Best Practice & Research Clinical Obstetrics and Gynaecology 23 (2009) 751–764

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Best Practice & Research Clinical

Obstetrics and Gynaecology
journal homepage: www.elsevier.com/locate/bpobgyn

Pathological assessment of intrauterine growth restriction

Phillip Cox, MBBS, PhD, FRCPath, Consultant Perinatal Pathologist *,
Tamas Marton, MD, PhD, Consultant Perinatal Pathologist
Birmingham Women’s Hospital NHS Foundation Trust, Metchley Park Road, Birmingham, B15 2TG, UK

Keywords:
Intrauterine growth restriction (IUGR) is a major cause of foetal and
pathology neonatal morbidity and mortality. During post mortem, the
IUGR pathologist is well placed to diagnose the presence and cause of
placenta IUGR in a stillborn baby. This article describes the approach of the
birth weight pathologist in diagnosing IUGR and some of the pitfalls. We distin-
brain/liver weight ratio guish between reduced growth potential (formerly symmetrical
centile IUGR) and nutritional IUGR (formerly asymmetrical IUGR). Aetio-
histology
logically, restricted growth can be of foetal, maternal and placental
origin. We discuss the importance of identifying the cause of IUGR in
a clinicopathological context and the pathological findings in some
of the more frequent causes of IUGR presenting at post mortem.
Based on an accurate gestational age, ideally determined by the
obstetrician in early pregnancy, the pathologist can derive a birth
weight centile. However, the pathologist is also able to identify
other indicators of IUGR, such as an elevated brain/liver weight
ratio, atrophic thymus and changes in other internal organs.
Placental examination plays a major role in the investigation as the
majority of IUGR cases have significant placental pathology. This
includes pre-eclampsia-related changes, abnormalities of the
villous parenchyma and pathology of the umbilical cord.
The potential benefit of a meticulous workup of IUGR foetuses is to
provide an explanation of the pathological condition and to
identify avoidable causes.
Ó 2009 Elsevier Ltd. All rights reserved.

Introduction

This article attests to the importance of intrauterine growth restriction (IUGR) in obstetrics. Other
articles examine the difficulties posed by the identification of IUGR in utero. In this article, we describe

* Corresponding author. Tel.: þ44 1216272729; Fax: þ44 1216074721.

E-mail address: [email protected] (P. Cox).

1521-6934/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bpobgyn.2009.06.006

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752 P. Cox, T. Marton / Best Practice & Research Clinical Obstetrics and Gynaecology 23 (2009) 751–764

the pathological findings by which the pathologist recognises IUGR at post mortem and also the
pathology of some of the many causes.

The importance of IUGR

IUGR is of huge importance in the practice of obstetrics. Modern classification systems of stillbirth,
such as ReCoDe, have shown that IUGR is the most common factor identified in stillborn babies. In
a recent study using customised birth weight centiles1, 43.0% had a birth weight below the 10th centile.
As a result, only 15.2% of stillbirths remained unexplained. This is in marked contrast to the traditional
Wigglesworth classification, which does not take foetal growth into account and consequently leaves
approximately two-thirds of stillbirths unexplained.2,3
In addition to being a major factor in stillbirth, IUGR has serious consequences for babies who
survive. IUGR is associated with increased risk of premature birth; increased morbidity among
premature neonates, including necrotising enterocolitis; hypoxic brain injury and its long-term
sequelae; the need for respiratory support and chronic lung disease; retinopathy of prematurity; and
mortality.4 In later life, growth-restricted infants are at increased risk of various disorders, including
obesity, diabetes and ischaemic heart disease.5–7 Furthermore, a number of the causes of IUGR are
associated with an increased risk of IUGR and intrauterine death (IUD) in the mother’s subsequent
pregnancies.
The pathologist plays a vital part in recognising the presence and cause of IUGR in the individual
stillborn infant and in advancing our understanding of this common problem.

Normal foetal growth

In order to understand IUGR, it is first necessary to be aware of the normal pattern of foetal growth
and the factors that influence it.

Foetal growth rate

Normal foetal growth follows a non-linear path. When viewed as mass gained in grams per week of
gestation, growth appears to follow something approaching an exponential curve between the end of
the first trimester and the latter part of the third trimester, with only a slight tailing off around term.
The greatest gain in mass per week occurs in the third trimester (Fig. 1). However, when the percentage
(rather than absolute) mass gained per week is considered, it is clear that the greatest rate of growth
occurs in early pregnancy (Fig. 2). This reflects the fact that early pregnancy, from conception to the
middle of the second trimester, is a period of very rapid cell division, whilst organogenesis occurs.
Thereafter, foetal growth is increasingly due to maturation and hypertrophy of the tissues and organs
rather than production of new cells.

Factors in foetal growth

Normal foetal growth depends on several components: the genetic growth potential of the foetus,
the ability of the placenta to transfer oxygen and nutrients to the developing foetus and the ability
of the mother to deliver these to the placenta for transfer to her baby. This, in turn, may be influenced
by the mother’s environment.
The growth potential at conception of an individual without a significant genetic disorder is
determined by the array of genes inherited from the parents. This will determine the size of the baby at
birth, given otherwise optimal conditions for growth throughout the pregnancy. This growth potential
can be adversely affected by a variety of inherited genetic disorders and acquired abnormalities. In
general, it is considered that genetic abnormalities affect the rate of cellular division and will therefore
result in poor growth in the earlier parts of pregnancy to a greater degree than later on. Whereas the
rate of cell division may be reduced in babies with chromosome abnormalities, placental development
is often also affected, resulting in poor nutrient supply in later pregnancy. Similarly, viral infection in
early pregnancy is often cited as a purely foetal cause of IUGR; however, congenital viral infections

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 P. Cox, T. Marton / Best Practice & Research Clinical Obstetrics and Gynaecology 23 (2009) 751–764 753

4000
Body wt

3500

3000

2500

2000

1500

1000

500

0
12 14 16 18 20 22 24 26 28 30 32 34 38 40
Gestational age (wk)

Fig. 1. Increase in body weight (g) vs. gestation from 12 weeks to term. Data derived from: Potter EL & Craig J (1972) Pathology of the
Fetus and Infant. Year Book Medical Publishers, Chicago; Gruenwald P & Minh HN. Evaluation of body and organ weights in perinatal
pathology. Am J Clin Pathol 34:247–253, 1960.

frequently result in inflammation and scarring in the placenta and may therefore also interfere with
nutrient supply.
The placenta is the interface between the maternal and foetal circulations and as such plays a critical
role in supporting normal foetal growth. The placenta is larger, relative to the foetus, in early gestation
than later on, as reflected by the steady fall in the ratio of foetal to placental weight as pregnancy prog-
resses. This probably reflects the changes that occur in the structure of the chorionic villi with gestation.
The villous surface area increases in relation to the placental weight, as does the capillary volume,

800
%inc/4wks
700

600

500

400

300

200

100

0
12-16 16-20 20-24 24-28 28-32 34-38
interval
Fig. 2. Percentage increase in body weight vs. gestation from 12 weeks to term. (Data derived as Table 1).

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754 P. Cox, T. Marton / Best Practice & Research Clinical Obstetrics and Gynaecology 23 (2009) 751–764

whereas the distance between the foetal and maternal blood falls with the formation of vasculosyncytial
membranes.8 As a result, transfer of oxygen and nutrients from mother to foetus becomes more efficient.
Pure placental causes of IUGR are rare. In the main, placental abnormalities are either part of a generalised
genetic disorder of the conceptus, or part of a maternal disorder. However, in both situations, it is
frequently the resulting placental pathology that is the major factor impairing foetal growth.
The mother hosts the developing foetus and, as such, is the sole supply of the nutrients and oxygen
necessary for foetal growth. This supply depends on both adequate levels of nutrients and oxygen in
the maternal circulation and adequate blood supply to the placenta. Maternal starvation (maternal
malnutrition and cachexia) reduces the supply of nutrients to the foetus and mothers whose weight
gain is poor during pregnancy have small neonates.9 It is also recognised that adolescent mothers tend
to have smaller babies. It has been suggested that this is due to underlying socioeconomic factors.
Underlying maternal disease is also associated with IUGR. This may be either through a direct effect on
placental blood supply or through generalised maternal debility.
Mean birth weight increases with parity. This may be a reflection of intrinsic maternal factors such
as placental blood supply or extrinsic ones such as improving socioeconomic status. It is clear that
other extrinsic influences can affect foetal growth. Maternal alcoholism and smoking, low socioeco-
nomic status and living at high altitude (where oxygen tension is lower) all have a negative effect on
the birth weight.

Intrauterine growth restriction

Definition

The standard clinical definition of IUGR is based on the birth weight centile. Many studies regard
a baby below the 10th centile, for the gestational age, as growth restricted.10,11 Other studies may use
different centiles as the cut-off, whereas some studies of perinatal disease use an absolute birth weight
such as 2.5 kg, being concerned with babies of low birth weight, regardless of the appropriate weight
for the baby’s gestation. These rather crude approaches to recognition of IUGR may be valid in large
population-based studies, but frequently fall down on an individual basis.
In its purest form, IUGR can be regarded as a failure of a foetus to reach its genetic growth potential.
Since birth weight at a given gestation is, more or less, normally distributed, some babies will fall below
the 10th centile and therefore be small for gestational age (SGA), but will be appropriately grown.
Equally, others with a birth weight above the 10th centile will have suffered nutritional deprivation and
thus fallen across centile lines and failed to reach their genetic ideal birth weight. These will not be
diagnosed as IUGR based on their birth weight.

Symmetrical versus asymmetrical IUGR

Many textbooks of obstetrics and perinatal pathology include the concepts of symmetrical and
asymmetrical IUGR (Table 1). As we indicated earlier, in the first few months of pregnancy, the embryo/
foetus grows very quickly as a result of rapid cell division. As pregnancy progresses, the rate of growth
becomes slower and much of it is due to maturation and enlargement of existing cells rather than cell
division.
Disorders affecting the embryo/foetus in the first few months of pregnancy will result in loss of one
or more cycles of cell division. As a result, the foetus will have fewer cells and therefore be smaller than
expected for its gestational age. The adverse influence will affect all organs equally and thus equally
affects the growth of the brain and the other internal organs. Recognition of this form of symmetrical
IUGR depends on an accurate dating of the pregnancy and can be recognised pathologically by the fact
that the maturity of the organs is greater than their size would predict. This form of IUGR can be
regarded as ‘impaired growth potential’.
In contrast, asymmetrical IUGR results from failure of foetal nutrition and/or oxygen supply in the
second half of pregnancy when growth is less dependent upon cell division and more upon adequate
nutrition. As a result of poor oxygen supply and nutrition, autoregulation preferentially directs blood to
the brain at the expense of the other organs, leading to maintenance of brain growth and poor growth

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Table 1
Comparison between ‘impaired growth potential’ (symmetrical) and nutritional (asymmetrical) IUGR.

Impaired growth potential Nutritional

(‘Symmetrical’ IUGR) (‘Asymmetrical’) IUGR
Onset Early onset Later onset
Growth curve Parallel to centile lines Crosses centile lines
Body weight centile Z Z
Brain/liver weight ratio Normal \
Thymus Normal/small Small
Internal organs Small size Small size, atrophic
Long term consequences No Yes
Possible hypoxic brain damage No Yes

of the viscera. In asymmetrical IUGR, the brain weight and the maturity of all organs are in keeping
with the gestational age, whereas the weight of the solid viscera, in particular the liver, is less than
expected for the gestation. Asymmetrical IUGR is typically the result of acquired pathology affecting
the placenta. This pattern of IUGR can be viewed as ‘impaired foetal nutrition’.
Although the distinction between symmetrical and asymmetrical IUGR appears well-founded in the
theory of embryonic and foetal growth, in routine pathological practice it is less clear cut. In reality,
cases of pure symmetrical IUGR are rarely seen at post mortem. The vast majority of stillborn foetuses
with IUGR show an asymmetrical pattern, even those with chromosome abnormalities and chronic
infections, the two most frequently cited causes of symmetrical IUGR. The most extreme example of
this is seen in cases of bimaternal triploidy. Affected foetuses have a complete extra set of chromo-
somes and might be expected to show symmetrical IUGR. However, in reality, they show extreme
asymmetry of growth, with a relatively well-developed head and brain and profound wasting of the
trunk, limbs and abdominal viscera. The asymmetrical IUGR in triploidy, and probably in other chro-
mosome abnormalities, is probably a consequence of abnormal placental development as a conse-
quence of the abnormal chromosome complement, leading to poor foetal nutrition. Similarly, many
congenital infections damage the placenta as well as the foetus and may thus lead to an asymmetrical
pattern of IUGR.

IUGR and foetal death

The clinical identification of IUGR during pregnancy is addressed elsewhere in this volume. In this
section, we examine the means by which the pathologist diagnoses IUGR at post mortem and highlight
some of the general pathological findings associated with IUGR in stillborn babies.

Pathological diagnosis of IUGR

Clinical studies typically take a birth weight below the 10th centile as an indicating IUGR. However,
the pathologist has the opportunity at post mortem to make a more detailed assessment of the still-
born baby, to determine the presence and severity of IUGR (Table 2). As with the clinical diagnosis of
IUGR, it is essential to know the gestational age of the foetus.

Table 2
General macroscopic and microscopic fetal findings in asymmetrical IUGR.

Macroscopic features Body weight <10th centile

Normal brain weight
Elevated brain/liver weight ratio (>4:1)
Elevated brain/thymus weight ratio/small thymus
Reduced subcutaneous fat
Microscopic features Thymus: atrophy of the cortex, prominent Hassall’s corpuscles (chronic stress)
Adrenals: fatty change of the fetal cortex (intrauterine stress)
Liver: possible fatty change of the hepatocytes (malnourishment)
Rib: irregular growth zone
Brain: hypoxic-ischaemic injury

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A simple comparison of the weight of the baby with the tables of gestation-based measurements that
appear in the standard textbooks of perinatal pathology may give a guide to the appropriateness of foetal
growth. However, many of these charts are based on data which are decades old and tend to underestimate
the mean weight at a given gestation. Comparison with charts of birth weight centiles is much more useful.
Charts based on the local, or at least the national, population are likely to be more reliable than those from
other countries or parts of the world. If earlier estimates of foetal weight from the mother’s antenatal
records are available, it may also be possible to show a fall across the centiles prior to birth, a strong
indication of IUGR. In the absence of this, a substantially lower birth weight centile than the centiles of
body length and head circumference suggests recent loss of weight. As with the clinical diagnosis of
IUGR, the use of growth charts customised for the mother’s height, weight, ethnic origin and parity and the
foetal sex appear to provide a more reliable assessment of the true birth weight centile than crude centiles
based on the entire population.12 For live babies, customised centiles result in 2.7–4.1% of babies being
reclassified as IUGR (i.e., below the 10th centile).13 A simple centile calculator, such as that available from
www.perinatal.nhs.uk/, allows quick calculation of a customised centile for an individual baby.
The use of weight at post mortem to assess IUGR comes with a number of provisos. It is recognised
that there is often loss of weight after delivery. This is the result of fluid loss through the skin. Weight
loss is generally greater as a percentage of birth weight for immature foetuses compared to term
babies, probably due the greater surface area:volume ratio of a small foetus. Because the majority of
IUGR stillbirths have a customised birth weight below the first centile (our data) this weight loss
infrequently leads to a spurious diagnosis of IUGR. If there is doubt, other markers of IUGR (vide infra)
will usually clarify the diagnosis. Oedematous or hydropic foetuses can also lose a considerable amount
of fluid after death, particularly if wrapped in absorbent material. The importance of this is difficult to
determine. Certainly, a truly hydropic foetus will have an artificially elevated birth weight centile. In
stillbirths, not associated with foetal hydrops, a degree of oedema is common and there are often
substantial collections of fluid in the body cavities. Whether this is purely due to the process of
maceration, or is in part a reflection of terminal cardiac failure and tissue hypoxia with fluid accu-
mulation, is not clear. If the latter is true, then loss of some of this fluid after death might return the
baby to a weight closer to that prior to its terminal decompensation.
In addition to weight loss after delivery, it has been suggested that babies lose weight in utero
following death. Some of this perceived weight loss may reflect failure to adjust the gestational age for the
period of time the baby has been retained in utero following death. However, it is impossible to dispute
that the most severely macerated foetuses (e.g., foetus papyraceous) have lost a large amount of their
body mass since death. Therefore the use of birth weight centile in severely macerated foetuses may over-
estimate the occurrence of IUGR. This does not appear to apply with lesser degrees of maceration.14

Brain:liver ratio

The pathologist has the advantage over the clinician of being able to take direct measurements of
the internal organs of the baby and examine them with the naked eye and under the microscope, rather
being reliant on inferences from ultrasound measurements. This allows various pieces of information
to be gathered with which to assess the presence and severity of IUGR and its consequences.
At post mortem, the most useful and reliable indicator of IUGR is the ratio of the brain weight to the
liver weight (brain:liver ratio – BLR). This is a reflection of the ‘brain-sparing effect’, that is, the redi-
rection of blood flow to the brain, at the expense of the abdominal viscera in babies suffering nutri-
tional and hypoxic stress. The HC/AC ratio measured by ultrasound is a marker of the same process.
Organ volumes can also be estimated in utero by 3D ultrasound or magnetic resonance imaging
(MRI)15; and in IUGR babies, the brain/liver volume ratio can be shown to increase16, supporting the
validity of the post mortem BLR as a marker of IUGR. At post mortem, organ weights are routinely
recorded and the BLR can be calculated. The original study17 describing the BLR stated that the normal
BLR is 2.8:1; however, the authors did not delineate the normal range. A loss of liver mass results in an
increased ratio, whereas hepatomegaly, as in gestational diabetes, causes a fall. Some pathologists have
regarded a ratio of above 3 as evidence of IUGR. However, this has been shown to have a very poor
sensitivity and specificity for the diagnosis of IUGR.18 The specificity increases substantially with
increasing BLR, reaching 85% for a ratio of 4, 93% for a BLR of 5 and 97% for 6.

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The BLR may also allow the recognition of babies showing nutritional impairment (i.e., early IUGR)
whose birth weight is above the 10th centile. Relying on a single birth weight centile measurement,
customised or not, will fail to identify a baby who has fallen from the 50th centile to the 20th. However,
the identification of an elevated BLR is evidence that the baby had suffered significant nutritional
impairment prior to death.
Despite the undoubted utility of the BLR as a marker of IUGR, an abnormal ratio should be assessed
carefully, as various pathological and technical factors may have an influence on it, leading to a spuriously
elevated BLR or masking a true elevation. A number of pathological situations result in an increase or
decrease in the weight of the brain or liver. For example, microcephaly either as a result of acquired disease
such as congenital cytomegalovirus (CMV) infection or due to genetic disorders will lead to a relatively low
brain weight/liver weight ratio, masking IUGR. In contrast, hydrocephalus leads to an increased brain
weight and potentially an elevated BLR unrelated to IUGR. Similarly, an enlarged liver as a result of chronic
foetal anaemia, congenital infection or intense congestion due to severe circulatory failure may result in
a normal BLR in an otherwise growth-restricted baby. Acute haemorrhage, due to ruptured vasa praevia or
fetomaternal haemorrhage, leads to a reduction in liver weight and spuriously elevated BLR.
Assessment of the BLR is further complicated in the macerated foetus. Firstly, moderate-to-severe
maceration may make it impossible to remove the foetal brain intact. The resulting loss of brain weight
will falsely mask an elevated BLR. Where disruption is severe, or in cases in which parental consent
does not permit removal of the brain, an estimate of the BLR can be obtained using the mean brain
weight for the gestation from standard charts, providing that the gestational age is known with
reasonable certainty. The second complicating factor is the possibility of progressive loss of weight by
foetal organs following death, as a result of maceration. A recent study14 suggests that this may be
substantial and may lead to spurious elevation of the BLR. As a result, although IUGR may be diagnosed
by a BLR of 4 or above in a fresh or mildly macerated stillbirth, it is probably advisable to use a higher
cut-off, perhaps 6, when there is severe maceration. It is also advisable to seek other pathological
features of foetal stress to support the diagnosis.
Although all organs are affected by the brain-sparing effect there has been little interest in the
consequence this has on other organ weight ratios. The thymus is particularly susceptible to intra-
uterine stress, rapidly becoming atrophic. We have recently examined the brain weight: thymic weight
ratio (BTR) as another marker of growth restriction/foetal stress. In a large series of stillbirths, we find
that those with normal birth weight centiles and no other features of IUGR or chronic intrauterine
disease have a BTR of approximately 30. A ratio of 70 or above is associated with significant foetal
disease and a ratio of over 100 is not uncommon. Elevation of other ratios, such as brain:kidney and
brain:heart are also frequently seen in the setting of IUGR (our data).

General pathology of IUGR

As noted in the previous section, the thymus is particularly sensitive to the effects of intrauterine
stress, including IUGR. In addition to losing weight, there is atrophy of the normal lymphoid tissue. This
results initially in loss of the normal sharp demarcation between the lymphocyte rich cortex and the
less cellular medulla. With time there is progressive loss of cortical lymphocytes, leading eventually to
complete cortical atrophy. At the same time the thymic epithelial elements, the Hassall’s corpuscles,
become increasingly prominent in response to chronic stress. Therefore, microscopic evidence of
chronic intrauterine stress in the thymus can lend support to a diagnosis of IUGR, when other
parameters such as birth weight or BLR are equivocal.
The adrenal glands are also susceptible to intrauterine stress. Severe IUGR is associated with reduced
adrenal weight. In their seminal work, Becker and Becker19 describe various patterns of fat accumu-
lation in the adrenal cortex in response to different forms of intrauterine stress. Demonstration of fat
requires frozen section histology, which may not be routinely available. However, in normal paraffin-
processed tissue, the presence of fat in the adrenal cortex can be inferred from the presence of rounded
vacuoles in the cortical cells. In cases of severe IUGR, lipid accumulates in the centre of the foetal cortex,
extending more peripherally with increasing severity of stress and hypoxia. Some severely growth-
restricted, usually relatively immature, foetuses can show fat accumulation throughout almost the
entire foetal cortical zone. The same pattern may also occur in response to severe foetal anaemia.

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IUGR has pathological effects on other organs as well. The kidneys are often relatively small in babies
with IUGR. At a histological level, the changes can be subtle and difficult to demonstrate. Renal growth
occurs through production of successive layers of glomeruli by the blastemal layer beneath the capsule.
The majority of glomeruli are produced between 23 and 34 weeks’ gestation, during which time
approximately one new layer of glomeruli appears per week. IUGR can result in reduced glomerulo-
genesis and thus smaller kidneys with fewer glomeruli. Kidneys from IUGR babies often have fewer
than the normal 13 glomerular layers. In addition to reducing the rate of glomerulogenesis, severe IUGR
may also lead to chronically reduced renal perfusion as part of the ‘brain-sparing effect’. This results in
atrophy of the proximal convoluted tubules and crowding of the glomeruli. This appearance is known
as renal tubular dysgenesis (RTD), but this ischaemic form should be distinguished from the genetic
form of RTD due to inherited abnormalities in the renin–angiotensin pathway.
The heart is often relatively small in IUGR babies and may show established areas of myocardial
necrosis. The lungs may also be small, even to the level of lethal pulmonary hypoplasia in severe IUGR.
In part, this may be a consequence of chronic oligohydramnios secondary to poor urine production by
the baby’s ischaemic kidneys. Histological examination of the costochondral junction may show
irregularity of the growth plate.
In the absence of an underlying genetic disorder or congenital infection, brain development would
be expected to be normal. Severe IUGR may eventually lead to a degree of failure of brain growth, and
a brain weight less than expected for the gestation. However, in general, the degree of reduction in
brain weight is less than for other organs.
Presumably due to the success of the protective effect of redistribution of blood to the brain,
evidence of old brain injury, that is, more than 48 h prior to death, is unusual in stillborn foetuses with
IUGR. A small proportion, particularly those at the more immature and or severe end of the spectrum,
show established white-matter necrosis with or without axonal mineralisation, possibly reflecting
episodes of circulatory instability in the days prior to death. Evidence of old neuronal necrosis,
infarction or gliosis is rare. In contrast, acute hypoxic–ischaemic brain injury is extremely common in
growth-restricted stillbirths. A high proportion of cases show a combination of eosinophilic neuronal
necrosis and neuronal karyorrhexis/apoptosis, indicating a period of vascular decompensation due to
failure of the autoregulatory mechanisms in the 24–48 h prior to death. The most severely growth-
restricted foetuses may also show widespread small fresh haemorrhages throughout the cerebral
hemispheres, cerebellum and brainstem, probably as a result of terminal hypoxia.

Pathological diagnosis of the cause of IUGR

The first task for the pathologist, when examining a stillborn baby, is to determine whether the
baby’s weight is normal for the gestational age, and if low, then to assess whether this is due to IUGR or
if the baby is less mature than was thought clinically. Once IUGR has been diagnosed, it is then
necessary to try to determine the cause. Although the majority of cases will be the result of utero-
placental ischaemia, a proportion will have another cause, which may carry a significant risk of
recurrence in a future pregnancy and which may require alternative management.
IUGR can result from abnormality of the foetus, placenta or mother and also from the mother’s
environment.
In general, when IUGR is of early onset, that is, before 28 weeks’ gestation, the cause is more likely to
be something other than simple pre-eclampsia, which is the predominant cause closer to term.
However, even late in pregnancy, a small proportion of cases of IUGR will have a different aetiology.
IUGR of foetal origin is typically of early onset and may show a more symmetrical than asym-
metrical pattern. The causes can broadly be divided into those due to chromosomal and genetic
disorders and those resulting from congenital infection.20

Foetal causes

Chromosome and genetic abnormalities

A wide range of chromosomal and genetic disorders are associated with IUGR. In addition to the
common autosomal trisomies, 13, 18 and 21, and triploidy, babies with unbalanced chromosome

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translocations and deletions frequently show IUGR. The On-Line Mendelian Inheritance in Man
(OMIM) database lists 77 syndromes characterised by intrauterine or prenatal growth restriction.
These include single-gene disorders such as Seckel syndrome and microdeletion syndromes (e.g.,
Williams–Beuren syndrome, due to a submicroscopic deletion at 7q11.23, and Silver–Russell
syndrome resulting from maternal uniparental disomy for chromosome 7). When IUGR results from
a genetic disorder, it will usually be associated with other abnormalities, such as a dysmorphic facial
appearance or congenital malformations. However, the abnormalities may be subtle, such as anal
stenosis or abnormal lobation of the lungs, and a dysmorphic appearance may be difficult to
recognise, particularly if there is maceration. It is therefore vital that a careful post-mortem exami-
nation is undertaken, including a foetal radiograph to detect minor skeletal abnormalities, and
photographs of the face and any abnormalities to facilitate discussion with colleagues from the
genetics department. Samples should be sent for karyotyping and DNA stored from any foetus with
IUGR in whom abnormalities are detected. The skin biopsy from a macerated foetus may fail to grow
in culture, but a sample from the placenta may still succeed, and when this is unsuccessful it may still
be possible to exclude common abnormalities by quantitative fluorescence polymerase chain reaction
(QF-PCR) on extracted DNA, or fluorescence in situ hybridisation (FISH) studies on cell suspensions.
Modern techniques, such as comparative genomic hybridisation and microarrays, may allow the
detection of small deletions and duplications, although their role in the area of IUGR remains to be
assessed.

Chronic foetal infections

Viral, bacterial and protozoal infections of the foetus may all be responsible for IUGR, although
apart from CMV, none is common. Infections with CMV and rubella viruses are well-recognised
causes of foetal infection and IUGR. Herpes simplex, varicella zoster and Epstein–Barr virus (EBV)
also occasionally lead to foetal infection and can be associated with IUGR.21,22 The role of other
viruses, such as HIV and measles, in causing IUGR is less clear-cut with conflicting reports in the
literature.23–25
Early viral infection may lead to a more symmetrical pattern of IUGR. Early CMV infection
frequently leads to loss of the pregnancy due to overwhelming infection and thus the development of
IUGR in later pregnancy is not an issue. IUGR in later-onset congenital CMV infection may, in part, be
due to direct infection of the foetus. However, in many cases, there is also a significant lympho-
plasmacytic chronic villitis, leading to loss of functional villous parenchyma. CMV viral inclusions in
the placenta may be scanty or even absent. As a result of the villitis, in the third trimester the pattern
of IUGR in CMV infection may be asymmetrical rather than symmetrical. Congenital rubella is now
very rare in Western countries, but is the archetypal cause of symmetrical IUGR. Villitis is not a major
feature of congenital rubella infection although lesions of the foetal placental vasculature have been
described.26
Congenital tertiary syphilis is extremely rare in developed countries, but leads to severe IUGR along
with characteristic lesions in the lungs (pneumonia alba), liver and bones. The placenta shows
a plasmacytic chronic villitis and onion-skin vascular lesions of the foetal placental vessels. IUGR is
probably due to a combination of the foetal infection and placental damage.
Foetal infection with the protozoal parasite Toxoplasma gondii is associated with IUGR, cerebral
necrosis and calcification and chorioretinitis. In the placenta, there is a lymphohistiocytic or even
granulomatous chronic villitis, which may be widespread. Toxoplasma cysts can often be found in the
villi or membranes of the placenta.27

The placenta and IUGR

The placenta forms the interface between the maternal and foetal circulation and as such is critical
for foetal nutrition and oxygenation. Therefore, pathology affecting the placenta is responsible for the
large majority of IUGR (Table 3). Growth restriction of placental origin is due to impairment of foetal
nutrition and therefore shows changes attributable to the brain-sparing effect of circulatory redistri-
bution. The pathology responsible for IUGR may be a primary abnormality of the placenta, or may be
secondary to disease in the mother.

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Table 3
Macroscopic and microscopic placental pathology in nutritional (asymmetrical) IUGR.

Macroscopic features Small placenta

Loss of parenchyma (infarcts, perivillous fibrin)
Retroplacental haemorrhage
Long/overcoiled umbilical cord
Microscopic features Advanced villous maturation (small, fibrotic tertiary villi, increased number of syncytial knots)
Terminal villous hypoplasia (sparse, small tertiary villi)
Infarcts
Unconverted maternal spiral arteries/acute atherosis/fibrinoid necrosis. (Decidual vasculopathy)
Massive perivillous fibrin deposition
Histiocytic intervillositis
Avascular villi and fetal vessel thrombosis
Chronic villitis of unknown etiology
Mesenchymal dysplasia
Chorangiosis
Chorangiomatosis

Primary and idiopathic placental pathology

A variety of pathological changes in the umbilical cord, foetal circulation and villous parenchyma
are associated with IUGR. Some carry a significant risk of recurrence in subsequent pregnancies and
may indicate possible management options.
The role of the umbilical cord in causing IUGR is not fully understood. There is a well-recognised
association between marginal and velamentous cord insertions and IUGR.28,29 The mechanism by
which such abnormalities of cord insertion lead to IUGR has not been entirely elucidated, but it has
been suggested that there is impairment of foetal blood flow, due to compression of the vessels in the
membranes or torsion of the cord at its insertion. Alternatively, an abnormal cord insertion may be
a reflection of disturbed implantation of the placenta in early pregnancy. Excessive coiling of the
umbilical cord is also associated with IUGR, although it is currently unclear whether the increased cord
coiling is the cause of IUGR or an effect.30
The foetal blood vessels within the placenta carry oxygen and nutrients from the chorionic villi to the
baby. Pathology affecting the foetal circulation can therefore lead to IUGR. In recent years, thrombotic
occlusion of the foetal circulation (foetal thrombotic vasculopathy – FTV) has been recognised increasingly
as a common complication of pregnancy.31 Where thrombosis occurs progressively through pregnancy,
groups of villi lose blood supply and become sclerosed. The non-functional avascular villi reduce the
vascular reserve of the placenta until the baby’s nutrition becomes impaired and IUGR develops. Further
thrombosis may eventually lead to foetal death.32 The causation of FTV is not always clear. Occasional cases
can be shown to have an inherited thrombotic tendency, such as protein S deficiency33 (personal obser-
vation PC). However, in the majority there is no evidence of thrombophilia. It has been suggested that many
cases of FTV are a consequence of sluggish blood flow due to umbilical cord overcoiling, an excessively long
cord or other abnormalities of the major placental vasculature.34 The risk of recurrence in subsequent
pregnancies, in the absence of demonstrable thrombophilic disorder, has not been defined.
Hamartomas of the foetal capillaries, known as chorangiomas, are common and, when small and
solitary, are of no significance. Large solitary chorangiomas may occasionally lead to foetal hydrops;
however, when the placenta contains numerous, small chorangiomas (chorangiomatosis), IUGR may
result.35 This is probably due to shunting of a significant proportion of the foetal blood in the placenta
through the non-functional vessels of the chorangiomas. Chorangiomatosis may also lead to foetal anaemia
and hydrops, due to either microangiopathic haemolysis or recurrent fetomaternal haemorrhages.
Placental mesenchymal dysplasia (PMD) is a hamartomatous overgrowth of the villous stroma and
may occur concurrently with chorangiomas. There are groups of enlarged villi with excessive stroma, in
which cisternal spaces, similar to the villi of molar pregnancies are found. Characteristically, dilated
tortuous blood vessels are found on the foetal placental surface. Around 30% of PMD is associated with
the Beckwith–Wiedemann overgrowth syndrome, but in 50% there is IUGR.36,37 In a few cases the
affected villi have been shown to carry post-zygotic chromosomal abnormalities or genetic aberra-
tion.38 Whether the observed IUGR is due to these changes or is a consequence of having significant
areas of non-functional villi is not known.

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Finally, in this section on primary or idiopathic disorders of the placenta, we consider two, possibly-
related, abnormalities of the villous parenchyma. As described earlier, various congenital infections
frequently also cause chronic inflammation of the chorionic villi. However, in the large majority of
cases of chronic villitis, no infectious cause can be identified. Minor degrees of chronic villitis are very
common, if diligently sought, but seem to be of no significance. However, when involving more than
10% or 15% of the villi, this idiopathic chronic villitis (or villitis of unknown aetiology – VUE) can lead to
IUGR and foetal demise. It is probably the result of breakdown in maternal immune tolerance as the
inflammatory infiltrate has been shown to be maternally-derived.39 When it has resulted in foetal
complications, VUE is associated with a significant risk of recurrence in subsequent pregnancies,
possibly as high as 20%.
Infiltration of the intervillous space with histiocytic cells (histiocytic intervillositis - HI) or fibrinoid
material, either diffusely (massive perivillous fibrin – MPVF) or in relation to the basal plate (maternal
floor infarction – MFI) may occur separately or together40, with inflammatory infiltration predominating
in some cases and fibrinoid in others. Histiocytic intervillositis is also a feature of maternal malaria
infection, which may lead to IUGR. Although rare in temperate countries, the possibility of placental
malaria should be considered in the appropriate clinical context and in countries where the disease is
common. Parasites are usually readily demonstrated in erythrocytes in the intervillous space. Minor and
focal degrees of perivillous fibrin are extremely common and small numbers of intervillous histiocytes
can often be found. However, extensive HI and/or MPVF/MFI are associated with IUGR and foetal death
and carry a similar risk of recurrence to VUE.41 The placenta in MPVF/MFI is typically of normal size or
enlarged, and the parenchyma may have a firm, glassy appearance on cut section. A few cases are
associated with thrombophilia, anti-phospholipid syndrome and autoimmune disease such as systemic
lupus erythematosus (SLE).42,43 Preventative treatment with aspirin and heparin has been suggested for
MPVF/MFI44 whereas aspirin and corticosteroids have been used in recurrent HI and VUE.45,46

Pathology of the uteroplacental circulation

Pathology of the uteroplacental circulation accounts for the majority of nutritional IUGR. Uteroplacental
blood flow can be impaired by a variety of disorders, including essential hypertension, pre-eclampsia,
insulin-dependent diabetes mellitus, anti-phospholipid syndrome and inherited thrombophilia.
Reduced blood supply to the placenta has a number of effects. The placenta is usually small for the
gestation, and there may be an increase in the ratio of foetal-to-placental weight. Kingdom and others
have performed detailed morphometric studies of placentas affected by early-onset and late-onset
IUGR.47 When reduced placental perfusion is of early onset, there is under-development of the terminal
villi, or terminal villous hypoplasia, recognised as an expanded intervillous space and elongated,
relatively poorly vascularised terminal villi with increased syncytial knots. In IUGR later in pregnancy,
the villi show advanced maturation, being of more mature appearance than would be expected at the
given gestation as a result of increased capillary branching. The villi are smaller, have less stroma and
better-developed vasculosyncytial membranes than in a normal placenta of the same gestation.48,49
This may successfully compensate for a degree of hypoxia for some time, but eventually may result in
premature exhaustion of the placenta. Non-specific chronic villitis may also occur in conjunction with
these ischaemic changes. It should be remembered that the peripheral parts of the cotyledons are
relatively ischaemic and thus similar changes can be seen in these regions in term placentas from
normal pregnancies. The majority of the cotyledon will appear normal in these cases.
Where the maternal blood supply has been completely occluded there will be infarction of the
associated area of the placenta. Placental infarcts can be bland or may have a central area of hae-
morrhage/thrombus. Such haemorrhagic infarcts should be differentiated from intervillous thrombi. In
the former, there is a distinct band of infarction around the thrombus, whereas there is little or no
infarction adjacent to an intervillous thrombus. The origin of the haemorrhage in an infarct may be
either a small area of placental abruption or a false aneurysm of the spiral artery. Small areas of
infarction within the placenta, not in continuity with the maternal surface, have been suggested to
represent watershed infarcts between adjacent poorly perfused territories.50
The pathological process that has resulted in the ischaemic changes in the placental villi may be
identified in the decidua of the maternal surface of the placenta (basal decidua) or attached to the
membranes (parietal decidua).

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Normal perfusion of the placenta depends on a process of physiological conversion of the spiral
arteries in the decidua and myometrium. Extravillous trophoblast invades the arterial walls and
replaces the smooth muscle with fibrinoid material containing scattered trophoblasts. The arteries are
converted into patulous vessels that allow greatly increased blood supply to the placenta as it grows.
Failure of this process results in reduced placental perfusion and may lead to IUGR. Evidence of failed or
incomplete conversion of the maternal spiral arteries can sometimes be identified in the basal decidua,
as persistence of small muscular arteries, or residual smooth muscle in the walls of partially converted
vessels. It should be remembered that the spiral arteries in the parietal decidua do not undergo
conversion and thus muscular arteries in this site are normal. In women with hypertension, essential or
pregnancy-related, arterial medial hypertrophy has been described.49
In severe pre-eclampsia, basal spiral arteries may show persistence of the physiological intravas-
cular trophoblast beyond 20 weeks’ gestation, and there may be evidence of vascular injury. The spiral
arteries may show deposition of brightly eosinophilic fibrinoid in their walls (fibrinoid necrosis) and
accumulation of foamy macrophages beneath the intima (acute atherosis).48 This decidual vasculop-
athy can be seen in the absence of hypertension and in association with anti-phospholipid syndrome51,
suggesting that the mechanism of vascular damage may not be the hypertension per se.
The maternal vascular lesions associated with inherited thrombophilias are less well characterised.
If there are associated pre-eclamptic features, then fibrinoid necrosis and acute atherosis might be
expected. Alternatively, thrombosis in the maternal vessels and possibly fibrinoid deposition in vessel
walls would be predicted. There is at least a theoretical association with increased perivillous fibrin
deposition in the placenta.52
Although gestational and type II diabetes are typically associated with foetal macrosomia and
a large placenta, in type I diabetes the presence of maternal small-vessel disease can result in IUGR,
with a small, ischaemic placenta. Such cases may show a more uneven pattern of villous maturation
with a mixture of small ischaemic villi and others appearing immature/dysmature. Chorangiosis, that
is, intravillous capillary proliferation, has also been described.49 The underlying maternal vascular
pathology is generally not apparent in the decidua.

Summary

In summary, IUGR is a very common finding in stillborn babies. Normal foetal growth is dependent
upon foetal, placental, maternal and environmental factors. The pathologist is ideally placed to assess
the presence and severity of IUGR at post mortem and may recognise evidence of nutritional
impairment in babies whose birth weight is above the 10th centile. Although the majority of IUGR is
a consequence of poor uteroplacental blood supply, a significant minority will be due to foetal genetic
disease or infection, or intrinsic pathology of the placenta. It is important to recognise these cases, as
they may have major implications with respect to the risk of recurrence and management in subse-
quent pregnancies.

Practice points

IUGR is a feature of around 40% of stillbirths.

IUGR can be due to impairment of growth potential or nutritional insufficiency.
Post mortem can differentiate between IUGR and a constitutionally small baby and can identify
incipient IUGR in babies whose weight is above the 10th centile.
Brain:liver weight ratio (BLR) is the most widely used marker of IUGR.
BLR of >4 indicates IUGR in the absence of confounding factors.
Other pathological features, for example, thymic atrophy, can support a diagnosis of IUGR.
Although the majority of IUGR is due to uteroplacental ischaemia (e.g., hypertensive disease and
pre-eclampsia), it is important to exclude other causes, which may have greater implications for
future pregnancies and therapeutic implications.

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 P. Cox, T. Marton / Best Practice & Research Clinical Obstetrics and Gynaecology 23 (2009) 751–764 763

Research agenda

A consensus over the criteria for diagnosis of IUGR in stillborn babies would facilitate studies into
the pathological effects and causation of this common problem.
Large clinicopathological studies into the less common causes of IUGR (e.g., chronic villitis,
massive perivillous fibrin deposition and foetal thrombotic vasculopathy) will assist clinicians to
advise affected parents of the risk of recurrence and may lead to more effective preventative
treatments for subsequent pregnancies.

Conflict of interest

None.

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