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Acetaminophen In Pregnancy: Risks Intellectual Disability In Children
Highlights:Numerous studies by physicians and clinicians indicate that the use of acetaminophen (paracetamol) during pregnancy could potentially elevate the chances of neurodevelopmental disorders in offspring. Hence, they advise that pregnant women should avoid using acetaminophen unless there is a medical need for it.
However, these discussions could be biased due to other factors like parental health and genetics, as neurodevelopmental disorders are known to be hereditary disorders. This may confuse that the neurodevelopmental disorder is due to acetaminophen.
The other factor could be the use of other medications during pregnancy; these medications too could have caused neurodevelopmental disorders.
The earlier studies had also been constrained by small sample sizes, resulting in varying and imprecise calculations (2✔ ✔Trusted SourceFDA Drug Safety Communication: FDA has reviewed possible risks of pain medicine use during pregnancy
Go to source).
Recently, a study was published in the journal JAMA (Journal of the American Medical Association), on 09 April, 2024, discussing the potential risk of acetaminophen on neurodevelopmental disorders in children.
The study aimed to examine the utilization of acetaminophen in pregnant women and its potential correlation with autism, ADHD (attention deficit hyperactivity disorder), and intellectual disability in children.
The study on matched full sibling pairs revealed no indication of heightened risk of autism (hazard ratio, 0.98), ADHD (hazard ratio, 0.98), or intellectual disability (hazard ratio, 1.01) linked to acetaminophen consumption.
'Did You Know?Autism is a common developmental disorder in the United States, impacting 1 out of every 44 children at the age of 8. The prevalence of ADHD is also increasing, impacting 9.4% of children between the ages of 2 and 17. #acetaminophen #pregnancy #neurologicaldisorders #medindia'Advertisement
Details of the Study The research study was a population-based, nationwide study, involving a large sample size of almost 2.5 million children in Sweden. The clinical diagnoses related to neurodevelopmental disorders were considered, along with sibling comparisons to address any hidden familial variables that could impact the results.The research considered every individual live born child in Sweden from July 1, 1995, to December 31, 2019, who possessed a personal identifier that could be linked (N = 2 489 721) and was followed up until December 31, 2021.
Children were monitored from birth, utilizing the child's age as the chronological reference, until the earliest occurrence of a neurodevelopmental disorder diagnosis, death, relocation, or conclusion of the monitoring period.
The primary outcomes were neurological disorders like autism, ADHD, and intellectual disability diagnoses identified using the International Classification of Diseases (ICD) codes from the National Patient Register.
The study was conducted on two groups, and statistical data was generated. The first group included single children (without sibling control) and the other group comprised of fully matched sibling pairs (3✔ ✔Trusted SourcePregnancy: Does Too Much Acetaminophen Heighten Risk for Autism or ADHD?
Go to source).
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Outcome of the Study A total of 185,909 children (7.49%) were subjected to acetaminophen while in the womb.The data generated in this study:
The findings of this study indicate that there is no link between the use of acetaminophen during pregnancy and the risk of autism, ADHD, or intellectual disability in children, as determined through sibling control analysis.
These results suggest that the slight rise in the likelihood of neurodevelopmental disorders in children linked to the usage of acetaminophen, as observed in statistical models without sibling control, might have been caused by factors that were not accounted for.
The findings of this investigation suggest that there is no causal link between the usage of acetaminophen during pregnancy and the occurrence of neurodevelopmental disorders.
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Constraints of the Study Despite the strengths of this study, such as a large, nationally representative sample, thorough confounding control, and systematic, prospective recording of acetaminophen use and clinical diagnoses of neurodevelopmental disorders, there were still some constraints.Although the diagnosis of autism condition was confirmed, the other two conditions, ADHD and intellectual disability were not authenticated
Furthermore, the assessment of exposure was not flawless. The antenatal information available in the Medical Birth Register merely indicated whether the birthing parent had used acetaminophen, without considering the specific dosage, duration, or timing.
Besides, the records of dispensing as per prescription may not accurately reflect the over-the-counter usage of acetaminophen.
US FDA Communication on Acetaminophen The potential risks associated with the use of pain medication during pregnancy have also been thoroughly evaluated by the FDA.The FDA recognizes the safety concerns surrounding prescription and over-the-counter (OTC) pain medications when used during pregnancy. Studies on this matter are scarce, leading the FDA to abstain from issuing precise recommendations solely relying on these studies.
It is crucial for pregnant women to seek guidance from their healthcare provider prior to consuming any prescription or over-the-counter medication. Furthermore, women who are contemplating pregnancy and are currently taking pain medication should also consult their healthcare professionals to evaluate the potential risks and advantages associated with the use of such medication. Healthcare professionals must adhere to the guidelines provided in the drug labels when prescribing pain medication to pregnant patients.
References:
Acetaminophen May Not Be As Safe For Heart Health As Previously Thought
Acetaminophen — the active ingredient in Tylenol — is a widely used over-the-counter (OTC) medication used for the treatment of mild to moderate pain, as well as for fever reduction.
Past studies show that in people with heart disease, acetaminophen is the preferred pain treatment over other types of pain medications like aspirin and ibuprofen, which are known as nonsteroidal anti-inflammatory drugs (NSAIDs).
A new study presented during the annual meeting of the American Physiological Society April 4–7 has discovered — using a mouse model — that acetaminophen changes proteins in the heart tissue.
These implications could potentially affect biochemical pathways needed for functions like energy production and antioxidant use.
For this study, researchers used a mouse model to study the effects of acetaminophen on heart tissue.
Some mice were given plain water, while others were administered water containing an amount of acetaminophen equivalent to 500 mg — the concentration found in one tablet of extra-strength Tylenol.
After seven days, researchers found significant changes in the heart tissue proteins of the mice given acetaminophen compared to the mice that only had water.
These protein alterations were associated with biochemical pathways responsible for many functions, including energy production, antioxidant usage, and the breakdown of damaged proteins.
The scientists found more than 20 different signaling pathways affected by the protein changes.
"We were surprised by the findings since we predicted that acetaminophen, when used at these concentrations, would have minimal effects on the heart," Gabriela Del Toro Rivera, a doctoral student in the laboratory of Aldrin Gomes, PhD, at the University of California, Davis, and the first author of this study, told Medical News Today.
"While existing literature primarily associates acetaminophen overuse with liver damage, our research suggests that acetaminophen may influence tissues beyond the liver."
Historically, acetaminophen has been the safest pain reliever for people with cardiovascular disease.
A study published in March 2015 found the use of acetaminophen was not linked to a higher risk of stroke, myocardial infarction, or any cardiovascular event.
Other recent studies have evaluated the safety of acetaminophen in people with heart disease.
Research published in 2022 found the use of sodium-containing acetaminophen as associated with increased risk for cardiovascular disease and all-cause mortality in people with or without high blood pressure.
Another 2022 study reported that regularly taking 4 grams of acetaminophen each day increased systolic blood pressure in people with high blood pressure, potentially increasing their heart disease risk.
"Since acetaminophen is one of the most commonly used over-the-counter drugs worldwide, gaining a better understanding of how acetaminophen may affect the heart is essential for improving patient safety, optimizing treatment decisions, managing comorbidities, and guiding future research and development efforts," Del Toro Rivera said.
"Findings regarding acetaminophen's effects on the heart have the potential to enhance doctor-patient communication by enabling more personalized recommendations, informed decision-making, and proactive management of potential risks associated with its use. Utilizing acetaminophen for the shortest duration and at the lowest effective dosage appropriate for an individual's ailment is likely advisable."
— Gabriela Del Toro Rivera, first study author
While both acetaminophen and NSAIDs assist with pain relief, NSAIDs also help lower inflammation, which acetaminophen does not do.
Past studies show that NSAID use is associated with an increased risk for several cardiovascular concerns, including:
"Non-steroidal anti-inflammatory drugs, such as naproxen, ibuprofen, and diclofenac, are associated with an increased risk of stroke, and our research suggests that these commonly used drugs alter signaling pathways and cause mitochondrial dysfunction in mouse hearts," Del Toro Rivera said.
"To determine if the anti-inflammatory properties of NSAIDs were responsible for the changes observed in mouse hearts from mice treated with NSAIDs, we investigated the impact of acetaminophen on proteins in heart tissue," she continued.
"Since acetaminophen is commonly used and does not contain anti-inflammatory properties, the effects on the heart that would be observed would not be due to anti-inflammatory results."
After reviewing this research, Cheng-Han Chen, MD, a board certified interventional cardiologist and medical director of the Structural Heart Program at MemorialCare Saddleback Medical Center in Laguna Hills, CA, told MNT he was surprised by the findings.
"We typically recommend acetaminophen as a medicine that people can take for pain that should not have any harm to the heart," Chen explained.
"(With) NSAIDs, we do worry about its effects such as increased risk of clotting and increasing blood pressure. Typically, we recommend (that) our heart patients take acetaminophen instead since most of our studies show that it does not have a harmful effect on the heart. With so many patients taking acetaminophen, It would definitely be important to know whether it has effects that we don't know about."
— Cheng-Han Chen, MD, cardiologist
MNT spoke with Rigved Tadwalkar, MD, a board certified consultant cardiologist at Providence Saint John's Health Center in Santa Monica, CA, about the study.
Tadwalkar said he was concerned and cautious about the implications of the study findings.
"The findings indicate that even at moderate doses considered safe for use, acetaminophen may have significant effects on signaling pathways within the heart tissue," Tadwalkar said.
"This suggests that the commonly used painkiller might not be as benign as previously thought, especially when used regularly over time."
"As a cardiologist, it is particularly troubling given that many of our patients rely on acetaminophen for pain relief, especially considering that other pain medications often pose significant risks," he added. "Understanding the potential risks associated with acetaminophen use underscores the need for increased awareness, in order to make better decisions for patient care."
— Rigved Tadwalkar, MD, cardiologist
Chen said the changes in how the heart responds to acetaminophen in mice show the heart was under more stress.
"It remains to be seen whether this also translates to humans," Chen said. "This mouse research should lead to human studies, probably starting from observational studies, to investigate whether there are cardiac outcome effects from acetaminophen."
Tadwalkar said the next steps for this research should involve further investigation into the mechanisms by which acetaminophen affects the heart and cardiovascular system and whether similar findings can be reproduced in humans.
"This should include studies in human subjects to determine if the findings observed in mice translate to humans," Tadwalkar said.
"It would be valuable to explore whether there are certain subpopulations of patients who may be more susceptible to the cardiac effects of acetaminophen, such as those with preexisting cardiovascular conditions or other comorbidities," he concluded.
No Link Between Acetaminophen Use During Pregnancy And Children's Risk Of Autism, ADHD, And Intellectual Disability, Says Large Sibling Study
In the largest study to date on the subject, researchers found no evidence to support a causal link between acetaminophen use during pregnancy and increased risk of autism, ADHD and intellectual disability in children. The findings, using data from a nationwide cohort of over 2.4 million children born in Sweden, including siblings not exposed to the drug before birth, were published today in the Journal of the American Medical Association (JAMA) from researchers at Drexel's Dornsife School of Public Health and Karolinska Institutetof Sweden.
Advertised as a pain reliever and fever reducer, the generic drug acetaminophen is the active ingredient in Tylenol and is an ingredient in versions of other drugs, such as Theraflu, Excedrin, and Mucinex, among others.
Following each child up to 26 years after birth, the team found a small increased risk of autism, ADHD and intellectual disability in the overall population -- as seen in similar previous studies that reported such a link. However, the authors found no increased risk of any of the conditions when comparing full siblings when one sibling was exposed to acetaminophen while in the uterus before birth and the other sibling was not. Because siblings share a substantial portion of their genetic background, as well as similar exposure to many of the same environmental factors during development, comparing siblings helps to control for these shared factors that are otherwise hard to measure in epidemiological studies, the authors noted.
"Users of acetaminophen differ from non-users in a number of ways and standard statistical analyses without a sibling control can't control for all of the differences," said co-senior author Brian Lee, PhD, an associate professor in Drexel's Dornsife School of Public Health, fellow at the A.J. Drexel Autism Institute, and research affiliate at the Karolinska Institutet. "Sibling comparisons allow us to control for familial characteristics that might explain an apparent relationship between acetaminophen use during pregnancy and risk of neurodevelopmental conditions."
Using data from Sweden's national health and prescription drug registers, the researchers gathered data on medication use throughout pregnancy for births from 1995 to 2019. Only about 7.5% of the study sample -- 185,909 children -- were exposed to acetaminophen during pregnancy. In previous studies, acetaminophen use during pregnancy varied greatly depending on the study setting; a study in Denmark reported 6.2% use while one study in the U.S. Reported 10-fold higher use. Previous studies suggested that many pregnant people, who may benefit from acetaminophen, do not take it for fear of side effects, such as a 2019 study that surveyed 850 pregnant Swedish persons, in which more than 60% considered medication use during early pregnancy to be "probably harmful" or "harmful."
"This study's findings may be welcome news for birthing people who use acetaminophen as a pain or fever management option, since there are few safe alternatives for relief available," said co-senior author Renee M. Gardner, PhD, of Sweden's Karolinska Institutet. "We hope that our results provide reassurance to expectant parents when faced with the sometimes fraught decision of whether to take these medications during pregnancy when suffering from pain or fever."
The authors say all patients should follow the guidance from their physician on whether acetaminophen is safe for them and their future children.
The study authors said that the statistically increased risk of neurodevelopmental disorders in children exposed to acetaminophen in the womb is likely due to other factors.
"Our study and others suggest there are many different health and familial factors that are associated with both acetaminophen use and neurodevelopmental disorders," said Lee. "Genetics likely play a role, but future work to elucidate this mechanism is crucial."
In 2015, the U.S. Food and Drug Administration said that studies on over-the-counter pain medicines "are too limited to make any recommendations," but noted that "severe and persistent pain that is not effectively treated during pregnancy can result in depression, anxiety, and high blood pressure in the mother." A 2021 consensus statement in Nature Reviews Endocrinology by an international group of scientists and clinicians recommended that pregnant individuals "minimize exposure (to acetaminophen) by using the lowest effective dose for the shortest possible time" due to research suggesting that prenatal exposure to the drug could increase the risk of neurodevelopmental and other disorders.
Although the Drexel and Karolinska study used data on prescribed acetaminophen and reports from pregnant people to their midwives during prenatal care and may not capture all over-the-counter use in all patients, the findings represent data from a large representative sample and controls for many other factors that may be linked to neurodevelopmental disorders.
The study was supported by National Institutes of Health's National Institute of Neurological Disorders and Stroke 1R01NS107607. Beyond funding, NIH had no role in carrying out the study or interpretation of its findings. Lee has received consulting fees for literature reviews for law firms, but has provided no expert litigation, and no external parties had any role in the study.
Other than Gardner and Lee, other authors on the paper include shared lead authors Viktor H. Ahlqvist, PhD, and Hugo Sjöqvist, Christina Dalman, MD, PhD, Håkan Karlsson, PhD, Olof Stephansson, MD, PhD, Stefan Johansson, MD, PhD, and Cecilia Magnusson, MD, PhD, all who hold academic appointments at the Karolinska Institutet.
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