Mary Beth Terry, PhD
Assistant Professor of Epidemiology
Joseph L. Mailman School of Public Health
Columbia University
New York, New York
Although there are substantial data linking the intrauterine environment with childhood cancer risk, less is known about the possible longer term influences of the intrauterine environment on adult cancers. Strong associations between maternal diethylstibestrol (DES) exposure while pregnant and a daughter's subsequent risk of clear cell vaginal cancer offered the first epidemiologic evidence that an intrauterine exposure, particularly a hormonal one, could causally lead to cancers later in life.
The study of intrauterine exposures and their potential impact on adult cancers is made difficult by the extensive time that has elapsed between potential exposures and outcome. Epidemiologic studies, therefore, are usually limited to studying either exposures that are routinely recorded and saved as part of the medical record or to those that can be reliably recalled decades after they occur. One exposure that can be assessed from existing records is birthweight. In addition to the demonstrated relationship between high birthweight and childhood cancers, there has been accumulating evidence that this factor also may be associated with adult malignancies such as testicular, prostate, and breast cancer. It is thought that high birthweight is a marker of intrauterine exposure to high levels of steroid and growth hormones that may influence cancer risk later in life.
To date, much of the research on intrauterine exposures and adult cancers has focused on breast cancer risk. In utero exposures may increase adult breast cancer risk by increasing the number of mammary cells and the number of in utero mutations, as well as accelerating the rate of cell division and imprinting the fetal ovary. Most epidemiologic studies support an association between higher birthweight and later breast cancer risk. This risk is more pronounced among premenopausal women: a 70% to 100% higher risk for premenopausal women born ≥ 4000 grams compared to premenopausal women born between 2500 and 2999 grams. The stronger birthweight association for pre- as opposed to postmenopausal breast cancer is consistent with the hypothesis that birthweight is associated with ovarian function in the premenopausal period.
In addition to birthweight, other indicators of large fetal size such as high placental weight and long birth length have been positively associated with breast cancer risk in the offspring. Interactions between placental weight and birthweight may be particularly important as they can indicate different effects of maternal nutrition at the pregnancy trimesters. A high placental to birthweight ratio also may indicate higher in utero estrogen exposure, as testosterone is converted to estrogen in the placenta. These data suggest that other markers of fetal size are important to measure and record. The placental weight as well as the placental to birthweight ratio may prove to be stronger markers of the intrauterine environment than birthweight alone.
In contrast to the positive association of high birthweight and breast cancer risk, preeclampsia has been associated with a 60% to 80% reduction in a daughter's breast cancer risk in some, but not all, studies. The hormonal profile of pregnant women with preeclampsia is almost the mirror image to that of mothers of high birthweight babies: low levels of maternal estrogens and maternal insulin-like growth factor 1(IGF-1) and high levels of maternal testosterone. These low levels of estrogens may be related to the reduced ability of the placenta to function properly in aromatizing androgens to estrogens in women with preeclampsia.
While accumulating data suggest a link between infant size and other birth conditions (e.g., maternal preeclampsia) and adult breast cancer risk, few studies have examined the importance of these markers of the intrauterine environment and early childhood growth patterns. There is a great need to understand how these markers of the intrauterine environment interplay with subsequent early life exposures and other indicators of breast cancer risk (e.g., early menarche and early breast development). The few studies examining infant and childhood growth suggest complex patterns and a joint effect on age at menarche. For example, even though birthweight is positively associated with childhood height and weight (both of which are associated with early menarche), recent studies suggest that low birthweight girls who experience rapid catch-up growth actually have the earliest age at menarche.
As more is learned about how early life factors relate to childhood growth, puberty, and adolescent risk factors, appropriate strategies for prevention can be developed and specifically targeted for exposures and time periods that may be most appropriate for effective intervention efforts. Birthweight is on the rise and is probably due to weight increases among pregnant women as well as a decrease in maternal smoking. Higher birthweight will improve many health outcomes in children and adults. However, any potential detrimental effects of extremely high birthweight, such as a potential higher cancer risk, need to be fully understood when considering recommendations on maternal weight gain during pregnancy and other factors that may affect the course of the pregnancy.
With regard to breast cancer risk, it may turn out that interventions could take the form of specific dietary interventions rather than lowering birthweight per se. For example, novel animal experiments using rats suggest that exposure to high dietary fat in utero (specifically n-6 polyunsaturated fats) increases mammary cancer risk later in life. These animal studies argue for the importance of collecting more epidemiologic data on early life factors because certain interventions can be targeted to the short-term pregnancy period rather than trying to alter diets and behavior over a longer period.
References
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- Innes KE, Byers TE. Preeclampsia and breast cancer risk. Epidemiology. 1999;10:722-732.
- Persson I, Ahlsson F, Ewald U, et al. Influence of perinatal factors on the onset of puberty in boys and girls: implications for interpretation of link with risk of long term diseases. Am J Epidemiol. 1999;150:747-755.
- Hilakivi-Clarke L, Onojafe I, Raygada M, et al. Breast cancer risk in rats fed a diet high in n-6 polyunsaturated fatty acids during pregnancy. J Natl Cancer Inst. 1996;88:1821-1827.
