For Childhood Cancer Survivors: New Data on Pregnancy Adverse Outcomes

From Medscape Medical News

Nick Mulcahy

July 22, 2010 — A new study of childhood cancer survivors provides information about the risks for stillbirth and neonatal death among the offspring of the survivors.

For the male survivors, there is good news: radiation to the testes did not affect the risk for these 2 adverse outcomes in their offspring.

For the female survivors overall, the data are sobering: radiation to the uterus and ovaries "greatly increased the risk of stillbirth and neonatal death."

However, the timing of the radiation to the pelvic region during childhood determined whether or not risk existed for women.

In women treated before menarche, various radiation doses were associated with as much as a 12-fold risk for stillbirth and neonatal death, report the study authors, led by Lisa B. Signorello, MD, from the International Epidemiology Institute in Rockville, Maryland, and the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

On a bright note, in women treated after menarche, there was no significantly increased risk — no matter what the radiation dose.

The study of 1148 men and 1657 women who survived childhood cancer, and who between them had 4946 pregnancies, was published online July 23 in the Lancet.

The study population comes from the well-chronicled Childhood Cancer Survivor Study (CCSS), which involves 25 institutions in the United States and 1 in Canada.

The study authors say that genetic damage is not the cause of the misfortunate outcomes. They cite the null findings for male gonadal exposure to irradiation and other evidence to support this hypothesis. The adverse events for women survivors are "most likely attributable to uterine damage," they write.

The study advances the state of our understanding of pregnancy outcomes for female survivors, said an expert in childhood survivors of cancer who was not involved with study.

"The association between radiation to the pelvic region in childhood and adverse pregnancy outcomes, including stillbirths and neonatal deaths, in later life has been known for more than 20 years," Charles Sklar, MD, from Memorial Sloan-Kettering Cancer Center in New York City, told Medscape Medical News.

"The current Lancet study provides more precise estimates of risk and additional data on the interaction between age at treatment and the dose thresholds of radiation that are associated with these outcomes," he explained.

High-Risk Care Needed

Dr. Sklar suggested that all female survivors in their child-bearing years should be presented with this information.

"It is currently standard practice to provide this [risk] information to our patients who have been treated with pelvic radiation," he said.

If pregnant, the women also require special obstetrical care.

"For those women at risk who become pregnant, we currently advise — and will continue to recommend — that they seek care in a high-risk obstetrical practice/unit," said Dr. Sklar.

Chemotherapy Not Implicated

All patients in CCSS were younger than 21 years at initial diagnosis and had survived for at least 5 years after diagnosis. The most common cancers were leukemias and lymphomas (57%).

The investigators gathered data about pregnancy outcomes and childhood treatments from the survivors' medical records and from questionnaires mailed to the survivors.

In the study, the definition of a stillbirth was a fetal death after the 20th week of gestation; a neonatal death was defined as death within the first 28 days of life.

About two thirds of the study participants (1174 of 2805) were given radiotherapy as children (1042 males, 732 females). This group reported 60 stillbirths or neonatal deaths and 3077 live births.

Age at menarche was known or estimated for 90% of the women.

Women treated with radiation to the pelvic region after menarche had no significantly increased risk for stillbirths or neonatal deaths, compared with survivors who were not treated with radiation at all, say the authors.

Being treated with radiation to the pelvis before menarche was another story.

For mothers treated before menarche with radiation in doses of 1.00 to 2.49 Gy, the risk for stillbirth or neonatal death was 3 per 69 offspring (4%; relative risk [RR], 4.7; 95% confidence interval [CI], 1.2 - 19.0); for doses of 2.5 Gy or more, the risk was 11 per 82 offspring (13%; RR, 12.3; 95% CI, 4.2 - 36.0). In both cases, the risk was significantly increased (P = .0006).

There were not enough girls treated at high doses of radiation, so the exposure categories were not extended to 10 Gy or more, the authors point out.

In addition to evaluating women's risk associated with radiation to the pelvic region, the investigators looked at radiation to women's pituitary glands and to men's testes. Neither was found to have a positive association with risk for stillbirth or neonatal death.

The investigators also did not find an increased risk for stillbirth or neonatal death in the offspring of the men and women who had received chemotherapy with alkylating drugs, such as cisplatin and cyclophosphamide. Nor did they find any pattern of increasing dose with increasing risk.

These findings about chemotherapy repudiate concerns from other studies, suggest the authors.

"Treatment with alkylating drugs (mutagenic chemotherapy drugs) was thought to be a confounder of the association of radiation with stillbirths or neonatal deaths (and a potential independent risk factor for stillbirths and neonatal deaths)," they write.

The investigators received funding from the Westlakes Research Institute, the National Cancer Institute, and the Children's Cancer Research Fund.

Lancet. Published online July 23, 2010.