REPORTS

Multiple Births and Risk of Epithelial Ovarian Cancer

David C. Whiteman, Michael F. G. Murphy, Linda S. Cook, Daniel W. Cramer, Patricia Hartge, Polly A. Marchbanks, Philip C. Nasca, Roberta B. Ness, David M. Purdie, Harvey A. Risch

Affiliations of authors: D. C. Whiteman, M. F. G. Murphy, Imperial Cancer Research Fund General Practice Research Group, University of Oxford, U.K.; L. S. Cook, University of Calgary, Alberta, Canada; D. W. Cramer, Harvard Medical School, Boston, MA; P. Hartge, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD; P. A. Marchbanks, Fertility Epidemiology Section, Centers for Disease Control and Prevention, Atlanta, GA; P. C. Nasca, University of Massachusetts, Amherst; R. B. Ness, University of Pittsburgh, PA; D. M. Purdie, Queensland Institute of Medical Research, Brisbane, QLD, Australia; H. A. Risch, Yale University School of Medicine, New Haven, CT.

Correspondence to: David C. Whiteman, M.B., B.S., Ph.D., Epidemiology and Population Health Unit, Queensland Institute of Medical Research, P.O. Royal Brisbane Hospital, Herston QLD 4029, Australia (e-mail: daveW{at}qimr.edu.au).


    ABSTRACT
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Background and Methods: Prevailing hypotheses about the causes of ovarian carcinogenesis predict that women with a history of multiple births (twins, triplets, etc.) should be at increased risk of epithelial ovarian cancer. However, the scant available evidence suggests that they may actually be at lower risk. To resolve this issue, we pooled data from eight studies involving 2859 parous women with epithelial ovarian cancer (case patients) and 7434 parous women without ovarian cancer (control women). In addition to assessing their history of multiple births (and the sex of the children, where available), we obtained information on age, parity, oral contraceptive use, and other reproductive factors for each woman. Details of tumor histology were available for all case patients. We estimated the relative risks of various histologic types of ovarian cancers associated with multiple births by using multivariable logistic regression analysis, adjusting for matching and confounding variables. Results: Among these parous women, 73 case patients (2.6%) and 257 control women (3.5%) had a history of multiple births. The adjusted summary odds ratio (OR) for developing all types of epithelial ovarian cancer that are associated with multiple births was 0.81 (95% confidence interval [CI] = 0.61–1.08). We found no evidence that risks associated with multiple births differed among women with borderline or invasive tumors and among women with same-sex and opposite-sex offspring from multiple births. The risk reductions appeared specific for nonmucinous tumors (n = 2453; summary adjusted OR = 0.71 [95% CI = 0.52–0.98]); in contrast, associations with mucinous tumors (n = 406) were heterogeneous across studies. Conclusions: Parous women with nonmucinous ovarian cancer are no more likely to have a history of multiple births than other parous women, counter to the predictions of current hypotheses for causes of ovarian cancer.



    INTRODUCTION
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Increasing epidemiologic and experimental evidence indicates that ovarian carcinogenesis is primarily driven by factors associated with reproduction and ovulation (1,2). At least two hypotheses have arisen to explain the causal pathway to ovarian cancer. The "incessant ovulation" hypothesis (3) proposes that the chronically repeated cycle of trauma and repair to the ovarian epithelium provides an opportunity for cellular mutation and subsequent neoplasia. The "gonadotropin" hypothesis (4) asserts that high levels of gonadotropins cause increased estrogen production by ovarian stromal tissue, which, in turn, promotes epithelial proliferation and malignant transformation.

Most findings from epidemiologic studies are in accordance with both hypotheses; however, several observations remain unexplained. In particular, women with a history of multiple births (i.e., twins, triplets, etc.) have higher levels of gonadotropins during their fertile years (5,6), have a higher incidence of double ovulation per menstrual cycle (7,8), and, thus, would be predicted to be at increased risk of epithelial ovarian cancer if either hypothesis is true. The few available data suggest that mothers of twins are not at higher risk (9) and may actually be at substantially lower risk of epithelial ovarian cancer than mothers of singletons (children born one at a time) (1012). These few isolated reports are far from conclusive evidence of a beneficial effect because the risk estimates have not controlled other factors known to powerfully influence risk of ovarian cancer (such as duration of oral contraceptive use) or have been statistically underpowered to test the association. We have, therefore, pooled the data from eight large case–control studies to explore the association between the risk of the various histologic types of ovarian cancer among women with a history of multiple births.


    SUBJECTS AND METHODS
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 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Data Ascertainment

Data on individual subjects were ascertained from six U.S. case–control studies (1318) that had collected data relating to multiple births and risk of epithelial ovarian cancer but had not published risk estimates for this exposure. Data were also obtained from two case–control studies conducted in Canada (19) and in Australia (12); only the latter had published a risk estimate for ovarian cancer associated with a history of twinning. The chief investigators of seven other case–control studies were also approached; however, these studies could not be included for the following reasons: Multiple birth data were not collected or were incompletely collected [three studies (2022)], multiple birth data were no longer available [three studies (2325)], and individual subject data were unable to be retrieved for multiple birth history [one study (26)]. All subject data submitted for the pooled analysis were anonymous.

The characteristics of the eight contributing studies are presented in Table 1Go; specific descriptions of study methodologies are provided in the original publications. The combined dataset included 12 674 women, of whom 2345 (18.5%) reported having no full-term pregnancies. Because the aim was to determine whether a woman's risk of ovarian cancer differed according to whether she had delivered multiple or singleton children, we excluded nulliparous women from all analyses, as well as 35 women with incomplete reproductive histories. The final dataset, therefore, included 10 293 women (2859 case patients with ovarian cancer and 7434 control women without ovarian cancer) who reported at least one full-term pregnancy and for whom details of all pregnancies were complete.


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Table 1. Characteristics of eight case–control studies of epithelial ovarian cancer
 
Exposure Information and Data Quality

From each case–control study, data were requested on the occurrence of multiple births for every woman as well as potential confounding factors, including age, number of full-term pregnancies (stillbirths and live births), durations of oral contraceptive use and breast-feeding, family history of breast or ovarian cancer, and history of hysterectomy or tubal ligation. Details of tumor histology were sought for case patients, and analyses were restricted to ovarian cancers of the epithelial type (including both borderline and frankly invasive tumors). All data were checked for internal consistency; where necessary, corrections or clarifications were requested from the original investigators.

We defined women as having a history of multiple births if they reported any full-term pregnancies resulting in the birth of more than one infant. In seven of the eight studies, multiple births were identified at the time of interview by specific questioning about the outcome of each pregnancy. For the remaining study (13), multiple births were identified at the time of data processing by an algorithm that assessed all pregnancy events in each woman's reproductive history for similar event dates; possible matches were then individually checked.

Statistical Analyses

The relative risk of ovarian cancer associated with multiple birth was estimated by the odds ratio (OR) and 95% confidence interval (CI). Risk estimates were calculated for all epithelial ovarian cancers in the first instance and then separately for nonmucinous (serous, clear cell, endometrioid, Brenner, and other epithelial types) and mucinous ovarian tumors because there is increasing evidence to support the hypothesis that these types of ovarian cancer are etiologically distinct (27,28). Crude ORs were calculated for each study, and a pooled OR was derived by the method of Mantel–Haenszel (29).

We then undertook multivariable logistic regression analyses to control for the potentially confounding effects of other factors. Because each study collected information on a different set of confounding factors (Table 1Go), we used two approaches to calculate adjusted risk estimates. First, we calculated partially adjusted risk estimates for multiple birth by adjusting only for the set of potential confounders that was common to all of the studies (i.e., age, duration of oral contraceptive use, number of full-term pregnancies, and hysterectomy). Second, we calculated fully adjusted risk estimates in a model that included terms for all of the common variables (as above), as well as terms for the remaining potential confounders of interest (i.e., average duration of breast-feeding per pregnancy, history of tubal ligation, and history of breast or ovarian cancer in a mother or a sister). Because four studies (1316) did not gather information for one or more of these three additional variables (Table 1Go), a separate category, named "not collected," was created to accommodate subjects from those studies. In practice, when we restricted the analysis to those studies with the full set of confounding variables, we found very little difference between the partially and fully adjusted risk estimates for multiple birth. We, therefore, considered that these additional variables were not substantive confounding variables and the assignment of some subjects to a "not collected" category was unlikely to introduce bias (30). We have presented only the fully adjusted estimates in the tables. We excluded from the analysis all subjects for whom exposure information was missing (as opposed to not collected). Continuous terms for age (in years) and age-squared (to adjust for residual nonlinear effects of age) and indicator variables for study were included in each regression model. We used the Breslow–Day statistic (31) to assess homogeneity of the ORs in the stratified analyses. In the regression analyses, an interaction term, study x multiple birth, was added to a simpler model without this term, and the change in the likelihood ratio statistic was used to assess homogeneity. Heterogeneity was assessed at the {alpha} = .10 statistical significance level. All P values given are from two-sided tests, and all analyses were performed in SAS version 6.12 (32).


    RESULTS
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We first estimated the relative risks for all types of epithelial ovarian cancer, regardless of histologic type (n = 2859). Pooling data from all eight studies for parous women, we found that women with ovarian cancer (73 case patients; 2.6%) were less likely to have a history of multiple births than women without ovarian cancer (257 control women; 3.5%) (Mantel–Haenszel OR = 0.77; 95% CI = 0.59–1.01). Adjustment for maternal age, study, number of full-term pregnancies, duration of oral contraceptive use and breast-feeding, history of hysterectomy or tubal ligation, and history of breast or ovarian cancer in a mother or a sister made little difference to this estimate (Table 2Go). There was no formal statistical evidence of heterogeneity of the ORs, although it was clear that the point estimate for one study (13) was considerably higher than the point estimates of the other seven studies (Table 2Go). The "outlying" study differed from the remainder in the sampling frame for control women and the way in which multiple births were identified. Because we could not exclude the possibility of bias arising from these methodologic differences, the summary estimates were recalculated after this dataset was excluded (Mantel–Haenszel OR = 0.71 [95% CI = 0.53–0.95]; fully adjusted OR = 0.74 [95% CI = 0.55–1.01]).


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Table 2. Odds ratio of epithelial ovarian cancer (crude and fully adjusted) among parous women associated with multiple births, analyzed according to histologic type and stratified by study*
 
Women with nonmucinous ovarian tumors (n = 2453) were less likely to have a history of multiple births than control women in seven of the eight studies (Table 2Go), and this was reflected in the summary Mantel–Haenszel OR (OR = 0.67; 95% CI = 0.49–0.91). Overall, the effect of statistical adjustment for other confounding factors was negligible (fully adjusted pooled OR = 0.71; 95% CI = 0.52–0.98). Again, we recalculated the summary OR after excluding the outlying study, but we observed little change from the earlier estimate (fully adjusted OR = 0.68; 95% CI = 0.49–0.94).

No consistent pattern of association was observed among the smaller number of women with mucinous ovarian tumors (n = 406). The impression of heterogeneity of the ORs for the crude and the adjusted models was supported by statistical evaluation. Summary ORs were calculated (Table 2Go); however, because of the heterogeneity, we view these estimates with caution.

We found no evidence that risks associated with multiple births differed among women with invasive (n = 2333) or borderline (n = 526) tumors (OR for invasive tumors = 0.84 [95% CI = 0.62–1.15]; OR for borderline tumors = 0.72 [95% CI = 0.40–1.32]). Information on the sex combination of multiple births was available for 141 women (47 opposite-sex sets and 94 same-sex sets) from five studies (4,1214,18). The adjusted OR for epithelial ovarian cancer (of all histologic types) among women with opposite-sex offspring from multiple births was 0.76 (95% CI = 0.39–1.45), and the adjusted OR among women with same-sex offspring was 0.80 (95% CI = 0.51–1.25). Restricting the analysis to include only those women with nonmucinous ovarian cancers, we observed ORs of 0.73 (95% CI = 0.37–1.47) and 0.79 (95% CI = 0.49–1.27) for opposite-sex and same-sex multiple birth sets, respectively.

Finally, we grouped women according to their total number of full-term pregnancies. We found similarly reduced ORs for nonmucinous epithelial ovarian cancers in each group, although none of the estimates was statistically significantly reduced (Table 3Go). We observed no such consistency of effect with mucinous ovarian cancers.


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Table 3. Odds ratio of epithelial ovarian cancer (by histologic type) associated with multiple births, stratified by number of full-term pregnancies*
 

    DISCUSSION
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Several models have been proposed to explain the etiology of ovarian cancer; principal among these have been the incessant ovulation (3) and gonadotropin (4) hypotheses. Although both of these models account for most epidemiologic observations in the occurrence of this disease, both models predict that women with a history of multiple births should be at increased risk for epithelial ovarian cancer. For example, double ovulations are more frequent among mothers of naturally occurring dizygotic twins than among mothers of singletons (7,8). If so, then under the incessant ovulation hypothesis, such women will cumulatively suffer more epithelial trauma and, therefore, be at higher risk of ovarian cancer than age-matched, equiparous mothers of singletons. The gonadotropin hypothesis postulates that factors that predispose to higher levels of gonadotropins will increase the risk of ovarian cancer (4). Because most published studies (5,6,33), but not all (8), have reported that mothers of twins have higher serum levels of gonadotropins than mothers of singletons, this hypothesis also predicts that such women ought to be at higher risk of ovarian cancer. Our finding that women with epithelial ovarian cancer were less likely to have a history of multiple births is, therefore, clearly at odds with both of these hypotheses.

Several features of our investigation suggest that our observations reflect a real reduction in risk and are not the result of artifact. The magnitudes of the risk estimates were remarkably consistent across the individual studies, and the effects persisted after adjustment was made for reproductive and other factors known to powerfully influence the risk of both ovarian cancer and multiple births. One factor that was not controlled in our analyses was the use of fertility treatments, principally because this information was not collected in most of the studies. The use of fertility treatments is potentially an important source of confounding because multiple births are more common among women who have taken fertility treatments and because these drugs have been associated with increased risks of ovarian cancer (34). It might, therefore, be argued that any association between multiple births and ovarian cancer is spurious and simply due to confounding introduced by differing levels of exposure to fertility treatments. If so, then one would expect women with a history of multiple births to have higher levels of exposure to these medications than other parous women and, therefore, to be at increased risk of epithelial ovarian cancer. We observed the opposite association in seven of the eight studies and conclude that, if confounding of this type did occur in these datasets, then the true effect of multiple births may be even more protective than we have estimated. Even so, the possibility of confounding by fertility drugs is remote because this analysis was restricted solely to parous women who had mostly completed their families before widespread availability of these treatments.

We cannot exclude a role for selection or information biases in contributing to these pooled results; however, overall, we consider the likelihood to be small. For example, it is possible that a woman's decision to participate in a study may have been influenced by whether or not she had a history of multiple births, but the fact that similar effects were observed regardless of the number of pregnancies argues otherwise. We have no reason to suspect that women with ovarian cancer systematically misclassified or underreported their multiple pregnancies (or the converse for control women). It is similarly unlikely that, within each study, interviewers systematically elicited multiple birth information differently for case patients and control women because this was not a primary hypothesis for any of the studies. The only study that did not specifically record multiple birth data at the time of interview was the only study to generate a risk estimate greater than 1. To analyze this study, we derived a multiple-birth variable by using a computer algorithm based on shared-event dates in the obstetric history. Because the prevalence of multiple births among control women in that study (2.2%) was noticeably lower than that in the other studies (3.6%), we suspect that this method may not have identified all women with a history of multiple births. Moreover, control women in that study were sampled from drivers' license files and, thus, may differ from the population in which the case patients arose in terms of social class, reproductive history, and other ways likely to influence risk. Consequently, despite the lack of formal evidence for heterogeneity, we took the precaution of repeating certain analyses after excluding those data.

Our findings of a reduced risk of epithelial ovarian cancer associated with multiple births are in general agreement with record linkage studies from Denmark (11) and Sweden (10), which reported lower risks of ovarian cancer among mothers of twins. Neither of those studies was able to control for important confounding variables, however, and neither conducted separate analyses for nonmucinous and mucinous tumors. Our analysis suggests that the effect of multiple births is specific for nonmucinous tumors and lends support to the hypothesis that ovarian neoplasms are etiologically heterogeneous (27).

Thus, the qualitatively consistent findings observed in case–control studies and record-linkage studies provide strong grounds for rejecting the notion that women with a history of multiple births are at increased risk of ovarian cancer, as predicted by the two prevailing hypotheses. The question arises as to why this should be. From the collected data, we infer that other factors, in addition to either ovulatory trauma or gonadotropin levels, must be operating that influence a woman's risk of ovarian cancer. One suggestion is that the surge in progesterone synthesis during pregnancy confers protection to the ovarian epithelium (2). It has been observed previously (35) that the reduction in risk conferred by each full-term pregnancy is greater than the benefit incurred by an equivalent period of amenorrhea alone, consistent with the notion that the hormonal milieu of pregnancy is beneficial in addition to the respite it affords from ovulatory trauma. Because progesterone levels during multiple pregnancies are considerably higher than during singleton pregnancies (3638), this same mechanism could explain why multiple pregnancies are super-protective over and above the benefits of other full-term pregnancies. We found reduced risks of ovarian cancer, regardless of the sex combination (and by inference, the zygosity) of the multiple births, which suggests that the effect is associated directly with the multiple-birth event and is not related to factors specifically associated with monozygotic or dizygotic twinning.

If progesterone (or some other hormone of pregnancy) does reduce the risk of ovarian cancer, it remains to be determined why the effect is additive and how it is produced. Adami et al. (39) have speculated that pregnancy clears the ovary of cells that have previously undergone malignant transformation and that this effect might be mediated by steroid hormones. This hypothesis awaits empirical testing at the cellular level but may explain our epidemiologic findings. Given the rarity of ovarian cancer and multiple births as well as the scarcity of studies that have collected information on both, we would encourage exploration of any other datasets that may further our understanding of the role of multiple births in ovarian cancer.


    NOTES
 
Work supported in its early stages by grant M3/95 from the Wellbeing/Royal College of Obstetricians and Gynaecologists. D. C. Whiteman was funded by a Nuffield Medical Research Fellowship from the University of Oxford.


    REFERENCES
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

1 Banks E, Beral V, Reeves G. The epidemiology of epithelial ovarian cancer: a review. Int J Gynecol Cancer 1997;7:425–38.

2 Risch HA. Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone. J Natl Cancer Inst 1998;90:1774–86.[Abstract/Free Full Text]

3 Fathalla MF. Incessant ovulation—a factor in ovarian neoplasia? Lancet 1971;2:163.[Medline]

4 Cramer DW, Welch WR. Determinants of ovarian cancer risk. II. Inferences regarding pathogenesis. J Natl Cancer Inst 1983;71:717–21.[Medline]

5 Martin NG, Robertson DM, Chenevix-Trench G, de Kretser DM, Osborne J, Burger HG. Elevation of follicular phase inhibin and luteinizing hormone levels in mothers of dizygotic twins suggests nonovarian control of human multiple ovulation. Fertil Steril 1991;56:469–74.[Medline]

6 Lambalk CB, De Koning CH, Braat DD. The endocrinology of dizygotic twinning in the human. Mol Cell Endocrinol 1998;145:97–102.[Medline]

7 Martin NG, Shanley S, Butt K, Osborne J, O'Brien G. Excessive follicular recruitment and growth in mothers of spontaneous dizygotic twins. Acta Genet Med Gemellol (Roma) 1991;40:291–301.[Medline]

8 Gilfillan CP, Robertson DM, Burger HG, Leoni MA, Hurley VA, Martin NG. The control of ovulation in mothers of dizygotic twins. J Clin Endocrinol Metab 1996;81:1557–62.[Abstract]

9 Wyshak G, Honeyman MS, Flannery JT, Beck AS. Cancer in mothers of dizygotic twins. J Natl Cancer Inst 1983;70:593–9.[Medline]

10 Lambe M, Wuu J, Rossing M, Hsieh CC. Twinning and maternal risk of ovarian cancer [letter]. Lancet 1999;353:1941.[Medline]

11 Olsen J, Storm H. Pregnancy experience in women who later developed oestrogen-related cancers (Denmark). Cancer Causes Control 1998;9:653–7.[Medline]

12 Purdie D, Green A, Bain C, Siskind V, Ward V, Hacker N, et al. Reproductive and other factors and risk of epithelial ovarian cancer: an Australian case–control study. Survey of Women's Health Study Group. Int J Cancer 1995;62:678–84.[Medline]

13 Nasca PC, Greenwald P, Chorost S, Richart R, Caputo T. An epidemiologic case–control study of ovarian cancer and reproductive factors. Am J Epidemiol 1984;119:705–13.[Abstract]

14 Hartge P, Schiffman MH, Hoover R, McGowan L, Lesher L, Norris HJ. A case–control study of epithelial ovarian cancer. Am J Obstet Gynecol 1989;161:10–6.[Medline]

15 The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. The reduction in risk of ovarian cancer associated with oral-contraceptive use. N Engl J Med 1987;316:650–5.[Abstract]

16 Chen MT, Cook LS, Daling JR, Weiss NS. Incomplete pregnancies and risk of ovarian cancer (Washington, United States). Cancer Causes Control 1996;7:415–20.[Medline]

17 Cramer DW, Harlow BL, Titus-Ernstoff L, Bohlke K, Welch WR, Greenberg ER. Over-the-counter analgesics and risk of ovarian cancer. Lancet 1998;351:104–7.[Medline]

18 Ness RB, Grisso JA, Cottreau C, Klapper J, Vergona R, Wheeler JE, et al. Factors related to inflammation of the ovarian epithelium and risk of ovarian cancer. Epidemiology 2000;11:111–7.[Medline]

19 Risch HA, Marrett LD, Howe GR. Parity, contraception, infertility, and the risk of epithelial ovarian cancer. Am J Epidemiol 1994;140:585–97.[Abstract]

20 Rosenberg L, Shapiro S, Slone D, Kaufman DW, Helmrich SP, Miettinen OS, et al. Epithelial ovarian cancer and combination oral contraceptives. JAMA 1982;247:3210–2.[Abstract]

21 Byers T, Marshall J, Graham S, Mettlin C, Swanson M. A case–control study of dietary and nondietary factors in ovarian cancer. J Natl Cancer Inst 1983;71:681–6.[Medline]

22 The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Epithelial ovarian cancer and combined oral contraceptives. Int J Epidemiol 1989;18:538–45.[Abstract]

23 Casagrande JT, Louie EW, Pike MC, Roy S, Ross RK, Henderson BE. "Incessant ovulation" and ovarian cancer. Lancet 1979;2:170–3.[Medline]

24 McGowan L, Parent L, Lednar W, Norris HJ. The woman at risk for developing ovarian cancer. Gynecol Oncol 1979;7:325–44.[Medline]

25 Hildreth NG, Kelsey JL, LiVolsi VA, Fischer DB, Holford TR, Mostow ED, et al. An epidemiologic study of epithelial carcinoma of the ovary. Am J Epidemiol 1981;114:398–405.[Abstract]

26 Whittemore AS, Wu ML, Paffenbarger RS Jr, Sarles DL, Kampert JB, Grosser S, et al. Epithelial ovarian cancer and the ability to conceive. Cancer Res 1989;49:4047–52.[Abstract]

27 Risch HA, Marrett LD, Jain M, Howe GR. Differences in risk factors for epithelial ovarian cancer by histologic type. Results of a case– control study. Am J Epidemiol 1996;144:363–72.[Abstract]

28 Marchbanks PA, Wilson H, Bastos E, Cramer DW, Schildkraut JM, Peterson HB. Cigarette smoking and epithelial ovarian cancer by histologic type. Obstet Gynecol 2000;95:255–60.[Abstract/Free Full Text]

29 Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22:719– 48.[Medline]

30 Vach W, Blettner M. Biased estimation of the odds ratio in case–control studies due to the use of ad hoc methods of correcting for missing values of confounding variables. Am J Epidemiol 1991;134:895–907.[Abstract]

31 Breslow NE, Day NE. Statistical methods in cancer research. I. The analysis of case–control studies. Lyon (France): International Agency for Research on Cancer; 1980. p. 142.

32 The SAS Institute. SAS version 6.12. Cary (NC): The SAS Institute; 1997.

33 Thomas HV, Murphy MF, Key TJ, Fentiman IS, Allen DS, Kinlen LJ. Pregnancy and menstrual hormone levels in mothers of twins compared to mothers of singletons. Ann Hum Biol 1998;25:69–75.[Medline]

34 Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian tumors in a cohort of infertile women. N Engl J Med 1994;331:771–6.[Abstract/Free Full Text]

35 Whittemore AS, Harris R, Itnyre J, Halpern J. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case–control studies. Collaborative Ovarian Cancer Group. Am J Epidemiol 1992;136:1175–83.[Abstract]

36 Batra S, Sjoberg NO, Aberg A. Human placental lactogen, estradiol-17ß, and progesterone levels in the third trimester and their respective values for detecting twin pregnancy. Am J Obstet Gynecol 1978;131:69–72.[Medline]

37 TambyRaja RL, Ratnam SS. Plasma steroid changes in twin pregnancies. In: Gedda I, Parisi P, Nance W, editors. Twin research 3. Progress in clinical and biological research. New York (NY): Alan R. Liss; 1981. p. 149.

38 Haning RV Jr, Kiggens AJ, Leiheit TL. Maternal serum progesterone, 17ß-estradiol and estriol are increased in pregnancies which follow treatment with human menopausal gonadotropins: effects of multiple gestation and maternal endocrine status. J Steroid Biochem 1985;22:823–9.[Medline]

39 Adami HO, Hsieh CC, Lambe M, Trichopoulos D, Leon D, Persson I, et al. Parity, age at first childbirth, and risk of ovarian cancer. Lancet 1994;344:1250–4.[Medline]

Manuscript received December 21, 1999; revised April 27, 2000; accepted May 10, 2000.


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