Facts Pertinent to the Etiology of Eclamptogenic Toxemia*

Obstetrics FACTS PERTINENT TO THE ETIOLOGY OF ECLAMPTOGENIC TOXEMIA* A Summation of Previous Observations ( i930-i955) R. A. BARTHOLOMEW, M.D., E. D. CoLVIN, M.D., W. H. GRIMES, JR., M.D., JoHN S. FisH, M.D., WM. M. LESTER, M.D., AND WM. H. GALLOWAY, M.D., ATLANTA, GA.

(From the Departments of Obstetrics and Gynecology, Emory University and Georgia Baptist Hospital)

I

N A search for the caul'{e of rclamptogenic toxemia, it is fortunate if one happens to find what aPJwars to !Je a significant piece in the jigsaw colleetion of phcn(nnena pertaining to this disease. ()nto this piece, if it be really significant, other pieces of the puzzle logieally fit ur pointedly suggest other pieces needed to fill in deficiencies. In this manner, just as a jigsaw puzzle becomes JtlOI'C WOrkable with further additions, SO may the mechanism of UCvelopment of prt>-eclampsia, Pelampsia, ant! a hruptio placenta<• begin to take form. Aduitional nec;dful data can then he purposely aiHl not accidentally supplincl. In recent years, attention has h
1. Placental Necrosis In 1930, one of us (R. A. B.) came to be impressed with the finding of what appeared to be areas of recent degeneration on the maternal surface of placentas, especially from cases of abruptio. Here was a finding· more suggestive of cause than effect since it represented uegenerating tissue in contact with the intervillous maternal blood stream, offering possibilities of dissemination of breakdown products of probable toxicity into the general circulation. •This investigation is supporteVelfare. National Heart Institute, H 1400(C-2). (j.J

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Thenceforth, a systematic gross and microscopic examination of formalinfixed placentas from both normal and toxic patients was undertaken and corrplatell with the clinical findings. It soon became apparent that areas of degenPratioll 1vere conspicllOUsly frequent in place11tas frotn toxie patic,nt;;; ( 85 to 90 per cent) and impressively infrequent in those f1·om normal patientx.' 'l'o be sure, there was a variety of lesions, but with emphasis on thosf' showing g-ross and microscopic evidence of acuk placental necrosis. By correlation with the clinical history it was possible to recognize amllabel specifically those which were slow forming and nonspecific for toxemia, d\'signated "A" (white) and "B" (ydlow), and thoRc which Wf'l'E' more acute aml specific for toxemia, d0signated "0" (yrllow brown), the morP a<·nt<· "D" (brown), and the most a(·ute ''E" (black). The R]Wcificity of tlw acute types of placental infarction for pre-cclampRin nnd <'!dampisa has bet>n verifieil and WE'll illustratrd by Pattrrson, Hunt, a11<1 .\"icoclemus,~ F'alkiner,o Steigrad,4 and mm·c· reeently by 'fhomflcn:>. 6 Failurn of other investigators to verify these findings can usually he ascribed to l'Xamining fresh rather than formalin-fixed placentas 7 or checking by erroneous standards. 8 • 9 The lesions in fresh placentas arc much ohscurC'd by blood. ThP eriteria by which areas of acute plae~'ntal infarction may lw l'Pcognizen a clinical diagnosis of toxen1ia of lYregnanry nnd the lJla('.<>ntal findings \VHR fh·st

thought to be explained in part by the ohviom; possibility that toxPmia lllaY have devPloped betwren the date of the last prenatal visit and the onset of labor. (\t;.:es illustrating this possibility c·oulfl now and thC'n he fou1Hl An additional and more important explanation of the 10 to 15 per cent deficit of complete enrrelation was founcl in tho diseovel'y that protdnuria of a wry Rig·nificant degree oeeasionally clrvdoped during lahor. 11 In a seriE>s of patients in whom the urine and blood pressure were normal on admission to the hospital in labor, proteinuria ranging from 2 to 4 plus was found to lw prPSf'llt :1t d<·livery with a frequency of JO per cent and to a l<'RsPr nd of labor or during the first day after (lelivrry. :;;imt' 49 per cent of the patients failed to develop proteinuria during labor, the physical strain of labor could not he implicated as a eausative factor, inasnnwh as rxE>rtion must have been the same in each group. Examination of the placentas flhowed characteristic dark, well-delineated areas of acute "E" infarction (Fig. 1, ~1). In general, the strips from these placentas appeared much darker than normal. As will ·be explained farther on, one could not escape the impression that the factor which initiated labor (hormonal?) may also have initiated a mechanism by which acute placental infarction developed and caused a very transient and seldom recognized period of intrapartum toxemia.

A..

B.

Fig. 1.-A, Strip of formalin-fixed placenta from a case of acute toxemia initiated during labor. Normal urine and blood pressure (110;70) on admission early In labor. Blood pressure 116/90 and flocculent proteinuria at delivery. One half of maternal surface of placenta appeared black-acute "E" infarction. Blood pressure an
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Toxemia of Pregnancy Presents Specific Placental Pathology.-It is thus possible to examine a numbered but unnamed placenta which has been fixed in 10 per cent formalin for three to four weeks, then cut it in strips 1 em. in width, and ascertain whether or not the patient's pregnancy was complicated by toxemia. 1 It is usually possible to state whether the toxemia was gradual or acute or whether it manifested itself as abruptio. Occasionally convulsions may occur during or shortly after labor accompani('d by little or no proteinuria or rise in blood pressure. Epilep;y is apt to be suspected rather than eclampsia. In such eases, examination of the placenta apparently offers the only means of diagnosing or ruling out toxemia of pregnancy. 11 Up to the present time obstetricians and pathologists have not recognized the value of this knowledge as a means of affirming or denying the presence of true toxemia of pregnancy and differentiating hypertension of true toxemia from that of uncomplicated hypertensive vasculal' difwase. Chot'ionic

Plo.t.e

Uter-ine

Ma.t>qina.l .sinus I

Utet:>ine Veins Fig. 2.-Diagrammatic from decidual arterioles into ally to margin of placenta, into uterine veins, and ( 5)

Uterlne wa.U

a.nd veins

representation of the course of the maternal blood, discharging ( 1) intervillus spaces to subchorionic plate, thence ( 2) peripherinto ( 3) marginal sinus. thence ( 4) through communications returned to the general circulation.

Mention has been made that many writers consider placental infarction the effect rather than the cause of toxemia of pregnancy. This view postulates that placental necrosis is the result of an unknown toxin present in the maternal circulation. According to a more favored viewpoint it is considered the result of ischemia of the placenta due to atherosclerosis or narrowing of the decidual arterioles. A consideration of the structure of the placenta and the course of the maternal intervillus circulation rrnclers these viewpoints untenable. Course of the Maternal IntervilTus Circulation.-The placenta is composed of cotyledons partially separated by decidual septa. The latter do not extend more than two thirds of the distance from the decidua to the chorionic plate, thus leaving a loose uninterrupted meshwork of villi beneath the chorionic plate which permits circulatory intercommunication among all cotyledons. Therefore, the cotyledons are not to be considered completely compartmented units each with its own independent inflow and outflow of maternal blood. The sinusoidal circulation of maternal intervillus blood, supplied by decidual arterioles, is constantly impelled by the maternal blood pressure to ascend to the chorionic plate at which level it must change direction and move peripherally to the margin of the placenta (Figs. 2, 3, A and B).

BARTHOLOM!.;\V ET AL.

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At this point the. plaeental chorion, deeidua. l'eficxa, awl amnion ,•xtend over the margin of thr plaeenta and breomr tlw <•horion laeve, decidua ·v era, and extraembryonic amnion, rcspectiyc]y, adhe1·ing to the uterine wall, and blocking further peripheral 14pread of the maternal blood, thus forming a pseudochannel, the marginal sinus, around the border of the plar.enta (Fig. 3,
R. Fig. 3. -

A., "In situ" strip of pl acenta, sho\.~ting course of dark njaternal blood strearn

beneath chorion ic plate. U t erine muscle below. B, Strip of placenta from a case of abruptio, showing thromboplastin-induced "in situ" thr ombosis of subchorionic mat ernal blool1 stream. Th e ac ute ly infarcted area lies b etween the tw o light areas; the t hrombo~ed maternal blood stream li es beneath the chorionic p la t e n ear the left end of the strip.

It is held by Romn ey' 7 that the deeid.ual septa cany fun ctioning· maternal arterioles high into the placent al substance, permitting discharge of blood into the· upper intervillus spaces, from which level it (~ourscs downward to l<'ave

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the placenta by decidual veins at the deciduoplacental junction. Sections of formalin-fixed placental tissue taken at various levels parallel to the placental attachment of an "in situ" placenta (Fig. 3, A), and transecting the decidual septa, do not support this concept. By way of differentiation, villm; stems are characterized by a chorionic epithelial covering, a fibrous and muscular stroma, and the presence of functioning villus vessels. Decidual septa are characterized by absence of epithelial covering, presence of decidual cells embedded in a homogeneous hyalinelike substance, and absence of functioning vessels. Nonfunctioning "ghost" vessels showing hyalinized wall and amorphous debris within the lumen may be seen (Fig. 4) . It does not appear, therefore, that maternal blood is discharged from the summit of decidual septa to course downward to the decidual base and find its way out of the cotyledon by maternal venous openings in the decidua. Since maternal decidual arterioles also discharge blood into the dcciduoplaccntal zone, a dual blood supply would produce paradoxical movements of arterial blood simultaneously in opposit•~ lli1·ections.

Fig.

~.-C . Sectinn from bord e r of pl a centa ( n.) . showing m~mbr anou s marginal sinu~ and the containeu thrombus (b), and the reflected portion of membra n ou s outer w a lt (c).

l<'urthermore, injection of a f resh specimen of uterus containing the "in situ" fetus and placenta shows that colored material inj ected into the uterine arteries proceeds from decidual arteries through intervillus spaces to the chorionic plate, thenc e peripherally to the marginal sinus, returning to the general circulation by way of communications with the uterine veins. Material injected into the uterine veins follows the reverse of this course. 15 • 13

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70

:\m. J. Ubst. & Gyne-t:. [uly, 19'i7

Should it he possible for any decidual arteriole to become blocked by atherosclerosis or other obliterative process, the dependent villi could still be supplied by the subchorionic blood stream, although blood at this level would probably be of inferior quality. 'l'herefore, in view of the ernal blood must lH'<·t•ssarily affect the entire placenta and produce generalized w·er·osis. < ln tlw <'ntas in cases of JH"t•-eelampsia atHl t•dampsia has shown that lH'<·t·osis is preponderantly of a locali;-:<·<1 charactfT limited to the clistrihution s

F'ig.

4.-"Ghost"

nonfunctioning maternal vessels in placenta.

a

decidual

septum of an

"in situ"

of fulminating abruptio (F'ig. 5, A. and B), and toxemia initiated during labor (Fig. 1, A, B, and C, and Fig. 11, ,t and B) which appear black with acute "E" infarction throughout most if not all of the placental strips. ln these cases the widespread spasms involving the vessrls on the fetal surface of the placenta lead one to believe that the sphincters of practically all placental veins on the surface or in the placental substance are in a state of spasm.

2. Vascular Spasm Mechanism of Placental Ischemia and lnfarction.-Some have questioned the appropriateness of the term "infarct" wh<>n applied to areas of villus necrosis. An area of necrosis of placental tissue resulting from occlusion of a fetal placental vein with resulting· enlargement of dependent villi, diminution of the intervillus blood spaces, and thrombosis of its intervillus maternal blood supply, is qualified to be termed an ''infarct" as truly as is an area of necrosis of the lung, deprived of its arterial blood supply by an embolic process, as the mechanism will show.

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In an early stage of this study, it was postulated that thrombosis possibly resulted from the impact of vigorous fetal movements on exposed fetal vessels on the surface of the placenta. Later on th e discovery of subendothelial fat cells suggested the possibility of atheromatous change and thrombus formation in fetal placental vessels. Neither of these theories could be sustained by convincing evidence of sufficient blockage to account for infarction and were therefore abandoned.

A.

B. Fig. 5.-A, Place nta l strip from case of superimposed fulminating severe abruptio in\'Oiving entire placenta, except at extreme right, with acute ''E" infarction. Prenata l visit near term showed blood pressure 135/85 and a trace of proteinuria. Twelve hours later. severe hemorrhage, abdominal pain, blood pressure 160/ 100, flocculent proteinuria, followed Spontaneous rapid labor, stillborn baby; 2,000 c.c. bloorl loss ; transfusions; by shock. recovery. B , Microscopically, distended capillaries causing enlargement and crowding of villi; narrowing or obliteration of intervillu s spaces ; anoxic necrosis of chorionic epithelium: thromboplastin-Induced !ntervlllus and subplacental thrombosis with abruptio.

Spanner's 15 researches on the placental circulation furnished a significant clue to the manner in which placental infarction occurs. By serial sections and injection methods he demonstrated not only the path of the intervillus maternal circulation and existence of the marg·inal sinus, but also the presence of definite sphincters in the fetal collecting veins both in the substance and on the fetal surface of the placcntaY· 16 This has readily been verified in placentas we have examined (Fig. 6, A, B, C, and D).

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The physiological function of these sphincters is not definitely known, but if they are susceptible to a humoral spasmogenic hormone, the exit of blood from the corresponding placental unit must Jw greatly impeded OJ' completely obstructed. If the placenta from a toxic patient is inspected on its fetal surface immedia.tely after the third stage, spasms of both arterioles and veins appear to be very numerous (Fig. 7, A), as compared with those of the rla centa of a patient who had JH•ithr·r· antt·- nor intrapartum evidenc·<· nf toxemia. Delayed spasm of fetal a rteri es and/ or veins scc·n on the surface of the plaeenta after delivery is generally considered to be of little significance and is attrihnti·
.4.

J<'ig. 6.-A, Sharp constrictions in ft-tal placental veins indicate sites of venous sphincte rs. B. Section through fetal ve in s phincter showing marked na rrowing of lumen, indicating possibilities of obstruction to exi t of blood from correspon
By way of investigating this impression, 100 placentas were inspected for spasms at the end of the third stage. Nine were rejected, examination having been delayed and not immediate. Fifty-six placentas (61 per cent) showed no vascular spasms. In 6 (10 per cent) of these, there was mild to moderate evidence of ante- or intrapartum toxemia. Hidden spasm within the placental substance remained a possibility. Thirty-six placentas showed vascular spasm. Twelve, or 33 per cent, of these showed mild to moderate evidences of anteor intrapartum toxemia. A larger series would have been desirable. Since the fetal heart continues to force blood into the obstructed units, the villus capillaries become greatly engorged and distended with resulting enlargement and crowding of villi, diminution or obliteration of the intervillus spaces, and exclusion of the maternal intervillus circulation on which

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B.

a.

D.

Fig. 6.-B, C, and D.

(For legend see opposite page.)

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the vitality of the chorionic epithelium de1)ends. Necrosis of the epithelium ensues, as may be readily recognized by pyl{nosis, karyorrhexis, and ultimately karyolysis of the nuclei (F'ig. 1, C, and Fig. 10, B). This process represents an indirect form of infarction in which the adequacy of the maternal intervillus arterial channels is entirely dependent on and affected by the size of the villi which, in turn, is dependent on the degree of spasm and blockage at the site of fetal vein sphincters. 'l'he hydropic hydatidiform villi and the edematous erythroblastotic villi, by virtue of their (~nlargcmcnt and crowding, occasionally produce the samP effeet, which may result in toxemia. Grossly, the placenta in the acutely infarcted area appears somewhat thicker because of enlargement of the innumera bl P individual villi; also much darker because of thrombosed intPrvillus am1 intracapillary blood (l stat(• of pre-c•elampsia may be associated with "D" infnrction of a brown (•olor chw to ehanges in the hemoglobin;"(;" infarction is of a gray-brown color and of still longer
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characterizf'd by frequent severe pains and rapid progress as if stimulated by au excess of Pitocin. Although labor may be initiated by mechanical means, the fact remains that oxytocin is outstanding in its ability to produce

A.

B.

Fig. 7.-A, Appearance of fetal surface of placenta from a case of eclampsia. Excess ive involvement of fetal placental veins and arteries with spasms as noted immediately after expulsion of placenta and promptly photographed. Arteries are smaller a nd override v eins. B, Note typical effect on size of villus and capillaries and the pyknotic fragmented (Unfortunately, a placental nuclear material of the chorion and capillary endothelium. strip was not photographed.)

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rhythmie uterine c·ontraf•tions anLl initiat(' or stimulate lahul'. \Vhen injected in dilute strength into tlw surfaee veins or arter ies of a frrshly d elivered plaecnta, it induc es marked loealizecl ancl elongated Ycnous spasms and elongated arterial spasms V('!'Y similar to thnse seen in a ft•t•shly d(•livf'r('(l placenta of a severely toxic patient.

B. Fig. 8.-A._. Placental strip from case of severe abruptio which developed during labor. Stillbirth and excessi ve hemorrhage. R ecovery. B lack portion is early " E" Infarction. Light portion is norma l. B, Microscopically, enlargenwnt and crowding of villi due to distended capillaries; thro!nbos!s in intervillous spaces.

\Vith the advent of pregnancy the interrelationship of hormones of the pituitary, ovaries, and adrenal glands becomes even more complex by the ad~ clition of placental substances, namely, gonadotrophic hormone, 20 adrenocorticotrophic hormone, 21 adrenocorticosteroids, 22 estrogen, 23 pitocinase, 24 progesterone,"" and aeetyleholinc."'; A vlaeental soun·.e of er>trog·on awl proger>~ teronc is indicat ed by the fal't that eastratio n of' p1·egnant women during thl' r>ec:ond and third trim est.t>r-s uf prC'gn ancy dot•s not prevent an increase in these hormones. 2 u

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Pituitary Gland.-It is significant that the pituitary gland doubles in size during pregnancy." 7 Increase in an antidiuretic substance during pregnancy28 may well be a manifestation of increased activity of the posterior lobe. The increase in pitocinasc 24 may also indicate a response to increased activity of tlw posterior -lobe. Although Pitressin is characterized by its pronouncecl vascular effects, it also exerts definite oxytocie effect. "9 'l'he gonaclotrophie activity of the pituitary is little or absent during pregnancy. 3 " Byrom 31 found that a tenfold increase in sem;itivity to Pitressin was manifested by prin1ing· with E'strogen. Adrenal G/(mds.-'l'oxcmia of pregnancy is known to occur in the presence of Addison's cliseaseY ,J ailervs demonstrated the presence of corticosteroids in the placenta of an Addisonian patient. The adn·nal glands hypertrophy in pregnancy, conceivably from stimulation by the increasing level uf estrogen or as a respons<' to <>xccss stimulation by placental adrenocortieotrophic hormone or by the anterior lobe of the pituitary gland. The excretion of urinary corticoids has bet:m found to show a fourfold increase in the third

Fig. 9.- 0bliterative process in f etal placental arteries, producing slow, white, firm infarction of "A" type.

as eompared with the first trimester. 33 Twenty-five per cent of the corticoirls Pxct·eted in the third trimester were of the desoxylike compound, 3 " which influences water and electrolyte metabolism and exerts hypertensive effect. 35 · 36 In this mechanism, salt in the arterial walls plays an important role. 37 'l'he desoxylike steroids have been found to be significantly elevated in severe toxemia. 34 The total corticoid excretion in toxemic women in the third trimester has been found to be almost twice as high as that of normal women. 34 • 38 The urine of toxemic patients contains abnormal amounts of desoxycorticosterone-like sodium-retaining substance. 39 The experimental administration of desoxycorticosterone to animals and man produces a gradual rise of blood pressure, 35 • 36 in the mechanism of which salt plays an important part. The simultaneous administration of salt and desoxycorticosterone distinctly increases the pressor effect of the latter, 40 • 41 whereas salt deprivation lessens it:12 Appal'ently any pressor attion of sodiun1 ehloride is dependent

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UpOn SUpport by the aurenal !llilleralOCOrticOiUS.LI 1t haS het•ll delUUllStratell that the arterial walls of hypertensiv0 individuals contain abnormally largr amounts of sodium.~· A,'n no1·cpinephrinc/' Pitressin, 4 " renin ( 8 VBM 4 " allreas active free f'st.rogen increases shortly lwforT labor. SJ-n<'rgism has lwen dnmonstr·att•d hd.weell ft·ec estl·ogcn and the oxytocic principh• of the posterior pituitary. Excess (\Strogcn caust•s hypert1·ophy of tho adr<·unls'·~ nnd i11duces water null sodium 1·etention. 3 '· "' 1t is beliPved that c·strog·en t'oiHlit.ions the mat.Pr·nal ynseuhu· system for mon· intensP netion on the pm·t nf the corticuitl honnonf•s.·''

!J.

Fig. 1 u.-A, Placenta! s trip from a case of fulminating abruptio; acute " E" infarcted areas beneath depressed area in center of mate rnal surface. " Nodula r ischemia" (Zeek). white a rea a t extreme left. B, Microscopically, marked en largement or villus du e to tlistencled capillaries; pyknosis and karyorrhexis of capillary endothelium due to trauma of stretch; fragmented nuclear material may be seen around the periphery of distended villus v essel, especially along rig ht border; pyknosis of chorionic endothelium due to stretch a nti a n oxia .

Progesterone.-Progesterone is inereased coincidentally with eoneeption and gradually increases to a peak two to three weeks before delivery. Thereafter it declines up to delivery. 25 • 55 It is antagonistic to estrogen and also to Pituitrin (Knaus'" reaction ). Haskins'' 7 foun1l that the progesterurw f'unten t.

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of normal placental tissue after spontaneous labor was apparently only one fourth of the amount obtained from the placenta at cesarean section before labor had begun. It has been shovm that pregnanediol excretion diminished prior to false labor, then increased for a time, but subsequently fell at the onset of true labor. 53 Snyder, 58 by artificially increasing the supply of progesterone through inducing ovulation in the rabbit near term, was able to prolong pregnancy and demonstrate complete resistance to administration of Pituitrin. From the foregoing collection of data pertaining to the behavior of the hormones especially concerned in pregnancy, it appears that oxytoein is held in abeyance during pregnancy by acetylcholine, progPsterone, and pitoeinase .

.4..

B. Fig. 11.-A, Severe prelabor toxemia; blood pressure 190/110; proteinuria 2 plus, increasing to 4 plus at delivery. Total acute "E" infarction of the placental strip except for light round area of Zeek "nodular ischemia" at right end of strip. B 7 Microscopically, characteristic appearance of enlarged cro\vded villi and distended capillaries, apparently due to generalized spasm of placental vein sphincters, causing obstruction of maternal !ntervillus circulation. Higher power would show pyknotic fragmented nuclei of capillary endothelium and chorionic epithelium.

Gradually, but at times precipitously, it appears, oxytocin is released from its inhibiting factors near term by a drop in progesterone and conjugated estrogen; also, the uterine muscle is sensitized to the action of Pitocin and Pitressin by the presence of free estrogen at term. Meanwhile the mineralocorticoids increase in the third trimester, sensitizing the vascular system to the effect of Pitressin with the result that arterioles and precapillary vessels decrease in caliber, as may be noted by ophthalmoscopic examination in the ninth month of pregnancy. 59 Landesman and Douglas60 have demonstrated this vascular

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J. Obst.

phenomenon in the bulbar conjunctival vessels late in pregnancy. The uterinP muscle, reacting at first in a haphazard ineffertive rhythm (false labor). t'ventually responds to the increasing· oxytoci<· stimulus awl assumes a rhythm of effective labor. Govann 1 found that tlw urine of a toxemic- woman t'ontaim·cl a substance whic-h <•.aust·s cxperinwntal animals to ))('eome highly I'H'nsitive to Pitnitrin. It is conceivable that the placental f<·tal \·<>ssch; and nnous sphinctct·s may, in a similat· manner, become st-ns1tized to the action of Pitressin atHl Pitocin, which, by increasing the tend<"ney to spasm, increases th(' liability to toxemia as term approaches, reaehing a maximum effeet during labor (Fig;. II ..l and B). It seems that the measure of a pregnant patient's susceptibility to toxemia c<:iuld lie in the titer of her uninhihited hlood oxytocin plus the degree of priming· of the p1aeental venous sphincters brought about b,v estrog<'n. dPsoxyeortieosterone, an(i sait sensitization. The Noxious and Lethal Components of Placental Nccrosis.-Tlms far i1 ean be asserted that (1) tme toxemia of pr<>gnaney (abruptio, pre-eelampsia. and celampsia) is eharaderized hy a speeific pln,eental pathology (aeute anr1 subacute placental infardiou) a1Hl ( 2) that the gToss aml microscO]Ii<~ charact<~risties of th<> infarction ean logically be explairH•d hy a spasmogrnie hormone; (oxytocin '!) aeting upon une or mon· of the Y<'lwns sphincters present in tlw fetal veins of the placenta. Vasc·ulnr Spasm.-If vaseular spasm, per se, Jwcomes gl'lH'ralizecl in th•· eourse of Pithe1· primary m· superimposed tox<>mia, it is capable of pl·odueingclamaging iRehf'mic effeets on vital organs or vulnerable tissuC's. If artrrinlnr r·<>tinal spasms an~ a dependable HH'asnr<' ol" their prcsene<' t"lS<'wher<' in tlw body, spasm is not a sn·ious factor until toxemia heeoml's severP. This is lltorr· lib·ly in snprrimposed tox<>mia. Then\ is a gradual increase in pre-existing· hypertension of hypert(•nsivc Yaseula1· cliscas<' in the Pighth and nint.h months. apparently due to irtcreascd Recretion of dPsoxycorticostcronc and

rl~trntinn

of salt, hut unassociated with appearanee of retinal spasms, signifieant degrees of proteinuria, or clinical symptoms of toxr·min. Tt is gen<>rally r·<·(·og·nized that these pati<>nh: at'<' partieularly prone to deYPlop suddf'n <'XlWl'rbatiou o i' hypertension, prntt'inuria. nnd clinical symptoms of toxemia-superimpos<·d toxemia-which prnba hly results from sudden spasm of the phtc·ental \'Pin :-:phinch•r of oxytocic (!) orig·in. It. is under these eircumstanec·s that retinal spasms heemne pronounced. Mark<'d Pxact•rhation of blood pn·s:-;m·<· or•<•m·s along with heayy pmteinuria and signifi(·ant elinieal symptoms. This swlrl<·JJ changc is assoeiat<'pithelium and the endothelium of the greatly dilated villus capillaries. Placental tissue and particularly deeidual tissue are known to be unusually rieh sources of thrombo1)lastin which initiates dot or thrombus formation by a several-stage proress of (1) formation of thromboplastin from tissue injury, (2) convc•rsion of prothrombin to thrombin by addition of calcium and thromboplastin, (3) formation of fibrin by action of thrombin on fibrinogen. The following ease illustrates the rapidity with which this proeess may produce abruptio placentae.

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Mrs. G., aged 30 years, gravida ii, para i, following a period of painful Braxton Hicks contractions in the thirty-first week of her first pregnancy, developed abruptio placentae and was delivered of a stillborn baby. 'l'he present pregnancy was likewise complicated by frequent Braxton Hicks contractions in the sixth and seventh months. In the thirtyfirst week, at a regular prenatal visit, at 2:30 P.~L, her blood pressure was 120/70, and the urine showed no proteinuria. Subjectively there were no symptoms of toxemia. Three hours later, at home, she develope
Dieckmann,'> 7 in 1936, called attention to the loss of clotting power of the blood in many cases of abmptio placentae and attributed it to the marked re abruptio. Hence, thct·e is an increased tendency to clotting in the former hut a decreased tendency in the latter if depletion of fibrinogen occurs. Separation of the placenta prpcludes absorption of possible additional breakdown produets of placrntal necrosis, which probalJly explains why so few patients manift>st both a])l'uptio and eelampsia. TABLE

I.

Trn;E 'fOXEMIA OF' PREG:
I. Partial Invol·vement of Veins apparently causes Localized infarcti.on ( s) and

fl. Complete Invol·vement of Veins apparently causes

Generalized infat·ction and Fulminat·ing toxemia

Subacute toxemia 1. Mild toxemia, to 2. Moderate toxemia, to 3. Severe toxemia, to 4. Pre·eelampsia, to 5. Abruptio phtcentat' 5. Eclampsia Course Co1trse Several hours to several days One to several weeks Eclampsia and abruptio placentae rarely combined

1. 2. 3. 4.

82

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As previously mentioned, the severity and rapidity of placental vein sphincter spasm and the extent of involvemrnt probably determine the course of the toxemia (Table I). In II, extensive spasm and resulting massive infarction of the placenta cause thromboplastin effeet to dominate. Renee, 8tages 1, 2, 3, alH1 4 arc bypassed and abruptio placentae occurs. It is only reasonable to believe that, as plaecntal ncerosis progresses, there must be early and late degradation products of nuclear and protein degeneration, some of which may be toxic. Practically all tissue cells possess intraeellular enzymes which, upon death of the cells, mpidly break clown the nuclear and protein cellular elemrnts, producing enclotoxins of potential toxicity. ....t\_n in1portant part of the JH'obleul is to 1~novv'" in vvhat rcspeets placr'ntal autolytic products may differ from those of othl~r tissues. It is believed that biochemical methods may make it possible to i<1Pntify products of placental autolysis and determine their toxicity or effects. 'l'he biochemieal products of normal placenta autolyzed in vitro and infal'cts ft·om toxic placentas in various stages of previous autolysis in vivo are being studied. It is hopc•d that blood may be ohtained from a uterine vein of a patient with severe pr·c·-eelampsia, (•e.lampsia, m· abruptio placentae who, on account of possible rPsistanet> to indu(·tion of Jahor, may requir·e delivery by cesarean SPetion. thus affnr·ding an opportunity to obtain autolytic. products directly from tht> sourc·e in the utems before sneh produets have passed through the general eit'(·nlation and hav(~ possibly lwcomc diminished or altered. Peripheral blood, removed at the samn tinw, should show differences in eomparison with ntc·rinc blood. 'l'his procedure has already been satisfactorily applied in a nontoxic patient requiring cesarean section, the results of whieh ease should serve as a control.

Conclusions This artiele is concerned with f•ertain signifieant anatomical, physiological, and pathological data whieh seem partienlal'ly j)('l'tincnt to the etiology of eelamptogenic toxPmia, setting fol't h a theory of the genc•sis of this disease as clictated by these farts and signifieant phenomena. The following eonelusions seem wa rrantP!1: ]. There is a specifie placental pathology in the form of aeutc and subacute placental infarction. best demonstrated in formalin-fixed placentas. which is pathognomonic for pr·e-rclampsia, eclampsia, and abruptio plaeentae. rPhis fact, first discovered by Young, is pertinrnt to the etiology of the disease. ~- Areas of placental ncerosis in eontac·t with maternal intervillus circulation present possibilitil'S of dissemination of procluets of plaeental autolysis, which may be highly toxic to the mother. 3. Placental infarction of the subaente ("C'') or acute ("D" and ''E") types of infarction is logically the eause and not tlw cffeet of toxemia of pregnancy. The paths and interrelationship of the fetal and maternal components of the placental circulation dictate this conclusion.

Voiurne i4

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83

4. The anatomical basis of placental infarction is found in the presence of smooth-muscle sphincters in the placental veins, first discovered by Spanner. 5. The trigger which excites spasm of few or many of the venous sphinctPrs is logically oxytocin, v1hich through changes in hormone balance in the latter part of pregnancy (lowered progesterone and presence of free estrogen) is apparently released from the inhibition exerted by its hormonal antagonists progestrrone and pitocinase. Increase in desoxycorticosteroids late in pregnancy, aided by salt, sensitizes the smooth muscle of vessel walls and probably that of placental vein sphincters to incrrased reactivity. 6. Spasm of the venous sphincters obstructs exit of fetal blood from the corresponding plaecntal units, causing distention of villus capillaries, enlargen1ent of villi, dilninution or obliteration of the intervill11S spaces and circulation, resulting in anoxic nrcrosis of chorionic epithelium, villus stroma, and capillary endothelium. 7. Thromboplastin, abundant in placental tissue, is apparently the first product of chorionic nrcrnsis, which, if infarction is extensive, causes abruptio by subplacental clot formation and Of'casionally afibrinogenemia with hemorrhagic tendency. 8. It is apparent that there is only one true toxemia of pregnancy-that due to placental infarction and necrosis. It comprises abruptio placentae, eclampsia, ancl its precursor, prc-celampsia. Other conditions presently includrd in the accepted classification of toxemias of pregnancy constitute predisposing causes rather than types of toxemia. 9. It is hoped that biochemical study of normal and toxic placentas and blood now in process may serve to identify the nature and effects of other degradation products of placental necrosis, which are probably more concerned with pre-eclampsia and eclampsia. A grant-in-aiJ has made it possible to pursue this line of investigation with the collaboration of Alfred Wilhelmi, Ph.D., Professor of Biochemistry, Emory Un,iversity School of Medicine, Charles Hoover, Ph.D., Biochemical Research Assistant in the project, an
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Am. j. Obst. 6: Vynec:. July, 1957

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