Third Trimester Estrogens and Maternal Breast Cancer: Prospective Evidence

Full-term pregnancy is associated with a transient increase and life-time decrease in maternal breast cancer risk. Estrone (E1), estradiol (E2), and estriol (E3) are in high concentration during the third trimester. E1 and E2 metabolism produces carcinogenic intermediaries, and E3 metabolism does not.

We tested the hypothesis that higher E3 in pregnancy is protective while higher E1 plus E2 increases risk.

Prospective case-cohort study (n = 620; 204 cases) nested in a 38-year follow-up of 15,528 pregnant women in the Child Health and Development Studies. We measured E1, E2, and E3 in archived third trimester serum and estimated associations with breast cancer.

Northern California Kaiser members receiving obstetric care from 1959 to 1967.

Breast cancer diagnosed through 1997.

Doubling of E1+E2 was associated with greater risk [hazard ratio (HR), 1.7; 95% confidence interval (CI), 1.2 to 2.4]. In contrast, doubling of E3 or the E3/E1+E2 ratio was associated with protection (HR, 0.7; 95% CI, 0.5 to 1.0; HR, 0.6; 95% CI, 0.4 to 0.8, respectively). Associations were stronger for diagnoses within 15 years after delivery compared with 16 to 38 years (Pinteraction = 0.0002) for gravidas >27 years at delivery vs ≤27 (Pinteraction = 0.01) and for primiparas vs multiparas (Pinteraction = 0.02).

Relatively high third trimester E3 levels might protect parous women from breast cancer and E1 and E2 might enhance the risk. If findings are confirmed, third trimester pregnancy estrogens could help explain how parity affects breast cancer.