Childhood Cancer Survivors More Likely to Face Pregnancy Problems

ROCKVILLE, Md., Oct. 18 -- Women who survive childhood cancer are at a moderately elevated risk of later pregnancy problems, according to researchers here.

Among cancer survivors who avoided premature menopause or uterine failure, those who later became pregnant were twice as likely to give birth prematurely as women unaffected by childhood cancer, said Lisa B. Signorello Sc.D., of the International Epidemiology Institute, and colleagues.

Significantly more of the survivors' children were born preterm (before 37 weeks gestation) compared with children born to a control group (21.1% versus 12.6%, odds ratio 1.9, 95% confidence interval 1.4 to 2.4, P<0.001), the team reported in the Oct. 19 issue of the Journal of the National Cancer Institute.

However, the risk of giving birth to children small for their gestational age, in the lowest 10th percentile, was not higher among cancer survivors (9.5% versus 9.2%, P=0.84).

The investigators analyzed data from the ongoing Childhood Cancer Survivor Study, which is the largest such study to have looked at pregnancy outcomes and one of the few that have looked at patients who received treatments other than pelvic or abdominal irradiation.

The analysis included 2,201 singleton live births to 1,264 female cancer survivors from 1968 to 2002 and another 1,175 singleton live births in a control group of 601 female siblings randomly selected from among the full cohort. Thirty-five percent of the reported pregnancies among cancer survivors and 29% among controls were excluded because they did not result in a live birth.

Low birth weight, defined as less than 2.5 kg, was more common in children of cancer survivors but seemed to be a consequence of early birth. The investigators reported:

• The mean birth weight among the children of survivors was significantly lower than among children of controls (3,312 g versus 3,447 g, P<0.001).
• The unadjusted risk of low birth weight was 9.0% among children of childhood cancer survivors and 4.2% among the control group's children.
• After adjusting for gestational age at birth, the association was no longer significant (OR 1.3, 95% CI 0.9 to 1.9, P=0.23).

High-dose radiotherapy to the uterus was particularly associated with an increased risk of early birth and fetal-growth restriction. Women who received more than 500 cGy radiotherapy to the uterus were more likely to have problems with their pregnancy than cancer survivors who did not receive radiotherapy. The data showed:

• A 3.5-fold higher risk of preterm birth (95% CI 1.5 to 8.0, 50.0% versus 19.6%, P=0.003),
• A 6.8-fold higher risk of low birth weight delivery (95% CI 2.1 to 22.2, 36.2% versus 7.6%, P=0.001), and
• A fourfold increased risk of a baby that was small for gestational age (95% CI 1.6 to 9.8, 18.2% versus 7.8%, P=0.003).

Radiation to the uterus in lower doses also increased later pregnancy risks (starting at 50 cGy for preterm birth and at 250 cGy for low birth weight). The data showed that:

• Low birth weight was 4.3 times more common among women who received 250 to 500 cGy uterine doses compared to those who received none (95% CI 1.4 to 12.8, 25.5% versus7.6%, P=0.01).
• Preterm birth was 1.8 times (95% CI 1.1 to 3.0) more common in women who received 50 to 250 cGy doses and 2.3-fold more common for those who received 250 to 500 cGy doses compared to those who received none (26.1% versus 39.6% versus 19.6%, both comparisons significant).

The participants overall were treated for a variety of cancer types when they were younger than 21 years old and each survived at least five years from diagnosis. Patients and controls filled out a baseline questionnaire in 1994 about pregnancies and those who had given birth were followed with a more detailed questionnaire.

The two groups were similar in most respects but the childhood cancer group reported diabetes during pregnancy significantly more often than the control group (P=0.001).

Also, participants' age at pregnancy was slightly higher for controls than survivors (mean 25.1 years versus 24.4 years, P<0.001). This difference may be important because survivors of childhood cancer appear to have a narrower fertility window in their lives, said Leslie Schover, Ph.D., of the University of Texas M.D. Anderson Cancer Center in Houston, in an accompanying editorial.

Most of the participants treated for childhood cancer had received chemotherapy (65%). Notably, those who were treated with the highest cumulative doses of alkylating chemotherapeutic agents, such as busulfan, Paraplatin (carboplatin), or Platinol (cisplatin), had a nonsignificant greater risk of preterm birth (OR 1.6, 95% CI 0.9 to 2.7, P=0.09). This finding is "somewhat novel, but it should be interpreted cautiously given its lack of statistical significance and lack of dose-response trend," Dr. Signorello and colleagues wrote.

There were no "convincing" associations between ovarian or pituitary radiation exposure and preterm birth. However, the timing of uterine irradiation -- pre- or postmenarche -- appeared to have some effect on pregnancy outcomes in women who had childhood cancer. The investigators found that:

• Low birth weight risk was similar in both groups who received at least 250 cGy to the uterus (premenarche OR 4.7, 95% CI 1.2 to 18.6 versus postmenarche OR 3.8, 95% CI 1.3 to 11.2), and
• Preterm birth risk was higher in those exposed to at least 250 cGy to the uterus before menarche (OR 4.9, 95% CI 1.7 to 13.9 versus postmenarche OR 1.9, 95% CI 0.7 to 4.9) but not significantly so based on a likelihood ratio test (P=0.44).

Young women who have survived cancer may consider consulting a high-risk obstetrician as part of planning a pregnancy, said Dr. Schover. Also, the findings should assist in counseling female pediatric cancer patients, she added.

Dr. Signorello and colleagues cautioned that the study was limited by the sometimes small number of adverse outcomes available for analysis and adjustment for several confounders.

This study was supported by Westlakes Research Institute, the National Cancer Institute, and the Children's Cancer Research Fund.