A population-based study of rates of childbirth in recurrence-free female young adult survivors of Non-gynecologic malignancies

We used four data sources:

Diagnostic and procedure codes used in this study are presented in Additional file 1.

Female YAS were identified using the OCR. While the definition of a YAS varies [13], we limited our cohort to women age 20 through 34 at diagnosis. All female young adults registered in the OCR between 1992 (when datasets became reliably linkable) and 1999 (to enable substantive follow up for all 5 year survivors) were eligible for inclusion. Women were excluded if they died within five years of diagnosis, were diagnosed with a gynaecological malignancy, were registered in OCR for a previous malignancy, or were not continuously eligible for provincial health insurance coverage for at least seven years after diagnosis (or until death).

Recurrence of malignancy is likely to have an influence on childbearing but the OCR does not include information on cancer recurrence. We therefore developed an algorithm to identify survivors with evidence of recurrent disease from physician claims and diagnostic codes based on use of chemotherapy, palliative care, or diagnosis of metastatic disease (Additional file 1). Patients with a solid tumor malignancy undergoing a second course of chemotherapy (or third course in the case of hematologic malignancies) after completion of adjuvant therapy, or delivery of a first course of chemotherapy more than 6 months after completion of cancer directed surgery were considered to have disease recurrence. Survivors identified with recurrent disease within the first 5 years of diagnosis were excluded entirely. Survivors developing recurrent disease after 5 years of survivorship were censored 6 months before the date recurrence was identified as the exact date of recurrence could not be obtained.

A female control population was selected using the RPDB. Eligible women from the general population were matched to the survivors based on calendar year of birth and geographic location. Five controls were randomly selected without replacement from all potential controls matched to a given survivor. Controls were assigned a referent date that corresponded to the date of diagnosis in the matched survivor. Controls were excluded if they had a diagnosis of cancer prior to the referent date (determined through linkage with the OCR), died within five years of the referent date, or were not continuously eligible for provincial health insurance for at least seven years after the referent date.

We identified women who had undergone a procedure consistent with surgical sterilization (tubal ligation, bilateral oophorectomy, hysterectomy) based on OHIP and CIHI-DAD codes. Survivors and controls with evidence of surgical sterilization at any time prior to diagnosis or up to 12 months after diagnosis or referent date were excluded. Individuals undergoing surgical sterilization more than 1 year after diagnosis or referent date were censored on the date of surgical sterilization.

We identified admission for childbirth for all members of our cohort from Jan 1, 1987 through March 31, 2011 from information from CIHI-DAD. Delivery of an infant, live or stillborn over 20 weeks gestational age, as coded in CIHI was considered evidence of childbirth for this study.

For survivors and controls we determined income quintile, defined by the census dissemination area where individuals lived at the date of diagnosis or referent date. We considered childbirth prior to the date of diagnosis or referent date a potential covariate. For the survivor group we evaluated rates of delivery by diagnosis, categorizing survivors into broad groups including the diagnoses with at least 100 women (brain, breast, Hodgkin lymphoma, non-hodgkin lymphoma [NHL], melanoma, thyroid and other malignancies).

We calculated descriptive statistics for study variables stratified for survivors and controls. The outcome of interest was childbirth occurring at least one year after the date of diagnosis (survivors) / referent date (controls). The one year interval was used to ensure that childbirth was a result of post-diagnosis pregnancy. We calculated the time between diagnosis or referent date to the time of admission to hospital for childbirth for each subject. Patients were censored at death, loss-to-follow-up, surgical sterilization, 6 months prior to evidence of recurrent disease, or March 31, 2011, whichever came first. Multivariate analyses with the Cox proportional hazards regression model were conducted to evaluate the relationship between time to childbirth and covariates such as YAS (yes or no), income quintile, age (treated as continuous), and previous childbirth (children born prior to diagnosis or referent date, yes or no). did not consider childbirth from 0–12 months from diagnosis/referent date in our analysis. We tested the interaction between the survivor indicator and previous childbirth. Since this interaction term was highly significant, we further matched survivors and corresponding controls on previous childbirth and stratified the analysis based on this variable. That is, the first and second stratum consists of all survivors and corresponding matched controls with and without, respectively, children born prior to diagnosis or referent date. The Cox regression model for each stratum included YAS, income quintile, and age. To account for the matched design with a variable number of controls per survivor (due to further matching by previous childbirth), we used a robust sandwich variance estimator approach to estimate the standard errors of the Cox regression parameter estimates [14]. The proportional hazards assumption was tested and was not violated. We repeated the analysis without censoring patients for recurrence after 5 years as a sensitivity analysis.

We analyzed data using SAS version 9.2 (Cary, North Carolina). All statistical tests were two-sided, and p-values less than 0.05 were considered statistically significant. The study was approved by the Research Ethics Board of St. Michael’s Hospital, Toronto, Ontario. All data analysis was conducted at the Institute for Clinical Evaluative Sciences, a Section 45 (1) prescribed entity in Ontario’s Personal Health Information Protection Act. The data used are not freely accessible; permission for the use of the data was given by the Institute for Clinical Evaluative Sciences.

This research was supported by the Canadian Institutes for Health Research and the Ontario Ministry of Research and Innovation. Dr Baxter holds the Cancer Care Ontario Health Services Research Chair and an Early Researchers Award from the Ontario Ministry of Research and Innovation. Dr. Paszat is supported by a clinician scientist salary from the Ministry of Health and Long-term Care of Ontario. The funding sources played no role in design, conduct, or reporting of this study. This study was supported by the Institute for Clinical Evaluative Sciences, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. The opinions, results and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by the Institute for Clinical Evaluative Sciences or the Ontario Ministry of Health and Long-Term Care is intended or should be inferred.