Torri D. Metz, MD

Intrahepatic cholestasis of pregnancy (ICP) occurs in the second and third trimesters of pregnancy and is characterized by pruritus and elevated serum bile acid concentrations. Its incidence has been estimated to range from 0.3% to 15% in various populations, with most estimates from 0.3% to 0.5%.

 While ICP poses little risk for women, it does confer risk to the fetus. The persistence and intensity of associated pruritis are uncomfortable, and the increased risk of stillbirth is a significant concern to both patients and health care professionals.

What is the differential diagnosis of pruritis in pregnancy?

Pruritis is a common complaint in pregnancy.

 In ICP, itching is often generalized but predominantly affects the palms of the hands and the soles of the feet, is worse at night, and is generally not associated with a rash.

 The most frequent pathologic causes of pruritus specific to pregnancy include atopic eruption of pregnancy, polymorphic eruption of pregnancy, pemphigoid gestationis, and ICP.

Q|How should a woman with pruritus in pregnancy be evaluated?

A detailed history and physical examination are imperative in making the diagnosis of ICP. In the process of taking the history and performing the physical examination, it is appropriate to consider and assess for other causes of pruritus without a rash 

. ICP should be considered in a woman who develops new-onset pruritus without a rash in the second half of pregnancy.

In evaluating a patient for other potential causes for pruritus, one should assess the onset, extent, severity, aggravating and alleviating factors, timing, medical history, medications (eg, narcotics), allergies, past medical/family history of atopy (eg, eczema, allergic rhinitis, asthma), amount of bathing, household contacts, pets, and travel history. Sexual history and any history of intravenous drug use should be assessed to ascertain the patient’s risk of hepatitis and HIV. A history of ICP in any prior pregnancies should be assessed as well.

Other significant signs and symptoms to assess include recent changes in weight, appetite, skin or eye color (jaundice), and sleep habits. Excessive fatigue, insomnia, malaise, and abdominal pain and colic are not common with ICP. If present, evaluation for other causes of pruritis and hepatic disease may be warranted.

The physical examination should assess for the presence of rashes, excoriations, papules, plaques, or bullae. Although ICP is not associated with a rash, the intensity of the pruritus can lead to the development of excoriations or prurigo nodularis, which may be mistaken for a rash.

 Dark urine and jaundice are not common with ICP and suggest other hepatic diseases.

Q|What laboratory evaluation is recommended for a pregnant woman with pruritis in whom ICP is suspected?

We recommend measurement of serum bile acid levels and liver transaminases in patients with suspected ICP (GRADE 1B).

 Mass spectrometry and liquid chromatography can evaluate for total and fractionated (cholic, chenodeoxycholic, and deoxycholic acid) bile acids. Total bile acids also can be assessed by enzymatic assay. Although the enzymatic assay does not provide fractionated bile acid levels, fractionated levels have limited utility, and the most clinically useful value is the total bile acid level.

The clinical diagnosis of ICP is based on pruritus symptoms and supported by the presence of elevated total serum bile acid levels and the absence of diseases associated with similar laboratory findings and symptoms. A serum total bile acid concentration of greater than 10 micromol/L often is used to diagnose ICP, although the data are limited and the diagnostic accuracy has been questioned.

 Increases in transaminases (eg, alanine aminotransferase and aspartate aminotransferase) can also sometimes be seen in ICP, although elevated transaminases are not necessary for the diagnosis. 

Although bile acid levels can be affected by a postprandial state, random bile acids can be used to diagnose ICP and are typically more convenient for the patient and practitioner than fasting bile acids. 

 lists other causes of ICP and elevated bile acid concentrations. Particularly in women with elevated bile acids before the second trimester of pregnancy, other etiologies should be considered.

Q|Are particular women or populations at risk for ICP?

Women with preexisting hepatobiliary disease are reported to be at higher risk for ICP. Patients with a history of ICP are at risk for recurrence. ICP has been associated with multiple gestations and advanced maternal age, and familial clustering of cases of ICP also suggests a genetic component.

 ICP likely results from both environmental and hormonal influences in women who are genetically susceptible.

Q|What are the complications of cholestasis of pregnancy?

ICP is associated with several adverse perinatal outcomes, including stillbirth, meconium-stained amniotic fluid, and preterm birth (both spontaneous and iatrogenic). Data suggest that the risk of stillbirth with ICP is associated with the total bile acid concentration,

 although some level of risk may still be present even with low bile acid concentrations.

Women with ICP and bile acid levels ≥40 micromol/L have been reported to have increased risks of adverse perinatal outcomes, including preterm birth, asphyxia or respiratory distress syndrome, and meconium-stained amniotic fluid.

 Increased rates of both indicated and spontaneous preterm birth are reported with ICP, with the incidence of prematurity varying greatly among studies. Pregnancies complicated by spontaneous preterm birth have been reported to have an earlier onset of pruritus, and the prevalence of spontaneous preterm birth increases with higher total bile acid concentrations.

 There also is evidence that patients with ICP are at increased risk for preeclampsia.

Q|What is the recommended treatment for cholestasis of pregnancy?

We recommend that ursodeoxycholic acid (UDCA) be used as the first-line agent for the treatment of maternal symptoms of ICP (GRADE

Three meta-analyses have summarized the data from randomized trials and have reported benefits in improving maternal symptoms.

 Compared with placebo or alternative agents (eg, cholestyramine or S-adenosyl methionine), UDCA is more effective in relieving pruritus and improving laboratory abnormalities and has no known adverse fetal effects. The typical starting dose for UDCA is 10 to 15 mg/kg per day, which can be divided into doses taken 2 or 3 times daily. Typical regimens are 300 mg taken 2 or 3 times daily or 500 mg twice daily. A decrease in pruritus usually is seen within 1 to 2 weeks. If pruritis is not relieved, the dose can be titrated to a maximum of 21 mg/kg per day. Biochemical improvement is usually seen within 3 to 4 weeks.

Alternative drugs, such as S-adenosyl methionine and cholestyramine, can be considered for patients who cannot take UDCA or have continued symptoms on the maximum dosage. It has been reported that rifampin can be combined with UDCA for refractory cases of ICP with improvement in pruritis.16 Antihistamines such as diphenhydramine or hydroxyzine also have been used for pruritis, although these may have limited benefit. Topical antipruritics (eg, menthol creams, calamine lotion) are also of limited use, given that itching is typically widespread. To date, none of these alternative treatments have been evaluated in randomized controlled trials.

Q|Is serial serum bile acid testing beneficial?

In patients with ICP, bile acid levels can increase during pregnancy and may increase rapidly near term. Given that higher serum total bile acid concentrations have been associated with adverse perinatal outcomes in some studies, repeat bile acid measurement has been suggested as potentially useful in guiding management. Follow-up laboratory testing may help guide delivery timing, especially in severe cases, but serial testing (eg, weekly) is not recommended.

Q|How should a pregnant woman with itching and normal bile acids be managed?

The pruritus in ICP can precede the rise in serum bile acids by several weeks. Therefore, if symptoms persist and no other explanation for pruritis exists, measurement of the total bile acid concentration and serum transaminases should be repeated. If UDCA is started empirically at the time testing is performed and before results are available, it is possible that elevated bile acid or transaminase levels may never be detected.

Q|Is antepartum testing indicated for patients with ICP?

We suggest that patients with a diagnosis of ICP begin antenatal fetal surveillance at a gestational age when delivery would be performed in response to abnormal fetal testing or at the time of diagnosis if the diagnosis is made later in gestation (GRADE 2C).

 The observed increased risk of stillbirth with ICP has prompted most practitioners to perform antenatal testing in this setting. However, the efficacy of antepartum fetal testing to prevent stillbirth in the setting of ICP is unknown. Several studies and case reports have reported stillbirth occurring within a few days of a reactive nonstress test.

 Antepartum fetal testing in ICP may not be useful because the mechanism of stillbirth is thought to be a sudden event rather than a chronic placental vascular process.

Recent clinical trials and meta-analyses support fetal surveillance with substantially lower rates of adverse perinatal outcomes compared with earlier reports, potentially due to more intensive monitoring with fetal surveillance and late-preterm or early-term delivery.

 The optimal frequency of testing is unknown and may be determined by criteria such as comorbidities or bile acid levels (eg, more frequent for total bile acid levels of 100 micromol/L or more). Due to the higher risk of stillbirth, patients with ICP should be placed on continuous fetal monitoring in labor.

Q| When should women with a diagnosis of cholestasis be delivered?

While the risk for late stillbirth is avoided with an early planned delivery, this must be weighed against risks to the neonate related to prematurity. The timing of delivery should be approached using risk stratification based on patient-specific factors, including total bile acid levels, in a shared decision-making model. 

We recommend that patients with total bile acid levels ≥100 micromol/L be offered delivery at 36 0/7 weeks of gestation, given that the risk for stillbirth increases substantially around this gestational age (GRADE 1B). We recommend delivery between 36 0/7 and 39 0/7 weeks of gestation for patients with intrahepatic cholestasis of pregnancy and total bile acid levels <100 micromol/L (GRADE 1C). 

Delivery timing for women with total bile acid levels <100 micromol/L should be individualized; it is reasonable for patients with bile acid levels of <40 micromol/L to be managed toward the later end of this time range, given the low risk for stillbirth seen in the studies referenced above, while women with total bile acid levels of ≥40 micromol/L should be considered for earlier delivery.

Delivery between 34 and 36 weeks of gestation can be considered in women with ICP, total bile acid levels of ≥100 micromol/L, and any of the following:

excruciating and unremitting maternal pruritus not relieved with pharmacotherapy;

a prior history of stillbirth before 36 weeks of gestation due to ICP with recurring ICP in the current pregnancy; or

preexisting or acute hepatic disease with clinical or laboratory evidence of worsening hepatic function.

Any patient delivered for ICP prior to 36 weeks of gestation should be extensively counseled about the absence of definitive evidence that the maternal and fetal benefits of delivery outweigh the potential morbidity of prematurity. 

We recommend antenatal corticosteroids for fetal lung maturity for patients delivered before 37 0/7 weeks of gestation if not previously treated (GRADE 1A).

For patients with early-term pregnancies (37 to 38 weeks of gestation) with pruritis suggestive of ICP, no rash, and no bile acid results yet available to confirm the diagnosis, management should be based on shared decision-making that involves a discussion of the uncertainty of the diagnosis, the risks of ICP vs early-term delivery, and the values and preferences of the patient. 

Diagnostic certainty, and thus advice about delivery management, is improved if there are elevated transaminases or a history of ICP in prior pregnancies, and it may be reasonable to deliver in the absence of bile acid results in these situations. 

We recommend against preterm delivery at <37 weeks of gestation in patients with a clinical diagnosis of ICP without laboratory confirmation of elevated bile acids (GRADE 1B).

The risk of recurrence of ICP in subsequent pregnancies may be as high as 90%, although data are insufficient to counsel patients on specific ranges.

 Some data also suggest that patients with a history of ICP are at higher risk for developing later hepatobiliary disease, particularly within the first year after the diagnosis of ICP. Given the risk for hepatitis C in these patients and the availability of an effective treatment, some experts advocate for routine testing for hepatitis C in patients with ICP.

It is important to consider reevaluation of liver function test results after delivery in patients with persistent pruritis or other signs or symptoms of a hepatobiliary disease, such as right upper quadrant pain or jaundice. If serologic study results remain abnormal, the patient should be referred to a liver specialist for evaluation for another underlying condition. 

1.Wikström Shemer E, Marschall HU, Ludvigsson JF, Stephansson O. Intrahepatic cholestasis of pregnancy and associated adverse pregnancy and fetal outcomes: a 12-year population-based cohort study. BJOG 2013;120:717-23.

2.Kenyon AP, Tribe RM, Nelson-Piercy C, et al. Pruritus in pregnancy: a study of anatomical distribution and prevalence in relation to the development of obstetric cholestasis. Obstet Med 2010;3:25-9.

3.Bechtel MA, Plotner A. Dermatoses of pregnancy. Clin Obstet Gynecol 2015;58:104-11.

4.Ambros-Rudolph CM, Glatz M, Trauner M, Kerl H, Müllegger RR. The importance of serum bile acid level analysis and treatment with ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: A case series from central europe. Arch Dermatol 2007;143:757-62.

5.Egan N, Bartels A, Khashan AS, et al. Reference standard for serum bile acids in pregnancy. BJOG : 2012;119:493-8.

6.Manzotti C, Casazza G, Stimac T, Nikolova D, Gluud C. Total serum bile acids or serum bile acid profile, or both, for the diagnosis of intrahepatic cholestasis of pregnancy. Cochrane Database Syst Rev 2019;7:Cd012546.

7.Pataia V, Dixon PH, Williamson C. Pregnancy and bile acid disorders. Am J Physiol Gastrointest Liver Physiol 2017;313:G1-g6.

8.Brouwers L, Koster MP, Page-Christiaens GC, et al. Intrahepatic cholestasis of pregnancy: maternal and fetal outcomes associated with elevated bile acid levels. Am J Obstet Gynecol 2015;212:100 e1-7.

9.Kawakita T, Parikh LI, Ramsey PS, et al. Predictors of adverse neonatal outcomes in intrahepatic cholestasis of pregnancy. Am J Obstet Gynecol 2015;213:570 e1-8.

10.Cui D, Zhong Y, Zhang L, Du H. Bile acid levels and risk of adverse perinatal outcomes in intrahepatic cholestasis of pregnancy: A meta-analysis. J Obstet Gynaecol Res 2017;43:1411-20.

11.Ovadia C, Seed PT, Sklavounos A, et al. Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses. Lancet 2019;393:899-909.

12.Williamson C, Hems LM, Goulis DG, et al. Clinical outcome in a series of cases of obstetric cholestasis identified via a patient support group. BJOG 2004;111:676-81.

13.Bacq Y, Sentilhes L, Reyes HB, et al. Efficacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: a meta-analysis. Gastroenterology 2012;143:1492-501.

14.Gurung V, Middleton P, Milan SJ, Hague W, Thornton JG. Interventions for treating cholestasis in pregnancy. Cochrane Database Syst Rev 2013;2013:Cd000493.

15.Kong X, Kong Y, Zhang F, Wang T, Yan J. Evaluating the effectiveness and safety of ursodeoxycholic acid in treatment of intrahepatic cholestasis of pregnancy: A meta-analysis (a prisma-compliant study). Medicine (Baltimore) 2016;95:e4949.

16.Liu J, Murray AM, Mankus EB, Ireland KE, Acosta OM, Ramsey PS. Adjuvant Use of Rifampin for Refractory Intrahepatic Cholestasis of Pregnancy. Obstet Gynecol 2018;132:678-81.

17.Alsulyman OM, Ouzounian JG, Ames-Castro M, Goodwin TM. Intrahepatic cholestasis of pregnancy: perinatal outcome associated with expectant management. Am J Obstet Gynecol 1996;175:957-60.

18.Herrera CA, Manuck TA, Stoddard GJ, et al. Perinatal outcomes associated with intrahepatic cholestasis of pregnancy. The Journal of Maternal-Fetal & Neonatal Medicine 2018;31:1913-20.

19.Lee RH, Incerpi MH, Miller DA, Pathak B, Goodwin TM. Sudden fetal death in intrahepatic cholestasis of pregnancy. Obstet Gynecol 2009;113:528-31.

20.Sentilhes L, Verspyck E, Pia P, Marpeau L. Fetal death in a patient with intrahepatic cholestasis of pregnancy. Obstet Gynecol 2006;107:458-60.

21.Chappell LC, Bell JL, Smith A, et al. Ursodeoxycholic acid versus placebo in women with intrahepatic cholestasis of pregnancy (PITCHES): a randomised controlled trial. Lancet 2019;394:849-60.

22.Wijarnpreecha K, Thongprayoon C, Sanguankeo A, Upala S, Ungprasert P, Cheungpasitporn W. Hepatitis C infection and intrahepatic cholestasis of pregnancy: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2017;41:39-45.

Articles

Intrahepatic cholestasis of pregnancy (ICP) occurs in the second and third trimesters of pregnancy and is characterized by pruritus and elevated serum bile acid concentrations.

Society for Maternal-Fetal Medicine Consult Series #53: Intrahepatic Cholestasis of Pregnancy

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.

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

National Partnership for Maternal Safety recommendations for antepartum outpatient prophylaxis

Women with prior VTE-especially if the episode was associated with pregnancy or use of estrogen-containing oral contraceptives-are at increased risk for recurrent VTE during pregnancy or postpartum. VTE risk also is increased in women with high-risk thrombophilias. Women with prior VTE and low-risk thrombophilias also are at increased risk. These data led to clear recommendations from the American College of Obstetricians and Gynecologists (

) for antepartum and postpartum prophylaxis for women with prior VTE and/or thrombophilias.

A simple step to reduce maternal death: Improve VTE prevention

National Partnership for Maternal Safety recommendations for postpartum prophylaxis after hospitalization for childbirth

Thromboprophylaxis is almost always initiated after vaginal delivery or cesarean, typically at least 6 hours later. This allows for safe administration of neuraxial analgesia or anesthesia and removal of a catheter. However, VTE may already have formed by that time, in which case, prophylaxis may be useless or less effective compared to when it is used prior to and during surgery. Another knowledge gap is the optimal duration of thromboprophylaxis. Heparin or low-molecular-weight heparin (LMWH) may be continued until the patient is ambulatory, until she is discharged from the hospital, through 10 days after delivery or 6 weeks after delivery.

 The relative merits of each time interval are uncertain. The same is true for various doses and drugs used for thromboprophylaxis. Although knowledge gaps exist, ACOG has a practice bulletin summarizing available regimens.

The authors report no potential conflicts of interest.

Inherited thrombophilias in pregnancy. ACOG Practice Bulletin Number 197. Obstet Gynecol. 2018;132:e18-34.

Thromboembolism in pregnancy. ACOG Practice Bulletin Number 196. Obstet Gynecol. 2018;132:e1-17.

The Royal College of Obstetricians and Gynaecologists. Reducing the risk of venous thromboembolism during pregnancy and the puerperium. Guideline No. 37a. London: RCOG; 2015.

Ob/gyns must be aware of the different treatment recommendations for various scenarios pre- and post-delivery.

NPMS recommendations: Antepartum vs postpartum prophylaxis

The death of a mother is a devastating obstetric complication. In 2015, there were an estimated 303,000 maternal deaths throughout the world,

which reflects a maternal mortality ratio of 216 per 100,000 live births. Maternal death is far less common in high-resource settings, but it still affects 12 per 100,000 live births.

In the United States in 2014, the maternal mortality ratio was 23.8 per 100,000 live births.

That is considerably higher than other countries with similar resources and represents a recent increase in maternal mortality.

Although the increase is largely due to increased ascertainment,

there is no doubt that it is possible to decrease maternal mortality in the United States.

Given the numerous causes of and risk factors for maternal death, often missing or vague available data in vital records, and variability among studies, it is difficult to precisely determine the proportion of deaths due to any single cause. Nonetheless, it is estimated that about 10% to 15% of maternal deaths in high-resource settings including the United States are due to venous thromboembolism (VTE).

VTE is an attractive target for reducing maternal deaths because, in theory, many are preventable. Indeed, in the UK, a concerted effort has been made to lower the rate of maternal death due to VTE. There, a comprehensive program was instituted involving better risk assessment and increased use of thromboprophylaxis.

The result was an apparent 50% reduction in maternal deaths due to VTE from 2006 to 2008 compared to 2003 to 2005.

In the United States, in contrast, the proportion of maternal deaths due to VTE remained relatively stable from 1987 through 2010.

Recent data indicate a maternal mortality ratio due to VTE of 1.01/100,000 in the UK versus 1.5/100,000 in the United States.

That may be a consequence of less aggressive recommendations for and implementation of VTE prophylaxis in the United States compared to the U.K., although it also may be due to chance. However, it is difficult to prove cause and effect since VTE, and especially death due to VTE is relatively uncommon. Thus, properly designed trials are difficult to conduct, and recommendations are largely based on expert opinion and theoretical benefits, rather than high-quality empirical evidence.

In addition, and despite prevention efforts, the rate of pregnancy-associated VTE may be increasing in the United States. For example, data from the Nationwide Inpatient Sample note that VTE associated with hospitalizations for childbirth increased 72% from 1998 to 2009.

This may be due to an increased prevalence of risk factors such as obesity, advanced maternal age, cesarean delivery and comorbid conditions such as diabetes and hypertension. 

Most maternal deaths associated with VTE occur after pulmonary embolism (PE). This is most often associated with cesarean delivery. However, recent data from the UK show that reductions in fatal PE can also occur in the antepartum period and after vaginal delivery.

Accordingly, prevention strategies must focus on both the antepartum and postpartum periods and after both vaginal and cesarean delivery. 

Recommendations for antepartum thromboprophylaxis

Some data exist with which to guide antepartum thromboprophylaxis. For example, women with prior VTE-especially if the episode was associated with pregnancy or use of estrogen-containing oral contraceptives-are at increased risk for recurrent VTE during pregnancy or postpartum. VTE risk also is increased in women with high-risk thrombophilias such as antithrombin deficiency, antiphospholipid syndrome, and homozygosity for the factor V Leiden or prothrombin G2010A mutations. Women with prior VTE and low-risk thrombophilias such heterozygosity for the factor V Leiden or prothrombin G2010A mutations also are at increased risk. These data led to clear recommendations from the American College of Obstetricians and Gynecologists (ACOG) for antepartum and postpartum prophylaxis for women with prior VTE and/or thrombophilias.

Less guidance is available for prevention of VTE during pregnancy in women with no prior history of or known risk factors for VTE. US guidelines (based on ACOG and American College of Chest Physicians [ACCP] recommendations) only advise using pharmacologic prophylaxis in women at highest risk for VTE.

In contrast, the Royal College of Obstetricians and Gynaecologists (RCOG) guidelines emphasize broad, risk factor-based assessment and widespread use of thromboprophylaxis. Their recommendations for antenatal and postpartum pharmacologic VTE prophylaxis are summarized in a “Green-top” guideline published in 2015 (Table 1).

These guidelines use a risk-scoring system to determine recommendations for prophylaxis with low-molecular-weight heparin (LMWH). They account for less profound but more common risk factors such as obesity, maternal age > 35 years and smoking.

Pharmacologic thromboprophylaxis is typically accomplished with prophylactic doses of heparin or LMWH. Examples include 5,000 units twice daily of unfractionated heparin or a daily dose of LMWH such as 40 mg daily of enoxaparin. This is typically administered during pregnancy and through six weeks postpartum. Discussion of the timing of anticoagulant therapy peripartum and intrapartum is beyond the scope of this article but reviews are available.

Data are scant with which to guide thromboprophylaxis for vaginal or cesarean delivery. Most authorities including ACOG advise uniform and routine use of mechanical thromboprophylaxis placed prior to cesarean delivery, as well as encouragement of early ambulation.

Data from a large US-based health care corporation noted a reduction in maternal deaths from VTE after universal use of pneumatic compression devices at cesarean delivery.

There were seven deaths from 2000 to 2006 prior to use of the devices. After implementation of mechanical prophylaxis, there was only one VTE maternal death between 2007 and 2012. In contrast, data from the nationwide Centers for Disease Control and Prevention Pregnancy Mortality Surveillance System failed to show a meaningful reduction in maternal deaths due to VTE from 1987 to 2010.

However, it is unknown what percentage of cesareans in the United States used mechanical thromboprophylaxis during this time.

Although they are of unproven efficacy, pneumatic compression devices are now used for virtually all cesarean deliveries in many hospitals. There is relatively little downside, other than cost and inconvenience. The devices are easily placed in a timely fashion prior to scheduled cesareans when the risk of VTE is low. However, they may be difficult to place in a timely fashion for emergency cases, when the risk of VTE is often higher. In addition, effectiveness is uncertain and may be adversely influenced by the lower-extremity edema that often occurs at the end of pregnancy. Also, many women dislike the devices, compliance is imperfect, and they may hinder early ambulation.

A cost-effectiveness analysis noted that the cost for the devices is $39,545.00 for each quality-adjusted life year.

It would be ideal to obtain high-quality data regarding the true benefits of mechanical thromboprophylaxis. 

Data regarding pharmacologic thromboprophylaxis and delivery are also lacking. Thromboprophylaxis is almost always initiated after vaginal delivery or cesarean, typically at least six hours later. This allows for safe administration of neuraxial analgesia or anesthesia and removal of a catheter. However, VTE may already have formed by that time, in which case, prophylaxis may be useless or less effective compared to when it is used prior to and during surgery. Indeed, other than small pilot studies, there are no data from high-quality studies regarding the efficacy of thromboprophylaxis for cesarean delivery. Another knowledge gap is the optimal duration of thromboprophylaxis. Heparin or LMWH may be continued until the patient is ambulatory, until she is discharged from the hospital, through 10 days after delivery or 6 weeks after delivery.

The relative merits of each time interval are uncertain. The same is true for various doses and drugs used for thromboprophylaxis. Although knowledge gaps exist, ACOG has a practice bulletin summarizing available regimens.

As with mechanical prophylaxis, downsides include expense, inconvenience, and lack of compliance. In addition, these medications may irritate skin and are associated with an increased risk for complications such as wound separation.

Unfortunately, high-quality studies assessing the efficacy and safety of pharmacologic thromboprophylaxis are unlikely to be performed. Such studies would be difficult to accomplish given the expense, large sample size required and reluctance on the part of clinicians to not use prophylaxis despite unproven efficacy. 

We are currently faced with a dilemma in trying to balance the pros and cons of strategies intended to decrease VTE-associated maternal deaths in the absence of quality data. The desire to do everything we can that might work to reduce VTEs is understandable but theoretical benefits must be weighed against potential harms and costs. To address this issue, the National Partnership for Maternal Safety (NPMS) published a consensus bundle on VTE in 2016.

The bundle includes recommendations intended to reduce VTEs, and it considers the lack of available high-quality data. As with other safety bundles, it is composed of four action domains: readiness, recognition, response, and reporting. 

The readiness component involves establishment of risk assessment strategies or tools for several time points during pregnancy. These time points include the first prenatal visit, all antepartum admissions, immediately postpartum, and on discharge home after delivery. The Caprini and Padua risk scoring systems are highly predictive of VTE risk in surgical patients and can be modified for use during pregnancy.

Recognition refers to the recognition of maternal risk after routine screening at the four time points, or in other words, the “use of the tool.” Response involves thromboprophylaxis in “high-risk” women. Recommendations from the NPMS for antepartum and postpartum thromboprophylaxis are summarized in Tables 2 and 3. 

The last part of the bundle involves reporting and systems learning. Each institution should conduct audits of risk factors, use of screening tools and implementation of prevention strategies. Adverse events also should be tracked and reported. A goal is to make this a “core measure” for quality. The NPMS document acknowledges a paucity of quality data and uncertainty regarding the specific population warranting thromboprophylaxis.

Given the relatively low rate of pregnancy-associated VTE, indirect measures such as screening and prophylaxis may be preferable metrics to assess than actual VTEs.

Also, since most serious postpartum VTEs occur after the delivery hospitalization, it is important to implement a system to ascertain events through at least 6 weeks postpartum.

Along with prevention of VTE, prompt recognition and treatment of VTE, especially PE, can potentially reduce mortality. Diagnosis can be difficult during pregnancy owing to the preponderance of non-specific symptoms such as leg swelling and shortness of breath. Also, there is a reluctance to use imaging studies during pregnancy due to concerns for possible untoward fetal effects. Given the increased risk of VTE and PE associated with pregnancy, all symptoms of DVT and PE should be fully and promptly evaluated. Although useful in non-pregnant individuals, D-dimer levels are not advised for screening pregnant women for VTE.

A reasonable approach for evaluating possible PE is to start with a chest x-ray. If it is normal, ventilation perfusion scan is advised. If the x-ray is abnormal, then computed tomography pulmonary angiography is indicated.

This algorithm may be modified based on testing availability and expertise in each institution. When there is high suspicion for DVT or PE and imaging is not available or feasible (for example, a patient in labor), anticoagulation can be initiated presumptively until a definitive diagnosis can be made.

As rates of VTE in pregnancy are increasing in the United States, ob/gyns must be vigilant in identifying women at risk and promptly instituting measures recommended by ACOG and other organizations