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ISSN: 1476-7058 (print), 1476-4954 (electronic)
REVIEW ARTICLE
Sheva, Israel
Abstract Keywords
‘‘What does it mean, Doctor?’’ and ‘‘Is it going to affect my baby in some way?’’. Chorioamnionitis, Grannum grade,
placental histology, pregnancy
outcomes, ultrasound
Those are the most typical questions of pregnant women to obstetricians. Answering is
sometimes easier but placental calcification is not the case, since placental architecture and
disease are two different faces of the same coin and the association between them is not History
completely clear. Placenta can function properly, even in the presence of architectural Received 13 January 2015
alterations, without any fetal consequences. So, remains the question, when does a placental Revised 11 February 2015
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structural anomaly become a sign of increased attention to maternal conditions, fetal Accepted 24 February 2015
development and well-being? The present review will analyze these concepts, with emphasis Published online 19 March 2015
on placental calcification, its pathogenesis, and the state-of-the-art regarding the influence of
this finding on pregnancy outcomes among low-risk pregnant patients.
calcification (physiological, dystrophic and metastatic calci- feto–placental perfusion (from day 9.5 of mouse gestation
fication) in these models [7–10]. [25]), then high concentrations of calcium may accumulate in
the area of the ectoplacental cone thereby inducing, in mice,
Physiological calcification metastatic calcifications at this site.
In humans, calcium is actively transported across the
In physiological calcification, as observed in teeth and bones,
placenta throughout gestation, making the fetus relatively
osteoblasts produce osteoid matrix providing hydroxyapatite
hypercalcemic [26,27]. This supports the growing fetal
formation in and on collagen fibers. This process, during the
skeleton and is mediated primarily by the fetal parathyroid-
embryonic period, is controlled by a group of molecules
related protein, which greatly increases its concentration
named bone morphogenic proteins (BPMs) that play an
throughout gestation, rather than the maternal parathyroid
important role in fetal development as well [9]. In mice, one
hormone [28]. Calcium binding proteins are thought to buffer
of these proteins, BMP7 (also known as osteogenic protein-1),
the process, preventing disruption of intracellular processes
is highly expressed, adjacent to the implantation site, in the
[29]. The hypothesis that aims to explain metastatic calcifi-
mesometrial region of the decidua, at 7.0–7.5 d gestation in
cations is based on the possibility that, a condition of
presence of extensive calcium deposition [4]. In humans,
abnormal fetal calcium utilization (as proposed in IUGR
BMP7 is expressed in placental cytotrophoblast cells in early
fetuses, showing delayed appearance of ossification sites [30])
pregnancy [7]. The same protein is capable of inducing
can lead to a passive placental diffusion of calcium back to
ectopic bone formation in vivo, in mice [11]. Also, other
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by HINARI on 07/09/15
to assess placental calcifications and maturity by ultrasound, calcification [35]. As a consequence, even if this system
and it was thought to represent a standard in the evaluation of is considered the gold standard for placental grading,
fetal health in late pregnancy [34]. It is a practical classifi- a Cochrane review recommended to perform future research
cation of placental maturity based on a review of multiple on placental textural assessment in late pregnancy [36].
ultrasound evaluations of placental texture over a 4-year
period. This classification grades placentas from 0 to 3
Correlation between ultrasonographic findings and
according to specific ultrasonic findings at the basal and
placental histology
chorionic plates as well as within the substance of the organ
itself [34]. Following this classification, a grade 0 placenta In most sonographic examinations, evaluation of the placenta
has an easily delineated, relatively straight chorionic plate and is confined only to identification of its site. Detailed
a homogeneous texture (Figure 1). A grade 1 placenta is assessment of placental architecture is performed mainly
characterized by an undulatory chorionic plate and scattered when maternal or fetal disease are suspected and definitive
echogenic areas (Figure 2). Grade 2 is recognized by the diagnosis of placental disease is generally obtained after
presence of small echogenic areas along the basal layer of the delivery, by pathological examination [37]. Unfortunately, the
placenta and comma-like echogenic densities that originate at correlation of antenatal detection of placental disease and
the chorionic plate (Figure 3). A grade 3 placenta is postnatal placental histology is limited. A recent report
characterized by echogenic indentations extending from the by Cooley et al. [37] has aimed to concentrate on such
chorionic plate to the basal layer dividing the placenta into an association. In that prospective study, 1011 low-risk
discrete components, resembling cotyledons (Figure 4). In primigravid patients were included. Placental sonographic
addition, irregular densities that cast acoustic shadows are characteristics were assessed at gestational age of 22–24 and
occasionally present near the chorionic plate. 34–36 weeks. Grannum grade was defined and placental
A shortcoming of the ultrasound is that, despite standar- calcifications were described at 34–36 weeks gestation. After
dized observational conditions, Grannum grading of the delivery, all placentas were evaluated by a clinical patholo-
placenta represents a subjective method to estimate placental gist. The presence of placental calcifications was associated,
4 S. A. Mastrolia et al. J Matern Fetal Neonatal Med, Early Online: 1–7
with a significantly higher incidence of placental infarctions prospective study aiming to provide a quantitative, reprodu-
identified after pathological examination (80% versus 21.5%; cible grading system based on the assessment of placental
p ¼ 0.009: r ¼ 0.115). Of interest, chorioamnionitis occur- calcifications, starting from 2D ultrasound images. Their so-
rence was noted with the increase of Grannum grade [37]. called placentometer, is a software for digital placental
The association between antenatal sonographic diagnosis analysis that was employed on 90 patients, undergoing
of placental calcifications and histologic findings of placental ultrasound examination, to assess fetal biophysical profile at
infarcts raises the importance of the ultrasound on the impact 41 + 5 weeks’ of gestation. Placentas had already been
of impaired placental blood flow. Placental infarcts, resulting evaluated 7 d before and assigned a Grannum grade by the
from chronic vascular placental impairment, are common at same experienced fetal medicine specialist.
term but fetal and neonatal morbidity increases when more This study found a significant correlation between the
than 5% of the placental bed is involved or when the diameter percentage of calcification, defined with the software, and
of the infarcts is larger than 3 cm [1]. Indeed, the association Grannum grades, but had several limitations represented by
between placental infarcts, preeclampsia, and fetal acidosis (1) the small number of participants and (2) the gestational
has been outlined in previous studies [37,38]. The evidence age of the patients, since finding placental calcifications
reported herein suggests that the sonographic detection of before 36 weeks has been associated with bad obstetrical
placental calcifications is correlated with placental and outcomes and is of the highest interest [38].
pregnancy pathologies and this correlation emphasizes the
value of placental antenatal assessment. Placental calcification and pregnancy outcomes
Placental calcifications commonly increase with gestational
Computerized assessment
age, becoming typically apparent after 36 weeks of gestation
In order to increase the objectivity in the diagnosis of [40]. A Grade 3 placental calcification has been described
placental calcifications, Moran et al. [39] designed a in 39.4% of women at term [41], reaching a peak of 54% at
DOI: 10.3109/14767058.2015.1023709 Meaning of placental calcification in low-risk pregnancies 5
42 weeks [42]. Many textbooks define this finding to be of no and those with a diagnosis of hypertension, diabetes, anemia
clinical significance [43,44]. or placenta previa were excluded from the study. They found
Moreover, data about the association between placental a significant difference between the three groups, in
calcifications and adverse pregnancy outcome are controver- maternal outcomes (including postpartum hemorrhage,
sial. Several studies have focused on the association between maternal transfer to the intensive care unit, placental
placental calcifications detected before 36 weeks gestation abruption) and fetal outcomes (low birth weight, low
and pregnancy outcome, finding an increased incidence Apgar score, neonatal death). After performing a logistic
of intrauterine growth restriction [45–48], low birth weight regression to compare the differences in pregnancy out-
[45,46,48,49], low Apgar score [49], fetal distress [48] and comes among the groups, adjusted for confounders (maternal
pregnancy-induced hypertensive disorders [45,47,50]. In age, body mass index, economic status, marital status, mode
contrast, other studies did not find the same association of delivery, parity) the risks of adverse pregnancy outcomes
[51–53] and suggested that preterm placental calcifications were higher in the group with placental calcifications
have little value in switching the pregnancy label from low detected before 32 weeks than the control group (postpartum
risk to high risk or increasing the level of attention into hemorrhage, OR 3.43; 95% CI, 1.251–9.388; placental
an already high-risk patient. abruption OR 6.52; 95% CI, 1.356–31.382; maternal transfer
The shortcoming of the above-mentioned conclusions to the ICU OR, 9.76; 95% CI, 1.826–52.195; preterm birth
stands in the fact that the majority of studies have small OR, 4.20; 95% CI, 1.775–9.940; low birth weight OR 4.58;
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by HINARI on 07/09/15
groups of participants and, in some of them, the effect of 95% CI, 2.201–9.522; low Apgar score OR 6.53;95% CI,
confounders like cigarette smoking, diabetes or hypertension 2.116–20.142; and neonatal death OR 9.04;95% CI, 1.722–
are not considered, increasing the risk for incorrect interpret- 47.411). No significant differences were found between
ation of the results. In addition, many different instruments patients with placental calcifications detected between 32
and study designs were used, drawing a confusing picture and 36 weeks and the control group.
from which extracting any conclusions or recommendations is The evidence presented herein suggests that isolated
hardly possible. In some cases, since they were performed placental calcifications can be associated, in an otherwise
many years ago, ultrasound equipment of poor resolution was low-risk pregnancy, to an increased risk of pregnancy
employed, making the results questionable. maternal complications with conflicting data regarding fetal/
Some more recent considerations have tried to clarify the neonatal outcomes. However, the most recent studies consider
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issue regarding the clinical meaning depicted by placental pregnancy maternal and fetal/neonatal outcomes only with
preterm calcification on pregnancy (maternal and fetal/ regard to Grannum Grade 3 calcifications and do not extend
neonatal) outcome. their analysis to the association between these conditions and
the other Grannum classification grades.
In light of the fact that the pathogenesis for the presence of
Placental calcification and pregnancy outcomes:
placental calcium crystals is not completely clear, an
recent evidences
approach exclusively based on the grading of calcium deposits
In 2005, McKenna et al. [41] studied prospectively 1802 low- is probably not justified.
risk patients at 36 weeks of gestation in order to (1) evaluate
the incidence of Grade 3 calcification using Grannum
Conclusion
classification and (2) investigate the association between a
Grannum Grade 3 placentas and pregnancy outcome. A challenge in modern obstetrics is to unmask high-risk
In their study, 3.8% (n ¼ 68) of patients have developed patients hidden within the low-risk pregnant population. The
Grade 3 placental calcifications at 36 weeks’ gestation. proper assessment of the association between placental
Among them, there was an increased risk for (1) induction of calcifications and pregnancy outcomes can be useful for the
labor due to signs of fetal compromise (RR 4.65; 2.57, 8.44; purpose.
p50.01); (2) delivery of low birth weight neonates below the Literature dealing with this topic is lacking and conflict-
10th percentile for weight at birth (RR 3.13; 1.81, 5.41; ing, but the reports regarding increased risk for adverse
p50.01); and (3) developing preeclampsia at term (RR 4.7; maternal and fetal/neonatal outcomes in presence of preterm
1.87, 11.83; p50.01). In addition, the finding of Grannum placental calcifications cannot be ignored. As a consequence,
Grade 3 placental calcifications was not associated, in this more attention should be paid to patients with preterm
study, with poor fetal/neonatal outcomes including the need placental calcifications and no risk factors for such a finding,
for neonatal resuscitation and admission to NICU [41]. even in pregnancies that are considered to be at low risk for
In another study, Chen et al. [54] evaluated prospectively developing complications.
a cohort of low-risk pregnancies in order to study the Further well-designed studies, with appropriate selection
significance of placental Grade 3 calcifications detected at of inclusion and exclusion criteria and the employment of
different gestational ages. Three groups were created: (1) adequate instrumental settings are needed to give more
patients with placental calcifications diagnosed before 32 convincing answers regarding the clinical significance of
weeks of gestation (n ¼ 63); (2) patients with placental placental calcifications and their impact on pregnancy. In
calcifications diagnosed between 32 and 36 weeks (n ¼ 192); addition, in order to improve the clinical interpretation of
and (3) a control group without placental calcifications placental disease, the task of a better correlation between
established between 28 and 36 weeks (n ¼ 521). Patients antenatal ultrasonographic and postnatal histopathologic
smoking cigarettes or drinking alcohol during pregnancy, placental evaluation should be addressed.
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