What’s new in obstetric anesthesia?

International Journal of Obstetric Anesthesia (2011) 20, 149–159 0959-289X/$ - see front matter c 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.ijoa.2010.10.008



REVIEW ARTICLE

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What’s new in obstetric anesthesia? J.M. Mhyre Department of Anesthesia, Division of Obstetric Anesthesia, Women’s Hospital, University of Michigan Health System, Ann Arbor, MI, USA ABSTRACT The current article covers some of the major themes that emerged in 2009 in the fields of obstetric anesthesiology, obstetrics, and perinatology, with a special emphasis on the implications for the obstetric anesthesiologist. c 2010 Elsevier Ltd. All rights reserved.



Keywords: Neuraxial Labor Analgesia; Maternal Obesity; Ultrasound Guidance; Epidural Catheter Design; Loss of Resistance Technique; Placebo; Nocebo; Consent; Communication; Progress Of Labor; Electrohysterography; Cesarean Delivery; Phenylephrine; Ephedrine; General Anesthesia; Awareness; Magnesium; Transversus Abdominal Plane Block; Chloroprocaine; Influenza A H1N1; Preeclampsia; Preterm Birth; Perinatal Neurologic Injury

Introduction Every year the Society for Obstetric Anesthesia and Perinatology (SOAP) nominates one individual to survey the prior year’s literature and to identify the most notable individual papers and emerging themes for the science and practice of obstetric anesthesiology. A previous review summarized new evidence relating to safety and quality in peripartum care.1 This review covers some of the additional topics published in 2009.

Neuraxial labor analgesia Maternal obesity may present some of the greatest technical challenges to an obstetric anesthesiologist, but new evidence confirms the clinical impression that not all obese women have difficult neuraxial block placements. An observational cohort study enrolled 427 women with body mass indices between 20 and 62 kg/m2 to test the hypothesis that body mass index (BMI) would predict neuraxial technique difficulty as measured by the required number of needle passes.2 Two predictors were significant: first, vaguely palpable or impalpable spinous Accepted October 2010 The 2010 Gerard W. Osteimer Lecture. Presented at the Annual Meeting of the Society for Obstetric Anesthesia and Perinatology, San Antonio, TX, USA Correspondence to: Jill M. Mhyre, MD, Department of Anesthesiology, University of Michigan Health System, Obstetric Anesthesiology Room L3622 Women’s Hospital, 1500 E. Medical Center Drive SPC 5278, Ann Arbor, MI 48109-5278, USA. E-mail address: [email protected]

processes, and second, the patient’s inability to create a convex contour at the skin when flexing her back. Obesity did not predict difficult placement directly, but did increase the likelihood of both difficult palpation and poor back flexion. A back examination should be performed as part of the standard anesthetic history and physical examination, and the probability of difficult neuraxial block placement factored in to any analgesic or anesthetic plan. Block insertion under ultrasound guidance may be considered for women with difficult palpation, poor back flexion, or a history suggestive of difficult neuraxial block placement. In a preliminary study to evaluate the usefulness of ultrasound to facilitate block insertion, a cohort of 46 obese and morbidly obese women was used to correlate ultrasound depth to the epidural space with epidural needle depth.3 Correlation was good (Pearson correlation coefficient 0.85 [95% confidence interval: 0.75–0.91]), with a tendency to underestimate true needle depth as the measured depth increased. Previous comparisons between multi- and single-orifice epidural catheters have focused on standard nylon designs.4 A 2009 trial randomized 486 women to compare two flexible epidural catheters with stainless steel coil reinforcement.5 The primary outcome was complete analgesia at 30 min, and was not different between groups, at 85% for the single-orifice end-hole polyurethane catheter (Arrow FlexTip Plus) and 80% for the multi-orifice side-port soft polyamide catheters (Spirrol catheter) (P = 0.23; 95% confidence interval (CI) of the difference 13% to 3%). There was also no difference in immediate or delayed epidural catheter replacement.

150 Regardless of catheter design, the need for catheter replacement decreased maternal satisfaction measured at 24 h from 98% to 70% (P < 0.001). Many studies have examined the safety and efficacy of loss of resistance to saline versus air to guide epidural needle insertion for standard epidural catheter placement.6 Grondin et al. enrolled 345 laboring women receiving the combined spinal–epidural (CSE) technique, in order to compare loss of resistance to saline versus air on resulting spinal and epidural analgesia.7 In the majority of patients (338/345), cerebrospinal fluid returned spontaneously from the spinal needle and bupivacaine with fentanyl was dosed. The resulting spinal analgesia failure rate measured at 15 min was not different between groups, regardless of whether the epidural space had been identified by air or saline (4.2% vs. 4.9%, P = NS). Likewise, the rate of epidural catheter replacement within the first 4 h was also similar between groups (2.9% vs. 5.1%, P = NS). The seven patients without spontaneous clear fluid return from the spinal needle had an epidural catheter inserted without a spinal dose, and experienced a significantly higher rate of catheter replacement in the first 4 h (28% vs. 3%, P < 0.001). The authors conclude that the loss of resistance technique is equally successful using air or saline, and the spontaneous return of clear fluid through the spinal needle increases the likelihood of successful epidural analgesia. In contrast, the practice of active aspiration may be unnecessary; spinal or epidural analgesic outcomes were not different regardless of whether additional clear fluid returned with aspiration before or after administering the spinal dose.

Endogenous analgesia Although neuraxial labor analgesia provides the most effective pain relief in contemporary practice, scientific understanding of placebo analgesia may lead to future analgesic techniques that are both effective and less invasive. Naloxone impairs placebo-induced analgesia, and functional magnetic resonance imaging (fMRI) studies have correlated this response to changes in pain-sensitive brain regions in the cortex. A healthy volunteer experiment combined a robust procedure to generate placebo analgesia, a randomized naloxone infusion, and fMRI, to show that placebo analgesia activates the entire descending opioidergic pain pathway8 from the cortex down to the ipsilateral dorsal horn of the spinal cord.9 Placebo analgesia is mediated not only through opioid, but also dopamine, and b-adrenergic pathways.10 Hyperalgesia, also known as the nocebo effect, is mediated through cholecystokinin and deactivation of dopimine.

Communication Language may influence placebo and nocebo effects among obstetric patients, acting through both conscious

What’s new in obstetric anesthesia 2010? and subconscious processes and responses.11 Communication practices including reflective listening, observing, acceptance, utilization, and suggestion may help to optimize patient experience. Words with negative emotional content such as ‘‘sting’’ should be avoided when possible unless the patient mentions them first, because these words can increase in the patient’s analgesic requirements and experience of pain. On the other hand, for the purpose of evaluation, a clear inquiry for specific symptoms (‘‘Do you have any pain?’’) is important to identify all patients who may benefit from treatment.12 A survey of 100 women following cesarean delivery found that open questions (‘‘How are you feeling?’’ and ‘‘Are you comfortable at the moment?’’) failed to identify a significant proportion experiencing any pain (25/65 [35%]), including those who desired additional pain medication (2/5 [40%]). An appropriate balance between clear communication and optimistic suggestion is particularly important in establishing rapport with patients while obtaining effective informed consent. The Obstetric Anaesthetists’ Association (OAA) has published a standardized epidural information card that describes the procedure, its benefits, common problems, and a dozen risks ranging in frequency from 1 in 8 for inadequate analgesia to 1 in 250 000 for paralysis or other severe injury.13 The card has been translated from English into at least 26 other languages. A survey of OAA members conducted in 2007 demonstrated widespread support for the national standardized information card.14 The challenge of rapidly obtaining informed consent from the obstetric patient in active labor may be particularly acute for anesthesiologists in training.15 Effective communication is central to high quality patient care, and innovative educational programs to develop communication and other non-technical skills are emerging.15–17 Writing about personally encountered ethical, practical, and relational challenges may help participants to engage more fully in these educational experiences.15 The informal curriculum is also important. Attentive faculty can identify interpersonal challenges in real time, model effective responses, and encourage resident physicians to consider and reflect on actual events.17

The progress of labor Several new methods to measure the progress of labor were described in the 2009 literature, including non-linear mixed effects modeling (NONMEM) and electrohysterography. NONMEM was originally developed to analyze pharmacokinetic and pharmacodynamic data, allowing for adjustment for correlations between repeated measures while adjusting for the effects of potential covariates. Recently this analytic technique was applied to build a sigmoidal mathematical model of

J.M. Mhyre labor pain.18 A retrospective cohort study used data from 500 laboring women who ultimately delivered vaginally to derive a biexponential equation to describe cervical dilation over time,19 and to show that patient weight, neuraxial analgesia, and Asian race each influence the progress of labor independently. Substantial individual variability was noted in both the labor pain and labor progress models. Ongoing work is evaluating for potential genetic contributions to this individual variation. Women who deliver by cesarean for arrest of dilation likely experience different labor curves than women who deliver vaginally. Interval-censored survival analysis is an alternative mathematical modeling technique that may be used to isolate specific intervals of the labor curve, to estimate the time required to dilate from each centimeter to the next, and to consider potential covariates that might prolong or accelerate each interval of cervical dilation.20–23 Electrohysterography is a very different approach to measuring the progress of labor. Previous studies have evaluated electrohysterography as a tool to predict preterm delivery among women experiencing preterm uterine contractions.24 A case-control study extended this work to term labor by comparing the spatiotemporal electrohysterographic patterns in women who ultimately delivered by cesarean for arrest of dilation, with those patterns in a matched cohort of eutocic controls at a comparable cervical dilation.25 Data were recorded from eight electrode locations across the abdomen, and a Gaussian model was used to determine the center of uterine activity over time. During a functional contraction the center of uterine activity starts or ends in the uterine fundus. In contrast, more than half of the 12 women who underwent cesarean delivery for labor arrest had a predominantly lower uterine segment direction of the center of uterine activity. This study raises the possibility of being able to diagnose both functional term and preterm labor, and evaluate the effect of interventions designed to either delay or promote functional uterine contractions.26

Neuraxial analgesia and the progress of labor Early neuraxial analgesia is associated with a prolonged labor and operative delivery, but this association does not reflect a causal relationship.27–29 A randomized controlled trial from China enrolled 12 793 nulliparous women in spontaneous labor with cervical dilation of 3 cm or less to reinforce the conclusion that standard epidural analgesia initiated in the latent phase of labor does not increase the risk of cesarean delivery.30 The control group received intermittent doses of meperidine to delay epidural catheter insertion to at least 4 cm cervical dilation. Participants experienced no difference in the rates of cesarean delivery (23.2% vs. 22.8%, P = 0.51), instrumental vaginal delivery (11.8% vs. 12.7%, P = 0.10) or

151 spontaneous vaginal delivery (65.0% vs. 64.5%, P = 0.57). Median satisfaction with analgesia was higher in the early placement group (VAS 84 vs. 62, P = 0.01), but the rate of breastfeeding success at 6 weeks was reduced (70.1% vs. 77.8%, P < 0.0001). Breastfeeding success was one of 28 secondary outcomes in this study, which had extensive statistical power. The accompanying editorial recommends that the breastfeeding result may be spurious and should be confirmed as a primary outcome in a future trial.31 Even among nulliparas undergoing induction of labor, there is no evidence of a causal relationship between early neuraxial analgesia and mode of delivery.32 This conclusion derives from a trial that randomized 806 women in early induced labor (cervical dilation 63 cm) to immediate versus delayed neuraxial analgesia. The study design replicates a previous trial by the same group that enrolled nulliparas in spontaneous labor.27 In both trials, the treatment group received a CSE technique dosed with intrathecal fentanyl followed by epidural analgesia at second analgesic request; the control group received up to two doses of hydromorphone to delay standard epidural catheter placement until a cervical dilation of 4 cm or more. The results confirm no difference in the cesarean delivery rate (32.7% vs. 31.5%, P = 0.65). Post hoc beta estimation suggests that a future trial would require at least 30 500 participants to detect a difference between these rates.

Anesthesia for cesarean delivery Conversion of epidural analgesia to anesthesia If unplanned cesarean delivery becomes necessary, conversion of epidural analgesia to anesthesia is a desirable option. Catheters that fail to provide optimal labor analgesia should be recognized early, and replaced or adjusted. Multiple recent studies identified the need for supplemental epidural boluses during labor and breakthrough pain as significant predictors for subsequent failure of epidural anesthesia.33–36 Epinephrine added to the epidural anesthetic solution can reduce the risk of anesthetic failure.33 Finally, catheter withdrawal by 1 cm facilitated successful anesthesia for greater than 80% of patients in whom an indwelling catheter initially failed to provide adequate surgical anesthesia.35

Post-spinal hypotension Maternal hypotension following spinal anesthesia may impair uteroplacental perfusion evidenced by decreased umbilical arterial pH values among infants born to mothers who received spinal versus general or epidural anesthesia.37 Although important, umbilical arterial pH is an intermediate measure, and evidence directly linking spinal anesthesia to clinically significant neonatal consequences is sparse. Laudenbach et al. completed a secondary analysis of a population-based cohort of

152 preterm cesarean deliveries (<34 weeks of gestation) performed in France in 1997, in order to evaluate the effect of anesthetic technique on neonatal mortality rate.38 The risk of neonatal death was increased among those infants delivered to mothers who received spinal anesthesia (adjusted odds ratio 1.7 [95% CI 1.1, 2.6]), based on a multivariate model controlling for over 12 covariates, including gestational age, intrauterine growth restriction, antenatal corticosteroids, and the hospital delivery volume for very premature infants. The association between spinal anesthesia and subsequent neonatal death may be the result of unmeasured confounders. It is also possible that among vulnerable infants, the consequences of maternal hemodynamic instability associated with spinal anesthesia can be severe. Future research is needed to confirm that modern maternal hemodynamic management would eliminate any such relationship between spinal anesthesia and neonatal mortality. Fluid loading is one strategy proposed to maintain maternal hemodynamic stability following spinal anesthesia. Either colloids or crystalloids may be administered as a preload (before spinal anesthesia) or as a coload (started as the spinal anesthetic is dosed and continued while it is developing). Three studies in 2009 compared a colloid preload versus coload on maternal cardiac output39 and on the incidence of post-spinal hypotension.39–41 Although a colloid preload 15 mL/kg increased maternal cardiac output in the 5 min following spinal anesthesia when compared with a coload,39 there was no difference in the incidence of subsequent maternal hypotension.39 Likewise, whether colloid 500 mL is administered as a preload or coload does not change the incidence of post-spinal hypotension or the need for a vasopressor to maintain an acceptable maternal blood pressure.40,41 In a fourth study, preloading with crystalloid 1.5 L, colloid 0.5 L, or colloid 1.0 L all increased pre-anesthetic maternal cardiac output and corrected flow time (a measure of intravascular volume) in a dose-response fashion, but no solution effectively prevented post-spinal maternal hypotension.42 Meta-analysis confirms that regardless of fluid composition or timing, approximately 60% of elective cesarean delivery patients require a vasopressor to maintain an acceptable blood pressure after spinal anesthesia.43 Phenylephrine has emerged as the preferred vasopressor to prevent and treat maternal hypotension during spinal anesthesia, based primarily on a series of trials published by Ngan Kee et al. comparing phenylephrine with ephedrine.44–46 Most recently, this group randomized 104 elective cesarean delivery patients to receive infusions of phenylephrine or ephedrine at the assumed equipotent ratio of 1:80 to prevent post-spinal maternal hypotension in order to evaluate neonatal outcomes including arterial pH, base excess, vasopressor and catecholamine concentrations.47 All participants received a spinal anesthetic

What’s new in obstetric anesthesia 2010? established with bupivacaine and fentanyl, left uterine displacement, and a rapid intravenous coload up to 2 L. Both median umbilical arterial pH and median base excess were decreased in the ephedrine group (7.25 [intraquartile range (IQR) 7.14, 7.29] vs. 7.33 [IQR 7.30, 7.35], P < 0.001; 4.8 [IQR 8.7, 3.0] vs. 1.9 [IQR 3.2, 0.6], P < 0.001), respectively. Ephedrine crosses the placenta to a greater extent than phenylephrine. The vasopressor concentration ratio between umbilical vein and maternal artery was greater in the group receiving ephedrine versus phenylephrine (median 1.13 [IQR 1.01, 1.23] vs. 0.17 [IQR 0.11, 0.22], P < 0.001). Furthermore, ephedrine undergoes less early metabolism and/or redistribution in the fetus compared with phenylephrine. In the ephedrine group, the concentration ratio between the umbilical artery and vein was also greater (0.83 [IQR 0.75, 0.91] vs. 0.71 [IQR 0.56, 0.84], P = 0.001). The associated increases in umbilical arterial lactate, glucose, and catecholamines support the hypothesis that depression of fetal pH and base excess with ephedrine is related to metabolic effects secondary to stimulation of fetal beta-adrenergic receptors. The overall effect of vasopressors on fetal oxygen supply and demand balance appears to favor phenylephrine. Phenylephrine may also be more effective for maintaining maternal blood pressure, heart rate and cardiac output. Dyer et al. published a double-blind randomized controlled trial that analyzed 38 elective cesarean delivery patients who received an arterial line, cardiac output monitoring, standard spinal anesthesia, left lateral tilt, and a crystalloid coload of 20 mL/kg.48 Participants were randomized to receive a rescue vasopressor bolus of phenylephrine or ephedrine as soon as the mean arterial blood pressure (MAP) fell 20% below baseline. Doses of phenylephrine 80 lg and ephedrine 10 mg were selected in a ratio of 1:125 based on the expectation of equipotency to restore the MAP to baseline. Approximately half the patients experienced a 20% drop in MAP before delivery and received the prespecified vasopressor. Among these patients, when MAP decreased by 20%, systemic vascular resistance (SVR) dropped by 35%, and cardiac output increased by 22.5%. The bolus of phenylephrine restored baseline MAP significantly faster than ephedrine, and reduced maternal cardiac output and heart rate back towards baseline values, when compared with ephedrine, which increased both cardiac output and heart rate further. A comparison between maternal heart rate and cardiac output demonstrated significant correlation (ephedrine r = 0.65, P < 0.003; phenylephrine r = 0.87, P < 0.001), and suggests that maternal heart rate may be a useful surrogate measure of cardiac output to direct vasopressor administration. If phenylephrine reduces the heart rate below baseline, then cardiac output is likely reduced as well, and further doses of phenylephrine should either be withheld, reduced, or replaced with ephedrine. Finally,

J.M. Mhyre this paper showed that a 2.5 IU bolus of oxytocin dosed after delivery causes a 50% drop in SVR that is reduced in half by co-administered phenylephrine. Onset and duration of action of oxytocin and phenylephrine differ. Nevertheless, the co-administration of phenylephrine with oxytocin may be a useful strategy to allow for more generous oxytocin dosing while maintaining maternal hemodynamic stability.

Maternal oxygen supplementation Supplemental oxygen is no longer recommended for patients undergoing elective cesarean delivery because it appears to increase oxygen free radical activity in both the mother and fetus, with minimal to no improvement in fetal oxygenation.49–51 On the other hand, for patients undergoing emergency cesarean delivery, supplemental oxygen improves oxygen delivery to the fetus, and improves maternal oxygenation in the event that conversion to general anesthesia becomes necessary. Khaw et al. enrolled 131 patients undergoing non-elective cesarean delivery under spinal anesthesia, and randomized participants to 60% versus 21% oxygen by Venturi face mask.52 Supplemental oxygen increased the umbilical arterial oxygen content (mean 6.6 ± 2.5 vs. 4.9 ± 2.8 mL/dL, P = 0.006) with no difference in lipid peroxidation, regardless of whether fetal compromise was considered present or not. Neonatal outcomes measured by Apgar scores and umbilical arterial pH values were also similar between groups.

General anesthesia Obstetric procedures carry a relatively high risk of undesired intraoperative awareness.53 A recent prospective survey of cesarean deliveries under general anesthesia performed in 13 centers in Australia and New Zealand documents an incidence of awareness of 1 in 382 (0.26%, 95% CI 0.03–0.9%).54 Magnesium may help to limit risk of maternal awareness during cesarean delivery under general anesthesia. A double-blind randomized controlled trial enrolled 72 women to receive either magnesium 30 mg/kg with the anesthetic induction followed by a magnesium infusion at 10 mg/kg/h, magnesium 45 mg/kg followed by 15 mg/kg/h, or saline control.55 Anesthesia was induced with thiopental 4 mg/kg and maintained with 1% endtidal sevoflurane with 50% nitrous oxide in oxygen. Initial paralysis with succinylcholine was maintained with atracurium to ensure a train-of-four ratio below three. Bispectral Index (BIS) scores were no different between groups in the 5 min following induction with thiopental. From 7.5 min through delivery, BIS scores in the 45 mg/kg group (mean 56 ± 8 at 7.5 min) were decreased compared with the 30 mg/kg group (mean 62 ± 8, P < 0.01 when compared with the 45 mg/kg group) and with the control group (mean 64 ± 9, P < 0.001).

153

Postcesarean analgesia Following delivery, maternal pain can be severe, and the severity of acute pain predicts the likelihood of chronic post-delivery pain and postpartum depression.56 A Cochrane review surveyed a wide range of local anesthetic infiltration techniques for postcesarean analgesia, and identified 20 studies enrolling a total of 1150 women.57 Abdominal wall nerve blocks were found to decrease postoperative opioid consumption among women who had general or neuraxial anesthesia without neuraxial opioids, based on a meta-analysis of three studies that evaluated iliohypogastric nerve blocks, or ilioinguinal nerve blocks, or both, and one study that evaluated transversus abdominal plane (TAP) blocks (175 participants total, mean difference 25.80 mg; 95% CI 50.39, 1.21).57,58 Two additional trials evaluated TAP blocks for postcesarean analgesia.59,60 Both studies were conducted in elective cesarean delivery patients receiving spinal anesthesia with bupivacaine and fentanyl. Both randomized patients in a blinded fashion to bilateral TAP blocks with either ropivacaine or saline. The study by Belavy et al. confirms that TAP blocks reduce total intravenous consumption in the first 24 h (TAP block group [n = 23] mean 23.8 ± 8.2 mg vs. placebo group [n = 24] mean 35.6 ± 9.7 mg; mean difference 11.8 mg; 95% CI 17.09, 6.51; mean values provided by the author).59 Costello et al. co-administered morphine 100 lg with the spinal anesthetic, and found that total morphine requirements for breakthrough pain in the first 23 h were similar between groups (TAP block [n = 47] 1.06 mg ± 2.38 vs. placebo [n = 49] 1.98 mg ± 3.21; mean difference 0.92 mg, 95% CI 2.07, 0.23; mean values provided by the author).60 Furthermore, the mean visual analog pain scores on movement at 24 h were also no different between the TAP block group (3.4 cm ± 2.4) versus the placebo group (3.2 cm ± 2.2; P = 0.47). Therefore, TAP blocks are effective, but provide minimal incremental analgesia in the presence of intrathecal morphine, and may be most appropriate for patients in whom long-acting neuraxial opioids are either undesirable or contraindicated, or for patients at increased risk of postcesarean breakthrough pain or chronic pain. Epidural 2-chloroprocaine interferes with the quality and duration of epidural morphine analgesia, based on previous studies that administered epidural morphine after 2-chloroprocaine. New evidence suggests that the relative timing of administration is important. Epidural morphine dosed 30 min before epidural 2-chloroprocaine provides a similar duration of analgesia as epidural morphine dosed after epidural lidocaine, based on the results of a double-blind randomized controlled trial of patients who received epidural anesthesia for postpartum tubal ligation.61 2-Chloroprocaine anesthesia

154 resolves rapidly, and it is possible that epidural morphine must be administered sufficiently early to provide effective analgesia before the anesthesia resolves. It is also possible that neuraxial opioids administered before 2-chloroprocaine may adhere to spinal opiate receptors, and inhibit direct antagonism of the opioid receptors by 2-chloroprocaine or one of its metabolites.

Maternal co-existing disease Obesity In 2009, the Institute of Medicine issued new guidelines for recommended weight gain in pregnancy.62 The updated guidelines stratify obesity according to the standard World Health Organization (WHO) criteria, with overweight defined as pre-pregnancy BMI between 25.0 and 29.9 kg/m2, and obesity defined with a BMI of 30 kg/m2 and above. Term pregnant women are described based on their pre-pregnancy BMI and whether weight gain was less than, within, or above the recommended ranges. Although the institute refrained from recommending a weight-neutral pregnancy for obese women, it did introduce an upper limit to gestational weight gain of 25 pounds (12 kg).

Influenza A H1N1 Influenza A H1N1, like previous influenza pandemics, disproportionately affected pregnant and recently delivered women.63 In the United States alone, there were 56 deaths among pregnant or recently delivered women between April and December, 2009.64 Early antiretroviral therapy is critical in mitigating the severity of disease.63,65–67 Compared with women who received treatment within 2 days of the onset of symptoms, those with treatment delayed more than 4 days had a six-fold increased risk of ICU admission, a 12-fold increased risk of mechanical ventilation, and over 50-fold increased risk of death.64

Preeclampsia Preeclampsia originates in the earliest stages of pregnancy, when fetal syncytiotrophoblasts fail to invade beyond the superficial uterine decidua to establish an efficient placental blood supply. Previous work has suggested that impaired immunoregulation and oxidative stress inhibit trophoblastic invasion. Using micro-array analysis, a case-control study compared banked chorionic villus samples collected at 10–12 weeks of gestation between eight women who were controls and four who went on to develop preeclampsia.68 The analysis identified 36 differently expressed candidate genes related to inflammation, immunoregulation, and cell motility. These data support the theory that placentation in preeclampsia is compromised in the first trimester by maternal and fetal immune dysregulation, or abnormal decidualization of the endometrium, or both. No

What’s new in obstetric anesthesia 2010? evidence was found for alterations in genes regulated by hypoxia or oxidative stress. Subsequent uteroplacental hypoxia does contribute to the development of overt maternal disease by stimulating the release of antiangiogenic factors from the placenta that injures both the placental and maternal vasculature. By definition, overt preeclampsia requires at least 20 weeks of gestation to manifest. Despite the prolonged latent phase of the disease, current first and second trimester screening techniques have insufficient sensitivity to warrant routine use.69 A case control study of Indonesian women identified a panel of seven cell-free messenger RNA (mRNA) markers in maternal plasma drawn between 15 and 20 gestational weeks, that predicted subsequent preeclampsia with a remarkable sensitivity of 84%, specificity of 95%, and area under the receiver operator curve of 0.927.70 mRNA species in the panel code for antiangiogenic proteins, including fms-like tyrosine kinase 1, vascular endothelial growth factor and endoglin. A scaled score combining results across markers correlates with the severity of subsequent disease. The significance of these results depends on the future development of effective therapies to treat women with preeclampsia. To date, the only known cure for preeclampsia is delivery. Induction of labor is associated with improved maternal outcome for women with mild hypertensive disease beyond 37 weeks,71 but expectant management may be appropriate for uncomplicated preeclampsia at an earlier gestational age.72 In the future, anesthesiologists may contribute to expectant management in preeclampsia remote from term. A randomized controlled dose-finding pilot trial enrolled ten women less than 32 weeks of gestation and found that antepartum epidural ropivacaine reduced uterine artery resistance in a dose-dependent fashion, with the effect localized to the uterine artery, which demonstrated higher baseline resistance.73 The contralateral uterine artery exhibited either increased vascular resistance or no change. Future studies are needed to determine if long-term segmental sympatholysis induced by epidural local anesthetics can improve uteroplacental perfusion and slow the release of antiangiogenic proteins and the progression to severe maternal-fetal disease.

Preterm birth Preterm birth complicates more than 12% of all pregnancies in the US,74 and is a leading cause of infant mortality and long-term morbidity. Anesthetic gas exposure may increase risk of preterm birth. An observational study of Australian veterinarians suggests that preterm delivery is more common among those women who report exposure to unscavenged anesthetic gases for one or more hours per week (hazard ratio 2.56, 95% CI 1.33, 4.91).75

J.M. Mhyre Poor dentition has been associated with preterm birth, and meta-analysis of seven randomized controlled trials including 2663 patients suggests that dental treatment may reduce likelihood of preterm birth (odds ratio 0.55, 95% CI 0.35, 0.86, P = 0.008).76 Unfortunately, three large randomized controlled trials were subsequently published, and none supports the hypothesis that treatment of periodontal disease during pregnancy reduces risk.77–79 Antenatal progesterone reduces the risk of recurrent preterm labor in women with a history of preterm delivery and in those with a sonographically detected short cervix,80 but does not prevent preterm delivery before 34 weeks in twin pregnancies (pooled odds ratio, 1.16; 95% CI, 0.89–1.51).81–83 The biology of preterm delivery may differ between singleton and twin gestations. Debate over the optimal tocolytic regimen continues.84,85 In many regions of the world, the oxytocin antagonist atosiban is emerging as the preferred tocolytic agent. Atosiban has similar efficacy to calcium channel blocking agents86 and beta-mimetics,87,88 and a significantly lower frequency of hypotension when compared with nifedipine,86,89 and lower frequency of tachycardia, dyspnea, chest pain, pulmonary edema, hyperglycemia, hypocalcemia, rebound hyperkalemia, and fetal tachycardia when compared with betamimetics.87–90 To date, no oxytocin antagonist has been approved by the US Food and Drug Administration. A meta-analysis of 58 randomized controlled trials of tocolysis concluded that prostaglandin inhibitors provide the greatest efficacy relative to side effects for delaying delivery at least 48 h and up to seven days,84 however premature closure of the ductus arteriosus and oligohydramnios limit its use after 32 weeks of gestation. Even if tocolytic therapy does extend the duration of pregnancy, it remains unknown whether tocolysis beyond the 48 h needed to deliver antenatal corticosteroids improves long-term outcomes in children.85,90–92 A single course of antenatal corticosteroids unequivocally improves birth outcomes in premature babies, but the magnitude of maximal benefit wanes after two weeks of continued pregnancy. When pregnancy is maintained for longer periods, multiple courses of corticosteroids impair fetal growth.93 In the case of a recurring threat of preterm birth before 34 weeks of gestation, a single 48-h rescue course of antenatal steroids improves neonatal outcome with no difference in birth weight, rates of intrauterine growth restriction, or head circumference.94

The timing of term birth Term pregnancy lasts between 37 and 42 weeks from the last menstrual period until delivery, but gestational age is a biologic continuum, and neonatal outcomes appear to be optimized for those infants born between 39 and 41 completed weeks of gestation.95–98 Elective delivery

155 before 39 weeks’ completed gestation has been endorsed as a useful quality measure by the National Quality Forum,99 the Institute of Healthcare Improvement,100 and the Joint Commission.101 The American Congress of Obstetrics and Gynecology also recommends that the elective induction of labor should be delayed until 39 weeks.102 As health systems establish policies to delay elective cesarean delivery until 39 weeks, the decreased risk of post-delivery complications must be weighed against the risk of intrauterine fetal demise during the 38th week of gestation, which has been estimated at 0.1%.97,103 In addition, postponing elective deliveries may increase rates of preeclampsia and unscheduled cesarean delivery performed for spontaneous labor before a planned date.97,104 Induction of labor at 41 weeks and beyond reduces the risks of cesarean delivery and meconium-stained amniotic fluid when compared with expectant management, based on a systematic review of 11 randomized controlled trials.105 In contrast, existing trials demonstrate no difference in the cesarean delivery rate between induction of labor and expectant management between 39 and 41 weeks.105 Further research is needed. Preventive induction of labor before 41 weeks of gestation may reduce the cesarean delivery rate among women with specific risk factors for cephalopelvic disproportion or uteroplacental insufficiency.106,107

Perinatal neurologic injury Antenatal magnesium reduces the risk of cerebral palsy for infants born before 34 weeks of gestation, without changing the risk of perinatal or childhood mortality, based on multiple meta-analyses of six randomized controlled trials.108–111 The magnitude of benefit depends on gestational age at birth.110 Fifty-two women at risk of preterm delivery before 34 weeks need to receive antenatal magnesium to prevent one case of cerebral palsy (95% CI 31, 154).109 If treatment is restricted to those women with threatened delivery before 28 weeks, the number needed to treat falls to 29.112 Recommended dosing includes a loading dose of 4–6 g of magnesium sulfate, followed by 1–2 g/h for 12–24 h.113 Magnesium may also improve neurologic outcome at discharge for term neonates with severe perinatal asphyxia,114 based on the results of a double-blind randomized controlled trial in 40 infants. The treatment group received 250 mg/kg of magnesium within 6 h of birth, and repeated every 24 h for a total of three doses, and the control group received saline. Two infants died in each group. Among the 36 survivors, the magnesium treated infants had a lower rate of abnormal neurologic examination findings at discharge (22% vs. 56%, P = 0.04). Larger trials are needed to confirm these results.

156 The mechanism by which magnesium provides cerebral protection is unknown, but magnesium likely relieves oxidative stress and excitotoxicity due to excessive glutamate stimulation of preoligodendrocytes in the periventricular white matter through several mechanisms.85,109 Magnesium inhibits ion flow through the N-methyl-D-aspartate (NMDA) receptor channel, hinders calcium influx into cells, may reduce inositol 1,4,5-triphosphate receptor binding, and may contribute to antioxidant defenses. On the other hand, as with any NMDA antagonist, high doses of magnesium may be neurotoxic; a neonatal mouse model demonstrated widespread apoptotic cell death following a dose of 1 g/kg of magnesium sulfate.115 Lower doses may induce selective apoptosis in humans, and studies that follow surviving children for many years are needed to evaluate for more subtle neurocognitive effects. The classic intervention to limit injury from suspected perinatal asphyxia is timely cesarean delivery. The WHO recommends a national cesarean delivery rate between 5% and 15%, but new evidence suggests that more liberal use of cesarean delivery may be an effective strategy to lower the perinatal mortality rate ascribed to intrapartum anoxia.116 Between 1988 and 2007, in Scotland, deaths attributed to intrapartum anoxia declined from 5.7 to 3.0 events per 10 000 births, and demonstrate an inverse relationship with the cesarean birth rate, which increased from 8.9% to 21.6%. Deaths attributed to other causes (such as fetal-maternal hemorrhage and infection) did not change.

Long-term childhood outcomes Perinatal death and cerebral palsy represent the extreme consequences of birth-related hypoxic injury. Mild cerebral injury at birth may remain clinically significant even if it causes subtle defects in cognitive function that are only detectable as the child grows. A population-based cohort study used resuscitation at birth among term infants as a measure of mild cerebral injury.117 The proportion of eight-year-old children with full-scale intelligence quotient (IQ) scores below 80 increased from 7% for those who did not require resuscitation at birth, to 10% for those children who had behaved normally after neonatal resuscitation (adjusted odds ratio 1.7, 95% CI 1.1, 2.4, P < 0.01), and 23% among those who had demonstrated signs of encephalopathy after neonatal resuscitation (adjusted odds ratio 6.2, 95% CI 1.6, 24.7, P < 0.001). Remarkably, because the vast majority of infants who require resuscitation remain asymptomatic for signs of encephalopathy, they may account for a greater proportion of the population with IQ <80, at 3.4% (95% CI 0.5, 6.3) versus 1.2% (95% CI 0.2, 2.2). Perhaps no controversy has bigger implications for obstetric anesthesiology than the long-term effects of

What’s new in obstetric anesthesia 2010? anesthesia on the developing brain.118–121 To evaluate influence of anesthetic exposure during birth on the risk of subsequent learning disabilities, a retrospective cohort study tied birth records to educational outcomes for a cohort of young adults born in Olmsted County, Minnesota between 1976 and 1982.122 The cumulative risk of learning disabilities was lowest for those children born by cesarean delivery under neuraxial anesthesia, and was not different between those born vaginally and those born by cesarean delivery under general anesthesia. This pattern persisted after adjusting for sex, birth weight, gestational age, exposure to anesthesia between ages zero and four, and maternal education (adjusted hazard ratio 0.64, 95% CI 0.44, 0.92; P = 0.017 for cesarean delivery under neuraxial anesthesia vs. vaginal delivery). Details about fetal heart rate tracings, umbilical arterial pH values, and the need for resuscitation at birth were not available. The fact that learning disabilities were no different between children born by cesarean under general anesthesia and children born vaginally suggests that the effects of brief intrapartum exposure to NMDA antagonists, c-aminobenzoic acid-A (GABA) agonists, or other anesthetics are likely outweighed by other factors, such as minor degrees of intrapartum hypoxia. To fully elucidate the respective impact of mild hypoxic injury and maternal anesthesia on long-term neurologic outcomes in children, future studies will need to integrate data on educational outcomes, maternal anesthetic dosages and timing, intrapartum oxygenation, and other important perinatal exposures such as magnesium and hypothermia. In addition to intrapartum fetal heart rate tracings and umbilical arterial pH values, increasingly sophisticated measures of hypoxia and neurologic injury include neonatal electroencephalography with amplitude-integrated recordings, neonatal cranial ultrasound and magnetic resonance imaging.121,123,124

Acknowledgments The author acknowledges with appreciation Linda Polley, Mary Lou Greenfield, Lawrence Tsen, John Sullivan, and the University of Michigan Health System Division of Obstetric Anesthesiology research assistants.

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