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Journal of Perinatology (2011) 31,73–84 r 2011 Nature America, Inc. All rights reserved. 0743-8346/11 www.nature.com/jp STATE-OF-THE-ART and in pregnancy: what are the implications for labor and cesarean delivery?

AJ Butwick and B Carvalho Department of Anesthesiology, Stanford University School of Medicine, Stanford, CA, USA

techniques in patients receiving anticoagulation. The most feared Neuraxial anesthetic techniques are commonly used during the peripartum complication is symptomatic spinal , which can be period to provide effective pain relief for labor and anesthesia during cesarean associated with devastating neurologic outcomes (such as lower- delivery. Major neurologic complications are rare after neuraxial anesthesia; limb paralysis). Early diagnosis and the patient’s pre-operative however, spinal hematoma is associated with catastrophic neurologic neurological status are important factors that determine outcomes (including lower-limb paralysis). Anticoagulant and antithrombotic neurological outcome after surgical decompression to treat spinal drugs can increase the risk of spinal hematoma after neuraxial anesthesia, hematoma.7,8 Anticoagulant is an important etiological and better understanding of the pharmacokinetics and pharmacodynamics of factor for spinal hematoma identified from case reports of patients has led to greater appreciation for withholding anticoagulation receiving neuraxial anesthesia.9 Spontaneous spinal hematoma before and after neuraxial anesthesia. A number of national anesthetic formation can also occur in patients who do not undergo spinal societies have produced guidelines for performing neuraxial anesthesia in instrumentation, and this has been recently reported in the patients receiving anticoagulation. However, there is limited information obstetric literature in a patient receiving therapeutic about anesthetic implications of anticoagulation during the peripartum anticoagulation with low-molecular weight (LMWH).10 period. This article will review the risks of spinal hematoma after neuraxial The anesthetic management of pregnant patients receiving anesthesia in pregnant patients; current guidelines for neuraxial anesthesia anticoagulation can be particularly challenging because of for anticoagulated patients; and relevant pharmacological data of specific additional risks of spinal hematoma associated with spinal or anticoagulant and antithrombotic . epidural anesthesia. The unpredictable timing of labor and delivery Journal of Perinatology (2011) 31, 73–84; doi:10.1038/jp.2010.64; may lead to uncertainty about using a neuraxial technique among published online 17 June 2010 anesthesiologists dealing with patients on anticoagulant or Keywords: neuraxial anesthesia; pregnancy; anticoagulants; antithrombotic drugs. In addition, new anticoagulants are being introduced into clinical practice (for example , ),11 and there is limited information related to their safety in patients receiving neuraxial anesthesia. As a result, many Introduction anesthesia care providers may ‘err on the side of caution’ and Important advances in neuraxial anesthetic practice have improved choose not to offer a neuraxial technique to pregnant patients the quality of pain relief during labor1 and enhanced post-cesarean receiving anticoagulation. The implications of this empirical analgesia,2,3 and reduced maternal morbidity and mortality method of decision making are that anesthetic options for providing (because of lower rates of general anesthesia for cesarean effective pain relief during labor and anesthesia for cesarean delivery).4,5 As a result, neuraxial anesthetic techniques, which delivery become more limited. Furthermore, neuraxial anesthetic include epidural, spinal, or combined spinal–epidural, have techniques are recommended for optimizing the anesthetic become established techniques for providing analgesia in labor and management for high-risk pregnant patients during the peripartum anesthesia for cesarean delivery.6 and postpartum periods. For example, airway management in Adverse neurologic outcomes associated with neuraxial morbidly obese patients undergoing general anesthesia for cesarean anesthesia are fortunately rare; however, there is substantial delivery can often pose major problems, and epidural catheter-based concern regarding the implications of performing neuraxial techniques for providing anesthesia are recommended for these patients.12 Balancing the risks versus benefits of neuraxial Correspondence: Dr AJ Butwick, Department of Anesthesiology (MC:5640), Stanford University anesthesia in pregnant patients receiving anticoagulation during the School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA. peripartum period requires careful consideration. E-mail: [email protected] Received 16 December 2009; revised 10 March 2010; accepted 21 March 2010; published online Current guidelines for the use of anticoagulation in pregnant 13 17 June 2010 patients from the Pregnancy and Working Group and Neuraxial anesthesia with anticoagulant drugs AJ Butwick and B Carvalho 74

American College of Chest Physicians14 include limited discussion anesthesia in Sweden from 1990 to 1999. Two cases of spinal of the implications of anticoagulation and the use of neuraxial hematoma were reported after spinal anesthesia and epidural anesthesia during the peripartum period. Guidelines for the safe catheter removal, both in patients with HELLP syndrome. The timing and administration of central neuraxial blockade in reported rates of spinal hematoma after obstetric epidural and patients receiving anticoagulant and antithrombotic agents have spinal blocks for cesarean delivery were 1:200 000 and 1:50 000, been produced by the American Society of Regional Anesthesia15 respectively. Data from other studies of complications after epidural and several European anesthetic societies.16–21 blocks in obstetric patients (meta-analysis and national audit) This review will acquaint obstetric care providers with summary indicate that the incidence of spinal hematoma is between 0 and information on the timing and provision of neuraxial anesthesia 0.5:100 000.27,28 A review of obstetric anesthesia claims for injuries for patients receiving anticoagulant and antithrombotic agents. In between 1990 and 2003 included four cases of epidural hematoma addition, suggested algorithms for the peripartum management of related to neuraxial anesthesia (out of a total of 426 claims).29 patients on prophylactic and therapeutic unfractionated heparin Unfortunately, no supplementary background information was (UFH) and LMWH will be outlined. The physiologic changes provided for each case.29 An earlier systematic review of safety and associated with pregnancy can lead to changes in the efficacy of LMWH use in pregnancy included a subanalysis of 440 pharmacokinetic (PK) and pharmacodynamic (PD) profiles of patients who received neuraxial anesthesia. In this study, no cases anticoagulant drugs, and relevant information is also described. of spinal hematoma were reported; however, specific details of the timing and mode of neuraxial anesthesia were not included.30 Although anticoagulant drugs can increase the risk of spinal Spinal Hematoma: what is the risk of neuraxial hematoma after neuraxial anesthesia, the true incidence of spinal anesthesia in pregnant patients receiving hematoma in obstetric patients receiving anticoagulant or anticoagulation? antithrombotic drugs remains unknown. Acquired or inherited conditions (associated with or diathesis) and anticoagulant drugs are important etiological factors for the development of spinal hematoma.9,22 Antenatal multi-disciplinary assessment for Neuraxial anesthesia, which involves instrumentation of the anticoagulated pregnant patients epidural or subarachnoid space, can further increase the risk of An antenatal anesthetic assessment and consultation is spinal hematoma formation in anticoagulated patients. Spinal cord recommended for anticoagulated patients before the onset of labor injury is thought to occur by direct compression from the overlying or delivery. At our institution, all anticoagulated patients are hematoma in the epidural space, or possibly by secondary ischemic referred by our obstetricians for an anesthesia consultation in injury of the spinal cord because of compression on spinal cord advance of their estimated date of delivery. This consultation allows vessels. The early diagnosis of spinal hematoma is important in us to fully inform patients and their obstetricians about the improving neurological outcomes, as the risk of permanent indications and timing of neuraxial anesthesia for labor and neurologic deficit (ranging from mild sensory deficit to paraplegia) delivery, and to discuss alternative anesthetic options if is increased if hematoma evacuation is delayed >12 h after the anticoagulant effects persist during the peripartum and early onset of neurologic symptoms.8,9 . Before the introduction of LMWHs, many anesthesiologists The indications for anticoagulant therapy in the antenatal considered that the risk of spinal hematoma after neuraxial period include the prophylaxis and treatment of VTE in pregnancy, anesthesia was theoretical.23 However, the introduction of LMWH in the prevention of systemic embolism in patients with mechanical the United States in 1993 for surgical thromboprophylaxis was valves, and the prevention of adverse pregnancy outcomes associated with an increase in the number of reported cases of (for example early recurrent pregnancy loss, placental abruption) spinal hematoma in patients receiving neuraxial anesthesia in patients with inherited or acquired . There is (>50 cases reported over a 5-year period).24 The Food and limited information available to guide physicians in managing Administration in the United States intervened by issuing a health anticoagulation during the peripartum period. The American advisory in 1997 for LMWHs,23,25 and manufacturers of LWMHs College of Chest Physicians guidelines recommend discontinuing and were requested to produce ‘boxed warnings’ about UFH or LMWH 24 h to 36 h before planned induction of labor or the risk of spinal hematoma after neuraxial anesthesia on their cesarean delivery for patients diagnosed with a venous products. thromboembolism during a current pregnancy.14 Intravenous UFH The results of several, large retrospective reviews suggest that the therapy during labor is recommended for patients at ‘very high risk of spinal hematoma after neuraxial blockade in obstetric risk’ (for example proximal deep or pulmonary patients seems to be very low. Moen et al.26 performed a embolism within 4 weeks of delivery) for recurrent venous retrospective review of adverse neurologic outcomes after neuraxial thromboembolism.14 No specific guidance is given for patients

Journal of Perinatology Neuraxial anesthesia with anticoagulant drugs AJ Butwick and B Carvalho 75 during the peripartum period requiring anticoagulation for other Table 1 Guidelines from the American and European societies of regional medical or obstetric indications. Owing to the lack of data, different anesthesia for the timing of neuraxial anesthesia (epidural or spinal) in patients approaches for managing anticoagulation have been described for receiving antithrombotic and anticoagulant drugs 31,32 laboring patients: to discontinue LWMH before or during labor, US guidelines15 European 33 switch to subcutaneous (s.c.) heparin before delivery, or use guidelines17 tailored intravenous heparin regimens in labor.34 A survey of American College of Obstetricians and Gynecologists fellows UFH s.c.: Before NB/CW No time interval 4h investigating physician practice for managing pregnant patients (for 5000 U twice daily)a with confirmed that similar variations in decision After NB/CW 1 h 1 h making exist for managing anticoagulation around the time of 35 delivery. As obstetric preferences for managing anticoagulated UFH i.v.: patients during the peripartum period may vary, it is important Before NB/CW ns (NB)/2–4 h (CW) 4 h that there is close communication between obstetricians and After NB/CW 1 h 1 h anesthesiologists. We recommend that multi-disciplinary agreement is obtained on the planned timing and duration for an LMWH (prophylactic dose) appropriate window period ‘off anticoagulation’ and for spinal/ Before NB/CW 10–12 h 12 h epidural anesthesia during the peripartum period. After NB/CW 6–8 h (first postoperative 2–4h dose with single-daily dosing) (NB)b/>2 h (CW)c Guidelines for performing neuraxial anesthesia in anticoagulated patients LMWH (therapeutic dose) Before NB/CW 24 h 24 h Guidelines and recommendations for neuraxial anesthesia from After NB/CW 24 h (NB)/>2 h (CW)c 2–4h the American Society of Regional Anesthesia15 and the European 17 Society of Regional Anaesthesia for patients receiving Fondaparinux s.c. anticoagulation and antithrombotic drugs have been published. Before NB/CW nsd 36–42 he For the purposes of this review, we have outlined relevant After NB/CW nsd 6–12 h information from these guidelines for the following drugs: UFH, f LMWH, fondaparinux, , (, Aspirin No CI No CI Clopidogrel before NB/CW 7 days 7 days ), and (Table 1). These anesthesia society Ticlopidine before NB/CW 14 days 10 days guidelines are limited by a lack of robust data assessing specific risk, and are based on consensus and expert opinion as well as Warfarin information about PK and PD. There is understandable concern Before NB/CW ns (NB)/INRp1.5 (CW)g INR<1.4 regarding the medico-legal implications of such guidelines on After NB/CW Restart after CW Restart after CW clinical practice, as well as uncertainty about whether these 36,37 Abbreviations: CI, contraindication; CW, epidural catheter withdrawal; INR, international guidelines can be described as ‘standard of care’. Nonetheless, normalized ratio; i.v., intravenous; LMWH, low-molecular weight heparin; NB, neuraxial it is likely that anesthesia care providers will adhere to these block; ns, not stated; s.c., subcutaneous; UFH, unfractionated heparin. national guidelines on neuraxial anesthetic practice for patients aCheck count before neuraxial block if heparin therapy >4 days. No specific recommendations for doses >10 000 U daily or if more than twice-daily dosing. receiving prophylactic or therapeutic anticoagulant drugs. bThe second postoperative dose of LMWH should occur >24 h after the first dose. Apply There is limited data of the pharmacological effect of these guidelines for therapeutic dosing for twice-daily intermediate doses. drugs in pregnant patients; therefore, descriptions of relevant cAdminister first postoperative dose of LMWH 2 h after catheter withdrawal for single- or twice-daily dosing. PK-PD data from non-pregnant patients have been included. d Recommend fondaparinux administration if single, atraumatic attempt at neuraxial Summary information of the PK data for UFH, LMWH, block placement occurs and indwelling neuraxial catheters are avoided. fondaparinux, aspirin, thienopyridines (clopidogrel, ticlopidine), eApplies for dose p2.5 mg day. Neuraxial blockade is contraindicated for therapeutic and warfarin is shown in Table 2. As many of these drugs are doses (5–10 mg per day). fOmit longer-acting anticoagulant 24 h before neuraxial block/catheter withdrawal if irreversible or slowly reversible, the PK of specific drugs may not combined with aspirin for perioperative thromboprophylaxis. Administer LMWH or necessarily predict the PD profile. fondaparinux between 36 and 42 h before or after neuraxial block/catheter withdrawal. gRecommend normal INR before neuraxial block placementFno specific values are stated in American Society of Regional Anesthesia guidelines. Unfractionated heparin UFH is a highly sulfated comprising a heterogeneous mixture of polysaccharide chains of varying lengths

Journal of Perinatology Neuraxial anesthesia with anticoagulant drugs AJ Butwick and B Carvalho 76

Table 2 A summary of pharmacologic data (based on non-obstetric patients) for unfractionated heparin, LMWH, fondaparinux, aspirin, clopidogrel, ticlopidine, and warfarin

Drug Mode of action Route of Onset of action Elimination half-life administration

Unfractionated Bind ATIII s.c.; i.v. Within 2 h (s.c.); immediate (i.v.) 30, 60, 150 min (25 IU kg–1, heparin 100 IU kg–1, 400 IU kg–1) LWMH Bind ATIII s.c. ±3–4 h 3–6 h; dose independent; prolonged in renal failure Fondaparinux Selective inhibition of factor Xa s.c. Within 2 h 17 h Aspirin Irreversible inhibition of COX-1 Oral Rapid (with 160 mg dose) 30 min Clopidogrel Inhibit ADP-induced platelet Oral Within 5 h 7.5 h (of main metabolite) aggregation Ticlodipine Inhibit ADP-induced platelet Oral 1–8 h 20–50 h aggregation Warfarin Inhibit g-carboxylation of factors II, Oral Within 90 min 36–42 h VII, IX, X

Abbreviations: AT, ; COX, cyclooxygenase; i.v., intravenous; IU, international units; LMWH, low-molecular weight heparin; s.c., subcutaneous.

(3000 to 30 000D). UFH binds to antithrombin III, which A lower incidence of heparin-induced and subsequently interacts with (factor IIa), factor Xa, XIIa, and less frequent injections are potential advantages of XIa, IXa, and . Current recommendations for the LMWHs compared with UFH.42 LMWHs are depolymerized porcine minimum time periods for heparin administration before and after muscoal heparin preparations, and the molecular weight of neuraxial anesthesia are outlined in Table 1. Guidelines from most individual LMWHs can vary between 4 and 8 kDa. The mechanism anesthetic societies emphasize the need for the patient to have of action of LMWHs occurs by binding with antithrombin III, normal activated partial thromboplastin time (APTT) and/or which augments the inhibitory effect of antithrombin III on activated clotting values before neuraxial anesthesia. In our thrombin, activated factor Xa, FIXa, FIIa, and kallikrein by a factor experience, obstetric care providers are likely to encounter pregnant of X1000.43 In addition, LMWHs also inhibit FVIIa/ patients receiving s.c. UFH for thromboprophlyaxis. However, high- (TF) complex formation,44 induce the release of TF pathway risk patients (for systemic or pulmonary emboli) may require inhibitor (TFPI) and augment the inhibitory effect of TFPI on intravenous heparin during the peripartum period.38 FVIIa/TF complex formation.45 The bioavailability of LMWHs is Normal heparin clearance is associated with a rapid distribution >90%, and t½ values are generally twice as long as for UFH. phase followed by a zero-order elimination phase. A first-order Current recommendations for the minimum time periods for process is assumed for heparin doses within the usual therapeutic LMWH administration before and after neuraxial anesthesia are range in the non-pregnant state.39 However, pregnant patients will outlined in Table 1. often be on higher dosing schedules because of pregnancy-induced There are marked differences in PK-PD properties between heparin resistance. Lower peak plasma concentrations, lower peak individual LMWH drugs, which are related to variability in the changes in APTT, more attenuated APTT responses, and shorter physicochemical structure of drugs in this class. In addition, onset times to peak plasma concentrations have been reported in anti-Xa activity assays, which are often used to estimate PD of third trimester pregnant patients receiving s.c. heparin compared LMWHs or monitor treatment, may vary because of individual with non-pregnant controls.40,41 These differences probably relate differences in assay technique. There is also no standardization to a physiological increase in glomerular filtration rate, and an of assay techniques used to assess anti-Xa- and anti-IIa-specific increase in non-specific protein binding and plasma volume with activity; therefore, differences in anticoagulant effects between advancing gestation. To maintain therapeutic efficacy, UFH different LWMH preparations should be reviewed cautiously.46 dosing/frequency may need to be increased because of the relative Earlier studies have investigated the PK-PD of LMWHs in pregnant increase in heparin resistance with advancing pregnancy. patients to assess the efficacy of thromboprophlyaxis in the antenatal and postpartum periods. Many of these studies used PK-PD data as a means of assessing thromboprophylactic efficacy Low-molecular weight in ‘at-risk’ pregnant patients for venous thromboembolism. LMWHs are commonly used for prophylaxis and treatment of An earlier study assessing thromboprophylaxis with s.c. venous thromboembolism in the antenatal and postpartum periods. tinzaparin (50, 75, or 100 IU kg–1; once a day) reported peak

Journal of Perinatology Neuraxial anesthesia with anticoagulant drugs AJ Butwick and B Carvalho 77 anti-Xa levels at 4 h post-.47 Patients receiving tinzaparin were significantly lower in patients receiving dalteparin and 50 IU kg–1 had significantly lower peak 4 h anti-Xa levels and tinzaparin compared with enoxaparin, respectively. No differences reduced 24-h therapeutic activity (compared with 75 and in TFPI levels were observed between groups. Future research is 100 IU kg–1) between 28 and 36 weeks gestation. Peak anti-Xa needed to better assess the effects of LMWHs on the kinetics of activity at 4 h also occurs with s.c. dalteparin (5000 units; once a thrombin generation and , as there is still uncertainty day) at 12, 24, and 36 weeks gestation.48 Blomback et al.49 studied about the association of these markers with bleeding risk. It is also the PK of s.c. dalteparin (2500 or 5000 units; once a day) in uncertain how specific changes in hemostasis affect the risk profile pregnant women at 32 to 35 weeks gestation and compared the associated with spinal hematoma after neuraxial anesthesia. results with historical controls. The maximal concentration (Cmax), lag-time (Tmax), and 24 h area under the curve values in the study group were 0.2 aXa IU ml–1, 3 h, and 1.9 aXa IU h–1 ml–1, Fondaparinux respectively, which were all lower than observed in the Fondaparinux is a synthetic pentasaccharide, which selectively control group. inhibits factor Xa. Fondaparinux binds with high affinity to Several studies have assessed the PK-PD of s.c. enoxaparin in antithrombin, leading to a 300-fold increase in factor Xa pregnant and postpartum patients. Casele et al. investigated the PK inhibition.57 Fondaparinux therapy may be indicated in cases of of s.c. enoxaparin (40 mg daily) at three different time points heparin-induced thrombocytopenia or severe cutaneous allergic (12 to 15 weeks gestation; 30 to 33 weeks gestation; 6 to 8 weeks reactions to heparin. No studies investigating fondaparinux PK-PD postpartum).50 Time to peak concentration was between 185 and exist in the pregnant population, but there is data in healthy non- 229 min in pregnant patients, which seems to be consistent with pregnant volunteers.58 After s.c. administration, the bioavailability 51 non-pregnant patients. Lebaudy et al. performed a large of fondaparinux approaches 100%. Cmax levels are achieved at 2 h population-based study assessing the PK of enoxaparin in after s.c. injection, with significant levels (Cmax/2) within 25 min pregnancy. In this study, the volume of distribution of enoxaparin of administration. Peak plasma levels and the area under the curve was higher in the first trimester compared with the third trimester of fondaparinux are linearly related to dose. Fondaparinux is and the early postpartum period (>4 days postpartum), primarily eliminated in a dose-independent manner through the respectively, which is probably related to the increase in plasma kidneys and its elimination half-life is 17 h. There are a few reports volume in early pregnancy. Furthermore, the volume of of prophylactic fondaparinux administration in pregnant patients; distribution returns to normal 4 days after delivery.51 Clearance of however, these reports lacked details about obstetric anesthetic enoxaparin is higher in first trimester compared with the non- management.59,60 No evidence of placental transfer of pregnant state, which is likely to be related to the pregnancy- fondaparinux was reported in an ex vivo study of high therapeutic associated increase in glomerular filtration rate that occurs in the doses of fondaparinux.61 However, Dempfle62 reported measurable first 16 weeks of gestation. The authors suggest that the reduction anti-Xa levels in umbilical cord , suggesting some placental in peak anti-Xa activity will be approximately 20 and p10% transfer in vivo. Current recommendations for neuraxial between the first trimester and the 9th month in pregnant patients anesthesia in the setting of patients receiving fondaparinux are receiving prophylactic (non-weight-adjusted) and therapeutic outlined in Table 1. (weight-adjusted) doses, respectively. LMWHs are predominately eliminated by the renal system after first-order kinetics. There are reported differences between LMWHs Aspirin for drug clearance (average apparent clearance for enoxaparin, Low-dose aspirin irreversibly inhibits platelet function by inhibition dalteparin, and nadropin are 15, 33, and 21 ml min–1, of platelet cyclooxygenase-1, which reduces production of respectively).52,53 A2 (vasoconstrictor and platelet aggregator). The assessment of anti-Xa levels to determine bleeding risk in Although the half-life of aspirin is only 15 to 20 min, its duration patients receiving LMWHs has been earlier called into question. of action is 7 to 10 days, consistent with the normal lifespan of Excessively high anti-Xa levels have been reported after .63,64 interruption of therapeutic LMWH therapy for >12 h54 and have An earlier study of examining the PK of aspirin (75 mg) in also been associated with an increased risk of bleeding.55 Ellison pregnant patients reported slower uptake and a lower peak level et al. compared changes in hemostatic markers (anti-Xa, plasma than in non-pregnant controls.65 No significant differences in PK TFPI, plasma thrombin–antithrombin complexes) in women were observed between patients at 27 and 29 weeks compared with receiving dalteparin, enoxaparin, or tinzaparin for patients at 36 and 38 weeks. Adequate in vivo hemostasis as thromboprophylaxis post-cesarean delivery.56 Anti-Xa levels were measured by thromboelastography has been reported in pregnant significantly higher in groups receiving enoxaparin and dalteparin patients after aspirin ingestion (600 mg).66 Kinouchi et al.67 found than the tinzaparin group. Plasma thrombin–antithrombin levels that ADP-induced platelet aggregation was decreased in pregnant

Journal of Perinatology Neuraxial anesthesia with anticoagulant drugs AJ Butwick and B Carvalho 78 patients receiving antiplatelet therapy (aspirin 40 mg per The maximal inhibition of platelet function occurs after 3 to 5 days day þ 150 mg per day), but remained within a of administration.75 The apparent elimination half-life is normal range; and APTT values were also not 24 to 36 h after a single oral dose;76 however, recovery of platelet prolonged. function after discontinuation of ticlodipine occurs slowly over No special precautions are required for patients receiving aspirin 3 to 8 days.74,75 Ticlodipine has non-linear PKs, and its clearance alone (75 to 300 mg daily) before neuraxial anesthesia (Table 1). decreases with repeat dosing.77

Thienopyridines (clopidogrel and ticlopidine) Warfarin The risk of acute is increased during The anticoagulant effect of warfarin occurs as a result of pregnancy, with an estimated incidence of 6 per 100 000 interference of g-carboxylation of glutamate residues (G1a) on the deliveries.68 Thienopyridines are indicated to prevent coronary stent N-terminal regions of K-dependent proteins (factors II, VII, thrombosis after percutaneous coronary intervention, and act by IX, and X). The dose response can differ between subjects,78 and irreversibly binding to receptors, which reduces ADP-induced genetic and environmental factors (drugs, diet, and disease states) activation of glycoprotein IIb/IIIa complexes. The drugs also bind can also affect PK-PD characteristics of warfarin.79 The thrombin receptor agonist peptide-induced fibrinogen and anticoagulant effects of warfarin are most commonly monitored P-selectin on platelet membranes. In vivo hepatic transformation using the prothrombin time. At the initiation of warfarin therapy, to active metabolites for each drug is the most likely mechanism prothrombin time is predominately affected by depression of factor for the antiplatelet effects. The antiplatelet effect of thienopyridines VII, which has the shortest half-life (5 h) of the vitamin affects between 60 and 70% of ADP receptors. Clopidogrel has a K-dependent clotting factors.80 The antithrombotic effect of more favorable side-effect profile than ticlodipine. Ticlodipine has warfarin occurs after reduction of prothrombin, which has a much been associated with aplastic anemia, thrombocytopenia, and longer half-life (60 to 72 h). thrombotic thrombocytopenic purpura. An earlier study comparing warfarin dosage in postpartum Current recommendations for non-pregnant patients requiring patients with non-pregnant patients found that postpartum patients neuraxial anesthesia who are receiving clopidogrel or ticlopidine required significantly longer time and higher doses of warfarin to are outlined in Table 1. Combination therapy attain therapeutic levels of anticoagulation.81 Higher factor II, VII, (aspirin þ clopidogrel or ticlodipine) has an additive effect on and X levels in the postpartum period probably substantiated platelet inhibition,69 and there are currently no recommended time higher therapeutic warfarin dosing in this patient subpopulation. interval recommendations before and after neuraxial anesthesia Guidelines for performing neuraxial anesthesia in patients on with this combination therapy. We are unaware of any studies that warfarin therapy are described in Table 1. have investigated the PK-PD of clopidogrel or ticlopidine in pregnant patients. In the non-obstetric population, maximal inhibition of Peripartum management ADP-induced platelet aggregation occurs within 5 h of clopidogrel The management of anticoagulated parturients during the administration (200 to 600 mg).70 Platelet aggregation inhibition peripartum and postpartum periods may vary between institutions reaches steady state with clopidogrel or ticlopidine after 6 days of and among individual physicians. In our experience, UFH and daily dosing (52 and 43% inhibition by 75 mg clopidogrel and LMWHs are the most common anticoagulants encountered in 250 mg b.i.d. ticlopidine daily, respectively).71 Normal platelet obstetric patients during the peripartum and postpartum periods. function is achieved in 7 days after termination of clopidogrel Suggested algorithms for managing pregnant patients receiving therapy; however, these assessments are based on recovery of prophylactic UFH and LMWH during labor and for cesarean bleeding times.71 Clopidogrel is rapidly absorbed from the delivery are shown in Figures 1–4. Suggested algorithms for after oral ingestion. A dose-proportional patients receiving therapeutic UFH and LMWH are outlined in increase in Cmax occurs with doses between 50 and 150 mg Figures 5 and 6. We have based these algorithms on published clopridogrel.72 Clopidogrel is extensively metabolized by the guidelines from American Society of Regional Anesthesia and cytochrome P450 system and is six times more potent than European anesthesia societies, as well as on our clinical ticlodipine. Inactive metabolites of clopidogrel are renally excreted experience. However, we acknowledge that optimal times for at a constant rate accounting for its linear PK profile. The Tmax of resuming anticoagulation (UFH and LMWH) after delivery may clopidogrel is 0.8 to 1.0 h, and the terminal half-life of the main vary between 12 and 24 h after delivery.13,82,83 These algorithms circulating metabolite is 7.5 h.73 should only be used as a general guide and management of these The oral bioavailability of ticlopidine is up to 90%, and the drug high-risk patients must be individualized. If patients require shows platelet inhibition as soon as 1 h after .74 epidural analgesia after cesarean delivery and anticoagulation is

Journal of Perinatology Neuraxial anesthesia with anticoagulant drugs AJ Butwick and B Carvalho 79

Figure 1 Algorithm for the timing of prophylactic subcutaneous heparin administration before and after vaginal delivery. Suggested time intervals for neuraxial anesthesia during the peripartum period are shown. sc ¼ subcutaneous.

Figure 2 Algorithm for the timing of prophylactic subcutaneous heparin administration before and after cesarean delivery. Suggested time intervals for neuraxial anesthesia during the peripartum period are shown. sc ¼ subcutaneous. restarted, then anesthesia consultation and review is necessary for should be instituted appropriate to the severity of bleeding. Patients deciding the optimal timing of epidural catheter removal require continuous clinical assessment and should receive early (according to national anesthesia society guidelines). intravenous fluid resuscitation to maintain hemodynamic stability. Anticoagulant therapy should be discontinued, and identification of surgical causes of bleeding is necessary. Early laboratory Management of anticoagulant-related bleeding assessment of the coagulation system is warranted (including The management of an anticoagulated parturient with severe prothrombin time, APTT, fibrinogen, platelet count) as well as obstetric hemorrhage can be challenging. The rate and magnitude anticoagulant drug levels (as appropriate). Transfusion of fresh of blood loss requires careful assessment, and therapeutic measures frozen plasma, , and factor concentrates should be

Journal of Perinatology Neuraxial anesthesia with anticoagulant drugs AJ Butwick and B Carvalho 80

Figure 3 Algorithm for the timing of prophylactic low molecular weight heparin administration before and after vaginal delivery. Suggested time intervals for neuraxial anesthesia during the peripartum period are shown. A typical prophylactic regimen for enoxaparin is 40 mg once a day. LMWH ¼ low molecular weight heparin; sc ¼ subcutaneous.

Figure 4 Algorithm for the timing of prophylactic low molecular weight heparin administration before and after cesarean delivery. Suggested time intervals for neuraxial anesthesia are shown. instituted if there is evidence of relevant clotting factor deficiency. sulfate can fully reverse the effects of UFH; however, there is Red blood cell transfusion may be needed for patients who are incomplete reversal for LMWH.88 Recombinant factor VIIa is hemodynamically compromised, if there is evidence of end-organ efficacious in reversing the anticoagulant effect of LMWH hypoperfusion or for symptomatic anemia. in vitro,89 and there are anecdotal reports of successful acute Therapeutic strategies and pharmacological agents for reversal of LMWH with recombinant factor VIIa.90 Although anticoagulant reversal have been described earlier.84–87 warfarin is not routinely used for anticoagulation during the

Journal of Perinatology Neuraxial anesthesia with anticoagulant drugs AJ Butwick and B Carvalho 81

Figure 5 Algorithm for the timing of therapeutic intravenous heparin administration before and after vaginal or cesarean delivery for obstetric patients receiving neuraxial anesthesia. IV ¼ intravenous; PCA ¼ patient controlled analgesia.

Figure 6 Algorithm for the timing of therapeutic low molecular weight heparin administration before and after vaginal or cesarean delivery. Suggested time intervals for neuraxial anesthesia are shown. A typical therapeutic regimen for enoxaparin is 1 mg/kg every 12 hours. sc ¼ subcutaneous; IV ¼ intravenous; LMWH ¼ low molecular weight heparin; PCA ¼ patient controlled analgesia. peripartum period, therapeutic measures for the acute reversal of neuraxial anesthesia. However, there is limited understanding of warfarin have been described earlier85 (including fresh frozen the dynamic changes in PK-PD of individual anticoagulant and plasma, prothrombin complex concentrates, or recombinant factor antithrombotic drugs that occur with advancing gestation, and VIIa). We recommend close consultation with hematology how these potential changes affect the risk profile of pregnant specialists for advice on managing the acute reversal of patients undergoing neuraxial anesthesia or surgical intervention. anticoagulation in the peripartum setting. Future studies are needed to assess management practices of high- risk anticoagulated patients during the peripartum period to minimize anesthetic (spinal hematoma after neuraxial anesthesia) Conclusion and surgical (postpartum hemorrhage) adverse outcomes. In Recommendations from national anesthetic societies should be addition, the development of novel anticoagulants and expanding used in all patients receiving anticoagulation before or after clinical applications for pregnant patients will pose unique future

Journal of Perinatology Neuraxial anesthesia with anticoagulant drugs AJ Butwick and B Carvalho 82

11 challenges to obstetric and anesthesia care providers. We 17 Gogarten W, Van Aken H, Bu¨ttner J, Riess H, Wulf H, Bu¨rkle H. Regional anaesthesia recommend that the decision to proceed with neuraxial anesthesia and thromboembolism prophylaxis/anticoagulationFrevised recommendations of the in parturients receiving anticoagulants or antithrombotic drugs German society of anaesthesiology and intensive care medicine. Anaesthesiol should be based on careful, individual risk-benefit assessment Intensivmed 2007; 48: S109–S124. 18 Kozek-Langenecker SA, Fries D, Gutl M, Hofmann N, Innerhofer P, Kneifl W et al. before delivery. Locoregional anesthesia and coagulation inhibitors. recommendations of the task force on perioperative coagulation of the Austrian society for anesthesiology and intensive care medicine. Anaesthesist 2005; 54: 476–484. Conflict of interest 19 Nederlandse Vereniging voor Anesthesiologie. Guidelines on neuraxial blockade and antithrombotic therapy. 2003. The authors declare no conflict of interest. 20 Societe Francaise d’anesthesie et de reanimation Les blocs perimedullaires chez l’adulte. Recommandations pour la pratique clinique 2006. 21 Vandermeulen E, Singelyn F, Vercauteren M, Brichant JF, Ickx BE, Gautier P. Belgian guidelines concerning central neural blockade in patients with drug-induced alteration References of coagulation: an update. Acta Anaesthesiol Belg 2005; 56: 139–146. 1 ACOG practice bulletin. Obstetric analgesia and anesthesia.number 36, July 2002 22 Vandermeulen EP, Van Aken H, Vermylen J. Anticoagulants and spinal-epidural American college of obstetrics and gynecology. Int J Gynaecol Obstet 2002; 78: anesthesia. Anesth Analg 1994; 79: 1165–1177. 321–335. 23 Horlocker TT, Wedel DJ. Spinal and epidural blockade and perioperative low molecular 2 Cohen SE, Subak LL, Brose WG, Halpern J. Analgesia after cesarean delivery: patient weight heparin: smooth sailing on the Titanic. 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