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

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Pathological assessment of intrauterine growth restriction

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

Keywords:pathologyIUGRplacentabirth weightbrain/liver weight ratiocentilehistology

* Corresponding author. Tel.: þ44 1216272729; FE-mail address: Phillip.cox@bwhct.nhs.uk (P. Co

1521-6934/$ – see front matter � 2009 Elsevier Ltdoi:10.1016/j.bpobgyn.2009.06.006

Intrauterine growth restriction (IUGR) is a major cause of foetal andneonatal morbidity and mortality. During post mortem, thepathologist is well placed to diagnose the presence and cause ofIUGR in a stillborn baby. This article describes the approach of thepathologist in diagnosing IUGR and some of the pitfalls. We distin-guish between reduced growth potential (formerly symmetricalIUGR) and nutritional IUGR (formerly asymmetrical IUGR). Aetio-logically, restricted growth can be of foetal, maternal and placentalorigin. We discuss the importance of identifying the cause of IUGR ina clinicopathological context and the pathological findings in someof the more frequent causes of IUGR presenting at post mortem.Based on an accurate gestational age, ideally determined by theobstetrician in early pregnancy, the pathologist can derive a birthweight centile. However, the pathologist is also able to identifyother indicators of IUGR, such as an elevated brain/liver weightratio, atrophic thymus and changes in other internal organs.Placental examination plays a major role in the investigation as themajority of IUGR cases have significant placental pathology. Thisincludes pre-eclampsia-related changes, abnormalities of thevillous parenchyma and pathology of the umbilical cord.The potential benefit of a meticulous workup of IUGR foetuses is toprovide an explanation of the pathological condition and toidentify avoidable causes.

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Introduction

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

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the pathological findings by which the pathologist recognises IUGR at post mortem and also thepathology 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. Ina 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 traditionalWigglesworth classification, which does not take foetal growth into account and consequently leavesapproximately two-thirds of stillbirths unexplained.2,3

In addition to being a major factor in stillbirth, IUGR has serious consequences for babies whosurvive. IUGR is associated with increased risk of premature birth; increased morbidity amongpremature neonates, including necrotising enterocolitis; hypoxic brain injury and its long-termsequelae; the need for respiratory support and chronic lung disease; retinopathy of prematurity; andmortality.4 In later life, growth-restricted infants are at increased risk of various disorders, includingobesity, diabetes and ischaemic heart disease.5–7 Furthermore, a number of the causes of IUGR areassociated with an increased risk of IUGR and intrauterine death (IUD) in the mother’s subsequentpregnancies.

The pathologist plays a vital part in recognising the presence and cause of IUGR in the individualstillborn 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 growthand 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 ofgestation, growth appears to follow something approaching an exponential curve between the end ofthe 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 growthoccurs in early pregnancy (Fig. 2). This reflects the fact that early pregnancy, from conception to themiddle 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 organsrather 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 abilityof the mother to deliver these to the placenta for transfer to her baby. This, in turn, may be influencedby the mother’s environment.

The growth potential at conception of an individual without a significant genetic disorder isdetermined by the array of genes inherited from the parents. This will determine the size of the baby atbirth, given otherwise optimal conditions for growth throughout the pregnancy. This growth potentialcan be adversely affected by a variety of inherited genetic disorders and acquired abnormalities. Ingeneral, it is considered that genetic abnormalities affect the rate of cellular division and will thereforeresult in poor growth in the earlier parts of pregnancy to a greater degree than later on. Whereas therate of cell division may be reduced in babies with chromosome abnormalities, placental developmentis often also affected, resulting in poor nutrient supply in later pregnancy. Similarly, viral infection inearly pregnancy is often cited as a purely foetal cause of IUGR; however, congenital viral infections

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

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frequently result in inflammation and scarring in the placenta and may therefore also interfere withnutrient supply.

The placenta is the interface between the maternal and foetal circulations and as such plays a criticalrole in supporting normal foetal growth. The placenta is larger, relative to the foetus, in early gestationthan 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,

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Fig. 2. Percentage increase in body weight vs. gestation from 12 weeks to term. (Data derived as Table 1).

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whereas the distance between the foetal and maternal blood falls with the formation of vasculosyncytialmembranes.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 generalisedgenetic disorder of the conceptus, or part of a maternal disorder. However, in both situations, it isfrequently 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 oxygennecessary for foetal growth. This supply depends on both adequate levels of nutrients and oxygen inthe maternal circulation and adequate blood supply to the placenta. Maternal starvation (maternalmalnutrition and cachexia) reduces the supply of nutrients to the foetus and mothers whose weightgain is poor during pregnancy have small neonates.9 It is also recognised that adolescent mothers tendto 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 onplacental blood supply or through generalised maternal debility.

Mean birth weight increases with parity. This may be a reflection of intrinsic maternal factors suchas placental blood supply or extrinsic ones such as improving socioeconomic status. It is clear thatother 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 onthe birth weight.

Intrauterine growth restriction

Definition

The standard clinical definition of IUGR is based on the birth weight centile. Many studies regarda baby below the 10th centile, for the gestational age, as growth restricted.10,11 Other studies may usedifferent centiles as the cut-off, whereas some studies of perinatal disease use an absolute birth weightsuch as 2.5 kg, being concerned with babies of low birth weight, regardless of the appropriate weightfor the baby’s gestation. These rather crude approaches to recognition of IUGR may be valid in largepopulation-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 belowthe 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 andthus fallen across centile lines and failed to reach their genetic ideal birth weight. These will not bediagnosed as IUGR based on their birth weight.

Symmetrical versus asymmetrical IUGR

Many textbooks of obstetrics and perinatal pathology include the concepts of symmetrical andasymmetrical 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 growthbecomes slower and much of it is due to maturation and enlargement of existing cells rather than celldivision.

Disorders affecting the embryo/foetus in the first few months of pregnancy will result in loss of oneor more cycles of cell division. As a result, the foetus will have fewer cells and therefore be smaller thanexpected for its gestational age. The adverse influence will affect all organs equally and thus equallyaffects the growth of the brain and the other internal organs. Recognition of this form of symmetricalIUGR depends on an accurate dating of the pregnancy and can be recognised pathologically by the factthat the maturity of the organs is greater than their size would predict. This form of IUGR can beregarded as ‘impaired growth potential’.

In contrast, asymmetrical IUGR results from failure of foetal nutrition and/or oxygen supply in thesecond half of pregnancy when growth is less dependent upon cell division and more upon adequatenutrition. As a result of poor oxygen supply and nutrition, autoregulation preferentially directs blood tothe brain at the expense of the other organs, leading to maintenance of brain growth and poor growth

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

Impaired growth potential(‘Symmetrical’ IUGR)

Nutritional(‘Asymmetrical’) IUGR

Onset Early onset Later onsetGrowth curve Parallel to centile lines Crosses centile linesBody weight centile Z Z

Brain/liver weight ratio Normal \

Thymus Normal/small SmallInternal organs Small size Small size, atrophicLong term consequences No YesPossible hypoxic brain damage No Yes

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of the viscera. In asymmetrical IUGR, the brain weight and the maturity of all organs are in keepingwith the gestational age, whereas the weight of the solid viscera, in particular the liver, is less thanexpected for the gestation. Asymmetrical IUGR is typically the result of acquired pathology affectingthe placenta. This pattern of IUGR can be viewed as ‘impaired foetal nutrition’.

Although the distinction between symmetrical and asymmetrical IUGR appears well-founded in thetheory 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 foetuseswith IUGR show an asymmetrical pattern, even those with chromosome abnormalities and chronicinfections, the two most frequently cited causes of symmetrical IUGR. The most extreme example ofthis 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 extremeasymmetry of growth, with a relatively well-developed head and brain and profound wasting of thetrunk, 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, manycongenital infections damage the placenta as well as the foetus and may thus lead to an asymmetricalpattern of IUGR.

IUGR and foetal death

The clinical identification of IUGR during pregnancy is addressed elsewhere in this volume. In thissection, we examine the means by which the pathologist diagnoses IUGR at post mortem and highlightsome 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 ofIUGR, it is essential to know the gestational age of the foetus.

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

Macroscopic features Body weight <10th centileNormal brain weightElevated brain/liver weight ratio (>4:1)Elevated brain/thymus weight ratio/small thymusReduced 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 zoneBrain: hypoxic-ischaemic injury

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A simple comparison of the weight of the baby with the tables of gestation-based measurements thatappear in the standard textbooks of perinatal pathology may give a guide to the appropriateness of foetalgrowth. However, many of these charts are based on datawhich are decades old and tend to underestimatethe meanweight 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 fromother countries or parts of the world. If earlier estimates of foetal weight from the mother’s antenatalrecords are available, it may also be possible to show a fall across the centiles prior to birth, a strongindication of IUGR. In the absence of this, a substantially lower birth weight centile than the centiles ofbody length and head circumference suggests recent loss of weight. As with the clinical diagnosis ofIUGR, the use of growth charts customised for the mother’s height, weight, ethnic origin and parity and thefoetal sex appear to provide a more reliable assessment of the true birth weight centile than crude centilesbased on the entire population.12 For live babies, customised centiles result in 2.7–4.1% of babies beingreclassified as IUGR (i.e., below the 10th centile).13 A simple centile calculator, such as that available fromwww.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 recognisedthat there is often loss of weight after delivery. This is the result of fluid loss through the skin. Weightloss is generally greater as a percentage of birth weight for immature foetuses compared to termbabies, probably due the greater surface area:volume ratio of a small foetus. Because the majority ofIUGR stillbirths have a customised birth weight below the first centile (our data) this weight lossinfrequently 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 amountof fluid after death, particularly if wrapped in absorbent material. The importance of this is difficult todetermine. Certainly, a truly hydropic foetus will have an artificially elevated birth weight centile. Instillbirths, not associated with foetal hydrops, a degree of oedema is common and there are oftensubstantial collections of fluid in the body cavities. Whether this is purely due to the process ofmaceration, 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 thebaby 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 uterofollowing death. Some of this perceived weight loss may reflect failure to adjust the gestational age for theperiod of time the baby has been retained in utero following death. However, it is impossible to disputethat the most severely macerated foetuses (e.g., foetus papyraceous) have lost a large amount of theirbody 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 ofthe internal organs of the baby and examine them with the naked eye and under the microscope, ratherbeing reliant on inferences from ultrasound measurements. This allows various pieces of informationto 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 theliver 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 thevalidity of the post mortem BLR as a marker of IUGR. At post mortem, organ weights are routinelyrecorded and the BLR can be calculated. The original study17 describing the BLR stated that the normalBLR is 2.8:1; however, the authors did not delineate the normal range. A loss of liver mass results in anincreased ratio, whereas hepatomegaly, as in gestational diabetes, causes a fall. Some pathologists haveregarded a ratio of above 3 as evidence of IUGR. However, this has been shown to have a very poorsensitivity and specificity for the diagnosis of IUGR.18 The specificity increases substantially withincreasing 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 nutritionalimpairment prior to death.

Despite the undoubted utility of the BLR as a marker of IUGR, an abnormal ratio should be assessedcarefully, as various pathological and technical factors may have an influence on it, leading to a spuriouslyelevated BLR or masking a true elevation. A number of pathological situations result in an increase ordecrease in the weight of the brain or liver. For example, microcephaly either as a result of acquired diseasesuch as congenital cytomegalovirus (CMV) infection or due to genetic disorders will lead to a relatively lowbrain weight/liver weight ratio, masking IUGR. In contrast, hydrocephalus leads to an increased brainweight and potentially an elevated BLR unrelated to IUGR. Similarly, an enlarged liver as a result of chronicfoetal anaemia, congenital infection or intense congestion due to severe circulatory failure may result ina normal BLR in an otherwise growth-restricted baby. Acute haemorrhage, due to ruptured vasa praevia orfetomaternal 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-severemaceration may make it impossible to remove the foetal brain intact. The resulting loss of brain weightwill falsely mask an elevated BLR. Where disruption is severe, or in cases in which parental consentdoes not permit removal of the brain, an estimate of the BLR can be obtained using the mean brainweight for the gestation from standard charts, providing that the gestational age is known withreasonable certainty. The second complicating factor is the possibility of progressive loss of weight byfoetal organs following death, as a result of maceration. A recent study14 suggests that this may besubstantial and may lead to spurious elevation of the BLR. As a result, although IUGR may be diagnosedby a BLR of 4 or above in a fresh or mildly macerated stillbirth, it is probably advisable to use a highercut-off, perhaps 6, when there is severe maceration. It is also advisable to seek other pathologicalfeatures of foetal stress to support the diagnosis.

Although all organs are affected by the brain-sparing effect there has been little interest in theconsequence 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 weightratio (BTR) as another marker of growth restriction/foetal stress. In a large series of stillbirths, we findthat those with normal birth weight centiles and no other features of IUGR or chronic intrauterinedisease have a BTR of approximately 30. A ratio of 70 or above is associated with significant foetaldisease and a ratio of over 100 is not uncommon. Elevation of other ratios, such as brain:kidney andbrain: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 intrauterinestress, including IUGR. In addition to losing weight, there is atrophy of the normal lymphoid tissue. Thisresults initially in loss of the normal sharp demarcation between the lymphocyte rich cortex and theless cellular medulla. With time there is progressive loss of cortical lymphocytes, leading eventually tocomplete 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 ofchronic intrauterine stress in the thymus can lend support to a diagnosis of IUGR, when otherparameters such as birth weight or BLR are equivocal.

The adrenal glands are also susceptible to intrauterine stress. Severe IUGR is associated with reducedadrenal 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 fatrequires 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 roundedvacuoles 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 theentire 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 babieswith IUGR. At a histological level, the changes can be subtle and difficult to demonstrate. Renal growthoccurs 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 timeapproximately 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 fewerthan the normal 13 glomerular layers. In addition to reducing the rate of glomerulogenesis, severe IUGRmay also lead to chronically reduced renal perfusion as part of the ‘brain-sparing effect’. This results inatrophy of the proximal convoluted tubules and crowding of the glomeruli. This appearance is knownas renal tubular dysgenesis (RTD), but this ischaemic form should be distinguished from the geneticform 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 myocardialnecrosis. 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 bythe baby’s ischaemic kidneys. Histological examination of the costochondral junction may showirregularity of the growth plate.

In the absence of an underlying genetic disorder or congenital infection, brain development wouldbe expected to be normal. Severe IUGR may eventually lead to a degree of failure of brain growth, anda brain weight less than expected for the gestation. However, in general, the degree of reduction inbrain 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 withIUGR. 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 reflectingepisodes 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 ingrowth-restricted stillbirths. A high proportion of cases show a combination of eosinophilic neuronalnecrosis and neuronal karyorrhexis/apoptosis, indicating a period of vascular decompensation due tofailure 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 cerebralhemispheres, 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 thebaby’s weight is normal for the gestational age, and if low, then to assess whether this is due to IUGR orif the baby is less mature than was thought clinically. Once IUGR has been diagnosed, it is thennecessary 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 ofrecurrence 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’senvironment.

In general, when IUGR is of early onset, that is, before 28 weeks’ gestation, the cause is more likely tobe 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 geneticdisorders and those resulting from congenital infection.20

Foetal causes

Chromosome and genetic abnormalitiesA 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–Russellsyndrome resulting from maternal uniparental disomy for chromosome 7). When IUGR results froma genetic disorder, it will usually be associated with other abnormalities, such as a dysmorphic facialappearance or congenital malformations. However, the abnormalities may be subtle, such as analstenosis or abnormal lobation of the lungs, and a dysmorphic appearance may be difficult torecognise, 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, andphotographs of the face and any abnormalities to facilitate discussion with colleagues from thegenetics department. Samples should be sent for karyotyping and DNA stored from any foetus withIUGR in whom abnormalities are detected. The skin biopsy from a macerated foetus may fail to growin culture, but a sample from the placenta may still succeed, and when this is unsuccessful it may stillbe 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 thedetection of small deletions and duplications, although their role in the area of IUGR remains to beassessed.

Chronic foetal infectionsViral, 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-recognisedcauses 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 otherviruses, such as HIV and measles, in causing IUGR is less clear-cut with conflicting reports in theliterature.23–25

Early viral infection may lead to a more symmetrical pattern of IUGR. Early CMV infectionfrequently leads to loss of the pregnancy due to overwhelming infection and thus the development ofIUGR in later pregnancy is not an issue. IUGR in later-onset congenital CMV infection may, in part, bedue 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 inthe placenta may be scanty or even absent. As a result of the villitis, in the third trimester the patternof IUGR in CMV infection may be asymmetrical rather than symmetrical. Congenital rubella is nowvery rare in Western countries, but is the archetypal cause of symmetrical IUGR. Villitis is not a majorfeature of congenital rubella infection although lesions of the foetal placental vasculature have beendescribed.26

Congenital tertiary syphilis is extremely rare in developed countries, but leads to severe IUGR alongwith characteristic lesions in the lungs (pneumonia alba), liver and bones. The placenta showsa plasmacytic chronic villitis and onion-skin vascular lesions of the foetal placental vessels. IUGR isprobably due to a combination of the foetal infection and placental damage.

Foetal infection with the protozoal parasite Toxoplasma gondii is associated with IUGR, cerebralnecrosis and calcification and chorioretinitis. In the placenta, there is a lymphohistiocytic or evengranulomatous chronic villitis, which may be widespread. Toxoplasma cysts can often be found in thevilli 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 criticalfor foetal nutrition and oxygenation. Therefore, pathology affecting the placenta is responsible for thelarge majority of IUGR (Table 3). Growth restriction of placental origin is due to impairment of foetalnutrition 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 besecondary to disease in the mother.

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

Macroscopic features Small placentaLoss of parenchyma (infarcts, perivillous fibrin)Retroplacental haemorrhageLong/overcoiled umbilical cord

Microscopic features Advanced villous maturation (small, fibrotic tertiary villi, increased number of syncytial knots)Terminal villous hypoplasia (sparse, small tertiary villi)InfarctsUnconverted maternal spiral arteries/acute atherosis/fibrinoid necrosis. (Decidual vasculopathy)Massive perivillous fibrin depositionHistiocytic intervillositisAvascular villi and fetal vessel thrombosisChronic villitis of unknown etiologyMesenchymal dysplasiaChorangiosisChorangiomatosis

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Primary and idiopathic placental pathologyA 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 andmay indicate possible management options.

The role of the umbilical cord in causing IUGR is not fully understood. There is a well-recognisedassociation between marginal and velamentous cord insertions and IUGR.28,29 The mechanism bywhich such abnormalities of cord insertion lead to IUGR has not been entirely elucidated, but it hasbeen suggested that there is impairment of foetal blood flow, due to compression of the vessels in themembranes or torsion of the cord at its insertion. Alternatively, an abnormal cord insertion may bea reflection of disturbed implantation of the placenta in early pregnancy. Excessive coiling of theumbilical cord is also associated with IUGR, although it is currently unclear whether the increased cordcoiling 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 thebaby. Pathology affecting the foetal circulation can therefore lead to IUGR. In recent years, thromboticocclusion of the foetal circulation (foetal thrombotic vasculopathy – FTV) has been recognised increasinglyas 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 thevascular reserve of the placenta until the baby’s nutrition becomes impaired and IUGR develops. Furtherthrombosis may eventually lead to foetal death.32 The causation of FTV is not always clear. Occasional casescan 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 manycases of FTV are a consequence of sluggish blood flow due to umbilical cord overcoiling, an excessively longcord or other abnormalities of the major placental vasculature.34 The risk of recurrence in subsequentpregnancies, in the absence of demonstrable thrombophilic disorder, has not been defined.

Hamartomas of the foetal capillaries, known as chorangiomas, are common and, when small andsolitary, are of no significance. Large solitary chorangiomas may occasionally lead to foetal hydrops;however, when the placenta contains numerous, small chorangiomas (chorangiomatosis), IUGR mayresult.35 This is probably due to shunting of a significant proportion of the foetal blood in the placentathrough the non-functionalvessels of the chorangiomas. Chorangiomatosis mayalso lead to foetal anaemiaand hydrops, due to either microangiopathic haemolysis or recurrent fetomaternal haemorrhages.

Placental mesenchymal dysplasia (PMD) is a hamartomatous overgrowth of the villous stroma andmay occur concurrently with chorangiomas. There are groups of enlarged villi with excessive stroma, inwhich cisternal spaces, similar to the villi of molar pregnancies are found. Characteristically, dilatedtortuous blood vessels are found on the foetal placental surface. Around 30% of PMD is associated withthe Beckwith–Wiedemann overgrowth syndrome, but in 50% there is IUGR.36,37 In a few cases theaffected 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 significantareas 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 infectionsfrequently also cause chronic inflammation of the chorionic villi. However, in the large majority ofcases of chronic villitis, no infectious cause can be identified. Minor degrees of chronic villitis are verycommon, if diligently sought, but seem to be of no significance. However, when involving more than10% or 15% of the villi, this idiopathic chronic villitis (or villitis of unknown aetiology – VUE) can lead toIUGR and foetal demise. It is probably the result of breakdown in maternal immune tolerance as theinflammatory infiltrate has been shown to be maternally-derived.39 When it has resulted in foetalcomplications, 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 fibrinoidmaterial, either diffusely (massive perivillous fibrin – MPVF) or in relation to the basal plate (maternalfloor infarction – MFI) may occur separately or together40, with inflammatory infiltration predominatingin some cases and fibrinoid in others. Histiocytic intervillositis is also a feature of maternal malariainfection, which may lead to IUGR. Although rare in temperate countries, the possibility of placentalmalaria should be considered in the appropriate clinical context and in countries where the disease iscommon. Parasites are usually readily demonstrated in erythrocytes in the intervillous space. Minor andfocal degrees of perivillous fibrin are extremely common and small numbers of intervillous histiocytescan often be found. However, extensive HI and/or MPVF/MFI are associated with IUGR and foetal deathand carry a similar risk of recurrence to VUE.41 The placenta in MPVF/MFI is typically of normal size orenlarged, and the parenchyma may have a firm, glassy appearance on cut section. A few cases areassociated with thrombophilia, anti-phospholipid syndrome and autoimmune disease such as systemiclupus erythematosus (SLE).42,43 Preventative treatment with aspirin and heparin has been suggested forMPVF/MFI44 whereas aspirin and corticosteroids have been used in recurrent HI and VUE.45,46

Pathology of the uteroplacental circulationPathology 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 thegestation, and there may be an increase in the ratio of foetal-to-placental weight. Kingdom and othershave performed detailed morphometric studies of placentas affected by early-onset and late-onsetIUGR.47 When reduced placental perfusion is of early onset, there is under-development of the terminalvilli, 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 thegiven gestation as a result of increased capillary branching. The villi are smaller, have less stroma andbetter-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 inpremature exhaustion of the placenta. Non-specific chronic villitis may also occur in conjunction withthese ischaemic changes. It should be remembered that the peripheral parts of the cotyledons arerelatively ischaemic and thus similar changes can be seen in these regions in term placentas fromnormal 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 theassociated 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. Inthe former, there is a distinct band of infarction around the thrombus, whereas there is little or noinfarction adjacent to an intervillous thrombus. The origin of the haemorrhage in an infarct may beeither a small area of placental abruption or a false aneurysm of the spiral artery. Small areas ofinfarction within the placenta, not in continuity with the maternal surface, have been suggested torepresent watershed infarcts between adjacent poorly perfused territories.50

The pathological process that has resulted in the ischaemic changes in the placental villi may beidentified in the decidua of the maternal surface of the placenta (basal decidua) or attached to themembranes (parietal decidua).

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Normal perfusion of the placenta depends on a process of physiological conversion of the spiralarteries in the decidua and myometrium. Extravillous trophoblast invades the arterial walls andreplaces the smooth muscle with fibrinoid material containing scattered trophoblasts. The arteries areconverted 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 orincomplete 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 convertedvessels. It should be remembered that the spiral arteries in the parietal decidua do not undergoconversion and thus muscular arteries in this site are normal. In women with hypertension, essential orpregnancy-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 spiralarteries may show deposition of brightly eosinophilic fibrinoid in their walls (fibrinoid necrosis) andaccumulation 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 beexpected. Alternatively, thrombosis in the maternal vessels and possibly fibrinoid deposition in vesselwalls would be predicted. There is at least a theoretical association with increased perivillous fibrindeposition in the placenta.52

Although gestational and type II diabetes are typically associated with foetal macrosomia anda 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 maturationwith a mixture of small ischaemic villi and others appearing immature/dysmature. Chorangiosis, thatis, intravillous capillary proliferation, has also been described.49 The underlying maternal vascularpathology is generally not apparent in the decidua.

Summary

In summary, IUGR is a very common finding in stillborn babies. Normal foetal growth is dependentupon foetal, placental, maternal and environmental factors. The pathologist is ideally placed to assessthe presence and severity of IUGR at post mortem and may recognise evidence of nutritionalimpairment in babies whose birth weight is above the 10th centile. Although the majority of IUGR isa consequence of poor uteroplacental blood supply, a significant minority will be due to foetal geneticdisease or infection, or intrinsic pathology of the placenta. It is important to recognise these cases, asthey 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 identifyincipient 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 andpre-eclampsia), it is important to exclude other causes, which may have greater implications forfuture pregnancies and therapeutic implications.

Research agenda

A consensus over the criteria for diagnosis of IUGR in stillborn babies would facilitate studies intothe 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 toadvise affected parents of the risk of recurrence and may lead to more effective preventativetreatments for subsequent pregnancies.

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Conflict of interest

None.

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