1 Department of Epidemiology and Public Health, Yale School of Medicine, New Haven, CT.
2 Department of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy.
3 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.
4 Department of Epidemiology and Biostatistics, McGill University, Montreal, Canada.
5 Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT.
6 Department of Pathology, Yale University School of Medicine, New Haven, CT.
Received for publication December 3, 2003; accepted for publication May 11, 2004.
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ABSTRACT |
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case-control studies; Connecticut; lymphoma, non-Hodgkin; menstruation; reproduction; risk factors; women
Abbreviations: Abbreviations: CI, confidence interval; OR, odds ratio.
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INTRODUCTION |
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Epidemiologic studies linking reproductive factors to non-Hodgkins lymphoma risk, however, have been inconsistent. One study from Sweden reported a reduced risk of non-Hodgkins lymphoma associated with parity (5), while another study from Italy reported an increased risk (4). Three other studies (79) also reported a slightly increased risk of non-Hodgkins lymphoma associated with parity. Later age at first full-term pregnancy was related to an increased risk of non-Hodgkins lymphoma in one study (6) but not in another (10). A study from Italy by La Vecchia et al. (10) also found no association among number of births, number of abortions, and risk of lymphomas.
So far, few studies have investigated the risk of non-Hodgkins lymphoma associated with menstrual and reproductive factors by non-Hodgkins lymphoma subtypes. This is important, however, because non-Hodgkins lymphoma represents a heterogeneous group of lymphoma disorders (20). Further study of menstrual and reproductive factors and non-Hodgkins lymphoma risk by subtype of non-Hodgkins lymphoma is clearly warranted. Here, we report the findings linking menstrual and reproductive factors to non-Hodgkins lymphoma risk using the data from a population-based case-control study of non-Hodgkins lymphoma among Connecticut women.
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MATERIALS AND METHODS |
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To provide accurate and consistent histologic classification of the cases, pathology slides (or tissue blocks) were obtained for all cases from the pathology departments where the cases were diagnosed. Each specimen was reviewed by two experienced study pathologists (S. F., G. T.). The non-Hodgkins lymphoma cases were classified according to the Working Formulation and grouped by grade: low (M-9670, 96919692, 96959696), intermediate (M-95919593, 9595, 9672, 96759676, 96809683, 9688, 9693, 96979698), and high (M-96849687, 9694); by histologic type: diffuse (M-95919593, 9595, 9670, 96729677, 96809684, 96869688, 9694) and follicular (M-96909693, 96959698); and by immunologic type: B cell (M-95919593, 9595, 96709674, 9677, 96809684, 96869688, 96909698) and T cell (M-97009723).
Population-based controls with Connecticut addresses were recruited using either random digit dialing methods for those below age 65 years or Centers for Medicare and Medicaid Service files for those aged 65 years or above. The participation rate for random digit dialing controls was 69 percent and for Centers for Medicare and Medicaid Service controls was 47 percent. Cases and controls were frequency matched by age in 5-year groups by adjusting the number of controls randomly selected in each age stratum every few months.
Data collection
All procedures were performed in accordance with a protocol approved by the human investigations committees at Yale University, the Connecticut Department of Public Health, and the National Cancer Institute. After approval by each subjects physician (for cases) or following selection through random sampling (for controls), potential participants were approached by letter and/or by phone. Those who consented were interviewed by trained interviewers, either in their homes or at a location convenient for the patient. A standardized, structured questionnaire was used to obtain information on menstrual and reproductive history and other major known or suspected risk factors that might confound the association between menstrual and reproductive history and risk of non-Hodgkins lymphoma.
Information on menstrual history was collected by asking subjects their age at first menstrual period and whether they still were having menstrual periods, not including those periods due to estrogen replacement therapy. For age at last menstrual period, we asked subjects to report their age at the last natural menstrual period. Information on age at surgical menopause was not collected in this study. Information on reproductive factors was collected by asking subjects whether they had ever had a pregnancy, their age at first livebirth (or stillbirth), and the numbers of pregnancies, livebirths, stillbirths, miscarriages, and abortions. Information on oral contraceptive use was collected, together with other medication uses, by asking participants the question, "Have you ever taken any medicines at least once a day for a period of 6 months or longer previous to 1 year ago?" If yes, subjects were asked to provide information on each medication they had ever taken, the ages at first and last use, and the total months of use.
Data on other potential confounding factors, including family history of cancer, diet, occupation, tobacco use, alcohol consumption, and demographic factors, were also gathered during the interview. Dietary information was collected using a scannable, semiquantitative food frequency questionnaire developed and validated by the Fred Hutchinson Cancer Research Center (23).
Statistical analysis
Age at menarche was defined as the age when subjects had their first menstrual period. Total months of ovulation were calculated according to the method described by Casagrande et al. (24): The age at first menstrual period was subtracted from the age at last natural menstrual period and converted into months by multiplying by 12. The total months of pregnancies (12 months for each livebirth or stillbirth (24, 25)) and the total months of oral contraceptive use were then subtracted to yield the total months of ovulation. As stated by Vorherr (25), the reason for assigning 12 months for each livebirth or stillbirth is that ovulation returns by 612 weeks postpartum in general.
Unconditional logistic regression was used to estimate the association between menstrual and reproductive factors and risk of non-Hodgkins lymphoma by histologic type, immunologic type, and tumor grade and to control for potential confounders. Potential confounding variables included in the final model were age, body mass index (<25, 2529.99, >29.9 kg/m2), family history of non-Hodgkins lymphoma among first-degree relatives, and menopausal status. Adjustments of other variables, such as race, level of education, fruit intake, daily total fat intake, daily animal protein intake, and farming history, did not result in material changes for the observed associations and, thus, were not included in the final model. Use of lifetime pack-years of cigarette smoking (or ever vs. never) and lifetime kilograms of alcohol consumption (or ever vs. never) to control for the potential confounding from smoking and drinking also did not result in material change in the association; thus, tobacco smoking and alcohol consumption were also excluded from the final model. Odds ratios and 95 percent confidence intervals were calculated using SAS statistical software (SAS Institute, Inc., Cary, North Carolina). The multivariate model used original values rather than categorical indexes for continuous variables to test for linear trends. For women who had never been pregnant, we treated their number of pregnancies and age at first pregnancy as missing values when the linear trend was tested.
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RESULTS |
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DISCUSSION |
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The relation between pregnancy or livebirths and non-Hodgkins lymphoma from previous epidemiologic studies has been inconclusive. In a nested case-control study from Sweden, Adami et al. (5) reported a weak, negative association between parity and risk of non-Hodgkins lymphoma (ptrend = 0.11). A 1040 percent reduced risk within 514 years after the last birth was observed among women with various parities in this study. The Iowa Womens Health Study (7) reported an odds ratio of 0.8 (95 percent CI: 0.6, 1.2) for women who had more than four livebirths compared with those who had only one or two livebirths. In that study, however, nulliparous status was also associated with a nonsignificantly reduced risk (OR = 0.6, 95 percent CI: 0.3, 1.1). A study by Tavani et al. (4) from Italy, however, reported a potentially increased risk of non-Hodgkins lymphoma associated with pregnancy among women aged less than 50 years. Compared with that for nulligravidas, odds ratios of 2.2 (95 percent CI: 1.1, 4.6) for parous women, 2.4 for women reporting one or two births, and 1.4 for those reporting three or more births were observed in the Italian study. Two other studies involving relatively small numbers of lymphoma cases also suggested a small, nonsignificantly increased risk of lymphatic and hematopoietic cancers (8) or lymphomas (10) associated with parity. Several earlier studies also investigated the relation among miscarriage (7, 9), abortion (4, 7, 9, 11), and non-Hodgkins lymphoma risk, and none of the studies found an association, which was consistent with our study results.
The biologic mechanisms linking pregnancy or birth to non-Hodgkins lymphoma risk are currently unclear. Since various primary and acquired immunodeficiencies are established risk factors for non-Hodgkins lymphoma (26, 27), it is natural to ask whether pregnancy affects non-Hodgkins lymphoma risk through pregnancy-related changes in immune function. However, as recently reviewed by Luppi (28), pregnancy is associated with a generalized inflammatory response; that is, the innate immune system is activated, while the adaptive immune system is suppressed. The net impact of pregnancy on immune function is a general balance between enhancement and suppression, leaving maternal defenses intact. Thus, in terms of immunodeficiency, pregnancy itself is unlikely to be strongly related to the risk of non-Hodgkins lymphoma.
On the other hand, pregnancy-related sex hormone changes may have an impact on the observed relation between pregnancy and non-Hodgkins lymphoma risk. Pregnancy is associated with a dramatic increase in circulating estrogen levels (12). Both experimental and observational studies have shown that estrogens inhibit interleukin-6 secretion (1317), which has been suggested as a potent growth factor for intermediate- and high-grade non-Hodgkins lymphoma (18, 19). In our study, pregnancy or livebirth was associated with a reduced risk of non-Hodgkins lymphoma (table 4), but a significantly reduced risk was seen only for intermediate- and high-grade non-Hodgkins lymphoma, which was consistent with these studies.
Interestingly, the Iowa Womens Study (7) reported a reduced risk of non-Hodgkins lymphoma associated with breastfeeding and suggested that a reduced cumulative exposure to estrogen from a delay in the reestablishment of ovulation or a heightened exposure to prolactin could be among the potential reasons for a link between breastfeeding and reduced non-Hodgkins lymphoma risk. Unfortunately, we are unable to evaluate the relation between breastfeeding and non-Hodgkins lymphoma risk, because we did not collect this information in our study.
As in our study, most of the earlier studies found no relation between age at first full-term pregnancy (or livebirth) and non-Hodgkins lymphoma risk (4, 5, 7, 9), except the study by Olsson et al. (6), which reported a sevenfold increased risk associated with women who had their first full-term pregnancy at age 30 years or above compared with those who had their first full-term pregnancy before age 30 years. This study also showed that women with a combination of late age at first full-term pregnancy and low parity are at special risk of developing malignant lymphoma. The interpretation of study results from this study, however, was hampered by the fact that the study included only 79 non-Hodgkins lymphoma cases.
To the best of our knowledge, only the Iowa Womens Study (7) reported the findings relating age at menarche and non-Hodgkins lymphoma risk. That study reported a slightly elevated but nonsignificant odds ratio of 1.2 among women who had their first menstrual period at age 15 years or above relative to those who reported having had their first menstrual period when they were below age 12 years (ptrend = 0.72). In our study, a borderline-significant, increased odds ratio of 1.5 was observed for women who had their first menstrual period at age 15 years or above compared with those who had their first menstrual period when they were below age 12 years. If exposure to a higher level of estrogens is the underlying reason linking pregnancy to a reduced risk of non-Hodgkins lymphoma, then later age at menarche would result in a later age at exposure to endogenous hormones at the critical development period, which may cause an increased risk of non-Hodgkins lymphoma associated with later age at menarche, as observed in our study.
Oral contraceptive use has been reported to reduce the risk of non-Hodgkins lymphoma. Schiff et al. (29) reported a reduced risk of primary central nervous system lymphoma among women who had ever used oral contraceptives compared with those who had never used oral contraceptives. A recent population-based case-control study from the Netherlands (30) reported an odds ratio of 0.6 (95 percent CI: 0.2, 2.3) for those with the longest duration of oral contraceptive use. Nelson et al. (9) found that use of oral contraceptives with longer duration (5 years or more) had an even stronger reduced risk of non-Hodgkins lymphoma compared with shorter-duration use of oral contraceptives, and people who had used oral contraceptives before 1970 had an even greater reduced risk than did people had used oral contraceptives after 1970. It is known that earlier formulations contained a higher level of estrogen than more recent formulations. Our results are consistent with the findings reported by Nelson et al. (9). In our study, while oral contraceptive use was not associated with the risk of non-Hodgkins lymphoma overall, there was a suggestion of reduced risk associated with longer duration of use and with uses started before 1970. Our recent investigation also showed a slightly reduced risk of non-Hodgkins lymphoma associated with hormone replacement therapy (31).
It is interesting to note in our study that an increasing number of pregnancies and use of oral contraceptives were associated with a reduced risk of non-Hodgkins lymphoma, while there was no clear risk relation with the estimated total months of ovulation. These results may indicate that exposure to very high levels of sex hormones may be needed to show a protective effect on non-Hodgkins lymphoma risk. Our results also showed that early age at menarche was associated with a reduced risk of non-Hodgkins lymphoma, while age at menopause was not associated with the risk. Early age at menarche and later age at menopause would result in a longer duration of ovulation and, thus, a longer duration of exposure to estrogens. This seemingly controversial result may also indicate that sex hormone exposures occurring early in life may be important for estrogens to have a protective effect against the development of non-Hodgkins lymphoma.
The strengths and limitations involved in our study need to be considered in interpreting the results. One of the advantages is that, in this population-based case-control study, all incident cases were histologically confirmed by two experienced and independent pathologists. The histologic confirmation not only reduced the potential for disease misclassification but also allowed us to evaluate the relation by non-Hodgkins lymphoma subtypes, which is necessary when considering the heterogeneity of the disease. Previous epidemiologic studies of reproductive factors and non-Hodgkins lymphoma risk have failed to examine the relation by non-Hodgkins lymphoma subtypes.
Menstrual and reproductive history was collected based on self-reporting by study participants. Previous studies have generally reported a high degree of reliability for reporting menstrual and reproductive history (3236). Moreover, since so little is known about the relation between menstrual and reproductive history and the risk of non-Hodgkins lymphoma, any misclassification by self-report of menstrual and reproductive history is likely to be nondifferential.
A potential limitation of the study is the relatively low response rate from potentially eligible subjects, particularly for older controls. However, it is unlikely that the refusal to participate in the study was related to their specific menstrual and reproductive history. In addition, given the several consistent associations observed in our studies with the majority of previous epidemiologic studies including age at first pregnancy, abortion, and miscarriage, selection bias resulting from the low participation rate is unlikely to play a critical role for the observed associations in this study. Finally, while the relatively large sample size allowed us to evaluate the overall relation between non-Hodgkins lymphoma and menstrual and reproductive factors, the statistical power by non-Hodgkins lymphoma subtype may still be limited. We could not look at specific subtypes separately for lack of power. The non-Hodgkins lymphoma subtypes used in this study in fact represent relatively broad histologic subtype groupings of non-Hodgkins lymphoma.
In summary, our study suggests a reduced risk of non-Hodgkins lymphoma associated with increasing number of pregnancies and an increased risk of non-Hodgkins lymphoma associated with late age at first menstrual period. The risk of non-Hodgkins lymphoma associated with menstrual and reproductive factors appears to vary according to non-Hodgkins lymphoma subtype. Future large population-based epidemiologic studies are needed to confirm the findings.
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ACKNOWLEDGMENTS |
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The authors assume full responsibility for analyses and interpretation of these data.
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NOTES |
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REFERENCES |
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