........................................................................

CHAPTER 16

V O L U M E T H I R T Y - S E V E N

ANESTHETIC EFFECTS ON THE

FETUS AND NEWBORN
SCOTT SEGAL, M.D.
ASSOCIATE PROFESSOR OF ANAESTHESIA
HARVARD MEDICAL SCHOOL
VICE CHAIRMAN FOR EDUCATION
BRIGHAM AND WOMEN’S HOSPITAL
BOSTON, MASSACHUSETTS

EDITOR: MEG A. ROSENBLATT, M.D.

ASSOCIATE EDITORS: JOHN F. BUTTERWORTH IV, M.D.
JEFFREY B. GROSS, M.D.

The American Society of Anesthesiologists, Inc.

........................................................................
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 Anesthetic Effects on the Fetus and Newborn

Scott Segal, M.D.

Associate Professor of Anaesthesia
Harvard Medical School
Vice Chairman for Education
Brigham and Women’s Hospital
Boston, Massachusetts

Obstetric anesthesia is remarkably safe. Modern regional anesthetic techniques

are much safer than such anachronistic techniques as paracervical block or twilight
sleep (parenteral morphine and scopolamine). Indeed, it can be argued that the field
has achieved ‘‘six sigma’’ status, at least with respect to maternal mortality, which is
approximately 1.3 per million live births.1 Obstetric anesthesiologists have enjoyed
such success in reducing maternal and neonatal mortality and morbidity over the
preceding few decades that we may have developed a sense of confidence (that
unfortunately may border on arrogance) that obstetric anesthetic interventions cause
no adverse effects whatsoever on the baby. Nonetheless, there are several areas of
ongoing concern regarding the effects of anesthetics on the fetus and newborn. This
Refresher Course reviews our current understanding of these effects and highlights
the areas of uncertainty for future research.

Effects on the Early Developing Fetus: Teratogenicity of Anesthetics

It is estimated that 1 to 2% of all pregnant women will undergo nonobstetric
surgery during gestation,2,3 resulting in some 75,000 developing fetuses being
exposed to anesthetic drugs. Fortunately, no anesthetics or commonly used adjunctive
drugs are known to be teratogens. Studies of human teratogenicity are virtually
nonexistent as a result of ethical concerns, so evidence regarding anesthetics comes
either from studies in other species or from epidemiologic surveys. The former can be
confounded by species differences, uncontrolled hemodynamics, and respiratory
status and from artificially long exposures to anesthetics. The latter are complicated by
uncontrolled variables, most notably the disease process requiring surgery itself.
Nonetheless, the news is generally good, although two agents are worthy of special
attention.
Nitrous oxide (N2O), which can inhibit methonine synthase in DNA synthesis and
methylation reactions (Fig. 1), was implicated as a teratogen in animal studies in the
1970s and 1980s. Twenty-four hours of exposure to 75% N2O on Day 8 or 9 of
a 21-day gestation led to significant increases in skeletal abnormalities and fetal
resorption in rats.4 However, folate supplementation, which should bypass methio-
nine synthase inhibition, does not block these effects, whereas addition of halothane
does.5 These curious findings suggest that the mechanism may not be enzyme
inhibition but perhaps changes in uterine blood flow (N2O can reduce uterine blood
flow; halothane is a vasodilator that may counteract this effect). More importantly,
human epidemiologic studies do not show an association between N2O exposure

Copyright Ó2009 American Society of Anesthesiologists, Inc. 189

190 SEGAL

FIG. 1. Effect of N2O on one-carbon metabolism (methylation reactions and synthesis of

DNA nucleotides). N2O inhibits methionine synthase, impairing both pathways. N2O ¼ nitrous
oxide; THF ¼ tetrahydrofolate. Reprinted with permission from Naughton NN, Cohen SE:
Nonobstetric surgery during pregnancy, Obstetric Anesthesia: Principles and Practice, 3rd
edition. Edited by Chestnut DH, Philadelphia: Mosby; 2004, p 261.

in utero and birth defects. Mazze (whose laboratory performed many of the rat
studies) studied 5,405 operations in 720,000 pregnancies recorded in a Swedish
birth registry. Surgery during pregnancy was not associated with any difference in
stillbirth or congenital abnormalities, although it was associated with low birth
weight and death within 1 week of delivery. Approximately 54% of mothers received
general anesthesia, 98% of whom received N2O.6 Similarly, a case--control study of
2,565 mothers in Manitoba, Canada, undergoing surgery during pregnancy found no
difference in congenital abnormalities but a small increase in early pregnancy loss
that was not attributable to the anesthetic technique.7
Benzodiazepines were once feared to be associated with cleft left and palate based
on weak epidemiologic studies of chronic use/abuse and a subset of studies using
animals and cell-culture models. More recent data contradict these earlier flawed
investigations, and benzodiazepines are likely safe, particularly in the small doses
used in anesthesia.8 A large systematic review of cohort and case--control studies
demonstrated no increased risk of major malformations or cleft lip/palate
in cohort studies but found a small increase in risk in the case--control studies.
However, the latter were frequently confounded by chronic and multiple medication
use; psychiatric diagnoses, epilepsy, and other medical conditions associated with
birth defects; and small sample size.9
Inhalation anesthetics, induction agents, opioids, and neuromuscular blocking
drugs are all considered free of teratogenic effect.3 Of course, a newborn exposed
in utero to most anesthetics immediately before delivery may be transiently
depressed and require respiratory support for a brief period.
A recent wrinkle in this story is the growth of assisted reproductive technologies,
including in vitro fertilization and other associated procedures, now numbering over
150,000 cycles per year in the United States. Recent epidemiologic evidence10
suggests that major birth defects are more common in babies born from in vitro
fertilization pregnancies compared with a controlled cohort of natural pregnancies
(odds ratio, 1.3). It remains to be determined whether infertility or underlying
conditions causing infertility, or the in vitro fertilization treatment itself, is responsible
for the increases. Because the oocytes retrieved for fertilization are exposed to
anesthetics at the time of harvest, it will be an important research question to
determine whether this exposure contributes to subsequent malformations.
In concluding our discussion of teratogenicity, it is reassuring to note the lack of
any clear association between common anesthetic agents and adjuncts and
 ANESTHETIC EFFECTS ON THE FETUS AND NEWBORN 191

congenital malformations. However, it is prudent to use any drug in pregnancy

thoughtfully and conservatively, for example, reserving benzodiazepines for truly
anxious patients.

Effects on the Fetal Brain: Behavioral Teratogenicity

Unlike the other major organs and structures of the fetus, which form in the first
few weeks of gestation, the brain continues to develop throughout gestation and
after birth (Fig. 2).2 Enduring change in behavior without obvious structural
abnormalities has been termed behavioral teratogenicity. For approximately 10
years, it has been clear that compounds that interact with N-methyl D-aspartate and
g-aminobutyric acid receptor type A receptors can trigger programmed cell death,
or apoptosis, in the developing brain.11 Although apoptosis is a normal part of
embryogenesis, some animal experiments have also demonstrated functional or
behavioral abnormalities accompanying the increase in cell death such as impaired
maze learning. These changes may persist at least into young adult life.12 Because
many anesthetic agents are N-methyl D-aspartate antagonists or potentiators of
g-aminobutyric acid receptor transmission, it is conceivable that anesthetic exposure
during brain development could lead to neurodegeneration.
Jevtovic-Todorovic et al.12 exposed neonatal rats to 6 hours of midazolam, N2O,
and isoflurane anesthesia at 7 days of age (which corresponds to the peak of
synaptogenesis in the rat, a period likely to span many weeks from midgestation to

FIG 2. Critical periods in human development. Gestational age is illustrated on the

horizontal axis, and vulnerable developmental periods for various organs are shown as bands.
Darker bands indicate periods of high sensitivity, which may induce major anomalies,
and lighter bands indicate periods of lower sensitivity, which generally lead to functional
defects and more minor anomalies. Central nervous system development spans the longest
period, from the third week of gestation through term. Reprinted with permission from
http://www.cerebralpalsychildren.com/CPFetal.html. Accessed December 12, 2008.
192 SEGAL

the postnatal period in humans). The authors used doses that produce a surgical
plane of anesthesia in the rat, which were substantially larger than those commonly used
in humans. They observed significant increases in staining for apoptosis throughout the
brain (Fig. 3) and evidence of impaired synaptic function in the hippocampus, important
for memory formation. Studies in animals allowed to mature into young adulthood
showed impaired learning in various maze tests compared with air and vehicle-treated
controls. No intraoperative blood gas abnormalities or other gross alterations in body or
sensory or motor function were observed.
Subsequent investigations by these and other laboratories have demonstrated
similar results with other anesthetics, including ketamine and propofol, in both
anesthetic and even subanesthetic doses.11,13,14 In addition, similar results have
been obtained in other species, including those in which synaptogenesis occurs
in utero.14 There are even some preliminary data in nonhuman primates that
g-aminobutyric acid receptor-mimetic agents can induce apoptosis in the developing
brain.13
Despite these tantalizing and frightening results, there remains substantial
controversy regarding the degree of risk anesthetics pose to humans undergoing
general anesthesia or fetuses exposed in utero to maternal anesthesia. As with all
nonhuman animal studies, extrapolation is difficult. The arguments posed by
skeptics are included in the work of Jevtovic-Todorovic and Olney,13 Loephe,15and
McClaine et al.16:

 Large doses and prolonged exposures are commonly used

 No surgical stimulation accompanies the anesthetics
 Hemodynamics, respiratory status, and glucose have not been uniformly
observed or controlled
 Neuroplasticity implies regeneration of neurons lost to apoptosis is likely
 Some effects are only observed when exposure occurs on certain develop-
mental days and not on others
 Most behavioral consequences have been observed only in rats

FIG. 3. Effect of a three-drug anesthetic (isoflurane, nitrous oxide, and midazolam) on

neonatal rat brains. (A), Control animal. (B, C), Animals exposed to the anesthetic. A and B
were stained to show cell death. C is stained to show activation of caspase 3, a marker of early
apoptosis, or programmed cell death. Reprinted with permission from Jevtovic-Todorovic
et al.12
 ANESTHETIC EFFECTS ON THE FETUS AND NEWBORN 193

 Human experience with neonatal anesthesia spans decades and does not
support significant neurotoxicity
 Some anesthetics such as xenon are N-methyl D-aspartate antagonists but cause
no toxicity or are even protective

In response to some of these criticisms, the same group studied guinea pigs
exposed to a similar anesthetic (isoflurane--N2O--midazolam) for 4 hours in utero.
This species is larger, has a longer gestation, and features predominantly antenatal
brain development. Compared with animals exposed only to induction of anesthesia
and mechanical ventilation during fentanyl anesthesia, or to untreated animals, the
animals exposed to the triple drug cocktail demonstrated increased apoptosis and
neuronal cell loss throughout the brain. Respiratory, cardiovascular, and glycemic
homeostasis was demonstrated.14 The field is currently in hot pursuit of data
applicable to humans. It is hoped that a better understanding of the mechanism of
toxicity will also lead to strategies to block the harmful effects. Although laboratory
and eventual clinical investigations proceed, it is prudent to assume that general
anesthetics are potentially toxic to the developing fetal brain, and their use in
obstetric anesthesia should continue to be a rare event reserved for emergencies.

Effects in the Peripartum Period: Epidural Analgesia and

Maternal Fever
Women receiving labor epidural analgesia experience a greater incidence of
clinical fever. Two decades ago, observational studies demonstrated a gradual rise in
temperature in women receiving epidurals compared with those receiving no
analgesia or systemic opioids alone.17,18 Although originally ascribed to altered
thermoregulation, it is now evident that this represents an artifact from averaging
afebrile women’s temperatures and those developing clinical fever.19,20 Substantial
evidence suggests that true clinical fever develops more often in women with epidurals
than in those without them. The data come from retrospective observations (which
attempt to statistically control for confounding factors such as longer labors, prolonged
rupture of membranes, and a number of cervical examinations), sentinel event studies
(in which epidural analgesia suddenly becomes available to a population), and
randomized, controlled trials.21--23 Once dismissed as a physiologic curiosity or artifact
of selection bias, this phenomenon can no longer be ignored.
The mechanism of epidural-associated fever remains unclear. Earlier, investigators
noting the very slow gradual rise in temperature on average hypothesized that
thermoregulation might be altered in laboring women with epidurals. For example,
by inhibiting sweating and hyperventilation, the block might impair heat dissipation.
Other investigators suggested that opioids given to women without epidurals might
be suppressing temperature elevation rather than the epidurals causing it. There is
some evidence from nonlaboring volunteers to support both of these mechanisms.
However, the observation that ‘‘epidural fever’’ is actually clinical fever in some
women averaged with normal temperature in others leads to a search for an
explanation of more frequent overt fever in some women with epidural analgesia.
Some evidence suggests that placental inflammation (chorioamnionitis) is more
common in febrile women with epidural analgesia.24 It is less clear, however, how
this could explain a higher incidence of fever in women randomly selected to receive
194 SEGAL

epidural analgesia.21 Possibly, the presence of an epidural alters obstetrical

management in ways that might increase the chance of chorioamnionitis (e.g., more
cervical examinations, earlier rupture of membranes).
Epidural-associated fever may have significant effects on the fetus and newborn.
One of the earliest recognized effects was an indirect one, namely, an influence on
the practice of neonatologists. Lieberman et al.22 demonstrated that babies born to
mothers with epidurals underwent evaluation for sepsis four times more frequently
than babies born to mothers electing natural childbirth or systemic opioids. Actual
sepsis was vanishingly rare and did not differ between epidural and no epidural
groups. This phenomenon may be a function of neonatology practice style, however,
because other institutions have reported different results.24 Other adverse effects
related to intrapartum maternal fever include an increased need for bag--mask
ventilation and an increased incidence of otherwise unexplained neonatal seizures.25
A far more worrisome possibility is that maternal fever may cause neonatal brain
injury. Fifty years ago, an association between cerebral palsy and maternal fever was
first noted, but the observation was not investigated further until recently. Sub-
stantial epidemiologic evidence now confirms a four- to ninefold increase in the risk
of otherwise unexplained cerebral palsy in term and near-term infants exposed to
maternal fever or to (clinical or pathologically diagnosed) chorioamnionitis.26,27
Other neonatal brain injuries have similarly been associated with maternal fever,
including neonatal encephalopathy (which often has devastating lifelong neurologic
consequences for the infant).28 Even babies not manifesting these profound
impairments may nonetheless experience neurologic injury. Dammann et al.29
found cognitive deficits at 9 years of age, as measured by the Kaufman Assessment
Battery for Children, were four times as common in children whose mothers had
fever at the time of delivery as in children whose mothers were afebrile.
The link between maternal fever and neurologic injury in the newborn is most
likely inflammation. In pregnant animals, bacterial intrauterine infection causes
white matter lesions in the fetuses. Yoon et al.30 injected Escherichia coli or saline
into the cervix of pregnant rabbits. Approximately 36% of infected dams delivered
fetuses with white matter lesions (6% of all fetuses of infected mothers had such
lesions), compared with 0% in the saline control group. Similarly, Rodts-Palenik
et al.31 demonstrated white matter lesions and enlarged cerebral ventricles in pups of
infected pregnant rats more frequently than in saline-treated rats. Importantly, these
lesions were not seen if the mothers were treated with the antiinflammatory
interleukin-10. Although such experiments do not definitively demonstrate that
maternal intrapartum fever causes neonatal brain injury via fetal inflammation in
humans, Yoon et al.32 have documented increased interleukin-6 and interleukin-8
(proinflammatory cytokines) in the amniotic fluid in a cohort of pregnancies resulting
in babies with cerebral palsy compared with controls with normal brain development.
Many questions remain. First, it is far from clear how epidural analgesia is
associated with maternal fever. If thermoregulatory mechanisms (increased heat
production and/or impaired heat dissipation) are not primarily responsible, then
a link between epidural blockade and maternal inflammation must be found. It is
difficult to speculate how a light regional blockade could cause chorioamnionitis
(unless it alters obstetrical practice, as noted previously). If the block itself causes
inflammation, the mechanism would be unique and startling. Second, it is not clear yet
whether fever itself can cause injury, or whether inflammation causes both fever and
inflammation. Many women with epidurals and fever do not seem to be clinically
infected. However, the animal models of intrauterine infection are quite suggestive.
 ANESTHETIC EFFECTS ON THE FETUS AND NEWBORN 195

Moreover, high-dose methylprednisolone (but not acetaminophen) given to laboring

women with epidurals blocks the febrile response.33 Unfortunately, this treatment also
leads to a substantial increase in asymptomatic bacteremia in the exposed babies,
making it unacceptable as a clinical strategy. Third, it is not known whether epidural-
associated fever is specifically associated with brain injury (as opposed to chorioamnio-
nitis). Fourth, it is unknown whether epidural-associated fever can be safely blocked.
These questions will likely be the subject of intense investigation in the near future.

Effects on the Postpartum Period: Epidural Analgesia, Neurologic

and Adaptive Capacity Score, and Breastfeeding
In 1982, Amiel-Tison et al.34 proposed a new scoring system for newborn
neurologic status, the Neurologic and Adaptive Capacity Score (NACS), which they
hoped would be a simpler way to test for the effects of medications used in the
puerperium than the widely used (at that time) Scanlon Early Neonatal Neuro-
behavioral Scale and Brazelton Neonatal Behavioral Assessment Scale. The latter
required specialized training and noxious stimuli, was time-consuming, and was not
easy to interpret. The NACS took only a few minutes, required no specialized
training or equipment, and produced a simple score from 0 to 40 (35 and above was
arbitrarily defined as ‘‘normal’’). Two editorials accompanying the original publica-
tion questioned the score’s sensitivity and noted that it should be treated
as a hypothesis or work in progress; nonetheless, the score rapidly gained popularity
in obstetric anesthesia research for assessing the effects of various analgesia
interventions on the neonate.35 Interestingly, the vast majority of the more than 70
publications that followed over the next two decades found little or no difference in
the NACS between groups of babies exposed to different interventions.35
More recently, the NACS has come under closer scrutiny and sharper criticism.
A systematic review found numerous inconsistencies in the way the test has been
used, scored, and interpreted.35 Halpern et al.36 used pairs of trained observers to
compare interobserver reliability and also testing twice within the first 2.5 hours of
life to compare test--retest reliability. In a cohort of healthy term newborns, they
found the NACS performed dismally in both regards and concluded that it was
unreliable and should not be used in obstetric anesthesia research. The reasons for
the test’s failure are likely numerous, including:

 Subjectivity and imprecision in the scoring (exactly 0, 1, or 2 points for a given

item)
 Use of ‘‘best score’’ on each item, resulting in poor sensitivity
 Internal inconsistency (e.g., irritable infants lose points for ‘‘consolability’’ but
earn points for muscle tone)
 Limited sensitivity of the tested parameters to anesthetic interventions

The popularity of the NACS has waned considerably in recent years, perhaps
reflecting awareness of these limitations (Fig. 4).
Unfortunately, the relatively poor quality of the NACS literature seems positively
‘‘Nobel Prize-worthy’’ when compared with reports on breastfeeding after obstetric
anesthesia. On the basis of, in part, NACS studies, a review article in the
breastfeeding literature in 1997 concluded that epidural analgesia was likely a cause
196 SEGAL

FIG. 4. Studies using the Neurologic and Adaptive Capacity Score by year of publication.
Articles retrieved by a Medline search (via PubMed.com) within 3-year intervals since
publication of the original article proposing the test.

of reduced breastfeeding success.37 As noted, any differences in the NACS (even in

1997) were small, probably irreproducible, and likely confounded by such factors as
obstetrical interventions, mode of delivery, systemic medications, and demographics
of mothers selecting epidural analgesia.38 Similar confounders likely were strong
influences in anecdotal or observational studies suggesting that epidural analgesia
interfered with breastfeeding. Nonetheless, the idea was persistent in the lactation
and lay birthing communities. In 2006, an apparently damning report appeared in an
online lactation journal, suggesting that intrapartum epidural analgesia was strongly
negatively correlated with breastfeeding success.39 The study was plagued with fatal
methodologic flaws, the greatest of which were that the delivery mode was un-
controlled and that all women self-reporting their analgesic choice as ‘‘epidural’’ also
received parenteral meperidine and possibly N2O.40 The authors did acknowledge that
the effect of epidural analgesia might not be causal. The worldwide popular press
seized on this investigation as a definitive indictment of epidural analgesia.
Is there better information on the effect of labor analgesia on breastfeeding? The
best data would be results from randomized, controlled trials in which women were
randomized to epidural versus alternative analgesia. This has been accomplished
more than a dozen times in the last 15 years, but none of these investigations has
examined breastfeeding success.21 Large, carefully performed retrospective studies
do not show any adverse effect of epidural analgesia.41--43 Conversely, it appears
that systemic opioids, or larger doses of epidural fentanyl, can interfere with
early breastfeeding success.44,45 Nearly all investigators agree that emotional and
professional lactation support are the most important factors predicting long-term
breastfeeding success.

Conclusions
Anesthesia for expecting mothers has never been safer and is likely to have few
adverse effects on the developing fetus. In particular, epidural analgesia is most likely
 ANESTHETIC EFFECTS ON THE FETUS AND NEWBORN 197

the safest form of pain relief for laboring women and their babies. However, there is
reason for some concern and definitely strong justification for research. The effects
of anesthetics, both general and regional, on the developing fetal brain remain the
subject of scientific debate. Resolving this conundrum should be a high priority.

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