The pathologist should examine the chorion to determine number, locate vascular anastomoses and identify other abnormalities. It is useful to have the obstetrician label which umbilical cord was associated with twin A (first born) and which with twin B (second born). If the placenta is received in pathology without labelled cords, the pathologist should identify the different cords, placental regions and membranes as twin 1 and twin 2.

Monochorionic twins share a single placental disk. However the placental zones surrounding each umbilical cord should be treated separately and sections submitted for each. Separate or partly fused placentas are examined identically to singleton placentas. For a single placental disc, a membrane roll from the dividing membrane or its junction on the placental surface (the "T-zone") is the most single important section. Gross examination of the dividing membrane usually reveals the number of amnions and chorions. The vascular bed associated with an individual umbilical cord (vascular equator) may not be the same as the division of the placental disc made by the dividing membrane. Discordant placental sizes may not be the sole determinant of discordant twin growth. While the normal weight of the singleton placenta for a given gestational age has been established, similar standards have not been published for twin placentas. In dichorionic diamniotic separate placentas, the weight is not double that expected for a singleton at the same gestational age. From personal experience, monochorionic placentas are usually one and one half times heavier than expected for a singleton placenta.

Superficial vascular anastomoses are seen in most monochorionic placentas, and are easy to identify by injecting air or milk into the vessels. The vessels involved can be distinguished by their orientation of the chorionic plate.  Arteries always cross over veins, and in each placental area should be a paired artery and vein. Deep anastomoses, the so-called "third circulation", most commonly involve an outflow artery-to-vein anastomosis balanced by a vein-to-artery inflow anastomosis. When unbalanced, the outflow vessel may be large,  calcified and not paired with a vessel returning to the same cord. The common indications for extensive evaluation of the placental circulation are: death of one or both twins, discordance of intrauterine growth or fetal well-being, and fetal anomalies.

Fetal death is a common complication of multiple gestation.  Cord accidents including cord entanglement complicate 50% of fetal demises in single sac twins. Prolapse of the umbilical cord of twin B during delivery of twin A is more common in monoamniotic placentas, but may occur in any type of placentation as the dividing membrane ruptures. During the first trimester, as many as 21% of twins may be lost. In early fetal losses, there may be no evidence of the fetus at the time of delivery (the "vanishing twin"). Fetal loss in the second or third trimester occurs in 0.5-6.8%. Death of one twin may be followed by death of the co-twin, since they may share a “hostile environment,” or premature delivery of the living twin. While maternal coagulopathy may occur with a retained dead fetus, it is very rare if only one of the pair dies. Focal embolic or thrombotic damage of brain, skin, kidneys, and intestine of the living co-twin may occur.  This may be related to passage of thromboplastins derived from dead tissue into the circulation of the surviving twin through placental vascular anastomoses. Alternatively, after the demise of the co-twin, the circulation of the dead twin loses vasomotor tone. The drop in blood pressure across anastomoses may cause hypovolemic/hypotensive ischemia and damage to the surviving twin. When one of a twin pair dies, the placenta of the dead twin is initially normal but will eventually atrophy due to hypoperfusion unless the living co-twin continues to perfuse its capillary bed through anastomoses.

At the beginning of twin gestation, the weight and size of both fetuses are equal and appropriate for gestational age. Twins follow the growth curves of singletons until the third trimester, when their rate of growth slows.  This may be due to uterine crowding, decreased placental reserve, or abnormal blood flow to one twin. The IUGR is usually asymmetric with “head sparing”. Discordant growth of monozygous twins may be due to unequal division of cytoplasmic mass during the equal division of the genetic material or the twin transfusion syndrome (discussed elsewhere). Discordant growth is seen almost as commonly in dizygous twins.  Chronic villitis, intraplacental thrombi, fibrosis, villous hypovascularity, villous infarcts and maternal decidual vasculopathy are seen more commonly in the smaller dichorionic twin. IUGR and fetal compromise are more common with velamentous cord insertion. Abnormal cord insertions are seen in 16% of all twins, compared to 1% in singletons. Marginal insertion is seen in 14% of monochorionic and 4% of dichorionic placentas. Velamentous insertion is seen in 9% of monochorionic and 5% of dichorionic placentas.

Though nearly all monochorionic placentas have vascular anastomoses, twin transfusion syndrome (TTS) occurs in from 7.5-30%. Chronic TTS occurs most often in monochorionic diamniotic placenta, infrequently in monochorionic monoamniotic placentas (thought due to nearly complete sharing of the placental substance), and rarely in dichorionic diamniotic fused placentas. TTS is the result of chronic unidirectional vascular "steal", from the artery of one twin (donor) through the "third circulation" to the other twin (recipient). When one twin's cord is inserted velamentously,  the fetal vessels are adjacent to the rigid myometrium, and not on the chorionic plate, and are more subject to compression.  This twin is more likely to become the donor. The donor is growth retarded, anemic, with delayed organ maturation and oligohydramnios.  The recipient becomes plethoric and is overgrown. Polyhydramnios and congestive heart failure due to volume overload, and polycythemia may occur. The placenta reflects the fetal abnormalities. Acute TTS may occur at the time of fetal demise, during delivery, or rarely in conjunction with chronic TTS. Placentas examined after selective feticide in cases of severe TTS show sclerosis of the chorionic circulation of the terminated twin.  Laser ablation of anastomotic vessels results in yellow-tan nodules which are either confined to the chorionic surface, or may extend the full thickness of the placenta. 

Higher-order multiple births  (triplets, quadruplets, etc.) are more frequent in recent years, due to delayed child bearing, use of fertility drugs and in vitro fertilization techniques. Natural occurring higher multiple births are infrequent occurrences (triplets 1/10,000 births, quadruplets 1/100,000 births). Higher-order multiple births may be a combination of mono- and di-zygous siblings. Evaluation of the placenta is done as described above, with particular attention paid to the number of chorions and amnions. Monochorionic placentation means monozygosity of those offspring, independent of other placental features.

Early fetal loss

Approximately 50% of spontaneous abortions are caused by fetal karyotypic abnormalities. Discordance of genetic composition of the trophoblast and the conceptus and placental post-mitotic errors may lead to confined placental mosaicism, and discordance between fetal and placental karyotype on chorionic villous sampling. If examination of the chromosomes of spontaneously aborted fetuses shows an abnormal fetal karyotype, the risk of subsequent pregnancy loss is less than if the karyotype were normal. If the karyotype is normal, addititional studies might be indicated especially if there were prior pregnancy losses or "habitual abortion". In women receiving therapy for recurrent spontaneous abortions, fetal karyotype is helpful in deciding if treatment has failed or if that particular pregnancy would have been lost despite treatment. Pathologic examination of products of conception (POC) should include but not be limited to tissue documentation of the fact of pregnancy, since examination of POC can contribute data relevant to patient counseling and future therapy.

The pathologic examination of POC is performed to determine the cause of pregnancy failure and retrospectively to evaluate placental and decidual integrity and fetal viability.  In genetically normal conceptuses, the tissues often reveal an embryo viable for most of the gestation. Abortion can be related to abnormalities of the placenta, decidua, or both.  In genetically abnormal conceptions, the embryo/fetus may be abnormal or have failed to form at all, and placental and decidual lesions are caused by embryo/fetal demise.

Fetal viability may be estimated by the type of erythroid elements in the placental circulation. Nucleated erythrocytes are produced in the yolk sac and circulate in the early weeks of pregnancy. With hepatic hematopoeisis (week 7-9), anucleate erythrocytes begin to circulate. The proportion of nucleated erythrocytes is closely correlated with crown-rump length. A greater proportion of nucleated erythrocytes than expected for fetal age indicates an abnormal hematopoietic stress. This occurs in a variety of conditions including but not limited to chromosomal aberrations (in particular triploidy and trisomies), hydrops fetalis, antiphospholipid antibody production and massive placental infarction, and in recurrent midtrimester losses with dense chronic intervillous inflammation. In a study of spontaneous loss, we grouped karyotype as euploid and aneuploid, and evaluated histology. Decreasing maternal age and increasing gestational age at loss, villous circulation indicative of fetal life to 10+ weeks, decidual vasculitis, chronic intervillositis and villous infarcts were significantly associated (p<0.01) with euploid and viable conceptions. Since almost all spontaneous abortions are retained in utero for some time following fetal demise and preceeding onset of clinical symptoms, there is a great deal of "baseline pathology" in all tissues of failed pregnancies regardless of etiology. Preliminary data indicate that multiple spontaneous abortions from the same mother will have similar histology, and likely to demonstrate a viable embryo/fetus. 

Late fetal loss

Genest and others have described placental features associated with different times of in utero retention after demise. In summary, after cessation of the fetal heart, the villous circulation collapses, becoming obliterated. The degeneration of the villous circulation after fetal death is characterized by intraplacental coagulation and endothelial disruption.  The circulatory lesions, therefore, are not specific to stillbirth, since they may be caused by any process which damages fetoplacental endothelium, including cocaine induced vasospasm, viral infection, fluctuating perfusion (hypoperfusion/ reperfusion), or cessation of perfusion (stillbirth). However, the lesions are generally more diffuse and extensive in stillbirth than in, for example, preeclampsia or IUGR. Villous vasoocclusion with fetal red cell fragmentation and intravillous bleeding was first described in placentas from stillborn fetuses, and was termed “hemorrhagic endovasculitis”. This lesion is not a true vasculitis, and in stillborn fetuses may be a postmortem event rather than a cause of death, and may occur in in vitro organ cultures or in retained secundines. It is associated with circulatory instability, and may be found adjacent to foci of chronic villitis, at the periphery of infarcts and intervillous thrombi and in infarcted chorangiomas. Chorionic and fetal stem vessel thrombi and avascular terminal villi are related lesions. Intraplacental vaso-occlusion may accompany antiphospholipid antibody-related pregnancy compromise or intraamniotic infection by endotoxin producing organisms. Placental venous thrombi may lead to fetal thromboemboli and cerebral damage. After the fetus dies, the villous stroma also becomes denser and more fibrotic, villous diameter is reduced, and trophoblast basophilia increases.

It is useful for the pathologist to know the clinically estimated time of fetal demise, and to have relevant data from postmortem fetal examination. Clinically, causes of “late fetal demise” differ with gestational age at demise. In the second trimester, fetal death in utero may be reflect fetal aneuploidy (e.g. Turner’s syndrome), “incompetent cervix” or acute intraamniotic infection.  While fetal demise may be caused by intraamniotic infection, fetal sepsis is uncommon in this country, at least in the community hospital. In the last trimester, uteroplacental insufficiency, cord accidents, and diffuse chronic villitis/congenital viral infection are most common, while fetal chromosomal abnormalities are uncommon causes of late fetal death. Abnormal uterine vascular adaptation chronically restricts fetal nutrients prior to fetal decompensation and death; many such fetuses are IUGR or have a low weight to length ratio (“ponderal index”), indicating abnormal weight gain prior to death. Chronic villitis may suggest congenital viral infection or maternal immune-related pathology.

Placental lesions reflective of antemortem feto-placental disease can point to a cause of death in many cases., but some lesions in placentas of dead fetuses are caused by fetal death.  As with "hemorrhagic endovasculitis", the dividing line between antemortem lesions and postmortem changes is not always clear. Often the difference among the placentas of a dead fetus, a damaged newborn, and a healthy newborn is the extent of the histologic lesion.

Low birth weight

Low birth weight (LBW) is the leading cause of perinatal morbidity and mortality. LBW is also associated with increased mortality in the early postnatal period and during infancy.  LBW is due either to premature delivery or to IUGR.  LBW is defined as birthweight less than 2500 grams, and “very low birthweight” (VLBW) as birthweight <less than 1500 grams.

Any placentas delivered spontaneously or iatrogenically prior to term is not a normal placenta. In a study of 249 infants with birthweight <1500 grams, more placental and decidual lesions were seen in preterm cases than at term. No lesion is specific for a particular clinical setting. Acute inflammation was more frequent in premature labor or premature membrane rupture than in preeclampsia. Defective placentation (generally characteristic of preeclampsia) and lesions of chronic placental inflammation are  seen in 49% of placentas of infants born at <1500 grams to non-hypertensive mothers, and may be linked to IUGR. In non-hypertensive LBW pregnancies, a low placental weight and chronic villitis are related to impaired fetal growth. In preeclamptic LBW cases, the cumulative burden of all decidual vascular lesions and not the presence of any individual lesion type is significantly related to reduced birthweight. IUGR is more common in preterm infants than infants born at term, and the growth failure may begin at any gestational age. It may predict distress during a normal labor and delivery. Longterm it may be associated with suboptimal neuro-developmental outcome. The factors which preclude a genetically intact fetus from reaching his/her full growth potential are not always obvious.  Those that can be recognized by examining the placenta include: 1) congenital viral infection, classically of TORCH origin, and manifested by chronic villitis, 2) reduced nutrient provision, classically seen in preeclampsia and related to decidual vascular pathology, and 3) confined placental mosaicism, in which a chromosomally abnormal placenta with impaired growth and function may compromise fetal growth.  This latter may be an extremely subtle finding.

Hydrops fetalis

Hydrops fetalis of any cause is almost always reflected by placental hydrops. Vice versa, placental abnormalities (e.g., chorangioma or venous obstruction) may be primarily responsible for fetoplacental hydrops. Microscopically, there may be increased mitoses in cytotrophoblasts, thickened trophoblastic basement membranes, increased fibrinoid necrosis of villi and syncytial knotting, and swelling of endothelial cells. Excess nucleated erythroblasts may be seen in either immune and nonimmune hydrops fetalis. There is often hemosiderin pigment in membranes, trophoblasts, Hofbauer cells, endothelium, villous stroma, and on basement membrane. Increased amounts of both intravillous and extravillous calcification  are seen with cardiac failure, IUFD, or when there is less demand for calcium due to fetal disease, such as osteogenesis imperfecta.

Oligohydramnios The early amnion rupture sequence (TEARS)

Decreased amniotic fluid production (e.g., decreased urine output in renal agenesis or lower urinary tract obstructions) or chronic amniotic fluid leak will result in amnion nodosum.  Amnion nodosum develops most often after vernix has accumulated (by 32 weeks). Small finely granular or greasy plaques are seen on the fetal surface, and much less often on free/reflected membranes or umbilical cord. These nodules are easily scraped off the placental surface. Mechanical trauma to the amnion due to decreased amniotic volume may cause amnion degeneration, which may be the only feature of early lesions.  Amnion nodosum should be distinguished from squamous metaplasia, a normal feature of mature placentas which occurs near the umbilical cord insertion and is not easily removed.