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Morning sickness drugs may not be as effective as originally thought
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A report published in PLoS One, revisiting a 1970s study that was never published, questions the efficacy of the drugs dicyclomine, pyridoxine, and doxylamine for the treatment of morning sickness.
Two of these drugs — doxylamine and pyridoxine — are in the American College of Obstetricians and Gynecologists’ and other guidelines as the first-line pharmacological therapies for nausea and vomiting for women who are pregnant.
“The fact that the results were not published should make us view the results with caution. Why would the manufacturer of a medication not publish the results of a valid study showing that its product works?” Nav Persaud asked rhetorically in an interview with Healio Family Medicine.
He pointed out other concerns about the 1970s study that led him to question the drugs’ effectiveness.
“The data for 30 patients recruited by one of the [original] investigators (who was one of the three recorded as actively collecting data) were excluded from the study following receipt of a March 19, 1975 letter from the Commissioner of Food and Drugs: ‘We find instances of overstatement of study duration; of data recording in absence of patient visits; instances where doubt exists concerning the identification of the product under investigation; and instances of non-reporting of the occurrence of 'pregnancies during the course of a contraceptive study’.’’
Persaud and his colleague, Rujun Zhang, PhD, also of the University of Toronto, released the information from the 1970s in accordance with the restoring invisible and abandoned trials (RAIT) initiative. According to BMJ, this initiative helps ascertain a treatment’s validity, with the hopes of avoiding situations where inaccurate conclusions were drawn solely because limited evidence was available.
Zhang and Persaud reviewed more than 7,000 pages of information related to the 1970s study, known as the 8-way Bendectin Study, through a Freedom of Information Act request to the FDA. The researchers also reached out to Health Canada, who provided 365 pages of data, of which more than half was redacted; and the European Medicine Agencies, which said it had no relevant information. Zhang and Persaud also reported they could not locate any of the original researchers (evidence suggested at least some of them had died) and attempts to have the original peer group publish the study, as outlined by RAIT initiative rules, were unsuccessful.
The 8-way Bendectin Study included 2,308 women in the first 12 weeks of their pregnancy who reported vomiting or nausea. These women were randomly assigned to one of the following treatment groups: doxylamine/pyridoxine/dicyclomine; doxylamine/pyridoxine; dicyclomine/pyridoxine; doxylamine; dicyclomine/pyridoxine; pyridoxine; dicyclomine; and placebo. Participants were told to take two tablets at bedtime, and another tablet, if needed, in the afternoon or morning for 1 week. At the study’s end, researchers analyzed data from 1,599 women and reported the proportion of participants who were “evaluated moderate or excellent” was greater in each of the seven active treatment groups when compared with placebo (57%): doxylamine/pyridoxine/dicyclomine (14% absolute difference vs. placebo; 95% CI, 4-24), doxylamine/pyridoxine (21%; 95% CI, 11-30), dicyclomine/pyridoxine (21%; 95% CI, 11-30) doxylamine (20%; 95% CI, 10-29), dicyclomine/pyridoxine (4%; 95% CI, -6 to 14), pyridoxine (9%; 95% CI, –1 to 19) and dicyclomine (4%; 95% CI, -6 to 14).
However, Zhang and Persaud reported a number of concerns about the findings, which they said were based on the available summary data of physician evaluation of symptoms and ignored missing data and data integrity issues. The researchers also indicated there was no information about how the original researchers adhered to trial interventions, the amount of the medications the patients took, a lack of baseline data, limited outcome data in the placebo group, and P values were “one-sided and not corrected” in the many comparisons made.
Zhang and Persaud noted a high risk of bias in the earlier study, given the lack of prespecified outcomes or analyses, the high attrition rate in a 7-day trial, and the exclusion of some data because of questionable data integrity. The most common adverse events in the 1970s study were fatigue and drowsiness, but Zhang and Persaud noted the information used to reach that conclusion was incomplete.
According to a study in the American Journal of Obstetrics and Gynecology, unrelated to the 1970s study, in April 2013, the FDA approved the delayed release combination of 10 mg doxylamine and 10 mg pyridoxine hydrochloride for women who were pregnant and experienced nausea and vomiting.
“This recent U.S. FDA review quoted the results of this 8-way study (e.g. ‘The control of nausea by doxylamine alone and by each of the three combinations which contain doxylamine was consistently statistically significantly (P < 0.01) superior to placebo by both physician’s records and patient’s records’) but did not mention any of the problems with the study described here, not even the problem with data integrity that was originally identified by the U.S. FDA,” Persaud told Healio Family Medicine.
According to the American Journal of Obstetrics and Gynecology article, the FDA’s 2013 decision ended a 30-year period in which there were no FDA-approved drugs for nausea and vomiting related to pregnancy. This same study showed the drug combination the FDA approved in 2013 mirrored the Bendectin one withdrew in 1983.
Persaud said the Bendectin withdrawal was voluntary and “related to lawsuits over claims about birth defects. After the withdrawal, other treatments were used including over-the-counter treatments. There may have also been a decrease in medication use,” he said.
The Bendectin withdrawal, according to the American Journal of Obstetrics and Gynecology article, “was associated with a 3-fold increased risk of hospitalization of women for the severe forms of [nausea and vomiting during pregnancy].”
Persaud said he has stopped prescribing doxylamine and pyridoxine to his patients. “Studies are needed to determine if medications work. Most women who take the medication get better. Some strongly believe that the medication worked; others have the opposite view,” he said, echoing the conclusions of at least one systematic review conducted over the past several years. – by Janel Miller
Disclosure:
The researchers report no relevant financial disclosures.
Further reading:
http://www.bmj.com/content/346/bmj.f2865
http://www.sciencedirect.com/science/article/pii/S0002937814008539
https://www.ncbi.nlm.nih.gov/pubmed/26348534
Perspective
Back to TopLaura Sirott, MD
“The study referenced is flawed as identified by the authors. It has a high dropout rate and questions the efficacy of the medication as researched over 30 years ago. In the intervening decades, the medication has continued to be used abroad by a large number of pregnant women. During those decades, there has been an absence of adverse outcomes. While studies have shown some efficacy, the medication presents a safe option for women to try. In my personal practice experience, many women have gained relief of their symptoms. I will continue to offer the medication as an option to my patients after counseling them on it as well as other options. There is nothing in this study that makes me concerned about safety.”
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