Not as easy as ABCD or X

Case scenario

Elli, 25 years old and 18 weeks pregnant, presents to your pharmacy asking if there is anything she can safely use in pregnancy for hay fever. Elli’s main symptom is significant daily nasal congestion, and she used beclomethasone nasal spray prior to pregnancy with good effect. Elli would prefer to use the beclomethasone again, if possible, as she knows it works well for her. She has not been using anything since finding out she is pregnant, due to safety concerns, but is now desperate for some relief.

Introduction

The Therapeutic Goods Administration (TGA) uses a categorisation system for prescribing medicines in pregnancy that was developed based on the available evidence of the risks associated with taking prescription and over-the-counter medicines during pregnancy.¹

This system is used by healthcare professionals, in addition to other evidence-based references, to aid decision-making and to support the safe use of medicines in pregnancy.¹

While the current categories present as a simplistic grading system, they do not always accurately communicate clinical risk, or always consider all important factors, such as dose, gestation at the time of exposure, or route of administration. There may also be more current safety and risk information that has become available since the categorisation was issued.^2-4

This article discusses the current system, potential issues relating to its use, and the key considerations when determining if a medicine is safe to use by a pregnant person.

Learning objectives After reading this article, pharmacists should be able to: Describe the current Australian categorisation system for prescribing medicines in pregnancy Discuss potential issues with the current Australian categorisation system for prescribing medicines in pregnancy Discuss key considerations when determining if it is safe for a patient to take a medicine in pregnancy Identify key evidence-based resources to utilise when assessing medicine safety in pregnancy. Competency (2016) Standards addressed: 1.1, 1.4, 1.5, 2.1, 2.2, 2.3, 3.1, 3.5 Accreditation number: CAP2404SYPNM Accreditation expiry: 31/03/2026

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The Australian categorisation system for prescribing medicines in pregnancy

The categorisation system has been developed by experts, and assesses medicines on their risk profile in pregnancy based on available information at the time of assessment.¹ 

The system applies a category to a medicine (A, B1, B2, B3, C, D or X).¹ 

The categorisation takes into account the known harmful effects of medicines on the developing baby, including the potential to cause birth defects, peripartum adverse effects (which may or may not be reversible) and the potential to cause problems later in life (where this information is available).¹ 

Due to legal considerations in Australia, manufacturers can apply (and have applied in some cases) a more restrictive category than that which can be justified by available information.¹

Animal studies can play a significant role, particularly during drug development, in identifying safety concerns in some medicines and can help inform the risk in humans.⁵ This is particularly relevant in category B and its subclassifications where human data is lacking or inadequate.¹

Overview of the categories 

A brief summary of each category, with the TGA definition, is highlighted below. Importantly, not all medicines within the same category carry the same level of risk, and the categories do not follow a hierarchical structure (i.e. the allocation of a B category does not mean it is necessarily safer than a medicine in category C).^1,2 

Category A 

This category includes medicines that ‘have been taken by a large number of pregnant women and women of childbearing age, without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the fetus having been observed’.¹ Category A medicines have a safety profile that is favorable for use in pregnancy. 

Amoxicillin is an example of a category A medicine where available information supports the safety profile in pregnancy.^1,6 

Category B 

This category has been further subdivided into B1, B2 and B3. The subcategorisation of medicines within this category is based on animal data, as human data is lacking or inadequate for medicines in this category.¹ 

Discussed further below, a major issue with the categorisation system is that the category is assigned when a medicine is first marketed, and this is not often reviewed or changed despite new evidence becoming available. This can make category B particularly difficult to navigate for pharmacists because some medicines in this category have significantly more human data available than the category suggests. This often results in other specialised references providing significantly different information regarding risk and safety.² 

Category B1 

These medicines ‘have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage’.¹ 

Cefazolin is an example of a B1 medicine which is considered safe to use in pregnancy when it is the recommended treatment. This is based on a limited number of human reports with support from experimental animal studies showing no harm.^1,6

Category B2 

These medicines ‘have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage.’¹

Cetirizine is an example of a B2 medicine which is considered safe to use in pregnancy by specialised resources, but recommended to be used at the lowest effective dose for the shortest duration possible.⁶ Animal studies have not shown anomalies, and maternal use has not been associated with increased risk of congenital malformations in most studies.^1,6 

Category B3 

These medicines ‘have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.’¹ 

A specific example of how navigating category B can be difficult is aciclovir (both oral and topical), which remains a category B3 medicine despite extensive human clinical experience having demonstrated no associated increased risk of congenital malformations and it being considered safe to use by specialised references.^1,6 

Category C 

This category includes medicines that ‘owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details’.¹ 

Metformin is an example of a category C medicine. Evidence-based resources indicate that metformin has not been found to be associated with an increased risk of malformations or adverse pregnancy outcomes; however, some studies have suggested it may contribute to increased subcutaneous fat or body mass index and adverse metabolic profiles in the child. Monitoring of both the pregnant person and fetus is recommended when it is used.^1,6 

Category D 

This category includes medicines ‘which have caused, are suspected to have caused, or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details’.¹ 

Medicines in category D are not absolutely contraindicated during pregnancy.¹ The use of a category D medicine in pregnancy may be justifiable in some cases where the benefits of treating the maternal condition outweigh the relative risks associated with the medicine for the developing fetus. The category D grading of a medicine may also not be relevant at all stages of a pregnancy or at all doses/dose forms. 

An example of this is nicotine replacement therapy (NRT). Despite being category D, it can be considered for use in pregnancy when non-pharmacological management is unsuccessful, as the risk of using NRT to the fetus is considered lower than the risk of tobacco smoking.^1,6,7, 

Category X 

This category includes medicines ‘which have such a high risk of causing permanent damage to the fetus that they should not be used in pregnancy or when there is a possibility of pregnancy.’¹ 

Isotretinoin is an example of a category X medicine. Exposure in pregnancy has been associated with an increased risk of congenital malformations, including craniofacial, cardiac and central nervous system defects, spontaneous abortion, perinatal mortality and premature birth.^1,6

Its use is contraindicated in pregnancy and for those planning to conceive.⁶

Identified issues with the system 

While these categories are intended to provide safety advice on medicine use in pregnancy, they are known to be ambiguous and provide limited detail in their analysis of risk.²

Identified issues include: 

• The categories are not a hierarchical system in terms of safety or a gradation of risk (i.e. a category B medicine is not necessarily safer than a category C medicine, despite the alphabetical nature of the categories potentially implying this).^1,2,8
• There is an assumption that all medicines in the same category hold the same level of risk, which is often incorrect.² 
• Categorisation is not often reviewed after the medicine is initially approved by the TGA and therefore is based only on the information available at that time. More current information regarding risks or even reassuring safety data may be available.^2,3 As noted, this is particularly significant for category B, where medicines are subcategorised based on animal studies due to inadequate or absent human data being available at that time.¹ 
• The categories do not identify potential risk or safety in relation to the timing of exposure during gestation. Depending on the medicine, and the potential risks involved, this may differ depending on trimester or gestation.^2-4 
• The dose and route of the medicine is not usually taken into account, which may affect the potential risk and safety profile.^2-4 
• In any pregnancy, there is a 3–4% ‘baseline risk’ of the baby having a birth defect. Only a small proportion of these are attributed to medicine use during pregnancy.^6,9 This, and the potential additional risk of an adverse outcome for a particular pregnancy when considering relevant factors such as advanced maternal age, smoking status, obesity or pre-existing medical conditions, is not addressed by the categorisation system.² Therefore, it is challenging to understand and communicate the absolute increase in risk of taking a medicine for a particular patient.² 

What to consider 

It is essential that current, evidence-based resources or medicines information services are used and considered alongside the classification, while considering the clinical context of the individual patient, to gain a clearer understanding of the risk versus benefit profile for each individual patient.³ See Table 1 for examples of these resources. 

Those planning a pregnancy, as well as those who are pregnant, must be appropriately counselled regarding the risks of treatment versus the risks associated with the untreated condition. Pharmacists play an important role in helping to weigh these individual risks and determining the best options for treatment. Pharmacists must focus on optimising treatment during pregnancy, acknowledging that the avoidance of all medicines is not necessarily the safest option. 

Pharmacists must obtain adequate information and understand the changes in pharmacokinetic/pharmacodynamic parameters in pregnancy. This will assist in formulating an individualised risk-benefit assessment for patients and providing a relevant, evidence-based approach. 

Listening to a patient’s concerns and acknowledging any information which has been accessed prior to seeking advice is essential. An online search and/or advice from friends and family can uncover concerning and frequently inaccurate information. This may result in a patient not treating a new condition or ceasing current treatment unnecessarily or inappropriately. Unfortunately, other healthcare professionals can also provide inaccurate or incomplete advice.^4,10

Key considerations, alongside the use of multiple evidence-based resources, include: 

Patient considerations 

• What is the clinical requirement for this medicine for this patient in pregnancy, and what is the likely benefit of treatment and/or potential risks of non-treatment?
• Pregnancy gestation. 
• Does the patient have a family history of malformations or other relevant risk factors?

Medicine considerations 

• Potential risks of using this medicine. 
• Dose, formulation, frequency and duration of treatment the patient requires. 
• If the medicine was taken in a previous pregnancy. 
• Possibility for the medicine to be ceased, or ceased temporarily and recommenced if needed, and the potential impacts of these options for the patient. 
• Whether a non-pharmacological option is appropriate. 
• Is there an option to change therapy to a ‘safer’ medicine without compromising the patient’s treatment? 

With reassuring counselling, provision of readily accessible evidence-based resources, and explaining why this advice may differ from information obtained elsewhere, pregnant patients can participate in shared decision-making when considering taking a medicine during pregnancy. 

The way forward 

In 2016, the Australian Medicines Handbook (AMH) removed reference to the TGA categorisation system and replaced this with a statement of risk based on human data and clinical experience that evaluates the available information and assesses the safety profile of each medicine.³ 

This change was due to confusion around the alpha-denominated system, the lack of specificity in relation to the timing of exposure during pregnancy, the fact that the categories did not necessarily change to reflect new information, and its inability to address the risks and benefits for an individual patient.^3,11 

In 2015, the United States Food and Drug Administration (FDA) moved away from a similar categorisation system, after recognising the need for improvement. They now use the Pregnancy and Lactation Labelling Rule, a narrative summary to describe fetal risk more clearly and to assist prescribing decisions and patient counselling.^4,12,13 This FDA change demonstrates a potential approach to address the problems encountered with the current Australian system. 

Knowledge to practice 

Pharmacists can use the current categorisation system, while acknowledging its potential limitations, to assist pregnant persons to make informed decisions about medicine use. The categorisation should never be used in isolation however, and must always be considered alongside current, evidence-based guidelines and references (see Table 1) while considering the clinical context of the patient. 

Conclusion 

Pharmacists are in an ideal position to support optimal pregnancy outcomes through the provision of current, evidence-based information and advice and recommendations on the safety of medicines during pregnancy.

Case scenario continued You discuss identifying and avoiding triggers and using saline nasal spray as a first-line management approach. If this is not possible or not effective, given Elli is having significant daily symptoms, an intranasal corticosteroid could be considered. You review the over-the-counter intranasal corticosteroids and note that budesonide is category A, and beclomethasone and others are category B3. You review the AMH, MotherSafe resources and the Women’s Pregnancy and Breastfeeding Medicines Guide. You note that despite being category B3, beclomethasone is considered safe to use, as when it is used intranasally it enters the bloodstream minimally and it has not been associated with an increased risk of congenital malformations. You explain this and refer Elli to the MotherSafe ‘Hay Fever in Pregnancy and Breastfeeding’ resource for reassurance.

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Key points 

• Understanding the Australian categorisation system for prescribing medicines in pregnancy, and its many limitations, is essential to supporting decision-making for pregnant persons.
• The categories should be considered alongside information obtained from current, evidence-based pregnancy specific resources (see Table 1) and the clinical context of the patient.
• The decision to use a medicine while pregnant should be tailored to each specific individual, with consideration of the potential risks of treatment versus the benefits of using the medicine to treat the maternal condition.
• Pharmacists can assist patients to access reputable, evidence-based resources to inform their decision-making, and provide appropriate advice and recommendations.

International Resources

• MotherToBaby is an online resource from the United States, published by the Organization of Teratology Specialists. It is freely available and includes FAQ (Frequently Asked Questions) style fact sheets explaining safety at all stages of pregnancy and includes information concerning paternal exposure. Each monograph is regularly updated and fully referenced.
• BUMPS (Best Use of Medicine in Pregnancy) produce leaflets from the UK Teratology Information Service (UKTIS). These leaflets are based on scientific material UKTIS produces for healthcare professionals and are freely available and based on all relevant published scientific studies.

References

1. Department of Health and Aged Care. Australian Categorisation System for Prescribing in Pregnancy Canberra, Australia 2023. At: tga.gov.au/australian-categorisation-system-prescribing-medicines-pregnancy
2. Kennedy DS. A to X: the problem of categorisation of drugs in pregnancy – an Australian perspective. Med J Aust 2011;195(10):572–4.
3. Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd; 2023.
4. Hill M. Critical caveats in using product information/pregnancy categories for pregnant or breastfeeding patients. Aust J Gen Pract 2018;47(12):883–8.
5. Medicines in Pregnancy Working Party, Australian Drug Evaluation Committee. Prescribing medicines in pregnancy: an Australian categorisation of risk of drug use in pregnancy. 4th ed. Canberra: Therapeutics Goods Administration, 1999.
6. Pregnancy and Breastfeeding Medicines Guide. Victoria, Australia. The Women’s. 2023. At: https://thewomenspbmg.org.au
7. Nicabate product information. eMIMS cloud; [2023]. At: www.emims.com.au/Australia/drug/search/?q=nicabate
8. McEwan, J. A history of therapeutic goods regulation in Australia. 2007. Therapeutic Goods Administration Canberra, Australia.
9. Congenital anomalies in Australia 2017–2018. Canberra, Australia: Australian Institute of Health and Welfare; 2023.
10. Grzeskowiak LE. Role of pharmacists in optimising medication management during pregnancy and lactation. J Pharm Pract Res2015 Mar;45(1):64–71.
11. Misko J, Rawlins MDM. Letter to the editor: Answering medication safety concerns in pregnancy: The difficulty for community pharmacists. Aust N Z J Obstet Gynaecol 2021;61(5):E27–e8.
12. Pregnancy labeling. FDA Drug Bull 1979;9(4):23–4.
13. S. Food & Drug Administration. Pregnancy and Lactation Labeling (Drugs) Final Rule. 2014. At: www.fda.gov/drugs/labeling-information-drug-products/pregnancy-and-lactation-labeling-drugs-final-rule

Our authors

NABEELAH MUKADAM BPharm (Hons), MPhil (Pharmacy), FANZCAP (Lead&Mgmt, ObsGynae), MSHP provides both clinical and operational support to the Western Australian Obstetric Medicines Information Service.

TAMARA LEBEDEVS BPharm, PostgradDipPharm, FANZCAP (MedInfo, ObsGynae), MSHP has extensive experience in the specialist practice of women’s and newborn health and has been pivotal in the expansion and promotion of the statewide Pregnancy and Breastfeeding Medicines Information Service in Western Australia.

Our reviewer

ELIZABETH HEINER BPharm (she/her) is a MotherSafe Teratology Information Specialist.