Risk Factors for Venous Thromboembolism in Women of Childbearing Age

Comment on: Venous Thromboembolism in Women of Childbearing Age: Insights from the START Registry Thromb Haemost 2023; 123(11): 1060-1068 DOI: 10.1055/s-0043-1769592 Venous Thromboembolism in Women of Childbearing Age: Insights from the START Registry Venous thromboembolism (VTE), encompassing deep vein thrombosis and pulmonary embolism (PE), affects 1 to 2 in 1,000 individuals annually.[ 1 ] Its incidence increases with age and although men and women are affected equally overall, VTE incidence is higher in women of childbearing age than in men of similar age, mainly due to the presence of hormonal risk factors, such as pregnancy and combined oral contraceptives (COCs) ([ Fig. 1 ]).[ 2 ] Pregnancy increases the risk of VTE by at least fourfold and pregnancy-associated VTE is one of the leading causes of preventable maternal morbidity and mortality.[ 3 ] [ 4 ] Likewise, COCs increase the risk of VTE by about three- to fourfold in users when compared with nonusers,[ 5 ] and considering their wide use, COC use is an important risk factor for VTE in women of childbearing age. In addition, women with a history COC-associated VTE have an increased risk of VTE recurrence during pregnancy and puerperium despite prophylaxis with low-molecular-weight heparin.[ 6 ] Nonetheless, little is known about specific risk factors (and their relative importance) for hormone-associated VTE in women of childbearing age, and how these differ from known risk factors for VTE in general. Fig. 1 Importance of individual risk factors, hormonal risk factors, and family history as predictors of venous thromboembolism (VTE) in women of childbearing age. Women have the potential to develop VTE during their lifetimes. The risk of VTE in women of childbearing age is modulated by the presence of individual risk factors (such as personal history of VTE, increasing age, smoking, inherited thrombophilia, immobility), exposure to hormonal risk factors (such as pregnancy and oral contraceptives), and family history. In pregnant women, multifetal pregnancy, preeclampsia or eclampsia, caesarean section, and use of artificial reproductive assistance can increase the risk of VTE. In women taking combined oral contraceptives (COC), a higher dose of estrogen, and the type of progesterone can increase the risk of VTE. VTE has a higher likelihood of occurring when the combination of risk factors crosses the threshold for thrombosis. Data from Grandone and colleagues enhance our understanding of the relative importance of family history as a risk predictor and suggest that family history is an even more powerful predictor for pregnancy- or COC-associated VTE than for VTE occurring outside of pregnancy or COC. In this issue of the journal, Grandone and colleagues compared the risk factors and the natural history of VTE among 532 women of childbearing age diagnosed with either pregnancy/postpartum-associated VTE (group A), or COC-associated VTE (group B), or other VTE (group C) from January 2011 to December 2021, who were enrolled in the START registry, a prospective, multicenter cohort study in Italy of adults (>18 years) starting anticoagulation therapy.[ 7 ] Unlike other epidemiological studies which examine risk factors by comparing patients with VTE with those without VTE, Grandone et al took an alternative approach by comparing women with pregnancy- and COC-associated VTE with those presenting with VTE occurring outside of these settings to quantify the relative strengths of specific risk factors for hormone-associated VTE. Their study has at least three clinically relevant findings concerning VTE in women of childbearing age. First, in adjusted analyses, compared with women with other VTE, family history of VTE was identified as the strongest predictor (threefold higher risk) for pregnancy- and COC-associated VTE, followed by younger age. Interestingly, the prevalence of smoking was higher in women with COC-associated VTE, and inherited thrombophilia or an acquired thrombophilia (e.g., cancer) was less prevalent in women with pregnancy- and COC-associated VTE than in those with other VTE. Second, the manifestations of VTE varied in the three groups. More cerebral venous sinus thrombosis and PE were observed in women who presented with COC-associated VTE. Third, in women with pregnancy-associated VTE, 55% of the events occurred postpartum, a period of highest risk, and caesarean section was a risk factor in two-thirds of these women, consistent with previous reports.[ 3 ] The strengths of this study include (1) the comprehensive description and comparison of risk factors, clinical manifestations, treatment, and outcomes in women of childbearing age presenting with VTE; (2) the specific focus on identifying and quantifying risk factors to inform on their relative importance for pregnancy- and COC-associated VTEs; and (3) the multicenter enrolment of participants throughout Italy to enhance generalizability. The limitations include the observational design of the study and the potential for bias and unmeasured confounders despite statistical adjustments; the potential for type 1 error with multiple comparisons; and the absence of a control group without VTE that complicates interpretation of the findings. Accordingly, confounding by indication and selection bias may explain the association between COC-associated VTE with younger age and the negative association between COC and presence of thrombophilia; and by conditioning on women of childbearing age with VTE, bias may occur that can distort the association between risk factors and the outcome. Their results confirm previous findings of epidemiological studies and provide further insights into the relative importance of risk factors for VTE in women of childbearing age. Large epidemiological studies in various populations have shown increasing age, a family history of VTE, presence of acquired and inherited thrombophilia, COC use, pregnancy, and smoking to be independent risk factors for VTE,[ 8 ] [ 9 ] and, in pregnant women, advanced maternal age, family history, caesarean section, multiparity, and multifetal pregnancies were found to be risk factors for pregnancy-associated VTE.[ 10 ] [ 11 ] Ethnic differences have also been observed in risk factors and the incidence of pregnancy-associated VTE.[ 12 ] Other studies indicate that family history of VTE is an important risk factor for VTE in women who are pregnant or who are taking COC, irrespective of thrombophilia status.[ 13 ] [ 14 ] [ 15 ] The results of Grandone and colleagues extend these findings, and suggest that family history of VTE has an even greater role in predicting COC- and pregnancy-associated VTE than those occurring outside these settings. In summary, an enhanced understanding of risk factors for hormone-associated VTE has the potential to improve our ability to identify women at risk of COC- or pregnancy-associated VTE, who may benefit from additional counselling, consideration of alternative contraceptive methods, or thromboprophylaxis during periods at high risk. Notwithstanding its limitations, the study by Grandone and colleagues adds to the understanding of risk factors for hormone-associated VTE and re-emphasizes the importance of screening for a family history of VTE in women of childbearing age ([ Fig. 1 ]), particularly those who are pregnant or using COC; or those contemplating pregnancy or use of COC. Publication History Received: 06 July 2023 Accepted: 06 July 2023 Accepted Manuscript online: 07 July 2023 Article published online: 28 July 2023 © 2023. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

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