The CMC Vellore CVT registry is the largest single-centre CVT cohort reported in the literature. This study assessed the changing epidemiology spanning three decades and identified the changing trends in epidemiological characteristics, including age and gender.

This study shows a gender shift in male predilection over the last 26 years. Narayan et al, in their series from South India, reported similar trends in gender ratio, with more men presenting with CVT than women.9 The risk of CVT in men has been almost two times that of women over the last decade. Population trends worldwide indicate that the share of females is just below 50%.10 In India, the population ratio of men to women has been constant over the past decade, which cannot explain the trend of gender reversal in CVT (figure 6). However, recent data on the population gender ratio of men to women in adolescence and young adulthood have shown a shift to more men, which returns to an equal number as the age increases (figure 7). This observation of men outnumbering women in adolescence and young adulthood could have contributed to the increasing incidence of CVT in men. This apparent shift, therefore, warrants similar studies in other nations where the gender ratios remain stable.

World data on the share of the population that is female (adapted from OurWorldInData.Org). Source: World Bank based on data from the UN Population Division. Note: Population is based on the de facto definition of population, which counts all residents regardless of legal status or citizenship.

Sex ratio by age in India (adapted from OurWorldInData.Org). Source: OWID based on UN (2002).

Our data show a decline in pregnancy-related CVT cases, driving the overall reduction in women presenting with CVT. Pregnancy-related CVT in developing nations like India most commonly occurs in the puerperal period.6 During the peripartum period, there occurs a relatively prothrombotic state, with a higher risk of blood clot formation. This prothrombotic state may further be accentuated by dehydration, blood loss and puerperal sepsis.11 In India, the maternal mortality ratio (MMR) was exceptionally high in the 1990s, with 556 women dying during childbirth per 100 000 live births.12 13 About 1.38 lakh women die every year due to pregnancy and childbirth complications. The global MMR at that time was much lower at 385. During this time, there was a high incidence of unsupervised home deliveries, and many traditional practices were employed, including denying women fluids and hydration due to an irrational and unscientific fear of them developing complications. A study from South India found that restricting water in the postpartum period was a potentially correctable risk factor for postpartum CVT.6 In another Iranian study among women fasting during Ramadan, including fluid intake restriction along with the use of CPs led to an increased risk of CVT.14

However, in the last decade, there has been a dramatic decline in the MMR in India to 167 (2011–2013) against a global MMR of 216 (2015).15 Maternal death has reduced by 68.7% in the same period. India’s share of global maternal deaths has also significantly declined to about 15%, per the MMEIG report.16 Padmanabhan et al, in their case study, delineated the efforts by the state government of Tamil Nadu to improve maternal care, leading to a reduction in MMR from 380 in 1993 to 90 in 2007.17 Better access to healthcare facilities and government-initiated financial assistance for pregnant women encourage in-hospital deliveries. The traditional practices contributing to morbidity have significantly reversed with public awareness about its harms, reflected in our study as a declining trend in postpartum CVT. Other studies across the globe report similar improving trends in MMR; between 2000 and 2020, Eastern Europe and Southern Asia documented the most overall reduction in MMR with a decline of 70% (from an MMR of 38 to 11) and 67% (from an MMR of 408 down to 134), respectively.13

Another important observation is the changing practices in women concerning oral CP use. Oestrogen is most often the culprit predisposing to venous thrombosis by various mechanisms, including acquired activated protein C resistance and an increase in the levels of procoagulant proteins18—the addition of first-generation progesterone to oral oestrogen compounds this risk. In women with an underlying prothrombotic state, CP use increases the risk of venous thrombosis.19 Some studies suggest that low oestrogen dose preparations reduce the incidence of venous thromboembolic events (VTE) even when arterial thrombosis remains high.18 20 The risk of VTE appears to be lower with second-generation progesterone CPs (norgestrel or levonorgestrel). These second-generation progesterone CPs are currently being prescribed, possibly reducing the incidence of VTE. There is also an increased preference for family planning procedures like tubectomy and vasectomy after the completion of the family, thereby reducing women’s overall use of CPs.21 22

The increase in male CVT cases could be relative to the reduction in female CVTs. Other risk factors, most importantly harmful alcohol consumption, may have a role in increasing the number of male CVTs. While 29.2% of men in India consume alcohol, the national average for women is only 1.2%.23 Alcohol consumption by men is highest in South India, especially in Tamil Nadu, where in certain areas, >45% of men regularly consume alcohol.23 Binge drinking leads to dehydration and is a risk factor in our cohort.

Despite the decline in female CVT-related hospitalisations, over the last few decades, there has been an overall increase in the incidence of CVT. A possible reason for this observation could be a higher level of clinical suspicion due to increased awareness and the widespread availability of imaging modalities to confirm the diagnosis. Our study reflects this change in trend, where there was an increase in the incidence from <0.05% to 0.1% of all admissions during the study period. Other reasons for this observation include increased harmful alcohol use and the occurrence of cancers and other prothrombotic states. The growing economy of South Indian states with improved literacy and better socioeconomic status could have also contributed to improved health-seeking behaviour and increased reporting of CVT; the socioeconomic status assessment was beyond the scope of this present study.

The incidence of CVT among adults in a Norwegian cohort was 1.96 per 100 000/years, which appears to be higher than the previously reported estimate of 0.3–0.5 per 100 000/years.24 In a hospital-based study from Portugal, the annual incidence was 0.22/100 000 between 1980 and 1998.25 A study from Hong Kong reported an incidence of 0.34/100 000/years between 1995 and 1998,26 and two tertiary care clinics in Iran reported 1.23/100 000/years between 2001 and 2004.27 More recent studies from Australia and the Netherlands reported an annual incidence of 1.57 and 1.32 per 100 000.28 Compared with these cohorts, the incidence in our study seems to be significantly higher and the highest reported among published literature.

Since this article highlights the increasing trends of CVT in men, it is also worthwhile to review the incidence, and the course of CVT among transgender adults, which is uniformly under-represented in all cohorts reported globally.29–31 In a systematic review and meta-analysis on the risk of venous thromboembolism among transgender adults, the overall rate of VTE in assigned men at birth (AMAB) trans people undergoing gender-affirming hormone therapy was 2%.30 To date, there is only a single case report on the occurrence of CVT in a trans-woman, indicating that it is under-reported and under-represented.32 Though we did not have any such subject in our cohort, it is essential to consider the potential adverse events of feminising hormones on men.