Fetal endoscopic surgery: indications and anaesthetic management

Best Practice & Research Clinical Anaesthesiology Vol. 18, No. 2, pp. 231–258, 2004 doi:10.1016/j.bpa.2004.01.001 available online at http://www.sciencedirect.com

3 Fetal endoscopic surgery: indications and anaesthetic management Laura B. Myers*

MD

Co-Director, Division of Fetal Anesthesia

Linda A. Bulich

MD

Co-Director, Division of Fetal Anesthesia Department of Anaesthesia, Perioperative and Pain Medicine, Harvard Medical School, Bader 3, Children’s Hospital Boston, 300 Longwood Ave, Boston, MA 02115, USA

Philip Hess

MD

Academic Director Obstetric Anesthesia, Harvard Medical School, Beth Israel Deaconess Medical Center, 330 Brookline Ave. East / St-308, Boston, MA, USA

Nicola M. Miller

MBchB, RPP

Wolfson and Weston Research Centre for Family Health, Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, Hammersmith Campus, Centre for Fetal Care, Queen Charlotte’s and Chelsea Hospital, Du Cane Road, London W12 0NN, UK

Fetal intervention for certain life-threatening conditions has progressed from being primarily experimental in nature to the standard of care in certain circumstances. While surgical techniques have advanced over the past few years, the anaesthetic goals for these interventions have remained the same; namely, minimizing maternal and fetal risk as well as maximizing the chances of a successful fetal intervention and optimize the conditions necessary to carry the fetus to term gestation. Fetal endoscopic techniques allow access to the fetus without the need for a hysterotomy incision, thus improving the chances of controlled post-operative tocolysis and term gestation after fetal intervention. This procedure, however, is not without associated risks to both fetus and mother. This chapter will address the fetal diseases that may benefit from fetoscopic intervention, the rationale behind why maternal and fetal anaesthesia is required, the various anaesthetics used for these cases and specific considerations of both maternal and fetal physiology that aid in the determination of the best anaesthetic technique for individual cases. Methods of intra-operative fetal monitoring and fetal resuscitation will also be discussed.

* Corresponding author. Tel.: þ1-617-355-7759; Fax: þ1-617-730-0894. E-mail address: [email protected] (L.B. Myers). 1521-6896/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved.

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Key words: fetoscopic surgery; twin – twin transfusion syndrome; twin-reversed arterial perfusion sequence; bladder outlet obstruction; congenital aortic stenosis; hypoplastic left heart syndrome; fetal anaesthesia; fetal resuscitation.

The advent of fetal intervention introduced the concept of surgically correcting a known congenital fetal defect in order to avoid certain fetal demise. With the associated improvements in prenatal imaging and refined surgical techniques, fetal interventions have grown to include not only those fetal diagnoses associated with intrauterine demise but also many diseases associated with significant postnatal morbidity. It is the goal of fetal intervention to thus improve the chances of normal fetal development and minimize postnatal morbidity. Advances in surgical techniques have changed some procedures from certain open fetal interventions, associated with significant maternal risk, to endoscopic techniques, thus improving the maternal riskto-benefit ratio as well as diminishing the incidence of post-operative uterine contractions associated with open procedures. Although not all fetal interventions performed to date can be successfully performed using endoscopic techniques, this chapter will discuss those fetal conditions that are amendable to endoscopic correction as well as the maternal, fetal and uteroplacental factors influencing the choice of an anaesthetic technique for a given intervention. The current techniques available for administering fetal anaesthesia as well as methods for fetal resuscitation will also be discussed.

FETAL DISEASES ELIGIBLE FOR ENDOSCOPIC SURGERY Twin –twin transfusion syndrome Twin – twin transfusion syndrome (TTTS) is a complication of multiple gestation in which abnormal vascular communications between the developing fetuses result in an imbalance of blood flow between the twins. In cases of severe TTTS, polycythemia, polyhydramnios and hydrops fetalis may develop in the favored twin with oligohydramnios and severe anaemia in the compromised twin.1 – 3 Fetal mortality has been reported to be as high as 60 –80% if TTTS developed before 26 weeks’ gestation and was left untreated.2,4,5 In a meta-analysis of the literature, Skupski et al6 noted a mortality rate of 80% in both twins in untreated pregnancies with severe second trimester TTTS. Until recently, TTTS was most commonly managed with serial reduction amniocentesis, although other treatment options such as amniotic septostomy, selective feticide and medical therapy (indomethacin, digoxin) have also been used, but with limited success.4,7 – 10 Serial amniocentesis is minimally invasive and is associated with a 50– 60% fetal survival rate for both twins past the neonatal period, but with a 25% incidence of abnormalities on neonatal cranial scan.11 Selective foetoscopic laser photocoagulation (SFLP) of abnormal placental vascular anastomoses is a more invasive procedure that has a similar survival rate when compared with serial amnio-reductions. Outcome studies also suggest better neurological outcomes than historical controls treated with serial amniocentesis.7,12 – 19 Prospective randomized controlled trials are currently underway to determine whether fetoscopic laser ablation is superior to reduction amniocentesis in the treatment of midtrimester TTTS.

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Figure 1. Externalisation of the uterus in a patient with an anterior placenta during selective fetoscopic laser photocoagulation in twin–twin transfusion syndrome.

There is very little data on the reported anaesthetic techniques used for fetoscopic laser ablation. The procedure has been performed under local, general, epidural, as well as combined general and epidural anaesthesia.18,20,21 Myers & Watcha22 described their experience with epidural and general anaesthesia for SFLP. In this retrospective study of 29 patients undergoing SLFP, patients with anterior placentas were more likely to receive a general anaesthetic secondary to the need to externalize the uterus to gain trocar access. (see Figure 1) Furthermore, patients receiving an epidural anaesthetic received significantly more intravenous (I.V.) crystalloid but less I.V. fentanyl than those receiving a general or combined technique. No SLFP procedures were performed under local anaesthesia at ar institution. Although these data strongly argue in favor of general anaesthetic techniques, larger patient series are needed to validate these conclusions. Factors that may influence the choice of anaesthetic technique include: (i) the planned surgical approach and probability of converting to open fetal surgery, (ii) maternal medical history and physical examination, including careful maternal airway examination, (iii) maternal preference and (iv) history of prior uterine activity. The surgical approach for SLFP is determined by (i) the location of the placenta (anterior versus posterior), (ii) the position of the fetuses and (iii) the potential window(s) for trocar insertion.22 Twin reversed arterial perfusion sequence Twin reversed arterial perfusion (TRAP) sequence denotes a common pathophysiology of several different conditions, all of which describe a twin pregnancy in which one twin is normal and the second twin exhibits multisystem malformations including encephaly or acardia.23 The twin with the haemodynamic advantage is denoted as the ‘pump’ twin, perfusing deoxygenated blood in a retrograde direction to the other twin. This eventually places the normal, or ‘pump’ twin, at a haemodynamic disadvantage, Since this normal twin provides cardiac output to both itself and it’s non-viable sibling. This anomaly places the ‘pump’ twin at risk of cardiac overload and congestive heart failure, often with associated hepatosplenomegaly.24 Perinatal complications with TRAP sequence range in severity, with reported death rates for the ‘pump’ twin ranging from 39– 59% in untreated pregnancies.24 Treatment

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Figure 2. Schematic representation of umbilical cord ligation in twin reserved arterial perfusion (TRAP) sequence.

options include observation, medical therapy with digoxin and indomethacin, selective delivery, umbilical cord blockade with a platinum coil or silk suture in alcohol and fetoscopic cord ligation (see Figure 2).25 Quintero et al26 and McCurdy et al27 first reported success with fetoscopic cord ligation in twin gestations exhibiting cardiac failure in the viable twin. Although all endoscopic procedures have the primary aim of interrupting umbilical cord blood flow to the non-viable twin, most practitioners currently recommend this invasive technique only after failed medical therapy or after signs of cardiac failure in the viable twin.28,29 Like TTTS, there is very little data available with regard to anaesthetic management for these cases. Galinkin et al30 reported a case of TRAP sequence with a successful treatment under maternal general anaesthesia. Regardless of the technique employed, maternal and fetal physiological considerations must be addressed to provide the safest environment for the mother and the viable fetus. Hydronephrosis: bladder outlet obstruction Bladder outlet obstruction is most commonly due to posterior urethral valves in males and urethral atresia in females.31 In severe cases, infants present at birth with respiratory insufficiency secondary to pulmonary hypoplasia and renal failure from renal dysplasia. In prenatal ultrasonographic examination, this severe form of bladder outlet obstruction is heralded by profound oligohydramnios, distended bladder, bilateral hydroureternephrosis and dysplastic changes in the kidneys. In some cases, pulmonary hypoplasia can lead to significant postnatal morbidity and is the leading cause of death during the neonatal period for patients afflicted with this disorder.32 Until recently, treatment options were limited to observation and serial prenatal ultrasonograms followed by neonatal surgical intervention. Some groups have attempted

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to restore amniotic fluid volume in an attempt to promote pulmonary development and avoid neonatal demise secondary to pulmonary hypoplasia.33,34 In animal studies, bladder decompression in utero has prevented the progression of renal dysplastic changes and has improved pulmonary development.35 Mandell et al36 have reported that the severity of renal dysplasia depends on both the timing and severity of obstruction before delivery, which suggests that relief of obstruction between 20 and 30 weeks’ gestation may significantly reduce the degree of renal dysplasia. These data have encouraged the development of vesicoamniotic shunts, first reported with poor outcomes.37 Although these procedures were associated with a very low maternal morbidity, many fetal risks, including iatrogenic gastroschisis, infection, catheter obstruction or dislodgement, inadequate decompression and fetal injury made this technique inappropriate for earlygestation urinary tract decompression as first line therapy. Harrison and Adzick38 reported a series of eight cases of obstructive hydronephrosis treated by open vesicostomy. Of the four survivors, three had no evidence of renal insufficiency during follow-up of up to 8 years. Fetoscopic techniques to create vesicocutaneous fistula for decompression and laser ablation of posterior urethral valves have been reported34,38 – 40 with promising initial outcomes. However, these procedures are technically difficult and the exact role of fetoscopic intervention for correction of bladder outlet obstruction has yet to be determined.

PERCUTANEOUS FETAL PROCEDURES Needle aspiration and placement of shunts A variety of fetal disorders may benefit from in utero needle aspiration or shunt placement. These disorders include posterior urethral valves, cystic adenomatoid malformation of the lung, aqueductal stenosis, fetal hydrothorax, ovarian cyst and fetal ascites. Various shunts have been attempted to provide long-term decompression with variable results.41 Although a detailed discussion of these disorders is beyond the scope of this chapter, the practitioner must remember that these interventions will elicit a significant fetal stress response and appropriate measures should be taken to minimize this response. This concept will be discussed in greater detail later in this chapter. Aortic valve dilation for hypoplastic left heart syndrome Perhaps one of the most exciting hypotheses in the last few years addresses fetuses with congenital heart defects. Certain congenital heart defects cause aberrations in blood flow that are usually secondary to valvular stenosis or regurgitation. Regardless of the aetiology, the end result is often an abnormally developed ventricle, which may or may not be able to perform its designated function after birth.42 – 44 Several case reports have characterized the progression of valvular stenosis to ventricular hypoplasia from reduced flow through the chamber during gestation.45 – 49 It has been hypothesized that relief of valvular stenosis in utero could reverse the progression towards ventricular hypoplasia. To date, the defect most amendable to correction is severe aortic stenosis (AS) with evolving hypoplastic left heart syndrome (HLHS).45 – 52 Without prenatal intervention, severe AS can lead to severe left ventricular dysfunction, diminished flow through the left heart, arrest of left ventricular growth and consequently HLHS. Staged palliative surgery (the Norwood/Stage 1 procedure) is the only postnatal therapeutic option for patients with HLHS. The primary aim of prenatal intervention for those fetuses with congenital

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aortic stenosis is to reverse the pathological process in an attempt to preserve cardiac structure and function, thereby preventing postnatal disease. This procedure may be performed percutaneously using continuous ultrasound guidance. Optimal fetal positioning or maternal habitus (i.e. obesity) may require exposure of the uterus through an abdominal incision in order to obtain ideal access to the fetal thorax. These procedures have been performed under both regional and general anaesthesia, although general anaesthesia is often preferred in order to obtain optimal uterine relaxation and an anaesthetized fetus. Preliminary results are promising with initial outcomes demonstrating the ability to prevent development of single ventricle physiology with second trimester intervention.53

ANAESTHETIC CONSIDERATIONS General goals Anaesthesia for fetoscopic intervention poses several unique challenges for the anaesthesiologist. The physician must care for two or possibly three patients at once, all with distinctive and, at times, conflicting requirements. The anaesthesiologist is required to provide both maternal and fetal anaesthesia and analgesia while ensuring both maternal and fetal haemodynamic stability. Fetal haemodynamic stability is often a result of maintaining uterine perfusion and uterine blood flow, often affected by common anaesthetic agents and thus appropriate adjustments are mandatory. Many patients with fetal disorders resulting in polyhydramnios may already be receiving tocolytic agents and may require additional uterine relaxation once surgery has commenced. In addition, these tocolytic agents may interact with certain anaesthetic agents, necessitating alterations in anaesthetic dosing. Since substantial evidence exists demonstrating the ability of the second trimester fetus to mount a neuroendrocrine response to noxious stimuli (see below), fetal pain management must be considered in every case. Furthermore, since both maternal and fetal stress and pain have been associated with initiation of premature uterine contractions (see below), adequate pain control for both mother and fetus during and after the procedure must be assured. Furthermore, a plan must be prepared to resuscitate the fetus if problems occur during intervention. Regardless of the anaesthetic administered, the surgical technique remains standardized. Ultrasonographic confirmation of placental location and positioning of the fetus(es) is performed prior to surgical incision. Trocar(s) are percutaneously inserted under continual ultrasound visualization through the uterus into the amniotic cavity. Once intrauterine access is obtained, a fetoscope is inserted through the trocar to aid in visualization and identification of the intended malformation. Degree of surgical difficulty is multifactorial and depends on surgical expertise, placental location, visibility and absence of fetal movement. Details of these various surgical techniques and potential complications have been described previously.54 – 60 Physiological alterations with pregnancy With any fetal intervention, one cannot over-emphasize the importance of maternal safety. Physiological alterations associated with pregnancy begin during the first trimester and have significant bearing on any anaesthetic delivered. A complete understanding of these physiological changes is necessary prior to administering any anaesthetic for fetal intervention. Certain anatomical, hormonal and functional adaptations are considered

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normal during pregnancy. Virtually every organ system undergoes significant changes as early as the first trimester in order to accommodate the developing fetus. While these changes are usually well-tolerated by most parturients, practitioners of fetal surgery should be aware of the potential impact of these changes, since even subtle aberrations can have a permanent effect on both maternal and fetal outcomes. A complete systematic review of organ system adaptations during pregnancy has been extensively documented elsewhere.61 reviews the major adaptations that will directly influence the choice of the delivered anaesthetic technique and will specifically address these alterations in relation to fetal intervention. Respiratory Pregnancy results in progressive increases in both oxygen consumption and minute ventilation. Since the growing uterus causes a decrease in residual volume and functional residual capacity, the mother is faced with a reduced oxygen reserve.62 An increase in oxygen consumption combined with a reduced oxygen reserve places the pregnant patient at risk for hypoxaemia. Pregnant patients are further prone to hypoxaemia when lung volumes fall below closing capacity, leading to atelectasis. While the closing capacity does not change during pregnancy, the functional residual capacity falls below the closing capacity in the supine position, causing areas of perfusion but no ventilation (intrapulmonary shunting) which also predisposes the mother to hypoxia.63 This decrease in functional residual capacity becomes more pronounced with obesity and with certain body positions (e.g. supine, trendelenburg, lithotomy).64 Progesterone and estrogen sensitize the respiratory centre to carbon dioxide to create an increase in respiratory rate and an even greater increase in tidal volume (40%).65 The net result of these physiological alterations is a 70% increase in alveolar ventilation. Despite an increased CO2 production, the relative increase in minute ventilation causes a decline in PaCO2 to approximately 30 mmHg by 12 weeks’ gestation. Furthermore, the effect of lower PaCO2 values on the hemoglobin dissociation curve is offset by an elevated 2,3-diphosphoglycerate level, which increases the P50 for hemoglobin and facilitates oxygen delivery to the fetus.64 These respiratory alterations make the pregnant patient and the fetal-placental unit a constant challenge during any fetal interventions. Apnea or hypoventilation will rapidly lead to hypoxia and hypercarbia. Even after adequate pre-oxygenation, the PaO2 in an apneic, anaesthetized parturient falls by about 80 mmHg more per minute when compared with the non-pregnant state.66 Acidosis rapidly develops from hypoxia and hypercarbia during difficult airway situations because of a decreased buffering capacity during pregnancy. Hyperventilation during periods of controlled ventilation can also have deleterious effects on the fetus. Since no gradient exists between end-tidal CO2 level (PETCO2) and (PaCO2) in pregnant patients, a PETCO2 below 30 mmHg may lead to uterine vessel vasoconstriction with decreased perfusion to the fetal-placental unit. Any discussion about respiratory alterations during pregnancy would be incomplete without emphasizing the known anatomical changes of the maternal airway. With increasing gestational age, maternal airway mucosa becomes edematous, abdominal contents shift the diaphragm upward with increasing uterine size and the laryngeal structures shift to a more anterior position. Pilkington et al67 photographed the oral cavity of pregnant women at 12 and 38 weeks’ gestation and demonstrated a 34% increase in the inability to view the oral structures. These changes increase the frequency of a difficult intubation. Indeed, failed intubation resulting from the inability to visualize the vocal cords occurs in 1/300 general anaesthetics in

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Table 1. Anaesthetic considerations in respiratory adaptations during pregnancy. A. Decreased functional residual capacity (FRC) a. Faster denitrogenation b. Rapid hypoxemia during apnoea c. Faster induction and emergence with halogenated anaesthetic agents B. Increased oxygen consumption a. Rapid hypoxamia during apnoea C. Capillary engorgement of respiratory mucosa a. Predisposes upper airway to trauma, bleeding and obstruction b. Laryngeal edema increases frequency of difficult intubation D. Decreased PaCO2 and minimal PETCO2-PaCO2 gradient a. Capnograph reading similar to PaCO2 b. Hyperventilation may lead to reduction in uterine blood flow and fetal hypoxemia

the obstetric population. The decreased pulmonary oxygen stores and increased oxygen consumption previously mentioned make pregnant patients even more susceptible than non-pregnant women to the consequences of difficult airway situations (see Table 1). Cardiovascular effects Cardiovascular function is appropriately increased during pregnancy in order to meet the increased metabolic demands and oxygen requirements of the mother. Studies involving parturients and non-pregnant controls demonstrate a significant increase in cardiac output by as much as 35– 40% by the end of the first trimester.68 Cardiac output continues to increase throughout the second trimester until it reaches a level 50% higher than in non-pregnant women, with the majority of the increase being a function of the increased heart rate during the first and second trimesters.68 The impact of aortocaval compression by the gravid uterus is significant and can cause up to a 30– 50% decrease in cardiac output. Lesser decreases are observed in the sitting or semirecumbent positions.69 Occlusion of both the inferior vena cava and the aorta occurs, to some extent, in all supine parturients. Although the epidural and azygos veins provide alternative routes for venous return, they do not provide adequate compensation. Most pregnant women do not become frankly hypotensive when supine (concealed caval occlusion) because the blood pressure is maintained by increases in systemic vascular resistance, heart rate and stroke volume. About 10% of women exhibit ‘revealed caval occlusion’ or ‘supine hypotensive syndrome’ with hypotension and diaphoresis occurring when they are placed supine for more than a few minutes. In these parturients, a reflex bradycardia combined with decreased vascular tone and compromised venous return causes a profound decrease in blood pressure. For these reasons, the supine position should always be avoided in the anaesthetized pregnant patient as the fetus may experience a decrease in blood flow and hence oxygenation. Although it is traditional to use left uterine displacement (LUD), right uterine displacement (RUD) can also be used and should be used in cases where there is fetal compromise despite extreme LUD. A gradual decrease in the colloid oncotic pressure (COP) occurs until 36 weeks’ gestation, with a further reduction occurring after delivery.70,71 The resulting fall in the COP to pulmonary capillary wedge (capillary hydrostatic pressure) gradient may place the parturient at higher risk of pulmonary aedema.72 Although most cases of acute lung injury in pregnancy are attributed to hydrostatic pulmonary aedema, there are several

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reports of increased permeability pulmonary aedema in parturients after fetal surgery who had received tocolytic agents.73,74 Those patients who received nitroglycerine infusions for tocolysis had a more severe lung injury with a longer time to resolution than patients treated with other tocolytic agents.73 It has been hypothesized that highdose intravenous nitroglycerin could act as a nitric oxide donor forming peroxynitrite, implicated in immune complex-mediated lung injury which damages type II alveolar cells and inhibits surfactant function.73,74 Because of these concerns, nitroglycerin is rarely used as a tocolytic agent for fetal surgery (see Table 2). Gastrointestinal system Anatomical changes associated with a gravid uterus predispose the pregnant patient to potentially life threatening acid aspiration pneumonia. The gravid uterus slowly causes the stomach to be displaced upward towards the left hemi-diaphragm. There is an axis rotation of 458 to the right from the normal vertical position and the intra-abdominal portion of the oesophagus is displaced into the thorax. These anatomical shifts cause a reduction in lower oesophageal sphincter tone throughout much of pregnancy, predisposing the mother to gastro-esophageal reflux and aspiration.75 Progesterone and opioids may also relax lower esophageal sphincter tone and reduce esophageal peristaltic time.76,77 The incidence of reflux increases with gestational age, with 72% of women being symptomatic by the third trimester of pregnancy. Nervous system During pregnancy, women are more sensitive to the action of many anaesthetic agents in part due to pregnancy-mediated analgesia, and require less local and volatile anaesthetic than their non-pregnant counterparts. Pregnancy-mediated analgesia is a multifactorial process involving spinal opioid antinociceptive pathways, ovarian sex steroids (estrogen and progesterone) and uterine afferent neurotransmission. Pregnancy-mediated analgesia elevates the woman’s threshold for pain during the latter stages of pregnancy prior to labor.78,79 Local anaesthetic dose requirements for spinal and epidural anaesthesia are decreased during pregnancy. The minimum alveolar concentration (MAC) of inhalational agents is decreased by approximately 30%80 during pregnancy although high concentrations of inhalational agents are still required for complete uterine relaxation. The use of high concentrations of inhaled agents can result in maternal tachycardia and hypotension that may require the use of vasopressors (ephedrine and phenylephrine) to maintain maternal blood pressure and fetal perfusion. Table 2. Anaesthetic considerations in cardiovascular adaptations during pregnancy. A. Aortocaval compression a. Supine position leads to decline in cardiac output b. May lead to supine hypotension syndrome c. Prevented by left or right uterine displacement B. Decreased colloid oncotic pressure a. Higher risk of pulmonary oedema, especially when tocolytic agents used C. Increased maternal blood volume a. May tolerate larger blood loss than non-pregnant controls b. Fetal acidosis develops with significant blood loss

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Pharmacology during pregnancy Pregnant women may be more sensitive to the commonly used induction agents. For example, the dose of thiopental required for induction is 17 –18% less when compared with non-pregnant women.81 However, the concentration of propofol required in early pregnancy (6 –12 weeks) at which patients would not respond to a verbal command was not different from non-pregnant controls, indicating that early pregnancy does not decrease the concentration of propofol required for loss of consciousness.82 Of note, propofol has been safely used for induction of anaesthesia for cesarean delivery in doses of 2 mg/kg with minimal effects on the neonate.83 Ketamine has also been used as an induction agent for parturients undergoing elective cesarean section, with an intravenous dose of 1.5 mg/kg associated with no neonatal depression at delivery.84 Pregnant women are also more sensitive to the anaesthetic action of the volatile agents than non-pregnant patients. The MAC is decreased by 27% for halothane and by 30% for enflurane at term.85 The MAC of isoflurane was reduced by 28% in pregnant women at 8– 12 weeks’ gestation compared with that of non-pregnant controls.86 Volatile halogenated agents are known to produce dose-dependent uterine relaxation. These agents have a greater depressant effect in the pregnant myometrium.87,88 Although 0.5 MAC of enflurane, isoflurane and halothane produce a 20% decrease in uterine contractility, larger concentrations (1.5 MAC) produce a 60% decrease in uterine contractility.89 Sevoflurane produces a dose-dependent depression of uterine muscle contractility with an ED50 of 0.94 MAC, while uterine activity is virtually abolished at concentrations of greater than 3.5 MAC.90 Pregnancy is associated with a larger dermatomal spread after administration of local anaesthetics using epidural or spinal anaesthesia.91,92 The underlying mechanism of an increased susceptibility to local anaesthetics during pregnancy is unknown, but mechanical, hormonal, biochemical and neural changes have been suggested. Bupivacaine-induced conduction blockade of A, B and C fibres of the isolated vagus nerve is faster in pregnant rabbits than in non-pregnant animals, and this difference may be related to a more rapid diffusion and shorter onset of block or to an enhanced sensitivity of the nerve membrane itself.93,94 As a result, the administration of standard doses of local anaesthetics during neuraxial anaesthesia may result in a higher than expected level of sensory and motor block in pregnant patients when compared to non-pregnant controls.

Rationale for fetal anaesthesia and analgesia Until as recently as 10 years ago, the ability of the fetus to respond to noxious stimuli was poorly understood and administration of pain medication to neonates undergoing surgical intervention was not considered routine. A substantial amount of both animal and human research demonstrated that the fetus is able to mount a substantial neuroendocrine response to noxious stimuli as early as the second trimester of pregnancy. Fetal neuroanatomical development further substantiates this research. Evidence also exists that suggests that these responses to noxious stimuli may, in fact, alter the response to subsequent noxious stimuli long after the initial insult. This is the rationale behind providing fetal anaesthesia and analgesia whenever surgical intervention is thought to potentially provide a noxious insult to the fetus. The following section addresses these conclusions in greater detail.

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Embryological development in the 2nd and 3rd trimesters Neurological development Central nervous system development begins in the 3rd week of gestation and synapses within the spinal cord develop as early as 8 weeks’ gestation. In general, motor synapses develop before the equivalent sensory ones and thus the first spinal reflexes are present from 8 weeks’ gestation. Maximal neuronal development occurs between 8 and 18 weeks’ gestation. Myelination begins in the spinal cord between 11 and 14 weeks’ gestation and is present in the brainstem and thalamus by 30 weeks. The first essential requirement for nociception is the presence of sensory receptors, which first develop in the perioral area at approximately 7 weeks’ gestation and are diffusely located throughout the body by 14 weeks.95 Thus, if the presence of sensory receptors were the limiting factor in pain perception, the fetus would feel pain from the 2nd trimester onwards. This, however, is unlikely. Sensory receptors are first involved in the sensation of stimuli that result in local reflex movements involving the spinal cord but not the higher cortical areas, which classical physiology has defined as necessary for pain perception. As these reflex responses become more complex, they in turn involve the brainstem, through which other responses such as increases in heart rate and blood pressure are mediated. However, such reflexes to noxious stimuli do not involve the cortex and, thus, not conscious perception. The thalamus is the structure responsible for relaying afferent signals from the spinal cord to the cerebral cortex. Thus, if cortical functioning is necessary for pain perception, arguably it cannot be until the thalamo-cortical connections are formed and functional that the fetus becomes aware of pain. The thalamus is first identified in a primitive form at day 22 post-conception. The final thalamocortical connections are thought to be in place by around 26 weeks, although estimates differ.96 Certainly, evoked potential studies illustrate cortical sensory impulses from 29 weeks’ gestation.97 Descending inhibition is the process whereby the sensation of pain transmitted in the ascending spinal neurons is dampened via inhibitory descending serotonin neurons of the dorsal horn of the spinal cord.98 These develop only late in gestation and are still immature at birth. This makes it possible that the third trimester fetus, far from being incapable of the sensation of pain, actually perceives pain as being more pronounced than in the adult. Pain/stress response of fetus in the 2nd and 3rd trimesters Given current knowledge it is impossible to know exactly when the fetus first becomes aware of pain. Instead one must rely on fetal responses that could serve as indicators of aversion to a stimulus. Different studies have used various indicators of a fetal response—all are physiological responses seen in times of stress in older children and adults. Observed responses fall into four main categories—motor responses, endocrine responses, circulatory redistribution and cortical activity. Motor response A motor response can first be seen as a whole body movement away from a stimulus and observed on ultrasound from as early as 7.5 weeks’ gestational age. The perioral area is the first part of the body to respond to touch at approximately 8 weeks, but by 14 weeks most of the body is responsive to touch. The fetus thus reacts to a stimulus in a comparable way to the neonate, although it is not known if the fetus is actually aware of the stimulus. However, absence of a motor

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response to a stimulus does not imply that the fetus is not sensing the stimulus since the limiting factor could be the motor component of the response. Fetal endocrine response to stress Human fetal endocrine responses to stress have been demonstrated from as early as 18 weeks’ gestation. Giannakoulopoulos et al99 first demonstrated increases in fetal plasma concentrations of cortisol and b-endorphin in response to prolonged needling of the intrahepatic vein (IHV) for intrauterine transfusion. The magnitude of these stress responses directly correlated with the duration of the procedure. Fetuses having the same procedure of transfusion, but via the non-innervated placental cord insertion, failed to show these hormonal responses. Gitau et al100 observed a rise in b-endorphin during intrahepatic transfusion from 18 weeks’ gestation, which was seen throughout pregnancy independent both of gestation and the maternal response. The fetal cortisol response, again independent of the mother’s, was observed from 20 weeks’ gestation.100 Fetal intravenous administration of the opioid receptor agonist, fentanyl, ablated the b-endorphin response and partially ablated the cortisol response to the stress of IHV needling, suggesting an analgesic effect.101 A similar, but faster, response is seen in fetal production of noradrenalin to IHV needling. This too is observed in fetuses as early as 18 weeks, is independent to the maternal response and increases to some extent with gestational age.102 Thus, from these studies one can conclude that the human fetal hypothalamic – pituitary –adrenal axis is functionally mature enough to produce a b-endorphin response by 18 weeks and to produce cortisol and noradrenalin responses from 20 weeks’ gestation. Although this does not indicate that the fetus is aware of pain at these gestational ages, the mechanisms for physiological endocrine reactions to pain are certainly in place. Methods for fetal anaesthesia and analgesia There are four methods currently practiced to deliver anaesthetic and analgesic medications to the fetus. Access to the fetus for the administration of anaesthesia and analgesia before the insult commences poses a considerable challenge. Potential methods include: direct intravascular, direct intramuscular, transplacental and intraamniotic administration. Each are associated with advantages and disadvantages that have a direct impact on the overall outcome of fetal intervention. Intravascular access Administration of drugs directly into the fetal circulation has obvious advantages. In addition to assuring immediate drug levels with expected effects, no additional dosing calculations need be performed, as placental perfusion does not significantly alter dosing. Intravascular access can be obtained via the umbilical cord (which is not innervated), larger fetal veins (i.e. hepatic), or intra cardiac as the surgical procedure dictates. One theoretical advantage of administering analgesia via the umbilical vein is the ability to provide analgesia prior to the surgical insult. Muscle relaxants (i.e. vecuronium 0.2 mg/kg), analgesia (fentanyl 10 mg/kg), vagolytic agents (atropine 20 mg/kg), as well as resuscitation drugs can be given with the assurance of immediate access to the fetal circulation with this delivery system. This method is also useful when alterations in peripheral blood flow occur (i.e. the central sparing response), which significantly diminish the blood distribution to sites of potential intramuscular access.

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Fetal intravascular access is not without risk, however. This method requires needling in a fetus that is often not sedated from maternally administered agents (i.e. local anaesthesia only). These needles, which are necessary to deliver fetal drugs, may in fact injure the moving fetus. In addition, a significant risk of bleeding from the fetus, umbilical cord and placenta exists. Uncontrolled bleeding could not only impair the surgical view, but also place the fetus and mother in jeopardy, as an open hysterotomy may be necessary to control bleeding. Intramuscular access The second method of fetal drug administration is direct intramuscular injection. This method involves inserting a needle under ultrasound guidance to a fetal extremity, preferably an upper extremity, in order to administer opioids, muscle relaxants and vagolytic drugs as needed. Due to the unknown and often variable rate of intramuscular absorption of drugs in the fetus, larger concentrations of drug doses may be needed. Unlike umbilical cord injection, a noxious stimulus to the fetus is provided at the time of intramuscular injection, thereby stimulating the fetal stress response. Although the risk of bleeding is less than with intravascular injections, the risk of bleeding and injury from the needle itself still exists. Furthermore, if the fetus is already stressed, blood will be diverted away from muscle (the site of drug administration) and towards the fetal heart and brain. In this case, it may be impossible to estimate how much drug has been absorbed, if any, from the intramuscular site. Transplacental access Many fetal interventions, both open and endoscopic, utilize the concepts of transplacental drug administration in order to provide anaesthesia and analgesia for both mother and fetus. Many, but not all drugs cross the placenta via Fick’s Law of passive diffusion. Lipid solubility, pH of both maternal and fetal blood, degree of ionization, protein binding, perfusion, placental area and thickness and drug concentration are some factors that influence the diffusion process.61 The most obvious disadvantage with this technique is that the mother must be exposed to every drug the fetus is intended to receive, often at much higher concentrations than otherwise necessary, in order to achieve an adequate fetal drug level. In addition, the uptake of drugs may be impaired if there is reduced placental blood flow. This has implications in terms of successful anaesthesia and analgesia for the fetus and the time interval that must be allowed from maternal administration to the start of fetal surgery. All inhaled anaesthetics cross the placental barrier, but uptake in the fetus takes longer than in the mother.61 However, since the fetus needs a lower alveolar concentration for anaesthesia, this takes no longer than maternal anaesthesia.103 Fetal anaesthesia is also important in order to reduce the fetal stress response, which, through catecholamine release, can reduce placental blood flow and exacerbate any asphyxia.104 Intra-amniotic access The fourth method of fetal drug administration is intra-amniotic instillation of a given drug. Although this method has been used for years in order to treat fetal supraventricular tachycardias, it is still considered experimental and not routinely practiced in fetal intervention. Perhaps one limiting factor is the design of proper pharmacodynamic and pharmacokinetic investigations determining the appropriate

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drug dosing, the rate of clearance and elimination and what the different fetal disease processes contribute to each of these factors. Sufentanil and digoxin have both been safely administered in large animal models with minimal maternal drug levels obtained in both studies.105,106 If this holds true, the safety and efficacy of intra-amniotic drug administration may be the preferred method of choice due to minimal maternal exposure and risk.

MATERNAL ANAESTHETIC MANAGEMENT Fetal endoscopic interventions have been successfully performed with various different anaesthetic techniques. With some endoscopic interventions, as in selective laser ablation of aberrant vessels seen in TTTS, the site of surgical intervention is not innervated and thus the fetus may not sense any noxious stimuli whatsoever. Other interventions, such as aortic valve dilation, require needle insertion into the fetal thorax, which certainly elicits a noxious stimulus and perhaps even fetal pain. Indeed, since surgical procedures differ, so too do the accompanying anaesthetic requirements and each case should thus be considered individually. In addition to surgical demands, each patient and fetus exhibits a unique physiological, pharmacological, and pathophysiological profile. The anaesthesiologist must weigh the advantages and disadvantages of each anaesthetic technique to select the safest intra-operative plan. Local anaesthesia Local anaesthesia involves the injection of lidocaine or bupivicaine into the proposed trocar insertion sites. No maternal or fetal medication is thus administered. The most obvious advantage to this technique is maternal safety, as the mother receives no medication whatsoever. Disadvantages of this technique include increased risk of injury to the moving fetus, no fetal anaesthesia or analgesia and no uterine relaxation. Those patients on tocolytic therapy or those with polyhydramnios and uterine contractions may be placed at further risk of worsening contractions with this technique. Sedation Intravenous sedation involves the maternal administration of benzodiazepines, narcotics, and/or low-dose induction agents in order to provide maternal monitored anaesthesia care. Advantages to this technique include potential anaesthesia and analgesia to the fetus via transplacental transfer of agents as well as decreased maternal anxiety. Depending on the amount and effect of drugs administered, this sedation may increase the mother’s risk of aspiration with an unprotected airway. Furthermore, this technique again provides no uterine relaxation. Regional neuraxial blockade Neuraxial techniques (spinal, epidural, or combined spinal epidural anaesthesia) have been used frequently with fetoscopic techniques. A T4 sensory level blockade is required for most surgical uterine manipulations. This technique has been used in cases of anterior placentas when externalization of the uterus is mandatory for safe trocar

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insertion with good success. Neuraxial techniques provide no uterine relaxation nor do they provide any fetal anaestheia or analgesia. Neuraxial anaesthesia is associated with an increased maternal risk (failed block, high spinal, total, spinal, intravascular injection of local anaesthetic, etc.) as discussed elsewhere in this chapter. In a recent series of 29 patients undergoing fetoscopic laser photocoagulation for T T TS, those who received epidural anaesthesia required significantly more intravenous fluid than those who received either general anaesthesia or a combination general/regional anaesthetic technique.22 A possible explanation is that with a complete sympathetic and motor blockade, as obtained with a high epidural technique, volume replacement and sympathomimetics may be required to maintain maternal preload and uterine perfusion pressure. Since uterine blood flow is a major determinant of placental blood flow, any factors that decrease uterine blood flow may jeopardise fetal well being.61 Thus, decreases in maternal blood pressure were treated quickly and aggressively with i.v. fluids and ephedrine to maintain uterine perfusion pressure. However, the administration of large amounts of intravenous crystalloid during fetal surgery may increase the risk of postoperative maternal pulmonary edema when tocolytic agents are also administered to this patient population.73 Regional neuraxial blockade with sedation The addition of intravenous sedation to regional anaesthesia may provide the fetus with anaesthesia and analgesia that it would otherwise not receive with regional techniques alone. Although i.v. fentanyl, propofol and benzodiazepines can be administered to patients receiving regional anaesthesia, it may place the mother at increased risk for bradyarrhythmias, respiratory depression and pulmonary aspiration. As previously stated, the acceptable level of sensory blockade for surgical manipulation of the uterus is T4, producing further alterations in respiratory mechanics already seen in pregnancy. In addition, the level of sympathetic blockade is often two to six levels higher than the sensory level.107 Hence, a T4 sensory block may completely block cardiac accelerator fibres that originate from T1 to T4. Severe bradyarrhythmias and cardiac arrest have been reported with T4 levels of sympathetic blockade in pregnant patients.108 – 110 When i.v. agents with vagolytic properties are administered in this clinical setting, the risk of significant bradyarrhythmias may be increased.111 General endotracheal anaesthesia General anaesthesia achieves many potential goals during fetoscopic intervention as it provides both maternal and fetal anaesthesia as well as providing dose-dependent uterine relaxation. The biggest risk with this method, however, is the risk of failed maternal intubation, as discussed earlier. In addition, general anaesthesia with halogenated agents can provide intra-operative uterine relaxation in patients who have received prior tocolytic therapy for preoperative uterine premature contractions. Halogenated agents provides anaesthesia for the fetus via placental transfer, while epidural anaesthesia with local anaesthetics does not.112 – 115 Combined regional/general endotracheal anaesthesia A combined regional and general anaesthetic technique is best utilized for those patients with anterior placentas in which externalization of the uterus is anticipated for

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safe trocar incision. In addition to providing the advantages of both the regional and general anaesthetic techniques listed previously, this method allows for planned postoperative pain control. In a recent series, patients with anterior placentas received a general or combined technique significantly more frequently than those with posterior placentas.22 The window for trocar insertion was often smaller in this patient group, necessitating either externalization of the uterus or extreme lateral decubitus position. Externalization of the uterus involved a large laparotomy incision, which is larger than the surgical incision for standard cesarean sections. Good post operative pain control was obtained with a continuous epidural infusion of bupivicaine 0.1% with 2 mg/cc fentanyl.

FETAL OXYGENATION One of the most important goals during any fetal intervention is the maintenance of fetal oxygenation. The fetus exists in an environment of low oxygen tension, with arterial pO2 being approximately a quarter that of the adult. In umbilical venous blood, pO2 is approximately 30 mmHg at its maximum. The hemoglobin oxygen dissociation curve is shifted to the left, due to the presence of hemoglobin F and the lower 2,3-diphosphoglycerate (2,3-DPG) concentration relative to that in the adult’. As 2,3-DPG has a high affinity for deoxyhemoglobin, the resultant binding reduces hemoglobin’s oxygen carrying capacity. However, 2,3-DPG exerts only approximately 40% of its effect on adult hemoglobin on fetal hemoglobin. Thus, for any given pO2 value, the fetus has a higher affinity for oxygen than the mother. The P50 (the pO2 at which hemoglobin is 50% desaturated) for an adult is approximately 27 mmHg, and for the fetus is 19 mmHg. The concentration of 2,3-DPG rises with gestation as does the concentration of hemoglobin A.116 Fetal blood also has a higher hemoglobin concentration than adult blood (18 g/dl), and therefore a higher total oxygen carrying capacity. Oxygen supply to fetal tissues depends on a number of factors. Firstly, the mother must be adequately oxygenated. Supplementary oxygen must be administered intraoperatively if necessary. Secondly, there must be adequate blood flow of welloxygenated blood to the uteroplacental circulation. Blood flow may be reduced for a number of reasons. Significant maternal haemorrhage reduces maternal blood volume and thus uterine blood flow. Care must be taken to keep the mother in a left or right uterine displacement during a procedure to prevent aorto-caval compression. Compression of the inferior vena cava reduces systemic venous return to the heart, increasing uterine venous pressure, which can reduce uterine perfusion. Additionally, aortic compression reduces uterine arterial blood flow.117 While the surgical incision of open hysterotomy reduces uteroplacental blood flow by as much as 73% in sheep, fetoscopic procedures with uterine entry have no effect.118 Despite the large reduction in uterine blood flow post-hysterotomy observed in that study, the fetus was still able to compensate and maintain normal oxygen consumption, although others have shown that similar reductions in blood flow render the fetus acidotic and cause vascular redistribution.118,119 The development of acidemia indicates that the fetus is unable to compensate, despite adaptations such as an increased heart rate and vascular redistribution. Even if the uterine circulation is adequate, the fetus is still dependent on uteroplacental blood flow and umbilical venous blood flow for tissue oxygenation. Increases in amniotic fluid volume increase amniotic pressure and impair uteroplacental

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perfusion.119,120 A study of pregnancies complicated by polyhydramnios found that 36% of fetuses had a venous pH and 73% had a venous pO2 below the reference range and that these values were negatively correlated with amniotic pressure.121 Animal studies suggest that uteroplacental perfusion has to be reduced by more than 50% before there are adverse effects on arterial fetal gas status.122 Placental vascular resistance can be increased, raising the fetal cardiac afterload, by the surge in fetal catecholamine production stimulated by surgical stress.123 Care must be taken not to interrupt umbilical vessel blood flow during a procedure. This can happen by kinking the cord, especially if a large amount of amniotic fluid is lost. Manipulation of the cord can result in vasospasm, impairing umbilical venous blood flow. Umbilical vasoconstriction can also occur as part of a fetal stress reaction, due to fetal production of stress hormones.

INTRA-OPERATIVE FETAL MONITORING Despite years of animal research, few practical devices have been created to provide insight into fetal physiology during surgical intervention. With open procedures, it is sometimes possible to gain access to a fetal extremity and apply a pulse oximeter for oxygen saturation measurements, obtain venous blood gases for analysis and even apply electrocardiographic devices. With fetal endoscopic techniques, there is no direct access to the fetal patient and these techniques are not available. Most practitioners rely on continuous fetal echocardiography to assess fetal well-being during surgical intervention. By using an ultrasound probe protected in a sterile sleeve, continuous recordings of fetal heart rate, ventricular function and ventricular volume can be assessed throughout the surgical procedure. Continuous fetal echocardiograms are not without limitations. An additional person must be present at an already crowded operating table and the ultrasound machine itself takes up valuable operating room space. In addition, interference from electrocautery will interrupt important fetal data, often at the most crucial times. Fetal electrocardiography (ECG) using recording leads placed on the maternal abdomen is becoming more reliable as methods of reducing electrical interference from the maternal heart are developed.124 However, to date, the fetal ECG is not yet a part of regular clinical practice.

INTRAOPERATIVE FETAL RESUSCITATION During any fetal intervention, there may be incidences in which fetal resuscitation is necessary. Indications depend on the endoscopic procedure itself and include fetal bradycardia (less than 80 –100 beats/minutes) and significantly reduced ventricular function. Since direct access to the fetus is not immediately available, several other treatments can be employed. Our group has had success with both intracardiac and intramuscular administration of epinephrine (1 –2 mg/kg) to treat severe sustained bradycardia during aortic valve dilations. Although intramuscular administration has a highly variable absorption rate secondary to the central sparing response, our team has had successful resuscitations in several of our cardiac interventions. Other maneuvres aim at improving uterine perfusion and hence fetal oxygenation. These include increasing maternal mean arterial pressure to 25% above awake values with volume loading and ephedrine or phenylnephrine as well as decreasing uterine vascular

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resistance by ensuring complete uterine relaxation. If fetal ECG indicates a decreased ventricular volume, a blood transfusion with O negative irradiated blood (5 –10 cc/kg) may be indicated.

PREVENTION OF POST-OPERATIVE PRETERM LABOR Preterm labor after fetal surgery is an iatrogenic complication of the surgical procedure that occurs after every open fetal procedure and with less frequency after fetoscopc intervention.125 Although the mechanisms are not well understood, the occurrence of contractions and preterm labor are common for the first few postoperative days. However, for many women the onset of surgically induced preterm contractions heralds premature labor and delivery that, at best, eliminates the positive results of the procedure and, at worst, ends in the loss of the pregnancy.126 In addition, significant maternal morbidity can occur as a consequence of the tocolytic agents used to prevent and treat preterm labor. Despite exhaustive efforts at prevention and treatment, preterm labor remains the single most common complication that limits the success and the potential of fetal surgery. Recently, Li et al127 demonstrated that the intracellular mechanism of uterine quiescence might be related to the concentration of Caldesmon, which acts to prevent the activation of the myosin and actin complex. The release of inhibition of uterine activity may be due to the activation of an (ERK) kinase-signalling pathway. This group also recently found that the administration of an ERK kinase inhibitor successfully prolonged pharmacologically induced premature labor in rats.128 Although the signal that causes the loss of this biochemical inhibition is not known, several of the complex steps leading up to labor have been elucidated in the past decades of research. Early work in sheep established a fetal hormonal signal for the onset of both term and preterm labor.129 In sheep, the onset of labor is heralded by the fetal hypothalamic – pituitary release of adrenocorticotripin, which increases the fetal adrenal production of cortisol.130 This stimulates the placental enzyme system to switch from the production of progesterone to favor estradiol.131 This fetal hormonal state produces an increase in prostaglandin and oxytocin production in the intrauterine tissues and increases the sensitivity of the myometrium to oxytocin. Indeed, administration of progesterone antagonists to rats will produce a predictably timed preterm delivery. In primates, however, this alteration in hormone production that sparks the onset of labor has not been uniformly discovered and may be a subtle switch toward fetal estrogen dominance without progesterone withdrawal; in humans, the putative hormone is estriol.129 Estriol levels remain low throughout pregnancy, but rise in the final weeks before delivery, whether term or preterm. In other words, estriol levels are predictive of the timing of the onset of labor. Some authors have suggested a role for prostaglandins in the initial steps of the labor cascade. Cortisol reaching the glucocorticoid receptors on the fetal trophoblasts evokes the expression of prostaglandin H synthetase type 2, which leads to an increase in prostaglandin E2. This hormone then up-regulates the enzyme responsible for the production of estrogens. No single anaesthetic has been implicated as a causative agent and it is more likely that the stress response of the mother to surgery leads to physiological changes that predispose the parturient to uterine irritability, contractions and preterm labor. As is discussed below, surgical stress and pain can produce hormonal changes in both parturients and in the fetus, which create a uterine environment that is prone to preterm labor. After fetal surgery, this stress response is magnified by the site of

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surgery being the fetus itself. Thus, even if the immediate post-surgical delivery can be avoided, a predictable and almost inevitable process can lead to premature delivery. After open fetal surgery, preterm labor can be examined with two patterns; the first being immediate post-surgical delivery, which most often results in fetal loss and the second a preterm delivery resulting after a successful delay of delivery for a number of weeks. The nature of preterm labor following a hysterotomy for fetal surgery is significantly different in character from spontaneous preterm labor in a normal pregnancy or even that due to the stress response after non-obstetric surgery. In early experimental work developing fetal surgical techniques, Harrison et al132 noted a 73% incidence of spontaneous abortion in primates after open hysterotomy. Several factors increase the risk of preterm labor after fetal surgery. Conditions that lead to preterm labour in the general population, such as polyhydramnios, are often present in this population. The state of health of both the parturient and the fetus are significant factors, as is the gestational age of the fetus during surgery.133 Other considerations include the size of the uterine incision, duration of surgery, the method of closure of the fetal membranes and, very possibly, the success of maternal and fetal analgesia. The key factors in the determination of the duration of gestation, or the onset of labor, are the expression of fetal cortisol and production of estrogens and prostaglandins. Maternal estrogen is known to be increased in primates after surgical procedures during pregnancy and may be a factor in increased uterine irritability and initiation of preterm labor.134 Surgical stress leads to the release of cortisol, as well as inflammatory cytokines, triggering the hormonal signal that leads to uterine maturation and premature contractions. Furthermore, fetal pain after the surgical procedure may lead to the release of cortisol, inducing the natural pathway that leads to the onset of labor. It has been suggested that the aggressive myometrial activity may be a natural attempt by the uterus to remove the fetus from a hostile environment.135 After hysterotomy, the myometrium becomes overwhelmed by the natural inflammatory reaction that initiates preterm labor. Both the cytokines produced during inflammation and thrombin produced during incision have been shown to produce preterm contractions. The inflammatory cytokines, including interleukin-1, interleukin-6, interleukin-8 and tumour necrosis factor, found in the amniotic fluid in preterm labour resulting from chorioamnionitis, may instigate premature contractions by increasing the production and inhibiting the metabolism of uterotonic prostaglandins.136,137 Increased amniotic fluid concentrations of cytokines, such as Interleukin-6 have been associated with preterm delivery and are believed to be part of the fetal systemic inflammatory response, a parallel process to the adult systemic inflammatory response.138 The recent finding that thrombin has significant uterotonic activity and that serum levels are elevated in women who delivered prematurely, may also help to explain the intensity of uterine contractions after hysterotomy.139 – 141 The size of the hysterotomy and the duration of surgery, both of which parallel the amount of thrombin generated, are known factors in the development of preterm labor after fetal surgery. Furthermore, the observation that fetoscopic surgery is associated with a lesser severity of preterm contractions supports this theory. After fetoscopic surgery, the incidence of premature contractions and labor has been reported to be lower than after open hysterotomy.142,143 Fetoscopic intervention appears to have lower requirements for tocolysis and a reduced rate of premature delivery.143 In rhesus monkeys, one study found no activity of the myometrium in the first 24 hours after fetoscopic access.144 However, the same group found a high incidence of uterine contractions in sheep (52%), which was essentially the same as the rate after open hysterotomy.145 Rosen et al142 reported the successful performance

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of a fetal procedure in a mother at risk for malignant hyperthermia. Because the use of inhalation anaesthetics was prohibited by the maternal disorder, they used epidural anaesthesia and an infusion of nitroglycerine for intraoperative uterine relaxation. They had a successful postoperative course with minimal requirements for tocolysis in the immediate postoperative period. The success of this regimen was probably only possible because of the small uterine incisions made during fetoscopic surgery. Unfortunately, the decrease in incidence and severity of premature contractions is balanced by an increase in the rates of preterm rupture of membranes (PROM). In fact, PROM is the most common complication after fetoscopic surgery, followed by chorionic membrane separation, preterm labor and chorioamnionitis.146 Access during fetoscopic surgery requires one or multiple punctures through the fetal membranes. These sites are not directly closed, leading to high rates of membrane rupture and amniotic fluid leak. While the risk of PROM after amniocentesis has been estimated at about 1 – 2%, the occurrence of this complication after single port fetoscopic cases reaches 5 –10%; of note, extremely high rates of 60% have been reported after fetal surgical procedures requiring multiple entry sites.146,147 PROM is a potentially devastating complication that can lead to ascending infection and chorioamnionitis, fetal compromise and preterm delivery. Several techniques that attempt to prevent the rupture of membranes after fetoscopic surgery have been developed, such as introducing a plug during the removal of the endoscopes and sealing the membrane rupture with fibrin glue.148,149 Thus far, no single technique has proven to be ideal. Fortunately, with the development of smaller endoscopic equipment and the advancement of surgical techniques, these cases have demonstrated improved outcomes in recent years.146 Regardless of the exact cause of preterm labor after fetal surgery, without the use of tocolytics, uterine incisions lead to an intolerably high rate of spontaneous abortion and if an immediate delivery can be avoided, the intrauterine environment makes preterm delivery almost inevitable. While several physiological processes are active, of particular interest to the anaesthesiologist is the control of the maternal and fetal stress response. Effective pain control for both patients is not only important but most probably essential to successful fetal surgery. Pain control after fetal surgery is an essential component of therapy, not only for humanitarian reasons, but also because it is believed that adequate pain control prevents the stress-induced hormonal impetus for preterm labor.126 Both maternal and fetal pain elicits the release of adrenocorticotripin hormone, the hormone that signals to the adrenal gland to increase production of cortisol.126 Pain-induced cortisol production leads to the deleterious changes in the placenta that increases fetal estrogen and prostaglandin production and probably promotes increased uterine activity. Adequate pain control is believed to block the fetal and maternal stress response and prevent the activation of the hormonal pathway to labor. Some experimental evidence has demonstrated that this is true. Tame et al134 administered normal or double-doses of opioids to baboons in a fetal surgery model. They found that the baboons that received a higher dose of analgesics had lower levels of maternal estrogens, cortisol and oxytocin than was found in the baboons that received a lesser dose. Furthermore, the activity of the myometrium, as measured by the frequency of uterine contractions, was significantly less in those animals that received more opioids. Other investigators have found that infiltration of ultra-long acting local anaesthetics (microspheres laden with bupivacaine) into the uterus at the time of surgery was effective in the prevention of preterm contractions, probably by blockade of transmission of uterine contractile impulses.150 Unfortunately, all of the fetuses in the experimental group died, possibly due to the deleterious effects of bupivacaine on uterine tone and blood flow.

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A retrospective analysis of a 10 year experience with tocolytic agents at the University of California San Francisco demonstrated a 0.5% overall rate of pulmonary oedema seen among parturients.137 There were 65 parturients treated using open fetal surgery between 1985 and 1995 and pulmonary edema developed in 23% of them. All parturients in whom fetal surgery was performed received multiple tocolytic agents simultaneously with generous intravenous hydration. The patients’ chest radiographs, degree of hypoxaemia, overall lung injury severity scores and the time to resolution were more severe and protracted than those patients with hydrostatic pulmonary edema, but were similar to the increased permeability pattern seen in parturients with an infectious etiology of edema.137 The fetal side-effects of tocolytics present a number of problems, albeit usually less so than in the mother. Beta-sympathomimetics cause fetal tachycardia.151 Cyclooxygenase (COX) inhibitors have been shown to be more effective than others in delaying labor in a meta-analysis.152 However, the side-effects of fetal oliguria and ductus arteriosus constriction, which occur even with the COX II selective inhibitors have limited their long-term use.153 After short term use these side-effects were all fully reversible within 72 hours from the cessation of treatment.153 Longer term use of indomethacin has been associated with renal dysfunction, and increased rates of necrotizing enterocolitis, intracranial hemorrhage and patent ductus arteriosus in infants delivered at # 30 weeks.154 Atosiban, an oxytocin antagonist, has not, so far, been found to cause any fetal side effects.155 Calcium channel blockers, such as nifedipine, inhibit contractility in smooth muscle cells. No adverse fetal effects have been reported in humans, although in animals nifedipine has been shown to cause a reduction in uterine blood flow and fetal metabolic acidosis.156,157 It has been suggested that these side effects were, in part, due to the ethyl alcohol administration vehicle and, thus, may not necessarily be extrapolatable to humans.158 Magnesium sulphate reduces fetal heart-rate variability159 and depresses fetal right ventricular function.160 Since this drug rapidly crosses the placenta, but is excreted more slowly by the fetal kidneys than by the maternal kidneys, there are concerns about fetal toxicity, resulting in respiratory and central nervous system depression.161 Nitric oxide donors, such as nitroglycerine appear to have minimal fetal side effects.162

SUMMARY Fetoscopic intervention presents many unique challenges to the anaesthesiologist, who must care for two or possibly three patients, each with specific and often conflicting requirements. A complete understanding of the fetal anatomical development, neuroendrocrine responses and pharmacological limitations are necessary prior to administering anaesthesia for these cases. In addition, maternal physiological adaptations to pregnancy may significantly alter anaesthetic techniques and requirements. Furthermore, different fetal disease processes may demand further alterations to the anaesthetic plan. As such, a thorough understanding of the underlying fetal disease process is necessary to make the best decision with regard to anaesthetic management. Finally, a thorough discussion with the surgical team will allow the opportunity to prepare for variations in both maternal and fetal anatomy. It is only by addressing these issues can appropriate anaesthetic care be administered. Perhaps the most important role the anaesthesiologist may play in fetal intervention, however, is the contribution of new ideas, methods, research and techniques that will hopefully address the many questions still left unanswered in this field.

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Practice points † a complete understanding of each fetal disease process is imperative in order to provide the safest anaesthetic possible † physiological alterations associated with pregnancy occur as early as the first trimester and must be considered for every case † maternal safety must be assured at all times † neuroendrocrine and neuroanatomical evidence exists suggesting that the fetus can respond to a noxious stimulus in the second trimester of pregnancy † the need for fetal anaesthesia and analgesia must be considered in each case † evidence exists demonstrating that postoperative pain in both mother and fetus contributes to uterine irritability and increases the chances of postintervention uterine contractions

Research agenda † additional studies are needed to determine the efficacy of fetoscopic intervention, with attention to long-term outcomes and patient morbidity † alternative methods to provide fetal anaesthesia and analgesia must be developed in order to maximise maternal safety † improvements in tocolytic techniques are imperative to optimize the chances of a successful intervention

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