Very Low Birthweight Infant’s Placentaand Its Relation to Pregnancy and FetalCharacteristics
ANNE R. HANSEN,1* MARGARET H. COLLINS,2 DAVID GENEST,3 DEBRA HELLER,4
SUSAN SCHWARZ,5 PETRA BANAGON,6 ELIZABETH N. ALLRED,7 AND ALAN LEVITON7
1Division of Newborn Medicine, Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA2Department of Pathology, Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard,Philadelphia, PA 19104, USA3Department of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA4Department of Pathology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, 185South Orange Avenue, Newark, NJ 07103, USA5Department of Pathology, St. Peter’s Medical Center, 254 Easton Avenue, New Brunswick, NJ 08903, USA6St. Luke’s Medical Center, 421 West 113th Street, New York, NY 10025, USA7Neuroepidemiology Unit, Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA
Received June 2, 1999; accepted September 21, 1999.
ABSTRACTOur objective was to relate pathology of the very lowbirthweight (VLBW) infant’s placenta to pregnancy andfetal characteristics. We correlated the pathologic fea-tures of 1146 placentas from infants with birth weightsof 500–1500 g who were born between 1/1/91 and 12/31/93 to the number of gestations per pregnancy, initia-tor of preterm delivery, gestational age, birth weight Zscore, and duration of rupture of membrane (ROM).Placental correlates of acute inflammation and villousedema were associated with preterm labor (PTL), pre-labor premature rupture of membranes (PROM), lowergestational age, and higher birth weight Z score. In PTLpregnancies delivered within 1 h of membrane rupture,61% of placentas already had membrane inflammation.Placental correlates of pregnancy-induced hypertension(PIH) were seen more commonly with PIH pregnancies,older gestational age, and lower birth weight Z score. We
found a more prominent histopathologic signature forsingleton than for multiple gestation placentas. The pla-cental pathologic findings associated with the clinicaldiagnoses of infection, PIH, and low–birth weight Zscores in our VLBW/preterm population are similar tothose in the literature regarding term pregnancies. Thepresence of multiple histologic findings consistent withinflammation in placentas of PTL pregnancies with du-ration of ROM lasting ,1 h suggests that some cases ofPTL are precipitated by a more long-standing infectionthan that previously suspected. Morphologic placentalfeatures appear to be correlates of the phenomena lead-ing to premature delivery. Examination of the VLBWinfant’s placenta provides insight into the etiology andmanagement of VLBW/preterm deliveries.
Key words: placenta, preterm, very low birth weight
INTRODUCTIONAlthough there is considerable understanding ofthe relationship between placenta histology and*Corresponding author
Pediatric and Developmental Pathology 3, 419–430, 2000
the characteristics of the term pregnancy and fetus[1–3], focus on the low–birth weight or pretermplacenta has been more limited [4–11]. Informa-tion that could be derived from such a readilyavailable tissue as the placenta would be valuableif it could improve our understanding and manage-ment of preterm delivery. This becomes increas-ingly important as the gestational age of viabilitycontinues to decline.
Our study of 1146 placentas from pregnanciesthat resulted in the live birth of a very lowbirthweight (VLBW) infant provides an opportunityto relate placenta histology to pregnancy and fetalcharacteristics in what may be the largest publishedsample of VLBW infants’ placentas. In this report, weexplore the relationships of placental pathologic fea-tures to the number of gestations per pregnancy,initiator of premature delivery (i.e., preterm labor[PTL], premature rupture of membranes [PROM],and pregnancy-induced hypertension [PIH]/pre-eclampsia), gestational age, birth weight Z score, andduration of rupture of membranes (ROM).
METHODSSampleThe sample for this study consisted of all pregnan-cies in which a live-born infant with a birth weightof 500–1500 g was delivered between January 1,1991 and December 31, 1993 at one of five univer-sity-affiliated hospitals. At four of the five institu-tions, physicians are routinely requested to submitthe placenta of every baby who weighs ,1500 g tothe pathologist for examination.
Collection and preparation of tissuePlacentas were refrigerated at 6°C prior to patho-logic examination in the fresh (unfixed) state. Theywere examined within 24 h on weekdays and 72 hon weekends. Gross characteristics assessed in-cluded placental weight, umbilical insertion (nor-mal versus marginal or membranous), and appear-ance of the membranes (clear versus opaque).Samples obtained for histologic examination in-cluded cross sections of the umbilical cord thatwere taken from both the placental and fetal ends,a full-thickness section (i.e., from fetal surface todecidual floor) of placental lobule taken near thecord insertion, a full-thickness placental sectiontaken half-way between cord insertion and margin,
and a membrane roll with the marginal placenta.Tissue was fixed in 10% neutral buffered formalin,routinely processed, and embedded in paraffin,and histologic sections were stained with hematox-ylin and eosin.
Histologic interpretationTo ensure uniformity of slide interpretation, wecreated a manual that defined morphologic char-acteristics based on those of others [12] and astructured data collection form. Membrane in-flammation was defined as polymorphonuclearleukocytes in the subchorion, chorion, or amnion.Fetal vasculitis was defined as polymorphonuclearleukocytes in the vessel wall of the chorionic plateor umbilical vessels. Old infarct was characterizedas loss of intervillus space with extensive loss ofhematoxylin stain. Maternal decidual arteriolarpathology (MDAP) referred to increased thicknessof vessel walls in the membrane roll, atherosis, orthrombosis of the spiral arterioles underlying theplacenta or membranes.
Data about pregnancy and fetusLabor was defined as the onset of contractions thatled to delivery. PTL was considered the initiator ofdelivery if labor began while membranes were in-tact. The initiator was considered to be PROM ifthe mother, obstetrician, or nurse acknowledgedthat before the onset of contractions, the mem-branes ruptured or vaginal fluid was fern and/ornitrazine positive. Hypertensive disorders wereconsidered to be the initiator if the obstetricianexpedited the delivery because of progressively se-vere PIH or preeclampsia. Because of the smallresidual sample size, all other reasons for prema-ture delivery were grouped under the rubric of“other.” Included under this heading were obste-trician-diagnosed placental separation, fetal dis-tress, and progressive fetal growth retardation.
The gestational-age estimate was based onthe following hierarchy: fetal ultrasound scan esti-mate obtained before the 13th week of gestation(30%), dates in the prenatal record (68%), and,when no other information was available, the ges-tational age recorded in the log of the neonatalintensive care unit (2%). The birth weight Z scoreis the number of standard deviations the infant’sbirth weight is above or below the median birth
420 A.R. HANSEN ET AL.
weight of infants of the same gestational age in astandard data set [13].
Data analysisThe following specific null hypotheses were evalu-ated:
1. The incidence of each morphologic placentacharacteristic does not vary between singletonand multifetal gestations.
2. The incidence of each morphologic placentacharacteristic does not vary with gestationalage, even within strata defined by initiator ofpreterm delivery.
3. The incidence of each morphologic placentacharacteristic does not vary with birth weight Zscore in all pregnancies, and when attention isconfined to infants delivered because of PIH.
4. The incidence of each morphologic placentacharacteristic does not vary with prematuritysubtype (e.g., PTL, PROM, PIH) in all pregnan-cies and when attention is confined to infantsdelivered within 1 h of membrane rupture.
Probability values for differences betweengroups were calculated. Emphasis was placed onidentification of consistent patterns within differ-ent subgroups. Because of the descriptive nature ofthis study, we elected not to make an adjustmentfor multiple comparisons [14].
RESULTSThe placental submission rate was 71%. Of the1146 placentas examined, the gestational age atbirth was ,26 weeks for 20%, 26–28 weeks for35%, and .28 weeks for 44% of the infants, with arange of 22–37 weeks and a median of 28 weeks.The median gestational age at birth was 28 weeks.The initiator of preterm delivery was PTL for 41%,PROM for 32%, and PIH/preeclampsia for 20% ofthe infants. Eight hundred and nineteen placentaswere from singleton pregnancies and 327 werefrom twin (n 5 254), triplet (n 5 68), and quin-tuplet (n 5 5) pregnancies, hereafter referred to asmultiple-gestation pregnancies.
Forty-eight percent of placentas had one ormore finding commonly associated with acute in-flammation (membrane inflammation, fetal vasculi-tis, or amnion epithelial necrosis). Of the placentaswith pathologic evidence of acute inflammation, 38%
of the mothers had a fever .101.4°F, 57% had re-ceived antenatal antibiotics, and 22% had a whiteblood cell count (WBC) .20K. This compared to16%, 24%, and 17%, respectively, of mothers whoseplacentas showed no features of acute inflammation.Seventy-five percent of the placentas of infants deliv-ered because of severe PIH/preeclampsia had at leastone morphologic feature that is commonly associ-ated with this clinical diagnosis (old infarcts in-creased syncytial knots, MDAP). This compared to26% of placentas of infants delivered prematurely forreasons other than PIH/preeclampsia. The mostcommon findings were old infarcts, increased syncy-tial knots, and increased thickness of walls of vesselsin the membrane roll, which occurred at least twiceas commonly as among infants born after PTL orPROM.
As expected, there was a strong correlationbetween Caesarean delivery and short duration oflabor and membrane rupture. Among the 682 Ce-sarean deliveries, 58% had ,1 h duration of mem-brane rupture and 43% had no labor.
A birth weight Z score of ,22 means that thebirth weight is .2 standard deviations below themedian for that gestational age. By definition, inthe general population, 2.5% of newborns are inthis group. Because our sample was determined bybirth weight rather than gestational age, with theupper weight limit of 1500 g being the median fora 31 to 32-week-gestation infant, it is not surpris-ing that 31% of the infants born after 28 weeks,thus eligible for inclusion in this sample, weregrowth retarded (i.e., had birth weight Z scores of,22). Growth-retarded infants accounted for ,7%of infants born to women who presented with PTLor PROM, but .36% of infants born to womenwith severe PIH/preeclampsia. Thus, in our sam-ple, birth weight Z scores are not distributed nor-mally and growth-retarded infants are overrepre-sented among the gestationally oldest infants andamong those born to preeclamptic women.
Sample characteristicsBabies of younger gestational age tended to be deliv-ered secondary to PTL or PROM, compared withbabies of older gestational age, who tended to bedelivered prematurely secondary to PIH (Table 1).Infants delivered because of maternal PIH tended tohave lower birth weight Z scores, were more likely to
VLBW INFANT’S PLACENTA 421
be singletons, and be delivered abdominally andwithin 1 h of membrane rupture compared withthose delivered following PTL or PROM. Multigesta-tion pregnancies tended to be delivered at a slightlyolder gestational age than singleton pregnancies.There was no remarkable or consistent pattern in thecomparison of multiple with singleton gestationpregnancies with regard to birth weight Z score orindicator of preterm delivery.
Initiators of preterm deliveryWe eliminated from presentation and discussionthose histologic lesions that occurred too infre-quently to analyze. Consistently throughout all of thesubanalyses, placental correlates of acute inflamma-tion (membrane opacification, membrane inflamma-tion, fetal vasculitis, and amnion epithelial necrosis)as well as villous edema were associated with PTLand PROM and were seen rarely in placentas of preg-nancies delivered because of PIH. Preterm delivery
secondary to PROM was associated with a slightlyhigher rate of placental correlates of infection thanpreterm delivery secondary to PTL. Placental corre-lates of PIH (old infarct, increased syncytial knots,and MDAP) were seen more commonly in pregnan-cies delivered because of PIH, but were seen in up to14% of placentas from pregnancies delivered prema-turely secondary to PTL and PROM. Marginal ormembranous insertion, intervillous thrombi, and vil-lous edema were seen relatively commonly in allplacentas, with a slightly increased incidence of mar-ginal or membranous insertion and intervillousthrombi in PIH pregnancies, and villous edema inPTL and PROM pregnancies. Chronic villitis wasmore strongly associated with pregnancies compli-cated by PIH than by PTL or PROM. The remainderof the placental findings were fairly rare, and did notfollow a consistent pattern regarding initiator of pre-term labor (Tables 2–5, especially Table 5, first 3columns).
Table 1. Sample characteristicsa
Gestational ageInitiator ofpreterm delivery Number of fetuses
PIH, pregnancy-induced hypertension; PROM, premature rupture of membranes; PTL, preterm labor; ROM, rupture of membranes.aMeasurements are percent of infants with the characteristics listed in each column who had the characteristic listed on the left.
422 A.R. HANSEN ET AL.
Placental pathology versus gestations perpregnancyTo determine if placentas from singleton- and mul-tiple-gestation pregnancies were similar enough tocombine them for the remainder of the analyses, wecompared these two groups (Table 2). In general, wefound a more prominent histopathologic signaturefor single than for multiple placentas. Among allprematurity subtypes, correlates of acute inflamma-tion, including membrane opacification, membraneinflammation, fetal vasculitis, and amnion epithelialnecrosis, occurred considerably more frequently inthe placentas of singleton pregnancies than in theplacentas of multifetal gestations. Even among thosedelivered vaginally following PTL, singletons hadmore pathologic findings consistent with acute in-flammation than did multiple gestations (data notshown). When we compared the placentas of pre-senting fetuses with those of nonpresenting fetusesin multifetal gestation, the placenta of the presentingfetus was more likely to show morphologic evidenceof acute inflammation, but not PIH or “other” fea-tures listed in Table 2. Histologic correlates of PIH,including old infarcts, increased syncytial knots, andMDAP occurred more commonly in singleton pla-centas than in those of multifetal gestations. AmongPTL and PROM pregnancies in this subsample, mar-ginal and membranous insertion occurred some-what more commonly in singleton placentas than inthe placentas of multifetal gestations. In light of all ofthese differences, we considered it inappropriate tocombine multifetal and singleton pregnancies anddecided to limit the remainder of the analyses toplacentas from singleton pregnancies.
Placental pathology versus gestational ageThe lower the gestational age, the higher the inci-dence of membrane opacification, membrane in-flammation, fetal vasculitis, amnion epithelial ne-crosis, and villous edema (Table 3). On the otherhand, the higher the gestational age, the higher theincidence of old infarcts, increased syncytial knots,MDAP, marginal or membranous insertion, inter-villous thrombi, and placental abruption. When welimited attention to the 572 placentas from infantswho were delivered because of either PTL orPROM, these gestational age trends are attenuated,most prominently for fetal vasculitis and MDAP.The prevalence of villous edema declined with in-
creasing gestational age. The finding of placentalpathologic correlates of infection in pregnanciesdelivered prematurely because of PIH is quite highat ,26 weeks gestation, and then decreases dra-matically after 26 weeks.
Placental pathology versus birthweight ZscoreThe higher the birth weight Z score (i.e., notgrowth restricted), the higher the incidence ofmembrane opacification, membrane inflamma-tion, fetal vasculitis, amnion epithelial necrosis,and villous edema (Table 4). The placentas of in-fants with prominent growth restriction tended tohave old infarcts, increased syncytial knots, MDAP,marginal or membranous insertion, intervillousthrombi, abruption, villous fibrosis, chronic villi-tis, and increased nucleated red blood cells. Evenamong infants born to women with PIH, thosewith the lowest–birth weight Z scores were morelikely than their heavier gestational-age peers tohave had placentas with MDAP, a marginal ormembranous insertion, abruption, villous fibrosis,and increased nucleated red blood cells.
Placental pathology versus duration ofmembrane ruptureBecause of the pivotal role of ascending infectionin premature delivery, we subdivided the sampleinto those deliveries that occurred within 1 h ofmembrane rupture and those that occurred aftermore than 1 h of membrane rupture (Table 5); weexpected that the role of ascending infection wouldbe minimized in those pregnancies deliveredwithin 1 h of membrane rupture. We evaluated therelationships between initiator of preterm deliveryand placenta morphology in the entire sample ofsingletons, and then compared the two sub-samples. PROM placentas from pregnancies deliv-ered ,1 h after membrane rupture are not in-cluded in Table 5 because, as expected, very few(seven) infants were born within 1 h of pre-laborPROM. Placentas from pregnancies with a shortduration of membrane rupture had a low inci-dence of pathologic findings consistent with acuteinflammation. However, it is striking that amongplacentas of PTL pregnancies delivered within 1 hof membrane rupture, 61% had membrane inflam-mation and 36% had fetal vasculitis. Placentas of
VLBW INFANT’S PLACENTA 423
Tab
le2.
Init
iato
ro
fp
rete
rmd
eliv
ery
stra
tifi
edb
yge
stat
ion
and
pre
gnan
cya
All
PT
LP
RO
MP
IHM
ult
iple
Sin
gle
Mu
ltip
leS
ingl
eM
ult
iple
Sin
gle
Mu
ltip
leS
ingl
eM
ult
iple
Pre
sen
tin
gN
on
pre
sen
tin
g
Acu
tein
flam
mat
ion
grou
p
Op
acifi
cati
onof
mem
bra
ne
2610
3111
3612
60
147
An
ym
emb
ran
ein
flam
mat
ion
5331
6833
7940
49
3827
Su
bch
orio
nit
is7
812
108
111
06
10
Ch
orio
nit
is8
612
711
81
310
4
Ch
orio
amn
ion
itis
3717
4417
6022
35
2213
An
yfe
tal
vasc
uli
tis
4016
4514
6528
33
2610
Um
bil
ical
vasc
uli
tis
3414
3611
5825
23
229
Ch
orio
nic
vasc
uli
tis
2711
359
4221
20
187
Am
nio
nep
ith
elia
ln
ecro
sis
199
277
2817
10
1316
PIH
grou
p
Old
infa
rct
174
64
52
495
54
Incr
ease
dsy
ncy
tial
knot
s24
1614
1410
1459
2614
18
MD
AP
256
145
137
5911
38
Oth
er
Mar
gin
al/m
emb
ran
ous
inse
rtio
n20
2816
2718
3326
1627
30
Inte
rvil
lou
sth
rom
bi
97
68
73
148
96
Pla
cen
tal
abru
pti
on6
27
24
39
04
1
Vil
lou
sfi
bro
sis
66
55
57
88
66
Ch
ron
icvi
llit
is5
11
13
19
31
2
Vil
lou
sed
ema
2721
3724
2721
1013
1922
Incr
ease
dn
ucl
eate
dR
BC
s6
13
14
011
51
2
N81
932
729
517
827
792
188
3812
519
6
MD
AP
,mat
ern
ald
ecid
ual
arte
riol
arp
ath
olog
y;M
ult
iple
,mu
ltip
le-g
esta
tion
pre
gnan
cy;P
IH,p
regn
ancy
-in
du
ced
hyp
erte
nsi
on;P
RO
M,p
rem
atu
reru
ptu
reof
mem
bra
nes
;PT
L,p
rete
rmla
bor
;RB
Cs,
red
blo
odce
lls;
Sin
gle,
sin
gle-
gest
atio
np
regn
ancy
.aM
easu
rem
ents
are
the
per
cen
tof
infa
nts
wit
hth
ech
arac
teri
stic
sli
sted
inea
chco
lum
nw
hos
ep
lace
nta
had
the
char
acte
rist
icli
sted
onth
ele
ft.N
um
ber
sin
bol
dfa
cein
the
“All
”co
lum
ns
dif
fer
from
each
oth
erto
ad
egre
eu
nli
kely
tob
ed
ue
toch
ance
(p,
0.0
5).
424 A.R. HANSEN ET AL.
Tab
le3.
Init
iato
ro
fp
rete
rmd
eliv
ery
stra
tifi
edb
yge
stat
ion
alag
ea
All
PT
LP
RO
MP
IH
<26
wee
ks
26–2
8w
eek
s>
28w
eek
s<
26w
eek
s26
–28
wee
ks
>28
wee
ks
<26
wee
ks
26–2
8w
eek
s>
28w
eek
s<
26w
eek
s26
–28
wee
ks
>28
wee
ks
Acu
tein
flam
mat
ion
grou
p
Op
acifi
cati
onof
mem
bra
ne
3829
1638
3122
4240
2714
27
An
ym
emb
ran
ein
flam
mat
ion
8058
3582
6654
8877
7414
53
Su
bch
orio
nit
is10
96
1413
76
711
00
1
Ch
orio
nit
is6
98
710
126
1212
03
0
Ch
orio
amn
ion
itis
5835
1755
3319
7056
3427
22
An
yfe
tal
vasc
uli
tis
6043
2655
4533
7365
6114
52
Um
bil
ical
vasc
uli
tis
4032
1933
2719
5554
449
31
Ch
orio
nic
vasc
uli
tis
3926
1339
2613
4639
289
21
Am
nio
nep
ith
elia
ln
ecro
sis
3522
938
2515
3630
200
20
PIH
grou
p
Old
infa
rct
213
290
812
15
843
4252
Incr
ease
dsy
ncy
tial
knot
s11
1735
512
2711
614
8656
58
MD
AP
1721
3216
1313
1214
1486
6057
Oth
er
Mar
gin
al/m
emb
ran
ous
inse
rtio
n15
2023
1716
1412
2218
2022
27
Inte
rvil
lou
sth
rom
bi
410
113
76
510
50
517
Pla
cen
tal
abru
pti
on4
67
67
63
45
09
9
Vil
lou
sfi
bro
sis
45
84
64
34
70
011
Ch
ron
icvi
llit
is2
47
12
11
42
295
9
Vil
lou
sed
ema
3734
1648
3922
2636
190
149
Incr
ease
dn
ucl
eate
dR
BC
s6
57
52
14
36
2914
9
N17
928
735
395
122
7873
102
102
743
138
MD
AP
,m
ater
nal
dec
idu
alar
teri
olar
pat
hol
ogy;
PIH
,p
regn
ancy
-in
du
ced
hyp
erte
nsi
on;
PR
OM
,p
rem
atu
reru
ptu
reof
mem
bra
nes
;P
TL
,p
rete
rmla
bor
;R
BC
s,re
db
lood
cell
s.aM
easu
rem
ents
are
the
per
cen
tof
infa
nts
wit
hth
ech
arac
teri
stic
sli
sted
inea
chco
lum
nw
hos
ep
lace
nta
had
the
char
acte
rist
icli
sted
onth
ele
ft.S
ingl
eton
son
ly.N
um
ber
sin
bol
dfa
cein
the
“All
”co
lum
ns
dif
fer
from
each
oth
erto
ad
egre
eu
nli
kely
tob
ed
ue
toch
ance
(p,
0.0
5).
VLBW INFANT’S PLACENTA 425
Tab
le4.
Init
iato
ro
fp
rete
rmd
eliv
ery;
stra
tifi
edb
yb
irth
wei
ght
Zsc
ore
a
All
PT
LP
RO
MP
IH
<2
22
2to
21
>2
1<
22
22
to2
1>
21
<2
22
2to
21
>2
1<
22
22
to2
1>
21
Acu
tein
flam
mat
ion
grou
p
Op
acifi
cati
onof
mem
bra
ne
1117
3221
3032
1730
394
59
An
ym
emb
ran
ein
flam
mat
ion
1435
6837
5872
4480
813
37
Su
bch
orio
nit
is2
510
36
133
128
10
0
Ch
orio
nit
is2
79
68
110
1910
00
3
Ch
orio
amn
ion
itis
920
4120
3136
2734
561
26
An
yfe
tal
vasc
uli
tis
1027
5132
3947
3965
680
39
Um
bil
ical
vasc
uli
tis
920
3520
2327
2747
530
06
Ch
orio
nic
vasc
uli
tis
615
2911
1728
2034
380
23
Am
nio
nep
ith
elia
ln
ecro
sis
512
2521
3626
1118
310
02
PIH
grou
p
Old
infa
rct
4134
626
183
1710
349
5540
Incr
ease
dsy
ncy
tial
knot
s46
3813
4727
1017
511
5762
56
MD
AP
4734
1721
2112
225
1464
5753
Oth
er
Mar
gin
al/m
emb
ran
ous
inse
rtio
n32
2316
2231
1318
1718
3919
16
Inte
rvil
lou
sth
rom
bi
159
711
65
115
714
1216
Pla
cen
tal
abru
pti
on10
94
018
617
33
148
2
Vil
lou
sfi
bro
sis
128
45
94
173
413
80
Ch
ron
icvi
llit
is10
63
50
10
33
911
4
Vil
lou
sed
ema
1414
345
3041
1715
3013
511
Incr
ease
dn
ucl
eate
dR
BC
s12
74
53
36
35
149
9
N13
515
652
819
3324
318
4021
969
7445
MD
AP
,m
ater
nal
dec
idu
alar
teri
olar
pat
hol
ogy;
PIH
,p
regn
ancy
-in
du
ced
hyp
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426 A.R. HANSEN ET AL.
PTL and PIH pregnancies delivered after .1 h ofmembrane rupture had a higher incidence ofpathologic features consistent with acute inflam-mation than placentas delivered before 1 h ofmembrane rupture. This differs from a recent re-port in which no correlation was found betweenduration of membrane rupture and histologic evi-dence of chorioamnionitis [9]. As expected, amongplacentas of PIH pregnancies, the prevalence ofPIH histologic correlates did not vary with dura-tion of membrane rupture.
DISCUSSIONBy and large, our findings are similar to those ofothers. The value of our study is that the largenumber of placentas of VLBW infants and our
multiple stratified analyses enables us to better
understand the relationship between histologic
features and such predictor variables as initiator of
prematurity, gestational age, and a measure of
growth restriction. The placental pathologic find-
ings associated with the clinical diagnosis of infec-
tion, PIH, and low birthweight Z score in our
VLBW/preterm population were similar to those
reported for term pregnancies. In term pregnan-
cies, the association between membrane opacifica-
tion, membrane inflammation, fetal vasculitis, and
amnion epithelial necrosis with infection is well
established [1,16,17]. The association in our pre-
term sample between the clinical diagnosis of PIH
and pathologic findings of infarcts, increased syn-
Table 5. Initiator of preterm delivery stratified by duration of membrane rupturea
MDAP, maternal decidual arteriolar pathology; PIH, pregnancy-induced hypertension; PTL, preterm labor; RBCs, red blood cells; ROM, rupture ofmembranes.aMeasurements are the percent of infants with the characteristics listed in each column whose placenta had the characteristic listed on the left.Singletons only. Numbers in boldface differ from the other(s) to a degree unlikely to be due to chance ( p , 0.05).
and atherosis of the maternal decidual arterioles,
villous fibrosis, and chronic villitis is consistent
with that found in the term placenta [1]. Also, as in
term pregnancies, the placentas of growth-re-
stricted fetuses compared to average for gesta-
tional age fetuses had a higher incidence of placen-
tal infarction, maternal vascular thromboses
(corresponding to our label of MDAP), chronic vil-
litis, and abruption [8,18].
We found the morphologic features of placen-tas from pregnancies delivered prematurely sec-ondary to PTL and PROM to be roughly compara-ble, and to be characterized by features of acuteinflammation. The tendency of the PROM group tohave a higher rate of these inflammatory findingsthan the PTL group probably reflects the longerduration of ROM in the PROM group as a whole(Table 1). This difference is attenuated when wecompare PTL placentas to the subgroup of PROMplacentas with duration of ROM .1 h. Our rela-tively low incidence of PIH features in both PTLand PROM placentas is in contrast to a previousreport’s finding of a subpopulation of PTL andPROM pregnancies with PIH placental correlates[19]. That study included no pregnancies carryingthe clinical diagnosis of PIH. The stronger associ-ation of chronic villitis with PIH than with PTL orPROM supports an immune phenomenon ratherthan an infectious one inducing an inflammatoryresponse. Its frequent occurrence early in the ges-tation of pregnancies complicated by PIH (29% ingestations of ,26 weeks) suggests a new signifi-cance for this generally uncommon lesion in pla-centas of very low–birth weight infants.
Among pregnancies delivered prematurelybecause of PTL and PROM, the placentas of eachfetus from multifetal gestation pregnancies tendedto have a lower incidence of histologic featuresassociated with acute inflammation than did theplacentas of singleton pregnancies. This is mostprominent for the placentas of nonpresenting fe-tuses, but is even true for the placentas of present-ing fetuses. Similarly, among PIH pregnancies, theplacentas of multifetal gestations tended to have alower incidence of histologic features associatedwith PIH. This may reflect obstetric management;multiple-gestation pregnancies are more likely to
be delivered rapidly by Cesarean section because ofthe higher incidence of breech presentation. Per-haps there is also a lower threshold for prematuredelivery of multiple gestations than for singletonsbecause of obstetric assessment of risks and bene-fits. Finally, the same maternal response, whetherto infection or PIH, may be diluted when spreadamong more than one fetoplacental unit.
Our finding that decreasing gestational age isassociated with an increased risk of membraneinflammation or fetal vasculitis is consistent withthose of previous reports [4,15,16,18–20] and withfindings that placenta and cord inflammation areassociated with PTL and PROM [21–26], whichtend to occur at a younger gestational age thanPIH. By contrast, our finding of a direct relation-ship between increasing gestational age and in-creased risk of vasculopathy is at odds with a pre-vious report of an increased prevalence ofvasculopathy in placentas of the gestationallyyoungest [4]. This discrepancy may be due to thisreport’s difference in the specific pathologic enti-ties evaluated, its less restrictive definition of pre-maturity as gestational age ,37 weeks, and itsexclusion of patients with PIH, chronic hyperten-sion, and intrauterine growth retardation. We didnot exclude placentas of mothers with PIH. Asexpected, the majority of placentas with vasculopa-thy were delivered by mothers with a clinical diag-nosis of PIH. The infants paired with these placen-tas were of relatively older gestational age, therebyincreasing the incidence of vasculopathy in the.28-week gestational age-group. The apparent de-cline, with increasing gestational age, in placentalcorrelates of infection in pregnancies deliveredprematurely because of PIH may be an effect of thesmall sample size of placentas delivered at ,26weeks gestation to women with PIH. However, itcould also be due to less accuracy in diagnosinginfection in very preterm placentas, or a true asso-ciation between PIH and infection early in gesta-tion.
Our finding among infants with lowbirthweight Z scores of an increased incidence ofold infarcts, increased syncytial knots, MDAP, vil-lous fibrosis, marginal/membranous insertion,chronic villitis, and increased nucleated red bloodcells is consistent with previous reports [5,7,10,27].However, our findings contrasted with a study that
428 A.R. HANSEN ET AL.
found that growth restriction in the absence ofmaternal hypertension is associated with chronicinflammation and is independent of decidual vas-culopathy, whereas growth restriction in the pres-ence of maternal hypertension is associated withdecidual vasculopathy [7]. We found not only thatgrowth restriction correlates with decidual vascu-lopathy independent of maternal hypertension butthat this correlation is strongest in the absence ofmaternal hypertension.
Although the incidence of a number of histo-logic features was associated with trends in gesta-tional age and birth weight Z score, such trendswere not seen within groups defined by initiator ofpreterm delivery. The incidence of these features,however, showed very prominent differences be-tween both the PTL and PROM groups comparedto the PIH group, even within gestational age andbirth weight Z score strata. Thus, the gestationalage and birth weight Z score correlations withhistologic features appear to be consequences ofthe tendency of PTL and PROM to occur atyounger gestational ages, and of PIH to occur atolder gestational ages and lower birth weight Zscores. Thus, we conclude that such morphologicfeatures are correlates of the phenomena leadingto premature delivery.
The occurrence of histologic correlates ofacute inflammation in singleton placentas fromPTL pregnancies delivered within 1 h of membranerupture provides support for an infectious etiologyof PTL, even when ascending infection is unlikely.Since funisitis in preterm infants is thought toreflect prolonged activation of the fetal immuneresponse [11,19], its presence in infants deliveredwithin 1 h of membrane rupture suggests that theinfection antedated membrane rupture in thesecases. Although our findings do not provide infor-mation about the precise role of this infectiousprocess in precipitating PTL or PROM, the fre-quency of histologic findings consistent with acuteinflammation suggests it is biologically important.The pathologic evidence that the infection pre-cedes the ROM, and perhaps the symptoms of PTL,has implications for screening and antibiotic ther-apy for at-risk mothers. The imperfect correlationbetween clinical and pathologic evidence of infec-tion raises concern regarding the use of tocolyticagents in cases of PTL.
This study has several limitations. Becausethe entry criterion was a birth weight of 500–1500g, the population of babies born to mothers withPIH/preeclampsia is skewed to overrepresentgrowth-retarded infants [28,29]. This confoundsthe placental correlates of PIH with those of intra-uterine growth retardation (IUGR). This study isnot able to do justice to the interesting subpopula-tion of babies delivered prematurely for reasonsother than PTL, PROM, or PIH. Unfortunately, thesample size of this “other” category, especiallywhen subdivided by specific diagnoses, is too smallto allow for statistical analysis.
Finally, the possibility of anticipation biascould contribute to the tendency for the data tocorrelate more strongly with maternal than withneonatal characteristics. If the field of placentalpathology has evolved with a primary focus onmaternal (e.g., PTL, PROM, PIH) rather than neo-natal (e.g., gestational age, birth weight Z score)conditions, then this would set up an internal ten-dency for maternal conditions to emerge as stron-ger correlates of pathologic findings. Since pre-term delivery has often been the concern thatprompted submission of a placenta for pathologicexamination, the pathologist directs significant at-tention to morphologic characteristics that havecome to be associated with PTL, PROM, and PIH.Thus there is a degree of circular logic, to concludethat such pregnancy and fetal characteristics asgestational age and birth weight Z score correlatestrongly with placental correlates of indicators ofpreterm delivery.
We found that placental pathologic findingscorrelated most strongly and consistently with theinitiator of preterm delivery, whether PTL, PROM,or PIH. The findings of multiple histologic featuresof inflammation in the placentas with ROM for ,1h supports the hypothesis that at least some casesof PTL are precipitated by a more long-term infec-tious process than previously suspected [30]. Thisstudy supports the claim that examination of theplacenta of the very low–birth weight infant canprovide insight into the etiology and managementof preterm delivery.
A C K N O W L E D G M E N T S
The authors are grateful to the women who agreedto be interviewed for this study and allowed data to
VLBW INFANT’S PLACENTA 429
be collected from their babies’ charts. Funds forthis project were provided by the National Instituteof Neurological Diseases and Stroke (NS 27306).
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