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American Journal of Epidemiology Advance Access originally published online on February 6, 2007
American Journal of Epidemiology 2007 165(9):1007-1014; doi:10.1093/aje/kwk105
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American Journal of Epidemiology Copyright © 2007 by the Johns Hopkins Bloomberg School of Public Health All rights reserved; printed in U.S.A.

ORIGINAL CONTRIBUTIONS

Preeclampsia, Pregnancy-related Hypertension, and Breast Cancer Risk

Mary Beth Terry1, Mary Perrin1, Carolyn M. Salafia1, Fang Fang Zhang1, Alfred I. Neugut1, Susan L. Teitelbaum2, Julie Britton2 and Marilie D. Gammon3

1 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY
2 Department of Community Medicine, Mt. Sinai School of Medicine, New York, NY
3 Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC

Correspondence to Dr. Mary Beth Terry, Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032 (e-mail: mt146{at}columbia.edu).

Received for publication July 17, 2006. Accepted for publication October 13, 2006.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Pregnancy conditions accompanied by high blood pressure, such as preeclampsia and pregnancy-related hypertension, have been associated with a lower risk of breast cancer in several epidemiologic studies. It is unknown whether length of gestation or multiple occurrence of these conditions alters the association with breast cancer. It is also unknown whether the inverse association between preeclampsia and breast cancer risk is modified by menopausal status at breast cancer diagnosis. Using data from a large, population-based case-control study of breast cancer conducted on Long Island, New York, during 1996–1997, the authors examined these questions among ever-parous women (1,310 cases and 1,385 controls) using multivariate logistic models. Preeclampsia was inversely associated with breast cancer (odds ratio = 0.7, 95% confidence interval: 0.5, 1.0); this association was even stronger among women who had multiple occurrences of preeclampsia (odds ratio = 0.3, 95% confidence interval: 0.1, 0.9). The risk reduction was more pronounced among postmenopausal women. Gestation length did not substantially alter the relation between preeclampsia and breast cancer risk. Pregnancy-related hypertension was also inversely associated with breast cancer risk, but the relations were not statistically significant after adjustment for preeclampsia. These data suggest that pregnancy conditions related to hypertension, particularly preeclampsia, play a role in reducing breast cancer risk. Possible biologic mechanisms underpinning these associations should be further explored.

breast neoplasms; hypertension, pregnancy-induced; pre-eclampsia; pregnancy

Abbreviations: CI, confidence interval; OR, odds ratio


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Preeclampsia is part of a spectrum of pregnancy-related conditions characterized by high blood pressure. The others include pregnancy-related hypertension (which is less severe and not accompanied by proteinuria), toxemia (a term formerly used synonymously with preeclampsia), and eclampsia (which is accompanied by seizures not attributable to other causes) (1, 2). Preeclampsia has been associated with a hormonal profile that may lead to lower breast cancer risk (3), including lower levels of estrogen (4, 5) and insulin-like growth factor I (6–8).

Polednak and Janerich (9) published the first epidemiologic study investigating this spectrum of conditions and breast cancer risk over 20 years ago. Linking New York State birth records to cancer records, they reported an odds ratio of 0.3 (90 percent confidence interval (CI): 0.1, 1.0) for premenopausal breast cancer risk among women who had preeclampsia/toxemia or eclampsia. Four other studies published since then have supported an inverse association, albeit less strong, with the magnitude of the odds ratios for self-reported hypertension (10), self-reported preeclampsia/toxemia (11), and preeclampsia and/or hypertension reported on the birth record (12, 13) ranging from 0.7 to 0.9. Only two studies did not find an inverse association (14, 15). One of these studies, a population-based cohort study, found that a history of preeclampsia increased the risk of breast cancer (odds ratio (OR) = 1.38, 95 percent CI: 1.0, 1.89) (15), while the other study found no association (14).

These findings raise several questions. First, none of the existing studies have examined whether or not women who experience these conditions in multiple pregnancies face a lower risk than women with a single occurrence. If such patterns are observed, this would suggest that preeclampsia lowers risk via cumulative exposure (e.g., to hormones or other factors) rather than permanent alternations to breast tissue from the first pregnancy. Second, most of these studies only examined women who were diagnosed with breast cancer at younger ages (<45 years (9, 11) and ≤55 years (10, 13)), so few data exist on whether these conditions also reduce postmenopausal breast cancer risk. If differences are observed among older women as well, this would also suggest that the impact of preeclampsia may operate via a long induction period. Third, there are few data on whether women who experience preeclampsia and/or pregnancy-related hypertension during a preterm pregnancy (<37 weeks) face a lower risk than women who experience these conditions during a full-term pregnancy (≥37 weeks). Placentas are smaller in women who give birth preterm. If hormonal exposures during pregnancy are the critical modulators of breast cancer risk, levels of growth factors and steroid hormones that depend on placental functional capacity would all differ between preterm and full-term preeclampsia.

To answer these questions, we analyzed self-reports of pregnancy-related hypertension and preeclampsia/toxemia collected during in-person interviews as part of the Long Island Breast Cancer Study Project, a population-based case-control study of pre- and postmenopausal breast cancer risk conducted during 1996–1997. Because participants were queried about pregnancy-related conditions and length of gestation with regard to each pregnancy, we were in a unique position to separately address the associations of preeclampsia and hypertension during pregnancy with breast cancer risk by number of occurrences, length of gestation, and menopausal status at the time of breast cancer diagnosis.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study population
The Long Island Breast Cancer Study Project is a population-based case-control study of breast cancer on Long Island, New York (Nassau and Suffolk counties). Details of the overall study design were provided by Gammon et al. (16) and are summarized briefly here. Cases comprised women with in situ or invasive breast cancer newly diagnosed between August 1996 and July 1997. There were no age or ethnicity restrictions, but subjects were restricted to English speakers. In total, interviews were completed for 1,508 cases (82.1 percent of eligible cases) ranging in age from 20 years to 98 years. Controls were selected through random digit dialing methods (for subjects under age 65 years) and Health Care Financing Administration lists (for subjects aged 65 years or older) and were frequency-matched to cases in 5-year age groups. Interviews were completed for 1,556 controls (62.8 percent of eligible controls). Analyses for this study were restricted to ever-parous cases and controls (1,310 and 1,385 women, respectively). A woman was categorized as parous if she had ever had a livebirth or stillbirth.

Exposure variable definition
Information on every pregnancy of each study subject was collected through in-person interviews. A reproductive calendar was used to mark significant events and jog memory. Each woman was asked, "During any of your pregnancies, did you ever develop..."

1) "...hypertension or high blood pressure?"
2) "...toxemia or preeclampsia?"

For each "Yes," the woman was asked during which pregnancy the condition had occurred. We were able to match this answer by pregnancy number to information on the pregnancy outcome (livebirth or stillbirth), age at pregnancy, sex of offspring, and gestation length. A woman was classified as having a single occurrence of pregnancy-related hypertension if she answered "Yes" once to question 1 above. She was classified as having multiple occurrences of pregnancy-related hypertension if she answered "Yes" for more than one pregnancy. Preeclampsia/toxemia was similarly categorized on the basis of answers to question 2.

There was very little missing exposure data. Information on whether or not preeclampsia/toxemia (hereinafter referred to as preeclampsia) occurred during a woman's pregnancy was missing for four cases and three controls. Information on whether or not hypertension occurred during a woman's pregnancy was missing for six cases and eight controls.

We further examined our exposure measure (for both preeclampsia and pregnancy-related hypertension separately) by combining information on gestation, age at pregnancy, sex of offspring, and pregnancy order. That is, we compared two exposure groups with unexposed women, as defined by characteristics of the pregnancy in which the condition (preeclampsia or hypertension) occurred: 1) gestation length (preterm (<37 weeks) or full-term (≥37 weeks)); 2) age at the pregnancy in which the condition occurred (<27 years or ≥27 years); 3) sex of the offspring (boy or girl); and 4) order of the pregnancy (first vs. others).

Statistical methods
We first compared differences between ever-parous cases and controls using the chi-square test for categorical variables and analysis of variance for continuous variables (17). We assessed confounding by first comparing each potential confounder with exposure among controls and comparing each potential confounder with breast cancer status among unexposed. Second, we compared the change in estimate for the exposure coefficient between statistical models with and without the potential confounder. Logistic regression was used to estimate odds ratios and 95 percent confidence intervals with adjustment for potential confounding variables (18). The potential confounders we considered fell into two groups: 1) variables that, a priori, we thought might be related to the exposure and also were risk factors for the disease and 2) variables that had been considered as confounders in previously published studies. Confounders in these two groups were as follows—group 1: age at diagnosis, age at first birth, parity, smoking status, and body mass index (weight (kg)/height (m)2) at age 20 years and at the reference age; group 2: menopausal status, age at menarche, family history, lactation status, education, and ethnicity. We examined confounding separately for preeclampsia and pregnancy-related hypertension. Effect modification by menopausal status was first examined through use of stratified analysis, with separate models for premenopausal women and postmenopausal women, and by including multiplicative interaction terms in the logistic regression model (18). Finally, we examined models with simultaneous adjustment for preeclampsia and pregnancy-related hypertension to understand the independent effect of each condition after controlling for the other.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Table 1 reports the overall association between preeclampsia and pregnancy-related hypertension and breast cancer risk. Age-adjusted analyses revealed an inverse association for both preeclampsia (OR = 0.64, 95 percent CI: 0.47, 0.87) and pregnancy-related hypertension (OR = 0.68, 95 percent CI: 0.51, 0.90). The association for multiple occurrences of preeclampsia, but not hypertension, was even lower (OR = 0.28, 95 percent CI: 0.11, 0.69).


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  		TABLE 1. Associations between preeclampsia and pregnancy-related hypertension and breast cancer risk among ever-parous women from the Long Island Breast Cancer Study Project, 1996–1997

 
Table 1 also reports the results from multivariate analyses. First, we examined whether the associations between preeclampsia and hypertension and breast cancer risk were independent of each other by simultaneously adjusting for the other condition. These analyses revealed similar associations for preeclampsia (for ever having preeclampsia, OR = 0.71, 95 percent CI: 0.50, 1.02; for multiple occurrences, OR = 0.29, 95 percent CI: 0.11, 0.77) (table 1, column 6). After simultaneous adjustment for preeclampsia, only a single occurrence of pregnancy-related hypertension, not multiple occurrences, was inversely associated with breast cancer risk (table 1, column 6: OR = 0.69, 95 percent CI: 0.49, 0.98). Further adjustment for potential confounding by age at first birth, body mass index, parity, smoking status, menopausal status, age at menarche, lactation, family history of breast cancer, ethnicity, and education did not change these conclusions (table 1, column 8: for ever having preeclampsia, OR = 0.71, 95 percent CI: 0.50, 1.02; for multiple occurrences, OR = 0.31, 95 percent CI: 0.11, 0.88). The similarity between effect estimates in columns 6 and 8 is supported by the fact that after adjustment for age and the other pregnancy condition, none of these potential confounders altered the parameter estimate for the exposure by more than 10 percent (except for the association between multiple occurrences of pregnancy-related hypertension and breast cancer risk, but this association did not differ from the null value of 1 after adjustment for preeclampsia). Table 1 also reports the association between having either preeclampsia or pregnancy-related hypertension and breast cancer risk (OR = 0.71, 95 percent CI: 0.55, 0.93).

Results stratified by menopausal status (table 2) suggested that the reduction in the odds ratio for the association between preeclampsia and breast cancer risk was more pronounced among women diagnosed with postmenopausal breast cancer (for postmenopausal women, multivariate adjusted OR = 0.63, 95 percent CI: 0.41, 0.98; for premenopausal women, OR = 0.99, 95 percent CI: 0.52, 1.88). Differences by menopausal status were much more subtle for pregnancy-related hypertension (for postmenopausal women, OR = 0.78, 95 percent CI: 0.51, 1.19; for premenopausal women, OR = 0.89, 95 percent CI: 0.51, 1.56). Formal tests of multiplicative interaction by menopausal status did not produce statistically significant results for either preeclampsia (p = 0.35) or pregnancy-related hypertension (p = 0.90). Combining measures for either conditions also suggested that the magnitude of the association was more pronounced for postmenopausal women (among premenopausal women, OR = 0.94, 95 percent CI: 0.59, 1.48; among postmenopausal women, OR = 0.63, 95 percent CI: 0.46, 0.88). When we further stratified the postmenopausal findings by age (<65 years vs. ≥65 years), we found similar estimates for having either preeclampsia or pregnancy-induced hypertension (for postmenopausal women aged <65 years, OR = 0.61, 95 percent CI: 0.38, 0.98; for postmenopausal women aged ≥65 years, OR = 0.65, 95 percent CI: 0.41, 1.03).


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  		TABLE 2. Associations between preeclampsia and pregnancy-related hypertension and breast cancer risk among ever-parous women from the Long Island Breast Cancer Study Project, by menopausal status, 1996–1997

 
We further examined whether the gestational length of the pregnancy associated with the pregnancy-related condition modified the association between preeclampsia and pregnancy-related hypertension and breast cancer risk. Table 3 reports the results of these analyses. Findings for preeclampsia or pregnancy-induced hypertension were similar when stratified by gestational length (for gestational length ≥37 weeks, OR = 0.72, 95 percent CI: 0.54, 0.96; for gestational length <37 weeks, OR = 0.71, 95 percent CI: 0.37, 1.36). Similar patterns were seen for preeclampsia and pregnancy-induced hypertension separately. However, results were only statistically significant for the combined measure among women with full-term births, probably because of sample size limitations for the women with preterm births.


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  		TABLE 3. Associations between preeclampsia and pregnancy-induced hypertension and breast cancer risk among ever-parous women from the Long Island Breast Cancer Study Project, by length of gestation, 1996–1997

 
The relation between preeclampsia and pregnancy-related hypertension was further examined (see table 4). Having only preeclampsia or only pregnancy-related hypertension was inversely associated with risk (for preeclampsia only, OR = 0.72, 95 percent CI: 0.47, 1.12; for pregnancy-related hypertension only, OR = 0.81, 95 percent CI: 0.55, 1.19) in comparison with women with neither condition. However, the association was slightly more pronounced among women who had had both preeclampsia and hypertension (OR = 0.58, 95 percent CI: 0.36, 0.94).


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  		TABLE 4. Associations between preeclampsia and pregnancy-related hypertension, separately and in combination, and breast cancer risk among ever-parous women from the Long Island Breast Cancer Study Project, 1996–1997

 
We also analyzed whether age at pregnancy or sex of the offspring altered the effect estimates for preeclampsia and hypertension. Neither factor altered the effect estimates for the relations between preeclampsia and pregnancy-related hypertension and breast cancer (data not shown). Finally, we did not find any strong evidence suggesting that the association with preeclampsia or pregnancy-related hypertension was stronger if it occurred during the first pregnancy as opposed to subsequent pregnancies (data not shown).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
In this study, we observed a 20–30 percent reduction in the odds ratio for the association between any self-reported occurrence of pregnancy-related hypertension or preeclampsia/toxemia and breast cancer risk. These results support the findings of five of the seven existing studies that have examined some or a combination of these conditions (9–13). We found a stronger association for more than one occurrence of preeclampsia versus only one occurrence relative to women who had never experienced preeclampsia during pregnancy. Multiple occurrences of preeclampsia were very rare, however, and were reported by only six cases (0.5 percent of all parous cases) and 23 controls (1.7 percent of all parous controls). In contrast, we did not find any support for a "dose-response" for pregnancy-related hypertension, as only women with a single occurrence had a lower risk than those with multiple occurrences.

The risk reduction for the association between preeclampsia and breast cancer was more pronounced among postmenopausal women. Most studies have examined the association of preeclampsia and/or pregnancy-related hypertension with breast cancer risk only among women who were diagnosed with breast cancer at younger ages (<45 years (9, 11), ≤54 years (10), and ≤55 years (13)). Only one study that included subjects spanning a range of ages from <30 years to 80 years reported results separately by age at diagnosis (<50 years vs. ≥50 years) (12). Those investigators found no difference by age at diagnosis between preeclampsia or hypertension in the first pregnancy and breast cancer risk. Because that cohort study used an age proxy for menopausal status and also combined measures of hypertension and preeclampsia (12), it is difficult to directly compare their results to those of our case-control study, and further investigation of potential differences by menopausal status may be warranted.

There are also few data on whether women who experience preeclampsia and/or pregnancy-related hypertension and give birth preterm (<37 weeks) face a lower risk than women with these conditions who deliver at term (≥37 weeks). If hormonal exposures during pregnancy are the critical modulators of breast cancer risk, levels of growth factors and steroid hormones that depend on placental functional capacity would all differ between preterm and full-term preeclampsia. Effect sizes for both preeclampsia and hypertension were similar in magnitude among women with preterm births and women who delivered at term; however, the estimates were statistically significant only among those women who delivered at term, probably because of the limited sample size for women who reported preterm delivery. The only other study to examine this question used record-linkage data and did not report a smaller association for women who delivered preterm (12). In addition to gestational length, we also examined other pregnancy characteristics such as age at pregnancy, sex of offspring, and order of pregnancy. We did not find any differences for preeclampsia or pregnancy-related hypertension by age at pregnancy or by gender of offspring. We also did not find that the inverse associations between these conditions and breast cancer were restricted to events that occurred during the first pregnancy.

Although we found inverse associations of similar magnitude between both preeclampsia and pregnancy-related hypertension and breast cancer risk, the associations with hypertension were no longer significant after adjustment for preeclampsia. In our data, these conditions were strongly associated with each other (p < 0.001). Previous studies did not separately analyze the risks from pregnancy-related hypertension and preeclampsia; however, we should be cautious in interpreting these data because the difficulty of distinguishing these events from self-reported data (1). However, if our data are replicated and a stronger relation exists for preeclampsia than for pregnancy-related hypertension, one plausible explanation may be that hormone levels change as one moves along the continuum from pregnancy-related hypertension to preeclampsia. It is also plausible that both preeclampsia and pregnancy-related hypertension reflect the same underlying truly causal condition (e.g., hormonal profile) and that simultaneous adjustment for each condition could attenuate the effect of the other. We have presented the effect estimates obtained both before and after adjustment for the other condition in order to show the empirical impact on the estimates of association.

Women with preeclampsia have been reported to experience lower levels of estrogen (4, 5) and insulin-like growth factor I (6–8) and higher circulating levels of androgens (19, 20), {alpha}-fetoprotein (21), and human chorionic gonadotropin (21, 22). These studies suggest that women with preeclampsia may experience a different hormonal profile than women with uncomplicated pregnancies; this hormonal profile would be more favorable in terms of future breast cancer risk (3). However, these results are not consistent across studies. For instance, Acromite et al. (19) reported that there was no difference between estrogen levels among women with and without preeclampsia, while Richardson et al. (23) found that levels of estrogen were actually higher in women with preeclampsia. Other investigators have reported similar levels of androgens (24), human chorionic gonadotropin (25), insulin-like growth factor I (26), and {alpha}-fetoprotein (22) between women with and without preeclampsia. More research is needed to unravel whether hormonal differences, if any, can explain inverse epidemiologic associations between preeclampsia and breast cancer risk.

Like two (10, 11) of the existing studies, ours was a case-control study which relied on self-reports and therefore may have been subject to recall and selection bias. Although retrospective reporting of pregnancy conditions is undoubtedly subject to error, particularly underreporting, there are few data suggesting that this reporting will differ by case-control status. For recall bias to explain our findings, not only would cases have to systematically underreport, but they would have to do so in a manner that would replicate the patterns we have seen here (e.g., in a dose-response fashion for preeclampsia). However, it is also possible that cases may have overreported certain conditions and events; therefore, if recall bias was present, the true association would likely be even stronger in the inverse direction. We were able to evaluate potential confounding by known risk factors for breast cancer, including age at first birth, body mass index (at the reference age and at age 20 years), parity, smoking status, menopausal status, age at menarche, lactation, family history of breast cancer, ethnicity, and education. Our analyses suggested that there was little confounding with these variables as measured. For residual confounding to explain the associations we found, the unmeasured confounders would also have to mimic the patterns we observed between preeclampsia and breast cancer risk.

Overall, 6.6 percent of cases and 9.5 percent of controls reported ever having hypertension, and 5.2 percent of cases and 8.0 percent of controls reported ever having preeclampsia. This compares very closely with the results of a medical record-linkage study (12), suggesting that while there may have been some underreporting of these conditions, it is unlikely to have been large.

We further analyzed the effect of time since pregnancy on reporting of these conditions by comparing the overall percentages reported by reference age. These analyses suggested that the percentage of women reporting prior preeclampsia changed little over time, ranging from 7.2 percent in women under 40 years of age at interview to 8.4 percent for women over 70 years of age at interview. In contrast, the percentage of women reporting prior pregnancy-related hypertension was highest among women under 40 years of age at interview (13.4 percent) and steadily declined as women aged, to a low of 4.3 percent for women over 80 years of age at interview. These data suggest that in the absence of either a change in the case definition of pregnancy-related hypertension over time or an increase in its incidence, women may have trouble recalling a less severe diagnosis of hypertension but do not have trouble recalling a more severe diagnosis of preeclampsia. Because nondifferential recall of exposure will bias the effect estimates towards the null (27), this may be one reason why the associations between hypertension and breast cancer risk are weaker. Because the bias is towards the null, however, this means that measurement error cannot account for the statistically significant associations between preeclampsia and breast cancer risk.

Conclusions
Overall, preeclampsia and pregnancy-related hypertension were associated with a 30 percent decrease in breast cancer risk, consistent with the existing literature. Simultaneous assessment of preeclampsia and pregnancy-related hypertension revealed that the associations with hypertension were no longer statistically significant after adjustment for preeclampsia. Multiple occurrences of preeclampsia were associated with even stronger risk reductions. The inverse association between preeclampsia and breast cancer risk was more pronounced among women diagnosed with postmenopausal breast cancer. Recall bias, selection bias, and residual confounding are unlikely explanations for our findings. Our findings, if replicated, suggest the need to pursue biologic mechanisms to explain the association between these pregnancy conditions and breast cancer risk reduction and to further examine whether there may be differences between pregnancy-related hypertension and preeclampsia. Although preeclampsia is relatively uncommon, continued study of its biology and epidemiology promises to reveal much about the effect of the underlying mechanisms of pregnancy on mammary carcinogenesis.


   ACKNOWLEDGMENTS
 
This research was funded in part by grants U01 CA/ES66572, P30ES10126, and K07CA90685 from the National Cancer Institute and the National Institute of Environmental Health Sciences and by gifts from private citizens.

For their valuable contributions to the Long Island Breast Cancer Study Project, the authors thank members of the Long Island Breast Cancer Network; the 31 participating institutions on Long Island and in New York, New York; their National Institutes of Health collaborators, Dr. Gwen Collman of the National Institute of Environmental Health Sciences and Dr. G. Iris Obrams, formerly of the National Cancer Institute; members of the External Advisory Committee to the population-based case-control study: Dr. Leslie Bernstein (Chair), Gerald Akland, Barbara Balaban, Dr. Blake Cady, Dr. Dale Sandler, Dr. Roy Shore, and Dr. Gerald Wogan; and other collaborators who assisted with various aspects of the data collection efforts, including Dr. Regina Santella, Gail Garbowski, Dr. Mary S. Wolff, Dr. Steven D. Stellman, Dr. Maureen Hatch, Dr. H. Leon Bradlow, David Camann, Martin Trent, Dr. Ruby Senie, Dr. Carla Maffeo, Pat Montalvan, Dr. Gertrud Berkowitz, Dr. Margaret Kemeny, Dr. Mark Citron, Dr. Freya Schnabel, Dr. Allen Schuss, Dr. Steven Hajdu, and Dr. Vincent Vinceguerra.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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