KEY POINTS
• Fetal therapy consists of prenatal interventions that are performed to maintain the well-being of the fetus while minimizing maternal complications.
• Improvements in prenatal imaging have led to earlier diagnosis of abnormalities at a time when interventions are still an option for improving fetal outcomes. They have assisted in risk stratification as well as operative planning.
• Referral to centers with experience in fetal intervention can be made when prenatal intervention may be needed or high-risk delivery is anticipated.
• Interventions can range from medical therapy administered to the mother to surgical interventions performed on the fetus, with trends now toward minimally invasive approaches and treatment of nonlethal conditions.
• Maternal safety and well-being are of paramount priority.
BACKGROUND
Central Nervous System
• Myelomeningocele (MMC) (1)
• Open spinal cord defect due to the failure of the neural tube to fuse during embryogenesis.
• One in 3000 live births but greatly depends on ethnic and geographic factors; also higher with anticonvulsants, obesity, diabetes, and low socioeconomic status (2).
• In an MMC, a portion of the spinal cord and surrounding nerves protrude through the spinal defect. It is thought that exposure of the spinal cord to the amniotic fluid results in progressive neurologic damage, while loss of cerebrospinal fluid (CSF) through the defect causes hindbrain herniation and a Chiari type 2 malformation.
• Fifteen percent of patients die within the 1st year of life but dependent on severity of defect, hindbrain herniation, and complications. Long-term prognosis is related to location of the defect.
• Long-term complications may include ventriculomegaly/hydrocephalus, paralysis, breathing and feeding difficulties, learning disabilities, mental retardation, problems with bowel and bladder control, and sexual dysfunction.
Head and Neck
• Cervical teratoma
• Neoplasm composed of all three germ layers located in the region of the neck; 1 in 20,000 to 40,000 live births and 3% to 6% of all teratomas (3).
• Mortality is 80% to 100% in untreated infants, regardless of size.
Forty percent to forty-five percent of mortality secondary to airway obstruction, respiratory compromise related to pulmonary hypoplasia, retention of secretions, pneumonia, and acute hemorrhage of the tumor (4)
Increased risk of intrauterine fetal demise (IUFD), polyhydramnios, and preterm labor
• Complications (2).
Laryngotracheomalacia, mandibular hypoplasia, and nerve compression (mandibular nerve, hypoglossal nerve, and recurrent laryngeal nerve) as a result of mass effect.
Transient or permanent hypoparathyroidism and hypothyroidism due to partial resection of glands or complete replacement by the tumor.
Developmental delay and mental retardation secondary to asphyxia and anoxia at birth.
Pulmonary hypoplasia (up to 30% of cases) as a result of hyperextension of the neck, pulling the trachea cephalad and the lungs into the apices of the thoracic cavities (4).
Rarely, the tumor may extend intracranially with increased morbidity and mortality.
The rate of malignant transformation is unknown.
• Epignathus
• Teratoma usually originates from the palate or pharynx (Rathke pouch) (3); less than 1% of all teratomas (5); 10% have associated anomalies.
• High risks of polyhydramnios, preterm labor and delivery, and significant prematurity.
• High mortality rate secondary to airway obstruction.
• Lymphangioma (2)
• Benign vascular malformation characterized by dilated cystic lymphatics more commonly located in the neck (cystic hygroma), axilla, thorax, and lower extremities; 1 in 1000 to 12,000 pregnancies, depending on inclusion of all perinatal deaths.
• More than 60% of cases are associated with syndromes or genetic abnormalities.
• High mortality when associated with nonimmune hydrops.
• Micrognathia
• Malformation characterized by mandibular hypoplasia affecting 1 in 1600 fetuses.
• Mandibular hypoplasia with posterior displacement of the tongue (glossoptosis) may obstruct the upper airway and predispose the patient to polyhydramnios and preterm labor.
• Agnathia or otocephaly (total absence of the mandible) is the lethal form.
• High frequency of associated anomalies and syndromes, including Pierre Robin syndrome (micrognathia, upper airway obstruction, and cleft palate) (2).
• Poor prognosis is secondary to congenital anomalies.
• Infants are at risk for aspiration, feeding difficulty, and airway obstruction.
• Congenital high airway obstruction syndrome (CHAOS)
• CHAOS entails complete obstruction of the fetal airway resulting in a constellation of pathognomonic signs (see “Diagnosis” section).
• Most common cause is laryngeal atresia. Other causes include subglottic stenosis or atresia, laryngeal or tracheal webs, tracheal atresia or agenesis, and laryngeal cyst (6).
• True incidence is unknown as many of these fetuses die in utero or are stillborn.
• May be associated with Fraser syndrome: autosomal recessive disorder characterized by laryngeal atresia, cryptophthalmos, syndactyly, and urogenital defects (6).
• Mortality approaches 100% if no intervention takes place:
A relatively better prognosis is seen if a decompressive fistula develops spontaneously in utero with resolution of hydrops and in those without other anomalies (6).
• The postnatal course of the survivors may be complicated by bronchopulmonary dysplasia, diaphragmatic dysfunction, laryngotracheomalacia, long-term ventilator dependence, profound capillary leak, and liver and intestinal dysfunction.
Cardiothoracic
• Hypoplastic left heart syndrome (HLHS) with intact or restrictive atrial septum (I/RAS)
• Condition of obstructed left ventricular (LV) outflow caused by abnormal development of left-sided cardiac structures including a hypoplastic left ventricle, an atretic or stenotic mitral valve, and a hypoplastic aorta and arch.
• Constitutes 0.016% to 0.036% of all live births and 1% to 3.8% of all congenital cardiac anomalies (7).
• HLHS with I/RAS manifests as profound hypoxia and pulmonary venous thickening as a result of in utero pulmonary hypertension and parenchymal damage.
• Pericardial, cardiac, and mediastinal teratomas (5)
• Pericardial teratomas originate from within the pericardium, while the more rare cardiac teratomas originate from the myocardium. Together, these account for 7.5% of teratomas.
• Mediastinal teratomas are also located in the anterior mediastinum but are noncardiac in origin, accounting for 2% to 3% of teratomas.
• Pericardial effusion may lead to atriocaval compression and tamponade with subsequent hydrops. Increased risks of IUFD can also be observed with large tumors that cause significant mass effects or hydrops.
• Survival is 75% for pericardial/cardiac and 69% mediastinal depending on whether pericardial effusions are controlled and surgical resection can be performed (5).
• Congenital pulmonary airway malformation (CPAM), aka congenital cystic adenomatoid malformation (CCAM)
• Multicystic or “solid” mass of pulmonary tissue that can have a minute communication with the tracheobronchial tree and a pulmonary blood supply.
Etiology is failure of bronchiolar structure maturation at the fifth to sixth week of gestation versus focal pulmonary dysplasia.
Related to a spectrum of lesions as a result of airway obstruction or bronchial atresia (8).
• One in 25,000 to 35,000 live births with no genetic or recurrence association (2).
• Predominately a unilobar disease; less than 2% are bilobar.
• Stocker classification (a histologic classification initially described in 1977 and revised in 2002).
Type 0 (formerly acinar dysplasia): Tracheobronchial; 1% to 3% of cases; a lethal, diffuse malformation of the entire lung
Type I: Bronchial/bronchiolar; 60% to 70% of cases; single or multiple large cysts
Type II: Bronchiolar; 15% to 20% of cases; numerous small diameter (less than 1 cm) cysts; high frequency of associated anomalies
Type III: Bronchiolar/alveolar duct; 5% to 10% of cases; large homogenous microcystic masses; cardiac compromise and hydrops more likely
Type IV: Distal acinar; 10% of cases; poorly differentiated large cysts (up to 10 cm), and associated with pleuropulmonary blastoma
• Spontaneous regression is reported, but this may actually be an inability to detect lesions by ultrasound as they become isoechogenic to the surrounding lung or are “outgrown” relative to the fetus (2).
• Prognosis is related to the size of the lesion and its growth. Mass growth can plateau in relationship to the fetus between 26 and 28 weeks’ gestation, decreasing the risk of developing hydrops.
• Large lesions causing mediastinal shift are at high risk for polyhydramnios, hydrops, and fetal demise. Mortality is 2% to 30% without hydrops but greatly increased when persistent.
• Long-term complications are malignant transformation (4% risk) and recurrent infection.
• Bronchopulmonary sequestrations (BPS)
• A nonfunctional mass of lung tissue not in communication with the bronchial tree and supplied by an anomalous systemic vessel (usually from the descending aorta) rather than the pulmonary circulation.
• Intralobar (same pleural cover as normal lung, 75% of cases) versus extralobar (separate pleural cover, intrathoracic or subdiaphragmatic) (2).
• Hybrid lesions (coexisting CCAM and BPS) have a systemic blood supply.
• Congenital diaphragmatic hernia (CDH)
• Diaphragm defect arising from the failure of the pleuroperitoneal canal to close by 9 to 10 weeks leading to herniation of abdominal contents into the thoracic cavity with resultant pulmonary hypoplasia and pulmonary hypertensive vasculopathy (9).
• One in 3000 to 5000 live births but 1 in 2200 births if all cases of prenatally diagnosed CDH are included (i.e., intrauterine demise and neonatal deaths prior to transfer to tertiary care facility).
• Eighty-five percent to ninety percent are left sided, 10% to 15% are right, and the remaining approximately 2% are bilateral (2).
• Sixty percent are isolated, and forty percent are associated with major anomalies or genetic syndromes such as Cornelia de Lange and Fryns (9).
• Mortality rates in population studies range from 60% to 70% compared to various institution studies with mortality rates less than 30%; this discrepancy, termed “the hidden mortality,” refers to a selection bias of not reporting terminations, stillbirths, or those that die before transfer to tertiary centers (10).
• Long-term complications (11).
Developmental delay and seizures (related to hypoxic events in neonatal period, extracorporeal membrane oxygenation [ECMO] use) and sensorineural hearing loss (related to prolonged antibiotic and furosemide use)
Prolonged ventilatory support, reactive airway disease
Failure to thrive, gastroesophageal reflux disease
Scoliosis, pectus deformities
• Fetal hydrothorax
• Pleural effusion that is primary (chylous leak) or secondary (associated with immune or nonimmune hydrops) and can be unilateral or bilateral.
• One in 15,000 pregnancies; the true incidence of primary hydrothorax is unknown due to underdiagnosis, spontaneous resolution, abortion, or death (12).
• Associated with CDH (20% of cases), congenital heart disease (5%), and chromosomal abnormalities (5%).
• Mortality for prenatally diagnosed chylothorax is up to 53% (12); improved prognosis when unilateral, tension-free, or spontaneously resolves. Mortality of secondary hydrothorax is related to associated anomalies and/or syndromes.
Abdominal–Pelvic
• Sacrococcygeal teratoma (SCT)
• Teratoma located in the sacrum/coccyx; 1 in 23,000 to 40,000 live births (2).
• The American Academy of Pediatrics Surgical Section (AAPSS) classification is based on the extent of external and presacral tumor (13):
Relates to the ability to make the diagnosis prenatally, ease of resection, and malignant potential secondary to a delay in diagnosis
• Coexisting anomalies are seen in 11% to 38% of cases, with many related to the development and mass effect of the tumor itself (14).
• Mortality in neonates with diagnosis made postnatally is 5%. With prenatal diagnosis, the mortality can be greater than 50% (14,15):
Postnatal mortality is related to tumor hemorrhages, difficulty of resection, and malignant degeneration.
Prenatal mortality is related to high-output cardiac failure (arteriovenous shunting or tumor hemorrhage/anemia), polyhydramnios and premature labor, and dystocia with tumor rupture.
• Long-term complications.
Neurogenic bowel, neurogenic bladder, and renal dysplasia are related to mass effect and obstruction in utero or complications from resection (16).
Recurrence rate is 11%. Malignant potential is 5% to 10% if the diagnosis is made prior to 2 months of age or excision performed before 4 months of age. This risk increases to 50% to 90% if the diagnosis is delayed after this (2).
– Malignant elements are histologically present in 7% to 30% of tumors, but this does not signify malignancy.
Genitourinary Tract
• Bladder outlet obstruction (BOO)
• Also known as lower urinary tract obstruction (LUTO).
• Posterior urethral valves (PUV) are the most common cause in males (1 in 4000 live births) and account for 10% of all urologic anomalies. Urethral atresia is the most common cause of BOO in females (2). Other causes include urogenital sinus, cloaca, and anterior urethral valves.
• Presentation can range from normal amniotic fluid to oligohydramnios and anhydramnios, renal dysplasia, and pulmonary hypoplasia when complete obstruction is present.
Multiple Gestations
• Twin–twin transfusion syndrome (TTTS)
• Complication of monochorionic twins resulting from unbalanced blood flow through vascular communications in the placenta (17).
• TTTS occurs in 5% to 15% of monochorionic twins:
Recipient: usually larger, hypervolemic with polyhydramnios; increased vascular preload results in right ventricular (RV) congestive heart failure
Donor: usually smaller, growth restricted with oligohydramnios related to poor renal perfusion from hypovolemia and vasoconstriction
• Quintero TTTS staging (18).
I: oligohydramnios in donor twin (deepest vertical pocket [DVP] less than 2 cm) and polyhydramnios in recipient twin (DVP greater than 8 cm)
II: nonvisualized bladder in donor
III: abnormal Doppler findings in one or both twins
IV: hydrops in one or both twins
V: death of one or both twins
• Cincinnati TTTS staging stratifies TTTS into three groups based on severity of cardiomyopathy in the recipient twin (A = mild, B = moderate, C = severe), defined using atrioventricular (AV) regurgitation, RV/LV thickness, and Tei index (17).
• Other staging systems exist (cardiovascular profile score [CVPS] and Children’s Hospital of Philadelphia [CHOP] system) with severity based on points assigned on echocardiographic and Doppler findings (17).
• Perinatal mortality is 60% to 100% for both twins if untreated (2).
• Long-term complications include health problems related to prematurity, central nervous system (CNS) sequelae ranging from mild disability or developmental delay to cerebral palsy, mental retardation, cardiomyopathy, and renal failure.
• Twin reversed arterial perfusion (TRAP) sequence
• Anomaly of monochorionic gestation characterized by one twin (acardiac twin) having an absent, rudimentary, or nonfunctioning heart (2).
“Pump” twin: the twin with a usually structurally normal heart perfusing the acardiac twin with deoxygenated blood along the umbilical artery, hence, reversed arterial perfusion.
Acardiac twin: the twin with rudimentary to no cardiac structure; most common form is absence of the head (anencephalic) with variable development of trunk and limbs (60% to 75% of cases) and hydrops.
• 1% of monozygotic twins (1 in 35,000 to 50,000 births), but this does not account for early pregnancy losses (2).
• The risk of aneuploidy is about 9%.
• When the ratio of the acardiac twin’s total body volume to the pump twin’s estimated fetal weight exceeds 0.7, the risk of adverse pregnancy outcome is greater than 90% (2,19).
• Complications are IUFD, polyhydramnios (~50%), preterm labor (~75%), and CNS sequelae.
Other Conditions
• Amniotic band syndrome (ABS)
• A constellation of defects (see “Diagnosis” section) occurring as a result of entrapment of fetal body parts by constrictive tissue bands causing a tourniquet-like effect or disruption of development; 1 in 1200 to 15,000 live births (2).
Results from amnion rupture, either spontaneously or secondary to instrumentation.
Alternatively, ABS may occur from vascular disruptions.
• 10% of cases involve the umbilical cord with very high risk of fetal demise without intervention.
• Chorioangioma
• A vascular tumor of placental origin. It is the most common placental tumor, occurring in 0.6% to 1% of placentas, and is benign in histologic presentation.
• Large tumors (greater than 4 cm) occur 1 in 3500 to 9000 placentas.
• Etiology is unknown, but it is associated with increased maternal age, diabetes, hypertension, and multiple gestation (20).
• Complications are polyhydramnios, abruptio placentae, and preterm labor.
• Fetal risks are anemia, consumptive coagulopathy, growth restriction, prematurity, cardiac failure, and hydrops.
• Perinatal mortality is 18% to 40% (20).
EVALUATION
History and Physical Exam
• The history should focus on the current obstetric history, past medical history, family history of related abnormalities, and current medical conditions that may affect management strategies, delivery modalities, and possible prenatal interventions.
• Surgical history should be reviewed, particularly if fetoscopic or open fetal procedures are being considered. All procedures that have previously been attempted (e.g., amnioreductions and thoracenteses) should also be reviewed.
• Physical exam should be thorough and include all maternal systems in addition to an evaluation of the fetus.
Laboratory Tests
• Physiologic changes typical of pregnancy should be acknowledged but still recognized as a possible derangement related to the fetal complication.
• Testing should include urinalysis for proteinuria, the presence of which can signify a preeclamptic condition known as maternal mirror syndrome.
• Amniocentesis for karyotype is performed to evaluate for possible chromosome abnormality before subjecting the mother to more invasive procedures.
Fetal Imaging (See “Diagnosis” Section for Specific Findings)
• Ultrasonography, fetal echocardiography, and fetal magnetic resonance imaging (MRI)
DIAGNOSIS
Central Nervous System
• Myelomeningocele (2)
• Maternal serum markers for open neural tube defects include alpha-fetoprotein (from CSF leakage into the amniotic fluid) and acetylcholinesterase.
• Ultrasonography can identify intracranial findings suspicious for a spinal abnormality earlier (12 to 16 weeks) than visualization of a developed vertebra (21). Vertebral defect level needs to be diagnosed for intervention candidacy.
Intracranial findings include small biparietal diameter or head circumference, absent or diminished cerebellum, cerebral ventriculomegaly or hydrocephalus, and lemon (frontal bone scalloping) and banana (compressed cerebellum) signs.
Arnold-Chiari type 2 malformation characterized by beaking of the tectum, hindbrain herniation, elongation and kinking of the medulla, and obliteration of the cisterna magna.
Spinal findings can be better visualized by 16 weeks’ gestation and include splaying or widening of the ossification centers, scoliosis or kyphosis, and cystic meningeal sac.
• MRI provides superior visualization of intracranial findings and may serve a role in assessment in situations where evaluations are hindered by maternal body habitus, oligohydramnios, low fetal head position, or posterior position of fetal spine (22).
Head and Neck
• Cervical teratoma
• Ultrasonography defines tumor features, growth, and physiologic effects:
Multiloculated, irregular masses with solid and cystic components that are typically well demarcated and unilateral.
– Differentiated from cystic hygroma (typically septated cystic masses with poorly defined borders in the posterior neck) and vascular malformations (relatively more vascular lesions usually without calcifications)
Evaluate for signs of hydrops and tracheal/esophageal obstruction including a small or empty stomach, hyperextension of the neck (flying fetus sign), and polyhydramnios (seen in 20% to 40% of cases) (2).
• Echocardiography to diagnose high-output cardiac failure or cardiac compromise.
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