A Nested Case-Control Study of Silicon Breast Implants and Risk of Rheumatoid Arthritis
The relation between silicone breast implants and connective-tissue diseases such as rheumatoid arthritis (RA) has been the focus of considerable medical discussion throughout the past decade. Although a number of epidemiologic investigations have assessed these relations, they have been hindered by methodological limitation, including small sample sizes, limited information on the exposures and the outcomes of interest. To provide a stronger quantitative basis for addressing the postulated relation, we analyze data from the Nurse’s Health Study (NHS) cohort.
To examine an association between silicone breast implants and RA.
Nested case-control study
Selection of subjects
NHS is a prospective cohort of 121,700 female nurses aged 30–55 years in 1976 living in 11 states in the United States. Information on medical history was collected from the participants every 2 years by questionnaire. Follow-up rate of the original cohort through 2004 is 95.5%.
Defining of Cases
Starting in 1982, participants were asked whether they had been diagnosed with RA by a physician. Then, all nurses who self-reported RA underwent a screening questionnaire for symptoms as described. Medical records will be requested to validate the diagnoses for all subjects who had reported RA and had positive questionnaires. The records will be then reviewed independently by two rheumatologists blinded to exposure. Definite RA will be identified according to the American College of Rheumatology Criteria. The analysis is based on records received through 2004. Participants are excluded if they had RA at the start of the cohort, or deny permission for medical record review. The cohort studied included 81,132 women followed from 1992 to 2004, among which we confirm 292 cases of RA.
Controls are a random sample of NHS participants without diagnosis of RA, and they are frequency matched to the cases by age (within decade), and race at a ratio of 4:1.
The sample size studied is sufficient for detecting an odds ratio of 2.0 for exposures present in 8% of the control group which a past study reported, with an alpha error of 0.05 and a power of 80%. An additional 10% is added to compensate for possible refusals. According to this estimate, the final sample size should have at least 289 cases and 1156 controls (four controls per case).
Ascertainment of Exposure to Silicone Breast Implants
All exposure information among cases and controls will be obtained by self-report from mailed questionnaires. The questionnaires are questions about whether participants have ever had silicon breast implantations. A supplementary questionnaire will be sent to women who report having received breast implants in order to confirm the breast-implant surgery and to ascertain the reason for the surgery (cancer treatment, prophylaxis, or cosmetic reasons), type of implant, and date of surgery. A validation study of self-reported information on breast implants will be conducted for all respondents who admit a history of surgery in order to confirm that surgery has been performed and to ascertain the information obtained.
A medical history obtained by questionnaire includes information on smoking, use of oral contraceptives, a history of breast cancer, cosmetic surgery except for breast implants and other connective tissue disorders except for RA and family history of connective tissue disorders.
Patients with unconfirmed diagnosis of RA with validation, RA diagnosed after 2004 or prior to a breast implant, and development of RA within 6 months post-implant are excluded from analysis of that disease. Crude and adjusted Odds ratios and its 95% confidential interval for the association of silicon implants with RA will be estimated from conditional logistic regression. Potential confounders will be considered and included in the final modes if confounding is present.
Our study has several limitations. First, the generalizability of our study may be limited due to the higher age in this restricted cohort as well as the study population composed of these female health professionals. Second, the chief limitation is the random misclassification on both breast implants and diagnoses of RA even though they are validated through medical chart review.
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