J Mol Hist (2012) 43:263–271
DOI 10.1007/s10735-012-9405-3
ORIGINAL PAPER
Structural analysis of human placental stem and terminal villi
from normal and idiopathic growth restricted pregnancies
Shaima M. Almasry • Magda A. Eldomiaty
Amr K. Elfayomy • Fawzia A. Habib •
Maha D. Safwat
•
Received: 29 December 2011 / Accepted: 11 March 2012 / Published online: 30 March 2012
Ó Springer Science+Business Media B.V. 2012
Abstract Studying in detail different histomorphological
and pathological findings in placental stem and terminal villi
of appropriate for gestational age (AGA) and idiopathic
intrauterine growth restricted (IUGR) fetuses, then analyzing their correlation to the neonatal birth weight and to the
some morphological features of the placenta. Fifty full-term
human placentae of idiopathic IUGR and 25 of AGA
pregnancies were processed for haematoxylin and eosin
staining and evaluated by light microscope aided with Image
Analyzer. The mean number of stem villous arteries, and the
mean number of terminal villous capillaries per field are
significantly lower in idiopathic IUGR group (4.63 ± 0.46,
Dr. Shaima M. Almasry and Prof. Magda A. Eldomiaty have
contributed to the work equally.
S. M. Almasry M. A. Eldomiaty (&) M. D. Safwat
Department of Anatomy, Taibah University,
Almadinah Almonawarah, Saudi Arabia
e-mail: [email protected]
S. M. Almasry
Department of Anatomy,
Al-Mansoura University, Al-Mansoura, Egypt
M. A. Eldomiaty
Department of Anatomy, Tanta University, Tanta, Egypt
A. K. Elfayomy F. A. Habib
Department of Obstetrics and Gynecology,
Taibah University, Almadinah Almonawarah, Saudi Arabia
47.09 ± 4.44, respectively) than in AGA group (12.36 ±
0.61, 73.35 ± 5.13, respectively) (p = 0.001). Both AGA
and idiopathic IUGR placentae share the presence of many
pathological features: (1) narrowing of stem villous arteries
appears in 38 (76 %) of IUGR cases and in 9 (36 %) of
AGA cases with significant difference between groups
(p = 0.001); (2) cellular infiltration (villitis) of the stem villi
is significantly higher in IUGR cases [24 (48 %)] than in
AGA cases [2 (8 %)] (p = 0.001). The study shows significant correlation between the birth weight and different
pathologic features in the stem villi as arterial number
(r = 0.494; p = 0.000), arterial narrowing (r = 0.283, p =
0.004), degenerative changes (r = 0.331, p = 0.001) and
villitis (r = 0.275, p = 0.005). There is also significant
correlation between neonatal birth weight and terminal
villous capillary number (r = 0.281, p = 0.001) but no
significant correlation is found between the birth weight and
terminal villous fibrotic changes (r = -0.098, p = 0.318).
Histomorphological and pathological changes in the stem
villi could explore the cause of idiopathic IUGR. Stem villous arterial number, arterial narrowing, degeneration and
villitis could be underlying mechanisms. Further researches
on the hormonal and cytokine level should be undertaken to
demonstrate the precipitating factors of these changes and
the possible preventing measures.
Keywords Intrauterine growth restriction Stem villous arteries Terminal villous capillaries Histopathologic changes Villitis
A. K. Elfayomy
Department of Obstetrics and Gynecology,
Zagazig University, Zagazig, Egypt
Introduction
M. D. Safwat
Department of Anatomy, Alexandria University,
Alexandria, Egypt
Intrauterine growth restriction (IUGR) is associated with
increased prenatal morbidity and mortality with smaller
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than normal placenta (Frederic et al. 1997). Understanding
the placental pathology of IUGR has resulted from an
appreciation of the developmental biology of the normal
villous tree. There is 30–50 % reduction in uteroplacental
blood flow as compared to that in normal pregnancies
(John et al. 2000). It is the placenta not the fetus that is
initially affected by a failure of transformation of the
uteroplacental circulation. It has been assumed that fetal
hypoxia is associated with hypoxia of the peripheral villous
tree and the intervillous space as a consequence of a
reduction in uteroplacental flow (Edmund et al. 1979).
Some pathological studies of placentae with IUGR reported
that the primary villous mal development might be the underlying event in such cases (Macara et al. 1995; Jackson et al.
1995; Macara et al. 1996). While others have reported that the
stem vessels in placentae could resemble the underlying cause
(Fok et al. 1990; Salafia et al. 1997; Sebire et al. 2001).
Many researchers suggested reduced number of placental villous stem arteries in IUGR cases (Giles et al.
1985; Sebire 2003), but more recent studies with systematic sampling techniques have been unable to confirm such
results (Hitschold et al. 1993; Jackson et al. 1995; Macara
et al. 1995).
Villitis of unknown etiology (VUE) is an important
pattern of placental injury occurring predominantly in term
placentae. Although overlapping with infectious villitis, its
clinical and histological characteristics are distinct. It is a
common lesion, affecting 5–15 % of all placentae and it is
an important cause of intrauterine growth restriction and
recurrent reproductive loss (Raymond and Redline 2007).
Studies in the field of placental morphometry in IUGR
cases indicate structural changes in the terminal villi as
hypercapillarization of the villous tree and persistence of
villous cytotrophoblastic cells (Qamar et al. 2009).
Giving attention to the pathogenesis of idiopathic IUGR,
the present study was designed to study in depth different
histomorphological and pathological findings in placental
stem and terminal villi of both appropriate for gestational
age (AGA) and idiopathic IUGR cases, then studying the
correlation of these changes to the neonatal birth weight
and selected morphological features of the placenta.
Materials and methods
Patient details
A total of 75 full-term (C37 weeks pregnancy) freshly
delivered placentae were collected either after normal deliveries or after Caesarean sections from department of Obstetrics and Gynecology at 2 University hospitals; ‘‘Al-Madinah
Maternity and Ohud Hospital’’ between April, 2010 and
March, 2011. Of these cases, 50 placentae were associated
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with idiopathic IUGR and 25 placentae from AGA pregnancies. The study was approved by Medical and Health Sciences
Research Committee of both hospitals and informed patients’
consents was obtained.
To eliminate the confounding effects of premature birth,
only term placentae were chosen. Gestational age was
estimated using the date of the last menstrual period and
confirmed by an ultrasound examination performed
11–13 weeks gestation (Hadlock et al. 1992).
The inclusion criteria for IUGR cases were; serial
ultrasound fetal weight below the 10th percentile for gestational age (Hadlock et al. 1991) and any two of the following criteria diagnosed on antenatal ultrasound;
abnormal umbilical artery Doppler flow velocimetry, oligohydramnios as determined by amniotic fluid index (AFI)
\5 (Cunningham et al. 2010) or asymmetric growth of the
fetus as quantified from the HC (head circumference) to
AC (abdominal circumference) ratio. Growth restriction
was confirmed at birth if neonatal weight was less than the
10th percentile (Williams et al. 1982; WHO 1995). To be
sure that only pregnancies complicated by IUGR of no
apparent etiology were included in the study, the exclusion
criteria for both AGA and idiopathic IUGR pregnancies
were; multiple pregnancies, maternal smoking, preeclampsia, prolonged rupture of the membranes, placental
abruption, intrauterine viral infection, maternal cardiovascular or autoimmune diseases, diabetes and fetal congenital
anomalies or chromosomal abnormalities.
Processing of the placenta
Each placenta was taken at the time of delivery, weighed by a
weighing scale and placental diameters were measured along
two perpendicular axes by a measuring tape, then the average
of the two diameters was calculated for statistical purposes.
Each placenta is examined for hematomas, fibrotic spots
and the sites of attachment of umbilical cord then placental
samples were obtained by standard procedure; full depth
cube of placental tissue (fetal through to maternal) from
macroscopically normal placental disk about 5 cm from the
umbilical cord insertion. For histopathological examination, each cube of tissue was processed to wax using routine laboratory techniques. The paraffin blocks were then
cut serially at 4 mm thickness sections, mounted on glass
microslides and processed for hematoxylin-eosin staining,
carried out according to conventional procedures.
Histological examination and statistical study
The placental sections of AGA and idiopathic IUGR
cases were examined by light microscope aided with
Image Analyser (Leica Q Win standard, digital camera
CH-9435 DFC 290, coupled to photomicroscope, Germany).
J Mol Hist (2012) 43:263–271
The stem villi were determined by their large fetal vessels
surrounded by a light microscopically identifiable media,
thick trophoblastic covering rare fetal capillaries and
missing sinusoids. Whereas the terminal villi were determined by their sinusoidally dilated fetal capillaries that
occupy more than 50 % of the villous stroma (Schweikhart
and Kaufmann 1986) and also by their diameter less
\80 lm (Egbor et al. 2006a).
The stem villi were examined for: (a) the number of
stem arteries. (b) any pathological findings in the stem
arteries as degeneration, herniation, dissection of the wall
and or thrombosis. (c) pathological changes in the interstitium of the stem villi as hyalinization or fibrosis. The
terminal villi were examined for the number of villous
capillaries and the fibrotic changes. Villitis is considered
when focal areas of cellular infiltration and areas of hyalinization were detected in hematoxyline and eosin sections
as was reported by Boog (2008).
For the statistical study, examination was performed in
randomly selected clearly stained 5 different high power
(2009) fields of each specimen and the Image analyzer was
used for counting the stem villous arteries and terminal
villous capillaries in these fields.
The score shown in Table 1 was used to determine the
degree of the pathological features in both IUGR and AGA
cases.
Using SPSS version 13, the mathematic means, statistical significance of difference and correlation between
different pathologic findings in control and idiopathic
IUGR placentae were evaluated by student’s ‘t’ test,
Mann–Whitney U test, Pearson’s test and Kendall’s test.
The difference was regarded statistically significant if the
p value less than 0.05.
Results
Maternal and fetal study
The mean neonatal birth weight is 3,396.47 ± 312.17 g for
AGA group and 2,203.59 ± 276.31 g for idiopathic IUGR
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group with significant difference between both groups
(p = 0.000).
The mean maternal age shows no significant difference
between AGA (29.75 ± 3.96 years) and idiopathic IUGR
cases (28.64 ± 4.07 years) (p = 0.264), whereas, the
gestational age is found to be significantly higher AGA
group (range 37–40 with mean = 38.88 ± 0.95 weeks)
than in idiopathic IUGR one (range 37–41 weeks with
mean = 38.11 ± 0.92 weeks) (p = 0.001).
Macroscopic study of the placenta
The statistical analysis of placental diameters, placental
weights, gross placental changes (fibrosis, hematomas) and
mode of insertion of the umbilical cord in both AGA and
IUGR groups are represented in Table 2.
The study reveals significant differences between AGA
and idiopathic IUGR groups regarding the placental diameters
(p = 0.000), placental weights (p = 0.000), and gross placental changes [fibrosis (p = 0.023) and hematomas (p =
0.033)], but no significant difference is detected regarding the
site of insertion of the umbilical cord (p = 0.149).
The placental weights and the average placental diameters are significantly correlated with the neonatal birth
weight (r = 0.650, p = 0.000; r = 0.619, p = 0.000,
respectively) (Fig. 1).
Microscopic study
Histopathological examination
Histological sections of AGA term placenta reveal the
intervillous spaces with huge number of villi in various
planes of section and with varying diameters from large
main stem villi containing large vessels to very small terminal villi with capillaries in their cores (Fig. 2). Varying
numbers of AGA term placentae show some of the pathological findings exhibited by the term idiopathic IUGR
placentae.
The stem villi of many term idiopathic IUGR placentae
show hyalinization of the interstitium and hypercellular
Table 1 The score for determination of some pathological features in both AGA and idiopathic IUGR cases
The pathological feature
Narrowing of the stem arteries
Villitis of stem villi (presence of cellular infiltration) (low-grade lesions
affecting less than 10 villi per focus were excluded)
Terminal villous fibrosis
The score
In more than 2 fields
Positive
In less than 2 fields
Negative
In 2 fields or more ± degenerative
changes in the stem villous
Positive
In less than 2 fields
Negative
In more than 2 fields
Positive
In less than 2 fields
Negative
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J Mol Hist (2012) 43:263–271
Table 2 Placental diameters, placental weights, gross placental changes and mode of insertion of the umbilical cord in AGA and Idiopathic
IUGR groups
Variable
AGA group
(n = 25) (mean ± SE)
Idiopathic IUGR
group (n = 50) (mean ± SE)
P value
Placental diameter (cm)
17.69 9 16.72
16.3 9 15.17
0.000*
[Mean of average ± SE]
[17.20 ± 1.14]
[15.73 ± 1.20]
Placental weight (gm) (mean ± SE)
Gross placental changes
532.80 ± 56.46
399.23 ± 93.84
0.000*
Fibrosis
2 (8 %)
16 (32 %)
0.023**
Hematomas
2 (8 %)
15 (30 %)
0.033**
Central
7 (28 %)
7 (14 %)
0.149
Eccentric
15 (60 %)
34 (68 %)
Marginal
2 (8 %)
3 (6 %)
Velamentous
1 (4 %)
6 (12 %)
Insertion of the cord (no. and %)
Significance was taken at p \ 0.05 for independent samples-t test (*) and Mann–Whitney U test (**)
Fig. 1 Placental weights and placental diameters correlate significantly with neonatal birth weight: with the increase in birth weights there are
increase in placental weights and placental diameters
stromal response. Others show tiny or focal areas of villous
necrosis and/or fibrosis (Fig. 3). Many stem arteries show
marked wall hypertrophy and narrowing of their lumina
and many arteries show wall herniation, hemorrhagic dissection of the vessel wall, focal inflammatory infiltrate and
or thrombosis (Fig. 4). The terminal villi of some specimens show marked fibrosis with deformed villi (Fig. 3).
The statistical analysis of the histopathological findings
in AGA and idiopathic IUGR placentae
The frequency of different pathological conditions in
AGA and idiopathic IUGR groups is shown in Tables 3, 4
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Image analyzing study of histological sections from idiopathic IUGR placentae show reduced number of villous
stem arteries compared with AGA specimens. The difference between the mean number of arteries per field in AGA
(12.36 ± 0.61) and idiopathic IUGR (4.63 ± 0.46) group
is statistically significant (p = 0.000). Also, in idiopathic
IUGR group the number of capillaries in the terminal
villi per field is significantly decreased compared with
AGA group (47.09 ± 4.44; 73.35 ± 5.13, respectively)
(p = 0.000).
The degenerative changes (hyalinization and necrosis)
in the stem villi and the presence of villitis (cellular infiltration) are significantly higher in idiopathic IUGR cases
J Mol Hist (2012) 43:263–271
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than in AGA ones (p = 0.000, p = 0.001, respectively).
Whereas, the degenerative or fibrotic changes in the terminal villi show no significant difference between both
groups (p = 0.370).
The narrowing of stem villous arteries is significantly
higher in idiopathic IUGR than in AGA group (p = 0.001),
whereas the degenerative findings in the stem arterial wall
show no significant differences between both groups
(p = 0.588).
Fig. 2 Photomicrograph of a histological section of placenta from
AGA pregnancy showing the intervillous space with large number of
villi in various planes of the section and with varying diameters from
large main stem villi containing large vessels to very small terminal
villi with capillaries in their cores (HE, original magnification 9100)
Fig. 3 Photomicrograph of histological sections of placentae from
pregnancies with idiopathic IUGR showing: a Intervillous space with
stem villous hyalinization and disappearance of stem arteries (HE,
original magnification 9100). b Intervillous space with marked
fibrosis of the villi (HE, original magnification 9100). c Intervillous
The correlation between the main pathological findings in
the placental tissue The number of stem villous arteries is
significantly correlated with the presence of villitis
(r = 0.243; p = 0.013) and with the degenerative changes
in the stem villi (r = 0.341; p = 0.001). It is also significantly correlated with the terminal capillary number
(r = 0.253; p = 0.002) and with the terminal villous
fibrosis (r = 0.243; p = 0.018).
The narrowed lumen of stem arteries is significantly
correlated with the presence of villitis in stem villi
space with foci of cellular infiltration in the stem villi (HE, original
magnification 9100). d Intervillous space with stem villous hyalinization, hypercellular stromal response and tiny or focal areas of
villous necrosis (HE, original magnification 9100)
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Fig. 4 Photomicrograph of histological sections of placentae from
pregnancies with idiopathic IUGR showing stem villi demonstrating:
a Stem villous artery with marked wall hypertrophy and narrowing of
the lumen (HE, original magnification 9100). b Stem villous artery
with herniation of its wall, other artery appears with marked wall
J Mol Hist (2012) 43:263–271
hypertrophy and narrowing of its lumen (HE, original magnification
9200). c Stem villous artery with hemorrhagic dissection of its wall.
Hyalinization and cellular infiltration is apparent in the villous
interstitium (HE, original magnification 9200). d Stem villous artery
with intraluminal thrombus (HE, original magnification 9100)
Table 3 Mean number of stem villous arteries and terminal villous capillaries in AGA and idiopathic IUGR groups
Variable
AGA group
n = 25
IdiopathicIUGR group
n = 50
P value
Number of stem villous arteries per field (mean ± SE)
12.36 ± 0.61
4.63 ± 0.46
0.000*
Number of terminal villous capillaries per field (mean ± SE)
73.35 ± 5.13
47.09 ± 4.44
0.000*
Significance was taken at p \ 0.05 for independent samples-t test (*)
Table 4 Frequency of different pathological conditions in AGA and idiopathic IUGR groups
The pathological condition
Frequency in AGA
group n = 25
Frequency in idiopathic
IUGR group n = 50
P
value
Narrowing of stem villous arteries
9 (36 %)
38 (76 %)
0.001*
Degeneration of the stem arterial wall (herniation, hemorrhagic dissection,
focal inflammatory infiltrate and or thrombosis)
6 (24 %)
15 (30 %)
0.588
Hyalinization and necrosis of the stem villi
13(52 %)
48 (96 %)
0.000*
Cellular infiltration (villitis) of the stem villi
2 (8 %)
24 (48 %)
0.001*
Terminal villous degeneration or fibrosis
3 (12 %)
3 (6 %)
0.370
Significance was taken at p \ 0.05 for Mann–Whitney U test (*)
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(r = 0.324; p = 0.005) and with the terminal capillary
number (r = 0.129; p = 0.046).
Interestingly, we found that the fibrotic changes in the
terminal villi are significantly correlated with the number
of stem villous arteries (r = -0.243; p = 0.018) but not
significantly correlated with the number of capillaries in
the terminal villi (r = -0.120; p = 0.830).
The correlation of the fetal and placental data with the
pathological changes The birth weight and the placental
weight are significantly correlated with the appearance of
degenerative changes in the stem villi (r = 0.33; p =
0.001, r = 0.345; p = 0.000).
The birth weight is significantly correlated with stem
arteries number (r = 0.494; p = 0.000), arterial narrowing
(r = 0.283, p = 0.004), terminal villous capillary number
(r = 0.281, p = 0.001) and villitis (r = 0.275, p = 0.005).
The placental weight is significantly correlated with
stem arteries number (r = 0.494, p = 0.000), arterial narrowing (r = 0.283, p = 0.004), villitis (r = 0.252, p =
0.009) and terminal villous capillary number (r = 0.281,
p = 0.000).
The average placental diameter is significantly correlated with stem arteries number (r = 0.330, p = 0.000),
arterial narrowing (r = 0.23, p = 0.023), villitis (r =
0.301, p = 0.002) and terminal villous capillary number
(r = 0.168, p = 0.042).
Discussion
The present work studied the histomorphological and
pathological changes in the stem and terminal villi of idiopathic IUGR and AGA placentae aiming to reach probable pathogenesis of idiopathic IUGR. The stem villi of
idiopathic IUGR placentae show different pathologic
findings including arterial changes, degenerative changes
and signs of villitis. Also, the terminal villi of some
specimens exhibit marked fibrosis. Importantly, these
pathologic pictures are also exhibited by varying numbers
of AGA term placentae.
Considering the feto-maternal results, no significant
difference is found regarding the maternal age between
AGA and idiopathic IUGR cases (p = 0.264) which is in
favor to the quality of chosen cases. The gestational age is
found to be significantly higher in AGA than in idiopathic
IUGR groups (p = 0.001) and this could be due to the
difference in range of the considered full term period in
both groups (37–40 weeks in AGA, but 37–41 weeks in
IUGR group).
The pathologic findings in this study are in line with
Salafia et al. (1992) who reported the presence of placental
269
infarction, chronic villitis, hemorrhagic endovasculitis, and
placental vascular thromboses in different cases of idiopathic IUGR at term. The presence of these pathologic
findings in both IUGR and AGA cases is in parallel
with Tomasa et al. (2010) who reported no difference in
histopathologic findings between idiopathic IUGR placentae and AGA ones. Also Salafia et al. (1992) found that one
or more pathologic changes were present in 55 % of IUGR
cases, and 32 % of non-IUGR cases.
In this study, the mean number of stem villous arteries,
and the mean number of terminal villous capillaries per
field are significantly lower in idiopathic IUGR (4.63 ±
0.46, 47.09 ± 4.44, respectively) than in AGA group
(12.36 ± 0.61, 73.35 ± 5.13, respectively) (p = 0.000,
p = 0.001, respectively). In line with our results, Giles
et al. (1985) and Sebire (2003) suggested that placentae
from pregnancies with IUGR and abnormal umbilical
artery (UA) Doppler findings were associated with reduced
number of placental villous stem arteries. Subsequently,
other authors confirmed these findings (McCowan et al.
1987; Bracero et al. 1989). Meanwhile, many studies with
systematic sampling techniques were unable to confirm
such results (Hitschold et al. 1993; Jackson et al. 1995). In
controversy with our results, Claude and Steven (1985) and
Lena et al. (1995) reported increased mean number of
capillaries in the placental tissue and explained that the
increased number of capillaries in the stromal core of terminal villi indicates hypoxia induced hypercapillarization
and vasodilatation in many systemic vessels.
In the present work, narrowing of stem villous arteries is
significantly higher in idiopathic IUGR (76 %) than in
AGA (36 %) cases. This narrowing might be due to wall
hypertrophy and/or vasoconstriction. Several authors have
reported the apparent luminal reduction and wall hypertrophy of stem vessels in placentae from cases of IUGR
consistent with marked, longstanding placental stem villous vasoconstriction (Van der Veen and Fox 1983; Sebire
et al. 2001). Many authors hypothesized that intrauterine
growth restriction, with or without etiology leads to chronic
fetal stress with chronic hypoxia and release of vasoactive
substances, which cause chronic vasoconstriction and
vascular hypertrophy (Subahash et al. 2000; Cunningham
et al. 2010).
On the other hand, our results reveals that the vascular
degenerative changes of the stem arteries (wall herniation,
hemorrhagic dissection of the vessel wall, focal inflammatory infiltrate and or thrombosis) show higher but non
significant difference in idiopathic IUGR (30 %) than in
AGA (24 %) cases. In comparison with the present
results, Salafia et al. (1992) found that hemorrhagic
endovasculitis was exhibited in 15 % of all IUGR cases,
whereas placental vascular thromboses presented in 9 %
of cases.
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Our results show that, the presence of villitis and the
degenerative changes in the stem villi are significantly
higher in idiopathic IUGR cases than in AGA ones. In
accordance with these results (Salafia et al. 1992) reported
higher percentage of chronic villitis and placental infarction in idiopathic IUGR cases than in AGA cases.
Discussing the causative mechanisms of idiopathic
IUGR, the present study proves significant correlation
between the birth weight and different pathologic features in
the stem villi as stem artery number (r = 0.494; p = 0.000),
arterial narrowing (r = 0.283, p = 0.004), stem villous
degenerative changes (r = 0.331, p = 0.001) and villitis
(r = 0.275, p = 0.005) and also significant correlation
between birth weight and the terminal villous capillary
number (r = 0.281, p = 0.001) but no significant correlation is detected between birth weight and the terminal villous
fibrotic changes (r = -0.098, p = 0.318). These results
could raise the hypothesis that the stem villi could represent
the mystery for the development of idiopathic IUGR.
In accordance with our finding that decreased number of
stem arteries and/or their narrowing might be causative
mechanisms for decreased birth weight and development of
idiopathic IUGR. Sebire (2003) hypothesized that reduced
placental stem artery number could be the first mechanism
proposed in IUGR and abnormal UA Doppler findings.
Also, Campbell et al. (1986) and Bower et al. (1991)
reported the reduction in uteroplacental blood flow as an
underlying event in most cases of IUGR. In the same time,
Fox (1997) found that the villous ischemic necrosis associated with severe IUGR is secondary to severe reduction
in oxygen delivery due to severe localized impairment of
uteroplacental intervillous blood flow.
That the stem arterial narrowing could be an underlying
mechanism in idiopathic IUGR is in line with Sebire and
Talbert (2001) and Sebire and Talbert (2002) who
explained the anatomical importance of the well developed
smooth muscle of stem villous arteries in controlling placental hemodynamic to minimize ventilation–perfusion
mismatch. Histopathological evidence for such changes
compatible with prolonged vasoconstriction have now been
well explained by the current theory that prolonged
reduction in maternal intervillous flow, and hence oxygen
delivery, would result in prolonged vasoconstriction with
secondary reduction in stem villous luminal diameter,
increased flow resistance and vascular medial hypertrophy
(Van der Veen and Fox 1983; Sebire et al. 2001).
The present study proves that the birth weight is significantly correlated with cellular infiltration and/or degenerative changes in the stem villi. This could raise the hypothesis
that stem villous degeneration and/or villitis especially of
unknown etiology (VUE) could be underlying mechanisms
of idiopathic IUGR. In accordance with this hypothesis,
Raymond and Redline (2007) stated that VUE (When low-
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J Mol Hist (2012) 43:263–271
grade lesions are excluded) is an important cause of intrauterine growth restriction and recurrent reproductive loss.
Also, Salafia et al. (1992) proved that 30 % of all idiopathic
IUGR cases were having chronic villitis that could be
accompanied by hemorrhagic endovasculitis.
That the terminal villous mal-development could be a
probable causative mechanism of idiopathic IUGR is a
point of discrepancy. Our study proved that the birth
weight is significantly correlated with terminal villous
capillary number (r = 0.281, p = 0.001) but not with the
terminal villous fibrotic changes (r = -0.098, p = 0.318).
The number of terminal villous capillaries is a point of
debate where many researchers proved hypocapillarization
of terminal villi with IUGR (Mayhew et al. 1999; Mayhew
et al. 2004; Egbor et al. 2006b), but others prove hypercapillarization (Claude and Steven 1985; Lena et al. 1995).
On the other hand, pathological studies of placentae with
IUGR and abnormal UA Doppler findings reported that the
terminal villi are often small, hypovascular and fibrotic
which prompted the hypothesis that primary villous maldevelopment may be the underlying event in such cases
(Macara et al. 1995; Macara et al. 1996). In consistent with
our results, Sebire (2003) declared that the underlying
mechanism of abnormal UA Doppler waveforms in most
cases of IUGR is secondary to significant reduction in
maternal uteroplacental flow rather than primary placental/
villous maldevelopment. He described that resistance to
flow in almost all organs is controlled at the level of the
small arteries/arterioles, not at the level of the capillary bed
itself. This could be in consistent with our findings that the
fibrotic changes in the terminal villi are significantly correlated with the number of stem villous arteries but not
with the number of capillaries in the terminal villi.
Conclusion and recommendations
Histomorphological and pathological changes in the stem
villi could explore the cause of idiopathic IUGR. Stem
villous arterial number, arterial narrowing, degeneration
and villitis could be underlying mechanisms. Further
researches on the hormonal and cytokine level should be
undertaken to demonstrate the precipitating factors of these
changes and the possible preventing measures.
Acknowledgments This work was supported by grant no. 29/230
from King Abdulaziz City for Science and Technology; Kingdom of
Saudi Arabia. The authors gratefully acknowledge Dr. Hanan Taiel,
Professor of Pathology, College of medicine, Taibah University for
her help in defining the pathological features in the specimens.
Thanks to research assistances for their help in recording and filing of
the research data.
Conflict of interest The authors disclose that there is no other
conflict of interest regarding this work.
J Mol Hist (2012) 43:263–271
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