About Zofran: How It Works & Link To Birth Defects

Zofran is a powerful anti-nausea drug manufactured and marketed by British pharmaceutical company GlaxoSmithKline. Over the last 25 years, Zofran has become one of America’s leading treatments for morning sickness, the sometimes-debilitating nausea and vomiting that affects most pregnant women during the first trimester. But recent research has found Zofran linked to birth defects, including increased risks for congenital heart defects and cleft palate.

What Is Zofran (Ondansetron)?

Zofran’s active ingredient is the chemical ondansetron. Ondansetron, which is also sold as ondansetron hydrochloride, was developed by GlaxoSmithKline during the 1980s as a drug to alleviate nausea and vomiting. Approved for the US market in 1991, Zofran is approved to treat severe nausea and vomiting in patients who are undergoing chemotherapy and radiation therapy as part of their cancer treatment.

Zofran is available in the following formats:

  • Tablets: 4mg, 8mg and 24mg;
  • Oral Solution: 4mg/5ml
  • Orally disintegrating tablets: 4mg and 8mg;
  • Injection: 2mg/ml
  • Premixed Injection: 32mg/50ml and 4mg /50ml

Today, more than 30 companies manufacture their own generic versions of Zofran’s active ingredient, ondansetron.

How Does Zofran Work?

Zofran belongs to a class of drugs known as 5-HT3 antagonists. Along with other drugs in the same class, Zofran alleviates feelings of sickness by blocking the natural chemical serotonin, which is believed to cause nausea and vomiting.

How Zofran Works
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Serotonin is a neurotransmitter, a chemical that carries signals between “neurons” – the cells in our brains that transmit messages from one section of the brain to another. As a neurotransmitter, serotonin plays an essential role in triggering feelings of happiness, anxiety and stabilizing mood. But serotonin’s importance in human physiology only begins in the brain. In fact, most of the body’s serotonin isn’t produced in the brain at all – but in the gut.

Up to 90% of the serotonin in your body is manufactured in the gastrointestinal tract, where the neurotransmitter controls muscle contractions and bowel movement. For our purposes, serotonin really kicks in when you ingest a substance that your body believes may be toxic or irritating. In the presence of a potentially-toxic substance, your GI tract ramps up serotonin production to trigger diarrhea, in an effort to eliminate the toxin as quickly as possible. But the serotonin that isn’t used to initiate bowel contractions gets picked up by the bloodstream, and carried to your brain.

Short-Circuiting The “Vomiting Center”

When serotonin reaches your brain, it meets the medulla oblongata, a portion of the brain stem. Specifically, the neurotransmitter comes into contact with a specific part of the medulla oblangata – the “area postrema.”

Most parts of the brain are protected behind the blood-brain barrier – a wall of tightly-connected cells that prevents dangerous substances in the bloodstream from reaching brain tissue. But the area postrema’s cells aren’t bound to one another tightly, which allows the organ to act like a filter, monitoring the contents of our blood for potential toxins. Once a toxin is identified, the area postrema can trigger a cascade of chemical effects that eventually leads to nausea and vomiting. The point is to eliminate potential toxins from the body as quickly as possible. Serotonin is the key to this reaction. Binding to special receptors in the area postrema, serotonin begins a series of chemical messages that eventually tell your body to start throwing up.

Ondansetron, the active ingredient in Zofran, short-circuits this chain reaction. The neurotransmitter gets between serotonin and a special receptor in the area postrema, cutting off your body’s natural response to dangerous substances – which is to feel sick and vomit.

Was Zofran Approved By The FDA?

Yes, Zofran was approved by the US Food & Drug Association in 1991. But the FDA has never approved the drug for use by pregnant women as a morning sickness treatment. Zofran’s approval is limited to treating nausea and vomiting in chemotherapy, radiation therapy and surgical patients.

Here’s how the nausea drug’s own labeling describes its approved indications:

INDICATIONS AND USAGE

  1. Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥ 50 mg/m2.
  2. Prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy.
  3. Prevention of nausea and vomiting associated with radiotherapy in patients receiving either total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the abdomen.
  4. Prevention of postoperative nausea and/or vomiting.

As you can see, there is no label instruction for taking Zofran to alleviate morning sickness in pregnancies. When obstetricians, gynecologists and other physicians prescribe Zofran to pregnant women, they are doing so “off label.” While “off label” drug prescription is surprisingly common, the practice is rarely backed by adequate scientific evidence. In most cases, doctors have very little information on the safety – and potential risks – of a drug when it is prescribed for an unapproved use.

Zofran During Pregnancy

“Off label” prescription is entirely legal. The FDA has very little, if any, control over what individual doctors do in their practice.

But pharmaceutical companies are prohibited from marketing their drugs as safe or effective treatments for unapproved uses. In 2012, the US Government accused GlaxoSmithKline of doing exactly that – marketing Zofran as a safe and effective treatment for morning sickness, in violation of federal law. GSK eventually entered into a settlement with the United States, resolving government allegations that the company had improperly marketed a number of drugs, including Zofran. The settlement agreement can be found here.

GlaxoSmithKline has never admitted to unlawfully marketing Zofran to obstetricians and gynecologists.

Does Zofran Cause Birth Defects?

Shortly after GlaxoSmithKline’s settlement, researchers in the United States published a troubling study – in which Zofran was found to increase the risk of birth defects. More epidemiological research would follow, coming from groups in Denmark and Sweden.

Zofran And Birth Defects Studies

Today, multiple studies have linked the use of Zofran during the first trimester of pregnancy to child birth defects, including cleft palate, cleft lip and congenital heart defects.

CDC and Sloan Epidemiology Center Report – 2012

In a 2012 study of 9,000 expecting mothers, researchers at the Sloan Epidemiology Center, with funding from the US Centers for Disease Control, found that taking Zofran during the first trimester can double the risk of a child being born with cleft palate.

A much larger study performed in Denmark analyzed over 900,000 births from 1997 and 2010. The findings of the study concluded that newborns were twice as likely to suffer a serious congenital heart condition as a result of the birth mother taking ondansetron during the first trimester of pregnancy to alleviate nausea.

New England Journal Of Medicine Study – 2013

In this study, over 600,000 pregnancies were analyzed from 2004 to 2011 in Denmark. The study classified pregnancies as being exposed to Zofran if the drug was taken in the first 12 weeks of pregnancy. After drilling down into the data, it appears that half of the exposed pregnancies reviewed involved Zofran being prescribed at week 10, which is after formation occurs in the fetus. Critics have questioned this study’s validity, since many of the women took Zofran after their first trimester – when the risk of birth defects is much lower.

In supplemental materials, data from the study suggests that Zofran taken during the first trimester of pregnancy may result in an increased risk of:

  • Septal defect by 22%
  • Ventrical septal defect by 41%
  • Atrioventrical septal defect by 400%

However, the report, published in the New England Journal of Medicine, concluded that ondansetron is not associated with increased malformation rates when used for morning sickness. These results were soon contradicted by the Andersen study.

The Andersen Study – August 2013

The Andersen study analyzed the same database used in the Pasternak study, but included around 300,000 more pregnancies. The Andersen report also expanded the years of birth analysis to include all Danish births from 1997 to 2010. This increased the number of pregnancies from 600,000 to over 900,000. The report showed that 1,248 pregnant women were prescribed Zofran for morning sickness or hyperemesis gravidarum during their first trimester. Of those prescribed ondansetron, 58 (4.7%) had newborns who suffered a congenital heart defect versus 3.5% in pregnancies where the fetus was not exposed to ondansetron.

The Andersen Study concluded that:

  • Mothers who took Zofran were more likely to have a child with a congenital heart defect
  • Mothers who took Zofran were 2 to 4 times more likely to have a baby with a cardiac septal defect
  • There was an overall increase in the risk of malformations by 30%

BioMed Research International – December 2013

This child birth defect study was carried out by doctors in Australia who were investigating the off-label use of ondansetron in pregnancy. The doctors reviewed all births in Western Australia between 2002 and 2005, which totaled 96,968 births. Ondansetron was prescribed to only 251 pregnant women from this sample size. The data revealed the following about children born to mothers who took Ondansetron during the first trimester:

  • an increased risk of stillbirth
  • there were 5 deaths before the age of one
  • there was a 20% increased risk of a major birth defect with first trimester exposure to ondansetron
  • there was an increased risk of “obstructive defects of renal pelvis and ureter”, also known as kidney defects

The overall conclusion of this study was that the sample size was too small to draw statistically significant conclusions.

The Toronto Star Report: “Birth defects blamed on unapproved morning sickness treatment

On June 25, 2014, the Toronto Star published an article on its findings after a detailed analysis of the FDA’s public side-effect report database on Canadian women who had taken ondansetron / Zofran during pregnancy. It noted that Health Canada approved Zofran for use in treating severe nausea in cancer patients, but it was never approved for prescription to mothers-to-be. In all cases, doctors prescribed Zofran for hyperemesis gravidarum, a very extreme form of morning sickness that has been in the media recently due to Princess Kate Middleton’s public diagnosis.

In reviewing the health records for 2012, The Star found 20 reported incidents of child birth defects in women who were prescribed and ingested Zofran “off-label”. These defects included:

The Star reported that there were two infants who died as a result of complications allegedly caused by Zofran.

The Danielsson Report – October 2014

In the Danielsson report, a study was performed on 1,501,434 babies born to women in Sweden from 1998 to 2012. The goal of the study was to investigate the risk of congenital cardiac malformations in child births where Zofran / ondansetron was ingested. The study reported that of the total births in that period:

  • 2.9% or 43,658 babies were born with “major malformations”;
    • 34% or 14,872 of these babies had cardiovascular defects;
    • 24% or 10,491 suffered cardiac septum defects.

The overall conclusion of this detailed analysis was that mothers who ingested Zofran for morning sickness or hyperemesis gravidarum in their first trimester had a 62% increased risk of having a baby with a cardiovascular defect, and had a 200% increase in the risk of the baby being born with a septal cardiac defect.

Doctors in China have also produced medical findings which substantiate the link between Zofran and birth defects. In a 2006 study, Chinese researchers examined the fetal tissue from 41 fetuses. The results of the study showed that Zofran was present in all fetuses.