January 5, 2017
One minute, you have that blissful pregnancy glow, and the next, you're green with nausea. You're not alone.
About 75% of women suffer nausea and vomiting during pregnancy due to morning sickness, and about 1% experience a severe form of the sickness called hyperemesis gravidarum.
Many moms-to-be are prescribed some type of treatment to ease their morning sickness, from vitamins to medications. Diclegis, also known as Diclectin in Canada, is the only Food and Drug Administration-approved prescription medicine for morning sickness, according to its website. It's so popular that reality star Kim Kardashian posted a promotional Instagram photo about it in 2015.
Now, a provocative new paper questions the efficacy of the drug.
There were flaws in the 1970s clinical trial that the FDA and the federal department Health Canada used to approve the drug, then known as Bendectin, according to the paper. It was published Wednesday in the journal PLOS One.
The clinical trial, known as the 8-way Bendectin Study, was never published in a scientific journal, said Dr. Nav Persaud, a physician and associate scientist at St. Michael's Hospital in Toronto and assistant professor at the University of Toronto, who co-authored the new paper.
"I was surprised that there were so many serious problems with a study that forms the basis for approval and prescribing," he said. "I have stopped prescribing this medication."
Duchesnay Inc., the Canadian pharmaceutical company behind Diclegis and Diclectin, responded that the medication's safety and efficacy have been proved in other more recent studies and meta-analyses. Other experts also stand by the drug, and the FDA called it "safe and effective."
"Based on the available data, the FDA determined that Diclegis has been shown to be safe and effective for the treatment of nausea and vomiting in pregnant women who do not respond to conservative management. The FDA's determination remains unchanged," according to a statement emailed by FDA spokeswoman Sarah Peddicord on Wednesday.
"Generally the FDA does not comment on specific studies, but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health. The FDA is reviewing the findings of the paper. The FDA remains committed to informing the public in a timely manner when the agency identifies concerns about approved drug products."
'This is a flaw'
In the mid-1950s, the combination of doxylamine and pyridoxine was approved by the FDA for the treatment of morning sickness under the name Bendectin. Starting in the late 1970s, a series of lawsuits and studies claimed that the drug was associated with birth defects. The medication was voluntarily withdrawn from the American market in 1983 due to falling sales and rising legal costs.
Then, "this company Duchesnay applied to start selling the same two active ingredients under the name Diclegis," Persaud said.
In 2013, the FDA approved Diclegis to treat pregnant women experiencing nausea and vomiting.
Persaud and Rujun Zhang, a colleague at the University of Toronto, submitted freedom of information requests to the FDA and Health Canada to obtain data from the 8-way Bendectin Study as part of an initiative to systematically restore and publish old trials, called RIAT.
In their paper, the researchers noted that they selected the trial because it was a critical component in the FDA approval and involved a commonly used drug.
The researchers reviewed about 36,000 pages of information from the FDA, of which about 7,200 were related to the clinical trial. They also obtained 359 pages from Health Canada, but 212 were redacted.
The researchers used the Cochrane Risk of Bias tool, a commonly used method, to assess the quality of the clinical trial.
After examining the papers and analyzing the original 8-way Bendectin Study, the researchers found that out of the 2,359 patients who initially enrolled in the weeklong trial, 31% never completed it.
"This is a flaw, because the missing data could change the findings and conclusions depending on what happened to those women," Persaud said. He added that the final results of the clinical trial also were missing.
Additionally, the clinical trial involved a scoring system to measure how patients responded to Bendectin compared with a placebo group, and the researchers found the system to be unclear.
Although the new paper does not suggest that Diclegis causes birth defects, the researchers wrote, "The questionable data integrity, high drop-out rate, and other methodological concerns mean that the prescribing of this medication should not be based on this trial."
Debate over drug drives on
Duchesnay has complete confidence in the safety and efficacy of Diclegis, company spokeswoman Amy Feldman said in an emailed statement Tuesday.
Diclegis is a combination of the antihistamine doxylamine and pyridoxine, or vitamin B6. The two active ingredients "are the most studied drug combination used in pregnancy," the statement said.
In July, Health Canada released a summary safety review confirming that the drug's benefits continue to outweigh its risks.
The drug's safety and efficacy "have been proven in 16 cohort studies, two meta-analyses, an ecological study, a neurological development study and numerous others," the statement said. "It is estimated that 35 million women around the world have used the combination of doxylamine succinate and pyridoxine hydrochloride to treat nausea and vomiting of pregnancy."
Indeed, the FDA required two studies—the 1970s study and a 2010 study published in the American Journal of Obstetrics and Gynecology—to approve Diclegis, Persaud said. Although the 2010 study showed the efficacy of the combination of doxylamine and pyridoxine in the drug, the 1970s study was referenced to show the efficacy of each ingredient individually.
In other words, "if you were to subtract the 1970s study, the FDA could not have approved Diclegis," Persaud said.
According to the FDA's statement, the agency "took into account the totality of the evidence submitted when deciding whether Diclegis could be approved."
The American Congress of Obstetricians and Gynecologists and the Association of Professors of Gynecology and Obstetrics still both consider Diclegis a first-line treatment for morning sickness when more conservative treatments fail, the Duchesnay statement said.
"I have no idea why they would dredge up data that is 35 years old," Dr. Laura Sirott, a practicing ob-gyn and California state legislative chairwoman for the American Congress of Obstetricians and Gynecologists, said in a separate email about the new paper.
"A multitude of data from this century exists to show the safety and efficacy of the drug. As stated in their article, what data they do have is heavily flawed," she said.
However, another expert expressed doubt.
With some information from the original 8-way Bendectin Study trial still missing, it is difficult to determine whether Diclegis is effective, said Marlena Fejzo, a medical scientist at the University of California, Los Angeles.
"So I would have to agree with the conclusion of the Cochrane review that there is insufficient evidence," said Fejzo, who has studied morning sickness but was not involved in the new paper.
"Given that it is prescribed for one out of every two live births in Canada, I would strongly recommend repeating an effectiveness study as soon as possible," she said.
For now, if you are experiencing morning sickness, Persaud recommended talking to your doctor about treatment options.
A controversial history
There's a controversial history around drugs used to treat morning sickness -- and accurate data about what's effective can be hard to come by, Fejzo said.
"This is due, in part, to the thalidomide disaster of the 1950s, when the drug was prescribed to women with hyperemesis gravidarum to relieve symptoms of nausea and babies were born with limb deformities," she said of the drug thalidomide, which is no longer prescribed for morning sickness in the United States. "This led to difficulty in developing and testing medications on pregnant women."
Pregnant women are often excluded from industry-sponsored clinical trials designed to test the efficacy of certain drugs, according to a 2013 paper published in the journal Obstetrics & Gynecology. The paper found that only about 1% of clinical trials between 2011 and 2012 were designed specifically for pregnant women.
Due to this lack of research, less than 10% of medications approved by the FDA since 1980 have enough data behind them to determine their risk for birth defects, according to a 2011 study published in the American Journal of Medical Genetics.
To help with this lack of data, Fejzo said, she recommends that all health care providers be required to report the medications they prescribe their patients during pregnancy.
"A centralized, national database to document treatments and medications and their effectiveness, and maternal and child outcomes could help us figure out which medications are safe and effective," Fejzo said.
"This would increase patient and provider confidence about using treatments during pregnancy. It would also reduce the risk of malpractice or class action suits, which make drug companies and doctors hesitant to test and prescribe new treatments," she said. "With so many women taking medications, both off-label and FDA-approved, to treat pregnancy nausea, the answer is there."
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