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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
The death of a mother is a devastating obstetric complication. In 2015, there were an estimated 303,000 maternal deaths throughout the world,1 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.1 In the United States in 2014, the maternal mortality ratio was 23.8 per 100,000 live births.2,3 That is considerably higher than other countries with similar resources and represents a recent increase in maternal mortality.1 Although the increase is largely due to increased ascertainment,3 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).4,5 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.6 The result was an apparent 50% reduction in maternal deaths due to VTE from 2006 to 2008 compared to 2003 to 2005.7
In the United States, in contrast, the proportion of maternal deaths due to VTE remained relatively stable from 1987 through 2010.5 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.5,8 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 2009.9,10 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.7 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.11,12
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.11-13 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).6 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.11-13
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.12Data 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.14 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 2010.5 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.15 A cost-effectiveness analysis noted that the cost for the devices is $39,545.00 for each quality-adjusted life year.16 It would be ideal to obtain high-quality data regarding the true benefits of mechanical thromboprophylaxis.
Intrapartum and postpartum care
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.6 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.12 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.17 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.
VTE safety bundle
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 2016.16 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.16 That strategy is also endorsed by ACOG.12 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.17 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.19 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.20 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.12 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.
In summary, tactics to reduce maternal death from VTE should include recognition of risk and prevention, as well as prompt diagnosis and treatment. Specific protocols may vary among institutions but should utilize the guidelines put forth by ACOG, NPMS, the Society for Maternal-Fetal Medicine, RCOG, ACCP and others. Most importantly, quality data are desperately needed to address the numerous knowledge gaps regarding VTE prevention. It is paramount to track the benefits and downsides of interventions in each institution and support the conduct of high-quality clinical trials regarding VTE prevention in pregnancy.
The authors report no potential conflicts of interest with regard to this article.