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Original articleScand J Work Environ Health 1990;16(2):102-107 doi:10.5271/sjweh.1811

Risk of spontaneous abortion among nurses handlingantineoplastic drugs.by Stucker I, Caillard JF, Collin R, Gout M, Poyen D, Hemon D

Affiliation: Unite de Recherches Epidemiologiques et Statistiquessur l'Environnement et la Sante, Villejuif, France.

This article in PubMed: www.ncbi.nlm.nih.gov/pubmed/2353192

Scand J Work Environ Health 1990;16:102-7

Risk of spontaneous abortion among nurses handlingantineoplastic drugsby Isabelle Stucker, PhD,1 Jean-Francois Caillard, MD,2 Renee Collin , MD,3Michele Gout, MD,4 Daniele Poyen, MD,5 Denis Heman, PhD1

STUCKER I, CAILLARD 1-1", COLLIN R, GOUT M, POYEN D, HEMON D. Risk of spontaneousabortion among nurses hand ling antineo plastic drugs. Scand J Work Environ Health 1990;16:102-7.The purpo se of the study was to evaluate the frequency of spontaneous abortion in two groups of women.One group consisted of women regularly involved in the preparation of cancer chemotherapy perfusionsand therefore considered to be exposed to cytostatic agents; the other consisted of women not occupa­tionally exposed to such agents. The study was carried out in four French hospitals. Four hundred andsixty-six women were involved; 534 pregnancies were described in which 139 were exposed and 357 wereunexposed . The results showed that the frequency of spontaneous abortion was 26 % for the exposedpregnancies and 15 070 in the unexposed ones (odds ratio 2.0). These results do not seem to be due eitherto the classic risk factors of spontaneous abortion (age, cigarette consumption during pregnancy, preg­nancy order) (adjusted odd s ratio I.7) or to possible errors concerning the retrospective evaluation ofprior gynecologic and obstetric history.

Key terms: cytostatics, occupation , pregnancy outcome, reproductive hazard .

Cytostatics are chemical agents which, because of theirantimitotic action, are often used in cancer chemo­therapy. Their mutagenicity, ca rcinogenicity, and ter­atogeni cit y have been amply documented by in vitroand in vivo experiments (1,2). Some particular agents,esp eciall y met ho trexate, have been shown to be ter­atogenic in pr egnant women being treated by cancerchemotherapy (3, 4). Moreover the re lat ionship be­tween the mec ha nisms of mutagenesis and teratogen­esis have been emphasized by several authors (5, 6) .

Several studies concerned with occupational ex­posure to these agents have shown a significant increasein urine mutagenicity in exposed subjects as comparedwith unexposed subjects (7-1 1). Other stud ies ha vedemonstrated that work preparing cyto static perfusionscan lead to an increase in the average number of sis­ter chromatid exchanges and to an increase in the fre ­qu ency of chro mosome ano malies in lymphocytes(12- 14). To our knowledge four studies provide someepidemiologic information on the relationship betweencytostatic exposure and reproductive hazards (15- 18).

I Unite de Recherches Epidern io log iqu es et Statistiques surJ'Environnement et la Sante, Villejuif Cedex, France.Preventive Medicine Department , Regional Hospital ofRouen, Rouen, France.

) Preventive Medicine Department, Regional Hospital ofGrenoble, Grenoble, France.

4 Preventive Medicine Departme nt of lnstitut GustaveRoussy, Villejuif', France.

S Preventive Medicine Department, Regional Hospita l ofMarseille, Marseille, France.

Reprint requests to: Dr I Stucker , Unite de RecherchesEpidemiologiques et Statistiques sur l' Environnement et laSante, INSERM U170, 16 Avenue Paul Vaillant Couturier.9480 7 Villeju if Cedex, France.

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McDonald et a l, in the frame of a case-referent sur ­vey on spontaneous abortions in a la rge general popu­lat ion , did not find a significant relationship betweencytostatic exposure and spontaneous abortion (15).Taski nen et a l observed an increased risk among poten­tially exp osed pregnancies, which was however no tsta tistically significa nt, in a case-referent study in thepharmaceutical industry (16). T he case-referent studyo f Hemminki et a l (17) was performed wit hin a co­hort of hospital nurses and did not show any increasedrisk of spontaneous abortion among nurses exposedto cytost atics. However , restricting their populationto specia lized departments where cytos ta tic exposurecan be thought to be higher, Hemminki et al (17)showed a sign ificantly higher risk of congenita l mal­formations in relation to this expo sure. Finally, Selevanet al (18), who performed a case-referent study wit hina cohort o f n urses wo rking in oncolog ic depar tments,observed a two fold inc rease in the risk of spontaneousabo rtio n among exposed nurses.

The present stu dy was aimed at evaluating th e po s­sible mo difi cations of parameters characteristic o f thereproductive funct ion in relat ion to the handl ing ofcytostatic drugs. The presented result s concern the fre­quency of spo nta neo us abor tion in two gro ups ofnurses, one in whi ch the nu rses prepared ca ncerchemotherapy perfusion s and th e other one in whichthey did not.

Subjects and methods

The frequency of spo ntaneous abortion was compa redbetween th e previous pregnancies of a gro up of nurseshandling perfusion s in cancer treatment unit s and those

o f a group of nurses who were no t so expo sed . Thedat a were collected by interview from May 1985 to May1986 in three Fren ch hospitals and in a large centerfor ca ncer treatment.

Choice of medical departments 'and eligibility ofthe subjectsThe cancer units selected were those in which the num­ber of cyto sta tic ph ials distrib uted a nnually by thehospital pharmacy corresponded to a minimum of tencytostat ic perfu sions prepared per week and per nurse.Consulting medical , cardiologic, endocrino log ic, andgenera l med ica l units were chos en as the referenceunits. All the female daytime nursing sta ff (hea dnurses , registered nurses , practical nur ses) aged 45years or less an d working in one of the selected un itswere ask ed to participate .

Co ffection of inf ormation

In each center , interviews were ca rried out by an in­vestigat ing ph ysician . The qu estio nnaire consisted ofthe fo llowing three part s: (i) general char act eristics o fthe subject ; (ii) description of pregnancies a nd classi­ca l risk fac tors invo lved in spo nta neo us abortio ns(pregnan cy order, age of the mot her at pregnan cy, andcigar ette co nsumpt io n); and (iii) job held by the sub­jec t at the time of the study and previou s jobs , in­cluding those o uts ide th e medi cal field . T o be able toeva lua te the relia bility of th e spo nta neous abortionsreported, the subjects were asked to define the methodused to diagnose the pregna ncy (lab oratory exam ina­tion , pharmaceut ical test , physician examinat ion or latemenstrua l period), the num be r o f weeks of gesta tio na t abortion, and the occurrence o f hospital izati on orcurettage. A sponta neo us a bo rt io n was defined as apregnan cy which ended before 28 weeks o f ges ta tion.In or der to avo id the underreporting of induced abor­tions, we preferred to exclude them fro m the interview.Th erefore , the freq uency of sponta neous abort ion wasdefined as the rate of the number o f sponta neous abor­tions over the number of pr egn a ncies, excluding in­du ced a bo rtions.

T he questionnaire enabled us to date pr ecisely oc ­cupat ion a l exposure to cytostat ics dr ugs, a nes theticagen ts, a nd formaldehyde. An y pre gn ancy occ urr inga fter or during a period of exposure to cytos ta tics wasconside red to be " exposed. " Similarl y, pregnancies oc­curri ng after expos ure to fo rmaldeh yde or a nes theticage nts were considered to be exposed to the respec ­tive substa nce. Exposure to cytos ta tics was fur therdescrib ed according to the fr equ en cy (regular, occa­siona l, rar e) and total durat ion o f expos ure . At th etime of the study, no special protective eq uipment,such as a fume hood , was in op erati on . Furth ermor e,the use o f personal pro tective equipment (surg icalgloves and masks) was not un ifo rm among the nurses,co ncerned o nly a few drugs (methotr exate), and wasa recen t co ncern for the nurses.

Stat istical analysisIn all the statistical analyses the different pregn an cieso f the same wo ma n were co nsidered to be statistica llyind ependent , even though th is is no t strict ly true.Statistical analysis was th us also carried out so lely forfirst pre gnancies to take into accou nt the variabil ityin the risk of spont a neous abo rtio n between women .

Results

Of the 535 wome n eligible for th e study, 39 co uld notbe co ntac ted du e to temporar y leave of ab sence (sickleave, materni ty leave, hol iday, pro fession al train ing),and 30 re fused to participate. The study therefore in­vo lved 466 women (rate of par ticipation 87 % ), 271belon ging to units in which cyt os tatics were handledand 195 to control units. The genera l charac teri sticso f th e women who participated are presented in tableI, and those of the 534 reported pregnancies are shownin tabl e 2.

Fo r 38 pregna ncies there was no availabl e informa­tion to enab le the determination of cytostatic expo sure .Among the 496 remaining pregn ancies, fo r which ex­posure informa tio n was available, there was no ex-

Table 1. Characteristics of the populatio n.

Characterist ic N % Mean SD

Total population 466

Age at interview (years) 31.2 6.5

Length of work periodin departm ent (years) 4.6 4.3

Length of total work period(years) 9.7 6.5

Percentage of exposed nurses 36.5

Exposed nurses 170

Frequency of exposureto cytostatics

Regul ar 153Occa sional 14Rare 3

Tim e of prior exposu reto cyt ost ati cs (years) 6.1 6.5

Numb er of perfus ions preparedper week by each nurse 18.6 2.2

Table 2. Characterist ics of the reported pregnancie s.

Charac terist ic N % Mean SD

Total number of pregn anciesdescribed 534

Nullipara wom en 43.1

Age of mother at pregnancy(years) 25.1 4.3

Pregnancy order 1.8 1.1

Frequency of spontaneousabor t ions 19.9

Length of pregnancy beforesponta neous abor t ion (weeks) 8.1 3.8- - - - -

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Tabl e 3. Frequency of spontaneous abortion and exposure to cytostatics drugs.

Exposed Unexposed 95 %pregnancies pregnancies Rate confidence

ratio intervalN % N %

All pregnancies 139 25.9 357 15.1 1.7 1.2-2.5

First pregnancy on ly 66 22.7 184 10.3 2.2 1.2- 4.1

Pregn anc ies with no previousexposure to anesthetic agents 132 25.8 . 340 15.0 1.7 1.2-2.5

Preg nancies with no previousexposu re to fo rmaldehyde 106 25.5 277 11.9 2.1 1.3-3.4

~_. _ -----

Table 4. Characteristics of the spontaneous abortions and thebirths with respect to risk factors . (SE = standard error of themean)

Spo ntaneou s Bir thsabortions (N = 428)Characteristi c (N = 106)

% Mean SE % Mean SE

Age of mo ther atpreg nancy (years) 27.1 0.5 24.7 0.2

Age at pregnancy> 30 years 20.8 8.5

Pregnancy order 2.2 0.1 1.7 0.1

Second or higherin the order ofpregnancies 62.2 47.2

Smokers duringpregnancy 22.2 11.0

Tabl e 5. Characteristics of exposed and unexposed pregnan­cies with respect to risk factors . (SE =standard error of themean)

Exposed Unexposedpregnancies pregnancies

Characteristic (N = 139) (N =357)

% Mean SE % Mean SE

Age of mother atpregnancy (years) 27.1 0 .3 24.4 0.2

Age at preg nancy>30 yea rs 18.0 8.2

Preg nancy orde r 1.8 0 .08 1.5 0.05

Second or hi gherin the order ofpregnancies 47.5 52.4

Smokers duringpregnancy 15.9 12.1

posure in 357 cases, exposure on ly prior to pregnancyin 24, exposure during pregnancy in 7, exposure bothprior to and during pregnancy in 105, and expos urefor an undetermined time in 3.

Becau se of the sma ll numbers, it was impossible toanalyze the effects of exposu re before and during preg­nancy separately. We therefore combined all the ex­posed pregnancies (N = 139).

The freque ncy of spontaneous abortion was signifi­cantly higher in the exposed group (25.9 %) than in

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the unexposed one (15.1 0/0) (P<O.OI). This result wasalso observed when the analysis was limited to the firstpregnancy of each woman (table 3).

A comparison of the reported gestational ages at thetime of the abortion did no t revea l any significantdifference between the exposed and unexposed groups .

The relationships between the occurrence of spon­taneous abortion an d well-known risk factors aredescribed in table 4. All of them were found to bestatistically significant in the present sample. The oc­currence of some of these factors was significantlydifferent between the exposed and unexposed groups(table 5). Adjustment for smoking during pregnancyon one hand, and for age at pregnancy on the other,did not explain the observed relationship between ex­posure and the frequency of spontaneous abortion.Furthermore this relationship was still stati stically sig­nificant when restricted to the first pregnancy of eachwoman. Adjustment for all these confounders (age atpregnancy, pregnancy order, smoking during preg­nancy) simultaneously in a logistic regression decreasedthe odd s ratio of the association from 2.0 [95 % con­fidence interval (95 % CI) 1.2-3.1] to 1.7 (95 % CI1.0-2.8) without modifying the statistical significance .

The pregnancies could have been exposed to form­aldehyde or to anesthetic agents. A pregnancy was con­sidered exposed to formaldehyde if it occurred dur­ing or after expos ure , defined as daily or freq uent, toformo l in connection with the disinfection of roomsand /or equipment. P revious exposure was thus foundto be negative for 383 pregnancies and positive for 50,the forma ldehyde exposure of the remaining 63 beingunknown . When the 113 pregnancies for which form ­aldehyde exposure was positive or unknown were ex­cluded , the results concerning cytostatics were notmodified (table 3). Similarly, excluding the 24 pregnan­cies with positive (N = 10) or unknown (N = 14) previ­ous exposure to anesthetic agents from the analysis didnot modify the results either (table 3).

Fina lly, in order to improve the social homogenei­ty of the sample, the analysis was restricted to preg­nancies of head nurses and registered nurses only (prac­tica l nurses being excluded). The results again demon­strated a statistically significant excess of spontaneousabortions among the exposed pregnancies in compar­ison with the rate among the unexposed ones .

In order to reduce the likelihood of bias due to anunderreporting of spontaneous abortion, we excludedthe ten spontaneous abortions corresponding to preg­nancies diagnosed solely by the women themselves onthe basis of late menstrual periods and spontaneousabortions which occurred after less than eight weekswithout a menstrual period from the analysis. In bothcases the frequency of spontaneous abortion was twiceas high among the exposed pregnancies as among theunexposed ones (P<O.OI). The same observation wasmade after the exclusion of extrauterine pregnancies.Finally, all these results were substantiated when onlyfirst pregnancies were assessed alone.

The frequency of spontaneous abortions did not dis­playa statistically significant association with dura­tion of exposure to cytostatic drugs prior to pregnan­cy (28, 24, and 24 010 of the spontaneous abortions for1-24, 25-60, and> 60 months of exposure prior topregnancy, respectively). Excluding the 24 pregnanciesexposed only prior to pregnancy did not modify theresults (rate ratio 1.7, 95 010 CI 1.1-2.5). Such wasalso the case for the relationship between spontaneousabortions and the frequency of exposure to cytostaticdrugs during pregnancy.

Discussion

The purpose of this study was to compare the frequen­cy of spontaneous abortion in relation to the handlingof cytostatics. A pregnancy was defined as being ex­posed if the woman had, prior to or during pregnan­cy, given perfusions in departments where the handlingof cytostatics was frequent at the time of the study (18perfusions per week per nurse prepared on the aver­age).

Spontaneous abortions were approximately twice asfrequent among the exposed pregnancies than amongthe unexposed ones. McDonald's population-basedcase-referent study did not show any significant rela­tionship between cytostatic exposure and spontaneousabortion (15). It may be thought however thatMcDonald's definition of cytostatic exposure couldonly be much broader than the one adopted in thepresent study, which concerned oncologic departmentsonly. Taskinen et aI's study (16) of women workingin the pharmaceutical industry showed an odds ratioof 2.8 in relation with cytostatic exposure. The num­ber of exposed subjects in their study was small how­ever, and this association was not statistically signifi­cant. Hemminki et aI's case-referent study (17) onspontaneous abortion was performed in a populationof hospital nurses, and no significant association withcytostatic exposure was observed. However, restrict­ing their population to nurses working in departmentswith frequent exposure to cytostatics, this group ofresearchers found a significant excess of malformedchildren among the exposed nurses. Finally, in a case­referent study performed within a population of nurses

working in oncology departments, Selevan et al (18)observed an increase in the frequency of handlingcytostatics in the group of subjects who had ex­perienced spontaneous abortions in comparison witha group of subjects who had given birth. The resultsof their study, which is the most closely comparableto the present one as far as the definition of exposureis concerned, showed a risk of spontaneous abortionthat was approximately twice as high for the exposedwomen as in our study.

Selection biasIn this study it was not technically possible to includesubjects having previously worked in the departmentsin question and having since left the hospital. Axels­son (19) observed that women leave work more fre­quently after giving birth than after a spontaneousabortion (19). The rate of spontaneous abortion couldtherefore have been overestimated among the womenremaining in the departments. It is however very un­likely in the present study that the influence of the out­come of pregnancy on subsequent employment dif­fered for the exposed and unexposed women. It cantherefore be thought that, if the rate of spontaneousabortion is overestimated without differential biases,the true relative risk will be in fact underestimated.

The study population was socially homogeneous, asonly nursing staff were included (head nurses, regis­tered nurses, practical nurses). Moreover restricting theanalysis to the head and registered nurses did not modi­fy the findings.

Information biasParticular attention was given to the problem of in­formation bias. The questionnaires were completedduring interviews. The study was presented to eachdepartment concerned as a study whose purpose wasto assess the reproductive characteristics in hospitalpersonnel without focusing on any particular risk fac­tors. Indeed, departments as different as consultingmedical units and care units in oncology or cardiolo­gy were included. Finally, the questionnaire separate­ly addressed the description of previous pregnancieson one hand and the work history of the subject onthe other. With these precautions, a normal value forthe frequency of spontaneous abortion among unex­posed pregnancies was observed (15.1010). Time sincepregnancy was significantly different for the exposedand unexposed pregnancies. However it was not sig­nificantly related to the frequency of spontaneousabortion when considered simultaneously withcytostatic exposure and maternal age in a logisticregression.

In addition excluding spontaneous abortions cor­responding to pregnancies diagnosed only by thewomen themselves following a late menstrual periodfrom the analysis did not modify our results. Con-

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versely, taking the somewhat restrictive hypothesis thatall women are aware of their pregnancy only after eightweeks without a menstrual period, we also restrictedour analysis to spontaneous abortions occurring aftereight weeks or more. Once again the results were notmodified. We therefore feel that it was unlikely thatthe increased frequency of spontaneous abortionsamong the exposed pregnancies resulted from infor­mation bias .

Confounders

The frequenc y of spontaneous abortions in this studywas significantly correlated with the classical risk fac­tors of age at pregnancy (20, 21), smoking during preg­nancy (22), and pregnancy order. The variations in thespontaneous abortion rate with pregnancy order hasbeen analyzed in detail (23) and involves both directand selection phenomena. Adjustment for these threefactors either separately or simultaneously in a logis­tic regression did not modify the results of our study.This was also the case when we took into account oc­cupational exposure to anesthet ic agents or formalde­hyde. In this stud y the existence of previous spon­taneous abortions can be considered either as an indi­cator for the existence of risk factors predisposing tospontaneous abortion or , alternatively, as the firstmanifestation of sensitivity to cytostatic exposure. Ofthe 43 exposed pregnancies that were second pregnan­cies, 10 were preceded by one previous spontaneousabortion, and all of the earlier pregnancies that hadresulted in a spontaneous abortion had been exposed.Consequently it was not possible to distinguish womenwho had a greater risk of spontaneous abortion fromwomen for whom previous spontaneous abortion wasthe manifestation of cytostatic exposure. It was for thisreason that we also decided to restrict the analysis tothe first pregnancy of each woman rather than takingprevious spontaneous abortions into consideration ina multiple regression.

Statistical analysis

Taking into account all the pregnancies of each womancould place too much weight on a small number ofwomen with a large number of spontaneous abortions.For this reason the analysis was also carried out forfirst pregnancies only. When the basic relationship, therelationship adjusted for classic risk factors, and therelationship studied in limited categories of spontane­ous abortion were taken into consideration, a statisti­cally significant twofold increase in the spontaneousabortion rate was observed for the exposed pregnan­cies as compared with the unexposed ones.

Detailed analysis of exposure

An increase in the frequency of spontaneous abortionwith an increase in the frequency or durat ion of ex­posur e was not observed. It must be noted however

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that only 25 010 of the exposed pregnancies were occa­sionally exposed. In addition no relationship with du­ration of exposure is to be expected if exposure dur ­ing pregnancy only leads to an increase in the risk ofspontaneous abort ion.

It is well known that a large variety of differentchemicals is used in cancer treatm ent. Moreover theyare very often used in association with the treatm entof a given patient. Consequentl y reliable info rmationon the exposure of nurses to parti cular drugs wouldbe very difficult to measure since the nurses handl edcytostatic drugs over a long period of time and treateddifferent types of cancer with different chemicals. Forthis reason we did not attempt to obt ain informationon specific exposure.

Selevan et al (IS) was able to obtain such informa­tion . They found that the four most frequently useddrugs were doxorubicin, cyclopho sphamide, fluoro­uracil, and vincristine, and indeed they observed thatthe exposure of pregnancies to these four drugs werehighly corr elated. Attempting however to evaluate therelation ship between spontaneous abortion and ex­posure to doxorubicin , cyclophosphamide, fluoro ­uracil, and vincristine separately, they finally con­cluded that it was not possible to separate the effectsof the individual dru gs.

This study, together with that of Selevan et al (I S),reveals a doubling in the frequency of spontaneousabort ion related to exposure to cytostatic drugs in on­cologic departm ents. This increase in risk should beconfir med in other populations.

We were only able to study general exposure tocytostatics. An interesting but difficult question wouldbe to try to identify the most hazardous drug s amongthe cytostatics and the critical exposure period s.

Acknowledgments

This work was financed in part by the Ministere desAffaires Sociales et de l'Emploi (Direction des Rela­tions du Travail) and by the Caisse Nationale d' As­suran ce Maladies des TravaiIIeurs Salaries (collabora­tion INSERM-CNAMTS).

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Received for publication: 28 July 1989

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