Premature Birth Complications: Short and Long-Term Health Effects
New Study Finds No Link Between Autism And Acetaminophen Use During Pregnancy
Countless news cycles have been spent discussing potential causes of autism and other neurodevelopmental disorders, many (most?) of which have historically involved unfairly and unscientifically blaming mothers. Several rounds in more recent years have been dedicated to acetaminophen, a popular fever and pain medication commonly known by the name brand Tylenol in the United States. This has left many parents confused and anxious over the decision to take what is generally considered to be a safe* medication for fever or aches and pains during pregnancy when other options, such as NSAIDS, have potential for causing serious problems.
To be fair, there have been several studies showing a potential link between use of this medication during pregnancy and adverse neurodevelopmental outcomes in children. In 2021, Nature Reviews Endocrinology published a Consensus Statement supported by 91 "scientists, clinicians and public health professionals from across the globe" that called the safety of acetaminophen into question:
We recommend that APAP should be used by pregnant women cautiously at the lowest effective dose for the shortest possible time. Long-term or high-dose use should be limited to indications as advised by a health professional. Packaging should include warning labels including these recommendations. Given the high prevalence of APAP use by pregnant women, the public health implications of use reduction might be substantial.
https://www.Nature.Com/articles/%20s41574-021-00553-7This is a bit more of an aggressive stance than what has been taken by the FDA or the American College of Obstetrics and Gynecology (ACOG). But it isn't as if ACOG has been telling pregnant women to cram handfuls of acetaminophen down their gullets indiscriminately. In fact, here is their response to the Consensus Statement:
ACOG and obstetrician-gynecologists across the country have always identified acetaminophen as one of the only safe pain relievers for pregnant individuals during pregnancy. This consensus statement, and studies that have been conducted in the past, show no clear evidence that proves a direct relationship between the prudent use of acetaminophen during any trimester and fetal developmental issues.
Neurodevelopmental disorders, in particular, are multifactorial and very difficult to associate with a singular cause. The brain does not stop developing until at least 15 months of age, which leaves room for children to be exposed to a number of factors that could potentially lead to these issues.
The authors are not recommending anything counter to what is already done by obstetrician-gynecologists when prescribing acetaminophen for a given clinical condition. ACOG's clinical guidance remains the same and physicians should not change clinical practice until definitive prospective research is done. Most importantly, patients should not be frightened away from the many benefits of acetaminophen. However, as always, any medication taken during pregnancy should be used only as needed, in moderation, and after the pregnant patient has consulted with their doctor.
https://www.Acog.Org/news/news-articles/2021/09/response-to-consensus-statement-on-paracetamol-use-during-pregnancyIn 2022, the inevitable lawsuits began piling up. These efforts targeted Johnson & Johnson, the manufacturer of Tylenol, but also companies that sell generic formulations like CVS, Walgreens, and Walmart. By October of that year, more than 500 of these lawsuits had been clumped together into one large federal multi-district litigation (MDL). In December of 2023, the judge presiding over the Tylenol MDL issued a ruling that appeared to signal an imminent dismissal:
Cote, in a 148-page ruling, found that none of the five expert witnesses proposed by the plaintiffs had offered a sound scientific methodology to support their opinion that Tylenol's active ingredient, acetaminophen, could cause autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD).
"Instead, the unstructured approach adopted by the plaintiffs' experts permitted cherry-picking, allowed a results-driven analysis, and obscured the complexities, inconsistencies, and weaknesses in the underlying data," she wrote.
https://www.Reuters.Com/legal/lawsuits-claiming-tylenol-causes-autism-lack-scientific-support-judge-finds-2023-12-19/Just last month, however, Judge Cote allowed testimony of a new expert introduced by plaintiffs and the defense has until July to object. And there are also hundreds of potential state lawsuits waiting in the wings, so things might still get ugly. But a new study out of Sweden has provided the best evidence to date on this issue, and the Johnson & Johnson legal team is likely feeling much better about their chances right now.
The study, which was run by researchers at the Karolinska Institute and Drexel University and published in JAMA earlier this week, looked at associations of acetaminophen use during pregnancy with the risk of autism, ADHD, and intellectual disability in children. Researchers looked at the medical records of about 2.5 million Swedish children born between 1995 and 2019, which also included prenatal data. And, quite importantly, this is a cohort study with matched sibling control analysis that is more capable of accounting for potentially confounding variables than any previous investigation.
Again, the sibling controls are the key to why this study is more reliable. They looked at exposures and outcomes in sibling pairs with the same biological parents, meaning that they had similar genetics and environments, and this included many instances where a mother used acetaminophen with one pregnancy but not during the other. This additional layer of analysis revealed that there was no evidence of higher risk.
One interesting finding illustrates the potential for finding associations that can be misleading. In the study, parents with neurodevelopmental disorders were more likely to have used acetaminophen during pregnancy. Parents with autism, for example, are more likely to have children with autism because it is highly heritable:
It is estimated at least 50% of genetic risk is predicted by common genetic variation and another 15-20% is due to spontaneous mutations or predictable inheritance patterns. The remaining genetic risk is yet to be determined.
https://www.Uclahealth.Org/news/new-genetic-clues-uncovered-largest-study-families-withThe arrow of causality is much more likely to travel through the DNA shared with a developing fetus than through exposure to a medication. Acetaminophen use during pregnancy was also more prevalent with mothers in a lower socioeconomic class or who had psychiatric or neurodevelopmental conditions. We say that correlation does not equal causation a lot, mostly because it is true, and it looks like earlier studies were likely fooled by hidden confounding factors.
*Acetaminophen when taken in excessive amounts, usually but not always in the setting of an intentional overdose, can be extremely toxic and result in permanent liver failure and even death. Appropriate dosing, however, is extremely safe and has fewer potential side effects of concern than other pain and fever reducers such as ibuprofen and aspirin, especially in children. It is, in fact, the only safe OTC medication for these purposes in young infants.
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.
Dangers Of Humans Taking Animal Drugs And Vice Versa
A woman gives a tincture to a cat.
gettyPrescription drugs indicated for use in veterinary medicine can be dangerous for humans. Conversely, medications approved for human use can pose a serious hazard for animals. And at the same time, some therapeutics can be prescribed to humans and animals and may work for both, so long as this is done with the appropriate dosage and formulation.
Ever wondered about the fact that your cat may be taking the same medication as you are? For example, cats can be administered transdermal doses of mirtazapine (brand name is Remeron or Mirataz) as an appetite stimulant. Mirtazapine is approved by the Food and Drug Administration for the treatment of depression in humans. Appetite stimulation and weight gain are common side effects, which is why it can be beneficial for patients who are experiencing weight loss and decreased appetite. Similar benefits may be achieved for animals, too.
Veterinarians can legally prescribe an approved human drug such as mirtazapine in animals under certain circumstances. This is called an extra-label use, as the American Veterinary Medical Association explains. It entails prescribing of an approved drug in a manner that deviates from the drug's approved labeling, yet meets the conditions set forth by the Animal Medicinal Drug Use Clarification Act of 1994 and FDA regulations. Here, deviations from FDA-approved labeling include use in another species, for another indication, at a different dose or frequency or route of administration.
The FDA is the legal authority in the U.S. To approve and regulate drugs for both humans and animals. A drug intended for use in animals is called a new animal drug. The FDA has a division named the Center for Veterinary Medicine which approves and regulates new animal drugs. And because every animal species responds differently to pharmaceuticals due to differences in physiology and metabolism, the FDA determines if a drug is safe and effective for a specific use in a particular animal species.
According to the National Community Pharmacists Association, the following four drugs that were developed and approved for humans are commonly administered to certain animals under the extra-label rubric: Diphenhydramine to help treat allergies, allergic reactions and motion sickness; hydrocortisone for raw, itchy or irritated skin; famotidine as a stomach acid reducer; and dimenhydrinate for motion sickness, though a better choice might be an FDA-approved animal treatment such as Cerenia (maropitant citrate).
But you don't want to ever play veterinarian with the human drugs in your medicine cabinet. Consult your vet before using any of the above drugs for your pets.
Nor should you ingest medications intended for animal use just because you may recognize a familiar active ingredient. In other words, people shouldn't use products marketed for veterinary use that have not been evaluated by the FDA for human safety or that are otherwise not suitable for human consumption. Those products may have adverse effects, including serious illness and death, when taken by people. Either the veterinary drug itself poses a considerable risk to humans, or the dosage or formulation.
Take xylazine, for instance. It is a non-opioid veterinary tranquilizer which is approved for animal but not human usage. Not only is the animal sedative dangerous when taken on its own by humans, fentanyl mixed with xylazine is known on the street as "tranq" and is fueling an alarming rise in overdoses and deaths.
Another example is the dissociative, hypnotic drug ketamine, which can be prescribed to humans for certain mental disorders. But ketamine has also become an illicit street drug used illicitly for recreational purposes. There are veterinary and human formulations of ketamine. The veterinary formulations are ten times stronger, which makes it potentially deadly if ingested by humans.
The reverse applies, too, that is, when animals use products intended for human use only, they can experience adverse effects such as serious illness and death. Some drugs are highly toxic and potentially lethal for cats, for example, bismuth subsalicylate and acetaminophen. The FDA lists drugs that are prohibited from extra-label use in animals.
In other instances, a drug such as fluoxetine—the active ingredient in the commonly used antidepressant Prozac—may have approved on-label uses in both humans and animals. For "lonely dogs with separation anxiety," Eli Lilly marketed Reconcile in 2007, which contains fluoxetine and is specifically formulated for animals. Dogs are often prescribed fluoxetine. This isn't a new phenomenon. Fifteen years ago the New York Times published an article on the rise in the practice of prescribing medications designed for humans to animals.
And then there's the special case of the broad spectrum antiparasitic ivermectin which has long had approved uses in humans and animals. However, animal ivermectin products are very different from those approved for humans. In veterinary medicine, it is indicated to prevent and treat heartworm and intestinal worms. You may have seen ads on television for Heartgard, which prevents heartworm disease in dogs, and treats and controls intestinal worms in animals. One of two active ingredients in Heartgard is ivermectin.
In humans, a topical ointment containing ivermectin can be prescribed to treat issues involving lice and rosacea, while a tablet is used for parasites, including intestinal strongyloidiasis and onchocerciasis (river blindness) and lymphatic filariasis.
During the Covid-19 pandemic a controversy erupted around the use of ivermectin in humans to treat or prevent Covid-19. The FDA in December 2021 warned Americans not to use ivermectin for this purpose. The FDA stated that there wasn't evidence to support ivermectin's use against Covid-19.
The agency went further by reminding us "never to use medications intended for animals on yourself or other people." While the latter statement is apt, technically it doesn't apply to ivermectin as the product isn't only for animals. Moreover, the statutory authority of the FDA does not extend to the issuance of medical advice or recommending against off-label uses of medicines.
While the FDA does not approve of ivermectin as a treatment for Covid-19, doctors can still prescribe it if they insist, however ineffective it appears to be for patients, as has been chronicled repeatedly in separate peer-reviewed studies during the past several years.
The FDA threw down the gauntlet when it posted a tweet in 2021 opposing the use of ivermectin: "You are not a horse. You are not a cow. Seriously y'all. Stop it." This drew the ire of some physicians who believed the FDA had overstepped its boundaries. In a lawsuit, the FDA has since agreed to delete and never republish the infamous tweet and other similar posts on social media, according to Newsweek.
Broadly, we can say that drugs that have approved uses in both humans and animals can be prescribed, so long as this is done with the appropriate dosage and formulation. Further, human medications can be used for pets and other animals in a limited number of instances—under the extra-label regulation—but only if recommended by your veterinarian and dosed and formulated appropriately. Finally, medicines intended for use in animals only shouldn't be taken by humans.
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