Healthcare workers who prepare or administer antineoplastic drugs, or who work in areas where these drugs are used can be exposed to these agents when they are present on contaminated work surfaces, drug vials and containers, contaminated clothing and medical equipment, and in patient excreta and secretions such as urine, feces, and sweat. The toxicity of antineoplastic drugs is well recognized and includes acute effects such as nausea and vomiting, blood count declines and skin and mucous membrane irritation. Also well recognized in treated patients are these drugs’ reproductive and developmental toxicity¹.

Routine work activities can result in spills, create aerosols or generate dust, thereby increasing the potential of exposure^1–4. Skin absorption and inhalation are the most common ways a healthcare worker is exposed to antineoplastic drugs. However, ingestion (from hand-to-mouth contact), accidental injection through a needle stick, or other sharps injury is also possible⁵. These workplace exposures to antineoplastic drugs have been associated with health effects such as skin disorders, adverse reproductive outcomes, and certain cancers^1,6–9. Workers with potential exposure include pharmacy and nursing personnel, physicians, physicians’ assistants, nurse practitioners, operating room personnel, shipping and receiving personnel, waste handlers, maintenance and housekeeping workers, laundry workers, laboratory personnel, and workers in veterinary practices and others working in healthcare settings who come into contact with drugs or drug waste¹.

An extensive review of the literature linking occupational exposure to antineoplastic drugs and adverse reproductive effects was conducted in February 2014 using the following databases: Canadiana, CI-NAHL, CISILO, DTIC, Embase, Health & Safety Science Abstracts, HSELine, NIOSHTIC-2, NTIS, OSHLine, PubMed, Risk Abstracts, Toxicology Abstracts, Toxline, Web of Science and WorldCat searching from 1980 to February 2014. Using the MeSH controlled vocabulary the following search was performed in PubMed: (“Antineoplastic agents/adverse effects”[Mesh] OR “antineoplastic agents/prevention and control”[Mesh] OR “Cytotoxins”[Mesh] OR “Hazardous Substances/adverse effects”[Mesh] OR “Hazardous Substances/toxicity”[Mesh] OR “Pharmaceutical Preparations/adverse effects”[Mesh] OR antineoplastic[TI] OR cytotoxic[TI] OR cytostatic[TI] OR chemotherap*[TI]) AND (“Personnel, Hospital”[Mesh] OR “Health Personnel”[Mesh]) AND (“Occupational Exposure”[Mesh:NoExp] OR “Occupational Diseases”[Mesh] OR “Environmental Exposure”[Mesh] OR occupational[TI]) AND (“Reproduction”[Mesh] OR “Infertility”[Mesh] OR “Fertility”[Mesh] OR “Pregnancy Complications”[Mesh] OR pregnan*[TI] OR infertility[TI] OR reproducti*[TI]). The other databases were searched using the following key word search strings: (antineoplastic OR chemotherapeutic OR cytotoxic OR cytostatic) AND (pregnan* OR infertility OR reproducti*) AND occupational.

The initial electronic database search was supplemented by manual searches of published reference lists, review articles and conference abstracts.

All English language, peer-reviewed publications that were obtained were included in this document. Meeting abstracts were not included. Overall, 18 individual studies were reviewed, some with multiple endpoints.

Table 1 summarizes studies of occupational exposure to antineoplastic drugs and congenital anomalies in offspring, including eight studies. The primary limitation of these studies is the small sample sizes; five of the eight studies had 10 or fewer exposed cases, and all studies had fewer than 20 exposed cases. The small sample sizes resulted in several other important limitations. These included a limited ability to adjust for confounding; the need to group anomalies that had different etiologies; and wide confidence intervals, which reflect poor statistical power. However, of the studies that had more than five exposed cases, three showed significantly increased risks associated with exposure ^69–71, and two showed increased risks that were not statistically significant^7.9. The odds ratios of adjusted models ranged from 1.36 (95% confidence interval, 0.59–3.14)⁷ to 5.1 (95% confidence interval, 1.1–23.6)⁷¹. A meta-analysis⁷² of four studies with exposure periods ranging from 1966 to 1985^7,69,71,73 reported a crude odds ratio of 1.64 (95% confidence interval, 0.91–2.94) for all congenital anomalies combined. Although these previous studies suggest an increased risk for congenital anomalies with maternal occupational exposure, the limitations and wide confidence intervals make the size of the adverse effect uncertain. In addition, studies are needed that reflect current exposure levels as the studies published to date include data that was collected prior to the year 2000.

Studies of maternal occupational exposure to antineoplastic drugs and miscarriage are shown in Table 2. We identified eight studies evaluating miscarriage, an additional three studies that analyzed combined outcomes of miscarriage and stillbirth, four studies of stillbirths, and two studies of tubal pregnancies. The studies of miscarriage had mixed results, and three of these studies were limited by small sample sizes (fewer than 20 exposed cases). The three largest studies^74–76 showed increased occurrence of miscarriages among women who reported handling of antineoplastic drugs during the first trimester. Most exposures were among oncology nurses or pharmacists. Other studies that did not find statistically significant associations had odds ratios ranging from 0.7 to 2.8. A meta-analysis²² that pooled the results of five studies^{7,71,74,75,77} found an overall adjusted increased risk of 46% among exposed workers (95% confidence interval, 11% to 92%)⁷². All studies published to date contain data collected prior to 2002.

More research is needed to examine the effects of occupational exposure to antineoplastic drugs and stillbirth because this is an uncommon outcome and therefore difficult to study. All of the studies of stillbirths (or of fetal loss which combined miscarriage and stillbirth) had insufficient numbers of exposed cases (n = 1 to 13), resulting in wide confidence intervals ^{9,70,71,73,75,78,79}. We found only two studies of tubal pregnancies, both with ten or fewer exposed cases, and the results varied widely from OR=0.95 (95% CI 0.39–2.31)⁸⁰ to OR 11.4 (95% CI 2.7–17.6)⁸¹.

We found only two studies of occupational exposure to antineoplastic drugs and fertility and time to pregnancy (Table 3), though the results suggest that exposure to antineoplastic drugs is associated with an increased risk of subfertility^79,82. Only one study evaluated menstrual cycle characteristics; it showed a statistically significant three-fold increased risk of menstrual cycle irregularities from occupational exposure to antineoplastic drugs⁸³. A study of Danish oncology nurses showed no statistically significant differences in birth weight, gestational age, or sex ratio among exposed mothers⁷, while a study of French oncology nurses exposed to antineoplastic drugs found the mean birth weight of offspring to be lower than that the unexposed⁸⁴.

Although there is some variability in the size of the adverse outcomes observed among occupational cohorts reviewed here, the findings are generally indicative of an increased risk of adverse reproductive outcomes with occupational exposure, especially with exposures during the first trimester of pregnancy. While all of the studies published to date were conducted before the release of the NIOSH Alert in 2004, environmental exposure studies since 2004 have documented that workplaces are still commonly contaminated with these drugs^{12,14,18,19,24–30} and hence, workers are likely chronically exposed to low levels of multiple agents known to be toxic to human reproduction. A workplace should be safe for all workers, regardless of their reproductive status and this includes workplaces where antineoplastic drugs are used⁸⁵. When the reproductive outcomes data reviewed here are considered in light of their biologic plausibility based on mechanisms of drug action and for their consistency with the results of animal and patient studies, a coherent body of evidence emerges. This evidence suggests the need for specific guidance for healthcare workers exposed to antineoplastic and other hazardous drugs, which assures protections for their reproductive health and the well-being of their offspring.

Given the unique vulnerability to exposure of the developing fetus and a newborn infant described above, and also given the potentially devastating impact of such exposures, several professional and government organizations have recommendations in place for alternative duty or temporary reassignment for healthcare workers who may be at risk of exposure to hazardous drugs during critical, vulnerable periods in reproduction^{3,4,47,86–91}. Typically, these vulnerable windows include times when couples (males and females) are actively trying to conceive and when women are pregnant or breast-feeding. Since 1995, OSHA has recommended that healthcare facilities have a policy in place regarding reproductive risks associated with occupational exposure of workers to hazardous drugs and that such a policy should be followed². Britain’s Health and Safety Executive and other professional bodies recommend that an initial risk assessment should be performed in order to determine if there is potential reproductive harm to the fetus or offspring^47,92. However, because there are no established permissible exposure limits (PELs) or other guidance values for these drugs¹, a classical risk assessment is often not possible. Therefore, other exposure assessments may be applied here. Although a precise dose of a hazardous drug may not be estimated for a given work task, the likelihood of some exposure can be assumed given the environmental contamination data described above. Beyond the benefits to the health of workers and their offspring, providing accommodations to expectant and nursing workers makes good business sense since it is estimated that 68% of working women will become pregnant at least once during their working life⁹³; moreover, according to the U.S. Census Bureau, two-thirds of women work during their first pregnancy, and more than half (55%) of all births are to working women⁹⁴. Family friendly workplace policies reduce turnover, and increase morale and productivity. Because of the possibility that healthcare workers may be exposed to low levels of many drugs with adverse reproductive effects, additional vigilance and protections might be required for those healthcare workers who are most vulnerable to the reproductive and developmental effects of hazardous drugs^{2,3,4,47,87,90,95}.

The primary limitation of the studies we evaluated is the era of the data collection; all studies published to date evaluate data collected prior to 2002, and most data were collected in the 1980’s. Though there has been a lot of attention recently to raise awareness of controlling exposures, studies continue to show that exposures are still occurring. Another important limitation of the literature is the small sample sizes, particularly the small numbers of exposed cases. Because of this limitation, studies were often unable to adjust for confounding factors and reported wide confidence intervals. However, most of the studies we reviewed that had larger relative sample sizes indicated an increased risk of adverse reproductive health outcomes. Though there are few studies of fertility, there appears to be an indication of a risk with exposure. A data gap we identified is a lack of data on later childhood health of offspring exposed in utero. One study that was published as a dissertation showed an increased risk of learning disabilities among offspring of workers exposed to antineoplastic drugs⁹⁶. Finally, most studies lacked enough statistical power or proper exposure assessment to evaluate dose. Thus, until more current studies are available on occupational exposures, we recommend reducing or avoiding exposures until better epidemiologic data show the risk is no longer occurring.

Considering the biologic plausibility of the mechanisms of action of many hazardous antineoplastic drugs, and observations of adverse reproductive and developmental health outcomes observed in treated cancer patients, this review suggests, fairly consistently that, there are also elevated risks to reproductive health for exposed workers. Workplace contamination studies indicate that hazardous drug exposure is widespread, commonly occurring during any handling activity, despite use of current safety guidance. Therefore, additional precautions to prevent exposure during uniquely vulnerable windows of fetal and newborn development should be considered.