Article Text

Cost effectiveness analysis of a population based screening programme for asymptomatic Chlamydia trachomatis infections in women by means of home obtained urine specimens
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1. Irene G M van Valkengoed1,
2. Maarten J Postma2,
3. Servaas A Morré3,
4. Adriaan J C van den Brule3,
5. Chris J L M Meijer3,
6. Lex M Bouter1,
7. A Joan P Boeke1
1. 1Institute for Research in Extramural Medicine, Vrije Universiteit, Amsterdam, Netherlands
2. 2Groningen University Institute for Drug Exploration, Groningen, Netherlands
3. 3University Hospital Vrije Universiteit, Department of Pathology, Section of Molecular Pathology, Amsterdam, Netherlands
1. Dr A J P Boeke, Institute for Research in Extramural Medicine, Vrije Universiteit, Van der Boechorststraat 7, 1081 BT Amsterdam, Netherlands ajp.boeke.emgo{at}med.vu.nl

## Abstract

Objectives: To evaluate the cost effectiveness of a systematic screening programme for asymptomatic Chlamydia trachomatis infections in a female inner city population. To determine the sensitivity of the cost effectiveness analysis to variation in the probability of developing sequelae.

Methods: A decision tree was constructed to evaluate health effects of the programme, such as averted sequelae of chlamydial infection. Cost effectiveness from a societal perspective was estimated for screening by means of a ligase chain reaction on mailed, home obtained urine specimens, in a population with a C trachomatis test prevalence of 2.9%. An extensive sensitivity analysis was performed for the probability of sequelae, the percentage of preventable pelvic inflammatory disease (PID), and the discount rate.

Results: The estimated net cost of curing one woman, aged 15–40 years, of a C trachomatis infection is US$1210. To prevent one major outcome (PID, tubal factor infertility, ectopic pregnancy, chronic pelvic pain, or neonatal pneumonia), 479 women would have to be screened. The net cost of preventing one major outcome is$15 800. Changing the probability of PID after chlamydial infection from 5% to 25% decreases the net cost per major outcome averted from $28 300 to$6380, a reduction of 78%. Results were less sensitive to variations in estimates for other sequelae. The breakeven prevalence of the programme ranges from 6.4% for the scenario with all probabilities for complications set at the maximum value to a prevalence of 100% for probabilities set at the minimum value.

Conclusions: Systematic screening of all women aged 15–40 years for asymptomatic C trachomatis infections is not cost effective. Although the results of the analyses are sensitive to variation in the assumptions, the costs exceed the benefits, even in the most optimistic scenario.

• cost effectiveness analysis
• Chlamydia trachomatis
• screening

## Introduction

Genital infections caused by the bacteria Chlamydia trachomatis are the most common sexually transmitted infections in industrialised countries. In women, C trachomatis can cause urethritis, cervicitis, pelvic inflammatory disease (PID) and, at a later stage, tubal factor infertility (TFI), ectopic pregnancy (EP), and chronic pelvic pain (CPP).1, 2 When giving birth an infected woman can pass the infection on to her child, who can develop a neonatal conjunctivitis or pneumonia as a result of the infection.3

Since genital chlamydial infection causes no or few symptoms, many infections remain undetected. Delayed treatment increases the risk of sequelae and transmission to sex partners. Screening is therefore indicated to prevent the spread of C trachomatis and also to prevent complications. Research in the United States and Sweden has shown that the detection and treatment of asymptomatic infections in women results in a reduction of complications.4, 5

Cost is an important factor, which should be taken into consideration before a screening programme is implemented. Cost effectiveness analyses of opportunistic screening programmes, focusing on patients attending healthcare clinics, or specific high risk groups, have shown that screening becomes cost effective at prevalences ranging from 2% to 6%.68 The introduction of sensitive DNA detection methods to test non-invasive specimens, such as urine, and the testing of mailed home obtained samples makes it possible to extend screening beyond the traditional settings.912 The cost effectiveness of systematic screening programmes in the general population has not been evaluated.

In most cost effectiveness studies to date the costs of organising the screening, including administrative costs, have not been included in the analysis. Furthermore, although some studies mention the imperfect specificity of the test, no study has taken the cost of follow up of false positive test results into account in the analysis. So far, only one study has reported a sensitivity analysis of risk estimates, although estimating the probability of complications based on the available literature leaves much room for variation.7

This paper reports on the cost effectiveness of a systematic screening programme for asymptomatic C trachomatis infections in women registered in general practice, based on mailed home obtained urine specimens. The sensitivity of the cost effectiveness analysis to variation in the probability of developing PID, EP, TFI, and CPP was determined.

## Methods

### RECRUITMENT

A random sample of 5541 women, aged 15–40 years, was selected from the computer registers of 16 inner city general practices in Amsterdam. Between November 1996 and October 1997 these women were invited by their general practitioner to participate in the screening programme. Coded research material was sent to the home address of potential participants. Participants were requested to mail a first void, first stream urine sample and a completed questionnaire to the department of pathology in a prestamped addressed envelope, which was included in the material.

The study has been approved by the medical ethics committee of the Vrije Universiteit in Amsterdam.

### DIAGNOSIS OF INFECTION

Urine samples were tested for the presence of C trachomatis by means of the ligase chain reaction (LCR) (Abbott Laboratories, Chicago, IL, USA) in the laboratory of the department of pathology of the University Hospital Vrije Universiteit.912 Tests were performed according to the instructions of the manufacturer.

The test results were reported back to the general practitioners, who were instructed to treat infected patients with a single dose of 1000 mg azithromycin, or erythromycin for pregnant women (4 × 500 mg for 5 days).

### CHARACTERISTICS OF PARTICIPANTS

Fifty per cent of the women who were invited participated in the screening programme; 25% of the participants were of non-Dutch origin. Of all participating women, 120 had never been sexually active. The prevalence of asymptomatic infection, as determined by means of the LCR on urine for women aged 15–20 years, 21–25 years, 26–30 years, 31–35 years, and 36–40 years was 2.4%, 4.4%, 2.8%, 2.5%, and 2.2%, respectively.

### DECISION TREE ANALYSIS

Figure 1 is a diagram of the decision tree used in the analysis. The sensitivity of the LCR on urine was estimated to be 85%, and the specificity 99%.9, 10 The assumptions for the risk of an untreated C trachomatis are listed in table 1. The risk of developing sequelae if treatment fails is assumed to equal the risk if a woman has not been tested or treated effectively.

Table 1

Estimates and ranges used for the sensitivity analysis of the cost effectiveness of a universal screening programme for asymptomatic Chlamydia trachomatis infections in a female population

Figure 1

Decision model for a population based screening programme for asymptomatic Chlamydia trachomatis infections in women. *Both A and B apply for all infected women. **Pregnancy wish is taken into account.

As shown in figure 1 and table 1, the probability of pregnancy wish is age specific.15 This was included in the model to estimate how many women would develop an EP or consult a specialist for TFI. In addition, only women who gave birth while infected with C trachomatis were included in calculations of the probability of having a child with neonatal conjunctivitis or neonatal pneumonia.15 For the infectious period, an average of 52 weeks was assumed.16

### DIRECT COSTS

The administrative costs and the costs of the materials sent to all women who were invited, were taken into account in the model (table 2).

Table 2

## Results

### BASELINE ANALYSIS

As can be directly derived from the assumptions made, the probability of an infected woman being detected by the screening and being effectively treated is estimated at 73%. The overall test prevalence of 2.9%, found among women in Amsterdam corresponds with an estimated prevalence of 2.2%, corrected for sensitivity and specificity of the test assumed in the model. In a screening programme aimed at women aged 15–40 years, 889 women would have to be screened to prevent one major outcome. Given the current participation rate, approximately twice this number of women would have to be invited for screening. The implementation of screening for all women aged 15–40 years in Amsterdam (n=161 065) could prevent a total of 59 episodes of PID, three TFIs, six EPs, and nine cases of CPP, and could also prevent 13 cases of neonatal pneumonia from occurring as a result of chlamydial infection.

The net cost per woman cured for a screening programme directed at women aged 15–40 years is $1210 per woman cured (table 3). Table 3 Cost effectiveness analysis of a screening programme for asymptomatic Chlamydia trachomatis infections in a low prevalence female population (in US$)

Limiting the programme to women aged 15–25 years reduces the net cost per woman cured to $790. Net costs per MOA are$15 800 and $11 100, respectively. ### SENSITIVITY ANALYSIS The results of the sensitivity analyses are presented in table 4. Changing the estimate for the probability of developing PID after chlamydial infection from 5% to 25% decreases the cost per major outcome averted from$28 300 to $6380, a reduction of 78%. Similarly, plausible ranges for the probability of ectopic pregnancy, infertility, and chronic pelvic pain result in variations of 12%, 5%, and 7%, respectively. Changing the value of the percentage of PIDs that can be prevented by screening from 75% to 25% results in a 63% decrease in cost per major outcome averted. Assuming a further technical development of tests, a test sensitivity of 90% and a specificity of 99.9% were also taken into consideration. Increasing the assumed specificity resulted in a decrease in cost per major outcome averted from$15 800 to $9540, a decrease of 40%. Table 4 Sensitivity analyses for a screening programme for women aged 15–40 years; variations in the probability estimates for sequelae, discount rate, and test characteristics (in US$)

Finally, changing the discount rate from 0% to 7% results in an increase of 1% in cost per MOA.

### BREAKEVEN PREVALENCE

Figure 2 shows the association between test prevalence and net cost per MOA of the programme aimed at women aged 15–40 years. The breakeven prevalence in the baseline analysis was 41.8%. The breakeven prevalences range from 6.4% for the best case scenario to 100% for the worst case scenario.

Figure 2

Breakeven prevalences for a screening programme for asymptomatic Chlamydia trachomatis infections in a female population: baseline assumptions, maximum probabilities, minimum probabilities. MOA = major outcome averted (either an episode of pelvic inflammatory disease (PID), chronic pelvic pain, ectopic pregnancy, tubal factor infertility, or neonatal pneumonia). Maximum probabilities: assumption for all PID 25%, tubal factor infertility 4%, ectopic pregnancy 4%, chronic pelvic pain 10%. Minimum probabilities: assumption for all PID 5%, tubal factor infertility 4%, ectopic pregnancy 4%, chronic pelvic pain 20%.

The breakeven prevalence of a programme aimed at women aged 15–25 ranges from 6.1% to 100% in the sensitivity analysis.

As a test prevalence of 2.9% was found among 15–40 year old women in Amsterdam, the range of cost per MOA, reflecting the range in probabilities, would be $1514 (maximum probabilities) to$48 604 (minimum probabilities). Similarly, at a test prevalence of 5%, the interval for net cost per MOA would range from $338 to$7485.

## Discussion

This is the first cost effectiveness analysis of a systematic, universal screening programme based on mailed home obtained urine specimens in the general population. The results show that the cost of a screening programme for women was found to exceed the benefits in both the baseline and the sensitivity analysis. Screening all women aged 15–40, under baseline assumptions, only becomes cost saving at a test prevalence of 41.8% or more.

The overall test prevalence in the study population was 2.9%. Cost effectiveness for the screening programme directed at women aged 15–40 years was estimated at $15 800 per MOA. Restriction of the programme to women aged 15–25 years lowers the net costs to$11 100 per MOA. Another frequently used outcome in cost effectiveness analyses of chlamydia screening is cost per PID averted. PID constitutes 66.3% of the cost per MOA at baseline.

Selective screening is one way of increasing the efficiency of screening. Several authors have suggested selective screening criteria for various settings.7, 8, 29 However, suitable selection criteria could not been identified for asymptomatic infections among the general population in Amsterdam30; thus, currently a comparison can only been made between a universal screening programme and no screening at all.

The risk estimates for chlamydial infection, used in the decision model, differ from estimates used in previous cost effectiveness analyses. Previous studies have used estimates for PID and tubal factor infertility of 25–30% and 10–12%, respectively.

However, no long term follow up studies of asymptomatic infections in a low prevalence population have yet been performed. Authors have based the estimates on studies among women with symptomatic infections, even though asymptomatic infections are most likely to be less virulent. In order to take that factor into account, lower estimates were used at baseline, and the estimates were varied over a wide range in the sensitivity analysis.

Similarly, the risk of a silent PID should be treated differently from the risk of an overt PID. Although several studies have attempted to study the association between silent PID and sequelae,31, 32 there is not insufficient evidence to quantify any association. Consequently, it was not possible to make a distinction between silent and overt PID in the analysis. Instead, the baseline probability of developing sequelae after PID was adjusted, and a sensitivity analysis was performed.

The results of the sensitivity analysis underscore the importance of valid risk estimation, since this can have a substantial impact on the outcome of the analysis. In this study, the cost per MOA was extremely sensitive to variations in the assumption reflecting the chance of developing PID. Increasing the estimate from 5% to 25% resulted in a 78% decrease in cost per MOA. A similar effect was seen when the percentage of preventable PIDs was changed from 75% to 25%. The model was also sensitive to the specificity of the test. No health gains or associated averted costs can be achieved among cases with a false positive test result; the costs decrease by 40% if the specificity of the test is estimated at 99.9% instead of 99%. Variations in the estimates for ectopic pregnancy, tubal factor infertility, chronic pelvic pain, test sensitivity, and discount rate had much less impact.

### COSTS CONSIDERED

All costs have been estimated for the Netherlands and converted into US\$. Cost in the model could reflect local differences in healthcare organisation and labour costs. Furthermore, the costs of health care and tests may change over time.

In the decision tree, the cost of all materials sent to participants and non-participants was included. Administrative costs, such as programme coordination, were also included. In practice, the costs will probably be higher, because of extra consultations for women who are worried about the potential consequences of the infection, the cost of media campaigns and other activities that would accompany the implementation of a programme. Furthermore, no physician fees for the screening were included, although other programmes—for example, influenza vaccination, that have been implemented in the Netherlands have included fees for physicians.33

In the analysis, complications of antibiotic treatment and referral and treatment of partners were not taken into consideration. Infected partners may reinfect females who have been screened, and can contribute to the spread of the infection in the population. It has been suggested recently, that men should always be included in a screening programme, and not just as “partners of infected women,”34 the reason for this being that targeting women only “stereotypes” them and affects their sexuality. Partner referral and screening aimed at men will be taken into account in a future evaluation of the effects of screening over time, using a more sophisticated dynamic model.

One hazard of cost effectiveness analysis is that it provides a unidimensional view of screening. The emphasis is placed on proving that the intervention is cost effective although, as this study shows, results can depend strongly on the assumptions included in a decision model. Moreover, other important aspects, such as invasion of privacy, psychological and social consequences of the test result, and the danger of medicalisation cannot be included in the model.

In conclusion, a universal screening programme for asymptomatic C trachomatis infections among 15–40 year old women is not cost effective. Although the results of the analyses are sensitive to variation in the assumptions, the costs exceed the benefits even in the most optimistic scenario.

## Acknowledgments

The authors would like to thank all practices and patients for taking the time to participate in the screening. This study was supported by the Zorg Onderzoek Nederland (previously called the Prevention Fund) grants 28-2588 and 28-1182-1.

Conflict of interest: none

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