Prenatal Use of Acetaminophen Linked to Early Puberty

By Pat Anson, PNN Editor

The daughters of women who took acetaminophen during pregnancy tend to start puberty early, according to a new study by Danish researchers.  

The study is the latest indication that prenatal use of acetaminophen – more commonly known as paracetamol outside the U.S. -- can have long term effects on children.

Researchers at Aarhus University studied health data on about 100,000 Danish women who provided detailed information about their use of acetaminophen during pregnancy.

Nearly 16,000 children born to those mothers between 2000 and 2003 were followed from the age of eleven and throughout puberty, with surveys every six months about different aspects of their development.

The study, published in the American Journal of Epidemiology, found that girls on average entered puberty between one-and-a-half and three months earlier if their mothers took the over-the-counter pain reliever for more than 12 weeks during pregnancy.

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"We found a 'dose-response' correlation. That is to say, the more weeks with paracetamol during pregnancy, the earlier puberty in girls, but not in boys," says lead author Andreas Ernst, a PhD student from the Department of Public Health at Aarhus University.

"While entering puberty one-and-a-half to three months earlier may seem unimportant, when taken together with the frequent use of paracetamol during pregnancy, our findings ought to make people take notice. Our results are certainly not the decisive factor that should change current practice, but the perception of paracetamol as 'the safe and harmless choice' during pregnancy ought to be challenged."

Early puberty development increases the risk of serious diseases in adulthood, such as obesity, diabetes, cardiovascular diseases and testicular and breast cancer.

The use of acetaminophen (paracetamol) has been increasing worldwide and studies have found that over half of pregnant women in the U.S. and European Union use the pain reliever at least once during their pregnancy. It is the active ingredient in Tylenol, Excedrin, and hundreds of pain medications.

Previous research has shown that prenatal use of acetaminophen is associated with slow language development, autism and attention deficit problems in young children.

Over 50 million people in the U.S. use acetaminophen each week to treat pain and fever. The pain reliever has long been associated with liver injury and allergic reactions such as skin rash. The FDA label for products containing acetaminophen warns about the risk of liver damage and other side effects but does not specifically warn pregnant women about using the pain reliever. The agency said in 2015 that the evidence was “too limited” to justify such a warning.  

In its 2016 opioid prescribing guidelines, the CDC recommends acetaminophen as an alternative to opioid pain medication. The guideline only briefly mentions that acetaminophen is involved in hundreds of overdose deaths annually and can cause liver problems.

The CDC guideline does warn pregnant women -- at length -- that opioids can cause birth defects, poor fetal growth, still births and neonatal opioid withdrawal syndrome.

Acetaminophen Linked to Kids’ Behavior Problems

By Pat Anson, Editor

Another study has linked acetaminophen to attention deficit and other behavioral problems in children whose mothers used the over-the-counter pain reliever while pregnant.

"Children exposed to acetaminophen use prenatally are at increased risk of multiple behavioral difficulties,” said lead author Evie Stergiakouli, PhD, of the University of Bristol. “Given the widespread use of acetaminophen among pregnant women, this can have important implications on public health advice.”

The study, published in JAMA Pediatricsinvolved nearly 7,800 mothers in the UK who used acetaminophen in 1991 and 1992.

Prenatal use of acetaminophen in the second and third trimesters was associated with a higher risk of behavior problems and hyperactivity in children. Use of acetaminophen at 32 weeks of pregnancy was also associated with a higher risk for emotional problems.

“We found stronger association between maternal acetaminophen use and multiple behavioral and emotional problem domains during the third trimester than during the second trimester, in agreement with previous studies that have included multiple measurement times during pregnancy," said Stergiakouli

"Given that there is active brain development and growth during the third trimester, this finding could indicate that there are developmental periods when the brain is more sensitive to acetaminophen exposure.” 

Acetaminophen (paracetamol) is one of the most widely used pain relievers in the world. It is the active ingredient in Tylenol, Excedrin, and hundreds of other pain medications. Researchers say over half the pregnant women in the United States and European Union use the drug.

"The risk of not treating fever or pain during pregnancy should be carefully weighed against any potential harm of acetaminophen to the offspring," said Stergiakouli

A recent study of over 2,600 Spanish women linked acetaminophen to autism and attention deficit problems in their children. Studies in Denmark and New Zealand have also linked acetaminophen with a higher risk of hyperkinetic disorders and attention-deficit hyperactivity disorder (ADHD).

Over 50 million people in the U.S. use acetaminophen each week to treat pain and fever. The pain reliever has long been associated with liver injury and allergic reactions such as skin rash.

Lyrica Linked to Birth Defects

By Pat Anson, Editor

A drug widely prescribed to treat fibromyalgia, neuropathy and other chronic pain conditions increases the risk of major birth defects, according to a new study published in Neurology, the medical journal of the American Academy of Neurology.

Women taking pregabalin were six times more likely to have a pregnancy with a major defect than women who were not taking the drug, the study found. The birth defects included heart defects and structural problems with the central nervous system (CNS) or other organs. Birth defects due to chromosomal abnormalities were not included in the results.

Pregabalin is the generic name of Lyrica, which is approved by the FDA to treat diabetic nerve pain, fibromyalgia, epilepsy, post-herpetic neuralgia caused by shingles and spinal cord injury. It is also prescribed “off label” to treat a variety of other conditions. Lyrica is Pfizer’s top selling drug, generates over $5 billion in annual sales, and is currently approved for use in over 130 countries.

The international study involved nearly 700 pregnant women in seven different countries. Four of the 125 women who took pregabalin during pregnancy had children with central nervous system defects, or 3.2 percent. That compares to a birth defect rate of just 0.5% in the 570 women who did not take pregabalin.

Of the women taking pregabalin, 115 were taking it to treat neuropathic pain, 39 were taking it for psychiatric disorders, including depression and anxiety, five were taking it for epilepsy, and one for restless leg syndrome.

Most of the women started taking pregabalin before they became pregnant. All of them stopped taking the drug at an average of six weeks into their pregnancies.

A small number of women also took another anti-seizure drug during their pregnancy. Women in that group had a 6 percent chance of a major birth defect, compared to 2 percent of the women who did not take another anti-seizure medication.

“We can’t draw any definitive conclusions from this study, since many of the women were taking other drugs that could have played a role in the birth defects and because the study was small and the results need to be confirmed with larger studies, but these results do signal that there may be an increased risk for major birth defects after taking pregabalin during the first trimester of pregnancy,” said study author Ursula Winterfeld, PhD, of the Swiss Teratogen Information Service and Lausanne University Hospital in Lausanne, Switzerland.

“Pregabalin should be prescribed for women of child-bearing age only after making sure that the benefits of the drug outweigh the risks and after counseling them about using effective birth control. In cases where women have taken pregabalin during pregnancy, extra fetal monitoring may be warranted.”

A spokesman for Pfizer said the study was small and the findings could have been influenced by other factors.

"As the authors agree, the study has significant limitations and cannot be used to draw definitive conclusions," Steven Danehy said in an email to Pain News Network. "The study was small, did not account for other medical conditions or medications, and the women taking Lyrica had higher rates of smoking and diabetes, all of which can negatively affect pregnancy outcomes."  

Because women are more likely than men to have a chronic pain condition such as fibromyalgia, they are the biggest consumers of Lyrica.

The FDA warning label for Lyrica does not specifically warn pregnant women not to take the drug. But it does caution them to consult with a doctor if they are pregnant or plan to become pregnant.

“It is not known if Lyrica will harm your unborn baby. You and your healthcare provider will have to decide if you should take Lyrica while you are pregnant. If you become pregnant while taking Lyrica, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry,” the label says.

The label also cautions men to see a doctor if they plan to father a child while taking Lyrica. 

“Animal studies have shown that pregabalin, the active ingredient in Lyrica, made male animals less fertile and caused sperm to change. Also, in animal studies, birth defects were seen in the offspring (babies) of male animals treated with pregabalin. It is not known if these problems can happen in people who take Lyrica,” the warning label states.

CDC Reports on Opioids Appear Biased

By Lynn Webster, MD, Guest Columnist

Like most people, I respect the opinion of the Centers for Disease Control and Prevention (CDC). It is our first and last line of defense against everything from chronic disease to full-fledged pandemics. That said, I am perplexed why the CDC would sound an alarm, while at the same time acknowledging that the fire doesn’t actually exist.

That’s more or less what the CDC did in a report finding that approximately a quarter of privately insured and a third of Medicaid-enrolled women of reproductive age (15-44 years) filled a prescription for an opioid each year from 2008 to 2012. The report went on to say that the trend of opioid prescriptions among childbearing women places unborn children at risk for birth defects. On this point, the report does not address how many of the women actually became pregnant and otherwise has a glaring absence of empirical data to support its claims.

If you are a clinician or scientist, the CDC report appears incomplete and biased against people in pain. If you are a patient or consumer of the news, the report is alarming. Neither of these outcomes advances medicine, nor do they help people who abuse prescription medication or those who experience chronic pain.

Without question, opioids must be replaced as a primary method of pain treatment in favor of safer and more effective therapies. It is clear that in many instances, the risks of opioid therapy far outweigh the benefits. However, many patients with pain have no other options, so until patients have access to effective alternatives, this type of reporting is counterproductive.

Because the report does not clarify the actual risks, nor compare them with the risks of continued pain in the absence of treatment, the CDC wades into dangerous territory of conjecture. Moreover, an overreliance on retrospective observational studies makes it difficult to evaluate the true impact of opioid use on the incidence of birth defects or whether other factors, such as the mother’s health status and co-occurring tobacco or alcohol use, were greater contributors. Although neonatal abstinence syndrome can definitely be traced to opioid use, the CDC investigators did not examine why the majority of infants born to opioid-consuming mothers do not develop it.

In addition to fuzzy reporting of the science, ethical issues are apparent in considering all women of childbearing age as fundamentally “prepregnant” when it comes to clinical decision making regarding opioid analgesia. These concerns were well delineated by Kristen Gwynne in an online article at RH Reality Check. Clinicians must always weigh potential benefits against potential harm before prescribing opioid therapy. But this has always been true of opioids and all medications, including nonsteroidal anti-inflammatory drugs, antidepressants and anticonvulsants.

The result of incomplete reporting could be the withholding of opioids from people based on gender and age, regardless of pregnancy status, even when strong pain-killing medications are indicated or when safer alternatives are not available. In fact, according to the American Congress of Obstetricians and Gynecologists, “Abrupt discontinuation of opioids in an opioid-dependent pregnant woman can result in preterm labor, fetal distress, or fetal demise.”

To be viable, alternatives to opioids must be effective and be covered by public and private insurance payers. Commentators who suggest opioids should not be prescribed often fail to present this important perspective and also imply that harm from opioids is inevitable, an error that contributes to the stigma and isolation felt by those whose lives would be crippled without their legally prescribed medications.

And yet, slanted reporting continues. In February, another CDC report appeared, endorsing scientifically vague opioid classifications of “stronger vs. weaker” than morphine. In analyzing the February report, June Dahl, PhD, properly pointed out the error in failing to consider the differing pharmacologic factors, mechanisms of action, formulations and the clinical relevance of relative effectiveness when comparing the medications.

Given the concerns with accuracy of scientific reporting, is it reasonable to increase federal funding to the CDC to battle prescription opioid abuse, as requested? Only with an understanding of the real reasons for the current opioid problem can we solve the problem. Perhaps more dollars should instead go to the National Institutes of Health, which is in desperate need of more funding for pain research and to develop safer alternatives to opioids.

Regardless, solutions cannot succeed in the absence of recognition that uncontrolled chronic pain is a major public health problem, worthy of focus similar to efforts to battle cancer, HIV/AIDS and other life-threatening diseases. Education of clinicians is good but cannot create treatment options or adequate insurance coverage where none exist. CDC officials and others must think about the problem differently and with less prejudice against people with chronic pain. Often the focus is on cutting supply alone; but in reality, this is difficult to accomplish without harming people with genuine pain when the payor system does not adequately cover evidence-based alternative therapies, including multidisciplinary integrative programs.

Instead payors, particularly government programs such as the Centers for Medicare & Medicaid Services and workers’ compensation, prefer the less costly opioid methadone, associated with more fatalities per prescription than any other.

Although a majority of opioid-prescribed patients do not abuse or become addicted, it is undoubtedly true that some people have contraindications for long-term prescribed opioids. These are potentially dangerous medications, which can be fatal. But effective solutions require a multifaceted approach and cannot ignore the needs of people in pain. Opioids formulated with abuse deterrents are needed as is greater funding and less stigmatization of people with the disease of addiction. Certainly, payors should cover safer and more effective therapies.

As I’ve said before, I hope opioids will one day not be needed, and commentaries like this one will be unnecessary. If the public health problem from opioids is too great, then it is the purview of the CDC to report on access to safer and more effective therapies in the interest of the other great public health problem: chronic pain. It is not an option to deny people in pain access to opioids if alternatives are nonexistent or unavailable.

Lynn Webster, MD, is Past President of the American Academy of Pain Medicine, and vice president of scientific affairs at PRA Health Sciences. He is a Pain Medicine News editorial board member and author of a forthcoming book, “The Painful Truth.”

This column is republished with permission from Pain Medicine News.

You can follow Dr. Webster on his blog, and on Twitter @LynnRWebsterMD, Facebook and LinkedIn.

The information in this column should not be considered as professional medical advice, diagnosis or treatment. It is for informational purposes only and represent the author’s opinions alone. It does not inherently express or reflect the views, opinions and/or positions of Pain News Network.