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Zofran Litigation Update

Concerns Over Fetal Defects From Zofran Use During Pregnancy

We have received questions expressing concern over the allegations of harm and lawsuits against the manufacturer of Zofran (generic is ondansetron), GlaxoSmithKline (GSK). Here are some important facts to know.

  1. Proving with certainty that a drug causes harm is extremely difficult as there are many variables and genetic differences that may impact fetal development.
  2. No medications are specifically approved for treating hyperemesis due to ethics and liability of testing women during pregnancy.
  3. About 3% of all babies in the US are born with major birth defects and 70% of pregnant women take at least one prescription medication during pregnancy.
  4. Animal studies have not found increased risk of infertility, birth defects or other adverse reproductive outcomes for Zofran. ONLY extremely high doses (equivalent to 10-37 times the usual dose given to humans) were associated with adverse fetal effects in rats.
  5. Nearly all research studies, large and small, find little if any increase in the number of cases of birth defects after mothers use Zofran. Some that find an increase in defects that are attributed to multiple possible causes including maternal health, weight/BMI, other medications, and factors not identified. Few studies actually confirm if a mother took the medication before 8-10 weeks which is during the developmental time where a defect could occur. (see table below) They assume usage because the medication was prescribed.
  6. A 2016 study of 771 HG pregnancies found fewer miscarriages and terminations in those taking Zofran, as well as a higher live birth rate, and no increased number of defects.
  7. Most lawsuits alleging Zofran caused fetal harm involve children with multiple birth defects that have not been found or suggested to be associated with Zofran in any published studies or animal trials.
  8. One of the original studies cited by attorneys as the strongest evidence in support of the litigation refers to a now removed abstract of an unpublished study listed on the Motherisk website. To our knowledge, this research has not undergone peer-review to determine its validity.
  9. Many research studies on treatment for HG involve conflicting interpretation of data, or research methods considered to be low quality evidence and thus not reliable. The latest studies looking at all available research find a lack of evidence of harm and poor quality of data in many studies such as those finding risks of harm. Another study finds little or no evidence of concern for 51 defects (a possible chance finding was noted for cleft and a kidney defect).
  10. Other concerns about the safety of Zofran to mothers involve giving a large, single dose or multiple medications with serotonin effects simultaneously, neither of which are done for HG.
  11. Congenital cardiac defects, the most common defect, are structural heart problems present at birth. They occur before 10 weeks, often before the mother knows she is pregnant. They range from minor (septal) to complex and also occur in babies of women who don't take medication. The cause is rarely able to be determined, and likely multifactorial.
  12. Prematurity and other health problems associated with malnutrition during pregnancy, as well as other concerns leads to more diagnostics, and may result in diagnosis of more defects in children born to mothers with HG, including "silent" defects that usually have no impact.
  13. GSK did not market Zofran for HG. The 2012 settlement GSK accepted to avoid further litigation focused on 3 other drugs. Zofran's small contribution to the settlement reimbursed the US government for health care charges arising from the use of Zofran off-label. Off-label use of medications is common practice for many conditions especially occurring during pregnancy when testing is deemed unethical, and those conditions given minimal grant funding like HG.
  14. It is likely that many babies born to HG mothers would not be here without medications that effectively minimize nausea and vomiting. Studies find more fetal losses (or terminations) in those not taking medications for HG.

    More research on HG

 

New England Journal of Med 2013;368:
814-23.

1970 Mothers who took Zofran during the first trimester in Denmark.

Receipt of ondansetron was NOT associated with
- significantly increased risk of spontaneous abortion
- significantly increased risk of stillbirth
- any major birth defect, preterm delivery, delivery of a low-birth-weight infant, or delivery of a small-for-gestational-age infant.

“Ondansetron taken during pregnancy was not associated with a significantly increased risk of adverse fetal outcomes.”

BioMed Research International. 2013;2013:909860.

251 Mothers who took Zofran during pregnancy in Western Australia, 2002–2005.

“Our study did not detect any adverse outcomes from the use of ondansetron in pregnancy...”

Reproductive Toxicology. 2014 Dec;50:134-7. 

1349 Infants of women who took ondansetron in early pregnancy between 1998-2012 in Sweden.

“No statistically significantly increased risk for a major malformation was found… The teratogenic risk with ondansetron is low but an increased risk for a cardiac septum defect is likely.”

Note: There were 17 septum (cardiac) defects out of 1349 (~1%) women exposed to Zofran (aka cases) compared to their control group where 315 septum defects were identified out of 41,388 (<1%) pregnancies exposed to meclizine. In both cases and controls approximately 99% of exposed babies did NOT have a cardiac septum defect. Further, only 899 women were exposed during the time required to impact heart development.

Birth defects research. Part A, Clinical and molecular teratology. 2012 January;94(1): 22–30.

514 Mothers who took Zofran in United States.

“Nausea and vomiting of pregnancy was not observed to be associated with an increased risk of birth defects, but possible risks related to three treatments (i.e. proton pump inhibitors, steroids and ondansetron), which could be chance findings, warrant further investigation.

Note: The increased risk was very small statistically.

Reproductive Toxicology 62 (2016) 87–91. 771 Mothers who took HG worldwide. (Unlike most studies, these mothers reported taking Zofran, not just receiving a prescription for it. Other studies have no verification if a mother actually took their medications.) Ventricular septal defects were reported in 2/952 of infants in the HG/Ondansetron-exposure group and 4/1286 in the No HG/No Ondansetron-exposure group. Cleft palate was reported in 1/952 live births in the HG/Ondansetron and 2/1286 in the No HG/No Ondansetron-exposure groups. Women with a history of HG who took ondansetron reported fewer miscarriages and terminations, and higher live birth rates. The overall results do not support evidence of teratogenicity ofondansetron.
Obstet Gynecol. 2016 May;127(5):878-83. A Systematic Review of recent studies. The 3 largest studies showed no risk of defects. The small risk in a few studies was not seen in the larger studies. The overall risk of birth defects associated with ondansetron exposure appears to be low. There may be a small increase in the incidence of cardiac (septal defects) abnormalities...
 2018 Aug;132(2):385-394. A review of 51 defects using data from two case-control studies with 628 women taking Zofran in 1st trimester. "For the majority of specific birth defects investigated, there was no increased risk associated with first-trimester use of ondansetron for treatment of nausea and vomiting of pregnancy compared with no treatment" and there a possible chance finding of associations with cleft palate and renal agenesis-dysgenesis.
J Obstet Gynaecol Can. 2018 Jul;40(7):910-918. Systematic review of 10 studies. Sample sizes ranged from 17 to 1 501 434.

Systematic review finds studies do show evidence for fetal harm.

"our results highlight the paucity [lack] of evidence linking prenatal exposure to ondansetron to an increased risk of congenital malformations."

 

The HER Foundation will continue analyzing data and studies on Zofran and post updates on the home page and Facebook.

RELATED INFORMATION

Updated on: Aug. 04, 2018

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