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The placenta has long been overlooked by medicine. It is the link between the developing fetus and the mother and it is more accurate to describe it in terms of the fetal-placental-maternal unit. Not every placenta is submitted for microscopic evaluation but all placentas are inspected at the time of delivery and determined if any gross abnormalities are present. In addition, conditions such as multiple gestations, pre-eclampsia, chromosomal abnormalities, or significant fetal distress are all indications for the placenta to be sent to the pathologist for detailed examination.

Gestational Trophoblastic Disease (Mole, Partial Mole, Choriocarcinoma)


Disease Associations  
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
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Histologic correlates of viral and bacterial infection of the placenta associated with severe morbidity and mortality in the newborn.

Satosar A, Ramirez NC, Bartholomew D, Davis J, Nuovo GJ.
Hum Pathol. 2004 May;35(5):536-45. Abstract quote  

The purpose of this study was to correlate the histologic features of the placenta with the in situ detection of viral or bacterial nucleic acids in cases of severe morbidity and mortality in the neonatal period.

The criteria for the cases were either fetal or neonatal death (11 cases with autopsy material available in 8 cases) or idiopathic severe respiratory distress or central nervous system-related symptoms at birth (49 cases). Controls included 11 placentas from births with no morbidity and 6 placentas that were associated with severe neonatal morbidity of known etiology (trisomy, ruptured uterus, prolapsed cord).

The 77 placental tissues were analyzed with a consensus bacterial probe and for a wide variety of viral infections. An infectious cause was found in 46/60 (76%) of cases; these were distributed as follows: enterovirus, 23 cases (22 were coxsackie virus); bacterial (consensus probe), 15 cases; cytomegalovirus (CMV), 4 cases; herpes simplex virus (HSV), 2 cases; parvovirus, 2 cases. The infectious agents localized primarily to Hofbauer cells and trophoblasts. In each of the 8 cases for which autopsy material was available, the same infectious agent that was detected in the placenta was also detected in the autopsy material (spleen, heart, central nervous system, or lungs). No infectious agent was detected in any of the 17 controls. Viral inclusions (only evident for DNA viruses) and stem vessel vasculitis were the 2 histologic findings that were associated with infectious disease in the placenta (P = 0.025).

These data show that infection of the villi is highly associated with neonatal morbidity and mortality and that the histologic findings are, in most cases, nonspecific for infection.
Hum Pathol 1985;16:727-731
Am J Obstet Gynecol 1990;163:935-938

Three well characterized syndromes include:
Maternal floor infarction
Chronic villitis
Thrombophilia-associated maternal vasculopathy
Placental pathology in fetal thrombophilia.

Ariel I, Anteby E, Hamani Y, Redline RW.
Hum Pathol. 2004 Jun;35(6):729-33. Abstract quote  

The aim of this study was to test the hypothesis that placental vascular lesions of the fetal circulation are caused by fetal thrombophilic mutations.

The study included 64 newborns of women with one or more of the following pregnancy complications: preeclampsia, placental abruption, and intrauterine growth restriction. The most prevalent inherited thrombophilias-factor V Leiden, factor II (prothrombin) G20210A, and homozygosity for methyltetrahydrofolate reductase C677T-were examined in maternal blood and fetal umbilical cord blood. One pathologist reviewed all of the slides for fetal vascular lesions. Associations between fetal thrombotic vasculopathy and fetal thrombophilia were tested for using Fisher's exact test; Z scores and gestational age were compared using the Student t-test. Fetal thrombophilic mutations were diagnosed in 19 of 64 newborns, 15 of whom had coexistent maternal thrombophilia. There was no statistical difference in the prevalence of thrombotic lesions of the fetal circulation between newborns with and without thrombophilia. The combination of maternal and fetal thrombophilia was also not associated with increased fetal vascular lesions.

The results indicate that fetal thrombophilia alone, even in the context of maternal underperfusion, is not associated with fetal vascular lesions of the placenta, although it may represent an underlying risk factor for lesions triggered by other process(es).



Myocytes of chorionic vessels from placentas with meconium-associated vascular necrosis exhibit apoptotic markers.

King EL, Redline RW, Smith SD, Kraus FT, Sadovsky Y, Nelson DM.

Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, USA.
Hum Pathol. 2004 Apr;35(4):412-7. Abstract quote  

Meconium-associated vascular necrosis (MAVN) is a histological abnormality of human placental chorionic vessels that is associated with poor neonatal outcome.

We tested the hypothesis that MAVN shows apoptosis in the walls of chorionic vessels. Archival placental specimens with MAVN (n = 5) were compared with specimens from uncomplicated pregnancies at term (n = 5) and from placentas with intense chorionic vasculitis associated with acute chorioamnionitis with (n = 5) or without (n = 5) a clinical history of meconium in the amniotic fluid. Sections from all placentas were processed by the TUNEL method, and 2 observers who were blinded to specimen diagnosis quantified the immunofluorescent TUNEL staining in both the amnion-facing and villous-facing walls of the larger chorionic vessels in each specimen. Compared with the other 3 groups, only the amnion-facing wall of chorionic vessels in MAVN showed a significantly greater number of apoptotic cells. This was verified by morphological criteria and caspase 3 staining. There were limited or no detectable TUNEL-stained cells in either the villous-facing walls of vessels in the MAVN specimens or in any of the vessels of the placentas from uncomplicated pregnancies. There was a negligible level of apoptosis in chorionic vessels of placentas with intense chorionic vasculitis, with or without meconium, despite the inflammatory response or presence of meconium.

We conclude that apoptosis contributes to the pathophysiology of MAVN.

Expression of vascular endothelial growth factor, placental growth factor, and their receptors Flt-1 and KDR in human placenta under pathologic conditions.

Kumazaki K, Nakayama M, Suehara N, Wada Y.

Departments of Molecular Medicine, Pathology and Laboratory Medicine, and Obstetrics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.


Hum Pathol 2002 Nov;33(11):1069-77 Abstract quote

The vascular endothelial growth factor (VEGF) family and its receptors have multifunctional activities besides angiogenesis, and some of these molecules are induced by hypoxia/ischemia. They are known to be expressed in human placenta, but little is known about their involvement in pathologic conditions.

We have investigated the expression patterns of VEGF, placental growth factor (PlGF), and their receptors fms-like tyrosine kinase (Flt-1) and kinase insert domain-containing region (KDR) in placentas with histopathological changes. Forty-two placentas from normal and complicated pregnancies delivered in the second and third trimesters were fixed with paraformaldehyde and embedded in paraffin. In situ hybridization and immunohistochemistry were performed on serial sections.

In the villi with characteristic hypoxic/ischemic changes (HIC), including increased syncytial knots, infarction, or hypercapillarization, intense immunostaining for VEGF was detected in the media of blood vessels, and increased staining for KDR was demonstrated in the endothelial cells. Strong PlGF immunoreactivity was localized to the degenerative trophoblasts around the infarctions. Marked Flt-1 mRNA expression in the syncytiotrophoblast layers of HIC villi was identified, but some samples did not show ligand expression in these regions. Positive immunostaining for VEGF, PlGF, and Flt-1 was observed in infiltrated neutrophils and macrophages in the placentas with chorioamnionitis (CAM).

These findings suggested that in the hypoxic/ischemic regions, VEGF and KDR expression is increased within the villous vessels by paracrine regulation, whereas the expression of PlGF and Flt-1 is enhanced in villous trophoblasts by autocrine regulation. The Flt-1 gene may also be up-regulated directly by hypoxia/ischemia independently of ligand mediation. Furthermore, the results indicated that VEGF and PlGF stimulate inflammatory cell migration by autocrine regulation via the Flt-1 receptor in the CAM placenta.

Thus, various functions of VEGF family members participate in the development of pathologic changes in the placenta.


Discrepancy in Pathologic Diagnosis of Placental Lesions.

Sun CC, Revell VO, Belli AJ, Viscardi RM.

Departments of Pathology (Drs Sun and Revell and Mr Belli) and Pediatrics (Drs Sun and Viscardi), University of Maryland, Baltimore, Md. Dr Revell is now with the Georgia Bureau of Investigation, Trion, Ga. Mr Belli is now with the New Hanover Regional Medical Center, Wilmington, NC.

Arch Pathol Lab Med 2002 Jun;126(6):706-709 Abstract quote

Context.-Placentas are routinely examined by surgical pathologists, but peer review of placental diagnosis is rarely performed. Objective.-To determine the frequency of discrepant placental diagnosis between general surgical pathologists and a pediatric pathologist. Design.-One hundred fourteen placentas from infants with intrauterine growth restriction (IUGR) and 170 placentas from infants appropriate for gestational age (AGA) were reviewed for 10 lesion types using standardized criteria.The review diagnosis was compared with original reports.

Results.-The review identified 333 lesions, 168 in the IUGR group and 165 in AGA group. Discrepant diagnosis occurred in 137 lesions (41.1%). There was no significant difference in the frequency of discrepant diagnosis between the IUGR (44.7%) and AGA groups (37.6%) (P >.05). Most discrepancies (92.7%) were due to underdiagnosis (identified on review but not mentioned in original diagnosis), but a few (7.3%) were due to misdiagnosis (mentioned in original report but disagreed on review). The common underdiagnoses with their corresponding rates were as follows: hemorrhagic endovasculitis (84.6%), fetal thrombotic vasculopathy (75%), massive perivillous fibrin deposition (68.4%), maternal floor infarction (66.7%), retroplacental hemorrhage (60.6%), intervillous thrombus (57.1%), decidual angiopathy (33.3%), placental infarction (25.4%), acute chorioamnionitis (22.7%), and chronic villitis (21.7%). Misdiagnosis was found in 10 cases: 5 cases of infarction (review diagnosis was perivillous fibrin deposits in 4, intervillous thrombus in 1), 3 cases of acute chorioamnionitis, and 2 cases of decidual angiopathy. Among the 8 general surgical pathologists involved, the frequency of discrepant diagnosis ranged from 31.5% to 58.6% (P >.05). The intraobserver discrepancy rate for the reviewer was 4.8%, significantly lower than the discrepancy rate for the 8 general surgical pathologists.

Conclusion.-It is common for general surgical pathologists not to recognize placental lesions, which may have clinical significance. Awareness of this deficiency, standardization of diagnostic criteria, and increased knowledge in placental pathology may improve the quality of diagnosis in this area.

Single artery (Two vessel cord) May be secondary to aplasia or atrophy of one of the arteries-this occurs in 0.2-1.1% of all live births
There is an increase in fetal malformations ranging from 25-50% of cases-some of the more common malformations include the sirenomelia sequence, VATER association, trisomy 13, trisomy 18, and Zellweger syndrome
Umbilical Cord Vestigial Remnants Remnants of the allantois and omphalomesenteric ducts are frequently present in the proximal (fetal) umbilical cord. Remnants of the Allantois Always centrally located between the two umbilical arteries. Consist of a collection of urothelial and mucous-producing epithelial cells without a lumen. Clinical Significance: Can swell and be a source of an edematous umbilical cord.
Umbilicial Cord-Diameter  

First-trimester sonographic umbilical cord diameter and the growth of the human embryo.

Ghezzi F, Raio L, Di Naro E, Franchi M, Bruhwiler H, D'Addario V, Schneider H.

Department of Obstetrics and Gynecology, University of Insubria, Varese, Italy.

Ultrasound Obstet Gynecol 2001 Oct;18(4):348-51 Abstract quote

OBJECTIVES: Experimental and clinical evidence have shown that the morphometry of the umbilical cord in the second half of gestation might be useful in predicting adverse perinatal outcome. The purposes of this study were to generate a nomogram for the umbilical cord diameter in the first trimester and, in an observational study, to investigate whether the sonographic measurement of the umbilical cord diameter early in gestation has the same clinical value as that late in gestation.

METHODS: The sonographic umbilical cord diameter, crown-rump length and biparietal diameter were measured in 439 fetuses at between 8 and 15 weeks of gestation. The perinatal outcome was recorded for all patients.

RESULTS: The umbilical cord diameter increased steadily from 8 to 15 weeks of gestation. A significant correlation was found between umbilical cord diameter and gestational age (r = 0.78; P < 0.001), umbilical cord diameter and crown-rump length (r = 0.75; P < 0.001) and umbilical cord diameter and biparietal diameter (r = 0.81; P < 0.001). No correlation was found between umbilical cord diameter values and either birth weight or placental weight. Among patients who had a miscarriage (n = 7) and pre-eclampsia (n = 8) the umbilical cord diameter was below 2 standard deviations from the mean in three cases (42.9%) and three cases (37.5%), respectively.

CONCLUSION: The measurement of the umbilical cord diameter in the first trimester is correlated with the growth of the embryo and may be a marker for identifying a subset of fetuses at risk of spontaneous miscarriage and pre-eclampsia.

Umbilical Cord-Length Length is largely determined by forceful stretching of the developing fetus. The greater the tension, the longer the cord and vice versa. A normal umbilical cord measures 55-60 cm and is 32 cm by 20 weeks gestation.

Short Umbilical Cord
An umbilical cord less than 32 cm at any gestational age greater then 20 weeks is short.

Clinical Correlation: Associated with decreased psychomotor development. Rare cases of "achordia" have been associated with abdominal wall defects. Umbilical cords less than 15 cm are often associated with abdominal wall defects, evisceration and spinal and limb deformities.

Long Umbilical Cord
Umbilical cord measures over 100 cm.

Clinical Correlation: Long cords may be a both a consequence and a cause of fetal entanglement. Neonates with long cords are relatively hyperkinetic when compared to neonates having shorter cords.
Cord Insertion The umbilical cord normally inserts centrally or near the center and surface vessels disperse from the cord in a relatively circumferential manner
Marginal or Battledore Placenta 7% of term placentas. Vessels splay unidirectionally over the placental surface.

Clinical Correlation: This vascular distribution is thought to be less effective in perfusion of the fetus. True marginal cords are less mobile and more prone to compromise.
Velamentous (Membranous) Insertion 1% of term placentas. Umbilical cord inserts on the membranes.

Clinical Correlation: Because the umbilical vessels course over the free membranes, they are vulnerable to trauma and compression during labor. Associated with twinning and a single umbilical artery. Note: The distance from the placental edge to the cord should be measured and umbilical vessels should be examined for their integrity.
Furcate Cord Insertion Rare. Umbilical vessels lose Wharton's jelly and separate just before they reach the surface of the placenta.

Clinical Correlation: The vessels are prone to thrombosis. Single Umbilical Artery Occurs in 1% of deliveries.

Clinical Correlation: More frequently seen with twins and velamentous cord insertions. About 20 percent will have other congenital anomalies. Anomalies are often multiple and most often genitourinary, cardiovascular, musculoskeletal, gastrointestinal, and central nervous systems.
False Knots They are not knots, but local redundancies of umbilical vessels. Clinical Correlation: No clinical consequence.
True Knots Occur in less than 1% of placentas.

Clinical Correlation: May cause obstruction to blood flow. Cord edema, thrombosis, grooving, and narrowing are morphologic changes indicating tightness sufficient to cause obstruction to blood flow. Without these, the knot is of no consequence.
Stricture or Torsion

Significant reduction in the size of the umbilical cord though to be due to a relative lack of Wharton's jelly. Very rare. Generally seen within the first 3 cm of the fetal end.

Clinical Correlation: Cause of fetal death. Chirality Refers to the spiraling of the umbilical cord. Orientation is from a fetal reference. A left (counter clockwise) spiral exceeds a right (clockwise) spiral by a ratio of 7:1. The reason for directionality is unknown.

Spiraling of the umbilical cord This is the result of fetal activity.

Clinical Correlation: Lack of Spiraling may reflect inactivity and possibly central nervous system disturbances. Infants who's cords lack spiraling exhibit more perinatal morbidity. Cords with a single umbilical artery are also more frequently untwisted.

Rare event. Secondary to other cord complications such as true knots, torsion, stricture, or prolapse.

Clinical Correlation: A cause of fetal death.


Generalized cord edema is found in approximately 10% of all deliveries. Umbilical vessels become cord-like strands within very loose Wharton's jelly.

Clinical Correlation: Related to prematurity, maternal diabetes, pre-eclampsia, abruption, and Rh incompatibility.

Umbilical cord lesions in early intrauterine fetal demise.

Singh V, Khanum S, Singh M.

Department of Pathology, Princess Durru Shehvar Children's & General Hospital, Purani Haveli, Hyderabad, India 500002.

Arch Pathol Lab Med. 2003 Jul;127(7):850-3 Abstract quote

CONTEXT: The cause for intrauterine fetal demise (IUFD) occurring in early gestation in a high percentage of spontaneous abortions is unknown.

OBJECTIVE: To determine the association, if any, of umbilical cord abnormalities with early IUFD.

DESIGN: All cases of IUFD occurring within 16 weeks of gestation that presented to our hospitals between August 1998 and July 2001 were prospectively studied. Once the fetal demise was diagnosed, pregnancy was terminated by medical induction, such that the products of conception were largely delivered intact. Cases with an intact umbilical cord connecting the fetus and placenta were considered in the study, whereas disrupted cord and curettage material was excluded from the study.

RESULTS: A total of 153 early IUFD cases were seen during the period of study. The medical induction yielded intact products of conception in 122 cases, whereas 31 cases had to be completed by curettage, as the expulsion of the conceptus was incomplete. Thirteen of the 122 IUFD cases showed abnormalities of the umbilical cord. The cord lesions most frequently encountered were constriction and coiling abnormalities. Other lesions seen included hemorrhage, thrombosis, edema, and amniotic band.

CONCLUSIONS: A significantly high number (10.7%) of IUFD in early gestation are associated with umbilical cord abnormalities. Routine assessment of umbilical cords in early pregnancy might help to detect pregnancies at risk.

Circummarginate Insertion The membranes insert on the disc with villous tissue extending beyond the vascular plate and a small ridge of fibrinoid is present where the membranes contact the placental surface. May involve all or only a part of the circumference of the placenta and can vary in width from 1 cm to over 10 cm.

Clinical Correlation: No recognized pathologic sequelae.
Circumvallate Insertion Similar to circummargination, however, there is a redundant doubled-back membrane fold at the point of membrane insertion. These placentas are thick.

Clinical Correlation: Associated with chronic bleeding, prematurity, low birth weight infants, and premature onset of labor.
Placental Disk Weight

When signing out a placental case, look at both the absolute weight and the fetus to placenta ratio. A normal term placenta weighs 350-700 grams.

Fetus:Placenta Ratio Gestational age and the weight of the baby need to be taken into account when evaluating the weight of a placenta. At term, the infant weighs approximately seven times the placental weight. This ratio decreases earlier in gestation.

Clinical Correlation
A relatively heavy or light placenta often indicates an abnormal pregnancy. Large placentas are seen in Rh incompatibility, chronic intrauterine infections, and maternal diabetes. Small placentas are seen in toxemia of pregnancy, hypertension, multiple congenital anomalies, intrauterine growth retardation, and severe diabetes.

Gestational Age (weeks)
Weight Range (grams)
200-300 g
250-350 g
280-410 g
300-465 g
315-500 g
340-525 g
350-545 g
Shape The placenta normally is ovoid and measures between 16 and 20 cm in diameter by 1.5 to 3.0 cm in thickness. A bilobate placenta has two approximately equal-sized lobes. The umbilical cord is inserted between the two lobes. A succenturiate lobe occurs when an accessory lobe is present connected to the main disk either by membranes or chorionic tissue.

Clinical Correlation: An accessory lobe may be retained in the uterus causing post-partum bleeding, located over the cervical os causing placenta previa, or cause fetal hemorrhage due to trauma to vessels.
Villous Maturation The central placenta is the best place to judge villous maturity, because it is better perfused. The margins of the placenta receive relatively less blood flow and will always look accelerated for the gestational age.

Accelerated Maturation The villi are small, possibly fibrotic, with increased syncytial knots.
Clinical Correlation Associated with decreased utero-placental blood flow. Examples include: pre-eclampsia, hypertension, and severe diabetes. Normally, twin and multiple gestations appear accelerated.

Delayed Maturation The villi are too large, Hofbauer cells and cytotrophoblast are prominent, and blood vessels are centrally located. The placenta has an "edematous" appearance.
Clinical Correlation Frequently associated with chronic villitis. Also seen with Rh incompatibility, some cases of diabetes, and Down's syndrome. Uneven Maturation Refers to placentas that have foci of both accelerated and delayed maturity.
Maternal Floor Infarct Not a true infarct but excessive fibrin deposited in the decidua basalis and intervillous space. The villi are entrapped within fibrin and atrophy. The maternal placental surface is smooth, and on cut section a yellow rind is seen on the maternal floor.

Clinical Correlation Associated with Herpes simplex Virus II, endometritis, and intrauterine fetal demise of long duration. Maternal floor infarcts recur in subsequent pregnancies, so that women initially diagnosed with this lesion are at high risk and should be followed appropriately.
Marginal Hematoma Blood extending onto the marginal surface, but it does not indent the parenchyma.

Clinical Correlation: Generally no clinical consequence.
Retroplacental Hematoma An acute hematoma is soft and easily detached. Older lesions depress the placental parenchyma, and may cause necrosis of the basal plate.

Clinical Correlation Can be a cause of third trimester bleeding. Increased with pre-eclampsia, but not with uncomplicated hypertension. Abruption is associated with retroplacental hematoma. Abruption may be seen with abdominal trauma, short cords, subdecompression of polyhydramnios, uterine compression of the inferior vena cava, lupus anticoagulant, hypertension, smoking, advanced maternal age, and chorioamnionitis.
Infarct Triangular lesion with the base of the infarct pointed towards the basal plate.

Histology Ischemic villi initially appear matted together. In a hyperacute infarct, the maternal intervillous space and fetal vessels are congested. Subsequently, there is necrosis of trophoblast with loss of normal staining. Fetal vessels and villi undergo progressive coagulation necrosis. Neutrophils may be seen at the periphery of an infarct. Adjacent villi may show reactive chorangiosis, excessive syncytial knots, or sometimes chronic villitis. Older infarcts become ghost-like.

Clinical Correlation In an otherwise normal placenta, up to 30% of the surface may be infarcted before the placental reserve is compromised. In cases where there are generalized placental vascular changes, 10% is enough to compromise fetal well being.
Chorangioma Grossly, chorangiomas are red-tan masses that bulge onto the fetal surface. Histology Proliferation of capillary or cavernous vascular channels in a fibrous stroma. Necrosis, hyalinization, calcification, and myxoid change can occur.

Clinical Correlation Small lesions are of no consequence. Large chorangiomas are associated with fetal cardiomegaly, neonatal anemia, edema, and thrombocytopenia.
Chorangiosis Defined as greater than 10 blood vessels per 10 villi in 10 different fields at 10x power. The normal villous has 1-6 vessels. Can be focal, at the periphery of an infarct, or diffuse.

Clinical Correlation Diffuse chorangiosis is associated with chronic villitis. Also associated with diabetes mellitus, pre-eclampsia, and Rh incompatibility.



Dating Fetal Demise in Edematous Cord

>6 hours-Red-brown discoloration Karyorrhexis of inflammatory cells in vessels.
>2 days-Fibromuscular sclerosis of villus vessels.
Inflammation In Utero Infection The fetal reaction is through vessels of the chorion and umbilical cord. Inflammation almost always begins first in the umbilical vein as margination of inflammatory cells.

In time, the cells migrate out of the vessel into the muscular wall and finally into Wharton's jelly producing a funisitis. Not generally grossly recognizable. There may be skip lesions, so it is important to sample multiple areas of the umbilical cord.
Funisitis Present in only 50% of chorioamnionitis. Necrotizing funisitis occurs with long-standing infection and is characterized by inflammatory debris and calcium surrounding the umbilical vessels. There are no lymphatic channels in the umbilical cord and macrophages are essentially absent. As a consequence, meconium-laden macrophages are not seen within Wharton's jelly. Hemosiderin is not formed in situ after intrafunicular hemorrhage, and necrotic and neutrophilic debris accumulate in funisitis and are not cleared.

Acute funisitis of preterm but not term placentas is associated with severe fetal inflammatory response

Chong Jai Kim, MD, Bo Hyun Yoon, MD, Sung-Shin Park, MD, Mi Ha Kim, MD, and Je G. Chi, MD

Hum Pathol 2001;32:623-629. Abstract quote

Acute funisitis, whose basic pathologic feature is umbilical vasculitis, constitutes a type of fetal inflammatory response to intrauterine infection.

In the present study, a comparative analysis was performed between the clinicopathologic profiles of acute funisitis in term and preterm placentas along with measurement of fetal plasma interleukin 6 (IL-6) levels by specific immunoassay to assess the different biologic implications for the fetus. Acute funisitis in preterm placentas showed a significantly higher incidence of umbilical arteritis (P < .000001), higher fetal plasma IL-6 level (P < .0001), and higher prevalence of major perinatal morbidities (P < .0001). To assess the possible variation in fetal cell response to infectious agents according to gestational age, amnion cells and placental villous tissues obtained at different gestational ages were treated with bacterial lipopolysaccharides, and the IL-6 level of the culture media was assayed. Amnion cells and placental villous tissues from preterm placenta showed a more pronounced cytokine response than those from term placenta.

The findings of this study indicate that the clinicopathologic significance of acute funisitis in term placentas is different from that of preterm placentas. Furthermore, they indicate that the robust inflammatory response of the fetus associated with elevated fetal plasma IL-6 level may reflect the biologic needs of the premature fetus to escape from the hostile intrauterine environment.

Candida Infections Characteristic microabscesses on the cord surface characterized by scattered yellow to white 1-2 mm plaques on the umbilical cord. Histologically, the umbilical cord in Candida funisitis shows necrotic debris filled with fungal pseudohyphae and yeast just below the amnionic epithelium.

Clinical Correlation: May cause a rash on the infant at birth.
Meconium Meconium Staining of Membranes

Occurs when the fetus passes meconium in the amnionic fluid. Meconium is not usually passed before 30 weeks of gestation, since the level of motilin, the hormone related to intestinal motor activity, is low in premature infants. Meconium generally results in a green to green-yellow discoloration of fetal membranes. Some placentas may show only vague surface opacity.

Meconium contains hair, squames, pigment, and mucin-positive material. Meconium stains amnionic epithelium and then diffuses into the basal lamina of the amnion where it is picked up by macrophages. Meconium reaches macrophages in the amnion in one hour and macrophages in the chorion within three hours. Amnionic epithelium undergoes necrosis, stratification, and vacuolization within hours after exposure. A histologic diagnosis of meconium staining is made when macrophages containing brown pigment or having diffuse, brown cytoplasm are observed. The macrophages may have vacuolated cytoplasm. Meconium-laden macrophages are mucicarmine and CEA positive. Meconium does not insight an inflammatory response in the membranes.

Clinical Correlation:
Traditionally, meconium passage is considered a response to fetal distress; however, meconium may be passed in the absence of fetal distress and not all fetuses with distress pass meconium

Morphologic Findings Time between passage of meconium and development of morphologic findings
Meconium staining of membranes, cord
1-2 hours
Pseudostratification, degeneration of amnion epithelium
1-3 hours
Pigmented macrophages in amnion
1-3 hours
Pigmented macrophages in chorion
2-3 hours
Meconium laden macrophages deep in extraplacental membranes
6-12 hours
Umbilical cord vessel necrotic arterial media with meconium laden macrophages
48 hours

Disappearance of meconium pigment in placental specimens on exposure to light.

Morhaime JL, Park K, Benirschke K, Baergen RN.

Departments of Pathology, Weill Medical College of Cornell University, New York, NY (Drs Morhaime, Park, and Baergen), and University of California San Diego, La Jolla, Calif (Dr Benirschke).


Arch Pathol Lab Med 2003 Jun;127(6):711-4 Abstract quote

Context.-Meconium discharge has been associated with fetal distress and poor neonatal outcome; thus, its presence is of clinical importance.

Objective.-Loss of meconium pigment in histologic sections from light exposure has been described. We sought to confirm this finding and to measure this loss quantitatively.

Design.-Sections of umbilical cord, fetal membranes, and fetal surface from 11 grossly meconium-stained placentas were processed swiftly to minimize light exposure. Two serial sections from each block were cut and stained; one set was reviewed immediately, and the other was exposed to 8 hours of direct fluorescent lighting. Each site and exposure was scored for pigment intensity (0, no staining; 1, weak expression; and 2, moderate/strong expression) and number of meconium-laden macrophages per 10 high-power fields (HPF). Results were compared on the same specimen using the chi(2) and the paired-samples t test.

Results.-The maximum meconium macrophage count was 13.2/10 HPF in the unexposed sections versus 6.1/10 HPF in the exposed sections (P <.001). Unexposed sections varied from 1+ to 2+ intensity, while exposed sections were all 1+ or negative (P <.001).

Conclusion.-Exposure to fluorescent laboratory lights for 8 hours resulted in a significant loss in the intensity and number of identifiable meconium macrophages in histologic sections. These findings have important implications in the handling of placental specimens, and we recommend that care be taken to minimize exposure to laboratory lights during processing.


Inflammation extending the full thickness of the fetal membranes. Common in pre-term deliveries (less than 20 weeks 100%, 30 weeks 40%, 36 weeks 25%, and 40 weeks 10%). Due to ascending infectious agents, and approximately 70 percent are bacterial.

Membrane Changes The route of infection is by way of the maternal genital tract. The membranes at the cervical os are first exposed to the ascending infecting organisms. Therefore, the inflammatory infiltrate is most severe at the site of membrane rupture (which should be at the center of the membrane roll taken for histologic section). The neutrophilic response comes from maternal decidual vessels; and, thus, the inflammatory cells in the membranes are maternal in origin.

Disk Changes The order in which neutrophils appear is as follows: a. Intervillous or Subchorionic Space b. Chorion c. Amnion d. Chorionic Plate Blood Vessels e. Umbilical Cord Vein f. Umbilical Cord Artery g. Wharton's Jelly (Funisitis) Subchorionic or Intervillous Space Lies immediately below the chorion. First area to show a maternal response to infection. Inflammation will be found in this area 24-48 hours before neutrophils are seen in the chorion. Neutrophils then infiltrate the chorion producing a chorionitis. Inflammatory cells then migrate towards the amnion in response to chemotactic agents in the amniotic fluid.

Fetal Response Derived from the chorionic vessels. Begins as margination of neutrophils. Progresses to an angiitis. Followed by migration of the neutrophils into the chorionic plate.

Clinical Correlation: The major importance of chorioamnionitis is that it causes prematurity. In twins, one never sees chorioamnionitis in the second twin's placenta in the absence of chorioamnionitis in the first born.

Re-evaluation of chorioamnionitis and funisitis with a special reference to subacute chorioamnionitis.

Ohyama M, Itani Y, Yamanaka M, Goto A, Kato K, Ijiri R, Tanaka Y.

Division of Neonatology, Obstetrics, and Pathology, Kanagawa Children's Medical Center, Yokohama, Japan.


Hum Pathol 2002 Feb;33(2):183-90 Abstract quote

Our purpose is to prove that prolonged inflammation of the chorionic plate, which we have termed subacute chorioamnionitis (SCAM), is a distinctive entity and should be differentiated from acute chorioamnionitis (ACAM) because it is an excellent prognostic indicator of chronic lung disease (CLD), including Wilson-Mikity syndrome (WMS).

Ninety singleton placentas with stage-3 chorioamnionitis were delivered at 23 to 32 weeks of gestation during 1993 to 1996, and the infants survived more than 28 days. There were 49 placentas with stage 3 SCAM, 33 placentas with stage 3 ACAM, and 8 placentas with subacute necrotizing funisitis (SNF) and without inflammation of the chorionic plate. Fifty-three of gestation- and birthweight-matched placentas without chorioamnionitis were selected as control. To determine the risk factors for CLD, 27 clinical and 6 histological variables were analyzed. Logistic regression analysis showed that amniotic necrosis (AN) (P =.0168) and low birthweight (P =.0341) were the major contributing risk factors for CLD. SNF was not significantly related to CLD. Patients with SCAM (AN+, SNF-) were highly susceptible to CLD.

In conclusion, SCAM, especially when associated with AN, seems to be a unique prognostic indicator of CLD.

Umbilical vein interleukin-6 levels correlate with the severity of placental inflammation and gestational age.

Rogers BB, Alexander JM, Head J, McIntire D, Leveno KJ.

Departments of Pathology and Obstetrics and Gynecology, The University of Texas Southwestern Medical School, Dallas, TX.

Hum Pathol 2002 Mar;33(3):335-40 Abstract quote

Interleukin-6 (IL6) and suppurating placental inflammation are markers of neonatal sepsis.

The purpose of this study was to define a relationship between IL6 and acute chorioamnionitis and funisitis of the placenta, and to compare IL6 levels in term and preterm neonates. Umbilical venous IL6 was measured in 137 term and 110 preterm neonates. Acute chorioamnionitis was graded as none, mild, moderate, severe, and necrotizing. Funisitis was graded as none, 1 vessel, 2 vessels, 3 vessels, or necrotizing. A 2-way analysis of variance with interaction was used to compare the IL6 levels. There was a stepwise progression of IL6 levels with increasing severity of acute chorioamnionitis and funisitis. Term neonates showed an IL6 elevation with mild acute chorioamnionitis and single-vessel vasculitis, which increased progressively until the inflammation became severe.

In contrast, IL6 levels in preterm neonates did not increase significantly until severe acute chorioamnionitis or 3-vessel vasculitis was seen. Statistically significant differences in IL6 levels were seen in term versus preterm infants when the acute chorioamnionitis was mild or moderate or when the funisitis involved either 1 or 2 vessels (P < 0.05).

The difference may be related to the relative immaturity of the preterm immune system, as has been demonstrated in vivo and in vitro. However, differences in management could be confounding factors. In conclusion, umbilical venous IL6 levels correlate with the severity of acute placental inflammation, with greater IL6 elevations in term infants compared to preterm infants until the inflammation becomes severe.

Squamous Metaplasia Gray or white elevated foci measuring a few millimeters in diameter. Generally multifocal and concentrated around the cord insertion. See keratinizing squamous epithelium histologically. Clinical Correlation: No clinical or pathologic significance.
Amnion Nodosum Consists of multiple, slightly raised, yellow to white foci scattered on the fetal surface of the placenta. Squamous metaplasia and amnion nodosum can grossly appear similar. The differentiating factor, is that amnion nodosum can be easily removed from the membranes. Composed of amorphous and fibrillar eosinophilic material, squamous epithelial cells, and hair. There is no associated inflammatory reaction. Clinical Correlation: Indicative of oligohydramnios and should alert the clinician to renal and/or urinary tract anomalies in the fetus (which cause oligohydramnios due to deficient or absent urinary output).
Decidua Deciduitis

Decidua shows large foci of acute inflammatory cells and necrosis. A few small foci of acute inflammatory cells are present in the decidua of most placentas. A diagnosis of deciduitis is not made in these cases. Clinical Correlation: Acute deciduitis often is accompanied by acute chorioamnionitis.

Decidual Vasculopathy The maternal arteries present in the decidua capsularis and decidua basalis may show vascular changes associated with pre-eclampsia and hypertension. The primary lesion is called decidual atherosis. Characterized by fibrinoid necrosis of the vascular wall, endothelial hyperplasia, and foamy histiocytes. Clinical Correlation: Was at one time felt to be unique to pre-eclampsia, but current belief is that this lesion occurs with any hypertensive disorder.
Obliterative Endarteritis Not a true arteritis. There is luminal reduction by endothelial swelling, thickening of the intima, and hypertrophy and fibrosis of the media. Complete obliteration of fetal stem vessels results in a sharply demarcated area of avascular villi. Clinical Correlation Associated with pre-eclampsia, diabetes, post maturity, smoking, Rh incompatibility, and intrauterine growth retardation. Not seen in fresh stillborns unless maternal hypertension or pre-eclampsia is present.
Hemorrhagic Endovasculitis (HEV)

Not a true inflammatory process and hence a better name is hemorrhagic endovasculosis.

Characterized by: Fetal vessel thrombosis associated with mural necrosis, intimal hyperplasia, and entrapment and fragmentation of red blood cells within the vessel walls. Endothelial damage in terminal villi as evidenced by nuclear debris, red cell fragments, stromal hemorrhage, and hypercellularity.

Clinical Correlation Once considered a post-mortem change, it is now thought to be associated with a severe intrauterine insult of unknown etiology. Associated with increased perinatal mortality, intrauterine growth retardation, and long-term developmental delays. Felt to be a recurrent in 50% of cases; therefore, women initially diagnosed with this lesion are considered high risk and should be followed accordingly.

Livebirths With Placental Hemorrhagic Endovasculitis
Interlesional Relationships and Perinatal Outcomes

C. Maureen Sander, MD, Dennis Gilliland, PhD, Cheryl Akers, MS, Ann McGrath, DVM, Tarek A. Bismar, MD, and Laura A. Swart-Hills, BS

From the Division of Human Pathology, College of Medicine (Drs Sander and McGrath and Ms Swart-Hills), Department of Statistics & Probability (Dr Gilliland), and Department of Microbiology & Molecular Genetics (Ms Akers), Michigan State University, East Lansing, Mich, and the Department of Pathology & Immunology, Lauren V. Ackerman Surgical Pathology Laboratory, Washington University Medical Center, St Louis, Mo (Dr Bismar)

Arch Pathol Lab Med 2002;126, No. 2, pp. 157–164. Abstract quote

Background and Objective.—Hemorrhagic endovasculitis (HEV) is a vasodisruptive alteration of fetal-placental blood vessels that has been associated with perinatal morbidity and mortality and abnormalities of growth and development. Clinicopathologic conditions that are often identified in pregnancies with HEV-affected placentas include villitis of unknown etiology, chorionic vessel thrombi, villous erythroblastosis, meconium staining, and maternal hypertension. The clinical implications of HEV are often disputed. This case-control study assesses the clinical relevance of HEV in placentas of viable infants and examines the interplay of coexistent intraplacental lesions.

Methods.—We reviewed clinical records and slides from 104 livebirths with placentas affected by HEV above a specified severity level (cases) and 104 matched livebirths with placentas that were not affected by HEV (controls). We evaluated incidences of perinatal complications with increasing HEV severity indices in placentas with and without coexistent lesions. Interlesional relationships were established by matching HEV severity indices with severity indices of coexistent lesions. Hemorrhagic endovasculitis was subcategorized into active, bland, and healed forms and clustered capillary lesions (hemorrhagic villitis).

Results.—Lesions that were frequently coexistent in HEV-affected placentas included villitis of unknown etiology, chorionic thrombi, villous fibrosis, erythroblastosis, and primary infarcts. Compared with the control group, the case group had higher incidences of abnormal fetal heart rate tracings (P < .003), fetal distress (P < .001), and growth restriction (P < .001). Increasing severities of HEV and coexistent lesions were associated with higher rates of perinatal complications. Complication rates were higher in HEV cases, with or without coexistent lesions. The complication rate was higher in cases affected by HEV and hemorrhagic villitis than in cases affected by HEV alone (P < .03). Significant interlesional relationships were evident between HEV and villitis of unknown etiology, chorionic thrombi, villous fibrosis, and erythroblastosis.

Conclusions.—Severe forms of HEV can occur in placentas of livebirths. The severity of HEV and associated lesions and the presence of hemorrhagic villitis have important clinical implications. Interlesional relationships between HEV and thrombotic, chronic inflammatory, and chronic vaso-occlusive lesions exist. Pregnancies with HEV-affected placentas with or without coexistent lesions are at risk for perinatal complications.

Intervillous Hematoma An intervillous hematoma is of fetal origin, but rarely can be due to hemorrhage in the wall of a spiral artery. Histology A fresh hematoma is composed of only blood with compressed villi at the periphery. Later, the clot will be laminated and composed of only fibrin. Organization with fibroblasts does not occur. Often associated with an infarct in the periphery of the same cotyledon.

Clinical Correlation Seen in 50% of term placentas and more commonly with Rh incompatibility. Large hematomas can be associated with intrauterine fetal demise, anemia, and hydrops.


Subchorionic Hematoma

Large subchorionic hematomas are also known as Breus mole and are due to fetal hemorrhage. Initially the blood is nonlaminated, but in older lesions only fibrin remains.

Clinical Correlation This lesion can be large and can separate the chorion from underlying villi. Very large lesions are associated with intrauterine fetal demise.
Chronic histiocytic intervillositis associated with recurrent reproductive loss Hum Pathol 2000;31:1389-1396
Diffuse histiocytic infiltration of the intervillous space without villitis
Retrospective study identifying 21 patients with recurrence rate for 67%


Implantation site intermediate trophoblasts in placenta cretas.

Kim KR, Jun SY, Kim JY, Ro JY.

1Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Mod Pathol. 2004 Dec;17(12):1483-90. Abstract quote

Placenta cretas are defined as abnormal adherences or ingrowths of placental tissue, but their pathogenetic mechanism has not been fully explained. During histologic examination of postpartum uteri, we noticed that the number of implantation site intermediate trophoblasts was increased in the placental bed of placenta cretas.

To validate our observation and to address the pathogenetic role of implantation site intermediate trophoblasts in placenta cretas, we examined postpartum uteri with placenta cretas (n=34) and noncretas (n=22), obtained from Cesarean or immediate postpartum hysterectomy specimens. Using antibody to CD146, a marker for implantation site intermediate trophoblasts, we found that placenta cretas had significantly thicker layer of implantation site intermediate trophoblasts (2300+/-1200 mum) than noncretas (1500+/-1200 mum, P<0.025). We also observed that the confluent distribution of cells was more frequent in placenta cretas (97%) than noncretas samples (45%, P<0.001), and that the total number of implantation site intermediate trophoblasts within the superficial myometrium of the placental bed was significantly higher in placenta cretas than noncretas. Using antibodies to Ki-67, Bcl-2 and cleaved caspase-3 to determine the proliferative index and apoptotic rates of implantation site intermediate trophoblasts, we found that they were close to zero in both groups and did not differ significantly.

These findings suggest that the increased number of implantation site intermediate trophoblasts observed in placenta cretas may be related to the pathogenesis of placental ingrowth, but the mechanism by which the increase in implantation site intermediate trophoblasts causes placenta cretas remains to be clarified.

Myometrial Fibers in the Placental Basal Plate Can Confirm but Do Not Necessarily Indicate Clinical Placenta

Accreta T. Yee Khong, MD, and Alice C. Werger

Am J Clin Pathol 2001;116:703-708 Abstract quote

Placental basal plate myometrial fibers reflect mild placenta accreta.

We tested the hypotheses that a macroscopically disrupted area relates to an area where the placenta is focally adherent and that the incidence of placenta accreta is higher than stated in the literature. Sagittal blocks were taken from the basal plate from macroscopically intact, disrupted, and mixed (viz, at the junction of intactness and disruption) areas, together with an en face block from 90 singleton placentas.

Histologic examination revealed that 11 of 23 placentas with a macroscopically disrupted maternal surface and 16 of 67 with a macroscopically intact maternal surface had placental basal plate myometrial fibers, a significant difference. More cases were detected with sampling from the mixed than from the intact area, while sampling from the wholly disrupted area was unrewarding. The en face block also was helpful for detecting myometrial fibers. Extensive and selective sampling of the basal plate revealed a much higher incidence of placental basal plate myometrial fibers.

Clinical chart review affirmed that their presence can confirm but does not necessarily correlate with a clinical diagnosis of mild placenta accreta.



Placental abruption and perinatal death.

Kyrklund-Blomberg NB, Gennser G, Cnattingius S.

Karolinska Institutet Danderyd Hospital, Division of Obstetrics and Gynaecology, Stockholm, Sweden. Nina.Kyrklund.

Paediatr Perinat Epidemiol 2001 Jul;15(3):290-7 Abstract quote

Studies of risk factors for abruptio placentae (AP) are partly conflicting and studies of risk factors for perinatal death in these pregnancies are scarce.

Using the population-based Swedish Birth Registry from 1987 to 1993, we were able to study these risks in 795,459 singleton pregnancies. Logistic regression analysis was used to estimate odds ratios (OR) for risk of AP and risk of perinatal death in pregnancies with and without AP. Risk factors for AP were: age, primiparity, high parity, not cohabiting with infant's father, low education, smoking, infertility, pregestational diabetes, essential hypertension, pregnancy-induced hypertensive diseases, preterm premature rupture of membranes, preterm birth and small-for-gestational-age (SGA) births. Risk factors for perinatal death in pregnancies with placental abruption were smoking (1--9 and > or =10 cigarettes/day; OR 1.4 and 1.7 respectively), severe pre-eclampsia (OR 2.0) and SGA (OR 1.9), whereas in pregnancies without abruption, risks were also increased in maternal age > or =35 years, primiparity, infertility, essential hypertension and pregestational diabetes.

These findings support the theory that, in cases of AP, a general impairment of the placenta and/or a defect placentation may be fatal.

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