Clinical Context

According to the current study by Castellsagué and colleagues, epidemiologic studies have consistently shown that the use of intrauterine devices (IUDs) reduces the risk for endometrial cancer, but the effect of IUD use on cervical cancer risk is not known. Because human papillomavirus (HPV) is now established as the cause of cervical cancer, HPV infection should be considered when the risk for cervical cancer with IUD use is examined.

This is a pooled analysis from 2 large studies consisting of 10 case-control studies done in 8 countries, and 16 studies of HPV prevalence from 16 countries. The goal of the analysis was to examine the risks for cervical cancer and HPV infection with IUD use.

Study Synopsis and Perspective

Women with a history of using IUDs have a reduced risk — by almost half — of developing cervical cancer, compared with women who never used the birth control devices, according to a new pooled analysis from European researchers.

Epidemiologic studies have consistently shown that IUD use reduces the risk for endometrial cancer, but the device's effect on the risk for cervical cancer has not been determined, say the researchers, led by Xavier Castellsagué, MD, from theInstitut Català d'Oncologia in Catalonia, Spain.

Previous studies have reported "inconsistent results" in cervical cancer, and none accounted for either HPV status or Pap screening history, they write in a paper published online September 13 in the Lancet Oncology.

IUD use has been suspected of causing cervical cancer since its clinical introduction in the 1930s, add the authors.

The epidemiologic study of nearly 20,000 women found that women who used IUDs had a 45% reduced risk for cervical cancer, compared with never users.

Specifically, the researchers found a "strong" inverse association between ever-use of IUDs and cervical cancer (odds ratio [OR], 0.55; P < .0001) after adjustment for "relevant covariates." Those variables include the number of previous Pap tests that a woman has undergone.

A protective association was also noted for the 2 major cervical cancer histologic types — squamous cell carcinoma (OR, 0.56; P < .0001) and adenocarcinoma or adenosquamous carcinoma (OR 0.46; P = .035). However, there was no protective association among HPV-positive women (OR, 0.68; P =.11).

Thus, IUD use did not protect women against HPV infection, but did protect against the development of cervical cancer.

The researchers summarized what all these associations mean.

"The associations found in our study strongly suggest that IUD use does not modify the likelihood of prevalent HPV infection, but might affect the likelihood of HPV progression to cervical cancer," they write.

The results are "surprising" and should provide "restored confidence in the safety of IUDs," writes Karl Ulrich Petry, MD, from the Klinikum Wolfsburg in Germany, in an editorial that accompanies the study. The study "provides high-level evidence to contradict a widespread assumption that IUD use increases the risk of cervical cancer," he writes.

How IUDs Might Prevent Cervical Cancer

The mechanism of action by which IUDs protects against cervical cancer is not known, but the authors offer several explanations.

"One of the mechanisms by which IUDs might exert this protective effect is through the induction of a reactive, chronic, low-grade, sterile inflammatory response in the endometrium, endocervical canal, and cervix that could modify, via changes in the local mucosal immune status, the course of HPV infections," write the authors.

Another possible explanation accommodates an interesting finding in the study.

The investigators found that there was no difference in the protective effect by years of IUD use. Short-term users and those with use as long as 9 years were found to be protected, according to the odds ratio estimates.

"It can be postulated that the local trauma to the cervical tissue associated with insertion or removal of the device induces local small foci of chronic inflammation and a long-lasting immune response similar to that noted in patients after colposcopically guided punch biopsies," write the authors.

A theory that incorporates the concept of local trauma and subsequent immune response also appeals to Dr. Petry, the editorialist.

"I postulate that the tissue trauma associated with loop insertion induces a cellular immune response that might finally clear persistent HPV infections and preinvasive lesions," he writes.

The study's findings challenge some key elements of the "current model of the natural history of cervical cancer," adds Dr. Petry.

If prospective trials confirm the protective role of cervical trauma via the IUD loop insertion, then the medical world would "need to accept," he says, "that most studies of the natural course of cervical lesions in fact describe an artificial course, manipulated by biopsies cervical brushes, loop insertion, and other procedures."

The implications are profound, he suggests.

"It is very likely that we underestimated the true risk of progression of HPV infections and associated lesions, based on studies that relied on biopsy-proven diagnoses."

All of this means that "today's standard information for patients — that less than 1% of HPV infections progress to cancer" — does not reflect the true natural history that exists outside of clinical interventions, such as biopsies, Dr. Petry says. "The 6.5% lifetime risk for cervical cancer observed in remote areas without screening probably mirrors the true natural risk," he adds.

What About Screening Bias?

The study consisted of a pooled analysis of individual data from 2 large studies by the International Agency for Research on Cancer and Institut Català d'Oncologia research program on HPV and cervical cancer.

One study included data from 10 case–control studies of cervical cancer conducted in 8 countries; the other included data from 16 HPV prevalence surveys of women from the general population in 14 countries. There were 2205 women with cervical cancer and 2214 matched control women without cervical cancer from the case–control studies, and 15,272 healthy women from the HPV surveys.

"An important challenge" in interpreting the results can be found in the possible effect of a screening bias, say the authors. The insertion, follow-up, and removal of IUDs often involves "several visits to the gynecologist, providing many opportunities for these women to be directly diagnosed or screened for cervical cancer, through visual identification or repeated cervical cytology."

This is important because "the reduced risk of cervical cancer seen in IUD users might not be due to the biological effect of the device, but rather to the higher likelihood of more intensive cervical screening or diagnosis in these women compared with non-users," the authors point out.

But the investigators accounted for that possibility. "We estimated associations by specific strata of number of previous Pap smears women had until 12 months before diagnosis or study entry," they write. They did not find that more visits resulted in a significantly different likelihood of cervical cancer. "History of previous Pap smears did not significantly affect the observed inverse association between IUD use and risk of cervical cancer," they conclude.

Furthermore, the study population is an argument against the potential for screening bias, they say. "Since most of the populations included in these analyses are from developing areas of the world, where screening is opportunistic and has little effect in preventing cervical cancer, it is unlikely that screening bias would explain the observed inverse association."

Funding for this study came from the Instituto de Salud Carlos III; Agència de Gestió d'Ajuts Universitaris i Recerca; Marató TV3 Foundation; Bill & Melinda Gates Foundation; International Agency for Research on Cancer; European Community; Fondo de Investigaciones Sanitarias, Spain; Preventiefonds, the Netherlands; Programa Interministerial de Investigación y Desarrollo, Spain; Conselho Nacional de Desenvolvimiento Cientifico e Tecnologico, Brazil; and Department of Reproductive Health & Research, World Health Organization. The authors have disclosed no relevant financial relationships.

Lancet Oncol. Published online September 13, 2011. Abstract, Editorial

Related Link
The Association of Reproductive Health Professionals provides a downloadable patient education brochure, available in both English and Spanish, entitled A Woman's Guide to Understanding IUDs.

Clinical Implications

• IUD use is associated with a reduced risk for cervical cancer.
• IUD use is not associated with a reduced or increased risk for HPV infection among women.

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