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Occupational Medicine 2006 56(8):532-543; doi:10.1093/occmed/kql115
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Maternal occupational exposure and risk of specific birth defects

Ane Marie Thulstrup and Jens Peter Bonde

Department of Occupational Medicine, Aarhus University Hospital, Aarhus-8000, Denmark

Correspondence to: Ane Marie Thulstrup, Department of Occupational Medicine, Aarhus University Hospital, Aarhus-8000, Denmark. e-mail: manemt{at}as.aaa.dk


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion and final remarks
 Conclusion
 Conflicts of interest
 References
 
Background Gregg identified the teratogenic effect of maternal rubella infection in 1941 and since then there has been a focus on risk factors for birth defects. In nearly 70% of all birth defects, there is still no known risk factor and close to 30% of all pregnancies end in a foetal loss or spontaneous abortion, often because of a defect in the foetus. A large percentage of the workforce consists of women of reproductive age.

Methods A search in MEDLINE for original literature and examination of the association between exposure during pregnancy and the risk of birth defects.

Results Five specific birth defects were identified: neural tube defects, cleft lip and cleft palate, congenital heart defects, urinary tract defects and limb defects. The next step was to include studies with information on occupational exposure during pregnancy.

Conclusion There seems to be growing concern as to whether organic solvents, including glycol ethers, pesticides and heavy metals may play a teratogenic role. There is no convincing evidence linking occupational exposure during pregnancy and birth defects.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion and final remarks
 Conclusion
 Conflicts of interest
 References
 
Birth defects or congenital malformations are inborn structural abnormalities of organs or body parts. The frequency is by definition measured as prevalence at the time of birth and occurs in ~3.5% of all live births. Severe malformations which are incompatible with foetal growth and do not survive to birth are not included in birth defect. Data on spontaneous abortion may be important for the detection of teratogenic factors [1]. Severe malformations may end in very early loss of conceptions that do not survive to clinical recognition and are never detected. Screening during pregnancy and improved medical technology, such as ultrasound and genetic methods, make it possible to detect some birth defects at an early stage, which may lead to induced abortion and affect the prevalence of birth defects.

In exposure of the foetus through the mother, the teratogenic effect may arise during the organogenesis phase, and in humans the most vulnerable period is the first 3–8 weeks of pregnancy. In this period, the three germ layers give rise to tissues and organs. Certain birth defects can come into existence after the critical period as well. It seems plausible that different types of structural malformations may share biological mechanisms and that a given teratogenic factor may cause several types of malformations depending on the time window and level of exposure. Most known human teratogens seem to cause specific birth defects [2].

A large percentage of the workforce consists of women and a considerable proportion are of reproductive age. Nearly 70% of all birth defects have no known risk factors, therefore attention to the risk of birth defects due to occupational exposure could be of great interest. Several reviews have addressed birth defects related to limited exposures, such as pesticides [3,4], glycol ethers [5] and inhalation anaesthetics [6], while others have included the entire range of diverse occupational settings and exposures [7–9]. In 1994, Sever [9] concluded that epidemiological research had not convincingly established an association between workplace exposure as a human teratogen and birth defects, but since then a large body of literature has suggested that organic solvents, pesticides and some heavy metals may be involved in the causation of birth defects in humans [3–6,9]. Specific birth defects are seen following pharmaceutical exposures such as limb defects related to thalidomide, genital anomalies linked to diethylstilbestrol, spina bifida linked to valproic acid, oral clefts related to phenytoin and vitamin A causing neural crest defects [5,10–12]. Against this background, a review was conducted of previous published literature on the association between occupational exposures during pregnancy and selected ‘specific birth defects’.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion and final remarks
 Conclusion
 Conflicts of interest
 References
 
Relevant studies were identified by computer search of English-language abstracts in the MEDLINE database from 1966 until the end of 2004. A restriction to only human data was made, and no formal attempt was made to identify unpublished studies. We included prospective and historical follow-up studies, case–control and cross-sectional studies. Studies with inadequate description of work status or unclear exposure status and obviously insufficient sample size were excluded. No case series were included. A variety of searches were conducted using combinations of the exposure subject heading terms: maternal occupation, occupational exposure and occupational risk. The most common types of birth defects arising from different germ layers were selected, neural tube defects, cleft lip and cleft palate, congenital heart defects, urinary tract defects and limb defects, while rare defects like the digestive tract and the respiratory system were not included. Following the computerized search, a number of studies were identified from reference lists and reviews. In the search, 26 original studies were retrieved for the final analysis in this review. Not included were accidents, since these are mainly reported as case reports.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion and final remarks
 Conclusion
 Conflicts of interest
 References
 
Neural tube defects
The prevalence of neural tube defects varies over time and from country to country [13]. The reported prevalence in Europe is ~1 per 1000 births [14]. In the UK, a 2-fold decrease of neural tube defects has been observed between 1984 and 1996, which may be explained by improved antenatal diagnosis and termination of pregnancy [15]. Established risk factors for neural tube defects are dietary with several randomized clinical trials demonstrating a protective effect of folic acid supplementation. The most referred to is the MRC Vitamin Study [16] where the relative risk of neural tube defect was 0.28 in the folic acid group compared to the non-folic acid group, with the same trend established in follow-up studies [10,17]. A high dietary intake or supplements of vitamin A (retinol) is teratogenic resulting in neural tube defects or heart defects [11,18].

Our literature search identified 10 original studies reporting estimates on occupational exposure during pregnancy and neural tube defects, namely two cohort studies based on registry data and eight case–control studies (Table 1).


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  		Table 1 Studies on maternal occupational exposure and the risk of neural tube defects

 
In two Nordic countries, there were no associations between occupational groups and the risk of giving birth to an infant with neural tube defects [19,20], but in exploratory analyses Matte et al. [21] found an association with the nursing occupation. Cordier et al. [22] conducted a large case–control study in Europe, where various types of birth defects and a variety of occupational exposures, assigned by an expert, were included, as part of the Occupational Exposure and Congenital Malformations Working Group, which is part of EUROCAT. The overall risk of neural tube defects was 1.94 when exposed to glycol esters during the first trimester compared with no exposure, but there were no increased risk with increasing exposure. Bianchi et al. [23] did not find any association between neural tube defects and four different occupational groups when using the EUROCAT.

An occupational case–control study among a series of papers from The Netherlands on risk factors for spina bifida was based upon 55 cases and reported an increased risk among women working in agriculture (RR 3.4 95% CI 1.3–9.0) or cleaning (RR 1.7 95% CI 0.9–3.4) [24]. Other occupations seemed not to play any role in the risk of birth defects. In another case–control study with 210 cases, Blatter et al. [25] observed an increased risk of high-located spina bifida for infants born to mothers with agricultural occupations and for those with jobs in industry and transportation. The study indicated that the location of the neural tube defects might be of importance when analysing risk estimates. Brender et al. [26] performed a case–control study among Mexican Americans living along the border between Texas and Mexico, where the prevalence of neural tube defects tended to be higher than among non-Hispanic whites. In the study, 184 cases were included, and there seemed to be an increased risk of neural tube defects if the mothers had an occupation in the cleaning industry, in health care, or worked with glycol ethers or highly volatile organic solvents. The risk seems high when compared with the studies by Blatter et al. [24,25] and Cordier et al. [22], but the study may be influenced by recall bias. Shaw et al. [27] did not identify an increased risk of neural tube defects if the mothers had been exposed to different chemical agents including glycol ethers during pregnancy. Furthermore, a review found the evidence insufficient to confirm or refute findings [5]. Others found no risk factors for neural tube defects, even though there was suspicion of increased risk of central nervous system (CNS) defects in mothers working in manufacturing industries [19–21]. Taskinen [8] and Sever [9] conducted reviews of occupational exposures and birth defects and concluded that exposure to organic solvent during pregnancy is associated with an increased risk of birth defects including neural tube defects, but both reviews focused on a diversity of birth defects and a range of occupational exposures.

A case–control study by Lin et al. [28] found no general association between maternal physical load and neural tube defects. Two registry-based follow-up studies from Norway found an increased risk among lead exposed [29] and electromagnetic exposed [30] for neural tube defects, but there were no cases in the high-exposed lead group of women and there were no other CNS defects among women exposed to electromagnetic fields during pregnancy.

In conclusion, findings in the few studies that have addressed risks for neural tube defects following maternal occupational exposure during pregnancy indicate possible risks among women working in health care, agriculture and cleaning. The risk seems to be following exposure to glycol ethers or lead but available evidence is too limited to confirm the existence of risks related to specific occupational exposure.

Cleft lip and cleft palate
Cleft lip and cleft palate are well-defined birth defects, with a prevalence of ~1.5 per 1000 births for cleft lip, and ~0.8 per 1000 births for cleft palate. These birth defects have been studied intensively and it is well accepted that genetic factors contribute to the aetiology [31]. Christensen [32] has analysed the prevalence of cleft lip and cleft palate in Denmark during a 50-year time span and found that the prevalence has not increased since 1962.

In analysing the recurrence of birth defects, Lie et al. [33] found that changing municipality between the first and second child increased the risk of birth defect. This is in contrast to Christensen et al. [34] who did not find any association with changing municipality. There was a reduced recurrence of cleft lip and cleft palate when the mother changed partner. A number of studies have analysed the association between smoking and cleft lip or cleft palate, and most of these studies have found a weak association [35,36]. A meta-analysis including 10 studies estimated a risk of 1.29 when exposed to maternal tobacco smoke compared with non-exposure [37]. In addition, nutrition seems to play a role in developing cleft lip or cleft palate, with an increased risk if having a high intake of vitamin A (>10 000 IU) [11] and a decreased risk with folic acid intake [38].

In our search for literature with the subheadings: maternal occupation and cleft lip or cleft palate, we identified 11 studies, two were registry-based follow-up studies, and nine were case–control studies (see Table 2).


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  		Table 2 Studies on maternal occupational exposure and the risk of cleft lip and/or cleft palate

 
In a registry-based case–control study by Bianchi et al. [23], four categories of maternal occupation were created, namely health care workers, hairdressers, textile workers and leather and shoe workers and 11 categories of birth defects were constructed. In the study, the authors adjusted for race, education, number of previous live births, illness during pregnancy and maternal age, but did not adjust for maternal smoking and alcohol intake. There was a significant association between oral clefts and mothers working in the leather and pelt manufacturing industries with an adjusted odds ratio (OR) of 3.9. When analysing cleft palate separately, the OR further increased to 5.4. A non-significant increased risk was seen among hairdressers and textile dye workers [23]. In a case–control study, Cordier et al. [22] used job descriptions given by the mother to evaluate an exposure during pregnancy to glycol ether. The chemist who classified the exposure was blinded to case status. The authors identified 100 cases and the estimated risk of cleft lip was 2.3 when the mothers were exposed to glycol ether during pregnancy compared with non-exposure. When using six different birth defects registers, a case–control study found an increased risk among hairdressers and housekeepers [39]. The study suggested that occupational exposure to aliphatic aldehydes or glycol ethers are associated with an increased risk of cleft lip or cleft palate. Laumon et al. [40] found in a case–control study that mothers exposed to organic solvents during pregnancy had an increased risk of giving birth to a child with cleft lip, but when stratified according to different types of organic solvents, the results were inconclusive because the numbers of exposed cases were too small. Holmberg et al. [41] conducted a registry-based case–control study and found an increased risk of cleft lip or cleft palate in infants born to mothers exposed to organic solvents compared with controls. Shaw et al. [42] examined maternal occupation exposure to 74 different chemical and genotypes of detoxification enzymes in a case–control study. The outcomes were different types of birth defects including 662 cases of cleft lip or cleft palate. In the study there were a few increased risk estimates, but the authors concluded that chemicals examined did not contribute substantially to the risk of cleft lip or cleft palate.

The association between the mother's physical work and cleft lip has been studied in a case–control study with an association between cleft lip and standing >75% of the working day (OR = 1.76), but the authors suggested it to be an artefact [28].

A large registry-based follow-up study examined the association between the maternal occupational exposure to magnetic fields and the risk of different types of birth defects. The study gave conflicting results, a significant decrease in the risk of cleft palate and an increase in cleft lip [30]. The registry-based follow-up study by Chia et al. [43] found no association between any occupation and cleft lip or cleft palate. Carmichael et al. [44] examined socio-economic status and the association with cleft lip or cleft palate and found no difference in risk between unemployment and different types of occupations. In Finland, Nurminen [45] found that professional applications of pesticide among pregnant women were associated with a 2-fold increased risk of cleft lip or cleft palate.

Some epidemiological studies have indicated that exposure to organic solvents in the workplace during pregnancy may lead to an increased risk of foetal loss or spontaneous abortion. The review by McMartin et al. [46] concluded that there was an association with major malformations, but there was no significant association between maternal exposure to organic solvents and cleft lip or cleft palate or other specific birth defects, although the risk for all birth defects pooled was 1.25 (95% CI 0.99–1.58).

In conclusion, employment during pregnancy in the leather industry or as a hairdresser has been suggested to be associated with increased risk of cleft lip or cleft palate in the infant. Exposures like organic solvents, glycol ethers and pesticides have been suggested in a number of studies, but the evidence is still very limited.

Heart abnormality
The prevalence of congenital heart defects is difficult to estimate since a proportion of the cases will be diagnosed later in life. Furthermore, the prevalence has increased simultaneously with the increasing survival of premature infants and technological advances in diagnosis. Additionally, we are dealing with a survival cohort, since the most serious heart abnormality is incompatible with life. The prevalence of congenital heart defects is ~4–6 per 1000 births.

We identified two registry-based follow-up studies and five case–control studies focusing on maternal occupation and risk of heart abnormality. Alcohol consumption during the first trimester, maternal diabetes mellitus, high body mass index and the use of antiepileptics may increase the risk of congenital heart defects (Table 3).


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  		Table 3 Studies on maternal occupational exposure and the risk of congenital heart defect

 
Maternal occupation in agriculture or fishing was associated with a 79-fold increased risk of congenital heart defects, but there was only one case in the exposed group [43], in a registry-based study. It has been reported that pesticide exposure during early pregnancy is associated with an increased risk of congenital heart defects [47], but others have not been able to confirm these findings [27,48].

Exposure to organic solvents in the workplace is among one of the most common chemical exposures. In one study, the risk of giving birth to an infant with heart defects was increased when the mother was exposed to organic solvents during pregnancy compared with no exposure [22]. Recent investigations of gene–environment interaction have suggested that genetic polymorphism may play a key role in solvent metabolism, since some mothers are slow metabolizers of toxic parent compounds, and thereby mediate the risk of congenital heart defects. A case–control study from Sweden could not corroborate any association between occupation and risk of giving birth to an infant with heart defects [49]. Finally, no associations have been found between socio-economic status or work with display screen equipment during pregnancy and congenital heart defects [44,50,51].

In summary, the evidence on occupational exposure as a risk factor for congenital heart defects is inconclusive.

Urogenital abnormality
The prevalence of hypospadias in newborns is in the range of 2–4 per 1000 and for cryptorchidism <4 per 1000 male births [52–54]. There is some evidence that the prevalence of hypospadias has increased during the past several years and the prevalence seems to differ within and between countries [53,55]. Changing procedures for identification and ascertainment of the disorder may explain part of the apparent secular trends in occurrence. In boys, hypospadias compromises some 10% of all birth defects recognized at birth [56].

Genetic defects are known to play a role in hypospadias, but only a few risk factors have been established in humans. Low birth weight and indicators of impaired intrauterine growth have been associated with hypospadias [54]. The evidence concerning maternal age is conflicting [52,57]. Occurrence of hypospadias is associated with cryptorchidism, risk of testicular cancer and possibly reduced semen quality [57]. Several indications that hypospadias is associated with a reduced couple fertility was corroborated in a recent case–control study, clearly indicating a dose-related association between years of involuntary childlessness and the risk of hypospadias [36,58]. Prima parity seems to increase the risk while smoking during pregnancy may decrease the risk of hypospadias.

We identified eight case–control studies published that explicitly addressed the risk of hypospadias according to maternal occupational exposures (Table 4). A recent comprehensive study on the entire English population during more than a decade did not demonstrate any convincing association between the occurrence of hypospadias and any maternal occupation [57]. This study and a more recent Dutch study did not find evidence that women with potential occupational exposure to chemicals with endocrine-disrupting activities are at an increased risk of delivering male newborns with hypospadias [57,59]. Other studies have addressed health care workers, hairdressers, textile workers and workers exposed to glycol ethers and pesticides [60,61]. The few studies addressing maternal occupational risk for cryptorchidism in boys are insufficient to allow any conclusions and the majority of findings are rather reassuring with no clear indication that occupational exposure during pregnancy imposes a risk for hypospadias.


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  		Table 4 Studies on maternal occupational exposure and the risk of urinary tract defects

 
Limb defects
Since the thalidomide disaster in the 1950s and 1960s there has been a focus pertaining to limb defects among newborns. The prevalence of congenital limb defects is ~0.5–1 per 1000 births [62]. Several studies reported that maternal smoking during pregnancy might increase the risk of limb defects [63–65], but it has also been proposed that gene interaction may modify the teratogenic effects of smoking [66].

We identified six published studies that had analysed the association between maternal occupational exposures and limb defects (Table 4). McDonald et al. [67] indicated an association between musculoskeletal defects and maternal agricultural work, while Hemminki et al. [68] found no association. Garry et al. [69] studied the association of pesticide use and risk of birth defects, and found an increased risk of birth defects in the musculoskeletal system. Since birth defects in the musculoskeletal system cover a range of diseases, they are not included in Table 5. Occupation as a health care worker [21], hairdresser [23], textile worker [23] or leather or shoe worker [23] has been associated with limb defects, while exposure to glycol ether has not [22]. Engel et al. [70] found that infants born to mothers working in the agricultural field are at increased risk of limb defects (OR = 2.6) compared to infants born to mothers working outside agricultural settings. Another case–control study from California published several years earlier reported an increased risk of limb defects [71,72], while Lin et al. [73] found that farming or high pesticide use was not associated with any type of limb defect. Furthermore, one review found that maternal environmental exposure to pesticides may increase the risk of limb defects, but stated that the evidence was inconclusive [45]. Finally, occupational exposure to pesticides in relation to birth defects has been reviewed by García [3] in 1998 and by Hanke and Jurewicz [4] in 2004 and the conclusions were that in the light of a large body of literature there is still limited evidence for adverse effects.


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  		Table 5 Studies on maternal occupational exposure and the risk of limb defects

 
The limited number of studies focusing on limb defects and other occupations or exposures is insufficient for assessment of risk.


   Discussion and final remarks
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion and final remarks
Conclusion
 Conflicts of interest
 References
 
In nearly 70% of all birth defects, there is no known risk factor but the present review of the original literature does not provide clear evidence for causal associations between maternal occupational exposures and specific birth defects. It seems that little progress has been made since Sever [9] in a review 10 years ago arrived at the same conclusion.

This review is based upon the assumption that occupational teratogens, like most known human teratogenic drugs, will cause specific birth defects. Consequently, a large body of literature that examined overall risk for malformation regardless of type has not been considered. If an exposure causes several types of malformations, it should also be detected in studies focusing on specific birth defects. Valid ascertainment of birth defects is one of several methodological issues that have raised concern [5,7,74], but ascertainment is likely to be more valid in studies that focus upon one or few specified malformations. Nevertheless, this review has not addressed several interesting findings in studies addressing ‘overall’ malformations. One example is the suspicion that an occupation as hairdresser during pregnancy may be associated with increased risk of birth defects, in view of the fact that hairdressers are exposed to a wide range of products, which may be potentially reproductive toxins. The previously published studies have been based on a small number of cases and with no uniform birth defects and a recent study with 7202 hairdressers and 195 major birth defects found a slight increased risk for all birth defects pooled [75].

Other important limitations of the reviewed studies are insufficient exposure assessment and/or limited study size. For these reasons, the very limited epidemiological research database does not rule out that specific exposures encountered during embryo- and foetogenesis may carry a risk for congenital malformations. To advance knowledge in this field, there is probably a need for studies with reliable and accurate assessments of specified exposures during the first trimester of pregnancy. Surveys of exposure levels among occupational populations, methods for measurement of exposure in relevant tissues and in vitro and in vivo data indicating possible teratogenic effects can support the identification of high priority exposures where additional research is warranted. Research in the field is overwhelmed with methodological problems.

Another example is the first prospective study of pregnancy outcome in a group of 125 women with occupational exposure to organic solvents that demonstrated an increased rate of major malformations in the offspring (RR 13.0, 95% CI 1.8–99.5, Khattak et al. [76]). These findings are consistent with a meta-analysis based upon five large studies of birth defects in the offspring of pregnant women exposed to organic solvents [46]. One of the criticisms of these studies has been lack of biological plausibility of the unspecific birth defects [77].

There is a growing body of evidence indicating that work in agriculture during pregnancy carries a considerable risk for limb defects but findings are not consistent across various regions in the world. If working in agriculture carries a causal risk for limb defects in the offspring, it seems that the risk factors are not always present or not present in all agricultural settings. There is an obvious need to define and investigate more specific hypotheses, for instance addressing exposure to specific pesticides that according to animal studies and exposure levels could be of importance. It would also be of interest to investigate whether other occupations that involve exposure to pesticides, for instance work in greenhouses, are associated with a risk.

There is a strong interaction between age, lifestyle factors, such as smoking status and alcohol intake, social class, nutritional factors and occupational exposure during pregnancy, which complicates the proper interpretation of associations observed in epidemiological studies.


   Conclusion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion and final remarks
 Conclusion
Conflicts of interest
 References
 
The position is that epidemiological research has not convincingly demonstrated any workplace exposure as a specific human teratogen but several concerns implying possible teratogenic effects of volatile organic solvents, glycol ethers, some pesticides and some heavy metals call for additional research. Furthermore, it seems to be difficult or impossible to establish exposure–response relationships. Such studies will probably require very large source populations and call for international research cooperation.


   Conflicts of interest
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion and final remarks
 Conclusion
 Conflicts of interest
References
 
None declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion and final remarks
 Conclusion
 Conflicts of interest
 References
 

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