Subsequent Cancer Risk of Women Receiving Hysterosalpingography: A Nationwide
Population-Based Retrospective Cohort Study
YEN-HSIU LIAO, MD
Department of Radiology, China Medical University Hospital; and School of Medicine, College
of Medicine, China Medical University, Taichung, Taiwan
CHENG-LI LIN, MSc
Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
PO-PANG TSAI, MD
Department of Radiology, China Medical University Hospital; and School of Medicine, College
of Medicine, China Medical University, Taichung, Taiwan
WU-CHUNG SHEN, MD
Department of Radiology, China Medical University Hospital; and Department of Biomedical Imaging and Radiological Science, College of Health Care, China Medical University,
Taichung, Taiwan
FUNG-CHANG SUNG, PhD, MPH
Management Office for Health Data, China Medical University Hospital; and Graduate Institute of Clinical Medical Science, School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
CHIA-HUNG KAO, MD
Graduate Institute of Clinical Medical Science, School of Medicine, College of Medicine, China Medical University; and Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan
INTRODUCTION
Among modern medical technologies, the use of radiation has become indispensable.
By using radiation to facilitate physicians’ understanding of human diseases, the need for other high-risk invasive examinations can be eliminated.
With the advancement of radiology, various X-ray devices have been developed for radiologists to provide accurate diagnoses. The frequency of
employing radiography is increasing (Shih et al. 2014). Long-term risks of performing X-ray procedures, such as dental X-rays, on patients for medical
diagnosis have raised significant concerns and increased the subsequent risks
of developing tumors (Claus et al. 2012; Huang et al. 2014; Lin et al.
2013).
Hysterosalpingography (HSG) is the first-line radiological examination for women undergoing an infertility investigation. In addition to possible infection and iatrogenic traumatic injury, another critical complication is the
effect of radiation on the reproductive organs of young females. Women who receive HSG are often young females who wish to become pregnant at some time in the future, and they are often concerned about the harmful effects of radiation (Damilakis et al. 2003; Karande et al. 1997).
One of the harmful effects of radiation is carcinogenesis. Based on fluoroscopic
technical development and the as low as reasonably achievable
(ALARA) concept of radiation protection, the effective doses for female HSG
have been determined to be 1.2 mSv (Damilakis et al. 2003). The estimated
excess risk estimates for cancer incidence by the effective doses, especially in the urinary bladder (0.49–1.82/1,000), ovary (0.06–
0.18/1,000), and colon (0.04–0.17/1,000), due to hysterosalpingography have also been
studied (Gyekye et al. 2012).
To estimate the cancer hazard ratio in women post-HSG in comparison with those who had not received HSG, we conducted a nationwide population-based historical cohort study.
METHODS Data Sources
The National Health Insurance Research Database (NHIRD) is a comprehensive
data set on more than 99 percent of the 23.74 million residents in Taiwan enrolled in the National Health Insurance (NHI) program (Cheng 2009). The NHIRD offers a complete set of patient clinical information, including data on
outpatients, inpatients, emergencies, traditional Chinese medicine services,
prescriptions, medical expenditures, and demographics, and is managed and publicly released by the Taiwan National Health Research Institutes (NHRI). The data used in the present study were derived from a subset of the NHIRD, which comprised data on one million randomly sampled beneficiaries enrolled in the NHI program from 1996 to 2000. All of the records on these individuals from 1996 to 2011 were collected. The diagnoses
and procedures were coded according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). The tumor sites were categorized as genital cancer, urinary system cancer, cancer in abdomen
except genitourinary system, cancer outside of the abdomen, and others.
We ensured that all data were de-identified and analyzed anonymously.
In addition, this study protocol was also approved by the Ethics Review Board of China Medical University (CMU-REC-101-012).
Study Patients and Clinical Outcome
Patients in the database who had received HSG examinations (procedure code in the NHI program: 33029B) between 1998 and 2005 were identified as the study sample. The first examination date for HSG was used as the index date. Patients with a history of cancer (ICD-9-CM codes 140–195, 200–208) before the index date, or with incomplete age or sex
information,
were excluded from the study. A total of 4,371 patients were extracted to comprise the study sample and were defined as the HSG cohort.
For each HSG patient, we randomly selected four patients who had
never received the HSG procedure during the same study period by using the same exclusion criteria and frequency-matching with the HSG cohort for
age, index year, and month, gathering a total of 17,484 patients to comprise
the non-HSG cohort. The study sample was followed up until the occurrence of cancer, death,
or the end of the study (December 31, 2011), whichever occurred first.
The
diagnoses of cancers were supplied by specialists who were required to provide the ICD codes with pathological and image results for verification
with the Registry for Catastrophic Illness Patient Database.
Definitions of Variables
The following variables were considered in the present study: age (<20 years, 20–34 years, and ≥35 years). The categories used for occupations
in this study included white-collar workers, blue-collar workers, and other occupations. White-collar workers were defined as women with
occupations
characterized by long indoor work hours, such as institutional workers, and business and industrial administration personnel. Blue-collar workers were defined as women with occupations characterized by long outdoor work hours, such as fishermen, farmers, and industrial laborers. Other
occupations
included primarily retired, unemployed, or low income populations. The level of urbanization was divided into four levels based on the NHRI report (Level 1 was the highest level of urbanization, and Level 7 was the lowest.
Because few people lived in Levels 5–7, we grouped the least urbanized populations in these three levels into Level 4).
Statistical Analyses
The baseline characteristics of the HSG and non-HSG cohort were compared
using the chi-square test. The incidence densities of cancer in the two cohorts
by demographic variables were calculated. Univariable and multivariable Cox
proportional hazard regressions were used to examine the relation of HSG to the risk of cancer using hazard ratios (HRs) with 95% confidence intervals
(CIs). The multivariable models were simultaneously adjusted for age and occupation both of which had significantly different distributions between those with and without HSG (Table 1) or were significantly related to HSG in the univariable Cox proportion hazard ratio regression. The purpose of computing incidence stratified by age, occupation, and urbanization was to
examine the risk differences associated with age, occupation, and urbanization
between the two cohorts. Incidence was used to show the absolute risks among groups and HRs were used to show the relative hazard
between
groups. No interaction was observed between HSG and age, occupation, or urbanization. A two-tailed p value of <0.05 was considered statistically significant.
All statistical analyses were performed by using the SAS statistical software (version 9.2 for Windows; SAS Institute, Inc., Cary, NC, USA).
The proportional hazard model assumption was examined using a test of scaled Schoenfeld residuals. Results showed no significant relationship between Schoenfeld residuals for HSG and follow-up time (p value = 0.99) in
the model evaluating cancer risk.
RESULTS
The mean age of the participants was 30.8 (±4.77) years for the HSG cohort
and 30.9 (±5.22) years for the non-HSG cohort. The proportions of HSG patients belonging to the <20, 20–34, and ≥35 years age groups in the HSG cohort were 0.85 percent, 81.4 percent, and 17.7 percent,
respectively.
Compared to the non-HSG group, the women in the HSG group were more likely to be employed in white collar occupations (72.0 percent versus
64.4 percent, p < 0.0001) and slightly more likely to live in highly urbanized
areas (35.7 percent versus 34.3 percent) (Table 1).
Overall, during the follow-up period, 76 of the 4,371 patients in the HSG cohort were diagnosed with cancer. The HSG cohort had a slightly higher incidence rate of cancer (1.72 per 1,000 person-years) than did the non- HSG cohort (1.69 per 1,000 person-years; incidence rate ratio (IRR) = 1.01,
95% CI = 0.78–1.30) (Table 2). According to the multivariable analyses, after
controlling for baseline characteristics, the HSG cohort did not have a significantly
greater risk of cancer (HR = 1.02, 95% CI = 0.79–1.31) than the
non-HSG cohort. The stratified analysis indicated that cancer risk did not differ by age,
occupation, or level of urbanization. Compared with the non-HSG cohort, the
HSG cohort had a non-significantly higher risk of cancer in those employed in blue-collar-occupations (HR = 1.40, 95% CI = 0.79–2.48), and in the second-highest level of urbanization group (HR = 1.37, 95% CI = 0.90–
2.08) (Table 2).
Additionally, in the stratified analysis of abdomen tumor sites, the HR was not significantly higher for genital cancer (HR = 1.32, 95%
CI = 0.77–2.25), followed by urinary system cancer (HR = 1.11, 95%
CI = 0.23–5.40) and abdominal cancer not involving the genitourinary system
(HR = 1.04, 95% CI = 0.53–2.03) (Table 3).
DISCUSSION
The hazard ratio for overall cancer risk in the HSG cohort was 1.02 (95%
CI = 0.79–1.31), indicating no significant increase in risk compared with that of the non-HSG cohort. When stratified by age, the hazard ratio for cancer risk for women less than 35 years of age for the HSG cohort was also not elevated compared with that of the non-HSG cohort. A notable difference was that the cancer risks in the HSG cohort were lower than those
of the non-HSG cohort for women more than 35 years old. When stratified according to cancer location, the genital cancer risk of the HSG cohort was 1.32-fold higher (95% CI = 0.77–2.25) than that of the non-HSG cohort.
The
cancer risks for the female urinary system and the abdomen were also not significantly higher in the HSG cohort than in the non-HSG cohort with a 1.11-fold and 1.04-fold higher risk, respectively. The cancer risks in the areas
exposed to radiation were also non-significantly higher than those in areas not exposed to radiation.
A higher accumulation of radiation was associated with a greater probability
of carcinogenesis and genetic mutation (Liao et al. 2014). In the past decade, clinicians and radiologists have worked diligently to reduce radiation
dose accumulation in female patients post-HSG. Radiologists and radiologic
technicians have studied methods for reducing fluoroscopic radiation doses
(Kramer et al. 2006; Sulieman et al. 2007). Other image modalities, including
transvaginal hysterosalpingo-contrast sonography (HyCoSy) with automated
three-dimensional coded contrast imaging (3D-CCI) software and magnetic resonance HSG (MRHSG), have also been studied as radiation-free
alternatives.
HyCoSy with 3D-CCI has been proven to have diagnostic accuracy
on tubal patency equal to that of HSG (Luciano et al. 2011). HyCoSy can also be used to visualize the ovaries, the endometrial thickness, and the myometrium, organs that HSG cannot detect. Furthermore, HyCoSy with 3D-CCI reduces the operator-dependent factor on diagnostic accuracy when
integrated with computed tomography (Exacoustos et al. 2013). MRHSG has a higher diagnostic accuracy on tubal patency than HSG does. Routine pelvis
MRI with MRHSG can be used to visualize clearly the uterus, fallopian tubes,
ovaries, and other organs in the pelvis (Ma et al. 2012).
A major limitation of this study was that due to the relatively young age of the study sample, a small number of participants developed cancer in the
HSG cohort, causing inadequate statistical power to detect potentially meaningfully
increased risks as statistically significant. The other major limitation
was the difficulty of quantifying the exposure to X-rays because each piece of equipment is designed differently. Exposure frequency might also have been underestimated because the data in the X-ray database were collected
only from contracted NHI practitioners and excluded non-NHI data (including
self-paying patients). In addition, X-ray data received prior to 1996 were unavailable in the NHRI data sets. Therefore, a misclassification of the X -ray
exposure status was possible, and some patients were thus likely misclassified
as non-exposed. However, the nearly comprehensive coverage of NHI reduced the likelihood of loss to follow-up, a strength of this study.
In conclusion, we found that the overall cancer incidence of the HSG cohort was not significantly increased (HR = 1.02, 95% CI = 0.79–1.31) compared
to that of the non-HSG cohort. Furthermore, the genital cancer
incidence of the HSG cohort was not significantly higher, 1.32-fold, than that of the non-HSG cohort. In women older than 35 years old, the cancer incidence rate of the HSG cohort was lower than that of the non-HSG cohort.
Most importantly, the increased cancer incidence rate of the HSG cohort was
not statistically significant. However, further study with longer follow up and
larger sample sizes are needed to rule out an increased risk in the cancer incidence in the HSG cohort. For an examination that uses radiation, clinicians
and radiologists should follow the ALARA radiation protection concept when making decisions and performing procedures to reduce the cancer risk
in female patients undergoing HSG.
