Abstract
Background Previous research showed women experiencing false-positive mammograms to have greater anxiety about breast cancer than women with normal mammograms. To elucidate psychological effects of false-positive mammograms, we studied impact on drug intake.
Methods We calculated the ratio of drug use for women with false-positive versus women with normal mammograms, before and after the event, using population-based registers, 1997–2006. The ratio of the ratios (RRR) assessed the impact.
Results Before the test, 40.3% of women from the false-positive group versus 36.2% from the normal group used anxiolytic and antidepressant drugs. There was no difference in use of beta blockers. Hormone therapy was used more frequently by the false-positive, 36.6% versus 28.7%. The proportion of women using anxiolytic and antidepressant drugs increased with 19% from the before to the after period in the false-positive group, and with 16% in the normal group, resulting in an RRR of 1.02 (95% CI 0.92–1.14). RRR was 1.03 for beta blockers, 0.97 for hormone therapy.
Conclusion(s) Drugs used to mitigate mood disorders were used more frequently by women with false-positive than by women with normal mammograms already before the screening event, while the changes from before to after screening were similar for both groups. The results point to the importance of control for potential selection in studies of screening effects.
Screening mammography has been adopted in many countries, and although there is evidence for its effect on breast cancer mortality [Citation1], the potential harms of screening remain controversial. Unavoidably, in a screening program some women will get a normal mammogram, and still develop breast cancer within the interval between two screens, and some women will get a positive mammogram but will after further assessment be declared free of breast cancer. The latter group is referred to as women with false-positive mammograms. The risk of receiving a false-positive mammogram varies considerably, especially between the US and Europe. This is true even when differences in targeted age-group and screening interval are taken into account [Citation2]. In the US, the risk is estimated to 63% [Citation3], while for example in Denmark, the risk is estimated to be 9–16% [Citation4].
Both qualitative [Citation5] and quantitative [Citation6] studies have reported adverse psychological effects for women receiving a false-positive mammogram. In a meta-analysis, women who experienced false-positive mammograms had greater distress, fear, anxiety, and worry about breast cancer than women who received normal mammograms [Citation7]. An observation supported by a later systematic review [Citation8,Citation9]. The International Agency for Research on Cancer (IARC) recently concluded that a false-positive mammogram has short-term negative psychological consequences for some women [Citation10].
To further elucidate the adverse psychological effects of false-positive mammograms, we studied the impact of false-positive mammograms on the intake of drugs, especially nervous system drugs used for mitigating anxiety and other mood disorders. We used data from a long-standing screening mammography program in Denmark combined with data from the nationwide drug prescription register. Previous studies of adverse effects of false-positive mammograms have focused exclusively on outcomes after the screening event. However, such a study design does not allow for control of a possible selection between women who later experience either a normal or a false-positive mammogram. In order to overcome this limitation, we included data on drug intake from both before and after the screening event.
Material and methods
The Copenhagen screening mammography program offers biennial screenings to women aged 50–69 years. The program started on 1 April 1991, and has direct access to the Central Registration System (CRS), which is used for identification of eligible women, who are personally invited to screening. Screening takes place at a specialized hospital clinic and is free of charge. The program has been described in detail elsewhere [Citation11]. The screening mammography register, based on the personal identification (CPR) number that all residents in Denmark have, includes data on invitations dates, participation, and outcome of screening and assessment. We used screening data from the years 1997 to 2006.
Women with false-positive mammograms were those with a positive mammogram and therefore recalled for further assessment, and where the assessment showed no breast cancer. Women were selected only at their first false-positive mammogram. Each woman with a false-positive mammogram was matched with a reference group of five women with the same age (year of birth) and time of screening (calendar year) and randomly selected from women with normal mammograms. After a false-positive mammogram a woman could not be sampled for the reference group. We included only women who according to CRS had been present in Denmark during the entire study period including two years before the screening event and two years after.
The Danish National Prescription Registry holds data on prescribed drugs in Denmark from the year 1995 onwards [Citation12]. Drug consumption is measured in units of Defined Daily Dose (DDD), which is defined as the assumed average maintenance dose per day for a drug used for its main indication in adults [Citation13]. The register furthermore holds information on number of packages, size of packages, date of dispenses, age at dispense date, name of medicament, Anatomical Therapeutic Chemical Classification System-code (ATC) and CPR number.
For the purpose of this study we included drugs from three categories: the nervous system drugs (N) including NO2 analgesics, NO5 psycholeptics, NO6 psychoanaleptics, and NO7 other nervous system drugs; the cardiovascular system drugs (C) including C07 beta-blocking agents, and C09 agents acting on the renin-angiotensin system, as these drugs are frequently used for treatment of anxiety; and from the genitourinary system and sex hormones drugs (G) including G03C estrogens, G03D progestogens, and G03F progestogens and estrogens in combination. We analyzed data for each drug group separately, and for the combined groups of N-, C- and G-products, respectively. For short we named these combined groups “anxiolytic and antidepressant drugs”, “beta blockers”, and “hormone therapy”, respectively. A consumption of more than 90 DDDs over two years (∼equal to three months consumption) was considered high-dose use, and less than or equal to 90 DDDs over two years was low-dose use.
By combining data from the screening mammography program and data from the prescription register we retrieved personal pre- and post-screening information on drug consumption in 1995–2008 for women screened between 1997 and 2006. Our intention was to determine whether the experience of a false-positive mammogram changed the drug consumption. With the inclusion of the reference group, we controlled for other changes from the before to the after period, e.g. the fact that the women got slightly older. For each woman we included the drug use during the two years preceding the screening test result and during the two years succeeding the test result.
For each combination of screening outcome (false-positive or normal), period (before and after the screening test), and drug we calculated the proportion of users, the proportion of high-dose users, and the proportion of low-dose users. Ninety-five percent confidence intervals (CI) were calculated assuming a binomial distribution. We calculated the ratio of the proportion for women with false-positive mammograms to that of women with normal mammograms both during the before and the after periods, and we calculated the ratio of the proportion for the after period to that of the before period both for women with false-positive mammograms and for women with normal mammograms. Finally, we calculated the ratio of the ratio from the after period to the ratio from the before period (RRR) to assess whether women experiencing a false-positive mammogram changed their drug consumption more or less than women experiencing a normal mammogram. As we had the same number of women in the respective groups in both the before and the after periods, this ratio of the ratios could be calculated as an odds ratio. Statistical analyzes were carried out with SAS 9.1. and Vassar Stats©Richard Lowry 1998–2015.
Results
A total of 11 436 women were included in the study, 1906 women with false-positive mammograms and 9530 women with normal mammograms (). The number of women with false-positive mammograms was low in 2003 and 2004, reflecting low activity in the screening program during these years.
Table 1. The study population by year: women with false-positive mammograms and reference group of women with normal mammograms, Copenhagen, Denmark 1997–2006.
During the two years before the test, 40.3% of women from the false-positive group versus 36.2% of women from the normal group used anxiolytic and antidepressant drugs, ratio 1.11 (95% CI 1.05–1.18) (). This difference derived from more women in the false-positive group using analgesics and psycholeptics. The distribution between high- and low-consumption users was the same for the false-positive and the normal groups. Equal proportions of women in the two groups used beta blockers, 13.4% and 12.8%, respectively, ratio 1.05 (95% CI 0.93–1.19), and the distributions between high- and low-consumption users were the same. Hormone therapy was used more frequently by the false-positive group, 36.6%, than by the normal group, 28.7%, ratio 1.28 (95% CI 1.19–1.36), a difference deriving from more users of combined progesterone and estrogen therapy, and from more high-consumption users in the false-positive group than in the normal group.
Table 2. Use of medicine in the two years preceding the screening test result, Copenhagen, Denmark 1997–2006.
During the two years after the test, 48.0% of women from the false-positive group versus 42.2% from the normal group used anxiolytic and antidepressant drugs, ratio 1.14 (95% CI 1.08–1.20), with more high-consumption users in the false-positive group (). The slight change came in particular from use of analgesics and psycholeptics. The use of beta blockers was 18.0% and 16.6%, respectively, ratio 1.06 (95% CI 0.96–1.18). The proportion of women from the false-positive group using hormone therapy remained constant at 36.6%, while the proportion increased slightly in the normal group to 29.5%, though still being significantly higher in the false-positive than in the normal group, ratio 1.24 (95% CI 1.16–1.33). In both groups, only use of estrogens increased from the before to the after period with a compensatory fall in the two other drug categories.
Table 3. Use of medicine in the two years succeeding the screening test result, Copenhagen, Denmark 1997–2006.
In the false-positive group, the proportion of women using anxiolytic and antidepressant drugs changed from 40.3% before the test to 48.0% after the test, ratio 1.19 (95% CI 1.11–1.28) ( and ). In the normal test result group the proportions changed from 36.2% to 42.2%, ratio 1.16 (95% CI 1.12–1.21). For beta blockers the ratios for after versus before were 1.35 (95% CI 1.16–1.56) and 1.30 (95% CI 1.22–1.40), respectively. For hormone therapy the ratios for after versus before were 1 (95% CI 0.92–1.09) and 1.03 (95% CI 0.98–1.07), respectively.
Finally, we calculated the RRRs to assess whether women experiencing a false-positive mammogram changed their drug consumption more or less than women experiencing a normal mammogram (). The difference in use of anxiolytic and antidepressant drugs between the false-positive and the normal groups increased from 4.1% in the before period to 5.8% in the after period, RRR 1.02 (95% CI 0.92–1.14). The difference between the two groups in use of beta blockers also remained fairly constant from 0.6% in the before period to 1.4% in the after period, RRR 1.03 (95% CI 0.86–1.23). The difference in use of hormone therapy also remained fairly constant from 7.9% in the before to 7.1% in the after period, RRR 0.97 (95% CI 0.87–1.10).
The sensitivity analysis including drug use from only one year before and one year after the screening event gave an RRR of 1.02 (95% CI 0.91–1.14) for anxiolytic and antidepressant drugs of 1.01 (95% CI 0.83–1.22) for beta blockers, and of 0.97 (95% CI 0.86–1.10) for hormone use. All results very close to those observed in the main analysis.
Discussion
Main results
Our study showed three important results concerning the association between a false-positive screening mammogram and the use of drugs. First, a selection effect, as women who later in their life experienced a false-positive mammogram were more frequent users of anxiolytic and antidepressant drugs and hormone therapy, even before this event, than women who later experienced a normal mammogram. Second, an aging effect, as the use of both anxiolytic and antidepressant drugs and beta blockers increased from the before to the after period for both women experiencing a false-positive mammogram and for women experiencing a normal mammogram. Third, an exposure effect that was, however, not statistically significant as the changes in drug use from the before to the after period were fairly similar for women experiencing a false-positive mammogram and for women experiencing a normal mammogram.
Strengths and weaknesses
The strengths of this study were its population-based design and use of only register data. This means that the study was not affected by non-responder and reporting biases. It was furthermore a strength that we included data from both before and after the screening event, which allowed us to assess the possible effect of selection. The Danish National Prescription Registry is considered to be of very high quality including data on all prescribed and retrieved drugs [Citation12]. However, the fact that a drug was retrieved did not necessarily translate into actual use, although use might be expected as patients have to pay for the drug at retrieval. The drug use was measured from the day after the screening, although normally a week will pass between the screening and the receiving of the screening result. Finally, it was not possible to include information on non-prescription drugs sold over the counter.
Previous studies
The majority of studies on effects of false-positive mammograms compared the outcomes, e.g. on psychometric scales, after the screening event between a false-positive and a normal group. In a meta-analysis of 17 studies from 2010, Salz et al. [Citation7] found that women who experienced false-positive mammograms had greater distress, fear, anxiety, and worry about breast cancer than women who received normal mammograms. Anxiety, not specifically related to breast cancer, was marginally higher in the false-positive than in the normal group, but there was no significant difference in other generic outcomes between the two groups. It was argued, however, that some of the general well being measures used in these studies aimed to uncover psychiatric disorders, which false positives are arguably unlikely to cause [Citation7].
Using a questionnaire designed specifically to measure consequences of screening in breast cancer, Brodersen and Siersma [Citation6] reported in 2013 that women with false-positive mammograms consistently scored higher on psychosocial outcomes as compared to women with normal mammograms up to three years after the screening event, with the largest differences seen for sense of dejection and anxiety.
A different study design was used by Barton et al. [Citation14] focusing on use of healthcare services within a large American health maintenance organization, and including also data from the year before the screening event. Before screening, women with false-positive mammograms had borderline significantly more breast-related visits than women with normal mammograms. After screening, this difference increased as clinicians initiated more breast-related visits for the false-positive group than for the normal group. Controlling for number of visits before, the false-positive outcome was associated with a significant increase in patient-initiated non-breast-related visits in the year after the mammogram, incidence ratio 1.18 (95% CI 1.09–1.28). However, in an earlier study, also from the Copenhagen program, re-participation in the mammography program was equal for women with false-positive results and women with negative results [Citation15].
An association between use of hormone therapy and the increased risk of false-positive mammograms is well documented [Citation16,Citation17].
Interpretation of findings
When we compared women with false-positive mammograms and women with normal mammograms after the screening event, our results were well in accordance with that of questionnaire-based psychometric tests, as the false-positive group had significantly more frequent users of anxiolytic and antidepressant drugs than the normal group. However, with the inclusion of the before screening period, our data pointed to a selection effect rather than an exposure effect, as the women who eventually experienced a false-positive mammogram had a higher consumption of anxiolytic and antidepressant drugs also before the screening event. This selection effect cannot be attributed to previous false-positive mammograms, as we included only women experiencing their first false-positive mammogram.
We included the before screening period in the present study to follow the “difference-in-differences” design we have used previously for measuring the effect of mammography screening on breast cancer mortality and overdiagnosis [Citation18]. The observation of a selection effect came as a surprise, though such an effect was to some extent also indicated in the study by Barton et al. [Citation14]. The clinical consequence of our finding is that the long-term adverse psychosocial outcomes after false-positive mammograms probably should be handled in a broader perspective also addressing each woman’s situation prior to the screening event. Further studies of screening effects including also data from before the screening event are highly warranted.
Our finding of a significantly more frequent use of hormone therapy in the false-positive group as compared with the normal group in the before period was expected, because hormone use is associated with increased breast density which again hampers the interpretation of screening mammograms. The level of hormone use was almost the same before and after the screening event. This might reflect combined effects of aging (from 48–68 years before to 50–72 years after) and the general decline in hormone prescriptions in Denmark after 2003 [Citation19]. It was nevertheless surprising that hormone use did not decrease for the false-positive group, although there was a slight change to the estrogen-only types.
Conclusion
In conclusion, the study showed that drugs used to mitigate anxiety and other mood disorders were consumed more frequently by women with false-positive mammograms than by women with normal mammograms. However, this difference existed also before the screening event, and the changes from before to after screening were fairly similar for the two groups of women. These findings stress the need for study designs with the ability to control for potential selection.
Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
This work was supported by Olga & Esper Boels Fund.
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