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.