Pedro Dantas, Suzanne C. Cannegieter, André Grenho, Sérgio Gonçalves.

Response/Recommendation: The incidence of postoperative venous thromboembolism (VTE) is increased in women who use oral contraceptives pills (OCP), as compared to women who do not. Cessation in all users is not recommended. However, OCP use should be taken into account when assessing the patient’s and the procedure’s estimated risk and hence, form a basis for decisions on thromboprophylaxis.

Strength of Recommendation: (A) Strong; (B) Limited.

Rationale: It is well established that women who use OCP have an increased risk of VTE as compared to women who do not. On the whole, their risk is about 3- to 4-fold increased but, considering that the absolute VTE risk in pre-menopausal women is low (~ 1 in 10,000 women per year), this does not lead to a substantially high-risk (~ 3 – 4 per 10,000 per year; 0.03 – 0.04% per year)^1,2.

It is also well known that the risk of VTE is increased after orthopaedic surgery, where the size of this risk, in addition to the presence or absence of patient-related risk factors, depends strongly on the duration of the procedure, the amount of tissue damage and the length of immobilization. Hence, overall, the VTE risk is lower, for example, after knee arthroscopy (~ 0.8% in the following 3 months) than after knee replacement (~ 1.5 – 2%)^3,4.

The question regarding whether the risk of VTE is additionally increased in women who undergo orthopaedic surgery and take OCP as compared to women who have the same surgery but do not use hormonal contraception has been studied previously. Most of these studies confirm an increased risk for these women for all types of surgery. Maletis et al., performed a retrospective cohort study of elective arthroscopic knee procedures using the administrative database of a large health maintenance organization. On the basis of the international classification of diseases version 9 – clinical modification (ICD – 9) – (CM) procedure codes, 20,770 patients undergoing knee procedures were identified. The incidence of VTE in female patients was found to be higher if they had been prescribed OCP at 0.63% compared with 0.30% in female patients with no such prescription⁵. In another large, routinely collected dataset, of almost 65,000 female patients between the ages of 16- and 40-years undergoing knee arthroscopy or anterior cruciate ligament (ACL) reconstruction, Traven et al., found that patients taking OCP had a 2-fold increased risk of a VTE compared with non-users, where the procedural subgroup (ACL reconstruction or simple knee arthroscopy), did not make a strong difference in risk⁶. Van Adrichem et al., found in a large case-control study in 4,000 VTE cases and 6,000 control subjects, out of whom 127 had undergone knee arthroscopy, that after this procedure the risk in women using OCP was 13 times higher than in women not using this treatment⁷.

In patients undergoing foot and ankle surgery, a similar picture emerges. Richey et al., performed a retrospective observational cohort study of 22,486 adults in whom an overall incidence of VTE was found to be 0.9%. In a nested case-control study within this population, they identified.

Four risk factors for an increased VTE risk, of which use of hormone therapy or OCP was associated with an 8.9-fold increased risk⁸.For arthroscopic shoulder surgery, however, Stone et al., evaluating 924 female patients found no significant difference in the incidence of VTE in patients taking vs. not taking OCP (2 [0.22%] vs. 150 [0.57%], respectively; p = 0.2). Still, the risk was more than doubled, and the fact that the relationship was not significant is likely to have been due to the low number of cases (insufficient power)⁹. The same holds true for hip arthroscopy. Khazi et al., identified 9,477 patients who underwent hip arthroscopy from an administrative claims database in whom the 90-day incidence was 1.14%. Multivariable analysis identified several risk factors for VTE in these patients, but OCP use was not one of them, which was again most likely due to low numbers¹⁰.

A following question that results from this conclusion is how to reduce VTE risk in women taking OCP who need to undergo elective orthopaedic surgery. An obvious solution would be to advise them to stop taking this treatment for a couple of weeks or months until the VTE risk due to the procedure has passed. However, let’s consider the numbers: if we take the risks as described by Maletis et al., as a basis (i.e., 0.63% with and 0.30% without OCP)⁵, we would have to let 303 (100/[0.63 – 0.30]) women stop taking the OCP to prevent one VTE (number needed to treat). Furthermore, should this for some reason fail, the consequences of an unplanned pregnancy are enormous. In a useful study to quantify the size of this problem, Dale et al., studied 78 healthy women in whom OCP were stopped prior to elective orthopedic surgery. Five pregnancies in 73 women in whom complete outcome data were available were reported, giving a pregnancy rate of 6.8%¹¹. If we apply this rate to the calculation above, about 21 pregnancies would occur (6.8% of 303 women) in an attempt to prevent one VTE. Even if the pregnancy rate could be reduced, this does not seem a viable option.

An alternative approach would be to quantify an individual’s VTE risk based on the risk associated with the procedure and other surgical risk factors, in combination with the presence or absence of patient-related risk factors, of which OCP would be one. Several studies have shown that the risk increases with the total number of risk factors present (such as higher age, higher body mass index (BMI), family history, presence of other comorbidities, etc.)^12,13. A recent prediction score that was developed to estimate an individual’s risk after knee arthroscopy, the Leiden-thrombosis risk prediction for patients after knee arthroscopy (L-TRiP[ascopy]) score showed good performance, which also persisted after external validation¹⁴. Targeted thromboprophylaxis based on a patient’s risk estimate would then be the next step but this option needs further study.

References:

1.  Blanco-Molina A, Trujillo-Santos J, Tirado R, Cañas I, Riera A, Valdés M, Monreal M; RIETE Investigators. Venous thromboembolism in women using hormonal contraceptives. Findings from the RIETE Registry. Thromb Haemost. 2009 Mar;101(3): 478-82. PMID: 19277408

2.         Rathbun S. Venous thromboembolism in women. Vasc Med. 2008;13(3): 255-266. doi:10.1177/1358863X07085404

3.         van Adrichem RA, Nemeth B, Algra A, le Cessie S, Rosendaal FR, Schipper IB, Nelissen RGGH, Cannegieter SC. Thromboprophylaxis after Knee Arthroscopy and Lower-Leg Casting. N Engl J Med. 2017; 376: 515-25. doi:10.1056/NEJMoa1613303

4.         Özcan M, Erem M, Turan FN. Symptomatic Deep Vein Thrombosis Following Elective Knee Arthroscopy Over the Age of 40. Clin Appl Thromb Hemost. 2019; 25: 1076029619852167. doi:10.1177/1076029619852167

5.         Maletis G, Inacio MCS, Reynolds S, Funahashi T. Incidence of Symptomatic Venous Thromboembolism After Elective Knee Arthroscopy. J Bone Joint Surg. 2012; 94(8): 714-720. doi:10.2106/JBJS.J.01759

6.         Traven SA, Farley KX, Gottschalk MB, Goodloe B, Woolf SK, Xerogeanes JW, Slone HS. Combined Oral Contraceptive Use Increases the Risk of Venous Thromboembolism After Knee Arthroscopy and Anterior Cruciate Ligament Reconstruction: An Analysis of 64,165 Patients in the Truven Database. Arthroscopy. 2021; 37(3): 924-931. doi:10.1016/j.arthro.2020.10.025

7.         van Adrichem RA, Nelissen RGHH, Schipper IB, Rosendaal FR, Cannegieter SC. Risk of venous thrombosis after arthroscopy of the knee: results from a large population-based case–control study. J Thromb Haemost. 2015;13(8):1441-1448. doi:10.1111/jth.12996

8.         Richey JM, Weintraub MLR, Schuberth JM. Incidence and Risk Factors of Symptomatic Venous Thromboembolism Following Foot and Ankle Surgery. Foot Ankle Int. 2019; 40(1): 98–104. doi:10.1177/1071100718794851

9.         Stone AV, Agarwalla A, Gowd AK, Jacobs CA, Macalena JA, Lesniak BP, Verma NN, Romeo AA, Forsythe B. Oral Contraceptive Pills Are Not a Risk Factor for Deep Vein Thrombosis or Pulmonary Embolism After Arthroscopic Shoulder Surgery. Orthop J Sports Med. 2019; 7(1): 1-5. doi:10.1177/2325967118822970

10.       Khazi ZM, An Q, Duchman KR, Westermann RW. Incidence and Risk Factors for Venous Thromboembolism Following Hip Arthroscopy: A Population-Based Study. Arthroscopy. 2019; 35(8): 2380-2384. doi:10.1016/j.arthro.2019.03.054

11.       Dale O, Skjeldestad FE, Rossvoll I. A prospective study of fertility and outcome of pregnancy after discontinuation of oral contraception in relation to elective orthopedic surgery. Acta Obstet Gynecol Scand. 1994; 73(7): 567-569. doi:10.3109/00016349409006274

12.       Sonnevi K, Bergendal A, Adami J, Lärfars G, Kieler H. Self-reported family history in estimating the risk of hormone, surgery and cast related VTE in women. Thromb Res. 2013; 132(2): 164-9. doi:10.1016/j.thromres.2013.06.003

13.       Westhoff CL, Yoon LS, Tang R, Pulido V, Eisenberger A. Risk Factors for Venous Thromboembolism Among Reproductive Age Women. J Womens Health. 2016; 25(1): 63-70. doi:10.1089/jwh.2015.5259

14.       Nemeth B, van Adrichem RA, van Hylckama Vlieg A, Bucciarelli P, Martinelli I, Baglin T, Rosendaal FR, le Cessie S, Cannegieter SC. Venous Thrombosis Risk after Cast Immobilization of the Lower Extremity: Derivation and Validation of a Clinical Prediction Score, L-TRiP(cast), in Three Population-Based Case-Control Studies. PLoS Med. 2015; 12(11): e1001899. doi:10.1371/journal.pmed.1001899