Context.—In utero hypoxia is an important cause of perinatal morbidity and mortality and can be evaluated retrospectively to explain perinatal outcomes, to assess recurrence risk in subsequent pregnancies, and to investigate for medicolegal purposes by identification of many hypoxic placental lesions. Definitions of some placental hypoxic lesions have been applied relatively liberally, and many of them are frequently underreported.

Objectives.—To present a comprehensive assessment of the criteria for diagnosing acute and chronic histologic features, patterns, and lesions of placental and fetal hypoxia and to discuss clinicopathologic associations and limitations of the use thereof. The significance of lesions that have been described relatively recently and are not yet widely used, such as laminar necrosis; excessive, extravillous trophoblasts; decidual multinucleate extravillous trophoblasts; and, most important, the patterns of diffuse chronic hypoxic preuterine, uterine, and postuterine placental injury and placental maturation defect, will be discussed.

Data Sources.—Literature review.

Conclusions.—The placenta does not respond in a single way to hypoxia, and various placental hypoxic features should be explained within a clinical context. Because the placenta has a large reserve capacity, hypoxic lesions may not result in poor fetal condition or outcome. On the other hand, very acute, in utero, hypoxic events, followed by prompt delivery, may not be associated with placental pathology, and many poor perinatal outcomes can be explained by an etiology other than hypoxia. Nevertheless, assessment of placental hypoxic lesions is helpful for retrospective explanations of complications in pregnancy and in medicolegal investigation.

Almost 90% of neurodevelopmental disorders are initiated before the intrapartum period.1  Prenatal asphyxia and severe, chronic fetal hypoxia are probably present in those disorders. In 88% of stillbirths, the direct cause of a major contributor to death was found in the placentas.2  The abnormal fetal/neonatal outcome, including cerebral palsy, has been proven to be related not only to acute chorioamnionitis but also to other placental lesions, including the hypoxic ones.1,3,4  Unfortunately, it is common for general surgical pathologists not to recognize placental lesions that may have clinical significance.5  Different aspects of gross and histologic placental examination are reported variably by different laboratories.2,6  Underreporting of placental abnormalities is common, but incorrect diagnoses are relatively infrequent.7  Failure to identify or interpret significant placental lesions is the major cause of the inability to explain severe injuries in newborns, including cerebral palsy.4,5,8 

There is no universally accepted system of classification for placental hypoxic lesions, and pathologists use different, sometimes only vaguely defined, terms to describe features and patterns in this respect. Although several excellent textbooks discuss the placental diagnosis of hypoxia913  and results of a consensus panel have been published,14  this review aims to summarize the recent literature data and my personal experience on this topic.

Histologic findings may indicate placental injury by decreased oxygen content, either occurring abruptly (acutely) or present chronically or as a fetal/placental reaction/adaptation to hypoxia, again developing relatively rapidly or during longer periods. Placental maturation is the most discriminative and by far the most important feature to assess in the diagnosis of chronic, in utero hypoxia, but it is also the most difficult to assess and the least-reproducible placental feature, even by experienced placental pathologists.15  It is impossible to assess placental maturation without a knowledge of gestational age, but, even if gestational age is known, the variation of maturation patterns is wide. The knowledge that, as pregnancy advances, terminal villi and syncytial knots become numerous, villous cytotrophoblasts and Hofbauer cells become less visible, the number of vascular profiles decrease, and the extracellular matrix of chorionic villi becomes denser, is of little help in individual cases, and the pathologist's experience is what matters. Thresholds of abnormality (Table 1) and reference range values for individual variables for gestational weeks can be helpful,1618  but they are not available for all hypoxia-related placental features.

Table 1.

Histologic Features of Placental and Fetal Hypoxic Lesions/Patterns

Histologic Features of Placental and Fetal Hypoxic Lesions/Patterns
Histologic Features of Placental and Fetal Hypoxic Lesions/Patterns

A normal placenta shows heterogeneous maturation because better-oxygenized centers of cotyledons (placentones) are less mature (larger chorionic villi with less syncytial knots) than are their peripheral parts, where the less-oxygenized blood returns toward the uterus.19  The accelerated heterogeneous hypermaturity (Figure 1, A) is a sensitive feature of uteroplacental malperfusion.20  Homogeneous placental maturation is always abnormal, the placentas being either hypomature (Figure 1, B) or hypermature (Figure 1, C). For obvious reasons, villous hypermaturity is easier to appreciate in preterm placentas and villous hypomaturity is easier in full-term placentas.

Figure 1. 

Histopathologic features of placental hypoxia. A, Heterogeneous hypermaturity, 21 weeks, early neonatal death. B, Homogeneous hypomaturity, 40 weeks, maternal substance abuse, abnormal cardiotocography, grade 1 maceration. C, Homogeneous hypermaturity, twin A, 29 weeks gestation, reversed end-diastolic blood flow. D, Villous hypervascularity, 40 weeks, nonreassuring fetal heart rate. E, Villous hypovascularity, 19 weeks, macerated growth restricted stillbirth. F, Decreased extracellular matrix, 29 weeks hemolysis, elevated liver enzymes, low platelets (HELLP). G, Villous edema with split artifact, 20 weeks, nonmacerated stillbirth. H, Increased extracellular matrix, 32 weeks, severe preeclampsia, fetal growth restriction, abnormal cardiotocography. I, Increased villous cytotrophoblasts, 37 weeks, fetal growth restriction, abnormal Doppler results. J, Increased villous cytotrophoblasts, better highlighted with double immunostain (E-cadherin-red, Ki-67 brown); E-cadherin stains membranes of villous cytotrophoblasts (some proliferating) and internal membranes of syncytiotrophoblasts (nonproliferating), 26 weeks, severe preeclampsia, late decelerations. K. Increased syncytial knotting, 28 weeks, fetal growth restriction. L, Syncytial sprouting (unknown clinical significance), 36 weeks, tetraploidy, fetal growth restriction, abnormal Doppler results and cardiotocography. M, Numerous Hofbauer cells, stillbirth, 24 weeks, oligohydramnios sequence, premature closure of ductus arteriosus, fetal anemia. N, Absent Hofbauer cells, preterm, premature rupture of membranes, 32 weeks. O, Stem perivascular edema and obliterative endarteritis, nonreassuring fetal heart rate, thick meconium, hypercoiled umbilical cord, 40 weeks (hematoxylin-eosin, original magnifications ×10 [A through C, E, F, L, and N] and ×20 [D, G through I, K, M, and O]; original magnification ×20 [J]).

Figure 1. 

Histopathologic features of placental hypoxia. A, Heterogeneous hypermaturity, 21 weeks, early neonatal death. B, Homogeneous hypomaturity, 40 weeks, maternal substance abuse, abnormal cardiotocography, grade 1 maceration. C, Homogeneous hypermaturity, twin A, 29 weeks gestation, reversed end-diastolic blood flow. D, Villous hypervascularity, 40 weeks, nonreassuring fetal heart rate. E, Villous hypovascularity, 19 weeks, macerated growth restricted stillbirth. F, Decreased extracellular matrix, 29 weeks hemolysis, elevated liver enzymes, low platelets (HELLP). G, Villous edema with split artifact, 20 weeks, nonmacerated stillbirth. H, Increased extracellular matrix, 32 weeks, severe preeclampsia, fetal growth restriction, abnormal cardiotocography. I, Increased villous cytotrophoblasts, 37 weeks, fetal growth restriction, abnormal Doppler results. J, Increased villous cytotrophoblasts, better highlighted with double immunostain (E-cadherin-red, Ki-67 brown); E-cadherin stains membranes of villous cytotrophoblasts (some proliferating) and internal membranes of syncytiotrophoblasts (nonproliferating), 26 weeks, severe preeclampsia, late decelerations. K. Increased syncytial knotting, 28 weeks, fetal growth restriction. L, Syncytial sprouting (unknown clinical significance), 36 weeks, tetraploidy, fetal growth restriction, abnormal Doppler results and cardiotocography. M, Numerous Hofbauer cells, stillbirth, 24 weeks, oligohydramnios sequence, premature closure of ductus arteriosus, fetal anemia. N, Absent Hofbauer cells, preterm, premature rupture of membranes, 32 weeks. O, Stem perivascular edema and obliterative endarteritis, nonreassuring fetal heart rate, thick meconium, hypercoiled umbilical cord, 40 weeks (hematoxylin-eosin, original magnifications ×10 [A through C, E, F, L, and N] and ×20 [D, G through I, K, M, and O]; original magnification ×20 [J]).

Close modal

Villous hypervascularity (Figure 1, D; Table 1) can be diffuse or focal, both either fulfilling or not fulfilling the Altshuler rule of tens.1,21,22  Capillary profiles can be highlighted by endothelial markers, for example, CD34, to facilitate counting; however, for the diagnosis of chorangiosis, the cutoff point of 20 lumens, instead of 10 lumens, on hematoxylin-eosin slide23  should be used as more vascular lumens are seen by immunohistochemistry. Villous hypovascularity/avascularity (Figure 1, E) can be diffuse and associated, for example, with prolonged stillbirth, or focal, as in fetal thrombotic vasculopathy.10,12,13 

The extracellular matrix of chorionic villi can be decreased, and the villous cores, thus, as pale as the intervillous space (Figure 1, F). Such a finding has to be distinguished from villous edema, where, in addition, a split artifact between the trophoblastic shell and the villous core is, at least focally, present (Figure 1, G).24  An increased, extracellular matrix of chorionic villi, produced in excess by villous fibroblasts in response to intravillous hypoxia associated with intervillous hyperoxemia,25,26  manifests as intense eosinophilia of villous cores (Figure 1, H).

Villous cytotrophoblasts are easily identified in the second trimester, but in the third trimester are not seen in abundance, except in chronic hypoxia that inhibits the trophoblast fusion and differentiation and stimulates proliferation, like in preeclampsia (Figure 1, I).2730  They can be more easily distinguished from endothelial cells and syncytiotrophoblasts using the E-cadherin/Ki-67 double immunostain, the former highlighting the cell membrane of villous cytotrophoblasts and the inner syncytiotrophoblastic cell membrane, and the latter staining the nuclei of proliferating cells (Figure 1, J).

Syncytial knots have transcriptionally inactive, condensed nuclei, without nucleoli, which can be either normal (granular, nonapoptotic) and due to tangential cutting (Figure 1, K), or smudgy (apoptotic) and due to nuclear aging31  (Figure 1, H). They should be distinguished from the transcriptionally active syncytial sprouting, which shows prominent syncytiotrophoblastic nucleoli (Figure 1, L) and is usually seen in the first and second trimesters,9,32,33  and the clinical significance of which is not clear at this time. The number of knots is positively correlated with the length of time and the severity of the hypertensive diseases of pregnancy.34 

Villous Hofbauer cells synthesize proteins that stimulate a villous proliferation in response to hypoxia.35  They are easily seen in the first and second trimesters, but not in the third trimester (Figure 1, M). A decrease in the amount of CD68+ cells during second and third trimester is continuous and gradual17  (Figure 1, N).

Stem obliterative endarteritis, a misnomer term applied to a swelling of intimal cells with occlusion of vascular lumen (Figure 1, O), due to hypoxia-stimulated medial vasoconstriction, is essentially a herniation of smooth muscle cytoplasm into the vascular lumen. It is linked to various pregnancy complications, particularly preeclampsia and fetal growth restriction (FGR),12  but also umbilical cord hypercoiling, where it tends to be associated with stem perivascular edema.36 

These developmental changes can be primary due to an intrinsic placental defect or secondary to intervillous hypoxemia. The patterns should not be confused with the clinical term placental insufficiency, which indicates a complication of pregnancy in which the placenta cannot carry enough oxygen and/or nutrients to the growing fetus and usually implies the presence of FGR.37 

The placental response to hypoxia does not follow a single pathway,21  the type of placental maturation and villous vascularity being the 2 key features used in classification of placental chronic-hypoxic patterns (Table 2). Features listed in Table 1 and discussed in the preceding section are also helpful.21,31,38 

Table 2.

Patterns of Chronic Hypoxic Placental Injury

Patterns of Chronic Hypoxic Placental Injury
Patterns of Chronic Hypoxic Placental Injury

The preuterine pattern (PR) of chronic, hypoxic placental injury features, histologically, homogeneous placental maturation (ie, the chorionic villi are plump and of similar size from field to field); increased villous vascularity, including practically all cases of diffuse chorangiosis; decreased extracellular matrix of chorionic villi and villous cytotrophoblasts; increased Hofbauer cells; and increased nonapoptotic syncytial knotting21,31  (Figure 2, A). Because of villous enlargement, the placenta looks hypomature, except for the focally increased syncytial knots, which is not, however, a constant feature. Placentomegaly and more-advanced gestational age are frequently seen.21,39  The pattern is evoked by maternal hypoxemia secondary to decreased oxygen pressure in the environment (pregnancies at high altitudes), decreased oxygen binding capacity of the maternal blood (maternal anemia), air pollution and maternal smoking, increased distension of the uterus (multiple pregnancy), and maternal diabetes mellitus (abnormal oxygen-hemoglobin dissociation curve).21,3844  Clusters of multinucleate giant cells in the decidua basalis and excessive numbers of extravillous trophoblasts are less commonly seen in this than in other patterns of diffuse hypoxic placental injury,21  most likely because of the association of PR with deep trophoblastic, myometrial invasion, which was proven, at least in maternal anemia.45  This pattern has a better prognosis than other types of chronic hypoxic injury,21  probably because of hypoxic preconditioning and resistance to ischemia-reperfusion injury during labor, as was proven in pregnancies at high altitudes46  and multiple pregnancies.43 

Figure 2. 

Basic patterns of hypoxic placental injury. A, Preuterine hypoxic pattern, 36-week pregnancy, maternal anemia; homogeneous villous hypomaturity, chorangiosis, focally increased syncytial knotting, decreased extracellular matrix of chorionic villi, increased Hofbauer cells and villous cytotrophoblasts. B, Uterine hypoxic pattern, 32 weeks, severe preeclampsia, focal villous hypermaturity, focally increased villous cytotrophoblasts (left side of microphotograph), decreased extracellular matrix of chorionic villi, increased Hofbauer cells and nonapoptotic syncytial knotting. C, Diffuse postuterine hypoxic pattern, 21 weeks, maternal substance abuse, retained stillbirth; homogeneous maturation, increased extracellular matrix decreased vascularity. D, Diffuse postuterine hypoxic pattern, 41 weeks, fetal growth restriction; homogeneous villous hypermaturity with terminal villous hypoplasia, increased extracellular matrix, decreased vascularity, villous cytotrophoblasts, increased apoptotic syncytial knotting. E, Focal postuterine pattern (fetal artery thrombosis), 34 weeks, gestational hypertension and fetal growth restriction; a cluster of avascular chorionic villi with increased extracellular matrix. F, Dysmature/hypomature placenta (villous maturation defect), 39 weeks, unexpected stillbirth; inset, CD34 immunostain highlighting poorly formed vasculosyncytial membranes (hematoxylin-eosin, original magnifications ×10 [A, B, and E], ×20 [C, D, and F], and ×40 [inset]).

Figure 2. 

Basic patterns of hypoxic placental injury. A, Preuterine hypoxic pattern, 36-week pregnancy, maternal anemia; homogeneous villous hypomaturity, chorangiosis, focally increased syncytial knotting, decreased extracellular matrix of chorionic villi, increased Hofbauer cells and villous cytotrophoblasts. B, Uterine hypoxic pattern, 32 weeks, severe preeclampsia, focal villous hypermaturity, focally increased villous cytotrophoblasts (left side of microphotograph), decreased extracellular matrix of chorionic villi, increased Hofbauer cells and nonapoptotic syncytial knotting. C, Diffuse postuterine hypoxic pattern, 21 weeks, maternal substance abuse, retained stillbirth; homogeneous maturation, increased extracellular matrix decreased vascularity. D, Diffuse postuterine hypoxic pattern, 41 weeks, fetal growth restriction; homogeneous villous hypermaturity with terminal villous hypoplasia, increased extracellular matrix, decreased vascularity, villous cytotrophoblasts, increased apoptotic syncytial knotting. E, Focal postuterine pattern (fetal artery thrombosis), 34 weeks, gestational hypertension and fetal growth restriction; a cluster of avascular chorionic villi with increased extracellular matrix. F, Dysmature/hypomature placenta (villous maturation defect), 39 weeks, unexpected stillbirth; inset, CD34 immunostain highlighting poorly formed vasculosyncytial membranes (hematoxylin-eosin, original magnifications ×10 [A, B, and E], ×20 [C, D, and F], and ×40 [inset]).

Close modal

The uterine (UH) pattern of chronic hypoxic placental injury (Figure 2, B) is typically seen in preeclampsia and late-onset FGR.31,38  The term uterine is used here to refer to the maternal portions of the uteroplacental circulation, including its myometrial and decidual segments, which are the cause of pathologic placental changes. It is favored over uteroplacental to avoid confusion as to whether the maternal or the fetal side of the placenta is primarily involved.47  Heterogeneous placental hypermaturity, with only focally increased villous vascularity, villous cytotrophoblast density, Hofbauer cells, and nonapoptotic syncytial knotting, and a decreased extracellular matrix of chorionic villi are the characteristic features. As with PR, the focal hypervascularity is an adaptive mechanism, reaching the level of chorangiosis in some cases, whereas, in other cases, the villous capillary profiles remain between 7 and 9 per chorionic villus (incipient or emerging chorangiosis).22  The UH pattern is frequently associated with other placental features of uteroplacental malperfusion related to shallow, trophoblastic invasion, such as an accumulation of extravillous trophoblasts in the placental membranes (Figure 3, A), characteristically with membrane chorionic microcyst formation (Figure 3, B), and in the chorionic disc (Figure 3, C), again, typically, with microcyst formations (Figure 3, D), decidual clusters of multinucleate trophoblasts (Figure 3, E) and basal-plate myometrial fibers, and occult placenta accreta (Figure 3, F).27,38,4854  Excessive amounts of extravillous trophoblasts must be distinguished from massive perivillous fibrin deposition/maternal floor infarction,49  which is associated with FGR, impaired neurologic development, recurrent fetal loss, and stillbirth,9,12,55  but not necessarily with UH. Pathogenesis of the massive, perivillous fibrin deposition is different,9  but it can evoke fetal hypoxia by virtue of eliminating a substantial amount of functional placental parenchyma. I regard the above-presented extravillous trophoblasts lesions, along with the decidual arteriolopathy (both hypertrophic and atherosis), as the complementary criteria for this type of chronic placental hypoxia in histologically borderline cases.21  The UH and associated histologic findings cluster with severe preeclampsia, but not with mild preeclampsia; gestational hypertension; hemolysis, elevated liver enzymes, and low platelets (HELLP); or eclampsia56  There is growing evidence that there are basic differences in the pathogenesis of mild and severe preeclampsia, the former usually occurring as a late onset, and the latter, usually having an early onset,5760  to which we recently contributed the molecular basis.61 

Figure 3. 

Extravillous trophoblastic hypoxic lesions. A, Increased amount of extravillous trophoblasts in placental membranes, double immunostain E-cadherin (red)/Ki-67 (brown), 31 weeks, severe preeclampsia. B, Membrane microscopic chorionic pseudocysts, 36 weeks, mild preeclampsia and fetal growth restriction, abnormal cardiotocography. C, Increased extravillous trophoblasts, stillbirth at 17 weeks; 4 cell islands are seen only in this field. D, Microscopic, chorionic pseudocysts of chorionic disc; nonmacerated stillbirth at 31 weeks. E, Multinucleate trophoblastic cells in decidua basalis, termination of pregnancy for double outlet right ventricle at 22 weeks. F, Occult placenta accreta, twin pregnancy, severe preeclampsia, 27 weeks, neonatal death on day 6 of life. No decidua is seen between myometrial fibers (left) and maternal flood extravillous trophoblasts (right). This lesion is associated with increased extravillous trophoblasts at the maternal floor57  (original magnification ×40 [A]; hematoxylin-eosin, original magnifications ×10 [B], ×4 [C through E], and ×40 [F]).

Figure 3. 

Extravillous trophoblastic hypoxic lesions. A, Increased amount of extravillous trophoblasts in placental membranes, double immunostain E-cadherin (red)/Ki-67 (brown), 31 weeks, severe preeclampsia. B, Membrane microscopic chorionic pseudocysts, 36 weeks, mild preeclampsia and fetal growth restriction, abnormal cardiotocography. C, Increased extravillous trophoblasts, stillbirth at 17 weeks; 4 cell islands are seen only in this field. D, Microscopic, chorionic pseudocysts of chorionic disc; nonmacerated stillbirth at 31 weeks. E, Multinucleate trophoblastic cells in decidua basalis, termination of pregnancy for double outlet right ventricle at 22 weeks. F, Occult placenta accreta, twin pregnancy, severe preeclampsia, 27 weeks, neonatal death on day 6 of life. No decidua is seen between myometrial fibers (left) and maternal flood extravillous trophoblasts (right). This lesion is associated with increased extravillous trophoblasts at the maternal floor57  (original magnification ×40 [A]; hematoxylin-eosin, original magnifications ×10 [B], ×4 [C through E], and ×40 [F]).

Close modal

The postuterine (PU) (postplacental) pattern of chronic hypoxic placental injury is due to primary villous changes resulting in decreased intake of oxygen from the intervillous space, as in retained stillbirth (Figure 2, C), subsets of FGR (Figure 2, D) and preeclampsia, and fetal thrombotic vasculopathy (only focally)13,38  (Figure 2, E). Clinically, abnormal Doppler flow velocity waveforms obtained from umbilical arteries that reflect the downstream blood flow impedance may give an indirect evidence of vascular tree abnormalities.62  The fetoplacental blood flow is compromised to a far greater extent in FGR with absent end-diastolic blood flow, such that maternal blood leaving the placenta has higher oxygen content than it does under normal circumstances.63  The PU features homogeneous placental hypermaturity and hypovascularity, with slender, pencillike chorionic villi; so-called terminal villous hypoplasia13 ; increased extracellular matrix of chorionic villi and apoptotic syncytial knots; and decreased villous Hofbauer cells and villous cytotrophoblasts.31  The clinical, umbilical cord compromise with focal placental lesions of decreased fetal blood flow, which is frequently a random pregnancy accident, did not correlate with diffuse PU, although they can produce the focal PU, so-called stasis-induced thrombotic vasculopathy, with clusters of avascular, fibrotic, and occasionally hemosiderotic chorionic villi.64,65  Also, severe, mass-forming, congenital anomalies that interfere with blood return from the placenta to the fetus can produce the placental stasis-induced thrombotic vasculopathy, but not the diffuse PU.66 

Hypomature placentas (placentas with maturation defect) are pale, normal sized or even larger than normal, with plumper terminal chorionic villi, superficially resembling intermediate villi,67  and show defective formation of both terminal villous sinusoids (although numerically usually normal) and vasculosyncytial membranes (Figure 2, F), which can be better highlighted with CD34 immunostain (Figure 2, F inset). Although the vasculosyncytial membranes are normally poorly formed in early pregnancy, they are well formed in term pregnancies and are absent in only 5% of chorionic villi at term.12  In this type of placental pathology in pregnancies of 35 weeks or longer, on average, 1 vasculosyncytial membrane per terminal villus was found as compared with, on average, 3 per chorionic villi normally seen.68  Villous hypomaturity is responsible for 22.5% of intrauterine deaths69  and has a 70-fold increased risk of associated fetal death, with a 10-fold risk for recurrence, compared with baseline.70  The fetuses die because of hypoxia,1  but they can be rescued by earlier delivery.70  There is an association between maternal diabetes mellitus71  and fetal anomalies72  and maturation defect placentas, but vasculosyncytial membranes are also decreased in umbilical cord hypercoiling.73  Diabetes mellitus is a state of chronic oxidative stress,74  and glycemia appears to have an affect on the capillary, but not the stromal component, of chorionic villi.75  Placental angiogenesis is stimulated by insulin via ephrin-B2 expression, a signaling molecule implicated in sprouting.76  Therefore, this subtype of PR chronic hypoxic pattern appears to include the PU component because of fetal hyperinsulinemia.

The above-discussed patterns of chronic hypoxic placental injury are of a developmental origin because they are programmed and initiated early in pregnancy, some of them probably due to fetal or maternal genetic causes, and are usually fully developed at the turn of the second and the third trimester or later. Serum biomarkers of preeclampsia have been shown to be altered at as early as 7 weeks gestation, indicating that the onset of placental abnormalities in preeclampsia occurs even earlier than the onset of maternal blood flow, when failure of transformation of spiral arteries are thought to occur.77  Maldevelopment of the maternal spiral arteries in the first trimester predisposes to placental dysfunction and suboptimal pregnancy outcomes in the second half of pregnancy.78  The UH is, therefore, a maternal, hypoxemia-induced, focal-adaptive villous change, whereas PU is associated with intervillous hyperoxemia. The patterns may predispose a patient toward a greater vulnerability for superimposed, acute hypoxic lesions (overlap patterns/lesions, see below) or may sometimes protect against acute hypoxia in labor because PR can be an adaptive placental response and, in fact, protect the fetus against birth-related hypoxia.46 

Although characteristic, histologic features were originally described for the above patterns,31  I have proposed, based on the histologic picture, that one can predict what the pathogenesis of villous hypoxia is because the 3 patterns cluster with various clinical settings and associated placental findings.56  The practical value of using the histologic terms PR, UH, and PU lies in keeping the pathologists aware that there is no single pattern of chronic hypoxic placental injury and, therefore, in expanding the pathologists' armamentarium in this respect.

In my experience,21  UH is most commonly associated with severe preeclampsia and the HELLP syndrome; PU, with abnormal Doppler results, induction of labor, clinical umbilical cord abnormalities, cesarean section rate, and FGR; and PR, with multiple pregnancies. Overall, PU is the most ominous and PR the least ominous histologic subtype of chronic in utero hypoxia. Sensitivity of placental injury from diffuse, chronic hypoxic placental injury is less than 50% for the main clinical conditions known to be associated with in utero hypoxia, and most cases of preeclampsia, pregnancy-induced hypertension, diabetes mellitus, nonreassuring fetal heart rate tracing, abnormal Doppler results (absent or reversed end-diastolic umbilical artery flow), and FGR were found in patients without diffuse placental hypoxic patterns. On the other hand, the high (>90%) specificity of the chronic hypoxic patterns of placental injury means that, in the presence of those histologic patterns, the clinical manifestations of chronic in utero hypoxia are very likely; therefore, the positive identification of one of the patterns is significant and unlikely to occur solely by chance.

Infarction is the tissue necrosis due to acute blood and oxygen deprivation either to placental membranes or decidua basalis (laminar necrosis) or villous tissue (villous infarction).

Membrane laminar necrosis (Figure 4, A), decidual, trophoblastic, or mixed, is a band of coagulative necrosis at the trophoblast/decidual interface and is associated with FGR,79  maternal hypertensive disorders, and other conditions linked to in utero hypoxia.48,80  It shows a characteristic evolutionary pattern (Figure 5, A). The significance of isolated amnion necrosis81  has not been independently confirmed, yet but most cases of amnion necrosis are meconium-induced (very common), whereas focal necrosis of the media of umbilical arteries of the umbilical cord is a rare response to meconium.1,82  Laminar necrosis of the decidua basalis has been also described.83  (Figure 4, B).

Figure 4. 

Acute hypoxic lesions. A, Laminar decidual necrosis of membranes, 38 weeks, abnormal intrapartum cardiotocography. B, Laminar necrosis of decidua basalis with focal calcification, 39 weeks, morbid obesity, and depressed neonate with meconium aspiration syndrome died at age of 6 hours. C, Intravillous hemorrhage (red infarction), 20 weeks, placental abruption. D, Villous infarction with zonation indicative of varying age of the lesion which may suggest that the lesion was enlarging with time, placental abruption, 32 weeks (hematoxylin-eosin, original magnifications ×10 [A, B, and D] and ×20 [C].

Figure 4. 

Acute hypoxic lesions. A, Laminar decidual necrosis of membranes, 38 weeks, abnormal intrapartum cardiotocography. B, Laminar necrosis of decidua basalis with focal calcification, 39 weeks, morbid obesity, and depressed neonate with meconium aspiration syndrome died at age of 6 hours. C, Intravillous hemorrhage (red infarction), 20 weeks, placental abruption. D, Villous infarction with zonation indicative of varying age of the lesion which may suggest that the lesion was enlarging with time, placental abruption, 32 weeks (hematoxylin-eosin, original magnifications ×10 [A, B, and D] and ×20 [C].

Close modal
Figure 5. 

Evolution of acute hypoxic membrane and villous lesions. A. Evolution of membrane laminar necrosis: immunostain for nitrotyrosin residues (a marker for oxidative stress, ×10), immunostain for M30 (an irreversible apoptosis marker, ×20), immunostain for complement 9 (a marker for necrosis, ×20), leukocytoclastic laminar necrosis (hematoxylin-eosin, ×10), von Kossa histochemistry stain highlighting focal dystrophic calcification (×20). B. Evolution of villous infarction, all stains are hematoxylin-eosin with lens magnifications: ×10, ×20, ×20, ×20, ×40, ×20.

Figure 5. 

Evolution of acute hypoxic membrane and villous lesions. A. Evolution of membrane laminar necrosis: immunostain for nitrotyrosin residues (a marker for oxidative stress, ×10), immunostain for M30 (an irreversible apoptosis marker, ×20), immunostain for complement 9 (a marker for necrosis, ×20), leukocytoclastic laminar necrosis (hematoxylin-eosin, ×10), von Kossa histochemistry stain highlighting focal dystrophic calcification (×20). B. Evolution of villous infarction, all stains are hematoxylin-eosin with lens magnifications: ×10, ×20, ×20, ×20, ×40, ×20.

Close modal

Acute restriction of focal, spiral artery blood flow or premature detachment of the placenta from the uterus causes villous infarction (Figure 4, C and D), the historically most frequently (or readily) diagnosed placental lesion, which starts to develop 2 to 4 hours to 4 days after an acute hypoxic event,13  the incidence thereof depending on gestational age, with preterm preeclamptic placentas being more vulnerable.57,84  Early coagulation necrosis of the placenta underlying a retroplacental hematoma of placental abruption begins in 4 to 24 hours13  but is not complete after more than 24 hours.85  A sequence of acute hypoxic placental lesions leads to formation of placental infarction, from congestion through agglutination of villi and intravillous stromal hemorrhage, at which time, it is irreversible (red infarction) (Figure 5, B). The accurate time frame of these sequential changes in humans is impossible to determine because, unlike, for example, in the myocardium, it is not possible to correlate the infarction histology with such factors as pain, serology, or electrocardiography, but results from monkey experimental studies, which revealed sequential placental infarction changes, were helpful.86  Villous infarctions have their diagnostic limitations because they occur not infrequently in otherwise uncomplicated pregnancies, indicating a substantial placental reserve. In an attempt to increase the specificity of the diagnosis, only infarctions in a central/paracentral location and occupying more than 5% to 20% of the placental parenchyma, are regarded as diagnostically significant.12,14,84  I use the lower threshold: central/paracentral infarction of at least 5% of placental parenchyma, and with that threshold, the sensitivity reaches 40% for preeclampsia.38  The sensitivity can be higher if the noninfarcted placental parenchyma shows features of diffuse global hypoxia (an overlap lesion, see below).

Of fetal hypoxic lesions, mild erythroblastosis of fetal blood (Figure 6, A) is regarded as the only reliable (and, therefore, the best) evidence of chronic, in utero hypoxia; however, fetal erythroblasts can also be released from their stores in response to acute hypoxia.9,13  Apart from hypoxia, nucleated red blood cells in fetal circulation can increase from infection; maternal diabetes mellitus; fetal anemia, as in erythroblastosis fetalis; and acute blood loss.10 

Figure 6. 

Placental lesions suggestive of fetal hypoxia. A, Erythroblasts in fetal blood, 38 weeks; mother was a heavy smoker. B, Necrosis of outer media of umbilical artery, meconium macrophages in Wharton jelly, umbilical cord vasculitis. Unprovoked decelerations, meconium-stained amniotic fluid, 41 weeks, clinically thick meconium (hematoxylin-eosin, original magnifications ×20 [A] and ×40 [B]).

Figure 6. 

Placental lesions suggestive of fetal hypoxia. A, Erythroblasts in fetal blood, 38 weeks; mother was a heavy smoker. B, Necrosis of outer media of umbilical artery, meconium macrophages in Wharton jelly, umbilical cord vasculitis. Unprovoked decelerations, meconium-stained amniotic fluid, 41 weeks, clinically thick meconium (hematoxylin-eosin, original magnifications ×20 [A] and ×40 [B]).

Close modal

Fetal erythroblastosis is stimulated by an increase in erythropoietin in response to hypoxia with a few hours' delay, with its umbilical blood level correlating with umbilical arterial pH.87,88  The finding of appreciable amount of nucleated red blood cells in the placental circulation requires 6 to 12 hours or more, with umbilical blood, nucleated red blood cells being the gold standard.89  However, a sample of umbilical blood may not be obtained at delivery, so nucleated red blood cell counts in histologic placental sections can be used as a surrogate test for fetal hypoxia.89  Placental erythroblastosis may require severe, ongoing hypoxic stress of at least days', if not weeks', duration, and stillborn fetuses, dying of hyperacute etiologies, characteristically do not exhibit normoblastemia.24 

Some authors advice counting nucleated red blood cells per 100 white blood cells because the placental counts correlate well with umbilical blood counts1,89 ; however, that is not practical, and most authors use subjective9  or semiquantitative73  criteria to assess the number of nucleated red blood cells. I regard more than 1 erythroblast per high-power field in the third trimester of pregnancy as abnormal. Using this approach, nucleated red blood cells were found with increased frequency in association with acute and chronic, placental hypoxic lesions38 ; multinucleated, trophoblastic giant cells in decidua52 ; and, clustered with PR.56  Some authors found elevated nucleated red blood cells not only in primarily maternal or primarily chorionic disc pathology but also in umbilical cord abnormalities.73,90 

Another fetal product commonly seen in placental sections is meconium, free or in macrophages. With free pigment/pigmented macrophages in membranes, I usually make my decision on hematoxylin-eosin slides to distinguish between meconium and hemosiderin because of granular refractibility of the latter, even if both pigments coexist. Presence of either pigment does not, however, appear to be strongly associated with acute, in utero hypoxia91  or with chronic placental separation,92  respectively. Hemosiderin forms in tissue after 2 to 3 days after bleeding,65  which can be useful when placental examination is a part of autopsy and timing is important. In that situation, I perform an iron stain if in doubt about nature of the pigment. Conspicuous meconium-laden macrophages at the chorionic surface of the placenta indicate that the fetus discharged meconium at least 2 to 3 hours before delivery. Abundant meconium-laden macrophages extensively deep in the placental membranes indicates meconium passage at least 6 to 12 hours before delivery.82,93  Within 12 to 20 hours, the amnion can show signs of pseudostratification, cell degeneration, and even necrosis.94  In the umbilical cord, necrotic arterial media with adjacent meconium-laden macrophages (Figure 6, B) indicates meconium discharge 12 to 16 hours before delivery by some authors95  or at least 48 hours before delivery by other investigators. Meconium macrophages are diagnosed on histologic placental examination more frequently than meconium-stained amniotic fluid clinically,21,48,38  possibly because after very recent meconium release, the membranes are not yet stained or because amniotic fluid can be cleared after a few days because of placental meconium phagocytosis. The primary cause of the meconium release (possibly hypoxia) may be difficult to separate from the toxic effects meconium has on fetal vessels. Histologic effects of meconium release depend not only on fetal stress/distress but also on meconium concentration in the amniotic fluid (thick meconium). Most authors agree that histologic meconium staining poorly correlates with clinical conditions that are potentially complicated by fetal hypoxia,9,91,96  and histologic meconium is not a feature of fetal distress.9  It is more common in term pregnancies,56  corresponding to the hypoxic-ischemic injury (also more common in term infants)13  and in association with chorionic disc diffuse and focal hypoxic lesions.38,97  I share the opinion that the presence of meconium macrophages is a nonspecific feature of fetal hypoxia and indicative of fetal stress, rather than distress, in most cases,91  unless numerous meconium macrophages are seen deep in the decidua parietalis.

The term hypoxic overlap lesions means the coexistence of different hypoxic lesions or patterns from the same group,56  such as, acute and chronic (Figure 7, A and B) or diffuse and focal (Figure 7, C through E). A decreased placental reserve by virtue of the presence of chronic, diffuse hypoxic injury can be more easily decompensated by an overlapping, acute hypoxia of a lesser degree (acute-on-chronic hypoxia) than would be required in an otherwise normal placenta.13,38  Mild erythroblastosis of fetal blood was 3 times more common in placentas with other hypoxic lesions than it was in those placentas without them.38  Therefore multiple placental hypoxic lesions, rather than as a single lesion, pose a greater risk of fetal growth restriction and neurologic impairment.8,38,98 

Figure 7. 

Overlap hypoxic lesions/patterns. A, Acute-on-chronic villous hypoxia with clustering of chorionic villi against a background of the uterine hypoxic pattern, 34 weeks, anhydramnios, preterm premature rupture of membranes. B, Acute-on-chronic membrane hypoxia; laminar necrosis and microscopic chorionic pseudocysts in the placental membranes, 36 weeks, mild preeclampsia and severe fetal growth restriction. C, Preuterine hypoxic pattern with intravillous hemorrhage, 19 weeks, amniotic sac infection syndrome complicated by placental abruption. D, Postuterine hypoxic pattern and placental infarction, 36 weeks, mild preeclampsia and fetal growth restriction. E, Fetal artery thrombosis (focal postuterine hypoxic pattern) over the preuterine hypoxic pattern, 40 weeks, macerated stillbirth, thick meconium (hematoxylin-eosin, original magnifications ×20 [A], ×4 [B, D, and E], and ×10 [C]).

Figure 7. 

Overlap hypoxic lesions/patterns. A, Acute-on-chronic villous hypoxia with clustering of chorionic villi against a background of the uterine hypoxic pattern, 34 weeks, anhydramnios, preterm premature rupture of membranes. B, Acute-on-chronic membrane hypoxia; laminar necrosis and microscopic chorionic pseudocysts in the placental membranes, 36 weeks, mild preeclampsia and severe fetal growth restriction. C, Preuterine hypoxic pattern with intravillous hemorrhage, 19 weeks, amniotic sac infection syndrome complicated by placental abruption. D, Postuterine hypoxic pattern and placental infarction, 36 weeks, mild preeclampsia and fetal growth restriction. E, Fetal artery thrombosis (focal postuterine hypoxic pattern) over the preuterine hypoxic pattern, 40 weeks, macerated stillbirth, thick meconium (hematoxylin-eosin, original magnifications ×20 [A], ×4 [B, D, and E], and ×10 [C]).

Close modal

In my collection of 5445 consecutive placentas older than 20 weeks, 47% of the placentas (n = 2564) did not show hypoxic features, and 53% (n = 2881) did. This illustrates the magnitude of the problem and the importance of diagnosing hypoxic lesions in the placenta. The purely placental hypoxic lesions dominated the purely fetal hypoxic lesions. The PR pattern was the most common, diffuse, chronic hypoxic pattern. More cases of preeclampsia, maternal diabetes mellitus, abnormal cardiotocography, abnormal dopplers, FGR, and cesarean sections and fewer cases of premature deliveries, congenital anomalies, and acute chorioamnionitis were seen in association with, or without, placental hypoxic lesions/patterns, respectively (Figure 8).99 

Figure 8. 

Placental hypoxic lesions in the author's material.

Figure 8. 

Placental hypoxic lesions in the author's material.

Close modal

Because placental oxygen consumption is 4 times higher than fetal oxygen consumption is, the placenta is affected by in utero hypoxia first, followed, only later, by fetal compromise in some cases, as was proven in experimental studies for midgestation.100  The placenta features a high reserve capacity so that placental signs of fetal hypoxia are far less common than are those of pure placental hypoxia.21,38  Fetal hypoxia can also occur acutely (eg, after an acute cord compromise or placental abruption), without any associated histologic placental hypoxic lesions. On the other hand, because of the large reserve capacity, despite the presence of hypoxic lesions, the fetus can be normoxic and well, so an absolute correlation between placental hypoxic lesions and the maternal and fetal condition should not be expected, particularly because many complications of pregnancy occur either acutely or are not primarily due to placental pathology.

In summary, various types of hypoxic patterns have been discussed here, and lesions are depicted in Figure 9. The systematic identification of those patterns in a particular case should help to identify more placental hypoxic lesions, not just those limited to poor uteroplacental perfusion, and to clarify the etiopathogenesis of a significant proportion of the complications of pregnancy and abnormal fetal or neonatal outcomes. Because the placenta does not respond in a single way to hypoxia, the histologic changes should be explained in the clinical context and in conjunction with the gross placental and umbilical cord findings. Moreover, because the frequency and degree of expression of many of placental features are qualitatively and/or quantitatively gestational age-dependent, 17,18,57,101,102  for precise evaluation (normal versus abnormal), the criteria presented in Table 1 may be insufficient, and comparison with tables of norms stratified by gestational age may be necessary, but those tables are not, however, available for all hypoxic variables. Such an approach can be helpful not only to better explain cases of perinatal morbidity/mortality and the mechanism of fetal injury, which could potentially be beneficial for management of future pregnancies, but also to help in medicolegal investigation of cases of perinatal morbidity/mortality.

Figure 9. 

Diagram of acute and chronic placental lesions with relation to fetal hypoxia. Abbreviations; ECM, extracellular matrix of chorionic villi; VCT, villous cytotrophoblasts; EVT, extravillous trophoblasts; MCC, microscopic chorionic (pseudo)cysts.

Figure 9. 

Diagram of acute and chronic placental lesions with relation to fetal hypoxia. Abbreviations; ECM, extracellular matrix of chorionic villi; VCT, villous cytotrophoblasts; EVT, extravillous trophoblasts; MCC, microscopic chorionic (pseudo)cysts.

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Author notes

The author has no relevant financial interest in the products or companies described in this article.

Competing Interests

Presented in part at the Intercongress Meeting of the European Society of Pathology, August 31–September 3, 2010, Kraków, Poland.