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Thromboprophylaxis After Cesarean Delivery

A Decision Analysis

From the ¹Division of Maternal–Fetal Medicine, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania; ²Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; ³Department of Obstetrics and Gynecology and Women's Health, University of Medicine and Dentistry of New Jersey, Newark, New Jersey; and ⁴Division of Maternal–Fetal Medicine, Department of Obstetrics and Gynecology, Columbia University, New York, New York.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
OBJECTIVE: To compare 4 strategies for managing patients after cesarean delivery.

METHODS: Using decision analysis, we compared universal subcutaneous (SC) heparin prophylaxis, heparin prophylaxis only for patients with a genetic thrombophilia, use of pneumatic compression stockings (PCS), and no thromboprophylaxis. Outcomes included heparin-induced thrombocytopenia (HIT), HIT-related thrombosis, major maternal bleeding, and venous thromboembolism (VTE).

RESULTS: Use of PCS was the strategy with the lowest number of adverse events. With heparin prophylaxis, 13 cases of HIT-induced thrombosis and hemorrhage would occur per VTE prevented. When heparin prophylaxis is administered only to thrombophilia-positive women, 1.2 cases of HIT-induced thrombosis and bleeding would occur per VTE prevented. In sensitivity analyses, the model was stable across virtually all variable ranges.

CONCLUSION: Use of PCS after cesarean delivery is the strategy with the lowest number of adverse events. Universal prophylaxis with SC heparin is associated with an excess risk of HIT-induced thrombosis and bleeding per VTE prevented compared with PCS use. Until future studies are completed, postcesarean thromboprophylaxis with PCS should be used if the clinician elects to provide prophylaxis.

Several randomized controlled trials have shown the benefits of perioperative subcutaneous heparin and intermittent compression devices to reduce VTE in the nonobstetric population.^8,9 However, few trials have investigated thromboprophylaxis specifically in cesarean patients, and a recent meta-analysis found insufficient evidence to base recommendations for thromboprophylaxis during pregnancy and the postpartum period.¹⁴ It remains unclear which, if any, thromboprophylactic therapy is optimal for patients after cesarean. Therefore, we developed a decision analytic model based on the available literature to evaluate and compare the risk-benefit tradeoff for the most prevalent approaches to thromboprophylaxis in the patient who undergoes cesarean delivery.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
We used decision analytic methods to compare 4 strategies of preventing thromboembolism in women delivered by cesarean. The primary aim of this study was to compare the safety and efficacy of these 4 thromboprophylactic strategies, as manifested by the frequency of thrombosis and therapy-related major adverse events. We used a hypothetical cohort of 1,000,000 women to estimate outcomes because there are approximately 4 million births a year in the United States, 25% of which are delivered by cesarean. The decision model starts with the choice of whether to use thromboprophylaxis (subcutaneous heparin, pneumatic compression stockings, or no therapy) in all patients or whether to prescribe heparin prophylaxis only for those women who screen positive for genetic thrombophilias (Fig. 1). The postcesarean therapeutic strategies include 1) universal prophylaxis with pneumatic compression stockings, 2) universal prophylaxis with heparin, 3) universal screening for inherited thrombophilia with heparin prophylaxis in screen-positive patients, and 4) no postoperative prophylaxis. The strategies are described in detail below.

View larger version (25K): [in this window] [in a new window]   Fig. 1. Decision model for thromboprophylaxis after cesarean delivery. Screening involves universal screening for inherited thrombophilia and heparin prophylaxis in only screen-positive patients. Quiñones. Thromboprophylaxis After Cesarean Delivery. Obstet Gynecol 2005.

Use of pneumatic compression stockings (PCS). In this strategy, women who undergo a cesarean delivery are prescribed PCS during surgery and the postoperative period until ambulatory. We assume that no other form of thromboprophylaxis is used.

Universal prophylaxis with subcutaneous (SC) heparin. This strategy involves prescribing SC heparin perioperatively to all women who undergo a cesarean delivery regardless of risk factors. Similar to the PCS strategy, prophylaxis is continued until the patient is ambulatory. We assume that either unfractionated or low molecular weight heparin is used and that the 2 drugs are equally effective in thromboprophylaxis.

Screening for inherited thrombophilias. In this strategy, all women are screened for inherited thrombophilias. We assume that only the women who screen positive for a thrombophilia are prescribed SC heparin for thromboprophylaxis. The women without a thrombophilia do not receive routine thromboprophylaxis. The thrombophilic conditions considered in our analysis include heterozygosity for factor V Leiden mutation, heterozygosity for the prothrombin gene (G20210A) mutation, protein C deficiency, protein S deficiency, and antithrombin III deficiency. We did not include screening for antiphospholipid antibodies in our model because the significance of these antibodies in the absence of other clinical criteria for antiphospholipid antibody syndrome is unknown and because women with clinical evidence of antiphospholipid antibody syndrome would, in most cases, already be treated with an anticoagulation regimen.¹⁵ Furthermore, patients that are already candidates for anticoagulation therapy based on the current standard of care, such as patients with antiphospholipid antibody syndrome or prior thromboembolic disease, are not appropriate for inclusion in this theoretic cohort. Although inherited thrombophilia screening is currently not a prevalent method for precesarean testing, we thought this strategy might provide a reduction in VTE while minimizing heparin's adverse effects by targeting therapy. Therefore, we included this less common strategy in the decision model.

Routine postoperative care without prophylaxis. In this strategy, women who undergo a cesarean delivery are managed with no routine VTE prophylaxis.

Probabilities. To obtain the probability estimates used in the models, we performed MEDLINE and PubMed searches using the key words "venous thromboembolism," "thrombophilia," "heparin," "heparin-induced thrombocytopenia," "bleeding," and "cesarean delivery." We then augmented the literature search by reviewing bibliographies of the identified publications for other sources of data. We reviewed the identified articles to assess the quality of the study methods and extract the relevant data for the probability estimates. Studies used included randomized controlled trials when available and prospective or retrospective observational studies. Each study was evaluated for quality according to the method outlined by the U.S. Preventive Services Task Force.

The following probability estimates were derived from the literature: the risk of VTE in pregnancy and the postpartum period in women with and in those without inherited thrombophilias, the risk of heparin-induced thrombocytopenia (HIT) and subsequent thrombosis, the risk of major bleeding complications with prophylactic and therapeutic heparin therapy, the prevalence of inherited thrombophilias in the population, and the reduction of VTE risk provided by the use of PCS or subcutaneous heparin. We calculated probability estimates for the model by averaging point estimates in the literature. Heparin-induced thrombocytopenia is defined in most studies by thrombocytopenia (platelet count less than 150,000 per cubic milliliter) along with a positive test for heparin-dependent immunoglobulin (Ig)G antibodies.

Table 1 lists the probability estimates used in the baseline model and the ranges around the point estimates used in the sensitivity analyses. Ranges of uncertainty for the probability estimates were either based on the range reported in the literature or set at a biologically plausible width when a published range was not available. Because few trials are available specifically addressing the use of thromboprophylaxis in postcesarean patients, we obtained data on most probabilities from research on gynecology and general surgery patients. We used the decision tree to identify the strategy that results in the fewest number of adverse events.

We performed sensitivity analyses to assess whether varying probability estimates within the range of uncertainty for each variable alters the results of our analysis. First, we performed a 1-way sensitivity analysis in which each probability is varied sequentially across its range to determine whether the outcomes are altered. Second, we performed 2-way sensitivity analyses, in which several probabilities are varied. In this study design, if the results of the decision analysis remain stable across the ranges of uncertainty for multiple variables, the sensitivity analyses suggest that the model is robust and the results are accurate. Conversely, if outcomes are markedly changed in the sensitivity analyses, the results may not be valid.

We chose the primary outcomes for the analysis to be thrombotic or major hemorrhagic events rather than utilities or quality-adjusted life years for 2 reasons. First, the primary aim of the study was to identify the strategy that best minimizes VTE risk and severe drug effects. Second, we could not identify health service measurement reports that specifically quantify a population's valuation of VTE-related and thromboprophylaxis-related outcomes. Assigning a summary valuation, or utility, to a specific outcome in the absence of health measurement data would be arbitrary, and in this case, not helpful in interpreting the model results. Our model assumes that all adverse outcomes, including VTE, pulmonary embolism, HIT-related thrombosis, and heparin-related hemorrhage are equally bad, and does not attempt to grade the adversity.

We made several assumptions in the model when information was not available in the literature. We assumed that heparin provided the same VTE risk reduction in individuals with and in those without an inherited thrombophilia. We also assumed that the risk reduction provided by PCS was the same in general surgery patients as in postcesarean patients with or in those without an inherited thrombophilia. The baseline probability for the development of a deep vein thrombosis (DVT) in postcesarean women with a thrombophilia was projected as 0.008 because women with an inherited thrombophilia are estimated to have approximately 8 times the risk of developing a DVT as are women without thrombophilia.^3,6,7 We used a wide range for this probability estimate (0.0002–0.01) in the sensitivity analysis to assess this uncertainty conservatively because the risk of thrombosis varies by the specific inherited thrombophilia.

The baseline prevalence of inherited thrombophilia for the model was 5%, which is the baseline rate of factor V Leiden heterozygosity in the population.² Because the prevalence of other inherited thrombophilias such as protein C, protein S, and antithrombin III deficiency (type I) is lower, the range used in the sensitivity analysis was broad, 0.5–15%.

The probabilities of HIT and HIT-induced thrombosis were obtained from studies that included older patients undergoing general and orthopedic surgery. Heparin-induced thrombocytopenia is estimated to be rare in pregnancy.¹⁶ Therefore, we used a broad range in the sensitivity analysis. We assumed that the risk of HIT was the same for individuals with as for those without an inherited thrombophilia because one study found that factor V Leiden heterozygosity did not confer an additional risk of thrombosis in patients with HIT.¹⁷

Outcomes. We included the following clinically relevant outcomes in the model: HIT and HIT-induced thrombosis with prophylactic and therapeutic heparin, bleeding with prophylactic and therapeutic heparin, and VTE, including first event, recurrent VTE, and pulmonary embolism. We considered HIT-induced thrombosis a clinically relevant outcome because it is associated with significant morbidity and its treatment involves discontinuation of heparin followed by treatment with other medications.¹⁸ Major bleeding was defined as hemorrhage that would require discontinuation of heparin therapy, a blood transfusion, or return to the operating room for exploration.

We assumed that women on prophylactic heparin in the universal prophylaxis and screening arms who develop HIT or bleeding discontinue heparin therapy and are at risk of developing HIT-induced thrombosis or a VTE unrelated to HIT. Those patients treated with low-dose heparin that do not develop a heparin-related adverse event have a residual, although reduced, risk of developing a VTE, despite prophylaxis, which results in the use of therapeutic (high-dose) heparin, with subsequent risks of HIT and bleeding. Similar to the heparin strategy, we assume that women in the PCS strategy have a residual risk of developing a VTE, which would require the use of therapeutic heparin with its associated risks of HIT and bleeding. We assume that patients in the strategy without prophylaxis who develop a VTE are treated with therapeutic heparin and, therefore, are at risk for HIT and bleeding. Patients also have a residual risk of recurrent VTE, despite therapeutic heparin. The decision analysis was performed with a commercially available software package, DATA 4.0, Healthcare Version (TreeAge Software, Williamstown, MA).

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Table 2 shows the outcomes for each strategy for the baseline analysis. The decision model showed that postcesarean thromboprophylaxis with PCS was the best strategy, resulting in the lowest rate of adverse events while reducing VTE risk to the same extent as the strategy that employed universal prophylactic SC heparin therapy. With universal heparin prophylaxis, 13 cases of HIT-induced thrombosis and major bleeding would occur for each VTE event prevented. If heparin prophylaxis is prescribed for only thrombophilia-positive women, 1.2 cases of HIT-induced thrombosis and major bleeding would occur for every VTE event prevented. Conversely, universal PCS use resulted in one case of thrombosis or major bleeding due to therapeutic heparin per 16 DVTs prevented.

In the sensitivity analysis, the model was stable across the range of virtually all variables. Even when we set the probability of HIT with either prophylactic or therapeutic heparin to be less than 1%, PCS remained the strategy with the lowest adverse event rate. Our results were sensitive to the probability of a DVT in women without a thrombophilia and the probability of a DVT in those using PCS. Using no thromboprophylaxis was the strategy with the least number of adverse events when the probability of a DVT in women without a thrombophilia was less than 0.3/1,000 and when the probability of a DVT in those using PCS was greater than 1.2/1,000.

In 2-way sensitivity analysis (Fig. 2), we varied the probability of a DVT in women without a thrombophilia and the probability of a DVT in those using PCS because our model was sensitive to these 2 probabilities. The strategy of PCS remained the optimal strategy over a wide range of probability estimates (as denoted by the large gray area in Fig. 2). Only at the extreme ranges of the probability estimates—when the probability estimates for a DVT without a thrombophilia and a DVT with PCS in nonthrombophilic patients were forced to the extreme high end of the ranges—did the strategy of no thromboprophylaxis arise as the preferred or most efficacious strategy. At no point in the sensitivity analysis did the other 2 strategies (universal heparin prophylaxis or screening) arise as the optimal approach in managing thromboprophylaxis after cesarean.

View larger version (25K): [in this window] [in a new window]   Fig. 2. Two-way sensitivity analysis on the probability of venous thromboembolism (VTE) in women without a thrombophilia, using pneumatic compression stockings (X axis) and the probability of VTE in women without a thrombophilia (Y axis). In this figure, we varied the probability of VTE in women without a thrombophilia and the probability of VTE in those using pneumatic compression stockings (PCS). The numbers at the X axis and Y axis represent the range of the probability estimates used in the sensitivity analysis. The PCS strategy was preferred at most ranges of the probability estimates. The other 2 strategies (heparin prophylaxis or screen) are not represented in the figure because neither arose as the preferred strategy across the range of probabilities. Quiñones. Thromboprophylaxis After Cesarean Delivery. Obstet Gynecol 2005.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Venous thromboembolism in the postpartum period is associated with significant maternal morbidity and mortality.¹⁹ However, studies addressing thromboprophylaxis after cesarean delivery are limited.^10,13 Using decision analytic methods, we found that the use of universal thromboprophylaxis with SC heparin, while reducing the risk of VTE in the postoperative period, would lead to an excessive number of adverse events such as major bleeding, HIT, and HIT-induced thrombosis. Conversely, a strategy of universal prophylaxis with PCS provides a VTE risk reduction in postcesarean women quantitatively similar to universal prophylaxis with heparin while avoiding the risks of heparin-related adverse events.

Our decision model has some limitations. Because of the lack of large studies on thromboprophylaxis in postcesarean women,¹⁴ some data were obtained from studies that included older, nonpregnant patients who underwent gynecologic, general surgery, or orthopedic procedures. Although the baseline DVT risk estimate is based on populations of pregnant patients, the risk of DVT in the presence of thromboprophylaxis was estimated with nonpregnant patients. One may argue that the risk of VTE despite thromboprophylaxis in these older patients may be higher and that therefore the probabilities obtained from this literature may bias our results. One may also argue whether VTE prophylaxis with PCS is as effective in pregnant patients as it is in nonpregnant patients because of pregnancy-induced changes in coagulation factors and venous stasis. However, sensitivity analyses developed to address the potential error in probability estimates showed that our model results were stable across a wide range of uncertainty in the probability estimates derived from the studies that included older patients. We found that when the baseline probability of VTE postcesarean was estimated to be very low (< 0.3/1,000), prescribing no prophylaxis was the preferred strategy. Therefore, this may be the optimal course of management in an extremely low-risk obstetrical population. The probabilities for HIT and HIT-induced thrombosis using unfractionated or low molecular weight heparin were also obtained from studies that included older men, many of whom underwent orthopedic procedures. Therefore, the risk estimates for these outcomes may be inflated. Moreover, HIT is estimated to be rare in pregnancy¹⁶ and is estimated to be an uncommon event with low molecular weight heparin. With sensitivity analysis, our results appear to be applicable to the obstetric population because altering the probability of HIT to be as low as 2/1,000 did not alter the outcomes of our model. We assumed that the risk reduction provided by SC heparin or PCS was similar in patients with or in those without an inherited thrombophilia because there is no evidence in the literature that supports or refutes that thromboprophylaxis efficacy varies between patients with and those without a thrombophilia. Our model results remained unchanged when the risk reduction estimate was varied, even with an 8-fold increase in risk of VTE among those with a thrombophilia.

We acknowledge that the baseline assumptions in our model are limited by the lack of large controlled studies on pregnant patients in the postoperative period. Our decision model is based on an exhaustive literature review and contains the most accurate estimates available at present. Although these study results are based on the best data available, we advise the reader to interpret the results with caution because many probability estimates were derived from populations different from the pregnant, postcesarean population. This type of analysis is limited in that we cannot readily evaluate the effect of other VTE clinical risk factors (eg, urgent cesarean, obesity, smoking, maternal age) on the safety and efficacy of thromboprophylaxis strategies. Although such an analysis would be interesting and clinically useful, the paucity of data on the independent and interactive effects of these risk factors prohibits us from including them in this analysis. Furthermore, including the effects of multiple risk factors would add a level of complexity to our decision model that would not only encumber the analysis but also hamper the investigators' and clinicians' ability to interpret the results. One study evaluating risk factors for VTE among pregnant women found obesity, cesarean delivery, and the presence of a thrombophilia to be significantly associated with peripartum VTE, with odds ratios of 4.4, 2.1, and 27.9, respectively (James A et al. Am J Obstet Gynecol 2004;191:S90 [abstract]).

A cost analysis is an important component of this clinical question. However, our main interest was not to address cost but to address whether clinical outcomes would be affected by the mode of thromboprophylaxis chosen. Preliminary data has shown that routine thromboprophylaxis at cesarean delivery with pneumatic compression stockings may be cost-effective (Casele H, Grobman W. Am J Obstet Gynecol 2004;191:S77 [abstract]).

By making the risk-benefit trade-off of each care strategy explicit, this decision analysis aids the obstetric practitioner in the difficult clinical decision of whether to use universal thromboprophylaxis in women who undergo a cesarean. Our data support that a policy of routine prophylaxis with subcutaneous unfractionated or low molecular weight heparin would decrease the rate of thrombosis, but at the cost of producing an excess number of adverse events such as HIT, HIT-induced thrombosis, and major bleeding, and that routine prophylaxis with PCS would reduce the risk of VTE while avoiding most of the risk of heparin-related events.

Based on our decision analysis results, the use of pneumatic compression stockings is the preferred strategy for perioperative thromboprophylaxis in patients undergoing cesarean delivery. This information should be useful to clinicians in determining whether to routinely prescribe a thromboprophylactic therapy in patients delivered by cesarean. Establishing the routine use of pneumatic compression stockings in postoperative cesarean patients may require medical staff education and reinforcement to ensure compliance and maximize efficacy because this practice is not currently standard at many institutions. Large, well-executed studies are needed to further characterize the risk reduction of VTE provided by thromboprophylaxis in postcesarean women.

	Footnotes

 
Dr. Quiñones is supported by a Reproductive Epidemiology Training Fellowship grant from the National Institute of Child Health and Human Development (T32 HD 07440-07). Dr. Macones is supported by a Midcareer Award in Patient-Oriented Research (K24 HD 01289) from the National Institute of Child Health and Human Development.

Presented at the Twenty-Fifth Annual Meeting of the Society for Maternal–Fetal Medicine, February 7–12, 2005, Reno, Nevada.

Corresponding author: Joanne N. Quiñones, MD, Division of Maternal–Fetal Medicine, Department of Obstetrics and Gynecology, University of Pennsylvania Health System, 3400 Spruce Street, 2000 Courtyard, Philadelphia, PA 19104; e-mail: jquinones{at}obgyn.upenn.edu.

doi:10.1097/01.AOG.0000178792.51401.3a

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