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Obstetric Anesthesiology: Review Article

What’s New in Obstetric Anesthesia? The 2013 Gerard W. Ostheimer Lecture

Palanisamy, Arvind MBBS, MD, FRCA

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doi: 10.1213/ANE.0000000000000101
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Abstract

The purpose of this review is to identify and summarize topics and themes relevant to the practice of obstetric anesthesia from articles published in the calendar year 2012. These important themes were presented in the 2013 Gerard W. Ostheimer Lecture “What’s New in Obstetric Anesthesia?” at the Society for Obstetric Anesthesia and Perinatology (SOAP) meeting in April 2013. Ninety-six journals were screened (Appendix 1), and 82 articles (Appendix 2) were chosen based on significance, clinical relevance, and public health impact. A detailed description of the methodology is provided in the Appendix 3. This review will focus specifically on articles that increase our understanding of the process of labor, pharmacological manipulation of labor, management of preterm labor, and practices that are immediately relevant to the clinical practice of obstetric anesthesia. Pertinent background is provided for controversial topics and, where possible, attempts made to resolve contradictory findings.

MATERNAL DISEASES

Preeclampsia continues to be one of the leading causes of significant maternal and neonatal morbidity and mortality.1 Although consensus guidelines have helped with overall management of preeclamptic patients, tailored and individualized management is challenging because of the lack of prognostic biomarkers to differentiate between different types of hypertensive disorders or predict adverse outcomes and preterm delivery. It is now well established that plasma levels of proteins released from the placenta, such as soluble Fms-like tyrosine kinase-1 (sFlt1) (an antiangiogenic factor) and placental growth factor (PlGF) (a proangiogenic factor), are altered in women with preeclampsia.2 Investigators have used these changes in relative plasma levels to identify combinations of biomarkers that can be used in the clinical setting; the most promising, thus far, is the SFlt1/PlGF ratio. Verlohren et al.3 characterized the sFlt1/PlGF ratio in 630 women with singleton pregnancy (388 healthy controls, 164 with preeclampsia, 36 with gestational hypertension, and 42 patients with chronic hypertension) at 2 different gestational windows: <34 weeks and ≥34 weeks. At <34 weeks of gestation, an sFlt1/PlGF ratio of ≥85 distinguished preeclampsia from other causes of hypertension in pregnancy such as gestational and chronic hypertension (P < 0.001). Furthermore, this study also showed that neither gestational nor chronic hypertension was associated with elevated sFlt1/PlGF ratios at <34 weeks’ gestation compared with healthy controls. Rana et al.4 calculated the sFlt1/PlGF ratio prospectively in 616 women admitted to their obstetric triage unit with signs and symptoms of preeclampsia. Plasma levels of sFlt1 and PlGF were determined at the time of initial diagnosis in the triage unit, and the authors tested for an association between the SFlt1/PlGF ratio and subsequent adverse maternal and perinatal outcomes within 2 weeks of the initial presentation. The adverse outcomes included placental abruption, elevated liver enzymes/low platelets, and small-for-gestational-age birth weight/abnormal umbilical artery Doppler measurements. The median ratio at presentation was significantly elevated in participants who eventually experienced adverse outcomes compared with those who did not (47.0 [interquartile range {IQR}, 15.5–112.2] vs 10.8 [IQR, 4.1–28.6]; P < 0.0001). Among those presenting at <34 weeks’ gestation (n = 167), the ratio was even more predictive of adverse outcomes (226.6 [IQR, 50.4–547.3] vs 4.5 [IQR, 2.0–13.5], P < 0.0001). The authors determined that an sFlt1/PlGF ratio >85 at 34 weeks’ gestation had 73% sensitivity, 94% specificity, and positive and negative predictive values of 86% and 87.3%, respectively, for detecting adverse outcomes. In addition, the sFlt1/PlGF ratio was inversely correlated to the duration of pregnancy; at < 34 weeks’ gestation, especially, delivery occurred within 2 weeks after presentation in 86.0% of women with a ratio ≥85 compared with 15.8% of women with a ratio of <85 (P < 0.0001). This ratio also performed remarkably better than other currently available laboratory tests and clinical signs currently used for predicting outcomes.

Thirty-five percent of infants born to diabetic mothers are in the 95th centile for birth weight. Fetal macrosomia not only increases the risk for adverse obstetric and neonatal outcomes but also increases the likelihood of obesity in childhood and cardiovascular complications later in life. Because glucose is the main substrate for fetal growth, Walsh et al.5 hypothesized that maternal dietary intervention would reduce the incidence of fetal macrosomia. In a randomized controlled trial involving patients who had previously delivered a macrosomic infant, the authors showed that a low glycemic index diet (n = 383) introduced during the second trimester was associated with a lower gestational weight gain (− 1.3 kg, 95% confidence interval [CI],−2.4 to −0.2; P = 0.01) and a lower incidence of abnormal glucose tolerance (21% vs 28%; P = 0.02) compared with a regular diet (n = 398). However, the overall incidence of macrosomia was not different between the 2 groups (approximately 51% in both groups).

With advances in medical and surgical management of complex congenital heart disease (CHD), the number of women with CHD desiring childbirth has increased dramatically. Opotowsky et al.6 established the epidemiology of adverse cardiovascular events among women with CHD hospitalized for childbirth in the United States. With the use of the Nationwide Inpatient Sample for the years 1998 to 2007, an administrative dataset representative of U.S. hospital admissions, the authors estimated odds ratios (ORs) for cardiovascular outcomes (arrhythmia, heart failure, cerebrovascular accident, embolism, death, or a combined outcome) for women with CHD compared with healthy controls without CHD. Women with CHD were more likely to suffer an adverse cardiovascular event (adjusted OR 8.4, 95% CI, 7.0–10.0). Arrhythmia was the most common adverse cardiovascular event, and heart failure (adjusted OR 7.0, 95% CI, 4.6–10.7), cerebrovascular accidents (adjusted OR 41.6, 95% CI, 25.8–67.1), and death (adjusted OR 6.7, 95% CI, 2.9–15.4) were more frequent in women with CHD.

LABOR AND DELIVERY

Labor Curve

The Friedman partograph, synthesized from a small group of genetically homogenous patients in the 1950s, remains the standard to judge progress of labor and help guide clinical decision making. Because of sweeping demographic changes, increasing incidence of obesity, and changes in obstetric practices, the current widespread use of the labor curve is under scrutiny.7 In a retrospective cohort study, Norman et al.8 studied the progress of labor in 5204 consecutive parturients who completed the first stage of labor; parturients were classified based on body mass index of <30 or ≥30 kg/m2, and labor curves were constructed by using repeated-measures analysis with polynomial modeling. After adjusting for confounders, the authors demonstrated that in patients with body mass index ≥30 kg/m2 the first stage of labor (from 4-cm cervical dilation) was significantly longer (4.7 vs 4.1 hours, P < 0.01), and this increase was predominantly due to slower cervical dilation between 4 and 6 cm (2.2 vs 1.9 hours, P < 0.01) compared with the <30 kg/m2 group. The authors surmise that use of a single ‘labor curve’ may have been partly responsible for the “overdiagnosis” of labor dystocia before 6-cm cervical dilation in obese parturients. However, these findings need to be confirmed in a prospective manner.

Given that the risk for cesarean delivery is 12% to 20% higher in women carrying a male fetus, another factor that might influence labor progress is fetal gender. To determine the association between fetal gender and the duration of first stage of labor, Cahill et al.9 performed a retrospective cohort study of 2373 parturients with singleton fetuses delivering consecutively and compared the duration of active first stage of labor by fetal gender. After adjusting for relevant covariates, male gender was associated with a significantly longer active first stage of labor (4.6 vs 4 hours, P = 0.002) than female gender. Although the exact mechanism(s) explaining this association is unclear, the authors suggest that the presence of a male fetus should be included as a factor in the decision-making algorithm of failed labor.

Some experts have suggested that genetic polymorphisms may contribute to individual variability in the duration of labor; Terkawi et al.10 identified that homozygosity for Thymine at the catechol-O-methyl transferase single nucleotide polymorphism (rs4633) and Guanine at the oxytocin receptor single nucleotide polymorphism (rs53576) was associated with slower latent phase of labor and delayed transition to active labor, respectively, compared with other genotypes at these positions. Collectively, these studies highlight the limitations of a standardized labor curve.

Management of Labor

Labor is electively induced in approximately 20% of pregnancies in the developed world.11. Though induction of labor has shown to decrease perinatal mortality in controlled trials involving pregnant women at or beyond term,12 it is unclear whether population-wide adoption of such a strategy at earlier gestational ages is beneficial. Owing to the large sample size required to study uncommon outcomes such as perinatal death, there is an understandable dearth of data to guide obstetric management. Stock et al.13 performed a large scale, population-based retrospective cohort study involving >1 million women with singleton pregnancies ≥37 weeks’ gestation who delivered in Scotland between the years 1981 and 2007. Data were obtained from birth and morbidity records, and stillbirth and infant surveys. Compared with expectant management, elective induction of labor at 40 weeks’ gestation was associated with decreased odds of perinatal death (adjusted OR 0.44, 99% CI, 0.27–0.71, P < 0.001), and this trend was noticed even at 1-week intervals of gestational age starting at 37 weeks’ gestation. However, elective induction of labor was associated with increased odds of admission to the neonatal intensive care unit at all gestational ages <41 weeks (adjusted OR 1.15, 99% CI, 1.10–1.21, P < 0.001).

Buchanan et al.14 in a retrospective cohort study using data extracted from birth and hospital records in New South Wales, Australia, assessed maternal and neonatal morbidity in nulliparous women who were either naïve to exogenous oxytocin (N = 31,516) or exposed to oxytocin (N = 29,711) during labor. Composite maternal and neonatal morbidity outcome indicators were used. The use of oxytocin for both induction and augmentation of labor was associated with increased odds for neonatal (adjusted OR, 1.31 [95% CI, 1.18–1.46] and 1.26 [95% CI, 1.12–1.42], respectively) and maternal morbidity (adjusted OR, 1.54 [95% CI, 1.35–1.78] and 1.38 [95% CI, 1.18–1.63], respectively) after adjusting for intrapartum factors compared with women who were not exposed to oxytocin during labor. With new studies suggesting the possibility of an association between oxytocin therapy and neurodevelopmental disorders,15,16 there is an overwhelming need for further randomized trials to understand and resolve these contradictory outcomes.

Another interesting question is the mode of administration of oxytocin for induction and augmentation of labor. The continuous administration of supraphysiologic doses of oxytocin starkly contrasts with the pulsatile release of endogenous oxytocin during normal labor. Furthermore, it is unclear whether oxytocin supplementation is required after onset of the active stage of labor. New studies shed more light on these intriguing questions. In 2 related randomized controlled trials, Tribe et al.17 showed that cesarean delivery rates were comparable in women receiving pulsatile or continuous infusion of oxytocin for induction of labor (38.3% vs 37.7%, respectively; risk ratio [RR] 1.01, 95% CI, 0.81–1.26, P = 0.9) but not for augmentation of labor. The use of pulsatile infusion of oxytocin for augmentation was associated with an increased risk for admissions to the neonatal special care unit (6.5% vs 2.0%, RR = 3.39, 95% CI, 1.27–9.04; P = 0.009). In another randomized trial, Diven et al.18 asked whether discontinuation of oxytocin therapy during the active phase of labor causes an increase in cesarean delivery rates. In this study, discontinuation of oxytocin after active onset of labor had no effect on the overall cesarean delivery rates (21.3% after oxytocin discontinuation vs 22.8 % when continued, P = 0.78). However, a significant limitation of the study was that almost 25% of patients randomized to the “discontinuation” group eventually received oxytocin therapy. In addition, the authors used 25% cesarean delivery rate at their institution as baseline, so the study is likely to be underpowered.

Preterm Labor

Preterm labor and delivery is one of the leading causes of perinatal mortality and morbidity.19 Delaying delivery significantly decreases perinatal morbidity and is widely considered the standard approach to management in the absence of mitigating circumstances. Typically, delaying delivery is accomplished through the use of tocolytic therapy with drugs; the delay allows time for the administration of corticosteroids (decreases the risk of neonatal respiratory morbidity) that can be completed in a timely fashion. Among tocolytics, nifedipine and atosiban appear to have the lowest incidence of maternal and fetal side effects. To compare the tocolytic efficacy of these 2 drugs, Salim et al.20 randomized women in preterm labor with intact membranes between 24 and 33 weeks 6 days of gestation to receive either atosiban or nifedipine for 48 hours. A crossover, “rescue tocolysis,” was performed if labor progressed after 1 hour after initiating treatment. In this study, atosiban was associated with higher tocolytic efficiency (48/70 [68.6%, 95% CI, 57.0–78.6] vs 39/75 [52%, 95% CI, 40.7–63.1], P = 0.03) and lower incidence of side effects (7.1% [95% CI, 2.7–15.1] vs 22.7% [95% CI, 14.3–33.2], adjusted OR 4.18 [95% CI, 1.38–12.68], P = 0.01) at 48 hours compared with nifedipine. However, women who received nifedipine remained pregnant longer compared with those who received atosiban (median gestational age 37 weeks [95% CI, 36.2–37.4] vs 35 weeks [95% CI, 34.1–35.6], respectively), and this difference persisted even after adjustment for gestational age at enrollment.

Currently, the best approach to manage patients with preterm premature rupture of membranes (PPROM) is unclear. The choice between induction of labor and expectant management until spontaneous onset of labor is guided by the clinical scenario, risk for chorioamnionitis, institutional practice, and discretion of the obstetric provider. To study whether induction of labor was associated with a lower incidence of neonatal sepsis and better maternal outcomes compared with expectant management, van der Ham et al.21 randomized women with PPROM between 34 and 37 weeks of gestation to one of these 2 methods of management. In this study, induction of labor (N = 100) did not decrease the risk of neonatal sepsis compared with expectant management (N = 95) (3.0% vs 4.1%, respectively; 95% CI, 0.17–3.2). Furthermore, there were no significant differences in neonatal intensive care unit admission rates, hospital length of stay, and the incidence of respiratory distress syndrome between the 2 modalities of management. Since this study was part of a larger trial, it was performed without a separate power calculation. Therefore, the study was underpowered for this outcome, and the results need to be interpreted with caution.

In women presenting with ruptured membranes at 37 weeks or beyond, expectant management is associated with an increased incidence of chorioamnionitis, postpartum fever, and prolonged hospital stay compared with induction of labor.22 To investigate whether prophylactic use of antibiotics would decrease the incidence of chorioamnionitis in term rupture of membranes, Passos et al.23 performed a randomized controlled trial in 161 women presenting at term with ruptured membranes. Although the decision to induce labor or wait for spontaneous onset of labor was made at the discretion of the attending obstetrician, there were no differences in their relative rates between the antibiotic and control groups. The incidence of maternal infection was lower in the antibiotic group (2.6% vs 13.2%, RR 0.89, 95% CI, 0.81–0.98, P = 0.01), as was the incidence of chorioamnionitis (2.6% vs 10.8%, RR 0.92, 95% CI, 0.84–0.99, P = 0.03), than the control group. Although the rate of neonatal infection was also lower in the antibiotic group, it did not achieve statistical significance.

Apart from premature rupture of membranes, one of the significant risk factors for spontaneous preterm delivery is the presence of a shortened cervix (≤ 25 mm). Pregnant women at high risk for spontaneous preterm delivery due to a short cervix are managed either conservatively or with an intervention such as cerclage or pessary. Cerclage is an invasive procedure that requires anesthesia, is of limited clinical benefit, and is associated with a risk for infection or preterm labor. In women with short cervical lengths, cervical pessary appears to be a promising noninvasive alternative although its efficacy has not been studied in a randomized trial. Goya et al.24 addressed this knowledge gap in a prospective, open-label, and randomized trial. In this study, the authors assigned 385 pregnant women with short cervical length to receive expectant management or a cervical pessary. Precautions were taken to exclude, identify, and/or treat preexisting cervicovaginal infection in both groups. The primary outcome of the study, spontaneous birth before 34 weeks of gestation, was significantly lower in pessary group than the expectant management group (6% vs 27%, respectively, odds ratio 0.18, 95% CI, 0.08–0.37; P < 0·0001). The use of a pessary was also associated with a significantly decreased rate of spontaneous delivery at 28 and 37 weeks of gestation. Furthermore, there were numerous secondary benefits associated with the intervention, including a reduction in the incidence of low birth weight infants, corticosteroid use for fetal lung maturity, and the composite of neonatal adverse effects including neonatal death. The major side effect associated with pessary use was an increased rate of vaginal discharge, but this was not accompanied by infection or chorioamnionitis. The remarkable results of this elegant trial need to be independently verified by other research groups in diverse populations before widespread adoption of the technique. However, without doubt, this technique holds major promise and has a tremendous potential for lasting impact on public health.

ADVANCES IN OBSTETRIC ANESTHESIA

Maintaining hemodynamic control is one of the key goals after administration of neuraxial anesthesia in the parturient. This is typically ensured by a combination of avoidance of the supine position to minimize the incidence of aortocaval compression by the gravid uterus, IV fluid therapy, early detection of hypotension and treatment with vasopressors. New studies in the year 2012 further our knowledge of variables influencing hypotension after spinal anesthesia and associated vasopressor use. Orbach-Zinger et al.25 designed an elegant observational study to assess the effect of preoperative anxiety on hypotension after spinal anesthesia in term parturients. Anxiety scores were calculated preoperatively with standardized questionnaires, and salivary amylase was used as an indirect marker of anxiety. There was a significant correlation between high anxiety scores and maximal percentage change in systolic arterial pressure (P < 0.05), but there was no correlation with salivary amylase. With the use of suprasternal Doppler ultrasonography to noninvasively measure cardiac output at varying degrees of lateral tilt in nonlaboring term pregnant women, Lee et al.26 determined that cardiac output was approximately 5% higher when patients were tilted ≥15° compared with <15°. The optimal method of administration of phenylephrine (infusion versus bolus) for treatment of hypotension associated with spinal anesthesia remains unknown.27 In a blinded, randomized trial, Doherty et al.28 found no differences in cardiac output between an intermittent bolus (120 μg) and a fixed-rate infusion (120 μg/min) regimen of phenylephrine (maximum change in cardiac output 1.87 ±1.68 L/min vs 1.90 ±1.46 L/min, respectively; P = 0.94). In addition, secondary outcomes (incidence of hypotension, hypertension, nausea and vomiting, bradycardia, umbilical blood gases, and low Apgar scores) were also no different except that the infusion group received significantly more phenylephrine than the intermittent group.

Given the long turnaround times of routine laboratory tests during management of postpartum hemorrhage (PPH), there is considerable interest in point-of-care testing such as thromboelastography (TEG®).29,30 However, the use of TEG® is limited by paucity of data on the reference ranges for coagulation parameters at different gestational ages and the postpartum period. Two recent studies provide important TEG® data that improves our knowledge of coagulation indices in healthy pregnant women up to and after the time of delivery. The first study, a prospective longitudinal study by Karlsson et al.,31 tracked changes in TEG® variables between 10 weeks of gestation and 8 weeks postpartum. The authors confirmed the hypercoagulable state prevalent during pregnancy by using 5 measurements approximately 8 weeks apart during pregnancy and the postpartum period. Compared with 8 weeks postpartum, the time until initiation of clot (R-value) was reduced by 23% to 26% until 28 to 30 weeks of pregnancy; the angle of clotting (α) and maximum amplitude (MA) were greater by 12% to 20% and 6% to 8%, respectively. Routine coagulation tests such as activated partial thromboplastin time (aPTT), prothrombin time (PT), and D-dimer were within normal limits during pregnancy. With this knowledge, the authors argue for alternative normal-range values for TEG® parameters during pregnancy.

In another observational study involving 50 healthy pregnant women presenting at term for elective cesarean delivery, Macafee et al.32 confirm the hypercoagulable state of late gestation by using TEG® and establish a range of reference values for the immediate perioperative period. Furthermore, similar to the previous study, the authors also confirm that the standard laboratory coagulation tests are not different in term gestation compared with the nonpregnant state. Collectively, these studies provide baseline reference points for future studies involving the use of TEG® to monitor coagulation status during the peripartum period.

OBSTETRIC COMPLICATIONS

A practically relevant approach to reduce maternal mortality and morbidity is prevention of PPH.33 IV oxytocin is widely used for this purpose in developed countries, but in low-resource settings, the lack of needles and appropriate storage limit its use. In this setting, use of prostaglandin E2 (misoprostol) is particularly appealing. Evidence from a wealth of clinical studies comparing misoprostol with oxytocin for prevention of PPH is contradictory. The major limitation to the use of misoprostol was the high incidence of side effects when used at a dose of 800 μg. Bellad et al.34 hypothesized that by powdering the misoprostol to enhance sublingual absorption, a smaller dose (400 μg) could achieve similar efficacy with minimal side effects. In a double-blind trial, pregnant women at or beyond 28 weeks’ gestation admitted for labor and delivery were randomized to receive either sublingual powdered misoprostol 400 μg (N = 321) or IM oxytocin 10 IU (N = 331) after vaginal delivery. Sublingual powdered misoprostol decreased both mean blood loss (194 ± 124 mL vs 366 ± 136 mL, P < 0.001) and the overall incidence of PPH (3.1% vs 9.1%, P = 0.002) compared with women who received IM oxytocin. The incidence of nausea, vomiting, and fever was significantly higher with misoprostol, although its use decreased the need for additional uterotonic drugs.

Tita et al.35 compared the efficacy of IV oxytocin 0, 40, and 80 IU administered over 1 hour to prevent PPH after vaginal delivery. The incidence of the primary outcome, a composite of any treatment of uterine atony or hemorrhage, in the 80-unit group (6%, RR 0.93, 95% CI, 0.62–1.4) and the 40-unit group (6%, RR 0.94, 95% CI, 0.61–1.47) was not different compared with the 10-unit group (7%). However, the use of oxytocin 10 IU necessitated additional use of oxytocin after 1 hour compared with the 80 IU group. However, this was not accompanied by increased use of other uterotonic drugs. Considering the risks associated with oxytocin use, this study strongly supports using oxytocin infusion rates of 40 IU/h or less for preventing PPH after vaginal delivery.

Low-molecular-weight heparins (LMWH) are increasingly used in obstetric patients,36 yet their effects on bleeding complications during labor and delivery are unknown. In an observational study, Knol et al.37 assessed the risk of PPH in women by using a high dose of LMWH during pregnancy. The overall risk of PPH after vaginal delivery was higher in LMWH-users compared with nonusers (30% vs 18%, OR 1.9, 95% CI, 1.1–3.5). However, the risk of severe PPH (defined as >1000 mL blood loss) was no different between the groups, nor was there an association between the timing of the last dose of LMWH and bleeding complications.

ANESTHESIA-RELATED COMPLICATIONS

Intrapartum temperature increase or overt fever is present in up to 30% of patients during labor.38 Though the etiology of intrapartum fever is likely multifactorial, multiple studies have suggested an association between epidural analgesia and intrapartum temperature increase. Intrapartum fever is associated with increased rates of cesarean delivery, neonatal sepsis evaluations, and more worryingly, neonatal brain injury. Two recent studies attempted to define this association between epidural analgesia, maternal temperature increase, and neonatal outcomes. In a retrospective cohort study involving nulliparous women delivering at term, Greenwell et al.39 categorized data based on the presence or absence of intrapartum temperature increase (defined as temperature >99.5°F [37.5°C]). The authors performed 2 separate analyses: neonatal outcomes in women receiving (N = 1538) and not receiving (N = 363) epidural analgesia in the absence of intrapartum temperature increase and neonatal outcomes within the epidural group (N = 2784) according to the level of temperature change. In the absence of an increase in maternal temperature, epidural analgesia was not associated with an increased incidence of adverse neonatal outcomes. Within the epidural group, however, there was a linear relationship between mean maternal temperature and adverse neonatal outcomes such as hypotonia, assisted ventilation, low Apgar scores, and early-onset seizures. This study did not control for covariates that are known to alter the temperature trajectory, nor was there a comparison group of women who developed fever in the absence of epidural analgesia.

Frölich et al.40 studied this phenomenon prospectively in 88 women admitted for induction of labor to determine the potential causes for intrapartum fever. Oral temperature was measured hourly, and temperature slopes were constructed for individual patients. Overall, there was a linear trend of temperature increase over time (0.017°C/h, P = 0.0093). With the use of regression analysis, they analyzed the impact of covariates in women with a positive temperature slope and reported that only the duration of rupture of membranes until delivery (P = 0.007) and high body mass index (P = 0.006) were correlated with temperature rise during labor. Epidural analgesia was not associated with an increase in maternal temperature; however, this study excluded all patients with a presumed diagnosis of chorioamnionitis. The precise mechanisms responsible for epidural-associated fever, and the reason for selective susceptibility of some, but not all, patients who receive epidural analgesia, remain elusive.

A solid line of animal research has firmly established that anesthetic drugs, both inhalational and IV, when administered during a critical period of brain development called the growth spurt cause widespread apoptosis of developing neurons. Retrospective studies in humans suggest the possibility of an association between anesthesia and surgery early in life and subsequent cognitive impairment. Recently, the fetal brain was shown to be similarly vulnerable to the behavioral teratogenicity of isoflurane administered to a pregnant rat in the second trimester. This finding is important, especially in the setting of non-obstetric surgery during the second trimester, where the rapidly developing fetal brain is exposed to maternally administered general anesthetics. To date, no study had investigated the vulnerability of fetal brain to anesthetic drugs in primates. Furthermore, no study has directly compared the extent of neurodegeneration after anesthetic exposure between fetuses and neonates. With the use of a rhesus macaque model, Brambrink et al.41 investigated the effects of a 5-hour ketamine infusion on both fetal (gestational day 120, equivalent to human second trimester) and neonatal (postnatal day 6) neurodevelopment. With the use of activated caspase-3 immunohistochemistry to study apoptotic neurodegeneration, the authors demonstrated that exposure to ketamine in utero was associated with more apoptotic neuronal cell death (> 2-fold) than in the neonatal period. This is the first study to suggest that the fetus may, in fact, be more vulnerable to developmental neurotoxicity of anesthetic drugs than the infant. Although ketamine is not frequently used in obstetric anesthesia, and the doses used in the study cannot be readily extrapolated to humans, this study firmly establishes that fetuses are equally, if not more, susceptible to the effects of anesthetic drugs than neonates.41 It remains to be seen whether volatile anesthetics or other IV anesthestic drugs such as propofol have similar effects on the fetal brain.

PROGRESS IN NEONATAL RESUSCITATION

The efficacy of antenatal magnesium sulfate (MgSO4) therapy in reducing the incidence of cerebral palsy is established by multiple studies. However, the impact of such therapy on the need for neonatal resuscitation in the delivery room is unknown. The American Academy of Pediatrics considers MgSO4 as a respiratory depressant in the neonate. In a secondary analysis of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network trial of MgSO4 for the prevention of cerebral palsy, Johnson et al.42 sought to determine the relationship between umbilical cord blood magnesium concentration and the need for neonatal resuscitation. Women at risk for imminent delivery between 24 and 31 weeks of gestation were randomized to receive MgSO4 (6 g bolus over 20 minutes followed by 2 g/h for at least 12 hour) or placebo. Total magnesium was measured in umbilical cord blood collected immediately after delivery, and neonatal delivery data, including the need for resuscitation, were documented. After adjusting for intrapartum factors, the authors found no correlation between magnesium level and the degree of neonatal resuscitation. Limitations of a retrospective analysis notwithstanding, the authors argue that concern over fetal hypermagnesemia should not deter clinicians from administering magnesium sulfate to women at risk for preterm birth.

One of the important questions in neonatal resuscitation is the long-term impact and consequences of successful resuscitation of neonates delivered between 22 and 28 weeks’ gestation. A study by Moore et al.43 compared developmental outcomes by using standardized scales at age 3 years in a cohort born at <27 weeks’ gestation during the year 2006, with another cohort born between 22 and 25 weeks’ gestation from the year 1995. Between the 1995 and 2006 cohorts, there were no significant differences in the proportion of survivors with significant disability (18% vs 19%, respectively). However, among babies admitted to the neonatal care unit, there was an increase in overall survival rates [(39%, 95% CI, 35%–43%) vs (52%, 95% CI, 49%–55%)], as well as an increase in survival rates without disability [(23%, 95% CI, 20%–26%) vs (34%, 95% CI, 31%–37%)] in the 2006 cohort compared with the 1995 cohort, respectively. This study, however, suffers from a low rate of follow-up in the 2006 cohort with multiple imputations for missing values.

Although the benefits of whole-body hypothermia for hypoxic-ischemic encephalopathy, such as reduced rate of death and/or disability, is well established for infants >35 weeks’ gestation,44 it is not known whether such therapy confers additional cognitive advantages for older survivors. To answer this question, Shankaran et al.45 evaluated the effect of whole-body hypothermia to 33.5°C for 72 hours on the rate of death, cognitive impairment, and behavioral outcomes at 6 to 7 years of age. Death or an IQ score <70, the primary outcome measure, occurred in 47% of subjects who were actively cooled compared with 62% who received usual care (relative risk after adjustment for center, 0.78; 95% CI, 0.61 to 1.01, P = 0.06). Furthermore, there were no differences in the rates of executive and visuospatial dysfunction in survivors of both treatments. These results suggest that whole-body hypothermia is not associated with lasting cognitive benefits despite a lower death rate and that it does not increase the rates of severe disability in survivors.

DISCLOSURES

Name: Arvind Palanisamy, MBBS, MD, FRCA.

Contribution: This author wrote the manuscript.

Attestation: Arvind Palanisamy approved the final manuscript.

This manuscript was handled by: Cynthia A. Wong, MD.

ACKNOWLEDGMENTS

The author extends his thanks to the Society for Obstetric Anesthesia and Perinatology (SOAP) for offering the wonderful opportunity to review and present the Gerard W. Ostheimer lecture. The author would like to thank these individuals who helped during the period of literature review both for their advice and as well their excellent critiques: Lawrence Tsen, MD, Bhavani Shankar Kodali, MD, Thomas McElrath, MD, Jill Mhyre, MD, Alexander Butwick, MD, and Paloma Toledo, MD. Finally, the author expresses overwhelming gratitude to his family for their unflinching support and encouragement during the period of lecture preparation.

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