Anesthesia for fetal surgery

Introduction

Fetal interventions are procedures that are performed on a fetus either during gestation or immediately prior to delivery. They are intended to correct a pathologic condition that would otherwise be associated with fetal or neonatal demise or significant postnatal morbidity. Although fetal procedures are performed for the benefit of the fetus, they come with significant risks to both the fetus and mother. Therefore strict selection criteria must be implemented to identify fetuses that will derive benefit from the procedure while minimizing risk to both patients. An appropriate anesthetic plan will provide adequate operating conditions while minimizing maternal and fetal risk. Designing an anesthetic for these procedures requires an understanding of the goals of fetal therapy, the perioperative conditions required to complete the procedure, and maternal-fetal physiology as it changes during gestation. Current indications for fetal intervention include vascular complications of monochorionic pregnancies, lower urinary tract obstruction, cystic lung lesions, congenital diaphragmatic hernia, congenital heart disease, amniotic band syndrome, myelomeningocele, sacrococcygeal teratoma, and fetal airway obstruction.

History of fetal surgery

The first modern fetal intervention was performed by William Liley in 1963. Liley used a percutaneous, needle-based approach to administer fetal intraperitoneal blood transfusions to fetuses with Rh incompatibility suffering from erythroblastosis fetalis ( ). This disorder was ideally suited to fetal intervention because it could be reliably diagnosed with maternal serum tests, was lethal without intervention, and no postnatal treatment option was available. Although the procedure carried a high risk of mortality, efforts to refine the procedural technique persisted through the 1960s because of a lack of alternative therapies ( ; ). Further development of fetal therapies was limited by inadequate prenatal diagnostic tools, incomplete understanding of the natural history of fetal disorders and maternal-fetal physiology, and a lack of appropriate surgical instruments to perform fetal interventions.

Advances in prenatal diagnostic technology, including fetal ultrasound and direct endoscopic fetal visualization, occurred in the 1970s ( ; ; ). At the same time, animal models were developed to better understand the natural pathophysiology of fetal disorders and to develop surgical techniques to correct structural lesions ( ). The first meeting of what eventually became known as the International Fetal Medicine and Surgical Society (IFMSS) occurred in 1982. Leaders in the field established guidelines for appropriate patient selection and, importantly, set a precedent for multidisciplinary care, ethical oversight, and data sharing to improve patient outcomes ( ). Subsequently, reports of successful open fetal surgeries for a variety of disorders, including hydronephrosis, congenital diaphragmatic hernia (CDH), myelomeningocele (MMC), sacrococcygeal teratoma (SCT), and congenital pulmonary airway malformation (CPAM) were published in the 1980s ( ; ). Despite the success of these procedures, the risk of maternal morbidity and preterm delivery after open fetal surgery limited their acceptance ( ; ). The improvement of digital optics and the miniaturization of cameras and endoscopes in the 1990s led to an increase in minimally invasive fetoscopic procedures ( ; ), which have been associated with a decrease in maternal morbidity ( ).

As the field of fetal surgery has evolved, efforts have been made to set standards for patient care and to enable multiinstitutional data sharing to advance knowledge in the field. The concept of a fetal therapy center (FTC) in which patient care is coordinated by a multidisciplinary team was originally proposed in 1982 ( ) and has subsequently been endorsed by a number of medical societies invested in fetal care ( ; ). The patient care team includes maternal-fetal medicine specialists, pediatric surgeons, neonatologists, and anesthesiologists. Additional pediatric medical and surgical specialists are required, depending on the fetal condition being treated. Diagnostic services, labor and perioperative nursing care, social workers, genetic counselors, palliative care or perinatal hospice services, and bioethicists are also essential parts of the patient care team ( ; ; ; ). FTCs may be free-standing centers, but they are often housed in and use the resources of established pediatric or obstetric departments. FTCs should provide high-quality diagnostic services, multidisciplinary patient counseling, access to necessary surgical interventions, alternative therapies (including expectant management with postnatal care, palliative care, and pregnancy termination), and comprehensive obstetric and neonatal care ( ; ; ). In addition, FTCs are ethically obligated to manage complications of fetal procedures and ensure appropriate training and institutional oversight of their actions ( ). As the number of FTCs has expanded, there has been significant debate regarding how to balance patient access to care with adequate patient volume to ensure expertise in these relatively rare procedures ( ; ). Collaborative networks, such as NAFTNet (North American Fetal Therapy Network) and the Eurofetus consortium, have created disease-specific clinical trials and registries to promote data sharing across institutions with the goal of improving innovation and patient care.

Ethical considerations

Fetal procedures are performed for the benefit of the fetus but carry significant risks to both the fetus and mother. The decision to offer fetal therapy presents an ethical dilemma because the mother is an “innocent bystander” who is subjected to medical risk but does not receive any personal benefit from the procedure. A fetus is considered to be a patient when it is viable or when the mother has made the decision to continue the pregnancy of a previable fetus. This decision can be reversed by the mother prior to viability ( ). Once the fetus is considered to be a patient, physicians have an ethical obligation to provide care for that fetus (beneficence). However, this responsibility must be balanced against obligations to the pregnant woman’s autonomy and a responsibility to act in her best interest (nonmaleficence) ( ). This ethical dilemma is further heightened by the fact that formal clinical research is often difficult to perform in this patient population because of a lack of appropriate animal models and small patient numbers for some conditions ( ), leading to a paucity of long-term outcome data. NAFTNet has published guidelines for the development of innovative fetal therapies intended to ensure the protection of both patients while also allowing for the research and development of new medical procedures ( ). These guidelines include recommendations for informed consent, ethical and institutional oversight, and the establishment of research networks and patient registries.

Fetal procedures are ethically justified only when they are potentially lifesaving or can prevent or mitigate serious or irreversible disease in the fetus. In addition, the procedure must have a low risk of mortality and a low or manageable risk of morbidity for both the mother and fetus ( ). The importance of informed consent in this situation cannot be overstated. The mother’s decision to proceed with an intervention is often affected by maternal guilt, family and societal expectations, and a therapeutic misconception that an intervention with no proven efficacy will eventually work solely because it is offered ( ). The informed consent process should involve input from maternal-fetal medicine specialists, neonatologists, appropriate pediatric subspecialists, and anesthesiologists. Oversight by an ethics committee or institutional review board may also be required. The consent process should address not only the anticipated outcomes of the fetal procedure, but also the risks of maternal complications, fetal prematurity or demise, and the impact on current and future pregnancies, other family members, and the mother’s psychological well-being ( ). All options, including proceeding with fetal therapy, expectant management with postnatal therapy, delivery with palliative care or perinatal hospice services, and pregnancy termination, must be offered to the patient in a nondirective manner ( ; ). It should be clear that the mother is not ethically obligated to undergo a procedure for her fetus ( ), and her informed refusal must be respected if she chooses not to undergo fetal therapy ( ). When possible, adequate time should be given for the mother to consider all options before making a decision ( ).

Patient selection

Patient selection criteria for fetal procedures were first proposed by . They noted that the only malformations amenable to fetal intervention were “simple structural defects that interfere with organ development and whose alleviation might allow fetal development to proceed normally” ( ). They also stressed the importance of determining which fetuses were most likely to benefit from the procedure. Fetuses with mild disease were better managed postnatally whereas those with severe disease or multiple anomalies would be unlikely to survive even with prenatal intervention. Intervening in a multiple gestation pregnancy would put the healthy fetus at risk of preterm delivery or demise. Therefore only singleton pregnancies with a reversible, isolated fetal anomaly causing significant, but not lethal, dysfunction were appropriate candidates for intervention ( ).

As fetal surgery has progressed since the 1980s, advances have also been made in the fields of neonatology and pediatric surgery. Treatments such as betamethasone for lung maturation, surfactant for lung mechanics, and magnesium sulfate for neuroprotection have improved the survival of premature neonates, and pediatric surgical techniques have been developed to treat anomalies that were previously difficult to manage ( ). Given these developments, elective preterm delivery at a tertiary care center with postnatal surgical intervention has become preferable to fetal intervention in many cases ( ; ). However, some conditions, such as those leading to permanent renal or neurologic damage, have devastating outcomes despite advances in neonatal care. It is for those anomalies that prenatal therapy has the most potential benefit ( ).

Current criteria for performing fetal procedures are summarized in Table 29.e1 . Candidates for fetal procedures should have a surgically correctable structural lesion that is expected to cause fetal demise or irreversible organ dysfunction with serious morbidity if left untreated ( ). The goal of intervention is to correct the anatomic abnormality and improve fetal physiology to enhance the likelihood of fetal survival. Increasingly, fetal procedures are being performed not only to ensure survival but also to improve the long-term functional and neurodevelopmental outcome of the child ( ). To increase the likelihood of fetal benefit, the prenatal diagnosis must be accurately established, and the natural history of the disorder must be known ( ). The procedure must be associated with an acceptable risk-to-benefit ratio for both the mother and fetus. Fetuses with comorbid conditions such as complex chromosomal or anatomic anomalies are likely to have significant morbidity or mortality despite fetal intervention. Pregnant women with complex medical issues and those with obstetric risk factors predisposing them to preterm delivery are at increased risk of anesthetic, surgical, and obstetric complications after fetal procedures ( ). These are all relative contraindications to fetal surgical intervention, as they negatively impact the risk-to-benefit ratio for performing the procedure.

Types of fetal interventions

Fetal procedures are broadly classified as minimally invasive (closed) or open procedures. Minimally invasive procedures are performed through needles or trocars that are inserted through the uterine wall without the need for a hysterotomy. They are generally performed percutaneously, but a laparotomy may be performed to expose the uterus for cases with a complete anterior placenta or during complex fetoscopic repairs ( ). Open fetal procedures require a hysterotomy to obtain direct surgical access to the fetus. These procedures are performed through a laparotomy and are associated with a higher risk of complications compared with minimally invasive procedures ( ). Most fetal procedures are performed at midgestation with the goal of correcting a structural anomaly and enabling more normal fetal development for the remainder of gestation. Ex-utero intrapartum treatment (EXIT) procedures are a subset of open procedures that are performed near term to assist in the transition from fetal to neonatal life ( ).

Minimally invasive procedures are further divided into needle-based (ultrasound-guided) and fetoscopic interventions. In both cases, ultrasound imaging is used to assess the location of the placenta, large vessels, and fetus to achieve safe entry into the uterus ( ). Needle-based procedures are performed through 1 to 2 mm diameter needles ( ). Ultrasound imaging is used for visualization throughout the procedure. Common indications include percutaneous umbilical blood sampling (PUBS) and intrauterine transfusion, fluid aspiration, shunt placement, cardiac interventions, radiofrequency ablation, and selective fetal reduction ( ; ; ) ( Table 29.1 ). Fetoscopic procedures are performed through flexible plastic or nondisposable rigid metal cannulas that are inserted percutaneously into the uterus. These ports accommodate fetoscopes and surgical instruments ranging from 1 to 4 mm in diameter ( ). Most procedures are performed with a single port requiring only a small skin incision. However, more complex repairs may require multiple ports and a laparotomy ( ). The procedure is performed under fetoscopic visualization, but ultrasound may also be used as an adjunct. If the amniotic fluid is not clear enough for visualization, an amnioexchange with warmed crystalloid may be performed ( ). Common indications for fetoscopic procedures include laser photocoagulation for twin-twin transfusion syndrome, endoluminal tracheal occlusion, myelomeningocele repair, release of amniotic bands, and ablation of posterior urethral valves ( ; ; ).

Open fetal procedures require a maternal laparotomy and hysterotomy to obtain surgical access to the fetus. After the uterus is exposed via a low transverse laparotomy, ultrasound imaging is used to map the placental location and identify fetal position. The hysterotomy is performed as far from the placenta as possible and extended parallel to the placental edge. After the initial opening of the uterus, the incision is extended with a hemostatic stapling device to minimize bleeding from the exposed uterine edges and anchor the membranes to the uterine wall. The fetus is then positioned within the incision, and the fetal procedure is performed. When the procedure is completed, amniotic fluid volume is replaced with warm saline, and an antibiotic is instilled into the uterus. The hysterotomy is then closed in multiple layers ( ). Profound uterine relaxation is required prior to uterine incision and for the duration of uterine manipulation. Tocolysis is continued postoperatively to prevent preterm labor. The most common indication for open fetal surgery is myelomeningocele repair. However, open procedures may also be performed for resection of large fetal lung masses or debulking of sacrococcygeal teratomas ( ) ( Table 29.1 ).

Ex-utero intrapartum treatment (EXIT) procedures are fetal interventions that are performed immediately prior to delivery while the fetus is still on “placental bypass” (receiving oxygen via the placental circulation). The procedure was initially developed to secure the airway for fetuses that had previously undergone in-utero fetal tracheal clip occlusion. The most common indication for an EXIT procedure is to secure the airway for fetuses with airway obstruction due to oropharyngeal or neck masses, congenital high airway obstruction syndrome (CHAOS), or severe micrognathia. Other indications include resection of intrathoracic tumors or sacrococcygeal teratomas ( ) ( Table 29.2 ). Because the procedure is performed while the fetus is still receiving placental support from the mother, a potentially fatal airway or cardiovascular emergency is avoided, and the delivery proceeds in a more controlled manner. Similar to other open procedures, profound uterine relaxation is achieved prior to hysterotomy and maintained for the duration of the fetal procedure. Once the procedure is completed, the umbilical cord is clamped, and the fetus is delivered. After delivery, uterine tone must rapidly be increased to prevent maternal hemorrhage ( ).

Complications of fetal procedures

Fetal procedures are associated with risks to both the fetus and the mother. The fetus is exposed to painful stimuli, anesthetic medications, and potentially profound alterations in normal maternal-fetal physiology. The combined effect of these exposures may result in perioperative fetal cardiac dysfunction or demise ( ) or preterm delivery with associated comorbidities of prematurity ( ). In addition, concern has been raised about the long-term neurocognitive effect of anesthetic exposure during the third trimester of fetal development, which may affect anesthetic management ( ; ).

The mother incurs risk during the surgical procedure, for the remainder of the index pregnancy, and during future pregnancies. Maternal complications occur in 21% of open fetal procedures and 6% of fetoscopic procedures ( ). Needle-based procedures likely have a lower complication rate than fetoscopic procedures ( ). Maternal complications include pulmonary edema and other side effects of tocolytics, surgical site infection, sepsis, and hemorrhage requiring transfusion or delivery ( ). Obstetric complications after minimally invasive procedures include preterm premature rupture of membranes (PPROM), chorioamniotic membrane separation, chorioamnionitis, oligohydramnios, and preterm labor ( ; ). Management of these complications may require additional tocolytic medications or long-term antenatal inpatient management, which also contribute to morbidity. The complication rate after minimally invasive procedures increases with the number of ports, the diameter of the surgical instruments ( ), and the length and complexity of the procedure ( ). Open procedures are associated with many of the same risks, but also have an increased rate of uterine dehiscence. In a review of patients who underwent open fetal myelomeningocele repair, merely 65% of women had an intact, well-healed hysterotomy at the time of cesarean delivery ( ). This places women at risk for uterine scar rupture during delivery. Women who have an open fetal procedure must have a cesarean delivery for the index and all future pregnancies. An interval of at least 2 years is advised prior to subsequent pregnancies ( ; ). Minimally invasive procedures are not a contraindication to subsequent vaginal deliveries ( ). Subsequent fertility is not affected by fetal procedures ( ).

Physiologic considerations

Maternal physiology

Pregnancy causes maternal physiologic changes across all organ systems to keep pace with the growth and metabolic demands of the uterus, placenta, and fetus. These physiologic changes may significantly impact anesthetic management during fetal intervention. A complete review of normal maternal physiologic changes is beyond the scope of this chapter, but they are summarized in Table 29.3 .

TABLE 29.3

Maternal Physiologic Changes of Pregnancy

Carlin, A., & Alfirevic, Z. (2008). Physiological changes of pregnancy and monitoring. Best Practice & Research Clinical Obstetrics & Gynaecology, 22 (5), 801–823; Hill, C. C., & Pickinpaugh, J. (2008). Physiologic changes in pregnancy. Surgical Clinics of North America, 88 (2), 391–401.

Cardiovascular system	Cardiac output increases 30%–50% by the end of the second trimester, with further increases in labor and a postpartum peak (because of autotransfusion at delivery). Stroke volume increases 20%–50%. Heart rate increases 20%. Systemic vascular resistance and blood pressure nadir at 24 weeks and return to prepregnancy values near term. Aortocaval compression with supine hypotension begins at 16–20 weeks gestation.
Respiratory system	Minute ventilation increases by 40%. Increased tidal volume (40%). Oxygen consumption increases by 30%–60%. Functional residual capacity decreases 10%–25%. Parturients are prone to rapid hypoxemia. Decreased Pa co 2 (normal 32–34 mm Hg). Decreased bicarbonate. Normal acid-base status. Increased edema and vascularity of the upper airway mucosa.
Hematologic system	Blood volume increases 45%–50%. 15%–25% increase in red blood cell mass. Dilutional anemia nadir at 30–32 weeks gestation (hemoglobin 11–12 g/dL). Gestational thrombocytopenia. Procoagulable state. Increase in most procoagulant clotting factors. Decreased fibrinolysis.
Central nervous system	Decreased neuraxial dosing requirements. Increased insensitivity to local anesthetics. Decreased epidural volume. MAC decreases 30%.
Gastrointestinal system	Stomach is anatomically displaced. Gastric motility decreases. Lower esophageal tone decreases. Parturients are at risk for aspiration after 16 weeks gestational age.

MAC, minimum alveolar concentration.

During gestation, both blood volume and cardiac output increase by nearly one half, resulting in an impressive increase in the amount of cardiac work that a pregnant woman must maintain. Cardiac output begins to rise in early gestation, plateaus at the end of the second trimester, and increases further in the peripartum period. Systemic vascular resistance and blood pressure fall in early pregnancy, reaching a nadir at 24 weeks gestation. Blood pressure recovers to prepregnancy levels by term gestation ( ). At 16 to 20 weeks gestation, the uterus begins to rise out of the pelvis, causing aortocaval compression with decreased venous return and blood pressure in the supine position. One study determined that 15 degrees of left lateral tilt was sufficient to relieve compression and restore cardiac output ( ).

Progesterone-induced changes in the central respiratory center induce hyperventilation, thus increasing respiratory work. Minute ventilation increases 30% to 50% and is primarily due to an increased tidal volume (40%) with an unchanged respiratory rate. This leads to respiratory alkalosis, with a Paco ₂ of 32 to 34 mm Hg in normal pregnancies. Renal excretion of bicarbonate increases to compensate for this change ( ). By term gestation, the parturient will have 30% to 60% higher oxygen consumption than nonpregnant women to fuel increased respiratory and cardiac work and meet the metabolic needs of the uterus, placenta, and fetus. Elevation of the diaphragm and bibasilar atelectasis lead to decreased functional residual capacity (FRC) and oxygen reserves ( ; ). The combination of increased oxygen consumption and decreased reserves ( Fig. 29.1 ) predisposes pregnant women to more rapid development of hypoxemia compared with their nonpregnant peers during times of apnea ( ). Maternal desaturation is further exacerbated by the fact that fetal hemoglobin efficiently extracts oxygen from maternal hemoglobin in the uteroplacental bed.

Hematologic changes in pregnancy include gestational anemia and thrombocytopenia. Gestational anemia is due to a disproportionate increase in blood volume compared with red cell mass. In addition, alterations in clotting factors generate a procoagulable state in pregnancy. Nearly all procoagulant factors increase, whereas anticoagulant factors remain unchanged or decrease ( ; ). Although this adaptation helps minimize blood loss during delivery, it also makes the parturient five times more prone to thromboembolic complications ( ), including deep vein thrombosis, stroke, and fetal loss. Although major thromboembolism in pregnancy remains a relatively rare event, based on current guidelines many pregnant women may be receiving thromboprophylaxis medications when admitted to hospital ( ), which should be considered when planning neuraxial anesthetics.

Anesthetic requirements are impacted by physiologic and anatomic changes within the central nervous system (CNS). Progesterone levels increase steadily throughout pregnancy. Β-endorphin levels reach a nadir during the second trimester, then increase toward the end of pregnancy and remain high for 2 weeks after delivery. Both progesterone and β-endorphins exert CNS-depressant effects, increasing sensitivity to sedatives and decreasing anesthetic requirements for both intravenous and inhaled agents ( ). Minimum alveolar concentration (MAC) for volatile agents is decreased by almost 30% from prepregnancy levels ( ). In addition, progesterone exposure alters neuronal membrane ion channels, resulting in increased sensitivity to local anesthetics, and endorphins activate κ-opioid receptors in the spine. Neuraxial dosing requirements also decrease for mechanical reasons. The gravid uterus compresses the inferior vena cava and exerts pressure on the epidural venous plexus, decreasing volume in the epidural space and the cerebrospinal fluid. The combination of increased sensitivity to local anesthetics and decreased volume of the epidural space and cerebral spinous fluid decreases neuraxial dosing requirements at term gestation. Parturients are particularly susceptible to unintended high neuraxial block.

Additional changes in the hepatic, renal, and gastrointestinal systems alter the clearance of many anesthetic drugs and increase the risk of gastric aspiration ( ; ). Reduced colloid oncotic pressure due to decreased albumin levels may put the parturient at an increased risk of pulmonary edema after midgestation fetal interventions, especially with concomitant use of tocolytics ( ).

Uteroplacental anatomy and physiology

The growing fetus is dependent on the placenta for the exchange of nutrients, gases, and waste. The placenta is also essential for maternal immunomodulation and produces several hormones, including chorionic gonadotropin, progesterone, and placental lactogen that are essential for pregnancy. Placental development begins at the time of implantation when the outer trophoblast cells invade the maternal uterine epithelium. Fetal tissue is organized into arboreal structures called villi. The maternal uterine and ovarian arteries anastomose near the uterine fundus to produce spiral arteries that pump maternal blood into the placental intervillous space. These spiral arteries form a high-flow, low-resistance vascular bed that allows maternal blood to flow into the intervillous spaces, effectively bathing the villi so nutrient and gas exchange can occur ( ).

The uteroplacental unit grows throughout pregnancy. By the third trimester, the uterus receives up to 25% of the maternal cardiac output, with blood flows as high as 650 mL/min. Despite its essential function, the gravid uterus has no autoregulatory mechanisms to ensure adequate placental blood flow in times of low perfusion ( ). Decreased uterine arterial pressure, increased uterine venous pressure, and increased uterine vascular resistance can all impair uterine perfusion ( Fig. 29.2 ), resulting in decreased fetal oxygen delivery. Maternal oxygen supplementation or hyperventilation cannot compensate for interrupted placental perfusion, so maintenance of uterine blood flow is one of the primary anesthetic goals during fetal intervention.

In addition to respiration, the placenta provides a mechanism for nutrient and drug transfer from mother to fetus. Most drug transfer occurs by diffusion down a concentration gradient. Important factors include molecular size, lipid solubility, protein binding, pKa, pH of fetal blood, and uteroplacental blood flow. In general, the placenta is impermeable to molecules with a high molecular weight, ionic charge, or poor lipid solubility ( ). All volatile anesthetics, intravenous induction agents, opioids, benzodiazepines, and atropine readily cross the placenta. Succinylcholine administered in large or repeated doses crosses the placenta. Anesthetic drugs that will not cross the placenta include nondepolarizing muscle relaxants, glycopyrrolate, anticholinesterases, and heparin ( ). No anesthetic agents are currently known to have teratogenic effects, except possibly nitrous oxide, which interferes with methionine synthetase and should probably be avoided in the first trimester. There is a concern based on animal studies and population-based data that anesthetic drugs may result in central nervous system apoptosis; however, neurotoxicity trials in human children have not demonstrated harm ( ; ; ).