<p>In the last three decades, sophisticated ultrasonographic imaging of the fetus has revolutionized the perinatal care of babies with congenital malformations. Sonography appears to be safe, both for the fetus and the mother, and is now routinely employed during pregnancies. However, it is important to remember that sonography is operator dependent. The accuracy and reliability of findings is directly proportional to the skill and experience of the sonologist and the level of sophistication of the machine (<xref ref-type="bibr" rid="bib001">1</xref>). This information is crucial to subsequent management. Since the decision often hangs between whether or not to continue the pregnancy, it is important that the sonologist understands all ramifications of the findings that he has identified; and, that the obstetrician is well informed. It is equally important that neonatologist and the surgeons who are familiar with the management of these lesions after birth and understand the natural history of these malformations be involved in the decision-making process and counseling.</p><p>Ultrasonography identifies only normal and abnormal anatomy. It does not give any direct measure of the effect on function of the affected organ. Any assessment of function is based on indirect evidence and indices. All of these are fraught with inaccuracies. When we wish to know about the natural history of a particular malformation and its possible outcome, we are more concerned with the functional derangement; and this is where sonography has been found wanting.</p><p>Another limiting factor is that though sonography may identify abnormalities in the first trimester, most malformations can be reliably picked up only around 20-24 weeks’ gestation. This gives very little time for a detailed functional assessment and counseling if termination is contemplated. It must be remembered that though sonographic prenatal diagnosis is becoming increasingly sophisticated, diagnostic errors are possible (<xref ref-type="bibr" rid="bib002">2</xref>). The nature of the malformation determines the perinatal management (<xref ref-type="table" rid="tab001">Table 1</xref>). For serious malformations that may be incompatible with life, particularly if associated with chromosomal abnormalities, the family may opt for termination of pregnancy. Most prenatally diagnosed malformations are best managed by surgical correction after a planned delivery near term at a tertiary center. Elective cesarean section is reserved only for those malformations that are associated with dystocia. Early delivery is required in those cases where it is expected that continued gestation will have progressive illeffects on the fetus. <table-wrap id="tab001"><label>Table 1</label><caption><p>Congenital malformations and their proposed management options</p></caption><table><tbody><tr><td><bold>Elective abortion</bold></td></tr><tr><td><list list-type="bullet"><list-item><p>Anencephaly, hydranencephaly</p></list-item><list-item><p>Severe anomalies associated with chromosomal abnormalities</p></list-item><list-item><p>Bilateral renal agenesis, infantile polycystic kidney disease</p></list-item><list-item><p>Untreatable metabolic abnormalities</p></list-item></list></td></tr><tr><td><bold>C-section</bold></td></tr><tr><td><list list-type="bullet"><list-item><p>Conjoined twins</p></list-item><list-item><p>Giant or ruptured omphalocele, gastroschisis</p></list-item><list-item><p>Severe hydrocephalus, large meningomyelocele</p></list-item></list></td></tr><tr><td><bold>Delivery at term</bold></td></tr><tr><td><list list-type="bullet"><list-item><p>Most malformations</p></list-item></list></td></tr></tbody></table></table-wrap></p></sec><sec id="sec002"><title>Thoracic Malformations

JNNFI

Journal of Neonatology

0973-21870973-2179

National Neonatology Forum

jn-19-2-012

Surgery Update

Prenatal Evaluation of Fetal Malformations

Krishna

Anurag

MCh, FAMSSenior Consultant

Department of Pediatric Surgery, Sir Ganga Ram Hospital, New Delhi 110 060 anuragkrishna@sgrh.com

42005

192169179

<p>In the last three decades, sophisticated ultrasonographic imaging of the fetus has revolutionized the perinatal care of babies with congenital malformations. Sonography appears to be safe, both for the fetus and the mother, and is now routinely employed during pregnancies. However, it is important to remember that sonography is operator dependent. The accuracy and reliability of findings is directly proportional to the skill and experience of the sonologist and the level of sophistication of the machine (<xref ref-type="bibr" rid="bib001">1</xref>). This information is crucial to subsequent management. Since the decision often hangs between whether or not to continue the pregnancy, it is important that the sonologist understands all ramifications of the findings that he has identified; and, that the obstetrician is well informed. It is equally important that neonatologist and the surgeons who are familiar with the management of these lesions after birth and understand the natural history of these malformations be involved in the decision-making process and counseling.</p><p>Ultrasonography identifies only normal and abnormal anatomy. It does not give any direct measure of the effect on function of the affected organ. Any assessment of function is based on indirect evidence and indices. All of these are fraught with inaccuracies. When we wish to know about the natural history of a particular malformation and its possible outcome, we are more concerned with the functional derangement; and this is where sonography has been found wanting.</p><p>Another limiting factor is that though sonography may identify abnormalities in the first trimester, most malformations can be reliably picked up only around 20-24 weeks’ gestation. This gives very little time for a detailed functional assessment and counseling if termination is contemplated. It must be remembered that though sonographic prenatal diagnosis is becoming increasingly sophisticated, diagnostic errors are possible (<xref ref-type="bibr" rid="bib002">2</xref>). The nature of the malformation determines the perinatal management (<xref ref-type="table" rid="tab001">Table 1</xref>). For serious malformations that may be incompatible with life, particularly if associated with chromosomal abnormalities, the family may opt for termination of pregnancy. Most prenatally diagnosed malformations are best managed by surgical correction after a planned delivery near term at a tertiary center. Elective cesarean section is reserved only for those malformations that are associated with dystocia. Early delivery is required in those cases where it is expected that continued gestation will have progressive illeffects on the fetus. <table-wrap id="tab001"><label>Table 1</label><caption><p>Congenital malformations and their proposed management options</p></caption><table><tbody><tr><td><bold>Elective abortion</bold></td></tr><tr><td><list list-type="bullet"><list-item><p>Anencephaly, hydranencephaly</p></list-item><list-item><p>Severe anomalies associated with chromosomal abnormalities</p></list-item><list-item><p>Bilateral renal agenesis, infantile polycystic kidney disease</p></list-item><list-item><p>Untreatable metabolic abnormalities</p></list-item></list></td></tr><tr><td><bold>C-section</bold></td></tr><tr><td><list list-type="bullet"><list-item><p>Conjoined twins</p></list-item><list-item><p>Giant or ruptured omphalocele, gastroschisis</p></list-item><list-item><p>Severe hydrocephalus, large meningomyelocele</p></list-item></list></td></tr><tr><td><bold>Delivery at term</bold></td></tr><tr><td><list list-type="bullet"><list-item><p>Most malformations</p></list-item></list></td></tr></tbody></table></table-wrap></p></sec><sec id="sec002"><title>Thoracic MalformationsCongenital diaphragmatic hernia

Congenital diaphragmatic hernia (CDH) affects approximately 1 per 2500 live births (3,4). It occurs as a result of failure of the pleuroperitoneal canal to close by 9-10 weeks of gestation. Herniation of the abdominal viscera through the defect into the chest adversely affects the development of the lung. There is a decrease in the number of bronchial branches. Though the number of alveoli per acinus remains the same, the total number of alveoli is decreased because of the decreased number of bronchial divisions (5,6). This pulmonary hypoplasia is the single most important determinant of outcome in babies with CDH. Though the changes are more pronounced in the ipsilateral lung, even the contralateral lung may be affected. It has been observed, however, that if herniation occurs later in gestation, there may be minimal effect on lung development.

A majority of CDHs occur on the left side; right sided are 10%. Associated anomalies are seen in 25-60% (7,8).These include congenital heart diseases, hydronephrosis, intestinal atresia and spina bifida.

Prenatal diagnosis

CDH may be detected by prenatal sonography as early as 20 weeks’ gestation. However, the average age at the time of diagnosis is 26.2 weeks. Fewer than 50% of the cases are detected by prenatal sonography (4). The diagnosis should be suspected if the stomach is not seen in its usual position. The definitive diagnosis is made if abdominal organs are seen in the chest. Additional findings include polyhydramnios and shift of mediastinal structures. The diagnosis of right sided hernias is more difficult as the echogenecity of the lung and liver is the same (9,10). The differential diagnosis includes congenital cystic adenomatoid malformation (CCAM), bronchopulmonary dysplasia and mediastinal tumors. The accuracy of sonographic diagnosis of CDH is about 97%. (11,12). False negatives may occur if there is lesser degree of visceral herniation.

A prenatal diagnosis of CDH does not change the obstetric management and does not mandate cesarean section.

Prenatally diagnosed CDH can have a spectrum of severity with some having an excellent prognosis following postnatal surgical correction. Others have a poor prognosis despite advances in postnatal management. These fetuses may benefit from fetal surgical correction. Prenatal sonography may help identify the severity of the defect based on certain identifiable criteria. Poor prognosis is expected if the liver herniates through the defect (liver-up CDH). The mortality in this group is 57% as compared to 7% in the liver-down CDH (13). Some studies have suggested that the right lungfetal head circumference ratio (LHR) may be predictive of survival in left-sided CDH. The LHR is determined by a transverse axial image through the chest at the level of the four-chamber view of the heart at 24-26 weeks’ gestation. An LHR of <1.0 is associated with 100% mortality, whereas LHR >1.4 has no mortality. In LHR between 1.0 and 1.4, the mortality is 60% (14,15). It was also believed that CDH detected early in gestation (<18 weeks) was associated with a high mortality, as also was the association with polyhydramnios (11,16). More recent data, has suggested that early prenatal detection of CDH may not necessarily mean a poor outcome (17).

These poor prognostic criteria became the basis for prenatal intervention in the form of fetal repair of the diaphragmatic defect. More recent data has challenged this premise and data from the CDH Study Group has failed to consistently show a relationship between prenatal diagnosis and outcome (18). Even the LHR criterion has not been validated by most centers. This has put a question mark not only on the entire fetal treatment program for CDH but also challenged the wisdom of advising termination of pregnancy when CDH is detected on prenatal sonography. The decision on whether or not to continue with the pregnancy should not be based only on diagnosis early in gestation or other nebulous criteria but rather on whether or not other malformations are present and the expertise of the center to handle this problem postnatally (10).

Prenatal treatment

In early patients, direct repair of the diaphragmatic defect was done through a hysterotomy. However, it was learnt that survival was no better when compared with the standard postnatal correction (19). Later techniques were limited to the subset of CDH with the liver-up position. In this group, it was observed that fetal tracheal obstruction could improve the pulmonary hypoplasia associated with CDH. This finding was applied to fetuses in the “plug the lung until it grows” or the PLUG strategy (20-22). This tracheal occlusion has been achieved by endoscopic techniques (FETENDO), thereby reducing morbidity. (23,24). The most recent techniques have employed placement of an intratracheal balloon. The technique of cesarean delivery has been modified to maintain fetoplacental circulation while the fetal airway in unplugged. Removal of the balloon and delivery of the fetus is accomplished using the ex utero intrapartum treatment (EXIT) strategy (25,26).

Congenital cystic adenomatoid malformation (CCAM)

Is characterized by an overgrowth of terminal bronchioles associated with cysts of varying sizes and a lack of normal alveolar pattern. The lesion is usually unilateral and only one lobe of the lung is affected in 80-95% of cases (27). Classically, three types of CCAM (Type I, II and III) have been described based primarily on the cyst size (27) with Type I (macrocystic) having the best and Type III (microcystic) having the worst prognosis (27,28). The prenatal sonographic findings of CCAM are variable. Type I and II lesions show echolucent cysts of varying size whereas Type III lesions are echogenic and solid (9). Hydrops and mediastinal shift may occur and polyhydramnios may be present in 70% of the cases (28). Esophageal compression by the thoracic mass interferes with fetal swallowing of amniotic fluid leading to polyhydramnios (29). Hydrops occurs due to direct cardiac compression, vena caval obstruction, protein loss from the tumor or unspecified humoral factors that increase capillary permeability (29).

Natural history

The prenatal course of these lesions varies greatly depending on the cyst size. Serial prenatal ultrasounds may show a decrease in size or complete resolution of the cysts (30-32). Lesions associated with hydrops are invariably fatal (30,33). Recently, CCAM volume has been determined sonographically using the formula – length x height x width x 0.52. A CCAM volume ratio (CVR) has been obtained by dividing the CCAM volume by head circumference. A CVR greater than 1.6 predicts increased risk (80%) of hydrops (34). By serial CVR measurements, it has been seen that CCAM growth usually reaches a plateau by about 28 weeks’ gestation (29).

Central Nervous System

Central nervous system (CNS) abnormalities were the first group of fetal malformations that were detected by prenatal ultrasonography.

An affected parent has a 3-5% chance of having a baby with spina bifida. Similarly if a previous child has spina bifida, the risk in subsequent pregnancy is 5% (35).

Neural tube defects

These occur as a result of failure of complete closure of the embryonic neural plate. This defect occurs early during the organogenesis period.

Anencephaly

This is the most common of open neural tube defects. In this abnormality the bony skull above the skull base and orbits is missing. This lesion can be reliably identified on second and third trimester ultrasound scans, but may be missed in first trimester scans due to the presence of significant brain tissue at that time (35). Nearly one-third to one-half such fetuses have associated abnormalities and polyhydramnios is common (36).

Spina bifida

This is the second most common neural tube defect. These abnormalities are classified as spina bifida occulta, spina bifida cystica and spina bifida aperta depending on the physical characteristics of the lesion and whether the neural plaque is exposed or not. These lesions are most common in the region of the lumbar spine. Almost all patients with myelomenigocele suffer from some degree of lower extremity, bowel or bladder weakness and sensory loss. In addition, 80-90% of treated patients develop hydrocephalus that requires a ventriculoperitoneal shunt (37).

Prenatal ultrasound imaging for spina bifida should include not only the entire spine but also the cranium. Spinal findings include widening of the postero-lateral spinal ossification centers, absence of continuity of skin over the spine, and a bulging sac over the spine. Cranial abnormalities include ventriculomegaly, small head size, elongation of the cerebellum with obliteration of the cisterna magna from a Chiari II malformation (banana sign); and scalloping of the frontal region (lemon sign). These signs are very sensitive, being present in nearly 97% of the cases (38). The lemon sign is highly sensitive only in the second trimester because the scalloping resolves by the third trimester due to increasing density of the fetal skull with advancing gestational age (39). Though absence of the lemon sign between 14 to 24 weeks’ gestation rules out the possibility of spina bifida, the presence is not diagnostic. Although the specificity of this test is 99%, the 1% error rate is very large for a disease that has an incidence of 1 per 1000 (in some geographical areas 1 per 250) (39). The banana sign in the second trimester is, both, sensitive and specific for open neural tube defects without the false positive rate of the lemon sign (39).

Management issues

The incidence of neural tube defects has decreased with the widespread use of dietary folic acid supplementation and the increasing use of abortions to terminate affected pregnancies. Still a large number of crippled babies are born that require life-long support. Little has changed in the management of spina bifida after the 1970s when most babies were treated aggressively with early spinal repair and subsequent CSF shunting. With long-term studies, it became clear that while this form of management ensured long-term survival, a multitude of associated problems were observed, commonly orthopedic deformities, urologic deterioration, CSF shunt complications, and mental function handicaps (40). This led researchers to direct their attention to fetal repair of the spinal lesions to minimize the damage to the exposed neural tissue. More than 250 intra-uterine myelomeningocele repairs (IUMRs) have been performed so far (37). The IUMR has a mortality rate of 4% and a morbidity of 11% with prematurity being the commonest problem (41). The benefits of IUMRs have been evaluated. There was no statistically significant difference in the incidence of hydrocephalus between patients operated in utero at an estimated gestational age (EGA) greater than 25 weeks and those treated postnatally. However, younger fetuses required shunt approximately 50% less than in controls. Patients with large lesions or large ventricles at the time of fetal repair also rarely benefited (37). In other smaller studies, the beneficial effect of fetal intervention in preserving limb or bladder function could also not be clearly established (42-44). Currently, a randomized controlled trial is in progress to determine the real benefits of IUMR if performed before 25 weeks gestation using minimally invasive technique employing the daVinci robotic system.

Hydrocephalus

The terms ventriculomegaly and hydrocephalus have been used interchangeably, albeit incorrectly. Ventriculomegaly or ventricular enlargement may be due to:

increased ventricular fluid due to, either, decreased resorption or, rarely, increased production. This truly constitutes hydrocephalus.

abnormal brain development

atrophy of existing brain

Hydrocephalus is estimated to occur in 0.8 cases per 1000 live births (45), the most common cause being aqueductal stenosis. Over three quarter of these babies will have associated abnormalities, abnormal karyotypes or genetic syndromes (35). Isolated cases account for only 20% of cases (46).

Prenatal diagnosis of ventriculomegaly can be easily made with fetal ultrasonography. Currently, measurement of the width of the atrium of the ventricle is the standard. This measurement is made in a transaxial plane just superior to the plane used for BPD measurement. A measurement above 10mm is considered abnormal (47-49). This measurement is independent of the gestational age between 15 to 35 weeks. False normal readings are not common. Interestingly, normal values in boy fetuses are higher than in girls (48). Some questions have been raised about the appropriateness of taking 10mm as the cut-off mark, as some fetuses that had measurements above 10mm turned out to be normal on neonatal assessment (49). It was observed that when the measurements were between 10-12mm, there was a 3.7% rate of abnormal karyotypes, and 7.7% developmental delays. However, mild isolated ventriculomegaly has a much better prognosis with nearly 80% fetuses being normal in the post-natal follow up.

Another sonographic parameter has been the lateral ventricular ratio (LVR). This is the ratio of the lateral ventricular width to the hemispheric width. This is 70% in early pregnancy but falls to 33% at 24 weeks. Thereafter, it remains stable (50). More recently, fetal MRI has been used for the evaluation of fetal ventriculomegaly. No doubt it gives much better delineation of the anatomy and helps detect associated malformations (51,52). Fetal MRI is safe for the mother and the fetus (53).

Management options for fetal hydrocephalus include

pregnancy termination

expectant management with delivery at or near term followed by postnatal shunting procedure, and

preterm delivery.

Effective treatment of neonatal hydrocephalus with CSF shunt operations has drastically reduced mortality to less than 15% with almost half the patients having an IQ greater than 80 and are able to work (54). The size of the pre-shunt cortical mantle does not correlate with the subsequent mental function. The diagnosis of fetal ventriculomegaly can be made as early as 15 weeks. While considering the treatment options, it is most important to establish if there are any associated malformations (55). If present, termination may be advised. Isolated ventriculomegaly is followed with serial ultrasounds. If it remains stable, the pregnancy is carried to term. There is no evidence to advise cesarean section in the absence of a large head in the term fetus (56). It must, however, be remembered that even in isolated ventriculomegaly there is a 30% mortality rate, and only about 60% survivors are normal (57). For rapidly progressive hydrocephalus, early delivery and shunting may be considered after 32 weeks. In utero treatment of hydrocephalus is currently not recommended. This is because placement of ventriculo-amniotic shunt has not been very successful due to frequent dislodgement or obstruction.

Agenesis of the corpus callosum

The corpus callosum is located in the middle of the cerebral hemispheres, and forms the roof of the lateral and third ventricles, and the floor of the interhemispheric fissure. It is formed by the 18 to 20 weeks of gestation. Agenesis of the corpus callosum (ACC) is seen in 0.7% of the general population (58), and can be either partial or complete. It may occur in both syndromic and nonsyndromic forms. CNS abnormalities may be associated in about 85% of the cases, and other anomalies in about 60% (59). Mental retardation (73%) and seizures (42%) have also been reported (60). This outcome data is probably not appropriate for prenatal estimates and counseling purposes as it is drawn from a selected patient population. In more recent studies, (61-63) ACC was an isolated finding in approximately 40% of cases. Over 80% of these were normal in the follow up. When other anomalies were associated, only 18% were normal, the others having significant mental-motor delay.

Choroid plexus cysts

In a recent review, nearly 1% of fetuses scanned showed choroids plexus cysts (CPC) (64). Most CPCs (87%) occur as an isolated finding (64). Isolated CPC is a benign condition, and usually regresses with advancing pregnancy. The earlier belief that CPCs are associated with Down syndrome has been shown to be incorrect (65,66). However, their presence may suggest an increased risk of an abnormal karyotype, specifically trisomy 18. Nearly 50% of trisomy 18 babies have been shown to have CPCs (64). In most cases, though, CPCs were seen along with other abnormalities. Only 4% of trisomy 18 have isolated CPCs. (67)

Hydronephrosis

With the routine use of antenatal ultrasound, more and more fetuses are being diagnosed as having hydronephrosis. Terms such as pelvi-caliectasis, caliectasis and hydronephrosis are being routinely reported by ultrasonologists. This leads to confusion in the minds of the obstetrician, the neonatologist and the pediatric surgeon as to the precise significance of this finding. It is important to first understand what is clinnically significant hydronephrosis.

A renal pelvis antero-posterior (AP) diameter of >10mm after 24-26 weeks of gestation is generally accepted as a reasonable criteria to denote significant dilatation (68,69). The presence of caliectasis is considered an additional factor indicative of significant hydronephrosis (70). More recently, there is evidence to suggest that milder degrees of dilatation may also be significant in that such babies may have vesicoureteral reflux (VUR) rather than obstruction (71-73). Currently, a renal pelvis diameter of at least 4mm before 33 weeks and 7mm after 33 weeks is considered significant (74).

What information is sought on an antenatal ultrasound scan?

While assessing the significance of the antenatal renal dilatation, particularly with a view to identify a possible cause and whether it is worth continuing pregnancy, the US must be done carefully and must give the following information:

Estimated fetal size and weight, and its comparison with normal for that gestational age

Amniotic fluid volume (AFV)

Whether dilatation is unilateral or bilateral, and whether ureters are dilated or not

Degree of dilatation (SFU grading) and dilatation of calyces

Bladder fullness, thickness and emptying

Appearance of external genitalia

Any other associated malformation

The initial study is usually done at 16-20 weeks gestation using a 5 MHz transducer. There are no specific guidelines on how frequently to image the fetus. It would be reasonable to do the US every 4 weeks till 32 weeks and two weekly thereafter, mainly to assess the AFV.

What is the current status of fetal intervention?

The rationale for fetal urinary decompression is that those with severe obstruction early in gestation have significant impairment of both renal and pulmonary development. It has been recognized that if the AFV is adequate upto 27 weeks gestation, then severe pulmonary hypoplasia is unlikely to occur (75). Percutaneous shunting of the bladder into the amniotic space is technically feasible with some morbidity. However, its role is extremely limited.

There is no place for any fetal intervention in unilateral hydronephrosis. Even with bilateral pelviureteric junction obstruction (PUJO), the AFV is normal and percutaneous drainage of the fetal kidneys or early delivery are not warranted for babies with posterior urethral valves (PUV), poor prognostic criteria include:

early severe oligohydramnios

renal cortical cysts suggesting renal dysplasia

bladder urine with sodium >100mEq/L, chloride >90mEq/L, osmolality >210 mOsm/L, increased β₂-microglobin

evidence of pulmonary hypoplasia

What is the natural history of antenatal hydronephrosis?

Spontaneous resolution of prenatally detected hydronephrosis occurs in 50-70% of all fetuses. This regression may occur antenatally itself or in the post-natal life upto 3 years (76-79). Furthermore, in a substantial number, even if the hydronephrosis does not resolve completely, the renal function does not deteriorate despite persistence of pelvic dilatation (80). On the other hand, 15-33% of patients show progressive renal deterioration during observation, necessitating surgery (81-83).

Follow up evaluation

Currently, no single test can reliably predict whether a hydronephrotic kidney will improve or deteriorate. Most people agree that nearly all infants with unilateral PUJ obstruction are initially managed conservatively if the diuretic renogram shows at least 35-40% differential renal function (79,84). Exception are infants with renal infection, tense renal lump (79) or pelvis AP diameter >50mm (82). Follow up US scan and diuretic renography is repeated at 3-6 months and if there is a deterioration in differential renal function, pyeloplasty is indicated (81-84). Nearly 20% infants will show deterioration on follow-up requiring pyeloplasty. This usually happens in the first year of life (80,81,83).

Children with lesser degree of hydronephrosis (upto pelvis AP diameter of <20mm) need to be followed up with an US scan at 3m, 1yr, then 2, 5, and 10years. Radionuclide study is done at 3m, 1yr and if required at 2, 5, and 10 years. If the renal function or degree of dilatation improves, there is no further need for the isotope study (82). Table 2

Grading of hydronephrosis (85)

Grade	Renal image

Central renal complex	Renal parenchymal thickness
0 Intact	Normal
1 Slight splitting	Normal
2 Evident splitting, complex confined within renal border	Normal
3 Wide splitting pelvis dilated outside renal border; calyces dilated	Normal
4 Further dilatation of pelvis	Thin

References1

Harrison

The fetus as a patient. In O’Neill

JrRowe

(eds.) Pediatric Surgery, Vol. 1, 5th edn., Mosby, St. Louis, 1998pp 33.2

Adzick

Management of fetal lung lesions.

Clin Perinatol2003; 30: 481-492.3

Harrison

Bjordal

Landmark

Congenital diaphragmatic hernia: The hidden mortality.

J Pediatr Surg1978; 13: 227-230.4

Langham

Kays

Ledbetter

Congenital diaphragmatic hernia: Epidemiology and outcome.

Clin Perinat1996; 23: 671-687.5

Inselmamn

Mellins

Growth and development of the lung.

J Pediatr1981; 98: 1-15.6

Areechon

Reid

Hypoplasia of the lung associated with congenital diaphragmatic hernia.

Br Med J1963; 1: 230-233.7

Greenwood

Rosenthal

Nodes

Cardiovascular abnormalities associated with congenital diaphragmatic hernia.

Pediatrics1976; 57: 92-96.8

Puri

Gorman

Lethal nonpulmonary anomalies associated with congenital diaphragmatic hernia: Implications for early intrauterine surgery.

J Pediatr Surg1984; 19: 29-35.9

Devine

Malone

Noncardiac thoracic anomalies.

Clin Perinatol2000; 27: 865-899.10

Bohn

Congenital diaphragmatic hernia.

Am J Respir Crit Care Med2002; 166: 911-915.11

Adzick

Harrison

Glick

Diaphragmatic hernia in the fetus: prenatal diagnosis and outcome in 94 cases.

J Pediatr Surg1985; 20: 357-361.12

Guibaud

Filiatrault

Garel

Fetal congenital diaphragmatic hernia: Accuracy of sonography in the diagnosis and prediction of outcome after birth.

AJR1996; 166: 1195.13

Albanese

Lopoo

Goldstein

Fetal liver position and perinatal outcome for congenital diaphragmatic hernia.

Prenat Diagn1998; 18: 1138-1142.14

Lipshutz

Albanese

Feldstein

Prospective analysis of lung to head ratio predicts survival for patients with prenatally diagnosed congenital diaphragmatic hernia.

J Pediatr Surg1997; 32: 1634-1636.15

Metkus

Filly

Stringer

Sonographic predictors of survival in fetal diaphragmatic hernia.

J Pediatr Surg1996; 31: 148-152.16

Adzick

Vacanti

Lillehei

Fetal diaphragmatic hernia: ultrasound diagnosis and clinical outcome in 38 cases.

J Pediatr Surg1989; 24: 654-657.17

Wilson

Fauza

Lund

Antenatal diagnosis of isolated congenital diaphragmatic hernia is not an indictaor of outcome.

J Pediatr Surg1994; 29: 815-819.18

Clark

Hardin

JrHirschl

Current surgical management of congenital diaphragmatic hernia: a report from the Congenital Diaphragmatic Hernia Study Group.

J Pediatr Surg1998; 33: 1004-1009.19

Harrison

Adzick

Bullard

Correction of congenital diaphragmatic hernia in utero. VII. A prospective trial.

J Pediatr Surg1997; 32: 1637-1642.20

Wilson

DiFiore

Peters

Experimental fetal tracheal ligation prevents the pulmonary hypoplasia associated with fetal nephrectomy: possible application for congenital diaphragmatic hernia.

J Pediatr Surg1993; 28: 1433-1439.21

Hedrick

Estes

Sullivan

Plug the lung until it grows (PLUG): a new method to treat congenital diaphragmatic hernia in utero.

J Pediatr Surg1994; 29: 612-617.22

Luks

Gilchrist

Jackson

Piasecki

Endoscopic tracheal obstruction with an expanding device in a fetal lamb model: preliminary considerations.

Fetal Diagn Ther1996; 11: 67-71.23

Albanese

Jennings

Filly

Endoscopic fetal tracheal occlusion: evolution of techniques.

Pediatr Endosurg Innov Tech1998; 2: 47-53.24

VanderWall

Skarsgard

Filly

Eckert

Harrison

Fetendo clip: a fetal endoscopic tracheal clip procedure in a human fetus.

J Pediatr Surg1997; 32: 970-972.25

Harrison

Albanese

Hawgood

Fetoscopic temporary tracheal occlusion by means of detachable balloon for congenital diaphragmatic hernia.

Am J Obstet Gynecol2001; 185: 730-733.26

Mychaliska

Bealer

Graf

Operating on placental support: the ex utero intrapartum treatment procedure.

J Pediatr Surg1997; 32: 227-230.27

Stocker

Madewell

JER

Drake

Congenital cystic adenomatoid malformation of the lung: Classification and morphologic spectrum.

Hum Pathol1977; 8: 155-171.28

Adzick

Harrison

Glick

Fetal cystic adenomatoid malformation: Prenatal diagnosis and natural history.

J Pediatr Surg1985; 20: 483-488.29

Adzick

Management of fetal lung lesions.

Clin Perinatol2003; 30: 481-492.30

Adzick

Harrison

Crombleholme

Fetal lung lesions: Management and outcome.

Am J Obstet Gynecol1998; 179: 884-889.31

Winters

Effmann

Nghiem

Disappearing fetal lung masses: importance of postnatal imaging studies.

Pediatr Radiol1997; 27: 535-539.32

Higby

Melendez

Heiman

Spontaneous resolution of nonimmune hydrops in a fetus with a cystic adenomatoid malformation.

J Perinatol1998; 18: 308-310.33

Barret

Chitayat

Sermer

The prognostic factors in the prenatal diagnosis of the echogenic fetal lung.

Prenatal Diagn1995; 15: 849-853.34

Crombleholme

Colemen

Howell

Elevated cystic adenomatoid malformation volume ratio (CVR) predicts outcome in prenatal diagnosis of cystic adenomatoid malformation of the lung.

J Pediatr Surg2002; 37: 331-338.35

Bronsteen

Comstock

Central nervous system anomalies.

Clin Perinatol2000; 27: 791-812.36

Golstein

Filly

Prenatal diagnosis of anencephaly: Spectrum of sonnographic appearances and distinction from the amniotic band syndrome.

AJR1988; 151: 547.37

Tulipan

Intrauterine myelomeningocele repair.

Clin Perinatol2003; 30: 521-530.38

Watson

Chescheir

Katz

The role of ultrasound in evaluation of patients with elevated maternal serum alpha-fetoprotein: A Review.

Obstet Gynecol1991; 78: 123.39

Van den Hof

Nicolaides

Campbell

Evaluation of the lemon and banana signs in one hundred thirty fetuses with open spina bifida.

Am J Obstet Gynecol1990; 162: 322.40

Bowman

McLone

Grant

Tomita

Ito

Spina bifida outcome: a 25 year perspective.

Pediatr Neurosurg2001; 34: 114-120.41

Tulipan

Sutton

Bruner

Cohen

Johnson

Adzick

The effect of intrauterine myelomeningocele repair on the incidence of shunt-dependent hydrocephalus.

Pediatr Neurosurg2003; 38: 27-33.42

Tubbs

Chambers

Smyth

Late gestational intrauterine myelomeningocele repair does not improve lower extremity function.

Pediatr Neurosurg2003; 38: 128-132.43

Rintoul

Sutton

Hubbard

A new look at myelomeningoceles: functional level, vertebral level, shunting and the implications for fetal intervention.

Pediatrics2002; 109: 409-413.44

Holzbeierlein

Pope

IVAdams

The urodynamic profile of myelodysplasia in childhood with spinal closure during gestation.

J Urol2000; 164: 1336-1339.45

Stoll

Alembik

Dott

An epidemiologic study of environmental and genetic factors in congenital hydrocephalus.

Eur J Epidemiol1992; 8: 797.46

Paidas

Cohen

Disorders of the central nervous system.

Semin Perinatol1994; 18: 266.47

Cardoza

Goldstein

Filly

Exclusion of fetal ventriculomegaly with a single measurement: The width of the lateral ventricular atrium.

AJR1988; 151: 767.48

Patel

Goldstein

Tung

Fetal cerebral ventricular atrium: Difference in size according to sex.

Radiology1995; 194: 713.49

Pilu

Falco

Gabrielli

The clinical significance of fetal isolated cerebral borderline ventriculomegaly: Report of 31 cases and review of literature.

Ultrasound Obstet Gynecol1999; 14: 320.50

Pretorius

Drose

Manco-Johnson

Fetal lateral ventricular ratio determination during the second trimester.

J Ultrasound Med1986; 5: 121-124.51

Levine

Barnes

Sher

Fetal fast MR imaging: Reproducibility, technical quality, and conspicuity of anatomy.

Radiology1998; 206: 540-554.52

Quinn

Hubbard

Adzick

Prenatal magnetic resonance imaging enhances fetal diagnosis.

J Pediatr Surg1998; 33: 553-558.53

Elster

Does MR imaging have any known effects on the developing fetus?

AJR1994; 162: 1493.54

Hirsch

Consensus: Long-term outcome in hydrocephalus.

Child Nerv Syst1994; 10: 64-69.55

Honda

Hidaka

Sato

Matsumoto

Intrauterine high-resolution magnetic resonance imaging in fetal hydrocephalus and prenatal estimation of postnatal outcomes with “perspective” classification.

J Neurosurg1998; 88: 685-694.56

Kuller

Katz

Wells

Cesarean delivery for fetal malformations.

Obstet Gynecol Surv1996; 51: 371-375.57

Gupta

Bryce

Lilford

Management of apparently isolated fetal ventriculomegaly.

Obstet Gynecol Surv1994; 49: 716.58

Grogono

Children with agenesis of the corpus callosum.

Dev Med Child Neurol1968; 10: 613.59

Parrish

Roessmann

Lehvinsohn

Agenesis of the corpus callosum. A study on the frequency of associated malformations.

Ann Neurol1979; 6: 349.60

Jeret

Serur

Wisniewski

Clinicopathological findings associated with agenesis of the corpus callosum.

Brain Dev1987; 9: 255.61

Bennett

Bromley

Benacerraf

Agenesis of the corpus callosum: Prenatal detection usually is not possible before 22 weeks of gestation.

Radiology1996; 199: 447.62

Gupta

Lilford

Assessment and management of fetal agenesis of the corpus callosum.

Prenat Diagn1995; 15: 301.63

Vergani

Ghidini

Strobelt

Prognostic indicators in the prenatal diagnosis of agenesis of corpus callosum.

Am J Obstet Gynecol1994; 170: 753.64

Peleg

Yankowitz

Choroid plexus cysts and aneuploidy.

J Med Genet1998; 35: 554.65

Bromley

Lieberman

Benacerraff

Choroid plexus cysts: not associated with Down syndrome.

Ultrasound Obstet Gynecol1996; 8: 232.66

Gupta

Cave

Lilford

Clinical significance of fetal choroid plexus cysts.

Lancet1995; 346: 724.67

Gupta

Thornton

Lilford

Management of fetal choroid plexus cysts.

Br J Obstet Gynecol1997; 104: 881.68

Grignon

Filion

Filiatrault

Urinary tract dilatation in utero: Classification and clinical applications.

Radiology160: 645, 1986.69

Mandell

Structural genitourinary defects detected in utero.

Radiology178: 193-196, 1991.70

Kleiner

Callen

Filly

Sonographic analysis of the fetus with ureteropelvic junction obstruction.

AJR Am J Roentgenol148: 359-363, 1987.71

Ouzounian

Castro

Fresquez

al-Sulyman

Kovacs

Prognostic significance of antenatally detected fetal pyelectasis.

Ultrasound Obstet Gynecol.1996; 7: 424-8.72

Persutte

Koyle

Lenke

Klas

Ryan

Hobbins

Mild pyelectasis ascertained with prenatal ultrasonography is pediatrically significant.

Ultrasound Obstet Gynecol.1997; 10: 12-8.73

Dudley

Haworth

McGraw

Clinical relevance and implications of antenatal hydronephrosis.

Arch Dis Child1997; 76: F31.74

Corteville

Gray

Crane

Congenital hydronephrosis: correlation of fetal ultrasonographic findings with infant outcome.

Am J Obstet Gynecol.1991; 165: 384-8.75

Mandell

Diagnosis and management of intrauterine urinary tract disorders.

InO’Donnell

Koff

(eds): Pediatric Urology.Oxford, Butterworth-Heinemann, 1997, pp 315-320.76

Kitagawa

Pringle

Stone

Flower

Murakami

Robinson

Postnatal follow-up of hydronephrosis detected by prenatal ultrasound: the natural history.

Fetal Diagn Ther1998; 13: 19-25.77

Grignon

Filiatrault

Homsy

Ureteropelvic junction stenosis: Antenatal ultrasonographic diagnosis, postnatal investigation, and follow-up.

Radiology160: 649, 1986.78

Homsy

Saad

Laberge

Transitional hydronephrosis of the newborn and infant.

J Urol144: 579, 1990.79

Koff

Campbell

The nonoperative management of unilateral neonatal hydronephrosis: Natural history of poorly functioning kidneys.

J Urol152: 593, 1994.80

DiSandro

Kogan

Ureteropelvic junction obstruction. Neonatal management. Role for early intervention.

Urol Clin North Am.1998; 25: 187-97.81

Ransley

Dhillon

Gordon

The postnatal management of hydronephrosis diagnosed by prenatal ultrasound.

J Urol.1990; 144(2 Pt 2): 584-7.82

Dhillon

Prenatally diagnosed hydronephrosis: the Great Ormond Street experience.

Br J Urol.1998 Apr; 81Suppl 2: 39-44.83

Palmer

Cartwright

Fernbach

Surgery versus observation in managing obstructive SFU grade 3-4 unilateral hydronephrosis: A report from the Society for Fetal Urology.

Presented at the Annual Meeting of the American Academy of Pediatrics, Boston, Massachusetts, 1997.84

Elder

Antenatal hydronephrosis: Fetal and neonatal management.

Pediatr Clinics N Am1997; 44: 1299-1321.85

Maizels

Mitchell

Kass

Outcome of nonspecific hydronephrosis in the infant: A report from the registry of the Society for Fetal Urology.

J Urol1994; 152: 232.