19 Diseases of the Placenta Deborah J

Home , Amnion nodosum, HELLP syndrome, Nuchal cord, Placental infarction, Umbilical cord prolapse, Uterine inversion

19 Diseases of the Placenta Deborah J. Gersell . Frederick T. Kraus

Normal Anatomy and Development ...... 1000 Insertion ...... 1054 Umbilical Vessels ...... 1056 Abnormal Placentation and Villous Development . . . 1003 Anomalous Shapes ...... 1003 Clinical Syndromes and Their Pathologic Extrachorial Placenta ...... 1004 Correlates in the Placenta ...... 1059 Placenta Accreta, Increta, and Percreta ...... 1005 Preeclampsia ...... 1059 Mesenchymal Dysplasia ...... 1007 Essential Hypertension ...... 1060 Diabetes Mellitus ...... 1060 Multiple Pregnancy ...... 1007 Preterm Birth, Preterm Labor, and Preterm Twin Gestation ...... 1007 Rupture of Membranes ...... 1060 Complications of Multiple Pregnancy ...... 1013 Post-Term Pregnancy ...... 1060 Higher Multiple Births ...... 1021 Fetal Growth Restriction, Intrauterine Growth Restriction (IUGR) ...... 1060 Placental Inﬂammation and Intrauterine Neonatal Encephalopathy (NE), Cerebral Infection ...... 1022 Palsy (CP), and ‘‘Birth Asphyxia’’ ...... 1061 Ascending Infection and Acute Fetal and Placental Hydrops ...... 1061 Chorioamnionitis ...... 1022 Nucleated Red Blood Cells in the Fetal Subacute Chorioamnionitis ...... 1027 Circulation ...... 1062 Villitis and Hematogenous Infection ...... 1027 Thrombophilias ...... 1063 Other Patterns of Placental Inﬂammation ...... 1032 Acute Fatty Liver of Pregnancy and HELLP Syndrome ...... 1063 Circulatory Disorders ...... 1033 Sickle-Cell Trait/Disease and Other Maternal Circulation ...... 1034 Hemoglobinopathies ...... 1063 Fetal Circulation ...... 1042 Storage Disorders ...... 1064

Fetal Membranes ...... 1045 Abortion, Stillbirth, and Intrauterine Fetal Death . . . 1064 Squamous Metaplasia ...... 1045 Early Abortion ...... 1064 Amnion Nodosum ...... 1046 Late Abortion, Stillbirth, and Intrauterine Amnionic Bands ...... 1046 Fetal Death ...... 1065 Meconium Stain ...... 1048 Gastroschisis ...... 1049 Nontrophoblastic and Metastatic Tumors ...... 1065 Extramembranous Pregnancy ...... 1050 Hemangioma (Chorangioma) ...... 1065 Hepatocellular Adenoma and Adrenocortical Umbilical Cord ...... 1050 Nodules ...... 1066 Normal Anatomy and Embryonic Other Placental ‘‘Tumors’’ ...... 1067 Development ...... 1050 Placental Metastases ...... 1067 Vestigial Remnants ...... 1050 Stasis Problems and ‘‘Cord Accidents’’ ...... 1051 Examination of the Placenta ...... 1067 Cord Length ...... 1051 Fetal membranes ...... 1068 Knots ...... 1052 Umbilical cord ...... 1068 Torsion ...... 1053 Placenta ...... 1068 Stricture ...... 1053 Sections ...... 1068 Cord Diameter ...... 1054 Special aspects of Multiple Pregnancy ...... 1069 Rupture ...... 1054 Special Techniques ...... 1069

R. J. Kurman, L. Hedrick Ellenson, B. M. Ronnett (eds.), Blaustein’s Pathology of the Female Genital Tract (6th ed.), DOI 10.1007/978-1-4419-0489-8_19, # Springer Science+Business Media LLC 2011 1000 19 Diseases of the Placenta

The placenta is crucial for fetal growth and survival, performing the most important functions of many somatic organs before birth. Thus, pathologic processes interfering with placental function may result in abnormalities of fetal growth or development, malformation, or stillbirth, and there is increasing recognition that some long-term (especially neurologic) disabilities can be traced to injury occurring before birth. The purpose of this chapter is to describe clinically important placental lesions and to emphasize the context in which these lesions are directly or indirectly important to the fetus, the mother, or both.

Normal Anatomy and Development

The monograph by Boyd and Hamilton [23] provides a detailed description and exquisite illustrations of the various stages of human implantation. The ovum is fertilized in the fallopian tube and develops rapidly, reaching the endometrial cavity as a blastocyst. At this stage, the outer cell layer of the blastocyst has differentiated into trophoblast, and there are only a few cells in the inner cell mass from which the embryo will develop. The trophoblast attaches to and penetrates the endometrium on the 6th to 7th postovulatory day, and by the 10th to 11th postovulatory day, the blastocyst is totally embedded in endometrial stroma that has reestablished continuity over the penetration defect. The trophoblast grows rapidly . Fig. 19.1 and circumferentially, invading maternal blood vessels. Implantation at 13 days. Trophoblast has differentiated into Blood-filled spaces (lacunae) separate the trophoblast into inner (cytotrophoblast) and outer (syncytiotrophoblast) > trabecular columns ( Fig. 19.1), with an outer syncytio- layers. Focally, the cytotrophoblast has proliferated to form trophoblastic layer oriented radially around central solid projections, the forerunners of the primary villi. The germ cores of cytotrophoblast. As the extraembryonic mesen- disk is located near the center (Reprinted courtesy of chyme penetrates the cytotrophoblastic cores, small blood Department of Embryology, Davis Division, Carnegie vessels form within it, and these eventually connect with Institute of Washington) each other and with those forming independently in the allantois of the body stalk (chorioallantoic placentation), establishing the fetoplacental circulation by the 5th–6th single, round–oval nuclei, clear cytoplasm, and distinct week. A shell of solid trophoblast remains at the periphery cell borders directly overlying the stromal core of the of the stem villi, anchoring them to the basal plate and villus. The syncytiotrophoblast (ST) overlies the CT continuing to grow and expand the intervillous space and is the terminally differentiated component of tropho- (> Fig. 19.2). blast responsible for transport functions, protection, and Successful implantation requires a series of complex, pregnancy-specific protein and hormone production. Its coordinated interactions between maternal tissue and abundant, often vacuolated cytoplasm is amphophilic trophoblast. The trophoblast consists of several morpho- with multiple small dark nuclei and a distinct brush bor- logically and functionally distinct cell types, each with der. Intermediate trophoblast (IT) is a constituent of vil- characteristic anatomic distribution. The great majority lous trophoblast, primarily in the anchoring cell columns, of cytotrophoblastic and syncytiotrophoblastic cells are but is most prevalent in extravillous sites. IT developing located on the villi (villous trophoblast). Cytotrophoblast from the trophoblastic shell invades the endometrium (CT), the germinative, mitotically active component of and myometrium at the implantation site. Subpopula- trophoblast, is present as a layer of uniform cells with tions of IT in the villi (villous IT), implantation site, Diseases of the Placenta 19 1001 and membranes (chorionic IT) are morphologically and keratin help distinguish IT (keratin positive) from decidua immunohistochemically distinct [172]. IT nuclei are irreg- (keratin negative). ular and hyperchromatic with coarsely granular chromatin. The IT that infiltrates the decidua and myometrium at Most cells are mononucleate, although multinucleate forms the implantation site is responsible for remarkable physio- occur. IT may be round, polyhedral, or spindle shaped logic structural modifications in the spiral arteries. In the depending on location with abundant eosinophilic, early weeks of pregnancy, IT invades the decidual segments amphophilic, or clear cytoplasm. The cytologic features of the spiral arteries, forming intraluminal plugs. Later, are generally sufficiently distinctive to identify IT, but between the 12th and 20th weeks of pregnancy, their intermingling with decidua at the implantation endovascular IT extends from the decidual into the site is so intimate that it may be difficult to characterize myometrial segments of the spiral arteries. Eventually, IT any particular cell as maternal or fetal by conventional and fibrinoid completely replace the endothelium and the light microscopy. When findings are equivocal (as in some muscular and elastic tissue of the media (> Fig. 19.3). abortion specimens), immunohistochemical stains for Altered by this process, the spiral arteries undergo progressive distension, eventuating in large funnel-shaped channels that augment blood flow to the implantation site. Dissolu- tion of the muscular media results in fixed vascular dilatation unresponsive to vasculospastic influences. As it grows and enlarges, the chorion undergoes gross structural modifications. Initially, villi surround the entire chorionic cavity, but as the chorion prolapses into the endometrial cavity, the villi oriented toward the uterine cavity undergo progressive atrophy to form the smooth chorion (chorion laeve) or fetal membranes (> Fig. 19.4). These atrophic villi are still apparent in sections of membranes in the mature placenta (> Fig. 19.5). The villi on the embryonic aspect of the chorion continue to prolifer- ate, forming the definitive placenta (chorion frondosum). Differential villous atrophy and proliferation reflect maternal blood flow. Departure from the usual pattern of villous growth and atrophy is thought to result in some . Fig. 19.2 of the aberrant placental shapes described below. Contin- Secondary villi. Mesenchyme has penetrated the ued growth and enlargement of the chorion results in trophoblastic cores. The trophoblastic shell is peripheral eventual obliteration of the uterine cavity through fusion

. Fig. 19.3 Normal spiral artery remodeling. Intraluminal IT (left) later invades and replaces the vascular media along with fibrinoid matrix (right) 1002 19 Diseases of the Placenta

. Fig. 19.4 . Fig. 19.6 Formation of chorion laeve. As the chorion prolapses into Immature intermediate villi. These are characterized by the endometrial cavity, the villi on the intracavitary aspect reticular stroma and channels containing Hofbauer cells atrophy to form the fetal membranes

and maturation. Five villous types have been detailed in the work of Kaufmann and others [17]. Mesenchymal villi are a primitive, transient stage in villous development. The loose stroma of mesenchymal villi is abundant with numerous Hofbauer cells, central small vessels, and an orderly surface bilayer of CT and ST. Mesenchymal villi predominate in early pregnancy but may be found in small numbers even at term. According to Kaufmann, mesenchymal villi begin to develop into immature intermediate villi around 7–8 weeks. Immature intermediate villi are defined by abundant loose reticular stroma with empty channels containing Hofbauer cells, features that may lead to erroneous interpretation as villous edema (> Fig. 19.6). Immature intermediate villi predominate through the second trimester, but small clusters persist in the center of . Fig. 19.5 lobules at term (normally 0–5% volumetrically). Immature Chorion laeve. Atrophied villous remnants remain in the intermediate villi are gradually transformed into stem villi as membranes at term their vessels acquire a distinct muscular media and progressively prominent adventitia and fibrous stroma. The stem villi divide progressively, and some insert into the basal of the decidua capsularis and the decidua vera of the plate, anchoring the placenta to the uterus. Stem villi sup- opposite uterine wall, usually around 20 weeks. In time, port the villous tree and transport blood but do not partic- the chorionic cavity is obliterated by progressive expan- ipate significantly in oxygen or nutrient exchange. Stem villi sion of the amnion. Irregular folds of the basal plate drawn comprise 20–25% of villi in a normal term placenta, with into the intervillous space by the relatively slow growth of highest concentration centrally beneath the chorionic plate. anchoring villi form septae, appearing at about 3 months. Beginning in the last trimester, newly formed mesen- IT islands are prominent in the septae. The septae parti- chymal villi transform into mature intermediate villi. tion the maternal surface incompletely and irregularly into Mature intermediate villi are long and slender with roughly 15 to 20 divisions that have no physiologic significance. the same diameter as terminal villi and numerous small Villous structure changes dramatically over the course of vessels and capillaries, comprising less than 50% of the a normal gestation reflecting placental growth, development, villus. Roughly one fourth of the villous volume at term is Diseases of the Placenta 19 1003 made up of mature intermediate villi. Terminal villi are the The placenta has two circulations À maternal and fetal. final ramifications of the villous tree produced along the Maternal blood is delivered to the intervillous space surfaces of mature intermediate villi during the third tri- through spiral arterial inlets in the basal plate. Maternal mester. Terminal villi have sinusoidally dilated capillaries blood flows toward the chorionic plate, disperses laterally, (occupying more than 50% of the villous stroma) that bulge percolates around the villi, and exits through venous outlets beneath overlying attenuated syncytiotrophoblast. Fusion concentrated peripherally in the placental floor. Deoxygen- of endothelial and trophoblastic basement membranes ated fetal blood reaches the placenta through the two umbil- results in the formation of vasculosyncytial membranes ical arteries that branch and divide in stem villi until they (> Fig. 19.7). In these areas, where the maternal and fetal ultimately terminate in the complex capillary network of circulations are most closely approximated, gas and nutri- the terminal villi. Oxygenated and fortified fetal blood ent exchange occur. Normally, terminal villi make up returns via venous tributaries to the umbilical vein. The more than 40% of the villous volume at term. placental circulation normally receives about 55% of the With villous maturation, the barrier between maternal fetal cardiac output. Lacking autonomic innervation, it and fetal circulations is reduced by thinning of syncytiotro- responds only to local factors such as pressure and flow. phoblast, diminution in cytotrophoblast, decrease in mean villous diameter, and apposition of fetal capillaries to the villous surface. The factors that normally control villous Abnormal Placentation and Villous maturation are not understood, but considerable evidence Development suggests that the maturational rate is altered in pathologic states. The villi in any placenta are not completely homo- Anomalous Shapes geneous. The peripheral villi and those beneath the chorionic plate tend to be smaller with more collagenous stroma The pattern of villous atrophy and proliferation that occurs and a thicker trophoblastic basement membrane than the during placental development resulting in ultimate placen- less mature villi located centrally in the fetal lobule. These tal shape and configuration is thought to be determined by regional differences, probably related to maternal blood maternal blood flow. The accessory or succenturiate lobe is flow, should always be considered when judging placental a common shape variation (3–6% of placentas) in which maturity, which is best assessed in standardized sections usually one but occasionally multiple discrete masses of from central placental zones. placental tissue are separated from the main placenta by fetal membranes (> Fig. 19.8). The umbilical cord usually

. Fig. 19.7 . Fig. 19.8 Third-trimester terminal villi, vasculosyncytial membranes. Accessory (succenturiate) lobe. A discrete mass of placental Fetal capillaries protrude beneath thinned tissue is separated from the main disk by fetal membranes syncytiotrophoblast cytoplasm between knots. The containing unsupported fetal vessels endothelial and syncytiotrophoblastic basement membranes fuse forming vasculosyncytial membranes 1004 19 Diseases of the Placenta

inserts into the main placental mass, and the fetal vessels supplying the accessory lobe traverse membranes unsupported by underlying villous parenchyma. If these membranous vessels are traumatized during delivery, severe fetal hemorrhage may result. Thrombosis of mem- Fetal vessels branous vessels may be associated with fetal thromboembolic events. Occasionally, an accessory lobe presents as Extrachorial placenta placenta previa or is retained in utero after delivery resulting in postpartum bleeding or infection. Succenturiate lobes have a tendency to atrophy or infarct but otherwise show no specific histologic changes. The bilobate or bipartite placenta is a variant in which two equally sized placental lobes are separated by fetal membranes or connected by a narrow isthmus of placental tissue. The umbilical cord . Fig. 19.9 often inserts centrally between the lobes. Diagram of an extrachorial placenta, fetal side. Vessels Other anomalous shapes are uncommon. Multilobate appear to terminate at the margin of the chorionic plate but placentas have multiple lobes defined by indentations continue peripherally in the extrachorial portion (After [44]) measuring >50% of the disc diameter. Placenta membranacea is a large, thin placenta with functional of extrachorial placentation including abnormally deep chorionic villi covering the entire gestational sac. In this implantation and premature fixation of the disc-membrane condition, differential atrophy of the chorion laeve and boundary. Recently, recurrent marginal hemorrhage re- proliferation of the chorion frondosum do not occur. sulting in circumvallation has been documented on serial The placental parenchyma may vary in thickness, but ultrasound images, providing evidence that recurrent hem- only exceptionally is there a dominant area resembling orrhage at the disk margin elevates and displaces the mem- a placental disk. Placenta membranacea occurs commonly brane insertion site centrally [151]. This may represent the in animal species but is extremely rare in humans. The few pathologic correlate of recurrent and persistent maternal reported cases have been complicated by antepartum bleeding throughout pregnancy (chronic abruption). bleeding and abnormal placental adherence relating to Amnionic fluid loss also contributes and is thought to be the obligate placenta previa that accompanies this form the primary mechanism in the circumvallation invariably of placentation. Nearly all cases are associated with pre- associated with extramembranous pregnancy. term delivery and high fetal mortality. The annular or Pathology. Historically, extrachorial placentas have cylindrical ring-shaped placenta is very rare. In fenestrate been subdivided into circummarginate and circumvallate placentas, focal absence of the villous parenchyma may types based on the nature of the transition from the result in a through-and-through hole or the chorionic chorionic plate to the fetal membranes. In circumvallate plate may remain intact over the parenchymal defect. placentas, the marginal membrane ring is often reflected centrally, folded, and rolled back upon itself (> Fig. 19.10). Variable amounts of fibrin and recent and Extrachorial Placenta old blood clot are often found in the reflected membrane fold, with focal, or in severe cases, diffuse hemosiderin Extrachorial placentation is a common gross structural deposits in the chorionic plate. A flat transition from the deviation in which the chorionic plate of the placenta is chorionic plate to the membranes without reflection or smaller than the basal plate. The chorionic plate does not prominent fibrin accumulation has been termed extend to the placental margin as in a normal placenta, but a circummarginate placenta (> Fig. 19.11). Either finding undergoes transition to fetal membranes central to the disk may be partial or complete, and they frequently merge edge, leaving a rim of bare placental tissue (extrachorial imperceptably with one another. Multiple authors have portion) extending beyond the limits of the chorionic suggested that the term circummarginate should be plate (> Fig. 19.9). Fetal vessels appear to terminate at abandoned and that all extrachorial placentas should be the margin of the chorionic plate but actually continue considered part of the spectrum of circumvallation [84]. their course peripherally in the deeper villous tissue. Clinical behavior. Estimates of the frequency of extra- Etiology and pathogenesis. There have been many theo- chorial placentation vary widely presumably because the ries attempting to explain the etiology and pathogenesis terms are not used uniformly. It is more common in Diseases of the Placenta 19 1005 Placenta Accreta, Increta, and Percreta

Placenta accreta, increta, and percreta are defined as abnormal adherence of the placenta to the uterine wall so that placental separation does not occur after delivery of the newborn. The degree of abnormal adherence/invasion is variable; placental villi may adhere to (placenta accreta) or invade the myometrium (placenta increta), sometimes penetrating through the serosa (placenta percreta.) The condition may be total (involving the entire placenta), partial (involving one or more cotyledons), or focal (involving isolated foci). Etiology. The pathologic basis of this condition is partial or complete absence of the decidua. Decidua normally regulates trophoblastic invasion during gestation and allows the placenta to separate from the myometrium after delivery. Lack of decidua explains the abnormal placental adherence that occurs in ectopic (cornual, tubal, or . Fig. 19.10 cervical) implantation or in scarred endometrium over Extrachorial placenta. The fetal membranes do not extend leiomyomas or cesarean section scars. to the peripheral margin of the disk, leaving a ring of Clinical features. The frequency of placenta accreta is placental tissue extending beyond the chorionic plate. This difficult to determine. Reported figures have varied widely membrane ring is rolled and reflected centrally from 1 in 540 to 1 in 70,000 pregnancies. Fox emphasized the particular tendency of placenta accreta to occur in multigravid and obstetrically elderly women [45]. A number of predisposing factors have been linked to this condition, the two most significant being placenta previa (placental implantation in the lower uterine segment near or overlying the cervical os) and previous cesarean section. In some reports, as many as 64% of placentas accreta have been associated with placenta previa, many occurring in cesarean section scars. Often only the portion of the placenta implanted in the lower uterine segment or over a cesarean section scar is abnormally adherent. Other risk factors include prior uterine instrumentation or intrauterine infection, previous man- ual removal of the placenta, uterine structural defects (leiomyomas, septae), and nonfundic implantation. The common endpoint in all these conditions is a deficiency . Fig. 19.11 in, or absence of, the decidua. In less than 10% of cases, no Extrachorial placenta. The membrane transition in this risk factors are identified. extrachorial placenta is flat Pathology. The diagnosis is usually obvious in a hysterectomy performed at the time of delivery. The multigravidas. The clinical sequellae seem to parallel the placenta is almost invariably implanted in the lower uter- amount of associated hemorrhage. Mild or focal circum- ine segment or cervix, often anteriorly in the region of vallation without hemorrhage is clinically insignificant. prior cesarean section (> Fig. 19.12). The myometrium is More severe cases with chronic marginal abruption and oli- variably but often markedly thinned. The uterus and pla- gohydramnios are associated with antepartum bleeding, pre- centa may be disrupted by attempts to remove the adher- term labor (PTL), intrauterine growth restriction (IUGR), ent placenta at the time of delivery. Microscopically, the and long-term neurologic impairment [145]. Circumvallate cardinal feature is partial or complete absence of the placentation may recur in successive pregnancies. decidua basalis. Placental villi adhere directly to, or invade 1006 19 Diseases of the Placenta

. Fig. 19.12 Placenta percreta. The placenta at left implanted over the cervical os (upper left) and penetrated the serosa. The placenta at right also penetrated the serosa in the anterior lower uterine segment at the site of three prior cesarean sections

. Fig. 19.13 Placenta increta. The placenta has invaded the myometrium almost to the serosa. Villi invade the myometrium without intervening decidua

into, the myometrium (> Fig. 19.13), penetrating through Clinical behavior and treatment. Placenta accreta is the uterine serosa in some instances. The diagnosis can compatible with normal fetal growth and development. also be established on placental exam. Microscopic sec- Although usually anticipated, it may not be suspected tions of grossly fragmented, low-lying, or manually until the placenta fails to separate in the third stage of removed placentas may show a thin layer of myometrial labor. Postpartum bleeding may be life threatening, ﬁbers adherent to the placenta without intervening requiring immediate hysterectomy, or bleeding may be decidua. Occasional smooth muscle cells in a basal plate delayed. Antepartum bleeding and premature labor are containing decidua is not diagnostic of accreta. The diag- common due to the high frequency of associated placenta nosis in a postpartum curettage calls attention to the previa. Uterine rupture may occur at any stage of preg- potential for further bleeding or infection if all the nancy or during labor. Maternal and fetal mortality are placental tissue is not removed. now uncommon. Diseases of the Placenta 19 1007 Mesenchymal Dysplasia Twin Gestation

Placentas with mesenchymal dysplasia are usually very Zygosity large, often over 1,000 g. The chorionic vessels are aneurysmally dilated and often thrombosed. Enlarged cys- Definition. Twins may arise from the fertilization of two tic stem villi are recognizable grossly (> Fig. 19.14). Micro- separate ova (dizygous or fraternal twins) or from the scopically, the stem villi are large and edematous with cyst division of a single fertilized ovum (monozygous or iden- formation and prominent thick-walled muscular stem tical twins). Monozygous twins are genetically and usually vessels (> Fig. 19.15). Terminal villi are usually normal phenotypically identical, but dizygous twins are geneti- but may show distal villous immaturity and chorangiosis. cally dissimilar like singleton siblings. Rare variants of Chorangiomas are common. There is no trophoblastic dizygous twinning result when ova are fertilized by hyperplasia. This rare lesion is often identified as partial sperm from different sources (superfecundation) or when hydatidiform mole on ultrasound. Over one half of reported ova are ovulated and fertilized at different times resulting cases have been associated with Beckwith Wiedemann syn- in twins of disparate developmental ages (superfetation). drome. Mesenchymal dysplasia is associated with IUGR, A rare variant of monozygous twins, monozygous hetero- intrauterine fetal demise (IUFD), and neonatal death karyotic twins, have different karyotypes and sometimes [71, 101, 116]. Females are disproportionally affected. even different sex [14]. These twins are thought to result from chromosome non-disjunction, most commonly Multiple Pregnancy involving the sex chromosomes, but on occasion the auto- somes as well. A third type of twinning, polar body or dispermic monovular twinning, presumably results from Multiple gestations are common and becoming more so fertilization of an oocyte and a polar body. Bieber with assisted reproductive techniques (ART). In the described a triploid acardiac/diploid twin gestation United States in 2000, ART accounted for 14% of all twin resulting from fertilization of an oocyte and its first births, and 45% of ART births were twins [153]. Multiples polar body [20]. Theoretically, fertilization of the oocyte are associated with a disproportionate share of complica- and second polar body could also occur. The frequency of tions including higher rates of morbidity, mortality, low this phenomenon is unknown. It has been hypothesized birth weight, anomalous development, and malformation that dispermic monovular twins are monochorionic due than singletons. Careful pathologic examination of the to the proximity of the oocyte and the polar body and placenta(s) can provide important insight into problems because cytoplasmic imbalance equips only the oocyte peculiar to multiples, and pathologists must be aware of with its more abundant cytoplasm to implant. the special considerations required in the examination of placentas from multiple births.

. Fig. 19.14 . Fig. 19.15 Mesenchymal dysplasia. The gross abnormalities in this Mesenchymal dysplasia. The stem villi are greatly enlarged placenta with mesenchymal dysplasia were identified on with abundant, focally degenerated cystic stroma and large antenatal ultrasound. The infant was normal thick muscular vessels 1008 19 Diseases of the Placenta

Frequency and etiology. Twins occur in about 1 in 80 microscopic manifestations of these processes are identical Caucasian pregnancies in the United States, and approxi- in the placentas of singletons and multiples, although mately 30% of these are monozygous. The frequency of some lesions are particularly pertinent to the problems monozygous twinning is relatively constant worldwide experienced by multiples. Comparison of the relative dis- (about 3.5 in 1,000 pregnancies), but there are marked tribution of lesions in the placental territories and corre- geographic differences in total twinning rate reflecting excess lation with the size and condition of the fetuses is an dizygous twinning in certain populations and families who important aspect of placental assessment in multiple have a genetic predisposition for high FSH and poly- gestation. Features unique to multiples include (1) the ovulation. Dizygous twinning is also age-related, increasing relationships of the disks and fetal membranes and with maternal age until 35 years, again probably reflecting (2) the pattern and degree of vascular anastomoses. a role for increasing FSH levels with age. The cause of monozygous twinning is unknown. Monozygous twinning Chorionicity, Amnionicity, and Placental Mass is increased in pregnancies following ART [98]. ART has Placentas in twin gestation are either monochorionic or changed the epidemiology of multiple pregnancy. It is as yet dichorionic. Virtually all dizygous twins have dichorionic unclear if or how this technology may affect developmental placentas (diamnionic dichorionic – DiDi). In double events [26]. So far, pathologic placental lesions do not ovulation, each blastocyst generates a placenta. If these appear to be increased in ART multiples [163]. implant in close proximity, varying degrees of fusion may result (DiDi fused); otherwise they are entirely separate. Monozygous twins may show any type of placenta- Placentation tion depending on when division occurs (> Fig. 19.16). If the single fertilized ovum divides very early, before differ- The object of placental exam in multiple gestation is the entiation of the chorion (first 5–6 days), the situation is same as in singleton gestation – to identify pathologic analogous to dizygous twinning; two placentas develop processes affecting placental function. The gross and that may be separate or fused (25% of monozygous

Placenta Chorion Amnion

Morula splits first four days of gestation Preimplantation blastocyst splits Postimplantation first week of gestation blastocyst splits second week of gestation

Dichorionic diamnionic Dichorionic Monochorionic Monochorionic (fused placentae) diamnionic diamnionic monoamnionic

. Fig. 19.16 Diagrammatic representation of twin placentation. (After [44] used with permission of the American Registry of Pathology/ Armed Forces Institute of Pathology) Diseases of the Placenta 19 1009 twins). If splitting occurs after formation of the chorion but before formation of the amnion (8th day after fertilization), there will be a single placenta with two amnionic sacs (diamnionic monochorionic – DiMo), occurring in about 75% of monozygous twins. A split after formation of the amnion (between the 8th and 15th days), will result in one placenta with one amnionic cavity (monoamnionic monochorionic – MoMo), and still later splitting, in conjoined twins (> Fig. 19.17). Practi- cally speaking, twins with monochorionic placentas are monozygous with very rare exceptions (monovular dispermic and one case of dizygous monochorionic twins) [178]. Twins with dichorionic placentas, whether separate or fused, may be either dizygous or monozygous. Obviously, different fetal sex establishes a dizygous relation, but further investigation (blood group analysis, HLA typing, and DNA analysis) is required to determine zygosity in like-sex dichorionic twins. Establishment of placentation type is important, not only as an initial step in determining zygosity, but primarily because it has an important relationship to the increased morbidity and mortality that occur in multiple gestations. Many factors contribute, importantly the premature onset of labor and delivery, but placentation is also a very signiﬁcant risk factor. Twins with monochorionic placentas have much higher mortality rates than those with dichorionic placentas, and monoamnionic placentation is associated with a fetal mortality rate as high as 50%. Placentation type is usually reliably established on gross . Fig. 19.17 examination. Two entirely separate placentas are obviously Conjoined twins. (Used with permission of the American dichorionic (DiDi separate), each requiring routine exam- Registry of Pathology/Armed Forces Institute of Pathology) ination. Frequently the disks are separate but the membranes are fused. The membranes of one twin may overlap the disk of the co-twin (irregular chorionic fusion) when there is differential expansion of the membranous sacs. When the blastocysts implant close to one another, the two placental disks fuse to form an apparently single disk with a dividing septum (DiDi fused). The principal task for the pathologist is to distinguish between monochorionic and dichorionic fused placentas. The nature of the membranous septum and the pattern of chorionic vascularization are critical in this distinction. The septum in dichorionic fused placentas is relatively thick and opaque due to the presence of chorionic tissue between the two amnionic layers (> Fig. 19.18). Because each embryo is developing within its own chorion, any fusion between them will contain chorionic tissue. The . Fig. 19.18 chorionic tissue in the septum is continuous with the DiDi fused placentas. The two placentas are fused but discrete. underlying placenta remaining ﬁrmly attached to the fetal The septal membrane is thick and the fetal vessels do not cross surface. If the amnions are separated, chorionic tissue will the line of fusion (Used with permission of the American remain as a ridge at the base of the septum. In contrast, the Registry of Pathology/Armed Forces Institute of Pathology) 1010 19 Diseases of the Placenta

septum in a diamnionic monochorionic placenta is thin (> Figs. 19.20 and > 19.21), although identical informa- and translucent, composed of two directly apposed layers of tion may be obtained from a section of the T zone where amnion (> Fig. 19.19). This septum, devoid of chorion, is the septum meets the fetal surface. The latter method is easily detached from the placental surface. Some patholo- particularly useful when the septal membrane has been gists peel the dividing membranes in order to identify torn or otherwise distorted and cannot be rolled. monochorionic placentas that require injection studies. The distribution of the fetal vessels on the chorionic Histologic examination of the membranous septum con- plate is equally helpful in distinguishing DiDi fused firms the gross impression. This is most easily accom- from DiMo placentas. In dichorionic placentas, the sep- plished in a section of rolled septal membranes tum represents the apposed borders of the two fused placentas and as such defines the vascular equator of the two placentas. In DiDi fused placentas, fetal chorionic vessels approach, but do not cross the area of fusion (> Fig. 19.18). In diamnionic monochorionic placentas, portions of the same placenta are shared by both fetuses, and the two vascular districts are intimately intermingled (> Fig. 19.22). The position of the membranous septum in the DiMo placenta is independent of, and does not necessarily conform to, the fetal vascular districts. Rarely, a monochorionic placenta presents as two apparently distinct disks, superficially resembling dichorionic separate placentas. The nature of the septum and the intermingling of the vascular districts with anastomosis identify these as monochorionic. The appearance of two separate ‘‘disks’’ is due to involution or atrophy of intervening villous tissue related to factors at the implantation site affecting maternal blood supply. Monoamnionic monochorionic placentas (MoMo) are . Fig. 19.19 very uncommon, accounting for less than 1% of twin DiMo twin placenta. The septal membranes are thin and gestations. In MoMo gestations, both twins develop within filmy. Note velamentous insertion of the cord into the a single amnionic sac. Before considering a monochorionic septal membranes (Used with permission of the American placenta to be monoamnionic, the amnion between the Registry of Pathology/Armed Forces Institute of Pathology) cord insertions should be complete and continuous.

. Fig. 19.20 . Fig. 19.21 DiDi septum. A central layer of fused chorion intervenes DiMo Septum. The septum is composed of two directly between amnions apposed amnions Diseases of the Placenta 19 1011

Because the amnion commonly separates from the under- typically closely inserted, usually within 6 cm of each other lying chorion and is often nearly completely detached at (> Fig. 19.23). Rarely there is partial cord fusion. Large delivery, more apparently single sacs are artifactual than vessel anastomoses are frequent but not invariable truly monoamnionic. Remnants of detached amnion and between the closely inserted cords. Cord entanglement is septum may be found encircling the cords or attached to the common and a signiﬁcant cause of morbidity and mor- free membranes when carefully sought. Although mem- tality (> Fig. 19.24). brane patterns are established early and persist through- The pattern and adequacy of chorionic vascularization, out pregnancy, intragestational disruption of diamnionic the relative proportion of the chorionic surface populated septae has been reported. This suggests that at least some by vessels from each twin, and the relative placental mass monoamnionic placentas may have been diamnionic orig- serving each twin are pertinent observations in multiple inally. The umbilical cords in monoamnionic gestations are gestations. Dichorionic fused placentas can be divided and weighed. Estimates of the placental mass serving monochorionic twins are based on the chorionic vascula- ture. The pattern of venous return is a good indicator of placental supply. Not all discordantly grown twins have asymmetric placentas, and not all twins with asymmetric placentas are discordantly grown, but these associations are not uncommon. In twins with discordant placental mass, the smaller placenta is frequently associated with a lesser number of chorionic vessels. Whether the smaller placenta impairs the growth of the fetus, or both fetus and placenta are small secondary to other inﬂuences is not always clear.

Vascular Anastomoses An important feature of monochorionic placentas is the presence of vascular communications between the two fetal circulations. The fetal circulation is established . Fig. 19.22 when small vessels developing independently within DiMo twin placenta. The fetal vessels are intimately the villous mesenchyme connect with larger vessels in intermingled, and some are anastomosed (Used with the chorionic plate and body stalk. When twins share the permission of the American Registry of Pathology/Armed same placenta, the potential exists for the two develop- Forces Institute of Pathology) ing circulations to merge in a number of different ways.

. Fig. 19.23 . Fig. 19.24 Cord insertion, MoMo. Close cord insertion is typical of Cord entanglement in MoMo. This cord entanglement MoMo placentation resulted in IUFD at 25 weeks 1012 19 Diseases of the Placenta

For example, the capillary bed supplied by an artery from one twin might establish continuity with a vein returning to its co-twin resulting in a parenchymal arteriovenous (A–V) anastomosis. In contrast, the two circulations in dichorionic twins are established independently explaining why vascular communications in DiDi-fused placentas are absent with rare exception. It is generally agreed that vascular communication is invariable in monochorionic placentas although the number, size, and type of anastomoses are highly variable. Anastomoses between large chorionic plate vessels are very common. The majority of large vessel anastomoses are between arteries (A–A); vein to vein (V–V) anastomoses are less common. Of greater physiologic significance are the arteriovenous (A–V) anastomoses that occur between capillaries deep within shared villous parenchyma. Vascular anastomoses may be compound with surface (large vessel) and parenchymal (villous capillary) . Fig. 19.25 connections involving the same vessels (> Fig. 19.25). A–A Types of vascular anastomoses in monochorionic placentas. anastomoses alone (20–28%) and A–A with A–V anasto- Large vessel anastomoses (artery-artery and vein-vein) are moses (25–40%) are most common. A–V anastomoses easily identifiable on the chorionic plate. Arteriovenous alone, unmodified by concomitant large vessel anastomo- anastomoses occur between capillaries in shared placental ses, are estimated to occur in 11–20% of cases. lobules. The presence of an unpaired artery penetrating the Large vessel anastomoses are easily identified grossly chorionic plate in the vicinity of an unpaired vein from its (> Fig. 19.22) and can be confirmed by moving blood co-twin suggests this possibility. Superficial (large vessel) back and forth between the contributing vessels or and capillary anastomoses may involve the same vessels highlighted by the injection of dye or air (> Fig. 19.26). (Used with permission of the American Registry of The size, diameter, location (central or peripheral), type Pathology/Armed Forces Institute of Pathology) (arteries cross over veins), and number of anastomoses should be recorded. A–V anastomoses are more important physiologically but are more difficult to identify as they occur between capillaries deep in the villous parenchyma and cannot be directly visualized. Potential sites of A–V anastomosis can be suspected when an unpaired artery from one twin penetrates the chorionic plate in close proximity to an unpaired vein from the co-twin (> Fig. 19.27). This configuration is highly suggestive of an underlying anastomosis as arteries and veins are normally paired. A simple method to confirm the presence of arteriovenous anastomoses is to inject air into the arterial branch supplying a suspected anastomosis and document its return to the venous district of the co-twin. This has the advantage of displacing blood from the shared placental district. The resulting pallor allows estimation of the volume of shared parenchyma. Air injection can be repeated at multiple sites in an attempt to document the extent of anastomoses. All injection studies are qualitative. They do not necessarily . Fig. 19.26 reflect the physiologic significance of an anastomosis, or Vascular anastomosis. This large anastomosis has been the overall balance of blood flow in vivo. Nevertheless, their highlighted by air injection (Used with permission of the documentation is essential if vascular anastomosis is to be American Registry of Pathology/Armed Forces Institute of invoked as a cause of, or contributor to, discordant fetal Pathology) Diseases of the Placenta 19 1013 growth. Injection studies are precluded by fixation and may be compromised by villous disruption.

Umbilical Cord Anomalies of the umbilical cord are much more common in multiple than in singleton gestations. The incidence of velamentous cord insertion in twins has been reported to be up to nine times higher than in singletons. The frequency of anomalous insertion (marginal and velamentous) increases with proximity of the twins (dichorionic separate < dichorionic fused < monochorionic). Anomalous cord insertion in multiples has the same significance as in singletons. In addition, there is some evidence that velamentous cord insertion is a factor that influences twin–twin transfu- . Fig. 19.27 sion and associated early delivery. Arteriovenous anastomosis. An unpaired artery from the Single artery cords are also more frequent in multiple umbilical cord barely visible at bottom penetrates the gestations, occurring in approximately 3% as compared to chorionic plate adjacent to an unpaired dilated vein from 0.53% of singletons. Most twins are discordant for single the co-twin at right (Used with permission of the American umbilical artery, although concordance is greater in Registry of Pathology/Armed Forces Institute of Pathology) monozygous than dizygous twins. The length of the umbilical cord is on average 7.6 cm shorter in twins than singletons, and the incidence of hypocoiled cords is also increased. Twins that share an amnionic cavity (monoamnionic) are at increased risk for cord entanglements. Cord entanglements of all types occur in monochorionic twins with a reported frequency between 53 and 71%, and they may be remarkably complex (> Fig. 19.28). Such entanglements may result not only in cord compression but in mistaken cord transection when one twin’s cord is looped around its co-twin at delivery. Cord entanglement as a factor in fetal mortality is most common prior to 24 weeks while there is still sufficient room for fetal movement. After 30–32 weeks and in higher multiples, cord entanglement is less common as opportunity for movement decreases. Cord entanglements may result in chronic vascular compromise or they may not become a problem until the forces of labor result in acute vascular obstruction.

Complications of Multiple Pregnancy

Twin–Twin Transfusion Syndrome (TTTS)

Vascular communications in monochorionic placentas create the potential for blood ﬂow between the twins. When there is a net ﬂow of blood from one twin to the other, the clinical manifestations depend on the size, number, and type of vascular communications. Capillary-sized arteriovenous (A–V) anastomoses involve the transfusion . Fig. 19.28 of small amounts of blood over long periods of time Complex cord entanglements in MoMo twins (a and b) 1014 19 Diseases of the Placenta

(chronic transfusion). A large volume of blood can chronic twin–twin transfusion may be similar if the be transferred rapidly through large caliber chorionic donor’s compensatory hematopoiesis has been sufficient. plate vessels often at the time of labor and delivery A relatively selective criterion is a recipient heart weight (acute transfusion). Not infrequently, both occur – an that is two to four times that of the donor. This feature is acute transfusion is superimposed on a chronic long- generally not present in any other process resulting in twin term process (acute on chronic transfusion). Large vessel weight–growth discordance. The disparity in heart size is anastomoses are likely to be bidirectional and A–V con- due not only to a generalized growth differential but also nections are likely to be unidirectional. to the increased cardiac work load associated with the hypervolemia, hypertension, and hyperviscosity experi- Chronic Transfusion enced by the recipient twin. Heart size discrepancy may Definition and etiology. Chronic TTTS is the most com- be the first manifestation of the chronic TTTS, evident on mon form of twin–twin transfusion, and is an important ultrasound as early as 10 weeks. Difference in overall fetal cause of perinatal mortality in monochorionic twins. size is usually apparent only later in gestation. Discrepant Schatz proposed the view that the chronic TTTS results amnionic fluid volumes, hydrops, and a ‘‘stuck twin’’ are when there is unbalanced flow of blood from one twin (the other ultrasound findings very suggestive of the TTTS. donor) to its co-twin (the recipient) through A–V anasto- Frequency. Recent studies indicate close correspon- moses deep within shared placental lobules (the ‘‘third dence between the number of cases with well-documented circulation’’) [17]. Chronic unidirectional diversion of twin–twin transfusion and the number of monochorionic blood results in anemia, relative deprivation, and growth twin placentas with A–V anastomoses without con- retardation of the donor as compared to the larger, poly- comitant large-vessel anastomoses [18]. This occurs in cythemic recipient. Hypervolemia and hypertension in 9–20% of monochorionic gestations. Superficial vascular the recipient result in increased urine output and anastomoses appear to mitigate against the effects of polyhydramnios, while hypotension and hypovolemia A–V transfusion probably by allowing transfer of blood in the donor lead to oliguria, oligohydramnios, and back to the donor from the recipient. In the absence of decreased movement (the ‘‘stuck’’ twin.) Either twin may superficial anastomoses, arteriovenous transfusions are be hydropic, reflecting cardiac dysfunction and congestive uncompensated, resulting in marked growth discordance, heart failure in the recipient and profound anemia in the hydramnios, early delivery, and high perinatal mortality. donor. The TTTS is not a significant cause of fetal mortality in Although vascular anastomoses are a necessary pre- monoamnionic twins presumably because the majority of condition for the development of the TTTS, additional MoMo twins have large-vessel anastomoses that modify factors beyond shifts of blood (differential protein, parenchymal connections. In addition, any intra-amnionic atriopeptin, growth factor concentration, or colloid pressure differences that potentially could affect blood flow osmotic pressure) may contribute. Velamentous cord in diamnionic twins are equalized in monoamnionic twins. insertion is significantly more common in monochorionic For unexplained reasons, the twin–twin transfusion syn- gestations with the TTTS. It has been proposed that drome is more common in females. velamentous cords are more easily compressed, resulting Gross and microscopic pathology. After delivery, there is in decreased umbilical vein flow and enhanced flow a marked discrepancy in the size and appearance of the through A–V anastomoses. Others have speculated that infants and their corresponding placental territories. The polyhydramnios may contribute to umbilical and chori- donor twin is smaller, pale, and anemic; the recipient is onic vessel compression providing the therapeutic ratio- heavier, edematous, plethoric, and polycythemic nale for amniocentesis. (> Fig. 19.29). Either twin may be hydropic. The organs The clinical definition of the TTTS is complicated of the recipient are larger and heavier than those of the because twins commonly show asymmetric growth for donor (> Fig. 19.30). The recipient’s heart especially is reasons other than a chronic twin–twin transfusion comparatively enlarged, with myocardial hypertrophy (maternal, fetal, umbilical cord, or placental factors). involving all chambers. Smooth muscle mass is increased A hemoglobin concentration difference >5 g/100 mL and in the media of pulmonary and systemic arteries and twin weight difference of 15–20% are considered definitive arterioles. Pulmonary arterial calcification has been criteria by some, although similar weight and hemoglobin described in the recipient twin. The donor heart is usually discrepancies are just as common in dichorionic twins small, and arterial muscle mass is decreased. Glomeruli are without an anatomic basis for transfusion [140]. Con- enlarged, up to twice normal size in the recipient twin, and versely, hemoglobin concentration in twins with the they are either normal or small in the donor. Diseases of the Placenta 19 1015

. Fig. 19.29 . Fig. 19.30 Twin–twin transfusion syndrome (TTTS). The donor twin Twin–twin transfusion syndrome (TTTS). The organs of the (left) is smaller and pale. The recipient twin (right) is larger recipient twin are larger and heavier. Congestion of the and plethoric (Used with permission of the American smaller (donor) organs and pallor of the larger (recipient) Registry of Pathology/Armed Forces Institute of Pathology) organs is a reversal of the expected pattern, suggesting that the recipient twin exsanguinated into the donor (Used with permission of the American Registry of Pathology/Armed The donor’s placental territory may be large, bulky, Forces Institute of Pathology) and pale reflecting fetal anemia (> Fig 19.31). The villi are large and edematous with numerous Hofbauer cells and capillaries containing nucleated red blood cells consequences of the twin–twin transfusion syndrome are (> Fig. 19.32). In other cases, the donor’s placenta has grave. Mortality rates are as high as 70–100% depending been described as pale and atrophied. Amnion nodosum on the gestational age at diagnosis and delivery. The earlier may be found when there is associated oligohydramnios. the syndrome is manifest, the more likely the outcome will The recipient’s placental territory is generally smaller, be fatal. When the condition develops in the second tri- firm, and deep red. The villi are appropriately mature mester, it is often associated with pre-term labor and with dilated and intensely congested vessels (> Fig. 19.33). death of one or both fetuses or significant morbidity Clinical features. Typically, the chronic TTTS is clini- if the neonates survive. Both twins are at great risk. cally manifest in the second trimester with acute The recipient twin is subject to cardiac failure, hemo- hydramnios and growth discrepancy between the twins, lytic jaundice, kernicterus, and thrombosis due to but it may be suspected earlier based on the ultrasound hemoconcentration. The donor twin may be severely ane- demonstration of different amnionic fluid volumes. The mic or hypoglycemic. Both twins are likely to suffer from 1016 19 Diseases of the Placenta

and the transfusion ceases, the situation may resolve itself. Alternatively, the surviving twin (usually the recipient) may exsanguinate into the suddenly relaxed circulatory system of the dead co-twin (usually the donor) (> Fig. 19.30). Acute hypotension and/or blood loss after co-twin death is considered a likely explanation for necrotic lesions in the surviving twin, a view supported by Doppler studies showing dramatic umbilical flow velocity changes in the surviving twin. It has been estimated that neurologic sequelae occur in as many as 27% of surviving twins. Cerebral lesions have been demonstrated sonographically in twins at birth and in utero, developing rapidly in some cases. These observations are important in attempting to explain the high incidence of cerebral palsy . Fig. 19.31 in twins, reportedly five times the incidence in singletons Twin–twin transfusion syndrome (TTTS). The donor’s and affecting primarily monozygous twins. Recognition placental territory (left) is larger and pale reflecting anemia. that lesions predictive of cerebral palsy are of prenatal The recipient’s territory is smaller and congested (Used with onset is important not only in medicolegal considerations, permission of the American Registry of Pathology/Armed but also when contemplating the possible consequences of Forces Institute of Pathology) intentional fetal reduction for the surviving twin. Attempts to alter TTTS have included treatment with indomethacin to reduce fetal urine output and polyhydramnios, digoxin to treat congestive heart failure, decompressive amniocentesis to prolong pregnancy and affect fetal blood flow, division of intervening membranes, selective feticide, and laser ablation of anastomoses. The latter approach requires accurate prenatal mapping of physiologically significant arteriovenous anastomoses and their successful ablation in vivo. Increasingly sophis- ticated Doppler studies are used to tailor treatment strategies to individual vascular patterns and to assess the results of intervention. Pathologic evaluation of laser sites and mapping of residual anastomoses play an important part in this treatment strategy. The enthusiasm for intervention must be tempered by the knowledge that the two fetal circulations are connected and that any . Fig. 19.32 manipulation will potentially affect both fetuses. Given Twin–twin transfusion syndrome (TTTS). The donor’s villi the complexity and uniqueness of the vascular anatomy, are large, relatively immature and edematous with it is difficult to predict the consequences. numerous immature erythroid precursors

Acute Transfusion complications of prematurity. Multiorgan necrotic lesions Plethora of one twin and pallor of the other do not always including white matter infarcts, leukoencephalopathy, signify a chronic transfusion, but may reflect acute shifts hydranencephaly, porencephaly, intestinal atresia, renal of blood through large superficial vascular anastomoses. cortical necrosis, and aplasia cutis (> Fig. 19.34)may A large blood volume may shift rapidly through large- occur in either or both twins. These lesions are attributed vessel connections. Simple acute transfusions are usually to the altered hemodynamics, transitory cardiovascular diagnosed at birth. The donor is pale and the recipient compromise, and hypoperfusion associated with complex plethoric, but there is no growth differential and hemo- fluctuating placental vascular connections. globin and hematocrit levels are equal in initial assess- Although most chronic transfusions progress, some ments. Acute transfusions may occur when one twin may fluctuate or even reverse. If one twin dies in utero experiences circulatory collapse for whatever reason or Diseases of the Placenta 19 1017

. Fig. 19.33 Twin–twin transfusion syndrome (TTTS). The recipient’s villi are appropriately mature but congested (left). The contrast between the donor and recipient placental territories is dramatic (right)

donor’s ﬂaccid vascular tree, or the acute transfusion occurs ﬁrst, overwhelming the capacity of the donor’s heart causing death is unknown. Both mechanisms may be operative. On occasion, an acute transfusion and/or fetomaternal hemorrhage may occur in twins with discordant growth for reasons unrelated to chronic transfusion. While this scenario may mimic an acute on chronic transfusion, lack of evidence for adaptation to chronic transfusion (no heart-size discrepancy, polyhydramnios, or oligohydramnios) may help exclude chronic transfusion as a relevant contributing factor.

. Fig. 19.34 Asymmetric Growth Twin–twin transfusion syndrome (TTTS). Both twins may have necrotic lesions including aplasia cutis as seen here in Established growth standards indicate that the growth the donor twin (Used with permission of the American curves for dichorionic and monochorionic twins approx- Registry of Pathology/Armed Forces Institute of Pathology) imate those of singletons prior to 30–34 weeks [7, 84]. Twins weigh progressively less than singletons as preg- when a twin exsanguinates through the unclamped cord of nancy advances. When twin growth is discordant, the its delivered co-twin. Although clinically documented larger twin approximates the growth of an age-matched simple acute transfusion is rare, silent cases occurring in singleton, and the growth rate of the smaller twin slows utero may account for the dramatic increase in cerebral and may gradually decline into the range of small for palsy in like-sex twins. gestational age (SGA). In dichorionic twins, growth discordancy is usually manifest around 25 weeks, but in Acute on Chronic Transfusion monochorionic twins, the onset is more variable, com- Superimposition of acute transfusion on established mencing in some cases as early as 18–20 weeks. chronic transfusion is more common than simple acute Twin birth weight discordance is strongly associated transfusion, and when this occurs, there is reversal in the with pre-term birth, perinatal death, and postnatal morbid- expected pattern with plethora of the smaller, original ity [28]. The majority of twins with discordant growth are donor twin and pallor of the larger, recipient twin dichorionic, and even among monochorionic twins, TTTS (> Fig. 19.30). Whether this pattern develops after the is not the most common cause of growth discrepancy. Even donor dies and the recipient’s blood drains into the when chronic transfusion occurs, other factors may 1018 19 Diseases of the Placenta

contribute as much or more to discordant growth. Cord death vary with gestational age but are essentially the anomalies including velamentous insertion and single same as in singletons with the important addition of the umbilical artery are associated with decreased fetal weight, specific complications of monochorionic placentation. and both are much more frequent in twin gestations. In one Monochorionic twins are greatly over-represented recent study, peripheral cord insertion (velamentous, mar- among twin deaths at all gestational ages. The pathologic ginal, and markedly eccentric) was the strongest predictor findings in intragestational fetal loss also depend on the of discordant growth and SGA in dichorionic and time of fetal death and duration of retention in utero. One monochorionic twins [140]. Velamentous and marginal or both twins may die, concordantly or discordantly, and cord insertion may be accompanied by differences in pla- they may be delivered at intervals or retained and deliv- cental vascularization; higher Doppler S–D ratios, and ered together. lower numbers of small muscular arteries in tertiary villi have been demonstrated in the smaller of discordant twins Vanishing Twin with peripheral cord insertion. Discordant birth weight is Twin gestations are commonly converted to singletons also associated with placental mass; smaller babies have with the embryonic/early fetal death of one twin smaller placentas. Since the fetal–placental weight ratio in (vanishing twin). Of twins diagnosed before 10 weeks, smaller twins is normal to decreased, maternal vascular about 70% are born as singletons. When a twin dies insufficiency is unlikely to be a major cause of impaired spontaneously early in the first trimester, it is often diffi- growth. Rather, poor placentation with asymmetrical cult or impossible to identify any residue. A flattened mass trophotropism and abnormal cord insertion, asymmetric of sclerotic placenta may remain as a vaguely thickened placental volume, and decreased placental vascularization area in the membranes of the surviving co-twin. Micro- are major causative factors in IUGR and twin growth dis- scopic examination may identify the membranous septum cordance. These factors may also explain the coexistence and establish chorionicity. Rarely there is an embryonic of oligohydramnic, growth-restricted, and polyhydramnic remnant, invariably severely degenerated (> Fig. 19.35). larger twins (twin oligohydramnios–polyhydramnios Electively reduced embryonic remnants are more easily sequence – TOPS) in dichorionic gestations and in identified (> Fig. 19.36). monochorionic gestations in which twin–twin transfusion has been carefully excluded by marker erythrocyte studies Fetus Papyraceus [24]. Whether placental and fetal growth asymmetries A twin dying in the second trimester may be retained, reflect a generalized problem in the conceptus or result progressively compressed, and flattened by the growth of from a primary placental problem is unclear. While discordant parenchymal lesions present a possible explanation for growth asymmetry, most placental disease processes involve twin placentas to similar degree; concordance for most findings is higher than might be expected based on their prevalence in singleton placentas. In one recent study, the only lesion significantly associated with discordant SGA twins was the finding of fibrotic avascular villi (FAV) [140]. This lesion, indicative of fetal vascular occlusion (fetal thrombotic vasculopathy) and associated with neurologic impairment in term infants, might contribute to the increased morbidity and mortality in twins. The incidence of fetal vessel thrombosis is higher in monochorionic than dichorionic placentas, correlating with peripheral cord insertion, vascular cushions, and IUGR [163].

. Fig. 19.35 Intragestational Fetal Loss Early twin demise. This growth disorganized tiny twin was delivered at term with its normal co-twin. The abnormal Multiples have higher mortality rates at all stages of ges- morphology suggests that this early twin death was the tation and after birth. The causes of intrauterine twin result of an abnormal karyotype Diseases of the Placenta 19 1019

fluid is resorbed. The corresponding placenta is generally pale, thinned, and sclerotic with avascular, fibrotic villi enmeshed in fibrin.

Survivors of Co-Twin Demise Abnormalities including intestinal atresia, skin defects, amputations, gastroschisis, and especially brain damage have been reported in twins surviving the in utero death of a co-twin. The risk of serious cerebral damage in surviving twins is reportedly around 20% and may be even higher in certain subsets. Monochorionic twins appear to be at greatest risk [117]. At all gestational ages, the risk of cerebral palsy is higher in like-sex surviving co-twins. . Fig. 19.36 Lesions occurring in surviving co-twins are similar to Multiple pregnancy with elective reduction. Reduced those in monochorionic twins with complex vascular fetuses are usually about the same size and relatively easily anastomoses, suggesting a similar pathogenesis. Survivors identified in the membranes (Used with permission of the of co-twin death also have a higher postnatal mortality American Registry of Pathology/Armed Forces Institute of rate. Pathology)

Duplication Abnormalities

Occasional monozygous twins show marked discrepancies in size and conﬁguration or varying degrees of incomplete separation. These asymmetric and incomplete duplica- tions include acardiac and parasitic twins and conjoined fetuses. A parasitic twin is a variably developed fetiform mass attached to its co-twin either internally or externally (> Fig. 19.38). Conjoined twins retain their overall sym- metry but are either incompletely separated or possibly secondarily fused during development. Neither parasitic nor conjoined twins show speciﬁc placental abnormalities.

Acardiac Twin (Chorangiopagus Parasiticus) Acardiac twinning is the commonest form of asymmetric . Fig. 19.37 duplication anomaly, occurring in 1% of monochorionic Fetus papyraceus twins. The acardius is a grossly malformed, often bizarre fetus of variable size, appearance, and degree of organo- genesis. No two are alike. Some are amorphous, shapeless the co-twin. Depending on the length of retention, this masses resembling teratomas (> Fig. 19.39) and others are ﬂattened dead twin, a fetus papyraceus, is variably altered remarkably well developed. Commonly, acardiac fetuses (> Fig. 19.37). Some are still easily recognizable and others have relatively well-developed legs and perineal structures, resemble amorphous necrotic material. Specimen radio- a trunk into which the umbilical cord inserts and graphs may reveal skeletal remnants. It has been estimated a rounded, dome-like upper body (> Fig. 19.40). A single that the creation of a fetus papyraceus takes about 10 body cavity may contain abdominal viscera, but thoracic weeks. The degree of maceration generally precludes structures and the heart are typically absent. Cardiac rem- establishment of the cause of death, although anomalous nants or a deformed heart may be identiﬁed on occasion. cord insertion and TTTS have been implicated in many Organ development is highly variable; some acardiacs may cases. Fetus papyraceus may occur in both monochorionic demonstrate absence of most organs, while in others, the and dichorionic gestations. The amnionic cavity of the organs may be well developed. Acardiacs may be hydropic, fetus papyraceus is gradually compressed as the amnionic and some are larger than the co-twin. 1020 19 Diseases of the Placenta

The essential feature common to all acardiac fetuses is and chorionic plate veins have been reported [179]. their circulation, which is maintained entirely by the co- Acardiacs may occur in diamnionic or monoamnionic twin (the ‘‘pump’’ twin). Blood from the normal ‘‘pump’’ monochorionic placentas, although monoamnionic pla- twin reaches the acardiac through an artery to artery centation is especially prevalent. Acardiacs are greatly anastomosis, ﬂows through the acardiac in reverse course, over-represented in triplet and higher multiple gestations. then returns to the normal twin through a vein to vein The pump twin is at risk for cardiovascular overload. anastomosis (twin reversed arterial perfusion – TRAP). The The extra work involved in circulating blood through the majority of acardiacs have a single umbilical artery. The acardiac may result in cardiomegaly and high output speciﬁc vascular communications between the acardiac failure associated with hydrops and hydramnios. Pump and pump twins are large, occurring at the level of the twins also tend to be growth impaired perhaps because the umbilical cord or chorionic plate. There are no placental blood diverted away from the placenta to the acardiac parenchymal vascular connections, and therefore the returns deoxygenated. Many pump twins have congenital acardiac is analogous to a conjoined twin and not to the TTTS. The histologic features of the placenta in acardiac twinning have not been described in detail. Villous immaturity and recent and remote thrombosis of umbilical

. Fig. 19.39 Acardiac fetus. This amorphous acardiac fetus had a single umbilical artery (Used with permission of the American Registry of Pathology/Armed Forces Institute of Pathology)

. Fig. 19.40 . Fig. 19.38 Acardiac fetus. A dome shaped upper body with lower Parasitic twin. This parasitic twin (a and b) was removed extremities is a relatively common configuration in acardiac from the abdominal cavity of its co-twin (Used with fetuses (Used with permission of the American Registry of permission of the American Registry of Pathology/Armed Pathology/Armed Forces Institute of Pathology) Forces Institute of Pathology) Diseases of the Placenta 19 1021 anomalies. Classiﬁcation of the acardiac anomaly based on volumes are assessed as in twins. Patterns of placentation prognostic factors including the cardiovascular condition vary depending on zygosity. Triplets, for example, may be of the pump twin and the size of the acardiac twin has monochorionic, dichorionic, or trichorionic with variable been proposed [191]. Strategies similar to those employed amnionicity (> Figs. 19.41 and > 19.42). Multichorionic in management of the twin–twin transfusion syndrome placentas are usually fused as space in the uterus is limited. have been successful in ameliorating the effects of cardiac Combinations of monozygous and polyzygous multiples overload in the pump twin [180]. are common. With increasing use of assisted reproductive techniques, triplets and even quadruplets or quintuplets are no longer unusual in many institutions (> Fig. 19.43). Higher Multiple Births Higher multiples experience the same complications as twins – prematurity, low birth weight, congenital anoma- Examination of placentas from higher multiple births lies, increased perinatal morbidity/mortality – all progres- extend the observations applied to twins. Chorionicity, sively problematic with increasing numbers. Acardiacs membrane relationships, cord insertion, chorionic vascu- are much more frequent in higher multiples as com- larity, potential vascular anastomoses, and relative placental pared to twins. Cord entanglement is less common in

Higher multiple birth triplets

Monochorionic monozygous

Triamnionic Diamnionic Monochorionic monoamnionic monoamnionic monoamnionic

Dichorionic mono or dizygous

Triamnionic Diamnionic dichorionic dichorionic

Trichorionic Placenta mono, di or trizygous Chorion Amnion

. Fig. 19.41 Triplet placentation (After [44])

. Fig. 19.42 Triplet placentation. Tri-Tri triplets (left). DiMo triplets (right). Although the placental territory at left is discrete, the fetal vascular pattern confirms monochorionicity. The middle and right triplets are monoamnionic 1022 19 Diseases of the Placenta

affected children may be severely handicapped, retarded, blind, or deaf. The social, ﬁnancial, and emotional burden posed by the support of these children is enormous.

Ascending Infection and Acute Chorioamnionitis

Frequency, etiology, and pathogenesis. ACA is the most common form of placental infection and inflammation in humans [134]. Histologic ACA is found in approximately 10–15% of term and in up to 50–70% of preterm placentas. This striking inverse relationship between ACA and gestational age emphasizes the strong association . Fig. 19.43 between ACA and PTB. The term ‘‘chorioamnionitis’’ Quintuplet placentas when used by clinicians to describe a symptom complex suggestive of intrauterine infection (maternal fever, uterine tenderness, or elevated white blood cell count) corre- monoamnionic higher-order multiples presumably due to lates poorly with histologic chorioamnionitis. limited opportunity for movement in the increasingly While historically controversial, it is now clear that crowded uterus. While the outlook in higher multiple ACA is a maternal and fetal acute inflammatory response births has improved, complications are common and the to infectious agents that have gained access to the gesta- outcome is often poor. Consequently, selective fetal reduc- tional sac. Microorganisms, usually bacteria, have been tion has been advocated, and there is now a substantial cultured from fetal membranes, amnionic fluid, cord body of accumulated experience. Remnants of reduced blood, and fetal tissues in a high percentage of cases fetuses are regularly identified when carefully sought. [194], and have been demonstrated by PCR in culture negative cases [48]. ACA can be produced experimentally Placental Inflammation and Intrauterine in animals by the intraamnionic injection of bacteria but Infection not by sterile exogenous irritants. Most cases of ACA result from the ascent of vaginal or cervical bacteria into the Placental inflammation is a common and important histo- uterus. Other potential sources of intrauterine infection logic finding. The character of a given inflammatory infil- include endometritis or contiguous spread of organisms trate and its pattern of involvement reflect, in general, its from the fallopian tubes, bladder, appendix, or intestines. etiology and determine its clinical significance [127]. Pla- Recent epidemiologic and experimental data have linked cental inflammatory infiltrates can be divided into two periodontal disease due to Fusobacterium nucleatum to major categories: (1) acute chorioamnionitis (ACA), an PTL and have suggested that these microorganisms may acute inflammatory reaction in the fetal membranes and reach the decidua hematogenously in some cases [57, 65]. umbilical cord; and (2) villitis – inflammation, usually ACA may either preceed or follow membrane rupture. chronic, of the villous parenchyma. ACA is invariably infec- There is a consistent and well-documented relationship tious due to microorganisms, usually bacteria, that ascend between chorioamnionitis and membrane rupture; the from the vagina or cervix (ascending infection). Villitis is longer membranes have been ruptured, the greater the almost invariably idiopathic, although rarely, it may be likelihood that ACA will occur. Ascending infection and infectious, caused by microorganisms (viruses, some bacte- ACA, however, frequently precede membrane rupture, ria, or protozoa) that reach the placenta through the mater- initiating premature rupture of membranes (PROM) nal blood (hematogenous infection). Passage through an and/or PTL, rather than following it, explaining the strong infected birth canal is an important mode of fetal infec- association between ACA and PTB. Outcome studies tion, but the placenta is not involved in this circumstance. would suggest that ACA with intact membranes is The consequences of intrauterine infection and a distinct entity with a greater risk to the developing inflammation include abortion, stillbirth, preterm birth fetus than ACA following membrane rupture, although (PTB), fetal malformation, active postnatal infection, and the histologic changes are identical [129]. The bacteria long-term sequelae, frequently neurologic. At worst, most commonly identified in women with spontaneous Diseases of the Placenta 19 1023

. Fig. 19.44 ACA, maternal response (early, stage 1). Maternal neutrophils migrate out of the intervillous space aggregating in the subchorionic fibrin (left) and from decidual vessels infiltrating the membranous chorionic trophoblast (right)

PTL and intact membranes are low-virulence vaginal and enteric organisms – Fusobacterium, Ureaplasma urealyticum, Mycoplasma hominis, Gardnerella vaginalis, Bacterioides and Peptostreptococcus species. Whether susceptibility to ACA is more related to factors that facilitate access of microorganisms to the intrauterine environment or to the virulence of, and host response to, a given infectious agent is unclear. Tosome extent, the maternal response to intrauterine infection is blunted by adaptations in the immune system that prevent rejection of the fetus [129]. Pathology. Maternal response: In most cases of ACA, the fetal membranes are macroscopically normal. In cases of particularly severe, long-standing infection, they may be opaque, friable, or foul smelling. Histologically there is a maternal and often a fetal inflammatory response to amnionic infection that progress sequentially and predict- . Fig. 19.45 ably as originally described by Blanc [21]. The initial ACA, maternal response (intermediate, stage 2). Maternal response is maternal, manifested by the migration of neutrophils migrate into the connective tissue of the maternal neutrophils from the intervillous space and chorion and amnion from vessels in the membranous decidua. Neutrophils accumulate first in the subchorionic fibrin (acute subchorionitis) and membranous chorionic trophoblast maternal inflammatory response has been proposed by (early acute chorionitis) (> Fig. 19.44), migrating pro- the Perinatal Section of the Society for Pediatric Pathology gressively through the connective tissue layer of the (> Table 19.1)[141]. The time course of progression in the chorion (acute chorionitis) and amnion (acute chorioam- maternal inflammatory response has been estimated based nionitis) (> Fig. 19.45) and into the amnionic fluid in on personal observation and clinical correlation as well as response to chemotactic factors released by the infecting experimental data. According to Redline, the initial mater- agent and/or inflammatory reaction. With time, the neu- nal inflammatory response (acute subchorionitis) occurs trophils undergo apoptosis and karyorrhexis followed by within 6–12 h of infection. Involvement of amnionic amnionic epithelial necrosis (necrotizing chorioam- connective tissue (ACA) most probably develops over nionitis) (> Fig. 19.46). 12–36 h after which the initial wave of neutrophils The sequential changes and disease progression (stage) undergoes apoptosis and karryorhexis (36–48 h) [131]. in the maternal inflammatory response are constant. Whether and how the timing of the maternal response A clinically relevant scheme for staging and grading the may be altered by maternal factors such as preexisting 1024 19 Diseases of the Placenta

. Fig. 19.46 ACA, maternal response (advanced stage 3, severe). Diffuse intense inflammation with karyorrhexis of neutrophils and amnionic epithelial necrosis (left) and chorionic microabscesses (right)

. Table 19.1 Ascending infection

Maternal response Stage 1 early: Acute subchorionitis/early chorionitis Stage 2 intermediate: Chorionitis/chorioamnionitis Stage 3 late: Necrotizing chorioamnionitis Subacute chorioamnionitis Grade severe: Subchorionic microabscesses Fetal response Stage 1 early: Umbilical phlebitis/chorionic vasculitis . Fig. 19.47 Stage 2 intermediate: Umbilical arteritis ACA, fetal response (early, stage 1). Fetal neutrophils Stage 3 late: Necrotizing funisitis migrate into the chorionic plate vessels (chorionic Grade severe: Intense chorionic vasculitis vasculitis)

maternal antibodies or the characteristics of the specific manifestation of a fetal inflammatory reaction is the causative organism is not understood. The intensity migration of fetal neutrophils into the umbilical vein (grade) of the maternal inflammatory response is more (umbilical phlebitis) and/or chorionic plate vessels (cho- difficult to quantify. Grading based on the number of rionic vasculitis). The migration of inflammatory cells is neutrophils in the most inflamed area of the chorionic crescent-shaped, oriented toward the source of infection plate has been suggested. The formation of subchorionic in the amnionic cavity (> Fig. 19.47). In later stages, fetal microabscesses has long been recognized as an indicator of neutrophils migrate from the umbilical arteries (umbilical severity since associated with fetal sepsis by Keenan arteritis) and into Wharton’s jelly. With increasing dura- (> Table 19.1)[78, 141]. tion, the neutrophils undergo necrosis forming necrotic Fetal inflammatory response: Depending on the gesta- bands around the umbilical vessels (necrotizing/subacute tional age and status of the fetal immune system, the fetus necrotizing funisitis) that may undergo calcification or may also respond to amnionic infection. A fetal leukocytic vascularization (> Fig. 19.48). Umbilical cord inflamma- response is often absent in gestations less than 19–20 tion is often segmental, sometimes identified in only one weeks and in fetuses less than 500 g. The first of multiple sections, often from the fetal end. Diseases of the Placenta 19 1025

. Fig. 19.48 ACA, fetal response (late, stage 3). Necrotizing funisitis. Prominent crescentic band of necrotic leukocytes around umbilical vessels can be appreciated grossly

. Fig. 19.49 . Fig. 19.50 ACA, fetal response (severe). Fetal neutrophilic infiltration Acute villitis. Bacterial colonies are prominent in villous of chorionic vessels with medial disarray and in this case capillaries and neutrophils have accumulated beneath the thrombosis trophoblast in the peripheral villous stroma

Progression of the fetal inflammatory response has same infectious insult. The acute inflammatory infiltrate also been staged (> Table 19.1), although the rate of pro- in chorioamnionitis is characteristically confined to the gression of the fetal inflammatory response is more vari- fetal membranes and umbilical cord. The villous paren- able than the maternal response, depending significantly chyma is not involved unless fetal septicemia results sec- on gestational age. The intensity (grade) of the fetal ondarily in villitis. In this event, bacteria (usually inflammatory response has important associations with Escherichia coli, group B streptococci) are present in vil- adverse fetal outcome. Scattered neutrophils in the chori- lous capillaries, often with accumulation of neutrophils onic plate or umbilical vessels are considered to be mild to beneath the trophoblastic basement membrane moderate (grade 1). Intense chorionic vasculitis (severe/ (> Fig. 19.50). Although the majority of leukocytes in grade 2) is characterized by near confluent neutrophilic the fetal membranes are maternal, fluorescence in situ infiltration of vessels accompanied by attenuation or dis- hybridization studies have demonstrated that the majority array of the vascular smooth muscle media (> Fig. 19.49). of neutrophils in amnionic fluid and fetal lung are fetal, Inflamed vessels may be thrombosed. emphasizing the important contributions of both mater- Amnionic infection, then, is a unique situation in nal and fetal immune systems. The character of the which two individuals, mother and fetus, respond to the inflammatory infiltrate is usually not specific enough to 1026 19 Diseases of the Placenta

identify a particular offending agent. In fact, it is relatively reduce spontaneous PTB and its associated mortality unusual to find bacteria in histologic sections even when and long-term morbidity. they have been demonstrated on smears of the amnion. Data accumulating from experimental and human Notable exceptions to this include infections with group studies are clarifying how bacterial infection and chorioam- B b-hemolytic streptococci in which colonies of the organ- nionitis result in spontaneous PTB. The inflammatory ism are frequently found without difficulty even in the response to bacterial invasion results in the production of absence of histologic evidence of chorioamnionitis. cytokines that initiate prostaglandin synthesis, resulting Fusobacterium species may also be visible on conventional in uterine contractions. Certain bacterial species commonly H&E stains as long (at least 15 mm), faintly basophilic associated with chorioamnionitis are high in phospho- wavy organisms often associated with very severe inflam- lipase A2, which releases the prostaglandin precursor mation and necrosis in the membranes. Fusobacteria may arachidonic acid from membrane phospholipids. The be demonstrated with silver stains but are only faintly inflammatory response also results in increased synthesis gram-negative on Brown and Hopps stain. In rare of metalloproteases that are thought to remodel and soften instances of Candida infection, tiny white fungal colonies cervical collagen and to degrade the extracellular matrix of 2–3 mm in size may be seen grossly on the amnionic the fetal membranes, leading to membrane rupture [85]. surface of the umbilical cord. Yeast and hyphal forms Placental villous edema in the context of ACA, most Candida may also be identified on conventional H&E often in preterms, has been correlated with increased stains, characteristically in small, superficial, crescentic morbidity, mortality, and neurologic impairment [105, microabscesses under the amnionic surface of the umbil- 144, 150]. ical cord (peripheral funisitis) (> Fig. 19.51). Approximately 30% of cases of ACA at less than 25 Clinical significance. Although there are maternal haz- weeks are associated with retroplacental hematoma even- ards associated with chorioamnionitis (maternal sepsis), tuating in death and delivery in many [129]. the principal clinical impact of chorioamnionitis is its Fetal inflammatory response syndrome (FIRS). Tradi- potential adverse affect on the fetus. tional thinking has attributed many of the neonatal Preterm birth (PTB). It is estimated that approximately complications of chorioamnionitis-induced PTB to pre- 70% of perinatal mortality and nearly half of long-term maturity, not to infection per se. Evidence is accumu- neurologic morbidity can be attributed to PTB [40]. Mul- lating that pathologic lesions predictive of long-term tiple factors contribute to PTB, but chorioamnionitis is morbidity (periventricular leucomalacia, intraventricu- implicated in a high percentage of cases. Intrauterine lar hemorrhage) are initiated in utero by the fetal re- infection as a cause of PTB is usually asymptomatic until sponse to placental infection (fetal inflammatory response labor begins or the membranes rupture prematurely, and syndrome – FIRS). Most data would not implicate infec- therefore, early diagnosis is difficult. Many recent strate- tious organisms as a direct cause of tissue damage but gies have been aimed at the identification of women at risk rather mediators of the fetal inflammatory reaction, prin- and the development of therapeutic interventions cipally cytokines (IL1, IL6, IL8, TNF-a) in the genesis of targeting infection and the inflammatory response to fetal lesions, especially white matter damage predictive of

. Fig. 19.51 Candida peripheral funisitis. Small yellow foci on the umbilical cord correspond to superficial microabscesses Diseases of the Placenta 19 1027 cerebral palsy [54, 88]. Cytokines may cause white matter occurrence, neonatal inflammatory response, or congeni- damage directly via a toxic effect or indirectly by activating tal infections have been associated. Such cases have been endothelium and microglia resulting in thrombosis or termed villitis of unknown etiology (VUE). Recent investi- increased vascular permeability. Whether endotoxins or gations have identified the villous inflammatory cells as exotoxins cross the placenta or blood–brain barrier to CD8 positive maternal T lymphocytes, supporting the directly injure the central nervous system is unknown. theory that VUE represents a maternal immune response The only histologic finding directly correlated with in fetal tissue (host versus graft reaction) [103, 135, 147]. CNS injury in ACA is the severity of the fetal inflammatory Very rarely, villitis may result from a hematogenous response. Umbilical arteritis is associated with higher levels infection in which infectious agents, usually viruses but of circulating fetal cytokines than inflammation of the also some bacteria and protozoa, reach the placenta umbilical vein alone [81, 157]. Intense chorionic vasculitis through the maternal blood (hematogenous infection). In has been associated with increased risk of cerebral palsy in contrast to chorioamnionitis, a local infection, placental term and preterm infants [130, 150]. The concomitant involvement in hematogenous infection is just one presence of mural thrombi in inflamed chorionic plate manifestation of maternal systemic disease. Although vessels is an additional risk factor for neurologic impair- catastrophic fetoplacental infections caused by ment in very low birth weight (VLBW) infants [150]. hematogenously acquired agents have been well Neonatal infection. ACA implies that the fetus has been documented, they are very infrequent. exposed to infection but not necessarily that the fetus is Pathology. Villitis is almost always discovered inciden- infected. The exposed fetus may be infected through the tally on microscopic examination. Typically, there is neither fetal skin, eyes, nose, or ear canals or by inspiring or clinical suspicion of nor gross pathologic clue to the under- swallowing infected amnionic fluid. Infants whose placentas lying inflammatory process. There may be nonspecific find- show ACA are at increased risk to develop sepsis and die in ings – the placenta may be small or large and edematous – the neonatal period. Although neither mother nor neonate is but only rarely are inflammatory foci identified grossly. The overtly ill in most cases, neonatal infection is an important essential feature common to all villitides is an inflammatory cause of perinatal death, and most serious neonatal infec- infiltrate in the villi, but its character and the nature of tions are associated with ACA. Fetal outcome is determined associated changes are variable from case to case. The by a number of factors including gestational age and caus- inflammatory infiltrate is usually chronic, composed of ative organism. Group B b-hemolytic streptococcus, E. coli, lymphocytes, histiocytes, and plasma cells in variable pro- and Haemophilus influenzae are the most common causes portion (> Fig. 19.52), but occasionally it may be granu- of significant neonatal infection. Placental features associ- lomatous, and rarely neutrophils are prominent. Usually ated with increased risk of neonatal infection include severe the inflammatory infiltrate is associated with appreciable maternal and fetal inflammatory responses [78, 194]. alterations in villous landmarks, but rarely it may infiltrate

Subacute Chorioamnionitis

Subacute chorioamnionitis is characterized by a mixed inﬂammatory inﬁltrate of mononuclear cells and degenerating neutrophils, usually concentrated in the upper chorion. This pattern may result from ongoing low-grade or repetitive infection, and has been associated with chronic lung disease in a subgroup of VLBW infants with concomitant amnionic necrosis. The maternal history may include repetitive bouts of vaginal bleeding [111].

Villitis and Hematogenous Infection

Etiology. Villitis, inﬂammation of the villous parenchyma, is almost never due to documented infection. No causative . Fig. 19.52 organism has been identiﬁed despite intensive study, and Villitis of unknown etiology (VUE). Villi infiltrated by no maternal symptoms, seasonal or geographic pattern of lymphocytes and histiocytes 1028 19 Diseases of the Placenta

. Fig. 19.53 . Fig. 19.54 Villitis of unknown etiology (VUE). Inflammation involving Active chronic villitis with intervillositis and villous necrosis. the perivillous space with agglutination of adjacent The villous stroma and intervillous space are infiltrated by inflamed villi neutrophils and chronic inflammatory cells. Fetal stem villous vasculitis, villous necrosis, and diffuse perivillous fibrin deposition result in grossly visible necrotic foci. passively. Necrosis, dystrophic calcification, and stromal Obliteration of stem vessels results in distal villous changes, hemosiderin deposition may be present in some cases. The here FAV inflammatory cells are generally concentrated within the villi, but may also extend into the surrounding intervillous . Table 19.2 space, a feature commonly associated with syncytiotro- Villous inflammation graded by extent phoblastic necrosis, intervillous fibrin deposition, and agglutination of contiguous inflamed villi (> Fig. 19.53). Grade 1: Only one or two foci of villous inflammation, and Occasionally an intervillous component (intervillositis) in each focus only a very few villi are involved may predominate. Inflamed villi are usually randomly Grade 2: Up to six foci of villous inflammation, each focus distributed, but in some cases may be concentrated in containing up to twenty villi the basal regions of the placenta or juxtaposed to the Grade 3: Multiple inflammatory foci, each occupying up to septa. The degree of villous involvement varies greatly half a low power microscopic field from case to case and may be graded semiquantitatively Grade 4: Large areas of villous inflammation in most or all as outlined by Fox and Sebire (grades 1–4) [45] or Redline of the four sections (focal, multifocal, patchy, and diffuse) [84] > Table 19.2. Focal: Small clusters of five-ten villi in a single slide Villitis of Unknown Etiology (VUE) Multifocal: Small clusters of five-ten villi in multiple slides Patchy: Larger foci (more than ten villi) More than 95% of villitides are of unknown etiology. Diffuse: Diffuse involvement of all sections by groups Although the extent and severity of VUE vary, it is very of more than ten inflamed villi mild/mild or focal/multifocal in the majority of cases (60–75%). The villous inflammatory infiltrate is typically composed of macrophages and lymphocytes, but giant silver stains) should be considered. The inflammatory cells are common and are not indicative of infection. An infiltrate is often confined to terminal villi but may also active component with perivillous neutrophils may be involve stem villi. Inflammatory obliteration of stem vil- present and when fulminant may be accompanied by lous vessels with downstream fibrotic avascular villi (VUE intervillositis and fibrin deposition with villous necrosis with fetal obliterative vasculopathy) has been associated (active chronic villitis)(> Fig. 19.54). Since this pattern with neurologic impairment (> Fig. 19.55)[84]. Chronic may be seen in some infectious villitides (gram-negative deciduitis and chronic chorioamnionitis may accompany bacteria, nonsyphilitic spirochetes), special stains (gram, VUE in some cases. Villitis involving basal/periseptal villi Diseases of the Placenta 19 1029

. Fig. 19.55 . Fig. 19.56 Villitis of unknown etiology (VUE) with obliterative fetal CMV placentitis. Plasmacytic villous infiltrate vasculopathy. Vasculitis and obliteration of stem vessels result in avascular villi

(basal villitis) is frequently mild, purely lymphocytic, and passive. This pattern represents a subgroup of VUE often associated with plasma cell deciduitis. Clinical significance. VUE is a common lesion involving 5–15% of third-trimester placentas [135]. When mild, VUE is usually clinically silent and the infant unaffected. More severe, extensive VUE is associated with IUGR, IUFD, cerebral palsy, and other forms of neurologic impairment [145]. These complications correlate directly with the severity of the villitis. In VUE, maternal cells enter not only the villi but the fetus itself [135]. Whether this contributes to perinatal morbidity or mortality is unclear. When fatal, VUE is generally massive, suggesting that impaired placental function may be a mechanism of injury. VUE may recur (10–25% when diffuse), and is associated with total . Fig. 19.57 reproductive failure. IUGR, IUFD, and preterm delivery CMV inclusions are especially likely in cases of recurrent VUE. related in part to gestational age. A plasmacytic villous Specific Infectious Villitides infiltrate and stromal hemosiderin, often deposited around the remnants of occluded vessels, are characteristic Rarely the morphologic features of a villitis suggest an (> Fig. 19.56). Foci of stromal necrosis, calcification, and infectious cause, although differences between the infec- fibrosis may be found. The diagnostic cytopathic viral tious villitides and VUE may be quite subtle. In general, changes, large eosinophilic intranuclear and smaller baso- infectious villitides tend to be more severe with more philic cytoplasmic inclusions, may be present in endothe- villous fibrosis, necrosis, calcification, and inflammation lial cells, Hofbauer cells, or trophoblast (> Fig. 19.57). of fetal membranes and umbilical cord. They are most numerous and easily found in early, severe infections; as gestation proceeds, viral inclusions are typ- Cytomegalovirus (CMV) ically scarce. When inclusions are not visualized on con- Pathology. The placenta may be normal, small (in cases of ventional H&E stains, CMV infection may be confirmed IUGR) or large and edematous. Histologically the villi by immunohistochemistry, polymerase chain reaction may exhibit any or all of a wide spectrum of changes (PCR), or in situ hybridization. 1030 19 Diseases of the Placenta

Clinical signiﬁcance. CMV is the commonest identiﬁed infectious cause of villitis. The prevalence of congenital infection ranges from 0.2 to 2.2% of all live births. Trans- mission to the fetus may occur in utero, at birth, or postna- tally. Intrauterine infection may result from either primary or recurrent maternal infection. Congenital infections resulting from reactivation of latent virus are less likely to produce fetal damage and late sequelae than those resulting from primary maternal infection. At the present time, CMV is the most commonly recognized infectious cause of developmental impairments. Late complications including mental retardation, chorioretinitis, seizures, and . Fig. 19.58 especially neurosensory hearing loss are most common Listeria placentitis. Yellow white necrotic areas may be among survivors of symptomatic congenital infection but grossly apparent in some cases may also occur later in children with no manifestations at birth.

Treponema pallidum Pathology. Infected placentas tend to be large and bulky. Histologically, the villi are large and relatively immature but not markedly edematous. The villous stroma is cellular as a result of the prominence of Hofbaur cells, and a lymphoplasmacytic infiltrate with subtrophoblastic neutrophils and microabscesses may be seen focally. Rarely, the inflammatory reaction has granulomatous features. Subendothelial and perivascular fibrosis resulting in luminal narrowing, recanalization, or occlusion of villous vessels is particularly characteristic. Marked decidual plasmacytic vasculitis and a chronic inflammatory infiltrate in the fetal membranes and umbilical cord have been noted in some cases. Necrotizing funisitis is a frequent finding but is not universal in, or specific for, congenital syphilis. The histo- . Fig. 19.59 logic changes in the placenta and umbilical cord are char- Listeria placentitis. Neutrophils aggregate in the acteristic but not diagnostic. Definitive diagnosis depends intervillous space. Entrapped villi undergo necrosis forming on identification of spirochetes, most easily demonstrated abscesses. Neutrophils accumulate peripherally in the in the umbilical cord whether inflamed or not. villous stroma beneath the trophoblast

Listeria monocytogenes Pathology. The placenta is usually grossly normal but may Brown–Hopps, Warthin–Starry, or Dieterle stains. Immu- contain minute yellow-white necrotic foci or rarely larger nohistochemical stains have been utilized to establish the abscesses or infarcts (> Fig. 19.58). The amnionic fluid is diagnosis and to exclude other infections (Campylobacter frequently meconium-stained. Unlike most other villitides, species, E. coli, H. influenzae, Francisella tularensis, neutrophils predominate in Listeria villitis. Villi are com- Streptococcus species, Brucella abortus, Chlamydia monly enmeshed in intervillous acute inflammation and psittaci, Coccidioides immitis) that have similar histologic fibrin, which, when extensive, may result in villous necrosis findings. and abscesses. Neutrophils in the villi are often localized Clinical significance. L. monocytogenes is a significant to a rim, often between the trophoblast and villous cause of intrauterine infection, spontaneous abortion, pre- stroma (> Fig. 19.59). Listeria villitis is usually accompa- maturity, and neonatal sepsis, morbidity, and death. Peri- nied by chorioamnionitis and often funisitis. Listeria natal listeriosis takes one of two forms. In the ‘‘early type,’’ monocytogenes is a small gram-positive motile bacillus congenital infection results in devastating neonatal sepsis with rounded ends that may be demonstrated with (granulomatosis infantisepticum) in which microabscesses Diseases of the Placenta 19 1031 similar to those in the placenta are disseminated in fetal are typically unassociated with inflammation, but once organs. The ‘‘late type’’ of perinatal listeriosis, presumably ruptured, the tachyzoites incite an intense inflammatory acquired during birth, presents as meningitis in the second reaction and necrosis. Identification of tachyzoites, very or third week of life. L. monocytogenes usually does not difficult on H&E stains, is aided by immunohistochemis- cause serious disease in adults, although gravidas may try, immunofluorescence, or PCR. experience a flu-like syndrome and fever. The most com- Clinical significance. Congenital infection appears to mon mode of infection is the ingestion of contaminated result mainly from primary maternal infection acquired food, often a milk product. A brief hematogenous phase is early in pregnancy, usually by the ingestion of oocytes in followed by fecal shedding until immunity is established. undercooked meat or by contact with cat feces. During the Placental infection can result from hematogenous dissem- parasitemic stage of maternal infection, the organism is ination or via the ascending route. The particular predis- transmitted to the placenta and fetus. The risk of fetal position for significant listerial infection in pregnant infection in these circumstances is about 50%. The likeli- women and the fetus appears to be related to local factors hood of fetal transmission increases with gestational age, at the maternofetal interface that compromise an effective although the severity of infection is greatest when the immune response [125, 126]. infection is acquired in the first trimester. The clinical spectrum of fetal involvement ranges from severe damage Toxoplasma gondii to the central nervous system and eyes to completely Pathology. The placenta infected with Toxoplasma gondii asymptomatic infection, recognized only by the develop- may be grossly normal but is commonly large and edem- ment of chorioretinitis after months or years of follow-up. atous. Microscopically, the changes are highly variable, Prenatal diagnosis (via fetal blood sampling or culture) ranging from a subtle low-grade lymphocytic villous infil- and antibiotic treatment seem to reduce the frequency of trate to a destructive process associated with necrosis or congenital infection. In the presence of maternal anti- fibrosis. True granulomas with central necrosis, palisaded bodies from past infections, fetal lesions, with rare excep- histiocytes, and Langerhans giant cells may predominate. tion, do not occur. Nodular accumulations of histiocytes beneath the trophoblast or extending into the intervillous space, decidual Parvovirus B19 plasmacytic infiltrates and vasculitis, and chronic inflam- Pathology. Pathologic changes in the placenta reflect fetal matory infiltrates in the fetal membranes and umbilical anemia. Parvovirus B19 preferentially infects actively rep- cord have been described. The encysted form of the organ- licating cells, especially erythroblasts, which are then ism may be found in the fetal membranes, chorionic plate, destroyed. Grossly, the placentas are large, pale, and fria- umbilical cord, or villi (> Fig. 19.60). Toxoplasma cysts ble. Microscopically, there is a uniform pattern of relative villous immaturity and edema. Diagnostic intranuclear eosinophilic inclusions with peripheral chromatin condensation are present in erythroblasts in the villous vessels (> Fig. 19.61). In situ hybridization and immunohistochemistry are somewhat more sensitive than conventional microscopy in identifying infected cells or PCR may be used to confirm the diagnosis. Unlike most other congenital hematogenous infections, there is no villous inflammation. Clinical Significance. Human parvovirus B19 is the agent of ‘‘fifth disease,’’ or erythema infectiosum, a mild, acute exanthematous disease of children. In adults, most infections are asymptomatic, although self-limited polyarthropathy is common especially in women, and aplastic crises occur in individuals with chronic hemolytic anemias. To date, the most commonly recognized consequences of fetal parvovirus infection are non-immune . Fig. 19.60 hydrops (which may resolve spontaneously) and abortion. Toxoplasma villitis. A toxoplasma cyst is present in this Most abortions occur between the 10th and 28th weeks of chronically inflamed villus pregnancy, but the risk of fetal loss is low, estimated to be 1032 19 Diseases of the Placenta

occurring in less than 5% of fetuses infected in the ﬁrst trimester. Reactivation of maternal zoster during pregnancy does not appear to be associated with severe fetal sequelae.

Rubella Congenital rubella infection is now rare due to the effec- tiveness of immunization programs. The placental ﬁnd- ings have been well documented during previous rubella epidemics, mainly in ﬁrst- and second-trimester abortions but in a few term placentas as well.

Human Immunodeficiency Virus . Fig. 19.61 Human immunodeficiency virus (HIV) may be transmit- Parvovirus infection. Erythrocytes in the villous capillaries ted to the fetus transplacentally, at the time of delivery, or show central nuclear eosinophilic inclusions with peripheral after birth (through breastfeeding). In utero transmission chromatin condensation can be confirmed by the detection of virus in infants by PCR or coculture within 48 h of birth. Several factors (maternal, fetal, obstetric, and virologic) affect mater- less than 10%. Neonatal anemia has been observed in a few nal–infant viral transmission, and timing of transmission infants infected in the third trimester, and malformations may determine the subsequent course of infection in the reminiscent of ocular rubella embryopathy have been infant. Antiretroviral therapy given to the mother before reported very rarely. and during delivery and to the infant after delivery has reduced vertical transmission substantially. No histopath- Herpes Simplex Virus ologic lesions directly attributable to HIV have been Disseminated herpes simplex virus infection is an impor- described in the placenta. Specifically, there have been no tant cause of devastating disease and death in the new- reports of villitis. Placentas from seropositive mothers born. Intrapartum infection of the fetus is the most have demonstrated an increased incidence of ACA. common, although ascending and transplacental dissemination have been described. Villous necrosis and aggluti- Other Organisms nation, lymphocytic villitis, and fibrinoid necrosis of Massive chronic histiocytic intervillositis may occur in villous vessels have been documented in cases of hema- malaria [112]. Recurrent villitis has been described in togenous infection. Acute necrotizing and chronic association with nonsyphilitic spirochetes [1]. The placen- lymphoplasmacytic chorioamnionitis, amnionic viral tal lesions associated with hematogenous spread of other inclusions, and funisitis have been described in cases of organisms are detailed elsewhere [45]. ascending infection. An increased frequency of spontaneous abortion and congenital malformations have been reported in patients with primary infection in the first 20 Other Patterns of Placental Inflammation weeks of pregnancy. Chronic Histiocytic Intervillositis Varicella Zoster Varicella infection in pregnancy is uncommon in the Chronic histiocytic intervillositis is the diffuse uni- United States because the majority of women of childbear- form infiltration of the intervillous space by monocyte– ing age (95%) are immune. In congenital infection, the macrophages accompanied by variable perivillous fibrin placenta may show small, grossly visible necrotic foci and deposition (> Fig. 19.62). Excluded from this category villous necrosis, vascular occlusion, lymphoplasmacytic are cases with concomitant villitis or polymorphous infiltrates, and granulomas with giant cells. Viral inclu- intervillous inflammation. Placentas are often small for sions have been reported in villi and decidua. The spec- gestational age. The histologic features are very similar trum of fetal manifestations is wide, ranging from to those in placental malaria, distinguished from it by completely asymptomatic babies to those with perinatal the absence of malarial pigment. Chronic histiocytic varicella/zoster or full-blown embryopathy, the latter intervillositis is idiopathic, encountered most often in Diseases of the Placenta 19 1033

. Fig. 19.62 . Fig. 19.63 Chronic histiocytic intervillositis. There is diffuse infiltration Chronic chorioamnionitis. Small lymphocytes infiltrate the of the intervillous space by monocyte-macrophages amnion and chorion

first-trimester spontaneous abortions. It is associated with plate may occur. Rarely, the large fetal vessels of the cho- recurrent spontaneous abortion, IUGR, IUFD, and a high rionic plate and umbilical cord are also chronically overall perinatality mortality rate. inflamed. Chronic chorioamnionitis is often accompanied by villitis and occasionally by chronic or subacute necrotizing funisitis. A specific infectious etiology is not identi- Chronic Deciduitis fied in the great majority of cases, although rarely chronic chorioamnionitis may occur in association with rubella, Chronic deciduitis has been defined as either the presence herpes simplex, T. pallidum,orT. gondii infection. of plasma cells or diffuse chronic inflammation (with or without plasma cells) in the decidua basalis. The chronic inflammatory response may be directed against maternal Eosinophilic/T Cell Vasculitis or fetal antigens or microorganisms. Chronic deciduitis is often associated with VUE at term and with ACA in Eosinophilic/T cell vasculitis is a chronic inflammatory preterm placentas, but it may also occur as an isolated infiltrate composed of fetal eosinophils and lymphocytes finding. involving chorionic plate and large stem villous vessels (> Fig. 19.64). There are no specific clinical associations, although in most reported cases there have been maternal Chronic Chorioamnionitis or fetal abnormalities [47].

Rarely, an inflammatory infiltrate occurring in the same distribution as ACA is composed of chronic inflammatory Circulatory Disorders cells (> Fig. 19.63). Typically, small mature lymphocytes predominate, but plasma cells, histiocytes, and rarely large The placenta is a vascular organ with separate fetal and lymphoid cells and immunoblasts are admixed [69]. In maternal circulations. The integrity of both circulations is some cases, the chronic inflammatory cells may be accom- essential to placental function. Clots, hematomas, and panied by a minor component of neutrophils, which may other pathologic processes affecting the vessels and spaces be either entirely distinct from, or intimately admixed in and around the placenta may cause both fetal and mater- with, the chronic inflammatory component. The inflam- nal injury depending on their size, location, and extent. matory infiltrate in chronic chorioamnionitis is com- Measurement of size and evaluation of extent is important monly focal and typically mild. It is generally confined to in assessing the significance of individual lesions. There the membranes, although involvement of the chorionic is, however, no absolute ‘‘cutoff’’ beyond which a bad 1034 19 Diseases of the Placenta

. Fig. 19.64 . Fig. 19.65 Eosinophilic T-cell vasculitis. Eosinophils and small Incomplete vascular remodeling. This basal plate artery lymphocytes invade the muscular wall of this chorionic retains its muscular wall plate vessel

outcome is inevitable or below which a good outcome is Decidual Vasculopathy, Incomplete assured. The normal placenta has considerable functional Physiologic Change, Acute Atherosis, and reserve. The potential for injury depends not only on the Maternal Vascular Underperfusion nature and extent of the pathology but also on the amount and functional status of the uninvolved parenchyma. Thus, Etiology. When normal physiologic trophoblastic even a relatively small lesion in a compromised or small remodeling of the spiral arteries does not evolve properly, placenta may have greater clinical significance than a larger arterial smooth muscle persists, the lumina fail to expand, lesion in an otherwise normal placenta. and uteroplacental blood flow is reduced. The maternal A balance between factors that favor coagulation and blood pressure rises, the maternal vascular endothelium is fibrinolysis is necessary for homeostasis; pregnancy itself injured, and the maternal syndrome of preeclampsia shifts that balance toward thrombosis. Within the mater- develops. nal intervillous space, clotting inhibitors such as annexin Pathology. Non-remodeled spiral arteries with persis- V at the syncytiotrophoblastic surface normally inhibit tent musculoelastic media (absence of physiologic change) clotting. Thrombogenic factors may overcome this, may be identified in the basal plate (> Fig. 19.65). Non- resulting in thrombi and infarcts [123, 124]. Within the remodeled spiral arteries are predisposed to develop fetal circulation, stasis, local injury from inflammation or a distinctive lesion, acute atherosis, characterized by necro- compression, or thrombophilic factors may result in sis and dense eosinophilia of the vessel wall with large clotting. The existence of an intravascular clot, regardless foamy macrophages and inflammation (> Fig. 19.66). of cause, confirms that the balance has been broken at least The lumens may be partly or completely occluded by locally, and may also promote or be associated with thrombus. Acute atherosis involves muscularized mater- clotting elsewhere in the circulation. nal arteries in the basal plate and membranous decidua. The latter is often the best place to find acute atherosis (> Fig. 19.67). Immature IT in the superficial basal plate Maternal Circulation and trophoblastic giant cells in the deep basal plate are increased [149]. These changes together with the charac- In relation to placental pathophysiology, the maternal cir- teristic vascular alterations have been referred to as super- culation includes the uterine arteries and their branches, ficial implantation [84]. the spiral arteries, the maternal intervillous space, and the Mural hypertrophy of membrane arterioles is a less com- venous drainage of the uterus. Many pathologic processes mon pattern of decidual vasculopathy that occurs espe- affecting the maternal circulation can be traced to abnormal cially in women whose preeclampsia is complicated by implantation and vascular remodeling [136]. diabetes mellitus [15]. The muscular walls of the affected Diseases of the Placenta 19 1035 vessels in the decidua parietalis are thickened, and there is into the maternal circulation as membrane bound packets. marked luminal narrowing (> Fig. 19.67). Mural hyper- In preeclampsia, the nuclei of the pathologic knots trophy is diagnosed when the mean wall diameter is undergo ischemic necrosis (‘‘aponecrosis’’) [67], releasing greater than 30% of the overall vessel diameter [139]. membrane fragments, DNA, and proteins into the mater- The most direct adverse effect of decidual vasculopathy nal circulation. This circulating cellular debris may con- is the reduction of maternal blood flow into the intervillous tribute to maternal endothelial injury in preeclampsia space (maternal vascular underperfusion) leading to re- [67]. Adhesions between syncytial knots undergoing duced placental growth and weight. Microscopic changes aponecrosis may result in the agglutination of small vil- include increased and prominent syncytiotrophoblastic lous clusters (>2 <20) that commonly show karyorrhexis knots (> Fig. 19.68). The nuclei in the small knots of and stromal fibrosis (villous agglutination)(> Fig. 19.69). a normal placenta undergo apoptosis and break away With more severe underperfusion, intervillous fibrin is increased, first around stem villi, and then around distal villi, accumulating as small nodules at sites of trophoblastic necrosis. Ultimately, large aggregates of villi may be enmeshed in fibrin [139]. Fibrin accumulation in the intervillous space may be the result of decreased maternal perfusion and stasis or to abnormal coagulation or both. When reduced maternal blood flow is severe and long- standing, the villi develop abnormally. The distal villi are decreased in number and slender with reduced branching, and terminal villi are very small with increased syncytial knots. This constellation of features is referred to as distal villous hypoplasia (synonyms: accelerated maturation, peripheral villous hypoplasia)(> Fig. 19.70). To be significant, these changes must be demonstrated centrally in the mid and basal zones of the placenta because similar changes occur normally in the less perfused peripheral . Fig. 19.66 and subchorionic regions [192]. Hypoxia-related gene Acute atherosis. The spiral arteries show fibrinoid necrosis expression in trophoblast occurs in these areas even in the and accumulation of foamy macrophages. The largest normal placenta [192] Localized areas of severe ischemia artery is thrombosed, and there is infarction of the result in infarcts that may be large and numerous in cases overlying placenta of severe preeclampsia (> Fig. 19.71). Long-standing

. Fig. 19.67 Acute atherosis (left) and mural hypertrophy of membrane arterioles (right). In mural hypertrophy, the vessel wall is greater than one third of the total vessel diameter 1036 19 Diseases of the Placenta

. Fig. 19.68 . Fig. 19.70 Maternal underperfusion. Increased syncytial knots. Maternal underperfusion. Distal villous hypoplasia. Chronic Syncytiotrophoblastic nuclei clustered in the distal villi severe maternal underperfusion results in distal villi that are thin and non-branched when cut longitudinally and very small when cut in cross section. Syncytial knots are prominent

. Fig. 19.69 . Fig. 19.71 Maternal underperfusion. Villous agglutination. Clusters of Maternal underperfusion. Infarcts of varying ages. Recent degenerating distal villi are adherent to one another infarct is red

maternal vascular underperfusion may cause fetal volume thrombi occur in the placenta when thrombotic thrombo- depletion, decreased extracellular ﬂuid, and an abnor- cytopenic purpura develops in pregnancy [70]. mally thin cord. Clinical signiﬁcance. Maternal vascular compromise with placental underperfusion is one of the major causes Infarct of IUGR. Severe maternal vascular underperfusion may result in IUFD and is associated with cerebral palsy Etiology. An infarct in the placenta, as in any other organ, is (CP) in VLBW infants [144]. Identical pathologic an area of ischemic necrosis resulting from obstruction of changes occur in the placentas of patients with systemic blood supply. The spiral arteries that supply the placenta lupus erythematosus [93], scleroderma [38], the anti- may be narrowed by acute atherosis, occluded by thrombi, phospholipid antibody syndrome [159], and occasionally or disrupted by a retroplacental hematoma. Extensive in the absence of hypertension. Similar changes in the spiral placental infarcts have been reported in association with arteries with constrictions, dilations, hyalinization, and thrombophilic states [9, 37, 80]. Diseases of the Placenta 19 1037

Pathology. Infarcts are wedge-shaped areas of indura- myometrium. It represents the pathologic lesion respon- tion often located at the placental margin. Fresh infarcts sible for the clinical diagnosis of placental abruption that are difficult to see; they differ little in color, but are firmer is made by the obstetrician based on the presenting signs and drier than the surrounding placenta. Older infarcts and symptoms manifested by the mother. These two terms grow progressively firmer and change from red to brown, should not be used interchangeably, a practice which leads then tan, yellow, or white (> Fig. 19.71). Microscopically, to confusion between a clinical diagnosis with grave impli- the earliest change is collapse of the intervillous space. The cations and a pathologically demonstrated clot whose villi are crowded, separated by only a thin layer of fibrin, impact depends primarily on size. and trophoblastic nuclei cluster together forming knots. Frequency. Retroplacental hematomas are found in The syncytiotrophoblast, vascular endothelium, and approximately 4.5% of placentas examined pathologically villous stroma undergo progressive necrosis until eventu- [45]. Based on data from the National Hospital Discharge ally only crowded, ghostlike villous outlines remain Summary, symptomatic abruption occurs in 1% of single- (> Fig. 19.72). The mummified infarcted villi are not ton deliveries. The incidence appears to be increasing [6]. removed by macrophages or replaced by fibrous tissue as Etiology. The pathogenesis of retroplacental hematoma occurs in other organs. A mild acute inflammatory is not known, but bleeding from a decidual artery followed response may occur at the margin of an infarct. by dissection of the enlarging clot is the presumed Clinical behavior. Infarcts occur in about 25% of oth- sequence in most cases. An occluded ischemic artery erwise normal term placentas. The finding of a small that undergoes reperfusion may rupture, leading to peripheral infarct in an otherwise normal placenta is of a retroplacental hematoma. Retroplacental hematomas no clinical significance. Multiple or large (>3 cm) infarcts, are increased threefold in women with preeclampsia, pre- central infarcts, or infarcts in the first or second trimester sumably due to the related vascular pathology. Other are indicative of significant, underlying maternal vascular associations include PTL, chorioamnionitis, anemia, disease, most often preeclampsia. Extensive placental smoking, cocaine abuse, trauma, diabetes mellitus, and infarction is associated with fetal hypoxia, IUGR, and short umbilical cord. Traumatic separation of the attached IUFD. These ill effects on the fetus are not simply the placenta followed by bleeding from a disrupted vessel result of the destruction of villous tissue but reflect the probably occurs, for instance, following an automobile superimposition of infarction on a placenta already accident. compromised by low maternal blood flow. Pathology. When confined by peripherally attached placenta, a retroplacental hematoma distorts and indents the overlying placental parenchyma (> Fig. 19.73). Sepa- Retroplacental Hematoma rated from its blood supply, the overlying placenta infarcts. The characteristic depression and overlying Definition. A retroplacental hematoma is a clot located in infarct are easily recognized even when the clot itself has the decidua between the placental floor and the become detached during delivery. Larger clots may dissect

. Fig. 19.72 Maternal underperfusion. Infarcts. The intervillous space is collapsed with necrotic villi undergoing progressive necrosis eventuating in ghost like villous remnants 1038 19 Diseases of the Placenta

into the basal region of the placenta. Older retroplacental evidence when clumps of decidua associated with strands hematomas may be much more subtle, forming only of fibrin are demonstrated. a thin, inconspicuous layer of red-brown clot beneath an Retroplacental hematomas consist of stratified red infarct. When retroplacental hematomas extend to the cells and fibrin, the proportion of fibrin increasing as the placental margin, the blood may be evacuated without lesion ages and the red cells degenerate. The time course of causing any indentation. Very recent extensive placental these evolutionary changes is unknown. The adjacent separation is typically associated with little, if any, gross or decidua may be necrotic. Macrophages containing hemo- histologic change in the placenta. These large hematomas siderin are often present around older clots and sometimes generally result in immediate fetal distress, necessitating involve the membranes. Organization may occur where emergent delivery. A large fresh clot behind a ‘‘floating’’ the clot interfaces with the uterus, but not where it inter- detached placenta observed at the time of cesarean section faces with the placenta. The placenta overlying the hema- may be the only objective sign of an acute retroplacental toma is often infarcted. Villous edema and villous stromal hemorrhage. Obstetricians should document this obser- hemorrhage are secondary placental abnormalities indi- vation and submit the clot along with the placenta. Micro- cating that the retroplacental hematoma has adversely scopic examination of the clot may offer supportive affected the fetus. Nucleated fetal erythrocytes are often increased (> Fig 19.74). Clinical significance. The clinical significance of a retroplacental hematoma is related primarily to its size. Retroplacental clots block the passage of blood from the spiral artery into the intervillous space. Small clots may have little effect, since adjacent spiral arteries may suffice to keep the overlying placental villi functional. The larger the clot and infarct, the more likely it will exceed the functional reserve capacity of the placenta, which may be already marginal in a background of chronic uteroplacental ischemia. Older chronic lesions associated with hemosiderosis in the membranes indicate the possibility of chronic reduction of placental function. Extensive . Fig. 19.73 accumulations of blood lead to the full clinical picture of Retroplacental hematoma. The placenta is compressed and abruption – pain, and shock in the mother and severe infarcted over this large retroplacental hematoma acute hypoxia in the fetus.

. Fig. 19.74 Villous stromal hemorrhage. Villous stromal hemorrhage is associated with acute retroplacental hematoma (left). nRBC are often increased (right) Diseases of the Placenta 19 1039

Marginal Hematoma antenatal bleeding. In this context, retroplacental hematomas and abruption are also more frequent. Definition. A marginal hematoma occurs where the lateral margin of the placental disk joins the fetal membranes. Etiology. Acute marginal hematomas are thought to Intervillous (Intraplacental) Hematoma result from rupture of uteroplacental veins at the margin of a low-lying placenta. Chronic recurrent venous hemor- Definition, frequency, and etiology. Intervillous hematomas rhage at the disk margin (chronic marginal hematoma, are clots in the intervillous space. They are common, chronic abruption) elevates and centrally displaces the found in 36–48% of placentas. Intervillous hematomas membrane insertion site, resulting in circumvallation. are thought to be initiated by fetal bleeding into the Pathology. Grossly, an acute marginal hematoma intervillous space through ruptured vasculosyncytial forms a crescent-shaped clot at the lateral margin of the membranes. Small amounts of fetal blood can be demon- placenta. On cut section, the clot is triangular with the strated, although most of the clot is composed of maternal apex at the junction of the membranous and villous cho- blood [75]. Factors cited as potential causes of villous rion. Microscopically, a recent marginal clot usually lies damage resulting in fetomaternal hemorrhage include entirely outside the placental disk but may occasionally trauma, amniocentesis, and external version. Basilar involve the intervillous space. With this exception, the intervillous hematomas may have a different etiology. presence of an acute marginal hematoma has no effect Pathology. Intervillous hematomas are round or oval on the adjacent villi. Chronic marginal hematomas are blood clots that may occur anywhere in the intervillous tan-brown clots usually occurring in the region of circum- space but are most common midway between the chori- vallate membrane insertion and associated with mem- onic and basal plates. They begin as red, fluid, or semifluid brane hemosiderin deposition (> Fig. 19.75). blood and become progressively laminated and Clinical significance. An acute marginal hematoma depigmented with age. They may be single, although mul- may be associated with antepartum bleeding, in some tiple lesions are common. Most are 1–3 cm in diameter. cases followed by onset of labor, but it does not have any Microscopically, the thrombi consist of layered red cells untoward effect on the fetus. Chronic marginal hemato- and fibrin, the proportion of fibrin increasing as the lesion mas and circumvallation are often associated with ages (> Fig. 19.76). Villi displaced to the margins of the clot may be infarcted or fibrotic and avascular. Clinical significance. An intervillous hematoma is significant in that it marks a site of hemorrhage from the fetal into the maternal circulation. Intervillous hematomas occur at the bleeding site. These are common and usually

. Fig. 19.75 . Fig. 19.76 Chronic marginal hematoma. Old brown clot is prominent Intervillous (intraplacental) hematoma. A typical lesion at the margin of this circumvallate placenta composed of laminated fibrin and red cells 1040 19 Diseases of the Placenta

do not indicate that a significant fetal blood loss has occurred. Occasionally, a larger fetomaternal hemorrhage results in fetal anemia and fetoplacental hydrops if it occurs slowly and chronically, or sudden unexpected death if severe and acute. Severe fetal morbidity and mortality result from hemorrhages of 150 mL or more, but lesser amounts can be significant if chronic bleeding has occurred episodically. It has been suggested that the risk is greater when the mother and fetus have compatible ABO blood types, perhaps because of deficient clot formation at the site of bleeding [195]. There is often no clinical evidence of fetal distress or injury, even in cases resulting in IUFD. The amount of fetomaternal hemorrhage can be quantitated using the Kleihauer–Betke test. Flow cytometry may be more sensitive [31, 41]. Correlation between the severity of fetomaternal hemorrhage and size and number of intervillous hematomas is variable. . Fig. 19.77 In some cases of severe fetomaternal hemorrhage, there Massive subchorial hematoma. Thick fresh clot separates may be no hematoma and a site of bleeding may not be the chorionic plate from the underlying placental identified. parenchyma Small amounts of fetal blood leak into the maternal circulation in virtually every pregnancy. Fetomaternal hemorrhage may lead to isoimmunization of Rh negative mothers resulting in hemolytic anemia and immune abnormal fibrin(oid) in the placenta. Massive perivillous hydrops in the fetus. fibrin (MPF) deposits occur extensively throughout the placenta. In maternal floor infarct (MFI), the same type of fibrin-like material is concentrated in the basal plate. Massive Subchorial Hematoma (Breus’ Mole) Etiology. Currently two types of fibrinoid or fibrin-like material are identified in the placenta [46, 186]. Matrix- The massive subchorial hematoma has been defined as type fibrinoid is composed of oncofetal fibronectin, colla- coagulated blood, at least 1 cm in thickness, separating gen IV, laminin, and tenascin and usually does not include the chorionic plate from the underlying placenta over fibrin. It is consistently associated with, and apparently much of its area (> Fig. 19.77). These are generally rela- produced by, extravillous trophoblast. This type of fibri- tively fresh, red hematomas that distort the chorionic noid and associated trophoblast surrounds the villi in both plate and protrude as nodular masses into the amnionic MPF and MFI. Fibrin-type fibrinoid has immunohisto- cavity. They may dissect into the chorionic plate or extend chemical features of blood clot product and lacks the into the intervillous space, sometimes as far as the basal cellular trophoblast component. This form of fibrin accu- plate. This is a rare lesion, the incidence estimated to be mulates in maternal vascular underperfusion associated 0.53 per 1,000 deliveries in one large study [170]. The with decidual vasculopathy and the syndrome of pre- etiology and pathogenesis are unknown. Most authors eclampsia. agree that the hematomas are maternal. The fact that the intervillous space is involved would Massive subchorial hematomas are usually acute seem to implicate a maternal circulatory abnormality. because catastrophic reduction in placental function Isolated reports have identified a group of associations results in abortion or IUFD. Rarely babies are liveborn. including antiphospholipid antibody syndrome [166], polymyositis [3, 66], long-chain L-3-hydroxyacyl-coA dehydrogenase deficiency [96, 122], chronic intervillositis Maternal Floor Infarct (MFI) and Massive [189], and thrombophilias [9, 76]. Two separate reports, Perivillous Fibrin Deposition (MPF) however, document involvement of only one of dichorionic twins, suggesting a role for the fetus [56, Definition. These two lesions have many similar features, 143]. Whether the fibrinoid material that encases the differing mainly in the extent and distribution of terminal villi in these disorders reflects coagulation Diseases of the Placenta 19 1041

. Fig. 19.78 Maternal floor infarct (MFI). The maternal surface is diffusely discolored and firm (left). The basal villi are entrapped in fibrinoid (right) secondary to stasis of maternal blood in the intervillous space or aberrant secretion of matrix by villous trophoblast is unknown. Pathology. Wide strands and interlacing clumps of hard waxy pale tan or gray material accumulate as a thickened rind in the basal portion and ramify throughout the placenta. When most of the material is concentrated basally, the term MFI best applies, even though other parts of the placenta may also be involved . Fig. 19.79 (> Fig. 19.78). In MPF, the deposition of fibrinoid is Massive perivillous fibrin deposits. Hard waxy material is diffuse without preferential basal concentration, although distributed throughout the placenta including the maternal there may be patchy, sometimes extensive involvement surface of the maternal floor as part of the process (> Fig 19.79). Classification based on fibrin distribution is subjective. When classified by criteria proposed by Katzman and Genest, 44% of lesions did not conform to any of the categories [77]. Microscopically, the villi are widely separated by pink amorphous matrix-type fibrinoid containing numerous mononuclear trophoblast cells (> Fig. 19.80). The syncytiotrophoblast and capillary endothelium disappear from entrapped villi, but the villous stroma and villous outlines persist. Clinical significance. The reported incidence ranges from 0.5 to 5 per 1,000 deliveries [143]. First-trimester spontaneous abortions, sometimes recurrent, and mid- and late-trimester IUFD are common when the process is massive. Survivors are often delivered preterm with IUGR or develop long-term neurologic impairment [2]. MFI may recur in successive pregnancies. Villi entrapped in fibrinoid are isolated and non-functional. MFI and MPF represent the most severe end of a continuum. Red- . Fig. 19.80 line and Patterson observed that perivillous fibrin deposits Massive perivillous fibrin deposition (MFD). Villi are that entrapped more than 20% of villi in the central basal separated by and enmeshed in dense perivillous fibrinoid portion of the placenta (thought to be the primary region containing IT 1042 19 Diseases of the Placenta

of gas and nutrient exchange) were significantly associated (factor V Leiden, protein S or C deficiency, etc.) and with an IUGR and low placental weight [148]. Milder acquired thrombophilias (antiphospholipidemias, lupus cases of perivillous fibrin deposition enveloping 5–20% erythematosus). The occurrence of a thrombophilic state of terminal villi showed a lesser degree of similar compli- in the mother or newborn does not by itself predict vas- cations. Fibrin deposits at the placental margin or beneath cular lesions in the placenta or fetus, but it may represent the chorionic plate do not appear to have any adverse a risk factor in association with other conditions [10]. affect on the fetus. Pathology. Thrombi in large vessels of the chorionic plate or umbilical cord are often visible on gross inspection (> Fig. 19.81). Villi in the distribution of a large Fetal Circulation thrombosed vessel form a pale triangular area often with the same consistency as the surrounding parenchyma The fetal circulation of the placenta begins with the paired (> Fig. 19.82). Older lesions may be firmer, gray-white, umbilical arteries, branches of the fetal iliac arteries. and better delimited. Both thrombi and villous lesions are The umbilical arteries pass through the umbilical cord subtle, sometimes better estimated after formalin fixation. to the placenta where they branch on the chorionic plate In the majority of cases, the occluded vessels are small, and progressively rebranch in smaller stem villi ultimately reaching the villous capillaries where oxygen and nutrient exchange occur across vasculosyncytial membranes. The fortified blood flows through progressively larger veins in the stem villi and chorionic plate, reaching the umbilical vein, which passes back through the umbilical cord to drain into the sinus venosus of the fetus.

Fetal Thrombotic Vasculopathy (FTV) and Fetal Stem Vessel Thrombi

Definition. Clots that form in the fetal circulation obstruct blood flow to the villi, rendering them nonfunctional for the transfer of oxygen and nutrients from the mother to the fetus. Fetal thrombotic vasculopathy (FTV) refers to the . Fig. 19.81 changes in stem vessels and villi that follow occlusion and Chorionic vessel thrombus. This large chorionic plate vessel cessation of blood flow. Related lesions or terms with is occluded by a hard white thrombus similar connotations include fetal stem artery thrombosis [43], fibrinous vasculosis [165], intimal fibrin cushion [35], avascular terminal villi [158, 160], and hemorrhagic endovasculitis [161, 162]. Etiology. The rules of Virchow’s triad apply to throm- boses in the placenta. Stasis, vascular injury, and a hypercoagulable state, especially in combination, may result in clots in the fetal circulation. The most common cause of stasis is chronic partial or recurrent intermittent umbilical cord compression resulting from cord entanglements or anatomic factors (excessive length, hypercoiling, etc.). Stasis may also result from compression of velamentous vessels or in the meandering vascular spaces of chorangiomas or mesenchymal dysplasia. Vascular injury may be due to a fetal inflammatory response to . Fig. 19.82 infection, exposure to cytokines or meconium, or Fetal vascular obstruction. When a large fetal vessel is vascular inflammation in VUE (VUE with obliterative occluded, the downstream villous changes are visible as vasculopathy). Hypercoagulable states occur in inherited a pale wedge shaped area Diseases of the Placenta 19 1043

. Fig. 19.83 . Fig. 19.84 Fetal vascular obstruction. Red cell extravasation and Fetal vascular obstruction, villous stromal-vascular septation in fetal stem vessels karyorrhexis. Fragmented red cells are extravasated and there is nuclear debris in and around terminal villous capillaries. These represent early changes in villi associated with small clusters of distal fibrotic avascular downstream from an occluded vessel villi that are identifiable only microscopically. The evolution of large vessel thrombi is similar to that in other sites except organization does not occur. Recent thrombi expand the vessel, are attached, and may have a layered appearance. The endothelium disappears and spindle-shaped cells invade the thrombus producing a multilocular pattern (septation)(> Fig. 19.83). The erythrocytes fragment and blend into adjacent connective tissue. Smooth muscle may disappear and the wall may calcify. The villi distal to an occluded vessel show a sequence of distinctive alterations. Early changes include karyorrhexis of intravascular, endothelial, and villous stromal cells with destruction of capillaries and extravasation of red cells (> Fig. 19.84). The stroma is mineralized and may be hypercellular. This constellation of alterations, currently termed villous stromal vascular karyorrhexis, is identical to hemorrhagic endovasculitis as originally described by . Fig. 19.85 Sander [161]. Eventually, the villi become fibrotic with Fetal vascular obstruction, fibrotic avascular villi. Fibrotic bland, densely collagenized, hyalinized stroma (fibrotic avascular villi reflect fetal vessel occlusion, contrasting with avascular villi – FAV)(> Fig. 19.85). The surrounding the functional villi in this placenta from a liveborn baby syncytiotrophoblast is preserved and often knotted. Larger stem vessels distal to the occlusion show fibromuscular sclerosis. The thrombosed vessel resulting in these distal suggested terminology and criteria for the reproducible villous alterations may or may not be apparent depending diagnosis of fetal vascular obstructive lesions. They on the plane of sectioning. The same sequence of changes emphasized that the prognostic importance of fetal vas- occurs diffusely throughout the entire placenta after cular obstructive lesions is related to their severity, IUFD. The diffuse versus focal nature helps distinguish recommending that the diagnostic term fetal thrombotic involutional from pathologic vascular alterations. vasculopathy (FTV) be reserved for cases with severe Clinical significance. A committee of the Perinatal involvement defined as an average of >15 affected villi Section of the Society for Pediatric Pathology has per slide [138]. FTV is associated with neonatal 1044 19 Diseases of the Placenta

encephalopathy [97], cerebral palsy [130], IUFD, and fetal hypertension, and intrapartem hypoxia. Emphasizing asso- and neonatal thromboocclusive disease [83, 146]. FTV ciated wall edema, Scott et al. described a similar lesion, represents a major placental pathologic finding in IUGR fibrinous vasculosis, associated with stillbirth and other and discordant twin growth [140]. adverse outcomes [165]. Currently these large vessel lesions The negative effects of FTV occur in at least two ways. are classified as intimal fibrin cushions and are thought to First, the presence of thrombi in fetal circulation of the be pressure-related changes affecting vessels between the placenta indicates the potential for thrombi to occur else- actual site of fetal vascular obstruction and the terminal where either as a result of generalized activation of the villi [138]. They are often associated with other evidence of fetal coagulation system or direct embolism. Thrombi or fetal vascular occlusion in distal villi including fibrotic emboli and infarcts in the fetal brain, kidney, lung, and avascular villi and villous stromal vascular karyorrhexis. liver causing severe perinatal liver disease have been reported [25, 30, 83]. While there is definite connection Fetal Vascular Narrowing and Increased when clots in the placenta and fetus occur together, the Umbilical Vascular Resistance finding of FTV in the placenta alone is not predictive. The prevalence of systemic thrombi or infarcts among new- Doppler velocimetry studies have identified a group of borns with placental FTV is low [87]. A second form of growth-restricted fetuses with increased resistance to injury results from reduction of placental reserve caused fetal blood flow. In general, these placentas are small by loss of a significant fraction of the placental circulatory with distal villous hypoplasia. Small fetal stem arteries in bed. The occurrence of multiple lesions in the same pla- such cases have been described as narrowed with thick- centa compounds the prospects for injury [138, 145, 187]. ened walls [53], an observation supported by morpho- metric studies [42, 100]. When severe and in the setting of a strong supporting clinical history, these changes may be Intimal Fibrin Cushions and Fibrinous noted, but they overlap significantly with post-delivery Vasculosis arterial vasospasm. DeSa described intimal fibrin cushions composed of intra- mural fibrin deposits and proliferating fibroblasts forming Villous Edema and Villous Stromal non-occlusive intraluminal protrusions, some calcified, in Hemorrhage chorionic veins (> Fig. 19.86)[35]. The finding was attributed to local injury from elevated venous pressure. Clinical Abnormal accumulations of fluid in the villous stroma associations included low birth weight, abruption, maternal occur in three different contexts, each with distinct pathologic features. The first and most obvious form is the gross villous swelling of hydatidiform mole and certain other abnormal karyotypes (triploidy, monosomy X). A second pattern occurs in intermediate and terminal villi that are expanded by fluid in small discrete stromal lacunar spaces. Normal immature intermediate villi have a similar appearance but lack the expanded outlines caused by edema. This pattern of edema is associated with more severe grades and stages of ACA, most often in premature and VLBW newborns. In this context, severe edema is predictive of neurologic impairment [105, 138, 145]. Occasionally villous edema may occur with ACA at or near term or with abruption. The third category of villous edema occurs in fetoplacental hydrops in which all villi, terminal and stem, are diffusely edematous and relatively immature. Hemorrhage into the villous stroma (villous stromal . Fig. 19.86 hemorrhage) is thought to result from capillary rupture Intimal fibrin cushion. Fibrin(oid) is deposited in the wall of due to acute ischemia. It is most common in pre- large chorionic plate vessel. Mural calcification is consistent term placentas with clinically suspected abruption with a long-standing process (> Fig. 19.74). Diseases of the Placenta 19 1045

Chorangiosis results from trauma to the chorionic vessels during delivery, especially after excessive traction on the umbilical cord. Villous chorangiosis is a form of villous hypervascularity Occasionally, particularly if the umbilical cord is short or in which villi have expanded outlines and contain numer- entangled, sufficient traction may develop during labor to ous capillaries. Groups of more than 10 terminal villi with cause vessel rupture and significant fetal blood loss. This is more than 10 capillaries (actually more than 15 are usually virtually impossible to distinguish from the common third- present) involving several areas per microscopic section is stage hemorrhage. Laceration of chorionic plate vessels definitional [4](> Fig. 19.87). The capillaries are centrally during amniocentesis may also lead to subamnionic hem- located with a thin basement membrane, and pericytes are orrhage, sometimes severe. Older subamnionic fibrin clots absent. This condition is distinguished from congestion in form dome-shaped blisters containing a mixture of brown- which capillaries are prominent but normally distributed tinged fluid and fibrin. Lesions diagnosed by ultrasound and not numerically increased. between the 18th and 30th weeks of gestation have been Chorangiosis occurs in approximately 7% of pla- associated with elevated maternal alpha-fetoprotein levels, centas, usually at or near term, and often large with vaginal bleeding, polyhydramnios, and IUGR [33]. delayed villous maturation. The changes are common in diabetics. The occurrence of chorangiosis in pregnancies at high altitude suggests that it is an adaptive response to Fetal Membranes hypoxia [177]. While frequent in cases with abnormal outcome, chorangiosis has not yet been shown to be an The fetal membranes and contiguous placenta form a sac independent causative factor [110]. containing amnionic fluid in which the fetus grows and In diffuse, multifocal chorangiomatosis, villous capil- develops. The fetal membranes provide a crucial barrier laries are also numerically increased, but unlike chorangiosis, against infection, contain the amnionic fluid, and have they are accompanied by pericytes, involve stem villi, and metabolic functions including the modulation of events usually occur in immature placentas of less than 32 weeks. related to the onset of labor. The fetal membranes examined The clinical significance of this recently described and in their natural anatomic configuration after reconstructing uncommon lesion has not been fully defined [110]. the gestational sac as it exists in utero permits assessment of size, completeness, membrane insertion, and point of rupture. The distance from the point of membrane rupture to Subamnionic Hematoma the edge of the placental disk reflects the site of uterine implantation; the lower the implantation, the closer the A subamnionic hematoma lies between the amnion and membrane rupture site is to the disk. A configuration indic- chorion on the fetal surface of the placenta. It most often ative of low implantation should prompt consideration of associated conditions such as marginal hematoma or placenta accreta. Microscopic sections of the fetal membranes include fetal amnion and chorion and maternal decidua. The amnion is composed of amnionic epithelium and a connective tissue layer separated from the surrounding chorion by a loose spongy layer. The chorion is also composed of a connective tissue layer and a cellular layer containing chorionic type IT and atrophied villi. The most peripheral layer is maternal decidua (> Fig. 19.5).

Squamous Metaplasia

Foci of squamous metaplasia are slightly elevated, sometimes targetoid, pearly-white macules that tend to be most numerous at the site of cord insertion (> Fig. 19.88). . Fig. 19.87 Although they are generally no more than a few millimeters, Chorangiosis. Small, central villous capillaries are greatly rarely they may form larger plaques. Histologically, foci of increased squamous epithelium, with or without keratinization, have 1046 19 Diseases of the Placenta

a sharp transition with the surrounding amnionic epithe- fragments (> Fig. 19.89). The amnionic epithelium may lium. Squamous metaplasia has no clinical significance, but be totally or partially preserved or absent beneath the it is important to distinguish from amnion nodosum, nodules, and a layer of amnionic epithelium is commonly which it superficially resembles grossly. present over their surfaces. Etiology and clinical features. Amnion nodosum is associated with oligohydramnios. The particulate debris and Amnion Nodosum cellular elements from the fetal epidermis, oral cavity, urinary and gastrointestinal tracts, and the amnion itself are Definition and pathology. Amnion nodosum is a rare con- abnormally concentrated when amnionic fluid is scant and dition in which the amnionic surface is studded with are deposited on the amnionic surface. The cause of the small (1–5 mm), irregular, yellowish elevated nodules oligohydramnios varies. In many cases, a fetal urinary tract (> Fig. 19.89). These nodules are generally concentrated abnormality (renal agenesis or urinary tract obstruction) is on the chorionic plate, particularly around the insertion responsible for diminished fetal urine resulting in decreased of the umbilical cord, although they may occur anywhere on amnionic fluid. Oligohydramnios may occur in association the amnionic surface. The nodules are composed of amor- with IUGR or in the donor twin in the twin–twin transfu- phous, eosinophilic material containing cells and hair sion syndrome. Long-standing amniorrhea is less likely to result in amnion nodosum than decreased amnionic fluid production, presumably because in the former, the cellular and particulate debris are lost along with the amnionic fluid. Amnion nodosum is a reliable indicator of oligohydramnios that should prompt an investigation for fetal abnormalities known to accompany it, including urinary tract anomalies and pulmonary hypoplasia.

Amnionic Bands

Deﬁnition. Separation of the amnion and chorion results in amnionic fragmentation, shredding, and exposure of mesoblastic tissue, leading to the formation of thin ﬁbrous strands. These encircle fetal limbs, digits, neck, and umbil- . Fig. 19.88 ical cord, causing characteristic constriction, amputation, Squamous metaplasia. Squamous metaplasia is visible as and syndactyly (> Fig. 19.90). Some babies with character- elevated white macules istic amnionic band defects have additional structural

. Fig. 19.89 Amnion nodosum. Irregular elevated amnionic nodules (left) correspond to nodular deposits composed of degenerating cell fragments and hair embedded in amorphous granular material (right) Diseases of the Placenta 19 1047

. Fig. 19.90 Amnionic bands. Amnionic bands entangle limbs (a), digits (b), and the umbilical cord (c)

anomalies, usually severe, including major limb deficien- Pathology. Gross identification of the bands and strings cies, body wall or open cranial defects, short umbilical cord, may be difficult, sometimes facilitated by submersion of club feet, or internal abnormalities. The wide spectrum of the placenta in water. The surface of the placenta may be anomalies in this condition has been variously referred to as dull and slightly roughened, also subtle findings. Micro- the amnionic band syndrome, amnionic band disruption scopically, the bands usually consist of fibrous tissue, complex, early amnion rupture sequence, limb–body wall but occasionally amnionic epithelium is recognizable. complex, and amnion adhesion malformation syndrome. Amnion is absent from the placental surface and the 1048 19 Diseases of the Placenta

chorion is fibrotic. In cases associated with body wall or Microscopically, free meconium consists of amor- open cranial defects, the amnion may be continuous with phous green-brown material and anucleate squames. The the fetal skin at the site of the defect. Broad adhesions may amnionic epithelium exposed to meconium shows degen- occur between the placenta and fetus. erative changes including heaping, stratification, and Etiology. Multiple theories have been proposed to eventually nuclear pyknosis and necrosis. There may be explain the abnormalities in this syndrome. Torpin marked edema of the spongy layer. With time, meconium strongly espoused the concept that amnionic bands is engulfed by macrophages in the amnion, chorion, and cause the structural defects [182]. The widely variable decidua (> Fig. 19.92). In vitro studies indicate that nature of the defects has been attributed to the timing of meconium appears in amnionic macrophages in 1 h and amnionic rupture; early rupture is thought to result in in deeper chorionic macrophages within 3 h [99]. How fetal compression, tethering, or swallowing of bands, closely these observations approximate events in vivo is resulting in severe multisystem defects, whereas constric- unknown. Meconium is usually scant in the umbilical tion and amputation defects in limbs and digits have been cord due to the paucity of macrophages. As meconium attributed to amnionic rupture later in pregnancy. Malformations are thought to result when a band inter- feres with the normal sequence of embryonic development. Kalousek maintains that the extent of amnionic bands is as important as the developmental stage at which they occur in determining of the pattern of fetal involvement [72]. The etiology of amnionic rupture is unknown. Amnionic bands have been noted rarely after trauma, amniocentesis, and in women with connective tissue disorders. Others have postulated that the amnionic bands are secondary and that the more severe fetal abnormalities are the result of vascular disruption or a primary embryologic defect. Clinical significance. The recognition of amnion rupture and its consequences are important in counseling parents because the risk of recurrence is negligible. Unless accompanied by typical constriction/amputation lesions, . Fig. 19.91 major craniofacial or body wall defects may be difficult to Meconium stained placenta diagnose. An important clue is the variety and asymmetry of the fetal defects, which are unlike the pattern of any heritable syndrome. No two cases are alike.

Meconium Stain

Definition and frequency. Meconium, the intestinal con- tents of the fetus, is commonly passed into the amnionic fluid. The reported prevalence ranges from 7 to 25%. Meconium passage is especially common in post-term placentas, present in up to 31%. It is unlikely to be present before 30 weeks. Pathology. Meconium can often be identified on gross examination, its appearance correlating roughly with the chronicity of meconium passage. Meconium passed shortly before delivery may be recognizable as such. The . Fig. 19.92 membranes become progressively green-stained and Meconium reaction. Amnionic epithelium is heaped and slimy, with longer exposure, dark and edematous, and stratified with macrophages containing meconium in the eventually dull, muddy brown (> Fig. 19.91). subjacent stroma Diseases of the Placenta 19 1049 passes through the membranes and cord, it eventually may represent the major injurious factors. Meconium may, reaches the large fetal vessels where the toxic effect of its however, potentiate the effects of these underlying patholo- constituents can lead to apoptotic cell death of medial gies. For example, the growth of group B streptococcus is smooth muscle cells at the periphery of umbilical or cho- enhanced by the presence of meconium, and meconium has rionic plate vessels (> Fig. 19.93). been shown to inhibit neutrophil function in vitro. Meconium must be distinguished from hemosiderin, Meconium may induce injury directly (in amnionic generally a larger, more refractile, and yellowish crystalline epithelium and umbilical and chorionic plate vessels) and granule. Iron stain is helpful when an ambiguous pigment has also been demonstrated to cause vasoconstriction, is encountered. Lipochrome and nonhemosiderin, a potential cause of ischemia [5, 173]. There is some nonmeconium pigments of unknown composition, have evidence that meconium may interfere with surfactant been identified in a variety of diverse clinical situations. It function and, in high enough concentrations, have has been hypothesized that these pigments may represent a direct toxic effect on type II pneumocytes, possibly metabolites of remotely passed meconium. contributing to the meconium aspiration syndrome [27]. Clinical significance. Meconium staining has long been The role of meconium as the primary factor in the meco- perceived as an indicator of perinatal morbidity. Meconium nium aspiration syndrome is controversial. Autopsy passage has been significantly associated with parameters of studies indicate that in most cases, meconium aspiration fetal distress including low Apgar scores, umbilical artery syndrome is of prenatal origin, especially in relation to pH of 7.0 or less, respiratory distress, seizures in the first intrauterine infection and chronic hypoxia [52]. 24 h, and need for delivery room resuscitation. Neonatal morbidity of all kinds has been significantly associated with meconium stained as compared to clear amnionic fluid Gastroschisis [84]. Equally clear is that many infants, especially at term or post-term, pass meconium as a reflection of physiologic Gastroschisis is a defect in the paraumbilical abdominal maturity, usually unassociated with significant problems. wall through which bowel protrudes. This is distinguished The role of meconium as the primary factor in perinatal from the more common omphalocele in which bowel injury is, therefore, controversial. The most important con- protrudes into a saccular defect at the cord insertion sideration is the circumstance under which meconium is but remains enclosed in peritoneum and amnion. passed. Meconium staining is often superimposed on other Gastroschisis is characterized by extensive fine, uniform significant pathologies, especially chorioamnionitis, that vacuolization of amnionic epithelial cells (> Fig. 19.94).

. Fig. 19.93 . Fig. 19.94 Meconium induced vascular changes. The outer smooth Gastroschisis. The amnionic epithelium in gastroschisis muscle in the wall of this umbilical artery has undergone shows fine vacuolation. The epithelial stratification in this apoptosis in response to prolonged meconium exposure. case is the result of meconium passage The nuclei are pyknotic and the cytoplasm is dense and eosinophilic 1050 19 Diseases of the Placenta

Ultrastructural studies confirm that the vacuoles contain The normal umbilical cord contains two arteries and lipid, but the origin of the lipid is obscure. These amnionic one vein suspended in Wharton’s jelly, a loosely structured changes are not present in omphalocele. myxoid tissue covered by firmly attached amnion. Wharton’s jelly is derived from the extraembryonic mesenchyme and consists of myofibroblasts and abundant Extramembranous Pregnancy ground substance. The combination of loose gel and contractile cells helps maintain turgor and protect the Rarely the amnion and chorion rupture completely leav- vessels against compression. The umbilical cord is sup- ing the fetus to develop outside the membranes. The plied by oxygen and nutrients from the umbilical vessels. placenta is invariably circumvallate and the umbilical No other vessels or lymphatics are found in the normal cord is short. Amnion nodosum and membrane hemosid- umbilical cord. Most umbilical arteries are either fused erin deposits are common. Pulmonary hypoplasia is com- or connected via an anastomosis (Hyrtl’s anastomosis) mon and often fatal. Compression deformities may occur. generally within 1.5 cm of the placental insertion site. There is often a maternal history of amniorrhea and vag- This connection is important to equalize flow and inal bleeding. distribute blood uniformly to the placenta. The normal umbilical cord is spiraled, usually counterclockwise (counterclockwise/clockwise = 7:1), and the average num- Umbilical Cord ber of coils is 0.2 coil/cm. The spiral is established early in the first trimester as demonstrated sonographically. Normal Anatomy and Embryonic Development Vestigial Remnants Early in gestation, the blastocyst is filled with a loose mesh- work of extraembryonic mesoderm that cavitates centrally Vestigial remnants dating back to formation of the to form the chorionic cavity. The embryonic structures are connecting stalk and umbilical cord are common micro- connected to the trophoblastic shell by a bridge of extra- scopic findings. The presence of vestigial remnants has not embryonic mesoderm, the connecting stalk, and forerunner been correlated with congenital anomalies, maternal age, of the umbilical cord. The yolk sac and the allantois pro- race, gravidity, or gestational age at delivery. Remnants of trude into the connecting stalk. As the amnion enlarges, the the allantoic duct are frequent (about 15%) in the proxi- embryo prolapses into the amnionic cavity, progressively mal portion of the cord. They are lined by flat or cuboidal lengthening the connecting stalk. The allantoic vessels con- cells reminiscent of transitional epithelium, with or with- nect with vessels developing independently in the villi to out a lumen (> Fig. 19.95). Allantoic remnants are located establish the fetoplacental (chorioallantoic) circulation. between the umbilical arteries. Rarely, they are large

. Fig. 19.95 Allantoic (left) and omphalomesenteric remnants (right) Diseases of the Placenta 19 1051 enough to expand the cord or they may remain patent better assessment of the relationship between pathologic predisposing to urinary leakage from the cord stump. findings and significant alterations in blood flow. Traces of the omphalomesenteric duct, which connects the fetal ileum and the yolk sac in the early embryo, are infrequent, occurring in 1.5% of umbilical cords. These Cord Length remnants are usually discontinuous, located peripherally, and lined by columnar cells resembling intestinal epithe- Umbilical cord length is an important parameter most lium (> Fig. 19.95). Omphalomesenteric remnants some- accurately documented in the delivery room before the times have a muscular wall, occasionally containing cord shrinks or cord segments are removed for other ganglion cells, liver, pancreas, gastric, or small intestinal studies. Cord length declines by as much as 7 cm during mucosa. Vitelline vessels may accompany omphalome- the first few hours after delivery. Standards for cord length senteric remnants or they may occur in isolation. These relative to gestational age have been established [84]. The are usually paired but sometimes clustered, lined by endo- mean cord length at term is about 55–60 cm. thelium lacking a muscular coat. Omphalomesenteric Cord length reflects factors that influence its growth – remnants are of little clinical significance. They are rarely mainly tensile forces related to fetal activity and intrauter- associated with Meckel’s diverticulum, small intestinal ine conditions affecting fetal movement. Umbilical cord atresia, or intestinal protrusion into the cord that may be growth slows during the last trimester as room for fetal inadvertently clamped or cut. Cystic omphalomesenteric movement declines, although some cord growth occurs remnants are rare, more common in males (M:F = 4:1). normally until term. Conditions restricting fetal mobility The yolk sac remnant is commonly visible as a small white – amnionic bands, oligohydramnios, and crowding (mul- nodule between the amnion and chorion composed of tiple pregnancy) – are often associated with relatively amorphous basophilic material histologically. short cords. Infants with Down’s syndrome have short cords. Naeye has correlated short cord with subsequent motor and mental impairment [104]. Whether cord Stasis Problems and ‘‘Cord Accidents’’ length as an indirect indicator of fetal movement can be correlated ultimately with antenatal neurologic develop- The umbilical cord is a crucial lifeline between the fetus and ment deserves further study. placenta. Cessation of or diminished umbilical blood flow Extremes of cord length are associated with potentially can result in severe fetal compromise or death. Umbilical adverse outcomes. Some consideration of relative as well flow may be compromised by mechanical factors (compres- as absolute cord length is appropriate. For example, a long sion), vessel damage (trauma, inflammation, or meco- cord with extensive looping may function as a relatively nium), or thrombosis. Cord abnormalities with the short cord. potential for obstruction of blood flow – abnormal coiling, stricture, abnormal length, true knots, entanglements, prolapse, and velamentous insertion – have been associated Short Cord with increased risk of IUFD, IUGR, and neurologic injury [12, 13]. Many of these conditions are related; true knots Definition and frequency: Gardiner’s calculation that and excessive coiling commonly occur in long cords, and a normal vertex delivery requires a minimum cord length stricture almost always occurs in a hypercoiled cord. of 32 cm provides a common definition of an abnormally Chronic partial or intermittent flow obstruction may be short cord [49]. Using this definition, between 0.4 and evidenced by umbilical, chorionic, or stem vessel dilata- 0.9% of umbilical cords are abnormally short. Berg and tion and thrombosis, intimal fibrin cushions, and/or vil- Rayburn found that 2% of cords are less than 35 cm [19]. lous alterations reflecting fetal vascular occlusion (FAV/ Clinical significance: Unduly short cords have been villous stromal–vascular karyorrhexis) [113]. Based on linked to fetal distress in some cases, although blood pH these findings, non-acute cord compression has been and base deficit values in short cords are reportedly the implicated in over half of unexplained fetal deaths. Acute same as in cords of normal length [19]. In the absence of flow obstruction may supervene when a knot or entangle- fetal anomalies, short cords have been associated with low ment tightens during delivery or there is cord prolapse. Apgar scores, neonatal hypotonia, and need for resuscita- Doppler studies have confirmed that cord obstruction and tion. Short cords may be associated with rupture or hem- compression impede venous return. Increasingly sophis- orrhage, delayed second stage of labor, abruption, ticated imaging techniques provide opportunities for subamnionic hemorrhage, and uterine inversion. At the 1052 19 Diseases of the Placenta

extreme, there may be complete or near-complete cord absence (acordia) characteristically associated with fetal anterior abdominal wall defects that are directly attached to the placenta.

Long Cord/Entanglements/Prolapse

Definition and frequency. Excessively long cords have been variously defined as greater than 70 [13], 80 [19], or 100 cm [84]. Cord entanglements encircling the fetal neck, body, and extremities are common, occurring in about 23% of deliveries, but they are much more common in excessively long cords. Umbilical cord prolapse is an obstetric emer- gency defined as presentation of the cord in advance of the . Fig. 19.96 presenting part, occurring in 0.25–0.5% of deliveries. True knots. Long cord with two true knots (Used with Clinical significance. Long cords have been associated permission of the American Registry of Pathology/Armed with IUGR, IUFD, brain imaging abnormalities, and poor Forces Institute of Pathology) neurologic outcomes [12, 13]. Histological evidence consistent with venous obstruction has been described in the placenta. Abnormally long cords are also associated with excess knotting, hypercoiling, entanglements, and prolapse. Most cord entanglements do not have adverse outcomes, but some may result in cord compression. Tight entanglements have been associated with low Apgar scores and stillbirths. Babies with sonographically documented nuchal cords have higher rates of cesarean section and NICU admission. Nuchal cords have been demonstrated as a cause of IUGR, indicating that the deleterious effect is long term in some cases [175]. Tight nuchal cords restricting venous return may result in neonatal anemia or even hypovolemic shock. Cerebral palsy has been linked to tight nuchal cords at delivery [109]. Cord prolapse has a perinatal mortality rate of 20% [91]. . Fig. 19.97 Pathologic changes. Constriction of the umbilical cord False knot and the encircled fetal part may be dramatic in some cord entanglements. Cord compression may be associated with edema, venous congestion, hemorrhage, and thrombosis and in association with excess amniotic fluid. They occur of umbilical or large chorionic plate vessels and/or villous with equal frequency in abortions and term deliveries abnormalities reflecting fetal vascular occlusion. indicating that they probably develop early in pregnancy when there is ample opportunity for movement. Pathology. Umbilical cord knots should be assessed for Knots evidence of chronicity, tightness, and circulatory compromise. In long-standing tight knots, there is grooving and Frequency and etiology. Between 0.35% and 0.5% of umbil- loss of Wharton’s jelly with constriction of blood vessels, ical cords contain true knots. True knots (> Fig. 19.96) changes that persist when the knot is untied. Thrombosis should be distinguished from false knots, which are focal of umbilical or chorionic plate vessels, sometimes calci- accentuations of the vascular spiral, a varicosity, or excess fied, and villous alterations reflecting fetal vascular Wharton’s jelly (> Fig. 19.97). True knots are thought to occlusion indicate chronic vascular obstruction. Acutely be related to fetal movement and are increased in long tightened knots may be associated with venous distention cords, male fetuses, monoamnionic twins, multigravidae, distal to the knot, edema, and villous vascular congestion. Diseases of the Placenta 19 1053

Clinical significance. True knots are associated with (> Fig. 19.100). Thrombosis of umbilical and chorionic an overall perinatal mortality rate of 8–11%, attributable plate vessels, intimal fibrin cushions, and vascular calcifi- to their potential for fetal circulatory obstruction cation suggest a chronic process in some cases. Hypocoiled (> Fig. 19.98). Either an acutely tightened or long- cords are often thin with decreased Wharton’s jelly. standing knot may be responsible for intrauterine or Clinical significance. Hypercoiled cords have the intrapartum fetal death [64]. False knots are generally potential for blood flow obstruction. Hypercoiling has of no clinical significance with only rare instances of been associated with adverse fetal outcome, including thrombosis. fetal IUGR, intolerance of labor, and IUFD [32]. Absent or minimal coiling is associated with fetal anomalies, chromosomal errors, fetal distress, and increased fetal Torsion and neonatal morbidity and mortality.

Definition and frequency. The normal umbilical cord aver- Stricture ages about 0.2 coils/cm (coiling index = no. of coils per cord length). Hypercoiled cords are generally considered Definition and etiology. An umbilical cord stricture is to be those in which the coiling index is >0.3 coils/cm, and a sharply defined, usually short narrowed segment with hypocoiled cords are those in which the coiling index is decreased Wharton’s jelly and vascular constriction <0.1 coils/cm [84]. In one study, 7.5% of 120 unselected placentas had hypocoiled cords and 20% had hypercoiled cords [92]. About 4–5% of cords are noncoiled. Umbilical cord coiling is thought to reflect fetal movement; it is decreased in association with uterine constriction or fetal abnormalities that affect movement. Hypocoiled cords have been reported to occur more commonly in twins and in babies with chromosomal abnormalities. Hypercoiling is more common in long cords, male fetuses, multigravidae (presumably due to more room for fetal movement), and in association with maternal cocaine use. Pathology. Hypercoiling may be localized or affect the . Fig. 19.99 entire cord (> Fig. 19.99) or be associated with stricture Hypercoiled cord

. Fig. 19.98 . Fig. 19.100 Tight knot resulting in intrauterine fetal demise (IUFD). Hypercoiled cord with stricture and intrauterine fetal (Used with permission of the American Registry of demise (IUFD). (Used with permission of the American Pathology/Armed Forces Institute of Pathology) Registry of Pathology/Armed Forces Institute of Pathology) 1054 19 Diseases of the Placenta

(> Fig. 19.100). The etiology is unknown, but it rarely Rupture occurs outside the setting of excess torsion. Alternatively, it has been hypothesized to be the result of a primary Complete cord rupture is very rare. Most cord ruptures deficiency of Wharton’s jelly, perhaps an exaggeration of complicate precipitous delivery, but rarely rupture may the normal gradual loss of Wharton’s jelly at the fetal end occur in the early stages of labor or before labor begins. of the umbilical cord. Short and velamentously inserted cords, trauma, or Pathology. Strictures are most common at the fetal end inflammation are proposed etiologic factors. of the cord, although occasionally they may occur at the placental end or elsewhere. They are usually associated with excessively long and hypercoiled cords. Many are Insertion seen in association with macerated fetuses, although the abnormality is not confined to abortions. The strictured Velamentous Insertion and Membranous segment shows decreased Wharton’s jelly and vascular, Vessels especially venous, compression. Placental surface vessels may be thrombosed. Definition and frequency. In velamentous insertion, the Clinical significance. Umbilical cord strictures are often cord inserts into the fetal membranes. associated with abortion [115]. Strictures have recurred in Velamentous insertion is a common anomaly, occur- successive pregnancies and have been proposed as a cause ring in about 1% of placentas. It is greatly increased in of non-immune hydrops. multiple pregnancies, extrachorial placentas, and in single-artery cords. Velamentous insertion is also reportedly increased in association with cigarette smoking and Cord Diameter advanced maternal age. An associated condition, vasa previa, occurs when membranous vessels in the fetal Umbilical cord diameter is affected by the number of membranes present in advance of a fetal part. vessels and the amount and fluid content of Wharton’s Pathology. After insertion, the umbilical vessels usually jelly. Nomograms generated from uncomplicated preg- branch in the fetal membranes (> Fig. 19.101). Having nancies indicate a progressive increase in sonographic lost their protective covering of Wharton’s jelly and cord diameter and cross-sectional area until 32 weeks unsupported by underlying villous tissue, membranous gestation with a decline thereafter presumably due to vessels are vulnerable to injury – traumatic rupture, hem- a reduction in fluid content of Wharton’s jelly. Patel and orrhage (> Fig. 19.102), compression, and thrombosis, colleagues established the normal cord circumference to especially when they traverse the cervical os in advance be 37.7 Æ 7.73 mm [114]. Silver and colleagues deter- of the fetus. The length of membranous vessels provides mined that cord diameter ranged from 1.25 to 2.00 cm and circumference from 2.4 to 4.4 cm [174]. The factors that determine the amount of Wharton’s jelly and its water content are poorly understood. More cord jelly and vascular spiraling have been associated with better fetal outcome, while compression patterns on fetal heart tracings occur more often in cords with decreased fluid content [174]. A thin (‘‘lean’’) cord with decreased or absent Wharton’s jelly may be associated with IUGR. At present, a lean cord is defined as one with a cross-sectional area less than the tenth percentile as assessed sonographically or 8 mm or less along its entire length [121, 139]. Diminished size appears to be due to a reduction in Wharton’s jelly. Lean cords tend to have a lower coiling index and reduced umbilical vein flow normalized for fetal weight [36]. Cord edema, focal or diffuse, occurs inconsistently in a variety of clinical situations, especially diabetes, but often the cause is unknown. Edema is more common in . Fig. 19.101 prematures. Velamentous insertion Diseases of the Placenta 19 1055

occur suddenly during labor. Although bleeding is most common from membranous vessels near the os at the time of labor, bleeding may also occur antepartum and from vessels located higher in the uterus. Thrombosis of membranous arteries and veins has been associated with major fetal thromboembolic events and fetal death. Velamentous cord insertion also provides a marker for poor placentation with decreased placental vascularization. This may explain its reported association with low birth weight, low Apgar scores, and abnormal fetal heart- rate patterns. Velamentous cord insertion has also been associated with congenital anomalies, occurring in 8.5% of infants and in as many as 25% of spontaneous abortions . Fig. 19.102 with velamentous cords. The structural anomalies associ- Velamentous insertion. A ruptured membranous vessel is ated with velamentous cord insertion are deformations associated with surrounding hemorrhage (Used with not malformations or disruptions indicating that they permission of the American Registry of Pathology/Armed and the velamentous insertion are both the result of com- Forces Institute of Pathology) petition for intrauterine space. Velamentous cord insertion is significantly more common in monochorionic gestations with the twin–twin transfusion syndrome than in those without it. one measure of the degree of their vulnerability. Membra- nous vessels are not limited to velamentously inserted cords but may arise aberrantly from marginally or even Marginal Insertion centrally inserted cords, and they regularly supply succenturiate lobes. As a site of significant pathologic Definition and frequency. Umbilical cord insertion at the alterations, all membranous vessels should be inspected edge of the placental disk is termed a marginal or carefully and included in sections for microscopic exam. Battledore insertion. Marginal insertion occurs in about Rarely a velamentously inserted cord retains its Wharton’s 7% of placentas and is hypothesized to develop via the jelly, running in the membranes before its vessels branch same mechanism as velamentous insertion (abnormal pri- (interposito velamentosa). mary implantation versus trophotropism). Etiology. Velamentous cord insertion may be due to Clinical associations. The clinical significance of mar- malpositioning of the blastocyst at implantation with ginal insertion is debated. Marginal insertion has been consequent aberrant body stalk – placental disk orienta- reported to occur with increased frequency in abortions tion (polarity theory). Alternatively, velamentous inser- and malformed infants and in association with neonatal tion may result when the placenta ‘‘moves’’ from its initial asphyxia and PTL, although these associations have not implantation site, leaving the cord insertion behind been confirmed by others. Peripheral cord insertion (trophotropism theory). This placental remodeling, prob- (velamentous, marginal, and markedly eccentric) has ably in response to uterine crowding and/or maternal been associated with discordant growth and SGA in vascular supply, involves simultaneous atrophy on one twins [140]. aspect and growth/expansion on the other. The increased frequency of velamentous cord insertion in multiples, in uteri with structural defects and foreign bodies and the sonographic documentation of eccentric placental expan- Furcate Insertion sion with conversion of placenta previa to a higher uterine position support the trophotropism theory. In furcate insertion, the cord loses Wharton’s jelly before Clinical features. Velamentous cord insertion has sev- insertion, leaving the umbilical vessels unsupported eral important clinical associations. The best-documented (> Fig. 19.103). Furcate cords may insert velamentously complications are related to the vulnerability of membra- or into the placental disk. nous vessels. Vessel compression with severe fetal distress The unsupported vessels are subject to the same com- or laceration with blood loss, even exsanguination, may plications as membranous vessels. 1056 19 Diseases of the Placenta

Tethered Insertion (‘‘Amnionic Web’’) abnormality. In prospective studies of consecutive deliveries, the frequency of single umbilical artery is consis- Amnionic webs or chorda are amnionic folds that encase tently somewhat less than 1%, although the frequency is the cord at the insertion site (> Fig. 19.104). considerably higher in perinatal autopsy studies (2.7– Large tight amnionic webs may limit mobility of the 12%) and in spontaneous abortions (1.5–2.7%). The fre- cord, potentially compromising blood flow. quency of single umbilical artery is higher in white women, diabetic mothers, multiples, and chromosome abnormalities especially trisomies. Umbilical Vessels The likelihood of diagnosing single umbilical artery is increased when fixed versus fresh cords are examined, and Numerical Variation histologic exam provides the most accurate means of establishing the diagnosis. Cord vascularity should be Single Umbilical Artery assessed at least 3–5 cm from the placental insertion site Definition and frequency. The presence of a single umbili- because the umbilical arteries frequently fuse close to the cal artery (SUA) is a common and important cord placenta. Etiology. Whether single umbilical artery is due to primary aplasia or secondary atrophy has long been debated. When specifically sought, histologic evidence of vascular remnants is demonstrable in some single artery cords. The higher incidence of single umbilical artery in fetuses as compared to early embryos provides circum- stantial evidence that single umbilical artery may be an acquired defect. Pathology. Muscular or elastic remnants of an atrophied vessel are identified in some cases. Single artery cords are commonly associated with velamentous insertion (as high as 12%), circumvallation, and a magistral pattern of chorionic blood vessels. On occasion, two umbilical arteries are present but are of markedly different size. A difference of at least 1 mm in umbilical artery diameter as established sonographically is considered discordance [120](> Fig. 19.105). Marked umbilical . Fig. 19.103 Furcate insertion

. Fig. 19.104 . Fig. 19.105 Tethered insertion Discordant umbilical arteries Diseases of the Placenta 19 1057 artery discordance may be associated with fetal Vascular Abnormalities anomalies similar to those encountered with single umbilical artery. Segmental Thinning Quereshi and Jacques reported segmental thinning of Clinical Significance Congenital malformations. There is umbilical vessels with virtual absence of the media in a well-documented association between single umbilical 1.5% of consecutively examined placentas [119]. The artery and fetal malformations, but there is no particular umbilical vein was involved in the majority of cases, organ or specific abnormality characterizing this asso- although on occasion, one or both arteries exhibited iden- ciation. Any organ system may be affected, and tical changes. Both superficial and medial aspects of the malformations are frequently multiple. Congenital vessels exhibited wall deficiencies. Segmental vascular malformations are most numerous and most severe in thinning was accompanied by fetal malformations in stillborn and aborted babies and those dying in the neo- a significant number of cases, and there was a high inci- natal period. Infants with single artery cords but no dence of fetal distress. detectable abnormalities at birth who survive the neonatal period are unlikely to have other significant abnormalities Meconium-Induced Necrosis detected subsequently. Single umbilical artery is almost Long-standing meconium exposure may induce muscle invariable in sirenomelia and acardiac fetuses. Whether necrosis in umbilical and chorionic plate vessels. single umbilical artery plays a role in the development of Myonecrosis usually involves the superficial aspects of congenital malformations or is just another manifestation the arteries closest to the surface. The necrotic cells are of them is unclear. rounded with dense eosinophilic-smudged cytoplasm and Perinatal mortality. The perinatal mortality rate of pyknotic nuclei (> Fig. 19.93)[82]. Meconium-associated infants with single umbilical artery is greatly increased vascular necrosis has been linked to cerebral palsy [145]. (11–41%). This is attributable to associated major In addition to vascular damage, meconium has been malformations in most instances, although otherwise nor- shown to cause vasoconstriction of umbilical vessels in mal infants with single umbilical artery have an increased vitro [5]. perinatal mortality rate as well. The sonographic demonstration of decreased Wharton’s jelly in single artery cords Ulceration may contribute to cord vulnerability. Linear ulceration of Wharton’s jelly with vascular necrosis, Low birth weight. Single umbilical artery is associated aneurysmal dilatation, and rupture may result in with low birth weight even when infants with mal- intraamnionic hemorrhage, profound fetal anemia, and formations are excluded from analysis. fetal death in utero (> Fig. 19.106). These cord anomalies

. Fig. 19.106 Ulceration of Wharton’s jelly. Necrosis of Wharton’s jelly with thinning and rupture of umbilical vessels resulted in IUFD in this baby with duodenal atresia (Used with permission of the American Registry of Pathology/Armed Forces Institute of Pathology) 1058 19 Diseases of the Placenta

have been described in association with fetal intestinal Etiology. In the great majority of cases, an obvious atresia. etiology is not apparent. Rarely, hemorrhage has a demonstrable origin from an umbilical vein or artery, Thrombosis and origin from omphalomesenteric vessels has been pro- Definition and frequency. Thrombosis of umbilical vessels posed. Rupture of a varix, traumatic damage at the time of may be occlusive or non-occlusive, and is often associated amniocentesis or percutaneous umbilical cord sampling, with similar changes in chorionic plate or stem villous or inflammation or structural anomalies of a vessel wall vessels. Thrombosis of umbilical cord vessels is uncom- have been suggested as possible mechanisms. mon, occurring in 1 in 1,300 deliveries, 1 in 938 perinatal Pathology. Most umbilical cord hematomas present as autopsies, and 1 in 250 high-risk pregnancies [164]. red-purple fusiform swellings (> Fig. 19.108). They are Etiology. Thrombi may be associated with cord com- usually single, but may be multiple or even involve the full pression, abnormal coiling, knots, stricture, hematoma, length of the umbilical cord. They are generally confined to inflammation, anomalous insertion, amnionic bands, or the cord, but on occasion, they may rupture into the entanglements. Other factors such as thrombophilic states amnionic cavity. Small collections of fresh blood usually could act synergistically to precipitate thrombosis. In reflect cord blood sampling or traction at the time of delivery. many instances, the etiology is obscure. Clinical significance. A perinatal mortality rate in the Pathology. Thrombi more commonly involve the range of 40–50% has been reported in association with umbilical vein alone (71%) with a lesser frequency of umbilical cord hematoma. Fetal death may be due to combined vein and artery thrombosis (18%) or arterial blood loss or umbilical vascular compression with circu- thrombosis alone (11%). Thrombi may be associated with latory compromise. vessel calcification and necrosis (> Fig. 19.107). The chorionic plate and stem villous vessels may be similarly Hemangioma affected. Definition. Hemangiomas are benign lesions composed of Clinical significance. Fetal morbidity and mortality is proliferating vessels sometimes associated with marked high, particularly with occlusion of both umbilical arter- myxoid degeneration of Wharton’s jelly (angiomyxoma). ies. Thrombi may embolize to the fetus causing infarcts in fetal organs or they may result in the loss of a significant fraction of the fetoplacental circulatory bed. Thrombi have also been associated with cerebral palsy, massive fetomaternal hemorrhage, IUGR, and IUFD.

Hematoma Deﬁnition and frequency. Umbilical cord hematomas are accumulations of blood in Wharton’s jelly. They are uncommon.

. Fig. 19.107 . Fig. 19.108 Thrombosed umbilical artery. This thrombosed umbilical Localized cord hematoma. (Used with permission of the artery, cause undetermined, is visible as a dark spiral and American Registry of Pathology/Armed Forces Institute of was completely necrotic (Used with permission of the Pathology) American Registry of Pathology/Armed Forces Institute of Pathology) Diseases of the Placenta 19 1059 Preeclampsia

Definition. A previously normotensive pregnant woman whose blood pressure reaches 140/90 mm Hg or greater after 20 weeks gestation on at least two occasions has pregnancy-induced hypertension. The addition of proteinuria (1+ or greater on urine dipstick confirmed by a 24 h collection containing 300 mg of protein) means that preeclampsia has occurred. Severe preeclampsia indicates the addition of one or more of the following: blood pressure over 160 mm Hg systolic or 110 mm Hg diastolic; proteinuria greater than 5 g/24 h or 3+ or greater on two dipstick evaluations at least 4 h apart; headache; visual . Fig. 19.109 disturbances, epigastric, or right upper quadrant pain; Umbilical cord hemangioma. (Used with permission of the oliguria; thrombocytopenia or liver enzyme elevation; American Registry of Pathology/Armed Forces Institute of fetal growth restriction; and/or pulmonary edema. The Pathology) HELLP syndrome is a form of severe preeclampsia with a specific triad of findings including hemolysis, elevated liver enzymes, and low platelet count. Seizures signify the onset of eclampsia. Delivery of the placenta, often prema- Pathology. Hemangiomas present as fusiform swelling ture, is the only effective medical intervention. of the umbilical cord usually at the placental end. They Etiology. The spiral arteries that supply maternal blood can attain substantial size (up to 900 g in one report) to the placenta must expand to accommodate the growing (> Fig. 19.109). Microscopically, these benign tumors placentofetal unit. This is normally accomplished by tro- show features similar to benign hemangiomas at other phoblastic remodeling of spiral arteries. A failure of this body sites. process results in decidual vasculopathy, reduced maternal Clinical significance. Hemangiomas with myxoid flow, placental ischemia, and the maternal syndrome of degeneration (angiomyxoma) can be associated with preeclampsia [90]. hemorrhage, increased alpha fetoprotein levels, and rarely In preeclampsia, there is generalized maternal endo- nonimmune fetal hydrops, presumably due to high output thelial dysfunction thought to be caused by soluble factors cardiac failure. produced by ischemic trophoblast. Endoglin and sFlt-1 are two factors that have been implicated. Both appear Aneurysm prior to disease onset and cause endothelial dysfunction Umbilical cord aneurysms are rare. They may be so large and hypertension in the mother. These factors act by as to compress adjacent vessels resulting in fetal death. neutralizing the angiogenic and vasodilatory effects of Umbilical artery aneurysm has been reported in trisomy vascular endothelial growth factor and placental growth 18 [168]. factor produced by the placenta [102]. When endoglin and sFlt-1 are overexpressed in an experimental rat model, the result is severe proteinuria, hypertension, and growth restriction as well as thrombocytopenia and liver dysfunc- Clinical Syndromes and Their Pathologic tion [185]. Correlates in the Placenta Pathology. Correlation between placental lesions and severity of maternal symptoms is poor. Two types of Placentas come to the pathologist with limited clinical abnormal placentas are associated with preeclampsia. data supplied by the obstetrician. The diagnoses or prob- The first and most common is the small placenta with lems listed do not necessarily provide insight into the decidual vasculopathy, especially acute atherosis, the path- nature of the pathologic abnormalities that the pathologist ologic changes characteristic of maternal vascular should look for. Here follow definitions of common clin- underperfusion, and thin umbilical cord. Less common ical conditions that lead to submission of a placenta for is the large placenta associated with a heterogenous group pathologic examination together with the relevant patho- of conditions including diabetes mellitus, placental logic lesions. hydrops, multiple gestation, and hydatidiform mole. 1060 19 Diseases of the Placenta

Essential Hypertension occur before the 34th week. The category of ‘‘VLBW’’ infants refers to live-born infants weighing between 500 Patients with preexisting hypertension not complicated by and 1,500 g. These are at greatest risk of neonatal death, superimposed preeclampsia may have similar but less neurologic injury, and pulmonary immaturity. PTB pronounced abnormalities in the villi. Arteriosclerotic occurs in 12–13% of all pregnancies in the United States. changes in the uterine or intramyometrial arteries may The result is a 40-fold increase in perinatal morbidity and be sufficient to produce some degree of placental ischemia. mortality. Most PTBs are due to ACA or preeclampsia. The two Diabetes Mellitus pathologic subgroups show very little overlap [8, 59]. ACA is most common, occurring in 61% of premature placentas delivered within 1 h of membrane rupture [58, Placentas associated with uncomplicated maternal diabe- 59]. ACA is more common in earlier PTB. Lesions tes mellitus vary. In about half of cases they appear nor- resulting from impaired blood flow are more common in mal, grossly, and microscopically. Correlation between later PTB [61]. Premature labor and delivery also have placental findings, metabolic control, and clinical severity a significant correlation with decidual hemorrhage, which are poor. When they are abnormal, diabetic placentas tend may directly initiate prostaglandin release and labor. to be large and heavy, with large and edematous umbilical cords. Villi in the larger placentas often show chorangiosis and distal villous immaturity, large distal villi with Post-Term Pregnancy increased central capillaries, macrophages, and interstitial fluid (> Fig. 19.110). Placental, fetal, and neonatal A gestation longer than 42 completed weeks (294 days) is thrombi are more frequent, a manifestation of the considered post-term. Perinatal mortality is increased. thrombophilia associated with diabetes. When compli- The postmature newborn has a characteristically slender, cated by hypertension or preeclampsia, the placenta may elongated body and limbs, dried, wrinkled, often meco- be small with evidence of low maternal flow. nium-stained skin, long fingernails, and an apprehensive expression. Meconium staining is more common in post- Preterm Birth, Preterm Labor, and Preterm term placentas, but otherwise there are no distinctive or Rupture of Membranes definitive pathologic changes in the placenta [17].

A term birth takes place between 37 and 42 weeks of gestation. The most severe sequelae for the newborn Fetal Growth Restriction, Intrauterine Growth Restriction (IUGR)

Prenatal evaluation of fetal growth is based on ultrasound measurements of abdominal circumference, head circumference, biparietal diameter, and femur length (among others), which may also be used to estimate fetal weight [152]. IUGR is a significant risk factor for poor outcome and stillbirth [184]. IUGR is symmetric when head and abdominal measurements are decreased proportionately, and asymmetric when there is a greater decrease in abdominal girth. When IUGR is identified, Doppler studies of blood flow through the umbilical cord, middle cerebral artery, or other sites may be obtained. Absent or reduced umbilical artery blood flow is a significant adverse finding, which may begin early and persist for weeks until delivery [154]. Infants whose birth weight lies below an . Fig. 19.110 expected percentile for gestational age (which may be Distal villous immaturity. Increased numbers of large distal arbitrarily set at the third, fifth, or tenth percentile) are villi with increased capillaries and evenly distributed classified as small for gestational age (SGA) and qualify as interstitial fluid growth-restricted. Diseases of the Placenta 19 1061

Maternal factors that contribute to IUGR include pre- retroplacental hematomas, meconium-associated vascular eclampsia, hypertension, diabetes mellitus, thrombo- necrosis, and severe chorioamnionitis, especially with philias, extreme malnutrition, chronic renal disease, intense chorionic vessel inflammation [145, 150]. Chronic tobacco and other drug abuse, and poor obstetric history lesions include chorionic vessel thrombi, fetal thrombotic in general. Fetal factors include chromosomal anomalies vasculopathy [97, 107], especially with cord abnormalities (including confined placental mosaicism), congenital [128], placental or fetal hydrops, diffuse chronic villitis, malformations, and multiple gestation [190]. Placental especially with obliterative fetal vasculopathy, diffuse lesions associated with IUGR include: (1) vascular lesions chorioamnionic hemosiderosis, and massive perivillous that reduce maternal blood flow (decidual vasculopathy or fibrin deposits [130]. chronic abruption), (2) vascular lesions that reduce fetal blood flow, (FTV, large chorangiomas, or umbilical cord abnormalities), and (3) lesions that greatly reduce the Fetal and Placental Hydrops amount of functional placenta (extensive chronic villitis, MPF, MFI, or multiple infarcts.) [167] Hydrops is a state of marked generalized edema, with accumulation of fluid in subcutaneous tissue, body cavi- ties, placenta, and umbilical cord. Most cases are now Neonatal Encephalopathy (NE), Cerebral detected by prenatal ultrasound. Prenatal investigation to Palsy (CP), and ‘‘Birth Asphyxia’’ assign a specific cause is urgent because many cases are potentially treatable. In fatal cases, determination of the Historically, the occurrence of abnormal neurologic find- cause is still important for parental counseling and for ings in the first week of life was assumed to have followed appropriate management of future pregnancies. Even in a period of asphyxia (severe hypoxia with metabolic aci- the absence of specific changes in the placenta, the pathol- dosis) during labor and delivery. This concept led to such ogist has a primary role in coordinating other forms of clinical terms as ‘‘birth asphyxia’’ and ‘‘hypoxic-ischemic laboratory testing, including cytogenetics, immunologic encephalopathy.’’ While episodes of pure hypoxia do and microbiologic studies, immunohistochemistry, and occur (acute abruption is a good example), other factors – fluorescence in situ hybridization. intrauterine infection and other acute and chronic placental Immune hydrops, caused by maternal iso- lesions – are much more common. The transient clinical immunization to the Rh (mainly D) antigen expressed state, characterized by hypotonia, apnea, coma, and sei- by the fetal red blood cells, still occurs, but is now rare zures, is now called neonatal encephalopathy. The incidence due to anti-D gammaglobulin (Rhogam) prophyllaxis. varies from 6 to 8 per 1,000 births. Nonimmune hydrops is now more common, but still infre- Cerebral palsy, by contrast, is a chronic, non- quent, with incidence figures from 1 in 1,400 to 1.34 per progressive neurologic disorder, most often a form of 1,000 live births [183]. There are numerous causes of spastic diplegia, hemiplegia, or quadriplegia, with an inci- non-immune placental or fetal hydrops. The main patho- dence of 2 per 1,000 births. It is usually not diagnosed physiologic categories are cardiac failure, anemia, and much before age 2 years, certainly not at the time of hypoproteinemia. Among the most important lesions are delivery. Approximately 50% of cases develop after full- cardiac malformations, chromosomal anomalies (45XO, term birth following an apparently normal gestation. The trisomies 21 and 18), thoracic lesions (congenital cystic remainder are divided between VLBW infants (<1.5 kg) adenomatoid malformation, pulmonary sequestration, or and a heterogeneous group of low-birth-weight and near- tumors), anemias (parvovirus infection or fetomaternal term infants, some with IUGR [133]. Extreme prematurity hemorrhage), fetal infections (TORCH group or syphilis), is a risk factor for both NE and CP [108]. In a large large tumors (sacrococcygeal teratoma or angiomas), and population-based study of term infants with neonatal urinary tract anomalies [156]. Chromosomal anomalies encephalopathy, 13% subsequently developed cerebral are more common prior to 24 weeks; cardiac and pulmo- palsy, while 24% of CP patients had a prior history of nary lesions are more common after 24 weeks [176]. NE [11]. The overall incidence of CP has not changed Hydrops caused by parvovirus anemia, cardiac arrhyth- much over the past 50 years despite advances in mias, and hydrothorax respond more favorably to prenatal intrapartum monitoring and antenatal diagnosis. treatment [176]. Clearly, the placenta from every newborn with NE A hydropic placenta is often massively enlarged deserves careful attention from the pathologist [79]. (exceeding 1,000 g), soft, friable, and pale (> Fig. 19.31). Acute lesions associated with NE include large Histologically, the villi appear enlarged, cytotrophoblast 1062 19 Diseases of the Placenta

. Fig. 19.111 Fetoplacental hydrops. The villi are immature and edematous (left). When due to fetal anemia, nucleated red blood cells and erythroblasts expand the villous capillaries as in this case of Rh incompatibility

cells are increased with occasional mitoses, villous capil- (demonstrable prior to deceleration), and after acute or laries are reduced or inconspicuous, and the stroma is repeated fetal hemorrhages [181]. Amniotic fluid levels are edematous (> Fig. 19.111). In cases of anemia, nucleated lower but persist longer. Episodic periods of hypoxia in red blood cells (nRBC – erythroblasts and normoblasts) cord entanglement may be reflected in this way even when are very prominent, often in clusters that expand the blood levels have returned to normal [60]. capillary outlines. The time interval between an acute event and nRBC elevation is not established. Elevated lymphocyte and platelet counts (as well as increased nRBC) may correlate Nucleated Red Blood Cells in the Fetal with the timing of prenatal neurologic injury; counts tend Circulation to be higher and last longer in newborns with long- standing hypoxic injury [106, 118]. nRBC are rare in sections of a normal term placenta or in Clinically significant nRBC elevations are usually evi- the blood of normal newborns. Absolute counts in the dent on microscopic examination of the placenta range of 500–1,000 nRBC/mm3 or 1–10 nRBC/100 white (> Fig. 19.74)[29, 137]. Redline found a highly significant blood cells in fetal or neonatal blood are normal; counts in correlation between cord blood counts and the number of excess of these figures are abnormal [63]. An increased nRBC observed in ten high-power fields (40Â objective) in number of nRBC in the circulation of newborns is a well- the placenta; 10 nRBC/10 HPF corresponded to an absolute recognized parameter of potential neonatal injury [63]. count of 2,500 nRBC/mm3 with 90% sensitivity and 82% nRBC elevation is believed to be caused by acute or specificity [137]. In this study of placentas from babies with chronic fetal hypoxia resulting in erythropoetin release. cerebral palsy, an elevated nRBC count was significantly The most dramatic nRBC elevations occur in the severe associated with placental lesions – multifocal avascular anemias associated with immune or non-immune villi (FTV) or chronic villitis. Meconium-associated necro- hydrops and congenital infections (especially parvovirus). sis in vessels of the chorionic plate or umbilical cord showed Anemia caused by fetomaternal hemorrhage, either acute a borderline association. Increased nRBC, with or without or chronic, may elicit a marked nRBC elevation. nRBC placental lesions, were unassociated with acidosis or birth elevation occurs in a number of other clinical settings asphyxia indicating that the underlying causes of nRBC including maternal diabetes, acidosis [89], IUGR, mater- elevation in this context antedated immediate peripartum nal smoking [193], and other infections [63]. events [137]. Persistent nRBC elevation in the first week of Erythropoetin can be measured in amniotic fluid as life of a preterm growth-restricted newborn has serious well as in fetal blood. Elevations occur in maternal diabe- implications for additional complications, including tes, fetal growth restriction, maternal smoking, fetal bronchopulmonary dysplasia, necrotizing enterocolitis, anemia, acidosis, prolonged heart rate deceleration and intraventricular hemorrhage [16]. Diseases of the Placenta 19 1063

Thrombophilias Placental pathology has poor predictive value in identifying patients with thrombophilia. Coagulation Inherited and acquired coagulation disorders are risk fac- studies are probably best focused on patients with specific tors for adverse pregnancy outcomes (early spontaneous clinical scenarios such as severe early onset or recurrent abortion, IUFD, abruption, IUGR, and preeclampsia) [37, pregnancy loss in association with typical placental 55, 94, 95, 132, 155]. lesions [132]. The most widely studied thrombophilias include the G1691A mutation in the factor V gene (factor V Leiden), the G20210A mutation in the prothrombin gene, the C677T Acute Fatty Liver of Pregnancy and HELLP mutation in the methylene tetrahydrofolate reductase Syndrome gene, deficiencies in protein S, protein C, antithrombin III, hyperhomocysteinemia, and acquired thrombophilic Both the HELLP syndrome (hemolysis, elevated liver states such as antiphospholipid antibody syndrome. enzyme levels, low platelet count) and acute fatty liver of Coagulopathies also occur in patients with diabetes pregnancy (AFLP) present as preeclampsia complicated by mellitus. The mere identification of an inherited liver malfunction. The HELLP syndrome is more common thrombophilia is not predictive for pregnancy complica- and usually has a reasonably good prognosis under appro- tions. Estimates of the risk for different outcomes in priate management. AFLP, although rare, has a significant mothers with specific thrombophilic conditions have mortality rate. Liver biopsy in AFLP shows characteristic been summarized recently [132]. changes including microvesicular steatosis. There is no specific placental lesion unique to or specific Although recognized by maternal diseases, one very for maternal thrombophilia. The placental pathology important cause is an inherited gene mutation in the fetus linking thrombophilia to adverse pregnancy outcome that causes a deficiency of long-chain 3-hydroxyl-CoA is essentially identical to other disorders associated dehydrogenase, resulting in abnormal fatty acid metabo- with chronic maternal vascular underperfusion (increased lism [68]. The mother’s acute problem is usually relieved syncytial knots, increased intervillous fibrin, infarcts, by delivery. The infant has severe liver dysfunction, hypo- retroplacental hematoma, distal villous hypoplasia, glycemia, cardiomyopathy, and neuromuscular abnormal- decreased placental weight, and thin cord) [9, 83, 95]. ities. Appropriate early dietary management may reduce Maternal thrombophilia has been associated with MPF/ morbidity and mortality. MFI and subchorionic hematomas in some reports [62, Fatty acids are an important source of energy for the 132]. Whether coagulation abnormalities are underlying fetus. More than 20 different genetically determined dis- causes of abnormal placentation or exacerbate preexisting orders of fatty acid metabolism have been recognized placental compromise is unknown. Acquired thrombophilic [171]. Although rare, together they represent the most states such as the antiphospholipid antibody syndrome common metabolic disorder with severe consequences may promote intraplacental clotting, possibly by blocking for the mother and fetus. Retrospective studies have iden- the normal antithrombotic annexin V phospholipid- tified these disorders in a significant number of binding protein and by activating complement [123, 169]. unexplained stillbirths and sudden infant deaths. A similar predisposition to placental clotting occurs in Placental lesions in the context of the HELLP syn- patients with lupus erythematosus [93] and scleroderma drome include all of the features of decidual vasculopathy [38]. IgG antiphospholipid antibodies may cross the found in severe preeclampsia. There is little information interhemal membrane to enter the fetal circulation. on the placenta associated with AFLP. In one instance, Fetal thrombophilic mutations studied to date are by a maternal floor infarct was found [96]. themselves not associated with fetal vascular thrombosis. The frequency of fetal thromboocclusive placental lesions in babies with fetal thrombophilias is not increased, and Sickle-Cell Trait/Disease and Other there is no increase in the prevalence of thrombophilic Hemoglobinopathies mutations in infants whose placentas have fetal thromboocclusive lesions. At most, fetal coagulation Sickled maternal cells in the intervillous space may iden- abnormalities may act in concert with other factors affect- tify sickle cell disease, although low oxygen tension in the ing fetal blood flow. FTV does have a clear and strong placenta may result in sickling of maternal erythrocytes in relationship with umbilical cord entanglement and cord sickle trait as well [22]. Clinical problems and placental abnormalities. lesions are unlikely in uncomplicated sickle trait. Sickle 1064 19 Diseases of the Placenta

cell disease has been associated with spontaneous abor- Late spontaneous abortion/stillbirth is more likely to be tion, stillbirth, premature delivery, and IUGR, although associated with placental and maternal factors. regular obstetric care and close hematologic surveillance have significantly reduced maternal and fetal morbidity. Placentas in sickle disease may be normal (with the excep- Early Abortion tion of sickled maternal erythrocytes) or small and infarcted. We have seen an occasional instance of extensive The embryonic stage of development extends to the 8th placental infarction and postnatal morbidity in instances gestational week. Early abortion includes losses up to the of sickle cell trait complicated by other hemoglobinopa- 12th week. More than half of early spontaneous abortions thies or maternal coagulopathies. Ultrastructural abnor- have demonstrable chromosomal anomalies, and most of malities in the umbilical vein have been attributed to these are eliminated in the embryonic period. Trisomies, hypoxia [34]. triploidy, and monosomy X are most common [86]. In spontaneously passed tissue, the chorionic cavity, intact or disrupted, may be identified. The chorionic cav- Storage Disorders ity is frequently empty but may contain remnants of cord or embryo. The amnionic sac, when present, is often Metabolic storage disorders are rare and placental findings abnormally large and prematurely fused to the chorion. are incompletely documented. Placental abnormalities in Embryos frequently exhibit generalized abnormal devel- some inherited metabolic storage diseases include vacuo- opment (growth disorganization), pointing to a high lar changes in trophoblastic, stromal, and Hofbauer cells. probability of a chromosomal anomaly (> Fig. 19.112). Placentas from two infants with Gaucher’s disease causing Localized developmental defects (facial fusion defects, nonimmune fetal hydrops and stillbirth were found to ocular anomalies, limb bud deformities, neural tube have circulating Gaucher cells. Genetic analysis and/or defects, and cervical edema) are also commonly geneti- enzymatic and biochemical studies may aid in the identi- cally determined, although specific morphologic defects fication of specific enzymatic defects. are often difficult to identify in the early embryo. These are more easily evaluated in the larger previable fetus. The finding of a well-developed, normal embryo suggests the Abortion, Stillbirth, and Intrauterine Fetal possibility of a maternal causative factor (infection, Death inflammation, immune rejection, or coagulopathy), although 20–25% of morphologically normal embryos Products of conception are commonly submitted for are also karyotypically abnormal, usually triploid. Accu- pathologic examination to confirm the presence of an rate assessment of embryo morphology requires intrauterine gestation, to exclude trophoblastic disease and, if possible, to explain why the pregnancy failed. The identification of embryonic or placental tissue – chorionic villi, implantation site infiltrated by IT, or isolated clumps of trophoblast – essentially confirms intrauterine pregnancy. Immunostaining for keratin highlights IT when findings are equivocal. When embryonic or placental tissue is not found, the possibility of an ectopic gestation cannot be excluded. It should be recognized that no combination of findings, including chorionic villi, can completely exclude an ectopic pregnancy because rarely intrauterine and tubal pregnancies occur simultaneously. Approximately one half of all human gestations abort, of which about half are recognized by the mother or her physician. Of clinically recognized pregnancies, those that abort can be divided into two significantly different groups, early (up to 12 weeks) and late (>12 weeks). In . Fig. 19.112 general, embryonic/fetal factors, primarily chromosomal Spontaneous abortion. The abnormal embryo in this early abnormalities, are responsible for most early abortions. abortion is closely correlated with an abnormal karyotype Diseases of the Placenta 19 1065 familiarity with normal developmental stages, which are intrauterine infections and inflammatory processes, well illustrated in the comprehensive work of Kalousek maternal and/or fetal circulatory compromise, destructive et al [74]. Gross assessment of the embryo and/or placenta placental lesions, cord accidents, and fetal malformations. is, at best, suboptimal in the dissociated tissues of curetted The gross and microscopic features of these conditions specimens. have been described throughout this chapter. Involutional The placenta is commonly retained in the uterus for changes that invariably occur following fetal death will be a variable period after fetal death, and villi in abortion superimposed to greater or lesser extent. Fetomaternal specimens often show alterations reflecting fetal death. hemorrhage is often overlooked as a cause of unexpected Regardless of cause, fetal death leads to progressive invo- stillbirth. A Kleihauer–Betke test should be performed in lution of fetal vessels diffusely throughout the placenta. all such cases. When the fetus is normally formed and the Involution begins with intravascular karyorrhexis (6 h), placental findings seem trivial, confined placental mosai- followed by septation of stem vessels (48 h) and ends with cism is a consideration. fibrous obliteration of vessels and villous stromal fibrosis Recurrent pregnancy loss may be associated with (when extensive >2 weeks) [39, 50, 51]. This sequence of thrombophilias, maternal vascular obstructive lesions, changes is identical to that which occurs locally in villi and VUE when these conditions are severe and of early distal to an occluded fetal vessel. onset. Massive perivillous fibrin deposition and chronic The villi of abortions with abnormal karyotypes histiocytic intervillositis are rare lesions, but they almost often appear abnormal, but the patterns are variable always lead to recurrent reproductive loss in affected indi- and nonspecific. Dysmorphic features suggestive of viduals [135, 188]. a chromosomal abnormality – villous enlargement with myxoid stroma, irregular villous outlines, multiple trophoblastic invaginations, and individual trophoblastic Nontrophoblastic and Metastatic Tumors cells in the villous stroma – are common and may be more marked in karyotypically abnormal abortions, but Hemangioma (Chorangioma) are found in abortions with normal karyotypes as well. Complete and partial moles are the only morphologic Placental hemangiomas (chorangiomas) occur in about entities with defined karyotypic abnormalities that can 0.5–1% of carefully examined placentas. They are usually be diagnosed with any degree of confidence, although small, entirely intraplacental, and may be difficult to their distinction is becoming more difficult with earlier appreciate, especially in the unfixed specimen. Large evacuation. Rarely, significant trophoblastic hyperplasia tumors distorting either the chorionic or basal plate are without molar change may occur in association with rare. Exceptionally a chorangioma is attached to the pla- chromosomal abnormalities, (especially trisomies 7, 15, centa by a thin pedicle. Chorangiomas are usually solitary 21, and 22.) [142] These cases are best managed with (> Fig. 19.113), but they may be multiple or, rarely, a follow-up serum HCG titer to assure return to baseline. Karyotyping may be clinically very useful in the evaluation of couples distressed by repeated spontaneous abortion. Trisomies can be identified by FISH in formalin fixed tissue. Occasionally, karyotypic abnormalities are confined to the placenta. In confined placental mosaicism, mosaicism is expressed in the placenta but not the fetus [73]. These placentas show no histologic abnormalities; their identification requires genetic evaluation of villous stroma and trophoblast and the fetus.

Late Abortion, Stillbirth, and Intrauterine Fetal Death

Chromosomal abnormalities still occur but are uncommon after 20 weeks. Important considerations in . Fig. 19.113 explaining late abortion, stillbirth, and IUFD include Placental hemangioma 1066 19 Diseases of the Placenta

involve the placenta diffusely (> Fig. 19.114). They may be but without nodular expansion have been termed local- brown, yellow, tan, red, or white and are usually firm and ized chorangiomatosis [110]. well demarcated from the surrounding parenchyma. Most The tendency for chorangiomas to be found beneath chorangiomas are composed of capillary-sized blood ves- the chorionic plate and at the placental margin in addition sels supported by inconspicuous, loose stroma. Occasion- to their association with preeclampsia and high-altitude ally, they may be more cellular or show prominent myxoid pregnancy suggest that decreased oxygen tension may play change, hyalinization, necrosis, or calcification. Mitotic a role in their development. Although the majority of figures and nuclear atypicality have been reported in chorangiomas are of no clinical significance, various com- some chorangiomas, but these have not behaved aggres- plications have been reported, usually in association with sively. Trophoblastic hyperplasia may be prominent [110]. large lesions. Hydramnios and premature delivery are the Localized groups of large stem villi with similar alterations most significant. Fetal cardiomegaly, congestive heart failure, and hydrops have been attributed the increased work- load in shunting blood through a large chorangioma. When significant amounts of blood are directed through the chorangioma away from functional villi, chronic hypoxia may lead to intrauterine growth retardation. Com- plications including fetal anemia and thrombocytopenia reflect sequestration or destruction of cellular elements as they traverse the chorangioma. Skin angiomas have been reported in a few babies with placental hemangiomas.

Hepatocellular Adenoma and Adrenocortical Nodules

Rarely small nodules of hepatocytes occur in the placenta. Termed hepatocellular adenoma, these nodules may contain hematopoetic foci but lack bile ducts and central veins (> Fig. 19.115). Their immunoproﬁle is typical of hepatocytes. Tiny nodules of adrenal cortical cells have been . Fig. 19.114 considered heterotopias. The pathogenesis of these Diffuse placental hemangioma unusual ﬁndings is not understood.

. Fig. 19.115 Hepatic adenoma. This discrete collection of hepatocytes showed extramedullary hematopoiesis Diseases of the Placenta 19 1067

Other Placental ‘‘Tumors’’ cord has been documented. The placenta involved by a metastatic fetal tumor is consistently hydropic, pale, Despite intraplacental location and inﬁltrative border, and bulky with tumor cells distending fetal vessels. careful molecular analysis of one intraplacental Pigmented nevus cells may involve the villi in association leiomyoma documented its maternal origin. Teratomas with giant nevi, but these are not considered to be malig- have been reported to occur rarely between the amnion nant or metastatic. and chorion on the chorionic plate and in the umbilical cord. Although teratomas have been distinguished from acardiac fetuses by lack of an umbilical cord and disorga- Examination of the Placenta nization of the component tissues, this distinction is a matter of dispute. A gross examination of all placentas should be performed and recorded at the time of delivery by the clinician. Some

Placental Metastases

Either maternal or fetal neoplasms may metastasize to the placenta but they are very rare. Malignant melanoma is the most common maternal tumor to metastasize to the placenta despite the fact that other tumors are more common in this age group. Other maternal neoplasms metastasizing to the placenta have included leukemia, lymphoma, breast carcinoma, and lung carcinoma. Malignant melanoma, leukemia, and lymphoma have been reported to metastasize to the fetus transplacentally [84]. Placentas harboring maternal metastases are often normal on gross inspection, although metastatic tumor deposits may be apparent grossly (> Fig. 19.116). Tumor cells are usually conﬁned to the intervillous space . Fig. 19.117 > ( Fig. 19.117). Villous or fetal vascular invasion is very Metastatic breast carcinoma. Metastatic tumor cells are uncommon, and even when present, does not correlate confined to the intervillous space well with fetal spread. Dissemination of a congenital fetal tumor to the placenta is also very rare. Neuroblastoma is most common, but rare cases of fetal leukemia, lymphoma, hepatoblastoma, sarcoma, and sacrococcygeal teratoma have metastasized to the placenta (> Fig. 19.118). Dissem- inated histiocytosis involving the vessels of the umbilical

. Fig. 19.116 . Fig. 19.118 Metastatic breast cancer. The metastatic tumor is visible as Metastatic fetal melanoma. This congenital scalp melanoma small nodules (Used with permission of the American metastasized to the placenta Registry of Pathology/Armed Forces Institute of Pathology) 1068 19 Diseases of the Placenta

information – length of umbilical cord, location of pla- Umbilical cord centa in utero, retroplacental hematoma, ruptured membranous vessels, completeness of membranes or maternal Length: Measure all pieces. The most accurate assessment surface – may be of immediate relevance and is best of cord length is obtained in the delivery room. Umbilical documented by the practitioner. Cultures for microorgan- cord length decreases by as much as 7 cm within a few isms and tissue for cytogenetics are best obtained at this hours of delivery. time. Placentas are most commonly submitted to the Diameter: Measure greatest and least. pathologist when either the mother or infant is abnormal, Insertion: Measure the distance between the insertion the course of pregnancy, labor or delivery is complicated, of the umbilical cord and closest placental margin. Note a gross placental abnormality is noted, or for the evalua- the mode and site of insertion and the condition of all tion of multiple pregnancy. Guidelines for submission of membranous vessels. placentas for pathologic exam have been established [84]. Vessels: Normally 3. A request for pathologic examination of the placenta Torsion: Degree of twist can be expressed as number of should include the reason for submission with specific coils per 10 cm. questions as well as a summary of the clinical history Other: Strictures, edema, thrombosis, hematomas, pertinent to that evaluation – the mother’s gravidity, par- ulceration, knots. ity, details concerning previous pregnancies, underlying Remove the cord flush with the placental surface. maternal disease, antepartum course, labor and deliver, and the infant’s gestational age, weight, and Apgar scores. Placentas not submitted to pathology can be retained in Placenta the event that a complete placental exam should become necessary. Measure: Measure the diameter and thickness. A good placental exam can be performed on a fresh or Weigh: Weigh after fetal membranes, umbilical cord fixed placenta. In our institutions, the placenta is exam- and large clots have been removed. Formalin fixation adds ined fresh to establish weight and pertinent measure- about 10% to placental weight. ments, perform vascular injection when indicated, and Shape: Note anomalous shapes. roll the membranes. After overnight fixation, the cut sur- Fetal surface: Evaluate color (blue, green, brown) and faces are examined and sections are submitted. Important chorionic vessels. Arteries cross over veins. abnormalities are unlikely to be overlooked when the Maternal surface: The maternal surface should be com- placenta is approached systematically as follows. plete. Missing fragments suggest retained placental tissue. Evaluate all clots for site, size, and related placental alterations. Breadloaf the placenta at 1 cm intervals. Fetal membranes Cut surface: Placental color reflects fetal blood content. Describe, measure, and locate focal abnormalities. Assess Point of rupture: Measure the distance between the point of percentage when large lesions or significant proportions of rupture and the closest placental margin. This provides the placenta are altered. information relating to the site of implantation (low-lying or placenta previa.) Completeness: By attempting to reconstruct the Sections amnionic sac, an estimation may be made as to whether membranes have been retained in utero. Two sections of umbilical cord and two sections of the Insertion: The membranes may insert at the margin of membrane roll can be included in one block. Do not the placenta or central to the placental margin (circum- section the cord within 2 cm of the insertion site – this vallate). Note extent (complete, partial) and associated may give a false impression of SUA. We routinely submit at changes. least three sections of placenta including two sections Color and opacity: Opaque or cloudy membranes sug- from grossly normal central placental parenchyma. Addi- gest infection. Green/brown staining suggests meconium tional sections to demonstrate pathologic alterations are or hemosiderin deposition. submitted as appropriate. Selection of microscopic sec- Roll the membranes to include the point of rupture tions should be tailored to the specific clinical scenario. and the placental margin. Remove the membranes. For example, additional sections of the membrane roll or Diseases of the Placenta 19 1069 basal plate optimizes evaluation of maternal vessels when References there is a history of preeclampsia. 1. Abramowsky C, Beyer-Patterson P et al (1991) Nonsyphilitic spiro- chetosis in second-trimester fetuses. Pediatr Pathol 11:827–838 Special aspects of Multiple Pregnancy 2. 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