have been no reported survivors after open fetal resection of a cardiac neoplasm. .... HLHS - hypoplastic left heart syndrome when is associated with a severely ...
Fetal therapy Indications, Procedures, Results
Marius Bogdan Muresan Premiere Hospital - Timisoara
Fetal Medicine S C E E N I N G
D I A G N O S T I C
T H E R A P Y
Overwiev Fetal intervention for congenital anomalies has evolved from a mere concept to a medical specialty over the past three decades. Advances in fetal imaging and diagnosis have allowed clinicians to accurately identify complex anomalies prenatally and stratify their severity. Fetal intervention has become an important option for fetuses who would otherwise not survive gestation or who would endure significant morbidity and mortality after birth.
Definition What is fetal intervention? A therapeutic intervention for the purpose of correcting or treating a fetal anomaly or condition. In almost every case, the fetus is at risk of intrauterine death (IUD) caused by the abnormality. While many diseases can now be accurately diagnosed before birth by genetic and imaging techniques, only a few, require intervention before birth.
selection of cases for intervention
International Fetal Medicine and Surgery Society
All fetal interventions are really maternal-fetal interventions and the most important consideration in all fetal interventions is the safety of the mother and her reproductive potential. The intervention is designed to benefit the fetus who has a problem, but the mother is an innocent bystander who assumes some risk for the interest of her unborn fetus. In estimating the risks versus the benefits of an intervention, the most important consideration is the mother, her health, her family and her ability to have other children.
History Fetal therapy began more than half a century ago when Liley reported the first intra-peritoneal transfusion for the treatment of fetal anaemia in Rhesus disease (Liley, 1963). This was to be replaced with intravascular transfusion, initially by fetoscopy and subsequently by ultrasound-guided cordocentesis. This is now a well- established therapy and one which was never subjected to rigorous evaluation.
Fetal Surgical Procedures Techniques used in fetal intervention have also evolved from maximally invasive (e.g. - open technique hysterotomy) to more minimally invasive techniques, such as fetal endoscopy, and image-guided percutaneous procedures.
Results from early experiences with fetal therapy generated a movement away from anatomic repair of congenital anomalies to physiologic manipulation of the developmental consequences (e.g., the shift from in utero repair of the CDH defect to balloon tracheal occlusion to promote lung growth). Advances in surgical techniques evolved parallel with developments in fetal imaging, fetal diagnosis and the advance of maternal tocolysis to prevent preterm labor.
The Techniques of Fetal Intervention Fetal Image-Guided Surgery (FIGS) Fetendo Fetal Surgery Open Fetal Surgery EXIT procedure
FIGS - Fetal Image Guided Surgery: Method of manipulating the fetus without either any incision in the uterus or an endoscopic view inside the uterus. The manipulation is done entirely under real-time crosssectional view provided by the sonogram. Amnioreduction/Infusion Fetal Blood Sampling/Transfusion Fetal Fluid Drainage Fetal Reduction - Anomalous Twins Vesico/Pleuro Amniotic Shunts Cord Monopolar Coagulation Balloon Valvuloplasty Intrafetal LASER Coagulation
FETENDO - Fetoscopic surgery: Was developed in the 1990s to avoid making an incision in the uterus and, hopefully, to minimize preterm labor. The ability to see the fetus through very small endoscopes, were refined to allow surgical manipulation of the fetus with very small instruments guided by direct fetoscopic view on a monitor. Fetoscopic Balloon Occlusion of Trachea (for CDH) - FeTO LASER Ablation of Vessels (for TTTS) Cord Ligation/Division Cystoscopic Ablation Valves (PUV) Amniotic Bands Division
OPEN SURGERY - Hysterotomy - In open fetal surgery, the mother is anesthetized, an incision is made in the lower abdomen to expose the uterus, the uterus is opened using a special stapling device to prevent bleeding, the surgical repair of the fetus is completed, the uterus followed by the maternal abdominal wall are closed and the mother awakened.
CCAM – Lobectomy SCT – Resection MMC – Repair Cervical Teratoma – Resection
EXIT procedure - planned specialized delivery Intervention that is performed at the time of delivery, keeping the fetus attached to the utero-placental circulation by delivering only a portion of the fetus through a hysterotomy incision.
CHAOS Removal of the Tracheal Occlusion Balloon (CDH) Pulmonary Sequestration CCAM
What is the risk to the mother? The risk varies with the invasiveness of the procedure.
- For open surgery, the risk is of general anesthesia and of the abdominal incision, but most important is the consequence of the incision in the uterus itself. The immediate consequence is preterm labor and the need for monitoring and drugs to control preterm labor. The longer term consequence is Cesarean delivery in this and subsequent pregnancies. This is because the incision in the uterus in midgestation is not the same is that used for elective Cesarean section at term.
- The risk of Fetendo procedures is less because the procedure is less invasive. Anesthesia may be regional or local, and an incision in the mother’s abdomen may not be necessary. However, the risk of piercing (2,7-3,3mm) the uterine muscle and, more importantly, the membranes lining the inside of the uterus remains a problem. There is still the risk of amniotic fluid leaking through the membranes and contributing to preterm labor. Unfortunately, this remains a significant risk and requires monitoring of the amniotic fluid volume, the membranes, and preterm labor. - The risk of FIGS is less than either Fetendo or open fetal surgery. FIGS-IT can usually be done under local or regional anesthesia and usually without the incision in the maternal abdomen. However, the problem with membrane puncture (1mm), subsequent leakage, separation of membranes and preterm labor persists.
Fetal anomalies that may benefit from in utero therapy • • • • • • •
Severe Fetal Anemia / Trombocytopenia Fetal Urinary Tract Obstruction Congenital Diaphragmatic Hernia (CDH) Fetal Tumors / Fluid acumulation - Causing Hydrops Fetalis MC Pregnancy Complication Neural tube defects Cardiovascular anomaly
Severe Fetal Anemia
Erythroblastosis Fetalis: Severe fetal anemia hepatosplenomegaly
Extramedullary hematopoiesis/ Hydrops Fetalis IUFD
In severe cases, fetal intrauterine transfusion (IUT) is performed to treat the fetal anemia.
History - IUT
•
1963 - First intraperitoneal transfusion (Liley)
•
1974 - Fetoscopy to obtain fetal samples (Hobbins, et al) 1981 - Fetoscopic transfusion (Rodeck, et al) 1982 - First ultrasound guided IUT (Bang, Bock & Troll) 1983 - First large study of IUT - 66 cases (Daffos, et al)
• • •
Hemolytic Disease/Alloimmunization Most commonly due to Rh blood system Complex system involving several antigens Presence of D —————> Rh positive Absence of D —————> Rh negative Overall, 15-16% Rh ”-„ in the US Rare in non-Caucasians (8% black, 1% asian) ABO incompatibility is somewhat protective
Infection (Parvovirus B19) There is no specific treatment or prophylaxis available against B19 infection, but counseling of non-immune mothers and active monitoring of confirmed maternal infections with intervention to correct fetal anemia is likely to decrease mortality.
TAPS (MC pregnancy)
Other Blood Group Antigens Causing Hemolytic Disease •
ABO hemolytic disease - uncommon, usually mild, not evident until after delivery
•
Anti-Kell - usually due to transfusion. Δ OD 450 can be falsely low, so low threshold for PUBS. Anti-c Anti-E Long list of other antigens (at least 43) which can cause hemolytic disease, but less clinically important than above
• • •
Rh Immunization Causes
Rh Immunization - Maternal Immune Response
• • •
Primary response is slow and is mostly IgM, which does not cross the placenta Secondary response is primarily IgG, which DOES cross the placenta Secondary response requires only low dose
Diagnosis of Rh Immunization
• • • • • •
Blood type of mother determined at first prenatal visit If Rh ”-”, evaluate father of baby If anti-D is present, titer is important Must know ‘critical titer’ for specific lab/institution If less than critical titer, needs to be followed Maternal history is important (previous infant with hemolytic disease, hydrops?)
Management of Rh Immunization •
•
• •
With history of hydrops or fetal demise, early amnio (16-18 weeks) for Δ OD 450 is indicated (?) Start amnios when critical titer is reached with timing of serial amnios based on Liley curve (?) Ultrasound to evaluated for hydrops (?) PUBS if hydrops, or upper zone 2 (lower threshold for Kell disease) (?)
The Liley Curve
• • •
• • •
Described in 1961, gestational ages 27-41 weeks In normal amniotic fluid, the spectral absorption curve is linear from 365-550 nm (logarithmic curve) Bilirubin peaks at 450 nm
The Δ OD 450 represents the difference between actual and expected Modified curve developed to extend to earlier gestational ages - extrapolation (Queenan, et al, 1993) Bilirubin normally peaks at 23-25 weeks
Management of Rh Immunization - actual -
•
Fetal cell free DNA - blood group of fetus
•
Determination of Antibody level (IU/ml)
•
Ultrasound PSV-MCA (over 1,5SD = severe fetal anemia)
Management of Rh Immunization • •
• •
IUT if anemic (Hct< 30%) = PSV-MCA 1,5MoM After IUT - Hct drops about 0,3-1% / day • Continue fetal monitoring and ultrasound between IUT’s (PSV-MCA reliable for first & second IUT, false positive-rates 14-90%) Timing of delivery (controversial) in past - 32-36 weeks. NOW (at Term) 37 weeks Overall survival good - 88% total, (96% if no hydrops, 78% in cases with hydrops) (Winnipeg data, Creasy & Resnik, 1999; Scheier et al.)
How Much to Transfuse
What to Transfuse
• • •
• • •
O negative donor blood / maternal blood Washed Irradiated
Hematocrit > 80% CMV negative (preferable) CMV safe (acceptable)
• •
•
•
Many ways to calculate Several formulas which use gestational age, fetal weight, starting and target hematocrit Transfuse up to desired Hct (upper 40’s-50’s), less if hydropic (will need subsequent procedure) 50 cc/kg estimated fetal weight
Intra Vascular Transfusion (IVT) - cordocentesis • •
• • • •
Ultrasound Guidance Target - umbilical vein cord insertion site vs free loop Confirm the sample is fetal (MCV) Saline flush Fetal paralysis for transfusion Watch cord for bleeding after procedure
Risks/Complications of Cordocentesis • • • • • • • •
Fetal Loss - risk variable depending on condition of fetus, overall 1-2%, range 2.0 required prenatal intervention compared to 3% of the fetuses with CVR 4cm, the presence of a “wandering” mass or rapid growth of the cyst should be indications for aspiration primarily to prevent torsion and loss of the ovary Overall, no fetal intervention is required for ovarian masses unless hydrops fetalis occurs.
Abdominal Cyst - choledochal cysts, - meconium pseudocysts, - infra-diaphragmatic pulmonary sequestration, - ovarian cysts, - duplication cysts, - mesenteric cysts, - simple cysts of the liver
Intracardiac and Pericardial Neoplasms - to date, there have been no reported survivors after open fetal resection of a cardiac neoplasm. Fetal Neck Mass - in the presence of fetal hydrops prior to 30 weeks gestation, open fetal resection may be considered although, to date, only one successful open fetal resection has been reported; -ex utero intra-partum treatment (EXIT) procedure has been advocated to permit adequate time for airway stabilization prior to complete delivery.
MC Pregnancy Complications TTTS TRAP sequence Selective FGR
Twin-Twin Transfusion Syndrome (TTTS): Monochorionic twins have a high frequency of placental vascular shunts that may lead to one twin (donor) over- perfusing the other (recipient). Complications include oligohydramnios and growth retardation (donor), polyhydramnios and hydrops fetalis (recipient), and both have risk for fetal death.
Twin-Twin Transfusion syndrome (TTTS) • • • • •
Occurs in monochorionic twins Vascular communication in placenta results in imbalance of blood flow 10-15% of MC BA pregnancy Donor fetus hypoperfused Recipient twin hyperperfused
Twin-Twin Transfusion syndrome Staging system “Qunitero Stage” Stage I: Oligo/polyhydramnios, but no fetal distress, bladders seen in both babies Stage II: Donor bladder no longer visible (donor also has severe oligo/ anhydramnios) Stage III: Abnormal Doppler signal in either baby, namely, absent or reversed end-diastolic velocity in the Umbilical Artery (indicating significant hemodynamic stress) Stage IV: Fetal hydrops
Stage V: Single or dual fetal demise
TTTS Limitations of staging . a) Disease evolution is unpredictable . b) Not all cases worsen, some spontaneously improve . c) Disease may skip stages or may remain same stage for several weeks
TTTS - Therapy •
Serial reduction amniocenteses (AR)
•
Septostomy
•
Photocoagulation (LASER) of anastomoses via fetoscope (FLA)
TTTS (fetoscopic laser ablation vs. amnioreduction)
Randomized controlled trials of FLA vs AR for severe TTTS mid gestation:
.
a. FLA significantly higher likelihood of survival of at least one twin (76% vs 56%) to 28 days of age
b. Babies with FLA had an 80% reduction in neurologic complications
c. Up to 25% of pregnancies result in double loss, even with FLA
Rossi AC, D'Addario V. Laser therapy and serial amnioreduction as treatment for twin- twin transfusion syndrome: a metaanalysis and review of literature. Am J Obstet Gynecol. 2008; 198:147.
TTTS - laser interv.
C. Berg - Universitats Klinikum Bonn
TRAP sequence If impending hydrops of normal twin
a. Digoxin administration (to mother) → transplacental to fetus: to counteract
cardiac failure
b. Definitive therapy is separating the vascular connections via US directed umbilical cord occlusion of acardiac mass with bipolar, radiofrequency ablation (RFA) or intrafetal LASER coagulation.
intrafetal LASER coagulation
Results Premiere Hospital - fetal medicine dep. •
1 case of TRAP at 10 w,
•
12/13w - intrafetal LASER coagulation (22 G needle / 0,6mm optic fiber - DiodaLaser) after procedures pump fetus was alive and Doppler on MCA /Umb.Artery = normal
•
24 h later, pump fetus
IUFD
only 1 case - NO CONCLUSION
Selective Fetal Growth Restriction s FGR Selective intrauterine growth restriction (sIUGR) in monochorionic twins is associated with a substantial increase in perinatal mortality and morbidity for both twins. Clinical evolution = combination of the effects of placental insufficiency in the FGR twin + inter-twin blood transfer through placental anastomoses. Clasification of sIUGR into types according to the characteristics of umbilical artery diastolic flow in the IUGR twin permits the differentiation of clinical and prognostic groups. • Type I has normal diastolic flow • Type II is defined by persistently absent/reverse end-diastolic flow • Type III is defined by the presence of intermittent absent/reverse end-diastolic flow (iAREDF)
Valsky DV1, Eixarch E, Martinez JM, Crispi F, Gratacós E., 2010
63 cases of sFGR 23 as type I (36.5%)
27 as type II (42.9%)
13 as type III (20.6%)
IUFD in FGR fetus
4.3% (1)
29.6% (8)
15.4% (2)
IUFD in large fetus
4.3% (1)
22.2% (6)
0.0% (0)
Neonatal death in sFGR fetus
0.0% (0)
18.5% (5)
0.0% (0)
Neonatal death in large fetus
0.0% (0)
11.1% (3)
23.0% (3)
Neurological abn. at 6 mo. in sFGR twins
4.3% (1)
14.8% (4)
23.1% (3)
Neurological abn. at 6 mo. in large twins
0.0% (0)
11.1%
38.5% (5)
The management strategy for sIUGR with abnormal umbilical artery Doppler (types II and III) may include: • elective fetal therapy • close surveillance with fetal therapy or elective delivery in the presence of severe fetal deterioration. Small clinical series reporting the use of cord occlusion or LASER therapy in severe cases suggest that the outcome of the larger twin might be improved. There is probably no single optimal strategy, since decisions will ultimately be influenced by the severity of IUGR, gestational age, parents' wishes and technical issues.
Neural Tube Defect Myelomeningocele - MMC -
Meningomyelocele (MMC): MMC is the first fetal intervention for a condition that is not life - threatening for the fetus. The primary outcome variable is the need for ventriculo-peritoneal shunt as treatment for hydrocephalus, which occurs in approximately 80% of infants after post-natal repair of MMC.
MMC - lesion
MMC - fetal surgery CHOP
Risks of Open Fetal Surgery
• • • • •
Preterm labor / delivery Infection Fetal risks of surgical procedure Need for high hysterotomy - risk of uterine rupture, need for Cesarean with all future pregnancies More procedures being done though scope, which lowers morbidity
Congenital Heart Disease - CHD -
Other Conditions: It is likely that other conditions will become subjects of attempted fetal correction or treatment. Currently, consideration is being given to fetal intervention - balloon valvuloplasty for certain cases of critical Ao stenosis and PS-PA with IVS and atrial septoplasty in restrictive or intact atrial septum associated with HLHS.
The earliest reported human fetal cardiac therapy of any kind was in 1975 and involved maternal-fetal transplacental administration of a beta-blocker in the setting of fetal ventricular tachyarrhythmia. The first open in utero cardiac procedure was reported a decade later, in 1986, with a pacemaker placement for complete heart block. Experimental studies on open fetal cardiac surgery began in the 1980s in animal models • Many factors attributing to placental dysfunction following a time on bypass (cytokine-mediated injury evidenced by the increase in prostanoids, vasoactive leucocytes, complement, and consequent endothelial dysfunction)
•
Fetal open cardiac surgery was largely abandoned.
The concept of performing balloon valvuloplasty in fetuses with stenotic heart valves followed the successful introduction of neonatal balloon valvuloplasty in the 1980s, with the first reported case performed in a fetus with aortic stenosis in 1989.
Indication for fetal intervention in CHD FIGS -Fetal Image-Guided Surgery • Fetal aortic valvuloplasty in severe stenosis • Restrictive or intact atrial septum • Fetal pulmonary atresia with intact ventricular septum (PA/IVS) •
Complete heart block with hydrops
Valvuloplasty in Ao stenosis
Critical Ao stenosis
C. Berg - Universitats Klinikum Bonn
Valvuloplasty in PS-PA/IVS
Restrictive or intact atrial septum in HLHS HLHS - hypoplastic left heart syndrome when is associated with a severely restrictive or intact atrial septum early mortality rate of 50%-90%. Atrial septoplasty is performed by placing a needle through the restricted septum into the fetal right atrium or, through the left atrial free wall. In one series, of the 19 successful cases following fetal atrial septoplasty, 12 required additional procedures in the immediate postnatal period and 7 remained stable until the Norwood procedure could be performed (two fetuses demised in utero) More than 50% of the cohort survived through the Norwood operation, as compared to only 10%-20% in whom fetal atrial septoplasty had not been performed. Marshall AC, Levine J, Morash D, et al. Results of in utero atrial septoplasty in fetuses with hypoplastic left heart syndrome. Prenat Diagn. Nov 2008;28(11):1023-8.
Complete heart block with hydrops
Treatment of third-degree or complete heart block, and fetuses with low intrinsic ventricular rates: - administration of corticosteroids to the mother; - administration of beta-mimetics to increase fetal heart rate have somewhat improved fetal survival.
Implantation of fetal pacemakers Eghtesady P, Michelfelder EC, Knilans TK, Witte DP, Manning PB, Crombleholme TM. Fetal surgical management of congenital heart block in a hydropic fetus: lessons learned from a clinical experience. J Thorac Cardiovasc Surg. Mar 2011;141(3):835-7.
Summary
Premiere Hospital - fetal medicine department FIGS • • • • •
IUT - severe fetal anemia / trombocytopenia; TAS - FPE/CCAM macrocystic/BPS with hydrops fetalis; VAS - LUTO; Shunting Abdominal Fetal Cysts (UPJ stenosis, megaurether, etc); Intrafetal LASER coagulation - TRAPS, BPS, SCT (?)
Future - FETENDO (?)
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