Associate Professor, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, RI
Dr. Allen reports she is a Nexplanon trainer for Merck.
SYNOPSIS: In this case-control study, levonorgestrel IUD use was associated with a slightly increased rate of CIN 2 but not CIN 3. Copper IUD use was not associated with CIN 2 or CIN 3.
SOURCE: Averbach S, et al. Recent intrauterine device use and the risk of precancerous cervical lesions and cervical cancer. Contraception 2018; Apr 17. doi: 10.1016/j.contraception.2018.04.008. [Epub ahead of print].
This was a case-control study of women enrolled in a single healthcare system (Kaiser Permanente Northern California) from 1996 to 2014. Cases were defined as women between 18 to 49 years of age with biopsy-proven cervical intraepithelial neoplasia (CIN) 2, CIN 3, adenocarcinoma in situ, or cervical cancer, and who had been enrolled at least 18 continuous months in Kaiser Permanente prior to the first CIN 2+ diagnosis (index date). Controls were women between 18 to 49 years of age with cytology screening and no diagnosis of CIN 2+ as of December 31 of the year (index date) of CIN 2+ diagnosis of the matched case. Five controls were matched to each case on age, cytology test in the system ≤ 12 months prior to the case’s CIN 2+ diagnosis, years in the health plan, and date of first health plan cytology test. Women who underwent a total hysterectomy prior to the index date were excluded. Recent intrauterine device (IUD) use was defined as IUD use for at least one month or more in the 18-month period prior to the diagnosis of CIN 2+ for cases and the index date for controls. Ever use of IUD was defined as IUD use at any time prior to the index date. The authors stratified their analysis for levonorgestrel and copper IUDs. Confounding variables, including sexually transmitted infection screening in the past 18 months as a proxy for sexual activity, smoking status, human papillomavirus (HPV) vaccination, other hormonal contraceptive use, parity, race/ethnicity, and number of outpatient visits in the health system, were collected.
There were 17,559 cases (3,080 women with CIN 2, 4,706 with CIN 2/3, 8,914 with CIN 3, and 859 with cancer) matched to 87,378 controls. Cases were more likely to be white and to smoke cigarettes than controls. After adjusting for sexually transmitted infection testing, smoking, HPV vaccination, other hormonal contraceptive use, parity, race, and number of outpatient healthcare system visits, recent IUD users had an increased rate of CIN 2+ (rate ratio [RR], 1.12; 95% confidence interval [CI], 1.05-1.18) but not CIN 3+ (RR, 1.02; 95% CI, 0.93-1.11) compared to non-IUD users. Levonorgestrel IUD use was associated with an increased rate of CIN 2+ (RR, 1.18; 95% CI, 1.08-1.30) but not CIN 3+ (RR, 1.05; 95% CI, 0.91-1.21). Copper IUD use was not associated with CIN 2+ (RR, 0.88; 95% CI, 0.75-1.04) or CIN 3+ (RR, 0.81; 95% CI, 0.64-1.02).
COMMENTARY
As the use of IUDs increases, it is important to understand any effect they may have on cervical dysplasia and cervical cancer. IUDs are known to cause inflammation in the genital tract. The levonorgestrel IUD may influence the cervix hormonally to make it more or less susceptible to HPV infection. There always has been a possible link between hormonal contraception and cervical cancer. Pooled data from 24 studies, including more than 16,000 women with cervical cancer and 35,000 women without cervical cancer, found that for current combined oral contraceptive pill users, the risk of invasive cervical cancer rose with increasing duration of use (RR for ≥ 5 years’ use vs. never use = 1.90; 95% CI, 1.69-2.13). The risk declined after use ceased; after 10 or more years, it returned to the risk level of never users.1 However, it is unclear to what degree sexual activity is a confounder in this relationship. In terms of IUDs, recent meta-analyses have found a decreased risk of cervical cancer associated with IUD use.2,3 Because these studies are limited by using an ever/never IUD exposure classification and evaluated only copper or inert IUD types, they have limitations. Averbach et al wanted to analyze the relationship between IUDs, cervical dysplasia, and cancer that could account for the type of IUD used and the timing of IUD exposure.
Similar to previous studies, this analysis did not find any association between copper IUDs and cervical dysplasia or cancer. In contrast, there was a slightly increased risk for CIN 2 with the levonorgestrel IUD but not CIN 3. Given the timing of this study, the only levonorgestrel IUD included was the 52 mg device. The authors speculated that this weak association might be due to residual confounding. Therefore, they performed another analysis comparing hormonal contraceptive users to IUD users (excluding women not using contraception), which failed to show any association between IUD use and CIN 2. This supports the possibility that sexual activity leading to HPV infection is a confounding factor. Furthermore, a relative risk of 1.18 indicates a very weak association that is unlikely to be clinically meaningful. It is unclear how levonorgestrel would affect the ability of the cervix to clear HPV infection. There is some speculation that levonorgestrel’s anti-inflammatory properties may hinder HPV clearance.4
This study had several strengths, including a large, well-screened population and the ability to identify IUD use before cervical dysplasia was diagnosed. Limitations include that IUD type was only able to be ascertained for 54% of the study population and that longer durations of IUD use were not accounted for. In addition, condom use could not be evaluated. Finally, the distinction between CIN 2 compared to CIN 3 is poorly reproducible among pathologists. Overall, the findings are reassuring for IUD users of both types. A history of cervical intraepithelial neoplasia or genital HPV infection is not a contraindication for hormonal contraception or IUD use.5 Women should be screened for cervical cancer according to national guidelines, regardless of contraceptive use.
REFERENCES
- International Collaboration of Epidemiological Studies of Cervical Cancer; Appleby P, et al. Cervical cancer and hormonal contraceptives: Collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies. Lancet 2007;370:1609-1621.
- Castellsagué X, et al. Intrauterine device use, cervical infection with human papillomavirus, and risk of cervical cancer: A pooled analysis of 26 epidemiological studies. Lancet Oncol 2011;12:1023-1031.
- Cortessis VK, et al. Intrauterine device use and cervical cancer risk: A systematic review and meta-analysis. Obstet Gynecol 2017;130:1226-1236.
- Lekovich JP, et al. Comparison of human papillomavirus infection and cervical cytology in women using copper-containing levonorgestrel-containing intrauterine devices. Obstet Gynecol 2015;125:1101-1105.
- Curtis KM, et al. US Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR Recomm Rep 2016;65:1-103.
In this case-control study, levonorgestrel IUD use was associated with a slightly increased rate of CIN 2 but not CIN 3. Copper IUD use was not associated with CIN 2 or CIN 3.
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