Venous thromboembolism (VTE) remains a major source of morbidity and mortality in the obstetric population with an incidence of 29.8/100,000 vaginal delivery hospitalizations in 2012.1 Cesarean delivery confers a 4-fold increased risk of thromboembolism when compared with vaginal delivery.2 Revised national guidelines now stipulate that the majority of women delivering via cesarean and of women at risk for VTE ante- and postpartum receive mechanical or pharmacological thromboprophylaxis.3–5 While some inpatient antepartum and postoperative obstetric patients will be treated with mechanical compression devices, an increasing number of obstetric patients will receive thromboprophylaxis with low-molecular-weight heparin (LMWH) and/or unfractionated heparins (UFHs). These practice changes will have a major impact on how anesthesiologists provide care to women during the peripartum period. Key decisions that will be affected include the timing of neuraxial blockade for labor analgesia or cesarean delivery anesthesia, the use of neuraxial analgesia for postoperative pain management, and the timing of epidural catheter removal. Neuraxial blockade remains the technique of choice for optimal labor pain management and cesarean delivery anesthesia due to its high reliability, superior pain relief, patient satisfaction,6–8 and very low incidence of complications.9,10
The overall incidence of spinal epidural hematoma (SEH) and its associated serious neurological sequelae has been particularly low in the obstetric population: 1:200,000 to 1:250,0009 compared to an estimated 1:3600 in the elderly orthopedic population.11 Protective factors in the obstetric population likely include the relative absence of underlying spinal pathology, the high compliance of the epidural space, and the hypercoagulability of pregnancy in this young and typically healthy population.
Current guidelines on regional anesthesia and anticoagulation from the American Society of Regional Anesthesia (ASRA) and the European Society of Anaesthesiology (ESA) group obstetric patients together with general surgical patients, despite pharmacokinetic and pharmacodynamic differences, such as drug volume of distribution, clearance, and elimination.12–14 For example, following a single dose of 143 U/kg of UFH subcutaneous (SQ), available data suggest that peak plasma heparin concentration and activated partial thromboplastic time response are decreased in term pregnant women compared with nonpregnant women.14 Peak anti-factor-Xa levels and duration of action of LMWH are similarly decreased in pregnant versus nonpregnant women.13,15
Unfortunately, there is a paucity of studies that specifically address the boundaries for safe use of neuraxial anesthesia (spinal, epidural, or combined spinal-epidural [CSE]) in obstetric patients receiving thromboprophylaxis. Therefore, we performed a systematic review to identify and report on all cases of SEH after neuraxial blockade in obstetric patients receiving thromboprophylaxis (primary outcome). We also report on SEH in obstetric patients receiving thromboprophylaxis and neuraxial anesthesia without adherence to the ASRA recommendations (secondary outcome).
This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.16 A protocol for the methods of this study was recorded in advance through the PROSPERO registry (CRD42016045751).
In all published reports, the primary outcome of interest was SEH in the setting of neuraxial anesthesia in an obstetric patient, receiving thromboprophylactic anticoagulation. Publications documenting UFH or LMWH thromboprophylaxis and neuraxial anesthesia without specific data on the time interval between the last anticoagulant dose and the neuraxial anesthetic were also included. Studies or reports were not restricted by publication date or study type. However, duplicate, non-English, and non-human studies or reports were excluded.
Obstetric patients were defined as pregnant or postpartum patients. Pregnancy was defined as the period from conception to delivery, and the postpartum period was defined as occurring within 6 weeks of delivery. Thromboprophylaxis was defined by the following doses of UFH: 5000 U SQ once daily or 2 or 3 times daily; 7500 U SQ twice daily; 10,000 U SQ twice daily based on the American Academy of Chest Physicians (ACCP),17 American College of Obstetricians and Gynecologists (ACOG),18 and Royal College of Obstetricians and Gynaecologists (RCOG)5 guidelines, as well as other published literature. Studies with LMWH thromboprophylaxis included the LMWHs detailed in the ACCP, ACOG, and RCOG guidelines: dalteparin, enoxaparin, and tinzaparin.
Our review focused on SEH, a rare but serious complication of neuraxial anesthesia that can cause permanent neurological impairment. SEH was considered to be present if the patient had documented signs or symptoms of new back pain, extremity weakness, sensory changes, or bowel or bladder symptoms, with magnetic resonance imaging (MRI) confirming the presence of blood in the epidural space. This definition for SEH has previously been described in the literature.19,20 The absence of these signs and symptoms was equated with the absence of a clinically significant SEH. All the SEHs described met this definition.
Published reports were identified through a literature search of the following databases: MEDLINE (via EBSCOhost), PubMed, Embase, CINAHL Plus with Full Text, The Cochrane Central Register of Controlled Trials, and Web of Science. In addition, individual study bibliographies and relevant journals were hand-searched. Attempts were made to contact 2 study investigators to supply missing data without a response. An example of the comprehensive Medline search strategy, created by a medical reference librarian at the Massachusetts General Hospital, can be found in Supplemental Digital Content 1, Table, http://links.lww.com/AA/B785. A sample of key words that were used to identify reports include “hematoma,” “epidural,” “spinal,” “pregnancy,” “obstetric,” “neuraxial,” “analgesia,” “anticoagulants,” “heparin,” “venous thromboembolism,” “dalteparin,” “enoxaparin,” “fondaparinux,” “tinzaparin,” “unfractionated heparin,” and “low molecular weight heparin.”
In addition, a separate analysis was conducted of the Anesthesia Closed Claims Project Database funded by the Anesthesia Quality Institute, the quality division of the American Society of Anesthesiology (ASA), for claims that occurred between 1990 and 2013 (Table 1). The database is composed of all the closed claims filed in 17 insurance companies in the United States with regard to anesthetic events. The methods of this structured evaluation of adverse anesthetic events have been published.21,22 The closed claims database has been previously used to investigate adverse maternal and neonatal outcomes related to obstetric anesthesia malpractice. For example, a 2009 analysis showed that claims after 1990 were more likely to be associated with maternal nerve injury or back pain and less likely to be associated with maternal or newborn death/brain damage compared to claims before 1990.23
All published reports were independently screened by 2 review authors (L.R.L., R.L.) by their titles and abstracts to determine eligibility. Both reviewers then independently assessed the full text for the subset of publications that potentially met the inclusion criteria. In the case of disagreement, consensus was reached through discussion between reviewers.
Risk of Bias in Individual Studies
Depending on the results of the query, the plan was to evaluate the quality of evidence using an appropriate quality assessment tool (eg, Cochrane Grade Scale).
Data were extracted by 2 review authors (L.R.L., R.L.) from eligible published reports through a systematic narrative review of demographics and the following additional characteristics were gathered from the publications: (1) publication type (case report, case series, audit, correspondence, cross-sectional study, randomized clinical trial), (2) number of women reported in publication, (3) relevant medical history, (4) anticoagulant type (UFH/LMWH), (5) time interval (when provided) between last dose of UFH/LMWH and neuraxial procedure, (6) neuraxial procedure characteristics (spinal, epidural, CSE), and (7) outcome (specifically, presence or absence of MRI-documented SEH).
The methodologies and limited data set precluded formal data aggregation for a meta-analysis. Therefore, no formal statistical analyses were conducted.
A total of 687 publications resulted from the electronic database search, in addition to 49 publications found through the other aforementioned sources. Of these 736 publications, 630 were excluded based on title and abstract; reasons for exclusion included (i) not relevant study population (ie, not obstetric), (ii) no thromboprophylaxis, (iii) no neuraxial anesthesia, (iv) different outcome (ie, no screening for SEH), (v) review or editorial, (vi) duplicate report, or (vii) non-human study (Figure). One hundred six publications were considered for full-text review, of which 96 were excluded based on the following criteria: (i) not relevant population (n = 3), (ii) no thromboprophylaxis (n = 11), (iii) no neuraxial anesthesia (n = 2), (iv) different outcome (n = 29), or (v) review or editorial (n = 51). A total of 10 publications met the inclusion criteria for our systematic review (Figure).
The 10 publications included in our final assessment were of heterogeneous design: 3 were case reports,24–26 1 was a correspondence,27 2 were retrospective case-control studies,28,29 1 was a short report,30 1 was a cross-sectional study,31 1 was a prospective cohort study,32 and 1 was a prospective audit33 (Table 2).
The 10 publications included 296 obstetric patients that received neuraxial anesthesia in the setting of UFH or LMWH thromboprophylaxis. Based on data from 6 reports, 28 parturients had their neuraxial blockade before the minimum ASRA-recommended time interval between the last anticoagulant dose and the neuraxial procedure. Based on data from 2 reports, 52 parturients received neuraxial anesthesia without their LMWH dose being discontinued during the intrapartum period.
Outcomes (Primary and Secondary)
No events that met the primary outcome definition of SEH were observed. Additionally, there were no reports of SEH for the secondary outcome24,27–33 (Table 3).
Risk of Bias Within Reports
Although the initial plan was to evaluate the quality of evidence using an appropriate quality assessment tool (eg, Cochrane Grade Scale), only 2 case reports were discovered for the primary outcome and a wide variety of study designs (with no randomized controlled trials) were observed for the secondary outcome. As such, the quality of the publications is qualitatively discussed instead.
Anesthesia Closed Claims Project
In the Anesthesia Closed Claims Project Database, there were 546 claims involving obstetric patients receiving neuraxial anesthesia. The claims involved women 15 to 55 years of age. Of the 546 claims, 5 cases involved SEH (Karen Posner, PhD, Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, WA [www.asaclosedclaims.org], personal communication, 2016). No patient was identified as taking anticoagulants (UFH or LMWH), although in 1 claim, the patient had severe preeclampsia and may have had some coagulation abnormalities. For completeness, gynecological claims were also searched using the same parameters. This search yielded 30 claims with no cases of SEH.
There are 2 publications describing 2 obstetric patients who developed MRI-confirmed SEHs and received enoxaparin and neuraxial anesthesia25,26 (Table 4).
In the case reported by Walters et al,26 an otherwise healthy obstetric patient received a CSE anesthetic for a planned cesarean delivery. She developed severe back pain and bilateral leg pain a few hours postoperatively, before receiving thromboprophylaxis (enoxaparin 40 mg SQ) that evening. Symptoms then progressed to bilateral leg weakness and numbness that were initially attributed to her postoperative patient-controlled epidural analgesia. An MRI 48 hours after symptom onset revealed SEH. Despite undergoing surgical decompression, the patient sustained permanent neurological injury.
Chiaghana et al25 described an obstetric patient with complex comorbidities (morbid obesity, Fontan circulation, and superficial phlebitis) who received a continuous spinal anesthetic for cesarean delivery. UFH, 7500 U SQ twice daily, was held for >24 hours prior to the neuraxial procedure and daily aspirin was continued. Twelve hours after epidural catheter removal, prophylactic enoxaparin 1 mg/kg SQ, daily, was restarted. On postoperative day 3, she was treated with “full dose” anticoagulation (enoxaparin 1 mg/kg SQ twice daily) for a pulmonary embolus. The next day she reported back pain, perineal paresthesia, and weakness in her extremities. An MRI confirmed an extensive SEH, which was evacuated during an emergent laminectomy with full neurological recovery.
Detailed descriptions of the included publications documenting neuraxial procedures on obstetric patients receiving intrapartum heparin are outlined in Table 3. The clinical scenarios related to these neuraxial procedures included elective cases (per local protocol) and emergency cases. None of these women developed SEH (Table 3).
In 1988, Hill et al30 evaluated blood loss during cesarean delivery in 50 obstetric patients in the United Kingdom receiving either UFH 5000 U or saline SQ 1 hour before surgery. Of the patients receiving UFH, 14 received epidural anesthesia and none suffered SEH.
In 1995, Campbell and Thompson24 described a cesarean delivery under CSE anesthesia in a woman (68 kg) with a history of myotonic dystrophy and prior VTE, receiving antepartum 20,000 U SQ UFH, total daily dose. UFH was stopped on the day before surgery. The epidural catheter was kept in place for postcesarean delivery pain management and UFH at 10,000 SQ twice daily was restarted immediately after the surgery. Although the epidural catheter became dislodged sometime the next day while the patient was still on thromboprophylactic therapy, there were no signs or symptoms of SEH.24
In 1996, Dulitzki et al28 described an Israeli cohort of 34 women with 41 pregnancies that received enoxaparin (40 mg SQ, daily prophylaxis) which was continued throughout labor, delivery, and into the early postpartum period with no excessive obstetric bleeding. Nine women received labor epidural analgesia without neurological complications, although the precise time interval between the neuraxial procedure and LMWH dose was not specified.
In 1997, Nelson-Piercy et al32 expanded on a previous report of 20 women34 to add the outcomes of 61 women (69 pregnancies, 43 neuraxial anesthetics) with a history of VTE receiving thromboprophylaxis (average dose enoxaparin 40 mg SQ, daily). LMWH was continued intrapartum and LMWH use “did not influence the mode of delivery or the choice of analgesia” as long as the activated partial thromboplastic times and prothrombin times were “not prolonged significantly.”32 Notably, anti-factor-Xa levels were not reported, thus limiting knowledge of the physiological effects of LMWH. These authors cite the cases of Dulitzki et al,28 10,000 nonobstetric patients of Bergqvist et al,35 and their 43 cases, all of which received ongoing LMWH thromboprophylaxis and neuraxial anesthesia without SEH, to support their practice of continuing LMWH thromboprophylaxis throughout labor and delivery.
In 1997, Hunt et al31 published data in a cohort of 32 women receiving dalteparin (mean dose 40 mg SQ, daily). The authors stipulated that at least 6 hours between a LMWH dose and the neuraxial procedure for labor and delivery was needed. Although the actual time interval between the LMWH dose and the neuraxial blockade was not specified, 9 of 32 women had epidural analgesia or anesthesia without developing SEH.
In 2003, Rowan et al33 presented results of a 3-year prospective audit evaluating the safety of prophylactic and therapeutic enoxaparin (40 mg daily vs 1 mg/kg twice daily). In the “prophylactic” group, most patients were converted to UFH (7500–10,000 U SQ, twice daily) at approximately 36 weeks gestational age. None of the 8 patients receiving neuraxial anesthesia developed SEH, including the one patient who received epidural anesthesia only 20 hours after a “therapeutic” dose.
In a 2004, a correspondence by Bird et al27 described a 24-year-old obstetric patient with twins who received epidural labor analgesia 22 hours after a dose of enoxaparin 1.5 mg/kg SQ, once daily for a pulmonary embolus. Her care team decided that the benefits of having a labor epidural in the setting of twins outweighed her risk of developing SEH. Although the patient developed the complication of a postdural puncture headache after an unintentional dural puncture, she did not develop SEH.27
In a 2005 retrospective study, Maslovitz et al29 compared a cohort of 284 Israeli women that received enoxaparin (“preventative”: 0.5–1.0 mg/kg daily or “therapeutic”: 1.5–2.0 mg/kg daily) with controls (N = 16,132) that did not receive enoxaparin, to evaluate hemorrhagic complications. Approximately 75% (N = 216) of the women on enoxaparin received epidural anesthesia with the last injection typically 12 to 24 hours before epidural placement. However, 2 women had spinal anesthetics for emergency cesarean deliveries 3 and 10 hours after receiving enoxaparin 40 mg SQ. None of the women in this series developed SEH.
Reporting on Anesthetic Outcomes.
The majority of the identified publications that investigated thromboprophylaxis in obstetric patients did not discuss the use of obstetric anesthesia or report on anesthesia-related outcomes. When obstetric anesthesia outcomes were reported, SEH was rarely the primary outcome of the study and important procedural details, such as difficulty of placement and equipment used, were not included. One article referenced previously published cases of obstetric patients with neuraxial anesthesia that developed SEH.36 However, review of the primary sources did not reveal any index cases of SEH in obstetric patients.
Definition of “Prophylactic” Anticoagulation.
There was considerable heterogeneity in the definition of prophylactic anticoagulation dosing in the reviewed publications. UFH thromboprophylactic regimens ranged from 5000 U SQ once,30 twice or 3 times daily,17,18 to 10,000 U SQ twice daily,24 or higher. For enoxaparin, the most commonly referenced LMWH in our reported cases, thromboprophylactic doses included variable weight-based regimens (0.5–1.0 mg/kg, SQ daily)29 and non-weight-based regimens (30–60 mg, SQ daily32 or 20–30 mg SQ, twice daily).
Our systematic review of relevant published literature (1952–2016) and of the Anesthesia Closed Claims Project Database (1950–2013) did not identify a single case of SEH after neuraxial blockade in obstetric patients receiving thromboprophylactic doses of UFH or LMWH (Table 1). The 2 cases of reported SEH that did occur in obstetric patients with neuraxial anesthesia in the setting of thromboprophylaxis with UFH or LMWH do not appear to be causally related to the thromboprophylaxis medication. In the first case, the patient with an indwelling epidural catheter for postcesarean pain management developed signs and symptoms of SEH before receiving a prophylactic dose of enoxaparin. In the second case, the patient developed signs and symptoms of SEH after receiving full-dose anticoagulation with enoxaparin (Table 4).
We have also identified a small number of cases in which the neuraxial procedure was done with the continuation of intrapartum thromboprophylaxis or with a shorter time interval between last dose and anesthetic procedure than is recommended in the ASRA or ESA guidelines. However, none of these patients developed SEH. In fact, a 2002 survey of 226 obstetric units in the United Kingdom revealed that 16% to 20% were willing to perform a “central nerve block” within 4 hours of a dose of LMWH (eg, enoxaparin, 40 mg SQ, daily), despite the published recommendations for a 10- to 12-hour time interval between LMWH and a neuraxial block.37
Considering that over 4 million births occur annually in the United States38 and the wide utilization of neuraxial analgesia and anesthesia in obstetric practices, the finding of no reported cases of this devastating neurological complication with thromboprophylaxis over a 60-year time period is encouraging. The contemporary practice of using wire-embedded polyurethane catheters with the associated decreased risk of epidural vein cannulation should only add to the safety of neuraxial anesthesia in the setting of thromboprophylaxis.39 The majority of women in the United States request epidural analgesia during labor; a recent workforce survey found that 71% of women in stratum I hospitals (annual deliveries >1500 per year) receive epidural labor analgesia.40 Cesarean delivery in the United States has increased over the past decades and now comprises 32% of births,38 and the vast majority of cesarean deliveries are performed under spinal or epidural anesthesia.40,41 Obstetric patients that do not receive neuraxial anesthesia will need general anesthesia for cesarean delivery, with the associated increased risk of failed intubation9,42,43 and other adverse events,44 including increased intraoperative blood loss45–47 and possible awareness under anesthesia.48 In addition, neuraxial anesthesia for cesarean delivery minimizes the need for additional opioids for postcesarean analgesia and reduces the risk of chronic postdelivery pain.49,50 For labor, these patients will be deprived of the benefits of neuraxial analgesia, including superior quality labor analgesia compared to intravenous opioids51 or inhaled nitrous oxide.52
There are inherent limitations to this systematic review. The overall very low level of evidence and high heterogeneity in study design make it challenging to draw firm conclusions. The quality of the data was variable with few publications reporting all the relevant data (eg, details of block placements, equipment used, precise time intervals between thromboprophylaxis dose and neuraxial procedure), which would greatly enhance the review. Reluctance to feature serious complications such as SEH in published case reports and positive reporting bias may have resulted in underreporting, particularly now that many journals require patient consent as a requirement for publication. However, by including the Closed Claims Database search as part of our systematic review, we likely have captured cases that involved litigation which otherwise might not have been voluntarily reported.
The introduction in the past decade of large-scale registries such as the Serious Complication Repository Project (SCORE) of the Society of Obstetric Anesthesia and Perinatology (SOAP) and the Multicenter Perioperative Outcomes Group (MPOG) that catalog anesthesia-related complications have validated the consistently reported very low incidence of SEH in obstetric patients.9–11 In the SCORE registry, 1 in 251,463 obstetric patients developed SEH. In the MPOG registry, 0 of 79,837 obstetric patients developed this complication, whereas 7 of the 62,450 nonobstetric patients developed SEHs. Despite the lack of denominator data, we found relatively few cases where obstetric patients on thromboprophylaxis received neuraxial procedures without the minimum recommended time delay between last dose and initiation of the neuraxial blockade.
In the future, best practices in reporting of SEH will come from expansion of these registries to include data on the details of thromboprophylaxis regimens and intervals between dosages and neuraxial procedures. New investigations that follow the Strengthening the Reporting of Observational Studies in Epidemiology guidelines will also allow for more rigorous aggregation of data. In the interim, optimal peridelivery care of obstetric patients will depend on multidisciplinary coordination between obstetric and anesthesia teams regarding plans for thromboprophylaxis to facilitate neuraxial anesthesia to optimize the care in nonurgent and elective setting. A Taskforce convened by SOAP is currently preparing a consensus statement that includes proactive tactics and decision-making tools to facilitate thoughtful weighing of the relative risks and benefits of providing versus withholding neuraxial anesthesia in favor of general anesthesia when unplanned events occur.53
We acknowledge Lisa L. Philpotts, BSN, MSLS, Department of the Treadwell Library at Massachusetts General Hospital, Boston, MA, for her contribution in doing a comprehensive search of the relevant literature.
Name: Lisa R. Leffert, MD.
Contribution: The author helped conduct the review, collect the data, analyze and interpret the data, write and revise the manuscript, and approve the final result.
Name: Heloise M. Dubois, BS.
Contribution: The author helped conduct the review, collect the data, interpret the data, write and revise the manuscript, and approve the final result.
Name: Alexander J. Butwick, MBBS, FRCA, MS.
Contribution: The author helped conceptualize the project, revise the manuscript, and approve the final result.
Name: Brendan Carvalho, MBBCh, FRCA, MDCH.
Contribution: The author helped conceptualize the project, revise the manuscript, and approve the final result.
Name: Timothy T. Houle, PhD.
Contribution: The author helped conceptualize the project, analyze and interpret the data, write and revise the manuscript, and approve the final result.
Name: Ruth Landau, MD.
Contribution: The author helped conduct the review, collect the data, analyze and interpret the data, write and revise the manuscript, and approve the final result.
This manuscript was handled by: Jill M. Mhyre, MD.
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