(CANCER RESEARCH 46, 4812-4816, September 1986)

Prenatal and Perinatal Risk Factors for Testicular CancerLinda Morris Brown,1 Linda M. Pottern, and Robert N. Hoover

Epidemiology and Biostatistics Program, National Cancer Institute, Bethesda, Maryland 20892

ABSTRACT

In an attempt to determine the risk factors responsible for the dramaticincreases in testicular cancer incidence in young adults, mothers oftesticular cancer cases and controls were questioned about in uteroexposures, pregnancy-related conditions, and perinatal factors duringtheir pregnancies with the 202 cases and the 206 controls. The strongestrisk factor was low birth weight with a greater than 12-fold risk (confidence interval = 2.8 to 78.1) for subjects weighing 5 Ib or less at birthcompared to those who weighed over 5 Ib. A statistically significant 2-fold increase in risk was associated with unusual bleeding or spottingduring pregnancy, regardless of whether medication was taken for thiscondition. Other exposures during pregnancy associated with a statistically significant increase in risk were: use of "sedatives"; alcohol con

sumption; and exposure to X-rays. No excess risk was associated withthe use of hormones during pregnancy. The findings for birth weight andabnormal uterine bleeding suggest that significant compromise of thenormal maternal-fetal environment may be associated with subsequentincrease in risk of testicular cancer. However, this increase in risk is notgreat enough to explain the dramatic increases in testicular cancer thathave occurred in young adults.

INTRODUCTION

The incidence of testicular cancer in the United States hasbeen increasing dramatically for young adult men, aged 15 to44 yr ( 1). Because these men were relatively young when theircancer was diagnosed, it has been speculated that pre- andperinatal factors may play a role in the etiology of young adulttesticular cancer (2). This paper presents the results of a case-control study of testicular cancer in which the biological mothers were questioned about in utero exposures, pregnancy-relatedconditions, and perinatal factors during their pregnancies withthe cases and controls.

MATERIALS AND METHODS

The potential study population consisted of the living biologicalmothers of 271 testicular cancer cases (88% of the cases identified) and259 other cancer controls (90% of the controls identified) who participated in an interview study during 1979 to 1981. The controls werepatients at the same hospital as the cases and were similar in age to thecases (±2yr of age). Study subjects were 18 to 42 yr old at the time ofdiagnosis (January 1976 to June 1981) and were ascertained at one ofthree Washington, DC area medical centers: NIHCC2; USUNH; and

WRAMC. Results from the interviews with cases and controls aredescribed elsewhere (3).

Two hundred twenty-five mothers of testicular cancer cases wereinterviewed as were 213 mothers of controls. Reasons for not interviewing the mothers were: not a biological mother (3 cases, 4 controls);mother deceased (21 cases, 25 controls); son refused permission formother to be interviewed (13 cases, 10 controls); mother unavailable (5cases, 3 controls); and mother refused to participate (4 cases, 4 con-

Received2/4/86; revised5/20/86; accepted6/6/86.The costs of publication of this article were defrayed in part by the payment

of page charges. This article must therefore be hereby marked advertisement inaccordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1To whom requests for reprints should be addressed, at Epidemiology andBiostatistics Program, National Cancer Institute, Landow Building, Room 3C1S,Bethesda, M D 20892.

2The abbreviations used are: NIHCC, NIH Clinical Center; USUNH, Uniformed Services University, Naval Hospital; WRAMC, Uniformed Services University, Walter Reed Army Medical Center, RR(s), relative risk(s); CI, confidenceinterval.

trois). A standardized questionnaire was used by trained interviewersover the telephone to obtain information about in utero exposures (e.g.,medications, X-rays, alcohol, cigarettes), pregnancy-related conditions(e.g., bleeding, nausea, toxemia), and perinatal factors (e.g., type ofdelivery, birth weight, gestational age) for the index pregnancy and allother pregnancies.

The measure of strength of association between testicular cancer andvariables of interest was the RR approximated by the odds ratio (4).Summary RR estimates adjusted for the variables birth weight inpounds (<=6.0,6.1 to 8.0, >8.0), number of packs of cigarettes smokedper day (none, <!,>=!), and number of drinks of alcoholic beveragesper week (<1, 1, >=2) were obtained by maximum likelihood procedures (5) with 95% CI as described by Gart (6). These same procedureswere used to adjust for the stratifying (matching) variables: hospitaland age at diagnosis. Since the RRs adjusted for hospital and age atdiagnosis were similar to the unadjusted RRs, RRs adjusted for thesetwo factors are not presented in this paper. / tests were used to testcase-control differences in mean birth weight and parental ages at studysubject's birth (7). Mantel's extension test (8) was used to test for trends

(2 tailed) in risk related to alcohol and cigarette consumption. ThePearson product moment correlations (9) were used to measure thecloseness of a linear relationship between birth weight in Ib (<=5.0, 5.1to 6.0, 6.1 to 7.0, 7.1 to 8.0, 8.1 to 9.0, >9.0), number of packs ofcigarettes smoked per day (none, <1, >=1), and number of drinks ofalcoholic beverages per wk (<1, 1, >=2). A binary logistic model (10,11) was used to simultaneously assess the effects of these three factorson the probability of being a case, x2 tests of homogeneity were used totest for case-control differences in referral patterns (12).

RESULTS

Ninety-six % of the case mothers and 97% of the controlmothers were White with the remainder either Black, Hispanic,Asian, or American Indian. A history of undescended testis wasreported for 10% of the cases and 3% of the controls (RR =3.4, CI = 1.3 to 8.8), based on a positive report by either theson or the mother. Many of the specific maternal factors underinvestigation (e.g., birth weight, gestational age, and hormoneuse) have been associated with the development of undescendedtestis or cryptorchidism (13, 14). Therefore, in order to eliminate the potential for confounding of these factors by a historyof undescended testis, only data for the 202 cases and the 206controls without a history of undescended testis were analyzed.

The mean age at diagnosis was 26 yr for both the testicularcancer cases and their controls. The percentage of study subjectsseen at each hospital was: NIHCC, 51%, USUNH, 22%; andWRAMC, 27%. There were no significant differences in thegeographical distribution between cases and controls (x2 = 6.6;

P = 0.25), minimizing the possibility of referral bias. Thediagnoses among the controls were as follows: Hodgkins disease(27%); non-Hodgkins lymphoma (19%); melanoma (17%); softtissue sarcoma (8%); leukemia (8%); bone tumors (7%); nervoussystems tumors (4%); and other cancers (10%).

The mean ages of the mother (26.7 yr for cases, 26.5 yr forcontrols; P = 0.745) and the father (28.6 yr for cases, 29.0 yrfor controls; P = 0.401) at the study subject's birth were similar

for cases and controls. No substantial differences in RR wereseen for study subjects (a) delivered vaginally head first (184cases, 190 controls), (b) delivered breech (6 cases, 9 controls),(c) who were twins (5 cases, 4 controls), and (d) who werefirstborn children (62 cases, 66 controls). Also, there was no

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BIRTH-RELATED RISK FACTORS FOR TESTICULAR CANCER

hernia in childhood associated with low birth weight (13). The chest films and dental X-rays. To date, human studies ofstrength and consistency of the association of low birth weightor premature delivery with testicular cancer and with two of themajor risk factors for testicular cancer suggest that these relationships may provide substantial clues to the etiology of testicular cancer. It will be of particular importance to determinewhether low birth weight and testicular cancer share commonrisk factors, or whether low birth weight (or its correlates) isitself a risk factor.

The two studies of testicular cancer previously referred to (2,18) suggested that a variety of factors possibly responsible forincreased estrogenic exposure during pregnancy were risk factors for testicular cancer in young men. These factors included:exogenous hormone exposure during the first trimester, including hormonal pregnancy tests; and nausea of pregnancy severeenough to require treatment, particularly when it was the woman's first pregnancy. No excess use of hormones during preg

nancy by the mothers of the cases was observed in this study.However, only seven mothers reported exposure to specifichormones, and only two reported having a hormonal pregnancytest.

Since so few case and control mothers were able to specifythe specific type of medication taken for bleeding during pregnancy, it is probable that the number of mothers who reportedhormone use during pregnancy is an underestimate. However,the percentage of control mothers who reported the use ofdiethylstilbestrol and other hormones during pregnancy (2.4%)was similar to findings reported by Schottenfeld et al. (19) forhis hospital controls (2.5%) and Depue et al. (2) (1.9%). Sincea considerably smaller percentage of our case mothers reportedhormone use (2.0%) compared to results published by Schottenfeld et al. (5.8%) and Depue et al. (7.3%), it is possible thatthe inability to recall the type of drug taken for bleeding andspotting may have resulted in a biased risk estimate for hormoneuse.

However, this study did find a statistically significant 2-foldincrease in risk associated with unusual bleeding or spottingduring the index pregnancy, regardless of whether medicationwas taken for this condition. This finding supports the hypothesis of an altered hormonal milieu within the mother being arisk factor for testicular cancer (2), although the type of alteration is unclear. Since a history of abnormal bleeding in otherpregnancies and a history of miscarriage were only slightlymore common among the case mothers, the alteration appearsto be pregnancy specific, rather than a more pervasive hormonaldisorder of the mother.

The risk of testicular cancer was only slightly increased fortreated or untreated nausea. Among firstborn subjects whosemothers were treated for nausea, the RR rose to 2.3. While notsignificant and less than the 4-fold risk previously reported (2),this lends some support to the previous findings.

Three other statistically significant associations that emergedfrom the analysis of exposures during pregnancy were: use of"sedatives"; exposure to X-rays during pregnancy; and alcohol

comsumption. However, these associations are difficult to interpret because the findings lack specificity or do not exhibit aclear dose response. Also, these associations could be due tochance, since a variety of pregnancy exposures were explored.Specifically, the category "sedatives" contained a variety of

different chemical compounds, and the risk associated with thecategory was not due to any particular compound. The highestrisk for X-ray exposure was observed for X-rays of the abdomenand pelvis; however, there were 2-fold excess risks for procedures involving little or no X-ray exposure to the fetus, such as

radiation and testicular cancer have not suggested an association (20), although some experimental evidence supports thepossibility that testicular tumors could be radiogenic (21, 22).While RRs were elevated for consumers of two or more drinksof alcoholic beverage per wk, a statistically significant trend inrisk was not seen when the number of drinks drunk per wk wasbroken into finer categories. Also, the high correlation betweensmoking and drinking makes it impossible to tell which factoris driving the association, even though no consistent relationship with amount smoked was apparent for the risk of testicularcancer.

Information about a variety of other exposures during pregnancy was collected in an attempt to uncover previously unidentified risk factors. It was reassuring that the two major typesof medication consumed during pregnancy, analgesics and vitamin/mineral preparations, were unassociated with risk oftesticular cancer.

As in any investigation, associations or the failure to findassociations could also be due to bias. Response rates werehigh, minimizing the opportunity for bias due to nonresponse.The nature of the control group also raises the possibility ofanother type of bias. It is possible that some of the pre- orperinatal exposures studied could play an etiological role in asubstantial proportion of all cancers in young adults. While wethink this unlikely, if this were the case, it is possible that animportant association of interest could have been "matchedout" since the comparison group was composed of young men

with other cancers. However, the choice of other cancers forthe comparison population was purposeful since pregnancy-related variables may be especially subject to recall bias. Becausethe case and control mothers were both being queried aboutexposures during pregnancy to sons who subsequently developed a malignancy, recall bias should not be an issue. Also,since the controls chosen had similar referral patterns as thecases, selection bias should not be a factor.

This study found a number of pre- and perinatal factorsrelated to testicular cancer, although none of these associationsappears to be responsible for the marked age and time patternsin the descriptive epidemiology of this tumor. The finding ofan elevated risk for low birth weight suggests that continuedexposure to the normal intrauterine environment in the laterstages of pregnancy conveys substantial protection against thedevelopment of testicular cancer. In addition, the excess riskfound for unusual bleeding or spotting also suggests that alteration of this normal maternal-fetal environment results in anexcess risk of testicular cancer. Whether the causal alterationsinvolve changes in estrogen levels as previously suggested (2)or some other hormonal or nonhormonal factor remains to beclarified. While the risks found for "sedatives," alcohol con

sumption, and X-ray exposure were not as consistent as thosefor birth weight and bleeding, the strength of the associationsnoted and/or the prevalence of these exposures in the generalpopulation warrant further investigation. Hopefully, the findings presented from this study may provide useful leads forother investigators studying the etiology of testicular cancer.

ACKNOWLEDGMENTSWe thank Dr. Nasser Javadpour, NIHCC, Dr. Kevin J. O'Connell,

USUNH, and Dr. Ray E. Stutzman, WRAMC, for allowing us accessto their patients; Jeanne Rosenthal and the staff of Westat, Inc. fordata management and interviewing; Dr. Linda W. Pickle, NationalCancer Institute, for statistical advice; and Theresa Pino, NationalCancer Institute, for manuscript preparation.

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1986;46:4812-4816. Cancer Res   Linda Morris Brown, Linda M. Pottern and Robert N. Hoover  Prenatal and Perinatal Risk Factors for Testicular Cancer

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