Placenta, Secret Witness of Infant Morbidities: The Relationship Between Placental Histology and Outcome of the Premature Infant
Ufuk ÇAKIR1, Duran YILDIZ1, Dilek KAHVECIOĞLU1, Emel OKULU1, Serdar ALAN1, Ömer ERDEVE1, Aylin OKÇU HEPER2, Begüm ATASAY1, Saadet ARSAN1
1Division of Neonatology, Department of Pediatrics, Ankara University Faculty of Medicine, ANKARA, TURKEY
2Department of Pathology, Ankara University Faculty of Medicine, ANKARA, TURKEY
Keywords: Chorioamnionitis, Neonatal morbidity, Placental pathology, Prematurity, Vasculopathy
The microscopic and macroscopic features of the placenta can contribute to the clinical understanding of premature delivery. The aim
of our study was to figure out the relationship between the histopathological findings of the placentas of premature deliveries and its effects on
neonatal morbidity and mortality.
Material and Method: The placentas of 284 singleton preterm infants with <35 weeks of gestation were examined. Three groups were created as
the normal, chorioamnionitis and vasculopathy groups according to the histopathological findings in the placentas of the subjects.
Results: The mean gestational age of the infants in the study group was 30.5 ± 3.2 weeks, and the mean birth weight was 1588 ± 581 g. The
pathology was normal in ninety-six (33.8%), vasculopathy in 153 (53.9%) and chorioamnionitis in 35 (12.3%). The gestation age of the infants
was lower in the chorioamnionitis group. Moreover, retinopathy of prematurity, early onset neonatal sepsis, and duration of respiratory support
were found to be higher in the chorioamnionitis group. In the vasculopathy group, preeclampsia and small for gestational age were found to be
Conclusion: Histopathological findings of the placentas from preterm deliveries provided important data in determining the etiology of preterm
delivery and outcomes of infants. Infants delivered by mothers with chorioamnionitis were particularly found to be more preterm, and these
preterm infants would have a longer hospital stay, higher respiratory support requirement, and more serious morbidities.
Prematurity is an important cause of serious morbidity and
mortality after delivery 1
. During pregnancy, the placenta
has essential roles in fetal nutrition, gas exchange and
removal of residual products of catabolism. The placenta
has a strategic position at the fetal-maternal interface
reflecting the problems of both the mother and the fetus
. The placenta also serves as a barrier to protect the fetus
against toxins and infective organisms 3
. Any damage to
the placenta, such a critical organ for fetal life, affects the
development of a normal fetus and may lead to an adverse
perinatal outcome 2
. Recently, data about placental
lesions have contributed to a better idea of how the placenta
functions. In addition, current findings indicate that
placental function abnormalities can cause severe morbidity
and mortality of mothers and fetuses 4
evidence has also indicated that placental dysfunction
during the antenatal period is an important risk factor for preterm birth and/or poor neurodevelopment outcomes
in the later life of live-born infants 5,6
. However, little is
known about the benefit of placental findings for neonatal
care among pediatricians 3
. Many of the abnormalities in
the placenta have long been known to affect fetal outcomes.
Therefore, our study was aimed to ascertain the relationship
between placental histology and outcomes of premature
The present study was prospectively conducted in the
neonatal intensive care unit (NICU) of the Children
Hospital of Ankara University Faculty of Medicine between
November 2012 and February 2015, The Local Ethical
Committee and the Institutional Review Board (IRB) of
Ankara University School of Medicine approved the study
(IRB No. 05-2014-15). Informed consent was obtained
from the mothers enrolled in the study. This study was
performed only in accordance with the ethical standards provided by the responsible committee of the institution
and in accordance with the Declaration of Helsinki.
Placentas of singleton pregnancies resulting in preterm
hospitalized babies less than 35 weeks of gestational age
were included. Multiple pregnancies, infants who were
born ≥ 35 weeks of gestation, infants with major congenital
anomaly and infants whose parents refused informed
consent were excluded from the study. Pregnancy-related
issues and neonatal outcomes such as neonatal morbidities
and mortality were retrieved from the medical records.
Data Collection (demographic characteristics and
Birth weight (BW), gestational age (GA), small for gestational
age (SGA), antenatal steroid exposure, preeclampsia,
gestational diabetes mellitus (GDM), gender, type of
delivery, premature rupture of membranes (PPROM),
preterm labor (PTL), early onset neonatal sepsis (EOS),
positive blood cultures (culture proven), requirement of
delivery room resuscitation, five minute Apgar score <7,
duration of mechanical ventilation (MV), noninvasive
ventilation (NIV) and oxygen supplementation, duration
of neonatal intensive care unit (NICU) stay and day of
starting full enteral feeding were recorded. Additionally,
clinical outcomes including respiratory distress syndrome
(RDS) 8, intraventricular hemorrhage (IVH) (grade ≥3),
hemodynamically significant patent ductus arteriosus
(hsPDA)(9), moderate or severe bronchopulmonary
dysplasia (BPD), retinopathy of prematurity (ROP)
requiring laser treatment, and necrotizing enterocolitis
(NEC) (grade ≥2), mortality were recorded.
Preeclampsia was identified according to the following
criteria including hypertension (blood pressure of mothers
≥130/90 mmHg) along with proteinuria (1+ or 2+ protein on
a dipstick recognized by using two different urine samples
that were checked with 6-hour intervals or proteinuria >0.3
grams after a 24-hour urine collection) 10. Gestational
diabetes mellitus, called pregnancy-induced diabetes, was
diagnosed by an abnormal glucose tolerance test 11.
Spontaneous rupture of membranes without onset of
labor < 37 weeks of gestation was determined as preterm
premature rupture of membranes 12.
Small for gestational age was determined as a birth weight
below the 10th percentile for GA according to Lubchencho
curves 13. Bronchopulmonary dysplasia was identified as
continuing oxygen supplementation in the post conceptual
36 weeks of age 14. Intraventricular hemorrhage was
diagnosed by transfrontal ultrasonography in the first week of life 15. Modified Bells criteria were used for the
diagnosis of NEC 16. Retinopathy of prematurity was
diagnosed by skilled ophthalmologists according to the
international classification of retinopathy of prematurity
revisited 17. Early onset sepsis was distinguished as
culture proven or clinical sepsis 18.
Preparation of Placental Tissues
The obtained placenta tissue samples were kept in formalin
for at least 24 hours. Then, at least four specimens were taken
from each placenta including two from the maternal and two
from the fetal side, and additional samples were obtained
from regions detected by macroscopic examination at the
same time. Moreover, tissue samples from four different
parts of the umbilical cord and placental membranes were
allocated. These obtained tissue samples were subjected
to alcohol and then paraffin embedded. Paraffin blocks
were cut in to 3-4 μm sections using a microtome (Leica
SM 2000, Germany). Slides were stained with hematoxylin
and eosin and evaluated under a light microscope for
histopathological findings. All histopathological analyses
described were performed by an investigator with no prior
knowledge of the groups. All sections were examined on
slides at x100 magnification.
Placentas were divided into three groups and assigned as
normal placenta, vasculopathy (VP) and chorioamnionitis
(CA) groups. The current Amsterdam Placental Workshop
Group Consensus Statement which provides eleven
different categories was used to evaluate and classify the
pathological findings of the placentas 19. Vasculopathy
was defined based on certain findings such as placental
vascular processes (maternal stromal-vascular lesions
and fetal stromal-vascular lesions). Chorioamnionitis
was defined as placental inflammatory-immune processes
(infectious inflammatory lesions and immune/idiopathic
inflammatory lesions) 19. Normal histopathological
findings were identified as the normal placental group
(Figure 1A-C). Histopathological examinations of the
placentas were performed at the Pathology Department of
Ankara University. All slides were examined by the same
pathologist in a blinded fashion.
Click Here to Zoom
|Figure 1: A) Normal placenta: indicating normal placental tissues (H&E; x100). B) Vasculopathy: indicating neutrophils as a vital reaction
to the retroplacental hemorrhage, syncytial knots and intervillous fibrin deposition (H&E; x100). C) Chorioamnionitis: indicating
neutrophils in the subchorial intervillous space (H&E; x100).
Statistical Package for Social Sciences (SPSS) version 15 for
Windows (SPSS Inc., St. Louis, MO) were used to compare
variables, and a p value < 0.05 was considered significant.
The t-test and/or Mann-Whitney U-test were implemented
to compare non-parametric continuous variables between
groups. Categorical variables were analyzed by using chi-square or Fishers exact tests. Continuous variables
were stated as mean ± standard deviation (SD), and/or
median (minimum-maximum). Categorical variables were
expressed as percentage and distribution of frequency.
During the study period, 298 singleton preterm infants, who
were born < 35 weeks of gestation, were evaluated among
1034 hospitalized newborns. The placentas of 4 patients
with major congenital malformation and 10 patients who
refused to participate in the study were excluded. The
pathology was normal in 96 (33.8%), VP in 153 (53.9%)
and CA in 35 (12.3%) (Figure 2
Click Here to Zoom
|Figure 2: Flow diagram of
assessing and including eligible
participants in the trial.
The mean GA of the infants in the study group was 30.5 ±
3.2 weeks, and mean BW was 1588 ± 581 g. Demographic
variables and clinical outcomes are shown in Table I and II.
The mean GA (28.5±3.2 weeks) and delivery by cesarean
section (51.4%) were found to be significantly lower in the
CA group compared with the other two groups of normal
pathology and VP groups. Additionally, in the CA group,
PPROM, EOS and PTL were determined to be significantly
higher than the other two groups (normal and VP groups)
(p<0.05). In the CA group, ROP requiring laser treatment,
duration of NIV and oxygen requirement, NICU stay were
shown to be significantly higher (p=0.010, p=0.002, p=0.015,
p=0.005) than in the normal and VP groups (Table I and II).
In the VP group, SGA, preeclampsia, and female sex were
found to be significantly higher (p=0.037, p<0.001, p=0.009,
p=0.022) when compared with the normal pathology and
CA groups (Table I). The birth weight was found to be
higher in the normal group (p <0.001) and day of starting
full enteral feeding were lower than in the other groups
(p=0.011) (Table I and II).
The outcomes were the same among all groups in terms of
antenatal steroid administration, GDM, positive bacterial
culture, requirement of delivery room resuscitation, five
minute Apgar score <7, the duration of MV, RDS, IVH
(grade ≥3), hsPDA, BPD, NEC (grade ≥2), and mortality
(p>0.05) (Table I and II).
In the literature, several studies have separated the placenta
as either CA or VP for histopathological examination, and
the results have been discussed after the main groups were
divided into subgroups. It is known that there are many
factors affecting placental pathology. The main aim of this
study was to evaluate the effects of placental pathologies on
preterm infants. As far as we know, our study included both
low gestational ages and all placental histopathologies for
the first time. Therefore, we did not divide the patients into
more subgroups, and the results obtained by comparing
these groups were discussed.
The placental histopathology, including term and preterm
deliveries have declared that the placental VP rate ranges
between 3.5% and 6.4% 20,21. The vasculopathy rate in
pregnancy induced hypertension are observed to rise to as
high as 82% 1. Particularly, VP was found to be higher
in pregnant women with preeclampsia, and according to
our findings, the present VP rate was consistent with the
recent literature data. This result emphasized the fact that
placental VP is associated more closely with prematurity
and SGA. These findings were obviously parallel to recent
literature data 22,23. In recent studies, the relationship
between preeclampsia / SGA and fetal and maternal face
placental pathology due to vascular mal-perfusion has been
shown based on the new placental classification 23-25.
That is, infants with small gestational age can be seen in
any of the subgroup of histopathological VP. This may be
a sign that placental perfusion is impaired for any reason.
The available evidence supports that there is no relationship
between placental pathology and gender 26,27. Kim et al.
found that the male gender ratio was high in the CA group
28. According to our results, the female gender ratio in
the VP group was higher. However, we did not have the
markers related to VP. It may be speculated that gender
could affect placental pathology.
Placental VP, which causes utero-placental deficiency,
may lead to fetal circulatory adaptive changes to hypoxia.
Necrotizing enterocolitis may develop after hypoxicischemic
injury of the bowel 12. It has been found in the
literature that there is a relationship between NEC and fetal
vascular obstructive lesions (fetal thrombotic vasculopathy,
congested villi, coagulation-related lesions), with a ORs
ranging from 2.6 to 9.1 3. These results support the idea
that placental lesions such as VP emerging at low GA in
utero have a slight effect on the NEC. Such contradictory
data suggest that pathophysiological mechanisms outside
of those related to histologic VP lesions may also be
responsible for adverse effects on the infants health. It is known that placental VP causes fetal hypoxemia and
may lead to PTL through cytokines 29. Although no
relationship has been found between CA and PPROM and
PTL in term infants, we found a fine association between
CA and PPROM and PTL in preterm infants 6,26,27.
Premature rupture of membranes is observed in 2-3.5%
of term, but in up to 30-40% of preterm deliveries 30,31.
PPROM increases the incidence of CA by up to 48% 32.
In our study, the PPROM incidence was determined to be
9.3% in the normal placenta group; however, it was 40%
in the CA group. As expected, we found that the EOS
incidence was higher (10-fold) in the CA group compared
to the normal placental group.
During pregnancy, the incidence of histopathological
CA varies from 11.5 to 57.3% 27. However, it has been
determined that the incidence of CA is 60-80%, 40-50%, and
5-30% in deliveries according to GA, involving <28 weeks,
between 29 and 34 weeks, and > 34 weeks, respectively 33.
In one study, the CA rate was particularly considerable in
deliveries less than 30 weeks with a rate of 83.3%. However,
mothers without CA have given birth on the 31st gestational
week on average. In contrast, in the CA group, the delivery
week has been observed to decrease to 27 weeks 18. In
our study, the CA rate was found to be lower (12.3%) than
in current data. This result suggests that VP may be a more
prominent placental lesion than CA as the gestational week
Although, preterm delivery rate was much lower in the
normal placental group than in CA and VP. Normal vaginal
delivery was found to be higher in the CA group due to
PPROM and PTL. Based on this data, day of starting full
enteral feeding and duration of NICU stay were found
to be shorter. Moreover, laboratory findings of sepsis
such as higher C-reactive protein, white blood cells and
interleukin-6 were remarkably increased, and EOS rate
was high in the CA group in the present study. However,
neonatal sepsis may not always be associated with CA
4,27. Our results supported and were consistent with
current evidences 28,34. Although the probable EOS rate
may be high in the CA group, culture-proven EOS may not
always be found.
Antenatal steroids have been reported to reduce some of
the adverse effects of CA such as IVH and RDS in preterm
infants and reduce mortality by suppressing inflammation
35. A study conducted by Perrone et al. has reported
that the application of antenatal steroids does not change
the frequency of CA in pregnant women 2. Additionally,
CA increases the rate of RDS unrelated to antenatal steroid
administration. In our study, antenatal steroid usage and RDS were similar among the groups. Current evidence
has shown the higher risk of RDS in infants with placental
abruption, and it is already known that CA decreases
the risk of RDS 36,37. In contrast, we did not find any
relationship between CA and risk of RDS 26,38.
Inflammatory conditions in the placenta affect the lung
development in utero and cause respiratory problems after
birth such as RDS and BPD. Current evidence supports that
CA reduces the incidence of RDS. CA can also promote BPD
3,39. However, in our study, RDS and BPD were found to
be similar among the groups. A recent study has supported
our results 40. Another study reported that funisitis
increases the risk of BPD 41. However, in many studies,
no association found between the presence of placental
funisitis and BPD 28,40,42-44. The relationship between
histopathological CA or subgroups and BPD is still unclear.
That means that RDS and BPD not only result from CA but
they might also arise from the adverse effects of preterm
delivery. Many factors (multiple hits hypothesis) involving
SGA, low gestational age, genetic predisposition, and
postnatal insults (hsPDA, sepsis and mechanical ventilation
therapy) have been suggested to be associated with BPD
40,45. Duration of respiratory support and NICU stay
were longer in infants subjected to CA in our study. It may
be due to prematurity and the nature of inflammation in
the lungs in CA group. This hypothesis suggests that BPD
emerges due to antenatal exposure to a proinflammatory
condition that is followed by postnatal triggering insults
45. In the present study, our findings could not rule out
Infectious and inflammatory events such as clinical CA
may be a risk factor for NEC, IVH, and PDA 26,46,47.
However, as supported with our results, CA might not
always be related to severe morbidities like NEC, IVH, PDA
and mortality 26,28,38,48. Retinopathy of prematurity is
another adverse effect of preterm delivery that is particularly
related to inflammatory lesions in the placenta 3. The
severity of ROP was also determined to be positively
associated with ascending intrauterine infections 45. Kim
et al. demonstrated that ROP requiring laser treatment
was found to be higher in infants exposed to CA 28. In
contrast, some evidence has indicated that there may not
be an association between inflammatory conditions and
ROP 26. Therefore, these results might be related to more
prematurity in the infants in the CA group.
We are aware of the study limitations. Our limitations can be
stated as follows: 1) inflammatory cytokine levels were not
measured in the cord blood, 2) the pH of umbilical arterial
PH could not be measured immediately after delivery, 3) the study groups had a relatively limited size, 4) placental
measurements of the subjects (placental weight, placental
area, cord length, birth weight/placental weight ratio) could
not be assessed, 5) the VP and CA criteria had a broad
range. It is a reality that many different factors affect the
placental pathology. However, this study aimed to evaluate
the effect of major placental pathologies like VP and CA on
In conclusion, it is obvious that placental pathologies affect
the outcomes of newborn infants from the intrauterine
to the postnatal period. Particularly infants delivered by
mothers with CA were found to be more preterm, and
these preterm infants could have a long hospital stay, higher
respiratory support requirement, and morbidities such as
EOS and ROP requiring laser treatment. Additionally, VP
leads to higher rate of SGA infants. In contrast to some
studies on placental pathology, our results demonstrated
a lower incidence of CA as well as a higher rate of VP.
All in all, each infant is born with the risks of his or her
own placenta and gestational age. The placenta is a secret
witness for every infant. Physicians should be aware that
the relationship between placental histology and the
outcome of the premature infant is a reality. Further studies
are warranted to evaluate the significance of placental
pathologies prior to making any clinical decision.
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.
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