Placental hemorrhagic endovasculitis: Risk factors and impact on pregnancy outcome

393

Int. J. G~xaecol. Obstet.. 1984, 22: 393-391 International

Federation

PLACENTAL PREGNANCY

of Gynaecology

& Obstetrics

HEMORRHAGIC OUTCOME

NANCY G. STEVENSa

and CHARLES

ENDOVASCULITIS.:

RISK

FACTORS

AND

IMPACT

ON

H. SANDERb

aDeparrment of Family Medicine. University of Washington and bPlacental Tissue Registry. Department qf Pathology.Michigan State University (U.S.A.) (Received (Accepted

February lOth, 1984) July 30th, 1984)

Abstract Stcwrls NG. Sander CH (Department of’ Fanlilj, Medicine, Uniwrsit)~ oj’ Washington and Placcrltal Tissue Registr.v, Dcpurtrncrlt Michigan State Uniwwit_v. oj’ Putholog)~, U.S.A. 1. Placental hemorrhagic crido~lusculitis. risk ,ftictor,s ar2d impact on prcgnanc?’ outCOIIlC. /nt J GJjnaecol Ohstet 22: 393~--397, I984 TKY~ hundred and cigh teen cases oj’ hemorrhagic cndovasculitis (HE V), a recently rewgrlizcd abnormalit.\, of’ human placentas. wcrc idctlt(fi’ed jiorn placentas submitted to the Michigurl Pluccntal Tissue Registry over u 7,.5-~,ear period. HEV appears to ,fOcus 011 jktal placental blood vessels with resultant jkagnlcntution and destruction oj’jktal RBCs. hemorrhage into villous stroma, micro thrombi in villous capillaries and non-exudative necrosis of medium sized chorionic vessels. Placentas without HE V submitted ,jor evaluation ,fionl the same ho.spita1.s \cwe selected jiv comparison. Women lvith HEV placentas Mvre o,f’ similar ugc, race and parity as control women. The se.~ oj’ the fetus o,f’HE V cases wus somewhat more ojien female (5 7% 1’s. 485%. P = of HE V appeared to have 0. CS). The presence a deleterious e,ffect or1 the outcome oj’~~rc~gnatlq’: 32% (I I2/218) of the HE V placentas \z’crc associated with stillborn infants, in cow trast to onlv 22% (891400) qf’coritrol placcntas. The d(fjkrencc in the proportion of stillbirths 1l’a.s greatest ,chen the gestational age 0020-7292/84/$03.00 0 1984 International I:cderation Published

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or greater. Other .sigll[ficutit was 3.5 ~wk.s positilv~ associatiow \\litli If15 V irlc llrdctl the prcscricc oj’ tliecotliillll ,stuiriirig. iritrairtcrirlc growth retardation. smaller p1ac~c~rltu.r. atul matcrrial tl?,pc~rtcri.siori or to.\-crniu. Puthologic fi‘ndings associu ted \l’ith IIE V \\we chronic vitlitis. cr~~tl~r~~blu,stc~.sis. throrr~bosis ufld cord abrlorrnalities. h’o u.s.sot’iatiolr \\v~,s ,fblctrd \i!itll hfirnt Apgur score or ,ti>tul UI/O~?Zalies. The association of’ III:‘ V \t‘ith II high of’ stillbirth.\ ill Ii/(> registr,~~ proportion .suggcsts that ,firrtticr rrli~lt~r.stioi~lit~g of this lcsiori might shed light otl the problclll of uncxplairlcd stillbirth.

Keywords: Pregnancy outcome; Hemorrhagic endovasculitis; Human placentas; Michigan Placental Tissue Registry; Fetal placental blood vessels; Stillborn infants. Introduction Late in 1977 an unusual abnormality was noted in the ,microscopic appearance of some placentas sent to the Michigan Placental Tissue Registry. A search of the literature and of microscopic material to presentation placental pathologists across the United States confirmed that the lesion was histologically distinct and had not been reported before. The process appears to focus on fetal placental blood vessels with resultant fragmentation and destruction of fetal red blood cells and

394

Stwens and Sander

hemorrhage within villous stroma. Microscopic thrombi are present within chorionic vessels in varying stages of organization. Microthrombi may be observed within terminal villous capillaries. The larger chorionic vessels show marked myointimal proliferation. Many large spindle cells with prominent nucleoli partially occlude the lumina of these vessels. Intimal proliferation may result in luminal septation with formation of apparent recanalized channels. Medium sized chorionic vessels reveal non-exudative necrosis of their muscular walls with diapedesis of red blood cells and their fragments through the damaged areas. The vascular alteration with red cell fragmentation has been termed hemorrhagic endovasculitis (HEV) [ 5 1. These events coupled with apparently enhanced intravascular coagulation suggest this is a microangiopathic process. A similar histologic appearance is found in the ‘microangiopathic hemolytic anemias, such as the hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura [ 21. Initial clinical data suggested that this destructive and distinctive vascular process within the placenta was associated with significant perinatal morbidity and mortality. The present study was undertaken to define more completely the demographic and clinical features of the pregnancies in which these placental abnormalities developed.

Methods Between January 1, 1978 and July 1, 1980, 1146 placentas were sent to the Michigan Placental Tissue Registry. (This is the period from first recognition of HEV to first publication of the finding in a widely read journal [ 51.) The registry’s services are available to any physician in the state. Placentas are usually sent because of .some unusual characteristic of labor, delivery, mother, baby, or placenta. Placentas are submitted together with information on maternal age, race, parity, prenatal disease, infant weight, sex, Int J Gynaecol Obstet 22

gestational age, viability, Apgar scores, placental weight, meconium, amount of amniotic fluid, and the reason for the submission. All placentas are examined in a standard manner, [ 11, according to the method of Bernirschke and by the same pathologist. While sections are viewed initially without reference to clinical information, the latter is reviewed by the pathologist (C.S.) before the final pathologic characterization is made. During this 2.5-year period, 225 cases of HEV were identified. An attempt was made to match two registry controls (women whose placenta showed no evidence of HEV) to each case according to hospital and date of submission. One hundred fifty nine cases were matched to the next same-hospital control before and after the case. Thirty cases were matched with two controls either forward or backward in time or from the same city but not the same hospital. An additional 22 cases were matched with a single control from the same hospital. Seven cases were excluded because of the lack of suitable controls. Significance of differences between HEV cases and controls were tested using the Chi Square Test with continuity correction and analysis of variance to compare means.

Results Maternal age, race and parity, in HEV cases and controls are shown in Table I. These maternal characteristics were not different in HEV cases and matched controls. The study population was similar in these respects to the state of Michigan as a whole. HEV cases were more likely to be female than matched controls (P = 0.05). The most striking difference between HEV cases and controls was the percentage associated with stillborns (Table II). The state of Michigan had 0.93% stillborns in 1977. Although the control’s stillborn percentage was much higher than this (22%), the stillborn percentage in HEV cases (52%) was particularly high (P = 0.0001). The difference be-

Placental Table 1.

Ilatcrnal

,ind t’etal characteristics

HkV

of HI-V cases compared

Michigan

0.47

Median age = 25

304/355(X6) 42/355(12) Y/355 (2)

0.50

White = 82.4% Non-white = 17.6%

156/373(42)

0.78

40%

177/366(48.4)

0.05

controls

endovasculitis

395

and the state of Michigan.

P

Non-HEV

cases

wifh controls

hemorrhagic

1977

Mean age

(S.D.) Kacc (‘4 ) White Black

25.7(5.6) 173/195(89) 17/195 (9) S;‘lY5 (3)

Orhe

I’crcznt I irqt birth\ (‘4) 1 etdl

23.3(5.X)

X7/207(42)

\e\ (percent

~___

I19!208(57)

t‘enlale)

_~

Table II. control\.

I requency

oi

stillbirth

in

HEV

cases

and

Ge\tational age (week\)

HEV cases (%)

Non-HEV controls (%)

P

All

117:217 (52) 616 (100)

X8/392(22) 22123 (96) 19/27 (70) 11136 (31) 9/40 (23)

0.000

B70 21 ‘5 29 33 37 -4

24 2x 32 36 40

I

617 II/14 14/21 25/50 30172 IX/41

(X6) (79) (67) (50) (42) (44)

I

2/63 (3) 12/l 1X(10) X/63 (13)

tween cases and controls ‘increased with increasing gestational age. Clinicians reported no known prenatal disease in 38% (74/l 93) of cases, and 33% (115/347) of controls (P = 0.75). Elevated blood pressure and/or toxemia was reported in 23% (45/193) of HEV cases and 15% (53/ 347) of controls (P = 0.02). No other prenatal diseases were reported with enough frequency to permit a reliable comparison. Table 111.

Gross and microscopic

pathologic

findings

Mean placental weight, :! (S.D.) Unusual appearance of placenta (clinician reported) C‘hronic Villitis (‘%) trythrohla\to\i\ (%) AhnormJ cord (e\tcluding thrombosis) (%) Thrombosi\ ot‘ cord ve$sel$ (‘Z) ThromboCs of placental ves$el$ (%)

(%)

associated

Pathologic findings associated with HEV are presented in Table III. First, placentas with HEV were significantly smaller than controls. Next, about 30% of placentas in both cases and controls were reported by the submitting clinician to be abnormal in Finally, appearance. several pathologic findings - chronic villitis, erythroblastosis, abnormalities of umbilical cord (edema, inflammation, true knot, cord around fetal and thrombosis of cord or fetal part), vessels - were more common when HEV was present than when it was not. Chronic villitis was present in 60% of HEV cases. Examination of fetal and infant characteristics and their distribution between HEV cases and controls revealed several associations (Table IV). Meconium, either in amniotic fluid or placental histiocytes, was consistently more common in HEV cases. Apgar scores at 1 and 5 min were not significantly different between HEV cases and controls. There was no association between with HEV. HEV cases

Non-HEV

controls

484 (227) 68/21X (31) 130/218 (60) 27/21X (12) 52/21X (24) 26/21X (12) 7412 18 (34)

533 (287) 1121395 (28) 80/395 (20) 13/395 (3) 211395 (7) 14/395 (4) 74/395 (19)

Int J Gynaecol

P 0.002 0.50 0.0005 0.0005 0.0005 0.0005 0.0005

Obstet 22

3%

Stevens and Sander Fetal and infant

Table IV.

characteristics

associated

with HEV.

Meconium staining (%) Liveborn Apgar six or less at 1 min (%) Liveborn Apgar six or less at 5 min (%) Fetal anomalies (%) Small for gestational age (clinician reported) (%) Weight less than tenth percentile for gestational age (%)

HEV and fetal anomalies. Clinicians reported small for gestational age infants more often in HEV cases than in controls. Infants with HEV in their placentas were significantly more likely than controls to fall below the 10th percentile in weight (based on a general population [ 31).

There are several potential sources of bias to consider when interpreting the results of this study. Clinicians voluntarily sent placentas of interest to them. Therefore, the registry is heavily weighted toward placentas with pathology, and it was no surprise that the stillbirth percentage in control placentas was far higher than that for all Michigan deliveries (though still far lower than the percentage in placentas with HEV). Was it possible that the clinicians could identify placentas with HEV by their gross appearance and preferentially send those associated with a stillbirth? This source of bias seems unlikely, since there was no difference between HEV cases and controls in the proportion of clinicians stating that they submitted the placenta because of its abnormal appearance (Table III). One pathologist looked at all specimens. This is a strength in consistency, but a weakPlacental

tissue registry

characteristics

Non-HEV

127/207(61) 29183 (35) 13/82 (16) 22/218(10) 18/218 (8) 62/l 89(33)

145/219(40) 106/231(46) 53/236(22.5) 30/395 (8) 17/395 (4) 61/323(19)

over the study

Percent

with HEV associated with stillborns (%) without HEV associated with stillborns (%) of submitted

placentas

Int J Gynaecol Obstet 22

found

to have HEV (%)

0.0005 0.10 0.30 0.40 0.05 0.00 1

years

1978 Placentas Placentas

P

controls

ness in confirmation of diagnosis. Initial examination of microscopic slides without knowledge of fetal outcome reduced bias. However, the fact that no final pathologic characterization was made until the pathologist had examined the clinical record may have produced bias in favor of the diagnosis of HEV in cases of stillbirth or other abnormal pregnancy outcome. Two findings suggest that this was not the case. First, there was consistency of the stillborn proportion between HEV cases and controls over the three study years, despite increasing attention to the lesion by the registry’s pathologist (Table V). Second, after the first study year the proportion of placentas found to have HEV in the registry stabilized at about 20%. Nonetheless, another study of this relationship in which placental pathology is diagnosed in the absence of clinical data is clearly needed. The way in which data were collected placed some limitations on the analysis. The clinical information form contained openended questions leading to incomplete data on many items. In addition there was no population base to which the registry placentas were referable. Therefore, questions such as the incidence and geographic distribution of HEV could not be addressed. The association of HEV with intrauterine

Discussion

Table V.

HEV cases

IS/35 (51) 49/246( 19.9) 35/281(12.4) _-

1979 57/109(52.3) 72/361(19.9) 109/470(‘3.2)

19x0 4OJXI (49.1) 6-t :3 14(20.1) RI ?95(70.5)

Placental

staining, meconium growth retardation, smaller placental size, and maternal hypertension would support a hypothesis that compromise of placental function is the mechanism of HEV effects. In the first publication of HEV, an association with infection with the TORCH group (rubella, syphilis, cytomegalovirous, herpes and toxoplasmosis) was suggested [ 51. Data in this study were insufficient to address this question. The association of chronic villitis with 6% of HEV cases suggests a possible common etiology. Russell has done a prospective analysis of 575 cases of chronic villitis drawn from examining 7507 consecutive singleton births over a Z-year period [4]. Compared to controls from their population the chronic villitis cases were farther along in gestation and were more likely to show intrauterine growth retardation. He found no difference in his study between cases with chronic villitis and controls with respect to any demographic features such as age or parity. In addition, he reported finding only twenty cases of TORCH group-related illness in his entire series. Of the 190 cases of chronic villitis in which he preformed serologies, none had titers suggestive of recent infection with TORCH agents. His data on chronic villitis is consistent with our data for HEV and suggests HEV may be a variant of chronic villitis. Prior to Russell’s study, chronic villitis was believed to be associated with much greater morbidity and mortality than he was able to show in a population based study. It is important that similar, more complete, data be collected on HEV. First, data collection in the registry needs to be stardardized to obtain more complete and relevant information.

hemorrhagic

endovasculitis

391

Second, a study examining all placentas in a defined population with complete prenatal and outcome data might be expected to yield more generalizable information. Third, a study is now underway to look at prenatal and hospital records for a group of HEV cases and controls from the present study to obtain more complete information on prenatal disease and outcome for mother and infant. In summary, despite the potential sources of bias, the increased association of HEV with stillbirth and intrauterine growth retardation is likely a real one. The strong association of HEV with chronic villitis and their mutual association with intrauterine growth retardation suggests placental compromise may be the mechanism of HEV effects. References Benirschke K: Examination of the placenta. Obstet Gynecol 28: 309, 1961. Brain MC, Dacic JV, Hourihane DO’B: Microangiopathic hemolytic anemias: the possible role of vascular lesions in pathogenesis. Br J Hematol8: 358, 1962. Lubchcnco LO, Searls DT, Brazic JV: Neonatal mortality rate: Relationship to birth weight and gestational age. J Pediatr 81: 814, 1972. Russell P: Inflammatory lesions of the human placenta. II. Villitis of unknown etiology in perspective. Am J Diag Gynecol Obstet I: 339, 1979. Sander CH: Hemorrhagic endovascuhtis and hemorrhagic villitis of the placenta. Arch Path01 Lab Med 104: 371. 1980. Address for reprints:

Nancy G. Stevens, M.D. Department of Family Medicine, University of Washington Seattle WA 98195, U.S.A.

RF-30