Luis D. Pacheco, MD

Venous thromboembolism (VTE) is a major cause of maternal morbidity and mortality. The estimated incidence of VTE during pregnancy and the postpartum period is 1 to 2 per 1,000 deliveries.

The risk of VTE is particularly high during the postpartum period and especially following cesarean delivery.

There is considerable variation in the approach to VTE prophylaxis in pregnancy, including following cesarean delivery. Recent guidelines by various professional organizations provide conflicting recommendations based on low-grade evidence, mainly from observational data. 

At present, the available VTE risk stratification tools used to decide for or against pharmacological prophylaxis have not been validated in women undergoing cesarean delivery. Individualization of care is recommended for women at very high risk of VTE.

Q| What are the current guidelines for VTE prophylaxis following cesarean delivery?

Several guidelines define risk factors for VTE, including those summarized in Table 1 from the American College of Chest Physicians (ACCP), Royal College of Obstetricians and Gynaecologists (RCOG), and National Partnership for Maternal Safety (NPMS).

The American College of Obstetricians and Gynecologists (ACOG) recommends that all women undergoing a cesarean delivery receive mechanical prophylaxis with the use of pneumatic sequential compression devices started preoperatively and continued until the patient is ambulatory.

The use of combined pharmacological and mechanical prophylaxis may also be supported based on individual risk assessment. ACOG does not endorse any specific risk stratification guidelines. Hospitals are encouraged to evaluate women for VTE risk factors and to implement a prophylaxis protocol weighing benefits, harms, and cost-effectiveness. If VTE risk factors persist during the postpartum period, up to 6 weeks of pharmacological prophylaxis should be considered.

The ACCP suggests that the benefits of thromboprophylaxis outweigh potential harm when the absolute risk of VTE is 3% or higher.

 The presence of 1 major risk factor, 1 minor risk factor in the setting of an emergent cesarean delivery, or 2 or more minor risk factors suggests a VTE risk above 3%. 

For women undergoing cesarean delivery with no risk factors for VTE, ACCP recommends no prophylaxis other than early mobilization. 

In women at very high risk for VTE, combined pharmacological and mechanical prophylaxis is suggested. If VTE risk factors persist during the postpartum period, up to 6 weeks of prophylaxis is suggested.

The RCOG recommends thromboprophylaxis with low-molecular-weight heparin (LMWH) for 10 days after delivery should be considered for all women who have had cesarean sections and those having an elective cesarean section who have any additional risk factors.4 Prophylaxis with LMWH is recommended for 10 days following delivery in intermediate-risk women and for at least 6 weeks following delivery in high-risk women.

The NPMS recommends universal pneumatic compression devices for all women undergoing cesarean deliveries.

The addition of pharmacological prophylaxis may be considered for women at high risk of VTE based on the use of either the RCOG guidelines or the modified Caprini scoring system. Hospitals may consider providing pharmacological VTE prophylaxis to all women undergoing a cesarean delivery because of the challenges in consistently identifying women with VTE risk factors.

Q| Is there sufficient evidence to recommend one specific guideline over the other?

In general, all women with a previous episode of VTE require prophylactic doses of LMWH or unfractionated heparin (UFH) for at least 6 weeks postpartum. Women with no previous personal history of VTE but who have tested positive for one of the high-risk inherited thrombophilias (antithrombin III deficiency, homozygous Factor V Leiden or G20210A, or heterozygous for both Factor V Leiden and G20210A) or who have a low-risk thrombophilia should also receive pharmacological VTE prophylaxis following cesarean delivery. 

Women with a previous diagnosis of antiphospholipid antibody syndrome should receive prophylactic or therapeutic doses of heparin (depending on previous history of VTE) during the puerperium irrespective of mode of delivery.

The main discrepancy among current guidelines concerns pharmacologic prophylaxis for women with no history of VTE and no inherited or acquired thrombophilia. Recommendations differ in part because they are based on observational studies and expert opinion due to a lack of clinical trial data. 

This presents a challenge for determining the true incidence of VTE and accurately assessing the risk-benefit ratio of pharmacological prophylaxis following cesarean delivery. The potential benefit of pharmacological prophylaxis needs to be weighed against the potential for adverse outcomes associated with the intervention. 

For instance, the use of pharmacological VTE prophylaxis following cesarean delivery has been associated with increased rates of wound separation and wound hematomas. In the absence of adequately powered clinical trials, accurate calculations of the number needed to treat (NNT) and number needed to harm (NNH) are limited. 

However, the available evidence suggests that the NNH may be lower than the NNT in most scenarios, particularly in the absence of risk factors or the presence of only a minor risk factor. 

Further, administrative and retrospective data obtained from analysis of large databases may overestimate the incidence of VTE, resulting in a similar overestimation of the benefit of any intervention aimed at preventing it.

Another consideration in making recommendations is that the use of risk assessment models (eg, Caprini and Padua) to predict VTE following cesarean delivery has not been adequately studied. 

The authors of a recent study questioning their utility during the peripartum period suggest the establishment of a maternal clinical registry and more extensive research to identify optimal models with which to predict VTE risk in the obstetrical population.

At present, the available evidence to suggest that universal (or near universal) pharmacological VTE prophylaxis effectively reduces maternal mortality is limited.

 Any attributable benefit of universal pharmacological VTE prophylaxis after cesarean delivery in maternal mortality will likely be low due to the rarity of the event. 

A recent study reported only 1 maternal death from VTE among 465,880 women undergoing a cesarean delivery when all women received mechanical prophylaxis (eg, sequential compression devices).

Q| Which pharmacological agents are commonly used for prophylaxis of venous thromboembolism?

The two most common agents used for VTE prophylaxis are LMWH and UFH. Current guidelines recommend LMWH (eg, enoxaparin) as the first-line pharmacological agent.

Enoxaparin is not recommended in patients with significant renal dysfunction, defined as creatinine clearance less than 30 mL/min. 

Compared with UFH, enoxaparin has the advantage of better bioavailability, longer half-life, more predictable anticoagulation effect, less bleeding risks, and less risk of heparin-induced thrombocytopenia and osteopenia. 

For prophylaxis purposes, the recommended enoxaparin dosage is typically 40 mg subcutaneously once a day. Obese women may require higher doses; however, the optimal dose is unknown. Some evidence supports the use of intermediate doses of enoxaparin (40 mg subcutaneously every 12 hours) for obese women.

UFH is a good choice in women with renal disease. Recommended prophylactic dosages range from 5000 to 10,000 units subcutaneously every 12 hours depending on gestational age (5000 units subcutaneously every 12 hours in the first trimester, 7500 units subcutaneously every 12 hours in the second trimester, and 10,000 units subcutaneously every 12 hours during the third trimester). 

In the postpartum period, doses of 5000 units subcutaneously every 8–12 hours are commonly utilized. There are insufficient data to recommend the use of new oral anticoagulants (eg, apixaban, rivaroxaban, dabigatran) during the postpartum period.

Q| When is the optimal time to start thromboembolism prophylaxis after a cesarean delivery?

Current ACOG guidelines recommend starting VTE mechanical prophylaxis with sequential compression devices preoperatively in all women undergoing a cesarean delivery.

The Society for Obstetric Anesthesia and Perinatology (SOAP) has addressed the optimal interval between neuraxial anesthesia and initiation of VTE pharmacological prophylaxis to prevent development of spinal or epidural hematomas.

Prophylactic doses of enoxaparin (40 mg subcutaneously every day) may be started postoperatively as soon as 4 hours after catheter removal but not earlier than 12 hours after the block was performed. Intermediate doses of enoxaparin (40 mg subcutaneously every 12 hours) and therapeutic doses may also be started as soon as 4 hours after catheter removal but not earlier than 24 hours after the block was performed. Prophylactic doses of UFH may be started as early as 1 hour after removal of the neuraxial catheter.

In addition to concerns about spinal hematomas, timing to start VTE prophylaxis should also consider the risk of postoperative bleeding. 

With prophylactic doses of anticoagulation, bleeding complications are usually mild and rarely result in life-threatening hemorrhage, unlike bleeding risks with the use of full-dose anticoagulation in the postoperative period. 

In cases with significant intraoperative bleeding complications, the decision of when to start pharmacological prophylaxis (if indicated) must be individualized, while recognizing that postpartum hemorrhage, blood transfusion, and prolonged surgery are risk factors for VTE. In these cases, initiation of UFH, which is reversible and has a shorter half-life, may be prudent.

VTE remains an important cause of maternal morbidity and mortality during pregnancy and the postpartum period. 

The use of mechanical prophylaxis sequential compression devices is an inexpensive, safe intervention and should be used in all women undergoing cesarean delivery until the woman is fully ambulatory. 

The decision to add pharmacological prophylaxis depends on the presence or absence of certain risk factors. Women with a previous personal history of deep venous thrombosis or pulmonary embolism and women with a personal history of an inherited thrombophilia should receive pharmacological prophylaxis following cesarean delivery. 

The use of universal or near-universal pharmacological prophylaxis for women undergoing cesarean delivery, other than those with a previous thrombosis or an inherited thrombophilia, cannot be recommended until further studies demonstrate that such a strategy is beneficial. 

Created in partnership with the Society for Maternal-Fetal Medicine. SMFM was established in 1977 to “give Maternal-Fetal Medicine (MFM) physicians and scientists a place to share knowledge, research and clinical best practices in order to improve care for moms and babies.”

Rodger M. Pregnancy and venous thromboembolism: 'TIPPS' for risk stratification. Hematology American Society of Hematology Education Program 2014;2014:387-92.

American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 196: Thromboembolism in Pregnancy. Obstetrics and gynecology 2018;132:e1-e17.

Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e691S-e736S.

Reducing the risk of venous thromboembolism during pregnancy and the puerperium. Green-top Guideline No. 37a. (Accessed February 4, 2019, at 

https://www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg37a/

D'Alton ME, Friedman AM, Smiley RM, et al. National Partnership for Maternal Safety: Consensus Bundle on Venous Thromboembolism. Obstetrics and gynecology 2016;128:688-98.

Tran JP, Stribling SS, Ibezim UC, et al. Performance of Risk Assessment Models for Peripartum Thromboprophylaxis. Reprod Sci 2018:1933719118813197.

Bain E, Wilson A, Tooher R, Gates S, Davis LJ, Middleton P. Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period. The Cochrane database of systematic reviews 2014:Cd001689.

Clark SL, Christmas JT, Frye DR, Meyers JA, Perlin JB. Maternal mortality in the United States: predictability and the impact of protocols on fatal postcesarean pulmonary embolism and hypertension-related intracranial hemorrhage. American journal of obstetrics and gynecology 2014;211:32.e1-9.

Leffert L, Butwick A, Carvalho B, et al. The Society for Obstetric Anesthesia and Perinatology Consensus Statement on the Anesthetic Management of Pregnant and Postpartum Women Receiving Thromboprophylaxis or Higher Dose Anticoagulants. Anesthesia and analgesia 2018;126:928-44.

Articles

The risk of venous thromboembolism is particularly high during the postpartum period and especially following cesarean delivery. 

Society for Maternal-Fetal Medicine Consult Series #51: Thromboembolism prophylaxis for cesarean delivery

Worldwide, hemorrhage is the most common cause of maternal mortality and the third leading cause in the United States of maternal deaths resulting from direct obstetric factors.

  Early recognition and aggressive treatment of obstetric hemorrhage are of paramount importance and most often lead to improved maternal outcomes. Recent trauma and intensive-care literature has questioned the classic understanding of acute coagulopathy and suggests novel therapeutic interventions for management of massive hemorrhage. Although most of these studies are based on limited data in nonobstetric populations, many US hospitals are widely adopting new transfusion protocols that are commonly applied in the setting of obstetric hemorrhage. 

Precautions for patients at risk of acute hemorrhage

Early transfer of care to a tertiary care facility

Advanced planning and interdisciplinary collaboration are fundamental for management of patients at risk of hemorrhage at delivery. Emergent non-planned deliveries after hours should be minimized. 

Recent recommendations from the Society for Maternal-Fetal Medicine suggest that patients with placenta previa, previous myomectomies, and previous classic cesareans should be delivered at 36 to 37 weeks.

  Similarly, patients with suspected placental accretism should be delivered at 34 to 35 weeks. 

Delaying delivery beyond 36 weeks has been associated with a significant risk of emergency delivery because of hemorrhage.

  In cases of placenta previa or accreta, cervical ultrasonography may help a clinician gauge the optimal time of delivery. Recent evidence suggests that patients with placenta previa and cervical lengths less than 30 mm have a higher risk of acute hemorrhage.

  If debate exists about whether to deliver at 34 weeks or no later than 37 weeks, clinicians can consider measuring cervical length with transvaginal ultrasound. For women whose cervices are shorter than 30 mm and with gestational ages greater than 34 weeks, we favor delivery to prevent emergent bleeding and emergent non-planned deliveries, rather than waiting a "few" more weeks. 

Preoperative autologous blood banking has not been evaluated in carefully designed studies, and is not common practice. Theoretically, a patient's hemoglobin will recover between donations (because of use of iron supplements).

  In practice, however, anemia is a limiting factor, and patients usually can donate only a few units throughout pregnancy (blood donation should be deferred if maternal serum hemoglobin is <10 g/dL). 

Another limiting factor is that blood can only be collected within 42 days of any planned surgical procedure (maximum accepted time to maintain packed red blood cells [RBCs] in the blood bank).

  This technique will not prevent the risks associated with blood collection, storage, and administration, and is not acceptable for Jehovah's Witnesses.

Overall, the technique is unlikely to reduce the amount of blood products transfused in emergency situations. Autologous donation should be used only in cases of rare blood types and/or patients with multiple antibodies (from previous alloimmunization) when availability of compatible blood products at the time of surgery may be limited. 

A look at new research on one of the leading causes for maternal mortality.

Luis D. Pacheco, MD

Articles

Society for Maternal-Fetal Medicine Consult Series #51: Thromboembolism prophylaxis for cesarean delivery

A review of new research on maternal hemorrhage