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Chronic villitis of unknown aetiology in placentae of idiopathic small for gestational age infants
Placenta (1982), 3, 309-3 I8
Chronic Villitis of Unknown Aetiology in Placentae of Idiopathic Small for Gestational Age Infants
CARLOS LABARRERE, OMAR ALTHABE & MARGARITA TELENTA Departments of Pathology and Obstetrics, Hospital ltaliano, Buenos Aires, Argentina Address correspondence to: Carlos A. Labarrere, MD, Department of Pathology, Gascon 45o, Buenos Aires (H81), Argentina
INTRODUCTION Fetal growth retardation is known to be associated with a variety of adverse maternal and uterine factors, but there is a group of cases in which growth retardation occurs in the absence of any known cause. Chronic inflammatory lesions of villi have been described in placentae from small for gestational age (SGA) infants (Gershon and Strauss, t 96 x; Gruenwald, 196 i; Altshuler, Russell and Ermocilla, I975). In such placentae Altshuler, Russell and Ermocilla (i975) found chronic inflammatory lesions in the villi in 24 per cent of cases and attributed these to a viral intrauterine infection. Russell (t98o), in a recent paper, found a correlation between the severity of chronic villitis and the degree of growth retardation. We report here a study of the incidence of chronic villitis in placentae from small for gestational age infants.
MATERIALS AND METHODS Placentae from 63 term pregnancies were studied. Of these, I9 were from uncomplicated pregnancies in which the neonate was of normal weight: these served as the control group. T h e remaining 44 placentae were from small for gestational age infants (SGA), 32 of these being from uncomplicated pregnancies (idiopathic small for gestational age s u b g r o u p ~ I S G A ) . The other I2 placentae were from pregnant mothers who had arterial blood pressure values of 14o/9o m m H g or increments in diastolic pressure of 15 m m H g or more even though abnormal levels of blood pressure were not reached: this subgroup was called 'transient hypertension small for gestational age' (THSGA). There were no statistical differences between the various groups in respect to maternal age (27.6 years +5. i), parity (2.2 + 1.2) or smoking habits (24 per cent of all mothers in each group, all smoking fewer than five cigarettes per day). Neonates whose weight at birth was under the ioth percentile of our ponderal curve were o143-4oo4/82/o3o3-3o9 $o2.oo
9 I982 W. B. Saunders CompanyLtd
3o9
3xo
C. Labarrere, O. Althabe, M. Telenta
considered as SGA. All the infants, both from the control and S G A groups, were physically and neurologically normal. T h e placentae were fixed whole in xo per cent formalin for several days. They were weighed after the membranes and cord were trimmed off and the placental index was calculated (placental weight/infant weight). After external examination the placentae were then cut into slices and standardized blocks were taken, using the technique described by Fox (I978a). A total of eight blocks of placental parenchyma were taken, six from the central and two from the marginal areas: in addition, a roll of membranes was prepared using the technique described by Benirschke (I96I). All histological sections were stained with haematoxylin and eosin: in selected cases sections were also stained with PAS or Masson's trichrome. In all cases in which the percentage of villi showing abnormalities is quoted the counts were made on villi in the maternal zone of the central portion (Fox, I978a). F o r statistical analysis the following tests were used: Student's t for independent samples, M a n n - W h i m e y U and X2 for association.
RESULTS Gross findings Mean weights of neonates and placentae and the averages of the placental index are shown in Table I for each group. In the S G A group the mean weight of the placentae was significantly lower and the average placental index was higher than in the control group. An interesting finding was that the proportion of females in the I S G A subgroup was twice that observed in the other groups (Table i). Table 1. Mean weights of placentae and infants, placental index and sex ratio for each studied group
Total Mean placental weight Mean infant weight Mean placental index Female/male ratio
Controls
ISGAa
THSGAb
4o9 g
505 g
357 g
389 g
2668 g
3540 g
2195 g
z3oo g
o.157
o.14,~
1.6
I. I
o.i6 4 2.2
1.4
Idiopathic small for gestationalage subgroup. b Transient hypertension small for gestationaiage subgroup. Intervillous space thrombosis and retroplacental haematomas were both found more frequently in the S G A group (27.3 and 18.2 per cent, respectively) than in the control group (xo.5 and 5-3 per cent). Placentae of the T H S G A subgroup had a higher incidence ofintervillous space thrombosis (42 per cent) than did those placentae of the I S G A subgroup (22 per cent). T h e incidence ofretroplacental haematomas was similar in both subgroups (17 and I9 per cent, respectively). Microscopical findings A chronic villitis was a common finding in all groups. This was characterized by a lymphocytic infiltrate, probably of fetal origin, of the stroma of the villi, and was often associated with fibrinoid necrosis, trophoblastic necrosis and/or stromal fibrosis. Fetal capillaries were obliterated or could not be recognized. Surrounding affected villi, an intense maternal inflam-
Chronic Villitis of Unknown Aetiology
3H
Figure z. This shows the characteristic features of a necrotizing chronic villitis. Villi with fibrinoid necrosis, stromal
mononuclear cell infiltration and trophoblastic necrosis are present. Surrounding these villi there is a maternal component of lymphocytes, monocytes and macrophages. H & E x Iz5. matory response, consisting of lymphocytes,
monocytes and macrophages,
was f r e q u e n t l y
observed. T h r e e d e g r e e s o f activity o f villitis w e r e d i s t i n g u i s h e d : n e c r o t i z i n g ( F i g u r e x), p r o l i f e r a t i v e
Figure ~. Proliferative chronic villitis. Villi show a predominantly stromal lymphocytic infiltration and also a maternal component of mononuclear cells. H & E x IzS.
312
C. Labarrere, 0. Althabe, M. Telenta
(Figure 2) and reparative with stromal fibrosis (Figure 3). In the great majority o f cases these varying degrees were seen in combination. In general, chronic villitis was found in the terminal villi, but in 16 cases inflammation was also noted in tertiary stem villi and in these instances fetal arterial thrombosis and a chronic
Figure 3. Reparative chronic villitis. Villi show stromal fibrosis with scanty lymphocytic infiltration. H & E x i2 5.
Figure 4. Stem villus showing, in the centre, a fetal vessel with lymphocytic infiltrate in its wall (chronic vasculitis). H &
E x I5o.
Cronic Villitis of Unknown Aetiology
3~3
Figure 5. This shows an anchoring villus with stromal lymphocytic infiltrate. The infiltrate can also be seen
surrounding the villus. H & E x IaS. vasculitis were often noted (Figure 4): I4 of these cases were from the S G A group and only two were from the control group. Chronic villitis was found in 68 per cent of all placentae in this study (43/63). In the control group this lesion was present in z6 per cent (5/I9) of the placentae while in the S G A group a villitis was found in 86 per cent (38/44) ( P < o.oo5). In the T H S G A and the I S G A subgroups the incidence of chronic villitis was similar (83 and 89 per cent, respectively). W h e n the degree of activity of chronic villitis was considered, 77 per cent (34/44) of the placentae in the S G A group were classified as showing a necrotizing and/or proliferative villitis and 9 per cent (4/44) as showing a reparative villitis with stromal fibrosis. In the control group these proportions were I6 per cent (3/I9) and 11 per cent (z/I9), respectively. In those placentae of the control group with a chronic villitis the mean proportion of inflamed villi was I.z per cent, while in the affected placentae of the S G A group a mean of Io per cent of the terminal villi were inflamed (P < o.oooo5). Within this latter group no correlation could be found between the percentage of inflamed villi and the weight of the neonate. Similarly, no association was found between neonatal weight and the activity of the inflammatory process. In 48 placentae a lymphocytic infiltrate was observed in anchoring villi within the basal plate. It was characterized not only by a lymphocytic infiltrate within the villi but also by the presence of numerous lymphocytes, probably of maternal origin (Figure 5), in the surrounding basal plate tissues. T h e incidence of this finding was similar both in the control group and the SGA group.
DISCUSSION A striking feature of our series is the very high incidence of chronic villitis found not only in the S G A group but also in placentae from normal pregnancies. This is a much higher incidence than that noted in other studies (Altshuler and Russell, i975; Altshuler, Russell and Ermocilla, 1975)
314
C. Labarrere, 0. Althabe, M. Telenta
and we can offer no explanation for this discrepancy. Nevertheless, it is important to point out that although a chronic villitis was found in 26 per cent of the placentae of the control group the proportion of inflamed villi in these placentae was very much lower than in the small for gestational age group. Various authors (Altshuler and Russell, I975; Altshuler, Russell and Ermocilla, i975; Fox, I978b; Russell, x98o) have attributed a chronic villitis to a viral infection although they were unable to demonstrate such infection in the mother or in the infant. In our series none of the mothers had a clinical history of infective or febrile episodes during her pregnancy and none of the infants showed any evidence of infection. In none of our cases of villitis did we see the histological lesions described for syphilis (Russell and Ahshuler, I974), toxoplasmosis (Benirschke and Driscoll, I967; Elliot, i97o), Chagas' disease (Bittencourt, I963), rubella (Driscoll, 1969; Ornoy et al, I973), cytomegalovirus infection (Rosenstein and NavarreteReyna, 1964), or herpesvirus infection (Witzleben and Driscoll, 1965). Serological tests 'for syphilis were performed in all patients and, in 15 cases of SGA, serological tests for toxoplasmosis, cytomegalovirus, Chagas' disease, herpes and rubella were performed in blood samples from mothers and infants. All these tests yielded negative results. In xo of the small for gestational age cases IgM levels were determined in cord blood samples and in three of these IgM levels were elevated although serological studies for infectious agents were negative. High cord blood values of IgM have, however, been described in both small for gestational age infants of unknown aetiology and neonates of toxaemic mothers (Altshuler, Russell and Ermocilla, i975; Loke, I978 ). Loke (1978) has suggested that this could be due to a leakage of maternal IgM into the fetal circulation across a damaged placenta and not to a primary production by the fetus. Russell (x98o) has suggested that chronic villitis may be a consequence of a pre-existing endometrial infection that extends into the placental parenchyma. We have, however, found a lymphocytic infiltrate around, and within, the anchoring villi in the basal plate both in the control and the SGA groups: this infiltrate was not observed in the rest of the basal plate. A similar finding was noted by Benirschke and Altshuler (I971). This makes Russell's hypothesis less probable, first because it is difficult to u~nderstand why a previous endometrial infection should be limited to the site of implantation of anchoring villi and second because it is dit~icult to accept that nearly all the mothers in our series were suffering from endometrial infections. The abnormalities of the basal plate, together with the finding of numerous maternal lymphocytes, macrophages and monocytes surrounding villi with chronic villitis, and the lack of any proof of an infective basis raises the possibility that these represent the histological expression of a maternal immunological reaction against fetal tissues. This possibility has to be considered against the background of recent studies of the placental vascular bed in pre-eclampsia and in normotensive pregnancies with fetal growth retardation and in the context of current immunological hypotheses of the aetiology of pre-eclampsia. Zeek and Assali (i95o) described an arterial vasculopathy (acute atherosis) in the spiral arterioles of pre-eclamptic patients and a similar lesion was also observed by Bonnar, Redman and Sheppard 0975) in cases of normotensive pregnancies with fetal growth retardation. Sheppard and Bonnar (i97~) also showed that there was an absence of physiological changes in the myometrial segment of the spiral arteries in cases of normotensive fetal growth retardation. Brosens, Dixon and Robertson (i977) and De Wolf, Brosens and Renaer (i98o) have further confirmed the lack of physiological change in the vessels of many cases of fetal growth retardation. Whilst, however, the former maintained that atherosis never occurs in normotensive pregnancies, De Wolf and his colleagues described atherosis in a small group of cases of normotensive fetal growth retardation and pointed out that similar vascular lesions occur not
Chronic Villitis of Unknown Aetiology
315
Figure 6. Vessel of the decidua with fibrinoid necrosis of the wall and clear cells corresponding to lipid laden
macrophages.The vesselis surroundedby a rim of lymphocytes.This lesionis similarto that knownas acuteatherosis. H & E x 15o. only in the placental bed arteries in pre-eclampsia but also in the vessels of the kidney of patients with malignant hypertension, haemolytic-uraemic syndrome, scleroderma and in rejected renal transplants. Abramowsky et al (i98o) have described a similar vasculopathy in placental decidua from patients with systemic lupus erythematosus. In our series a vascular lesion similar to acute atherosis was observed in parietal decidua (four cases) and basal decidua (two cases) in cases of SGA (Figure 6). Moreover, an absence of physiological vascular changes of pregnancy was found in basal decidua in four cases (Althabe, Labarrere and Telenta, in preparation). A possible immunological origin of atherosis is suggested by the finding of immunoglobulin deposits in the walls of vessels in placentae from patients with pre--eclampsia showing this lesion and in systemic lupus erythematosus (Kitzmiller and Benirschke, 1973; Abramowsky et al, I98o). This could accord with the view that immunological factors play an important role in the pathophysiology of pre-eclampsia (Need, I979). It has been suggested (Scott and Beer, 1976; Jenkins, Need and Rajah, I977; Marti and Herrmann, I977; Willems, I977) that in preeclampsia there is a defect of blocking factors (enhancing antibodies) which may be essential for the survival of the fetal allograft and the maintenance of normal pregnancy. This defect would permit the activity of immune attack mediated by the T--cell subpopulation of lymphocytes and the effector lymphocytes could produce cytotoxic damage to placental tissue and the fetus. In our series placentae from small for gestational age infants of idiopathic type had the same histological lesions as those observed in placentae of pre-eclamptic pregnancies, this suggesting the possibility of a similar pathogenic mechanism for both entities. Taking all these factors into account it seems reasonable to postulate that villitis may be the morphological hallmark of a maternal immune attack against placental tissue rather than an infective lesion. Clearly more studies must be performed in order to prove that chronic villitis is of immunological, rather than infectious, origin but this concept offers a new perspective into the aetiology of villitis and the pathogenesis of small for gestational age infants.
316
C. Labarrere, O. Althabe, M. Telenta
SUMMARY Placentae from 63 term pregnancies were studied. O f these, I9 were from normal pregnancies in which the neonates were within the normal weight range for their gestational age. T h e remaining 44 placentae were from pregnancies in which the infants were small for their gestational age (SGA). A chronic villitis was found in 68 per cent of all placentae. In the control group this lesion was present in 26 per cent but a mean o f only 1.2 per cent o f villi in these cases was inflamed. In the S G A group 86 per cent of placentae showed a chronic villitis and in these an average o f l o per cent of the villi were inflamed. L y m p h o c y t i c infiltrates in basal plate anchoring villi were observed in 48 o f the 63 placentae and there were no differences a m o n g the various groups. Vascular lesions were found, similar to those described in placental bed arteries in preeclampsia and more recently in biopsies o f the placental bed o f S G A infants and in the decidua of mothers with systemic lupus erythematosus: this type o f v a s c u l o p a t h y has also been described in rejection o f renal transplants. It is suggested that the cellular infiltrate around and inside anchoring villi and free villi in cases o f chronic villitis may represent the histological hallmark o f an immunological reaction between m o t h e r and fetus rather than a response to infection.
ACKNOWLEDGEMENTS We are indebted to Professor H. Fox for his assistance with this paper, and we thank Miss Nieves Cordon and Silvia Turano for their collaboration in preparing the material for microscopical examination, and Miss Gladys Pereyra for typing the manuscript. REFERENCES Abramowsky, C. R., Vegas, M. E., Swinehart, G. & Gyves, M. T. (198o) Decidual vasculopathy of the placenta in lupus erythematosus. New England Journal of Medicine, 303, 668-672. Ahshuler, G. & Russell, P. (x975) The human placental villitides. A review of chronic intrauterine infection. In Current Topicsin Pathology (Ed.) Grundmann, E. & Kirsten, W. H. Volume 6o, pp. 63-1 x2. Berlin: Springer-Verlag. Ahshuler, G., Russell, P. & Ermocilla, R. (t975) The placental pathology of small for gestational age infants. American Journal of Obstetrics and Gynecology, t21, 351-359. Benirscb_ke, K. (I961) Examination of the placenta. Obstetrics and Gynecology, x8, 3o9-333. Benirschke, K. & Ahshuler, G. F. (197I) The future of perinatal physiopathoiogy. In Symposium on the Functional Physiopathology of the Fetus and Neonate: Clinical Correlations (Ed.) Abramson, H. pp. 164-166. St Louis: C. V. Mosby. Benirschke, K. & Driscoll, S. G. (I967) The Pathology of the Human Placenta. pp. 37o-374. Berlin: Springer-Verlag. Bittencourt, A. C. (1963) Placentite chagasica e transmissao congenita da docnca de chagas. Revista do lnstituto de Medicina Tropical de Sao Paulo, 5, 62-67Bonnar, J., Redman, C. W. G. & Sheppard, B. L. (t975) Treatment of fetal growth retardation in utero with heparin and dipyridamole. In Human Placentation (Ed.) Brosens, I. A., Dixon, G. & Robertson, W. B. pp. i23-i34. Amsterdam: Excerpta Medica. Brosens, I., Dixon, H. G. & Robertson, W. B. (I977) Fetal growth retardation and the arteries of the placental bed. British Journal of Obstetrics and Gynaecology, 84, 656-663. De Wolf, F., Brosens, L. & Renaer, M. (i98o) Fetal growth retardation and the maternal arterial supply of the human placenta in the absence of sustained hypertension. British Journal of Obstetrics and Gynaecology, 87, 678-685. Driscoll, S. G. (I969) Histopathology of gestational rubella. American Journal of Diseases of Children, It8, 49-53Elliott, W. G. (*97o) Placental toxoplasmosis, Report of a case. American Journal of Clinical Pathology, 53, 413-417. Fox, H. (I978a) Pathology of the Placenta. pp. 473-476. London: W. B. Saunders. Fox, H. (1978b) Pathology of the Placenta. pp. z48-25I. London: W. B. Saunders. Gershon, R. & Strauss, L. (I961) Structural changes in human placentae associated with fetal inanition of growth arrest ('placental insufficiency syndrome'). American Journal of Diseases of Children, Io2, 645-646. Gruenwald, P. (I961) Abnormalities of placental vascularity in relat!on to intrauterine deprivation and retardation of fetal growth. Significance of avascular chorionic villi. New York State Journal of Medicine, 6z, 15o8-I513. Jenkins, D. M., Need, J. & Rajah, S. M. (1977) Deficiency of specific HLA antibodies in severe pregnancy preeclampsia/eclampsia. Clinical and Experimental Immunology, 27, 485 486.
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Kitzmiller, J. L. & Benirschke, K. (i973) lmmunofluorescent study of placental bed vessels in preeclampsia of pregnancy. American Journal of Obstetrics and Gynecology, I x5, z48 z5 I. Loke, Y. W. (1978) Immunology and lmmunopathology of the Human Foetal-Maternal lnteraction. 189 pp. Amsterdam: Elsevier North-Holland Biomedical Press. Marti, J. J. & Herrmann, U. (1977) Immunogestosis: a new etiologic concept of'essential' EPH gestosis, with special consideration of the primigravid patient. Preliminary report of a clinical study. American Journal of Obstetrics and Gynecology, 128, 489-493 . Need, J. A. (1979) Immunological phenomena in pre--eclamptic toxaemia. Clinics in Obstetrics and Gynaecology, 6, 443-46o. Ornoy, A., Segal, S., Nishmi, M., Simcha, A. & Polishuk, W. Z. (1973) Fetal and placental pathology in gestational rubella. American Journal of Obstetrics and Gynecology, I I6, 949456. Rosenstein, D. L. & Navarrete-Reyna, A. (x964) Cytomegalic inclusion disease. Observation of the characteristic inclusion bodies in the placenta. American Journal of Obstetrics and Gynecology, 89, 22o-224. Russell, P. (198o) Inflammatory lesions of the human placenta. III: the histopathology of villitis of unknown aetiology. Placenta, l, 227-244. Russell, P. & Altshuler, G. (t974) The placental abnormalities of congenital syphilis. AmericanJournal of Diseases of Children, i28, t6o-~63. Scott, J. R. & Beer, A. E. (I976) Immunological aspects of preeclampsia. American Journal of Obstetrics and Gynecology, iaS, 4t8-4z 7. Sheppard, B. L. & Bonnar, J. (1976) The ultrastructure of the arterial supply of the human placenta in pregnancy complicated by fetal growth retardation. British Journal of Obstetrics and Gynaecology, 83, 948-959 9 Willem-s, J. (1977) The etiology of preeclampsia. A hypothesis. Obstetrics and Gynecology, 50, 495-499. Witzleben, C. L. & Driscoil, S. G. (1965) Possible transplacental transmission of herpes simplex infection. Pediatrics, 36, 192-I99. Zeek, P. M. & Assail, N. S. (I95o) Vascular changes in the decidua associated with eclamptogenic toxemia of pregnancy. American Journal of Clinical Pathology, zo, IO99-I Io9.
Chronic Villitis of Unknown Aetiology in Placentae of Idiopathic Small for Gestational Age Infants
CARLOS LABARRERE, OMAR ALTHABE & MARGARITA TELENTA Departments of Pathology and Obstetrics, Hospital ltaliano, Buenos Aires, Argentina Address correspondence to: Carlos A. Labarrere, MD, Department of Pathology, Gascon 45o, Buenos Aires (H81), Argentina
INTRODUCTION Fetal growth retardation is known to be associated with a variety of adverse maternal and uterine factors, but there is a group of cases in which growth retardation occurs in the absence of any known cause. Chronic inflammatory lesions of villi have been described in placentae from small for gestational age (SGA) infants (Gershon and Strauss, t 96 x; Gruenwald, 196 i; Altshuler, Russell and Ermocilla, I975). In such placentae Altshuler, Russell and Ermocilla (i975) found chronic inflammatory lesions in the villi in 24 per cent of cases and attributed these to a viral intrauterine infection. Russell (t98o), in a recent paper, found a correlation between the severity of chronic villitis and the degree of growth retardation. We report here a study of the incidence of chronic villitis in placentae from small for gestational age infants.
MATERIALS AND METHODS Placentae from 63 term pregnancies were studied. Of these, I9 were from uncomplicated pregnancies in which the neonate was of normal weight: these served as the control group. T h e remaining 44 placentae were from small for gestational age infants (SGA), 32 of these being from uncomplicated pregnancies (idiopathic small for gestational age s u b g r o u p ~ I S G A ) . The other I2 placentae were from pregnant mothers who had arterial blood pressure values of 14o/9o m m H g or increments in diastolic pressure of 15 m m H g or more even though abnormal levels of blood pressure were not reached: this subgroup was called 'transient hypertension small for gestational age' (THSGA). There were no statistical differences between the various groups in respect to maternal age (27.6 years +5. i), parity (2.2 + 1.2) or smoking habits (24 per cent of all mothers in each group, all smoking fewer than five cigarettes per day). Neonates whose weight at birth was under the ioth percentile of our ponderal curve were o143-4oo4/82/o3o3-3o9 $o2.oo
9 I982 W. B. Saunders CompanyLtd
3o9
3xo
C. Labarrere, O. Althabe, M. Telenta
considered as SGA. All the infants, both from the control and S G A groups, were physically and neurologically normal. T h e placentae were fixed whole in xo per cent formalin for several days. They were weighed after the membranes and cord were trimmed off and the placental index was calculated (placental weight/infant weight). After external examination the placentae were then cut into slices and standardized blocks were taken, using the technique described by Fox (I978a). A total of eight blocks of placental parenchyma were taken, six from the central and two from the marginal areas: in addition, a roll of membranes was prepared using the technique described by Benirschke (I96I). All histological sections were stained with haematoxylin and eosin: in selected cases sections were also stained with PAS or Masson's trichrome. In all cases in which the percentage of villi showing abnormalities is quoted the counts were made on villi in the maternal zone of the central portion (Fox, I978a). F o r statistical analysis the following tests were used: Student's t for independent samples, M a n n - W h i m e y U and X2 for association.
RESULTS Gross findings Mean weights of neonates and placentae and the averages of the placental index are shown in Table I for each group. In the S G A group the mean weight of the placentae was significantly lower and the average placental index was higher than in the control group. An interesting finding was that the proportion of females in the I S G A subgroup was twice that observed in the other groups (Table i). Table 1. Mean weights of placentae and infants, placental index and sex ratio for each studied group
Total Mean placental weight Mean infant weight Mean placental index Female/male ratio
Controls
ISGAa
THSGAb
4o9 g
505 g
357 g
389 g
2668 g
3540 g
2195 g
z3oo g
o.157
o.14,~
1.6
I. I
o.i6 4 2.2
1.4
Idiopathic small for gestationalage subgroup. b Transient hypertension small for gestationaiage subgroup. Intervillous space thrombosis and retroplacental haematomas were both found more frequently in the S G A group (27.3 and 18.2 per cent, respectively) than in the control group (xo.5 and 5-3 per cent). Placentae of the T H S G A subgroup had a higher incidence ofintervillous space thrombosis (42 per cent) than did those placentae of the I S G A subgroup (22 per cent). T h e incidence ofretroplacental haematomas was similar in both subgroups (17 and I9 per cent, respectively). Microscopical findings A chronic villitis was a common finding in all groups. This was characterized by a lymphocytic infiltrate, probably of fetal origin, of the stroma of the villi, and was often associated with fibrinoid necrosis, trophoblastic necrosis and/or stromal fibrosis. Fetal capillaries were obliterated or could not be recognized. Surrounding affected villi, an intense maternal inflam-
Chronic Villitis of Unknown Aetiology
3H
Figure z. This shows the characteristic features of a necrotizing chronic villitis. Villi with fibrinoid necrosis, stromal
mononuclear cell infiltration and trophoblastic necrosis are present. Surrounding these villi there is a maternal component of lymphocytes, monocytes and macrophages. H & E x Iz5. matory response, consisting of lymphocytes,
monocytes and macrophages,
was f r e q u e n t l y
observed. T h r e e d e g r e e s o f activity o f villitis w e r e d i s t i n g u i s h e d : n e c r o t i z i n g ( F i g u r e x), p r o l i f e r a t i v e
Figure ~. Proliferative chronic villitis. Villi show a predominantly stromal lymphocytic infiltration and also a maternal component of mononuclear cells. H & E x IzS.
312
C. Labarrere, 0. Althabe, M. Telenta
(Figure 2) and reparative with stromal fibrosis (Figure 3). In the great majority o f cases these varying degrees were seen in combination. In general, chronic villitis was found in the terminal villi, but in 16 cases inflammation was also noted in tertiary stem villi and in these instances fetal arterial thrombosis and a chronic
Figure 3. Reparative chronic villitis. Villi show stromal fibrosis with scanty lymphocytic infiltration. H & E x i2 5.
Figure 4. Stem villus showing, in the centre, a fetal vessel with lymphocytic infiltrate in its wall (chronic vasculitis). H &
E x I5o.
Cronic Villitis of Unknown Aetiology
3~3
Figure 5. This shows an anchoring villus with stromal lymphocytic infiltrate. The infiltrate can also be seen
surrounding the villus. H & E x IaS. vasculitis were often noted (Figure 4): I4 of these cases were from the S G A group and only two were from the control group. Chronic villitis was found in 68 per cent of all placentae in this study (43/63). In the control group this lesion was present in z6 per cent (5/I9) of the placentae while in the S G A group a villitis was found in 86 per cent (38/44) ( P < o.oo5). In the T H S G A and the I S G A subgroups the incidence of chronic villitis was similar (83 and 89 per cent, respectively). W h e n the degree of activity of chronic villitis was considered, 77 per cent (34/44) of the placentae in the S G A group were classified as showing a necrotizing and/or proliferative villitis and 9 per cent (4/44) as showing a reparative villitis with stromal fibrosis. In the control group these proportions were I6 per cent (3/I9) and 11 per cent (z/I9), respectively. In those placentae of the control group with a chronic villitis the mean proportion of inflamed villi was I.z per cent, while in the affected placentae of the S G A group a mean of Io per cent of the terminal villi were inflamed (P < o.oooo5). Within this latter group no correlation could be found between the percentage of inflamed villi and the weight of the neonate. Similarly, no association was found between neonatal weight and the activity of the inflammatory process. In 48 placentae a lymphocytic infiltrate was observed in anchoring villi within the basal plate. It was characterized not only by a lymphocytic infiltrate within the villi but also by the presence of numerous lymphocytes, probably of maternal origin (Figure 5), in the surrounding basal plate tissues. T h e incidence of this finding was similar both in the control group and the SGA group.
DISCUSSION A striking feature of our series is the very high incidence of chronic villitis found not only in the S G A group but also in placentae from normal pregnancies. This is a much higher incidence than that noted in other studies (Altshuler and Russell, i975; Altshuler, Russell and Ermocilla, 1975)
314
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and we can offer no explanation for this discrepancy. Nevertheless, it is important to point out that although a chronic villitis was found in 26 per cent of the placentae of the control group the proportion of inflamed villi in these placentae was very much lower than in the small for gestational age group. Various authors (Altshuler and Russell, I975; Altshuler, Russell and Ermocilla, i975; Fox, I978b; Russell, x98o) have attributed a chronic villitis to a viral infection although they were unable to demonstrate such infection in the mother or in the infant. In our series none of the mothers had a clinical history of infective or febrile episodes during her pregnancy and none of the infants showed any evidence of infection. In none of our cases of villitis did we see the histological lesions described for syphilis (Russell and Ahshuler, I974), toxoplasmosis (Benirschke and Driscoll, I967; Elliot, i97o), Chagas' disease (Bittencourt, I963), rubella (Driscoll, 1969; Ornoy et al, I973), cytomegalovirus infection (Rosenstein and NavarreteReyna, 1964), or herpesvirus infection (Witzleben and Driscoll, 1965). Serological tests 'for syphilis were performed in all patients and, in 15 cases of SGA, serological tests for toxoplasmosis, cytomegalovirus, Chagas' disease, herpes and rubella were performed in blood samples from mothers and infants. All these tests yielded negative results. In xo of the small for gestational age cases IgM levels were determined in cord blood samples and in three of these IgM levels were elevated although serological studies for infectious agents were negative. High cord blood values of IgM have, however, been described in both small for gestational age infants of unknown aetiology and neonates of toxaemic mothers (Altshuler, Russell and Ermocilla, i975; Loke, I978 ). Loke (1978) has suggested that this could be due to a leakage of maternal IgM into the fetal circulation across a damaged placenta and not to a primary production by the fetus. Russell (x98o) has suggested that chronic villitis may be a consequence of a pre-existing endometrial infection that extends into the placental parenchyma. We have, however, found a lymphocytic infiltrate around, and within, the anchoring villi in the basal plate both in the control and the SGA groups: this infiltrate was not observed in the rest of the basal plate. A similar finding was noted by Benirschke and Altshuler (I971). This makes Russell's hypothesis less probable, first because it is difficult to u~nderstand why a previous endometrial infection should be limited to the site of implantation of anchoring villi and second because it is dit~icult to accept that nearly all the mothers in our series were suffering from endometrial infections. The abnormalities of the basal plate, together with the finding of numerous maternal lymphocytes, macrophages and monocytes surrounding villi with chronic villitis, and the lack of any proof of an infective basis raises the possibility that these represent the histological expression of a maternal immunological reaction against fetal tissues. This possibility has to be considered against the background of recent studies of the placental vascular bed in pre-eclampsia and in normotensive pregnancies with fetal growth retardation and in the context of current immunological hypotheses of the aetiology of pre-eclampsia. Zeek and Assali (i95o) described an arterial vasculopathy (acute atherosis) in the spiral arterioles of pre-eclamptic patients and a similar lesion was also observed by Bonnar, Redman and Sheppard 0975) in cases of normotensive pregnancies with fetal growth retardation. Sheppard and Bonnar (i97~) also showed that there was an absence of physiological changes in the myometrial segment of the spiral arteries in cases of normotensive fetal growth retardation. Brosens, Dixon and Robertson (i977) and De Wolf, Brosens and Renaer (i98o) have further confirmed the lack of physiological change in the vessels of many cases of fetal growth retardation. Whilst, however, the former maintained that atherosis never occurs in normotensive pregnancies, De Wolf and his colleagues described atherosis in a small group of cases of normotensive fetal growth retardation and pointed out that similar vascular lesions occur not
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Figure 6. Vessel of the decidua with fibrinoid necrosis of the wall and clear cells corresponding to lipid laden
macrophages.The vesselis surroundedby a rim of lymphocytes.This lesionis similarto that knownas acuteatherosis. H & E x 15o. only in the placental bed arteries in pre-eclampsia but also in the vessels of the kidney of patients with malignant hypertension, haemolytic-uraemic syndrome, scleroderma and in rejected renal transplants. Abramowsky et al (i98o) have described a similar vasculopathy in placental decidua from patients with systemic lupus erythematosus. In our series a vascular lesion similar to acute atherosis was observed in parietal decidua (four cases) and basal decidua (two cases) in cases of SGA (Figure 6). Moreover, an absence of physiological vascular changes of pregnancy was found in basal decidua in four cases (Althabe, Labarrere and Telenta, in preparation). A possible immunological origin of atherosis is suggested by the finding of immunoglobulin deposits in the walls of vessels in placentae from patients with pre--eclampsia showing this lesion and in systemic lupus erythematosus (Kitzmiller and Benirschke, 1973; Abramowsky et al, I98o). This could accord with the view that immunological factors play an important role in the pathophysiology of pre-eclampsia (Need, I979). It has been suggested (Scott and Beer, 1976; Jenkins, Need and Rajah, I977; Marti and Herrmann, I977; Willems, I977) that in preeclampsia there is a defect of blocking factors (enhancing antibodies) which may be essential for the survival of the fetal allograft and the maintenance of normal pregnancy. This defect would permit the activity of immune attack mediated by the T--cell subpopulation of lymphocytes and the effector lymphocytes could produce cytotoxic damage to placental tissue and the fetus. In our series placentae from small for gestational age infants of idiopathic type had the same histological lesions as those observed in placentae of pre-eclamptic pregnancies, this suggesting the possibility of a similar pathogenic mechanism for both entities. Taking all these factors into account it seems reasonable to postulate that villitis may be the morphological hallmark of a maternal immune attack against placental tissue rather than an infective lesion. Clearly more studies must be performed in order to prove that chronic villitis is of immunological, rather than infectious, origin but this concept offers a new perspective into the aetiology of villitis and the pathogenesis of small for gestational age infants.
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SUMMARY Placentae from 63 term pregnancies were studied. O f these, I9 were from normal pregnancies in which the neonates were within the normal weight range for their gestational age. T h e remaining 44 placentae were from pregnancies in which the infants were small for their gestational age (SGA). A chronic villitis was found in 68 per cent of all placentae. In the control group this lesion was present in 26 per cent but a mean o f only 1.2 per cent o f villi in these cases was inflamed. In the S G A group 86 per cent of placentae showed a chronic villitis and in these an average o f l o per cent of the villi were inflamed. L y m p h o c y t i c infiltrates in basal plate anchoring villi were observed in 48 o f the 63 placentae and there were no differences a m o n g the various groups. Vascular lesions were found, similar to those described in placental bed arteries in preeclampsia and more recently in biopsies o f the placental bed o f S G A infants and in the decidua of mothers with systemic lupus erythematosus: this type o f v a s c u l o p a t h y has also been described in rejection o f renal transplants. It is suggested that the cellular infiltrate around and inside anchoring villi and free villi in cases o f chronic villitis may represent the histological hallmark o f an immunological reaction between m o t h e r and fetus rather than a response to infection.
ACKNOWLEDGEMENTS We are indebted to Professor H. Fox for his assistance with this paper, and we thank Miss Nieves Cordon and Silvia Turano for their collaboration in preparing the material for microscopical examination, and Miss Gladys Pereyra for typing the manuscript. REFERENCES Abramowsky, C. R., Vegas, M. E., Swinehart, G. & Gyves, M. T. (198o) Decidual vasculopathy of the placenta in lupus erythematosus. New England Journal of Medicine, 303, 668-672. Ahshuler, G. & Russell, P. (x975) The human placental villitides. A review of chronic intrauterine infection. In Current Topicsin Pathology (Ed.) Grundmann, E. & Kirsten, W. H. Volume 6o, pp. 63-1 x2. Berlin: Springer-Verlag. Ahshuler, G., Russell, P. & Ermocilla, R. (t975) The placental pathology of small for gestational age infants. American Journal of Obstetrics and Gynecology, t21, 351-359. Benirscb_ke, K. (I961) Examination of the placenta. Obstetrics and Gynecology, x8, 3o9-333. Benirschke, K. & Ahshuler, G. F. (197I) The future of perinatal physiopathoiogy. In Symposium on the Functional Physiopathology of the Fetus and Neonate: Clinical Correlations (Ed.) Abramson, H. pp. 164-166. St Louis: C. V. Mosby. Benirschke, K. & Driscoll, S. G. (I967) The Pathology of the Human Placenta. pp. 37o-374. Berlin: Springer-Verlag. Bittencourt, A. C. (1963) Placentite chagasica e transmissao congenita da docnca de chagas. Revista do lnstituto de Medicina Tropical de Sao Paulo, 5, 62-67Bonnar, J., Redman, C. W. G. & Sheppard, B. L. (t975) Treatment of fetal growth retardation in utero with heparin and dipyridamole. In Human Placentation (Ed.) Brosens, I. A., Dixon, G. & Robertson, W. B. pp. i23-i34. Amsterdam: Excerpta Medica. Brosens, I., Dixon, H. G. & Robertson, W. B. (I977) Fetal growth retardation and the arteries of the placental bed. British Journal of Obstetrics and Gynaecology, 84, 656-663. De Wolf, F., Brosens, L. & Renaer, M. (i98o) Fetal growth retardation and the maternal arterial supply of the human placenta in the absence of sustained hypertension. British Journal of Obstetrics and Gynaecology, 87, 678-685. Driscoll, S. G. (I969) Histopathology of gestational rubella. American Journal of Diseases of Children, It8, 49-53Elliott, W. G. (*97o) Placental toxoplasmosis, Report of a case. American Journal of Clinical Pathology, 53, 413-417. Fox, H. (I978a) Pathology of the Placenta. pp. 473-476. London: W. B. Saunders. Fox, H. (1978b) Pathology of the Placenta. pp. z48-25I. London: W. B. Saunders. Gershon, R. & Strauss, L. (I961) Structural changes in human placentae associated with fetal inanition of growth arrest ('placental insufficiency syndrome'). American Journal of Diseases of Children, Io2, 645-646. Gruenwald, P. (I961) Abnormalities of placental vascularity in relat!on to intrauterine deprivation and retardation of fetal growth. Significance of avascular chorionic villi. New York State Journal of Medicine, 6z, 15o8-I513. Jenkins, D. M., Need, J. & Rajah, S. M. (1977) Deficiency of specific HLA antibodies in severe pregnancy preeclampsia/eclampsia. Clinical and Experimental Immunology, 27, 485 486.
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Kitzmiller, J. L. & Benirschke, K. (i973) lmmunofluorescent study of placental bed vessels in preeclampsia of pregnancy. American Journal of Obstetrics and Gynecology, I x5, z48 z5 I. Loke, Y. W. (1978) Immunology and lmmunopathology of the Human Foetal-Maternal lnteraction. 189 pp. Amsterdam: Elsevier North-Holland Biomedical Press. Marti, J. J. & Herrmann, U. (1977) Immunogestosis: a new etiologic concept of'essential' EPH gestosis, with special consideration of the primigravid patient. Preliminary report of a clinical study. American Journal of Obstetrics and Gynecology, 128, 489-493 . Need, J. A. (1979) Immunological phenomena in pre--eclamptic toxaemia. Clinics in Obstetrics and Gynaecology, 6, 443-46o. Ornoy, A., Segal, S., Nishmi, M., Simcha, A. & Polishuk, W. Z. (1973) Fetal and placental pathology in gestational rubella. American Journal of Obstetrics and Gynecology, I I6, 949456. Rosenstein, D. L. & Navarrete-Reyna, A. (x964) Cytomegalic inclusion disease. Observation of the characteristic inclusion bodies in the placenta. American Journal of Obstetrics and Gynecology, 89, 22o-224. Russell, P. (198o) Inflammatory lesions of the human placenta. III: the histopathology of villitis of unknown aetiology. Placenta, l, 227-244. Russell, P. & Altshuler, G. (t974) The placental abnormalities of congenital syphilis. AmericanJournal of Diseases of Children, i28, t6o-~63. Scott, J. R. & Beer, A. E. (I976) Immunological aspects of preeclampsia. American Journal of Obstetrics and Gynecology, iaS, 4t8-4z 7. Sheppard, B. L. & Bonnar, J. (1976) The ultrastructure of the arterial supply of the human placenta in pregnancy complicated by fetal growth retardation. British Journal of Obstetrics and Gynaecology, 83, 948-959 9 Willem-s, J. (1977) The etiology of preeclampsia. A hypothesis. Obstetrics and Gynecology, 50, 495-499. Witzleben, C. L. & Driscoil, S. G. (1965) Possible transplacental transmission of herpes simplex infection. Pediatrics, 36, 192-I99. Zeek, P. M. & Assail, N. S. (I95o) Vascular changes in the decidua associated with eclamptogenic toxemia of pregnancy. American Journal of Clinical Pathology, zo, IO99-I Io9.