The Role of Preterm Placental Calcification in High-Risk Pregnancy as a Predictor of Poor Uteroplacental Blood Flow and Adverse Pregnancy Outcome

Abstract

This prospective cohort study aims to clarify the role of preterm placental calcification in high-risk (i.e., hypertension, diabetes, placenta previa or severe anemia) pregnant women as a predictor of poor uteroplacental blood flow (absent or reverse end-diastolic velocity [AREDV]) and adverse pregnancy outcome. Monthly ultrasound was performed starting at 28 weeks' gestation to establish the diagnosis of Grade III placental calcification, with measurement of Doppler velocimetry in the umbilical vessels at 32 weeks' gestation. The participants were classified into three groups: Group A (n = 776), a low-risk group without antenatal complication; group B (n = 42), a high-risk group with preterm (28 to 36 weeks) placental calcification; and group C (n = 71), a high-risk control group without preterm (<36 weeks) placental calcification. Analyzed by logistic regression, the risks of AREDV (OR 4.32, 95%CI 1.25 to 14.94), adverse maternal outcome including postpartum hemorrhage (OR 3.98, 95% CI 1.20 to 13.20), placental abruption (OR 4.80, 95% CI 1.19 to 19.35), maternal transfer to intensive care unit (OR 3.83, 95% CI 1.10 to 13.33) and adverse fetal outcome including preterm birth (OR 3.86, 95% CI 1.32 to 11.29), low birth weight (OR 2.99, 95% CI 1.11 to 8.03), low Apgar score (OR 5.14, 95% CI 1.64 to 16.08) and neonatal death (OR 4.52, 95% CI 1.15 to 17.73) were greater in group B compared with group C. In contrast, the risks of AREDV and adverse pregnancy outcome were significantly lower in group A than those in group C, except postpartum hemorrhage (OR 0.53, 95% CI 0.19 to 1.46). We conclude that in high-risk pregnant women, the presence of preterm placental calcification is a predictor of poor uteroplacental flow and adverse pregnancy outcome, requiring closer surveillance for maternal and fetal well-being. This finding helps identify the most dangerous population among high-risk pregnant women.

Full text

This article appeared in a journal published by Elsevier. The attached
copy is furnished to the author for internal non-commercial research
and education use, including for instruction at the authors institution
and sharing with colleagues.
Other uses, including reproduction and distribution, or selling or
licensing copies, or posting to personal, institutional or third party
websites are prohibited.
In most cases authors are permitted to post their version of the
article (e.g. in Word or Tex form) to their personal website or
institutional repository. Authors requiring further information
regarding Elsevier’s archiving and manuscript policies are
encouraged to visit:
http://www.elsevier.com/copyright

Author's personal copy
dOriginal Contribution
THE ROLE OF PRETERM PLACENTAL CALCIFICATION IN HIGH-RISK
PREGNANCY AS A PREDICTOR OF POOR UTEROPLACENTAL BLOOD FLOW
AND ADVERSE PREGNANCY OUTCOME
KUO-HUCHEN,
*yz
LI-RUCHEN,
x{
and YU-HSIANG LEE
*
*Department of Obstetrics and Gynecology, Buddhist Tzu-Chi General Hospital, Taipei Branch, Taipei, Taiwan;
y
School of
Medicine, Tzu-Chi University, Hualien, Taiwan;
z
Graduate Institute of Health Care Organization Administration, College of
Public Health, National Taiwan University, Taipei, Taiwan;
x
Mackay Memorial Hospital, Taipei, Taiwan; and
{
School of
Biomedical Science and Engineering, National Yang-Ming University, Taipei, Taiwan
(Received 22 October 2011; revised 6January 2012; in final form 5February 2012)
Abstract—This prospective cohort study aims to clarify the role of preterm placental calcification in high-risk (i.e.,
hypertension, diabetes, placenta previa or severe anemia) pregnant women as a predictor of poor uteroplacental
blood flow (absent or reverse end-diastolic velocity [AREDV]) and adverse pregnancy outcome. Monthly ultra-
sound was performed starting at 28 weeks’ gestation to establish the diagnosis of Grade III placental calcification,
with measurement of Doppler velocimetry in the umbilical vessels at 32 weeks’ gestation. The participants were
classified into three groups: Group A (n5776), a low-risk group without antenatal complication; group B (n5
42), a high-risk group with preterm (28 to 36 weeks) placental calcification; and group C (n571), a high-risk
control group without preterm (,36 weeks) placental calcification. Analyzed by logistic regression, the risks of
AREDV (OR 4.32, 95%CI 1.25 to 14.94), adverse maternal outcome including postpartum hemorrhage (OR
3.98, 95% CI 1.20 to 13.20), placental abruption (OR 4.80, 95% CI 1.19 to 19.35), maternal transfer to intensive
care unit (OR 3.83, 95% CI 1.10 to 13.33) and adverse fetal outcome including preterm birth (OR 3.86, 95% CI 1.32
to 11.29), low birth weight (OR 2.99, 95% CI 1.11 to 8.03), low Apgar score (OR 5.14, 95% CI 1.64 to 16.08) and
neonatal death (OR 4.52, 95% CI 1.15 to 17.73) were greater in group B compared with group C. In contrast, the
risks of AREDVand adverse pregnancy outcome were significantly lower in group A than those in group C, except
postpartum hemorrhage (OR 0.53, 95% CI 0.19 to 1.46). We conclude that in high-risk pregnant women, the pres-
ence of preterm placental calcification is a predictor of poor uteroplacental flow and adverse pregnancy outcome,
requiring closer surveillance for maternal and fetal well-being. This finding helps identify the most dangerous pop-
ulation among high-risk pregnant women. (E-mail: alexgfctw@yahoo.com.tw)Ó2012 World Federation for
Ultrasound in Medicine & Biology.
Key Words: Preterm placental calcification, High-risk pregnancy, Doppler velocimetry, Maternal outcome,
Fetal outcome.
INTRODUCTION
Grade III placental calcification, characterized by signifi-
cant formation of indentations or ringlike structures within
the placenta (Harris and Alexander 2000)(Fig. 1), is often
found in pregnancy at term and regarded as a physiological
aging process (Harris and Alexander 2000;Nolan 1998;
Spirt and Gorden 2001). However, its earlier presence,
before 36 weeks’gestation (preterm placental calcification)
may represent an unusual pathological change. The preva-
lence of preterm placental calcification ranges widely from
3.8% (McKenna et al. 2005)to23.7%(Chitlange et al.
1990). Given the placenta’s importance in oxygen and
nutrition transportation, many structural (e.g.,jellylike
(Raio et al. 2004)) and functional abnormities of the
placenta contribute to fetal growth restriction and adverse
fetal outcomes. Although many textbooks state that
placental calcification is of no clinical significance
(Harris and Alexander 2000;Nolan 1998;Spirt and
Gorden 2001), McKenna et al. (2005) observed that finding
Grade III placental calcification at 36 weeks’ gestation was
associated with pregnancy-induced hypertension and fetal
growth restriction. Furthermore, we have found that early
preterm placental calcification (noted at 28 to 32 weeks’
gestation) is an indicator of adverse pregnancy outcomes
Address correspondence to: Professor Kuo-Hu Chen, Department
of Obstetrics and Gynecology, Buddhist Tzu-Chi General Hospital, Tai-
pei Branch, No. 289, Jianguo Road, Xindian, New Taipei City, Taiwan.
E-mail: alexgfctw@yahoo.com.tw
1011
Ultrasound in Med. & Biol., Vol. 38, No. 6, pp. 1011–1018, 2012
Copyright Ó2012 World Federation for Ultrasound in Medicine & Biology
Printed in the USA. All rights reserved
0301-5629/$ - see front matter
doi:10.1016/j.ultrasmedbio.2012.02.004

Author's personal copy
(Chen et al. 2011). Nevertheless, both studies focus on the
low-risk pregnancy population. The role of preterm
placental calcification in high-risk (i.e., hypertension, dia-
betes, placenta previa or severe anemia) pregnant women,
as a predictor of poor uteroplacental blood flow and adverse
pregnancy outcome, remains unclear. Being an extension
of the existing studies in low-risk population, this research
aims to find the relationship between preterm placental
calcification and poor uteroplacental blood flow, as well
as adverse pregnancy outcome in high-risk populations.
In a review of the literature, the clinical significance
of placental calcification for pregnancy outcome appears
controversial. Some studies revealed that preterm
placental calcification is associated with intrauterine
growth restriction (Chitlange et al. 1990;Hills et al.
1984;McKenna et al. 2005;Patterson et al. 1983), low
birth weight (Chitlange et al. 1990;McKenna et al.
2005;Patterson et al. 1983;Proud and Grant 1987), low
Apgar score (Proud and Grant 1987), fetal distress
(Chitlange et al. 1990) and pregnancy-induced hyperten-
sion (Hills et al. 1984;Kazzi et al. 1984;McKenna et al.
2005), whereas other studies (Hill et al. 1983;Miller et al.
1988;Vosmar et al. 1989) reported that preterm placental
calcification is not associated with such negative findings
and is of little value in predicting pregnancy outcome
(Quinlan et al. 1982). Conflicting conclusions drawn
from these articles with different instruments and
different research designs are confusing. Nonetheless,
the major limitation of previous studies is that, except
for the work of McKenna et al. (2005) and our study
(Chen et al. 2011) in low-risk women, most studies
were done many years ago with ultrasound of poorer reso-
lution and fewer participants, which makes their conclu-
sions questionable. In addition, the finding time, the
grading of placental calcification and the division of
risk level in pregnancy were not distinct in many studies.
Furthermore, the mediating effects of potential
confounders such as cigarette smoking or alcohol
consumption were not considered in some studies and
thus some conclusions could be incorrect or misleading.
Moreover, there is a paucity of research evaluating the
effect of preterm placental calcification on maternal and
fetal outcome in high-risk women, among whom earlier
identification of an aggravating indicator would be bene-
ficial. It is, therefore, important to clarify the role of
preterm placental calcification in high-risk pregnant
women as a predictor of poor uteroplacental blood flow
and adverse pregnancy outcome, with more participants,
newer instruments of better resolution, and stricter selec-
tion criteria to reach a reliable conclusion.
MATERIALS AND METHODS
Study design and sample
Between July 2007 and June 2009, this prospective,
cohort study was conducted in a tertiary hospital with an
average of 200 or more deliveries per month. The hospital
provided ordinary obstetric clinics (available to all
women) for general low-risk pregnant women and special
obstetric clinics (requiring referral) for high-risk preg-
nancy. All pregnant women could receive prenatal care
in the ordinary obstetric clinic without referral. In
contrast, pregnant women in the ordinary obstetric clinic
who were noted to have antenatal complications and who
were referred form other hospitals because of antenatal
complications, were transferred to the special obstetric
clinic for evaluation and management of high-risk
pregnancy.
The study was approved by the local Institutional
Review Board of the hospital. Pregnant women in the
ordinary obstetric clinics and special obstetric clinics
were invited to participate in the study, and the volunteers
were screened by ultrasound for detection of placental
calcification. A written informed consent to participate
in the study was obtained from the volunteers before their
enrollment and screening for placental calcification.
Monthly ultrasound was performed starting at 28 weeks’
gestation to establish the diagnosis of preterm placental
calcification. Grade III placental calcification is recog-
nized by the presence of echogenic indentations extend-
ing from the chorionic plate to the basal layer dividing
the placenta into discrete components, resembling cotyle-
dons. The first ultrasound examination for the volunteers
was done between 28 and 32 weeks’ gestation and the
subsequent ultrasound examinations were arranged
once per month until delivery. Doppler velocimetry of
uteroplacental blood flow in the umbilical vessels was
performed at 32 weeks’ gestation. All ultrasound exami-
nations were performed using a Voluson 730 (GE
Medical Systems, Zipf, Austria) equipped with a 2.8- to
Fig. 1. Grade III placental calcification (according to the Gran-
num classification), showing diffuse echogenic lines (indenta-
tions) extending from the chorionic plate to the basal layer.
1012 Ultrasound in Medicine and Biology Volume 38, Number 6, 2012

Author's personal copy
10-MHz transabdominal transducer by one qualified
obstetrician to avoid interobserver bias. All images
were further reviewed by another experienced obstetri-
cian to ensure the accuracy of the diagnosis.
The participants were classified into three groups
according to the level of the risk in pregnancy, and the
time when placental calcification was initially confirmed
(Fig. 2): Group A consisted of low-risk pregnant women
without any notable antenatal complication before
delivery, irrespective of the time of presentation of
placental calcification; group B consisted of high-risk
pregnant women with notable preterm placental calcifica-
tion at 28–36 weeks’ gestation; group C (the control
group) consisted of high-risk pregnant women without
notable preterm placental calcification before 36 weeks’
gestation. ‘‘High-risk’’ pregnancies refer to pregnancies
complicated by chronic or pregnancy-induced hyper-
tension (including preeclampsia), severe anemia
(hemoglobin ,8 g/dL), placenta previa or diabetes
(either overt or gestational) when noted on antenatal
examination.
Poor uteroplacental blood flow was confirmed when
absent or reversed end-diastolic velocity (AREDV) was
found on Doppler velocimetry of the umbilical arteries.
Evaluated maternal outcomes at delivery included post-
partum hemorrhage (total blood loss $500 mL during
delivery), placental abruption and maternal transfer to
the intensive care unit (ICU). Evaluated fetal outcomes
at delivery included preterm delivery (delivery before
37 weeks’ gestation), low birth weight (,2500 g), low
Apgar score (,7 at 5 min after delivery) and neonatal
death.
Because smoking (Brown et al. 1988;Christianson
1979;Harris and Alexander 2000;Proud and Grant
1987;Ahluwalia et al. 1997) and alcohol consumption
(Wenman et al. 2004) are two major confounding factors
in placental calcification and pregnancy outcome, women
who smoked or drank alcohol during their pregnancies
were excluded from this study. In addition, multifetal
gestation is a risk factor for preterm delivery and post-
partum hemorrhage, and any woman carrying a fetus
with major congenital anomalies is at increased risk of
preterm delivery, low birth weight and poor neonatal
outcome. Therefore, women with multifetal gestations
or major fetal congenital anomalies found on antenatal
examination were also excluded from this study. Except
for the women who met the exclusion criteria mentioned
before, all pregnant women in the obstetric clinics were
Pregnant women who underwent
antenatal examination in the
clinic 2007–2009 (n = 1220)
Pregnant women willing to
participate in the study (n = 962)
Pregnant women who met the
inclusion criteria: enrolled
participants (n = 889)
Excluded: (n = 73)
Pregnant women who smoked or
consumed alcohol during
pregnancy; multifetal gestation;
major fetal congenital anomalies
Group A: low-risk women without
any notable antenatal complication
before delivery, irrespective of the
presenting time of placental
calcification (n = 776)
Group B: high-risk women with
notable preterm placental
calcification at 28–36 weeks’
gestation (n = 42)
Group C (the control group):
high-risk women without notable
preterm placental calcification
prior to 36 weeks’ gestation (n =
71)
Fig. 2. Flow chart for selection and grouping of the participants, with placental calcification noted at different stages
of pregnancy.
Preterm placental calcification in high-risk pregnancy and adverse pregnancy outcome dK.-H. CHEN et al. 1013

Author's personal copy
asked to volunteer for the study. Participants were re-
cruited by means of ordinary survey rather than obstetri-
cian’s preference (highly selected samples) to decrease
the selection bias.
Basic information on the participants, including age,
body mass index, economic status, marital status, parity
and medical history, were obtained at the first antenatal
visit. The determination of gestational age was based
principally on the last menstrual period, and the valida-
tion of true gestational age was confirmed by ultrasound
measurement of fetal development in early pregnancy. If
there was a significant discrepancy (.1 week) between
them, another ultrasound scan of growth measurement
was arranged to determine the practical gestational age.
With regard to economic status, ‘‘poor’’ was defined as
having a per capita income ,50% of the median accord-
ing to the definition of the European Union (Haughton
and Khandker 2009). Ascertainment of smoking or
alcohol consumption during pregnancy, identification of
major congenital anomalies or placenta previa by ultra-
sound and the diagnosis of pregnancy-induced hyperten-
sion, pre-eclampsia and gestational diabetes were made
on subsequent visits between 12 and 28 weeks’ gestation.
We recorded the conditions of participants and newborns
at delivery and monitored the infants for three months
after delivery.
Data analysis
Data were collected and analyzed using SPSS 16.0
(SPSS Inc., Chicago, IL, USA). The statistics we used
in this study included descriptive statistics, c
2
test, log
linear analysis (for expected numbers ,5) and analysis
of variance (ANOVA) to compare the differences in
personal characteristics and in poor uteroplacental blood
flow, as well as in pregnancy outcomes in the three
groups. We performed logistic regression analyses to esti-
mate the risks of AREDV and adverse pregnancy
outcomes in groups B and A when compared with group
C (the control group). The odds ratios (OR) and 95%
confidence intervals (CIs) for each group were calculated
and presented after adjusted by the effects of maternal
age, body mass index, economic status, marital status,
parity and type of delivery on AREDV and maternal
and fetal outcomes.
RESULTS
Characteristics of participants
A total of 889 participants were divided into three
groups: group A (n5776), a low-risk group without
any notable antenatal complication during pregnancy;
group B (n542), a high-risk group with notable preterm
placental calcification at 28–36 weeks’ gestation; and
group C (the control group, n571), a high-risk group
without notable preterm placental calcification at 28–36
weeks’ gestation (Fig. 2).
The characteristics of the participants in the three
groups are shown in Table 1. The total numbers of
divorced and widowed women were both ,10 and were
included in the married category. There were no signifi-
cant differences in economic status, marital status, parity,
maternal age and body mass index among the three
groups. In all three groups, the majority of women were
married and nulliparous at presentation, had a vaginal
delivery and were classified as ‘‘non-poor’’ in economic
status. In all three groups, the average maternal age was
about 26 y, and the average body mass index was about
21 kg/m
2
.
There were notable differences in the distribution of
delivery type (p,0.01), Apgar score at delivery (p,
0.001), gestational length (p,0.001) and neonatal birth
weight (p,0.001) among the three groups. As expected,
the women with high-risk pregnancies in groups B and C
had higher rates (42.9% and 49.3%, respectively) of
cesarean delivery when compared with that (32%) of
women with low-risk pregnancies in group A. For women
in groups A, B and C, the mean gestational lengths were
38.42, 35.21 and 36.56 weeks, respectively, and the mean
birth weights were 3189.44, 2260.12 and 2731.41 g,
respectively. Post hoc examination of one-way ANOVA
revealed that women in Group B had shorter gestations
and lower-birth-weight newborns compared with those
in group A and group C (the control group).
Outcome
Doppler velocimetry of uteroplacental blood flow in
the umbilical vessels and pregnancy outcomes of the
women in the three study groups are listed in Table 2.
Because of preterm delivery before the scheduled time
for ultrasound examination and other personal reasons,
19 women in group A, 5 women in group B and 6 women
in group C did not undergo Doppler velocimetry of utero-
placental flow. AREDV and maternal and fetal outcomes
were compared by c
2
test and log linear analysis. Among
the three groups, remarkable differences were noted in
the ratios of AREDV (p,0.001), maternal outcomes
including postpartum hemorrhage (p,0.001), placental
abruption (p,0.001) and maternal transfer to the ICU
(p,0.001), as well as fetal outcomes including preterm
birth (p,0.001), low birth weight (p,0.001), low
Apgar score (p,0.001) and neonatal death (p,0.001).
Further analysis was performed using logistic
regression to compare the differences of Doppler veloc-
imetry of uteroplacental blood flow and pregnancy
outcomes among the three groups, adjusted by maternal
age, body mass index, economic status, marital status,
type of delivery and parity (Table 3). The risks of AREDV
(OR 4.32, 95% CI 1.25 to 14.94) and adverse maternal
1014 Ultrasound in Medicine and Biology Volume 38, Number 6, 2012

Author's personal copy
outcome including postpartum hemorrhage (OR 3.98,
95% CI 1.20 to 13.20), placental abruption (OR 4.80,
95% CI 1.19 to 19.35) and maternal transfer to the ICU
(OR 3.83, 95% CI 1.10 to 13.33) were greater in group
B than in group C (the control group). Similarly, the risks
of adverse fetal outcome, including preterm birth (OR
3.86, 95% CI 1.32 to 11.29), low birth weight (OR
2.99, 95% CI 1.11 to 8.03), low Apgar score (OR 5.14,
95% CI 1.64 to 16.08) and neonatal death (OR 4.52,
95% CI 1.15 to 17.73) were also greater in group B
than in group C. In contrast, the risks of AREDV, as
well as adverse maternal and fetal outcomes were all
significantly lower in group A than in group C, except
for the outcome of postpartum hemorrhage (OR 0.53,
95% CI 0.19 to 1.46).
DISCUSSION
The results reveal that women with high-risk pregnan-
cies who develop preterm placental calcification (noted
between 28 and 36 weeks’ gestation) have higher inci-
dences of poor uteroplacental blood flow (AREDV);
adverse maternal outcomes including postpartum hemor-
rhage, placental abruption and maternal transfer to the
ICU; and adverse fetal outcomes including preterm birth,
low birth weight, low Apgar score and neonatal death
compared with the control group. As expected, the inci-
dences of AREDV, as well as adverse maternal and fetal
outcomes, were all lower in the women with low-risk preg-
nancies (group A) than in the control group (group C),
except for the outcome of postpartum hemorrhage. In
high-risk pregnant women, the presentation of preterm
placental calcification mayserve as a predictor of poor ute-
roplacental blood flow and adverse maternal and fetal
outcomes, requiring closer surveillance for maternal and
fetal well-being. Appropriate information and suggestions
should be provided to the high-risk pregnant women in case
of finding preterm placental calcification to facilitateearlier
intervention or referral because both the mothers and
fetuses are at greater risk for poorer pregnancy outcomes.
There are two possible explanations for our findings.
First, preterm placental calcification itself is the primary
cause of poorer uteroplacental blood flow and also
adverse fetal outcome by means of gradual occlusion of
vessels, with deposition of calcium and fibrin (Emmrich
1992), which impairs uteroplacental function and
Table 1. Characteristics of the women in the three study groups
Characteristic
Group
p-value
A(n5776) B (n542) C (n571)
n%n%n%
Economic status 0.236
Poor 111 14.3 10 23.8 10 14.1
Non-poor 665 85.7 32 76.2 61 85.9
Marital status 0.216
Unmarried 57 7.3 6 14.3 7 9.9
Married
z
719 92.7 36 85.7 64 90.1
Parity 0.769
0 423 54.5 20 47.6 36 50.7
1 246 31.7 15 35.7 22 31.0
$2 107 13.8 7 16.7 13 18.3
Type of delivery 0.006*
Vaginal 528 68.0 24 57.1 36 50.7
Cesarean 248 32.0 18 42.9 35 49.3
Apgar score at delivery
x
,0.001
y
7–10 759 97.8 30 71.4 65 91.5
4–6 12 1.5 6 14.3 3 4.2
0–3 5 0.6 6 14.3 3 4.2
Mean SD Mean SD Mean SD p-value
Maternal age (y) 26.79 2.05 26.36 2.34 26.87 1.84 0.36
Body mass index (kg/m
2
) 21.57 1.17 21.44 1.16 21.86 1.49 0.11
Gestational length (wk) 38.42 1.77 35.21 3.43 36.56 2.03 ,0.001
y
Birth weight (g) 3189.44 443.06 2260.12 694.86 2731.41 454.81 ,0.001
y
Group A 5low-risk pregnant women; group B 5high-risk pregnant women with preterm placental calcification at 28–36 weeks’ gestation;
group C (control group) 5high-risk pregnant women without preterm placental calcification before 36 weeks’ gestation.
*p,0.01.
y
p,0.001: c
2
test for categorical factors of expected numbers .5, log linear analysis for categorical factors of expected numbers ,5, one-way
ANOVA for continuous factors.
z
Includes divorced and widowed women.
x
Apgar score measured 5 min after delivery.
Preterm placental calcification in high-risk pregnancy and adverse pregnancy outcome dK.-H. CHEN et al. 1015

Author's personal copy
eventually results in poorer fetal outcomes. This hypoth-
esis is supported by the evidence that pathologic exami-
nation of the placentas in fetal Bartter syndrome
(polyhydramnios, fetal hypokalemia and hypercalciuria)
showed extensive basement membrane mineralization
(Ernst and Parkash 2002), focal calcification and acute
atherosclerosis in the placental vessels (Dane et al.
2010). Another report confirmed the findings of calcifica-
tion and thrombi, both of which occluded the chorionic
and umbilical vessels and contributed to severe
intrauterine fetal growth restriction, associated with the
findings of AEDV in the umbilical artery (Klaritsch
et al. 2008). The second hypothesis is that there stands
an unknown and uninvestigated root cause, which results
in concurrent preterm placental calcification, poor utero-
placental blood flow and adverse fetal outcomes. This
theoretical view has not been sufficiently supported by
direct research exploring these relationships. Finally,
current studies fail to answer which explanation is true,
even if some research supports the first hypothesis.
The true mechanism seems complicated and remains
for future research to address the primary etiology
underlying the clinical manifestations and outcomes.
In the available data, there is no publication
describing the causal relationship between placental
calcification and maternal outcome. We suppose that
the placenta with preterm calcification is subject to early
detachment via some pathway, which is mediated by
hormones contributing to tissue breakdown and myome-
trial contraction in the interface. The latter behavior may
be similar to what takes place at term, i.e., cleavage of
deciduas spongiosa and formation of retroplacental
hematoma (Cunningham et al. 2010). Consequently,
premature separation and expulsion of the placenta result
in placental abruption, postpartum hemorrhage and even-
tual maternal admission to the ICU. A detailed explora-
tion of the pathophysiology will aid in understanding
the real process in the event.
Regarding the etiology of placental calcification,
possible mechanisms of tissue calcification involve phys-
iological (similar to that of bone), dystrophic (ischemia-
related) and metastatic processes (mineralization in
a supersaturated environment) (Anderson 1983). Poggi
et al. (2001) examined the calcium:phosphate weight
ratio and bone morphogenetic proteins and concluded
that the process of placental calcification was consistent
Table 2. Doppler velocimetry of uteroplacental blood flow and pregnancy outcomes in the three study groups
Outcome
Group
p-value
A(n5776) B (n542) C (n571)
n%n%n%
Poor uteroplacental blood flow
AREDV ,0.001*
Yes 20 2.6 10 27.0 5 7.7
No 737 97.4 27 73.0 60 92.3
Maternal outcome
Postpartum hemorrhage ,0.001*
Yes 26 3.4 10 23.8 5 7.0
No 750 96.6 32 76.2 66 93.0
Placental abruption ,0.001*
Yes 8 1.0 8 19.0 4 5.6
No 768 99.0 34 81.0 67 94.4
Maternal transfer to the ICU ,0.001*
Yes 6 0.8 10 23.8 5 7.0
No 770 99.2 32 76.2 66 93.0
Fetal outcome
Preterm birth ,0.001*
Yes 30 3.9 12 28.6 7 9.9
No 746 96.1 30 71.4 64 90.1
Low birth weight ,0.001*
Yes 50 6.4 13 31.0 10 14.1
No 726 93.6 29 69.0 61 85.9
Low Apgar score
y
,0.001*
Yes 17 2.2 12 28.6 6 8.5
No 759 97.8 30 71.4 65 91.5
Neonatal death ,0.001*
Yes 8 1.0 8 19.0 4 5.6
No 768 99.0 34 81.0 67 94.4
Group A 5low-risk pregnant women; group B 5high-risk pregnant women with preterm placental calcification at 28–36 weeks’ gestation; group C
(control group) 5high-risk pregnant women without preterm placental calcification before 36 weeks’ gestation.
*p,0.001: c
2
test for categorical factors of expected numbers .5, log linear analysis for categorical factors of expected numbers ,5.
y
Apgar score ,7 at 5 min after delivery.
1016 Ultrasound in Medicine and Biology Volume 38, Number 6, 2012

Author's personal copy
with a metastatic mechanism. These placental deposi-
tions are composed of calcium phosphate (Poggi et al.
2001) and arranged predominantly near the basement
membrane, where it is believed to be the site where the
placental calcium pump responsible for calcium transport
to the fetus lies (Kasznica and Petcu 2003). In recent
years, nanobacteria were recognized as the initiators of
pathologic tissue calcification (Kajander and Ciftcioglu
1998) by propagating and causing cell death, resulting
in kidney or gall stone formation, psammoma calcifica-
tion in ovarian cancer and coronary artery calcification
(Kajander 2006). On the basis of electron microscopy
examinations, nanobacterial infection was confirmed to
induce early, pathological placental calcification
(Agababov et al. 2007;Pasquinelli et al. 2010). The
details of mechanism are still under investigation.
The results of our study suggest that preterm
placental calcification in high-risk pregnant women is
not physiologic but pathologic, which implies that early
calcification should have a different mechanism from
that of placental calcification at term. Because the
calcium pump responsible for maternal-fetal calcium
transport seems to be located at the placental basement
membrane (Kasznica and Petcu 2003), disorders in the
pump could contribute to excessive calcium build-up in
the placenta. Therefore, calcium deposition proceeds in
such a supersaturated environment and eventually results
in marked calcification of the placental basement
membrane. As mentioned in the studies by Agababov
et al. (2007) and Pasquinelli et al. (2010), nanobacteria
could play a critical role in the initiation of early patho-
logic calcification despite their limited case numbers.
Detailed discussion of the calcification cascade is beyond
the scope of our study, but we believe that further effort
could be done to explore the relationships between the
calcium pump, nanobacteria and pathologic placental
calcification.
CONCLUSIONS
In high-risk pregnancy, preterm placental calcifica-
tion is not an aging progress but a reflection of underlying
placental dysfunction when noted at 28–36 weeks’ gesta-
tion. More attention should be given to women with
preterm placental calcification because this ominous
sign is often representative of great danger for the mother
and fetus. In these women, closer antepartum surveillance
should be considered for the evaluation of fetal
well-being, and monitoring and preparation should be
intensified during delivery because of increased risk for
maternal complications.
Our study has some limitations. First, we recruited
pregnant women who received care in a large hospital.
Thus, generalization of the conclusions to other women
visiting smaller hospitals or local clinics should be made
with caution. Second, some characteristics of the pregnant
women, including race and educational status, were not
considered in our study, and these could have affected
the results. As a longitudinal study, the last limitation
concerns some uncontrolled factors varying with time
and the change of medical policies. A longer follow-up
investigation could overcome this problem and provide
more precise results.
Acknowledgments—We are particularly grateful to the women who
participated in the study. This research was supported by a grant from
Buddhist Tzu-Chi General Hospital, Taipei Branch, Taiwan
(TCRD-TPE-96-35).
SUPPLEMENTARY DATA
Supplementary data related to this article can be found online at
doi:10.1016/j.ultrasmedbio.2012.02.004.
REFERENCES
Agababov RM, Abashina TN, Suzina NE, Vainshtein MB,
Schwartsburd PM. Link between the early calcium deposition in
placenta and nanobacterial-like infection. J Biosci 2007;32:
1163–1168.
Ahluwalia IB, Grummer-Strawn L, Scanlon KS. Exposure to environ-
mental tobacco smoke and birth outcome: Increased effects on
pregnant women aged 30 years or older. Am J Epidemiol 1997;
146:42–47.
Anderson HC. Calcific diseases: A concept. Arch Pathol Lab Med 1983;
107:341–348.
Table 3. Comparison of poor uteroplacental blood flow
and adverse pregnancy outcomes of the women in the
three study groups
Outcome
Group
A (low risk) B (high risk)
OR 95% CI OR 95% CI
Poor uteroplacental blood flow
AREDV 0.31*(0.11–0.88) 4.32*(1.25–14.94)
Maternal outcome
Postpartum
hemorrhage
0.53 (0.19–1.46) 3.98*(1.20–13.20)
Placental abruption 0.23*(0.07–0.82) 4.80*(1.19–19.35)
Maternal
transfer to the ICU
0.12
y
(0.04–0.43) 3.83*(1.10–13.33)
Fetal outcome
Preterm birth 0.41*(0.17–0.99) 3.86*(1.32–11.29)
Low birth weight 0.47*(0.22–0.99) 2.99*(1.11–8.03)
Low Apgar score
z
0.29*(0.11–0.77) 5.14
y
(1.64–16.08)
Neonatal death 0.22*(0.06–0.76) 4.52*(1.15–17.73)
Group A 5low-risk pregnant women; group B 5high-risk pregnant
women with preterm placental calcification at 28–36 weeks’ gestation;
group C (control group) 5high-risk pregnant women without preterm
placental calcification before 36 weeks’ gestation.
*p,0.05.
y
p,0.01: ORs are expressed compared with the control group C,
calculated by logistic regression and adjusted by maternal age, body
mass index, economic status, marital status, type of delivery and parity.
z
Apgar score ,7 at 5 min after delivery.
Preterm placental calcification in high-risk pregnancy and adverse pregnancy outcome dK.-H. CHEN et al. 1017

Author's personal copy
Brown HL, Miller JM Jr, Khawli O, Gabert HA. Premature placental
calcification in maternal cigarette smokers. Obstet Gynecol 1988;
71:914–917.
Chen KH, Chen LR, Lee YH. Exploring the relationship between
preterm placental calcification and adverse maternal and fetal
outcome. Ultrasound Obstet Gynecol 2011;37:328–334.
Chitlange SM, Hazari KT, Joshi JV, Shah RK, Mehta AC. Ultrasono-
graphically observed preterm grade III placenta and perinatal
outcome. Int J Gynaecol Obstet 1990;31:325–328.
Christianson RE. Gross differences observed in the placentas of smokers
and nonsmokers. Am J Epidemiol 1979;110:178–187.
Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse DJ,
Spong CY. Parturition. In: Cunningham FG, (ed). Williams obstet-
rics. New York: McGraw-Hill; 2010. p. 146–147.
Dane B, Dane C, Aksoy F, Cetin A, Yayla M. Antenatal Bartter
syndrome: Analysis of two cases with placental findings. Fetal Pe-
diatr Pathol 2010;29:121–126.
Emmrich P. Pathology of the placenta. X. Syncytial proliferation, calci-
fication, cysts, pigments and metabolic disorders [in German]. Zen-
tralbl Pathol 1992;138:77–84.
Ernst LM, Parkash V. Placental pathology in fetal bartter syndrome.
Pediatr Dev Pathol 2002;5:76–79.
Harris RD, Alexander RD. Ultrasound of the placenta and umbilical
cord. In: Callen PW, (ed). Ultrasonography in obstetrics and gyne-
cology. Philadelphia: W.B. Saunders; 2000. p. 602–604.
Haughton J, Khandker SR. Poverty lines. In: Haughton J, Khandker SR,
(eds). The handbook on poverty and inequality. Washington, DC:
World Bank; 2009. p. 39–65.
Hill LM, Breckle R, Ragozzino MW, Wolfgram KR, O’Brien PC. Grade
3 placentation: Incidence and neonatal outcome. Obstet Gynecol
1983;61:728–732.
Hills D, Irwin GA, Tuck S, Baim R. Distribution of placental grade in
high-risk gravidas. AJR Am J Roentgenol 1984;143:1011–1013.
Kajander EO, Ciftcioglu N. Nanobacteria: An alternative mechanism for
pathogenic intra- and extracellular calcification and stone formation.
Proc Natl Acad Sci U S A 1998;95:8274–8279.
Kajander EO. Nanobacteria—propagating calcifying nanoparticles. Lett
Appl Microbiol 2006;42:549–552.
Kasznica JM, Petcu EB. Placenta calcium pump: Clinical-based
evidence. Pediatr Pathol Mol Med 2003;22:223–227.
Kazzi GM, Gross TL, Rosen MG, Jaatoul-Kazzi NY. The relationship of
placental grade, fetal lung maturity, and neonatal outcome in normal
and complicated pregnancies. Am J Obstet Gynecol 1984;148:
54–58.
Klaritsch P, Haeusler M, Karpf E, Schlembach D, Lang U. Spontaneous
intrauterine umbilical artery thrombosis leading to severe fetal
growth restriction. Placenta 2008;29:374–377.
McKenna D, Tharmaratnam S, Mahsud S, Dornan J. Ultrasonic
evidence of placental calcification at 36 weeks’ gestation: Maternal
and fetal outcomes. Acta Obstet Gynecol Scand 2005;84:7–10.
Miller JM Jr, Brown HL, Kissling GA, Gabert HA. The relationship of
placental grade to fetal size and growth at term. Am J Perinatol 1988;
5:19–21.
Nolan RL. The placenta, membranes, umbilical cord, and amniotic fluid.
In: Sauerbrei EE, Nguyen KT, Nolan RL, (eds). A practical guide to
ultrasound in obstetrics and gynecology. Philadelphia: Lippincott-
Raven; 1998. p. 438–439.
Pasquinelli G, Papadopulos F, Nigro M. Nanobacteria and psammoma
bodies: Ultrastructural observations in a case of pathological
placental calcification. Ultrastruct Pathol 2010;34:344–350.
Patterson RM, Hayashi RH, Cavazos D. Ultrasonographically observed
early placental maturation and perinatal outcome. Am J Obstet Gy-
necol 1983;147:773–777.
Poggi SH, Bostrom KI, Demer LL, Skinner HC, Koos BJ. Placental
calcification: A metastatic process? Placenta 2001;22:591–596.
Proud J, Grant AM. Third trimester placental grading by ultrasonog-
raphy as a test of fetal wellbeing. BMJ 1987;294:1641–1644.
Quinlan RW, Cruz AC, Buhi WC, Martin M. Changes in placental ultra-
sonic appearance. I. Incidence of Grade III changes in the placenta in
correlation to fetal pulmonary maturity. Am J Obstet Gynecol 1982;
144:468–470.
Raio L, Ghezzi F, Cromi A, Nelle M, Durig P, Schneider H. The thick
heterogenous (jellylike) placenta: A strong predictor of adverse
pregnancy outcome. Prenat Diagn 2004;24:182–188.
Spirt BA, Gorden LP. Sonography of the placenta. In: Fleischer AC,
Manning FA, Jeanty P, Romero R, (eds). Sonography in obstetrics
and gynecology. Principles and practice. New York: McGraw-Hill;
2001. p. 195–197.
Vosmar MB, Jongsma HW, van Dongen PW. The value of ultrasonic
placental grading: No correlation with intrauterine growth retarda-
tion or with maternal smoking. J Perinat Med 1989;17:137–143.
Wenman WM, Joffres MR, Tataryn IV. Edmonton Perinatal Infections
Group. A prospective cohort study of pregnancy risk factors and
birth outcomes in Aboriginal women. CMAJ 2004;171:585–589.
1018 Ultrasound in Medicine and Biology Volume 38, Number 6, 2012