Slightly less than one third of the patients (53 of 165, 32.1%) had any known risk factor for thromboembolism, as noted in Table 3. Among those with a prior episode of thromboembolism, antepartum deep venous thrombosis was not significantly more frequent than postpartum deep venous thrombosis (16 of 94 compared with seven of 33, P = .78). Patients with a history of venous thromboembolism who had antepartum deep venous thrombosis did not have an earlier onset compared with those without history of thrombosis (16.9 ± 3.7 compared with 17.4 ± 1.4 weeks' gestation, P = .8).
The presenting signs and symptoms of the study cases are listed in Table 4. At the time of initial presentation, the triad of pain, tenderness, and unilateral leg swelling was present in 85.7% of the patients with deep venous thrombosis. Although an enlarged leg was measured in 75% of the cases, slightly fewer than half had Homan's sign.
Nearly all deep venous thromboses identified occurred in the lower extremity (125 of 127, 98.4%). The left leg was more commonly affected than the right leg (104 of 127 compared with 22 of 127, P < .001), with one case of bilateral lower extremity deep venous thrombosis. Among antepartum deep venous thromboses, those in the right leg did not have an earlier onset (18.7 ± 1.9 compared with 15.4 ± 2.9 weeks' gestation, P = .38), nor were they more extensive in nature than those in the left leg. Overall, deep venous thrombosis was more common antepartum than postpartum (94 of 127 compared with 33 of 127, P < .001), with a mean gestational age at time of diagnosis of 16.8 ± 2.4 weeks. As seen in Figure 1, approximately half of the cases were detected before 15 weeks' gestation (47 of 95, 49.5%), with only 28 cases occurring after 20 weeks (P < .001). The mean time of postpartum deep venous thrombosis was 16.7 ± 3.9 days (range 1–42 days). Among the 33 cases of postpartum deep venous thrombosis, there was no increased incidence with surgical procedures, including cesarean delivery (n = 12), second trimester dilatation and evacuation (n = 4), and ectopic gestation (n = 1) compared with vaginal delivery (n = 16) (P = .9). Postpartum deep venous thromboses that occurred after spontaneous vaginal delivery, however, did occur earlier than those associated with cesarean (2.3 ± 0.7 compared with 6.3 ± 1.1 days, P = .004).
Although most pulmonary embolisms occurred postpartum (23 of 38 compared with 15 of 38), this was not statistically significant (P = .1). Those that did occur postpartum, however, were strongly associated with cesarean delivery (19 of 36,470 cesareans compared with four of 232,032 vaginal deliveries, P < .001). Only two patients (1.6%) had pulmonary embolism while on heparin therapy for deep venous thrombosis. All three maternal deaths were caused by surgically associated pulmonary embolism, with two occurring intraoperatively and the other taking place 1 day after cesarean. There were four (3.2%) recurrences of deep venous thrombosis, three of which were related to subtherapeutic heparin levels and one to patient noncompliance. Other recorded complications (n = 11) related to antepartum or postpartum heparin anticoagulation included thrombocytopenia, allergic reaction, and wound hematoma. We noted one case of protein S deficiency, four cases of protein C deficiency, two cases of anti-thrombin III deficiency, and four cases of activated protein C resistance. These patients did not have an earlier onset of antepartum deep venous thrombosis compared with those without hereditary thrombophilia. There were no fetal or neonatal complications resulting from maternal anticoagulation.
This study represents a large compilation of cases of objectively diagnosed thromboembolism during pregnancy. We found that, although thromboembolism rarely occurs in pregnancy, the incidence might be overestimated on the basis of previous reports. Most deep venous thrombosis cases occurred in the antepartum period, especially during the early second trimester. Only a few patients had the classic risk factors for thromboembolism.
In most previous reports, thromboembolism in pregnancy was diagnosed exclusively based on clinical signs and symptoms. During the 1950s, the frequency of thrombophlebitis was estimated to be 0.13–0.2%.8 A rate of 1.8% was reported by Bergqvist in 1979.9 Among 32,337 women delivering between 1951 and 1969, Aaro and Juergens10 noted 64 cases of deep thrombophlebitis and 13 cases of pulmonary embolism (0.24%). In the few recent studies requiring objective testing for diagnosis, the incidence of thromboembolism appears to be much lower. Kierkegaard11 found only 11 cases of deep venous thrombosis among 14,869 patients (0.07%). In the study by Bergvist and Hedner12 encompassing the years 1974–1980, the incidence of deep venous thrombosis was 0.07%. The present study likewise ound that the risk of thromboembolism during pregnancy was very low, 0.06% (one per 1627 births).
In the older studies, the risk of deep venous thrombosis traditionally was considered to be greatest during the late third trimester and postpartum period.9–11 Postpartum thrombosis was said to be three to five times as frequent as antepartum events and three to 16 times more common after cesarean compared with vaginal delivery.10,11 In accord with several recent reports3,12–15 this study confirmed that the antepartum period is the period of highest risk of deep venous thrombosis. Earlier postpartum ambulation, the shift from prolonged bedrest after uncomplicated vaginal and cesarean deliveries, avoidance of estrogenic suppression of lactation, and increased use of elastic compression stockings with graded pressure have contributed to this shift in frequency. The immediate postpartum period after cesarean continues to be the period of greatest risk for pulmonary embolism.13
In accord with the findings of several other objective studies, we found that the risk of venous thromboembolism appears to begin early in pregnancy.3,10,12,14–17 Progesterone-mediated increases in venous distensibility and capacity are evident early in gestation.5,18 Under the influence of estrogen, levels of coagulation factors I, II, VII, VIII, IX, XII, and fibrinogen are elevated by the end of the first trimester. Thrombin production, as measured by either fibrinopeptide A or thrombin-antithrombin III complex concentrations, is also higher by the end of the first trimester.19 The fibrinolytic system is inhibited, mostly in the third trimester.4,5 The relatively low incidence of venous thrombosis during the third trimester could be due to the presence of a placentally produced dermatan sulfate antithrombotic glycosamnioglycan.20
There was a clear left-sided predominance of antepartum deep venous thrombosis in this study. In the study by Ginsberg et al,16 58 of 60 women (96.7%) had venous thrombosis in the left leg alone and two women had bilateral venous thrombosis. Among the 48 cases of proximal thrombi described by Tengborn et al,3 81% occurred in the left lower extremity. Two other studies10,14 found that 75–82% of antepartum cases involved the left deep venous system. Although the exact explanation for this is unknown, increased venous stasis in the left deep venous system could be the cause. During pregnancy, the right iliac artery has an overly exaggerated compressive effect on the left common iliac vein.21 The enlarging gravid uterus could also selectively induce a compressive effect on the common iliac vein.
In this large retrospective study spanning nearly 20 years, we acknowledge that ascertainment and recall bias might be present. As most deep venous thromboses are initially silent and fewer than one third show classic symptoms, we might have underestimated the true incidence of the disease process. Using fibrogen scanning, Friend and Kakkar7 noted that three of 100 women had asymptomatic calf thrombi in the postpartum period. Because of the changing diagnostic modalities used during the years of our study, there could have been a higher incidence in the early years when ultrasound and CT and MRI were not used primarily. For example, the pregnancy-related changes of increased intra-abdominal pressure, obesity, and decreased venous return associated with lower extremity edema can be associated with false-positive diagnosis by impedance plethysmography. Although duplex Doppler ultrasound has been reported to have a 90% sensitivity and specificity for proximal vein thrombosis, it will not detect approximately 50% of small calf thrombi because of collateral venous channels.13 It is likewise possible that some of the individuals whose diagnosis of deep venous thrombosis or pulmonary embolism was clinical actually had thromboembolic phenomena. Our reported incidence of thromboembolism might be falsely low, as some of the women might have presented to other hospitals for postpartum evaluation. Finally, our reported incidence of pregnancy-associated venous thromboembolism might not reflect the actual rates in other patient populations, because of the different frequencies of heritable thrombophilias in certain ethnic groups.22
If venous thrombosis remains undiagnosed and untreated, in 15–24% of patients pulmonary embolism will develop.4,13 The embolism is fatal in nearly 15% of these individuals, with two thirds of the deaths occurring within 30 minutes of the embolic event.13 Only through early detection of venous thromboembolism and subsequent heparinization can this high maternal mortality rate be diminished. Although venous thromboembolism complicating pregnancy is a rare event, all pregnant individuals should be considered at risk. Although the patient might not have the traditional risk factors or might present early in gestation, diagnostic testing should be done immediately.
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© 1999 The American College of Obstetricians and Gynecologists
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