Article Text

The placenta in pre-eclampsia and intrauterine growth restriction
  1. D J Roberts1,
  2. M D Post2
  1. 1
    Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
  2. 2
    Department of Pathology, University of Colorado Health Sciences Center, Aurora, Colorado, USA
  1. Dr D J Roberts, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; djroberts{at}


Placental examination in pregnancies with complications such as pre-eclampsia/toxaemia of pregnancy (PET) or intrauterine growth restriction (IUGR) can provide insight into specific diagnoses, recurrence risk and chronicity. Placental findings have clinical significance as they can identify the aetiology of the IUGR (as in inborn errors of metabolism) and predict recurrence (as in maternal floor infarcts). Evaluation of obstetric pathology in such pregnancies should be an integral part of clinical care. This review will highlight the placental findings in IUGR and PET.

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Take-home messages

  • Pre-eclampsia is a clinical term for a biological process that likely differs based on gestational age at presentation.

  • Preterm pre-eclampsia is usually more severe in terms of placental pathology.

  • Term pre-eclampsia typically has limited placental pathology.

Intrauterine growth restriction (IUGR) is defined as fetal growth less than the 10th percentile for gestational age, although clinically, less than the 3rd percentile is probably a more reliable cut off for associated perinatal morbidity.1 Clinicians segregate IUGR into symmetric and asymmetric types based on whether the head is spared or not. Symmetric IUGR is thought to be an early event, constitutional, and has a defined differential diagnosis such as chromosomal anomalies and uniparental isodisomy in confined placental mosaicism. Cases of symmetric IUGR often have small placentas by weight but otherwise no pathological findings. In contrast, head sparing IUGR (asymmetric IUGR), defined by abdominal growth restriction more severe than that of the head, often has significant placental pathology. In general, most placental causes of IUGR involve maternal vascular compromise resulting in placental ischaemia, often associated with hypertensive disorders.

Hypertension during pregnancy can be essential or pregnancy specific. The obstetric significance of hypertension is related to the severity of the ensuing vascular damage (which relates to placental ischaemia) as well as to the absolute level of pressure (with higher pressures a risk for abruption). The diagnosis of pre-eclampsia requires maternal hypertension and proteinuria,2 and, although most common at term, can occur at any gestational age. Pre-eclampsia/toxaemia of pregnancy (PET) is thought to be caused by abnormal implantation resulting in placental ischaemia. Shallow or incomplete invasion of the trophoblast into maternal tissues and inadequate “physiological” conversion of the spiral arteries needed to perfuse the placenta have long been believed to be the basic biology behind placental ischaemia,3 4 although the root cause of the abnormal implantation is unknown. Placental ischaemia stimulates a release of factors into the maternal vascular system resulting in systemic endothelial dysfunction and its sequelae of hypertension, oedema and proteinuria. The search for both the cause of dysfunctional placental implantation and specific circulating factors has thwarted many scientists throughout history. Recently there has been much excitement about the discovery of two factors which appear to play critical roles in the symptomatology of PET: sFLT1 (soluble fms-like tyrosine kinase 1)5 and endoglin (soluble TGF-b co-receptor) (fig 1).6 These factors are raised in response to placental ischaemia and may even be biomarkers for the disease.7

Figure 1 Healthy non-ischaemic placenta secretes normal (balanced) soluble fms-like tyrosine kinase (sFLT) leading to normal levels of provasodilatory and anticoagulant factors available for binding to fms-like tyrosine kinase 1 (FLT1) on endothelial cells systemically, leaving healthy and responsive endothelium. Ischaemic placenta secretes increased sFLT which binds circulating factors depleting their availability to FLT1 binding. The result is a dysfunctional endothelial cell leading to maternal systemic vasculopathy. Adapted from Karumanchi’s publications.6365


Gross placental pathological findings in PET

Placental examination in pregnancies complicated by PET can show many pathological findings, but may also be grossly normal and histologically appropriate for gestational age, even in cases of fulminant toxaemia. If present, placental findings can be confirmatory, but when absent should not be used to exclude disease, as term and post-partum PET is generally pathologically bland. This vexing truth is likely due to our incomplete understanding of the phenotype versus the biology. As was true of “fever”, which used to be thought of as a disease8 and is now known to be a symptom of a multitude of diseases, what is clinically termed PET is likely a set of symptoms with more than one specific aetiology.

Knowing relatively few facts about the biology of PET, one would predict the placental pathology to be those features indicative of chronic ischaemia (table 1). Unfortunately, the presence of these features is essentially restricted to cases of severe preterm PET9; they are generally not present in the more common term or post-partum cases.10 This suggests that late onset PET is due to a different biology than abnormal implantation which, by definition, must have occurred early in development! Therefore, this review will focus on those findings which are classic for global placental ischaemia and which, if present, are diagnostic of chronic severe uteroplacental insufficiency and thus characteristic of preterm PET.

Table 1 Placental pathological findings in chronic placental ischaemia

Grossly, chronic ischaemia leads to a small placenta (trimmed weight often much less than the 10th percentile) with a thin umbilical cord (less than 1 cm in diameter). Placental infarcts of the usual type are common; however, smaller and multifocal infarcts can also be present and are characteristic (see below). Evidence of acute or chronic abruption may be seen as well.

There are, in general, at least five types of placental infarcts.11 Maternal perfusion by the spiral arterioles may be occluded by thrombus leading to placental infarction generally pyramidal in shape and nearly always involving the base/maternal floor of the placenta (fig 2A). These are common at term and have no sequelae in an otherwise normal placenta (normal weight), but are distinctly abnormal and rare when seen preterm or occupying greater than 5% of the estimated placental volume. More than one infarct is unusual and suggests a significant vascular occlusion. We find small, round infarcts centrally located in the parenchyma which are less likely to involve the maternal floor to be quite characteristic of pre-term PET (fig 2B). We think of these types of infarcts as lying in the “watershed” zone of relatively ischaemic villi between the flow of spiral arterioles, which therefore are the first affected by global ischaemia. Placental villi can also become infarcted by “strangulation” of increased perivillous or intervillous fibrin/fibrinoid deposition (fig 2C). This has been associated with maternal diabetes, coagulopathies and specific aetiologies (such as maternal floor infarcts, see below).1216 An infarct accompanies chronic abruptions as the retroplacental haematoma indents and infarcts its overlying villi (fig 2D).17 Finally, villi may become infarcted if the fetal circulation is impaired; this is termed fetal thrombotic vasculopathy (fig 2E), and has its own differential diagnosis.1820 Of these, in general, only the increased fibrin/fibrinoid and the large usual-type infarct can be appreciated grossly.

Figure 2 Placental infarcts. (A) Usual type: pyramidal shaped infarcts involving the maternal floor are due to occlusion of a maternal spiral arteriole and have no clinical significance when isolated, small and seen at term. (B) Hypertensive type: multiple small rounded infarcts located centrally within the parenchyma are most often seen in association with pre-term pre-eclampsia/toxaemia of pregnancy. This is an example of a full-thickness infarct, but still has the overall appearance of a hypertensive-type infarct. (C) Increased perivillous fibrin: excess fibrin or fibrinoid deposited in the intervillous space leads to “strangulation” of the villi and infarction. (D) Chronic abruption: a rim of infarcted villi is present, immediately overlying the retroplacental haematoma. (E) Fetal thrombotic vasculopathy: lack of blood flow to villi is caused by a fetal circulatory problem and results in clusters or broad regions of fibrotic avascular villi, often with an intact syncytiotrophoblast layer. This is usually a regional phenomenon adjacent to normally perfused villi.

Histological features of PET-affected placentas

The hallmark of maternal vascular disease is vascular wall damage; however, care must be taken in rendering this diagnosis as the histological features of maternal vascular disease can be mimicked by the physiological conversion of implantation arterioles. A normal component of implantation is maternal vascular invasion with replacement of the smooth muscle and endothelium by trophoblast, and the alteration (often associated with necrosis) of the vascular wall. To make the diagnosis of maternal vascular damage due to hypertensive disease, one must look at vessels away from the implantation site and, therefore, we look at maternal vessels in the decidua capsularis. Features characteristic of systemic, or at least uterine, vascular changes due to hypertension include: muscular hypertrophy, endothelial thickening, vascular thromboses, vascular ectasia, fibrinoid necrosis of the vascular wall, presence of histiocytes in the vascular wall (atherosis), and close “hugging” of peripheral inflammatory cells (fig 3). These features are termed “decidual vasculopathy” (DV) with or without atherosis.

Figure 3 Decidual vasculopathy. (A) Mild: maternal vessels in the decidua capsularis show smooth muscle hypertrophy, endothelial hyperplasia and a cuff of inflammatory cells. (B) Severe: the vessel is ectatic and the vascular wall has been completely replaced by dense pink fibrinoid. (C) Atherosis: foamy histiocytes are present within the fibrinoid rimming the vessel. This finding is most closely linked to severe hypertension and poorer fetal outcomes.

Although decidual vasculopathy and atherosis are characteristic lesions of PET, they are present in other disorders as well, such as additional hypertensive disorders, autoimmune diseases and intrauterine growth restriction.14 2124 Regardless of the aetiology, these findings are evidence of severe prolonged ischaemia to the placenta and have been associated with fetal and paediatric evidence of neurocompromise.25

Most of the histopathological features associated with PET have to do with chronic placental ischaemia26 or maternal hypertension27 28 and are listed in table 1. These features are uncommon when PET presents at term or after delivery, but are common in preterm PET.10 Nevertheless, they should be sought in all placentas examined with a history of hypertension or IUGR due to their association with fetal neurocompromise.29 To maximise the opportunity to make the diagnosis of DV, more than one membrane roll should be sampled in these cases. Careful examination of the parenchyma for subtle, smaller, infarcts is needed as well.

The villous findings of ischaemia include evidence of premature branching: too many tertiary villi with large knots, lots of “empty” intervillous space, and sclerosis of the villi (fig 4). We think of this as villous cachexia with little cytoplasm in the villous stroma; they looked collapsed and thin and have few capillaries instead of the normal ∼3 per tertiary villus. It is important not to overcall these findings. The villi closest to the chorionic plate are relatively ischaemic in all placentas and will often mimic the villous changes of ischaemia, as do the villi close to infarcts. It is essential that the diagnoses of hypermaturity of the villi or villous features consistent with chronic ischaemia are made by examining many fields of villi away from the chorionic surface and distant from infarcts.

Figure 4 Hypermature villi. There are small, sclerotic villi with increased syncytial knots and expansive, empty intervillous space.

Review of one year’s experience, PET

We reviewed the pathology of placentas that came with the clinical history of PET or pre-eclampsia at the Massachusetts General Hospital in 2007. We identified 105 placentas; 40 were preterm (less than 37 weeks gestational age) and 65 were term or post-term. There were 15 cases of twin gestation and 1 triplet (including 2 monochorionic pregnancies); 14 of the multi-gestation cases were in the preterm group. The preterm placentas were somewhat more commonly small (less than the 10th percentile for gestational age by weight) in 15 of 40 (38%), compared with 21 of 65 of the term/post-term placentas (32%). Of the 25 preterm PET placentas that were above the 10th percentile by weight, 10 were multi-gestations; 2 of these were above the 90th percentile weight for gestational age, as well as 1 singleton (overall, 3 of 40 (8%) heavy preterm PET placentas). There were 9 of 65 (14%) heavy term/post-term placentas. Table 2 presents the histopathological findings in these groups.

Table 2 Cases with clinical history of pre-eclampsia/toxaemia of pregnancy (PET) or pre-eclampsia, Massachusetts General Hospital, 2007

Summary of placental pathology in PET

The placental pathology of pre-eclampsia is a function of severity and chronicity. The findings are related to chronic ischaemia of the placenta and likely begin at implantation. The cause of the implantation abnormality is unknown but the biology behind its signs and symptoms is rapidly being discovered (fig 1). The placental correlates of chronic ischaemia (table 1) are commonly present in preterm pre-eclampsia placentas and are rare in later gestational ages. The most common finding for all gestational ages is a trimmed weight less than the 10th percentile.


Gross placental findings in IUGR

IUGR, as discussed with PET, is not a pathological diagnosis but a clinical one with many pathological aetiologies. Understanding the cause of the IUGR in any specific pregnancy is critical to clinical management of future pregnancies and neonatal care. The list of specific causes of IUGR is exhaustive, most aetiologies being rare, but there are some characteristic placental findings. Most placentas weigh less than the 10th percentile for gestational age and many show findings associated with vascular compromise from either the maternal or fetal sides.

Maternal vascular compromise to the placenta may be due to hypertensive disorders, already discussed, or may be due to a myriad of other aetiologies, most of which are poorly understood. Decreased maternal blood flow may be due to vessel obstruction. Fibrin/fibrinoid deposition in the intervillous (maternal) space is a common finding at term but can be pathological if massive or obstructive. Two specific pathological diagnoses involving abnormal fibrin deposition in the placenta which are often associated with IUGR include maternal floor infarction and massive chronic intervillositis.

In maternal floor infarction (MFI), fibrin/fibrinoid encases the villi along the maternal floor to such an extent that normal flow to the “superficial” villi is impeded (fig 5B). The distinction between maternal floor infarction and massive intervillous fibrin deposition30 may be inconsequential as both probably belong to the same family of disorders and have similar associated morbidities.3133 However, MFI has the classic gross appearance of an “orange rind” like thickening of the maternal floor measuring several millimetres in thickness (fig 5A). This finding is necessary for the diagnosis and is quite specific. A significant portion of the maternal floor should be involved (at least one third).34 Although MFI is a well described gross and histological entity with significant fetal morbidity, its biological aetiology remains unclear. There have been noted associations with maternal thrombophilias,32 3537 enzyme deficiencies38 and autoimmune diseases.39

Figure 5 Maternal floor infarction. (A) Grossly the maternal surface of the placenta has a thick “orange-rind” covering of fibrin. (B) Histologically there is a thick band (>3 mm) of infarcted villi present over most of the maternal floor.

Massive chronic intervillositis (MCI, fig 6) has one of the highest recurrence rates of all placental pathologies.40 41 It has a characteristic histopathology with a dramatic infiltrate of maternal histiocytes in the maternal space usually admixed or associated with increased fibrin.4144 Fetal death and growth restriction are often ascribed to this lesion which can occur at any gestational age. MCI may be a variant of a much more common lesion, villitis of unclear/unknown aetiology (VUE), that is also associated with recurrences (although much less common) and IUGR.45 46 Chronic villitis occurs in haematogenously spread infections,47 which are quite rare, but also occurs in non-infectious cases in upwards of 10% of all gestations. The aetiology of these cases is unknown (hence its name) and, as in MFI and MCI, is thought to be immunologically based due to its recurrence risk.24 45 46 The histopathology (fig 7) is of a maternally-derived mononuclear or giant cell infiltrate into the villi, often with villous vascular occlusion20 29 which, we believe, is the aetiology of the IUGR and intrauterine fetal demise seen in a small percentage of these cases.

Figure 6 Massive chronic intervillositis. Maternal histiocytes fill much of the intervillous space admixed with an increased amount of fibrin. The aetiology of this lesion is unknown but it has a high recurrence rate and is associated with recurrent spontaneous abortions in some women. The inset shows a high power view of intervillous histiocytes.
Figure 7 Villitis of unclear aetiology. Present in up to 10% of all gestations, this non-infectious villitis is composed of maternal mononuclear cells infiltrating the villi and causing vascular occlusion. Although individual villi can be affected, there is commonly “agglutination” or clumping of villi, as seen here.

There are also fetal vascular obstructive lesions associated with IUGR, most notably fetal thrombotic vasculopathy (FTV).18 This is diagnosed by the presence of villous vascular thrombi19 48 49 (fig 8A), endothelial necrosis (haemorrhagic endovasculitis)5053 (fig 8B) or avascular villi20 (fig 2E), and provides evidence of villous infarction from fetal perfusion anomalies. The differential diagnosis is long and includes: anatomical vascular compromise (umbilical cord lesions: true knots, velamentous insertions) (fig 9A), toxic effects (meconium associated myonecrosis)5456 (fig 9B), inflammatory response (chorionic plate and umbilical “vasculitis”) (fig 9C), chronic villitis, placentas from infants of diabetic mothers, congenital neoplasms and inherited coagulopathies.37 57

Figure 8 Fetal thrombotic vasculopathy. (A) Villous vascular occlusion: a remote thrombosis is seen in a stem villous. (B) Haemorrhagic endovasculitis: endothelial necrosis results in extravasated red blood cells present around a stem villous vessel without an associated inflammatory infiltrate. Downstream avascular villi are often found in association (fig 2E).
Figure 9 Umbilical cord lesions. (A) Velamentous insertion: note the vessels coursing through the membranes before contacting the fetal surface of the placenta. Without the protective covering of Wharton’s jelly, these vessels are particularly vulnerable to various insults. (B) Meconium myonecrosis: the toxic effects of meconium lead to necrosis of the smooth muscle cells surrounding umbilical cord vessels, seen here as dense eosinophilic cells with pyknotic nuclei. Inset shows higher power view of meconium within necrotic myocytes. (C) Umbilical cord “vasculitis”: neutrophils are marginating in the umbilical vessel and infiltrating the smooth muscle coat.

There are many other aetiologies of IUGR that may be evidenced in the placenta, including inborn errors of metabolism,58 metastatic malignancies and chromosomal anomalies (constitutional or confined to the placenta21); however, these are very rare.

Review of one year’s experience, IUGR

We reviewed the pathological diagnoses from all placentas with the obstetric history of IUGR from the year 2007 at the Massachusetts General Hospital (table 3). There were 89 cases, including 9 sets of twin gestations. Of the 89, 74% (66 cases) had a trimmed weight at or below the 10th percentile for gestational age59; of these, 20% (13 cases, 15% of total) had a trimmed weight less than the 5th percentile. The most common histopathological finding was chorangiosis (35 cases, 39%), a lesion in which the villi have increased numbers of capillaries and which has been associated with maternal hypoxaemia and tobacco smoking.11 6062 Other al findings included placental ischaemia (16 cases, 18%), VUE (12 cases, 13%), FTV (7 cases, 8%), velamentous umbilical cord insertion (2 cases), maternal sickle cell trait (1 case) and placenta accreta (1 case). Of interest, 22 cases (26%), including 4 twins, had placental weights within the normal range; one placenta was greater than 90th percentile for gestational age. We saw no cases of MFI or MCI associated with a clinical diagnosis of IUGR.

Table 3 Cases with clinical history of intrauterine growth restriction, Massachusetts General Hospital, 2007


Placental findings in cases complicated by maternal hypertension or fetal growth restriction can add to the clinical care of the mother and newborn by explaining the biology of the disease, predicting recurrence, and identifying specific disorders. Placental examination should be included in the care of all such pregnancies.


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  • Competing interests: None.

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