J Clin Pathol 1981;34:819-835

Review article

Examination of products of conception frompreviable human pregnanciesDI RUSHTON

From the Department ofPathology, Birmingham Maternity Hospital, Edgbaston, Birmingham BS15 2TG

SUMMARY The incidence, aetiology, and mechanisms of spontaneous abortion are outlined. Asimplified classification of products of conception specifically orientated for routine histopatho-logical laboratories rather than research centres is presented. Its introduction should not in itselfgreatly increase the work load of a service laboratory already examining such material. Specificpractical problems are discussed and these are related to the clinical situation. The importance isemphasised of proper examination of tissues from pregnancies aborting after diagnostic amniocen-tesis, as well as those from therapeutic terminations performed for fetal abnormality or disease.Special techniques are suggested for processing suspected procured abortions. Finally the value isstressed of routine examination of spontaneously aborted material in the current and future manage-ment of the patient, in the furtherance of our knowledge of fetal diseases and of some of the majorcontributory factors to perinatal morbidity and mortality.

Recent advances in obstetrical and gynaecologicalpractice, the introduction of antenatal screening anddiagnostic services, and the growth of geneticcounselling have revealed major deficiencies in ourknowledge of the pathophysiology of early humanpregnancy and of the natural history of diseaseprocesses in the developing embryo and fetus. Whileit must be accepted that infertility, subfertility, andthe assessment of clinical disturbances of earlypregnancy are major growth areas in modernmedicine, it is also true that the histopathologist hasfailed to keep pace with these clinical advances.Today most patients who abort spontaneously arecounselled either on an empirical basis or on theirpast obstetric history, yet there is growing evidenceto indicate that the developmental status of theaborted conceptus is of value in predicting the out-come of future pregnancies.' In addition to con-tributing to the management of these patients, theexamination of products of conception may even-tually lead to a better understanding of the patho-physiology of prematurity, intrauterine growthretardation, and pre-eclamptic toxaemia. These allimportant complications of pregnancy are almost

Accepted for publication 4 February 1981

certainly the end result of pathological processesbeginning in the first and second trimesters of preg-nancy. Epidemiological studies of malformationsamong abortions may eventually permit the use ofthese data to monitor for environmental teratogens.There are therefore compelling reasons for the properroutine acquisition of basic data relating to earlypregnancy failure. Such data can only be obtained bypathologists serving obstetric and gynaecologicalunits. It is hoped that the following techniques willdemonstrate that the collection of this data shouldnot be considered as a research project, but that itshould form part of the normal routine servicecommitment of histopathology departments. Inaddition the use of a standard classification willallow comparison of data from different populationsor geographic regions.

In order that the pathologists' contribution to themanagement of these patients is better understood,it is necessary to have a basic knowledge of theincidence, aetiology, and anatomy of spontaneousabortion.

Incidence and aetiology

Clinically-apparent spontaneous abortion occurs in819

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between 10 and 150% of pregnancies,2 though thelevel of wastage is greatly influenced by the method ofassessment. However, the clinically-apparent abor-tion is but the tip of an iceberg of pregnancy wastage.If the fate of all eggs coming into contact with spermis considered then it has been estimated that only30-40% of them result in births of 28 weeks gestationor more.3 A recent prospective study of post-implantation pregnancy wastage4 revealed a preg-nancy failure rate of 43 %, only just over one fifth ofcases being clinically recognised as spontaneousabortions. It must therefore be readily apparent thatmaterial submitted for pathological examination ishighly selected and biased towards late abortions.The aetiology of spontaneous abortions is diverse

but, simply, it may be considered to be the result ofeither a fault in the seed (the fertilised ovum) or inthe soil (the uterine environment). In general abor-tion occurs at an earlier gestation in the formercategory, the majority of midtrimester abortionsfalling into the latter group. The principal abnor-mality of the early abortus, and therefore of thefertilised ovum, is an abnormal karyotype. Manystudies of the chromosomal constitution of spon-taneous abortions have been made and the resultsare typified by those of Boue and Boue.5 In an analy-sis of 1498 abortions, these authors found 615%had an abnormal karyotype, the three majorabnormalities being autosomal trisomy 520%, trip-loidy 19-8% and monosomy X 15-30%. Many of thechromosomal abnormalities in spontaneous abor-tions are extremely rare in later life some of whichhave not been described in full-term infants. Thedegree of selection among individual karyotypes isvery variable. Approximately one third of concep-tuses with trisomy 21 may survive to term while lessthan one per cent of those with triploidy will do SO.6In general the earlier the abortion occurs the higherthe incidence of chromosomal abnormalities.7 Itmust be emphasised that in spite of this high incidenceof chromosomal anomalies, routine cytogeneticstudies on such material are neither warranted norjustified as the vast majority of these anomalies arisede novo and are not likely to recur in subsequentpregnancies. It is neither possible to discuss themechanisms involved in the genesis of, nor thereasons for, such a high incidence of chromosomalanomalies in abortions, but the interested reader willfind such information in texts on genetics andteratology. With a few notable exceptions, themorphology of the conceptus does not allow thepathologist to determine the karyotype fromanatomical and histological examination alone.

Aetiological factors associated with wastage in themidtrimester as a result of "poor soil" includedevelopmental abnormalities of the female genital

tract, cervical incompetence, abnormal placentation,disorders of implantation and uterine pathology.Infection and maternal disease may also influence theuterine environment.

Mechanism and anatomy of spontaneous abortion

The mechanisms of spontaneous abortion are notwell understood. Expulsion of the conceptus mayfollow an acute intrauterine catastrophe such asretroplacental haemorrhage or premature rupture ofthe membranes through an incompetent cervix. Inthese circumstances sudden changes in the normalenvironment after partial placental separationassociated with haemorrhage or a sudden diminutionof uterine contents through the loss of amniotic fluidmay be responsible. However in the majority ofcases the processes associated with pregnancywastage act over a more prolonged period with agradually declining hormonal milieu.8 9 Many deadfetuses and embryos are retained in utero for severalweeks. The inability of the trophoblast to obtain anadequate maternal blood supply either as a primarydisorder or as secondary to abnormalities of placen-tal structure (particularly related to failure of theembryonic and fetal circulation in the villi) results inabnormalities of the trophoblast evident to thehistopathologist (vide infra). As trophoblasticfunction declines, the maternal vascular changes inthe placental bed'0 associated with pregnancyinitially fail to progress and then begin to regressleading to yet further trophoblastic failure, decidualnecrosis, and uterine irritability which eventuallyleads to expulsion of the conceptus.The anatomy of the early conceptus is often falsely

interpreted in the light of knowledge of the full termpregnancy. While the three basic components,decidua, placenta, and embryo or fetus are presentthroughout pregnancy their relative proportions varydramatically from conception to term. In the first4-6 wk of pregnancy the decidual component pre-dominates, during the next 10-12 wk the placentagains ascendency and after 16 wk the fetus rapidlyoutgrows the other components. In many earlyspontaneous abortions, the failure of embryonicdevelopment together with deficient placental growthresults in the majority of the products of conceptionconsisting of decidua.

Products of conception submitted for examinationmay therefore consist of any one or any combinationof these elements, there being a minimum of fourplanes of cleavage in the intact intrauterine preg-nancy (Fig. 1). The mix may be further modified bythe use of the curette either before, during or afterthe patient has begun to abort. It should be empha-sised hat with the introduction of ultrasound,

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Examination ofproducts of conception from previable human pregnancies

abnormalities of early pregnancy can be diagnosedbefore their spontaneous expulsion and such preg-nancies may be terminated by curettage.

Classification of spontaneously aborted products ofconception

Many classifications of abortions have been intro-duced, the most notable being those of Mall andMeyer," Fujikura et al.12 and Hertig.13 These classi-fications were to a large extent based on characteris-tics of the embryo and little attention was paid to theplacenta. As such they were not ideally suited toroutine histopathological procedures. In an attemptto overcome these deficiencies, the following classi-fication was proposed.14

It has the advantage that it should not increase thework load of routine histopathology laboratories nordoes it require special training techniques. Indeedmost pathologists will be familiar with the pathologydescribed, though many will not have reported whatthey have observed or attempted to classify theseobservations.

CLASSIFICATION

Group I Blighted ova

(a) in which the majority of the villi show micro-scopic hydatidiform change.

(b) intermediate or mixed pattern (between (a)and (c)).

(c) in which the majority of villi show stromalfibrosis and vascular obliteration.

Group II Macerated embryos or fetuses (normalor abnormal)

(a) with an embryo or fetus(b) without an embryo or fetus

Group III Fresh embryos or fetuses (normal orabnormal)

(a) with an embryo or fetus(b) without an embryo or fetus

Groups II and III are classified on the basis of theappearances of the fetus wherever possible, but in theabsence of a fetus, the histological appearances ofthe placenta usually allow accurate classification.The characteristics of these groups will now bediscussed in more detail.

Group I Blighted ovaThe blighted ovum is typified by the intact saccontaining clear slightly mucoid fluid with no evi-dence of an embryo or cord root (Fig. 2). In additionsacs containing amorphous, stunted, or cylindricalembryos are included. Stunted embryos are charac-terised by a gross discrepancy between their actualsize and the predicted size as determined from thelast menstrual period. The embryos are invariablymacerated and often measure only 4-5 mm in lengthat 10-14 wk gestation. These conceptuses show arelatively narrow gestational age distribution with amean ovulation age of 9 4 wk.14 The incidence ofchromosomal anomalies is highest in this group. Inmany instances only placental fragments areavailable, but this does not preclude assignment ofcases to this group. The abnormalities in the placentarelate to the time at which embryogenesis is dis-turbed. If this occurs before the establishment of theembryonic circulation in the placental villi, then thevilli will be predominantly avascular, hydropic andwill have an attenuated trophoblast (Fig. 3). Ifviewed under the dissecting microscope in the freshstate, they appear as miniature forms of molar villi,hence the author's preferred term of microscopichydatidiform change though others prefer the termhydropic abortion.15 If the embryonic villal circula-tion is established either in part or in full then thecessation of the blood flow will result in increasedstromal cellularity, stromal fibrosis and vascularobliteration. Initially the trophoblast retains anormal bilaminar configuration though the surfaceof the villi becomes irregular and indented, eventuallyleading to the appearance of trophoblastic inclusions

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Fig. 2 Blighted ovum aborted at 10wk. Intact sac 2 cm in diameter withno embryo.

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in the stroma. These changes become more apparentin group II cases. In addition, in these placentae,trophoblastic cells may be isolated in the villalstroma (Fig. 4). These are believed by some authorsto be indicative of trisomy,16 though personal experi-ence suggests they may also occur in conceptuseswith a normal karyotype.

Group IH Macerated embryos or fetuses (normalor abnormal)The diagnosis of fetal maceration is not difficult if the

fetus is available for examination. Even in theabsence of a fetus, it is usually possible to identifysuch cases from examination of the placenta. Thereis some overlap between group I (c) and group II

cases. The major histological changes are:(i) Collapse of the villal vasculature, the vessels

frequently containing degenerate, nucleatedred cells which eventually become impreg-nated with iron- and calcium-containing salts.

(ii) Obliteration of the villal vessels associatedwith stromal fibrosis (Fig. 5).

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(iii) Increased syncytial knotting, irregularity ofvillal shape, and the development of intra-villal trophoblastic islands surrounded by ademonstrable basement membrane (Fig. 6).

(iv) The deposition of iron and calcium salts inthe stroma of the villi, and in particular on the

vascular and trophoblastic basement mem-branes.

(v) Increasing perivillous and intervillous fibrindeposition particularly in the region of thebasal plate of the placenta. The accumulationof such material at this site may become visible

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Fig. 6 Fibrotic villi withfocal calcification ofvessels (small arrows)and a trophoblasticinclusion surrounded bybasement membrane(broad arrow). Haema-toxylin and eosin x 116.

Fig. 7 Maternal floor infarction ofplacenta showing fibrinoid deposition on the maternal surface (arrowed).Approximately normal size.

macroscopically (Fig. 7), and is known as within the placenta and it must be admitted that inmaternal floor infarction of the placenta.17 the vast majority of cases the cause of fetal death

It is probable that most, if not all, of these changes remains uncertain.are secondary to cessation of the fetal circulation

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Examination ofproducts of conception from previable human pregnancies

Group III Fresh embryos or fetuses (normal or

abnormal)Fresh fetuses provide no difficulty in diagnosis.Placental development is usually normal or more

advanced than the clinical dates suggest. Theacceleration of placental development is frequentlyartefactual in that comparison of fetal size withexpected sizefrom the clinical gestational age by datesshow the fetal size is also greater than expected.Since the peaks of error occur at approximately 4and 8 wk before the true dates, it suggests the patienthas underestimated the duration of the pregnancy.The most likely reason for this is that bleedingoccurred at the time of the first or second period or

both after conception. Since many of these abortionsoccur as the result of abnormalities in the uterineenvironment (as suggested above), these dataindicate the possible relevance of disturbances inimplantation to midtrimester abortions.

It will be apparent that this classification takeslittle account of anatomical malformations in theembryo or fetus. Obvious malformations such asanencephaly, spina bifida, or major limb and facialabnormalities will of course be recorded, but itshould be remembered that the relation between ananatomical malformation and spontaneous abortionis far from clear. Thus fetuses with harelip or

polydactyly apparently have lower survival ratesthan those with anencephaly.18 It is naive to argue

that abortion occurs because the fetus is malformedunless that malformation can be clearly implicatedin the failure of an essential fetal or placental func-tion, such as gross malformations of the heart forexample, which would preclude intrauterine survival.The classification is necessarily simple and deals witha broad spectrum of lesions even within individualgroups. In essence it categorises spontaneousabortions according to the end stage pathologypresent at the time of expulsion. However, the meangestational ages of each of these groups (Table 1)suggest that the biological mechanisms concernedin the process of abortion may be different in eachgroup and that this classification may more closelyreflect the timing of the original insult to the develop-ing conceptus.

It must be stressed that while classification in thismanner is a relatively simple task it does not absolvethe pathologist from describing more specific lesions

Table 1 Distribution and mean gestational age in threegroups ofspontaneously aborted products of conception

Group Description % distribution Mean gestation (OA) (wk.)

I Blighted ova 43 9.4It Macerated 29 14-1III Fresh 28 18 6

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when present, nor does it preclude the need toindicate, whenever circumstances allow, the im-mediate factors leading to abortion. This is nowheremore important than in the examination of purportedspontaneous abortions occurring subsequent todiagnostic amniocentesis. It cannot be overempha-sised that the process of gradual failure of the con-ceptus outlined above occurring over a period ofdays or weeks can be initiated by the introductionof the diagnostic needle into the gestation sac duringthe 14th to 20th week of pregnancy. It is neither safenor biologically correct to assume that there is anarbitrary time limit after diagnostic amniocentesiswhich allows both obstetrician and pathologist toconclude that the failure of the pregnancy is notrelated to the earlier diagnostic procedures.

Laboratory techniques

The type of material submitted for examination willdepend on the population served by the hospital.Macroscopic categories are indicated in Table 2together with the possible final classification of thespecimen.

CURETTINGSCurettings are usually received in fixative unless

Table 2 Macroscopic findings in products of conception

Product Proposedgrouping

1 Gestation sac(a) Intact containing

(i) Fluid only(ii) Stunted, amorphous, or cylindrical embryo I(iii) Macerated embryo or fetus 11(iv) Fresh embryo or fetus IlI

(b) Ruptured(i) I(ii) Identifiable cord root

(a) Macerated I or 11*(b) Fresh III(c) Equivocal 1, 11, or II*

2 Embryo or fetus(i) Stunted, amorphous, or cylindrical I(ii) Macerated II(iii) Fresh 1ll(iv) Equivocal 11 or 111*

3 Placenta(i) Absent cord root I(ii) Identifiable cord root

(a) Macerated II(b) Fresh 111(c) Equivocal I, 11, or 111*

4 Curettings(i) Placental tissue U*

(ii) Decidua U(iii) Blood clot U(iv) Other U

*These specimens may be classifiable after examination of placentalhistology.U = unclassifiable.Identifiable pathological abnormalities other than those listed may berecorded but do not influence the grouping.

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specific infections such as tuberculosis are suspected.Frequently blood clot is the major component andcare should be taken to obtain tissue fragments byteasing out the clot with a scalpel or probe. The

nature of the conceptus can only be commented uponif adequate placental villi are available for micro-scopy. Pregnancy may be confirmed in the absenceof villi, membranes, and embryo if the placental bed

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Examination ofproducts of conception from previable human pregnancies

is included (Fig. 8), but care should be taken indiagnosing pregnancy in the presence of deciduaalone, since hormone treatment and ectopic preg-nancy may decidualise the endometrium and apronounced deciduoid reaction may be present inpremenstrual endometrium. In curettings obtainedsometime after clinical abortion, or in associationwith missed abortion, difficulty may be encounteredwith grossly inflamed endometrium. In such speci-mens, particular attention should be paid to theuterine vessels which may show regressive postpartumchanges (Fig. 9) in the absence of any products ofconception.

UTERINE CASTS AND EARLY GESTATION SACSA common presentation is the uterine cast consistingof a pyriform or ovoid, often fluctuant mass of tissuetogether with a variable quantity of blood clotattached to the surface most commonly at the endsof the specimen. If the sac within has ruptured andcollapsed, the surface coat may have a corrugatedappearance. Occasionally the cast may consistalmost entirely of decidua or blood clot or both, thegestation sac and placenta having been extrudedseparately. If a sac is present, be it intact or collapsed,it should be opened and the contents examined. Inparticular, evidence of an embryo or cord rootshould be sought, the latter being confirmed by thepresence of vessels in the chorionic plate. Where thecord is present without an embryo, there is usually asmall nubbin of tissue at the embryonic attachmentof the cord, indicating that maceration has occurred.Slicing the sac will usually reveal a localised area ofvillal growth though this is better displayed bydissection from any decidua and blood clot. In someearly anembryonic conceptuses, villi will be dis-tributed irregularly over the entire surface of the sac.These specimens usually arrive in the laboratory infixative, but should the clinical history of the patientsuggest special bacteriological, virological, or cyto-genetic investigation, special arrangements should bemade with the obstetrician concerned. A furtheradvantage of fresh material is that it is easier to teaseout the sac from blood clot with a blunt-endedprobe, particularly when this requires the use of adissecting microscope. Dissecting microscopy isinvaluable for the examination of minute embryosand embryonic remnants.

EMBRYOS AND FETUSESIn larger specimens the embryo or fetus and theplacenta can be examined separately. Techniques forexamination of the embryo or fetus have recentlybeen described.'9 Specimens may be examined in thefresh or fixed state. In fetuses under 20 wk gestation,it is the author's practice to perform an external

examination on fresh tissue and then to open thebody cavities and fix the fetus whole before internaldissection. Any samples required for microbiological,cytogenetic, or biochemical studies can be removedduring this initial examination. Dissection isperformed as for zoological specimens with the fetuspinned out on a cork board. This technique isvaluable if serial illustrations of the dissection arerequired.The examination of the embryo or fetus should

include measurements of weight and foot length. Thevalue of crown rump and crown heel length and ofhead and abdominal circumference measurementshas been questioned,19 because they are technicallymore demanding and subject to greater observererror. Many of these parameters are being measuredby ultrasound scanning in utero and, in the author'sopinion, the pathologist should attempt to gain theskill required to make these measurements to be ableto confirm the clinical findings. Rarely discrepancybetween crown heel and crown rump lengths may bethe initial indication of dwarfism. It should be notedthat head circumference is not a reliable indicator ofhydrocephaly in midtrimester fetuses and it isessential that ventricular size be assessed. In thisrespect ultrasonic scanning of the intact head is ofvalue if available within the hospital.

External examinationExternal examination of the fetus is extremelyimportant and apart from recording gross abnor-malities, particular care should be exercised in theexamination of the facies, hands, feet and genitalia.External examination of the fetus at around 20 wkgestation is not as productive as examination of thefull-term infant, since many of the abnormalitiesrecognisable in the latter may not be identifiable atan early gestation. Thus mongoloid facies cannot beidentified (Fig. 10), though transverse palmarcreases and prominent clefts between the first andsecond toes may be suggestive. However, chromo-somal analysis would be required to confirm thediagnosis. Other chromosomal anomalies may besuggested by external appearances, thus cyclopia isassociated with trisomy 13, abnormalities of thefingers, hands and feet with trisomy 1820 and bottle-shaped lower limbs with triploidy.21 The mostcharacteristic abnormality associated with a chromo-somal anomaly is undoubtedly the presence ofnuchal and subaxillary cystic hygromata with the45 XO karyotype (Fig. 1 1).22

Difficulty will almost certainly be encountered inthe interpretation of facial appearances. ThusPotter's facies, sometimes missed, in prematureinfants is often impossible to identify in midtrimesterfetuses with renal agenesis. This may be because the

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..u.... .....w .Fig. 10 22 wk mongol fetus. The typical mongoloidfacies of the newborn are not yet apparent.

Fig. 11 45 XO fetus aborted at 23 wk gestation.Nuchal cyst and swelling of the limbs are typical.

period of intrauterine existence is too short and theface is therefore relatively immature. In suchcircumstances, and in any situation where there isdoubt about the normality of a limb or organ-forexample, mild talipes, rocker bottom feet, or low setears, a photographic record should be obtained ifpossible and the pictures retained with the pathologyreport. These may be particularly valuable forcomparative purposes if the patient loses anotherpregnancy at a similar gestation.

Macerated fetuses present even greater difficulties,but they should not be ignored or discarded asvalueless. Many are grossly distorted as a result ofmoulding following resorption of amniotic fluid afterintrauterine death. However, such changes do notpreclude examination to exclude major malforma-tions and some minor lesions such as harelip,syndactyly, or polydactyly. The most valuablemeasurement is foot length and this may be combinedwith radiological identification of the vertebralossification centres19 to assess the gestation at thetime of death. Apart from malformations, there maybe indications of the cause of death such as a nuchalcord or cord entanglement in monoamniotic twins.If diagnostic amniocentesis has been performed,there may be evidence of fetal injury, this beingapplicable to both fresh and macerated fetuses.

Case report The importance of these examinations isillustrated by thefollowing case history: a 37-year-oldwoman presented at 10 wk in her fourth pregnancyhaving had an anencephalic baby in her first preg-nancy, followed by a miscarriage, and a normaldelivery after cervical suture in her third pregnancy.A cervical suture was inserted and an amniocentesisperformed at 15 wk gestation. Two weeks afteramniocentesis she was readmitted with light brownvaginal loss and no fetal heart was heard. Eighteendays after amniocentesis she aborted a maceratedseverely moulded female fetus weighing 45 g corre-sponding to a gestation of 15-16 wk by size. The siteof amniocentesis puncture could not be identified inthe placenta nor were there any external injuries tothe fetus. However internal examination revealed aleft haemothorax with displacement of the medias-tinum to the right and compression of the right lung(Fig. 12). The left leaf of the diaphragm was dis-placed downwards. The evidence clearly suggeststhat this fetus sustained a lethal injury at the time ofamniocentesis which would not have been detectedif the fetus had not been examined. Such cases maywell be passed off as spontaneous abortions unrelatedto amniocentesis.

Internal examinationIn ideal circumstances full dissections should be

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Examination ofproducts of conception from previable human pregnancies

Fig. 12 Post amniocentesis (L) haemo-thorax. Displacement of mediastinumand depression of (L) leaf of diaphragm.

carried out on both fresh and macerated fetuses andsuch examinations are mandatory on materialaborted after an earlier amniocentesis. They are alsoessential if reliable epidemiological data are required.In the immediate clinical situation where the priorityis to exclude lesions likely to recur in subsequentpregnancies, the need for complete dissections isopen to argument since the return in positive findingsis very small; though each positive result is clearly ofgreat importance to the individual patient. In theauthor's experience, if the fetus has a normalexternal appearance then the likelihood of finding a

clinically significant internal abnormality is less than2%, though this figure may increase if some of thediseases with known patterns of inheritance becomediagnosable by routine histological, histochemical,or immunohistochemical techniques-for example,Duchenne muscular dystrophy, cystic fibrosis, andother metabolic disorders. The risk of missingdetectable lesions of importance in genetic counsel-ling may be further reduced by excluding congenitalheart disease, hydrocephaly, polycystic disease of thekidneys, and hepatic fibrosis, the latter two disordersrequiring histological examination of the appro-

priate organs.

PLACENTA, CORD, AND MEMBRANES

Examination of the placenta, cord, and membranesis as important as examination of the embryo or

fetus. Indeed these may be the only tissues availableto the pathologist. A standard technique should befollowed so that important lesions are not missed.The author's practice is outlined below:The placenta may be received fresh or more com-

monly in fixative. If infection is suspected or ifbiochemical or cytogenetic studies are indicated,fresh tissue is mandatory.

Weights and measurements of the placenta and

cord may be recorded though difficulties in separa-tion of placental tissue from decidua and blood clotmay be contraindications to determination ofplacental weight. An attempt should be made toassess the completeness of the placenta and mem-branes. The number of vessels in the cord should berecorded and is best confirmed histologically. Thecolour and translucency of the membranes isrecorded and careful search made for nodules,needle punctures, and other evidence of trauma.Blood clot adherent to the fetal surface should besubmitted for haematological examination todetermine whether it is of maternal or fetal origin.This is particularly important in abortions followingamniocentesis. If infection is suspected (vide infra)tissue or swabs may be submitted for bacteriologicalor virological studies or both. The maternal surfaceshould be examined for attached blood clot andexcavating lesions. The placental disc should then besliced into strips 05-10 cm in width at right anglesto the chorionic place and any lesions noted-forexample, infarcts, intervillous thrombosis, sub-chorionic thrombosis (subchorionic haematoma),areas of pallor, molar change, and excavation.Macroscopically-identified lesions should be con-firmed by histological examination of appropriateblocks.There are four major indications for examination

of the placenta:(i) To exclude the presence of pathology likely to

modify the immediate clinical management ofthe mother.

(ii) To attempt to demonstrate lesions im-mediately responsible for or related to theexpulsion of the conceptus.

(iii) To attempt to identify lesions responsible forfetal death.

(iv) To distinguish between primary lesions of

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aetiological significance and secondary lesionsresulting from death of the embryo or fetusin utero. The latter are frequently mis-interpreted as primary indicators of theaetiology of abortion.

(i) Pathology likely to influence immediatetreatment of the mother

(a) Hydatidiform change and trophoblastic diseasePerhaps the most clinically important, though rarelyencountered, problem arising from the examinationof spontaneously aborted placental tissue is theassessment of the significance of macroscopic ormicroscopic molar change. The incidence of molarchange is highest in blighted ova and in many series20-40% of abortions have been affected.23-25 In thevast majority of these cases there is no difficulty ininterpreting the histology. It is now clear that thereare at least two distinct types ofmolar degeneration.26Partial molar degeneration characterised by anadmixture of hydropic and normal villi, the lattersometimes showing secondary lesions characteristicof embryonic or fetal death, is associated withchromosomal abnormalities, particularly triploidyand trisomy 16. An amniotic sac with or without anumbilical cord, embryo or fetus is frequentlyidentifiable.Complete or "true" molar degeneration in which

all villi are affected to a variable degree is usuallyassociated with an apparently normal female karyo-type though the studies of Kajii and his colleagues27have shown that the chromosomes of such moles areall paternally-derived. Evidence of an amniotic sacis extremely unusual in these cases. Microscopicstudies may further aid the distinction of the twotypes of molar degeneration.

Partial moles, as has been indicated, include aproportion of non-molar villi which may containformed vessels or in the case of a dead embryo orfetus, evidence of earlier vascularisation. Thetrophoblast on the surface of the molar villi isgenerally attenuated and may be reduced to a singlelayer of cells. The trophoblast on the surface of thevascularised villi is usually bilaminar. In "true"moles the trophoblast is very variable in appearanceand in many instances degenerate. However somevilli are usually found to show trophoblastic hyper-plasia and occasionally this will be the predominantfeature. It is important to distinguish between thesetwo types of molar degeneration since "true" molescarry a significant risk of subsequent persistenttrophoblastic disease and chorioncarcinoma. Thepathologist should make it clear in his report if hesuspects there may be a risk of recurrence. This isbest achieved by suggesting that the patient be

followed uip as a molar pregnancy.Greater difficulty may be encountered where only

curettings are available for examination. These havebeen discussed by Elston and Bagshawe.15 28 In aseries of 54 patients, they examined curettings from38 being followed up after delivering a hydatidiformmole, 12 after normal pregnancies and 4 afterspontaneous abortions. They identified three histo-logical groups:

(a) Villous curettings, all of which came from thecases with previous hydatidiform mole.

(b) Simple or suspicious trophoblast. These couldbe subdivided into those with small fragmentsof trophoblast with irregular hyperchromaticnuclei and poor differentiation into syncytio-trophoblast, and those with large sheets oftrophoblast showing clear differentiation intosyncytiotrophoblast.

(c) Trophoblast diagnostic of chorioncarcinomacharacterised by invasion of endometrium andmyometrium by large sheets of well-organisedtrophoblast.

The fact that all the curettings with villi come frommolar pregnancies indicates that problems in thedistinction between "true" moles and other forms ofmolar degeneration arising in spontaneous abortionsare rarely encountered. The same is true of villi fromnormal pregnancies where the trophoblast is almostinvariably degenerate. The authors emphasise thatchorioncarcinoma should not be diagnosed in thepresence of villi though 10% of this group sub-sequently developed malignant trophoblastic lesions.

In group (b), the clinical history was of greatimportance in the interpretation of the findings. Inthose cases where a previous mole had been deliveredclinical follow-up was already established. In caseswhere simple or suspicious trophoblast was identi-fied after a spontaneous abortion or normal preg-nancy the authors recommended that a presumptivediagnosis of chorioncarcinoma be made until provedotherwise.

(b) Placental site reaction Invasion of the decidua,basal endometrium and myometrium by wanderingtrophoblastic cells is a feature ofnormal pregnancy,29the histological appearances being termed syncytialendometritis by Ewing.30 Occasionally an exag-gerated response may be encountered and mis-interpreted as chorioncarcinoma. This is particularlylikely after molar pregnancies. Elston15 like manyothers considers that this change is essentially apersistence of placental site cells rather than a trueneoplasm and in his experience is rarely associatedwith serious clinical problems.

In spite of these aids to diagnosis, problem caseswill undoubtedly continue to occur and full clinical

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Examination ofproducts of conception from previable human pregnancies

follow-up must be recommended. The final analysismust include careful correlation of the clinical,endocrinological and pathological data. A definitivediagnosis on histopathological grounds alone isfrequently impossible and may be unwise.

If there are doubts in the pathologist's mind theseshould be clearly expressed to his clinical colleagues,so as to ensure patients are adequately monitored.

(c) Miscellaneous In rare instances products ofconception may reveal evidence of maternal diseaserequiring follow-up or treatment that has not beensuspected clinically. Theoretical examples includeinfections such as listeriosis, tuberculosis, candidiasisand cytomegalovirus or herpes virus lesions ofthe genital tract. Fragments of cervical tissue may

reveal evidence of dysplasia or even frank malig-nancy. Occasionally the first evidence of sickle celldisease may be the identification of sickle cells in theintervillous space.

(ii) Lesions responsible for or associated withexpulsion of the conceptus

(a) Retroplacental haemorrhage These are mostlikely to be demonstrated in midtrimester abortionsassociated with faults in the uterine environment.Retroplacental blood clot, frequently localised to themargin is a common finding in apparently normal,fresh midtrimester abortions. It is not always clearwhether it is a cause or an effect of abortion. How-ever, if such clots are associated with major placentalexcavation and infarction of the overlying placentaltissue it is reasonable to suspect that they haveplayed a significant role in the abortion of theconceptus. Equally if the thrombus is laminated andof varying age, the oldest portion lying nearest theamniotic cavity it may be deduced that recurrenthaemorrhages have occurred. The extent of theselesions will clearly be of paramount importance inassessing their clinical significance. Retroplacentalhaemorrhage may be related to the track of needlesused to perform amniocenteses.

(b) Infection The role of infection as a cause ofabortion is controversial. The most common mani-festation of infection is inflammation of the placentalmembranes, this being found in one third of mid-trimester abortions.31 Less commonly there isevidence of inflammation of the umbilical cord andfetal tissues, particularly the skin and lungs. Manyorganisms have been implicated notably myo-plasmas,32 toxoplasma,33 Listeria monocytogenes,-34rubella virus,35 vibrio fetus,36 and Candida albicans.37However in the majority of cases inflammation of themembranes is associated with colonisation by

organisms derived from the normal vaginal andperineal flora. In these circumstances it is debatableas to whether the infection leads to abortion byweakening and rupturing the membranes or whetherthe infection is secondary to rupture occurring forunknown reasons followed by ascending colonisationof the amniotic sac.

Since infection and inflammation is not un-common, it is often preferable to examine the pla-centa in the fresh state. Evidence of infection isoccasionally apparent from the odour of the speci-men, this being particularly true of the septic pro-cured abortion. More obvious macroscopic changesinclude loss of translucency of the membranes whichmay be creamy yellow in colour. Breakdown ofblood pigments may result in red-brown staining ofthe membranes and cord. Most bacterial infectionseventually involve the membranes diffusely butcertain specific infections may produce localisedlesions. These include listeriosis, candidiasis andherpes simplex infection. These may be reflected inspots or nodules on the surface of the amnion andfetal skin (Fig. 13). While bacteriological or viro-logical studies may be considered unnecessary withdiffuse involvement of the membranes, all placentaewith focal lesions should be subject to a full micro-biological investigation. Further causes of nodularityof the membranes include amnion nodosum andsquamous metaplasia.38 Both these lesions may bepresent in midtrimester abortions though the lesionstend to be correspondingly small and may be missed.Careful examination of the amnion with a smallpowerful light source at an oblique angle with orwithout the aid of a dissecting microscope willfacilitate identification in the majority of cases. Inall placentae where nodules are identified on themembranes, their nature should be clarified byhistological examination. If amnion nodosum isconfirmed, special care should be taken to examinethe fetal urinary tract.

Inflammation of the villi (villitis) is much lesscommon and since it is usually unrecognisablemacroscopically, it is often only demonstrated afterthe remnants of the placenta have either been dis-carded or fixed. While it is often suspected thatvillitis is an indication of viral infection it is fre-quently impossible to prove this. If the fetus iswell-preserved further evidence may be forthcomingfrom histological studies, but all too often villitis isfound in the presence of a severely macerated fetus.In these circumstances the role of the suspect infec-tion in fetal death can only be conjectural. Screeningfor evidence of a recent viral infection in the mothermay occasionally be productive, but in the author'sexperience, the aetiology of villitis usually remainsunknown.

831

Rushton

Fig. 13 Amniotic surface with multiplenodules 2-3 mm in diameter due to candi-diasis x 30.

The key histological feature of villitis is infiltrationof the villal stroma with inflammatory cells whichmay include polymorphs, lymphocytes, and plasma-cytoid cells. Villal involvement is usually patchy andisolated villi with increased stromal content ofinflammatory cells are not uncommon at the marginof placentae. It is doubtful ifsuch lesions are clinicallysignificant. In overt viral infections, the inflammationmay be associated with focal necrosis of the villalstroma and trophoblast. The cells may appear toform a pallisade-like pattern around foci of necrosis(Fig. 14). Villitis may also be found in overwhelmingbacterial infections such as maternal and fetalsepticaemia which may follow procured abortion.Local marginal inflammatory lesions of the placentainvolving the decidua and membranes may involvevilli by contiguous spread and may be significantcauses of membrane rupture. Rarely, there may bediffuse involvement of the placenta, cord, membranesand fetus. The cut surface of the placenta is palegrey-pink in colour and the normal spongy appear-ance and consistency is lost being replaced by firmconsolidated tissue.

(c) Criminal abortion Fortunately a rare occurrencetoday in the United Kingdom, the criminally inducedabortion requires special consideration. It is essentialthat the products of conception be examined in thefresh state. Wherever possible, the following pro-cedures should be instituted:

(a) a sample of any free fluid, even if heavilyblood-stained should be preserved for possibleanalysis for injected material.

(b) a sample of fetal blood should be obtained for

grouping.(c) careful search should be made for foreign

material.(d) both placenta and fetus (if available) should be

examined to exclude any injuries produced byinstruments.

(e) bacterial cultures from the tissues should beestablished.

(f) detailed descriptions of the placenta and fetusincluding weights and dimensions should berecorded with photographs if appropriate. Ifonly fetal parts are available measurements ofthe foot length may be of particular value inthe assessment of gestational age.

(g) histological studies of the placenta and fetallungs should be performed. Both may revealevidence of infection and the lungs may containaspirated material used to procure theabortion. The gastric contents of the fetusshould be preserved for similar reasons.

(h) All remaining tissues should be preserved infixative.

(d) Therapeutic abortion The placenta should becarefully examined for evidence of injury resultingfrom earlier amniocentesis or fetoscopy. Particularcare should be taken to evaluate haemorrhages onthe fetal surface of the placenta and retroplacentalblood clot should be described as above. Specificlesions related to the mode of termination have beendescribed but are only of academic interest.39

(iii) Lesions responsible for fetal deathThe majority of lesions of the placenta likely to result

832

Examination ofproducts of conception from previable human pregnancies

Fig. 14 Vaccinial placentitis. Centralnecrotic zone surrounded by inflam-matory infiltrate showing palisading.Haematoxylin and eosin x 200.

',4Lt. ..

.s. ....

F.....k.-.

Fig. 15 Slices ofplacenta. Infarctionold (arrow heads) andfresh (small arrow).The old infarct is asso-ciated with retropla-cental haemorrhage.Approximately anatural size.

in fetal death in utero have been discussed in thepreceding section. Retroplacental haemorrhage,placental abruption, trauma, and infection may allbe evident from examination of the placenta. Thereremains one further important cause, uteroplacentalischaemia. In later pregnancy major degrees ofplacental infarction-that is, over 10%, are almostinvariably associated with maternal hypertensionand in particular with pre-eclamptic toxaemia andeclampsia. In pregnancies of less than 28 wk durationsevere pre-eclampsia may also result in fetal deathassociated with placental infarction and abruption.However a small number of placentae show veryextensive infarction in the absence of clinicalmanifestations of pre-eclampsia or essential hyper-tension. Many of these fetuses are growth-retarded.Uterine vascular lesions similar to those described inpre-eclampsia have been recorded in association withintrauterine growth retardation.40 It is possible thatsuch examples represent cases of clinically latent

pre-eclampsia. Whatever the aetiology of the infarctsin these few abortions it is clear that the basic lesionis likely to involve the uterine blood supply to theplacenta, and in particular the uterine spiral arteries.4'It is important that the pathologist identifies thisgroup since they show distinct differences in theirpathogenesis from the majority of abortions. Theiridentification may have prognostic significance infuture pregnancies and may also contribute to ourknowledge of the aetiology of pre-eclamptic tox-aemia.The identification of placental infarcts (Fig. 15) is

usually straightforward, but in early pregnancy theytend to be more irregular in shape since placentalremodelling is not always complete. It is thereforecircumspect to take material for histologicalexamination. Placental infarcts are areas of ischaemicnecrosis of the placenta, the trophoblast bearingthe brunt of the ischaemia. They vary from dark redthrough red-brown, brown, brown-yellow, yellow to

833

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Rushton

yellow-white in colour. They are best diagnosed inthe sliced placenta and care should be exercised in theinterpretation of lesions in the intact placenta. Thelesions are characteristically triangular in shape. Theyare most common at the placental margins where inisolation they are of little significance. Centrallesions, particularly if multiple, are almost invariablyan indication of severe generalised uterine vasculardisease. Further descriptions of the lesions anddiscussion of their aetiology may be found else-where.42 It should be noted that placental infarctionmay continue to occur after fetal deatn.

(iv) Distinction ofprimary and secondary lesionsThe lesions found in the placenta associated withintrauterine fetal death have been detailed above inrelation to group II of the classification. It is import-ant not to interpret these lesions as causative of fetaldeath. The most characteristic macroscopic lesion ismaternal floor infarction which is present to a varyingextent in approximately 30% of group II placentae.

In pregnancies where embryonic or fetal death isfollowed by retention of the conceptus for days or

weeks, the declining function of the placental tissueoften results in the uterine vasculature undergoingregressive changes before the conceptus is expelled(Fig. 9). Such vascular lesions should not be mis-interpreted as the causes of embryonic or fetal deathbut rather as evidence of the mechanism underlyingabortion.

Conclusions

It will be obvious that it has not been possible todiscuss the entire spectrum of pathology associatedwith early pregnancy wastage. It may be argued thatthe case for examination of products of conceptionis as yet unconvincing and that current work loadspreclude the use of techniques outlined above. Whilesome of our clinical colleagues may be disillusionedby the information we provide and therefore are notunduly disturbed if such material goes unexamined,there is increasing pressure from the unfortunatemothers whose pregnancies have failed to know whythey aborted. Empirical counselling is becoming lessacceptable to both patient and obstetrician. Thus itmay be worthwhile asking what our obstetric andgynaecological colleagues are hoping to learn fromour efforts.There are five major contributions that might be

made if proper examinations of products of concep-tion were made:

(i) To confirm or obtain a clinical diagnosis.(ii) To provide data of value in the assessment of

the clinical prognosis and in genetic coun-selling.

(iii) To provide insight into the aetiology andnatural history of disease processes in theembryo and fetus. In this respect it must notbe overlooked that the most important factorsinfluencing perinatal mortality-that is, pre-maturity, intrauterine growth retardation andpre-eclampsia may all stem from pathologicalprocesses which have their inception in thefirst 28 wk (or 20 wk) of pregnancy.

(iv) To provide an objective data base for epi-demiological studies of patterns of abortionand of congenital malformations in earlypregnancy. Such data might be of value in thedetection of environmental teratogens.

(v) To assess the effectiveness or otherwise oftherapeutic regimens purported to reduce orprevent abortion.

Addendum

SPONTANEOUS ABORTION AND CYTOGENETICEXAMINATIONSince a minimum of 100 000 spontaneous abortionsmay be expected annually in the United Kingdom itis clear that cytogenetic studies cannot be performedas a routine. Indeed as has been indicated earliersuch investigations are unwarranted. There are,however, specific areas where cytogenetic studiesmay be of value. The following indications aregenerally acceptable.

(a) Patients having habitual abortions-that is,three or more successive spontaneous abor-tions, particularly if they consistently occur ata similar gestation and are pathologicallyclassified into a single group especially group 1.In such cases maternal and paternal bloodsshould be examined initially rather than theproducts of conception. If parental bloodsreveal abnormalities then amniocentesis maybe indicated in future pregnancies and anyfurther abortions should be examined cyto-genetically.

(b) All pregnancies terminated as the result ofantenatal diagnosis of a fetal karyotypicabnormality must have this diagnosis con-firmed on fetal and or placental tissue. Ifmosaicism is suspected multiple fetal tissues-for example, skin, lung, kidneys, gonads, etcshould be examined.

(c) Fetuses with unusual or multiple malforma-tions or fetuses showing features indicative ofa specific chromosomal abnormality.

Since many cytogenetic laboratories are working ator beyond their ideal capacity, individual cases arebest discussed with the cytogeneticist. The patholo-gist aware of cases likely to require cytogenetic

834

Examination ofproducts of conception from previable human pregnancies

studies should attempt to ensure his clinical col-leagues are fully aware of the need to receive thetissues as soon as possible after expulsion in a freshstate.

The author wishes to thank all those obstetriciansand gynaecologists who co-operated in the collectionof specimens which form the basis on which theobservations in this paper are based. I also wish tothank Mrs 0 Brooke for her help in the preparationof the manuscript.

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3 Witschi E. Teratogenic effects from overripeness of the egg.In: Fraser FC, MuKusick VA, eds. Congenital mal-formations: proceedings of the third internationalconference, Amsterdam. New York: Excerpta Medica,1970:157-69.

4 Miller JF, Williamson E, Glue J, Gordon YB, GrudzinskasJD, Sykes A. Fetal loss after implantation. Lancet 1980;ii :554-6.

Bou6 A, Boue J. Consequences of chromosome aberrationson the development of human conceptuses. In: van

Juhsingha EN, Tesh JM, Fara GM, eds. Advances in thedetection of congenital malformations. European Tera-tology Society, 1978:33-49.

Rushton DI. Developmental Genetics. In: Fraser GR,Mayo 0, eds. Textbook of Human Genetics. Oxford:Blackwell, 1975:169.

7 Mikamo K. Anatomic and chromosomal anomalies inspontaneous abortion. Am J Obstet Gynecol 1970;106:243-54.

8 Friedman S, Gans B, Eckerling B, Goldman J, KaufmanH, Rummy M. Placental hormone activity after removalof the fetus in a case of advanced abdominal pregnancy.J Obstet Gynaec Brit Cwlth 1969;76:554-8.

9 Duff GB, Evans JJ, Legge M. A study of investigationsused to predict outcome of pregnancy after threatenedabortion. Br J Obstet Gynaecol 1980;87:194-8.

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Mall FP, Meyer AW. Studies on abortuses: a survey ofpathologic ova in the Carnegie embryological collection.In: Contributions to embryology Vol 12. Publications ofthe Carnegie Institution, 1921:1-364.

12 Fujikura T, Froehlich LA, Driscoll SG. A simplifiedanatomic classification of abortions. Am J ObstetGynecol 1966;95:902-5.

13 Hertig AT. Human trophoblast. Springfield, Illinois:Charles Thomas, 1968:167.

14 Rushton DI. Simplified classification of spontaneousabortions J Med Genet 1978;15:1-9.

15 Elston CW. The histopathology of trophoblastic tumoursJ Clin Pathol 1976;29, suppl 10:11 1-31.

16 Honor6 LH, Dill FJ, Poland BJ. Placental morphology inspontaneous human abortuses with normal and abnor-mal karyotypes. Teratology 1976;14:151-66.

17 Benirschke K, Driscoll SG. The pathology of the humanplacenta. New York: Springer-Verlag, 1967:232.

18 Nishimura H, Takano K, Tanimura T, Yasuda M. Normal

and abnormal development of human embryos: firstreport on the analysis of 1213 embryos. Teratology 1968;1:281-90.

19 Berry CL. The examination ofembryonic and fetal materialin diagnostic histopathology laboratories. J Clin Pathol1980;33:317-26.

20 Butler LJ, Snodgrass GJAI, France NE, Sinclair L,Russell A. E (16-18) trisomy syndrome: analysis of 13cases. Arch Dis Child 1965;40:600-11.

21 Gosden CM, Wright MO, Paterson WG, Grant KA.Clinical details. cytogenetic studies and cellular physiol-ogy of a 69XXX fetus with comments on the biologicaleffect of triploidy in man. J Med Genet 1976;13:371-80.

22 Rushton DI, Faed MJW, Richards SEM, Bain AD. Thefetal manifestations of the 45XO karyotype. J ObstetGynaec Brit Cwlth 1969 ;76:266-72.

23 Hertig AT, Edmunds HW. Genesis of hydatidiform mole.Archives ofPathology 1940;30:260-91.

24 Nilsson L. Hydatidiform degeneration in aborted ova.Acta Obstet Gynecol Scand 1957;36, suppl 7:1-80.

21 Abaci F, Aterman K. Changes of the placenta and embryoin early spontaneous abortion. Am J Obste. Gynecol1968;102:252-63.

26 Vassilakos P, Riotton G, Kajii T. Hydatidiform mole: twoentities. Am J Obstet Gynecol 1977;127:167-70.

27 Kajii T, Ohama K. Androgenetic origin of hydatidiformmole. Nature 1977;268:633-4.

28 Elston CW, Bagshawe KD. The diagnosis of trophoblastictumours from uterine curettings. J Clin Pathol 1972;25:111-8.

29 Park WW. Possible functions of nonvillous trophoblast.Eur J Obstet Gynaecol Reprod Biol 1975;5:35-46.

30 Ewing J. Chorioma: a clinical and pathological study.Surg Gynecol Obstet 1910;10:366-92.

31 Rushton DI. Unpublished data.32 McCormac WM. Genital mycoplasmal infections: their

relation to prematurity and other abnormalities ofreproduction. J Clin Pathol 1976;29, suppl 10:95-8.

33 Weinman D. Toxoplasma and abortion: a field for furtherinvestigation. Fertil Steril 1960;11:525-30.

34 Rappaport F, Rabinowitz M, Toaff R, Krochkin N.Genital listeriosis as a cause of repeated abortion. Lancet1960;i :1273-5.

35 Dudgeon JA. Viral infections. J Clin Pathol 1976;29, suppl10:99-106.

36 Klein JO, Remington JS, Marcy SM. An introduction toinfections of the fetus and newborn infant. In: RemingtonJS, Klein JO, eds. Infectious diseases of the fetus andnewborn infant. Philadelphia: WB Saunders, 1976:1-33.

3 Cumming DC, Wren FD. Abortion associated withintrauterine infection by Candida albicans. Br J ObstetGynaecol 1979 ;86:741-4.

38 Fox H. Pathology of the placenta. London: WB Saunders,1978:459-63.

39 Ibidem: 277-81.40 Sheppard BL, Bonnar J. The ultrastructure of the arterial

supply of the human placenta in pregnancy complicatedby fetal growth retardation. Br J Obstet Gynaecol 1976;83 :948-59.

41 Wigglesworth JS. Vascular organisation of the humanplacenta. Nature 1967;216:1120-1.

42 Fox H. Pathology of the placenta. London: WB Saunders,1978:115-23.

Requests for reprints to: Dr DI Rushton, PathologyDepartment, The Birmingham Maternity Hospital,Queen Elizabeth Medical Centre, Edgbaston, BirminghamB15 2TG, England.

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