A nationwide cohort study in more than 1.1 million Danish children shows that the use of combined estrogen and progestin oral contraceptives in the 6 months before conception or during pregnancy is associated with a small increase in the risk for any type of childhood leukemia, particularly the nonlymphoid types.
The increased risk for leukemias was mainly associated with the use of oral combined contraceptive products containing estrogen, and not with progestin-only contraceptives.
In exploratory analyses, the risk for leukemia became nonsignificant when the use of hormonal contraception ended more than 6 months before conception.
The authors emphasize that the absolute risk for childhood leukemia remains low and that the safety of hormonal contraceptives is not a major concern.
During the median study follow-up period of 9 years, they estimate that maternal use of hormonal contraception could have resulted in about 25 additional cases of leukemia in Denmark, or one additional case of leukemia for every 50,000 exposed children.
The study, led by Marie Hargreave, PhD, from the Danish Cancer Society Research Center, Copenhagen, Denmark, was published online September 6 in The Lancet Oncology.
"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.
Association, Not Causation
When approached for comment, Rita W. Driggers, MD, associate professor of gynecology and obstetrics at Johns Hopkins University School of Medicine in Washington, DC, agreed, noting that the study shows an association, not causation, between use of combined oral contraceptives and increased risk for nonlymphoid leukemia.
Like the authors, Driggers, who is medical director of Maternal Fetal Medicine at Sibley Memorial Hospital Johns Hopkins Medicine, pointed out that the association has been investigated previously in case-control studies, with conflicting results.
"Patients and providers will have to weigh the extremely low absolute increase in nonlymphoid leukemia risk (2.12 cases per 100,000 years) to the risks and costs of unintended pregnancy," Driggers told Medscape Medical News.
For the study, the researchers used the Danish Medical Birth Registry to identify 1,185,157 children born between January 1, 1995, and December 31, 2014, and their parents. The Danish Cancer Registry was used to identify children with leukemia. Genetic subtypes of acute lymphoid leukemia were identified by using the Danish Registry of Childhood Cancer.
The prospectively collected data showed that children born to women who used any type of hormonal contraception were at higher risk for any leukemia than were the children of women who never used hormonal contraception (hazard ratio [HR], 1.46; P = .011). For women who used hormonal contraception during pregnancy, the risk for leukemia in their children was even greater (HR, 1.78; P = .070).
There was no association between timing of hormonal contraception use and risk for lymphoid leukemia, either for previous use (HR, 1.23; P = .089) or for recent use (HR, 1.27; P = .167). However, compared with nonusers, women who used hormonal contraception had more than twice the risk for nonlymphoid leukemia in their children (HR, 2.17; P = .008). This risk was almost quadrupled compared with nonusers when hormonal contraception was used during pregnancy (HR, 3.87; P = .006).
"This finding might point to the potentially different causes of lymphoid and non-lymphoid leukemias, where lymphoid leukaemia appears to be mainly linked to an infectious origin and non-lymphoid leukaemia to environmental risk factors," the authors say.
Analysis showed that only combined hormonal contraception in the 3- to 6-month period before conception was associated with an increased risk for any leukemia (HR, 1.38; P = .031) compared with nonuse. 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).
"We found that the risk for leukemia increased with 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.
Risk Factors for Leukemia
In an accompanying editorial, Maria S. Pombo-de-Oliveira, MD, PhD, from the Pediatric Hematology-Oncology Research Program at the Instituto Nacional de Câncer, in 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.
This study was funded by the Danish Cancer Research Foundation, the Arvid Nilssons Foundation, the Gangsted Foundation, the Harboe Foundation, and the Johannes Clemmesens Foundation. Hargreave reports grants from the Danish Cancer Research Foundation, the Arvid Nilssons Foundation, the Gangsted Foundation, the Harboe Foundation, and the Johannes Clemmesens Foundation. Another author reports speaker fees from Jazz Pharmaceuticals and Shire Pharmaceuticals. The other authors, Driggers, and Pombo-de-Oliveira have disclosed no relevant financial relationships.
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Cite this: Oral Contraceptive Use Link to Childhood Leukemia - Medscape - Sep 13, 2018.