FETUS, PLACENTA, AND NEWBORN

The placental pathology of small-for-gestational age infants GEOFFREY PETER

ALTSHULER, RUSSELL,

RUFINO Cincinnati,

There (SGA).

M.B.B.S

M.B.B.S.

ERMOCILLA,

M.D.

Ohio

is a lack of placental In a gross and light

studies of newborn infants who are small for gestational microscopy evaluation of 63 referred placentas associated

age with

singleton SGA infants, abnormalities were found in 58. In many instances these were considered of causal significance. Abnormalities included ischemic lesions (43 per cent), often related to a history of pre-eclampsia. In this group of specimens, severe X-cell proliferation was present, possibly related to a mechanism of delay of the onset of labor. Approximately 25 per cent of the placentas showed villitis of unkown etiology. This is presumed to be of infectious etiology, probably viral. Sixteen per cent of the infants died.

N u M E R o u s clinical studies have been made of newborn infants who are small with respect to their gestational age.l-” Many terms exist, according to the views of the investigators, regarding the etiology and clinical condition of the infants: small for gestational age (SGA) , small for dates, intrauterine growth retardation, dysmaturity, low birth weight, pseudo-prematurity, fetal malnutrition, chronic fetal distress, placental dysfunction, placental insufFrom the Departments the Cincinnati Children’s Department of Pathology, Hospital, the University Center. Supported Pediatric Received Revised Accepted

in part

ficiency. Despite these many clinical studies, little investigation of the associated placentas has been carried out and only rarely has there been histologic as well as gross placental appraisal.5-‘, 3os31 There has been a lack of knowledge of the pathogenesis of disturbances of intrauterine growth. Because of our concern to show that placental pathology correlates with clinical problems of newborn infants we now present our experience of the placental abnormalities associated with this particular group of infants. We have chosen to use the term SGA, originally presented by Battaglia,s in description of those neonates whose birth weight is less than the tenth percentile with respect to their gestational age. We consider that it is additionally important to emphasize the high incidence of placental villitis of unknown etiology associated with SGA infants.g Previously we suggested that these characteristic inflammatory placental lesions are caused by nonbacterial infections, most likely vira1.l” The following study shows that the vast majority of

of Pediatrics and Pathology, Hospital, and the Cincinnati General of Cincinnati Medical

by the Fels Division

of

Research. for publication August August

July

8, 1974.

23, 1974. 30, 1974.

Reprint requests: Geoffrey Altshuler, M.B.B.S., Department of Pathology, Children’s Hospital Medical Center, Cincinnati, Ohio 45229.

351

352

Altshuler,

Table

Russell,

and

I. Populations

February I, 1975 Am. J. Obstet. Gynecol.

Ermocilla

Table IV. The

examined

I

No.

Primary

C.G.H. Black White

25 9

Referred (C.C.H. and other) Black White

1 28 z

Table II. Percentile

I

No.

< 3rd 3rd-10th

54 9 G

Table III. Gestational Age

(wk.)

I

37 and over

10 53

SGA infants are small probably because of pathologic processes and not because of inherited traits. and

of 63 SGA

diagnoses*

“circulatory

Placental infections: Villitis, unknown Villitis, cytomegalovirus Chorioamnionitis Abnormal placentation, umbilical artery

/

disturbances”+

excluding

anomalies (2 of which “normal”) “Normal” placentas

No.

/ Per

cent

27

43

15 2 1

24 3 1

5 3

8 5

7 3

11 5

single

are

63

100

*Primary diagnoses: Many placentas included more than one pathologic feature, in which situation the classification was made according to the lesions considered to significance. disturbances”

as classified

by Benirschke

NO.

G

Materials

Placental

be of primary t“Circulatory and DriscolLls

age of SGA infants

28-36

pathology

Placentas with single umbilical artery Placentas associated with congenital

status of SGA infants

Percentile

placental

infants

methods

All placentas obtained from the obstetric delivery rooms of the Cincinnati General Hospital are stored at 4’ C. for one week following delivery. The purpose of this storage is to provide neonatologists with the opportunity to request a gross and light microscopy placental examination relating to a perinatal death or infant who manifests serious disease in the first few days of life. Complete gross and light microscopy studies were performed on placentas associated with neonates hospitalized in the Cincinnati Children’s Hospital. This is a referral hospital with a large population of “at risk” neonates. Placentas received in consultation from other hospitals of the Greater Cincinnati Area were similarly examined. Thus between July, 1970, and February, 1974, exclusive of a 6 month period therein, a total of 2,200 placentas were assessed by a complete gross and light microscopy evaluation at the request of neonatologists. The method of placental examination was that of Benirschke.ll A comprehensive clinical history, with follow-up of the neonatal outcome of the patients was generally available. Several infants have been followed for 2 years. Of the

2,200 placentas, 63 were associated with singleton SGA infants, the study excluding instances of SGA associated with multiple birth. Table I summarizes the data of these infants according to the populations examined ; Table II, the percentile status; Table III, the gestational age. Results

Deaths. Nine of the 63 SGA infants died in the neonatal period and a tenth infant at 3 months of age. In two cases, included in a previous report, there were autopsy findings separately of disseminated intravascular coagulation and of hyaline membrane disease.lO The other deaths included a case each of trisomy 21 and trisomy 18, four cases each of multiple congenital anomalies of unknown cause, and, finally, an infant who died with intraventricular hemorrhage complicating hyaline membrane disease. In the remaining instance autopsy was not done and death was attributed to hyaline membrane disease and intraventricular hemorrhage. Placental abnormalities were present in all instances. In three placentas there was a focal villitis of unknown etiology. Two specimens had a single umbilical artery (SUA) and a sixth death was associated with a placenta which included ischemic changes and decidual arteriopathy, features which are typically seen in pre-eclampsia of pregnancy. Classification. Details of the placental pathology associated with the 63 cases of SGA infants are provided in Table IV. Table V briefly summarizes

Volume Number

Fig. and

121 3

Placental

1. Placenta. Focal proliferative eosin; original magnification

villitis. x200.)

-.

(Hematoxylin

.-

clinicopathologic

Circulatory

correlation

disturbances.

in small-for-gestational

age

infants

353

Fig. 3. Placenta. Focal villitis showing chronic inflammatory cell infiltration of the villi associated with vascular occlusive lesions. (Hematoxylin and eosin; original magnification x80.)

-

Fig. 2. Placenta. Focal reparative villitis. Note the developing stromal fibrosis in addition to the chronic infammatory cells. (Hematoxylin and eosin ; original magnification x180.) the

pathology

of

each

case.

This classification was applied to 27 of the 63 SGA infants’ placentas. The criteria for categorizing this group included increased nuclear knotting of the syncytiotrophoblast (“Tenney effect”), fibrin deposition within and between the villi with proliferation of X-cells, acute and old infarcts, decidual arteriopathy, and maternal floor infarction.12 In 18 of the 27 placentas the degree of X-cell proliferation was so severe as to occupy more than 10 per cent of the total area of placental tissue studied. This degree of X-cell proliferation appears to be severely pathologic, irrespective of gestation. Of the 27 specimens, 16 were associated with a clinical history of pre-eclampsia of pregnancy. It is of interest that, in relation to obliterative lesions of the stem and terminal fetal blood vessels, eight of the specimens which featured

Fig. 4. Placenta. Evanescent eosin; original magnification

villitis. x180.)

villitis of unknown etiology included and chronic placental ischemia.

(Hematoxylin

and

areas of acute

Villitis. Unknown etiology. Of the 63 specimens, 15 (24 per cent) included villitis whose etiology is not known. In 12 of the 15 cases, serologic and cluture studies failed to reveal any etiologic agent, specifically excluding cytomegalovirus (CMV), herpesvirus, rubella virus, toxoplasmosis, and syphilis. The lesions were focal in 14 instances, the features being as previously described. lo These lesions included severe infiltration by inflammatory cells. They were often necrotizing (Fig. 1) but, within the same specimen, were frequently of reparative or evanescent type (Figs. 2 to 4). In many of these specimens there was an endovasculitis within the vessels of the stem villi and the terminal villi. Often this was associated

354

Altshuler,

Table V.

and

Clinicopathologic Gest. (wk.)

No. C.G.H

Russell,

February 1, 197.5 Am. J. Obrtet. Gyneml.

Ermocilla

correlations

Birth

wt.

(Gm.)

Percentile wt.

Clinical

comments

Placental

findings

easer: 1

31

1,020

37 43 35 40 38 43 42 36

1,600 2,480 1,510 1,580 2,020 1,860 1,930 2,190

10

40

2,080

3

Black

11 12 13 14

39 37 39 35

2,100 1,620 2,200 1,740

3 3 3

15

40

2,470

16 17

40 37

2,220 2,150

18

39

2,000

3

White ; pre-eclampsia Black ; pre-eclampsia Black ; pre-eclampsia Black; cord IgM level 34 mg./lOO ml. Black; cord IgM 45 mg./ml., CMV in urine Black White; cord IgM level 34 mg./lOO ml.; CMV in urine White

19 20 ;:

39 40 38 36

2,030 1,680 2,110 1,800

3 3 3 3

Black White Black Black

23

38

2,030

3

24 25 26 27 28 29 30 31 32 33

39 42 38 36 40 41 39 40 41 38

1,545 2,230 2,160 1,780 2,435 2,440 2,160 2,480 2,500 1,700

3 3 3 3 3 3 3 3 3 3

34

35

1,530

3

White; cord IgM level 17 mg./lOO ml. Black Black; mother heroin addict Black Black Black Black Black ; pre-eclampsia White Black ; pre-eclampsia White ; maternal VDRL +; infant normal White

Referred 35 36 37 38

caseJ: 41 43 41 38

1,810 2,280 2,665 1,850

3 3

39 40

39 39

1,500 1,460

3 3

41

40

2,490

3

42 43

36 39

1,600 2,090

3 3

*Neonatal death. +A11 tabulated X-cell

3 3 3-10 3 3 3 3 3 3-10

3-10 3 3 3-10

3-10

percentages

3

Black*; multiple congenital anomalies Black Black Black White; pre-eclampsia Black ; jaundice Black ; pre-eclampsia Black : pre-eclampsia Black

White* White ; White; White; natal White; White ;

Down’s syndrome pre-eclampsia biopsy-proved neohepatitis pre-eclampsia maternal hypertension

White; multiple congenital anomalies, died at 3 mo. of age White; duodenal atresia White; pre-eclampsia relate

to the

area

of

placenta

SUA SUA, chronic ischemia Chronic ischemia, decidual arteriopathy Chronic ischemia, meconium stained Widespread infarction, X-cells 50%t Chronic ischemia Acute/chronic ischemia. fetal thrombi. X-cells 50% Confluent microinfarctsj X-cells 50% ’ Circummarginate membranes, moderate chronic &hernia Maternal floor infarction, chronic ischemia, X-cells 30% Acute/chronic ischemia, X-cells 40% Old infarcts, X-cells 5% Chronic &hernia, X-cells 10% No significant abnormality CMV

villitis

Maternal Hydropic

floor infarction, villitis of CMV

X-cells

5%

Circummarginate membranes, acute/chronic ischemia Chorioamnionitis with triple umbilical vasculitis SUA, succenturiate lobe No significant abnormality Chronic ischemia, circumvallate membranes, X-cells 10% Villitis of unknown etiology Villitis Diffuse Chronic Chronic Villitis Chronic Chronic Chronic Multiple Severe

of unknown etiology, chronic ischemia villitis, relative immaturity of villi ischemia ischemia of unknown etiology ischemia &hernia, widespread infarcts, X-cells ischemia, X-cells 15% chronic infarcts, X-cells 25% chronic ischemia, X-cells 30%

Circummarginate ischemia

membranes,

moderate

chronic

Severe chronic &hernia with infarcts, X-cells Chronic ischemia, X-cells 20% Moderate ischemia, X-cells 12% Villitis of unknown etiology, fetal thrombi, nucleated red blood cells in fetal vessels Villitis of unknown etiology, fetal thrombi Severe acute/chronic infarcts, circummarginate membranes No significant abnormality

Acute/chronic Widespread studied

in

infarcts chronic ischemia, which

X-cells

are

X-cells present.

10%

35 %

15%

Volume Number

121 3

Placental

pathology

in

small-for-gestational

age

infants

355

Table V-Cont’d Gest.

Birth wt. (Cm.)

Percentile wt.

NO.

(wk.)

Referred 44 45

cases: 41 42

2,240 2,480

46

37

1,520

3

47

40

2,400

3

48 49

38 40

1,840 1,900

3 3

50

39

2,025

3

White White* ; multiple congenital abnormalities White; cord IgM 43 mg./lOO ml., raised bilirubin for 1 wk. Black ; patent ductus arteriosus, ventricular septal defect White ; pre-eclampsia White: large head with wide sutures White : pre-eclampsia

51 52

37 39

1,450 1,910

3 3

White* White*

53 54

37 42

1,600 2,120

3 3

55

39

2,400

56

37

1,980

3

57 58 59 60

40 40 37 36

1,860 1,900 2,230 1,960

3 3

61 62

36 39

1,815 1,840

63

39

2,521

White ; pre-eclampsia White; maternal rubeola at 20 wk. gestation White* ; diaphragmatic hernia, cataracts, rubella 1 : 512, placenta, and autopsy, viral culture negative White ; recurrent reproductive failure, HA rubella titers 1:2048, 1:512, no virus cultured White White White*; trisomy 18 White”; RDS, consumption coagulopathy White* ; RDS, cataracts White; cord IgM level 30 mg./lOO ml. White ; jaundice, progressive head enlargement

*Neonatal death. $A11 tabulated X-cell

3 3-10

3-10

3-10 3 3 3 3-10

percentages

Clinical

relate

comments

; pre-eclampsia

to

the

area

with endovascular sclerosis and fetal thrombi. In these areas avascular villi or infarcts were present. In four of the instances of focal villitis of unknown etiology, clinical and pathologic study suggested chronic intrauterine infection (Table V, cases 46, 56, 61, and 63). In the fifteenth placenta the villitis was diffuse, with widespread stromal hypercellularity, relative immaturity of the villi, and abundant nucleated red blood cells and erythroblasts in the fetal blood vessels (Fig. 5). This placenta was associated with an 1,850 gram boy, of 38 weeks’ gestation, whose clinical features within the first week of life suggested neonatal hepatitis. A liver biopsy at 4 weeks of age showed neonatal hepatitis and cirrhosis. The infant was tested for Australia antigenemia and elevation of serum IgM; neither was present.

Placental

of placenta

No significant

Villitis No

abnormality

of unknown

significant

Extensive Extensive

fzndings SUA

etiology,

chronic

ischemia

abnormality

chronic ischemia, acute ischemia

infarction

Meconium stained, severe acute ischemia, X-cells 5% Severe acute/chronic infarcts, X-cells 15% Meconium stained, almost totally infarcted, X-cells 50%) Severe ischemia, decidual arteriopathy, SUA Cord 10 cm. long, extensive fetal thrombi, X-cells 50% Villitis of unknown etiology

Villitis of unknown thrombi, C-type

etiology, widespread fetal viral particles in trophoblast

Villitis Villitis SUA Villitis

of unknown of unknown

etiology etiology,

of unknown

etiology

Villitis Villitis

of unknown of unknown

etiology etiology

Villitis

of unknown

etiology

studied

in

which

X-cells

mild

are

chronic

ischemia

present.

CMI,’ placentitis. In tvro specimens there were typical features of CMV placentitis. The appearances were similar to those previously described.l”

Abnormal placentation, excluding single umbilical artery. Five specimens were classified in this category. Circummarginate placentation was present in four and the fifth featured an umbilical cord that was more than 100 cm. long. In this specimen an extensive dissemination of thrombotic lesions in the fetal blood vessels was associated with severe acute and chronic infarcts and severe X-cell proliferation. Variable degrees of ischemic change were also present in the other placentas of this group.

Placentas with single umbililcal artery. Five of 63 placentas

had a single umbilical

artery.

Of these,

356

Altshuler,

Russell,

and

Ermocilla

Fig. 5. Placenta. The villi feature “relative immaturity,” a pathologic state characterized by a lack of syncytiotrophoblast, an excessive persistence of cytotrophoblast and stromal hypercellularity. (Hematoxylin and eosin; original magnification x180.) two were separately associated with trisomy 18 and multiple congenital anomalies and are therefore classified with this latter group. There were three neonatal deaths associated with this group, one being attributable to anomalies of trisomy 18 and another to multiple anomalies of unknown cause. In the third instance no autopsy was available. In the other two instances the placentas were ischemic but there were no other relevant clinicopathologic data.

Placentas associated with congenital anomalies. Seven placentas were categorized in this group of primary diagnoses. Five of them had varying degrees of gross and microscopic abnormality classifiable as a secondary diagnosis to those “primary” pathologic groups already outlined. Two of the seven showed no significant abnormality. The associated congenital anomalies included duodenal atresia, imperforate anus, tracheoesophageal fistula, congenital heart disease, trisomy 21, trisomy 18, and renal agenesis. Comment Despite many diagnostic terms, knowledge of the pathogenesis of the entity of the SGA infant is limited. From clinical studies, Scott and Usher have stated that the “small fetus for gestation is nutritionally, not gestationally, produced.“l” Warkany, Monroe, and SutherlandI gave much less emphasis to the role of nutritional factors but rather emphasized genetic, infectious, chemical, and actinic factors. They stated that there is “little proof of a causal relationship, in the majority of cases, between placental anomalies and intrauterine growth re-

tardation,” but admitted, however, that in theix own series of cases there was a lack of available placental examinations. They stated that ‘Yn some instances, the placental changes probably accompany those of the fetus and are the result of the same adverse factors which bring about the intrauterine growth retardation.” Recently Gruenwald16 has made similar suggestions. Gruenwald,5g 6 more so than any other investigator, has provided comprehensive studies of the placental pathology of SGA infants. His observations of the significance of avascular placenta villi to retardation of fetal growth6 were confirmed by other investigators73 I7 in addition to those of the present study. It is of interest that Gruenwald”, 6 observed chronic inflammatory infiltrates in placentas of SGA infants, but chose not to interpret their significance. Gershon and Strauss’ were particularly concerned with these infiltrates but did not pursue their meaning. The opinion of Benirschke--that these lesions were morphologically indistinguishable from rubella placentitis-led us to pursue the possibility that SGA infants often are born as a consequence of viral infection. Indeed Blanc,l’ commenting on the occurrence of “avascular villi” in known viral placental infections, had suggested that these lesions could be a cause of fetal growth retardation in addition to the effect of concomitant viral sepsis. In the present study 17 of 63 specimens (27 per cent) feature placental villitis, for which reason it is our belief that placental infection is of important significance to the pathogenesis of SGA infants. While in only two instances was a specific infectious agent proven (CMV), there is evidence that the villitis is in fact due to chronic intrauterine infection. We have accumulated over 60 cases, including those presently reported, whose placentas feature villitis of unknown etiology. In all cases, reports have been issued that the lesions are indistinguishable from rubella placentitis and are therefore probably of viral cause. In none of these instances has clinical follow-up provided a diagnosis of rubella, CMV infection, herpesvirus infection, toxoplasmosis, or syphilis. Observations of disease in the associated infants, however, confirm the possibility of infectious cause. These observations include hydrocephalus, myelomeningocele, hepatitis, cataracts, and congenital heart disease. It is emphasized that in many instances where smallness for gestational age has been considered to be associated with

Volume 121 Number

3

placental infarcts, there has been a striking difference in histologic appearances from those seen in placentas with villitis. The acute infarctive lesions occasionally attract slight acute inflammatory cells at their margins but never include severe intrinsic inflammatory cell infiltrates as seen in villitis. Kecently, by ultrastructural study, Vernon, McMahon, and Hackett’” have shown C-type viral particles beneath the syncytiotrophoblast in one of our specimens of placental villitis. The significance of this is uncertain since Vernon and associatesls have seen these viral particles in normal placentas of normal infants. The highest percentage of abnormalities in our SGA study occurred in relation to placental circulatory disturbances (40 per cent). In 16 of our 25 specimens thus categorized there was a clinical history of pre-eclampsia of pregnancy. In these placentas we observed that X-cell proliferation was most marked in those instances where the pregnancy had progressed to term or beyond. Although X-cells are fetal in originl” they are nonproductive of chorionic gonadotropin or human placental lactogen.?” It is known that prostaglandins are poorly metabolized in placentas which have advanced and widespread ischemic change”l and Russell has stated in personal communication that from biochemical studies he has found that this placental tissue contains low concentrations of polyunsaturated fatty acids. This is of interest because of the ultrastructural observation that many of these X-cells have lipid-laden lysosomes with a crystalline substructure. These latter features (Figs. 6 and 7) suggest functional change rather than cell degeneration. The significance of X-cell proliferation is unknown.” Since we have observed severe X-cell proliferation only in the placentas of pre-eclamptic women whose pregnancy continues toward or beyond term, we have speculated upon two possibilities. Either X-cell proliferation represents a nonspecific progression throughout pregnancy or, because of the aforementioned ultrastructural and biochemical observations, it represents an effect wherein X-cell function is associated with a mechanism of delay of the onset of labor. Within our classification of placental diagnoses associated with SGA infants, seven specimens were coded as being associated with congenital anomalies and three additional placentas were tabulated as being normal (Table IV). Within these 10 placentas gross or microscopic abnormalities were present in five instances, even though these lesions

Placental

pathology

in small-for-gestational

age

infants

357

Fig. 6. Placenta. X-ceil

showing portion of intact nucleus, abundant ergastoplasm (rough endoplasmic reticulum), large Golgi complex (C), numerous cytoplasmic filaments, and large lysosomes (L). Mitochondria (M) show highamplitude swelling in this particular cell. The ergastoplasm (ER) contains a large amount of proteinaceous materia1, suggesting synthesis for secretion. (Original magnification xl 8,500.)

may have been coincidental and of no significance in the causation of the infants’ SGA status. Kecognixing this, however, it remains that 58 of 63 specimicroscopic placental mens had gross and/or lesions. In the majority of these instances the placental lesions were considered to be the primary cause of the infant’s SGA status and the remainder to be noncausal correlates or markers of common pathologic processes in both the infant and placenta. While it is recognized that placentas may be small or have other gross abnormalities because of genetic reasons, it seems unwise to ignore the significance of 16 clinical instances of pre-eclampsia of pregnancy and the asserted significance of 17 instances of placental villitis. Our experience of this latter lesion has been that the severity of the villitis does not correlate with the degree of clinical illness in the associated infant.l” In one placenta with chorio-

358

Altshuler,

Russell,

and

Ermocilla

February Am.

J. Obstet.

1, 1975 Gynecol.

Fig. 7. Same as Fig. 6. Higher magnification of the lysosomes. The contents appear to be lipid in nature. The crystalline substructure is most unusual. The lattice spacing is about 60 A. (Original magnification x96,500.) amnionitis this finding was almost certainly a correlate, rather than a cause, of the infant’s being SGA. In addition to the already mentioned studies of Gruenwald5s 6 and of Gershon and Strauss,’ there have been several other studies which have provided knowledge of the pathogenesis of infants who are SGA.“2-30 We consider, however, that the study of Laga, Driscoll, and Munro30 is of particular importance. This was a meticulous morphometric comparison of 18 placentas of a middle-class Boston population and 20 of a Guatemalan population of low socioeconomic status. Although primarily concerned with effects of nutrition upon placental structure, Driscoll emphasized in that study that villous placental inflammation was both more frequent and more severe in the Guatemalan specimens, 20 per cent of which were considered to have lesions suggestive of chronic infection. It is of interest that many SGA infants and their hazards have been shown to relate to race and socioeconomic status31 In the present study we did not feel able to assess this relationship reliably. In depth considerations of nutrition,32 immuno-

logic phenomena,33 chromosome function,34 biochemical aspects,35 and geographical36 considerations have been provided but, until there is more investigation of the placental pathology of SGA infants, it is unlikely that there will be complete clarification of pathogenesis. Addendum Since the preparation of this manuscript we were fortunate to read the Doctoral Thesis of Bengt Sandstedt, Karolinska Institutet, Stockholm 60, Sweden, 1974. This is a most comprehensive study of the placental pathology of the low-birth-weight infant, including clinicopathological correlations and light, electron, and scanning electron microscopy. Max Menefee, M.D., Ph.D., provided the ultrastructural studies of the placental X-cell (Figs. 6 and 7). Virologic studies referred to in the text were separately provided by the laboratories of Gilbert Schiff, M.D., Division of Infectious Diseases, University of Cincinnati Medical Center, and of John L. Sever, M.D., Infectious Diseases Branch, National Institute for Neurological Diseases and Stroke.

Volume 121 Number 3

REFERENCES

1.

Ounsted, M., and Ounsted, C.: In On Fetal Growth Rate, Philadelphia, 1973, William Heinemann Medical Books. 2. Andrews, B. F., editor: Pediatr. Clin. North Am. 17: 1, 1970. F., editor: Human Development, Philadel3. Falkner, phia, 1966, W. B. Saunders Company, p. 644. 4. Van den Berg, B. J., and Yerushalmy, J.: J. PEDIATR. 69: 531, 1966. 5. Gruenwald, P.: Biol. Neonate 5: 215, 1963. 6. Gruenwald, P.: N. Y. State J. Med. 61: 1508, 1961. R., and Strauss, L.: Am. J. Dis. Child. 102: 7. Gershon, 645, 1961. 8. Battaglia, F.: AM. J. OBSTET. GYNECOL. 106: 1103, 1970. 9. Benirschke, K., and Altshuler, G.: In Symposium on the Functional Physiopathology of the Fetus and Neonate. St. Louis, 1971, The C. V. Mosby Company, pp. 158-168. 10. Altshuler, G.: J. Reprod. Med. 11: 215, 1973. 11. Benirschke, K.: 0bstet. Gynecol. 18: 309, 1961. 12. Benirschke, K., and Driscoll, S.: In The Pathology of the Human Placenta, New York, 1967, SpringerVerlag, pp. 216-234. 13. Altshuler, G., and McAdams, AM. J. OBSTET. GYNECOL. 111: 295, 1971. R.: AM. J. OBSTET. GYNE14. Scott, K. E., and Usher, COL. 94: 951. 1966. 15. Warkany, J., Monroe, B. B., and Sutherland, B. S.: Am. J. Dis. Child. 102: 249, 1961. 16. Gruenwald, P. : i\bstract presented, Pediatric Pathology Club, March 11, 1972, p. 31. 17. Blanc, W.: In The Future of Antepartum Morphologic Studies in Diagnosis and Treatment of Fetal

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Disorders, New York, 1969, Springer-Verlag, p. 34. Vernon, M. L., McMahon, J. M., and Hackett, J. J.: J. Natl. Cancer Inst. 52: 987, 1974. G.: AM. J. OBSTET. 19. Ermocilla, R., and Altshuler, GYNECOL. 117: 1137, 1973. 20. Kim, C. K., Naftolin, F., and Benirschke, K.: Anr. J. OBSTET. GYNECOL. 111: 672, 1971. 21. Alan, N. A., Clary, P., and Russell, P. ‘I’.: Pmstaglandins 4: 363, 1973. D. R.: Pediatr. Clin. North Am. 17: 25, 22. Shanklin, 1970. 23. Aherne, W., and Dunnill, M. S.: Br. Med. Bull. 22: 5, 1966. 24. Wigglesworth, J. S.: J. Obstet. Gynaecol. Br. Commonw. 71: 871, 1964. 25. Naeye, R. L.: Arch. Pathol. 79: 284, 1965. 26. De Sa, D. J.: Arch. Dis. Child. 46: 495, 1971. 27. Tremhlay, P. C., Sybulski, S., and Maughan, G. B.: AM.J.OBSTET.GYNECOL. 91:597,1965. 28. Younoszai, M. K., and Haworth, J. C.: AM. J. OBSTET. GYNECOL. 103:265, 1969. 29. Busch, W.: Arch. Gynaek. 216: 167, 1974. 30. Laga, E. M., Driscoll, S. G., and Munro, H. N.: Pediatrics 50: 24, 1972. R. L., Diener, M. D., Harcke, H. I., Jr., and 3 1 . Naeye, Blanc, W. A.: Pediatr. Res. 5: 17, 1971. 32. Winick, M.: Clin. 0bstet. Gynecol. 13: 526, 1970. 33. Warburton, D., and Naylor, A. F.: Am. J. Hum. Genet. 23: 41, 1971. A. T. I,., Chan, Y.-K., and Falek, A.: Hum. 34. Chen, Hered. 21: 543, 1971. 3 5 Rosado, .4., Bernal, A., Sosa, A., Morales, M., Urrusti, J., Yoshida, P., Frrnk, S., Velasco, L., Yoshida, T., and Metcoff, J.: Pediatrics 50: 568, 1972. H., and Arias-Stella, J.: AM. J. OBSTET. 36. Kruger, GYNECOL. 106: 586, 1970. 18.

The placental pathology of small-for-gestational age infants.

There is a lack of placental studies of newborn infants who are small for gestational age (SGA). In a gross and light micorscopy evaluation of 63 refe...
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