Handling veterinary medicines and pregnancy
Many people who prescribe veterinary medicines or who handle them (or bodily fluids that may contain them or their active metabolites) are not aware of the potential harmful effects they may have on human reproduction (BSAVA 2018). This module gives up-to-date, evidence-based guidance on which drugs and methods of handling are hazardous; information on the relevant regulations relating to the safe handling of such medicines; and practical guidance on avoiding harm in veterinary practice. By doing this module you will:
- understand the principles of reproductive toxicity;
- understand how data on the harmful effects of medicines are generated;
- be aware of the evidence on reproductive harm in veterinary practice;
- understand what practical measures to take to avoid harm;
- know where to find helpful information on medicines and pregnancy.
A teratogen is an agent or condition that can have toxic effects on the fetus. Exposure of the mother or father to teratogens around the time of conception, or of the developing baby via the mother during pregnancy and around the time of birth, can cause a wide variety of adverse developmental outcomes, including:
- structural or functional birth defects
- fetal death
- impaired fetal growth
- neonatal adaptation disorders
- impaired neurodevelopment or behaviour
- increased susceptibility to diseases like cancer. (Kallen et al. 2013; Lazic et al. 2015; Bromley 2016; Huo et al. 2017).
Occupational exposure to veterinary medicines that may lead to concerns about reproductive toxicity, and which are likely to be common include:
- anaesthetic gases
- medicines (dispensing, preparing or administering them, clearing bodily fluids containing them)
- vaccinations (inadvertent self-exposure through needle stick injury) (Scheftelet al. 2017).
In one study of 344 women who had worked as veterinary practitioners during pregnancy in Finland before 2000, 50% reported being exposed to medication and disinfectants during pregnancy and 13% reported being exposed to anaesthetic gases (Reijula et al. 2003). There may also be situations when a medicine with known or suspected adverse reproductive effects is needed by an animal with an owner who is, or may become, pregnant.
Exposure to a human teratogen alone is not enough to produce fetotoxic effects. There are several important cofactors that can lead to such effects in the developing fetus, particularly in women (Wilson 1974).
The timing of teratogen exposure. Primarily, teratogenic effects occur because specific developmental pathways are disrupted to produce distinct and reproducible effects on developing cells, tissues and organs. (See table 1 below for the different phases of fetal development). The highest risk is when fetal tissues and structures are forming, particularly in the first trimester. However, the developmental processes that occur during gestation are constantly changing, and teratogenicity can occur during any period of growth or development (Bromley 2016; Polanska 2015). It is important to be aware that the first sign of pregnancy is usually the first missed period, which is about 2 weeks after conception. So a woman may be unaware that she is pregnant for several weeks, and therefore the potential for drugs to harm a fetus must be considered in all women of child-bearing potential.
The dose-response relationship. A key general principle of toxicology is the dose-response relationship and it also holds for human teratogens (Tomson 2015; Patra 2011; Cotrufo 2002). There are two key assumptions of this relationship: once a maximum response has been achieved, exposure to increased doses will not produce additional adverse effects; conversely, any exposure that occurs below a certain dose or threshold will not produce detectable toxic effects (Fox 2017).
The route of exposure. For a fetus to be exposed to a teratogen after maternal contact, there needs to be transfer across the placenta. It is generally accepted that exposure resulting in high systemic concentrations produces the highest rate of fetal exposure (Grafmuller2013). So, for example, drugs taken orally or parenterally would pose more of a risk than those applied topically.
Ability to cross the placenta. Most medicines are able to cross the placenta, except perhaps higher molecular weight compounds such as heparin (Bajoria 1992). For some, such as monoclonal antibodies, transfer may depend on the gestational age (e.g. IgG antibodies need active transport, which is only expected to occur after 20 weeks’ gestation) (Weber-Schoendorfer2015).
Inter-individual variation. There is variation in susceptibility to damage from a teratogen, both between mothers (in terms of the way their bodies handle medicines) and fetuses (in terms of how the teratogen affects them) (Tomson 2015). In the father, there is minimal risk of transferring medicines through seminal fluids (Garritsen 2017). However, there may be an increased risk of birth defects when a drug has the potential to alter paternal DNA, which can vary between individuals (Day 2016).
Table 1: The phases of fetal development in human pregnancy
For ethical reasons, it is rare for the teratogenic effects of drugs to be assessed in humans using industry-standard methods (e.g. randomised controlled trials) unless the drug is being used to treat a pregnancy-specific complication. Scientific evidence used to define a drug as a teratogen is mainly collected using laboratory-based experimental teratology studies in pregnant animal models and epidemiological surveillance of human exposure.
Laboratory studies can be poor predictors of human risk because of the considerable inter-species differences between the animals used and humans. Several methods are used to collect human exposure and pregnancy/infant outcome data including: spontaneous adverse event reporting systems; case reports; pregnancy exposure and disease registries; regional/national birth cohorts and administrative datasets; and health-insurance datasets. However, all these methods are subject to bias, for example, because of confounding and selection bias, which makes assessing causality difficult (Grzeskowiak 2012).
Several drugs are known or suspected to increase the risk of major congenital malformation following direct maternal use in pregnancy (Niebyl et al 2008). The two situations thought to be of most concern for veterinary employees are cytotoxic medications and anaesthetic gases.
Studies have shown that occupational exposure to some cytotoxic drugs can result in systemic absorption (Sugiura 2011). We know of 15 published controlled studies and two meta-analyses relating to occupational cytotoxic exposure in human pregnancy, which collectively provide the outcomes of more than 9,000 unique exposed pregnancies (UK Teratology Service 2017). The limitations of these studies include retrospective reporting of exposure and outcome, job-title-defined exposure status and variation in adherence to health and safety, and changes in occupational hygiene measures over time.
Some of these studies described increased risks of congenital malformation (Hemminki 1986; McDonald 1988), spontaneous abortion (Stucker 1990; Valanis 1999), ectopic pregnancy (Saurel-Cubizolles 1993), preterm delivery (Fransman 2007; Zhang 2016) and low infant birth weight (Fransman 2007). However, the findings were often conflicting, and meta-analyses have shown that, overall, the data do not provide sufficient evidence of an increased risk of either major congenital malformation (Dranitsaris 2005) or spontaneous abortion (Quansah 2010) after occupational exposure to cytotoxic drugs. Nevertheless, because there is a lack of evidence to show that this exposure is completely without risk, caution is advised where possible.
Commonly used anaesthetic gases (such as isoflurane and sevoflurane) readily cross the placenta (Schaefer 2015), so fetal exposure as a consequence of maternal occupational exposure in pregnancy could occur. A number of early studies investigated unscavenged anaesthetic gases (but not in veterinary medicine settings specifically), and identified possible associations between operating room occupational anaesthetic gas exposure and increased risks of both spontaneous abortion (Hemminki 1985; Vessey 1980) and low infant birth weight (Ericson 1979; Rosenberg 1978). However, more recent studies have failed to replicate these findings (Lawson 2012), suggesting that these risks may have been attributable to the use of inferior scavenger system technologies compared to those used today. The results of one study of infant neurodevelopment suggested that increased exposure to occupational anaesthetic gases in pregnancy could be linked with poorer neurocognitive outcomes (limitations in fine motor function and lower IQ) (Ratzon 2004). However, this study was small (n=40), so more research is needed to confirm or refute the finding.
A limited number of studies have assessed the risk of adverse reproductive outcomes among veterinary medicine employees (all female) after exposure to drugs, and these have mainly been retrospective, so the results are subject to bias and confounding. Overall, findings from these studies suggest an increased risk of spontaneous abortion and preterm delivery (Vaughan 1984; Wilkins 1998). However, the available data are conflicting; some studies found no statistically significant increased risk of spontaneous abortion, while the increase in risk in others appeared to be limited to times when there were less stringent health and safety/occupational hygiene recommendations (Schenker 1990; Steele 1996; Lindbohm 2000).
Specifically, an increased risk of spontaneous abortion has been described after veterinary occupational exposure to unscavenged anaesthetic gases (Johnson 1987; Shirangi 2008), and one study described a statistically significant increased risk of preterm delivery after unscavenged anaesthetic gas exposure (Shirangi 2009). Another study also described a statistically significant increased risk of birth defects after handling of cytotoxic medicines (Shirangi 2014). Importantly, however, in this study, no association was seen when the data were restricted to pregnancies that occurred after 1981. This suggests that the finding was likely to have been because of inadequate health and safety/occupational hygiene recommendations.
There are no national guidelines specifically on avoiding occupational exposures during pregnancy. However, the Control of Substances Hazardous to Health (COSHH) regulations require employers to control substances that are hazardous to health (HSE 2018). To comply with COSHH Regulations and prevent or reduce exposure to a hazardous substance, which includes medicines, an employer must:
- assess the risks
- decide what precautions are needed
- prevent or adequately control exposure
- ensure that control measures are used and maintained
- monitor exposure
- carry out appropriate health surveillance
- prepare plans and procedures to deal with accidents, incidents and emergencies
- ensure employees are properly informed, trained and supervised. (BSAVA 2018)
If a practice employs five or more people, the assessment(s) must be recorded in writing. Failure to adequately control hazards can lead to prosecution under the COSHH Regulations and civil action from injured or ill employees.
Areas that need assessing in relation to occupational exposure to medicines include: general medicines handling; handling cytotoxic medicines; and spillage of medicines (BSAVA 2018). Veterinary medicines can be classified as low, medium or high risk (see table 2 below for examples) (BSAVA 2018). Risks associated with handling low- and medium-risk medicines can be adequately controlled by assessing therapeutic group, type and route of administration. The information in summaries of product characteristics (SPCs) or safety datasheets should be used to do risk assessments. (For more on SPCs see the Veteirnary Prescriber module on prescribing information). However, often these sources of information state that exposure in pregnancy should be avoided, more because of a lack of sufficient safety data rather than sufficient evidence of teratogenic/fetotoxic effects. A practice can then produce standard methods for the control of exposure to such medicines, but with any specific risks identified (e.g. penicillin allergy). For high-risk substances, specific and detailed assessments and the resulting control methods should be done (BSAVA 2018). All operating and recovery rooms should have effective and well-maintained ventilation or scavenging systems (VMD 2018).
Table 2: Low-, Medium-, and High-risk medicines
In general, when handling medicines, people working in veterinary medicine must:
- Treat all medicinal products as potentially harmful.
- Be aware of the hazards associated with medicines and know the results of the COSHH and risk assessments.
- Wear disposable gloves when handling any open or loose products.
- Be familiar with the practice standard operating procedure for handling medicines and use additional protective clothing and equipment when specified.
- Inform the health and safety officer if they are, or expect to, become pregnant. In the case of pregnancy, be aware of and avoid handling teratogenic medicines likely to harm the unborn child or medicines likely to cause miscarriage
- Inform the health and safety officer if they experience any allergies or adverse effects thought to be caused or made worse by the handling of, or exposure to, veterinary medicinal products
- Wash hands after handling medicines, even if disposable gloves have been worn. (BSAVA 2018)
There are also general guidelines on limiting occupational exposure to cytotoxic medicines among health professionals from the Health and Safety Executive (HSE 2018). These state that exposure prevention should begin with a workplace assessment, identifying all potential exposures that could arise. For any that need to be avoided, use of the exposure should be limited to an enclosed work area with an adequate air extraction system. This should be used with personal protective equipment (that is, gloves, sleeves and face masks). Eating and drinking in areas where possible exposure could occur should always be avoided, and hands should be washed regularly to reduce transfer to the mouth.
As has been described, extremely limited evidence is available about occupational exposure to specific drugs and much of it is highly confounded. It is therefore difficult to provide useful information about the reproductive and developmental effects of such exposures. Larger amounts of data are available for exposure to medication when a person is being treated. This type of exposure in the mother or father would be expected to produce higher systemic concentrations and hence higher rates of fetal exposure, but these data may be useful for assessing potential risks.
Clinical information on therapeutic exposure is provided by the UK Teratology Information Service (UKTIS) to NHS health professionals via a dedicated telephone advice service (0344 892 0909; between 9am and 5pm, Monday to Friday, excluding bank holidays). However, it can only be provided to NHS health professionals, so any concerned employee working in a veterinary medicine setting should seek an appointment with a GP, midwife or obstetrician who can contact the service on their behalf.
The Service also produces written summaries of the fetal effects of maternal environmental exposure using information from observational epidemiological studies that have been published in the scientific literature. UKTIS summaries for health professionals are currently available for over 700 environmental exposures, most of which focus on maternal medication use in pregnancy. Summaries are published as key message abstracts on the UKTIS website. Click here to look at the UKTIS website. A particularly useful one for practising veterinary medicine employees may be the summary on occupational exposure to cytotoxic medication. Click here to view it. Patient information leaflets are also freely available in full via the UKTIS patient information website – called “bumps” (for Best Use of Medicines in Pregnancy). Click here to go to the website. This resource currently contains information for more than 200 medicines.
Other useful English-language resources include: the North American equivalent of the UKTIS the Organization of Teratology Information Specialists (OTIS), its patient site MotherToBaby and affiliate patient site – Motherisk; and an Australian patient site Mothersafe. Patient information in Dutch (www.lareb.nl/teratologie-nl) and German (www.embryotox.de) is also available.
The term ‘teratogen’ is generally used to describe environmental exposures that can affect gestational development.
Resulting adverse effects can include structural or functional birth defects, fetal death, impaired fetal growth, neonatal adaptation disorders, impaired neurodevelopment and behaviour, and even increased susceptibility to diseases like cancer.
Information about the effects of veterinary medicine occupational exposure specifically is highly limited. The results of a few methodologically limited studies have suggested increased rates of spontaneous abortion and preterm delivery among women working in veterinary medicine (specifically preterm delivery with unscavenged anaesthetic gas exposure, and congenital malformation with cytotoxic medication handling). But these need confirming.
Veterinary employers must comply with COSHH Regulations to prevent or reduce exposure to hazardous substances, which includes medicines.
All medicines, including anaesthetics, should be treated as potentially harmful.
Veterinary medicine employees who have concerns relating to a specific occupational exposure should either seek an appointment with a GP, midwife or obstetrician who can contact the UK Teratology Information Service (UKTIS) for patient-specific advice, or should look for information on the UKTIS or bumps websites.
How we produced this module
Our modules start with a detailed outline and electronic literature search. We commission a collaborating author, who is a specialist in the module topic, to write a draft module. The collaborating author on this module was Luke Richardson. The draft is circulated unsigned to a wide range of commentators, include practising first-opinion vets, other topic specialists, the companies that market any mentioned drugs and other organisations and individuals, as appropriate. They can raise points about the interpretation of evidence, ask questions that are important to clinical practice, and present alternative viewpoints. There is a rigorous editing and checking process and the result is a module that is evidence-based, impartial and relevant to clinical practice. The final module is unsigned because it is the result of collaboration.
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