Abstract
Background
The likelihood of pregnancy and risk of obstetrical or perinatal complications is inadequately documented in female survivors of pediatric cancer.
Methods
We assembled a population-based cohort of female survivors of cancer diagnosed at age 21 years and younger in Ontario, Canada, between 1985 and 2012. Survivors were matched 1:5 to women without prior cancer. Multivariable Cox proportional hazards and modified Poisson models assessed the likelihood of a recognized pregnancy and perinatal and maternal complications.
Results
A total of 4062 survivors were matched to 20 308 comparisons. Median (interquartile range) age was 11 (4-15) years at cancer diagnosis and 25 (19-31) years at follow-up. By age 30 years, the cumulative incidence of achieving a recognized pregnancy was 22.3% (95% confidence interval [CI] = 20.7% to 23.9%) among survivors vs 26.6% (95% CI = 25.6% to 27.3%) among comparisons (hazard ratio = 0.80, 95% CI = 0.75 to 0.86). A lower likelihood of pregnancy was associated with a brain tumor, alkylator chemotherapy, cranial radiation, and hematopoietic stem cell transplantation. Pregnant survivors were as likely as cancer-free women to carry a pregnancy >20 weeks (relative risk [RR] = 1.01, 95% CI = 0.98 to 1.04). Survivors had a higher relative risk of severe maternal morbidity (RR = 2.31, 95% CI = 1.59 to 3.37), cardiac morbidity (RR = 4.18, 95% CI = 1.89 to 9.24), and preterm birth (RR = 1.57, 95% CI = 1.29 to 1.92). Preterm birth was more likely in survivors treated with hematopoietic stem cell transplantation (allogenic: RR = 8.37, 95% CI = 4.83 to 14.48; autologous: RR = 3.72, 95% CI = 1.66 to 8.35).
Conclusions
Survivors of childhood or adolescent cancer are less likely to achieve a pregnancy and, once pregnant, are at higher risk for severe maternal morbidity and preterm birth.
Many adult survivors of childhood or adolescent cancer have concerns about their fertility and reproductive health and the health of their offspring (1-3). Unfortunately, most survivors are no longer engaged with the cancer system, and primary care providers are frequently unfamiliar with the risks faced by this population (4-6).
Female survivors of childhood or adolescent cancer treated with gonadotoxic therapies are at risk for ovarian insufficiency, making them less likely to conceive than noncancer comparison groups (7-9). Among survivors who maintain fertility, some studies have found an elevated risk for adverse obstetrical and perinatal outcomes (2,8,10). However, data are conflicting; most studies have relied on self-reported outcomes and are not population based, introducing bias (1,7,11,12).
We used population-based health-care administrative databases in Ontario, Canada, to determine the risk of adverse outcomes across the pregnancy course. We compared cancer survivors with women without prior cancer on the outcomes of achieved pregnancy, likelihood of carrying a pregnancy over 20 weeks of gestation, and pregnancy-related maternal and perinatal complications. We explored which demographic-, disease-, and treatment-related risk factors were related to adverse outcomes among survivors to identify women who might benefit from high-risk obstetrical care.
Methods
Study Design and Participants
This study was a retrospective matched-cohort study. Ontario healthcare is funded through a single-payer insurance program that covers medically necessary services. Administrative datasets capture health-care contacts on a population-wide basis, allowing for identification of all hospitalizations and physician encounters (Supplementary Table 1, available online). These datasets are held at ICES, an independent, nonprofit research institute whose legal status under Ontario’s health information privacy law allows it to collect and analyze health-care and demographic data, without consent, for health system evaluation and improvement. Ethics approval was obtained from the Hospital for Sick Children.
The survivor cohort comprised female survivors of childhood or adolescent cancer diagnosed in Ontario before age 21 years between 1985 and 2012. Eligible survivors were identified through 2 sources. The Pediatric Oncology Group of Ontario’s Networked Information System is a cancer registry that prospectively captures detailed demographic, disease, treatment, and outcome data for all children younger than 18 years treated in any of the 5 provincial pediatric cancer centers (13). We excluded patients who did not reach an attained age of 14 years during the follow-up period. Patients aged 15-21 years treated at adult centers were identified through the Initiative to Maximize Progress in Adolescent and Young Adult Cancer Therapy, a provincial adolescent cancer database that captured data for patients with 1 of 6 common cancers (leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, soft tissue sarcoma, bone sarcoma, or testicular cancer) diagnosed between 1992 and 2012 (14). Patients were followed from age 14 years and older, and 9 months and over, after completion of their cancer therapy until the earliest of relapse or progression, death, or the end of study follow-up (December 31, 2017). Death was considered a competing risk event.
The comparison cohort consisted of women without a history of cancer before age 21 years identified from the Registered Persons Database, a population-based registry containing demographic information for Ontario residents with valid health cards. Each survivor was matched to 5 individuals with no prior cancer diagnosis based on date of birth (±6 months) and postal code at the time of cancer diagnosis (hereafter referred to the index date for survivors and comparisons). Because postal code information is not available prior to April 1991, survivors diagnosed prior to that date were matched on data available as of April 1991.
Individuals were linked deterministically to health services databases using unique identifiers. Newborns were linked to their mothers through MOMBABY, a database that includes all inpatient admission records for mothers and their newborns as well as pregnancies that did not lead to livebirths.
Outcomes
We examined outcomes across the pregnancy course using validated algorithms (15,16). We examined recognized pregnancies (induced abortion, miscarriage, livebirth, stillbirth). Among individuals who had a pregnancy, we compared the risk of not carrying a pregnancy over 20 weeks of gestation. Finally, we assessed maternal outcomes among women who carried a pregnancy over 20 weeks of gestation and perinatal outcomes among women from 22 weeks of gestation up to and including 27 days after birth.
Adverse maternal outcomes included preeclampsia, gestational diabetes mellitus, cesarean birth, a composite of severe maternal morbidity (SMM), and a cardiac morbidity composite outcome. SMM is a validated measure that captures 42 severe in-pregnancy, delivery, or postpartum complications (Supplementary Table 2, available online) (16-18). Cardiac morbidity was defined as any of heart failure, arrhythmia, valvular disease, pericardial disease, coronary artery disease, or cardiac-related death (19-22). Perinatal outcomes included preterm birth (<37 weeks gestation), small for gestational age (SGA; birthweight <10th percentile), any congenital anomaly, and low 5-minute Apgar score (<7) (Supplementary Table 3, available online).
Potential Covariates
Demographic, disease, treatment, prepregnancy health conditions, gestational, and neonatal variables were examined for their potential associations with outcomes among survivors.
Disease and treatment variables included age at cancer diagnosis (0-4 years, 5-9 years, 10-14 years, 15-20 years), diagnosis period (1985-1990, 1991-1998, 1999-2005, 2006-2012), radiation involving the brain and/or abdomen or pelvis (yes or no), exposure or cumulative doses of alkylating agent (yes or no; 1-3999, 4000-7999, 8000+ mg/m2 or no), exposure to anthracycline chemotherapy (yes or no), and hematopoietic stem cell transplantation (HSCT; autologous, allogenic, or no). Prepregnancy health conditions were captured within the year preceding the estimated date of conception and included chronic hypertension, diabetes mellitus, and kidney disease (yes or no). Gestational variables included maternal age at delivery (14-20 years, 21-35 years, ≥36 years), multiple birth pregnancy (yes or no), gravidity (primigravid or multigravida), and parity (0, 1, ≥2). Perinatal variables included gestational age (<31 weeks, 32-36 weeks, 37-42 weeks) and birthweight (<2499 g, 2500-3499 g, ≥3500 g).
Statistical Analyses
We generated descriptive data using means and SD or medians and interquartile ranges. The proportions of survivors and comparisons who had each outcome were compared using χ2 tests. Cumulative incidence functions and Cox proportional hazard regression models were used to estimate the rate of a first recognized pregnancy in each group, adjusting for income quintile and rurality, and compared using a 2-sided Gray’s test. The assumption of proportionality was verified graphically. Robust sandwich variance estimation approaches accounted for the matched study design. Among women who achieved a recognized pregnancy, modified Poisson regression models with robust error variance were used to generate a relative risk (RR) of not carrying a pregnancy over 20 weeks of gestation, adjusting for income quintile and rurality.
Among those who carried a pregnancy over 20 weeks of gestation, relative risks were calculated for each complication. Comparisons of maternal and perinatal complications were adjusted for income quintile, rurality, maternal age, and multiple births. We used pregnancy-level analysis to compare obstetrical and perinatal complications; correlations among pregnancies in the same woman were addressed using a modified Poisson regression approach with robust variance estimation.
Among survivors, factors associated with each outcome were determined using similar modeling techniques. Inclusion of covariates in the multivariable models was based on examination of the univariate estimates (at P < .1 in univariate analyses) and with a priori inclusion of variables with previously established associations with complications (Supplementary Methods, available online). Specific variables varied by outcome examined. Statistical significance was defined as P < .05. Missing data were considered missing completely at random and handled by complete case analysis, which has shown to produce unbiased estimated regression parameters and conservative results (23,24). Sensitivity analyses excluding HSCT recipients were completed. Analyses were performed using SAS software (version 9.4; SAS Institute, Cary, NC). All statistical tests were 2-sided.
Results
Cohort Description
Of 5964 female children or adolescents diagnosed with cancer, 4062 survivors met the inclusion criteria and were successfully matched to 20 308 comparisons (Figure 1). Median (interquartile range) age among survivors was 11 years (4-15 years) at cancer diagnosis and 25 years (19-31 years) at follow-up. Missingness for all variables was less than 2%. Cohort characteristics are listed in Table 1 (and Supplementary Table 4, available online).
Figure 1.
Creation cohort, recognized pregnancies, and pregnancies resulting in a livebirth or stillbirth 20 weeks of gestation and over among cancer survivor and the comparisons. AYA = adolescent and young adult; IMPACT = Initiative to Maximize Progress in Adolescent and Young Adult Cancer Therapy; POGONIS = Pediatric Oncology Group of Ontario’s Networked Information System.
Table 1.
Characteristics of the cohort of children or adolescent cancer survivors and their matched counterparts without prior cancer
| Characteristic | Survivors | Comparisons | P a |
|---|---|---|---|
| (n = 4062) | (n = 20 308) | ||
| Age at indexb, No. (%), y | .98 | ||
| 0-4 | 1068 (26.3) | 5325 (26.2) | |
| 5-9 | 790 (19.5) | 3984 (19.6) | |
| 10-14 | 1031 (25.4) | 5106 (25.1) | |
| 15-20 | 1173 (28.9) | 5893 (29.0) | |
| Age at indexb, y | |||
| Median (IQR) | 11 (4, 15) | 11 (4, 15) | |
| Income quintile, No. (%) | <.001 | ||
| 1 (lowest) | 698 (17.2) | 4053 (20.0) | |
| 2 | 789 (19.4) | 3913 (19.3) | |
| 3 | 802 (19.7) | 4013 (19.8) | |
| 4 | 903 (22.2) | 4200 (20.7) | |
| 5 (highest) | 849 (20.9) | 3976 (19.6) | |
| Missing | 21 (0.5) | 153 (0.8) | |
| Rurality, No. (%) | .71 | ||
| Rural | 605 (14.9) | 2981 (14.7) | |
| Urban | 3451 (85.0) | 17 327 (85.3) | |
| Missing | ≤6c | 0 | |
| Died after index dateb, No. (%) | 464 (11.4) | 68 (0.3) | <.001 |
| Follow-up time from indexb, y | |||
| Median (IQR) | 16 (9, 22) | 17 (12, 23) | |
| Age at end of follow-up, y | |||
| Median (IQR) | 25 (19, 31) | 27 (22, 33) | |
| Childhood or adolescent cancer, No. (%) | |||
| Leukemia or lymphoma | 1929 (47.5) | — | |
| CNS tumor | 758 (18.7) | — | |
| Solid tumors or other | 1375 (33.9) | — | |
| HSCTd, No. (%) | |||
| Allogenic | 159 (4.1) | — | |
| Autologous | 165 (3.9) | — | |
| None | 3743 (92.2) | — | |
| Cranial radiation, No. (%)e | |||
| Yes | 546 (13.4) | — | |
| No | 3516 (86.6) | — | |
| Abdomen or pelvic radiation, No. (%)e | |||
| Yes | 427 (10.5) | — | |
| No | 3635 (89.5) | — | |
| Alkylating agent chemotherapy, No. (%) | |||
| 1-3999 mg/m2 | 660 (16.0) | — | |
| 4000-7999 mg/m2 | 328 (8.1) | — | |
| 8000+ mg/m2 | 631 (15.5) | — | |
| No | 2404 (59.2) | — | |
| Missing dose | 49 (1.2) | — | |
| Anthracycline chemotherapy, No. (%) | |||
| 250 mg/m2 | 1214 (29.9) | — | |
| 250 mg/m2 | 793 (19.5) | — | |
| No | 1986 (48.9) | — | |
| Missing dose | 69 (1.7) | — | |
| Relapse or progression (14 y old), No. (%) | |||
| Yes | 322 (7.9) | — | |
| No | 3,740 (92.1) | — | |
| Cancer diagnosis era, No. (%) | |||
| 1985-1990 | 579 (14.3) | — | |
| 1991-1998 | 1304 (32.1) | — | |
| 1999-2005 | 1213 (29.9) | — | |
| 2006-2012 | 966 (23.8) | — |
Determined by a 2-sided χ2 test. Not characteristics found among comparison cohort. CNS = central nervous system; HSCT = hematopoietic stem-cell transplantation; IQR = interquartile range.
Index date is the date of primary cancer diagnosis among survivors; comparisons are assigned the corresponding date of their matched counterparts.
Small cells suppressed due to institutional privacy regulations.
Individuals with both autologous and allogeneic HSCT captured n > 4062.
Patients.
Likelihood of Having a Recognized Pregnancy
Survivors were less likely than comparisons to achieve a recognized pregnancy (Figure 1). After adjustment, there was a 20% difference in recognized pregnancies between groups (hazard ratio [HR] = 0.80, 95% confidence interval [CI] = 0.75 to 0.86). By age 30 years, the cumulative incidence of having a recognized pregnancy was 22.3% (95% CI = 20.7% to 23.9%) among survivors compared with 26.6% (95% CI = 25.6% to 27.3%) among comparisons (Figure 2). Among those 30 years old and older, 14.1% survivors vs 16.3% comparisons had a recognized pregnancy as their first event.
Figure 2.
Cumulative probability of achieving first recognized pregnancy among survivors of childhood and adolescent cancers compared with matched comparisons. The 95% confidence interval is indicated around the cumulative incidence. All statistical tests are 2-sided.
In multivariable analysis, younger age at diagnosis (5-9 years: HR = 1.96, 95% CI = 1.53 to 2.51), brain tumor diagnosis (HR = 0.65, 95% CI = 0.50 to 0.85), urban residence (rural: HR = 1.24, 95% CI = 1.03 to 1.49), more recent diagnostic era (2006-2012: HR = 0.14, 95% CI = 0.10 to 0.20), HSCT (allogenic: HR = 0.44, 95% CI = 0.25 to 0.78; autologous: HR = 0.50, 95% CI = 0.25 to 1.01), alkylating agent chemotherapy (HR = 0.81, 95% CI = 0.68 to 0.97), and cranial radiation (HR = 0.66, 95% CI = 0.52 to 0.84) were statistically significantly associated with a decreased likelihood of having a pregnancy among survivors (Table 2).
Table 2.
Factors associated with a recognized pregnancy among 4062 survivors of childhood or adolescent cancera
| Covariate | Unadjusted HR (95% CI) | P b | Adjusted HR (95% CI) | P b |
|---|---|---|---|---|
| Age at cancer diagnosis, y | ||||
| 0-4 | 1.00 (ref.) | 1.00 (ref.) | ||
| 5-9 | 1.62 (1.27 to 2.06) | <.001 | 1.96 (1.53 to 2.51) | <.001 |
| 10-14 | 2.45 (1.96 to 3.07) | <.001 | 3.28 (2.61 to 4.12) | <.001 |
| 15-21 | 4.70 (3.83 to 5.77) | <.001 | 6.17 (4.98 to 7.66) | <.001 |
| Income quintile | ||||
| 1 | 1.51 (1.21 to 1.89) | <.001 | 1.75 (1.40 to 2.18) | <.001 |
| 2 | 1.03 (0.81 to 1.30) | .81 | 1.00 (0.79 to 1.27) | .97 |
| 3 | 1.14 (0.91 to 1.43) | .26 | 1.16 (0.92 to 1.46) | .20 |
| 4 | 1.00 (0.80 to 1.27) | .94 | 1.03 (0.82 to 1.29) | .82 |
| 5 | 1.00 (ref.) | 1.00 (ref.) | ||
| Rurality | ||||
| Rural | 1.24 (1.03 to 1.49) | .03 | 1.24 (1.03 to 1.49) | .03 |
| Urban | 1.00 (ref.) | — | ||
| Diagnosis era | ||||
| 1985-1990 | 1.00 (ref.) | 1.00 (ref.) | ||
| 1991-1998 | 0.83 (0.70 to 0.98) | .03 | 0.61 (0.51 to 0.73) | <.001 |
| 1999-2005 | 0.39 (0.32 to 0.49) | <.001 | 0.26 (0.21 to 0.32) | <.001 |
| 2006-2012 | 0.28 (0.20 to 0.39) | <.001 | 0.14 (0.10 to 0.20) | <.001 |
| Cancer diagnosis | ||||
| CNS tumor | 0.58 (0.47 to 0.72) | <.001 | 0.65 (0.50 to 0.85) | .001 |
| Solid tumor or other | 0.76 (0.65 to 0.90) | .001 | 0.88 (0.73 to 1.06) | .18 |
| Leukemia or lymphoma | 1.00 (ref.) | 1.00 (ref.) | ||
| Alkylating agent chemotherapy | ||||
| Yes | 0.91 (0.78 to 1.05) | .19 | 0.81 (0.68 to 0.97) | .02 |
| No | 1.00 (ref.) | 1.00 (ref.) | — | |
| Alkylating agent cumulative dose, mg/m2 | ||||
| 1-3999 | 0.82 (0.67 to 1.01) | .06 | — | |
| 4000-7999 | 1.12 (0.86 to 1.44) | .41 | — | |
| 8000+ | 0.90 (0.72 to 1.12) | .34 | — | |
| None | 1.00 (ref.) | — | ||
| Anthracycline chemotherapy | ||||
| Yes | 1.25 (1.08 to 1.44) | .003 | 0.91 to 1.35 | .30 |
| No | 1.00 (ref.) | 1.00 (ref.) | ||
| HSCT | ||||
| Allogenic only | 0.54 (0.31 to 0.93) | .03 | 0.44 (0.25 to 0.78) | .004 |
| Autologous only | 0.43 (0.22 to 0.86) | .02 | 0.50 (0.25 to 1.01) | .05 |
| None | 1.00 (ref.) | 1.00 (ref.) | ||
| Abdomen or pelvic radiation | ||||
| Yes | 1.09 (0.86 to 1.38) | .50 | 0.98 (0.76 to 1.26) | .87 |
| No | 1.00 (ref.) | 1.00 (ref.) | ||
| Cranial radiation | ||||
| Yes | 0.78 (0.62 to 0.97) | .03 | 0.66 (0.52 to 0.84) | .001 |
| No | 1.00 (ref.) | 1.00 (ref.) |
Income quintile, rurality, alkylating agent chemotherapy, and abdomen or pelvic radiation were included in the model a priori regardless of univariate statistical significance. Accounts for clustering due to matching (using the sandwich variance estimator). Alkylating agent cumulative dose was not included in adjusted model due to P > .1 in unadjusted analyses. CI = confidence interval; CNS = central nervous system; HR = hazard ratio; HSCT = hematopoietic stem-cell transplantation; ref. = referent
Determined by a 2-sided χ2 test.
Likelihood of Carrying a Pregnancy Over 20 Weeks
Among women who had a recognized pregnancy, there was no statistically significant increase in the risk of not carrying the pregnancy over 20 weeks of gestation in survivors compared with comparisons (adjusted RR [aRR] = 1.01, 95% CI = 0.98 to 1.04; Supplementary Table 5, available online). Among survivors, a solid tumor, low-income quintile, and urban residence increased the risk; cancer treatment–related covariates were not statistically significantly associated (Supplementary Table 6, available online).
Obstetrical Complications
Absolute risks are presented in Table 3. Survivors were at a statistically significantly increased risk for SMM (aRR = 2.31, 95% CI = 1.59 to 3.37) and cardiac morbidity (RR = 4.18, 95% CI = 1.89 to 9.24). Of the 87 survivor pregnancies complicated by SMM, 21 (24.1%) had a postpartum hemorrhage requiring blood transfusion, 25 (28.7%) developed a cardiac condition, 9 (10.3%) had puerperal sepsis, and 24 (27.6%) required an Intensive Care Unit (ICU) admission. There were no statistically significant differences between groups in the risk for preeclampsia (aRR = 1.11, 95% CI = 0.75 to 1.63), cesarean section (aRR = 1.05, 95% CI = 0.93 to 1.19), or gestational diabetes (RR = 0.87, 95% CI = 0.31 to 2.46). Among survivors, allogenic HSCT and older age at diagnosis were statistically significantly associated with the risk of SMM (Table 4).
Table 3.
Maternal characteristics and outcomes among survivors of childhood or adolescent cancer and women in cancer-free cohort
| Category | Survivors |
Comparisons |
P c Pregnancy | ||
|---|---|---|---|---|---|
| Pregnancy levela | Individual levelb | Pregnancy levela | Individual levelb | ||
| No. with recognized pregnancy | 1731 | 816 | 11 772 | 5277 | |
| No. with pregnancy ≥20 wk | 1358 | 789 | 9118 | 5156 | |
| Type of recognized pregnancy, No. (%)d | |||||
| Induced abortion | 218 (12.6) | 183 (22.4) | 1554 (13.2) | 1269 (20.8) | .49 |
| Miscarriage | 155 (9.0) | 136 (16.7) | 1100 (9.3) | 954 (18.1) | .60 |
| Stillbirth | 11 (0.6) | 11 (1.4) | 51 (0.4) | 51 (1.0) | .31 |
| Livebirth | 1347 (77.8) | 784 (96.1) | 9067 (77.0) | 5150 (97.6) | .01 |
| No. of recognized pregnancies, No. (%) | |||||
| 1 | — | 281 (34.4) | — | 1603 (30.4) | |
| 2 | — | 295 (36.1) | — | 1965 (37.2) | .13 |
| 3 | — | 151 (18.5) | — | 1015 (19.2) | |
| 4 | — | 56 (6.9) | — | 424 (8.0) | |
| ≥5 | — | 33 (4.0) | — | 270 (5.1) | |
| Maternal age at delivery (20 wk), No. (%) | .77 | ||||
| 14-20 y | 135 (9.9) | — | 871 (9.6) | — | |
| 21-35 y | 1143 (84.2) | — | 7742 (84.9) | — | |
| ≥ 36 y | 80 (5.9) | — | 507 (5.6) | — | |
| Maternal age, y | |||||
| Median (IQR) | 28 (24, 31) | — | 28 (24, 31) | — | |
| Pregnancy era (20 wk), No. (%) | .22 | ||||
| 1988-1995 | 31 (2.3) | — | 168 (1.8) | — | |
| 1996-2003 | 183 (13.5) | — | 1246 (13.7) | — | |
| 2004-2010 | 488 (35.9) | — | 3108 (34.1) | — | |
| 2011-2017 | 656 (48.3) | — | 4596 (50.4) | — | |
| Delivery gestational age, No. (%) | <.001 | ||||
| 31 wk | 28 (2.0) | — | 106 (1.2) | — | |
| 32-36 w | 105 (7.7) | — | 510 (5.6) | — | |
| 37-42 wk | 1072 (78.9) | — | 7519 (82.5) | — | |
| Missing | 153 (11.3) | — | 983 (10.8) | — | |
| Delivery gestational age, No. (%) | |||||
| Median (IQR) | 38 (38, 40) | — | 39 (38, 40) | — | |
| Gravidity, No. (%) | .18 | ||||
| Primigravid | 588 (43.3) | — | 4127 (45.3) | — | |
| Multigravida | 770 (56.7) | — | 4991 (54.7) | — | |
| Parity, No. (%) | <.001 | ||||
| 0 | 776 (57.1) | — | 4749 (52.1) | — | |
| 1 | 428 (31.5) | — | 2999 (32.9) | — | |
| ≥2 | 154 (11.3) | — | 1354 (14.9) | — | |
| Missing | – | — | 16 (0.2) | — | |
| Multiple birth pregnancy, No. (%) | 16 (1.2) | — | 151 (1.7) | — | .36 |
| Preexisting health conditions, No. (%) | <.001 | ||||
| Kidney disease | 32 (3.9) | — | 41 (0.8) | — | |
| Chronic hypertension | 71 (8.7) | — | 206 (3.9) | — | |
| Diabetes | 41 (5.0) | — | 158 (3.0) | — | |
| Newborn birth weight, No. (%) | .006 | ||||
| 2499 | 107 (7.9) | — | 513 (5.6) | — | |
| 2500-3499 | 668 (49.2) | — | 4613 (50.6) | — | |
| ≥3500 | 557 (41.0) | — | 3869 (42.4) | — | |
| Missing | 26 (1.9) | — | 123 (1.4) | — | |
| Newborn birth weight, g | |||||
| Median (IQR range) | 3317 (2986-3720) | — | 3364 (3056-3734) | — | |
| Obstetrical complication, No. (%) | |||||
| Preeclampsia | 30 (2.2) | 30 (3.8) | 193 (2.1) | 175 (3.4) | .83 |
| Gestational diabetes | ≤6e | ≤6e | 31 (0.3) | 30 (0.6) | .79 |
| Cesarean delivery | 355(26.1) | 262 (33.2) | 2,273 (24.9) | 1,532 (29.7) | .34 |
| SMM | 87 (6.4) | 50 (6.3) | 248 (2.7) | 156 (3.0) | <.001 |
| Cardiac morbidity | 20 (1.5) | 13 (1.7) | 33 (0.4) | 17 (0.3) | <.001 |
| Perinatal complication, No. (%) | |||||
| Preterm | 128 (9.4) | — | 574 (6.3) | — | <. 001 |
| Congenital anomalies | 64 (4.7) | — | 374 (4.1) | — | .29 |
| SGA (10th percentile)f | 36 (6.0) | — | 315 (7.9) | — | .11 |
| Low Apgar score (<7)f | 16 (2.7) | — | 69 (1.7) | — | .11 |
Accounts for each pregnancy (ie, >2 pregnancies may be accounted for the same woman). No results found at the specific level. IQR = interquartile range; SGA = small for gestational age; SMM = severe maternal morbidity.
Accounts for at least 1 type of recognized pregnancy or obstetrical complication for a woman over the follow-up period.
Determined by a 2-sided χ2 test.
Does not add to Nindividual. If individual had a type of recognized pregnancy at any point during the follow-up period, they were counted in each category.
Small cells suppressed due to institutional privacy regulations.
Only available between 2006 and 2012 due to data availability (survivors: n = 599; comparisons n = 4000).
Table 4.
Multivariable model describing factors associated with obstetrical complications among survivors of childhood or adolescent cancera
| Covariate | Preeclampsia |
Severe maternal morbidity |
Cesarean section |
|||
|---|---|---|---|---|---|---|
| Adjusted RR (95% CI) | P b | Adjusted RR (95% CI) | P b | Adjusted RR (95% CI) | P b | |
| Age at cancer diagnosis, y | ||||||
| 0-4 | — | 1.00 (ref.) | 1.00 (ref.) | |||
| 5-9 | — | 1.20 (0.54 to 2.69) | .66 | 0.62 (0.41 to 0.94) | .02 | |
| 10-14 | — | 0.85 (0.33 to 2.19) | .73 | 0.68 (0.48 to 0.97) | .03 | |
| 15-20 | — | 0.39 (0.16 to 0.94) | .04 | 0.60 (0.42 to 0.86) | .006 | |
| Income quintile | ||||||
| 1 (lowest) | 2.80 (0.75 to 10.44) | .13 | 0.62 (0.25 to 1.57) | .31 | 1.22 (0.84 to 1.77) | .31 |
| 2 | 1.37 (0.32 to 5.92) | .67 | 0.96 (0.38 to 2.46) | .93 | 1.28 (0.87 to 1.89) | .21 |
| 3 | 2.20 (0.59 to 8.23) | .24 | 0.41 (0.15 to 1.16) | .09 | 1.45 (1.02 to 2.06) | .04 |
| 4 | 1.40 (0.33 to 5.90) | .65 | 0.51 (0.21 to 1.22) | .13 | 1.00 (0.67 to 1.50) | .99 |
| 5 (highest) | 1.00 (ref.) | 1.00 (ref.) | 1.00 (ref.) | — | ||
| Rurality | ||||||
| Rural | 1.12 (0.44 to 2.86) | .82 | 0.70 (0.28 to 1.72) | .42 | 0.87 (0.63 to 1.21) | .41 |
| Urban | 1.00 (ref.) | 1.00 (ref.) | 1.00 (ref.) | |||
| Diagnosis era | ||||||
| 1985-1990 | — | — | 1.00 (ref.) | |||
| 1991-1998 | — | — | 0.98 (0.73 to 1.32) | .91 | ||
| 1999-2005 | — | — | 1.50 (1.04 to 2.15) | .03 | ||
| 2006-2012 | — | — | 0.67 (0.30 to 1.51) | .33 | ||
| Cancer diagnosis | ||||||
| Brain tumor | 0.66 (0.12 to 3.75) | .64 | 1.80 (0.53 to 6.09) | .35 | 0.95 (0.61 to 1.48) | .83 |
| Solid tumor or other | 1.80 (0.73 to 4.43) | .20 | 1.07 (0.54 to 2.12) | .84 | 1.11 (0.82 to 1.52) | .50 |
| Leukemia or lymphoma | 1.00 (ref.) | 1.00 (ref.) | 1.00 (ref.) | — | ||
| Alkylating agent chemotherapy | ||||||
| Yes | 1.18 (0.55 to 2.53) | .67 | 1.31 (0.64 to 2.70) | .46 | 0.76 (0.57 to 1.00) | .05 |
| No | 1.00 (ref.) | 1.00 (ref.) | 1.00 (ref.) | |||
| Anthracycline chemotherapy | ||||||
| Yes | 1.11 (0.47 to 2.64) | .82 | 1.61 (0.72 to 3.64) | .25 | 1.26 (0.92 to 1.73) | .15 |
| No | 1.00 (ref.) | 1.00 (ref.) | 1.00 (ref.) | |||
| HSCT | ||||||
| Allogenic | 2.15 (0.44 to 11.82) | .37 | 3.81 (1.33 to 10.93) | .01 | — | |
| Autologous | 1.06 (0.19 to 5.79) | .95 | 1.70 (0.44 to 6.65) | .44 | — | |
| No | 1.00 (ref.) | 1.00 (ref.) | — | |||
| Abdomen or pelvic radiation | ||||||
| Yes | 1.32 (0.55 to 2.54) | .61 | 0.62 (0.24 to 1.64) | .33 | 1.30 (0.93 to 1.82) | .12 |
| No | 1.00 (ref.) | 1.00 (ref.) | 1.00 (ref.) | |||
| Cranial radiation | ||||||
| Yes | 2.06 (0.65 to 6.53) | .22 | 0.50 (0.17 to 1.49) | .21 | 1.38 (0.96 to 1.99) | .08 |
| No | 1.00 (ref.) | 1.00 (ref.) | 1.00 (ref.) | |||
| Preexisting hypertension | ||||||
| Yes | 4.79 (2.09 to 11.02) | <.001 | 1.46 (0.84 to 6.39) | .11 | 1.28 (0.92 to 1.79) | .15 |
| No | 1.00 (ref.) | 1.00 (ref.) | 1.00 (ref.) | |||
| Preexisting kidney disease | ||||||
| Yes | — | 2.31 (0.70 to 3.07) | .32 | — | ||
| No | — | 1.00 (ref.) | — | |||
| Maternal age, y | ||||||
| 14-20 | — | — | 1.00 (ref.) | |||
| 21-34 | — | — | 2.06 (1.34 to 3.16) | .001 | ||
| ≥ 35 | — | — | 2.89 (1.68 to 4.98) | <.001 | ||
| Multi-birth pregnancy | ||||||
| Yes | — | — | 2.03 (1.40 to 2.95) | <.001 | ||
| No | — | — | 1.00 (ref.) | |||
Income quintile, rurality, primary cancer diagnosis, alkylating agent and anthracycline chemotherapy, and abdomen/pelvic and cranial radiation were included in the model a priori regardless of univariate statistical significance. Accounts for clustering due to matching (using the sandwich variance estimator). Covariates that were not statistically significant in univariate analysis (P < .1) or were not included a priori in the adjusted analyses. CI = confidence interval; ref. = referent; RR = relative risk.
Determined by a 2-sided χ2 test.
Perinatal Complications
Risk for preterm births differed statistically significantly between the groups (9.4% vs 6.3%; aRR = 1.57, 95% CI = 1.29 to 1.92; Supplementary Table 5, available online). Alkylating agent exposure (aRR = 0.57, 95% CI = 0.37 to 0.89) and HSCT (allogenic: aRR = 8.37, 95% CI = 4.83 to 14.48; autologous: aRR = 3.72, 95% CI = 1.66 to 8.35) were statistically significantly associated with risk for preterm birth (Table 5). No statistically significant difference was found for congenital anomalies (4.7% vs 4.1%; aRR = 1.19, 95% CI = 0.91 to 1.56), SGA (6.0% vs 7.9%; aRR = 0.72, 95% CI = 0.51 to 1.03), or low Apgar score (2.7% vs 1.7%; aRR = 1.58, 95% CI = 0.87 to 2.87). Among survivors, preexisting kidney disease was statistically significantly associated with risk for a low Apgar score, and a solid tumor diagnosis increased the risk of SGA (Table 5).
Table 5.
Multivariable model describing factors associated with perinatal complications among survivors of childhood or adolescent cancer
| Covariate | Preterm birth <37 wk gestation |
SGA<10th percentile |
Low Apgar score <7 |
SGA <10th percentile |
||||
|---|---|---|---|---|---|---|---|---|
| Adjusted RR (95% CI) | P a | Adjusted RR (95% CI) | P a | Adjusted RR (95% CI) | P a | Adjusted RR (95% CI) | P a | |
| Income quintile | ||||||||
| 1 (lowest) | 1.50 (0.67 to 3.35) | .33 | 1.10 (0.60 to 2.03) | .75 | 1.78 (0.37 to 8.62) | .48 | 0.60 (0.15 to 2.39) | .46 |
| 2 | 0.99 (0.41 to 2.39) | .98 | 0.97 (0.52 to 1.84) | .93 | 0.52 (0.05 to 5.40) | .58 | 2.11 (0.71 to 6.30) | .18 |
| 3 | 0.87 (0.35 to 2.17) | .77 | 1.02 (0.53 to 1.95) | .95 | 1.22 (0.23 to 6.35) | .81 | 1.10 (0.33 to 3.62) | .88 |
| 4 | 1.56 (0.70 to 3.45) | .28 | 1.25 (0.66 to 2.35) | .50 | 2.66 (0.50 to 14.32) | .25 | 1.45 (0.51 to 4.15) | .49 |
| 5 (highest) | 1.00 (ref.) | 1.00 (ref.) | — | 1.00 (ref.) | — | 1.00 (ref.) | — | |
| Rurality | ||||||||
| Rural | 0.49 (0.22 to 1.10) | .08 | 0.75 (0.43 to 1.30) | .31 | 1.76 (0.56 to 5.49) | .33 | 1.16 (0.47 to 2.90) | .75 |
| Urban | 1.00 (ref.) | 1.00 (ref.) | — | 1.00 (ref.) | — | 1.00 (ref.) | — | |
| Cancer diagnosis | ||||||||
| CNS tumor | 0.56 (0.20 to 1.58) | .27 | 0.64 (0.32 to 1.31) | .22 | 0.70 (0.13 to 3.97) | .69 | 2.27 (0.75 to 6.82) | .15 |
| Solid tumor/other | 1.14 (0.61 to 2.15) | .68 | 0.88 (0.55 to 1.41) | .58 | 2.25 (0.74 to 6.82) | .15 | 3.06 (1.38 to 6.76) | .01 |
| Leukemia/lymphoma | 1.00 (ref.) | 1.00 (ref.) | — | 1.00 (ref.) | — | 1.00 (ref.) | — | |
| Alkylating agent chemotherapy | ||||||||
| Yes | 1.43 (0.79 to 2.57) | .24 | 0.57 (0.37 to 0.89) | .01 | 0.87 (0.23 to 3.35) | .84 | 1.71 (0.82 to 3.58) | .16 |
| No | 1.00 (ref.) | 1.00 (ref.) | — | 1.00 (ref.) | 1.00 (ref.) | |||
| Anthracycline chemotherapy | ||||||||
| Yes | 0.82 (0.42 to 1.59) | .55 | 0.99 (0.62 to 1.56) | .95 | 1.46 (0.28 to 7.72) | .65 | 1.00 (0.46 to 2.18) | .75 |
| No | 1.00 (ref.) | 1.00 (ref.) | — | 1.00 (ref.) | 1.00 (ref.) | |||
| HSCT | — | — | — | — | ||||
| Allogenic | 0.83 (0.18 to 3.90) | .81 | 8.37 (4.83 to 14.48) | <.001 | ||||
| Autologous | 1.56 (0.47 to 5.16) | .47 | 3.72 (1.66 to 8.35) | .002 | ||||
| No | 1.00 (ref.) | 1.00 (ref.) | ||||||
| Abdomen or pelvic radiation | ||||||||
| Yes | 0.66 (0.27 to 1.62) | .36 | 1.13 (0.69 to 1.88) | .63 | 0.51 (0.06 to 4.02) | .52 | 0.69 (0.18 to 2.60) | .58 |
| No | 1.00 (ref.) | 1.00 (ref.) | — | 1.00 (ref.) | 1.00 (ref.) | |||
| Preexisting diabetes | ||||||||
| Yes | — | — | 1.81 (0.93 to 3.51) | .08 | — | — | — | — |
| No | 1.00 (ref.) | — | ||||||
| Preexisting kidney disease | ||||||||
| Yes | — | — | — | — | 6.66 (2.15 to 20.63) | .001 | — | — |
| No | 1.00 (ref.) | |||||||
| Preexisting hypertension | ||||||||
| Yes | 1.70 (0.84 to 3.44) | .14 | — | — | — | — | 2.12 (0.80 to 5.64) | .13 |
| No | 1.00 (ref.) | 1.00 (ref.) | ||||||
Income quintile, rurality, primary cancer diagnosis, alkylating agent and anthracycline chemotherapy, and abdomen or pelvic radiation were included in the model a priori regardless of univariate statistical significance. Accounts for clustering due to matching (using the sandwich variance estimator). Covariates that were not statistically significant in univariate analysis (P < .1) or were not included a priori in the adjusted analyses. CI = confidence interval; HSCT = hematopoietic stem cell transplantation; ref. = referent; RR = relative risk; SGA = small for gestational age.
Determined by a 2-sided χ2 test.
Sensitivity Analyses
No differences were found when HSCT survivors were removed (Supplementary Tables 7 and 8, available online).
Discussion
In this population-based cohort that included over 4000 female survivors of childhood and adolescent cancer, survivors were 20% less likely than women without a history of cancer to have a recognized pregnancy. Once pregnant, survivors were as likely to carry the pregnancy longer than 20 weeks of gestation and to have a live birth. However, they were at an elevated risk for SMM and cardiac morbidity, and their offspring were at elevated risk for preterm birth.
Our findings are consistent with previous literature that reported a decreased rate of pregnancies among childhood or adolescent cancer survivors compared with the general population (3,12,25). Fewer pregnancies may be attributed to several factors, including sub- or infertility because of treatment and the psychosocial impacts of having had cancer. Radiation therapy that affects the ovaries or the hypothalamic-pituitary axis and higher doses of alkylating agents have been shown to decrease fertility (26,27). In our cohort, women who had undergone an HSCT (which frequently includes alkylating agents and/or total body irradiation for conditioning) or had been treated with cranial radiation were statistically significantly less likely to have a recognized pregnancy. Studies have found that childhood cancer survivors are less likely to marry or have a life partner, which may affect their likelihood of having children. North American and European studies have shown that 37%-47% of survivors are life-partnered compared with approximately 60% of the general population (28-30). The choice to have children can be further influenced by factors including concerns of a shorter life expectancy and fear of passing cancer to their offspring (31,32).
SMM has been established as an important risk factor for maternal death (16,33,34). In our study, survivors were twice as likely as comparisons to develop a serious morbidity. Survivors treated with an allogenic HSCT were at greatest risk for SMM. Approximately 4% of survivors who carried a pregnancy over 20 weeks had a history of HSCT. Of these, 16% had a SMM event in contrast to 6% of survivors who had not had an HSCT. In the general population, women who become pregnant at an advanced maternal age (>40 years) and those with preexisting health conditions (eg, diabetes, cardiovascular disease) or multiple gestation are at an increased risk for pregnancy and perinatal complications (34-38). A large US population-based study found that 4.6% of women older than 40 years and 6.9% of women with a preexisting health condition had an SMM event (35). Prior publications have recommended that these women be referred for more intensive obstetrical and neonatal monitoring (34,35). Our findings indicate that the risk of SMM is even higher among survivors of childhood or adolescent cancer—these survivors may benefit from referral to appropriate obstetrical care.
We found no increase in risk for preeclampsia, cesarean delivery, or gestational diabetes. Although some studies have reported an elevated risk for preeclampsia (2,10,25,39), others have mirrored our findings (40,41). Importantly, survivors in our cohort with preexisting hypertension were almost 5 times as likely as normotensive survivors to develop preeclampsia. A previous US cohort study showed that survivors had a 2.6-fold (95% CI = 1.6 to 4.7) higher prevalence of hypertension compared with individuals in the general population, that 1 in 12 survivors had undiagnosed hypertensive blood pressure, and more than 20% of those previously diagnosed with hypertension had persistent uncontrolled high blood pressure, demonstrating the importance of monitoring blood pressure in survivors of childbearing age (42). In contrast to our study, Scandinavian and Australian population-based cohort studies have reported a small but statistically significant increased risk of cesarean delivery among childhood and adolescent survivors (2,9,10,43). In the last few decades, cesarean deliveries have increased dramatically worldwide (44); the rates of cesarean deliveries among the general population in Canada are particularly high, possibly leading to an absence of observable differences between survivors and comparisons (44).
Preterm birth is an established risk factor for neonatal morbidity and mortality. In our study, 9.4% of infants of survivors were delivered prematurely, a rate 50% higher than in the comparison cohort. Survivors with a history of allogenic HSCT had an eightfold increased risk of preterm birth, whereas those with a history of autologous HSCT had an almost fourfold increased risk. Alkylating agent chemotherapy was statistically significantly associated with a decreased risk for preterm birth. This is inconsistent with prior literature that has shown that chemotherapy either increases the risk for preterm delivery or has no impact (7,11,41,45). Unless shown in other studies, we believe this to be a spurious finding. We did not observe that abdomen/pelvic radiation was a risk for preterm birth, in contrast to prior studies (2,11,39,45) that have posited that radiation can impair pelvic and uterine growth, leading to constraint of uterine volume or compromised vascular supply to the fetus therefore leading to preterm birth (1,10-12,43,45,46). However, only 88 of 427 survivors (20.6%) who had pelvic radiation had a pregnancy, so this analysis may be underpowered. Encouragingly, we observed no increased risk for congenital anomalies, low Apgar score, or SGA. SGA and low Apgar were previously found to be elevated in survivors in other studies; however, in recent studies, there was no evidence of an increased risk for congenital anomalies in the offspring of childhood cancer survivors (1,7,8,11,12).
Our study has several strengths. Through administrative data, we had access to detailed and complete demographic, diagnostic, and treatment factors for a large population-based cohort of survivors. This mitigates biases associated with self-reported data or the use of cohorts not representative of the general population. There was low missingness in the data, so excluding the small proportions of records to conduct a complete case analysis had minimal impact on the results. However, our study had several limitations. We could not measure fertility because we did not have data regarding which survivors were attempting to conceive. We were also unable to capture spontaneous abortions for which a doctor was not seen, nor did we capture homebirths and/or midwife births. However, this is not likely to have affected the overall results because approximately 3% of Ontario women give birth outside of a hospital (47). Prior research has shown that home birth is not associated with an increased risk for an adverse outcome (stillbirth, low Apgar score, or resuscitation) compared with hospital births (48). Despite a long period of follow-up, the average age of our cohort at the end of study was still relatively young. Existing literature is inconsistent as to whether survivors become pregnant later than the general population. A Swedish study found that survivors were younger at their first live birth than population comparisons (mean age = 27.6 years vs 32.1 years) (9). However, a Finnish study found maternal age statistically significantly higher among survivors than among siblings (mean age = 29.7 years vs 27.6 years) (40).
Although survivors in our cohort were less likely than women without a cancer history to become pregnant, they were equally likely to carry a pregnancy over 20 weeks of gestation once pregnancy occurred. Although there were no differences between cohorts for several obstetrical complications, survivors were at elevated risk for SMM and cardiac morbidity, and their infants were more likely to be born prematurely. Previous studies, including a large meta-analysis in young women with breast cancer, have raised similar concerns regarding the lower likelihood of pregnancy as well as higher risk of maternal complications in cancer survivors (49). Current guidelines, including recently published guidelines from the European Society of Human Reproduction and Embryology (50), have primarily focused on fertility preservation options and less so on pregnancy management or complications. Further, they are limited in their provision of age-specific information and counseling for adolescents or young adults. Guidelines should be updated to address this vulnerable age group and provide recommendations across the reproductive journey. Our findings can inform the counseling of children and their parents at the time of cancer diagnosis and guide at-risk survivors to the appropriate endocrine, obstetrical, or reproductive counseling. Considering that most adult survivors of childhood or adolescent cancer do not attend specialized survivorship clinics, it is essential that primary care providers are aware of these risks and ensure that at-risk survivors, particularly those who have undergone an HSCT, receive appropriate obstetrical, perinatal, and neonatal care.
Funding
This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health (MOH) and the Ministry of Long-Term Care (MLTC). This study also received funding from a Canadian Institutes of Health Research (CIHR) Foundation Grant (CIHR, 388395) (PI: P. Nathan) and the SickKids Research Training Competition (Restracomp) Scholarship (A. Zgardau). This research study was conducted with the further support from the C17(partially funded by Childhood Cancer Canada Institutes of Health Research (CIHR, 133618)), a Young Investigator Award from Alex’s Lemonade Stand, and a CIHR Foundation Grant (CIHR 148470) awarded to Dr Nancy Baxter.
Notes
Role of the funder: The funders had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication.
Disclosures: The authors have no conflicts of interest to report.
Author contributions: AZ: Conceptualization; Methodology; Data analysis; Writing—review and editing. JGR: Conceptualization; Methodology; Writing—re- view and editing. NNB: Funding acquisition; Methodology; Writing—review and editing. CN: Data curation; Writing—review and editing. ALP: Methodology; Writing—review and editing. SG: Conceptualization; Methodology; Writing—review and editing. PN: Conceptualization; Funding acquisition; Methodology; Supervision; Writing—review and editing.
Acknowledgements: Parts of this material are based on data and information compiled and provided by Ontario Health (OH), Ontario’s Ministry of Health and Long-Term Care (MOHTLC), and Canadian Institute for Health Information (CIHI). This study is based in part on data provided by Better Outcomes Registry and Network (BORN), part of the Children's Hospital of Eastern Ontario. The interpretation and conclusions contained herein do not necessarily represent those of BORN Ontario. This research was facilitated by Pediatric Oncology Group of Ontario Networked Information System, financially supported by Ontario’s Ministry of Health and Long-Term Care. Lastly, parts of this report are based on Ontario Registrar General (ORG) information on deaths, the original source of which is ServiceOntario.
Disclaimers: The analyses, conclusions, opinions, and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred. The opinions, analyses, results, views, interpretations, and conclusions expressed herein are those of the author and do not necessarily reflect those of ICES, Better Outcomes Registry and Network (BORN) Ontario, Ontario Health (OH), Ministry of Health and Long-Term Care (MOHLTC), Canadian Institute for Health Information (CIHI), Ontario Registrar General (ORG) or the Ministry of Government and Consumer Services.
Prior presentations: Pediatric Oncology Group of Ontario Symposium, Toronto, Ontario (November 2019). Canadian Cancer Research Conference, Ottawa, Ontario (November 2019). American Society of Clinical Oncology Annual Meeting (May 2020). International Society of Paediatric Oncology (SIOP) (October 2020).
Data Availability
The dataset from this study is held securely in coded form at ICES. Legal data sharing agreements between ICES and data providers (eg, health-care organizations and government) prohibit ICES from making the dataset publicly available. The full dataset creation plan and underlying analytic code are available from the authors upon request, understanding that the computer programs may rely upon coding templates or macros that are unique to ICES and are therefore either inaccessible or may require modification.
Supplementary Material
Contributor Information
Alina Zgardau, The Hospital for Sick Children, Division of Haematology/Oncology, Toronto, ON, Canada.
Joel G Ray, ICES, Toronto, ON, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada; Department of Obstetrics and Gynaecology, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada.
Nancy N Baxter, ICES, Toronto, ON, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada; Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada; Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.
Chenthila Nagamuthu, ICES, Toronto, ON, Canada.
Alison L Park, ICES, Toronto, ON, Canada.
Sumit Gupta, The Hospital for Sick Children, Division of Haematology/Oncology, Toronto, ON, Canada; ICES, Toronto, ON, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
Paul C Nathan, The Hospital for Sick Children, Division of Haematology/Oncology, Toronto, ON, Canada; ICES, Toronto, ON, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The dataset from this study is held securely in coded form at ICES. Legal data sharing agreements between ICES and data providers (eg, health-care organizations and government) prohibit ICES from making the dataset publicly available. The full dataset creation plan and underlying analytic code are available from the authors upon request, understanding that the computer programs may rely upon coding templates or macros that are unique to ICES and are therefore either inaccessible or may require modification.