Why is it so hard to get drugs approved for use during pregnancy?

Nobody wants to see another Thalidomide tragedy^[1].

The drug was prescribed to pregnant women during the 1950s and early 1960s to treat nausea. But it led to more than 10,000 children^[2] worldwide with irreversible birth defects, ranging from limb deformities to facial malformations.

Pregnant people need access to medication that is effective, safe and evidence-based. But many drugs that may be safe are now never tested due to ethical concerns, cost and legal risk.

This leaves many using drugs in ways that haven’t been approved – or not taking the medications they need out of fear they could cause harm.

The legacy of Thalidomide

The Thalidomide tragedy^[3] has an important influence on how medicine use during pregnancy is regulated and viewed today.

Thalidomide was not tested in pregnant women during first trimester prior to marketing. This devastating episode has taught us valuable lessons about how drugs can affect fetal organ development. It also changed how medicine use during pregnancy is viewed by the wider community, the pharmaceutical industry, regulators and ethics committees responsible for approving clinical trials.

But despite societal fears, medication use in pregnancy has increased over the last decade.

A 2024 nationwide registry of 1.4 million Danish pregnancies found^[4] the frequency of at least one prescription being dispensed during pregnancy increased from 57% in 1998 to 63% in 2018. This coincides with an increased use of multiple medicines (35% in 2018).

Medicines are used to manage pregnancy-specific conditions (such as morning sickness), incidental symptoms (including colds) and pre-existing conditions (such as asthma). Yet most pregnancy use remains “off-label”.

Off-label medication use during pregnancy

The term “off-label^[5]” applies when a medicine is prescribed to be used in a way that hasn’t been licensed by a regulatory authority, such as the Australian Therapeutic Goods Administration (TGA).

This might mean it is:

• used for a different condition
• in a different dose
• administered in a different way (for example, injecting into the vein rather than the muscle)
• for a patient group not included in the approved product information.

Off-label prescribing in pregnancy is common. One UK study^[6] of almost 18,000 inpatient antenatal prescriptions found 74% were used off-label, with the manufacturer cautioning or contraindicating 55% in pregnancy.

What are the barriers to testing medicines during pregnancy?

1. Historical exclusion

Off-label prescribing often occurs because pregnant women are excluded from pre-registration trials. The approved use therefore does not include them, even if later studies confirm efficacy and safety in this group.

Historically, human research ethics committees have excluded pregnant women from medicine trials, as “vulnerable” participants or women of child-bearing age have been required to use contraception.

However, attitudes are slowly changing. The World Health Organization^[7] (WHO) now says pregnant people should be considered “complex” rather than “vulnerable”, and should not be presumed to be ineligible for trials.

Instead, pregnant women should be included in carefully conducted research. Having more information about how they respond to drugs and their specific needs during pregnancy is in fact the best way to ensure their safety.

The WHO calls this approach “protection through research” rather than “protection from research.”

2. Unwilling drug companies

Pharmaceutical companies must apply to market a new medicine, or to change the way an available medicine is used. They have to provide the Therapeutic Goods Administration^[9] with clinical trial evidence to demonstrate it is safe and effective.

However, there are few incentives^[10] for them to run trials during pregnancy.

To include pregnant participants, companies have to consider ethical concerns, greater regulatory oversight and the potential risk of the fetus being exposed to substances that could interfere with their development. Many are unwilling to take on the medico-legal risks.

A US audit^[11] of 558 industry-sponsored studies evaluated already-registered medicines. They found only five (1%) enrolled women of childbearing potential, with 95% of protocols specifically excluding pregnancy.

The costs and risks mean many companies decide testing a medicine’s use during pregnancy is not commercially viable, especially given pregnant women represent a small population of potential users.

3. Prescriber and patient concerns

Off-label prescribing is legal. But a clinician who prescribes a medication for a use that hasn’t been approved takes on the legal burden, rather than the pharmaceutical company, if the patient experiences an adverse effect where the drug is determined as the cause.

Prescribers also have to consider clinical and ethical concerns, weighing up the need to heal against duty of care to “first do no harm^[12]”.

Pregnant women tend to focus more on whether a medication is safe than if it’s effective. A significant proportion^[13] overestimate risk. This can lead some women to stop taking their regular medications when they become pregnant.

When a medicine is prescribed off-label, it is important the woman is fully informed of all available evidence – both its benefits and harms. She should be able to ask questions and decide whether or not to use the medication.

Whatever the outcome, the discussion and informed consent (where a patient decides to use the medicine) must be documented.

Ongoing medicine supply shortages^[14] and local discontinuations of several older obstetric medicines – such as fast-acting oral nifedipine tablets to reduce risk of pre-eclampsia – have made off-label use unavoidable.

Without greater investment^[15] by both pharmaceutical companies in trials during pregnancy and government regulators, this situation is likely to continue placing pregnant women at risk.

References

1. ^{^} Thalidomide tragedy (academic.oup.com)
2. ^{^} 10,000 children (www.thalidomidetrust.org)
3. ^{^} Thalidomide tragedy (academic.oup.com)
4. ^{^} found (pubmed.ncbi.nlm.nih.gov)
5. ^{^} off-label (pubmed.ncbi.nlm.nih.gov)
6. ^{^} UK study (pubmed.ncbi.nlm.nih.gov)
7. ^{^} World Health Organization (www.who.int)
8. ^{^} Ground Picture/ Shutterstock (www.shutterstock.com)
9. ^{^} Therapeutic Goods Administration (www.tga.gov.au)
10. ^{^} few incentives (pubmed.ncbi.nlm.nih.gov)
11. ^{^} audit (pubmed.ncbi.nlm.nih.gov)
12. ^{^} first do no harm (www.health.harvard.edu)
13. ^{^} significant proportion (pubmed.ncbi.nlm.nih.gov)
14. ^{^} shortages (pubmed.ncbi.nlm.nih.gov)
15. ^{^} greater investment (ranzcog.edu.au)