Family history of venous thromboembolism is a risk factor for venous thromboembolism in combined oral contraceptive users: a nationwide case-control study

The study was approved by the Ethics Committee of Lund University, Sweden (approval number 409/2008, with amendments approved on September 1 2009 and January 22 2010). It was performed in compliance with the Declaration of Helsinki. Consent was not obtained but the presented data are anonymised and there is no risk of identification.

We linked comprehensive register and health care data from multiple nationwide Swedish sources to form a database using the unique individual Swedish 10-digit personal ID numbers assigned to all residents. These ID numbers were replaced with serial numbers in order to preserve confidentiality. Our database contained the following sources [38‐42]: the Swedish Hospital Discharge Register, which included all hospitalizations in Sweden in 1964-2010; the Multi-Generation Register, which included information on family relationships for all individuals born in Sweden in 1932 and later; the Swedish Prescribed Drug Register, which included all prescriptions in Sweden picked up by patients between July 1 2005 and December 31 2010; the Swedish Cause of Death Register, which contained all causes of death and times of death from 1961-2010; and the Outpatient Care Register, which included information from outpatient clinics covering all geographic regions in Sweden from 2001-2010.

The dataset for these analyses was created by identifying from the Swedish Hospital Discharge Register and the Outpatient Care Register all females aged 15-49 with diagnoses of VTE during the period 2006 to 2010. We defined VTE based on the following ICD-10 codes: I636 (cerebral infarction due to cerebral vein thrombosis), I676 (cerebral vein thrombosis), I80 (venous thrombosis of the lower extremities [except I80.0, i.e. superficial thrombophlebitis]), I81 (portal vein thrombosis), I82 (other venous embolism or thrombosis) and I26 (pulmonary embolism). We used only main diagnoses to guarantee high validity (N = 7,795 VTE cases). Numbers of cases by each kind of venous thromboembolism are presented in Table 1. Furthermore we required that the patients retrieved from the pharmacy an antithrombotic agent within 14 days from the date of their VTE diagnosis (requirement 1). Antithrombotic agents were defined according to the following ATC codes: B01AA, B01AB (except B01AB02), B01AE, B01AF and B01AX. We also required that both the father and mother were registered in the Multi-Generation Register (requirement 2). Individuals with previously registered diagnoses of any type of VTE in the Swedish Hospital Discharge Register (from 1964) and/or the Outpatient Care Register (from 2001) were excluded (requirement 3). Any type of VTE was defined by the ICD-7, ICD-8, ICD-9 and ICD-10 codes found in Additional file 1: Table S1 [32‐35]. Individuals registered in the Swedish Hospital Discharge Register with the following prior to their VTE diagnosis were also excluded (requirement 4): Hysterectomy (surgical procedure codes LCD, 7220, 7221, 7222 and 7223), Bilateral oophorectomy (surgical procedure codes LAE20, LAE21, LAF10, LAF11, 7021, 7022, 7031 and 7032), Unilateral oophorectomy twice (surgical procedure codes LAF00, LAF01, 7020 and 7030), sterilization (surgical procedure codes LGA00-LGA98, 7150, 7151, and 7152), coronary heart disease (ICD10: I20-I25; ICD9: 410-414; and ICD8: 410-414), Heart failure (ICD10: I50, ICD9: 428, ICD8: 428), or cerebrovascular disease (ICD10: I60-I69; ICD9: 430-438; and ICD8: 430-438). The following exclusion criteria were additionally applied: diagnosis of any form of cancer in the Swedish Hospital Discharge Register within 5 years before or 1 year after their VTE diagnosis (cancer defined by the following ICD 10 codes: C00-C99) (requirement 5); treatment for infertility (ATC code G03G in the Swedish Prescribed Drug Register) (requirement 6); registered pregnancy within 9 months before or 3 months after the date of the VTE diagnosis (requirement 7); women who stopped use of any contraceptives prior to the VTE diagnosis according to the daily defined dose (DDD) from last retrieved recipe (requirement 8). We defined contraceptives by the following ATC codes: G03AA (except G03AA13) and G03AB. From the date the individual retrieved the drug from the pharmacy we used the DDD in order to calculate when they stopped using the drug. For example, if an individual retrieved the drug on January 1 2006 and the number of DDDs were 90 we considered the individual to have stopped using the drug 90 days after January 1 2006. However, if an individual retrieved a new COC within the 90 day period or less than 30 days after the 90 day period we continued to consider the individual as a user of contraceptives until the next period of use ended. Individuals who stopped using contraceptives prior to their VTE were excluded from the study. As the Prescribed Drug Register only contains data from July 1 2005 onwards we used a 6 month wash-out period. Hence, a VTE case could only be defined from the January 1 2006. In total we included 2,409 cases with VTE. In total, 5386 cases with VTE were excluded due to the mentioned exclusion criteria. Numbers of cases and controls excluded by each requirement (1-8) are shown in Table 2.

Each case was matched to five controls based on year of birth and education level. Socioeconomic data on education correlate with lifestyle factors [39]. Adjusting for education could help to diminish confounding by lifestyle factors [39]. Education level was categorized into three groups: low (0-9 years), middle (10-11 years) and high (12 years or more). For individuals 25 years and younger we selected the highest education level achieved by either the mother or father. In order to be eligible to be a control individual we applied the same criteria as for cases (requirements 2-8). Furthermore, the control individual had to be alive and registered in Sweden at the time of the case’s VTE diagnosis. An individual could only be selected as a control individual once. Moreover, 98 cases could not be matched to five controls and were excluded from the analysis. In total we included 2,311 cases and 11,555 controls in the analyses (Table 2).

As the main predictor variables in the models we used contraceptive use and family history of VTE. Contraceptive use was defined as described above; however, in order to be defined as a user cases had to be using contraceptives at the time of their VTE diagnosis. Controls had to be using contraceptives on the day of the VTE diagnosis in the corresponding case. Family history was defined as any type of VTE (see definition above) among first-degree relatives (mother, father and/or sibling(s)). The VTE in relatives had to be registered prior to the contraceptive prescription date for the case/control and in situations where the individual had no contraceptive use prior to the date of the VTE diagnosis in cases.

We used conditional logistic regression in order to study the effects of contraceptives, family history of VTE and their interaction on VTE. In models A1 and A2 we separately investigated the effects of contraceptives and family history of VTE on VTE, respectively. In model B we included both variables in the same model. Model C also included the interaction between contraceptives and family history of VTE. As the results from the conditional logistic regression are on the multiplicative scale we also used a hierarchical regression model (i.e., using the identity link) in order to get the interaction results on an additive scale.

In additional analyses, using conditional logistic regression, we investigated whether different generations of combined oral contraceptives had different effects. Both fixed combination (G03AA) and sequential preparations (G03AB) were considered. Contraceptives were categorized into five groups according progestogen content [43]: first-generation progesterone (ATC codes: G03AA03 [lynestrenol, G03AA05 [norethisterone], G03AA01 [ethynodiol], G03AB02 [lynestrenol], G03AB04 [norethisterone]); second-generation progesterone (ATC codes: G03AA06 [norgestrel], G03AA07 [levonorgestrel], G03AB03 [levonorgestrel]); third-generation progesterone (G03AA09 [desogestrel], G03AA11 [norgestimate], G03AB05 [desogestrel], G03AB06 [gestodene]); fourth-generation progesterone (ATC code: G03AA12 [drospirenone]); and undefined (ATC code: G03AA14 [nomegestrol]). In the models we created one term for contraceptives (yes/no) and one categorical variable defining each generation. We used the first generation as the reference in the analysis. Furthermore, we explored whether the effect of contraceptives on VTE was stronger among individuals who were newly prescribed contraceptives. We arbitrarily use 6 months prior to the date of VTE diagnosis as the cut-off. Individuals who had used contraceptives for less than 6 months were defined as new users. Finally, we investigated whether the effect of contraceptives was different for diagnosis of VTE at different ages. We included an interaction term between contraceptives and age at VTE diagnosis (mean 36.4 years). In the models the main effect of age is not included but only the interaction between COC use and age [44]. All statistical analyses were performed in SAS 9.3.