Protective Effect Of Oral Contraceptives Research Articles

Contraceptive use and the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation

BackgroundBRCA1 and BRCA2 (BRCA) mutation carriers face a high lifetime risk of developing ovarian cancer. Oral contraceptives are protective in this population; however, the impact of other types of contraception (e.g. intrauterine devices, implants, injections) is unknown. We undertook a matched case-control study to evaluate the relationship between type of contraception and risk of ovarian cancer among women with BRCA mutations.MethodsA total of 1733 matched pairs were included in this analysis. Women were matched according to year of birth, date of study entry, country of residence, BRCA mutation type and history of breast cancer. Detailed information on hormonal, reproductive and lifestyle exposures were collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) associated with each contraceptive exposure.ResultsEver use of any contraceptive was significantly associated with reduced risk of ovarian cancer (OR = 0.62; 95% CI 0.52–0.75; P < 0.0001), which was driven by significant inverse associations with oral contraceptives (OR = 0.66; 95% CI 0.54–0.79; P < 0.0001) and contraceptive implants (OR = 0.30; 95% CI 0.12–0.73; P = 0.008). We observed a similar effect with use of injections (OR = 0.37; 95% CI 0.10–1.38; P = 0.14), but this did not achieve significance. No significant associations were observed between patterns of intrauterine device use and risk of ovarian cancer.ConclusionsThese findings support a protective effect of oral contraceptives and implants on risk of ovarian cancer among women with BRCA mutations. The possible protective effect of injections requires further evaluation.

Protective effect of oral contraceptive against Helicobacter pylori infection in US adult females: NHANES 1999–2000

Recently, the antibacterial properties of oestrogen and progestogen were discovered. The aim of this study was to find the cross-sectional association between oral contraceptive use and Helicobacter pylori seroprevalence. Data were obtained from the US National Health and Nutrition Examination Survey (NHANES). The H. pylori immunoglobulin G (IgG) enzyme-linked immunosorbent assays were used to categorise participants as seropositive or seronegative. The study population included 799 female participants who had information on H. pylori seroprevalence and all other covariates and had not been taking any medications (except oral contraceptives). The bivariate Rao-Scott chi-square test indicated a significant association between H. pylori seroprevalence and contraceptive use (P < 0.01). The variables of race, education, poverty income ratio, smoking, and blood lead and cadmium levels were also significantly associated with H. pylori seroprevalence (P < 0.01). Multiple logistic regression analysis of the age-adjusted model revealed that contraceptive users are 65% less likely of being H. pylori seropositive as compared to non-contraceptive users (odds ratio (OR): 0.35, 95% confidence interval (CI): 0.18-0.68). This association is stronger with the final multivariate model (OR: 0.46, 95% CI: 0.23-0.89). Conclusions: This finding reveals the potential protective effect of oral contraceptives against H. pylori infection and serves as a foundation study for further investigations.

Meta-analysis of oral contraceptives and rheumatoid arthritis risk in women.

Background and objectivesEpidemiological investigations of the relationship between oral contraceptives and rheumatoid arthritis (RA) risk have reported controversial results. Therefore, a meta-analysis of case-control or cohort studies was performed to evaluate the role of oral contraceptives in relation to risk of developing RA.MethodsEligible studies were identified from databases PubMed and EMBASE by searching and reviewing references. Random effect models were utilized to summarize the relative risk (RR) estimates with 95% confidence intervals (CIs).ResultsA total of 12 case-control studies and five cohort studies were eligible for our analysis. No statistically significant association was observed between oral contraceptives and RA risk (RR=0.88, 95% CI=0.75–1.03). In the subgroup of geographic area, a decreased risk of borderline significance was observed for oral contraceptive users in European studies (RR=0.79, 95% CI=0.62–1.01), but this association did not emerge in the North American studies group (RR=0.99, 95% CI=0.81–1.21). No evidence for publication bias was detected (P for Egger’s test =0.231).ConclusionOur results of meta-analysis do not support the hypothesis of a protective effect of oral contraceptives on the risk for RA in women.

Oral contraceptive use and impact of cumulative intake of estrogen and progestin on risk of ovarian cancer

Oral contraceptive use decreases the risk of ovarian cancer, but no previous studies have assessed the impact of cumulative intake of estrogen and progestin on ovarian cancer risk. We used data from a population-based case–control study conducted in Denmark in 1995–1999 among women aged 35–79 years; 554 women with epithelial ovarian cancer and 1,564 age-matched controls were included in the analyses. Data were analyzed in multiple logistic regression models. The use of combined oral contraceptives only and the mixed use of combined and progestin-only pills decreased the risk of ovarian cancer, while no association was found with exclusive use of progestin-only pills. No major differences in risk were found for users of combined oral contraceptives with high- and low-potency estrogen and progestin. There was no effect of cumulative progestin intake, but decreased risks of ovarian cancer with increasing cumulative intake of estrogen (OR = 0.82; 95 % CI 0.67–0.99, per 100 mg estrogen) and increasing duration of oral contraceptive use (OR = 0.95; 95 % CI 0.92–0.98, per year of use) were found. No effect of cumulative estrogen intake was found, however, after adjustment for duration of oral contraceptive use. The protective effect of oral contraceptives against ovarian cancer may be sufficiently explained by duration of anovulation. This suggests that if the estrogen and progestin doses are sufficient to cause anovulation, a higher intake of estrogen or progestin confers no extra protection against ovarian cancer.

Endometriosis and estroprogestins: the chicken or the egg causality dilemma

Dysmenorrhea as a reason to initiate estroprogestins is significantly more common in women with endometriosis than in women without the disease. This might explain the previously reported mild association between endometriosis and past use of oral contraceptives.

Hormonal contraception and risk of cancer

Fear from increased cancer risk is one of the most significant reasons for low acceptance of reliable contraceptive methods and low compliance. In this review, we included all cohort and case-control studies published in English up to December 2008. They were identified through a search of the literature using Pubmed and EMBASE. Data about breast cancer risk indicate a slightly increased risk among current users of oral contraceptives (OC), an effect which disappears 5-10 years after stopping. Combined OC have a significant protective effect on the risk of ovarian cancer, and the protection increases with duration of use (relative risk decreased by 20% for each 5 years of use). The significant risk reduction has been confirmed for BRCA 1 and 2 mutation carriers. The risk of endometrial cancer is reduced by about 50% in ever users, a benefit which is greater with increasing duration of use. An association has been found between increased risk of cervical cancer and long-term OC use. Current OC use has been associated with an excess risk of benign liver tumours and a modest increased risk of liver cancer. None of large prospective cohort studies with prolonged follow-up has observed an increased overall risk of cancer incidence or mortality among ever users of OC, indeed several have suggested important long-term benefits. Specifically, protective effect of OC can be used as chemoprevention in young women who are BRCA mutation carriers. Women wishing to use combined OC can be reassured that their decision is unlikely to place them at higher risk of developing cancer.

Combined Oral Contraceptive Use and Epithelial Ovarian Cancer Risk

Although the protective effect of oral contraceptives (OCs) use against epithelial ovarian cancer is well-established, there remain gaps in our understanding of the contributions of time-related characteristics of OC use to risk. This population-based case-control study, carried out in Hawaii and Los Angeles 1993-2006, included 813 cases of epithelial ovarian cancer and 992 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. Epithelial ovarian cancer risk was reduced 5 or more years after initiation of OC use (OR = 0.18; CI = 0.08-0.39). Each year of use provided a 5% reduction (CI = 2%-8%) in risk. A positive gradient in risk with time since first OC use was independent of duration of OC use. The inverse association of OCs with risk was attenuated decades after last use, but was not affected by age at first or last use. OC use for <1 year was associated with decreased ovarian cancer risk (OR = 0.45; CI = 0.26-0.79) only among recent users (< or =20 years from diagnosis/interview). Women who used OCs for a year or more were protected for at least 3 decades after they stopped use. Reduction in epithelial ovarian cancer risk associated with OC use became apparent after a short latency period and short duration of use, and was long-lasting. Time since first use and time since last use seem to modify the association of OCs with ovarian cancer risk independently of duration of use.

Effect of oral contraceptive with and without associated estriol on ultrasound measurements of breast fibroadenoma: randomized clinical trial

Fibroadenomas are the most common benign tumors of the female breast. The aim of this study was to evaluate the proliferative activity of breast fibroadenoma as shown by ultrasound measurements, following administration of oral contraceptives with and without associated estriol. This was a randomized, double-blind, placebo-controlled clinical trial carried out in the Mastology Sector, Department of Gynecology, Universidade Federal de São Paulo. We studied 33 women with fibroadenomas. Ten were placed in group 1 and took an oral contraceptive consisting of levonorgestrel and ethinyl estradiol together with placebo material in the same capsule, for four consecutive cycles with a seven-day interval between them. The other 23 patients constituted group 2 and took the oral contraceptive as above together with estriol in the same capsule, in the same way as done by the group 1 patients. We took ultrasound measurements of their tumors (in three dimensions) before and after the intake of medication. At the end of the study, all the patients had their tumors removed by surgery. We observed decreased fibroadenoma width among the users of oral contraceptives with placebo, and this decrease was statistically significant. In the other group, we did not observe any changes (in width, length or height). The results confirm that estriol may block the protective effect of oral contraceptives on fibroadenomas, since we observed decreased fibroadenoma width among the group 1 patients but not the group 2 patients.

Atypical Squamous Cells of Undetermined Significance: Human Papillomavirus Testing in Adolescents

To estimate the age-stratified prevalence of oncogenic human papillomavirus (HPV) infection and to evaluate risk factors for HPV acquisition among women with atypical squamous cells of undetermined significance (ASC-US). This was a chart review of all women with ASC-US smears who underwent oncogenic HPV testing between July 2002 and February 2004. To be eligible, HPV DNA results had to be available. Data extracted from charts included demographic information as well as certain patient characteristics historically associated with HPV acquisition or carriage. Of 527 eligible women with ASC-US, 357 (68%, 95% confidence interval [CI] 64-72%) tested positive for oncogenic HPV. As compared with women who tested negative, this population was significantly younger and less likely to be married. When stratified by age, 77% of the women aged younger than 20 years were positive for high-risk subtypes, compared with 58% of women aged older than 25 years (P < .01). In the multivariate analysis, young age (relative risk [RR] 1.30, 95% CI 1.14.-1.49), current smoking (RR 1.14, 95% CI 1.03-1.25) and a history of chlamydial infection (RR 1.20, 95% CI 1.09-1.32) were associated with an increased likelihood of HPV infection, while oral contraceptive use (RR 0.86, 95% CI 0.72-1.03) had a marginal protective effect. The protective effect of oral contraceptives was most pronounced among adolescent women (RR 0.57, 95% CI 0.31-1.03). Given that the rate of oncogenic HPV infection approached 80% in our population of adolescent women with ASC-US, the usefulness of HPV testing in this age group requires further investigation. II-3.

The Premenstrual Period and Exacerbations in Multiple Sclerosis

The aim of this study was to assess whether an association exists between the premenstrual period and exacerbations of multiple sclerosis (MS). The subjects were 56 premenopausal patients with relapsing MS and a regular menstrual cycle. Data over the previous 2 years were gathered from a structured MS database and a comprehensive questionnaire. 42% had exacerbations starting in the premenstrual phase. Within this group the proportion of premenstrual exacerbations was significantly higher than in the remaining period of the menstrual cycle, and in 45% all exacerbations had started during the premenstrual phase. There was no relationship with the premenstrual syndrome, and there was no protective effect of oral contraceptives. Our results suggest that the premenstrual period triggers exacerbations in a subgroup of females with MS.

Long-term effects of oral contraceptives on ovarian cancer risk.

Several epidemiologic studies have reported a protective effect of oral contraceptives (OCs) on ovarian cancer. However, there remain open issues, including better quantification of time-related factors such as time since last use, age at first use and time since first use. We performed a collaborative reanalysis of 6 case-control studies conducted between 1978 and 1999 in the United Kingdom, Greece and Italy, including a total of 2,768 incident, histologically confirmed cases of epithelial ovarian cancer and 6,274 hospital controls under age 70 years. A reduced risk of ovarian cancer was found for ever- compared to never-users [odds ratio (OR) = 0.66, 95% confidence interval (CI) 0.56-0.79], and a stronger reduction was observed for women who had used OCs for > or =5 years (OR = 0.50, 95% CI 0.33-0.76) compared to those who had used them for <5 years. The protective effect of OCs on ovarian cancer was consistent across strata of age, parity, menopausal status and family history of breast or ovarian cancer. After allowance for duration of use, no other time factor was related to ovarian cancer risk: the reduced risk was similar for women who stopped OC use > or =20 years before compared to <10 years; likewise, no significant modification of risk reduction was observed for age at first OC use and time since first OC use. The present analysis indicates that, after taking into account duration of OC use, the OC protection from ovarian cancer persists for a long time after stopping use.

Oral contraception and ear disease: findings in a large cohort study

A number of authors have suggested that oral contraceptives may increase the risk of certain ear diseases, especially otosclerosis and vestibular disorders, although the amount of published information on this topic is limited. We have analyzed the available data on ear disease in the Oxford-Family Planning Association contraceptive study that includes 17,032 women followed for periods of up to 26 years. No evidence of any adverse effect of oral contraceptives on ear disease was detected. A protective effect of oral contraceptives against wax in the ear has been described in the Royal College of General Practitioners oral contraception study. The amount of data available in the Oxford-Family Planning Association study was too small to permit confirmation or refutation of this finding.

Controversy of Oral Contraceptives and Risk of Rheumatoid Arthirtis: Meta-analysis of Conflicting Studies and Review of Conflicting Meta-analyses with Special Emphasis on Analysis of Heterogeneity

The authors analyze the heterogeneity present in the combined results of past observational studies that investigated the association between oral contraceptive use and rheumatoid arthritis. The authors also evaluate discrepancies among meta-analyses that focus on the same relation. Of the 15 initially reviewed studies, 10 were selected for this meta-analysis, which also includes a qualitative summary of study characteristics and a critical appraisal of study quality. The authors used the direct method to combine the study results when there was no evidence of heterogeneity and the DerSimonian-Laird method when heterogeneity was present. Using a meta-regression to assess the sources of heterogeneity, the authors weighted summary estimates by sample size and undertook a sensitivity analysis. There was a strong indication of heterogeneity when combining all studies (x2 = 29.34, p = 0.00060) with the source of controls explaining most of the heterogeneity. The most important factor in explaining the differences among the overall summary estimates given by the meta-analyses is that different effect estimates had been selected for the same studies. There is no conclusive evidence of a protective effect of oral contraceptives on the risk of developing rheumatoid arthritis. Consensus is needed on how meta-analyses of observational studies should be conducted.

Cancer risk in women receiving estrogen-progestin replacement therapy

Objectives and methods: The epidemiological literature was reviewed in order to evaluate the relationship between hormone replacement therapy and risk of cancer in the breast and reproductive organs. Results: For breast cancer, there is no evidence of an overall increase in the risk. According to several studies, but not all, the duration of intake seems to affect the risk. Many years of intake of both estradiol compounds and conjugated estrogens can be assumed to increase the risk of breast cancer 1.5-2-fold. The addition of progestins does not seem to alter (reduce) the duration-risk relationship. The magnitude of risk increase is likely to be small and may be explained partly by methodological problems, or by differences in study populations. The prognosis in patients with HRT-related breast cancer seems to be more favourable than for non-exposed breast cancer patients. Because of the importance of the issue, and inconsistencies in results, further research is urgent. Especially, there is an urgent need to define sub-groups of women who would be susceptible to an adverse influence of HRT. Regarding endometrial cancer, a duration-dependent strong risk relationship with long-term intake of estrogens only is established. The level of risk increase is about 10-fold after 10 or more years of intake, a risk relationship that seems to decrease after discontinuation of treatment. Added progestins for at least 10 days per cycle can reduce or eliminate the risk increase. Tumors occurring after estrogen replacement have favourable biological characteristics. Future research will be needed to define the long-term safety of various progestin regimens. Ovarian cancer risk does not seem to be affected by HRT. Available data are inconsistent and contradictory. Due to the pronounced protective effect of oral contraceptives, further research is needed to measure effects of estrogen-progestin combined regimens. Cervical cancer risk has not been shown to be affected by HRT. Conclusions: It is concluded that hormone replacement therapy, with estrogens alone or estrogens combined with progestins, may have important effects on the risk of cancer, particularly in the breast and endometrium. Therefore, when making a risk-benefit assessment of long-term HRT, possible risk relationships should be considered.

Ovarian Cancer

Ovarian cancer incidence rates are highest and stable in white populations; in Asia previously low incidence rates may be increasing. Most cases present with disseminated disease, and mortality rates remain high despite the use of aggressive polychemotherapy. Mortality among younger women has decreased, which has been attributed to widespread use of oral contraceptives. Studies consistently show a protective effect of oral contraceptives that increases with duration of use; no dose effect has been identified to date. Risk decreases substantially with increasing numbers of pregnancies; periods of lactation are relatively less protective. Periods of oral contraceptive use are less protective than equal periods of pregnancy. These factors may protect against ovarian cancer due to inhibition of ovulation or due to suppression of another aspect of ovarian function. Hysterectomy and tubal ligation are both protective, perhaps by preventing the ascent of environmental carcinogens that are as yet unidentified. A positive family history substantially increases risk; mutations in the BRCA1 gene may be responsible for about 5% of cases. No other exposures have been consistently associated with disease risk. Whether risk is modified by ovarian damage mediated by dietary galactose is being evaluated; studies to date have conflicting results. The effect of infertility and its treatments on ovarian cancer risk is controversial; two studies suggest that infertility treatments increase risk.

Recent trends in incidence of and mortality from breast, ovarian and endometrial cancers in England and Wales and their relation to changing fertility and oral contraceptive use.

Reproductive-related factors play a major role in the aetiology of cancers of the breast, ovary and endometrium. Pregnancy history influences the risk of each of these cancers, and oral contraceptive use modifies the risks of ovarian and endometrial cancers, although its effect on breast cancer risk is less certain. We analysed recent time trends in the incidence and mortality of these cancers in England and Wales and assessed whether they can be explained by changes in fertility and oral contraceptive use. During 1962-87, there were significant increases in the overall incidence of breast cancer (0.95% increase per annum) and ovarian cancer (0.76% per annum) but little increase in endometrial cancer (0.13% per annum). At young ages incidence of each of the cancers has declined in recent years, whereas at older ages there have been substantial increases. Mortality data show similar time trends. In analyses by birth cohort, incidence of each of the cancers increased steeply for successive cohorts born before the turn of the century, and more slowly for cohorts thereafter, reaching a maximum for those born in the 1920s, and decreased for those born subsequently. The increases in incidence for women born before the turn of the century paralleled marked declines in their fertility. The fall in risk for women born after the 1920s was not accompanied by significant increases in their fertility, but coincided with the introduction and increase in use of oral contraceptives. For ovarian and endometrial cancers this accords with strong evidence from person-based studies of the protective effect of oral contraceptives. For breast cancer, the reasons for the recent decline are not clear. It would accord with recent suggestions of a long-term protective effect of oral contraceptives, on which further studies are needed. It is also possible, however, that changes in other risk factors such as dietary fat intake and menarcheal age might have contributed to the recent declines in the risk of these cancers.

Ultrasound screening in women at risk for ovarian cancer.

As no unobjectionable study has yet been published on ovarian cancer screening with ultrasound and/or tumor markers in the general population or in risk groups, it is not possible to determine if screening would decrease the mortality in ovarian cancer. Because the medical gain is unclear, the cost per life gained can not be estimated. At present, there is not sufficient scientific evidence to recommend screening for ovarian cancer with any method. It may be worthwhile to perform a large randomized trial to discover if early detection is of value, as ultrasound is already being used on a large scale in asymptomatic women in order to detect ovarian cancer. Such a study will also gain knowledge about the early stages of ovarian cancer. Moreover, methods for investigation of lesions detected by ultrasound (i.e., color Doppler and puncture) could be evaluated. Only through a large-population study would we be able to know if prophylaxis for ovarian cancer (oral contraceptives) is more efficient than screening. Studies on lung cancer have shown that persuading people to stop smoking more effectively decreases the mortality of lung cancer than screening. A population study would be a giant enterprise, but probably the only way to determine whether screening for ovarian cancer with ultrasound is of any value. The following attitude to ultrasound examination in risk groups is proposed as long as the value of screening is unclear: Women with hereditary ovarian cancer (one or two first degree relatives with ovarian cancer) should be made aware of the risks, and regular ultrasound check-ups seems advisable for psychologic reasons and because the risk for cancer is high. The surveillance proposed by Lynch seems reasonable: ultrasound at least once a year, possibly in combination with CA-125, and discussion concerning surgical removal of the ovaries after childbearing is complete or around 40 years of age. The protective effect of oral contraceptives should be emphasized. Women at risk should be made aware of the fact that mesothelial cancer can develop even after ovarian removal. If possible, these women should be registered and their family history noted. Thus, their risk of contracting ovarian cancer can be estimated and compared to the outcome when the ovaries are removed. Mesothelial cancers after oophorectomy must be noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Osteoporosis in anorexia nervosa: The influence of peak bone density, bone loss, oral contraceptive use, and exercise

Anorexia nervosa occurs early in life and predisposes to osteoporosis. Exercise may be protective. We asked: (1) Does failure to attain peak bone density contribute to the deficit in bone density? (2) Does oral contraceptive use protect against osteoporosis? (3) Is any protective effect of exercise confined to weight-bearing sites? Areal bone density (g/cm2) and body composition were measured by dual x-ray absorptiometry in 65 patients with anorexia nervosa and 52 controls. Comparing the 12 patients with primary amenorrhea and the 37 patients with secondary amenorrhea, bone density (mean +/- SEM) at the lumbar spine was 0.88 +/- 0.04 versus 1.06 +/- 0.03 (P = 0.001), respectively. Bone density at the femoral neck was 0.80 +/- 0.04 versus 0.92 +/- 0.03 (P < 0.05), respectively. These values differed before, but not after, adjusting for the respective duration of illness (73.0 +/- 10.3 versus 34.1 +/- 4.8 months, P < 0.001) and fat-free mass (31.6 +/- 1.3 versus 35.4 +/- 0.5 kg, P < 0.01). Bone density at the lumbar spine in the 16 patients with 31.8 +/- 8.3 months of contraceptive exposure was higher than in the 49 patients with no contraceptive exposure (1.14 +/- 0.05 versus 1.02 +/- 0.02 P < 0.02) but was lower than in controls (1.14 +/- 0.05 versus 1.27 +/- 1.02, P < 0.01). No protective effect of contraceptive exposure was detectable at the femoral neck.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral contraceptive type and functional ovarian cysts

We tested the hypothesis that multiphasic, low-dose monophasic, and high-dose monophasic oral contraceptives share a common protective effect against functional ovarian cysts. We conducted a cohort study using the automatic files of Maine Medicaid to assemble a population of 7462 women between the ages of 15 and 44 who were prescribed an oral contraceptive between Jan. 1, 1987, and Dec. 31, 1988. We included as cases 32 women with a principal diagnosis of a functional ovarian cyst confirmed by medical records as being greater than 20 mm in diameter. At comparison with the absence of an oral contraceptive prescription, we observed decreasing rates of functional ovarian cysts among women prescribed multiphasic pills (rate ratio 0.91, 95% confidence interval 0.3000 to 2.31), low-dose monophasic pills with less than or equal to 35 micrograms estrogen (rate ratio 0.52, 95% confidence interval 0.17 to 1.33), and high-dose monophasic pills with greater than 35 micrograms estrogen (rate ratio 0.24, 95% confidence interval 0.01 to 1.34). The protective effect of oral contraceptives against functional ovarian cysts reported previously for high-dose monophasic pills may be attenuated with newer pills of lower hormonal potency.

Reconsidering the IUD

Critical comment is provided on the risk of pelvic inflammatory disease (PID) with the use of IUDs, and specifically the Dalkon Shield. The reopening of the issue of IUD and PID was precipitated by the reanalysis of the Women's Health Study (WHS) data by Kronmal et al. The focus of the discussion is on the description of an epidemiological case control study, the WHS, assessing the criticisms of the study, the possible biases, and an interpretation of the conflicting analyses. The WHS was conducted in 8 health care centers in the US between 1976-78 and included hospitalized PID cases. Controls were other hospitalized patients. Burkman in 1981 and Lee et al, in 1983 published results of their analyses of the WHS data. Burkman estimated a 1.6 risk of PID among IUd users relative to all other contraceptive users and 1 or 2.1 relative to women with no history of PID. Lee estimated risk among Dalkon Shield users as 8.3 relative to women not using any contraceptive method prior to hospitalization, and 1.6 among users of other IUDs; analysis excluded women with a prior history of PID. Recently Kronmal et al, found fault with the WHS on 10 counts, which are provided in detail. Their reanalysis indicates there is no increased risk of PID for IUd users. However, the question is raised as to the appropriate reference group, -all other users of contraceptives or nonusers. Another question pertains to whether subjects should all, or just those without a prior PID history, be included. Due to the protective effect of oral contraceptives, the reference group should be nonusers of any type as analyzed by Lee et al. Lee et al. also excludes those with a prior PID history, which is the best solution to the 2nd question. The Kronmal analysis allowed those with a prior PID history, and the reference group was all women regardless of use. The Kronmal analysis also describes ways in which selection bias is involved in the higher risk of PID among Dalkon Shield users relative to nonusers. Some of the reasons are that women using the Dalkon Shield may have been less likely to seek early medical care, to have a greater likelihood of having their diseases properly diagnosed, and to identify more easily the Dalkon Shield as their IUD type. This reasoning is found to be excessive and unrealistic to explain a difference between a risk of 8.3 vs. 1.6, and the Dalkon Shield was deservedly removed as an unsafe product. Support for the IUD is better served by discussing the careful selection of users to reduce PID, meticulous insertion techniques, and close monitoring.