Key Points
The cancer risk during the first year after a pregnancy-related venous thromboembolism episode is higher than expected.
An aggressive search for cancer in women with pregnancy-related venous thromboembolism is probably not warranted, due to low absolute risk.
Introduction
Cancer increases the risk of venous thromboembolism (VTE) through direct interaction between tumor cells and the hemostatic system and due to tumor pressure.1 In nonpregnant patients, VTE and superficial venous thromboses are associated with an increased prevalence of occult cancer.2-5 The association is particularly strong for cancers of the lungs, ovaries, pancreas, brain, and liver, as well as for non-Hodgkin lymphomas.2 It is unclear whether a VTE occurring during pregnancy or the postpartum period is a marker of occult cancer as well.2-5 Given the trend of postponing childbirth6 and the increasing risk of most cancers with age, the number of women giving birth who are at risk of cancer is expected to increase.7,8 Pregnancy itself is protective against gynecological cancers, most nongynecological cancers, and breast cancer over the long term.7,9,10 VTE risk increases with advancing gestation and peaks in the days around delivery.10-14 Obesity, hospitalization, postpartum bleeding, and cesarean section are risk factors for antepartum and postpartum VTE.11,14
In one previous Norwegian study based on data from 577 pregnant women with first-time VTE, Wik et al reported a long-term follow-up, age-adjusted hazard ratio of 2.6 (95% confidence interval [CI], 1.3-5.6) for cancer diagnoses compared with a control group of women without VTE who delivered at the same time as the matching cases. However, the cancer risk was not elevated when compared with female, age-specific cancer rates obtained from the Norwegian Cancer Registry (standardized incidence ratio [SIR], 1.0, 95% CI, 0.6-1.7)15 making the data difficult to interpret.
Methods
We conducted a large, nationwide study to examine whether VTE episodes (both incident and recurring VTE, including deep VTE and superficial venous thrombosis) during pregnancy and the postpartum period is associated with an increased risk of a subsequent malignancy diagnosis. The tax-supported Danish health care system ensures equal and income-independent free access to health care services to all residents. Those born in or immigrating to Denmark receive a unique Civil Personal Register number, enabling linkage among Danish registries at the individual level.16 This nationwide cohort study made use of data from the Danish National Patient Registry (DNPR),17 the Danish Cancer Registry (DCR),18,19 the Medical Birth Registry (MBR),20 and the Civil Registration System.16 The DNPR has recorded data on all admissions and discharges from Danish nonpsychiatric hospitals since 1977 and from emergency and specialist outpatient clinic visits since 1995.17 Each hospital discharge or outpatient visit is coded in the DNPR according to the International Classification of Diseases, Eighth Revision from 1977 until the end of 1993 and Tenth Revision thereafter. The DCR includes prospectively collected complete and valid data on all incident cases of primary cancer diagnosed in Denmark since 1943.18,19 The DCR records information on tumor staging at diagnosis according to TNM (tumor, node, metastasis) and Ann Arbor classifications. Reporting to the DCR has been mandatory for all hospital departments from 1987 and for general practitioners from 2004 ensuring national completeness of the register.18,19 The DCR data are linked to the National Pathology Register for ensuring high validity of the diagnoses; 89% of the malignancy diagnoses in the DCR are with histopathological verification. Furthermore, continuous manual and electronic quality control ensures the high quality of the DCR.19 The MBR contains prospectively collected data on all deliveries in Denmark since 1 January 1973.20
We used the MBR to identify all cancer-free women delivering a child from 1 January 1978 to 30 November 2013. The postpartum period was defined as the first 12 weeks after the delivery date, divided into the early (first 6 weeks after delivery) and the late (6-12 weeks after delivery) postpartum period.11 We linked MBR data with DNPR data to obtain information on VTE (including superficial thrombosis) and with DCR data to identify cancer diagnoses. We included all inpatient and outpatient hospital diagnoses recorded in the DNPR, with the date of discharge defined as the VTE diagnosis date. Cardiovascular diagnoses, including VTE diagnoses, in the DNPR have positive predictive values of 70% to 100%.21-23 We obtained information from the DNPR on risk factors for VTE (obesity, smoking, surgery, fracture, trauma, cesarean section, and postpartum bleeding) and comorbid conditions known to increase the risk of cancer (diabetes, chronic rheumatological diseases, and inflammatory diseases).
We followed women from the VTE diagnosis date until a diagnosis of cancer recorded in the DCR, death or emigration documented in the Civil Registration System, or the end of the study period (30 November 2013), whichever came first. We categorized the end points as cancers overall and cancers at selected sites as well as VTE overall and superficial and deep venous thrombosis separately. We obtained data on tumor staging at the time of diagnosis for all cancer cases according to tumor, node, metastasis classification and Ann Arbor classification. We computed the proportion of cancers being localized, with regional or metastatic spread. Using indirect standardization, we computed the SIR for cancer as the ratio of the observed number of cases and the number of cancer cases expected in women from the general population of the same age and in the same calendar period, as drawn from the DCR.24 We investigated the association of cancer within <6 months, 6 to 12 months, and 1 year after VTE diagnosis and stratified the results by age, obesity at the time of VTE diagnosis, and timing of the thrombotic event (antepartum or postpartum). We computed the number needed to screen for cancer occurring within 1 year after the VTE event as (1/[observed cancers/expected cancers]). All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC). The study was approved by the Danish Data Protection Agency (record number 1-16-02-1-08).
Results and discussion
We followed 3934 women diagnosed with a VTE during pregnancy or the postpartum period for a median of 14.8 years (interquartile range, 6.7-24.2 years) (Table 1). In the cohort, 8.8% had a previous history of VTE. During follow-up, 250 women were diagnosed with cancer: 64 (25%) after a VTE occurrence during pregnancy, and 186 (75%) after a VTE occurrence during the postpartum period (Table 2). Table 2 shows the cancer risk estimates for superficial and deep venous thrombosis separately. At the time of cancer diagnosis, 147 (59%) of the cancer cases were localized tumors, 53 (21%) were tumors with regional spread, 19 (8%) were tumors with distant metastases, and 31 (12%) had missing data on tumor staging.
Table 1.
Characteristics of women diagnosed with deep or superficial VTE during pregnancy or the postpartum period in Denmark, 1978-2013
| N (%) | |
|---|---|
| Women, total | 3934 (100.0) |
| VTE during pregnancy | 1427 (36.3) |
| Deep venous thrombosis | 1150 (29.2) |
| Superficial venous thrombosis | 277 (7.0) |
| VTE during the postpartum period | 2507 (63.7) |
| Deep venous thrombosis | 1969 (50.1) |
| Superficial venous thrombosis | 538 (13.7) |
| Age at VTE diagnosis, y | |
| ≤17 | 14 (0.4) |
| 18-34 | 3130 (79.6) |
| 35-49 | 790 (20.0) |
| Calendar year of VTE diagnosis | |
| 1978-1985 | 754 (19.2) |
| 1986-1993 | 814 (20.7) |
| 1994-2001 | 856 (21.8) |
| 2002-2009 | 949 (24.1) |
| 2010-2013 | 561 (14.3) |
| Timing of the VTE event | |
| First trimester* | 245 (6.2) |
| Second trimester* | 602 (15.3) |
| Third trimester* | 710 (18.0) |
| Early postpartum period† | 2261 (57.5) |
| Late postpartum period | 116 (2.9) |
| VTE location | |
| Pulmonary embolism | 522 (13.3) |
| Deep and superficial thrombosis of the lower extremities | 3023 (76.8) |
| Other locations | 389 (9.9) |
| Covariates | |
| Obesity‡ | 536 (13.6) |
| Maternal smoking | 517 (13.1) |
| Diabetes§ | 30 (0.8) |
| Chronic renal failure§ | 7 (0.2) |
| Previous VTE§ | 346 (8.8) |
| Other inflammatory or rheumatoid disease§ | 38 (1.0) |
| Surgery‖ | 76 (1.9) |
| Fracture‖ | 31 (0.8) |
| Cesarean section | 348 (8.8) |
| Bleeding during the postpartum period | 94 (2.4) |
Maternal body mass index data available from 2004. Smoking data available from 1991.
First trimester: from conception up to and including 12 weeks of gestation (84 days from conception). Second trimester: from 85 days after conception up to and including 197 days from conception. Third trimester: from 198 days of conception until the day of delivery.
Early postpartum period: from the day after the delivery date until 6 weeks after delivery date. Late postpartum period: 6 to 12 weeks after delivery.
Body mass index, ≥25 kg/m2.
Any time before the VTE event.
Within 90 days before the VTE event.
Table 2.
SIRs of cancer among women with VTE during pregnancy and the postpartum period in Denmark, 1978-2013.
| Cancer cases | All years | Within 6 months after VTE | Within 6-12 months after VTE | >12 months after VTE | ||||
|---|---|---|---|---|---|---|---|---|
| N | SIR (95% CI) | N | SIR (95% CI) | N | SIR (95% CI) | N | SIR (95% CI) | |
| All | 250 | 1.01 (0.89-1.14) | 4 | 1.77 (0.48-4.53) | 3 | 1.24 (0.26-3.63) | 243 | 1.00 (0.88-1.13) |
| VTE during pregnancy | 64 | 1.24 (0.96-1.59) | 0 | — | 3 | 3.27 (0.67-9.56) | 61 | 1.23 (0.94-1.58) |
| Deep venous thrombosis | 53 | 1.27 (0.95-1.66) | 0 | — | 3 | 4.15 (0.86-12.12) | 50 | 1.24 (0.92-1.63) |
| Superficial venous thrombosis | 11 | 1.14 (0.57-2.03) | 0 | — | 0 | — | 11 | 1.18 (0.59-2.11) |
| VTE in the postpartum period | 186 | 0.94 (0.91-1.09) | 4 | 2.86 (0.78-7.33) | 0 | — | 182 | 0.94 (0.81-1.08) |
| Deep venous thrombosis | 155 | 0.92 (0.78-1.08) | 4 | 3.84 (1.05-9.84) | 0 | — | 151 | 0.91 (0.77-1.06) |
| Superficial venous thrombosis | 31 | 1.09 (0.74-1.54) | 0 | — | 0 | — | 31 | 1.11 (0.76-1.58) |
| VTE location | ||||||||
| Deep and superficial thrombosis of the lower extremities | 215 | 1.01 (0.88-1.15) | 3 | 1.76 (0.36-5.15) | 1 | 0.55 (0.01-3.06) | 211 | 1.00 (0.87-1.15) |
| Pulmonary embolism | 18 | 0.91 (0.54-1.43) | 0 | — | 2 | 5.87 (0.71-21.19) | 16 | 0.83 (0.48-1.35) |
| Other sites | 17 | 1.14 (0.67-1.83) | 1 | 4.22 (0.11-23.49) | 0 | — | 16 | 1.11 (0.64-1.81) |
| Site-specific cancers | ||||||||
| Large intestine | 9 | 1.21 (0.56-2.30) | 1 | 29.65 (0.75-165.13) | 0 | — | 8 | 1.09 (0.47-2.14) |
| Lung, bronchi, and trachea | 10 | 0.72 (0.34-1.32) | 0 | — | 0 | — | 10 | 0.72 (0.34-1.32) |
| Malignant melanoma | 18 | 1.05 (0.62-1.66) | 0 | — | 0 | — | 18 | 1.10 (0.65-1.73) |
| Skin cancer (excluding basal cell carcinoma) | 4 | 0.80 (0.22-2.06) | 0 | — | 0 | — | 4 | 0.82 (0.22-2.09) |
| Other connective tissue | 3 | 2.33 (0.48-6.80) | 1 | 38.64 (0.98-215.20) | 0 | — | 2 | 1.62 (0.20-5.85) |
| Breast | 74 | 1.05 (0.82-1.32) | 0 | — | 1 | 2.15 (0.05-11.96) | 73 | 1.05 (0.82-1.32) |
| Cervix of uterus | 17 | 1.30 (0.76-2.08) | 0 | — | 1 | 2.78 (0.07-15.50) | 16 | 1.29 (0.74-2.10) |
| Uterus | 3 | 0.47 (0.10-1.36) | 0 | — | 0 | — | 3 | 0.47 (0.10-1.37) |
| Ovary | 4 | 0.55 (0.15-1.41) | 0 | — | 0 | — | 4 | 0.56 (0.15-1.44) |
| Brain | 4 | 0.66 (0.18-1.69) | 0 | — | 0 | — | 4 | 0.69 (0.19-1.77) |
| Spinal cord, cranial nerves, and central nervous system | 4 | 2.04 (0.56-5.23) | 1 | 33.45 (0.85-186.31) | 0 | — | 3 | 1.58 (0.33-4.62) |
| Thyroid gland | 3 | 0.84 (0.17-2.44) | 0 | — | 0 | — | 3 | 0.87 (0.18-2.55) |
| Non-Hodgkin malignant lymphoma | 7 | 1.29 (0.52-2.66) | 0 | — | 1 | 20.53 (0.52-114.37) | 6 | 1.13 (0.41-2.46) |
| Basal cell carcinoma | 63 | 1.14 (0.88-1.46) | 1 | 2.52 (0.06-14.06) | 0 | — | 62 | 1.14 (0.87-1.46) |
For site-specific cancers, only cancer types with ≥3 cases were included.
The number of cancer cases observed within 6 months after a VTE event was higher than expected (absolute risk, 0.10%; 95% CI, 0.04-0.25 and SIR, 1.77; 95% CI 0.48-4.53), especially after a postpartum VTE event (SIR, 2.86; 95% CI, 0.78-7.33). Cancer risk in women with VTE during pregnancy remained increased during the 6- to 12-month interval after VTE (SIR, 3.27; 95% CI, 0.67-9.56). This cancer risk was still moderately increased after 1 year (SIR, 1.23; 95% CI, 0.94-1.58) and returned to the expected levels during the remaining follow-up period (absolute risk, 20.13%; 95% CI, 16.55-23.98 and SIR, 1.01; 95% CI, 0.89-1.14). The number needed to screen for detecting the excess cancer cases within 1 year after the VTE was 1689.
The present study suggests that VTE occurring during pregnancy or the postpartum period may be a marker of an underlying occult cancer; the risk of having a cancer diagnosed within the first months after a VTE episode in relation to pregnancy seems increased. However, our data does not suggest any increased cancer risk in the years after a VTE event during pregnancy or the postpartum period.
Our results including a larger number of cases in women with both first-time and recurrent VTE events, with separate risk estimates within a short period after the VTE, support those in the smaller study conducted by Wik et al, although that study did not observe an excess cancer risk in the comparison with female age-adjusted cancer rates from the Cancer Registry of Norway.15 Our study was based on prospectively collected nationwide data with complete coverage. Still, data for the first year of follow-up were sparse, yielding imprecise risk estimates for site-specific cancers. We showed that the risk of having a diagnosis of malignancy in the first year after a VTE episode during pregnancy or the postpartum period was higher than expected in the general female population of same age and in same calendar years, although the possible excess risk was low in absolute numbers. Given the large number needed to screen, an aggressive search for a hidden cancer in a pregnant woman with VTE is therefore not warranted.
Acknowledgments
The Program for Clinical Research Infrastructure was supported by the Lundbeck Foundation and the Novo Nordisk Foundation provided salary support for H.T.S.
Authorship
Contribution: H.T.S. and E.H.-P. contributed substantially to the study’s concept and design, interpretation of data, and revision of the intellectual content and provided final approval of the version to be published; A.T.H. contributed substantially to the study’s concept and design, analysis and interpretation of data, drafting of the paper, and critical review and revision of the intellectual content and provided final approval of the version to be published; K.V. performed the statistical analyses and contributed substantially to interpretation of the data, revision of the intellectual content, and final approval of the version to be published; and V.E. and P.P. contributed substantially to interpretation of the data and critical review and revision of the intellectual content and provided final approval of the version to be published.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Anette Tarp Hansen, Section for Hematology and Coagulation, Department of Clinical Biochemistry, Aalborg University Hospital, Hobrovej 18-22, 9000 Aalborg, Denmark; e-mail address: anette.tarp.hansen@dadlnet.dk.
References
- 1.Falanga A, Russo L, Milesi V. The coagulopathy of cancer. Curr Opin Hematol. 2014;21(5):423-429. [DOI] [PubMed] [Google Scholar]
- 2.Sørensen HT, Sværke C, Farkas DK, et al. Superficial and deep venous thrombosis, pulmonary embolism and subsequent risk of cancer. Eur J Cancer. 2012;48(4):586-593. [DOI] [PubMed] [Google Scholar]
- 3.Sørensen HT, Mellemkjaer L, Steffensen FH, Olsen JH, Nielsen GL. The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N Engl J Med. 1998;338(17):1169-1173. [DOI] [PubMed] [Google Scholar]
- 4.Baron JA, Gridley G, Weiderpass E, Nyrén O, Linet M. Venous thromboembolism and cancer. Lancet. 1998;351(9109):1077-1080. [DOI] [PubMed] [Google Scholar]
- 5.Prandoni P, Lensing AW, Büller HR, et al. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N Engl J Med. 1992;327(16):1128-1133. [DOI] [PubMed] [Google Scholar]
- 6.Danmarks Statistik. Statistikbanken. statistikbanken.dk. Accessed 7 May 2017.
- 7.Langagergaard V. Birth outcome in women with breast cancer, cutaneous malignant melanoma, or Hodgkin’s disease: a review. Clin Epidemiol. 2010;3(1):7-19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Horowitz NA, Lavi N, Nadir Y, Brenner B. Haematological malignancies in pregnancy: An overview with an emphasis on thrombotic risks. Thromb Haemost. 2016;116(4):613-617. [DOI] [PubMed] [Google Scholar]
- 9.Högnäs E, Kauppila A, Hinkula M, Tapanainen JS, Pukkala E. Incidence of cancer among grand multiparous women in Finland with special focus on non-gynaecological cancers: A population-based cohort study. Acta Oncol. 2016;55(3):370-376. [DOI] [PubMed] [Google Scholar]
- 10.Farge D, Bounameaux H, Bauersachs RM, Brenner B. Women, thrombosis, and cancer: A gender-specific analysis. Thromb Res. 2017;151(suppl 1):S21-S29. [DOI] [PubMed] [Google Scholar]
- 11.Abdul Sultan A, West J, Stephansson O, et al. Defining venous thromboembolism and measuring its incidence using Swedish health registries: a nationwide pregnancy cohort study. BMJ Open. 2015;5(11):e008864. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Andersen BS, Steffensen FH, Sorensen HT, Nielsen GL, Olsen J. The cumulative incidence of venous thromboembolism during pregnancy and puerperium–an 11 year Danish population-based study of 63,300 pregnancies. Acta Obstet Gynecol Scand. 1998;77(2):170-173. [PubMed] [Google Scholar]
- 13.Brenner B. Haemostatic changes in pregnancy. Thromb Res. 2004;114(5-6):409-414. [DOI] [PubMed] [Google Scholar]
- 14.Jacobsen AF, Skjeldestad FE, Sandset PM. Ante- and postnatal risk factors of venous thrombosis: a hospital-based case-control study. J Thromb Haemost. 2008;6(6):905-912. [DOI] [PubMed] [Google Scholar]
- 15.Wik HS, Jacobsen AF, Fagerland MW, Sandvik L, Sandset PM. Long-term mortality and incidence of cancer after pregnancy-related venous thrombosis: results of a population-based cohort study. Thromb Res. 2013;131(6):497-501. [DOI] [PubMed] [Google Scholar]
- 16.Schmidt M, Pedersen L, Sørensen HT. The Danish civil registration system as a tool in epidemiology. Eur J Epidemiol. 2014;29(8):541-549. [DOI] [PubMed] [Google Scholar]
- 17.Schmidt M, Schmidt SA, Sandegaard JL, Ehrenstein V, Pedersen L, Sørensen HT. The Danish National Patient Registry: a review of content, data quality, and research potential. Clin Epidemiol. 2015;7:449-490. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Storm HH, Michelsen EV, Clemmensen IH, Pihl J. The Danish Cancer Registry--history, content, quality and use. Dan Med Bull. 1997;44(5):535-539. [PubMed] [Google Scholar]
- 19.Gjerstorff ML. The Danish cancer registry. Scand J Public Health. 2011;39(7 suppl):42-45. [DOI] [PubMed] [Google Scholar]
- 20.Knudsen LB, Olsen J. The Danish medical birth registry. Dan Med Bull. 1998;45(3):320-323. [PubMed] [Google Scholar]
- 21.Sundbøll J, Adelborg K, Munch T, et al. Positive predictive value of cardiovascular diagnoses in the Danish National Patient Registry: a validation study. BMJ Open. 2016;6(11):e012832. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Larsen TB, Johnsen SP, Møller CI, Larsen H, Sørensen HT. A review of medical records and discharge summary data found moderate to high predictive values of discharge diagnoses of venous thromboembolism during pregnancy and postpartum. J Clin Epidemiol. 2005;58(3):316-319. [DOI] [PubMed] [Google Scholar]
- 23.Virkus RA, Løkkegaard EC, Lidegaard Ø, et al. Venous thromboembolism in pregnancy and the puerperal period: a study of 1210 events. Acta Obstet Gynecol Scand. 2013;92(10):1135-1142. [DOI] [PubMed] [Google Scholar]
- 24.Schmidt SA, Veres K, Ording AG, Farkas DK, Fogh K, Sørensen HT. Venous ulcers and risk of occult hematological or other cancers: a nationwide cohort study. Blood. 2016;128(6):874-877. [DOI] [PubMed] [Google Scholar]