function: its nature and assessment the histopathology of ...j. clin. path., 29, suppl. (roy. coll....

J. clin. Path., 29, Suppl. (Roy. Coll. Path.), 10, 1-8

Feto-placental function: its nature and assessment

The histopathology of placental insufficiencyH. FOX

From the Department ofPathology, University ofManchester

Voltaire, regarded by some as a realist and by othersas a cynic, remarked that 'if God did not exist itwould be necessary to invent him'. One suspects thatthis comment is equally applicable to placentalinsufficiency, a concept that has similarly attractednot only faithful adherence but also bewilderedagnosticism or defiant disbelief.

Placental insufficiency has been largely defined inclinical terms, principally by those who believe thatthe placenta is, during a normal pregnancy, extendedto the full limit of its functional capacity. Adherenceto this belief implies that any factor which adverselyinfluences trophoblastic function, by no matter howlimited an extent, will restrict the fetal supply ofoxygen and nutrients, this resulting in fetal growthretardation, wasting, hypoxia or, in extreme cases,death. This clinical concept has been supported, tosome extent, by placental function tests which,however, measure principally the biosynthetic andendocrinological activities of the trophoblast ratherthan its capacity for transferring oxygen andnutrients to the fetus. The final court of appeal forconfirmation of a diagnosis of placental insufficiencyis the pathologist who finds that the apparentlyinadequate placentae presented to him for appraisalmay be large or small and can vary from beingextensively infarcted and heavily calcified at oneextreme to complete normality at the other. Manypathologists faced with this situation are forced intoan attitude of diagnostic nihilism and are content notto pursue with any great degree of tenacity thequestion, to which this paper is directed, of whether asatisfactory pathological basis for placental in-sufficiency can be defined.

Clearly the syndrome of chronic fetal deprivationmay have any one of three fundamental bases: (1)a deficient supply of oxygen or nutrients to theplacenta either because of an abnormal constitutionof the maternal blood or because of an inadequatematernal uteroplacental circulation; (2) a failure ofthe placenta to transfer adequately oxygen andnutrients from maternal to fetal blood; (3) a failureof the fetus either to take up, or to utilize adequately,nutrients and oxygen.

It is only the second of these possibilities whichwill be examined here in detail, for if the term'placental insufficiency' has any meaning it must bethat a placenta receiving an adequate supplyof nutrients and oxygen is unable to transfer these toa normal fetus in quantities sufficient to ensurenormal growth and development.

Placental Pathology in Fetal Deprivation

The functional unit of the placenta is the terminalvillus and a placenta that is physiologically inade-quate must have either (a) a decreased number offunctioning villi or (b) a normal number of villi whichare, however, functionally inefficientA lesion which clearly reduces the total population

of functioning villi is placental infarction (fig 1) inwhich a number of villi undergo ischaemic necrosisand become aggregated together to form an easilyvisible white plaque. Small infarcts are both commonand unimportant but necrosis of more than 10 to 15per cent of the placental parenchyma is associatedwith a very high incidence of fetal deprivation anddeath (Fox, 1967a); indeed, it has been this findingwhich has prompted the suggestion that theplacenta has little or no functional reserve capacity.That this is too simplistic a view is, however,indicated by a consideration of two other lesionswhich cause a reduction not, it is true, in the totalnumber of villi, but in the population of function-ing villi, these being perivillous fibrin depositionand fetal artery thrombosis. In the former (fig 2) aportion of the intervillous space is obliteratedby fibrin which is laid down around the villi as aconsequence of eddy currents and stasis of maternalblood and forms an irregular white plaque that isoften called an infarct. This is a regrettable mis-nomer but it has to be accepted that the villi em-bedded within the fibrinous mass might just as wellbe infarcted for they are no longer available tofulfil their transfer function. Similarly, followingfetal artery thrombosis (fig 3), an event whichusually occurs for no discernible reason, theavascular villi normally supplied by the occluded

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Fig 1 A placental infarct: this isseen in the left halfof the field and ischaracterized by aggregation ofvilli, obliteration of the intervillousspace and necrotic changes in thevilli(H&E x 56).

vessel play no part in transferring oxygen or nutrientsto the fetus. It is therefore surprising that neither ofthese lesions appears to affect adversely the fetus, thisapplying not only to small lesions but also to those inwhich as many as 30 per cent of the villi are renderedfunctionally inactive (Fox, 1967b) That the placentacan withstand the loss of nearly a third of itsfunctional parenchyma without any fetal embarrass-ment bears eloquent witness to the fact that, far frombeing physiologically extended, it has a very con-siderable functional reserve capacity. Why then theparadox that a similar, or even much less substantial,loss of villi because of infarction is of such gloomyimport for fetal growth and development? Placentalinfarction is due either to a retroplacental haema-toma or thrombosis of a maternal utero-placentalvessel; if those due to retroplacental bleeding are, forthe moment, excluded it is clear that extensiveinfarcts are due to widespread thrombosis ofmaternal arterioles (Brosens and Renaer, 1972), aphenomenon that would not be expected to occur ina healthy vascular tree. Indeed, a significant degree ofinfarction is found only in placentae from womensuffering from the hypertensive complications ofpregnancy and these are precisely the conditions inwhich the utero-placental vessels are markedlyabnormal (Robertson et al, 1975) and in which, as aconsequence, maternal blood flow through theplacenta is diminished. Extensive infarction is

usually therefore the visible hallmark, and onlyoccurs as a complication, of a severely compromisedutero-placental circulation and it is this, rather thanthe simple loss of villi, that is the true cause of thefetal complications.As already mentioned, infarction may also be due

to retroplacental bleeding. A sharp distinctionhas been drawn between the chronic condition ofpremature separation of the place'ita and the acutecatastrophe of abruptio placentae (Gruenwald et al,1968); tbe former results in the formation of aretroplacental haematoma which indents the basalplate of the placenta and causes infarction of theoverlying villi but does not usually produce anyclinical symptoms whilst the latter produces adramatic clinical picture, is usually followed rapidlyby delivery of the fetus and may not leave anypathological imprint on the placenta. Retro-placental haematomata are found in about 5 per centof pregnancies but the vast majority are small and ofno importance; they are only associated with fetaldeprivation if more than a third of the placentalparenchyma is separated by the haematoma from thematernal utero-placental vessels or if the bleedingoccurs in a pregnancy already complicated by ahypertensive condition.

It could, of course, be argued that the mostobvious manner in which the villous population isdiminished, namely, by the development of an

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The histopathology ofplacental insufficiency

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Fig 3 Avascular villi resulting from thrombosis ofafetal stem artery (H & E x 350).

Fig 2 Perivillousfibrin deposition: the intervillous spaceis filled in byfibrin which completely envelops the widelyseparated villi (H & E x 350).

unusually small placenta, is often associated withpoor fetal growth and that in such cases theinadequate growth of the fetus is a direct result of thesmall placental size. If, however, fetal growth wererigidly limited by placental size it would indicate thatthe placenta is functioning at the limit of its capacity,a view which appears to be incorrect. It is much moreprobable that the reverse situation is the case andthat when the fetus is small the placenta, being afetal organ, shares in the generally diminishedgrowth of the fetus, the small placenta being thus amanifestation, rather than a cause, of poor fetalgrowth (Gruenwald, 1975).

Clearly, a very extensive loss of functioning villi,ie, of more than 30 per cent, will dissipate the reservecapacity of the placenta and thus be of considerablesignificance; extensive lesions of this type are,however, most rare and the vast majority of lesionsthat reduce the villous population are of littleimportance, the stress that has been placed uponthem in the past being largely due to the fact that they

are readily visible and thus serve as convenient pegsupon which to hang a diagnosis of placentalinadequacy. This perhaps emphasizes that themacroscopic study of the placenta is not often of anygreat value to the pathologist concerned withdefining placental insufficiency. It is true that thismay reveal the crater marking the site of an oldretroplacental haematoma or the very uncommonlarge haemangioma which may, possibly because itacts as an arteriovenous shunt and thus allows thereturn of unoxygenated blood to the placenta, beassociated with fetal deprivation and that circum-vallate placentation is accompanied unduly often bya minor degree of fetal growth retardation but mostother visible lesions are quite banal. Thus sub-chorionic fibrin plaques, intervillous thrombi, smallhaemangiomata, septal cysts, marginal haematomataand calcification in no way influence trophoblasticfunction; it is perhaps necessary to stress thatcalcification, often thought of as a hallmark ofplacental degeneration or senescence, is of noclinical or pathological significance and, in par-ticular, is no more common in placentae from pro-longed pregnancies than in those from full-termgestations (Brandt, 1973).

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If therefore neither the macroscopic pathology ofthe placenta nor a reduction of villous mass can beconsidered as offering a plausible basis for a diagnosisof placental insufficiency it must be postulated thatthe assumed functional inadequacy of the organ isdue to an overall reduction in the ability of thetrophoblast to fulfil its transfer role. Amongst thepossible factors that have been variously suggested as

influencing villous function in this manner are

ischaemic, inflammatory or immune damage,deficient fetal perfusion, trophoblastic senescence,

failure of villous maturation and inadequate tropho-blastic differentiation.Changessecondary to utero-placental ischaemia are

certainly seen in a fairly high proportion of placentaefrom deprived fetuses. The most obvious histologicalevidence of this (fig 4) is hyperplasia and proliferation

Fig 4 An undue prominence and increased number ofvillous cytotrophoblastic (Langerhans) cell in a placentafrom a woman with preeclampsia. One of these cells isarrowed (P.A.S. x 560).

of the villous cytotrophoblastic cells (Wigglesworth,1962); these are the stem cells from which thesyncytiotrophoblast is derived and they form whatcan be considered as a regenerative zone which is,

H. Fox

in the mature placenta, normally quiescent but whichbecomes activated when the syncytium suffersischaemic damage. The cytotrophoblastic prolifera-tion represents an attempt to repair and replacedamaged syncytium, and, as such, the degree ofproliferative activity provides an approximate guideto the severity of the ischaemia to which the placentahas been subjected. This repair activity appears to bestrikingly successful, for at both light and electronmicroscopic level the ischaemic syncytium showsremarkably little evidence of structural change. Thisbeing so, it is difficult to believe that the functionalcapacity of the placenta is severely restricted undersuch circumstances and the evident ability of thetrophoblast to repair itself indicates that in conditionsof ischaemia the placenta is probably working asefficiently as the diminished maternal blood flow willallow; thus any failure of fetal nutrition in these casesis probably not due to placental inadequacy but tothe diminished maternal supply of nutrients andoxygen.The reverse situation, inadequate fetal perfusion,

is seen in, but is not confined to, placentae fromprolonged pregnancies in which there is, for reasonsthat are presently obscure, an apparent collapse ofthe fetal circulation through the placenta, with thevillous capillaries, instead of being sinusoidallydilated, appearing small and inconspicuous. Underthese circumstances, and in all others in which fetalvillous blood flow is restricted, eg, fetal arterythrombosis, the underperfused villi show excessivestromal fibrosis and a markedly increased formationof syncytial knots (Fox, 1969). These villous changesmay be, but often are not, associated with fetaldeprivation but there is no convincing evidence thateither a diminished fetal blood flow or the resultingvillous abnormalities impair placental function, and,indeed, ultrahistochemical studies show that tropho-blastic enzymatic activity is either unimpaired orincreased in placentae from prolonged pregnancies(Jones and Fox, in preparation). It seems highlyprobable therefore that any fetal deprivation whichdoes occur in association with fetal underperfusionof the placenta is due not to trophoblastic inadequacybut to a diminished ability of the fetus to take upoxygen and nutrients from the placenta; an alterna-tive explanation that must be kept in mind is, ofcourse, that the decreased fetal circulation throughthe placenta is a consequence, rather than a cause, offetal deprivation.The question of whether the placenta can suffer

immune-mediated damage is a moot one but it issufficient to note here that there is no evidence, evenof the most tentative nature, that immune damage tothe trophoblast is a cause of placental insufficiency;thus the lesion which is often quoted as being a



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hallmark of immune attack, namely, villous fibrinoidnecrosis, involves too few villi to be of any possiblefunctional significance whilst a prolonged ultra-structural search for deposition ofimmune complexesin placentae from deprived fetuses has provedunrewarding (Jones and Fox, unpublished observa-tions). It is also perhaps worth noting that underexperimental conditions increasing degrees ofmaterno-fetal incompatibility with regard to H locilead, not to a small fetus, but to increasingly largeplacentae and fetuses, presumably as a result ofhybrid vigour (Lanman, 1975; Beer, 1975).

It has been claimed that inflammatory damage tothe placenta as a result of bacterial or viral infectioncan produce a functional inadequacy, this claimbeing based on the finding that placentae showingvillositis are commonly associated with an infant oflow birth weight (Altshuler et al, 1975). The effectsof villous inflammation on placental physiology arenot known but it is difficult to accept that thefunctional capacity of the trophoblast is seriouslyimpaired by a villositis for the affected villi are bothfew and scattered. It could be postulated that thevillositis is a red herring and that the real brunt of theinflammatory damage falls on the maternal vascula-ture, for in certain veterinary infections, eg,

aspergillosis of the ungulate placenta, there may be awidespread necrotizing vasculitis of the utero-placental vessels with, of course, dire consequencesfor the fetus; there is, however, no evidence that an

inflammatory lesion of this type ever occurs in thehuman placenta. In considering the effects ofplacental infection it must be borne in mind that theorgan presents a very easily breached barrier andthat in most, probably all, cases of villositis thefetus is also infected; almost certainly it is the directeffect of such infection on the fetus that is responsiblefor the retarded growtl rather than the inflammatorydamage to the placenta. To this rule one apparentexception must be noted, for heavy malarial infesta-tion of the placenta, without fetal involvement, isoften associated with an unduly small baby (Jelliffe,1967); the malarial parasites do not, however, causeany damage to, or destruction of, placental tissue andthe inadequate nutrition of the fetus appears to bedue to the massive histiocytic infiltration of theintervillous space which is found in such cases andwhich acts as a barrier to separate the trophoblastfrom the maternal blood.Not only villositis, which is caused by a haemato-

genous infection, but also chorioamnionitis, which isdue to an ascending infection, is often found to beassociated with a baby of low birth weight. There canbe little doubt, despite intermittent claims to thecontrary, that the dominant aetiological factor inchorioamnionitis is prolonged rupture of the

membranes (Fox and Langley, 1971) and thus it is ofinterest that Lind and Hytten (1969) have shown thatthe lower the weight of the fetus the longer is theaverage time interval between membrane rupture anddelivery, possibly because the strength of themyometrial contractions is related to the bulk of theuterine contents. Hence the chorioamnionitis oftenfound in placentae from small babies is probably aresult, rather than a cause, of the low birth weight.The question of whether the placenta ages during

its short life span is extraordinarily difficult toanswer. Certainly, the villi, during the course ofpregnancy, undergo a series of morphologicalchanges which have been interpreted by some as anaging phenomenon but which should more correctlybe considered as a progressive maturation (Vorherr,1975). One cannot define with any degreeof assurancechanges in the placental villi that could be consideredas morphological evidence of senescence though ithas been maintained that the abnormality usuallyknown as villous fibrinoid necrosis is actually a formof senile amyloidosis, the amyloid being deposited asa result of immune attack on trophoblastic cellswith misspecified protein synthesis (Burstein et al,1973); this is a hypothesis that is open to someconsiderable doubt but even if it were true the villiinvolved are insufficiently numerous for their lossto be of any real functional significance. At theultrastructural level changes of an apparently agingnature have been observed in trophoblastic nucleiand nucleoli and these have been thought to beindicative of impaired protein biosynthesis in latepregnancy as a result of a programmed senescence(Martin and Spicer, 1973). Whether this interpreta-tion of the rather subtle electron-optical abnormali-ties which have been observed is fully justified is aquestion to which, at the moment, no firm answercan be given.

Irrespective of whether or not the trophoblast agesas pregnancy progresses there can be no doubt thatthe villi undergo a progressive morphologicalmaturation; they decrease progressively in diameterand their vessels, which in early pregnancy are smalland centrally placed, become sinusoidally dilatedand eventually come to occupy most of the cross-sectional area. It is assumed that these changes tendto facilitate materno-fetal transfer and it has beensuggested that they are of the type which would beexpected if the organ was changing from one inwhich active transfer dominated to one in whichsimple diffusion was of prime importance. Placentalmaturation is not, however, simply a reflexion of fetalmaturation, for an asynchrony between the twomaturation rates can occur, and it is by no meansunknown for an undoubtedly full-term fetus to havea placenta in which most of the villi have failed to

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mature beyond the stage expected for a gestationalage of 24 to 28 weeks (fig 5). Such fetuses are, thoughmature, very often unduly small and it is thought thatthis is because the incomplete villous maturationleads to a functional inadequacy during late preg-nancy (Becker, 1975).

.....

Fig 5 A placenta from a pregnancy of40 weeks inwhich the fetus was of low birth weight. The villi areuniformly immature (H & E x 56).

It is not always fully appreciated that villousmaturation appears to be accompanied by a pro-gressive topographic differentiation of the tropho-blast, the two processes being intertwined thoughprobably independent of each other. The villoustrophoblast has both a synthetic and transferfunction and it would be reasonable to assume thatdifferent areas become adapted for one or other ofthese two roles. This assumption has received supportfrom electron optical studies of first trimestervillous trophoblast which have shown that despitethe apparent morphological homogeneity of thistissue at light microscopic level there is considerableultrastructural evidence of regional functionaldifferentiation (Dempsey and Luse, 1971). In themature placenta the villous syncytiotrophoblast is

clearly not morphologically homogeneous for thereare, in many villi, thinned anuclear areas of tropho-blast which directly overlie and, on light microscopy,appear to fuse with the wall of a dilated fetalcapillary (fig 6). These attenuated areas have been

Fig 6 A vasculo-syncytial membrane (arrowed) in amature placenta (H & E x 560).

called 'vasculo-syncytial membranes' (Getzowa andSadowsky, 1950) and although electron microscopyshows that there is no real fusion between tropho-blast and vessel wall it is clear that they differmarkedly from the non-thinned nucleated areas ofthe trophoblast. The membranous areas bulge intothe intervillous space and they are not simply due tomechanical stretching of the trophoblast by dilatedfetal vessels, for scanning electron microscopy showsthat they are randomly sited and very localized,often occurring along the course of a vessel as adome-shaped swelling protruding from the lateralwall of a villus (Fox and Agrofojo-Blanco, 1974);this pattern of distribution argues strongly against amechanical explanation for their formation and ithas been suggested that they are specialized areas oftrophoblast for the facilitation of gas transfer acrossthe placenta. This suggestion has been principally

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based on the fact that where the trophoblast isfocally thinned the fetal and maternal circulationscome into their closest approximation to each other;this would, however, only facilitate gas transferacross the placenta if membrane resistance were an

important limiting factor in this process and there isconsiderable evidence that this is not the case (Longo,1972). The trophoblastic thinning is, however, onlyone indication of the specalized nature of themembranous areas for not only do they differ bothhistochemically (Amstutz, 1960) and ultra-structurally (Burgos and Rodriguez, 1966) from thenon-membranous areas of the trophoblast butscanning electron microscopy shows that there is asharply localized loss of microvilli over theirsurface. It thus appears that the functional segrega-tion which is discernible in the trophoblast during thefirst trimester becomes more blatant in the matureplacenta and the view that trophoblastic transferfunction is largely confined to the membranousareas and synthetic activity to the non-membranousareas would appear to be a reasonable one.

This concept is strengthened by the finding that adeficiency of vasculo-syncytial membranes in themature placenta is associated with a high incidence offetal deprivation (Fox, 1967c); such a paucity ofmembranous areas can be considered as a failure oftrophoblastic maturation-a failure that appears tosubject the fetus to considerable risk. A lack oftrophoblastic differentiation may be simply onefacet of villous immaturity and it is possibly thisfailure of differentiation that lends to villousimmaturity its serious import. In some placentaewhich lack vasculo-syncytial membranes the villiare, however, fully mature and here there appears tobe solely a defect in trophoblastic differentiation.

The Nature of Placental Insufficiency

Does an acceptable pathological basis for thesyndrome of placental insufficiency emerge from acritical review of the morphological changes foundin placentae from deprived fetuses? Certainly, mostof the lesions often thought to account for placentalinadequacy are either of no clinical importance orare secondary to events occurring outside theplacenta, either in the fetus or in the mother. Theonly lesions capable of serving as a basis for aprimary failure of placental function are inadequatevillous maturation and defective trophoblasticdifferentiation. Changes of this type are, however,found in only a relatively small proportion ofplacentae from deprived fetuses and it must beconcluded that in most cases no abnormality can befound within the placenta which could serve toexplain its apparent inadequacy. Three possible

explanations could be proposed to resolve thisdilemma:-

1 Placental insufficiency is usually secondary toan external factor, such as utero-placental ischaemia.2 The changes occurring in the insufficient

placenta are too subtle to be observed by therelatively crude techniques of conventional micro-scopy.

3 Placental insufficiency is a very uncommoncondition and is grossly overdiagnosed.

It is certainly tempting to consider that placentalinsufficiency is often secondary to a maternal factor.There is, however, much to suggest that the placenta,when faced with an unfavourable maternal environ-ment, far from being inadequate, may be functioningmore efficiently than normal in an attempt toovercome the disadvantage at which the fetus isplaced. Thus, for instance, the placenta is oftenlarger than normal in severe pregnancy anaemia(Beischer et al, 1970; Agboola, 1975), in pregnancyat high altitude (McLung, 1969), and in pregnanciescomplicated by decompensated maternal heartdisease (Clavero and Botella Llusia, 1963), allconditions often associated with a fetus of low birthweight. In the hypertensive complications ofpregnancy the placenta appears fully able to repairany damage resulting from utero-placental ischaemiaand it appears highly likely that the placenta isfunctioning reasonably adequately; indeed it isworthy of note that in preeclampsia the placental/fetal weight ratio is often increased (Holzl et al,1974) and that women with essential hypertensionnot uncommonly give birth to unusually large babies(Gruenwald, 1966).The possibility that placental insufficiency may be

due to changes not detectable on ordinary micro-scopy merits some attention. Jones and Fox (1976),using an ultrahistochemical technique, have recentlyshown that in some mature placentae from under-weight babies there is a phosphatase-dependenttransfer system similar to that normally found in thefirst trimester placenta. Whether this is due to afailure of functional maturation or is indicative of acompensatory mechanism is unknown but it iscertainly possible that relatively subtle changes ofthis type may be of greater importance than is nowthought to be the case.

Currently, however, the conclusion must be thatplacental insufficiency, occurring as either a primaryor a secondary phenomenon, is a relatively rare, andmuch overdiagnosed, condition. Assali et al (1975)have, although mixing their metaphors, stated theposition succintly . . . 'the term (ie placental in-sufficiency) has become an umbrella to cover ourignorance of the aetiology and pathogenesis ofchronic utero-placental-fetal disturbances; it has also

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served as a waste basket to dump a variety ofdisorders interfering with maternal supply ofnutrients to the fetus or with fetal metabolism or withdisorders related to abnormal placental function.'

In most cases of fetal deprivation the fault liesoutside the placenta which, being a vigorous,versatile and energetic organ having a considerablereserve capacity, is usually functioning with optimalefficiency.The great danger ofan insufficiently criticalacceptance of a diagnosis of placental inadequacy isthat it promotes a false feeling of having solved, or atleast localized, the problem and that in this lulledstate attention is diverted away from the true causesof fetal deprivation and new avenues of investigationremain unexplored.

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Altshuler, G., Russell, P., and Ermocilla, R. (1975). Theplacental pathology of small-for-gestational age infants.Amer. J. Obstet. Gynec., 121, 351-359.

Amstutz, E. (1960). Beobachtungen uber die Reifung derChorionzotten in der menschlichen Placenta mit besondererBerucksichtigung der Epithelplatten. Acta Anat. (Basel),42, 12-30.

Assali, N. S., Nuwayhid, B., and Brinkman, C. R. (1975).Placental insufficiency: problems of etiology, diagnosis andmanagement. Europ. J. Obstet. Gynec. reprod. Biol., 5,87-91.

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Beer, A. E. (1975). Immunogenetic determinants of the size ofthe fetoplacental unit and their modus operandi. Europ. J.Obstet. Gynec. reprod. Med., 5, 135-146.

Beischer, N. A., Sivasamboo, R., Vohra, S., Silpisornkosal,S., and Reid, S. (1970). Placental hypertrophy in severepregnancy anaemia. J. Obstet. Gynaec. Brit. Cwlth, 77,398-409.

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