Pathology of the Placenta in Maternal Diabetes Mellitus H. FOX, MD, MC PatH In the placentas of 48 diabetics, gross lesions were uncommon, but inconsistent abnormali- ties of villous maturation were common. Prin- cipal histologic abnormalities seen in the dia- betic’s placenta were an obliterative endarteritis, of the fetal stem arteries, thickening of the trophoblastic basement membrane, and villous fibrinoid necrosis; all may result from immu- nologic damage. Villous fibrosis and excess syncytial knot formation were frequently ob- served; they are probably secondary to the fetal arterial abnormalities. OME WORKERS have claimed that pla- centas from diabetic women show no unusual features;*- ®: 41-47 others, although noting frequent abnormalities in such pla- centas, have failed to agree on any consistent pathologic pattern. Thus, reports of exces- sive infarction®: 9.2337 or calcifica~ tion’: 42 have not been confirmed by others;!®. 4 similarly, while some studies of the diabetic’s placenta have shown histologic villous lesions, such as syncytial degen- eration, °# excess syncytial knot forma- 4 stromal fibrosis,"® thick- ening of the trophoblastic basement mem- brane,* * or villous fibrinoid necrosis, ** others have failed to reveal any of these ab- normalities.#2 #3 Furthermore, reports as to whether these placentas are characterized by villous immaturity,?#-® 25. 26.9. 4 abnor- malities of villous vascularization,®. ® 24 42.43 or lesions of the fetal stem arteries* ¢ tion, © 9 11. 25. From the Department of Pathology, University of Manchester, England. Submitted for publication April 21, 1969. 792 1, 12, 18, 36. 37. 42. 45 have been totally con- tradictory. This confusion is partly due to the inclu- sion, in many studies, of specimens from gravidas in whom there was either a super- added preeclamptic toxemia or intrauterine fetal death; these complications obscure the significance of any placental lesions that may be present. A further factor has been the examination, in some series, of only a small number of placentas, while in very few studies have the placental findings been com- pared with those in a control series from un- complicated pregnancies of the same gesta- tidnal age, In this study of placentas from diabetic women, all complicating factors were spe- cifically excluded. MATERIAL AND METHODS Forty-eight placentas were examined. All were from women who were known to have been suffering from diabetes mellitus before the onset of their current pregnancy, and all were from live births. Patients with complicating hypertension, _preeclamptic toxemia, rhesus incompatibility, or ante- partum bleeding were excluded. The pla- centas were obtained soon after delivery, fixed whole for several weeks in 4% formalin, and then cut into vertical strips 0.5 cm. thick, Full-thickness blocks of macroscopically normal tissue were taken from the central zone of.each of 4 centrally situated slices and sections from each were stained with hematoxylin and eosin, periodic Obstetrics and GynecoloayPLACENTA acid-Schiff, and Van Gieson, One hundred terminal villi were examined in the maternal subdivision of each block, and thus 400 villi were studied in each placenta. Villous counts were made for various morphologic findings, principally stromal fibrosis, trophoblastic basement membrane thickening, syncytial knots, Langhans cells, Hofbauer cells, and fibrinoid necrosis. The results were expressed as a percentage incidence and, according to previously determined “normal” levels ob- tained for these variables in placentas from uncomplicated pregnancies," were then classed as “normal” or “high.” The fetal stem arteries included in the sections were also examined and an attempt was made to assess the over-all villous maturity, taking into account, for this purpose, the size of the villi, the number of syncytial knots, the de- gree of stromal condensation, and the posi- IN DIABETES tion and size of the fetal villous capillaries. Alll visible lesions in the placentas were also examined histologically. The results so obtained were compared with those found in a series of 170 pla- centas from full-term uncomplicated preg- nancies and 64 placentas from prematurely terminated but otherwise normal pregnan- cies. RESULTS Gross lesions The incidence of gross lesions is shown.in Table 1. Disturbances of villous maturation Disturbances of villous maturation were present in over half of the diabetic pla- centas but there was no consistent patter 14 (29.2%) showed accelerated maturation, Taste 1. INCIDENCE OF Gross LESIONS IN PLACENTAS FROM UNCOMPLICATED AND DIABETIC PREGNANCIES Premature Full term Normal Diabetic Normal Diabetic Lesion (Wo) (%) (No) (%) (No) (%) (No) (%) ‘No. of patients 64 - 31 - 170 - 17 - Lesions Infarction 3 47 5 16.1 4B 25.3 0 = 4 6.2 2 6.5 4l 24.1 1 5.9 an 3.1 oO - 39 22.8 3 17.6 Retroplacental hematoma 3 4.7 1 3.2 3 es 0 _ Intervillous thrombi 5 7.8 8 26.8 62 3 7 41.2 TaBLe 2. INCIDENCE OF HistoLOGic ABNORMALITIES AND FETAL ARTERIAL LESIONS IN PLACENTAS FROM UNCOMPLICATED AND DIABETIC PREGNANCIES Premature Full term Abnormality Normal Diabetic Normal Diabetic Hisrotocic ABNoRMALITIES (%) Excess syncytial knots oO 3.2 1.8 5.9 | Villous fibrosis. 4.7 22.5 TA 29.4 Excess villous fibrinoid necrosis 18.5 54.6 0 58.8 Trophoblastic basement membrane thickening 6.2 9.7 4.1 23.5 Excess Langhans cells 26.6 20 1.8 31.25 FeTat ARTERIAL LESIONS (%) Fetal artery thrombosis 3.1 12.9 3.5 5.9 Obliterative endarteritis. 4.7 22.6 8.8 23.5 Calcification 0 oO 0 0 Belenber Yabo 793Fig 1. Villi in plocenta from terminated ot Week 39 of ges Proportion show fibrinoid necrosis. (PAS, X90) Fig 3. Villous edema in placenta from (H & E, X70) Fig 4. Marked villous congestion in placenta from diabetic woman. (H & E, X90) 794 OPS ecsiogyPLACENTA 13 (27.1%) showed delayed maturation, and 21 (43.7%) were normally mature for their gestational age. (Fig 1). Villous abnormalities The principal histologic differences be- tween the diabetic and normal groups of pla- centas (Table 2) were that the diabetic placentas tended to show more syncytial knots, an excess of fibrotic villi, a greater number of villi with a thickened tropho- blastic basement membrane, and a marked excess of villous fibrinoid necrosis (Fig. 2). Another notable feature of the villi in the diabetic group was the large number of Langhans cells; these were seen principally, however, in immature villi and rarely in numbers that were out of proportion to the degree of villous immaturity. Villous edema was very conimon in the diabetic placentas (Fig 3); although often quite marked it was never sufficiently severe for the placenta to be classed as hydropic. Hofbauer cells were also present in considerable numbers in the diabetic group of placentas but were seen only in immature or edematous villi and not in numbers out of proportion to the degree of either immaturity or edema. Villous vascularity varied, but in most mature villi in the diabetic placentas the ves- sels were fully sinusoidal and not unduly numerous; villous telangectasia or “choran- giomatosis” was not seen. In many placentas there was, though, rather marked villous congestion (Fig 4). Abnormalities of fetal stem arteries At all stages of pregnancy the diabetics’ placentas showed an excessive incidence of obliterative endarteritis in the fetal stem ar- teries (Table 2). There was also an in- creased incidence of fetal artery thrombosis, usually in otherwise normal arteries. Calci- fication of the fetal arteries was not seen. DISCUSSION In general, there was no excess of gross Vol. 34, Now 6 December 1969 IN DIABETES lesions in placentas from diabetic women. Calcification was not a feature of these pla- centas, and the over-all incidence of infarc tion was lower than in those from uncompli- cated pregnancies. Those placentas from prematurely delivered diabetics did, how- ever, show an increased incidence of infarc- tion. This group included most of the pla- centas from severely diabetic patients, who for obstetric reasons tend to have their preg- nancies prematurely terminated. It would appear possible therefore that severe dia- betics have a slightly increased risk of pla- cental infarction, this risk being absent for mild diabetics. In no placenta in this series, however, was extensive infarction seen. Those placentas showing an excess of villous syncytial knots usually also showed an excessive degree of villous stromal fi- brosis. Such placentas were almost invari- ably characterized also by an obliterative endarteritis of the fetal stem arteries. It is probable that the villous abnormalities were the result of the arterial lesion: evidence de- rived from morphologic* and experimental studies" indicates that both fibrosis and syncytial knot formation may result from a reduction in fetal blood flow through the villi, It is possible that the high incidence of fetal arterial lesions, of villous fibrinoid ne- crosis, and of trophoblastic basement mem- brane thickening in placentas from diabetic women was the result of an immunologic reaction, for it has been shown’ that fluo- rescein-labeled insulin is bound in the walls of the fetal arteries, on the trophoblastic basement membrane of the villi, and in villi showing fibrinoid necrosis when applied to placentas from diabetic women; insulin- binding was not found in placentas from healthy women, It has been suggested that the binding of insulin in these sites was due to an antibody and that the lesions present were due to an antigen-antibody complex. It is certainly true that many patients develop antibodies against exogenous insulin,* ** but 795FOX there is also some evidence that anti-insulin antibodies may occur in patients who have never received insulin therapy.** It is of particular interest that in one study® anti- insulin antibodies were found in all pregnant diabetics studied but in no normal pregnant patient; the antibodies were also found in the infants of diabetic mothers. It is further known that a condition closely resembling diabetes mellitus may be produced experi- mentally by the stimulation of anti-insulin antibodies,!* 27 and some evidence has been obtained to suggest that the renal, retinal, and vascular complications of human dia- betes are due to the local formation, or de- position, of antigen-antibody complexes; * 4.10 it could be suggested therefore that the placental lesions have a similar histogene- sis, Although at the moment this can be no more that a hypothesis, it is of note that the lesions seen, namely fibrinoid necrosis, vas- cular abnormalities, and basement mem- brane changes, are all common morphologic expressions of an immunologic reaction. There was no evidence that ischemic le- sions were of significance in the diabetic group of placentas; there was an excess of villous Langhans cells and such an excess may be an indication of placental ische- mia;\*. * these cells were, however, usually present in placentas showing villous imma- turity and were not disproportionally nu- merous for the degree of immaturity. Evi- dence of Langhans cell proliferation was not seen, That placental ischemia is not an im- portant factor in diabetics is not surprising, for there is no firm evidence that the utero- placental arterioles are abnormal in these patients. Driscoll has described hyaline change, fibrinoid necrosis, and atherosis of the decidual arterioles in diabetics but noted “this lesion is recognized especially in dia- betics afflicted by toxemia of pregnancy and/or by nephropathy”; other workers: * have been unable to find any vascular ab- normalities in placental-bed biopsies from diabetic women. 796 The increased incidence of fetal artery thrombosis in the diabetics’ placentas was independent of the fetal arterial lesions. There does appear to be a tendency for thrombosis to occur in the vessels of the fetus in maternal diabetes—for renal vein thrombosis is unusually common in autopsy studies of such fetuses.*® It is difficult to suggest any explanation for the maturation disorders seen in these placentas. Diabetes mellitus is a complex and still largely ill-understood metabolic and endocrine disorder. 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