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 Table of Contents    
REVIEW ARTICLE
Year : 2018  |  Volume : 62  |  Issue : 9  |  Page : 717-723  

Foetal surgery: Anaesthetic implications and strategic management


University of Maryland Medical Center, University of Maryland, Baltimore, Maryland, USA

Date of Web Publication10-Sep-2018

Correspondence Address:
Dr. Bhavani Shankar Kodali
Department of Anesthesiology, University of Maryland Medical Center, 22 S Green Street, Baltimore, MD 21201
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ija.IJA_551_18

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Intrauterine surgery is being performed with increasing frequency. Correction of foetal anomalies in utero can result in normal growth of foetus and a healthier baby at delivery. Intrauterine surgery can also improve the survival of babies who would have otherwise died at delivery, or in the neonatal period. There are three commonly used approaches to correct foetal anomalies: open surgery, where the foetus is exposed through hysterotomy; percutaneous approach, where needle or foetoscope is inserted through the abdominal wall and the uterine wall; finally, ex utero intrapartum treatment (EXIT) surgery, where the intervention is performed on the baby before terminating the maternal umbilical support to the baby. Anaesthetic management of the mother and the foetus requires good understanding of maternal physiology, foetal physiology, and pharmacological and surgical implications to the foetus. Uterine relaxation is a critical requisite for open foetal procedures and EXIT procedures. General anaesthesia and/or regional anaesthesia can be used successfully depending on the nature of foetal intervention. Foetal surgery poses complications not only to the foetus but also to the mother. Therefore, the decision for undertaking foetal surgery should always consider the risk to the mother versus benefit to the foetus.

Keywords: Anaesthesia for foetal surgery, EXIT procedure, foetal surgery, foetoscopy, intrauterine surgery


How to cite this article:
Kodali BS, Bharadwaj S. Foetal surgery: Anaesthetic implications and strategic management. Indian J Anaesth 2018;62:717-23

How to cite this URL:
Kodali BS, Bharadwaj S. Foetal surgery: Anaesthetic implications and strategic management. Indian J Anaesth [serial online] 2018 [cited 2018 Dec 12];62:717-23. Available from: http://www.ijaweb.org/text.asp?2018/62/9/717/240832




   Introduction Top


Intrauterine surgery is becoming popular for treating foetal congenital anomalies.[1] This has provided many foetuses with significant anomalies to survive to full-term pregnancy and beyond.[2] Many factors have contributed to the success of this newly evolved field such as improvements in diagnostic and therapeutic technology, advances in understanding foetal pathophysiology, and the natural history of many of these conditions. Foetal intervention procedures include open foetal surgery, minimally invasive foetal surgery, ex utero intrapartum treatment (EXIT) procedures (intervention at caesarean delivery), foetal endoscopic surgery, and laser ablation of umbilical cords in twin pregnancies. An important consideration of intrauterine foetal intervention is that it should not jeopardise the safety of the mother. In most cases, foetal intervention is performed during pregnancy and pregnancy is continued to term. In some instances, EXIT surgery is performed on the foetus on placental support, followed by delivery. An understanding of maternal and foetal implications of anaesthetics is critical for optimum management of mother and foetus during foetal intervention. It is also critical to understand the physiological changes in pregnancy that influence anaesthetic management [Table 1]. [Table 2]a and [Table 2]b summarise essential guidelines of anaesthetic management of a pregnant woman undergoing surgery.
Table 1: Anatomical and Physiological Changes of Pregnancy

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Approximately over 1000 such cases are performed every year. This number is likely to increase in the future with advances in technology, attainment of foetal intervention skills, and enthusiasm to perform foetal interventions based on positive results of published data.

Procedures amenable to foetal intervention

[Table 3] lists indications of foetal interventions that are currently being performed. With further proficiency, new indications are forthcoming.[3],[4],[5],[6],[7],[8],[9],[10],[11] One of the most common indications is aortic valvoplasty in the foetus. This improves the growth and performance of the left ventricle at birth. Generally, each center of foetal intervention offers one or two procedures which may be considered their field of expertise.
Table 3: Intrapartum foetal interventions

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Anaesthesia for minimally invasive procedures

The choice of anaesthesia depends on invasive procedure. Regional anaesthesia is the preferred technique where feasible. The impact of anaesthetic drugs on the foetus is minimal with regional anaesthesia. During our experience of over two decades, we have transitioned from general anaesthesia to regional anaesthesia for minimally invasive procedures [aortic valvoplasty, [Table 4] and [Figure 1].[12] General anaesthesia was a preferred technique during the earlier phase of our practice. This was based on the perception that uterine relaxation and foetal analgesia were essential requirements of foetal intervention.[12],[13] Foetuses undergoing procedures at mid to late gestation may have the requisite neural development for pain and stress response.[14] Hormonal and haemodynamic stress responses do suggest that foetuses respond to noxious stimuli.[15],[16] Therefore, foetal analgesia is a prime concern to be addressed during anaesthesia for foetal surgery. Although it was our belief two decades ago that uterine relaxation was necessary for minimally invasive surgery, such as aortic valvoplasty, experience over a decade suggests that uterine relaxation for minimally invasive procedures was not essential. Moreover, administration of minimum alveolar concentration (MAC) over 1.5 can have depressant effect on the foetal myocardium. Administration of foetal intramuscular fentanyl (ultrasound-guided) can resolve the foetal pain concern. Foetal intramuscular injection of fentanyl along with a neuromuscular blocking agent ensures foetal immobility and foetal analgesia. Combined spinal epidural anaesthesia provides optimum conditions for minimally invasive procedures such as aortic valvoplasty. One milliliter of hyperbaric bupivacaine 0.75% with dextrose, with or without fentanyl 10 μg, provides an adequate level for foetal intervention. Left uterine displacement and monitoring of blood pressure are essential to maintain blood pressures within close limits of baseline. Recently, we have been using a noninvasive cardiac output device to continuously monitor cardiac output. The cardiac output data and blood pressure data provide valuable information while choosing the appropriate vasopressors [maternal intravenous (IV) phenylephrine and/or ephedrine]. Maintenance of maternal haemodynamics near normal values assures a steady cardiovascular state at the time of foetal intervention. Medications that may be used for foetal anaesthesia and immobility are fentanyl 10–50 μg/kg and vecuronium 0.1–0.3 mg/kg. Resuscitation medications for the foetus include epinephrine 1 μg/kg, and atropine 0.02 mg/kg. If foetal packed red blood cell transfusion becomes necessary, cytomegalovirus-free, leukocyte-depleted O-negative blood can be considered.[1],[17]
Table 4: Data from reference 12, 1999–2005

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Figure 1: Ultrasound-guided needle placement into foetal left ventricle. A balloon catheter placed through the needle across the aortic valve to facilitate aortic valvuloplasty

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Open foetal surgery

Surgery on the foetus is facilitated by a hysterotomy. An epidural can be placed before induction of general anaesthesia for providing postoperative pain relief. As an alternative, administration of a preoperative intrathecal opioid can be used. Both methods are equally efficacious in providing postsurgical pain relief. General anaesthesia by a rapid sequence induction, followed by maintenance of anaesthesia using inhalational anaesthetic agents, is a preferable technique as inhalational agents provide dose-dependent uterine relaxation necessary for optimum foetal surgical exposure.[18],[19] Isoflurane, sevoflurane, and desflurane have been used successfully, although the latter two are more potent than isoflurane.[20] To prevent hypotension and foetal bradycardia, supplemental IV medications can be used in the initial stages of anaesthesia and inhalational agents are used when foetal exposure is required.[21] A two to three MAC concentration of inhalational agents is required for desired uterine relaxation and exposure. An arterial line will be helpful to monitor maternal blood pressure accurately. Central venous pressure monitoring is rarely required. Additional nitroglycerine boluses (50–100 μg IV) or infusion (0.5–1 μg/kg/min) can be used to supplement uterine relaxation, when inhalational agents are not sufficient. If neuraxial anaesthesia is being used for foetal surgery, IV nitroglycerine offers a good method to achieve uterine relaxation. However, this may be associated with maternal tachycardia, tachyphylaxis, methaemoglobinemia, headache, and pulmonary oedema.[22],[23] Before uterine incision, placental position is ascertained. Uterine incision is made with a stapling device to prevent excessive uterine bleeding. The amniotic sac membranes are sealed to the endometrium. Amniotic infusion with warm lactated Ringer's solution is used to maintain foetal temperature, maintain uterine volume, and avoid compression of umbilical cord.[23] Vasopressors are required to maintain blood pressure during the procedure because of vasodilatory effects of inhalational agents and/or nitroglycerine. Additional monitoring of cardiac output through arterial line is a good adjuvant in maintaining cardiovascular stability. Guarded administration of IV fluids is recommended to prevent maternal pulmonary oedema following foetal surgery. Foetal monitoring during the procedure can be achieved with pulse oximetry, continuous or intermittent echocardiography, foetal scalp electrodes, and umbilical blood sampling.[18]

Despite the transfer of inhalational agents from maternal to foetal circulation, which may be unpredictable, fentanyl for analgesia and muscle relaxant for foetal immobility can be administered intramuscularly to the foetus. Volatile anaesthetics can be discontinued or decreased soon after uterine closure. Anaesthesia can be maintained by propofol infusion. Maternal postoperative pain should be controlled with IV opioids. An intrathecal narcotic, if given prior to general anaesthesia, can adequately supplement analgesia to decrease postoperative pain. If an epidural is placed prior to general anaesthesia, epidural postoperative analgesia can be provided. Extubation should be performed with minimal coughing to avoid uterine dehiscence. Adequate postoperative pain control is associated with lower oxytocin concentrations in the blood, thereby decreasing premature uterine contractions.[24] Preoperative rectal indomethacin (50 mg) and postprocedure magnesium sulphate (4–6 g IV loading dose followed by 1–2 g/h IV infusion) are administered for tocolysis.[25] Terbutaline and nifedipine are used as supplements if above are ineffective.

EXIT (ex utero intrapartum treatment procedures)

This is also known as operation on placental circulation. The intervention can be performed with vaginal or caesarean delivery. The latter is preferable as it offers greater control and longer duration of placental support. Usually, these procedures are reserved for foetuses who are unable to oxygenate upon delivery due to airway abnormalities. An example of this is securing the baby's airway at the time of delivery, where the airway is compressed by a tumor (cystic hygroma), and while the baby is supported by the maternal circulation through umbilical cord [Figure 2] and [Figure 3]. EXIT procedures also facilitate transition to extracorporeal membrane oxygenation for oxygenation of the baby and maintaining on the system until cardiorespiratory anomaly is corrected and the baby can oxygenate well on its own. Once the oxygenation of the baby is assured without the need of maternal support, the baby is delivered from the uterus and umbilical circulation is terminated. Procedures involving longer than 2 h have been successfully performed using EXIT procedures.[26]
Figure 2: A foetus with a neck tumor. Airway being secured before disrupting uteroplacental–umbilical cord blood flow (EXIT)

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Figure 3: (a) Airway secured at EXIT procedure. (b) Surgical exicision of cystic hygroma

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The majority of EXIT procedures are performed under general anaesthesia using high concentrations of volatile anaesthetics at the time of hysterotomy to facilitate uterine relaxation.[23] Uterine relaxation is essential for facilitating the controlled delivery of the foetal head and maintaining the placental circulation by preventing placental separation from the uterus. Vasoactive medications will be necessary to maintain blood pressure. Arterial blood pressure monitoring is preferable for titration of vasoactive medications. Cardiac output monitoring can provide additional data for choosing vasoactive medications. Maintaining maternal blood pressures and cardiac output closer to baseline ensures adequate placental blood flow.

The usual precautions of general anaesthesia for caesarean delivery apply to EXIT procedures. After the baby is delivered, uterotonics should be administered and inhalational agents are terminated. As the concentration of induction agents decrease, IV propofol can be administered for maintaining general anaesthesia. A Bispectral Index Monitor can assure adequate depth of anaesthesia for this transition and maintain optimal depth of general anaesthesia. Postoperative analgesia can be achieved through an epidural route if there is a preexisting catheter. If not, systemic analgesics can be used. A transverse abdominal plane block can offer additional analgesia. Overall risk of haemorrhage is increased due to atonic uterus. Crossed match blood should be available for these procedures.

Foetoscopy procedures

Foetal endoscopic surgery ('Fetendo') obviates the need for a large uterine incision and may reduce the overall risks of foetal surgery by causing less uterine trauma and ultimately less preterm labor. In 1973, Schrimgeour introduced the term foetoscopy after exposing the uterus at laparotomy and inserting a 2.2-mm needle scope to view the amniotic cavity and foetus.[27] Foetoscopy surgery can be performed by two methods. In the first method, trocars are introduced into the uterine cavity through a laparotomy. In the second, less invasive method, a trocar is introduced percutaneously. Foetoscopy has since then adapted to many foetal interventions. Temporary tracheal occlusion is a promising strategy to enlarge the lungs in foetuses with congenital diaphragmatic hernia. Aberrant vessels leading to twin–twin transfusion syndrome can be ligated to prevent foetal death. Similarly, radiofrequency ablation or coagulation of nonviable twin's umbilical cord in twin reversed arterial perfusion, division of amniotic bands in amniotic band syndrome, and laser ablation of posterior urethral valves through foetal cystoscopy are other procedures undertaken using foetoscopy. A combined epidural spinal anaesthesia as described below with sedation is suitable for these procedures.

Mirror syndrome

Mirror syndrome is the development of maternal pulmonary oedema in the setting of severe foetal hydrops. These patients can present with preeclampsia-like symptoms which can make distinguishing between this condition and preeclampsia difficult.[7] The most common maternal symptoms are weight gain and maternal oedema (89.3%), followed by elevated blood pressure (60.7%), mild anaemia and haemodilution (46.4%), albuminuria and proteinuria (42.9%), elevated uric acid and creatinine (25%), mild elevated liver enzymes (19.6%), oliguria (16.1%), and headache and visual disturbances (14.3%). Severe maternal complications including pulmonary oedema occur in 21.4% of cases.[28] The average rate of intrauterine death and stillbirth is 35.7%, and the average time until maternal symptoms disappear is about 8.9 days.[28] The etiology remains unclear, but the maternal symptoms are reversible by successful foetal intrauterine therapy or, in certain cases with poor foetal prognosis, by foetal termination.[29] Foetal intervention includes placement of a peritoneal-amniotic shunt. This resolves the foetal hydrops and maternal mirror syndrome in some cases.[30] For foetoscopy procedures, anaesthesia is induced and maintained by combined spinal–epidural technique, with subarachnoid injection of administrations of 2.5 mg of bupivacaine and 25 mcg of fentanyl. Additional anaesthesia is provided through epidural catheter by administering 6–9 mL of 1%–2% lidocaine with epinephrine (1 in 200,000) or 0.25% bupivacaine, as required. This cautious approach prevents hypotension which may require fluid boluses, thus predisposing parturient to the risk for developing mirror syndrome (Ballantyne syndrome). Hence, it is prudent to avoid fluid overload in these patients undergoing foetal therapy.

Postoperative precautions

The foetal heart is closely monitored in the immediate postoperative period. The duration of monitoring depends on the nature of intervention and may extend to 24–48 h following open foetal intervention. Premature labour should be avoided with uses of tocolytics. Left lateral tilt of the patients in the postoperative period and haemodynamics and oxygenation monitoring should be adopted. Venous thromboprophylaxis should be considered.

Complications

Apart from the complications related to anaesthesia for caesarean delivery, or interim nonobstetric surgery, there is susceptibility towards postoperative pulmonary oedema due to tocolytic use or foetal anomaly (hydrops foetalis). In addition, foetal surgery can predispose the mother to other potential maternal risks such as haemorrhage, premature rupture of membranes, chorio-amnion membrane separation, preterm labour, preterm delivery, foetal demise, chorioamnionitis, placental abruption, and increased need for maternal transfusion at the time of delivery.


   Summary Top


Foetal surgery requires a coordinated multidisciplinary approach. The benefit to the baby should be weighed against the risk to the mother. With advancements in technology and skill of interventional clinicians, many more foetal anomalies will be diagnosed in utero with proposed novel interventions. The temptation to undertake novel approaches will require careful evaluation of maternal risk. The anaesthetic approach must consider a technique that ensures maternal and foetal cardiovascular stability, sustained placental blood flow, minimal depression of foetal organ functions, foetal analgesia, foetal immobility, adequate blocking of the foetal stress response, and uterine relaxation during surgical procedure. For EXIT procedures, return of uterine tone is critical after delivery of the baby. International consensus from academic societies is guiding future strategies of management. For example, an international MOMs trial supports foetal repair of meningomyelocele for normal growth and function of neuraxial system in the foetus and beyond after delivery.[31]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Sviggum HP, Kodali BS. Maternal anesthesia for fetal surgery. Clin Perinatol 2013;40:413-27.  Back to cited text no. 1
    
2.
ACS Surgery News. Myelomeningocele Repair Drives Changes in Fetal Surgery; 17 October, 2012. Avaialble from: https://www.mdedge.com/acssurgerynews/article/56082/obstetrics/myelomeningocele-repair-drives-changes-fetal-surgery/page/0/4. [Last accessed on 2018 Aug 23].  Back to cited text no. 2
    
3.
Casella DP, Tomaszewski JJ, Ost MC. Posterior urethral valves: Renal failure and prenatal treatment. Int J Nephrol 2012;2012:351067.  Back to cited text no. 3
    
4.
Deprest J, Nicolaides K, Done' E, Lewi P, Barki G, Largen E, et al. Technical aspects of fetal endoscopic tracheal occlusion for congenital diaphragmatic hernia. J Pediatr Surg 2011;46:22-32.  Back to cited text no. 4
    
5.
Kohl T, Tchatcheva K, Merz W, Wartenberg HC, Heep A, Müller A, et al. Percutaneous fetoscopic patch closure of human spina bifida aperta: Advances in fetal surgical techniques may obviate the need for early postnatal neurosurgical intervention. Surg Endosc 2009;23:890-5.  Back to cited text no. 5
    
6.
Lee H, Wagner AJ, Sy E, Ball R, Feldstein VA, Goldstein RB, et al. Efficacy of radiofrequency ablation for twin-reversed arterial perfusion sequence. Am J Obstet Gynecol 2007;196:459.e1-4.  Back to cited text no. 6
    
7.
Llurba E, Marsal G, Sanchez O, Dominguez C, Alijotas-Reig J, Carreras E, et al. Angiogenic and antiangiogenic factors before and after resolution of maternal mirror syndrome. Ultrasound Obstet Gynecol 2012;40:367-9.  Back to cited text no. 7
    
8.
Marshall AC, van der Velde ME, Tworetzky W, Gomez CA, Wilkins-Haug L, Benson CB, et al. Creation of an atrial septal defect in utero for fetuses with hypoplastic left heart syndrome and intact or highly restrictive atrial septum. Circulation 2004;110:253-8.  Back to cited text no. 8
    
9.
Roberts D, Gates S, Kilby M, Neilson JP. Interventions for twin-twin transfusion syndrome: A cochrane review. Ultrasound Obstet Gynecol 2008;31:701-11.  Back to cited text no. 9
    
10.
Roberts D, Neilson JP, Kilby M, Gates S. Interventions for the treatment of twin-twin transfusion syndrome. Cochrane Database Syst Rev 2008;23:CD002073.  Back to cited text no. 10
    
11.
Tworetzky W, Wilkins-Haug L, Jennings RW, van der Velde ME, Marshall AC, Marx GR, et al. Balloon dilation of severe aortic stenosis in the fetus: Potential for prevention of hypoplastic left heart syndrome: Candidate selection, technique, and results of successful intervention. Circulation 2004;110:2125-31.  Back to cited text no. 11
    
12.
Silva V, Tsen LC, Wilkins-Haug L, Kodali BS. A Womb with a view: Anesthetic, obstetric, and neonatal care issues for in-utero fetal surgery. Anesthesiology 2006;104 Suppl:A12.  Back to cited text no. 12
    
13.
Glover V, Fisk NM. Fetal pain: Implications for research and practice. Br J Obstet Gynaecol 1999;106:881-6.  Back to cited text no. 13
    
14.
Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003;23:876-82.  Back to cited text no. 14
    
15.
Giannakoulopoulos X, Sepulveda W, Kourtis P, Glover V, Fisk NM. Fetal plasma cortisol and beta-endorphin response to intrauterine needling. Lancet 1994;344:77-81.  Back to cited text no. 15
    
16.
Lee SJ, Ralston HJ, Drey EA, Partridge JC, Rosen MA. Fetal pain: A systematic multidisciplinary review of the evidence. JAMA 2005;294:947-54.  Back to cited text no. 16
    
17.
Saxena KN. Anaesthesia for fetal surgeries. Indian J Anaesth 2009;53:554-9.  Back to cited text no. 17
[PUBMED]  [Full text]  
18.
De Buck F, Deprest J, Van de Velde M. Anesthesia for fetal surgery. Curr Opin Anaesthesiol 2008;21:293-7.  Back to cited text no. 18
    
19.
Van de Velde M, De Buck F. Fetal and maternal analgesia/anesthesia for fetal procedures. Fetal Diagn Ther 2012;31:201-9.  Back to cited text no. 19
    
20.
Yoo KY, Lee JC, Yoon MH, Shin MH, Kim SJ, Kim YH, et al. The effects of volatile anesthetics on spontaneous contractility of isolated human pregnant uterine muscle: A comparison among sevoflurane, desflurane, isoflurane, and halothane. Anesth Analg 2006;103:443-7.  Back to cited text no. 20
    
21.
Boat A, Mahmoud M, Michelfelder EC, Lin E, Ngamprasertwong P, Schnell B, et al. Supplementing desflurane with intravenous anesthesia reduces fetal cardiac dysfunction during open fetal surgery. Paediatr Anaesth 2010;20:748-56.  Back to cited text no. 21
    
22.
Garcia PJ, Olutoye OO, Ivey RT, Olutoye OA. Case scenario: Anesthesia for maternal-fetal surgery: The ex utero intrapartum therapy (EXIT) procedure. Anesthesiology 2011;114:1446-52.  Back to cited text no. 22
    
23.
Olutoye OO, Olutoye OA. EXIT procedure for fetal neck masses. Curr Opin Pediatr 2012;24:386-93.  Back to cited text no. 23
    
24.
Santolaya-Forgas J, Romero R, Mehendale R. The effect of continuous morphine administration on maternal plasma oxytocin concentration and uterine contractions after open fetal surgery. J Matern Fetal Neonatal Med 2006;19:231-8.  Back to cited text no. 24
    
25.
Adzick NS. Open fetal surgery for life-threatening fetal anomalies. Semin Fetal Neonatal Med 2010;15:1-8.  Back to cited text no. 25
    
26.
Hirose S, Farmer DL, Lee H, Nobuhara KK, Harrison MR. The ex utero intrapartum treatment procedure: Looking back at the EXIT. J Pediatr Surg 2004;39:375-80.  Back to cited text no. 26
    
27.
Barbachowska AB, Krzanik K, Zamlynski M, Bodzek P, Olejek A. Intrauterine fetal surgery. World Sci News 2017;76:5-15.  Back to cited text no. 27
    
28.
Braun T, Brauer M, Fuchs I, Czernik C, Dudenhausen JW, Henrich W, et al. Mirror syndrome: A systematic review of fetal associated conditions, maternal presentation and perinatal outcome. Fetal Diagn Ther 2010;27:191-203.  Back to cited text no. 28
    
29.
Chimenea A, García-Díaz L, Calderón AM, Heras MML, Antiñolo G. Resolution of maternal mirror syndrome after succesful fetal intrauterine therapy: A case series. BMC Pregnancy Childbirth 2018;18:85.  Back to cited text no. 29
    
30.
Heyborne KD, Chism DM. Reversal of ballantyne syndrome by selective second-trimester fetal termination. A case report. J Reprod Med 2000;45:360-2.  Back to cited text no. 30
    
31.
Kitagawa H, Pringle KC. Fetal surgery: A critical review. Pediatr Surg Int 2017;33:421-33.  Back to cited text no. 31
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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