Bakken, Inger Johanne PhD*; Skjeldestad, Finn Egil MD, PhD*; Lydersen, Stian PhD†; Nordbø, Svein Arne MD‡
CHLAMYDIA TRACHOMATIS IS A HIGHLY prevalent sexually transmitted disease.1–3 Although there is no systematic screening program in Norway, testing rates among young women are high, as are the positivity rates.4 At the age of 25, 1 in 6 Norwegian women has been diagnosed with C. trachomatis at least once.4 Chlamydial infections have potential long-term consequences such as pelvic inflammatory disease, tubal factor infertility, and ectopic pregnancy,5 and women diagnosed with the infection are often anxious about their future fertility.6,7
The link between C. trachomatis infection and ectopic pregnancy was established in case-control studies where antibody status of women with ectopic pregnancy was compared with that of women without ectopic pregnancy.8–12 The fertility prospects for women diagnosed with C. trachomatis are however not well described.13 Ectopic pregnancy incidence rates in the study area14 and in the whole of Norway15 have decreased strongly during the time period of the current study. Declining ectopic pregnancy trends have also been reported from Finland16 and Sweden,17 whereas stable trends have been reported from Australia.18 Declining ectopic pregnancy rates in areas with high C. trachomatis testing frequency might indicate that such screening is efficient.19
Recently, we20 and other21,22 Scandinavian research groups have published studies where data on C. trachomatis tests have been linked to hospital and registry data on long-term reproductive tract complications. The results from these studies are contradictory. Although we found a significant association between previous C. trachomatis infection and subsequent ectopic pregnancy,20 a reduced risk of ectopic pregnancy after C. trachomatis infection was reported from Denmark,21 and no association was found in the Swedish study.22
In the Danish and Swedish studies, the C. trachomatis databases covered the time periods 1985–1996 and 1984–1993, respectively, whereas our C. trachomatis database covered more recent years (1990–2003). In our previous study we investigated prior C. trachomatis infection among women with ectopic pregnancy applying a nested case-control design.20 In the current study we applied a retrospective cohort design to investigate ectopic pregnancy rates and birth rates by test result among women tested for C. trachomatis in a routine clinical setting.
Materials and Methods
The study was carried out in Sør-Trøndelag County, central Norway. Of the county's 270,000 inhabitants ∼150,000 are living in the major city, Trondheim.
In Norway, all citizens are given a unique 11-digit identification number at birth or at immigration. In the current study, we used 3 databases, all containing the personal identifier and data on residency.
In Sør-Trøndelag County, a single laboratory is responsible for all C. trachomatis diagnostics.4 The C. trachomatis database contains information on all tests (date, diagnostic method, and test outcome) in the county from November 1990 to December 2003 with person as the unit of analysis. Data on specimens collected within 60 days from a previous test were excluded from the analyses.
The ectopic pregnancy database covers all women hospitalized with the diagnosis during 1970–2004 at the 2 hospitals in the county (Orkdal Hospital and the Trondheim University Hospital). Patients with ectopic pregnancy were identified through computerized hospital in- and outpatient registries by using the International Classification of Diseases (ICD) eighth Revision code 631 over the period 1970–1978, the ICD ninth Revision code 633 during 1979–1998 and the ICD 10th Revision codes O00.0–O00.9 over the years 1999–2004. All medical records were reviewed, and only diagnoses verified with histology and/or ultrasound were defined as cases. The ectopic pregnancy database is described in detail elsewhere.14
The complete history of births for each woman registered in the C. trachomatis database was obtained from the Medical Birth Registry of Norway (data updated until December 31, 2004).
Several methods were used for C. trachomatis detection throughout the study period.4 Briefly, the IDEIA Chlamydia Test, Celltech Diagnostics/Novo BioLabs/DAKO was replaced by PACE 2, GenProbe in 1992, whereas Amplicor from Roche Molecular Systems became the routine detection method in 1999. Overall, 18% of tests were carried out using the IDEIA Chlamydia Test, 31% were analyzed using PACE 2, while 51% of tests were analyzed using the Amplicor system.
During November 1, 1990 to December 31, 2004, 90,309 women were tested for C. trachomatis, among whom 61,283 were resident in Sør-Trøndelag County (Fig. 1). We excluded 1706 women without a valid personal identification number. We furthermore excluded 37,655 women born before 1970 or after 1984. By including only women who were 20 years old or younger when computerized registration of test results started in 1990, we obtained a study population with a nearly complete testing history. We finally excluded 1160 women who were registered with a pregnancy before their first registered C. trachomatis test, either an ectopic pregnancy (n = 70) or a birth (n = 1090). The final study population consisted of 20,762 women who had not given birth or experienced an ectopic pregnancy before their first C. trachomatis test.
Confidence intervals (95%) for proportions were calculated using the Wilson-method in CIA software.23 All other analyses were carried out using SPSS for Windows, version 13.0 (SPSS, Chicago, IL).
For estimation of hazard ratio for ectopic pregnancy by C. trachomatis status we used Cox regression analysis with months from the first C. trachomatis test as the time variable. C. trachomatis status and parity were entered as time-dependent covariates. C. trachomatis status changed at the date of a positive test. Correspondingly, parity status changed at the date of delivery. Analyses were adjusted for age at first test. Women were followed up until the first date of hospitalization with a diagnosis of ectopic pregnancy or censored on December 31, 2004.
Analyses of births were carried out with C. trachomatis status as a time-dependent covariate and adjustment for age at first test. Women were followed up from the date of their first registered C. trachomatis test until the date of their first birth or censored on December 31, 2004.
We finally analyzed the risk of ectopic pregnancy by C. trachomatis status in a model where the study population was limited to women registered with an ectopic pregnancy or a birth during the follow-up period (N = 10,794).
The study was approved by the Regional Committee for Medical Research Ethics, Central Norway, and the Norwegian Data Inspectorate. Authorization for the use of laboratory data and data retrieved from medical records was obtained from the Norwegian Directorate of Health and Social Affairs.
The total follow-up time from time of first C. trachomatis infection until first ectopic pregnancy or censoring was 166,846 person-years. The average duration of the follow-up period was 8.2 person-years (SD 3.9 person-years).
A total of 72,405 tests were registered among the 20,762 women in our study cohort during the follow-up period. The average age at first test was 19.8 years (SD 3.2). A single test was registered for 5668 women (27%). Four thousand one hundred and eight (20%) women were registered with 2 tests, 3079 (15%) women had 3 tests, and 7907 (19%) had 4 or more tests. There was a large variation in the time intervals between tests. We calculated the time interval between the first 2 tests and the second and the third test. For 4236 women, both the time interval between the first 2 tests and the time interval between the second and the third test were 18 months or shorter, indicating that 20% of the total study population were screened on fairly regular basis.
Overall, the proportion of positive tests was 6.2% (4503 of 72,405). The proportion of positive tests was highest early in the study period; 1990–1993: 8.2% (889 of 11,737), 1994–1996: 6.9% (991 of 14,368), 1997–1999: 5.4% (903 of 17,617), 2000–2003: 6.6% (1720 of 27,692).
When we restricted the analysis to the first test for each women we observed the following prevalences; 1990–1993: 8.1% (513 of 6371), 1994–1996: 7.8% (345 of 4445), 1997–1999: 6.0% (259 of 4308), 2000–2003: 8.4% (477 of 5645).
During the observation period, 18% of the women in the cohort were infected with C. trachomatis at least once (3659 of 20,762). A single infection was registered for 2978 women (14%), 546 (3%) were registered with 2 infections, and 131 (1%) with 3 or more infections.
At least 1 reproductive event (birth and/or ectopic pregnancy) was registered for 10,828 out of the 20,759 women in the cohort (52%). As first reproductive event, we observed 10,728 births and 100 ectopic pregnancies (average maternal age 24.3 [SD 3.6] and 24.3 [SD 4.1], respectively). We observed 70 first ectopic pregnancies among women with prior births.
Twenty-six out of the 3,321 women with prior C. trachomatis infection experienced an ectopic pregnancy as their first reproductive event (0.78%; 95% CI, 0.53–1.14). The corresponding number among the 17,441 women without prior infection was 74 (0.42%; 95% CI, 0.33–0.53).
The proportion of women experiencing ectopic pregnancy only, or an ectopic pregnancy as first reproductive event followed by intrauterine pregnancy, was slightly higher among women with positive C. trachomatis status compared with women with negative C. trachomatis status (Table 1). However, the proportion of women experiencing an ectopic pregnancy after an intrauterine pregnancy was similar in the 2 groups.
Irrespective of C. trachomatis status at the end of the observation period, births greatly outnumbered ectopic pregnancies (Table 1). In either study group, approximately 50% of the women gave birth during the observation period.
Ectopic Pregnancies Incidence, Total Cohort
Table 2, model no. 1, shows that the incidence of ectopic pregnancy was higher for women with 1 or more prior infections compared with women with negative tests only (hazard ratio, 1.82; 95% CI 1.27–2.60). The risk of ectopic pregnancy increased in a dose-dependent manner with increasing number of prior infections (Table 2, model no. 2).
Incidence Rates of Births, Total Cohort
Overall, 10,784 women in the cohort experienced at least 1 birth. We observed that women with at least 1 prior positive C. trachomatis test had a slightly elevated risk of giving birth compared with women without prior infection (hazard ratio 1.07; 95% CI 1.01–1.12) (Table 3).
Ectopic Pregnancies in the Subgroup of Women With Registered Pregnancy
We finally estimated the risk of ectopic pregnancy in the subcohort of women with registered pregnancy (N = 10,794). The risk estimates were slightly higher in these models compared with the models including all women. The adjusted hazard ratio for women with 1 or more infections was 2.03 (95% CI 1.28–3.22) with women with negative tests only as the reference group (Table 4, model no.1). We observed that the risk of ectopic pregnancy increased in a dose-dependent manner with increasing number of prior infections (Table 4, model no. 2).
This registry-based cohort study shows that women diagnosed with C. trachomatis infection had twice the risk of ectopic pregnancy compared with women with only negative tests, while birth rates were similar in the 2 groups.
The current study is unique in that we had access to data on all C. trachomatis tests over a long time period (1990–2003) within a well-defined geographic region (county) for a young cohort with a high testing frequency,4 at least compared with previous registry studies.21,22 By comparison with data from Statistics Norway, we estimate that our population represents ∼80% of all women born 1970–1984 in the study area (data not shown). We identified all cases of ectopic pregnancy through hospital in- and outpatient registries14 and retrieved the complete history of births for all women in the cohort from the Medical Birth Registry, which is a mandatory national registry.
The study's main limitation is that our study population consists of women tested for C. trachomatis in a routine clinical setting. Because the women were not systematically screened, the number of tests for each woman varied, as did the interval between tests. Furthermore, over the study period, there was a change in test technology towards more sensitive tests. We did not have access to data on the use of contraception, sexual activity, or intention to conceive among the women in our study population.
We found a higher ectopic pregnancy incidence rate among women diagnosed with C. trachomatis infection than among women with negative tests only. An elevated risk for ectopic pregnancy related to prior C. trachomatis infection was observed not only in the total study population but also when we restricted the study population to women with a registered pregnancy. The findings were in concordance with results from our previous case-control study where women with ectopic pregnancy more frequently had been diagnosed with C. trachomatis than controls.20 We found a dose-dependent association between prior C. trachomatis infections and the risk of ectopic pregnancy, in line with a study from the United States.24 In a Swedish registry-linkage study,22 however, women with previous C. trachomatis infection were found to have no elevated risk of ectopic pregnancy compared with women with negative test results only. Furthermore, in a recent Danish registry study,21 women with previous C. trachomatis infection were found to be at lower risk than women with negative tests only. The most important difference between the Swedish and Danish studies and ours is that while we had access to nearly complete data on C. trachomatis testing, testing history was only known for parts of the observation period in the other studies. The C. trachomatis databases covered the time periods 1984–1993 and 1985–1996 in the studies from Denmark and Sweden, respectively, whereas outcomes were assessed until 2002 and 1999. Missing data on testing history and a large proportion of tests analyzed with less sensitive technology will tend to bias the results towards the null because of misclassification of infection status.
Although the current study showed higher ectopic pregnancy incidence rates among women with prior positive tests than among women with negative tests, incidence rates for ectopic pregnancy were low in either group. Birth rates were high and comparable in the 2 groups, in concordance with the results in the Danish registry study.21 The observation that women with 1 or more positive C. trachomatis test were at higher risk for giving birth probably reflects a higher total pregnancy rate among these women.
In our opinion, it seems likely that at least part of the decline in ectopic pregnancy reported from Norway,14,15 Finland,16 and Sweden17 is due to extensive screening for C. trachomatis and treatment of women diagnosed with the infection. Also, a randomized, controlled trial from the United States has shown that women screened for C. trachomatis were at lower risk for ectopic pregnancy compared with women outside the screening intervention.25
It has been suggested that the relatively low incidence of lower genital tract complications among women diagnosed with C. trachomatis infection indicate that the benefits of chlamydia screening programs might have been overestimated.22 However, registry studies include women tested for C. trachomatis, and it seems unlikely that a large proportion of women with such infection were left untreated. The low ectopic pregnancy incidence rates also among women with positive tests might rather suggest that screening for chlamydial infection benefits female reproductive health. The findings in the current study and in the other Scandinavian registry studies21,22 indicate that women with positive test results, often anxious about their future fertility,6,7 can be reassured that the risk of long-term reproductive health consequences is low, at least when it comes to ectopic pregnancy.
In conclusion, the current study shows a clear link between a diagnosis of C. trachomatis infection and ectopic pregnancy. However, ectopic pregnancy was a rare event also among women with prior infections, and birth rates were independent of C. trachomatis history. These results together with the strong recent decline in ectopic pregnancy indicate that screening for C. trachomatis should be continued.
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