Current Status of Fetal Surgery
http://www.100md.com
《美国医学杂志》
Department of Pediatric Surgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India, India
Abstract
Abstract. The allure of fetal surgery is the possibility of interrupting in utero progression of an otherwise treatable condition. In spite of advances in prenatal diagnosis and refinements in surgical techniques, this field has not yet got off the ground because the risks to the mother and fetus, during and after the procedure far outweigh the benefits, and the infrastructure required to support such activity is prohibitively expensive. The various surgical conditions in which fetal surgery has been attempted and the present status of this specialty are discussed. [Indian J Pediatr 2005; 72 (5) : -436]
Keywords: Fetal surgery; Prenatal diagnosis; Congenital diaphragmatic hernia; Cystic lung lesion; Obstructive uropathy, Sacrococcygeal teratoma; Spina bifida
Fetal intervention is feasible in conditions, which interfere with the normal development of the fetus and when corrected will allow it to develop normally. It is contraindicated in conditions that are incompatible with life whether because of the severity of the affliction, other associated life threatening anomalies or chromosomal anomalies. The requirements before such an intervention are -experimental work to prove the pathophysiology of the defect and careful study of the natural history of the untreated disease. Research in fetal surgery is ethically controversial as it poses a risk both to the fetus and the pregnant woman. Developing appropriate surgical techniques, devising fetal and uterine monitoring and preventing uterine contractions after surgery (tocolysis) are major hurdles in its development.
The first successful therapeutic fetal procedure was reported by Sir A.W. Liley, who transfused a hydropic fetus with Rh. disease in 1965. Dr Michael Harrison and his team at the University of California pioneered modern fetal surgery after extensive work on animal models. Many of the successes in animal models however, could not be translated to the human conditions. His team did the first open fetal surgical procedure in 1982 for obstructive uropathy.[1] The baby expired in the neonatal period because of unrecognized pulmonary and renal dysplasia. Nevertheless, it was the dawn of a new era of fetal intervention. Successful fetal interventions have now been performed for surgical conditions like congenital diaphragmatic hernia, cystadenomatoid malformation of the lung, sacrococcygeal teratoma, obstructive uropathies etc.
Investigations
This is one of the most important aspects of management before embarking on fetal intervention. The two important modalities are ultrasonography (US) and magnetic resonance imaging (MRI). The views may be poor, even with high resolution US, because of maternal obesity and oligohydramnios. Three-dimensional US, mainly used in detecting surface abnormalities like cleft lip and spina bifida, now allows accurate measurement of volume of any fetal organ. MRI (echo-planar) is especially useful in evaluating the fetal central nervous system and also as an adjunct to ultrasound in diagnosing complex anomalies.[2] With ultrafast scanning techniques, images of the fetus can be obtained in 300-400 ms without sedation.
Maternal and Fetal Considerations and Risks
The unique physiology of the fetus with additional problems of associated anomaly and the difference in physiology of a pregnant from a non-pregnant woman makes anesthesia and surgery all the more formidable. All fetal intervention procedure series have repeatedly and consistently shown premature delivery, often before 30 weeks triggered by breaching the uterus, whether by puncture or incision. Tocolytic therapy is therefore, always required, which often leads to pulmonary edema. Delivery after fetal surgery and all future pregnancies require Cesarean section, as the hysterotomy for fetal surgery is done in the upper uterine segment. Absorbable materials are used to close the uterus, since the uses of nonabsorbable/metal staplers appear to have affected fertility in animal models. Intra-operative blood loss requiring transfusion, amniotic fluid leaks from the operated sites/vagina, wound infection, intrauterine infection as well as behavioral changes can also occur. In case of hydrops, the mother has to be monitored for 'maternal mirror syndrome', i.e. the mothers develop high output cardiac failure and physiological manifestations that "mirror" those of the distressed fetus. Fetal surgery, unfortunately often does not cure this.
The incidence of chorioamniotic membrane separation is around 47%, which in turn is associated with an increased incidence of premature rupture of membranes (63%), preterm labor (57%) and chorioamnionitis (29%).[3] Further, damage to the fetal organ that is being operated upon, embolic events which can lead to intestinal atresia and renal agenesis; premature closure of ductus arteriosus leading to cardiac failure and neonatal death can occur. Long-term studies have shown a 21% incidence of central nervous system injury, which may be due to sudden fluxes in cerebral blood flow, induced by maternal hypoxia or tocolytic drugs.
Techniques
Deep inhalation anesthesia is usually induced with isoflurane. Prior to this, all patients receive epidural anesthesia, which is maintained post-operatively. These two factors appear to reduce early uterine irritability. However, the depth of anesthesia required to give adequate uterine relaxation can produce fetal and maternal myocardial depression and affect placental perfusion. Intravenous nitroglycerine (a nitric oxide donor) has been tried to counteract this effect. The mother is monitored with pulse oximetry, ECG as well as with central venous and arterial catheters. Euvolemia is maintained to avoid post-operative pulmonary edema.
There are two approaches to the fetus: open hysterotomy and minimally invasive techniques.
Open Hysterotomy : The uterus is exposed through a low, transverse abdominal incision. It is displaced to the left to avoid compression of the inferior vena cava. Intra-operative ultrasound (US) locates the placenta and identifies the fetal position. The fetus is injected with a narcotic and a paralytic agent. The uterus, fully relaxed at the time of incision is opened anteriorly or posteriorly depending on the position of the placenta. It is not opened in the lower segment to avoid an increased risk of amniotic fluid leak, chorioamnionitis and preterm labor. Absorbable staples compress the myometrium and control the membranes, maintaining hemostasis.[1] A rapid infuser replenishes lost amniotic fluid with warm Ringer's lactate solution. The fetus is monitored with echocardiography and a miniature pulse oximeter. Only the part of the fetus undergoing surgery is brought out, the rest remains submerged in amniotic fluid.
After surgery, the uterus is closed in two layers retaining the staples. During closure, Magnesium sulphate bolus followed by continuous infusion is given. Tocolytic regimen with indomethacin is started 4 hours after surgery. Both these agents are continued for 48-72 hours after surgery. Outpatient tocolysis is by oral or subcutaneous terbutaline or nifedipine. These agents and betamimetics, successful in animal models, have not shown the same safety and efficacy in humans. Uterine irritability and amniotic fluid volume are monitored and fetal well being assessed by its movements and echocardiography.
Minimally Invasive Fetal Endosurgical (FETENDO) Technique: Uterine irritability is thought to be less with this technique.[4] Guided by intraoperative US, 5 and 10mm trocars with compressive flanges and balloons are placed with continuous irrigation of warm fluid via the sheath of a 12mm hysteroscope.
Congenital Diaphragmatic Hernia (CDH)
CDH has a mortality of 58%, inspite of best postnatal care. Several babies also die in utero. Currently the most reliable prenatal predictor of postnatal outcome is the LHR: the right lung volume divided by the head circumference. The survival rate, even with ECMO (extra corporeal membrane oxygenator), with LHR ￡ 1.0 is 11% and that for ￡ 0.6 is almost 0%. The only approach with the potential to improve such dismal natural history in severe cases therefore, appears to be fetal intervention.
However, in utero "CDH 2 step', i.e. thoracotomy and laparotomy to reduce contents and repair the defect is not safe in presence of liver herniation as it leads to kinking of the umbilical vein. Further it has not shown any increased survival compared to standard postnatal therapy, when the liver is not incarcerated in the left hemithorax.
The second technique is tracheal occlusion. In animal models, this was shown to induce proliferative lung growth, improve lung compliance and reduce herniated viscera from the chest by retaining the lung fluid which stimulates growth and prevents lung collapse. In the open method, after exposure, a hemoclip is applied. The current selection criteria are - isolated CDH at < 26 weeks gestation, liver herniation and an LHR ￡ 1.0. However, this has been associated with fetal scalp edema, ascites and maternal irritability requiring early delivery, often before 34 weeks. Occlusion can also be achieved by the FETO (fetoscopic) technique using a balloon. An improvement in survival has been noted with its use in the second rather than third trimester, and removal of the balloon in the immediate prenatal period.[5]
The morbidity in survivors includes gastro-esophageal reflux requiring fundoplication, tracheal injury requiring repair or tracheostomy and recurrent hernias after diaphragmatic repair. Premature rupture of the membranes and preterm delivery have been found to be significantly higher in the group receiving intervention than in the group receiving standard care (p<0.001). Pathological changes associated with pulmonary hypoplasia persist, the lung remaining abnormal with low radial alveolar counts and increased alveolar size.[6] With no improvement in morbidity or survival, many centres have now abandoned fetal tracheal occlusion.[7]
Ex-utero intrapartum treatment procedure (EXIT) is used for clip removal. Only the head and shoulders are delivered maintaining fetoplacental circulation. After clip removal, the fetus is intubated allowing delivery with a secure airway. EXIT has also been used for establishing airway in a controlled manner in neck masses and congenital high airway obstructions.[8]
Congenital Cystic Adenomatoid Malformation (CCAM)
Diagnosis is made by US, echocardiogram and color Doppler. Appearance of hydrops in a fetus with isolated CCAM and immature lungs invariably leads to fetal death. Currently this is the only indication for fetal intervention. Large lesions require careful US surveillance to detect hydrops early. Once placentomegaly is detected and maternal pre-eclampsia sets in, it is too late for therapeutic fetal intervention. Thoracoamniotic shunt insertion into a dominant cyst, percutaneous intrauterine laser application and resection in utero has been used.[9] In all others, need for surgery should be based only on appropriate postnatal investigations.
Obstructive Uropathy
More than 90% kidneys can be reliably seen by 22 weeks gestation by transabdominal maternal US. Renal abnormalities account for around 17% of all the anomalies diagnosed prenatally, 50% of which are renal pelvic dilatations.[10] This can be due to obstruction at the ureteropelvic junction, vesicoureteric junction, and bladder outflow tract, or because of reflux. Often in the milder form, it is a normal variant. The anteroposterior diameter (APD) of the pelvis measured in the axial plane is the most common information acquired. Pathological outcome is more likely with progression of dilatation in utero, an AP diameter of 310 mm in the third trimester, increased renal echogenicity with or without cysts and calyceal dilatation. These findings warrant early postnatal ultrasound examination.[11] Prognosis may be poor in association with oligohydramnios. There is an increased risk of aneuploidy, especially in the presence of other associated anomalies on sonography. A study on 148 infants concluded that when the fetal pelvic APD of 34mm before 33 weeks and 37mm from 33 weeks onwards is detected, repeat prenatal scans and detailed postnatal evaluation is indicated. If an APD 34mm before 33 weeks has disappeared at the post 33-week scan, no further investigation is required.[12] Fluctuating renal pelvic diameter of more than 4mm is often an indicator of high-grade vesicoureteric reflux and a marker of renal damage[13]. In utero intervention is necessary only in very rare cases of unilateral gross hydronephrosis. This should not be undertaken lightly as it can lead to loss of the kidney.[14] In others, conservative treatment with postnatal management offers the best outcome.
Patients only with an infravesical obstructive uropathy appear to be candidates for antenatal intervention. The cardinal signs of posterior urethral valves (PUV) include persistent dilatation of the urinary bladder and proximal urethra with a thickened bladder wall, upper tract dilatation and varying degrees of oligohydramnios. Poor prognostic features in PUV are detection before 24 weeks gestation, oligohydramnios, loss of corticomedullary differentiation, renal cortical cysts, increased cortical echogenicity and fetal urine values of calcium > 8mg/L, Sodium>100meq/L, Chloride >90meq/L, and beta- 2 microglobulin >4 mg/L.[11] Many of these features in fact indicate renal dysplasia, which will not reverse with fetal intervention.
One of the in utero therapeutic approaches in such cases is placement of a vesicoamniotic shunt. Double-reversed pigtail catheters with stylets for puncture are used. However, blockage (10-15%), dislodgement (20-30%), migration, iatrogenic abdominal wall defects, maternal amnioperitoneal leaks and chorioamnionitis have been reported. Endoscopic creation of a vesicocutaneous fistula and placement of an expandable wire mesh stent may possibly reduce shunt migration rates. Open procedures have included vesicostomy and ureterostomies. Another method is valve ablation by electrocoagulation or laser. However, direct visualization is difficult and surrounding tissues can get damaged. Fetal mortality of 43% has been reported following intervention for PUV, inspite of favorable urinary electrolytes. Only the fetuses with bilateral severe hydronephrosis that have good renal function but develop oligohydramnios require treatment as restoration of amniotic fluid may prevent development of fatal pulmonary hypoplasia.[15] The fetus with a low-pressure system that continues to have good urine output and adequate amniotic fluid volume requires no intervention.
Sacrococcygeal Teratoma (SCT)
Large tumors early in gestation may result in placentomegaly, hydrops and fetal death and a pre-eclampsia like syndrome in the mother. This is due to high output cardiac failure in the fetus caused by arteriovenous shunting through the tumor. Occurrence of pulsations in the umbilical vein of a hydropic fetus correlates with a poor fetal outcome.[16] Fetuses with hydrops and lesions larger than 5 cm diagnosed after 30 weeks gestation should be delivered by cesarean section as soon as pulmonary maturity is ascertained. Those with similar features diagnosed before 30 weeks have a poor outcome and excision in utero has been tried with limited success. In one series, 81% of 26 pregnancies with SCT had significant complications like polyhydramnios, oligohydramnios, preterm labor and pre-eclampsia. Fetal intervention included cyst aspiration, amnioreduction, amnioinfusion and open fetal surgical resection. Of the 4 tumors resected in fetus, 3 survived. However, the mean gestation age at delivery was only 29 weeks and subsequently the babies required a hospital stay of 16-34 weeks.[17] Another intervention technique is to dessicate the host blood vessels by radiofrequency ablation (RFA).[18] A 3mm needle is placed through the mothers abdomen into the fetus under ultrasound and color Doppler guidance, and energy is applied until blood flow to the tumor is halted.
Spina bifida
Movement of legs and feet seen early on by US is often not seen later in pregnancy implying damage to the open neural plaque by amniotic fluid. Early fetal intervention is thought to improve neurologic outcomes and reduce the hindbrain herniation associated with the Arnold- Chiari malformation More Details More Details. The conclusion of a study on 178 fetuses that underwent intrauterine repair show that fetuses with a ventricular size below 14 mm at the time of surgery,
< 25 weeks of gestation and defects located at or below L4 level were less likely to require ventriculoperitoneal shunt for hydrocephalus during the first year of life.[19]
The results of a prospective randomized trial MOMS (Management Of Myelomeningocele Study), comparing prenatal meningomyelocele repair with postnatal repair are eagerly awaited.[20] This 5-year study, started in early 2003 in 3 centers in the USA, will recruit 200 women. Half will be randomized to undergo prenatal intervention (open or endoscopic repair) before 25 weeks while the other half will be treated by postnatal surgery. Percutaneous intrauterine placement of ventricular shunts has also been tried in the past for relieving congenital hydrocephalus.[21]
Indian Scenario
As of now, the authors are not aware of any centre in India, which offers fetal surgery. Some centres have attempted fetal interventions by way of aspiration of cysts and like. But these are exceptions rather than the rule. The authors have successfully conducted in the eighties, experimental fetal surgery in rhesus monkeys. However, in Indian set up, obvious congenital anomalies are commonly missed (44%) on a routine antenatal ultrasound scan because of varying experience of the sonologists, located in various places. False negative rates (failure to detect) of 38% and false positive rate of 6% is also reported.[22]
Conclusion
0The ethics of performing fetal surgery is still debated. The high rate of risks to the mother and fetus, management of the severe complications associated with prematurity and the high costs has to be kept in mind before embarking on fetal surgery. In this country given this scenario, parents are more likely to opt for another child. Fetal centers in the USA are moving away from open methods to minimally invasive techniques. The second trend is a movement away from total in utero repair towards only manipulating fetal pathophysiology in order to reverse life-threatening events, reduce operative time and lessen morbidity.[18]
As of now, accurate prenatal diagnosis is what one with limited resources at disposal should concentrate on. This will help one to decide on the time and place of delivery in advance in a tertiary centre as near term as possible, offering the best hope for these unborn patients
References
1. Shaaban AF, Kim HB, Flake AW. Fetal surgery, diagnosis and intervention. In Ziegler MM, Azizkhan RG, Weber TR, eds. Operative Pediatric Surgery, McGraw Hill, New York, 2003; 21-35.
2. Levine D. Fetal magnetic resonance imaging. J Matern Fetal Neonatal Med 2004; 15 : 85-94 .
3. Sydorak RM, Hirose S, Sandberg PL, Filly RA, Harrison MR, Farmer DL et al. Chorioamniotic membrane separation following fetal surgery. J Perinatol 2002; 22 : 407-410.
4. Albanese CT, Harrison MR. Prenatal diagnosis and surgical intervention. In Ashcraft KW, ed. Pediatric Surgery , WB Saunders, Philadelphia, 3rd edn. 2000; 137-145.
5. Deprest J, Gartacos E, Nicolaides KH. FETO Task group. Fetoscopic tracheal occlusion (FETO) for severe congenital diaphragmatic hernia: evolution of a technique and preliminary results. Ultrasound Obstet Gynecol 2004; 24:121-126.
6. Heerema AE, Rabban JT, Sydorak RM, Harrison MR, Jones KD. Lung pathology in patients with congenital diaphragmatic hernia treated with fetal surgical intervention, including tracheal occlusion. Pediatr Dev Path 2003; 6: 536-546.
7. Harrison MR, Keller RL, Hawgood SB, Kitterman JA, Sandberg PL, Farmer DL et al. A randomised trial of fetal endoscopic tracheal occlusion for severe fetal congenital diaphragmatic hernia. N Eng J Med 2003; 349 : 1916-1924.
8. 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 : 375-380.
9. Davenport M, Warne SA, Cacciaguerra S, Patel S, Greenough A, Nicolaides K. Current outcome of antenatally diagnosed cystic lung disease. J Pediatr Surg 2004; 39 : 549-556.
10. Reddy PP, Mandell J. Prenatal diagnosis. Therapeutic implications. Urol Clin North Am 1998; 25 : 171-180.
11. Chitty LS, Masturzo B. Prenatal diagnosis of fetal abnormalities. In Gearhart JP, Rink RC, Mouriquand PDE, eds. Pediatric Urology, WB Saunders, Philadelphia, 2001; 58-91.
12. John U, Kahler C, Schul S, Mentzel HJ, Vogt S, Misselwitz J. The impact of fetal renal pelvic diameter on postnatal outcome. Prenat Diagn 2004; 24 : 591-595.
13. Anderson NG, Allan RB, Abbott GD. Fluctuating fetal or neonatal renal pelvis: marker of high-grade vesicoureteral reflux. Pediatr Nephrol 2004; 19 : 749-753. E-pub 2004.
14. Lunacek A, Oswald J, Schwentner C, Gassner I, Bartsch G, Radmayr C. Prenatal puncture of a unilateral hydronephrosis leading to fetal urinoma and postnatal nephrectomy. Urology 2004; 63 : 982-984.
15. Holmes N, Harrison MR, Baskin LS. Fetal surgery for posterior urethral valves: long-term postnatal outcomes. Pediatrics 2001; 108 : E7.
16. Neubert S, Trautmann K, Tanner B, Steiner E, Linke F, Bahlmann F. Sonographic prognostic factors in prenatal diagnosis of SCT. Fetal Diagn Ther 2004; 19 : 319-326.
17. Hedrick HL, Flake AW, Crobleholme TM, Howell LJ, Johnson MP, Wilson RD et al. Sacrococcygeal teratoma: prenatal assessment, fetal intervention, and outcome. J Pediatr Surg 2004; 39 : 430-438.
18. Hirose S, Farmer DL. Fetal surgery for sacrococcygeal teratoma. Clin Perinatol 2003; 30 : 493-506.
19. Bruner JP, Tulipan N, Reed G, Davis GH, Bennett K, Luker KS et al. Intrauterine repair of spina bifida: preoperative predictors of shunt-dependent hydrocephalus. Am J Obstet Gynecol 2004; 190 : 1305-1312.
20. Walsh DS, Adzick NS. Fetal surgery for spina bifida. Semin Neonatol 2003; 8: 197-205
21. Abramowicz J, Jaffe R. Diagnosis and intrauterine management of enlargement of the cerebral ventricles. J Perinat Med 1988; 16: 165-173
22. Punj R, Handa R, Ravindranath G. Efficacy of routine antenatal ultrasonography in detection of congenital fetal anomalies. M.S. thesis submitted to Delhi University, Delhi, 2003(Menon Prema, N. Rao KL)
Abstract
Abstract. The allure of fetal surgery is the possibility of interrupting in utero progression of an otherwise treatable condition. In spite of advances in prenatal diagnosis and refinements in surgical techniques, this field has not yet got off the ground because the risks to the mother and fetus, during and after the procedure far outweigh the benefits, and the infrastructure required to support such activity is prohibitively expensive. The various surgical conditions in which fetal surgery has been attempted and the present status of this specialty are discussed. [Indian J Pediatr 2005; 72 (5) : -436]
Keywords: Fetal surgery; Prenatal diagnosis; Congenital diaphragmatic hernia; Cystic lung lesion; Obstructive uropathy, Sacrococcygeal teratoma; Spina bifida
Fetal intervention is feasible in conditions, which interfere with the normal development of the fetus and when corrected will allow it to develop normally. It is contraindicated in conditions that are incompatible with life whether because of the severity of the affliction, other associated life threatening anomalies or chromosomal anomalies. The requirements before such an intervention are -experimental work to prove the pathophysiology of the defect and careful study of the natural history of the untreated disease. Research in fetal surgery is ethically controversial as it poses a risk both to the fetus and the pregnant woman. Developing appropriate surgical techniques, devising fetal and uterine monitoring and preventing uterine contractions after surgery (tocolysis) are major hurdles in its development.
The first successful therapeutic fetal procedure was reported by Sir A.W. Liley, who transfused a hydropic fetus with Rh. disease in 1965. Dr Michael Harrison and his team at the University of California pioneered modern fetal surgery after extensive work on animal models. Many of the successes in animal models however, could not be translated to the human conditions. His team did the first open fetal surgical procedure in 1982 for obstructive uropathy.[1] The baby expired in the neonatal period because of unrecognized pulmonary and renal dysplasia. Nevertheless, it was the dawn of a new era of fetal intervention. Successful fetal interventions have now been performed for surgical conditions like congenital diaphragmatic hernia, cystadenomatoid malformation of the lung, sacrococcygeal teratoma, obstructive uropathies etc.
Investigations
This is one of the most important aspects of management before embarking on fetal intervention. The two important modalities are ultrasonography (US) and magnetic resonance imaging (MRI). The views may be poor, even with high resolution US, because of maternal obesity and oligohydramnios. Three-dimensional US, mainly used in detecting surface abnormalities like cleft lip and spina bifida, now allows accurate measurement of volume of any fetal organ. MRI (echo-planar) is especially useful in evaluating the fetal central nervous system and also as an adjunct to ultrasound in diagnosing complex anomalies.[2] With ultrafast scanning techniques, images of the fetus can be obtained in 300-400 ms without sedation.
Maternal and Fetal Considerations and Risks
The unique physiology of the fetus with additional problems of associated anomaly and the difference in physiology of a pregnant from a non-pregnant woman makes anesthesia and surgery all the more formidable. All fetal intervention procedure series have repeatedly and consistently shown premature delivery, often before 30 weeks triggered by breaching the uterus, whether by puncture or incision. Tocolytic therapy is therefore, always required, which often leads to pulmonary edema. Delivery after fetal surgery and all future pregnancies require Cesarean section, as the hysterotomy for fetal surgery is done in the upper uterine segment. Absorbable materials are used to close the uterus, since the uses of nonabsorbable/metal staplers appear to have affected fertility in animal models. Intra-operative blood loss requiring transfusion, amniotic fluid leaks from the operated sites/vagina, wound infection, intrauterine infection as well as behavioral changes can also occur. In case of hydrops, the mother has to be monitored for 'maternal mirror syndrome', i.e. the mothers develop high output cardiac failure and physiological manifestations that "mirror" those of the distressed fetus. Fetal surgery, unfortunately often does not cure this.
The incidence of chorioamniotic membrane separation is around 47%, which in turn is associated with an increased incidence of premature rupture of membranes (63%), preterm labor (57%) and chorioamnionitis (29%).[3] Further, damage to the fetal organ that is being operated upon, embolic events which can lead to intestinal atresia and renal agenesis; premature closure of ductus arteriosus leading to cardiac failure and neonatal death can occur. Long-term studies have shown a 21% incidence of central nervous system injury, which may be due to sudden fluxes in cerebral blood flow, induced by maternal hypoxia or tocolytic drugs.
Techniques
Deep inhalation anesthesia is usually induced with isoflurane. Prior to this, all patients receive epidural anesthesia, which is maintained post-operatively. These two factors appear to reduce early uterine irritability. However, the depth of anesthesia required to give adequate uterine relaxation can produce fetal and maternal myocardial depression and affect placental perfusion. Intravenous nitroglycerine (a nitric oxide donor) has been tried to counteract this effect. The mother is monitored with pulse oximetry, ECG as well as with central venous and arterial catheters. Euvolemia is maintained to avoid post-operative pulmonary edema.
There are two approaches to the fetus: open hysterotomy and minimally invasive techniques.
Open Hysterotomy : The uterus is exposed through a low, transverse abdominal incision. It is displaced to the left to avoid compression of the inferior vena cava. Intra-operative ultrasound (US) locates the placenta and identifies the fetal position. The fetus is injected with a narcotic and a paralytic agent. The uterus, fully relaxed at the time of incision is opened anteriorly or posteriorly depending on the position of the placenta. It is not opened in the lower segment to avoid an increased risk of amniotic fluid leak, chorioamnionitis and preterm labor. Absorbable staples compress the myometrium and control the membranes, maintaining hemostasis.[1] A rapid infuser replenishes lost amniotic fluid with warm Ringer's lactate solution. The fetus is monitored with echocardiography and a miniature pulse oximeter. Only the part of the fetus undergoing surgery is brought out, the rest remains submerged in amniotic fluid.
After surgery, the uterus is closed in two layers retaining the staples. During closure, Magnesium sulphate bolus followed by continuous infusion is given. Tocolytic regimen with indomethacin is started 4 hours after surgery. Both these agents are continued for 48-72 hours after surgery. Outpatient tocolysis is by oral or subcutaneous terbutaline or nifedipine. These agents and betamimetics, successful in animal models, have not shown the same safety and efficacy in humans. Uterine irritability and amniotic fluid volume are monitored and fetal well being assessed by its movements and echocardiography.
Minimally Invasive Fetal Endosurgical (FETENDO) Technique: Uterine irritability is thought to be less with this technique.[4] Guided by intraoperative US, 5 and 10mm trocars with compressive flanges and balloons are placed with continuous irrigation of warm fluid via the sheath of a 12mm hysteroscope.
Congenital Diaphragmatic Hernia (CDH)
CDH has a mortality of 58%, inspite of best postnatal care. Several babies also die in utero. Currently the most reliable prenatal predictor of postnatal outcome is the LHR: the right lung volume divided by the head circumference. The survival rate, even with ECMO (extra corporeal membrane oxygenator), with LHR ￡ 1.0 is 11% and that for ￡ 0.6 is almost 0%. The only approach with the potential to improve such dismal natural history in severe cases therefore, appears to be fetal intervention.
However, in utero "CDH 2 step', i.e. thoracotomy and laparotomy to reduce contents and repair the defect is not safe in presence of liver herniation as it leads to kinking of the umbilical vein. Further it has not shown any increased survival compared to standard postnatal therapy, when the liver is not incarcerated in the left hemithorax.
The second technique is tracheal occlusion. In animal models, this was shown to induce proliferative lung growth, improve lung compliance and reduce herniated viscera from the chest by retaining the lung fluid which stimulates growth and prevents lung collapse. In the open method, after exposure, a hemoclip is applied. The current selection criteria are - isolated CDH at < 26 weeks gestation, liver herniation and an LHR ￡ 1.0. However, this has been associated with fetal scalp edema, ascites and maternal irritability requiring early delivery, often before 34 weeks. Occlusion can also be achieved by the FETO (fetoscopic) technique using a balloon. An improvement in survival has been noted with its use in the second rather than third trimester, and removal of the balloon in the immediate prenatal period.[5]
The morbidity in survivors includes gastro-esophageal reflux requiring fundoplication, tracheal injury requiring repair or tracheostomy and recurrent hernias after diaphragmatic repair. Premature rupture of the membranes and preterm delivery have been found to be significantly higher in the group receiving intervention than in the group receiving standard care (p<0.001). Pathological changes associated with pulmonary hypoplasia persist, the lung remaining abnormal with low radial alveolar counts and increased alveolar size.[6] With no improvement in morbidity or survival, many centres have now abandoned fetal tracheal occlusion.[7]
Ex-utero intrapartum treatment procedure (EXIT) is used for clip removal. Only the head and shoulders are delivered maintaining fetoplacental circulation. After clip removal, the fetus is intubated allowing delivery with a secure airway. EXIT has also been used for establishing airway in a controlled manner in neck masses and congenital high airway obstructions.[8]
Congenital Cystic Adenomatoid Malformation (CCAM)
Diagnosis is made by US, echocardiogram and color Doppler. Appearance of hydrops in a fetus with isolated CCAM and immature lungs invariably leads to fetal death. Currently this is the only indication for fetal intervention. Large lesions require careful US surveillance to detect hydrops early. Once placentomegaly is detected and maternal pre-eclampsia sets in, it is too late for therapeutic fetal intervention. Thoracoamniotic shunt insertion into a dominant cyst, percutaneous intrauterine laser application and resection in utero has been used.[9] In all others, need for surgery should be based only on appropriate postnatal investigations.
Obstructive Uropathy
More than 90% kidneys can be reliably seen by 22 weeks gestation by transabdominal maternal US. Renal abnormalities account for around 17% of all the anomalies diagnosed prenatally, 50% of which are renal pelvic dilatations.[10] This can be due to obstruction at the ureteropelvic junction, vesicoureteric junction, and bladder outflow tract, or because of reflux. Often in the milder form, it is a normal variant. The anteroposterior diameter (APD) of the pelvis measured in the axial plane is the most common information acquired. Pathological outcome is more likely with progression of dilatation in utero, an AP diameter of 310 mm in the third trimester, increased renal echogenicity with or without cysts and calyceal dilatation. These findings warrant early postnatal ultrasound examination.[11] Prognosis may be poor in association with oligohydramnios. There is an increased risk of aneuploidy, especially in the presence of other associated anomalies on sonography. A study on 148 infants concluded that when the fetal pelvic APD of 34mm before 33 weeks and 37mm from 33 weeks onwards is detected, repeat prenatal scans and detailed postnatal evaluation is indicated. If an APD 34mm before 33 weeks has disappeared at the post 33-week scan, no further investigation is required.[12] Fluctuating renal pelvic diameter of more than 4mm is often an indicator of high-grade vesicoureteric reflux and a marker of renal damage[13]. In utero intervention is necessary only in very rare cases of unilateral gross hydronephrosis. This should not be undertaken lightly as it can lead to loss of the kidney.[14] In others, conservative treatment with postnatal management offers the best outcome.
Patients only with an infravesical obstructive uropathy appear to be candidates for antenatal intervention. The cardinal signs of posterior urethral valves (PUV) include persistent dilatation of the urinary bladder and proximal urethra with a thickened bladder wall, upper tract dilatation and varying degrees of oligohydramnios. Poor prognostic features in PUV are detection before 24 weeks gestation, oligohydramnios, loss of corticomedullary differentiation, renal cortical cysts, increased cortical echogenicity and fetal urine values of calcium > 8mg/L, Sodium>100meq/L, Chloride >90meq/L, and beta- 2 microglobulin >4 mg/L.[11] Many of these features in fact indicate renal dysplasia, which will not reverse with fetal intervention.
One of the in utero therapeutic approaches in such cases is placement of a vesicoamniotic shunt. Double-reversed pigtail catheters with stylets for puncture are used. However, blockage (10-15%), dislodgement (20-30%), migration, iatrogenic abdominal wall defects, maternal amnioperitoneal leaks and chorioamnionitis have been reported. Endoscopic creation of a vesicocutaneous fistula and placement of an expandable wire mesh stent may possibly reduce shunt migration rates. Open procedures have included vesicostomy and ureterostomies. Another method is valve ablation by electrocoagulation or laser. However, direct visualization is difficult and surrounding tissues can get damaged. Fetal mortality of 43% has been reported following intervention for PUV, inspite of favorable urinary electrolytes. Only the fetuses with bilateral severe hydronephrosis that have good renal function but develop oligohydramnios require treatment as restoration of amniotic fluid may prevent development of fatal pulmonary hypoplasia.[15] The fetus with a low-pressure system that continues to have good urine output and adequate amniotic fluid volume requires no intervention.
Sacrococcygeal Teratoma (SCT)
Large tumors early in gestation may result in placentomegaly, hydrops and fetal death and a pre-eclampsia like syndrome in the mother. This is due to high output cardiac failure in the fetus caused by arteriovenous shunting through the tumor. Occurrence of pulsations in the umbilical vein of a hydropic fetus correlates with a poor fetal outcome.[16] Fetuses with hydrops and lesions larger than 5 cm diagnosed after 30 weeks gestation should be delivered by cesarean section as soon as pulmonary maturity is ascertained. Those with similar features diagnosed before 30 weeks have a poor outcome and excision in utero has been tried with limited success. In one series, 81% of 26 pregnancies with SCT had significant complications like polyhydramnios, oligohydramnios, preterm labor and pre-eclampsia. Fetal intervention included cyst aspiration, amnioreduction, amnioinfusion and open fetal surgical resection. Of the 4 tumors resected in fetus, 3 survived. However, the mean gestation age at delivery was only 29 weeks and subsequently the babies required a hospital stay of 16-34 weeks.[17] Another intervention technique is to dessicate the host blood vessels by radiofrequency ablation (RFA).[18] A 3mm needle is placed through the mothers abdomen into the fetus under ultrasound and color Doppler guidance, and energy is applied until blood flow to the tumor is halted.
Spina bifida
Movement of legs and feet seen early on by US is often not seen later in pregnancy implying damage to the open neural plaque by amniotic fluid. Early fetal intervention is thought to improve neurologic outcomes and reduce the hindbrain herniation associated with the Arnold- Chiari malformation More Details More Details. The conclusion of a study on 178 fetuses that underwent intrauterine repair show that fetuses with a ventricular size below 14 mm at the time of surgery,
< 25 weeks of gestation and defects located at or below L4 level were less likely to require ventriculoperitoneal shunt for hydrocephalus during the first year of life.[19]
The results of a prospective randomized trial MOMS (Management Of Myelomeningocele Study), comparing prenatal meningomyelocele repair with postnatal repair are eagerly awaited.[20] This 5-year study, started in early 2003 in 3 centers in the USA, will recruit 200 women. Half will be randomized to undergo prenatal intervention (open or endoscopic repair) before 25 weeks while the other half will be treated by postnatal surgery. Percutaneous intrauterine placement of ventricular shunts has also been tried in the past for relieving congenital hydrocephalus.[21]
Indian Scenario
As of now, the authors are not aware of any centre in India, which offers fetal surgery. Some centres have attempted fetal interventions by way of aspiration of cysts and like. But these are exceptions rather than the rule. The authors have successfully conducted in the eighties, experimental fetal surgery in rhesus monkeys. However, in Indian set up, obvious congenital anomalies are commonly missed (44%) on a routine antenatal ultrasound scan because of varying experience of the sonologists, located in various places. False negative rates (failure to detect) of 38% and false positive rate of 6% is also reported.[22]
Conclusion
0The ethics of performing fetal surgery is still debated. The high rate of risks to the mother and fetus, management of the severe complications associated with prematurity and the high costs has to be kept in mind before embarking on fetal surgery. In this country given this scenario, parents are more likely to opt for another child. Fetal centers in the USA are moving away from open methods to minimally invasive techniques. The second trend is a movement away from total in utero repair towards only manipulating fetal pathophysiology in order to reverse life-threatening events, reduce operative time and lessen morbidity.[18]
As of now, accurate prenatal diagnosis is what one with limited resources at disposal should concentrate on. This will help one to decide on the time and place of delivery in advance in a tertiary centre as near term as possible, offering the best hope for these unborn patients
References
1. Shaaban AF, Kim HB, Flake AW. Fetal surgery, diagnosis and intervention. In Ziegler MM, Azizkhan RG, Weber TR, eds. Operative Pediatric Surgery, McGraw Hill, New York, 2003; 21-35.
2. Levine D. Fetal magnetic resonance imaging. J Matern Fetal Neonatal Med 2004; 15 : 85-94 .
3. Sydorak RM, Hirose S, Sandberg PL, Filly RA, Harrison MR, Farmer DL et al. Chorioamniotic membrane separation following fetal surgery. J Perinatol 2002; 22 : 407-410.
4. Albanese CT, Harrison MR. Prenatal diagnosis and surgical intervention. In Ashcraft KW, ed. Pediatric Surgery , WB Saunders, Philadelphia, 3rd edn. 2000; 137-145.
5. Deprest J, Gartacos E, Nicolaides KH. FETO Task group. Fetoscopic tracheal occlusion (FETO) for severe congenital diaphragmatic hernia: evolution of a technique and preliminary results. Ultrasound Obstet Gynecol 2004; 24:121-126.
6. Heerema AE, Rabban JT, Sydorak RM, Harrison MR, Jones KD. Lung pathology in patients with congenital diaphragmatic hernia treated with fetal surgical intervention, including tracheal occlusion. Pediatr Dev Path 2003; 6: 536-546.
7. Harrison MR, Keller RL, Hawgood SB, Kitterman JA, Sandberg PL, Farmer DL et al. A randomised trial of fetal endoscopic tracheal occlusion for severe fetal congenital diaphragmatic hernia. N Eng J Med 2003; 349 : 1916-1924.
8. 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 : 375-380.
9. Davenport M, Warne SA, Cacciaguerra S, Patel S, Greenough A, Nicolaides K. Current outcome of antenatally diagnosed cystic lung disease. J Pediatr Surg 2004; 39 : 549-556.
10. Reddy PP, Mandell J. Prenatal diagnosis. Therapeutic implications. Urol Clin North Am 1998; 25 : 171-180.
11. Chitty LS, Masturzo B. Prenatal diagnosis of fetal abnormalities. In Gearhart JP, Rink RC, Mouriquand PDE, eds. Pediatric Urology, WB Saunders, Philadelphia, 2001; 58-91.
12. John U, Kahler C, Schul S, Mentzel HJ, Vogt S, Misselwitz J. The impact of fetal renal pelvic diameter on postnatal outcome. Prenat Diagn 2004; 24 : 591-595.
13. Anderson NG, Allan RB, Abbott GD. Fluctuating fetal or neonatal renal pelvis: marker of high-grade vesicoureteral reflux. Pediatr Nephrol 2004; 19 : 749-753. E-pub 2004.
14. Lunacek A, Oswald J, Schwentner C, Gassner I, Bartsch G, Radmayr C. Prenatal puncture of a unilateral hydronephrosis leading to fetal urinoma and postnatal nephrectomy. Urology 2004; 63 : 982-984.
15. Holmes N, Harrison MR, Baskin LS. Fetal surgery for posterior urethral valves: long-term postnatal outcomes. Pediatrics 2001; 108 : E7.
16. Neubert S, Trautmann K, Tanner B, Steiner E, Linke F, Bahlmann F. Sonographic prognostic factors in prenatal diagnosis of SCT. Fetal Diagn Ther 2004; 19 : 319-326.
17. Hedrick HL, Flake AW, Crobleholme TM, Howell LJ, Johnson MP, Wilson RD et al. Sacrococcygeal teratoma: prenatal assessment, fetal intervention, and outcome. J Pediatr Surg 2004; 39 : 430-438.
18. Hirose S, Farmer DL. Fetal surgery for sacrococcygeal teratoma. Clin Perinatol 2003; 30 : 493-506.
19. Bruner JP, Tulipan N, Reed G, Davis GH, Bennett K, Luker KS et al. Intrauterine repair of spina bifida: preoperative predictors of shunt-dependent hydrocephalus. Am J Obstet Gynecol 2004; 190 : 1305-1312.
20. Walsh DS, Adzick NS. Fetal surgery for spina bifida. Semin Neonatol 2003; 8: 197-205
21. Abramowicz J, Jaffe R. Diagnosis and intrauterine management of enlargement of the cerebral ventricles. J Perinat Med 1988; 16: 165-173
22. Punj R, Handa R, Ravindranath G. Efficacy of routine antenatal ultrasonography in detection of congenital fetal anomalies. M.S. thesis submitted to Delhi University, Delhi, 2003(Menon Prema, N. Rao KL)