Society for Obstetric Anesthesia and Perinatology

Section Editor: Cynthia A. Wong

E Review Article

Whats New in Obstetric Anesthesia? The 2013

Gerard W. Ostheimer Lecture
Arvind Palanisamy, MBBS, MD, FRCA
The Whats New in Obstetric Anesthesia? keynote lecture was established by the Society
for Obstetric Anesthesia and Perinatology in memory of the eminent obstetric anesthesiologist, Dr. Gerard W. Ostheimer. From a wide selection of journals encompassing the fields of
obstetric anesthesia, obstetrics, and perinatology, the designated lecturer identifies articles of
significant impact and interest published in the preceding year. The Ostheimer lecture, delivered
this year at the annual meeting of the Society in April 2013 in San Juan, Puerto Rico, included
highly relevant papers that have the potential to change obstetric anesthesia practice or impact
public health. This review summarizes 5 categories of pertinent articles that were published
in 2012 and discussed in the 2013 Ostheimer lecture: maternal diseases, labor and delivery,
advances in obstetric anesthesia, obstetric complications, and anesthesia-related complications.(Anesth Analg 2014;118:3606)

he 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 Whats 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
From the Department of Anesthesiology, Perioperative and Pain Medicine,
Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts.
Accepted for publication December 2, 2013.
The author declares no conflicts of interest.
Funding: None.
Reprints will not be available from the author.
Address correspondence to Arvind Palanisamy, MBBS, MD, FRCA,
Department of Anesthesiology, Perioperative and Pain Medicine, Brigham
and Womens Hospital, Harvard Medical School, 75 Francis St., Boston, MA
02115. Address e-mail to apalanisamy@zeus.bwh.harvard.edu.
Copyright 2014 International Anesthesia Research Society
DOI: 10.1213/ANE.0000000000000101

360 www.anesthesia-analgesia.org

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 etal.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}, 15.5112.2] vs
10.8 [IQR, 4.128.6]; P < 0.0001). Among those presenting
at <34 weeks gestation (n = 167), the ratio was even more
predictive of adverse outcomes (226.6 [IQR, 50.4547.3] vs
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4.5 [IQR, 2.013.5], 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,
7.010.0). Arrhythmia was the most common adverse cardiovascular event, and heart failure (adjusted OR 7.0, 95%
CI, 4.610.7), cerebrovascular accidents (adjusted OR 41.6,
95% CI, 25.867.1), 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 etal.8 studied the progress of labor in 5204

February 2014 Volume 118 Number 2

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 etal.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 etal.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, 0.270.71, P < 0.001), and this trend was
noticed even at 1-week intervals of gestational age starting

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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, 1.101.21, 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 nave 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, 1.181.46] and 1.26 [95% CI, 1.121.42], respectively) and
maternal morbidity (adjusted OR, 1.54 [95% CI, 1.351.78]
and 1.38 [95% CI, 1.181.63], 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 etal.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,
0.811.26, 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, 1.279.04;
P = 0.009). In another randomized trial, Diven etal.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

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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 etal.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, 57.078.6]
vs 39/75 [52%, 95% CI, 40.763.1], P = 0.03) and lower
incidence of side effects (7.1% [95% CI, 2.715.1] vs 22.7%
[95% CI, 14.333.2], adjusted OR 4.18 [95% CI, 1.3812.68],
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, 36.237.4] vs 35 weeks [95% CI,
34.135.6], 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 etal.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, 0.173.2). 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 etal.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, 0.810.98, P = 0.01), as was the incidence of
chorioamnionitis (2.6% vs 10.8%, RR 0.92, 95% CI, 0.840.99,
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.

anesthesia & analgesia

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, 0.080.37;
P < 00001). 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 etal.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

February 2014 Volume 118 Number 2

<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 etal.28 found no differences in cardiac output between an intermittent bolus
(120 g) and a fixed-rate infusion (120 g/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 etal.,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 () 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 etal.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

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of side effects when used at a dose of 800 g. Bellad

et al.34 hypothesized that by powdering the misoprostol
to enhance sublingual absorption, a smaller dose (400 g)
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 g
(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, 0.621.4) and the
40-unit group (6%, RR 0.94, 95% CI, 0.611.47) 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, 1.13.5). 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 >99.5F [37.5C]). 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)

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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.
Frlich etal.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 (0.017C/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 etal.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

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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
etal.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 33.5C for
72 hours on the rate of death, cognitive impairment, and
behavioral outcomes at 6 to 7 years of age. Death or an IQ

February 2014 Volume 118 Number 2

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. E
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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