubled," said Dr. Nelson.

Further evidence of an association between acetaminophen use during pregnancy and wheezing in offspring was drawn from the Nurses' Health Study, an investigation of factors influencing women's health in 48,000 American nurses who were followed prospectively for 6 years. Information was gathered on the use of acetaminophen, and this was related to the development of physician-diagnosed asthma.

"Those who used acetaminophen for over half of the days, compared with those who didn't use it at all, had an increase in asthma of 60%" (odds ratio, 1.62) reported Dr. Nelson.

He referred to a recent study conducted by researchers at Columbia University in New York City, who compared total intake of acetaminophen by women during pregnancy with wheezing in children at age 5. They showed a highly significant dose-response relation for those with no exposure, 1 day of exposure, 2 to 4 days of exposure, and more than 5 days of exposure.

The researchers found that 34% of mothers reported acetaminophen use during pregnancy, and 27% of their children had wheezing at 5 years. On analysis, prenatal acetaminophen exposure predicted current wheeze (multivariate relative risk, 1.71; 95% confidence interval, 1.20 to 2.42; P = .003), and the risk was found to increase with increasing number of days of prenatal acetaminophen exposure (P < .001).

It has been suggested that acetaminophen interferes with the glutathione defense mechanism against oxidative stress in the lungs and with T-regulatory cell development, Dr. Nelson noted.

The researchers looked at the glutathione S-transferase Pi (GSTP) polymorphism in the study children and found that the association between acetaminophen exposure and wheezing was limited to children with a polymorphism in the GSTP gene. "Unaffected children have AA alleles, whereas affected children have at least 1 copy of the GSTP1 minor allele (AG or GG)."

Dr. Nelson particularly welcomed this study because it avoided selection bias. "If there was a bias that caused women with a knowledge of [the association] to avoid acetaminophen, there was still no way they would have known about their genetic make-up. I think this study is really clear of selection bias because it only occurred in the two thirds of the participants with the GSTP polymorphism. The one third that didn't have the polymorphism had no risk."

"This is the strongest argument so far that this is real," concluded Dr. Nelson.

Commenting on the study, Richard Lockey, MD, president of the WAO and director of the Division of Allergy and Immunology at James A. Haley Veterans' Hospital in Tampa, Florida, said that Dr. Nelson addressed a very important aspect of medicine. "Probably the most compelling evidence for such an association is with passive smoking, smoking, and with newer information, particularly acetaminophen."

He added that establishing a causal relation is complicated. "Asthma is so complex that I suspect there are many factors that predispose us to develop this disease — our genes, certain prenatal exposures, diet, exposure to certain kinds of infections, cats, dogs, and dust mite exposure in our environment both before and after we are born, among others."

Finally, Dr. Lockey cautioned that it is too soon to conclude that these findings will alter the prevalence of asthma in the near future. "While some avoidance is possible, much more information is necessary about these associations in particular to determine whether we can change the prevalence of asthma by changing what we do during pregnancy and during childhood."

Dr. Nelson and Dr. Lockey have disclosed no relevant financial relationships.

World Allergy Organization (WAO) 2010 International Scientific Conference. Presented December 7, 2010.

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