Abortion, Miscarriage, and Breast Cancer Risk: 2003 Workshop

In February 2003, the National Cancer Institute (NCI) convened a workshop of over 100 of the world’s leading experts who study pregnancy and breast cancer risk. Workshop participants reviewed existing population-based, clinical, and animal studies on the relationship between pregnancy and breast cancer risk, including studies of induced and spontaneous abortions. They concluded that having an abortion or miscarriage does not increase a woman’s subsequent risk of developing breast cancer. A summary of their findings can be found below in the Summary Report: Early Reproductive Events and Breast Cancer Workshop.

Updated information on studies of cancer risk and abortion and other reproductive history factors is available in the Reproductive History and Cancer Risk fact sheet.

Background

A woman’s hormone levels normally change throughout her life for a variety of reasons, and these hormonal changes can lead to changes in her breasts. Many such hormonal changes occur during pregnancy, changes that may influence a woman’s chances of developing breast cancer later in life. As a result, over several decades a considerable amount of research has been and continues to be conducted to determine whether having an induced abortion, or a miscarriage (also known as spontaneous abortion), influences a woman’s chances of developing breast cancer later in life.

The relationship between induced and spontaneous abortion and breast cancer risk has been the subject of extensive research beginning in the late 1950s. Until the mid-1990s, the evidence was inconsistent. Findings from some studies suggested there was no increase in risk of breast cancer among women who had had an abortion, while findings from other studies suggested there was an increased risk. Most of these studies, however, were flawed in a number of ways that can lead to unreliable results. Only a small number of women were included in many of these studies, and for most, the data were collected only after breast cancer had been diagnosed, and women’s histories of miscarriage and abortion were based on their “self-report” rather than on their medical records. Since then, better-designed studies have been conducted. These newer studies examined large numbers of women, collected data before breast cancer was found, and gathered medical history information from medical records rather than simply from self-reports, thereby generating more reliable findings. The newer studies consistently showed no association between induced and spontaneous abortions and breast cancer risk.

Ongoing Research Supported by the National Cancer Institute

Basic, clinical, and population research will continue to be supported to investigate the relationship and the mechanisms of how hormones in general and during pregnancy influence the development of breast cancer.

Important Information about Breast Cancer Risk Factors

At present, the factors known to increase a woman’s chance of developing breast cancer include age (a woman’s chances of getting breast cancer increase as she gets older), a family history of breast cancer, an early age at first menstrual period, a late age at menopause, a late age at the time of birth of her first full-term baby, and certain breast conditions. Obesity is also a risk factor for breast cancer in postmenopausal women.

Summary Report: Early Reproductive Events and Breast Cancer Workshop

Introduction

The Early Reproductive Events and Breast Cancer Workshop convened February 24-26, 2003, and the outcomes of the meeting were reviewed and discussed at the joint meeting of the NCI Board of Scientific Advisors (BSA) and Board of Scientific Counselors (BSC) held March 3, 2003.

The Workshop was established to provide an integrated scientific assessment of the association between reproductive events and the risk of breast cancer. Participants represented a diversity of breast cancer expertise, including epidemiologists, clinicians, basic scientists and breast cancer advocates. The Workshop evaluated the current strength of evidence of the characteristics of pregnancy related to cancer (epidemiologic studies), the biologic changes resulting from pregnancy that may be involved in modifying breast cancer risk (clinical studies), and the biologic mechanisms identified (animal studies).

This report summarizes the epidemiologic, clinical and animal studies findings related to early reproductive events and breast cancer risk, and each finding is given a Strength of Evidence Rating*. Gaps in research knowledge for each scientific area are identified, and recommendations for future research directions are provided.

Epidemiologic Findings

Early age at first term birth is related to lifetime decrease in breast cancer risk. (1)
Increasing parity is associated with a long-term risk reduction, even when controlling for age at first birth. (1)
The additional long-term protective effect of young age at subsequent term pregnancies is not as strong as for the first term pregnancy. (1)
A nulliparous woman has approximately the same risk as a woman with a first term birth around age 30. (1)
Breast cancer risk is transiently increased after a term pregnancy. (1)
Induced abortion is not associated with an increase in breast cancer risk. (1)
Recognized spontaneous abortion is not associated with an increase in breast cancer risk. (1)
Long duration of lactation provides a small additional reduction in breast cancer risk after consideration of age at and number of term pregnancies. (1)
Pregnancy-induced hypertension is associated with decreased breast cancer risk. (2)
Maternal DES exposure is associated with an increase in breast cancer risk. (3)

Epidemiologic Gaps

By what mechanism does pregnancy at an early age protect against breast cancer?
Do pregnancy and age at pregnancy modify radiation-induced breast cancer risk?
What are the effects of age at pregnancy on subgroups of women (e.g., those with BRCA-1 and BRCA-2 mutations)?
What is the mechanism by which lactation affects breast cancer risk?
What is the temporal pattern of breast cancer risk following lactation?
What is the effect of lactation on women with BRCA-1 and BRCA-2 mutations?
Does gender of offspring have an effect?
Does birth weight of offspring have an effect?
What is the impact of multiple births in the same pregnancy, with and without assisted reproductive technology?
What are the breast cancer risk implications of abnormal pregnancies (e.g., spina bifida, late fetal death, fertility treatment-induced pregnancy, preterm delivery, small for gestational age offspring)?
What is the mechanism by which pre-eclampsia reduces breast cancer risk?
Is there a distinction between hypertension and pre-eclampsia with respect to breast cancer risk?
Is gestational diabetes associated with breast cancer risk?

Clinical Findings

There are long-lasting decreases in mammographic density following pregnancy. (2)
There may be changes in breast histology that can be correlated with risk in premenopausal women. (3)
Prolactin, estradiol, and IGF-1 are decreased after pregnancy. (3)

Clinical Gaps

What are the levels, determinants, and interactions of pregnancy-related mammotrophic factors, ligands, and receptors?
What is the time course of pregnancy-related hormonal changes?
Are pregnancy-related hormonal changes influenced by genetic polymorphisms?
What is the precise nature of pregnancy-related changes in breast histology?
How is the epithelial/stromal relationship altered in pregnancy?
Can pregnancy-related changes in breast histology be correlated with ductal lavage findings?
Can noninvasive procedures for assessing breast composition (e.g., MRI and other imaging techniques, particularly functional imaging) substitute for histology?
What are the molecular changes in the breast during and after pregnancy?
What are the histologic and molecular characteristics of breast tumors during and after pregnancy?
Are there immune system changes that may be relevant to breast cancer risk following pregnancy?
Are there pregnancy-related, non-hormonal metabolic changes relevant to breast cancer risk?

Animal Model Findings

Pregnancy protects against subsequent chemical carcinogen-induced breast cancer in rats and mice. (1)
Estrogen and progesterone combinations and hCG protect against carcinogen-induced cancer in rodents by mimicking pregnancy. (1)
Short-term estrogen exposure, at levels of estrogen mimicking pregnancy, is protective for carcinogen-induced cancer in rats. (1)

Animal Model Gaps

What are the mechanisms of hormone action when they are given before or after chemical carcinogen exposure?
What is the relationship between pregnancy and risk of preneoplastic lesions?
What are the levels, determinants, and interactions of pregnancy-related mammotrophic factors, ligands, and receptors?

Future Research Directions

Develop additional animal and treatment models, including further examination of existing models.
Examine the molecular mechanisms of hormone-induced protection, including epithelial/stromal interactions.
Integrate the methodology of genomics and proteomics into the study of pregnancy in relation to risk of breast cancer.
Pursue descriptive studies about human breast development in order to formulate new hypotheses.
Pursue international studies to develop hypotheses for observed international differences in breast cancer risk.
Develop surrogate markers to identify risk of breast cancer following pregnancy.
Translate knowledge about protective effects of pregnancy into intervention trials with human populations.
Promote interactions among epidemiologists, clinicians, and basic scientists.
Consider a funding mechanism aimed at interdisciplinary research concerning pregnancy and breast cancer.
Develop high-throughput technology for hormone measurement.
Support the collecting, archiving, and sharing of relevant biospecimens.

Boards' Response

The NCI Board of Scientific Advisors and Board of Scientific Counselors reviewed and discussed the results of the Early Reproductive Events and Breast Cancer Workshop, and unanimously approved the Workshop findings. One additional gap in our clinical understanding of breast cancer was identified: Do breast cancers diagnosed during pregnancy have different morphologic or molecular characteristics than those diagnosed at other times? It is hoped that the outcomes of this Workshop will help guide the Institute's future research agenda and public communication materials.

Regular Evidence Review

NCI regularly reviews and analyzes the scientific literature on many topics, including various risk factors for breast cancer. Considering the body of literature that has been published since 2003, when NCI held this extensive workshop on early reproductive events and cancer, the evidence overall still does not support early termination of pregnancy as a cause of breast cancer. To view regular updates on this topic, please go to the Breast Cancer Prevention (PDQ®) summary.

*Strength of Evidence Ratings Key

Strength of Evidence Ratings: Epidemiology

1 = Well established
2 = Weight of evidence favors
3 = Suggested from human population studies, but speculative
4 = Suggested from laboratory or theoretical considerations but essentially unevaluated in human populations

Strength of Evidence Ratings: Biologic Changes

1 = Well established
2 = Weight of evidence favors
3 = Suggested by human evidence, but speculative
4 = Suggested from laboratory findings or theoretical considerations but essentially unevaluated in humans

Strength of Evidence Ratings: Biological Mechanisms from Laboratory Studies

1 = Well established
2 = Weight of evidence favors
3 = Suggested by experimental evidence, but speculative
4 = Not supported by experimental evidence

Minority Dissenting Comment

One invited participant to the Early Reproductive Events and Breast Cancer Workshop, held February 24-26, 2003, submitted to the National Cancer Institute a public comment regarding the outcomes of the workshop. Submitted as a "minority report," the participant conveyed partial disagreement with the findings of the workshop report presented to the joint meeting of the NCI Board of Scientific Counselors and the NCI Board of Scientific Advisors. The participant remains "convinced that the weight of available evidence suggests a real, independent, positive association between induced abortion and breast cancer risk." In a general statement, the participant noted that the workshop summary report contained no comment of dissent.