Hypertensive Disorders of Pregnancy and Pre-Pregnancy Hypertension with Subsequent Incident Venous Thromboembolic Events

The incidence of venous thromboembolism (VTE) during pregnancy in the United States (U.S.) is low at up to 1.72 per 1000 deliveries [1]. During pregnancy, VTE risk is approximately five times higher, and in the 3 months subsequent to delivery is 60 times higher than in non-pregnant women [2]. This is of public health importance as VTE represents a leading cause of severe maternal morbidity and mortality [3,4]. Furthermore, VTE rates are higher among Black women compared to women of other races [1,2,3]. Hypertensive disorders of pregnancy (HDP) including gestational hypertension, preeclampsia and eclampsia are significant complications affecting nearly 10% of pregnancies [5,6]. Compared with non-Hispanic White (NHW) women, chronic hypertension and HDP rates are higher in non-Hispanic Black (NHB) women [7,8,9,10]. Moreover, the risk of maternal and fetal/neonatal serious morbidity and mortality from HDP is elevated and varies by race and ethnicity [10,11,12]. Post-pregnancy cardiovascular outcomes associated with HDP, including mortality, can occur long term [13,14,15,16].

Although the causes and treatments differ for VTE and arterial cardiovascular disease, the pathophysiology between them is shared to some extent [17,18,19,20,21]. Preeclampsia, a type of HDP, and thrombophilia share pathogenic mechanisms resulting in an increased risk of developing VTE. During pregnancy, the risk of VTE is higher, due to anatomic and physiologic changes including the occurrence of a hypercoagulable state of the blood [22]. VTE history is associated with an increased risk of preeclampsia and placenta-mediated pregnancy complications [23]. Thus, a biologically plausible mechanism for placenta-mediated complications including preeclampsia [24,25,26,27,28] and VTE may be thrombophilia or thrombosis [29,30,31]. While relationships have been reported between preeclampsia and other HDP with VTE during pregnancy or postpartum by international studies [32,33,34,35], U.S. studies and evidence regarding potential differences by race/ethnicity are lacking. Therefore, we aimed to evaluate the association between HDP and pre-pregnancy hypertension with incident VTE events among women within one and five years after delivery and over the entire study period (up to fourteen years). We examined the risk of post-pregnancy incident VTE events and related mortality, as well as racial and ethnic group differences.

Sociodemographic and clinical characteristics are shown by exposure group in Table 1. Women with pre-pregnancy hypertension or both conditions were more likely than those with HDP or neither condition to be older and have a rural residence and a previous C-section. Women with pre-pregnancy hypertension, HDP, or both conditions were more likely to be NHB, WIC eligible during pregnancy, and to have pre-pregnancy or gestational diabetes mellitus, induced labor, Medicaid, a lower annual household income, a C-section, and a higher BMI pre-pregnancy than women with neither condition. They were also more likely to have a lower gestational age at delivery and to have received intensive or adequate (women with pre-pregnancy hypertension and HDP) prenatal care, as measured using the R-GINDEX than women with neither condition.

Our overall findings are consistent with those of recent studies. A Dutch nationwide cohort study (n = 1,919,918; 24,531,118 person-years) reported the adjusted risk of VTE during pregnancy and ≤3 months after delivery was doubled in women with hypertension during pregnancy compared to those with pregnancy complications and was nearly 8-fold higher among women with preeclampsia than women without pregnancy complications [35]. Over the follow-up period (≤13 years after first delivery), women with hypertension during pregnancy (1.5-fold) and preeclampsia (2.1-fold) were at increased VTE risk after adjustment [35]. Moreover, the risk attenuated slightly although it remained significant over the follow-up period after limiting VTE events to >3 months postpartum [35]. The aforementioned study did not consider pre-pregnancy hypertension or involve deaths. We were interested in including women exposed to HDP as well as pre-pregnancy hypertension to evaluate fatal and non-fatal incident VTE events across four exposure groups compared to women with neither condition. Thus, our findings provide an important contribution to the literature and evidence from a U.S. study as many studies have been international.

Most recently, in a nationwide cohort study in Denmark with 10.2 years median follow-up, a 43% elevated risk of VTE was observed among primiparous women with and without preeclampsia following adjustment [31]. A 2020 review by Hart et al. reported a number of pregnancy-related factors that have been associated with VTE including preeclampsia (3-fold increase) [22]. The odds of VTE were 1.5 times higher among women with prior HDP than without prior HDP after adjustment for age at enrollment and race in the prospective, observational United Kingdom Biobank study [41]. Studies conducted in Norway (registry-based case-control) and Canada (retrospective cohort) found women with preeclampsia compared to those without preeclampsia had a 3.8-fold increase in odds [32] and a 2.2-fold higher risk [33] of post-pregnancy VTE after covariate adjustment, respectively. Women with eclampsia experienced a 4.4-fold increase in the odds of post-pregnancy VTE than those without eclampsia after adjustment in the Norwegian study [32]. Increased postpartum VTE event risk was similarly reported to be tripled among women with preeclampsia after adjustment by a Swedish retrospective population-based study [34]. Using the U.S. Healthcare Cost and Utilization Project National Readmissions Database, of the more than 6 million delivery hospitalizations between 2013 and 2014, VTE readmissions within 60 days of discharge were estimated as being 4.7/10,000 [42]. Preeclampsia and gestational hypertension diagnoses were present among 8.2% and 19.7% of women with VTE readmissions, respectively (p 42]. Women with preeclampsia or gestational hypertension had twice the odds of being readmitted for VTE [42]. Potential race or ethnic differences could not be examined as this information was not available. However, not all studies have found a relationship. The U.S. National Inpatient Sample (2000–2001) did not observe an independent association between preeclampsia and gestational hypertension with VTE (OR = 0.9, 95% CI: 0.7–1.0), although certain medical conditions including hypertension increased the risk of pregnancy-related VTE 1.8-fold [43].

We had the advantage of being able to compare racial/ethnic differences among NHW and NHB women, whereas other studies were limited in their ability to assess potential racial or ethnic differences due to homogeneous populations [32,33,34] with only one study assessing descent (Dutch, Hindustani, other) in VTE risk among women with hypertension during pregnancy [35]. NHB women are a critical group to study because of their high risk of cardiovascular disease risk factors as well as HDP and related outcomes in general [44,45]. In a U.S. statewide case-control study, the odds of VTE at delivery or during the three months postpartum were 1.5-fold higher for Black women and 0.67-fold lower for Asian women than NHW women after covariate adjustment including preeclampsia [46]. Among White and Black women with adverse pregnancy outcomes, any thrombophilia was found to be more common among White women due primarily to Factor V Leiden mutation, whereas Black women were more likely to be diagnosed with protein S or antithrombin deficiencies [47]. A history of pregnancy loss(es), preeclampsia, preterm delivery, placental abruption, and intrauterine growth restriction defined adverse pregnancy outcomes with pregnancy losses making up about 90% [47]. Sickle cell disease or other comorbidities, resistance to fibrinolysis, and higher coagulation-factor levels (e.g., fibrinogen) are possible reasons that Black women are more likely to experience pregnancy-associated VTE [48,49]. However, the evidence is lacking, and a gap currently exists in the literature regarding differences that may exist by race/ethnicity in the relationship between HDP and VTE. Our study is the first to our knowledge to compare the risk of VTE following HDP by race/ethnicity. The public health implications of the findings from the current study as well as future investigations include the possibility of improved screening and monitoring of women of racial/ethnic minority groups and other subgroups found to be at high risk of adverse pregnancy-related outcomes. Additional research could be conducted to identify factors associated with health disparities in the relationship between HDP and VTE. This, in turn, could contribute to a reduction in poor pregnancy-associated outcomes for women with pre-existing risk factors including comorbidities, especially those at high risk.

VTE risk is higher in pregnancy, during which anatomic and physiologic changes are present including the occurrence of a hypercoagulable state of blood [22]. Physiologic anticoagulants are decreased, whereas some coagulation factors are increased in pregnancy. Preeclampsia begins with abnormal placentation followed by induced endothelial damage [50] that can possibly also result from delivery-related trauma. As the uterus expands, the inferior vena cava and pelvic veins in the lower extremities are compressed, and venous dilatation can result from progesterone levels [22]. Because the clinical characteristics are continuously changing, VTE is a dynamic condition [51] that can be due to hereditary and/or acquired causes. Hypercoagulability is also a cause of VTE in addition to damage to the vascular tissue and abnormal hemodynamics [52]. Hereditary risk factors for VTE include Factor V Leiden, Prothrombin G20210A, and deficiency in protein S, protein C, or antithrombin, whereas some therapies and many disorders (e.g., heart failure, obesity, pregnancy) are acquired risk factors [53]. High venous resistance, elevated coagulability and inflammation, as well as endothelial lining damage are related to higher VTE risk [52]. History of VTE has been reported to increase the risk of preeclampsia 50% as well as other placenta-mediated pregnancy complications [23]. A biologically plausible mechanism for placenta-mediated complications including preeclampsia [24,25,26,27,28] and VTE could be thrombophilia or thrombosis [29,30,31].

Women with a history of VTE events are treated with anticoagulation during pregnancy and postpartum. Anticoagulation is also used under other clinical circumstances including after C-section in patients with risk factors for VTE events such as obesity, admission with COVID-19-related complications, and prolonged hospitalization. For instance, all patients admitted to the antepartum unit for ≥72 h receive prophylactic anticoagulation. Although these preventive measures result in short-term VTE risk reduction, our findings are consistent with others that demonstrate the continued association of HDP with VTE events remote from delivery, independent of pre-pregnancy hypertension in the maternal venous system. It is also possible a shared biological risk factor increases the risk of both HDP and VTE [31].