Affiliation of authors: Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden.
Correspondence to: Magnus Kaijser, M.D., Berzelius väg 15C, S-171 77 Stockholm, Sweden (e-mail: magnus.kaijser{at}mep.ki.se).
It has been suggested that hormonal exposures in utero influence the risk of breast cancer later in life (1). Estrogens are well-established risk factors for breast cancer (2), and there is a pronounced association between birthweight and antenatal estrogen exposure (3). Several epidemiologic studies (46) have found that preeclampsia, a perinatal event characterized by low maternal estrogen levels, is associated with a decreased risk of breast cancer, but the results in different studies (68) of the association between birthweight and breast cancer risk are not entirely consistent.
One possible reason for the divergent results could be the narrow range of antenatal estrogen exposure seen in singleton pregnancies. Twin pregnancies are characterized both by a broader range (9) and higher levels (911) of pregnancy estrogens. There is some evidence that these phenomena are even more pronounced in dizygotic twin pregnancies compared with monozygotic pregnancies (9,12), and most (5,1316), but not all (8), studies of cancer risk among dizygotic twins show an increased risk of breast cancer. Dizygotic twins, therefore, constitute a suitable group for further studies of the association between antenatal hormonal exposures and breast cancer risk.
We chose to restrict our study to opposite-sexed pairs for two reasons: All opposite-sexed pairs are dizygotic, and, for twins not given names while still at the hospital, the uncertainty of who is who that can be present for same-sexed twins does not occur. This greatly facilitates data collection. We, therefore, conducted a study on the association between birthweight and breast cancer among female twins of opposite-sexed twin pairs. The study was approved by the Research Ethics Committee at the Karolinska Institutet, Stockholm, Sweden.
We used information retrieved through the Swedish Twin Registry on twins born between 1926 and 1967 (17). In the Twin Registry, 13 820 pairs were opposite sexed (18). Using the unique national registration number given to all Swedish citizens alive after 1947, we identified study subjects through record linkage between the Swedish Twin Registry and the Swedish Cancer Registry (19). Eligible case subjects were female twins with male co-twins who developed breast cancer between 1972 and 1995. Control subjects were drawn from the same population, age matched, and eligible if alive and without breast cancer at the time of diagnosis for the corresponding case subject.
We selected two control subjects for each case subject; however, when the first was located, we stopped searching for the other. Because of simultaneous data collection at different delivery units, we sometimes gathered information on both. We initially obtained birth records for 104 case and 127 control subjects. We restricted the study to twins with a reported gestational age of 33 weeks or more according to the last menstrual period, since being born before the 33rd gestational week has been reported to be an independent risk factor for breast cancer (5). This process left us with 90 pairs of case and control subjects.
Odds ratios (ORs) were modeled through conditional logistic regression, and adjustment variables were male sibling birthweight and gestational-duration categories (20). All P values are two-sided. Since our intention was to obtain a broad range of birthweight categories, we categorized birthweight in groups of 500 g. For trend tests, we used equidistant scores for the categories; for the analysis of interaction, we performed likelihood ratio tests.
The risk of breast cancer increased stepwise with increasing birthweight categories (Tables 1 and 2). Compared with women with a birthweight of 2000 g or less, women with a birthweight of more than 3500 g had a 12-fold increase in breast cancer risk. Adjusting for male co-twin birth weight and duration of gestation only marginally affected the association. The P value for trend was .007 for the unadjusted model, whereas it was .03 for the adjusted model. Although statistically significant, these estimates were based on small numbers in the extreme categories. However, when the data were categorized in more equally sized groups, the associations were similar and retained statistical significance, albeit with lower point estimates.
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When stratifying the analysis on male co-twin birthweight and duration of gestation, no statistically significant effect modification could be found (P = .53 and P = .62, respectively). Because of a few observations in some strata, however, the power of this analysis was limited.
The study design was a population-based, casecontrol study, and data were obtained from birth records completed prospectively. All records were not found, but it is almost inconceivable that there would be any association between birthweight among infants born after the 32nd gestational week and the possibility to retrieve the birth record 3573 years later. We could not adjust for known risk factors for breast cancer; however, since these risk factors are not likely to be associated with female birth weight, we consider it unlikely that they confound our observed results.
Our findings are in accordance with the findings of Michels et al. (7), although more pronounced. The strong association between birthweight and breast cancer risk in our study could suggest that antenatal exposure to other factors present in an opposite-sexed twin pregnancy is important for breast carcinogenesis.
Howdeshell et al. (21) have found that a chemical estrogen, bisphenol A, can reduce the time to puberty in mice when the mice are exposed to high endogenous estrogen levels, whereas it has no effect on those exposed to low levels. It is possible that our results mirror a similar mechanism. Androgens interact with estrogens through competitive binding to sex hormone-binding globulin, and female twins with male co-twins and high birthweight are exposed in utero both to androgens from their brothers (22,23) and to high endogenous estrogen levels (10,11,2426). A similar interaction between endogenous hormone levels and exposures of different exogenous hormonal factors could also be the reason for the discrepant results of the studies of birthweight and breast cancer risk among singletons (5,7,8).
In conclusion, we have found that, among female twins with male co-twins, high birthweight constitutes a strong independent risk factor for breast cancer. These results give further credence to the hypothesis that breast cancer risk is influenced by hormonal exposures in utero.
NOTES
Supported by contract FAIR 984756 from the European Commission, Directorate-General XII, Science, Research and Development, Brussels, Belgium.
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Manuscript received May 24, 2000; revised October 30, 2000; accepted November 1, 2000.
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