At the completion of this article, the reader should be able to improve their management of pregnant and/or breastfeeding patients, including:
- Understand the importance of shared decision-making in discussing risks with these patients
- Recognise the challenges posed by the lack of clinical trials involving pregnant and breastfeeding patients and how to approach ‘off-label’ drug use
- Recognise the limitations and gaps in drug safety information for pregnant and breastfeeding patients and how to mitigate risks in practice
- Be more familiar with the TGA’s categorisation system for drug safety during pregnancy
Alex Hui
OD, PhD, GradCertOcTher, FAAO
Adjunct Associate Professor, School of Optometry and Vision Science
Faculty of Medicine and Health, UNSW Sydney
Hesitancy can set in for optometrists when presented with pregnant or breastfeeding patients due to concerns about potential risks. However, Dr ALEX HUI says it’s essential to overcome this and seek out reliable information on best practices, especially with many medications lacking clear guidelines.
There is often hesitancy in the therapeutic management of patients who are pregnant and/or lactating. This concern is understandable, considering the lifetime potential health and liability impacts should treatments cause harmful effects in the developing child.1
Teratogens
When considering use of agents during pregnancy, a teratogen is any substance which may cause a non-heritable birth defect in a developing foetus via a toxic effect.2 There are numerous known teratogens among pharmaceutical agents. For example, isotretinoin, a treatment for acne, is known to cause serious birth defects, including death, as well as miscarriage or premature birth.3 As such, not only is the use of this drug contraindicated for use while pregnant, but prescribing guidelines or recommendations in some jurisdictions often require use of two forms of birth control during use to ensure no pregnancy occurs.3
Alcohol is another well-known example of a teratogen, as heavy ingestion can lead to foetal alcohol syndrome, resulting in poor foetal growth, mental retardation and behavioural issues.4
For the eyecare practitioner, hesitancy in managing conditions therapeutically during pregnancy and lactation is likely common. It stems not only from a lack of experience or exposure but is also because information regarding prescribing in this population is often unavailable from official documentation. Regardless, practitioners should familiarise themselves with the best practices in managing these patients as they can and will get diseases which need to be treated.
‘Therapeutic orphans’
While in the ideal scenario patients who are pregnant would not be utilising any medications, this is often unrealistic practically in most cases. About 60% of pregnant women will use a prescribed medication to manage an ongoing condition or condition induced by pregnancy itself.5 Further, 70% of patients who are lactating take some form of medication or supplement during this period.5
Unfortunately, while common, these patients are often relying on ‘off-label’ usage of these medications, as there is often little to no official information in the prescribing documents for how the drugs should be used in pregnant or lactating women.5 It is estimated that upwards of 90% of drugs on the market lack the appropriate information for how they should or should not be used while pregnant or lactating.5 This is a significant problem. In the literature, pregnant and lactating women, along with children, are often termed ‘therapeutic orphans’ as they are often excluded from clinical trials that investigate the safety and efficacy of drugs coming to the market.2
Recommendations to the entire industry are to include these patients as part of trials, to recognise that these are patients who will require treatments, and that pregnancy should not be seen as an inconvenience or complication in clinical trial and regulatory study design.2
In Australia, the Therapeutic Goods Administration (TGA) utilises a letter system to indicate the level of evidence to support or not support the use of a drug formulation during pregnancy. This ranges from Category A to Category X, with descriptors found in further detail in Table 1 below.
Explaining the TGA’s drugs categories
The TGA explains that it considers pharmacological information in making the decision as to which category a drug formulation falls into. This can include pharmacokinetic information such as the dose, regimen and route of administration as well as pharmacodynamic information such as the potential mechanisms of action that the drug may have to act as a teratogen on a developing fetus.6
These decisions have numerous implications for what is and isn’t considered by the regulator when making the letter determination. For example, the category assigned is associated with the use of the drug formulation as intended, and so it does not consider things such as if they were used via a different route or in cases of overdose.6
It also does not take into account rare adverse reactions, or if there is occupational exposure to the formulation.6 This can be illustrated with the example of the aminoglycoside antibiotics tobramycin. This drug is known to potentially cause ototoxicity and nephrotoxicity, so oral or intravenous preparations of this are pregnancy ‘Category D’.7 The ‘Category D’ classification indicates that there are known long-term impacts of using it while pregnant, but also reflects that even with this it is not absolutely contraindicated, as there may be instances where use of the drug to combat a susceptible infection may be warranted on balance of the risks and benefits.
In contrast, ophthalmic formulations of tobramycin eye drops are pregnancy ‘Category B3’.8 This demonstrates how the formulation can impact the pregnancy categories. The active ingredient in the ocular formulation has not changed compared to the oral or intravenous preparation, and thus the inherent risk to the foetus if exposed has not changed.
What is different is that the topical formulation, when used as intended on the eye, likely does not allow for significant levels to reach the developing foetus during pregnancy to exert their adverse effects. The TGA thus seeks to answer in making their category decision whether the drugs of interest, in the formulation of interest, reaches the developing foetus in significant enough quantities to be of concern, when making these pregnancy category decisions.
Criticisms
There has been criticism of the category and letter system used by the TGA and other regulatory agencies worldwide, as it inherently implies categories are more or less safe than others. However, the TGA explicitly states that the categories are not hierarchical. Rather, they merely reflect the amount of information which is known (or not known) when that formulation is used in pregnancy.6
Unfortunately, practitioners or patients often erroneously will have the mindset to seek use of drugs in the A or B categories, as they are ‘safer’ than those in C or D, but this is explicitly not the intention of the classification system, and subcategories of B are merely based on animal rather than human data.6
It should also be understood that the category of the drug is in some ways influenced by the drug sponsor, who may apply for a more restrictive category than justified by the available data for legal or liability reasons.2
The FDA PLLR
The Food and Drug Administration (FDA) in the US has undergone an overhaul of its pregnancy labelling system.9 They have removed the use of categories, and have replaced it with a narrative write up specified in the new ‘Pregnancy and Lactation Labelling Rule’ (PLLR) section.10 Sponsors for drugs are required to have specific sections detailing what is known or not known about a formulation if used during pregnancy, lactation and a new requirement for comments on use by males or females of reproductive potential.11
This requirement has had some positive impact. The availability of studies of the use of formulations in pregnant patients are becoming more common. Announced in 2015 with a five-year implementation period, all approved formulations from 2020 should follow this new label and information, with the intention that medicines approved before 2015 will be required to change their labels gradually.9 To date, no ophthalmic medication has received a new PLLR label.
Lactation
Lactation presents a similar situation to pregnancy in that for many years there was little to no information on the passage of drugs into the breastmilk and in what quantities, and what impact this may have after ingestion by infants.12
To supplement the lack of official information from the product information sheets, resources such as the Australian Medicines Handbook (AMH) and LactMed by the National Institute of Health in the USA are often used by practitioners for information. LactMed will typically provide a summary of recommendations for the use of specific active ingredients and will also provide the supporting evidence as part of the write up.
In contrast, the AMH may have specific recommendations for not just active ingredients but also when they are in particular formulations such as eye drops versus systemic formulations and will helpfully also note if recommendations are based on large amounts of clinical experience and exposures.13 The AMH is also a strong go-to resource for the use of formulations in pregnancy. Statewide programs in Australia, such as the information service ‘Mothersafe’ from New South Wales can also be live resources for practitioners to discuss the safety of medications.14
While eyecare practitioners rightly should be concerned when using medications in patients who are pregnant or breastfeeding, understanding the information which may or not be available regarding the use of a formulation to treat ocular conditions is an important first step in being able to communicate the levels of risk to patients, so that a shared decision on the risk-to-benefit ratio can be made, with the hope of preserving the health and safety of both developing foetus, infants and mothers.
More reading
Ocular associations in pregnancy
Neuropathic pain in the eye – A/Prof Alex Hui
Aussie-based authors among CORE’s top-tier papers; Dr Alex Hui appointed head of biosciences
References
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7. Pfizer Australia Pty Ltd. DBL Tobramycin Injection (Tobramycin) 2022 [Available from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2011-PI-03575-3.
8. Alcon Laboratories Inc. TOBREX (tobramycin ophthalmic solution) 0.3% 2012 [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/050541s024lbl.pdf.
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13. Pharmaceutical Society of Australia, Royal Australian College of General Practitioners, Australasian Society of Clinical Experimental Pharmacologists and Toxicologists. Australian medicines handbook 2018. AMH. Adelaide SA: Adelaide SA : Australian Medicines Handbook; 2018.
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