Shirangi, Adeleh MPH, PhD; Fritschi, Lin MBBS, PhD; Holman, C D’Arcy J. MBBS, MPH, PhD; Bower, Carol MBBS, PhD
* Demonstrate familiarity with current knowledge on the risk of birth defects associated with radiation and other exposures among health care workers, as well as female veterinarians.
* Characterize the excess risk of birth defects in female veterinarians, along with the relevant risk factors.
* Present advice regarding reproductive health and measures to reduce the risk of birth defects for female veterinarians, including areas of uncertainty where further research is needed.
The World Health Organization has estimated that 3% to 6% of all live born infants will have congenital anomalies, which include neural tube defects, cardiovascular system malformations, and oral-facial clefts.1 The frequency depends on the time of observation after birth, the definition and types of malformations included, geographic variation and the differences in reporting and statistical procedures.
Occupational and environmental agents are suspected causes of at least some of the approximately 65% of birth defects for which etiology is unknown.2 Some occupations in health care workers and occupational exposure to radiation have been suggested as being associated with increased risk of birth defects such as nursing occupations,3 medical radiographers,4 and other hospital personnel.5
Conversely, a study in female veterinary staff and some studies in other occupations have not revealed any association between exposure to ionizing radiation and malformations.6–8 A study in the US compared female veterinarians with lawyers and reported a higher rate of reportable birth defects among the veterinarians than among the lawyers (relative risks [RR]: 4.2; 95% CI: 1.2 to 15.1), although this study was not designed to detect an increase in birth defects.9 Most of the existing evidence in humans indicates no associations between occupational exposures to inhaled anesthetic gases and increased risk of congenital birth defects.6,8,10 There has been no evidence of significant association between exposure to pesticides in health care workers and increased risk of birth defects, although maternal involvement in agricultural activities and occupational exposure to pesticides has showed an association.11,12
In a recent cross-sectional survey of the same cohort population, we addressed the prevalence of exposure to potentially harmful occupational exposures including radiation, anesthetic gas and pesticides and showed that considerable variability of exposure still exists within the profession.13 We have also investigated maternal occupational exposures and risk of spontaneous abortion in veterinary practice in this cohort.14 The present report investigates the risk of birth defects in offspring of female veterinarians exposed to occupational hazards such as radiation, anesthetic gases, pesticides and working hours compared with those veterinarians unexposed to these agents.
Materials and Methods
The Health Risks of Australian Veterinarians study (HRAV) was the first complete national survey of health aspects of veterinary practice in Australia and was conducted in 2002.13–18 The survey was a questionnaire-based survey of all graduates from Australian veterinary schools during the 40 year period 1960–2000. Of 2028 eligible female veterinarians who were sent the questionnaires, 1197 replied (response fraction 59%). Of 1197 female veterinarians who participated in the survey, 631 had never been pregnant and 566 had at least one pregnancy. The study was approved by the Human Research Ethics Committee of The University of Western Australia.
The mailed self-administered questionnaire contained items about demographic details, a section on all veterinary jobs held for more than 6 months since graduation, history of smoking and reproductive history for women. Information obtained for each job included start date, end date, job type, practice type and work hours, number of x-ray films taken per week, restraint of animals during x-rays, number of hours doing surgery per week, use of scavenger equipment for anesthetic gases (yes, no, do not know, not applicable), driving (number of hours per week to see patients), and use of pesticides at work (daily, weekly, rarely, never) including anti-tick agents, anthelminthics, and flea treatments.
Reproductive history was assessed by asking (for up to six pregnancies) the number of months trying to become pregnant, the year the pregnancy ended, the number of weeks the woman was pregnant, whether it was a single or multiple birth, and the sex of each child. Reproductive outcomes were assessed by using information about live births, stillbirths, terminations (induced abortions), miscarriage (spontaneous abortions), and birth defects. The outcome of a congenital anomoly was defined as a structural or functional abnormality that was present at conception or occurred before the end of pregnancy, and was diagnosed by 6 years of age.19 Each individual defect was coded by the Western Australian Birth Defects Registry staff according to the inclusion and exclusion criteria used by the Registry and using the 5-digit British Pediatric Association International Classification of Diseases, 9th revision system and without knowledge of the exposure status of the mother.19,20 For infants with more than one defect, each defect was counted separately. Therefore, the number of birth defects reported exceeded the number of affected infants. It was not possible to verify the self-reported birth defects by veterinarians as we did not have access to their medical records.
We reorganised the structure of the data file such that pregnancy became the unit of observation. For the assessment of occupational exposures during pregnancy, we needed to evaluate each exposure for each pregnancy (third to eighth weeks of pregnancy). We had information about the work history of each woman in the study after graduation and we had the date of the end of the women’s pregnancy (actual delivery date) in our database. So, we reshaped our database by cross-referencing work history data to the year before the end of the woman’s pregnancy date to assess occupational exposure during pregnancy. So, we evaluated exposure for each pregnancy for the time from the few months immediately before conception to the end of the pregnancy which has covered the critical times of vulnerability (third to eighth weeks of pregnancy).
A series of eligibility criteria were applied to restrict the domain of the study to women with past singleton pregnancies, who were unquestionably exposed to veterinary work while pregnant. We excluded the following pregnancies: those current at the time of the survey (n = 23); those that commenced before graduation from veterinary college (n = 48); twin pregnancies as we only had information on one twin (n = 14); those where the mother had not worked up to the time of conception and during the pregnancy (n = 163); and those who were not employed exclusively as clinical practice practitioners at the time of conception and during the pregnancy (n = 167), pregnancies that ended in miscarriages (n = 146) and terminations of pregnancies after 20 weeks of gestation without birth defects (n = 14). After all these restrictions, of 1355 pregnancies (566 women) in the file 780 pregnancies in 412 women were eligible for the final analysis.
Prevalence ratio, overall prevalence of birth defects and indirectly standardized congenital anomoly prevalence ratio were estimated. We have followed the advice of a recent article which recommended the use of the term “prevalence” rather than “incidence” as the preferred measure to represent the occurrence of birth defects.21
The numerator data comprised birth defects as recoded by the WA Birth Defects Registry staff occurring in live births and stillbirths and in pregnancies terminated because of fetal malformation.19 The denominator data for the prevalence ratio included live births and stillbirths at 20 weeks gestation or more. Note that this result is an estimate that is a ratio, not a proportion because all the outcomes included in the numerator do not appear in the denominator. The denominator data for overall prevalence comprised live births and stillbirths plus terminations of birth defects before 20 weeks gestation. There were 10 birth defects cases associated with terminations.
The indirect standardized congenital anomoly prevalence ratio22 was calculated using as a standard the Western Australian 5-year maternal age groups for 1983–2002.
The crude risk of birth defects overall was calculated as the number of congenital anomoly cases among singleton live births, still births, and terminations of birth defects before 20 weeks gestation. Crude birth defects risk, crude RR, and 95% CIs were calculated using RR and 95% CI formulae.23
An unconditional multiple logistic regression procedure in the Stata v9.0 software package was adopted to calculate adjusted RR of birth defects. We used the Huber-White sandwich estimator of variance to take into account the potential autocorrelation created by more than one pregnancy for a single woman.24,25
The following occupational variables were examined as exposures, with the reference category mentioned first: working hours (≤45, >45 hours), x-ray exposure (none, 1 to 10 films per week, >10 films per week), using pesticide at work (never or rarely, at least once a week), surgery (none or surgery in the presence of scavenger, surgery in the absence of scavenger), practice type (small, mixed, large), and years in job (continuous). The following variables were treated as potential confounders: animal restraint (never or rarely, at least once a week), driving (none, at least 1 hour driving per week to see patients), maternal age (≤35 years and >35 years), graduation year, university of graduation, history of smoking (yes, no), age at the time of survey, sex of child, birth order, gravidity, parity, weeks of pregnancy, and time to pregnancy in months. Final decisions for inclusion of a covariate were based on the magnitudes of regression coefficients and on theoretical considerations as to the importance of the risk factors. The associations of potential confounders with exposure variables were assessed by cross-tabulations, χ2 tests and also using the Mantel-Haenzel adjusted odds ratio (OR). If the difference between the crude OR and the adjusted Mantel-Haenzel OR was less than 10%, the covariate was not considered a confounder. After confirming the confounders, an unconditional multivariate logistic model was implemented, adding each of the variables previously selected, including those that changed the OR by 10% or more. Adjusting for age at the time of survey, sex of child and university of graduation, history of smoking, birth order, graduation year and time to pregnancy had no substantial impact on the magnitudes of the risk estimates, so these covariates were excluded from the final chosen model. Adding weeks of gestation in the model increased the magnitude of the risk estimate particularly in the first pregnancy model but as it is not a risk factor for birth defects it could introduce bias, so we have excluded it from the model. In the final model, the associations of birth defects with occupational exposures (anesthetics, long working hours, x-rays, and pesticides) were assessed adjusting for practice type, years in job, maternal age, parity, gravidity, restraint of animals and driving.
Analysis was repeated for the subgroup of pregnancies reported by veterinarians employed exclusively in small animal practices, for those who graduated between 1980 and 2000 and for their first pregnancy. Interaction effects of factors related to birth defects were tested, but none contributed significantly to the model.
Respondents were born between 1938 and 1976 with a median age of 39.8 years in 2002, and 95% of respondents were more than 30 years old. Nearly 86% of respondents were born in Australia and 6% were born in UK. Approximately 72% of them graduated after 1980 with a median graduation year of 1984 and a median graduation age of 23 years.
Of the 780 pregnancies, 764 resulted in live births, 6 in stillbirths, 10 resulted terminations of pregnancy with birth defects. The percentages of male and female infants were approximately the same.
The overall prevalence ratio of birth defects (1960–2002) was 6.4% and the indirectly standardized congenital anomoly prevalence was 7.2% compared with 5.9% in the general population. Cardiovascular defects were the most common type of congenital anomoly reported (prevalence ratio of 1.4%), 22% of all birth defects (Table 1). Defects which were reported by participants, but which were not registrable according to the criteria of the WA Birth Defects Registry had a prevalence rate of 1.1%.
The overall crude risk of birth defects in women in veterinary clinical practice was 0.075 (Table 2). Risk of birth defects was the highest in women who graduated before 1970 (Table 2).
The crude relative risk was significantly higher in veterinarians who worked in large animal practices compared with those in small animal practices (Table 3). There was no excess of birth defects in veterinarians working 2 years or more in clinical practice compared with those who had worked less than 2 years. There was a slight excess of birth defects in women who used pesticides at work compared with those who did not. Risks were highest in veterinarians who were exposed to radiation and in those women who worked long hours per week. There was no excess of birth defects in women who were exposed to anesthetic gases, restrained animals or who did more driving (Table 3).
A multiple logistic regression analysis adjusted for 11 covariates (the four exposures and seven confounders) (Table 4) showed there was an approximately more than 5-fold significant increase in the risk of birth defects in women exposed to radiation for taking 10 or more film per week (OR: 5.73; 95% CI: 1.27 to 25.80) compared with those who did not take x-rays. There was also approximately 3-fold increased risk of birth defects in those veterinarians who took 1 to 10 films per week (OR: 3.21; CI: 0.87 to 11.78) compared with those who did not take x-rays.
There was no excess risk of birth defects in women exposed to unscavenged anesthetic gases compared with the reference group (veterinarians who had never done surgery and those who had done surgery in the presence of scavenger). There were also no statistically significant increase risk of birth defects in those who used pesticides at work, worked for long hours, years in the veterinary job, driving for work or restraint of animals during x-ray.
In a separate analysis restricted to those veterinarians who graduated between 1980 and 2000, the adjusted OR for exposure to radiation decreased from 5.73 to 3.32 in those who took more than 10 films per week and the OR for large animal practice increased from 1.92 to 4.47 (95% CI: 1.30 to 15.41). Similar results were found in veterinarians employed exclusively in small-animal practices except for the pesticide exposure where there was a more than 2-fold increased risk of birth defects in veterinarians who used pesticide for at least once per week (OR: 2.39 CI: 0.99 to 5.77) (Table 4). First pregnancies also had similar results, although no statistically significant effects were found.
This is the first national survey among female veterinarians to examine the prevalence ratio of birth defects in female veterinarians and to evaluate the association of birth defects with occupational exposures including ionising radiation, anesthetic gases, pesticides, and long working hours. The age standardized birth defects prevalence ratio was 7.2%, which was higher than the average prevalence of 5.9% more than 20 years (1983–2002) for Western Australia,19 New South Wales for the period of 1995–2001 (2.05%),26 Victoria 1983–2004 (3.7%),27 and South Australia 1996–2005 (5.7%).28
The high prevalence of birth defects in offspring of female veterinarians is consistent with the findings of Schenker et al.9 They found an increased risk for major birth defects in female veterinarians when compared with lawyers (RR: 4.2; 95% CI: 1.2 to 15.1), although their study was not designed specifically to detect an increased risk of birth defects. Canadian researchers suggested that pregnant veterinary staff exposed to inhaled anesthetics or radiation did not seem to have an increased risk for major malformations.6 However, this study was only based on four cases (4.8%) in the study group and 3 (3.4%) in the control group. A previous study showed a decrease in the ORs for births with congenital defects for use of diagnostic x-rays or with exposure to waste anesthetic gases in female veterinarians.29 The effects for use of x-rays, however, were not statistically significant.
In this exploratory study of the relationship of occupational hazards to birth defects in female veterinarians, exposures to radiation and pesticides were implicated as potential risk factors after controlling for significant covariates. Veterinarians who took more than 10 x-rays per week (N = 85) had greater than a 5-fold increased risk of having birth defects in their offspring. The epidemiological evidence to which these findings could be related is sparse. The findings reported here are consistent with the associations between neural tube defects and potential maternal exposures to ionising radiation observed in mothers employed in nursing occupations.3 However, these findings were based on only three cases and thus should be interpreted cautiously. Neural tube defects also showed a significant association with parental preconception exposure to low-level ionising radiation in a US case-control study, which was one of the few studies that used quantitative individual measurements of exposure to radiation, although again the numbers of cases were small.30 A study of medical radiographers showed an excess of chromosomal anomalies other than Down syndrome in the children of female radiographers (RR: 3.9, 95% CI: 1.3 to 9.0; based on five observations).4 Occupational exposure to ionising radiation among orthopaedic surgeons and among obstetricians and gynaecologists revealed a higher rate of congenital abnormalities as compared with the non-exposed population in both groups (P < 0.001).31 Risks of congenital malformation for infants whose mothers were exposed to radiation before and during early pregnancy have also been reported in a case-control study conducted in 29 hospitals in Shanghai, China (OR:1.9; 95% CI: 0.7 to 5.3 for exposure before pregnancy; and OR: 1.9; 95% CI: 0.7 to 4.9 for exposure during the first trimester of pregnancy).5 However, not all studies have found associations between occupational exposure to ionising radiation and malformations.7,8
About 2½-fold increased risk of birth defects was also observed for women reporting use of pesticides at work and working in small animal practice. In a recent cross-sectional survey of the same cohort population, we found that small and mixed animal practitioners had about four times the risk of using pesticide at least once a week compared with the large animal practice,13 which may explain the association found in small animal practice and the lack of significant association in the whole sample. We also found similar results when we observed this association (occupational exposure to pesticide in relation to birth defects) in those veterinarians graduated between the years 1980 to 2000 and worked in small animal practice, but the OR decreased from 2.39 to 1.78. Most previous studies in the literature have examined the association between maternal exposure to agricultural work or pesticides and congenital malformations and significant associations have been observed for some of these associations, with the estimates below 2.00.32 Elevated estimated risk of birth defects in those with occupational exposure to pesticides during the first trimester of pregnancy were observed by Garcia et al (OR: 3.2, 95% CI: 1.1 to 9.0),5 Nurminen et al (OR: 1.4, 95% CI: 0.9 to 2.0),11 and Zhang et al (OR: 1.8, 95% CI: 0.3 to 10.5).33 Increased risk for congenital anomalies were also observed for women reporting household use of pesticides and living within 0.25 miles of an agricultural crop at any time during the month before conception and the first trimester of pregnancy.34
The result reported here of a lack of significant association between birth defects and maternal exposure to anesthetic gases is consistent with other studies in veterinarians.6,29 Some studies in other occupations also showed no association between exposure to waste anesthetic gases and birth defects,35–37 whereas others showed an association.3,38–41
The significantly elevated OR for birth defects observed in large animal practice (OR: 4.47, P = 0.01) in those who graduated between 1980 and 2000 indicates a possible detrimental effect of working in large animal practice on the developing embryo or fetus. However, the result was not significant in all eligible pregnancies and was not consistent with first pregnancies.
There was a slight but statistically not significant increased risk of birth defects in women who worked more than 45 hours per week. There were no previous studies which had evaluated this association. Using data from the same cohort, we previously found that veterinarians who worked more than 45 hours per week had increased exposure to occupational hazards in veterinary practice such as exposure to x-ray, anesthetic gases, and pesticides.13 Working hours might have an indirect effect on birth defects in off-spring of female veterinarians by increasing exposure to radiation and anesthetic gases. However, any employment during pregnancy has also been suspected to increase the risk for an adverse pregnancy outcome. In a Finnish investigation, all types of malformations were less common in the children born to housewives than among employed women and students,42 whereas another study reported no differences.43
There were some limitations to this study, especially the self-reported nature of the data, and a possible selection bias because of a suboptimal but not unusual response rate (59%). However, we tried to reduce as many as possible of the potential biases of epidemiological studies. We included a large cohort of female veterinarians from all types of clinical practice and from all ages in Australia, suggesting that our study was generally representative of female veterinarians. In addition, we performed an analysis to identify the main reasons for non-participation from 195 veterinarians who acknowledged the receipt of questionnaires but refused to participate. The reasons included: working for a postgraduate qualification (for example in research area or in teaching); outside the profession for a long time and working temporarily overseas, suggesting that those not in clinical practice or veterinary work were less likely to participate. Nonparticipants were also more likely to be older graduates than respondents. So, the effect of selection bias due to response rate is likely to have been minimal. There is an argument that women who have experienced a reproductive difficulty were more likely to respond to the survey. However, the principal focus of the HRAV was to determine if veterinarians are at increased risk of a range of health outcomes such as cancer, injury, zoonoses, adverse reproductive outcomes and occupational stress and the study information did not stress adverse reproductive outcomes above other diseases.
Another limitation was the method used to estimate exposure, which was based on questionnaire responses rather than on actual measurements. The detailed occupational exposure information collected from these highly educated women may have minimized this type of information bias. In addition, previous surveys have supported the use of exposure data from retrospective self-reports.44 Moreover, information on personal habits, lifetime working histories, and fertility can only be obtained through questionnaire-based studies.
To reduce the problem of misclassification of malformation cases, the birth defects were reviewed and coded without knowledge of exposure status by an expert in Western Australian Birth Defects Registry according to 5-digit British Pediatric Association codes. However, we were not able to verify the self reported birth defects by Australian states medical records. Medical records and hospital data, where medical diagnoses are recorded at the time of the event, and population-based birth defects registries, where active monitoring for birth defects yields relatively accurate ascertainment, may be more reliable sources of information on birth defects.45
There is a possibility of underestimating true numbers in studies that only include congenital malformations present at birth, because many birth defects are associated with a high prenatal mortality and many are diagnosed after birth.46 We reduced the risk of selection bias by including all abnormalities where the pregnancy was terminated, present at birth and malformations diagnosed by the age of 6 years.
To reduce the effect of misclassification of exposure status, we asked direct questions about the hazards and their dose. We were able to examine the potential dose-response relationships using partial quantification of differences according to durations of exposure, but not a more complete quantification that included the average intensities of exposures. It is also important whether protective devices were used. We were able to assess anesthetic gases in the presence or absence of a scavenger system; however, we did not have information about radiation protective practices during the relevant exposure times. A cross-sectional analysis from this survey regarding radiation protection in their current job, indicated that, even though protective devices were usually available in the workplace, they were not always used.13
We were also able to control for important variables in the analysis including key potential confounding factors such as maternal age and parity. The potential confounding effects of alcohol, use of contraceptives, marital status or social background could not be evaluated, as the relevant information was unavailable. The relatively homogeneous social background of the veterinarians probably partly controlled for the effects of lifestyle factors. However, we did not have information about some other potentially confounding factors such as medical history (infections and drug treatment), alcohol use, prenatal care, pregnancy-related factors, nutrition, folic acid supplement use, maternal zinc deficiency, maternal diabetics, weight gain during and before pregnancy, local water supply and paternal occupational exposures.1,47–51
In humans, the period of organogenesis, about the third to eighth weeks of pregnancy, is the most susceptible time period in which an exposure may have a teratogenic effect on the fetus.52,53 Although, we were not able to look at exposure specifically during the third to eighth weeks of pregnancy in relation to birth defects, we have examined this outcome in relation to occupational exposures from a few months immediately before conception to the end of the pregnancy which has covered the critical times of vulnerability.
We were unable to analyze the data by specific malformations due to small sample size and the loss of statistical power. Analyzing all “birth defects” as a group, as presented here, may decrease biological validity even if the grouped malformations are suspected to have a similar etiology.2,45 There are many different birth defects included in this sample and there may be many different etiological pathways to them.
The results of this study indicate a higher prevalence of birth defects in female veterinarians compared with the general population of Australia and suggest that occupational exposures to radiation, pesticides and working in large animal practice are risk factors for birth defects in offspring of female veterinarians. The risk of birth defects was not statistically associated with maternal exposure to anesthetic gases, working hours, restraining animals during x-ray, years in job and driving.
Ionising radiation at high doses is historically known to be embryotoxic and teratogenic. Female veterinarians and all personnel working in this area should be informed of the possible reproductive effects of radiation and using of pesticide and should avoid exposures particularly during periods when they are planning to become pregnant. There is a need for further research determining whether working in large animal practice per se or working in close contact with animals is associated with birth defects in the offspring of female veterinarians.
The authors thank Alumni organizations, Australian Veterinary Association, and Australian State Veterinary Registration Board for providing the names and addresses of all veterinarians participated in the project. The authors also thank Mr Robin Mina for his assistance to reshape the database, and Dr Lesley Day who assisted with the development of the HRAV survey.
Supported by National Health and Medical Research Council of Australia, the Cancer Foundation of Western Australia and the University of Western Australia Research Grants.
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