Morning sickness pill study finds small link to increased risk of clefts but 'not a cause for alarm'

When a pregnant woman feels persistent nausea and even has to throw up, she might see whether ...

Posted: Dec 18, 2018 3:27 PM
Updated: Dec 18, 2018 3:27 PM

When a pregnant woman feels persistent nausea and even has to throw up, she might see whether ginger can help settle her stomach, or perhaps plenty of water.

If that doesn't help, a physician might prescribe doxylamine and pyridoxine, a drug combination often used to treat nausea and vomiting in pregnant women. Still no relief? Then, a physician might recommend something else: ondansetron.

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The anti-nausea medication, sold under the brand name Zofran, comes in tablet form and primarily is used to prevent nausea and vomiting after cancer chemotherapy, radiation therapy or surgery.

Although it's not formally approved for this purpose, ondansetron also may be prescribed to treat nausea and vomiting during pregnancy, including hyperemesis gravidarum, which is extreme, persistent nausea and vomiting during pregnancy.

Yet there have been some questions around whether ondansetron is safe to use during pregnancy or whether it's tied to an increased risk of birth defects.

A new study, published in the medical journal JAMA on Tuesday, appeared to put that question to rest by finding no association between ondansetron and an increased risk of heart-related malformations or other malformations in newborns overall.

The study also found a small increased risk of oral clefts, including cleft lip and cleft palate, in babies born to women who used ondansetron.

That increased risk accounted for about three additional cases of oral clefts per 10,000 women taking ondansetron in the study -- which is smaller than had been suggested in other research, said Krista Huybrechts, an associate professor of medicine at Harvard Medical School and an epidemiologist at the Brigham and Women's Hospital, who was first author of the new study.

"There have been some studies conducted in the past that have suggested that there might be a doubling in the risk of cardiac malformations and a doubling in the risk of oral clefts associated with ondansetron use during the first trimester of pregnancy," Huybrechts said.

"Our study is much larger than any of the others that have been published in the literature so far," she said. "We ended up seeing no association for cardiac malformations, no association for malformations overall, and then a much smaller potential increase in the risk of oral clefts than what had been suggested by previous studies."

Huybrechts and some of her co-authors reported that their institutions have received research grants from various pharmaceutical companies, including GlaxoSmithKline, the first developer of Zofran. The study itself was funded by the National Institutes of Health, and GSK had no involvement.

In 2012, GlaxoSmithKline agreed to plead guilty and to pay $3 billion to resolve allegations of fraud and failure to report safety data related to various prescription drugs, including Zofran. The agreement resolved allegations that GSK promoted certain forms of Zofran for the off-label use of treating morning sickness in pregnant women, according to the US Department of Justice.

The new study seems to fall in line with previous research on ondansetron. One study, published in the journal Reproductive Toxicology in 2016, found no evidence to support a link between ondansetron and adverse fetal outcomes.

Another report, published in the journal Obstetrics & Gynecology this year, found no increased risk associated with using ondansetron for nausea and vomiting in the first trimester of pregnancy, compared with no treatment. That study was from the Slone Epidemiology Center at Boston University, in collaboration with the US Centers for Disease Control and Prevention.

The majority of pregnant women, about 70% to 80%, experience some type of nausea and vomiting, or morning sickness, according to the American Pregnancy Association.

For some, those symptoms can be severe. Hyperemesis gravidarum occurs in up to 3% of pregnancies, according to the American College of Obstetricians and Gynecologists.

As it turns out, the use of ondansetron to treat these symptoms has been on the rise among moms-to-be in America, used in less than 1% of pregnancies in 2001 but in 22.2% in 2014, according to a study published last year in the journal Pharmacoepidemiology & Drug Safety.

'This is not a cause for alarm'

For the new study, researchers took a close look at health data on more than 1.8 million pregnant women in the United States between 2000 and 2013. The data came from the nationwide database Medicaid Analytic eXtract.

The data showed that 88,467 women filled at least one ondansetron prescription during their first trimester. The data also showed medical claims recorded for each mother's newborn.

The researchers found that the risk of oral clefts in newborns was 14 per 10,000 pregnancies exposed to ondansetron, versus 11.1 per 10,000 unexposed pregnancies.

The study had some limitations, including that an association in the data does not mean causation, and just because the women filled an ondansetron prescription does not mean they used the drug. Also, the data included only live births, so any birth defects that resulted in losing a pregnancy were not included, and the data included only women with Medicaid insurance.

"It's also important to note that we're just looking at congenital malformations as a potential outcome here. So obviously, this study does not address any questions in terms of other potential adverse events that might be associated with treatment, or it doesn't address comparative effectiveness of ondansetron versus other treatment," Huybrechts said.

"But at least with respect to the potential risk of congenital malformations, which is something that is always at the forefront of women's minds, we hope that this study will provide reassurance," she said.

Dr. Shaun Carstairs, an emergency physician and medical toxicologist at the University of California, San Diego's School of Medicine, has seen the symptoms of frequent vomiting and nonstop nausea during pregnancy many times.

"Working in the emergency department, I see a lot of patients who come in with nausea and vomiting due to pregnancy -- and it certainly can be a very challenging condition to treat sometimes, because there are a number of medications that women can use, sometimes women don't get any benefit from some of these medications," said Carstairs, who was not involved in the new study but authored a 2016 Obstetrics & Gynecology study that found the overall risk of birth defects associated with ondansetron exposure to be low.

For that study, he reviewed eight previously published studies on ondansetron use in early pregnancy. The new JAMA study adds to that body of research, he said.

"My bottom line take on this study is that, number one, this is not a cause for alarm for the general public. This is one study in the context of an entire body of literature on this subject of ondansetron and birth defects," Carstairs said.

"I think it's also important to keep in mind that the risks of any medication -- whether it's ondansetron or any other medication -- need to be balanced against the risks of inadequate treatment or no treatment, particularly in those patients that have severe nausea and vomiting in pregnancy, or hyperemesis gravidarum," he said. "Those conditions carry some real risks themselves -- dehydration, electrolyte abnormalities -- and a lot of these patients require admission to the hospital if they're not adequately treated."

The history of concerns around taking medicine while pregnant

Marlena Fejzo, a faculty researcher at the University of California, Los Angeles' David Geffen School of Medicine, called the new study "reassuring."

"It would be helpful in the future to determine exactly which week of first trimester exposure is associated with the increase in risk of oral clefts. Then patients could avoid exposure specifically during that time," said Fejzo, who was not involved in the study but has conducted separate research on ondansetron in pregnancy and adverse outcomes.

After all, there is a long history of prescribing medications off-label to treat symptoms of pregnancy in women, she added.

"This is because of the thalidomide disaster, where women took thalidomide to treat [hyperemesis gravidarum] in the 1950s and '60s and babies were born with limb deformities. After that, pharmaceutical companies stopped testing medications in pregnant women," Fejzo said, and so often, the data is lacking on how a certain medication may affect a woman's pregnancy.

Also, in 1979, the US Food and Drug Administration began reviewing all prescription and over-the-counter medications to develop risk categories for use in pregnancy.

"Society would benefit greatly from a national database and a requirement of providers to report exposure timing and outcomes for off-label prescriptions to pregnant women. With so many pregnant women taking ondansetron in the US, we could have a final answer on this very quickly," she said. "The answer is out there, and we owe it to pregnant women and their children to get it."

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