anesthetic effects on the fetus and newborn
DESCRIPTION
TRANSCRIPT
Anesthetic Effects on the Fetus and Anesthetic Effects on the Fetus and NewbornNewborn
Effects on the Early Developing Fetus: Teratogenicity of AnestheticsEffects on the Early Developing Fetus: Teratogenicity of Anesthetics
• It is estimated that 1 to 2% of all pregnant women will undergo
non-obstetric surgery during gestation, resulting in about 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.
Nitrous oxide (N2O)
• Nitrous oxide (N2O) can inhibit methonine synthase in DNA
synthesis and methylation reactions.
• 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. However, folate supplementation, which
should bypass methionine synthase inhibition, does not block these
effects, whereas addition of halothane does .• 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 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. Similarly, a case—control study of 2,565 mothers in
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
.
Benzodiazepines
• Benzodiazepines were once feared to be associated with cleft lip and
palate, More recent data contradict these earlier investigations,
and benzodiazepines are likely safe, particularly in the small doses.
• a small increase in risk was confounded by chronic and
multiple medication use; psychiatric diagnoses, epilepsy, and other
medical conditions associated with birth defects.
• Inhalation anesthetics, induction agents, opioids, and neuromuscular
blocking drugs are all considered free of teratogenic effect. 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.
• It remains to be determined whether infertility or underlying
conditions causing infertility, or the in vitro fertilization treatment itself,
is responsiblefor 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.
• Recent epidemiologic evidence suggests that major birth defects are
more common in babies born from in vitro fertilization pregnancies compared with natural pregnancies
• it is reassuring to note the lack of any clear association between
common anesthetic agents and adjuncts and congenital malformations.
However, it is prudent to use any drug in pregnancy thoughtfully and
conservatively, for example, reserving benzodiazepines for truly
anxious patients
In concluding our discussion of teratogenicity
Effects on the Fetal Brain: Behavioral TeratogenicityEffects 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.
• 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.
• 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.
• 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), lead to significant increases in staining
for apoptosis throughout the brain 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.
• Similar results with other anesthetics, including ketamine and propofol
in both anesthetic and even sub-anesthetic doses
• Despite these tantalizing and frightening results, there remains
substantial controversy regarding the degree of risk of anesthetics
exposure to humans undergoing general anesthesia or fetuses exposed
in utero to maternal anesthesia.
• 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 andMaternal Fever
• Women receiving labor epidural analgesia experience a greater
incidence of clinical fever than those without them.
• 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. Some evidence
suggests that placental inflammation (chorioamnionitis)
is more common in febrile women with epidural analgesia.
• 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. 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,however,
Actual sepsis was vanishingly rare and did not differ between epidural
and no epidural groups.
• 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.
• 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. Substantial epidemiologic evidence
now confirms a four- to nine fold increase in the risk of otherwise
unexplained cerebral palsy in term and near-term infants exposed
to maternal fever.
• Other neonatal brain injuries have similarly been associated with
maternal fever, including neonatal encephalopathy.
• cognitive deficits were four times as common in children whose
mothers had fever at the time of delivery than 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. Importantly,
these lesions were not seen if the mothers were treated with the
antiinflammatory interleukin-10.
• increased interleukin-6 and interleukin-8 (proinflammatory cytokines)
was observed in the amniotic fluid in a cohort of pregnancies
resulting in babies with cerebral palsy compared with controls with
normal brain development.
•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). 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 injury. Many women with
epidurals and fever do not seem to be clinically infected. However, the
animal models of intrauterine infection are quite suggestive
Many questions remain.
• Moreover, high-dose methylprednisolone given to laboring
women with epidurals blocks the febrile response. 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.
•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.
Conclusions
•Anesthesia for expecting mothers has never been safe and is likely to
have few adverse effects on the developing fetus.
• In particular, epidural analgesia is most likely 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 thesubject of scientific debate.