Summary Safety Review - Gadolinium-Based Contrast Agents - Assessing the Potential Risks of Congenital Anomalies, Stillbirth and Neonatal Death

Review decision

A Summary Safety Review complements other safety related information to help Canadians make informed decisions about their use of health products. Each summary outlines what was assessed in Health Canada’s review, what was found and what action was taken by Health Canada, if any.


Issued: 2021-09-22

Product

Gadolinium-based contrast agents

Potential Safety Issue

Birth defects (congenital anomalies), death of the unborn baby (stillbirth) and baby's death in the first month of life (neonatal death)

Key Messages

  • Gadolinium-based contrast agents (GBCAs) are authorized for sale in Canada to make certain body tissues easier to see during a magnetic resonance imaging (MRI) or a magnetic resonance angiography (MRA) scan.
  • Health Canada reviewed the potential risks of birth defects (congenital anomalies), death of the unborn baby (stillbirth) and baby's death in the first month of life (neonatal death) with the use of GBCAs during pregnancy. The review was triggered by updates made by the United States Food and Drug Administration (US FDA) to the product safety information of all GBCAs to include the potential risks of stillbirth and neonatal death with the use of these agents during pregnancy.
  • Health Canada's review of the available information found no link between the use of GBCAs during pregnancy and the risk of congenital anomalies. However, at this time, there is not enough information to rule out a link between the use of GBCAs during pregnancy and the risks of stillbirth and neonatal death.
  • As a precaution, given the potential for serious harm to unborn babies (fetuses) and infants, Health Canada will work with the manufacturers of GBCAs to include the potential risks of stillbirth and neonatal death in their Canadian Product Monographs (CPMs) to raise awareness among healthcare professionals and encourage reporting of these potential safety issues.

Overview

Health Canada reviewed the potential risks of congenital anomalies, stillbirth and neonatal death with the use of GBCAs during pregnancy. This safety review was initiated following updates made by the US FDA to the product information for all GBCAs to include the potential risks of stillbirth and neonatal death with the use of these agents during pregnancy.

At the time of the review, the CPMs for GBCAs include warnings to limit the use of these agents during pregnancy unless the potential benefit justifies the potential risk to the fetus, and that the use of a specific type of GBCA may be preferable during pregnancy. The purpose of this review was to assess whether additional warnings or other actions were required in Canada.

Use in Canada

  • GBCAs are authorized for sale in Canada to make it easier to view certain body structures on MRI or MRA scans, allowing healthcare professionals to see abnormal tissues.
  • GBCAs are available in vials as a solution to be injected into the veins. Gadolinium is the chemical element present in the active ingredients of these health products. GBCAs are classified into 2 types based on their chemical structure: linear agents and macrocyclic agents. Both types are presently marketed in Canada. In 2019, the majority of GBCAs used in Canada were of the macrocyclic type, which may be preferable in pregnancy. There are currently 8 GBCAs authorized for sale in Canada:
    • Linear agents: Magnevist (gadopentetate dimeglumine) and 1 generic drug product, MultiHance (gadobenate dimeglumine), Omniscan (gadodiamide), Primovist (gadoxetate disodium),
    • Macrocyclic agents: Dotarem (gadoterate meglumine), Gadovist (gadobutrol), ProHance (gadoteridol).
  • From 2015 to 2019, more than 2 million vials of GBCAs were sold in Canada.

Safety Review Findings

  • Health Canada reviewed information from searches of the Canada Vigilance databasea , the World Health Organization's Adverse Drug Reaction Databaseb , and the published literature.
  • At the time of the review, Health Canada had not received any Canadian or international reports of stillbirth nor neonatal death with the use of GBCAs during pregnancy.
  • Health Canada reviewed 3 international case reports of congenital anomalies with the use of GBCAs from the Canada Vigilance database. There were no Canadian reports of congenital abnormalities related to GBCA use at the time of the assessment. The review concluded it was unlikely that congenital anomalies were linked to GBCA use during pregnancy for 1 case, while 2 cases did not have enough information in the reports for further review.
  • Health Canada also looked at additional information from 7 published studies on the use of GBCAs in pregnancy and congenital anomalies, stillbirth and neonatal death.
    • One large Canadian study found a higher risk of stillbirth or neonatal death with the use of GBCAs during pregnancy. However, it was not possible to conclude there was a link between these potential risks and the use of GBCAs during pregnancy due to weaknesses in the study design.
    • The other 6 studies did not support a link between congenital anomalies, stillbirth, or neonatal death and the use of GBCAs in pregnancy. These studies also had weaknesses in their design.

Conclusions and actions

  • Health Canada's review of the available information found no link between the use of GBCAs during pregnancy and the risk of congenital anomalies. However, at this time, there is not enough information to rule out a link between the use of GBCAs during pregnancy and the risk of stillbirth and neonatal death.
  • As a precaution, given the potential for serious harm to fetuses and infants, Health Canada will work with the manufacturers of these products to include the potential risks of stillbirth and neonatal death in the CPMs for all GBCAs.
  • Health Canada will continue to monitor safety information involving GBCAs, as it does for all health products on the Canadian market, to identify and assess potential harms. Health Canada will take appropriate and timely action should any new health risks be identified.

Additional information

The analysis that contributed to this safety review included scientific and medical literature, Canadian and international information, and what is known about the use of GBCAs both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.

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