Article

physiology

Abnormalities of the Human Placenta

Kurt Benirschke*

Objectives
1. 2. 3. 4. 5.

After completing this article, readers should be able to:

Author Disclosure Dr Benirschke did not disclose any nancial relationships relevant to this article.

Describe the pathologic ndings of the placental surface indicating chorioamnionitis. Describe common errors in placental shape. Explain the consequences of umbilical cord abnormalities. List the most common maternal disease to cause placental lesions. Describe common placental complications associated with multiple gestations.

Introduction
There are so many abnormalities in placentation that several textbooks have been devoted to the subject, and a new one has just appeared in print. In fact, the great variation in the placentas encountered routinely raises the question of what is really normal. In the rst review in these pages on this subject (The Placenta: Structure and Function. NeoReviews. 2004;5:e252-e261), the rst picture illustrates placental variability. Thus, a considerable background knowledge of seeing many placentas is required before judging what is really abnormal and, more importantly, what is for the fetus a meaningful placental aberration from the normal. To make this review succinct, it is subdivided into ve arbitrary categories: 1) Infections, 2) Errors in shape, 3) Abnormalities of the umbilical cord and its larger branches, 4) Abnormalities caused by maternal disease, and 5) Changes important in adjudicating the placenta of multiple pregnancies. Of course, this leaves out many specic diseases, such as hydatidiform moles, choriocarcinoma, spontaneous abortions, and a few other details that can be found in appropriate books or on the Internet through PubMed.

Infections
Ascending infection leads to chorioamnionitis, which is clearly the most important condition in current obstetrics and perinatology. The reason for this bold statement is that chorioamnionitis is the most important cause of severe prematurity; that is, birth between 20 and 30 weeks gestation. Even with neonatologists becoming more adept at supporting preterm infants, those weighing less than 1,000 g remain somewhat problematic, and many of the smallest ones suffer the most important central nervous system (CNS) lesions: periventricular leukomalacia and intraventricular hemorrhage. These are the antecedents for cerebral palsy, the most unfortunate long-term outcome of prematurity after blindness due to retinopathy of prematurity. Ascending infections result from the defective barrier of the endocervix that normally is occluded by a thick, tenacious mucus plug containing antibodies and immune cells. When severe chronic endocervicitis prevents the formation of adequate endocervical mucus, bacteria or fungi can ascend to reach the forelying decidua capsularis of the fetal membranes, where they cause deciduitis. With the intense inammatory exudate comes the local production of phospholipase, which leads to local production of prostaglandins. Prostaglandins cause initiation of labor and dilatation of the cervix (incompetent cervix is a misnomer for this sequela). The cervical dilatation becomes irrevocable and is untreatable with antibacterials. Organisms penetrate the membranes and cause inammation on the surface of the placenta (chorioamnionitis), which progresses to the surface of the umbilical cord, and cord vasculitis ensues. In some cases, pneumonia or gastritis may result when bacteria and pus are inhaled or swallowed. It
*Emeritus Professor of Pathology, University of California at San Diego, San Diego, Calif. e414 NeoReviews Vol.6 No.9 September 2005

physiology human placenta

Figure 1. Immature placenta with marked chorioamnionitis (surface opacity) showing the marginal clot frequently seen.

is the now incompetent cervix (not the infection itself) that causes preterm birth with all of its sequelae. The pathologist can diagnose this condition by examining the placental surface, which is cloudy, opacied by the interposition of polymorphonuclear leukocytes between the surface and deeper placental tissue (Figs. 1,

Figure 3. Massive chorioamnionitis, with inltration of the fetal placental surface by maternal and fetal inammatory cells, creating some abscesses. The amnion (red top layer) is totally necrotic.

2, 3, 4). Because of the inammation and destruction of the decidua and forelying membranes, local hemorrhage frequently is present at this edge of the placenta, and a clot may be mistaken for abruptio placentae. The hemorrhage even may extend beneath the edge of the placenta, but this type of hemorrhage differs substantially from the true abruptio placentae that is usually related to pre-eclampsia or trauma. Other infections traverse the villous tissue. Probably the most common of these infections is the spirochetal disease syphilis, with round cell inltration, whose origin appears now to be maternal immunocytes. Cytomegalovirus infection is the second most common and leads to villous damage with thrombosis, inclusion body-bearing cells, and obliteration of vill (Fig. 5). Commonly it is followed by growth restriction and more widespread fetal inammation. Varicella, rubella, toxoplasmosis, and parvovirus B19 infections are other notable causes whose recognition relies on pathologic evaluation by the microscope. Their microscopic manifestations vary somewhat, but they share the same pathway. Amazingly, despite the widespread occurrence of malaria and its frequent recognition in intervillous erythrocytes, transplacental infection is rare. The organisms causing Chagas disease are so lethal that most fetuses and placentas are destroyed by them.

Figure 2. Chorioamnionitis begins with a polymorphonuclear

Errors in Shape
Errors in placental shape are numerous and subtle; their recognition also requires knowledge of what constitutes
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leukocyte collection (maternal) under the chorionic plate (blue cells) that inltrate into the membranes above.

physiology human placenta

Figure 6. Bilobed placenta with marginal cord insertion and

membranous vessels that can easily break and bleed.

Figure 4. Later in the development of ascending amnionic sac

infection, the umbilical vein becomes inamed, as shown by the inltration of some polymorphonuclear leukocytes into the muscular wall.

normal. Perhaps the most easily recognized are errors of cord insertion. Normally, the umbilical cord arises from somewhere near the center of the placental disk; a marginal insertion occurs in approximately 5% of placentas, and a membranous (velamentous) cord insertion occurs in 1% of placentas examined (Fig. 6). These errors of cord insertion are much more frequent in multiple births, which is why they have been believed to arise because multiple placentas create (in utero) an atmosphere of competition for space. In truth, we are not certain why these occur. They are important nevertheless because a single umbilical artery (SUA) is more frequent in these cases. SUA is associated with congenital anomalies and more common fetal demise. It is not known

Figure 5. Completely atrophied villi in long-standing fetal cytomegalovirus infection. Some villi may contain inclusion body cells or hemosiderin.
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which is the cause and which the result, but neonatologists must provide extra care for neonates who have SUA. In addition, velamentous cord insertion may lead to thrombosis in the membranous vessels (that are now not protected by Wharton jelly as in the cord itself), and they may tear, with ensuing acute and sometimes massive fetal hemorrhage. This occurs most commonly in vaginal deliveries, when the membranous vessels may course over the internal os and be torn when the membranes are ruptured. Placenta previa also can be considered an error of outline, at least of placentation. The egg implants in ideal circumstances in the upper portion of the endometrial cavity, but when it locates near the internal os, the placenta may spread over the cervical canal completely, partially, or marginally. All have signicant sequelae, not only because major hemorrhage may ensue, but also because the upper portions of the endocervical canal do not undergo a normal process of decidua formation. Thus, in the absence of decidua basalis, the placenta removes the mucosa and adheres to the myometrium, with the subsequent development of a placenta accreta. This is a common development in placenta previa and requires curettage at times to remove the placental remains that adhere to the myometrium after the placenta has been pried away. There is now a much greater incidence of placenta percreta at the former sites of cesarean sections because the incidence of cesarean sections has increased and because sonographic surveillance of pregnancies recognizes these defective uteri more often. Many nonpathologists believe that a percreta is a placenta that has aggressively and deeply invaded the uterus. This is not so. The percreta of the anterior lower uterine segment occurs because of inadequate healing when the

physiology human placenta

Figure 8. Fetal cord strictures (red) related to cord length.

some bleeding and, therefore, the placental surface may be green from hemosiderin.

Figure 7. Placenta accreta on a submucous leiomyoma. There

Cord Abnormalities and Pathology of the Large Placental Vessels

The cord is the lifeline to the fetus, and measurement of its length reects substantial variability. The average length of the umbilical cord at term is approximately 55 cm. Excessively long cords tend to entangle in the fetus (arm, leg, neck) and make knots more often, which can kill the fetus (Fig. 8). I believe the variability in cord length is due to excessive fetal mobility. When the fetus is immobile (as in osteogenesis imperfecta, when amnionic bands tie the fetus down, in myopathies, in acardia), the cord is excessively short and not spiraled (Fig. 9). Generally, the cord is also shorter in multiple gestations, presumably because there is less room to move. Excessively long cords are often supercoiled, and ex-

is no decidua basalis because of the pressure atrophy from the leiomyoma.

uterus is repaired following cesarean section. The 1,000-g term pregnant uterus shrinks rapidly (within a few days or weeks) to a more normal 50- to 100-g organ. Thus, the once-tight suture of a cesarean section wound quickly becomes dehisced. Moreover, smooth muscle of the myometrium does not provide healing; it is connective tissue and peritoneum (or the posterior bladder wall) that seals over the wound site. When the uterus becomes distended by a new gestation, this former wound enlarges, and when a placenta is located over the site by chance, it will stick out through the uterine dehisced defect. It may attach to the bladder or peritoneum as though it was a peritoneal gestation, but it has not aggressively grown through the uterus. There is usually little decidua, and accreta/percreta are, thus, admixed. In addition, a placenta accreta may occur when the placenta accidentally implants on a submucous leiomyoma over which the decidua is often atrophied (Fig. 7). Bilobed placentas occur occasionally, as do succenturiate (additional) lobes. Generally they are of no importance unless the vessels traversing from one lobe to the other rupture and bleed. The membranes may not attach perfectly marginally, but they are doubled up in a ring at the edges, the so-called circumvallate placenta. It is not a common entity, and although it may relate to some cases of prematurity, quantitatively it does not play an important role in placental pathology. The site often engenders

Figure 9. Unusually short umbilical cords are associated with

osteogenesis imperfecta (because it hurts when the fetus moves and breaks its bones, it does not move) and other anomalies of extremities that have similar constraints.
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physiology human placenta

Figure 11. Thromboses (arrows) in distended placental sur-

face vessels in an excessively long umbilical cord.

Figure 10. Spontaneous abortion with fetal death due to

excessive spiraling and blood ow obstruction at arrow.

periments have shown that coiling increases uid resistance; the fetus must pump blood harder than when there is less coiling. Hypercoiled cords often have more thrombi in placental surface veins because the ow is more sluggish, and when coiling becomes excessive, the fetus can strangle circulation in the cord vessels. This is commonly seen in abortions and is located at the surface of the abdomen because the fetus had moved (Fig. 10). (You can experiment with this by twisting a cord it is always at the twisters end that strangulation occurs.) This common feature of abortus specimens betrays that coiling (and movements, I believe) begin very early in development. Why 80% of cords are twisted in a counterclockwise direction has remained a mystery. Chronic exposure (probably for days) to meconium causes degenerative changes in the cord substance. As the cells degenerate, the cord may dissolve and expose the blood vessels free of jelly, and the vascular wall (especially
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arterial) undergoes constriction and degeneration. This alters the perfusion signicantly, which we believe is a major cause of meconium damage of sick neonates. This has signicant medicolegal ramications, especially because meconium has been considered to be a sign of stress. It is much more likely that the accidental discharge of meconium (most commonly after term) leads to fetal compromise. Observations on surface vessels are equally critical. They allow the macroscopic identication of varices and thrombi (as yellowish streaks) and, in multiple pregnancies, they delineate the existence or absence of connections between fetal circulations. It is important to differentiate between arteries and veins because both have a similar macroscopic and microscopic appearance, contrary to expectations. In most cases, the arteries lie on top of the veins. Thus, by following the vessels from the cord insertion into the periphery, it is easy to identify vessels to their nal destiny, the perfusion of a single cotyledon. In addition, the larger surface vessels often show cushions eccentric thickenings and restructurings of the walls. They arise as the result of thrombi or possibly from hypertension in the fetal circulation (Figs. 11 and 12 ). They are often combined with regions of avascular villi and stem vessel thrombi and, thus, may lead to fetal growth restriction. The placental villous architecture is complex; it can be difcult to discern intermediate from terminal villi, especially so in immature placentas. In addition to capillaries, the villi also contain macrophages, the Hofbauer cells, that ingest local hemorrhages and manufacture

physiology human placenta

Figure 12. Vessels have undergone remodeling, with cush-

ions forming.

hemosiderin from them. The Hofbauer cells also are prominent in chronic infections and isoimmune conditions. The most interesting condition of the villous architecture is chorangiosisa numerical increase in capillaries of villi that occurs, for example, in gestations at high altitude. In these cases, chorangiosis presumably represents an adaptation of the fetal vasculature to hypoxia. Chorangiosis also plays a prominent role in medicolegal discussions of prenatal hypoxia with ensuing cerebral palsy. Not only can these vessels increase numerically, but they can be associated with chorangiomas, which are benign tumors consisting of proliferations of capillaries and mesenchymal cells. Chorangiomas can become large and affect fetal perfusion. Thus, they can be associated with fetal cardiac failure and hydramnios. Chorangiomas also may involute spontaneously when thrombosis occurs in their vessels. The pathologic features of conditions that occur in the placental membranes are conned primarily to infections and degenerations and are a part of other conditions. Amnion nodosum is a nding that results from anhydramnios (Fig. 13). In the absence of fetal kidneys or with urethral obstructions, there is no amnionic uid. Inasmuch as the amnion is partly nourished by this uid, focal degeneration of its epithelium occurs, and vernix caseosa from the fetus is rubbed into the defects, causing the nodules that can be observed grossly. The nodules vary in size and are shown histologically in Figure 13. They also are found in the amnion of the twin-twin transfusion syndrome (TTTS) donor twins membranes. Further, a typical vacuolation (due to lipids) occurs in amnion epithelium of neonates who have gastroschisis. The origin of the lipid is unknown. Finally, meconium macrophages are recognized when meconium has been present for several hours. This yellow pigmentation must be differentiated from the hemosiderin that results when retromembranous hemorrhages (eg, in circumvallate placentas) occur. Amnionic bands develop when the amnionic sac rup-

Figure 13. Amnion nodosum (vernix impaction) in a case of anhydramnios.

tures for unknown reasons prior to its attachment to the chorion (12 wk).

Maternal Conditions Reected in the Placenta

The most common and prominent maternal disease to cause placental lesions is pre-eclampsia (toxemia of pregnancy). The principal lesions occur primarily in the maternal (decidual) arterioles as so-called atherosis (Fig. 14). Atherosis, which is the inltration of cholesterolladen macrophages into the intima and muscularis of arterioles, follows a primary deciency of the normal process of remodeling the vessels by extravillous trophoblast. This deciency leads to brinoid necrosis of the arteriolar wall and nally to atherosis. Thrombosis may follow, and local hemorrhages also can occur that may lead to abruptio placentae. The restriction of intervillous

Figure 14. Maternal decidual spiral arteriole with atherosis in pre-eclampsia.

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physiology human placenta

Figure 15. Placental infarct in pre-eclampsia (top left portion

of picture).

Figure 16. Chorangiosis in a patient who has diabetes mellitus, as indicated by a massive increase in villous capillaries.

blood ow that ensues from the vascular lesions is the cause of the common placental villous infarcts (Fig. 15) and growth restriction of the fetus. In addition, because less blood ows in the intervillous space, fewer nutrients reach the fetus, and the fetal hematocrit rises. Changes in the placental architecture reect fetal hydration. Thus, the villi shrink (premature aging), and the trophoblastic surface buckles. Syncytial knots are more frequent (more than 30% of villi) in this condition and are referred to as the Tenney-Parker change. The abnormal vessels can be easiest to identify in the decidua capsularis of the membrane roll because the delivery process causes them to be disrupted in most placentas at the placental base. Maternal sepsis (eg, in listeriosis) may deposit abscesses into the placental intervillous space, a relatively infrequent nding. Malaria parasites are readily seen in the maternal erythrocytes of the intervillous space, as are sickle cells in affected mothers. They commonly also lead to villous infarcts. The placentas seen in poorly controlled maternal diabetes, even gestational diabetes, are larger and very plethoric and contain less brous tissue, making them very soft. Chorangiosis may be found (Fig. 16), and when hypoxia (in this condition as well as others) has existed for a substantial period of time, nucleated red blood cells are found in fetal blood. This an important indicator of longer prenatal hypoxia.

Multiple Pregnancies
The frequency and distribution of so-called identical and fraternal twins or higher multiples has changed substantially in recent years because of assisted reproductive technology (ART). As currently understood, monozye420 NeoReviews Vol.6 No.9 September 2005

gotic (identical) twins occur randomly, are not inherited, and form a spectrum of placentas that depends greatly on the day of embryo splitting. When the embryo divides into two during its tubal descent, before implantation (rst 3 to 4 d), two completely separate placentas may develop. After the blastocyst cavity has developed, a monochorionic placenta develops (the most common type), and when the amnion has formed, monoamnionic twins (rare) ensue. The latest time an embryo can split is on day 13 to 14 of its existence; at that time, conjoined twins most commonly result. Thus, the type of placentation dictates to some extent the outcome of the embryonic development. In the earliest stages, with two placentas, the pregnancy is much like that of fraternal twins. The most common monochorionic placenta (diamnionic, monochorionic) nearly always has some blood vessel connections between the two fetal circulations. The most common type of a connection is the artery-toartery (A-A) anastomosis (Fig. 17), which may lead to some exchange of blood between the twins. However, if one twin dies, the survivor may rapidly bleed into the now dead twin and suffer CNS hypotension, with cerebral palsy being the end effect, or he or she may die from the acute hemorrhage, as occurred with Eng once Chang of the original Siamese twins died. The most complex anastomosis is the artery-to-vein connection. As was explained previously, normally one cotyledon is serviced by only one fetal vascular branch. In normal circumstances, the blood is returned via the vein to the same fetus. In TTTS, however, the vein returns the blood from the donor fetus to the recipient (Fig. 18). Therefore, the recipient becomes constantly over-

physiology human placenta

Figure 17. Diamnionic, monochorionic (DiMo) twin placenta of identical twins with one large artery-to-artery (A-A) anastomosis at arrow. The arteries were injected with milk.

loaded with blood and adapts to this condition by developing cardiac hypertrophy, having high hematocrit concentrations (even thromboses), becoming larger (even hydropic), and urinating more (leading to hydramnios). The donor loses nutrients, atrophies, does not urinate, and becomes the stuck twin in a tightly enclosing amnion. The degree of disparity in development is dictated by the size of the vascular shunts, their numbers, and directions (they may go both ways). In general, when an A-A anastomosis exists simultaneously, the syndrome is least severe or may be absent. It is difcult to identify such blood vessel connections denitively, and many placentas require injection with colored uids for their demonstration. One such common district or third circulation is shown in Figure 19. With better understanding of the condition, it has become feasible to observe the placental surface with fetoscopy, and obstetricians have coagulated the offend-

Figure 19. Injection of yellow dye into a terminal artery of one twin that dips into ramications of the cotyledon and eventually emerges into the vein (bottom) of the recipient in the TTTS. The normal arrangement is seen at the left, where the vein returns blood from the same cotyledon to the same fetus.

Figure 18. Diagram of the twin-to-twin transfusion syn-

drome. The gray-shaded area is the common cotyledon.

ing vessels with lasers. In many such cases, remarkable recovery of normalcy follows laser ablation, but in some cases, the ablation leads to further complications. When such a lasered placenta is studied subsequently, the vascular arrangement may be so disturbed that it is impossible to reconstruct what once was the surface architecture. It is important to recognize that one of these TTTS twins may die spontaneously in utero. If that happens (usually in the later trimesters), irrespective of the nature of anastomoses, so much back-bleeding into the now-dead twin may take place acutely that CNS hypoperfusion occurs in the survivor, with cerebral palsy being a possible ultimate outcome. Another, albeit rare complication of larger anastomoses is the development of an acardiac twin. Such twins are always identical (ie, monozygotic) twin offspring, even though they differ remarkably. The syndrome has been labeled the TRAP (twin reversed anastomosis perfusion) sequence. One large A-A and one large vein-to-vein connection exist between the two twins in the placenta. One twin overcomes the pressures of the other fetus circulation and reverses it. Thus, blood enters the aorta, reversing the entire fetal ow. Subsequent, no heart and usually little of the skull structures and internal organs develop, but the best-perfused legs and pelvis may be normal. A nal comment needs to be made about the multiple gestations that follow ART and hormonal stimulation of ovulation, usually used to achieve pregnancies in older
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women. I have examined a sextuplet placenta of very immature fetuses resulting from hormonal superovulation. Three fused placentas were anterior in the uterus and three fused placentas were posterior. Two or three cords were located at the placental margin, there was irregular fusion and competition for space, but there were no anastomoses. The sextuplets all survived but had prolonged stays in the intensive care nursery. When several blastocysts are placed in such cases of ART, one or the other placenta commonly is abnormally shaped, perhaps because of collision during placental expansion or because the embryo (in the blastocyst cavity) was abnormally located. Thus, velamentous or marginal cord insertions are more common. In very exceptional cases, vascular connections developed between the placental circulations of fraternal twins that led to blood chimerism. Also, because some such multiple gestations are

treated with embryo ablation, placentas may contain one or more fetus papyraceus. The most challenging observation is the presence of more fetuses (and placentas) than the number of embryos implanted; that is, one gestational product has split, and identical twins have developed in addition to the fraternal embryos. The reasons for this relatively frequent event elude us at present, but it is speculated to relate to the length and manner of embryo handling before implantation.

Suggested Reading
Benirschke K, Kaufmann P. The Pathology of the Human Placenta. 4th ed. New York, NY: Springer-Verlag; 2000 Kraus FT, Redline RW, Gersell DJ, Nelson DM, Dicke JM. Atlas of Nontumor Pathology. Placental Pathology. Washington, DC: Armed Forces Institute of Pathology; 2004

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NeoReviews Quiz
1. An ascending intrauterine infection is caused by a defective barrier of the endocervix. Microorganisms invading the fetal membranes produce a local inammatory reaction, which leads to the production of prostaglandins that initiate labor. Of the following, the most common microorganism that traverses the villous tissue and produces a round cell inltration is: A. B. C. D. E. Parvovirus B19. Rubella virus. Toxoplasma gondii. Treponema pallidum. Varicella zoster virus.

2. Abnormalities of the placenta involving its location, number of lobes, and attachment to the myometrium are common and can be a source of perinatal complications. Of the following, the placenta most associated with poor uterine wound healing after a cesarean section is: A. B. C. D. E. Bilobed placenta. Circumvallate placenta. Placenta accreta. Placenta percreta. Succenturiate placenta.

3. The length of the umbilical cord varies directly with the gestational age of the fetus and is believed to be determined by the level of fetal mobility. Of the following, the length of the umbilical cord in a 30-week normal fetus is closest to: A. B. C. D. E. 20 30 40 50 60 cm. cm. cm. cm. cm.

4. Placental lesions often reect various maternal diseases. Of the following, the most common maternal disease to cause placental lesions is: A. B. C. D. E. Anemia. Diabetes. Hemoglobinopathy. Pre-eclampsia. Sepsis.

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