Fetal endoscopic surgery

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 primarilyexperimental in nature to the standard of care in certain circumstances. While surgicaltechniques have advanced over the past few years, the anaesthetic goals for these interventionshave remained the same; namely, minimizing maternal and fetal risk as well as maximizing thechances of a successful fetal intervention and optimize the conditions necessary to carrythe fetus to term gestation. Fetal endoscopic techniques allow access to the fetus without theneed for a hysterotomy incision, thus improving the chances of controlled post-operativetocolysis and term gestation after fetal intervention. This procedure, however, is not withoutassociated risks to both fetus and mother. This chapter will address the fetal diseases that maybenefit from fetoscopic intervention, the rationale behind why maternal and fetal anaesthesia isrequired, the various anaesthetics used for these cases and specific considerations of bothmaternal and fetal physiology that aid in the determination of the best anaesthetic techniquefor individual cases. Methods of intra-operative fetal monitoring and fetal resuscitation will alsobe discussed.

1521-6896/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved.

Best Practice & Research Clinical AnaesthesiologyVol. 18, No. 2, pp. 231–258, 2004

doi:10.1016/j.bpa.2004.01.001available online at http://www.sciencedirect.com

* Corresponding author. Tel.: þ1-617-355-7759; Fax: þ1-617-730-0894.E-mail address: [email protected] (L.B. Myers).

http://www.sciencedirect.com

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

The advent of fetal intervention introduced the concept of surgically correcting aknown congenital fetal defect in order to avoid certain fetal demise. With theassociated improvements in prenatal imaging and refined surgical techniques, fetalinterventions have grown to include not only those fetal diagnoses associated withintrauterine demise but also many diseases associated with significant postnatalmorbidity. It is the goal of fetal intervention to thus improve the chances of normal fetaldevelopment and minimize postnatal morbidity. Advances in surgical techniques havechanged some procedures from certain open fetal interventions, associated withsignificant maternal risk, to endoscopic techniques, thus improving the maternal risk-to-benefit ratio as well as diminishing the incidence of post-operative uterinecontractions associated with open procedures. Although not all fetal interventionsperformed to date can be successfully performed using endoscopic techniques, thischapter will discuss those fetal conditions that are amendable to endoscopic correctionas well as the maternal, fetal and uteroplacental factors influencing the choice of ananaesthetic technique for a given intervention. The current techniques available foradministering fetal anaesthesia as well as methods for fetal resuscitation will also bediscussed.

FETAL DISEASES ELIGIBLE FOR ENDOSCOPIC SURGERY

Twin–twin transfusion syndrome

Twin–twin transfusion syndrome (TTTS) is a complication of multiple gestation inwhich abnormal vascular communications between the developing fetuses result in animbalance of blood flow between the twins. In cases of severe TTTS, polycythemia,polyhydramnios and hydrops fetalis may develop in the favored twin witholigohydramnios and severe anaemia in the compromised twin.1–3 Fetal mortalityhas 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 severesecond trimester TTTS.

Until recently, TTTS was most commonly managed with serial reductionamniocentesis, 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 isassociated 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 Selectivefoetoscopic laser photocoagulation (SFLP) of abnormal placental vascular anastomosesis a more invasive procedure that has a similar survival rate when compared with serialamnio-reductions. Outcome studies also suggest better neurological outcomes thanhistorical controls treated with serial amniocentesis.7,12–19 Prospective randomizedcontrolled trials are currently underway to determine whether fetoscopic laserablation is superior to reduction amniocentesis in the treatment of midtrimester TTTS.

232 L. B. Myers et al.

There is very little data on the reported anaesthetic techniques used for fetoscopiclaser ablation. The procedure has been performed under local, general, epidural, as wellas combined general and epidural anaesthesia.18,20,21 Myers & Watcha22 described theirexperience with epidural and general anaesthesia for SFLP. In this retrospective study of29 patients undergoing SLFP, patients with anterior placentas were more likely toreceive a general anaesthetic secondary to the need to externalize the uterus to gaintrocar access. (see Figure 1) Furthermore, patients receiving an epidural anaestheticreceived significantly more intravenous (I.V.) crystalloid but less I.V. fentanyl than thosereceiving a general or combined technique. No SLFP procedures were performed underlocal anaesthesia at ar institution. Although these data strongly argue in favor of generalanaesthetic techniques, larger patient series are needed to validate these conclusions.

Factors that may influence the choice of anaesthetic technique include: (i) theplanned surgical approach and probability of converting to open fetal surgery, (ii)maternal medical history and physical examination, including careful maternal airwayexamination, (iii) maternal preference and (iv) history of prior uterine activity. Thesurgical approach for SLFP is determined by (i) the location of the placenta (anteriorversus posterior), (ii) the position of the fetuses and (iii) the potential window(s) fortrocar insertion.22

Twin reversed arterial perfusion sequence

Twin reversed arterial perfusion (TRAP) sequence denotes a common pathophysiologyof several different conditions, all of which describe a twin pregnancy in which one twinis normal and the second twin exhibits multisystem malformations including encephalyor 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. Thiseventually places the normal, or ‘pump’ twin, at a haemodynamic disadvantage, Sincethis normal twin provides cardiac output to both itself and it’s non-viable sibling. Thisanomaly 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 deathrates for the ‘pump’ twin ranging from 39–59% in untreated pregnancies.24 Treatment

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

Fetal endoscopic surgery 233

options include observation, medical therapy with digoxin and indomethacin, selectivedelivery, umbilical cord blockade with a platinum coil or silk suture in alcohol andfetoscopic cord ligation (see Figure 2).25 Quintero et al26 and McCurdy et al27 firstreported success with fetoscopic cord ligation in twin gestations exhibiting cardiacfailure in the viable twin. Although all endoscopic procedures have the primary aim ofinterrupting umbilical cord blood flow to the non-viable twin, most practitionerscurrently recommend this invasive technique only after failed medical therapy or aftersigns of cardiac failure in the viable twin.28,29

Like TTTS, there is very little data available with regard to anaesthetic managementfor these cases. Galinkin et al30 reported a case of TRAP sequence with a successfultreatment under maternal general anaesthesia. Regardless of the technique employed,maternal and fetal physiological considerations must be addressed to provide the safestenvironment for the mother and the viable fetus.

Hydronephrosis: bladder outlet obstruction

Bladder outlet obstruction is most commonly due to posterior urethral valves in malesand urethral atresia in females.31 In severe cases, infants present at birth withrespiratory insufficiency secondary to pulmonary hypoplasia and renal failure from renaldysplasia. In prenatal ultrasonographic examination, this severe form of bladder outletobstruction is heralded by profound oligohydramnios, distended bladder, bilateralhydroureternephrosis and dysplastic changes in the kidneys. In some cases, pulmonaryhypoplasia can lead to significant postnatal morbidity and is the leading cause of deathduring the neonatal period for patients afflicted with this disorder.32

Until recently, treatment options were limited to observation and serial prenatalultrasonograms followed by neonatal surgical intervention. Some groups have attempted

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


to restore amniotic fluid volume in an attempt to promote pulmonary development andavoid neonatal demise secondary to pulmonary hypoplasia.33,34 In animal studies, bladderdecompression in utero has prevented the progression of renal dysplastic changes and hasimproved pulmonary development.35 Mandell et al36 have reported that the severity ofrenal dysplasia depends on both the timing and severity of obstruction before delivery,which suggests that relief of obstruction between 20 and 30 weeks’ gestation maysignificantly reduce the degree of renal dysplasia. These data have encouraged thedevelopment of vesicoamniotic shunts, first reported with poor outcomes.37 Althoughthese 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 early-gestation urinary tract decompression as first line therapy.

Harrison and Adzick38 reported a series of eight cases of obstructive hydrone-phrosis treated by open vesicostomy. Of the four survivors, three had no evidence ofrenal insufficiency during follow-up of up to 8 years. Fetoscopic techniques to createvesicocutaneous fistula for decompression and laser ablation of posterior urethralvalves have been reported34,38 –40 with promising initial outcomes. However, theseprocedures are technically difficult and the exact role of fetoscopic intervention forcorrection 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 shuntplacement. These disorders include posterior urethral valves, cystic adenomatoidmalformation of the lung, aqueductal stenosis, fetal hydrothorax, ovarian cyst and fetalascites. Various shunts have been attempted to provide long-term decompression withvariable results.41 Although a detailed discussion of these disorders is beyond the scopeof this chapter, the practitioner must remember that these interventions will elicit asignificant fetal stress response and appropriate measures should be taken to minimizethis 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 withcongenital heart defects. Certain congenital heart defects cause aberrations in blood flowthat are usually secondary to valvular stenosis or regurgitation. Regardless of theaetiology, the end result is often an abnormally developed ventricle, which may or may notbe able to perform its designated function after birth.42–44 Several case reports havecharacterized the progression of valvular stenosis to ventricular hypoplasia from reducedflow through the chamber during gestation.45–49 It has been hypothesized that relief ofvalvular stenosis in utero could reverse the progression towards ventricular hypoplasia.To date, the defect most amendable to correction is severe aortic stenosis (AS) withevolving hypoplastic left heart syndrome (HLHS).45–52 Without prenatal intervention,severe AS can lead to severe left ventricular dysfunction, diminished flow through the leftheart, arrest of left ventricular growth and consequently HLHS. Staged palliative surgery(the Norwood/Stage 1 procedure) is the only postnatal therapeutic option for patientswith HLHS. The primary aim of prenatal intervention for those fetuses with congenital


aortic stenosis is to reverse the pathological process in an attempt to preserve cardiacstructure and function, thereby preventing postnatal disease.

This procedure may be performed percutaneously using continuous ultrasoundguidance. Optimal fetal positioning or maternal habitus (i.e. obesity) may requireexposure of the uterus through an abdominal incision in order to obtain ideal access tothe fetal thorax. These procedures have been performed under both regional andgeneral anaesthesia, although general anaesthesia is often preferred in order to obtainoptimal uterine relaxation and an anaesthetized fetus. Preliminary results are promisingwith initial outcomes demonstrating the ability to prevent development of singleventricle physiology with second trimester intervention.53

ANAESTHETIC CONSIDERATIONS

General goals

Anaesthesia for fetoscopic intervention poses several unique challenges for theanaesthesiologist. The physician must care for two or possibly three patients at once, allwith distinctive and, at times, conflicting requirements. The anaesthesiologist is requiredto provide both maternal and fetal anaesthesia and analgesia while ensuring bothmaternal and fetal haemodynamic stability. Fetal haemodynamic stability is often a resultof maintaining uterine perfusion and uterine blood flow, often affected by commonanaesthetic agents and thus appropriate adjustments are mandatory. Many patients withfetal disorders resulting in polyhydramnios may already be receiving tocolytic agents andmay require additional uterine relaxation once surgery has commenced. In addition,these tocolytic agents may interact with certain anaesthetic agents, necessitatingalterations in anaesthetic dosing. Since substantial evidence exists demonstrating theability of the second trimester fetus to mount a neuroendrocrine response to noxiousstimuli (see below), fetal pain management must be considered in every case.Furthermore, since both maternal and fetal stress and pain have been associated withinitiation of premature uterine contractions (see below), adequate pain control for bothmother and fetus during and after the procedure must be assured. Furthermore, a planmust be prepared to resuscitate the fetus if problems occur during intervention.

Regardless of the anaesthetic administered, the surgical technique remainsstandardized. Ultrasonographic confirmation of placental location and positioning ofthe fetus(es) is performed prior to surgical incision. Trocar(s) are percutaneouslyinserted under continual ultrasound visualization through the uterus into the amnioticcavity. Once intrauterine access is obtained, a fetoscope is inserted through the trocarto aid in visualization and identification of the intended malformation. Degree ofsurgical difficulty is multifactorial and depends on surgical expertise, placental location,visibility and absence of fetal movement. Details of these various surgical techniques andpotential complications have been described previously.54–60

Physiological alterations with pregnancy

With any fetal intervention, one cannot over-emphasize the importance of maternalsafety. Physiological alterations associated with pregnancy begin during the first trimesterand have significant bearing on any anaesthetic delivered. A complete understanding ofthese physiological changes is necessary prior to administering any anaesthetic for fetalintervention. Certain anatomical, hormonal and functional adaptations are considered


normal during pregnancy. Virtually every organ system undergoes significant changes asearly as the first trimester in order to accommodate the developing fetus. While thesechanges are usually well-tolerated by most parturients, practitioners of fetal surgeryshould be aware of the potential impact of these changes, since even subtle aberrationscan have a permanent effect on both maternal and fetal outcomes.

A complete systematic review of organ system adaptations during pregnancy hasbeen extensively documented elsewhere.61 reviews the major adaptations that willdirectly influence the choice of the delivered anaesthetic technique and will specificallyaddress these alterations in relation to fetal intervention.

Respiratory

Pregnancy results in progressive increases in both oxygen consumption and minuteventilation. Since the growing uterus causes a decrease in residual volume andfunctional residual capacity, the mother is faced with a reduced oxygen reserve.62 Anincrease in oxygen consumption combined with a reduced oxygen reserve places thepregnant patient at risk for hypoxaemia. Pregnant patients are further prone tohypoxaemia when lung volumes fall below closing capacity, leading to atelectasis. Whilethe closing capacity does not change during pregnancy, the functional residual capacityfalls below the closing capacity in the supine position, causing areas of perfusion but noventilation (intrapulmonary shunting) which also predisposes the mother to hypoxia.63

This decrease in functional residual capacity becomes more pronounced with obesityand with certain body positions (e.g. supine, trendelenburg, lithotomy).64

Progesterone and estrogen sensitize the respiratory centre to carbon dioxide tocreate 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 alveolarventilation. Despite an increased CO2 production, the relative increase in minuteventilation causes a decline in PaCO2 to approximately 30 mmHg by 12 weeks’gestation. Furthermore, the effect of lower PaCO2 values on the hemoglobindissociation curve is offset by an elevated 2,3-diphosphoglycerate level, which increasesthe P50 for hemoglobin and facilitates oxygen delivery to the fetus.64

These respiratory alterations make the pregnant patient and the fetal-placental unita constant challenge during any fetal interventions. Apnea or hypoventilation will rapidlylead to hypoxia and hypercarbia. Even after adequate pre-oxygenation, the PaO2 in anapneic, anaesthetized parturient falls by about 80 mmHg more per minute whencompared with the non-pregnant state.66 Acidosis rapidly develops from hypoxia andhypercarbia during difficult airway situations because of a decreased buffering capacityduring pregnancy. Hyperventilation during periods of controlled ventilation can alsohave 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 leadto uterine vessel vasoconstriction with decreased perfusion to the fetal-placental unit.

Any discussion about respiratory alterations during pregnancy would be incompletewithout emphasizing the known anatomical changes of the maternal airway. Withincreasing gestational age, maternal airway mucosa becomes edematous, abdominalcontents shift the diaphragm upward with increasing uterine size and the laryngealstructures shift to a more anterior position. Pilkington et al67 photographed the oralcavity 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 thefrequency of a difficult intubation. Indeed, failed intubation resulting from theinability to visualize the vocal cords occurs in 1/300 general anaesthetics in


the obstetric population. The decreased pulmonary oxygen stores and increased oxygenconsumption previously mentioned make pregnant patients even more susceptible thannon-pregnant women to the consequences of difficult airway situations (see Table 1).

Cardiovascular effects

Cardiovascular function is appropriately increased during pregnancy in order to meetthe increased metabolic demands and oxygen requirements of the mother. Studiesinvolving parturients and non-pregnant controls demonstrate a significant increase incardiac output by as much as 35–40% by the end of the first trimester.68 Cardiac outputcontinues 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 functionof the increased heart rate during the first and second trimesters.68

The impact of aortocaval compression by the gravid uterus is significant and cancause up to a 30–50% decrease in cardiac output. Lesser decreases are observed in thesitting or semirecumbent positions.69 Occlusion of both the inferior vena cava and theaorta occurs, to some extent, in all supine parturients. Although the epidural andazygos veins provide alternative routes for venous return, they do not provideadequate compensation. Most pregnant women do not become frankly hypotensivewhen supine (concealed caval occlusion) because the blood pressure is maintained byincreases in systemic vascular resistance, heart rate and stroke volume. About 10% ofwomen exhibit ‘revealed caval occlusion’ or ‘supine hypotensive syndrome’ withhypotension and diaphoresis occurring when they are placed supine for more than afew minutes. In these parturients, a reflex bradycardia combined with decreasedvascular tone and compromised venous return causes a profound decrease in bloodpressure. For these reasons, the supine position should always be avoided in theanaesthetized pregnant patient as the fetus may experience a decrease in blood flowand 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 caseswhere 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 theCOP to pulmonary capillary wedge (capillary hydrostatic pressure) gradient may placethe parturient at higher risk of pulmonary aedema.72 Although most cases of acute lunginjury in pregnancy are attributed to hydrostatic pulmonary aedema, there are several

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


reports of increased permeability pulmonary aedema in parturients after fetal surgerywho had received tocolytic agents.73,74 Those patients who received nitroglycerineinfusions for tocolysis had a more severe lung injury with a longer time to resolutionthan patients treated with other tocolytic agents.73 It has been hypothesized that high-dose intravenous nitroglycerin could act as a nitric oxide donor forming peroxynitrite,implicated in immune complex-mediated lung injury which damages type II alveolar cellsand inhibits surfactant function.73,74 Because of these concerns, nitroglycerin is rarelyused as a tocolytic agent for fetal surgery (see Table 2).

Gastrointestinal system

Anatomical changes associated with a gravid uterus predispose the pregnant patient topotentially life threatening acid aspiration pneumonia. The gravid uterus slowly causesthe stomach to be displaced upward towards the left hemi-diaphragm. There is an axisrotation of 458 to the right from the normal vertical position and the intra-abdominalportion of the oesophagus is displaced into the thorax. These anatomical shifts cause areduction in lower oesophageal sphincter tone throughout much of pregnancy,predisposing the mother to gastro-esophageal reflux and aspiration.75 Progesteroneand opioids may also relax lower esophageal sphincter tone and reduce esophagealperistaltic time.76,77 The incidence of reflux increases with gestational age, with 72% ofwomen being symptomatic by the third trimester of pregnancy.

Nervous system

During pregnancy, women are more sensitive to the action of many anaesthetic agentsin part due to pregnancy-mediated analgesia, and require less local and volatileanaesthetic than their non-pregnant counterparts. Pregnancy-mediated analgesia is amultifactorial process involving spinal opioid antinociceptive pathways, ovarian sexsteroids (estrogen and progesterone) and uterine afferent neurotransmission.Pregnancy-mediated analgesia elevates the woman’s threshold for pain during thelatter stages of pregnancy prior to labor.78,79 Local anaesthetic dose requirements forspinal and epidural anaesthesia are decreased during pregnancy. The minimum alveolarconcentration (MAC) of inhalational agents is decreased by approximately 30%80 duringpregnancy although high concentrations of inhalational agents are still required forcomplete uterine relaxation. The use of high concentrations of inhaled agents can resultin 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


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 whencompared with non-pregnant women.81 However, the concentration of propofolrequired in early pregnancy (6–12 weeks) at which patients would not respond toa verbal command was not different from non-pregnant controls, indicating thatearly pregnancy does not decrease the concentration of propofol required for lossof consciousness.82 Of note, propofol has been safely used for induction ofanaesthesia for cesarean delivery in doses of 2 mg/kg with minimal effects on theneonate.83 Ketamine has also been used as an induction agent for parturientsundergoing elective cesarean section, with an intravenous dose of 1.5 mg/kgassociated with no neonatal depression at delivery.84

Pregnant women are also more sensitive to the anaesthetic action of the volatileagents than non-pregnant patients. The MAC is decreased by 27% for halothane and by30% for enflurane at term.85 The MAC of isoflurane was reduced by 28% in pregnantwomen at 8–12 weeks’ gestation compared with that of non-pregnant controls.86

Volatile halogenated agents are known to produce dose-dependent uterinerelaxation. These agents have a greater depressant effect in the pregnantmyometrium.87,88 Although 0.5 MAC of enflurane, isoflurane and halothane producea 20% decrease in uterine contractility, larger concentrations (1.5 MAC) produce a 60%decrease in uterine contractility.89 Sevoflurane produces a dose-dependent depressionof uterine muscle contractility with an ED50 of 0.94 MAC, while uterine activity isvirtually abolished at concentrations of greater than 3.5 MAC.90

Pregnancy is associated with a larger dermatomal spread after administration of localanaesthetics using epidural or spinal anaesthesia.91,92 The underlying mechanism of anincreased susceptibility to local anaesthetics during pregnancy is unknown, butmechanical, hormonal, biochemical and neural changes have been suggested.Bupivacaine-induced conduction blockade of A, B and C fibres of the isolated vagusnerve is faster in pregnant rabbits than in non-pregnant animals, and this difference maybe related to a more rapid diffusion and shorter onset of block or to an enhancedsensitivity of the nerve membrane itself.93,94 As a result, the administration of standarddoses of local anaesthetics during neuraxial anaesthesia may result in a higher thanexpected level of sensory and motor block in pregnant patients when compared tonon-pregnant controls.

Rationale for fetal anaesthesia and analgesia

Until as recently as 10 years ago, the ability of the fetus to respond to noxious stimuliwas poorly understood and administration of pain medication to neonates undergoingsurgical intervention was not considered routine. A substantial amount of both animaland human research demonstrated that the fetus is able to mount a substantialneuroendocrine response to noxious stimuli as early as the second trimester ofpregnancy. 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 therationale behind providing fetal anaesthesia and analgesia whenever surgical interven-tion is thought to potentially provide a noxious insult to the fetus. The following sectionaddresses these conclusions in greater detail.


Embryological development in the 2nd and 3rd trimesters

Neurological developmentCentral nervous system development begins in the 3rd week of gestation and synapseswithin the spinal cord develop as early as 8 weeks’ gestation. In general, motor synapsesdevelop before the equivalent sensory ones and thus the first spinal reflexes arepresent from 8 weeks’ gestation. Maximal neuronal development occurs between 8 and18 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 arediffusely located throughout the body by 14 weeks.95 Thus, if the presence of sensoryreceptors were the limiting factor in pain perception, the fetus would feel pain from the2nd trimester onwards. This, however, is unlikely. Sensory receptors are first involvedin the sensation of stimuli that result in local reflex movements involving the spinal cordbut not the higher cortical areas, which classical physiology has defined as necessary forpain perception. As these reflex responses become more complex, they in turn involvethe brainstem, through which other responses such as increases in heart rate and bloodpressure are mediated. However, such reflexes to noxious stimuli do not involve thecortex and, thus, not conscious perception.

The thalamus is the structure responsible for relaying afferent signals from the spinalcord 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 thatthe fetus becomes aware of pain. The thalamus is first identified in a primitive form at day 22post-conception. The final thalamocortical connections are thought to be in place byaround 26 weeks, although estimates differ.96 Certainly, evoked potential studies illustratecortical sensory impulses from 29 weeks’ gestation.97

Descending inhibition is the process whereby the sensation of pain transmitted inthe ascending spinal neurons is dampened via inhibitory descending serotonin neuronsof the dorsal horn of the spinal cord.98 These develop only late in gestation and are stillimmature at birth. This makes it possible that the third trimester fetus, far from beingincapable of the sensation of pain, actually perceives pain as being more pronouncedthan 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 becomesaware of pain. Instead one must rely on fetal responses that could serve as indicators ofaversion to a stimulus. Different studies have used various indicators of a fetalresponse—all are physiological responses seen in times of stress in older children andadults. Observed responses fall into four main categories—motor responses,endocrine responses, circulatory redistribution and cortical activity.

Motor responseA motor response can first be seen as a whole body movement away from a stimulusand observed on ultrasound from as early as 7.5 weeks’ gestational age. The perioralarea is the first part of the body to respond to touch at approximately 8 weeks, but by14 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 isnot known if the fetus is actually aware of the stimulus. However, absence of a motor


response to a stimulus does not imply that the fetus is not sensing the stimulus since thelimiting factor could be the motor component of the response.

Fetal endocrine response to stressHuman fetal endocrine responses to stress have been demonstrated from as early as 18weeks’ gestation. Giannakoulopoulos et al99 first demonstrated increases in fetalplasma concentrations of cortisol and b-endorphin in response to prolonged needlingof the intrahepatic vein (IHV) for intrauterine transfusion. The magnitude of thesestress responses directly correlated with the duration of the procedure. Fetuses havingthe 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-endorphinduring intrahepatic transfusion from 18 weeks’ gestation, which was seen throughoutpregnancy independent both of gestation and the maternal response. The fetal cortisolresponse, 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 thestress of IHV needling, suggesting an analgesic effect.101 A similar, but faster, response isseen in fetal production of noradrenalin to IHV needling. This too is observed in fetusesas early as 18 weeks, is independent to the maternal response and increases to someextent 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-endorphinresponse by 18 weeks and to produce cortisol and noradrenalin responses from 20weeks’ gestation. Although this does not indicate that the fetus is aware of pain at thesegestational ages, the mechanisms for physiological endocrine reactions to pain arecertainly in place.

Methods for fetal anaesthesia and analgesia

There are four methods currently practiced to deliver anaesthetic and analgesicmedications to the fetus. Access to the fetus for the administration of anaesthesia andanalgesia before the insult commences poses a considerable challenge. Potentialmethods include: direct intravascular, direct intramuscular, transplacental and intra-amniotic administration. Each are associated with advantages and disadvantages thathave a direct impact on the overall outcome of fetal intervention.

Intravascular access

Administration of drugs directly into the fetal circulation has obvious advantages. Inaddition to assuring immediate drug levels with expected effects, no additional dosingcalculations need be performed, as placental perfusion does not significantly alterdosing. Intravascular access can be obtained via the umbilical cord (which is notinnervated), larger fetal veins (i.e. hepatic), or intra cardiac as the surgical proceduredictates. One theoretical advantage of administering analgesia via the umbilical vein isthe 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 (atropine20 mg/kg), as well as resuscitation drugs can be given with the assurance of immediateaccess to the fetal circulation with this delivery system. This method is also useful whenalterations in peripheral blood flow occur (i.e. the central sparing response), whichsignificantly diminish the blood distribution to sites of potential intramuscular access.


Fetal intravascular access is not without risk, however. This method requiresneedling 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 infact 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 thesurgical view, but also place the fetus and mother in jeopardy, as an open hysterotomymay be necessary to control bleeding.

Intramuscular access

The second method of fetal drug administration is direct intramuscular injection. Thismethod involves inserting a needle under ultrasound guidance to a fetal extremity,preferably an upper extremity, in order to administer opioids, muscle relaxants andvagolytic drugs as needed. Due to the unknown and often variable rate of intramuscularabsorption 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 ofintramuscular injection, thereby stimulating the fetal stress response. Although the riskof bleeding is less than with intravascular injections, the risk of bleeding and injury fromthe needle itself still exists. Furthermore, if the fetus is already stressed, blood will bediverted away from muscle (the site of drug administration) and towards the fetal heartand brain. In this case, it may be impossible to estimate how much drug has beenabsorbed, if any, from the intramuscular site.

Transplacental access

Many fetal interventions, both open and endoscopic, utilize the concepts oftransplacental drug administration in order to provide anaesthesia and analgesia forboth mother and fetus. Many, but not all drugs cross the placenta via Fick’s Law ofpassive diffusion. Lipid solubility, pH of both maternal and fetal blood, degree ofionization, protein binding, perfusion, placental area and thickness and drugconcentration are some factors that influence the diffusion process.61 The mostobvious disadvantage with this technique is that the mother must be exposed to everydrug the fetus is intended to receive, often at much higher concentrations thanotherwise necessary, in order to achieve an adequate fetal drug level. In addition, theuptake of drugs may be impaired if there is reduced placental blood flow. This hasimplications in terms of successful anaesthesia and analgesia for the fetus and the timeinterval 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 takeslonger than in the mother.61 However, since the fetus needs a lower alveolarconcentration for anaesthesia, this takes no longer than maternal anaesthesia.103 Fetalanaesthesia is also important in order to reduce the fetal stress response, which,through catecholamine release, can reduce placental blood flow and exacerbate anyasphyxia.104

Intra-amniotic access

The fourth method of fetal drug administration is intra-amniotic instillation of a givendrug. Although this method has been used for years in order to treat fetalsupraventricular tachycardias, it is still considered experimental and not routinelypracticed in fetal intervention. Perhaps one limiting factor is the design of properpharmacodynamic and pharmacokinetic investigations determining the appropriate


drug dosing, the rate of clearance and elimination and what the different fetal diseaseprocesses contribute to each of these factors.

Sufentanil and digoxin have both been safely administered in large animal modelswith minimal maternal drug levels obtained in both studies.105,106 If this holds true, thesafety and efficacy of intra-amniotic drug administration may be the preferred methodof choice due to minimal maternal exposure and risk.

MATERNAL ANAESTHETIC MANAGEMENT

Fetal endoscopic interventions have been successfully performed with various differentanaesthetic techniques. With some endoscopic interventions, as in selective laserablation of aberrant vessels seen in TTTS, the site of surgical intervention is notinnervated and thus the fetus may not sense any noxious stimuli whatsoever. Otherinterventions, such as aortic valve dilation, require needle insertion into the fetalthorax, which certainly elicits a noxious stimulus and perhaps even fetal pain. Indeed,since surgical procedures differ, so too do the accompanying anaesthetic requirementsand each case should thus be considered individually.

In addition to surgical demands, each patient and fetus exhibits a uniquephysiological, pharmacological, and pathophysiological profile. The anaesthesiologistmust weigh the advantages and disadvantages of each anaesthetic technique to selectthe safest intra-operative plan.

Local anaesthesia

Local anaesthesia involves the injection of lidocaine or bupivicaine into the proposedtrocar insertion sites. No maternal or fetal medication is thus administered. The mostobvious advantage to this technique is maternal safety, as the mother receives nomedication whatsoever. Disadvantages of this technique include increased risk of injuryto the moving fetus, no fetal anaesthesia or analgesia and no uterine relaxation. Thosepatients on tocolytic therapy or those with polyhydramnios and uterine contractionsmay 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 monitoredanaesthesia care. Advantages to this technique include potential anaesthesia andanalgesia to the fetus via transplacental transfer of agents as well as decreased maternalanxiety. Depending on the amount and effect of drugs administered, this sedation mayincrease the mother’s risk of aspiration with an unprotected airway. Furthermore, thistechnique again provides no uterine relaxation.

Regional neuraxial blockade

Neuraxial techniques (spinal, epidural, or combined spinal epidural anaesthesia) havebeen used frequently with fetoscopic techniques. A T4 sensory level blockade isrequired for most surgical uterine manipulations. This technique has been used in casesof anterior placentas when externalization of the uterus is mandatory for safe trocar


insertion with good success. Neuraxial techniques provide no uterine relaxation nor dothey provide any fetal anaestheia or analgesia. Neuraxial anaesthesia is associated withan increased maternal risk (failed block, high spinal, total, spinal, intravascular injectionof local anaesthetic, etc.) as discussed elsewhere in this chapter.

In a recent series of 29 patients undergoing fetoscopic laser photocoagulation forT T TS, those who received epidural anaesthesia required significantly moreintravenous fluid than those who received either general anaesthesia or a combinationgeneral/regional anaesthetic technique.22 A possible explanation is that with a completesympathetic and motor blockade, as obtained with a high epidural technique, volumereplacement and sympathomimetics may be required to maintain maternal preload anduterine perfusion pressure. Since uterine blood flow is a major determinant of placentalblood flow, any factors that decrease uterine blood flow may jeopardise fetal wellbeing.61 Thus, decreases in maternal blood pressure were treated quickly andaggressively with i.v. fluids and ephedrine to maintain uterine perfusion pressure.However, the administration of large amounts of intravenous crystalloid during fetalsurgery may increase the risk of postoperative maternal pulmonary edema whentocolytic 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 withanaesthesia and analgesia that it would otherwise not receive with regional techniquesalone. Although i.v. fentanyl, propofol and benzodiazepines can be administered topatients receiving regional anaesthesia, it may place the mother at increased risk forbradyarrhythmias, respiratory depression and pulmonary aspiration. As previouslystated, the acceptable level of sensory blockade for surgical manipulation of the uterusis 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 thesensory level.107 Hence, a T4 sensory block may completely block cardiac acceleratorfibres that originate from T1 to T4. Severe bradyarrhythmias and cardiac arrest havebeen 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, therisk of significant bradyarrhythmias may be increased.111

General endotracheal anaesthesia

General anaesthesia achieves many potential goals during fetoscopic intervention as itprovides both maternal and fetal anaesthesia as well as providing dose-dependentuterine relaxation. The biggest risk with this method, however, is the risk of failedmaternal intubation, as discussed earlier. In addition, general anaesthesia withhalogenated agents can provide intra-operative uterine relaxation in patients whohave received prior tocolytic therapy for preoperative uterine premature contractions.Halogenated agents provides anaesthesia for the fetus via placental transfer, whileepidural anaesthesia with local anaesthetics does not.112–115

Combined regional/general endotracheal anaesthesia

A combined regional and general anaesthetic technique is best utilized for thosepatients with anterior placentas in which externalization of the uterus is anticipated for


safe trocar incision. In addition to providing the advantages of both the regional andgeneral anaesthetic techniques listed previously, this method allows for plannedpostoperative pain control. In a recent series, patients with anterior placentas receiveda general or combined technique significantly more frequently than those withposterior placentas.22 The window for trocar insertion was often smaller in this patientgroup, necessitating either externalization of the uterus or extreme lateral decubitusposition. Externalization of the uterus involved a large laparotomy incision, which islarger than the surgical incision for standard cesarean sections. Good post operativepain control was obtained with a continuous epidural infusion of bupivicaine 0.1% with2 mg/cc fentanyl.

FETAL OXYGENATION

One of the most important goals during any fetal intervention is the maintenance offetal oxygenation. The fetus exists in an environment of low oxygen tension, witharterial pO2 being approximately a quarter that of the adult. In umbilical venousblood, pO2 is approximately 30 mmHg at its maximum. The hemoglobin oxygendissociation curve is shifted to the left, due to the presence of hemoglobin F and thelower 2,3-diphosphoglycerate (2,3-DPG) concentration relative to that in the adult’. As2,3-DPG has a high affinity for deoxyhemoglobin, the resultant binding reduceshemoglobin’s oxygen carrying capacity. However, 2,3-DPG exerts only approximately40% 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 atwhich hemoglobin is 50% desaturated) for an adult is approximately 27 mmHg, and forthe fetus is 19 mmHg. The concentration of 2,3-DPG rises with gestation as does theconcentration of hemoglobin A.116 Fetal blood also has a higher hemoglobinconcentration than adult blood (18 g/dl), and therefore a higher total oxygen carryingcapacity.

Oxygen supply to fetal tissues depends on a number of factors. Firstly, the mothermust be adequately oxygenated. Supplementary oxygen must be administeredintraoperatively if necessary. Secondly, there must be adequate blood flow of well-oxygenated blood to the uteroplacental circulation. Blood flow may be reduced for anumber of reasons. Significant maternal haemorrhage reduces maternal blood volumeand thus uterine blood flow. Care must be taken to keep the mother in a left or rightuterine 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 incisionof 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 reductionin uterine blood flow post-hysterotomy observed in that study, the fetus was still ableto compensate and maintain normal oxygen consumption, although others have shownthat similar reductions in blood flow render the fetus acidotic and cause vascularredistribution.118,119 The development of acidemia indicates that the fetus is unable tocompensate, despite adaptations such as an increased heart rate and vascularredistribution.

Even if the uterine circulation is adequate, the fetus is still dependent onuteroplacental blood flow and umbilical venous blood flow for tissue oxygenation.Increases in amniotic fluid volume increase amniotic pressure and impair uteroplacental


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 andthat these values were negatively correlated with amniotic pressure.121 Animal studiessuggest that uteroplacental perfusion has to be reduced by more than 50% before thereare adverse effects on arterial fetal gas status.122 Placental vascular resistance can beincreased, raising the fetal cardiac afterload, by the surge in fetal catecholamineproduction stimulated by surgical stress.123 Care must be taken not to interruptumbilical 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 resultin vasospasm, impairing umbilical venous blood flow. Umbilical vasoconstriction canalso 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 provideinsight into fetal physiology during surgical intervention. With open procedures, it issometimes possible to gain access to a fetal extremity and apply a pulse oximeter foroxygen saturation measurements, obtain venous blood gases for analysis and even applyelectrocardiographic devices. With fetal endoscopic techniques, there is no directaccess to the fetal patient and these techniques are not available. Most practitionersrely on continuous fetal echocardiography to assess fetal well-being during surgicalintervention. By using an ultrasound probe protected in a sterile sleeve, continuousrecordings of fetal heart rate, ventricular function and ventricular volume can beassessed throughout the surgical procedure. Continuous fetal echocardiograms are notwithout limitations. An additional person must be present at an already crowdedoperating table and the ultrasound machine itself takes up valuable operating roomspace. 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 maternalabdomen is becoming more reliable as methods of reducing electrical interference fromthe maternal heart are developed.124 However, to date, the fetal ECG is not yet a partof regular clinical practice.

INTRAOPERATIVE FETAL RESUSCITATION

During any fetal intervention, there may be incidences in which fetal resuscitation isnecessary. Indications depend on the endoscopic procedure itself and include fetalbradycardia (less than 80–100 beats/minutes) and significantly reduced ventricularfunction. Since direct access to the fetus is not immediately available, several othertreatments can be employed. Our group has had success with both intracardiac andintramuscular administration of epinephrine (1–2 mg/kg) to treat severe sustainedbradycardia during aortic valve dilations. Although intramuscular administration has ahighly variable absorption rate secondary to the central sparing response, our team hashad successful resuscitations in several of our cardiac interventions. Other maneuvresaim at improving uterine perfusion and hence fetal oxygenation. These includeincreasing maternal mean arterial pressure to 25% above awake values with volumeloading and ephedrine or phenylnephrine as well as decreasing uterine vascular


resistance by ensuring complete uterine relaxation. If fetal ECG indicates a decreasedventricular 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 procedurethat occurs after every open fetal procedure and with less frequency after fetoscopcintervention.125 Although the mechanisms are not well understood, the occurrence ofcontractions and preterm labor are common for the first few postoperative days.However, for many women the onset of surgically induced preterm contractionsheralds premature labor and delivery that, at best, eliminates the positive results of theprocedure and, at worst, ends in the loss of the pregnancy.126 In addition, significantmaternal morbidity can occur as a consequence of the tocolytic agents used to preventand treat preterm labor.

Despite exhaustive efforts at prevention and treatment, preterm labor remains thesingle most common complication that limits the success and the potential of fetalsurgery. Recently, Li et al127 demonstrated that the intracellular mechanism of uterinequiescence might be related to the concentration of Caldesmon, which acts to preventthe activation of the myosin and actin complex. The release of inhibition of uterineactivity may be due to the activation of an (ERK) kinase-signalling pathway. This groupalso recently found that the administration of an ERK kinase inhibitor successfullyprolonged pharmacologically induced premature labor in rats.128 Although the signalthat causes the loss of this biochemical inhibition is not known, several of the complexsteps leading up to labor have been elucidated in the past decades of research. Earlywork in sheep established a fetal hormonal signal for the onset of both term andpreterm labor.129 In sheep, the onset of labor is heralded by the fetal hypothalamic–pituitary release of adrenocorticotripin, which increases the fetal adrenal production ofcortisol.130 This stimulates the placental enzyme system to switch from the productionof progesterone to favor estradiol.131 This fetal hormonal state produces an increase inprostaglandin and oxytocin production in the intrauterine tissues and increases thesensitivity of the myometrium to oxytocin. Indeed, administration of progesteroneantagonists to rats will produce a predictably timed preterm delivery. In primates,however, this alteration in hormone production that sparks the onset of labor has notbeen uniformly discovered and may be a subtle switch toward fetal estrogen dominancewithout progesterone withdrawal; in humans, the putative hormone is estriol.129 Estriollevels 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 ofthe onset of labor. Some authors have suggested a role for prostaglandins in the initialsteps of the labor cascade. Cortisol reaching the glucocorticoid receptors on the fetaltrophoblasts evokes the expression of prostaglandin H synthetase type 2, which leadsto an increase in prostaglandin E2. This hormone then up-regulates the enzymeresponsible for the production of estrogens.

No single anaesthetic has been implicated as a causative agent and it is more likelythat the stress response of the mother to surgery leads to physiological changes thatpredispose the parturient to uterine irritability, contractions and preterm labor. As isdiscussed below, surgical stress and pain can produce hormonal changes in bothparturients and in the fetus, which create a uterine environment that is prone topreterm labor. After fetal surgery, this stress response is magnified by the site of


surgery being the fetus itself. Thus, even if the immediate post-surgical delivery can beavoided, a predictable and almost inevitable process can lead to premature delivery.

After open fetal surgery, preterm labor can be examined with two patterns; the firstbeing immediate post-surgical delivery, which most often results in fetal loss and thesecond a preterm delivery resulting after a successful delay of delivery for a number ofweeks. The nature of preterm labor following a hysterotomy for fetal surgery issignificantly different in character from spontaneous preterm labor in a normalpregnancy or even that due to the stress response after non-obstetric surgery. In earlyexperimental work developing fetal surgical techniques, Harrison et al132 noted a 73%incidence of spontaneous abortion in primates after open hysterotomy. Several factorsincrease the risk of preterm labor after fetal surgery. Conditions that lead to pretermlabour in the general population, such as polyhydramnios, are often present in thispopulation. The state of health of both the parturient and the fetus are significantfactors, as is the gestational age of the fetus during surgery.133 Other considerationsinclude the size of the uterine incision, duration of surgery, the method of closure of thefetal 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 oflabor, are the expression of fetal cortisol and production of estrogens andprostaglandins. Maternal estrogen is known to be increased in primates after surgicalprocedures during pregnancy and may be a factor in increased uterine irritability andinitiation of preterm labor.134 Surgical stress leads to the release of cortisol, as well asinflammatory cytokines, triggering the hormonal signal that leads to uterine maturationand premature contractions. Furthermore, fetal pain after the surgical procedure maylead to the release of cortisol, inducing the natural pathway that leads to the onset oflabor. It has been suggested that the aggressive myometrial activity may be a naturalattempt by the uterus to remove the fetus from a hostile environment.135 Afterhysterotomy, the myometrium becomes overwhelmed by the natural inflammatoryreaction that initiates preterm labor. Both the cytokines produced during inflammationand thrombin produced during incision have been shown to produce pretermcontractions. The inflammatory cytokines, including interleukin-1, interleukin-6,interleukin-8 and tumour necrosis factor, found in the amniotic fluid in preterm labourresulting from chorioamnionitis, may instigate premature contractions by increasing theproduction and inhibiting the metabolism of uterotonic prostaglandins.136,137 Increasedamniotic fluid concentrations of cytokines, such as Interleukin-6 have been associatedwith preterm delivery and are believed to be part of the fetal systemic inflammatoryresponse, a parallel process to the adult systemic inflammatory response.138

The recent finding that thrombin has significant uterotonic activity and that serumlevels are elevated in women who delivered prematurely, may also help to explain theintensity of uterine contractions after hysterotomy.139–141 The size of the hysterotomyand 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 lesserseverity of preterm contractions supports this theory.

After fetoscopic surgery, the incidence of premature contractions and labor hasbeen reported to be lower than after open hysterotomy.142,143 Fetoscopic interventionappears to have lower requirements for tocolysis and a reduced rate of prematuredelivery.143 In rhesus monkeys, one study found no activity of the myometrium in thefirst 24 hours after fetoscopic access.144 However, the same group found a highincidence of uterine contractions in sheep (52%), which was essentially the same asthe rate after open hysterotomy.145 Rosen et al142 reported the successful performance


of a fetal procedure in a mother at risk for malignant hyperthermia. Because the use ofinhalation anaesthetics was prohibited by the maternal disorder, they used epiduralanaesthesia and an infusion of nitroglycerine for intraoperative uterine relaxation. Theyhad a successful postoperative course with minimal requirements for tocolysis in theimmediate postoperative period. The success of this regimen was probably onlypossible because of the small uterine incisions made during fetoscopic surgery.

Unfortunately, the decrease in incidence and severity of premature contractions isbalanced 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 chorionicmembrane separation, preterm labor and chorioamnionitis.146 Access during fetoscopicsurgery requires one or multiple punctures through the fetal membranes. These sites arenot 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%, theoccurrence of this complication after single port fetoscopic cases reaches 5–10%; ofnote, extremely high rates of 60% have been reported after fetal surgical proceduresrequiring multiple entry sites.146,147 PROM is a potentially devastating complication thatcan lead to ascending infection and chorioamnionitis, fetal compromise and pretermdelivery. Several techniques that attempt to prevent the rupture of membranes afterfetoscopic surgery have been developed, such as introducing a plug during the removal ofthe endoscopes and sealing the membrane rupture with fibrin glue.148,149 Thus far, nosingle technique has proven to be ideal. Fortunately, with the development of smallerendoscopic equipment and the advancement of surgical techniques, these cases havedemonstrated improved outcomes in recent years.146

Regardless of the exact cause of preterm labor after fetal surgery, without the use oftocolytics, uterine incisions lead to an intolerably high rate of spontaneous abortion andif an immediate delivery can be avoided, the intrauterine environment makes pretermdelivery almost inevitable. While several physiological processes are active, of particularinterest 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 probablyessential to successful fetal surgery.

Pain control after fetal surgery is an essential component of therapy, not only forhumanitarian reasons, but also because it is believed that adequate pain controlprevents the stress-induced hormonal impetus for preterm labor.126 Both maternal andfetal pain elicits the release of adrenocorticotripin hormone, the hormone that signalsto the adrenal gland to increase production of cortisol.126 Pain-induced cortisolproduction leads to the deleterious changes in the placenta that increases fetal estrogenand prostaglandin production and probably promotes increased uterine activity.Adequate pain control is believed to block the fetal and maternal stress response andprevent the activation of the hormonal pathway to labor. Some experimental evidencehas demonstrated that this is true. Tame et al134 administered normal or double-dosesof opioids to baboons in a fetal surgery model. They found that the baboons thatreceived a higher dose of analgesics had lower levels of maternal estrogens, cortisol andoxytocin than was found in the baboons that received a lesser dose. Furthermore, theactivity of the myometrium, as measured by the frequency of uterine contractions, wassignificantly less in those animals that received more opioids. Other investigators havefound that infiltration of ultra-long acting local anaesthetics (microspheres laden withbupivacaine) into the uterus at the time of surgery was effective in the prevention ofpreterm contractions, probably by blockade of transmission of uterine contractileimpulses.150 Unfortunately, all of the fetuses in the experimental group died, possiblydue to the deleterious effects of bupivacaine on uterine tone and blood flow.


A retrospective analysis of a 10 year experience with tocolytic agents at theUniversity of California San Francisco demonstrated a 0.5% overall rate of pulmonaryoedema seen among parturients.137 There were 65 parturients treated using open fetalsurgery between 1985 and 1995 and pulmonary edema developed in 23% of them. Allparturients in whom fetal surgery was performed received multiple tocolytic agentssimultaneously with generous intravenous hydration. The patients’ chest radiographs,degree of hypoxaemia, overall lung injury severity scores and the time to resolutionwere more severe and protracted than those patients with hydrostatic pulmonaryedema, but were similar to the increased permeability pattern seen in parturients withan infectious etiology of edema.137

The fetal side-effects of tocolytics present a number of problems, albeit usually lessso than in the mother. Beta-sympathomimetics cause fetal tachycardia.151 Cyclo-oxygenase (COX) inhibitors have been shown to be more effective than others indelaying labor in a meta-analysis.152 However, the side-effects of fetal oliguria and ductusarteriosus constriction, which occur even with the COX II selective inhibitors havelimited their long-term use.153 After short term use these side-effects were all fullyreversible within 72 hours from the cessation of treatment.153 Longer term use ofindomethacin has been associated with renal dysfunction, and increased rates ofnecrotizing enterocolitis, intracranial hemorrhage and patent ductus arteriosus ininfants 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 asnifedipine, inhibit contractility in smooth muscle cells. No adverse fetal effects havebeen reported in humans, although in animals nifedipine has been shown to cause areduction in uterine blood flow and fetal metabolic acidosis.156,157 It has been suggestedthat 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 reducesfetal heart-rate variability159 and depresses fetal right ventricular function.160 Since thisdrug rapidly crosses the placenta, but is excreted more slowly by the fetal kidneys thanby the maternal kidneys, there are concerns about fetal toxicity, resulting in respiratoryand central nervous system depression.161 Nitric oxide donors, such as nitroglycerineappear to have minimal fetal side effects.162

SUMMARY

Fetoscopic intervention presents many unique challenges to the anaesthesiologist, whomust care for two or possibly three patients, each with specific and often conflictingrequirements. A complete understanding of the fetal anatomical development,neuroendrocrine responses and pharmacological limitations are necessary prior toadministering anaesthesia for these cases. In addition, maternal physiologicaladaptations to pregnancy may significantly alter anaesthetic techniques and require-ments. Furthermore, different fetal disease processes may demand further alterationsto the anaesthetic plan. As such, a thorough understanding of the underlying fetaldisease process is necessary to make the best decision with regard to anaestheticmanagement. Finally, a thorough discussion with the surgical team will allow theopportunity to prepare for variations in both maternal and fetal anatomy. It is only byaddressing these issues can appropriate anaesthetic care be administered. Perhapsthe most important role the anaesthesiologist may play in fetal intervention, however, isthe contribution of new ideas, methods, research and techniques that will hopefullyaddress 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 toprovide the safest anaesthetic possible

† physiological alterations associated with pregnancy occur as early as the firsttrimester 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 post-intervention uterine contractions

Research agenda

† additional studies are needed to determine the efficacy of fetoscopicintervention, with attention to long-term outcomes and patient morbidity

† alternative methods to provide fetal anaesthesia and analgesia must bedeveloped in order to maximise maternal safety

† improvements in tocolytic techniques are imperative to optimize the chancesof a successful intervention


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