Anesthetic Toxicity to the Fetus: Teratogen or Not?

The human embryo is most vulnerable to the teratogenic effects of a drug between the third and eighth weeks of gestation. However, no anesthetic agents have been shown to be teratogenic at any gestational age when used in the normal standard concentrations for surgery. Opioids, local anesthetics, intravenous induction agents, and inhalational anesthetic agents have been consistently associated with safety in pregnancy. Although benzodiazepines were initially associated with an increased risk of cleft palate in the first trimester, subsequent studies have been unable to demonstrate similar results. Nitrous oxide has been labeled a teratogen in rodents because of an increased incidence of fetal resorption and skeletal and visceral anomalies. It has also been shown to increase adrenergic tone in animal studies, leading to vasoconstriction of the uterine vessels and a possible decrease in uterine blood flow when administered alone or a decrease in central vascular tone leading to possible intracranial hemorrhage in preterm fetuses. In addition, nitrous oxide inhibits methionine synthetase and could theoretically affect DNA synthesis in the developing fetus. Nevertheless, despite the aforementioned theoretical concerns, no adverse effects have been demonstrated with the use of nitrous oxide in humans. Large studies in this population show no increase in congenital abnormalities but a greater risk of abortion, growth restriction, and low birth weight attributable to primary disease and the surgical procedure rather than anesthetic exposure. Teratogenicity has never been conclusively demonstrated in humans. Most clinicians, however, avoid the repetitive use of benzodiazepines or nitrous oxide in the first trimester because of its questionable safety profile in animal studies. The inability to adequately test new drugs for safety in this population before release makes extra caution a necessity.

With recent studies showing widespread apoptotic neurodegeneration in animals with fetal or newborn exposure to general anesthetics and the concern of subsequent learning or memory impairments, the use of general anesthesia in pregnancy and newborns has become a hot topic of debate. Palanisamy and colleagues demonstrated abnormal neurobehavioral performance in adult male rats exposed to clinically relevant concentrations of isoflurane in utero. According to the authors, these behavioral changes were attributed to direct effects because maternal physiology and variables were maintained during these experiments. The equivalent of the second trimester (14 days for fetal rats) was identified as the period of highest risk for nonobstetric surgery or fetal interventions because of the appearance of gamma-aminobutyric acid (GABA) receptor subunits. Most anesthetics act by potentiation of GABA _A receptors, and it is this mechanism of action that is thought to induce widespread neuronal apoptosis when given during periods of synaptogenesis (brain growth spurt). Animal studies are, however, plagued by several limitations. Rats have a relatively brief brain developmental process, and it is difficult to extrapolate changes induced by a single anesthetic in a rodent to the long, more gradual development of the human brain. Even though a previous study in guinea pigs, an animal with a more gradual brain developmental process, did show an induction of neuroapoptosis with a 4-hour exposure to isoflurane during synaptogenesis, more consistent data are needed. Most are behavioral studies with no insight into causative mechanisms. Parallel measures of histopathology and behavior would be more informative. These studies are also often underpowered in that male rats are sometimes used for experiments instead of female rats.

The substantial and prolonged use of volatile anesthetics (VA) in the fetus is probably more concerning in ex utero intrapartum treatment (EXIT) procedures in which the parturient is often exposed to high concentrations of VA, mostly exceeding 2 minimum alveolar concentration (MAC) to maintain uterine relaxation. EXIT procedures are very rare but are designed to allow partial delivery of the fetus with a potentially difficult airway (e.g., large fetal neck mass) with subsequent management of the neonatal airway while oxygenation is maintained via the placenta. The high concentration of VA provides surgical anesthesia for the mother, tocolytic effects on the gravid uterus, and intraoperative anesthesia for the fetus. More extensive prospective studies assessing the effects of high concentrations of VA on cognition and learning in children who required EXIT procedures in utero need to be performed for more definite conclusions on the effect of neuroapoptosis on cognition.

The appearance of recent epidemiologic studies showing the lack of an increased incidence of learning disabilities in children exposed to general and regional anesthesia for cesarean and vaginal deliveries compared with those unexposed to any anesthetics has reduced the recent concern about early anesthesia exposure to a certain degree. Nevertheless, the use of epidemiologic studies alone to study the association between general anesthesia and learning disabilities remains suboptimal because of the possibility that fetuses of mothers who needed general anesthesia may already be at an increased risk of learning difficulties compared with the general population. In addition, surgery can induce an inflammatory process that can subsequently induce changes in the central nervous system. The need for randomized clinical trials cannot be overemphasized.

Fetal Monitoring during Surgery

Although fetal homeostasis is maintained by avoiding maternal hypotension and hypoxemia, maternal hemodynamic stability does not always guarantee adequate placental perfusion and fetal oxygenation during surgery. Is fetal heart rate (FHR) monitoring needed during surgery to effectively monitor these variables? Unfortunately, the false-positive rate for performing a cesarean section with the use of electronic FHR monitoring is 99.8%, and the use of FHR monitoring has still not been shown to be superior to intermittent fetal auscultation. Such lack of a definite measure of fetal well-being during surgery has led to the recommendation of specific guidelines by both the ASA and ACOG for fetal monitoring during surgery. If a fetus is considered previable (less than 23 to 24 weeks of gestation), it is generally sufficient to obtain FHR by Doppler before and after the procedure. At a minimum, if the fetus is viable, simultaneous electronic FHR and contraction monitoring should be obtained before and after the procedure to assess for fetal well-being and the absence of contractions. Intraoperative electronic fetal monitoring (EFM) may be appropriate if all the following apply: the fetus is viable, intraoperative EFM is possible, an obstetric provider is available and willing to intervene for fetal indications, and the parturient has consented to emergency cesarean delivery if necessary. Intraoperative EFM may also be considered for previable fetuses to facilitate positioning and oxygenation interventions. Nevertheless, the decision to use fetal monitoring should be individualized and necessitates a multidisciplinary team approach. Skilled personnel should be available to accurately interpret the FHR and uterine contraction tracing. The goals of FHR monitoring during surgery are to maintain adequate uterine perfusion and identify fetal compromise or preterm labor (PTL). Although the actual use of FHR monitoring to achieve such goals is flawed, early detection of a change in a trend could lead to possible therapeutic interventions such as position changes, increasing maternal oxygenation, improving placental blood flow by increasing maternal blood pressure, changing the site of surgical retraction, and tocolysis by increasing maternal depth of anesthesia to decrease uterine tone, all of which could be considered before delivery of the fetus. Transvaginal probes have been used for abdominal surgeries in which access via a transabdominal approach remains a challenge. With continuous monitoring under general anesthesia and the use of sedatives, loss of beat-to-beat variability is expected. Fetal bradycardia and decelerations are not normal and may indicate the need for intervention, as already indicated. Nonetheless, monitoring has still not been shown to improve fetal outcomes ( Figure 67-1 ).

Algorithm with Recommendations for Fetal Monitoring during Nonobstetric Surgery in a Parturient following ASA and ACOG Guidelines. At all stages, it is important to note that decision should be made by a multidisciplinary team approach (anesthesia, obstetric care providers, surgery, pediatrics, and nursing) for optimal safety of the woman and the fetus.

*Three prerequisites for proceeding to surgery with any fetal heart rate monitoring (FHRM): (1) institution must have neonatal and pediatric services, (2) availability of obstetrician with C-section privileges, and (3) availability of qualified staff to interpret FHR and contraction patterns. GA, gestational age.

^† Preliminary interventions: position change (left uterine displacement), increasing maternal oxygenation, improving placental blood flow, changing site of surgical retraction, and tocolysis (increasing depth of anesthesia to decrease uterine tone).

^‡ Five criteria for performing intraoperative/continuous electronic fetal heart rate monitoring (EFHRM) and contraction monitoring (CM): (1) viable fetus, (2) physically possible to perform EFHRM and CM, (3) availability of health care provider with obstetric surgery privileges who is willing to intervene during surgery for fetal indications, (4) informed consent from parturient for emergency cesarean delivery if possible, and (5) ability to safely interrupt surgical procedure for emergency delivery.

Preterm Labor after Nonobstetric Surgery

The prevention of preterm labor or delivery (PTL/D) remains one of the greatest concerns of anesthesiologists in the postoperative parturient. Most epidemiologic studies of nonobstetric surgery during pregnancy demonstrate an increased incidence of PTL/D and abortion with unclear conclusions about the etiology. Manipulations of the uterus, the particular surgery (specifically intra-abdominal procedures), and underlying maternal disease have all been considered possible culprits. Anesthetic management has not been shown to be a causative factor. In addition, no evidence has currently associated any anesthetic agents with an increased risk of PTL/D. According to Mazze and Kallen, second trimester procedures and those not involving uterine manipulation carry the lowest risk of PTL/D. Prophylactic tocolytic therapy is controversial and has not been shown to be effective in preventing PTL/D but is, instead, associated with an increased risk of maternal adverse effects.

Although prior studies have shown both the risk of teratogenicity and spontaneous labor or PTL to be less in the second trimester, Palanisamy and colleagues describe the second trimester as the period of highest risk for nonobstetric surgery or fetal interventions in light of apoptotic neurodegeneration and subsequent learning impairments. More studies are needed to reconcile these issues and identify the least vulnerable period for performing emergent nonobstetric surgeries during pregnancy by weighing the risk–benefit ratio.

Use of Laparoscopy during Pregnancy

Most of the abdominal surgeries prevalent in pregnancy are amenable to the use of the laparoscopic surgical approach. The use of laparoscopy has therefore remained a relevant topic in this patient population. In a cohort study of 2783 pregnancies with an operative incidence of 1.3%, the majority of the cases were conducted for gallbladder disease with a 3 to 1 ratio of cholecystectomy to appendectomy (the second most frequent procedure). The use of laparoscopy has been demonstrated to be safe in pregnant patients in any trimester and is no longer considered a contraindication in pregnancy. A Swedish study of more than 2 million deliveries favored laparoscopic surgery to an open procedure. Other studies have shown laparoscopy to be no more dangerous than laparotomy to either the mother or the fetus. Although several studies have outlined clear maternal benefits of minimal invasive surgery, fetal outcomes have been shown to be similar irrespective of the surgical approach. Advantages of laparoscopy include less fetal exposure to anesthetics, smaller incisions, decreased blood loss, decreased postoperative analgesia requirements, shorter hospital stays, and an earlier return to activities of daily living. Disadvantages, however, include a decrease in venous return and cardiac output with a subsequent decrease in uteroplacental perfusion due to increased intra-abdominal pressure from pneumoperitoneum and aortocaval compression; alterations in maternal and fetal blood gases due to absorption of CO ₂ or hypoventilation; and direct uterine or fetal injury from trocar insertion. Theoretically, the risk of hypercarbia, hypoxemia, and hypotension is increased. However, animal studies in near-term sheep demonstrate that CO ₂ pneumoperitoneum does not cause hypoxia or significant fetal hemodynamic changes but can induce fetal respiratory acidosis. On the other hand, work in preterm animals indicates that laparoscopically induced hypercapnia and acidosis are accompanied by prolonged fetal hypoxia and cardiovascular depression, even after insufflation is discontinued. The exact clinical significance as it relates to the developing human brain is still unknown. A major limiting factor to the laparoscopic approach as described by Buser was the skill of the surgeon and the awareness of one’s own capabilities and limitations. Guidelines to prevent adverse effects from laparoscopy include an open technique to enter the abdomen to avoid uterine or fetal trauma; low insufflation pressures of less than 12 to 15 mm Hg; cautious and limited use of the Trendelenberg and reverse Trendenlenberg positions; and gradual position changes while maintaining left uterine displacement to minimize uterine compression of the great vessels. Vasopressors (e.g., phenylephrine and ephedrine) may also be needed to treat hypotension as well as pneumatic stockings to promote venous return. FHR and uterine activity is monitored through the transvaginal route when necessary. The uterus is protected with lead shielding during radiation.