Maternal use of oral contraceptive linked to leukemia in children

The maternal use of combined estrogen and progestin oral contraceptive during pregnancy or 6 months before conception increases the risk of childhood leukemia, particularly the nonlymphoid types, according to a new study.

The study, published in The Lancet Oncology finds that the increased risk for leukemias was mainly associated with the use of oral combined contraceptive products containing estrogen, and not with progestin-only contraceptives. The risk for leukemia became nonsignificant when the use of hormonal contraception ended more than 6 months before conception.

• Between Jan 1, 1996, and Dec 31, 2014, the 1 185 157 liveborn children accumulated 11 114 290 person-years of follow-up (median 9·3 years, IQR 4·6–14·2), during which 606 children were diagnosed with leukemia (465 with lymphoid leukemia and 141 with non-lymphoid leukemia).


• Children born to women with the recent use of any type of hormonal contraception were at higher risk for any leukemia than children of women who never used contraception (HR 1·46, 95% CI 1·09–1·96; p=0·011); and for exposure during pregnancy, the risk was 1·78 (0·95–3·31; p=0·070).


• No association was found between timing of use and risk for lymphoid leukemia (HR 1·23, 95% CI 0·97–1·57, p=0·089, for previous use and 1·27, 0·90–1·80, p=0·167, for recent use); however, the HRs for non-lymphoid leukemia were 2·17 (1·22–3·87; p=0·008) for recent use and 3·87 (1·48–10·15; p=0·006) for use during pregnancy.


• No increased risk was seen with oral contraceptive use 6 to 12 months before the start of pregnancy or if oral contraceptive had been used more than 1 year earlier (HR, 1.22 [P = .159]; HR, 1.24 [P = .108], respectively).


• Hormonal contraception use close to or during pregnancy might have resulted in one additional case of leukemia per about 50 000 exposed children, or 25 cases during the 9-year study period.

The authors emphasize that the absolute risk for childhood leukemia remains low and that the safety of hormonal contraceptives is not a major concern.

"These associations seemed to be driven by oral combination contraceptives, the most commonly used hormonal contraceptives today," the authors write. "Since almost no risk factors have been established for childhood leukemia, these findings suggest an important direction for future research into its causes and prevention."

Hargreave and colleagues note that to date, only ionizing radiation has been significantly linked with both lymphoid and nonlymphoid leukemias.

"We found that the risk for leukemia increased with the maternal use of hormonal contraception up to and during pregnancy, indicating that the proximity of the exposure to pregnancy is relevant to risk," the authors say.

In an accompanying editorial, Maria S. Pombo-de-Oliveira, the Pediatric Hematology-Oncology Research Program at the Instituto Nacional de Câncer, Rio de Janeiro, Brazil, agreed that maternal use of hormonal contraception could soon join the list of risk factors for childhood leukemia. Currently, this includes tobacco, pesticides, and infectious agents.

"Hargreave and colleagues have re-opened an avenue to explore a new risk factor associated with child vulnerability and disease susceptibility," she writes, noting the robust statistical value of the study cohort.

"Our findings suggest the maternal hormonal use affects non-lymphoid leukemia development in children. Since almost no risk factors have been established for childhood leukemia, these findings suggest an important direction for future research into its causes and prevention," concluded the study authors.