—  SHORT COURSE #06  —

Placental Development, Indications for and Methods of Examination

Section 8 - Pathology of the Umbilical Cord

Phyllis C. Huettner, M.D.


The umbilical cord provides the vital link between the developing fetus and its source of nutrients in the placenta. Abnormalities of the umbilical cord can have a severe impact on fetal growth and development and conditions involving the cord such as prolapse are responsible for acute decompensation during labor. Cord abnormalities are identified in about 10% of cases of intrauterine fetal demise at both early and late gestational ages.

Case 9: Umbilical Cord Thrombosis
In addition to the smaller vessels of the chorionic villi (see case 2), fetal vessels of large caliber, such as those in the umbilical cord, can also undergo thrombosis. Thrombosis of the umbilical cord is an uncommon event seen in about 1 in 1300 deliveries but in as many as 1 in 250 high-risk gestations. Thrombosis can be recognized microscopically as a plug of agglutinated platelets, leukocytes and layers of fibrin. Umbilical cord thrombi do not have to be occlusive to be clinically significant and may involve only a focal area of the cord. Thrombosis of the umbilical vein alone occurs in the majority of cases (71%). Umbilical artery and vein thrombosis is seen in 18% of cases and arterial thrombosis without vein involvement in 11%. Fetal morbidity and mortality from umbilical cord thrombosis is very high; two-thirds are stillborn and nearly one-third experience neonatal distress or die in the newborn period. The mortality rate is particularly high with occlusion of both umbilical arteries. In only 3% of such cases has the infant been born alive and well. In infants with umbilical cord thrombosis who present at autopsy, the vast majority have one or more additional obstetrical and/or umbilical cord complications such as increased cord length, excessive twisting, velamentous insertion or marked acute funisitis which likely contribute to the grave outcome.

Embryonic Remnants
The umbilical cord forms during the fifth week of gestation by joining of the omphalomesenteric (vitelline) duct and the allantoic duct (urachus). The omphalomesenteric duct and allantoic duct are usually obliterated by the end of the first trimester but remnants of these structures are commonly found in the umbilical cord, in as many as 23.1% of systematically examined umbilical cords. About 13% of systematically examined umbilical cords exhibit more than one embryonic remnant.

Allantoic duct remnants account for most of these and are located between the two umbilical arteries most commonly at the fetal end of the cord. They are lined by flattened or transitional-type or occasionally mucinous epithelium and rarely have surrounding smooth muscle. Cysts of allantoic duct remnants are quite rare but may be associated with a patent urachus.

Omphalomesenteric duct remnants are less common and are located at the peripheral margin of the cord usually at the fetal end. These are lined by cuboidal or columnar epithelium which may contain intracellular mucin and may be surrounded by a coat of smooth muscle. Occasionally, omphalomesenteric duct remnants display gastric, small intestinal, colonic or pancreatic differentiation. Omphalomesenteric duct cysts are rare but when they occur, are more common in males (4:1) as are complications of omphalomesenteric ducts such as Meckel's diverticula.

About 30% of embryonic remnants are remnants of embryonic vessels. These are located at the peripheral aspect of the cord, usually, at the fetal end. These small, thin-walled, vessels are usually grouped in pairs and are clearly distinct from the main umbilical cord vessels.

No correlation has been demonstrated between the presence of any of these embryonic remnants in the umbilical cord and congenital anomalies, maternal age, race, gravidity or gestational age.

Single umbilical artery
The umbilical cord usually contains one umbilical vein transporting oxygenated blood from the placenta to the fetus and two umbilical arteries transporting deoxygenated blood from the fetus to the placenta. Single umbilical artery (SUA) is one of the most common congenital anomalies and is associated with abnormalities in the fetus and placenta in a high percentage of cases.

The incidence of SUA is estimated at 1% but the incidence depends on the method of cord examination and the population studied. Gross examination only and examination of unfixed cords will underestimate the incidence. There are often anastomoses and fusion between the two umbilical arteries at the placental end of the cord. This fusion may occur as far as 18 cm from the insertion site; therefore sections of cord should be sampled from multiple areas, avoiding the area of insertion. Optimally, cord sections should be examined microscopically before a diagnosis of SUA is made. The incidence is lowest in blacks (0.5%) and Asians and highest in whites of eastern European decent (1.2%). Twins have three to four times the incidence of SUA as singletons.

SUA has a higher incidence among infants who are malformed or stillborn than among normal or liveborn infants. About 21% of infants with SUA in prospective studies and 69% in autopsy series have other major congenital malformations. In prospective studies of infants with SUA this translates into a seven-fold increased risk of malformations compared to a control group. No particular pattern of malformations is seen. The mean mortality rate for SUA from prospective studies is about 20% representing a five-fold increase in mortality compared to the control population. Malformations cause the majority of these deaths. Even in cases without malformations, however, the mortality for SUA is higher, probably related to an increased incidence of low birth weight and intrauterine growth retardation when there is a single umbilical artery, although this is controversial.

SUA may play a role in the development of congenital malformations. It has been postulated that decreased blood flow to the placenta may cause increased fetal cardiac workload resulting in cardiovascular malformations. Decreased fetal blood flow could lead to chronic hypoxia of tissues and, if severe, to visceral malformations. Interestingly, it is nearly always the smaller of twins that exhibits SUA. Ultrasonographers are now able to detect single umbilical artery prenatally although as many as 38% of cases may be missed. When detected prenatally a directed search for other anomalies is recommended. Since about 5% of cases thought to have isolated SUA will have abnormal cardiac echos, some recommend fetal echocardiogram in this situation. Apparently isolated SUA is highly unlikely to be associated with an abnormal karyotype.

There is circumstantial evidence that SUA is an acquired defect, representing atrophy of a previously normal vessel. The incidence of SUA is lower in early embryos than in fetuses and infants at later gestational ages. Sometimes a small, atrophic vessel is seen in cord sections with "SUA." The side of the missing artery is not related to the presence of anomalies, the severity of anomalies, the likelihood of karyotypic abnormalities or the outcome. The lack of familial predisposition to SUA and the discordance of SUA in those cases associated with twinning, even monozygous twinning, is evidence against a genetic etiology.

SUA is strongly associated with abnormal cord insertion. Cases of SUA have a 9.3% incidence of velamentous insertion (vs. 1.2% in controls) and an 18% incidence of marginal insertion (vs. 5.9% in controls). Placentas with a SUA are more likely to show placenta extrachorialis, bilobation, succenturiate lobe, placenta previa, increased infarction and chorangiomas than those without.

There is no correlation between the presence of SUA in the fetus and maternal factors such as age, gravidity and prior fetal loss. The relationship between SUA and maternal diabetes, toxemia and hypertension is controversial.

Follow-up studies of liveborn infants with SUA indicate that infants with external anomalies have a high likelihood of having internal anomalies. Whether asymptomatic infants without external anomalies should be screened in an attempt to detect internal anomalies is controversial but suspicions should be raised if symptoms develop. Infants without external anomalies who remain asymptomatic are not at increased risk of developing major malformations in later life. Infants without anomalies who are growth retarded at birth will catch up with their peers.

Abnormalities of Cord Length
The umbilical cord has a mean length of 55 to 60 cm. It is thought that the length of the umbilical cord is related to the amount of tension or stretch placed upon it. Although growth of the umbilical cord slows during the last trimester as room to move decreases, growth continues up until term. The relationship between umbilical cord length and maternal factors such as height and weight are controversial.

Short umbilical cords, defined as <40 cm, were found in 6% of cases in a large series of singleton pregnancies that excluded cases of congenital malformations and umbilical cord trauma. Short cords are associated with conditions of decreased fetal movement such as amniotic bands, oligohydramnios, abdominal and other body wall defects, acardia, fetal neuromuscular disorders, severe arthrogryposis and female sex. Mothers of infants with short cords are more likely to be better educated and primiparous and less likely to be on Medicaid and to be overweight. No association with maternal smoking or alcohol use was noted in one large study. In the absence of congenital anomalies, short cords are associated with low Apgar scores, neonatal jitters and trembles, hypotonia and the need for positive pressure resuscitation. Short cords were associated with subsequent psychomotor abnormalities in one study with long term follow-up. Both short and long cords are significantly associated with abnormal fetal heart rate tracings.

Long cords, defined as >80 cm, occur in about 6% of term deliveries and are associated with a variety of abnormalities such as encirclement of the cord around the neck or other body parts, cord knots, umbilical cord prolapse, and marked cord twisting. Increased parity (3 or more) significantly increases the likelihood of having an abnormally long cord. A recent large series also noted a significant association between long cords and microscopic placental abnormalities that may reflect a fetal or placental response to hypoxia such as nucleated red blood cells, chorangiosis, fetal vascular thrombi, and meconium stained macrophages. In this series, 52% of infants with cords >90 cm had abnormal CNS imaging studies, neurologic abnormalities or both on follow-up. Women whose placentas had long cords in one pregnancy were significantly more likely to have a long cord in a subsequent pregnancy.

Knots and Encirclements
The umbilical cord often shows eccentric dilatations of umbilical vessels called varices or "false knots" but true knots are seen in between 0.3% and 2.1% of umbilical cords. They are associated with increased umbilical cord length, male fetuses, multiparity, hydramnios, gestational diabetes, monoamniotic twinning, fetal growth retardation, genetic amniocentesis and possibly subclinical extracellular matrix disorders. Most are thought to develop between 9 and 12 weeks of gestation. The majority are associated with no adverse outcome but the overall mortality for umbilical cord knots is estimated at 5-11%. To attribute a poor fetal outcome to a cord knot there should be evidence of chronic or acute tightening. Longstanding knots have persistent grooving and curling after untying as well as focal loss of Wharton's jelly. Knots with acute tightening exhibit edema, congested vessels or occlusive thrombi on one side of the knot. Some require collapse of the cord between the knot and the infant abdominal wall to be certain of clinical significance. True knots of the cord are difficult to detect by prenatal ultrasound.

Nuchal cords, those that encircle the fetal head, are common, occurring in about 25% of deliveries. They are more common in male fetuses and are associated with long cords. Very long umbilical cord (>115 cm) are associated with at least one nuchal loop in 90% of cases. Loose nuchal cords that can be slipped over the fetal head prior to delivery are not associated with increased morbidity or mortality but tight nuchal loops have been associated with prolonged first stage of labor, significantly lower Apgar scores than loose nuchal cords, increased mortality, and otherwise unexplained spastic quadriplegic cerebral palsy. A recent study found that tight nuchal cords occurred more often in normal or short cords. Other studies fail to show prolonged labor or adverse outcomes with nuchal cord or knots.

Abnormalities of Insertion
The umbilical cord usually inserts slightly to one side of the center of the placental disk. In between 5.9% and 18% of cases the cord inserts at the margin of the placenta (marginal or battledore). In about 1% of cases the cord insertion is velamentous; the vessels insert into the fetal membranes. The vessels may branch within the membranes (insertio velamentosa, 75%) or remain together within the membranes (interposition velamentosa, 25%). A rare form of insertion also includes insertio furcata, in which the insertion does not occur within the membranes but the vessels branch and lose Wharton's jelly prior to insertion. The incidence of velamentous insertion is higher in twins (as high as 8.5%) and is seen in decreasing frequency in monochorionic, fused dichorionic and separate dichorionic twin placentas. Velamentous cord insertion may play a role in the pathogenesis of twin-twin transfusion syndrome; compression of intramembranous vessels may cause blood flow shifts through placental vascular anastomoses. Velamentous cord insertion is also increased with SUA, malformed infants, maternal smoking, advanced maternal age, diabetes mellitus and conception through in vitro fertilization.

Benirschke has hypothesized that velamentous cord insertion is the result of competition between fetus and placenta for space, which may explain the increased frequency in cases of uterine structural defects and in twins. The incidence of velamentous cord insertion is even greater in triplets and higher order multiple gestations.

Infants with velamentous insertion of the umbilical cord have an increased rate of congenital anomalies usually of the deformation type (altered shape or structure of a previously normal structure, ie. club foot). These deformations fit with Benirshcke's crowded uterus theory. Early embryos have a higher rate of velamentous cord insertion (15.3%) and have associated malformations in about 25% of cases.

Laceration, compression and thrombosis of the vulnerable intramembranous portions of vessels that are not surrounded by protective Wharton's jelly can be seen with velamentous cord insertion. The intramembranous vessels should be carefully examined grossly and microscopic sections should be taken to look for thrombi or recent hemorrhage, particularly in cases associated with an adverse fetal outcome.

Vasa previa is a very rare condition occurring in about 1 in 5000 deliveries and 1 of every 50 velamentous cord insertions, where membranes containing vessels present in advance of a fetal part. Compression, laceration or rupture of these vessels during labor can result in severe anoxia or sudden exsanguination. The diagnosis is rarely made before the onset of bleeding and the mortality rate is very high, in the range of 30 to 100%.

Aberrant vessels that run in the membranes may be present even when the cord is not velamenously inserted such as with a marginal insertion, succenturiate lobe or even with an otherwise normal insertion and placenta. These vessels may also show laceration or thrombosis.

Hematoma and Rupture
Hematomas of the umbilical cord occur in about 1 in 5500 deliveries and have a 50% perinatal mortality rate, although a recent study has documented small hematomas after 1.5% of ultrasound-guided umbilical cord blood sampling with little fetal morbidity or mortality. Blood leaks from one of the umbilical cord vessels, usually the vein, into the surrounding Wharton's jelly. If the amniotic covering of the cord remains intact, the presence of blood will cause an increase in pressure that can compress the remaining vessels, resulting in asphyxia and death.

Hematomas of the cord present as a fusiform swelling that may extend a considerable length but which usually involves the fetal end of the cord. Although some cases are related to short cord or trauma from conditions such as prolapse or a nuchal cord, in most cases the exact cause cannot be determined. In the few cases of hematoma arising from an umbilical artery, a microscopic abnormality of the vessel such as degeneration or thinning has been detected. Before making a diagnosis of umbilical cord hematoma one must be sure that the blood found in Wharton's jelly is not a result of clamping or blood sampling during delivery.

Umbilical cord rupture is uncommon but almost always leads to fetal exsanguination. Causes, reviewed by Heifitz, include short cord or functionally short cord (nuchal cord) with traction, precipitous delivery, tight torsion or stricture, abnormal cord insertion, inflammation, and trauma, among others.

Spiral
The normal umbilical cord is coiled with an average of 10 turns, most often in a counter-clockwise direction. Spiraling of the cord can be detected as early as 6 weeks and both the number of turns and their direction appear to be established in most cases by 9 weeks gestational age. Coiling increases cord turgor, reducing compression on the vessels. It may also actively augment venous return from the placenta to the fetus. Although the exact cause of umbilical cord coiling is unknown, abnormalities in cord coiling, both too little and too much, have been correlated with adverse fetal outcomes.

An umbilical cord index can be calculated by counting the number of complete turns of the cord, divided by the length of the cord. Standards are available in several references; it is best to use a standard from a population that is similar to the population seen at your institution. About 5% of umbilical cords will exhibit no coiling, a finding that has been correlated with increased fetal mortality, operative delivery for fetal distress, the presence of meconium, abnormal karyotype, preterm delivery, and fetal heart rate abnormalities. Maternal risk factors for uncoiled cords include obesity, gestational diabetes and preeclampsia. Uncoiled cords may be less able to withstand compression during labor resulting in these adverse outcomes. Similarly hypocoiled cords, defined as umbilical cord index below the tenth percentile, has been linked to an increase in preterm delivery, growth retardation, operative delivery for distress, meconium, aneuploidy, oligohydramnios, decelerations and the presence of a nuchal cord. Hypercoiled cords are associated with an increased rate of premature delivery, lower birth weight, and increased incidence of maternal cocaine use, fetal death and abnormal cord insertion. Maternal risk factor for hypercoiled cords is extremes of maternal age.

Most cords exhibit a left-handed twist but about 1 in 7 exhibit right-handed twists. Right handed twists are associated with an increased incidence of placenta previa and vaginal bleeding. Both previa and unusual cord direction may be related to abnormal implantation.

It is possible to determine the coiling index accurately on prenatal ultrasound. Coiling index is related to the Doppler flow characteristics in the umbilical vein. In one study, low coiling index determined prenatally at 15 weeks of age was the best predictor of small for gestational age infants and could indicate that infants with this finding need more careful follow-up during gestation.

Constriction and Torsion
Constriction of the umbilical cord is a rare event associated with a high rate of stillbirth. In most cases the constricted area is located very near the umbilicus. Often there is a localized depletion of Wharton's jelly in the area and associated torsion. The fetal vessels may be markedly thinned or occluded at the constriction site. Constriction of the umbilical cord appears to be more common early in gestation than at later gestational ages. Some have suggested that long cords and excessive fetal movement are risk factors. Heifetz believes that most cases of constriction/torsion represent postmortem artifacts secondary to autolysis that begins at the fetal end of the cord. He requires venous congestion and edema distal to the torsion and/or intravascular antemortem thrombi to attribute a fetal death to this process. Rarely umbilical cord constrictions have been noted in successive pregnancies.

Umbilical Cord Ulceration
Ulceration of the umbilical cord is an uncommon finding that may result in massive fetal hemorrhage. Several cases have been reported in which the infant also had intestinal atresia. Longstanding exposure to meconium (greater than 16 hours) may induce vascular myocyte necrosis and may also be associated with linear ulceration of the umbilical cord.

Abnormalities in Cord Thickness
Both edematous cords and abnormally lean cords have been correlated with adverse fetal outcomes. Increased cord edema, defined as a cross sectional area greater than 1.3 cm2, has been associated with preterm delivery, delivery by Cesarean section, maternal history of gestational diabetes and Rh isoimmunization, respiratory distress in the newborn and abruptio placentae, especially those associated with stillbirth or large retroplacental hematomas. Lean cords have been associated with fetal distress and intrauterine growth retardation. In some of these cases there is an absence of Wharton's jelly, particularly around the umbilical arteries, a finding associated with stillborn infants. In a recent study in which cord diameter was assessed by prenatal ultrasound, a cord diameter less than the 10 percentile for gestational age was significantly related to delivery of a small for gestational age infant, meconium-stained amniotic fluid, 5 minute Apgar scores of <7 and oligohydramnios at delivery with intact membranes.

Occasionally the cord exhibits marked segmental thinning. This has been correlated with deficient tunica media, usually in the umbilical vein, and appears to be associated with an increased likelihood of congenital anomalies and a variety of perinatal problems.

Umbilical Cord Hemangioma
Umbilical cord hemangiomas are very rare. Most occur near the placental end of the cord. Many cases are associated with marked myxoid degeneration and even formation of large pseudocytsts that account for the bulk of the mass. Microscopically, in addition to myxoid stroma, there are lobulated collections of small vessels some of which may have thrombi. Associated changes include calcification, necrosis, and ossification and associated hematoma. Cytologic atypia and malignant behavior have not been reported.

About half of reported cases have been associated with stillbirth, preterm delivery or some form of fetal morbidity such as nonimmune hydrops fetalis, severe fetal hemorrhage and intrauterine growth retardation. Causality of these adverse outcomes by the hemangioma is not definite in all cases but it is thought that compression of the major umbilical vessels by the hemangioma may be contributory. In one case, described by Kamitomo et al, the hemangiomatous vessels grew into the lumens of one umbilical artery and the umbilical vein leading to stenosis of these vessels and resulting in fetal death in utero. Other cases have shown atrophy or hypoplasia or cord vessels.

Many cases are detected early in gestation by ultrasound. In some cases, ultrasound is prompted by an elevated maternal serum alpha fetoprotein level. Unlike chorangioma, umbilical cord hemangiomas are rarely associated with polyhydramnios, a feature that can be explained by differences in the structure of the amnion in the placenta and cord resulting in less transudation of fluid in the cord leading to increased pressure and myxoid degeneration. Occasionally, the infant demonstrates hemangiomas of the skin or visceral organs.

The pathogenesis of umbilical cord hemangiomas is unclear. They are likely hamartomas, a disorganized collection of tissue native to this site, rather than true neoplasms. Some cases probably arise from the umbilical arteries or vein. Other possibilities include an origin from vestigial vitelline vessels or from angiogenic differentiation of primitive cord mesenchyme.

References

General:
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Embyronic remnants:
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Single umbilical artery:
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Length:
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Knots and encirclements:
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Abnormalities of insertion:
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  4. Robinson LK, et al . The nature of structural defects associated with velamentous and marginal insertion of the umbilical cord. Am J Obstet Gynecol 1983; 146:191-3.
Hematomas:
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  2. Duchatel F et al. Complications of diagnostic ultrasound-guided percutaneous umbilical blood sampling: analysis of a series of 341 cases and review of the literature. Eur J Obstet Gynecol Reprod Biol 1993; 53:95.

  3. Heifetz SA. Pathology of the umbilical cord. In: Lewis SH, Perrin E, eds., Pathology of the Placenta. New York: Churchill Livingstone:1999; 107-135.
Spiral:
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  3. Herman A, Zabow P. Segal M. Extremely large number of twists of the umbilical cord causing torsion and intrauterine fetal death. Int J Gynecol Obstet. 1991; 35:165-167.

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  6. Rana J, Ebert GA, Kappy KA. Adverse perinatal outcome in patients with an abnormal umbilical coiling index. Obstet Gynecol 1995; 85:573-7.
Constriction and torsion:
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  2. Glanfield PA and Watson R. Intrauterine death due to umbilical cord torsion. Arch Pathol Lab Med 1986; 110:357-8.

  3. Hallak M, et al. Constriction of the umbilical cord leading to fetal death: a report of three cases. J Reprod Med 1994; 39:561-65.

  4. Heifetz SA. The umbilical cord: obstetrically important lesions. Clin Obstet Gynecol 1996; 39:571-87.

  5. Sun Y, et al. Umbilical cord stricture and intrauterine fetal death. Ped Pathol Lab Med. 1995; 15:723-32.
Umbilical Cord Ulceration:
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  2. Altshuler, G. and S. Hyde, Meconium-induced vasoconstriction: a potential cause of cerebral and other fetal hypoperfusion and of poor pregnancy outcome. J Child Neurol, 1989; 4(2): p. 137-42.

  3. Bendon RW et al.. Umbilical cord ulceration and intestinal atresia: a new association? Am J Obstet Gynecol, 1991; 164(2): p. 582-6.

  4. Khong TY et al. Umbilical cord ulceration in association with intestinal atresia in a child with deletion 13q and Hirschsprung's disease. Arch Dis Child Fetal Neonatal Ed, 1994; 71(3): p. F212-3.

  5. Yamanaka M. et al. Umbilical cord ulceration and intestinal atresia. Eur J Obstet Gynecol Reprod Biol, 1996; 70(2): p. 209-12.
Abnormalities in Cord Thickness:
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  2. Goodlin R, Fetal dysmaturity, "lean cord," and fetal distress. Am J Obstet Gynecol 1987;156:1357.

  3. Labarrere C et al. Absence of Wharton's Jelly around the umbilical arteries: an unusual cause of perinatal mortality. Placenta 1985; 6:555-559.

  4. Quresh F, Jacques S. Marked segmental thinning of the umbilical cord vessels. Arch Pathol Lab Med 1994; 118:826-830.

  5. Raio L et al. Prenatal diagnosis of a lean umbilical cord: a simple marker for the fetus at risk of being small for gestational age at birth. Ultrasound Obstet Gynecol 1999l; 13:176.
Umbilical Cord Hemangioma:
  1. Dombrowski, MP et al Fetal hemorrhage from umbilical cord hemangioma. Obstet Gynecol 1987; 70 (3 Pt. 2): 439-42.

  2. Heifetz, SA and Rueda-Pedraza ME. Hemangiomas of the umbilical cord. Pediatr Pathol. 1983;1:385-98.

  3. Kamitomo M et al Hemangioma of the umbilical cord: stenotic change of the umbilical vessels. Fetal Diagn Ther 1999; 14:328- 31.

  4. Miller KA and Gaudere MW. Hemangioma of the umbilical cord mimicking an omphalocele. J Pediatr Surg 1997; 32:810-2.

  5. Resta RG et al. Umbilical cord hemangioma associated with extremely high alpha-fetoprotein levels. Obstet Gynecol 1988; 7293 Pt 2): 488-91.

  6. Seifer DB et al Nonimmune hydrops fetalis in association with hemangioma of the umbilical cord. Obstet Gynecol 1985; 66:283-6.