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Adverse effects of neuraxial analgesia and anesthesia for obstetrics

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Adverse effects of neuraxial analgesia and anesthesia for obstetrics Author Gilbert J Grant, MD

Section Editor David Hepner, MD

Deputy Editor Vanessa A Barss, MD

Last literature review for version 17.1: enero 1, 2009 | This topic last updated: enero 28, 2009 INTRODUCTION — Regional anesthetic techniques, such as epidural and spinal anesthesia, provide the most effective means of pain relief during labor, which is likely the most severe pain that a woman experiences during her lifetime [1]. The prevention and treatment of adverse effects of these techniques will be reviewed here. Specific issues related to pain management of labor and delivery and administration of neuraxial anesthesia are discussed separately. (See "Pharmacologic management of pain during labor and delivery" and see "Neuraxial analgesia and anesthesia for labor and delivery: Techniques"). SYSTEMIC TOXICITY — Systemic toxicity of local anesthetics is related to high plasma drug concentrations. The most common etiology is accidental injection of local anesthetic into a blood vessel. Systemic toxicity manifests in the central nervous system (CNS) as tinnitus, disorientation, and (ultimately) seizures; in the cardiovascular system toxicity manifests as hypotension, dysrhythmias, and cardiac arrest. CNS toxicity typically precedes cardiovascular toxicity, thus patients may experience cerebral signs without hemodynamic compromise. Bupivacaine toxicity does not adhere to this sequence; cardiac toxicity may occur in the absence of CNS toxicity [2]. High plasma drug levels may cause systemic toxicity after epidural administration, but are unlikely after spinal administration because lower doses of drug are given. The likelihood of systemic toxicity can be reduced by aspirating the catheter before injecting to help ascertain that its distal aperture(s) is (are) not located within a blood vessel. Other measures to reduce the risk of toxicity include adding epinephrine to the solution to delay intravascular absorption, using a test dose, injecting a local anesthetic with a lower toxicity profile, reducing the total dose injected, and administering the dose incrementally. If CNS signs of local anesthetic toxicity develop, the injection should be stopped immediately. Seizures cay be treated with a small dose of benzodiazepine (eg, midazolam 2 to 5 mg) or barbiturate (eg, thiopental 50 to 75 mg). Oxygen should be administered, as seizure activity increases maternal oxygen consumption, which will decrease oxygen delivery to the fetus. The patient should be protected from injuring herself during the seizure. In the event of cardiovascular toxicity, advanced cardiac life support (ACLS) should be provided with certain considerations specific to local anesthetic toxicity. Airway management is critical, as cardiotoxicity is exacerbated by hypercapnia, hypoxia, and acidosis. Dysrhythmias are difficult to control, especially those resulting from bupivacaine toxicity. Currently, amiodarone, a primary drug in the ACLS arrhythmia treatment algorithm, is the favored treatment for severe bupivacaine-induced arrhythmias [3]. Early administration of lipid emulsion is another component in resuscitation of bupivacaine-induced cardiotoxicity. However, the dysrhythmias are often recalcitrant to therapy; emergency cardiopulmonary bypass may be lifesaving until the drug dissociates from cardiac tissue [4]. Treatment of hypotension with vasopressin, 40 units IV, rather than epinephrine is preferred because epinephrine may exacerbate local anesthetic-induced arrhythmias. Other drugs that should be avoided in the management of local anesthetic induced cardiotoxicity include calcium channel

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blockers and phenytoin as both may worsen local anesthetic induced toxicity. (See "Overview of advanced cardiovascular life support in adults" and see "Neuraxial analgesia and anesthesia for labor and delivery: Drugs", section on Bupivacaine). Use of test dose — After insertion of an epidural catheter, a small test dose may be injected to exclude intravascular or intrathecal placement. A typical test dose is 3 mL of 1.5 percent lidocaine with 1:200,000 epinephrine (ie, 45 mg lidocaine and 15 mcg epinephrine). The patient is monitored for signs and symptoms of intravascular or intrathecal injection. If this test dose is injected intravascularly, the lidocaine produces tinnitus, circumoral numbness, a metallic taste, and dizziness, and the beta-1 adrenergic agonist effect of epinephrine results in tachycardia. However, the wide variations in heart rate that occur with labor pain may mask epinephrine-induced increases in heart rate. Thus, to maximize sensitivity, the test dose should be administered immediately after a uterine contraction. The subjective sensation of palpitations is a reliable symptom of intravascular administration, irrespective of the monitored heart rate. Intrathecal injection of the test dose causes rapid onset of dense lower extremity motor block. The choice of drug and need for a test dose are controversial. As an example, epinephrine's alpha adrenergic effects may produce uterine artery constriction and decrease placental blood flow. Substituting a pure beta adrenergic agonist (eg, isoproterenol) would avoid utero-placental vasoconstriction if intravascular injection were to occur. Alternatively, air may be used for the test dose because intravascular injection of 0.5 to 1 mL of air is easily appreciated as a characteristic "swishing" sound by Doppler monitoring of the maternal precordium. The low concentration of local anesthetics currently used for epidural analgesia techniques for labor are unlikely to cause untoward effects if they are accidentally injected intravascularly. Under these circumstances, the test dose is more likely to be used to recognize accidental intrathecal injection of local anesthetics. Furthermore, the introduction of softer, more flexible epidural catheters have decreased the incidence of venous cannulations from 5.7 to 1.1 percent [5]. For this reason, some anesthesiologists have abandoned the intravascular test dose when very low concentrations of local anesthetics are used. Many anesthesiologists do not use an intravascular test dose with "walking epidural" solutions because they are inherently safe since they are so dilute. Furthermore, a test dose of 3 mL of 1.5 percent lidocaine with 1:200,000 epinephrine may produce motor block, an effect that is undesirable during labor. Another undesirable side effect of the 1.5 percent lidocaine with 1:200,000 epinephrine test dose is maternal hypotension, which is less likely to occur if the test dose is omitted before the dilute "walking epidural" solution is administered. However, the use of a 3 mL test dose is essential when administering more concentrated solutions of local anesthetic, such as 2 percent lidocaine with epinephrine for a cesarean delivery. When relatively high concentrations of local anesthetics are administered, a test dose should always be used. Allergic reactions — (See "Allergic reactions to local anesthetics"). HIGH SPINAL — A high spinal refers to more cephalad progression of the level of anesthesia than planned when the neuraxial block was administered. The outcome can be disastrous if the situation is not recognized and corrected immediately. Consequences of high spinal may include: Massive sympathectomy that results in hypotension. Block of the cardiac accelerator fibers (T1 to T4), which inhibits compensatory tachycardia. Hypoperfusion of the brainstem causing respiratory depression and nausea. Dyspnea resulting from anesthesia of the chest. Complete diaphragmatic paralysis if the C3 to C5 roots are blocked. Aspiration of gastric contents due to loss of consciousness and compromise of airway reflexes. One cause of high spinal is accidental intrathecal injection of a local anesthetic dose intended for the

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epidural space. This is a potential problem when high concentrations of local anesthetics are used, but not as great a risk with ultra-low doses, as the drug mass is insufficient to produce cardiorespiratory compromise. Total spinal may result from a relative drug overdose or from enhanced cephalad spread within the cerebrospinal fluid (CSF) due to issues involving baricity and maternal position. As an example, injection of a hyperbaric solution (relative to CSF) and placing the parturient in a steep Trendelenburg position or injection of a hypobaric solution and positioning the parturient in a seated position will result in exaggerated cephalad spread. Treatment of a high spinal may require intubation of the trachea to maintain adequate ventilation and protect the lungs from aspiration. The use of supportive care with assisted ventilation and 100 percent oxygen is often sufficient until the small amount of local anesthetic that migrated cephalad dissipates. The cardiovascular system must be supported with vasopressors and inotropes as necessary to maintain blood pressure. HYPOTENSION — Hypotension is a common side effect of local anesthetics administered into the neuraxis [6]. It is caused by block of sympathetic nerves, dilation of vascular beds, and decrease of venous return. The precise definition of hypotension in this setting is controversial; criteria include a 20 percent reduction in mean arterial pressure from baseline, or a systolic blood pressure <100 mmHg. These criteria do not account for the pain of labor, which tends to increase baseline blood pressure; specific maternal conditions associated with elevated blood pressure, such as preeclampsia; or a parturient with a low baseline systolic pressure. Hypotension is considered clinically significant if it is associated with maternal symptoms such as lightheadedness and nausea and/or deterioration of the fetal heart rate, a sign of compromised uteroplacental perfusion. Maintenance of left uterine displacement to avoid aortocaval compression is an important maneuver to decrease the incidence of hypotension. (See "Maternal cardiovascular and hemodynamic adaptation to pregnancy", section on supine hypotensive syndrome). Symptomatic hypotension should be treated with small intravenous doses of ephedrine (5 mg) or phenylephrine (100 mcg) [7], and intravenous fluids. Prophylactic ephedrine has also been used successfully (see "Fetal bradycardia" below) [8,9]. These drugs have no adverse effects on uterine blood flow. Hypotension with current techniques of labor analgesia — The incidence of hypotension is related to the speed of onset of the neuraxial block. Epidural block with a high concentration of local anesthetic results in a significant incidence of hypotension. In one study, administration of 4 to 6 mL of 0.5 percent bupivacaine resulted in hypotension in 17 percent of parturients [10]. Another trial reported 12 mL of 0.25 percent bupivacaine caused hypotension in 20 percent of women [11]. However, the use of ultra-low dose local anesthetic techniques (eg, bupivacaine 0.04 percent) is associated with a lower incidence (9 percent) of hypotension [12]. This may be explained by the slow block onset that allows time for compensatory vasoconstriction to occur in unblocked regions. Prehydration prior to neuraxial anesthesia — The routine practice of intravenous hydration with crystalloid prior to initiation of epidural block has been questioned. The newer ultra-low dose "walking epidural" techniques are associated with a lower incidence of hypotension. As an example, one study of 95 normotensive women randomized to receive one liter of crystalloid or no preload prior to administration of epidural anesthesia found no difference in the frequency of hypotension between the two groups (6 and 10 percent, respectively) [13]. The concentration of bupivacaine administered was 0.1 or 0.2 percent, considerably higher than the 0.04 percent that we use in our "walking epidurals." In addition, a large intravascular fluid bolus may transiently inhibit uterine contractions [14]. Several techniques for avoiding maternal hypotension are described in detail separately. (See "Anesthesia for cesarean delivery", section on Avoidance of hypotension). Neuraxial opioids (except meperidine, which has local anesthetic effects) usually do not produce hypotension. Reports of hypotension after intrathecal opioid administration during active labor probably represent a relative decrease in blood pressure as a consequence of pain relief, and not a direct effect of the opioid [15]. A study in non-laboring parturients showed no decrease in blood

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pressure after intrathecal fentanyl 25 mcg [16] and another study showed that prehydration in not necessary in parturients receiving intrathecal fentanyl for labor analgesia [17]. FAILED BLOCK â&#x20AC;&#x201D; A failed neuraxial block may be defined as inadequate analgesia/anesthesia following an epidural, spinal, or CSE. The precise incidence of failed block is unknown; it was 12 percent in one retrospective review [18]. Failed block may be caused by inadequate drug dosing, technical issues, or patient factors [19]. If the volume and/or concentration of administered analgesics/anesthetics are insufficient to adequately block the required spinal segments, pain relief will be incomplete. The dose of intrathecal anesthesia needed to obtain a satisfactory block for cesarean is independent of age, weight, height or body mass index [20]. Failed block may also be caused by impatience (eg, underestimating the latency of the administered drug and not allowing sufficient time to pass before declaring the block as failed). Operator or equipment related technical issues may also result in a failed block. As an example, if the epidural or spinal needle tip is not properly positioned, the injected drug will not be delivered to the desired location. If the aperture of the epidural or spinal needle is not wholly within the epidural or intrathecal space, respectively, a portion of the injected dose may not reach the intended site. With continuous epidural techniques, despite proper needle placement, the epidural catheter tip may not find its way into the epidural space, or may come to rest too far unilaterally, or protrude through an intervertebral foramen. These situations are more likely to occur if too great a length of catheter is threaded through the needle. More commonly, the catheter is initially inserted correctly within the epidural space, but later moves out of the space, toward the skin. Ideally, the length of epidural catheter inserted is sufficient to prevent inadvertent dislodgement, but not too great so as to minimize the likelihood of unilateral placement. In laboring patients, the optimal catheter length to insert into the epidural space appears to be 5 cm [21]. Other technical causes of failed block relate to patient anatomy (eg, post-surgical scarring that inhibits the spread of medication administered into the epidural space). Some unusual causes of failed spinal anesthesia have been described, and include rare anatomic malfomations such as dural ectasia, an abnormal ballooning of the thecal sac, and dural cyst. Injection of local anesthetic into an isolated area of the thecal sac may limit drug exposure to the target neural tissue [22]. Enlarged thecal volumes per se, even in the absence of dural ectasia or cysts, may cause dilution or poor distribution of the hyperbaric local anesthetic dose [23]. Failure of a block due to an inactive drug is possible, although very unlikely, particularly for amide-linked local anesthetics, which are very stable molecules. PRURITUS â&#x20AC;&#x201D; Pruritus is a common side effect of neuraxial opioid administration. As an example, in one series, fentanyl (25 mcg) and bupivacaine (2 mg) were injected intrathecally, pruritus occurred in 100 percent of parturients, and 45 percent required treatment [24]. Pruritus does not occur after the administration of local anesthetics alone. The etiology appears to be modulation of nociceptive reception, not histamine release. Thus, treatment with an antihistamine such as diphenhydramine is not indicated, but is often used for its soporific effects. The ideal treatment for neuraxial opioid-induced pruritus is a small intravenous dose of an opioid antagonist such as naloxone (40 to 160 mcg) or the opioid agonist-antagonist nalbuphine (2.5 to 5 mg). Small doses of opioid antagonists are known to selectively reverse opioid side effects without affecting analgesia [25]. A common approach is to administer 40 to 80 mcg naloxone intravenously, and titrate additional small doses to effect. A single dose of naloxone sometimes prevents recurrent itching. Alternatively, the patient may be given intravenous patient-controlled analgesia (PCA) naloxone, to allow her to self-titrate 40 mcg every five minutes [26]. NAUSEA AND VOMITING â&#x20AC;&#x201D; Nausea occurs commonly in laboring patients due to visceral pain. Epidural and spinal local anesthetic block effectively diminish or eliminate pain, but can also precipitate nausea and vomiting. The mechanism is a decrease in blood pressure causing hypoperfusion of the area postrema in the medulla or cephalad spread of opioids to the

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chemoreceptor trigger zone. The incidence of nausea and vomiting after neuraxial opioid is much greater with the relatively poorly lipid soluble morphine compared to more lipid soluble agents, such as sufentanil, because morphine tends to travel cephalad within the aqueous CSF. The optimal treatment for opioid-induced nausea is administration of an opioid antagonist such as naloxone or the opioid agonist-antagonist nalbuphine (see "Pruritus" above for dosing). Nausea and vomiting resulting from hypotension are treated by administration of vasopressors. RESPIRATORY DEPRESSION — Respiratory depression due to cephalad spread of opioids to brainstem respiratory centers after neuraxial block is a rare complication in laboring patients. Factors that increase the likelihood of respiratory depression include a large opioid dose, poor opioid lipid solubility (eg, morphine), and concomitant use of additional sedatives and opioids by other routes. Treatment is with a specific opioid antagonist, such as intravenous naloxone. The dose should be titrated to effect (40 to 80 mcg increments) and then an infusion of a dose sufficient to maintain an adequate respiratory rate should be instituted until the effect of the opioid has dissipated (eg, 1 to 2 mcg/kg/min) [27]. SPINAL HEADACHE — Spinal headache after neuraxial analgesia is due to leakage of CSF through a dural rent, traction on cranial structures, and cerebral vasodilation. The pathognomonic quality of this headache is its positional nature, worsened by sitting or standing and relieved by lying down. If the headache does not have this quality, other causes of headache should be sought. Incidence — The introduction of pencil point spinal needles has diminished the incidence of post dural puncture headache. In a randomized trial of 1000 patients comparing various types of cutting and pencil point needles, the incidence of headache was significantly lower with use of pencil point needles (headache with cutting needles: 5 to 8.7 percent versus headache with pencil point needles 2.8 to 4 percent) [28]. In particular, the incidence of severe headache (as indicated by the need for treatment with epidural blood patch) fell from 55 to 66 percent to 0 to 12.5 percent of headaches. A post-dural puncture headache is likely (approximately 80 percent) if the dura is punctured with an epidural needle, due to its large size (17 or 18 gauge). Fortunately, the incidence of accidental dural puncture with an epidural needle is relatively low for an experienced operator (approximately 1 to 2 percent). The high incidence (up to 80 percent) of headache after dural puncture with the epidural needle has prompted some practitioners to perform a prophylactic epidural blood patch (see below) after repositioning the epidural catheter at the end of labor and prior to its removal. In one trial in which women were randomly assigned to receive or not receive a prophylactic blood patch, there was no difference in the incidence of headache (56 percent in both groups), although women who received prophylactic patches had shorter median duration of symptoms [29]. Threading an epidural catheter into the intrathecal space and leaving it in situ for 24 hours has also been reported to reduce the incidence of headache [30,31], but the efficacy of this approach has not been established in randomized trials. If this is done and medication is injected into the catheter, it is important to remember that the catheter is now intrathecal, and no longer in an epidural location, so the dose of medication needs to be adjusted accordingly. Injection of a few milliliters of saline may produce immediate resolution of a headache, but the effects will be temporary [32]. Treatment — Epidural blood patch is the treatment of choice for severe, debilitating post dural puncture headache. An epidural blood patch is performed by injecting 10 to 20 mL of the patient's blood into the epidural space to form a clot over the dural defect. The clot prevents leakage of CSF while the dura heals. Conservative management with symptomatic therapy (eg, oral analgesics, caffeine) may be indicated if the patient does not desire epidural blood patch or if the headache is not severe. Most headaches will resolve in 7 to 10 days if untreated. (See "Post-lumbar puncture headache", section on Treatment). BACKACHE — In 1990, a retrospective study of 11,701 women found that long-term backache occurred after delivery more frequently in women who had an epidural during labor than in women

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who did not have one (19 versus 11 percent), and concluded there was a causal relationship between epidurals and backache [33]. Subsequently, a series of prospective studies by these authors and others found NO correlation between epidural labor analgesia and an increased incidence of long-term backache [34-40]. MATERNAL TEMPERATURE ELEVATION â&#x20AC;&#x201D; Randomized trials and observational studies have observed a frequent and significant association between the use of epidural analgesia and rise in maternal temperature [41-49]. The etiology of the temperature increase is not clear, but may be related to reduced heat loss in women receiving epidurals since they have less pain-induced hyperventilation and less perspiration because of sympathetic block. Another explanation is that both epidurals and increased maternal temperature share risk factors such as nulliparity, induction of labor, internal monitoring, more vaginal examinations, longer labor, and longer duration of rupture of membranes, which are also risk factors for intraamniotic infection. Noninfectious inflammation and an abnormality in maternal thermoregulation are other possible causes [50]. Administration of acetaminophen does not prevent the maternal temperature elevation [51]. Data from an historical cohort study of maternal temperature before and after availability of epidural analgesia suggest that the epidural itself is the cause of the increased maternal temperature. When epidural usage increased from 1 to 83 percent, the incidence of maternal temperature greater than 100.4 degrees F also increased from 0.6 to 11 percent [43]. The rise in maternal temperature correlates with the duration of epidural analgesia [52,53]. In one study, there was no discernible effect during the initial four to five hours, but thereafter maternal temperature increased approximately 0.10 degrees C per hour [53]. This may explain why epidural-related fever is more common in nulliparas than multiparas since the latter tend to have shorter labors [47]. The presence of an elevated temperature may be misinterpreted as a sign of infection, since intrapartum fever is the most objective clinical sign of intraamniotic infection. Prompt antibiotic administration and diagnostic work-up may be instituted. The increase in maternal temperature associated with epidural analgesia has been implicated as the cause of an increased rate of neonatal sepsis investigations and morbidity, but is not associated with an increased rate of proven neonatal sepsis [54]. In a retrospective analysis, only four of 416 neonates evaluated were found to be septic, raising questions regarding the clinical criteria used to trigger such evaluations [44]. The decision to perform a neonatal septic work-up must be guided by factors in addition to maternal temperature. Triggers for septic work-up in neonates include low birth weight, prematurity, hypothermia at birth, maternal group B beta-hemolytic streptococcal colonization, preeclampsia, and maternal hypertension [55]. Prior to initiating antibiotic therapy, the clinician should consider whether there was prolonged use of epidural analgesia. Maternal shivering that occurs before the fever developed and a rapid fall in temperature after the epidural is discontinued suggest a noninfectious etiology [56]. URINARY RETENTION â&#x20AC;&#x201D; Some women who have a neuraxial anesthetic may not be able to sense when their bladder is full and may not be able to void spontaneously [57]. Catheterization is indicated in these women. SPINAL/EPIDURAL HEMATOMA â&#x20AC;&#x201D; Hemorrhage into the neuraxis, an unusual complication of spinal and epidural techniques, may occur if a vascular structure is punctured by a needle and/or catheter. Hematoma is less likely with a single-shot spinal technique, due to the relatively small size of the spinal needle [58] and the lack of an indwelling catheter. Accumulation of even a small quantity of blood may compress neural structures and produce ischemia because the spinal space is nonexpandable. Neural ischemia results in loss of sensory, motor, and bladder and bowel function; severe pain is not a common finding. The appropriate treatment is prompt surgical intervention, usually a laminectomy, and evacuation of the blood. Timely decompression of the hematoma is essential to avoid permanent loss of neurologic function. In one study, as an example, good outcomes were obtained in 50 percent of patients when surgery was performed within eight hours of diagnosis [58]. The diagnosis of

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spinal/epidural hematoma is complicated by the concealed nature of the bleeding, thus a high index of suspicion must be maintained. Since low-dose techniques for labor analgesia produce minimal motor block, their use permits continuous monitoring of lower extremity function in patients at risk for development of neuraxial hematoma. Neuraxial analgesia and the anticoagulated patient â&#x20AC;&#x201D; Pregnant women may be treated with anticoagulants for a variety of indications. The most common indication for anticoagulation is the presence of a thrombophilia such as factor V Leiden mutation, prothrombin gene mutation, antithrombin deficiency, protein C deficiency, or protein S deficiency. The risk of hemorrhage into the neuraxis is increased in anticoagulated patients, thus one must consider the type of anticoagulant used, the dose, and the timing of its administration. For all patients in whom a bleeding tendency is suspected, an evaluation of coagulation status is indicated prior to neuraxial analgesia. (See "Anticoagulation during pregnancy"). The recommendations below are based on the Second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation [59]. The use of aspirin should not influence the decision to place a neuraxial block. Clopidrogel has been associated with several case reports of epidural hematomas. The American Society of Regional Anesthesia and Pain Medicine (ASRA) currently recommends a waiting period of 14 days between the last dose of ticlopidine and 7 days after the last dose of clopidrogel and the placement of a neuraxial block. Anticoagulation regimens, such as mini-dose aspirin and low-dose subcutaneous heparin (5000 units every 12 hours) are NOT associated with increased risk of spinal/epidural hematoma and do not need to be halted prior to spinal or epidural analgesia. Standard unfractionated intravenous heparin therapy is usually discontinued with the onset of labor. Subcutaneous heparin therapy is stopped 24 hours prior to a planned induction or cesarean section or with the onset of spontaneous labor. Neuraxial anesthesia may be administered when the partial thromboplastin time returns to normal. If anticoagulation with standard intravenous heparin is required in patients who have recently had epidural catheterization, heparin should not be given for at least one hour after the epidural catheter has been inserted or removed. In patients receiving intravenous heparin, the epidural catheter may be removed two to four hours after the last heparin dose, after the patient's coagulation status has been evaluated. Since heparin-induced thrombocytopenia may occur, patients receiving heparin for more than four days should have a platelet count assessed prior to neuraxial block and catheter removal. Low molecular weight heparin â&#x20AC;&#x201D; Many disorders are currently being treated with fractionated low molecular weight heparin (LMWH). This therapy presents particular challenges because standard laboratory tests cannot be used to assess its activity. Many cases of spinal hematoma have been reported among nonpregnant patients receiving neuraxial analgesia in the presence of LMWH [60], some of whom had received other anticoagulant medications. Neuraxial blocks should not be performed until at least 12 hours after the last dose of low dose (prophylactic) LMWH (eg, enoxaparin 40 mg), and not until at least 24 hours after the last dose in patients receiving high-dose (therapeutic) LMWH (eg, enoxaparin 1 to 1.5 mg/kg every 12 hours). In addition: If postoperative LMWH is to be used, the first dose should not be administered prior to 24 hours postoperatively if a twice-daily dosing regimen is planned, and not prior to six to eight hours postoperatively if a single-daily dosing regimen is planned. For the twice-daily dosing regimen, epidural catheters should not be left in place. For the single-daily dosing regimen, epidural catheters may be maintained, but the catheter should not be removed

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for at least 10 to 12 hours after the last LMWH dose. In cases where blood is noted during the insertion of the spinal or epidural needle or catheter, even if the single daily dosing regimen is planned, LMWH should not be administered for the first 24 hours postoperatively. For both twice-daily and single-daily dosing regimens, if the patient has an indwelling epidural catheter postoperatively (eg, for postoperative analgesia), the LMWH should not be initiated until at least two hours after catheter removal. If LMWH prophylaxis must be instituted in the presence of an indwelling catheter, low-dose epidural techniques should be used to permit careful monitoring of neurologic function. Concomitant administration of antiplatelet medications or other anticoagulants in patients receiving LMWH may increase the risk of neuraxial hematoma. Warfarin â&#x20AC;&#x201D; Neuraxial blocks should not be performed until laboratory tests of coagulation (prothrombin time, International normalized ratio [INR]) are normal in patients receiving oral anticoagulants (warfarin). Patients receiving therapy with a combination of anticoagulants are at particular risk of developing spinal/epidural hematoma. Neuraxial analgesia and low platelets â&#x20AC;&#x201D; Thrombocytopenia (platelet count <150,000/microL) occurs in approximately 7 percent of pregnancies [61]. Nearly all women with low platelet counts in the third trimester may be classified as having gestational thrombocytopenia, immune thrombocytopenic purpura (ITP), or thrombocytopenia related to severe preeclampsia or HELLP syndrome. Gestational thrombocytopenia is the most common etiology, ITP occurs much less frequently. An important difference between ITP and gestational thrombocytopenia is that ITP may be associated with severe neonatal thrombocytopenia. However, with regard to the mother, neither gestational thrombocytopenia nor ITP is associated with a rapid decline in platelet count. This contrasts with hypertensive thrombocytopenia, which may accompany severe preeclampsia or the HELLP syndrome. In hypertensive thrombocytopenia, the platelet count may decline precipitously, and the platelet function may be abnormal as well. With gestational thrombocytopenia and ITP, platelet function is usually normal. (See "Thrombocytopenia in pregnancy"). An insufficient platelet number or deficient platelet function predispose to an increased risk of spinal/epidural hematoma upon neuraxial instrumentation. The precise platelet count needed to safely perform neuraxial analgesia is unknown. Currently, practitioners routinely perform neuraxial analgesia with platelet counts below 100,000/microL, although few will instrument the spinal/epidural space if the platelet count is below 50,000/microL. It is not necessary to routinely obtain a platelet count before administration of regional anesthesia in uncomplicated parturients [62]. When determining whether it is safe to instrument the epidural or intrathecal space in women with thrombocytopenia, the rate of decline of the platelet count is much more important than the absolute platelet number. The platelet count should be assessed prior to performing a neuraxial block, and compared to previous counts. As an example, a relatively low but stable platelet count of 55,000/microL likely presents less of a problem than a platelet count of 60,000/microL that had been 95,000/microL three to four hours previously. A compelling report from the pediatric oncology literature showed that spinal hematoma did not occur with lumbar puncture even with very low platelet counts [63]. In that study, 742 patients had platelet counts of 21,000 to 50,000/microL, 170 had platelet counts of 11,000 to 20,000/microL, and 29 had platelet counts <10,000/microL. Adequacy of platelet function must also be considered, but the laboratory tests needed to assess platelet function are not readily available on an emergency basis. The clinician often must assess the integrity of the coagulation system with a careful history and a physical examination focusing on the presence of petechiae, ecchymoses, or obvious oozing from intravenous catheter sites. (See "Preoperative assessment of hemostasis"). Neuraxial anesthesia has been utilized in patients with platelet counts around 70,000/microL, and

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without evidence of bleeding [61]. The etiology of the thrombocytopenia, the trend in the platelet number, and the history and physical examination are more important than the absolute platelet count per se. In addition, it may be reasonable to perform a spinal anesthetic with a platelet count under 70,000/microL if there is a compelling indication to do so based on a risk-benefit analysis [64]. A spinal technique is less traumatic than an epidural, and is preferred once the platelet count is under 70,000/microL. Soft, flexible catheters are preferred for an epidural technique, as they have a lower incidence of venous cannulation. When determining whether it is safe to instrument the epidural or intrathecal space in women with thrombocytopenia, the rate of decline of the platelet count is much more important than the absolute platelet number. The platelet count should be assessed prior to performing a neuraxial block, and compared to previous counts. As an example, a relatively low but stable platelet count of 55,000/microL likely presents less of a problem than a platelet count of 60,000/microL that had been 95,000/microL 24 hours previously. INFECTION â&#x20AC;&#x201D; Aseptic technique is important to minimize risk of infection [65]. Epidural abscess or meningitis are uncommon complications of neuraxial block. Epidural abscess is more likely to occur after epidural techniques, whereas meningitis typically occurs after the dura has been punctured, either intentionally as part of a spinal anesthetic, or unintentionally as a complication of an epidural procedure. (See "Adverse effects of neuraxial analgesia and anesthesia for obstetrics", section on Spinal headache). A meta-analysis of reports published between 1990 and 2005 identified the incidence of "deep epidural infection" in obstetric patients as 1 in 145,000 [66]. A review of postdural puncture bacterial meningitis found 179 reported cases from 1950 to 2005 [67]. The most commonly isolated bacteria were mouth commensals. Presumably, droplet contamination from medical personnel was the source of the CSF infection, which argues for a mandatory policy of wearing masks during instrumentation of the neuraxis. Postdural puncture meningitis may be more common than appreciated, with an incidence as great as 1:50,000 to 1:10,000 [68]. Skin bacteria may also be introduced into the neuraxis during instrumentation, emphasizing the importance of meticulous skin cleansing prior to the procedure. Providone iodine is most commonly used for this purpose in the United States. Although chlorhexidine is a superior agent for skin decontamination, it is not currently approved for neuraxial block skin preparation by the US Food and Drug Administration because of concerns about potential neurotoxicity. PNEUMOCEPHALUS â&#x20AC;&#x201D; Introduction of air into the CSF during placement of neuraxial block may result in acute onset of severe headache and other neurologic signs and symptoms [69]. This relatively rare complication may occur when air, rather than saline, is used to identify the epidural space with the loss-of-resistance technique. If the dura is inadvertently punctured, air may be injected into the CSF. If the parturient is sitting, the onset of headache and other neurologic symptoms may occur within a few seconds, as the air rapidly ascends to the brain, where it exerts its irritating effects. Use of saline rather than air for the loss-of-resistance technique can minimize the likelihood of this complication. FETAL EFFECTS â&#x20AC;&#x201D; Maternal hypotension resulting from local anesthetic-induced sympathetic block may reduce placental perfusion. The placental bed is not autoregulated and, therefore, its perfusion is entirely dependent upon maternal systolic blood pressure. A decrease in perfusion pressure will result in decreased fetal oxygenation, which is manifested by deterioration in the fetal heart rate pattern (eg, bradycardia, repetitive late decelerations). However, in the absence of hypotension, epidural local anesthetics have been shown to improve intervillous blood flow [70], to have minimal effect on uterine or fetal umbilical vasculature as assessed by Doppler velocimetry [71], and to be associated with improved neonatal acid-base status [72]. A relatively large dose of opioid is required when administered as the sole agent for labor analgesia by the epidural route. Neuraxial opioids may affect the fetus and/or neonate by gaining access to the maternal circulation and undergoing transplacental passage as the plasma kinetics following injection

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of epidural morphine are similar to those seen after an intramuscular injection [73]. In one study, as an example, a dose of 5 mg epidural morphine produced substantial fetal and maternal plasma levels [74]. The small doses of opioid used for intrathecal administration are generally safe for the fetus. However, fetal bradycardia may be precipitated by intrathecal administration of opioid. Although the mechanism is not yet defined, the incidence is nearly twice as high that after epidural opioid administration [75]. Fetal bradycardia â&#x20AC;&#x201D; A nonreassuring fetal heart rate after induction of neuraxial anesthesia may be due to maternal hypotension or uterine hyperactivity [8]. The administration of opioids intrathecally may induce a tetanic uterine contraction leading to fetal bradycardia [76]. A meta-analysis of nine trials reported fetal bradycardia within one hour of intrathecal opioid administration occurred in 39 of 535 (7.3 percent) patients versus 19 of 392 (4.8 percent) controls (RR 1.81, 95% CI 1.04-3.14) [75]. Despite a higher risk of fetal heart rate abnormality, the rate of cesarean delivery was not increased in women receiving intrathecal opioids. One proposed explanation is that the fetal bradycardia is due to intrathecal opioid-induced uterine tetany. The tetany is postulated to be due to rapid onset of analgesia, which causes a sudden decrease in plasma epinephrine and subsequent withdrawal of epinephrine's beta-sympathomimetic relaxant effects on the myometrium [77]. Uterine tetany may be reversed with one or two doses of intravenous nitroglycerin (60 to 90 mcg) [78]. The hypotension that predictably results is treated with ephedrine (5 to 10 mg) or phenylephrine (40 to 800 mcg). Persistent hypertonus can be treated with another dose of nitroglycerin or a beta agonist, such as terbutaline 0.25 mg intravenously; however, terbutaline results in a longer period of uterine relaxation and maternal tachycardia. Prophylactic administration of ephedrine to prevent maternal hypotension and fetal bradycardia has also been studied: A randomized trial showed that prophylactic administration of ephedrine (10 mg injected intravenously followed by a continuous drip of 20 mg over one hour) at the time of epidural initiation reduced the frequency of fetal heart rate changes within 40 minutes of anesthetic administration [8]. Fetal heart rate changes occurred in 2 of 72 treated patients versus 11 of 73 controls who did not receive prophylactic ephedrine upon initiation of their epidurals. Seven patients would need to be treated to prevent one case of abnormal fetal heart rate tracing. In another randomized trial, a single intramuscular dose of ephedrine (25 mg) or placebo was administered to 100 parturients immediately prior to receiving combined spinal epidural analgesia [9]. Significantly fewer women in the ephedrine group developed hypotension (10/50 versus 34/50 in controls), but they were more likely to develop fetal tachycardia than controls. There were no significant differences in the prevalence of fetal heart rate decelerations during the hour after the analgesia was administered (variable, late, prolonged) between the two groups. Prophylactic administration of ephedrine may be appropriate in patients who will be receiving relatively high concentrations of local anesthetics (eg, for cesarean), but is not necessary for those receiving walking epidural techniques with low concentrations of local anesthetics or opioids. Continuous infusion of ephedrine is not recommended because it has been associated with fetal acidosis in patients undergoing elective cesarean delivery under spinal anesthesia [79]. We infrequently use combined spinal-epidural for laboring patients to avoid potential complications, such as maternal hypotension and fetal heart rate abnormalities. Some prefer the low-dose "walking epidural," which takes effect relatively slowly and therefore is less likely to cause these problems. NEONATAL EFFECTS â&#x20AC;&#x201D; An early study found that neonates of mothers who received epidural

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analgesia with local anesthetics had lower scores as assessed by the Early Neonatal Neurobehavioral Scale (EENS) than neonates of mothers who received no analgesia [80]. A subsequent study using the EENS found no difference in scores in neonates of mothers who had received epidural analgesia with bupivacaine, 2-chloroprocaine, lidocaine, or no analgesia [81]. Other studies of neurobehavior in neonates of mothers receiving epidural analgesia or systemic opioid analgesia have shown either no difference [82] or improved scores in neonates of mothers receiving epidurals [83]. By comparison, a meta-analysis reported neonates of mothers receiving epidural analgesia were more alert than those of mothers who received systemic opioids or no medication [84]. The cumulative effect of opioids delivered as part of continuous epidural infusions is another concern. This may result in a potentially significant total opioid dose over time. However, neurobehavioral assessment of neonates using the Neurologic and Adaptive Capacity Score (NACS) has not shown perceptible changes after prolonged epidural infusions of sufentanil [85] or fentanyl [86]. Breastfeeding â&#x20AC;&#x201D; There is no definitive evidence that epidural analgesia interferes with breastfeeding success. One observational study of 171 postpartum women found that epidural labor analgesia with local anesthetics and opioids did not impede breastfeeding success when assessed at six to eight weeks after delivery [87]. A subsequent randomized, prospective trial examined the effect of fentanyl given epidurally during labor on breastfeeding [88]. Women received either 0, <150, or >150 mcg of fentanyl during labor. At 24 hours postpartum, there were no differences between the groups with regard to breastfeeding difficulties. However, at six weeks postpartum, significantly fewer women who received more than 150 mcg fentanyl in the epidural during labor were still breastfeeding. These results should be interpreted with caution due to methodological concerns, and lack of an obvious physiologic or pharmacologic mechanism by which the fentanyl might influence the incidence of breastfeeding six weeks after delivery [89]. The American College of Obstetricians and Gynecologists concluded that breastfeeding is not affected by choice of anesthetic; thus the choice should be based upon other considerations [62]. AREAS OF CONTROVERSY â&#x20AC;&#x201D; There is considerable controversy concerning the non-analgesic effects of neuraxial pain relief. As an example, two meta-analyses have come to different conclusions about the effects of epidural anesthesia on length of the first stage of labor, cesarean delivery rate, breastfeeding success, and postpartum urinary problems (show table 1) [6,90]. One group reported data on these variables were inconclusive [90] while the other concluded that epidural anesthesia had no effect on the first three variables but may transiently increase postpartum urinary incontinence [6]. A critique of these two meta-analyses, which were performed in parallel and at the request of an invitational symposium, was published in the same journal as the analyses [91]. Effect of neuraxial analgesia on the progress and outcome of labor â&#x20AC;&#x201D; A longstanding perception holds that neuraxial analgesia tends to slow labor and result in increased rates of instrumental and cesarean delivery. These attitudes are currently under intense scrutiny. A meta-analysis of 20 trials concluded epidural analgesia did not significantly increase the risk of cesarean delivery (RR 1.07, 95% CI 0.93 to 1.23); however, it was associated with an increased risk of instrumental vaginal birth (RR 1.38, 95% CI 1.24 to 1.53) [92]. The reason for the increased frequency of instrumental delivery in patients with epidural analgesia is unclear. One possible explanation is that the presence of epidural analgesia prompts a difference in obstetric management of the second stage of labor. In one study, as an example, there were significantly more instrumental deliveries in patients with epidurals when residents were allowed to use elective outlet forceps or vacuum [93]. It may be that the presence of effective pelvic analgesia encourages the use of instrumental delivery. The concentration of local anesthetics used for the epidural may affect the incidence of instrumental delivery. The concentration of local anesthetic used with current epidural techniques is, in some cases, 1/10th of the strength that was used in the past. Newer low-dose techniques, by achieving sensory block while preserving motor strength, have been shown to promote spontaneous vaginal delivery (or decrease the rate of instrumental delivery). For example, a study of low-dose techniques

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randomly assigned 1054 nulliparous women requesting epidural pain relief to traditional (intermittent 10 mL boluses of 0.25 percent bupivacaine), low-dose combined spinal epidural (bupivacaine 2.5 mg and fentanyl 25 mcg, followed by a 15 mL bolus of 0.1 percent bupivacaine and 2 mcg/mL fentanyl when the spinal component wears off with intermittent 10 ml boluses of this combination of drugs), or low-dose infusion epidural (bolus of 15 mL 0.1 percent bupivacaine and 2 mcg/mL fentanyl followed by an infusion of 10 mL/hr of same) [94]. The spontaneous vaginal delivery (SVD) rates in the three groups were 35, 43, and 43 percent, respectively. The higher SVD rate among women receiving low-dose techniques was entirely accounted for by a reduction in the number of instrumental vaginal deliveries; the cesarean delivery rate was 28 to 29 percent in all three groups. Therefore, low-dose techniques should be recommended over traditional epidural administration to reduce the rate of operative vaginal delivery [95]. The following examples illustrate findings from several studies: One randomized study of 318 nulliparous women examined the rate of cesarean delivery in patients receiving systemic opioids versus those administered epidurals (using an intentto-treat analysis) [96]. There was no significant difference in cesarean delivery rate between groups (approximately 14 and 10 percent, respectively) [96]. Similar findings were noted in a trial that randomly assigned 459 nulliparous women to receive either epidural analgesia or intravenous meperidine analgesia via a patient controlled pump [45]. The cesarean delivery rate was equivalent for the two groups, 7 and 9 percent, respectively, with protocol violations in 8 percent. Another retrospective analysis of 18,333 deliveries reported that obstetric practice style, but not epidural use, correlated with the cesarean delivery rate [97]. Although there is an association between epidural use and the cesarean delivery rate (observational studies report a more than four-fold increased risk of cesarean and instrumental deliveries), there is no causative link. One review reported that epidural analgesia doubled the risk of oxytocin augmentation, but did not increase the risk of cesarean delivery either overall or for dystocia, nor did it significantly increase the risk of instrumental vaginal delivery in clinical trials [98]. The authors concluded that low-dose epidural analgesia may increase the risk of oxytocin augmentation, but not of cesarean delivery, and although most studies showed a longer labor among women with epidural analgesia than without it, most used inappropriate statistical analysis (see "Timing of epidural administration" below). Pain as a marker of dysfunctional labor â&#x20AC;&#x201D; A potential confounding variable of all studies examining the effect of regional analgesia on the progress and outcome of labor is that pain itself may be predictive of dysfunctional labor and an increased likelihood of instrumental or operative delivery [99]. This is important because patients with severe pain and protracted, dysfunctional labors are more likely to request or receive epidural or spinal analgesia. Thus, it may be falsely concluded that neuraxial techniques are causally related to poor labor outcomes, whereas the relationship may simply be an associative one. As an example, one study found that patients who experienced pain and distress very early (during the latent phase of labor) had prolonged labor and high rates of instrumental and cesarean delivery compared to patients who experienced mild pain with which they were able to cope [100]. Future studies need to account for this potential confounder. Potential benefits of delayed pushing â&#x20AC;&#x201D; Obstetric practice in the United States often dictates that the parturient begin pushing when the cervix attains full dilation (10 cm). However, randomized prospective studies have questioned this practice and suggested delaying pushing until the presenting fetal part descends [101-104]. As an example, a large (n =1862) randomized multicenter study documented that delayed pushing was an effective means of reducing difficult deliveries in nulliparous women (relative risk 0.79; 95 percent CI 0.66 to 0.95) [102]. The greatest effect was on midpelvic procedures (relative risk 0.72; 95 percent CI 0.55 to 0.93). Delayed pushing predictably increased the duration of the second stage (by 54 minutes), and resulted in lower umbilical cord blood pH, but no difference was detected in overall neonatal morbidity. If delayed pushing is an effective means of

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reducing instrumental delivery rates, effective epidural analgesia that preserves muscle strength will be of great assistance. Similar findings were reported in a meta-analysis that included this study [104]. Timing of epidural administration â&#x20AC;&#x201D; An American College of Obstetricians and Gynecologists Committee Opinion concluded that "maternal request is sufficient medical indication for pain relief during labor" and that neuraxial anesthesia does not increase the frequency of cesarean delivery [105]. Although some obstetricians have advocated withholding epidural analgesia until a significant cervical dilation, most commonly 4 to 5 cm, has been achieved, there are no data to support this practice. The best data on the safety of early epidural comes from two large randomized trials that showed that the cesarean delivery rate was not increased when neuraxial analgesia was given in early labor and early administration of neuraxial analgesia was associated with a significant decrease in time to full dilatation [106,107]. The first trial included 750 nulliparous women at term, in spontaneous labor or with spontaneous rupture of membranes, and with cervical dilatation less than 4 cm (mean 2 cm) who were randomly assigned to receive intrathecal fentanyl plus epidural bupivacaine and epinephrine or parenteral hydromorphone at their first request for analgesia [106]. Women in the intrathecal group received epidural analgesia upon request throughout labor. Women in the parenteral group continued to receive parenteral analgesia at the second request for analgesia if their cervix was less than 4 cm, but received epidural analgesia if their cervix was â&#x2030;Ľ4 cm. Major findings from this trial were: - Early administration of neuraxial analgesia did not increase the rates of cesarean delivery or instrumental delivery, which were similar in both groups (cesarean 17.8 and 20.7 percent, instrumental 19.6 and 16 percent). - Early administration of neuraxial analgesia was associated with significant decreases in times to full dilatation and vaginal delivery compared to women who received parenteral analgesia (time to full dilatation 295 versus 385 minutes, time to vaginal delivery 398 versus 479 minutes). - Pain scores after first administration of analgesia were significantly lower in the neuraxial group (2 out of 10 versus 6 out of 10, where 0 is no pain and 10 is severe pain). Over 90 percent of patients in both groups received oxytocin, but the infusion was begun before the first request for analgesia in three-quarters. The second trial included 449 nulliparas at term in labor with cervical dilatation less than 3 cm who were randomly assigned to immediate epidural at first request for analgesia or delay in epidural placement until the dilatation of at least 4 cm [107]. The mean cervical dilatation in the two groups at epidural placement was 2.4 and 4.6 cm, respectively. As with the trial above, there were no significant differences in cesarean or instrumental delivery rates between groups (cesarean 13 and 11 percent, instrumental 17 and 19 percent), but the duration of the first stage was significantly shorter in the early epidural group. Thus, a reasonable approach is to allow the parturient to receive neuraxial analgesia when she desires it, as long as the diagnosis of labor has been established or a commitment to deliver has been made. It is also reasonable to insert an epidural catheter before pain is severe so that analgesics can be injected when the patient begins to experience discomfort. In particular, women should not be required to reach an arbitrary cervical dilation such as 4 to 5 cm before receiving epidural anesthesia. SUMMARY AND RECOMMENDATIONS Epidural and spinal anesthetic techniques provide optimal pain relief for parturients.

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Although generally quite safe, these techniques are also associated with various untoward effects. Side effects such as systemic local anesthetic toxicity or spinal headache are caused by technical factors and/or dosing, such as inadvertent intravenous injection or unrecognized dural puncture. Spinal hematoma is a rare complication, and is more likely in patients receiving anticoagulants. Meticulous attention to proper technique reduces the risk of these complications. Should they occur, prompt treatment is indicated. Other untoward effects are caused by known pharmacological effects of the analgesic medications, such as hypotension, pruritus, nausea and vomiting and respiratory depression. These side effects are optimally managed by administering small doses of an opioid antagonist. A variety of other side effects have been attributed to regional analgesic techniques, such as long-term backache, effects on the progress and outcome of labor and effects on breastfeeding success. Although an association between regional analgesia and these side effects may exist, a cause-and-effect relationship has not been established. The risk of potential unwanted effects must be weighed against the unparalleled pain relief these techniques provide.

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GRAPHICS Unintended effects of epidural anesthesia for labor pain results of two meta-analyses [1,2]

Variable Length of first stage of labor Length of second stage of labor Rate of instrumental vaginal delivery Cesarean delivery rate Intrapartum fever Successful breast-feeding at six weeks Urinary problems in early postpartum period

Conclusions of meta-analysis No difference [1], possibly increased [2] Increased [1,2] Increased [1,2] No difference [1], possibly increased [2] Increased [1,2] No difference [1], insufficient data [2] Increased [1], insufficient data [2]

1. Leighton, BL, Halpern, SH. The effects of epidural analgesia on labor, maternal, and neonatal outcomes: A systematic review. Am J Obstet Gynecol 2002; 186:S069. 2. Lieberman, E, O'Donoghue, C. Unintended effects of epidural analgesia during labor: A systematic review. Am J Obstet Gynecol 2002; 186:S031.

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Adverse effects of neuraxial analgesia and anesthesia for obstetrics