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Ultrasound Obstet Gynecol 2011; 37: 328–334

Published online 28 January 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.7733

Exploring the relationship between preterm placental


calcification and adverse maternal and fetal outcome
K. H. CHEN*†‡, L. R. CHEN§¶ and Y. H. LEE*
*Department of Obstetrics and Gynecology, Buddhist Tzu Chi General Hospital, Taipei Branch, Taipei, Taiwan; †School of Medicine, Tzu Chi University,
Hualien, Taiwan; ‡Graduate Institute of Health Care Organization Administration, College of Public Health, National Taiwan University, Taipei,
Taiwan; §Mackay Memorial Hospital, Taipei, Taiwan; ¶School of Biomedical Science and Engineering, National Yang Ming University, Taipei, Taiwan

K E Y W O R D S: birth weight; fetal outcome; maternal outcome; preterm placental calcification

ABSTRACT Group 3. In contrast, there were no significant differences in


adverse pregnancy outcome between Groups 2 and 3.
Objectives To explore the relationship between preterm Conclusions Early preterm placental calcification is asso-
placental calcification and adverse pregnancy outcome, ciated with a higher incidence of adverse pregnancy outcome,
including maternal and fetal outcomes. and may serve as an indicator of adverse mater-nal and fetal
outcomes when noted on ultrasonography. Conversely, women
Methods In this prospective cohort study, monthly
with late preterm placental calcifica-tion are not at greater
ultrasonography was performed starting at 28 weeks’
risk for adverse pregnancy outcome. Copyright 2011 ISUOG.
gestation to establish the diagnosis of Grade III placental
Published by John Wiley & Sons, Ltd.
calcification. Women were classified into three groups: Group
1, the early preterm group, with placental calcification found
prior to 32 weeks (n = 63); Group 2, the late preterm group,
with placental calcification found between 32 and 36 weeks (n
= 192); and Group 3, the control group, without placental INTRODUCTION
calcification noted between 28 and 36 weeks (n = 521).
Women who smoked cigarettes or drank alcohol during Placental calcification, often noted on ultrasound exami-nation
pregnancy, or who had hypertension, diabetes, significant during pregnancy, is characterized by widespread deposition
antenatal anemia or placenta previa were all excluded. of calcium on the placenta, resulting in echogenic foci 1,2.
Logistic regression analysis was used to estimate the risks of When the process has advanced to the deposition of calcium
adverse pregnancy outcome in Groups 1 and 2 by calculating on the basal plate and septa, calcification may appear to be
odds ratios (OR) with 95% CIs, adjusted by maternal age, linear or even circular3,4. Under the Grannum classification
body mass index, economic status, marital status, type of for ultrasound grad-ing, placental calcification of this degree
delivery and parity. is designated Grade III, with significant formation of
indentations or ring-like structures within the placenta (Figure
1)5. Pla-cental calcification commonly increases with
Results Risks for adverse maternal outcome includ-ing gestational age, and becomes apparent after 36 weeks’
postpartum hemorrhage (OR, 3.43; 95% CI, 1.251 – 9.388), gestation. When it becomes notable prior to 36 weeks’
placental abruption (OR, 6.52; 95% CI, gestation, it is considered to be preterm placental
1.356 – 31.382) and maternal transfer to the intensive care calcification5. The prevalence of preterm placental
unit (OR, 9.76; 95% CI, 1.826 – 52.195) and for adverse fetal calcification has been reported as 3.8% (measured only at 36
outcomes including preterm birth (OR, 4.20; 95% CI, 1.775 –
weeks)6; 9% (before 28 weeks)7; 15% (at 34 – 36 weeks)8;
9.940), low birth weight (OR, 4.58; 95% CI, 2.201 – 9.522),
low Apgar score (OR, 6.53; 95% CI, 2.116 – 20.142) and and 23.7% (at 31 – 34 weeks)9. Miller et al.10 reported that
neonatal death (OR, 9.04; 95% CI, Grade III placental calcification was found in 39.4% of
1.722 – 47.411) were much higher in Group 1 than in pregnant women at term.

Correspondence to: Dr K. H. Chen, Department of Obstetrics and Gynecology, Buddhist Tzu Chi General Hospital, Taipei Branch, No.
289, Jianguo Road, Xindian City, Taipei County, Taiwan (e-mail: alexgfctw@yahoo.com.tw)
Accepted: 14 June 2010

Copyright 2011 ISUOG. Published by John Wiley & Sons, Ltd. ORIGINALPAPER
Preterm placental calcification and pregnancy outcome 329

Some studies, however, have observed that preterm placental


calcification has significant effects on fetal outcome.

There are discordant conclusions regarding the rela-tionship


between placental calcification and adverse preg-nancy
outcome. Some studies have reported that preterm placental
calcification is associated with a greater inci-dence of

intrauterine growth restriction6,9,20 22
, low birth
6,8,9,21 – 23 8 9
weight , low Apgar score , fetal distress , and
pregnancy-induced hypertension6,20,22,24, while other
studies have reported that preterm placental calcification is not
associated with a greater incidence of intrauter-ine growth
restriction10,16, low birth weight25, low Apgar score25 or
fetal distress26, and is of little value in predicting high-risk
pregnancy7. Conflicting conclusions drawn from these studies
using different instruments and different research designs are
confusing. However, the major prob-lem with previous studies
– except for that of McKenna et al.6 in 2005 – is that most of
them were carried out many years ago with ultrasound
equipment of poorer resolution than is currently available and
they involved relatively few participants, rendering their
conclusions questionable. Furthermore, the mediating effects
of poten-tial confounders such as cigarette smoking, diabetes
and hypertension were not considered in some studies, thus
some conclusions might be incorrect or misleading. More-
over, there is a paucity of research evaluating the effect of
preterm placental calcification on maternal outcome. We felt,
therefore, that it was important to clarify the relationship
between preterm placental calcification and pregnancy
outcome, including both maternal and fetal outcomes, by
including more participants and using newer instruments of
Figure 1 Ultrasound images of Grade III placental calcification
better resolution, with stricter selection criteria.
according to the Grannum classification, showing: (a) diffuse
echogenic lines along the basal plate representing prominent
calcification and (b) indentations of the chorionic plate, central
hypoechoic areas and irregular marginal echodensities with acoustic
shadowing. METHODS

Study design and participants


Placental calcification is usually thought to represent a
physiological aging process3 – 5. Nevertheless, it can be a This prospective cohort study was conducted in a tertiary
pathological change resulting from the effects of hospital with an average of 200 or more deliveries per month.
environmental factors on the placenta. Possible mechanisms The hospital provides routine obstetric clinics for the general
of tissue calcification involve physiological (similar to that of population of pregnant women and special obstetric clinics
bone), dystrophic (ischemia-related) or metastatic processes
(where a referral is needed) for high-risk pregnancies.
(mineralization in a supersaturated environment)11. Previous
Pregnant women who are found to have antenatal
studies have shown that factors predisposing to placental
complications in the routine clinic, and those who are referred
calcification include smoking5 ,6,8,12 – 14, low parity4,6,8,15 from other hospitals because of antenatal complications, are
and young maternal age6,8,13, despite some disagreement transferred to the special obstetric clinic for evaluation and
regarding the role of smoking in placental calcification16. management of high-risk pregnancy. Between July 2007 and
Alcohol consumption is not associated with placental June 2009, pregnant women without significant antenatal
calcification6. complications were invited to participate in the study, and the
With regard to adverse pregnancy outcome, smoking is a volunteers were screened with ultrasound for placental
major risk factor for preterm delivery and low birth calcification. Monthly ultrasound scans were performed
weight17,18. Studies have also revealed that alcohol starting at 28 weeks’ gestation to establish the diagnosis of
consumption17 and young maternal age19 are risk factors for preterm placental calcification. The first ultrasound
poor birth outcome; however, the clinical significance of examination for the volunteers was done at between 28 and 32
placental calcification for pregnancy outcome remains weeks’ gestation and subsequent ultrasound examinations
controversial. Many textbooks3 – 5 state that placental were arranged once a month. All ultrasound examinations
calcification is believed to be of no clinical significance. were

Copyright 2011 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2011; 37: 328–334.
330 Chen et al.

Women who underwent


antenatal examination in the
clinic, 2007–2009 (n  1049)

Women willing to
participate in the study
(n  862) 86 women excluded because of:
smoking; use of alcohol during
pregnancy; antenatal
complications e.g.
hypertension, diabetes,
significant anemia
Women who met
inclusion criteria: enrolled
participants (n  776)

Group 1: women with Group 2: women with Group 3: control group


early preterm placental late preterm placental (women without
calcification (noted at calcification (noted at placental calcification
28–32 weeks’ gestation) 32–36 weeks’ gestation) at 28–36 weeks’ gestation)
(n = 63) (n = 192) (n  521)

Figure 2 Flow chart for selection and grouping of the women in the study groups with placental calcification noted at different stages of pregnancy.

performed using a Voluson 730 machine (GE Medical confirmed maternal thalassemia, placenta previa or diabetes
Systems, Zipf, Austria) equipped with a 2.8 – 10-MHz (either overt or gestational). In addition, multiple gestation is a
transabdominal transducer, by one qualified obstetrician to risk factor for preterm delivery or postpartum hemorrhage,
avoid interobserver bias, and all images were further reviewed and any fetus with major congenital anomalies is at increased
by another experienced obstetrician to ensure the accuracy of risk of preterm delivery, low birth weight and poor neonatal
the diagnosis. outcome. Therefore, pregnancies complicated by multiple
Women were classified into one of three groups according gestation or major congenital anomalies found on antenatal
to the time when placental calcification was initially examination were excluded from this study. Except for the
confirmed: an early preterm placental calcification group high-risk patients mentioned above, all pregnant women in the
(Group 1, n = 63), in whom placental calcification was found routine obstetric clinic were asked to volunteer for the study if
prior to 32 weeks’ gestation; a late preterm placental they met the inclusion criteria. Participants were recruited by
calcification group (Group 2, n = 192), in whom placental means of survey rather than obstetrician’s preference (highly
calcification was found at between 32 and 36 weeks’ selected samples) so as to avoid selection bias.
gestation; and a control group (Group 3, n = 521), in whom
placental calcification was not seen between 28 and 36 weeks’
gestation (Figure 2). Basic information on the participants, including age, body
Maternal outcomes evaluated included: postpartum mass index, economic status, marital status, parity and past
hemorrhage (a total of 500 mL or more of blood loss during medical history was obtained at the first antenatal visit.
delivery), placental abruption and maternal transfer to the Determination of gestational age was principally based on the
intensive care unit. Fetal outcomes evaluated include: preterm last menstrual period and validation of true gestational age
delivery (delivery before 37 weeks’ gestation), low birth was confirmed by ultrasound measurement of fetal
weight (< 2500 g), low Apgar score (< 7 at 5 min) and development in early pregnancy. If there was a significant
neonatal death. discrepancy (> 1 week) between them, a further ultrasound
As mentioned above, smoking and alcohol consumption are scan was arranged to determine the true gestational age. With
two important confounding factors in placental calcification regard to economic status, ‘poor’ was defined as having a per
and pregnancy outcome, therefore women who smoked or capita income of < 50% of the median according to the
drank alcohol were excluded from the study. Also excluded definition of the European Union27. Ascertainment of
were women who had complications noted on prenatal smoking or alcohol consumption during pregnancy,
examination, such as chronic or pregnancy-induced identification of major congenital anomalies or placenta previa
hypertension (including pre-eclampsia), severe anemia by ultrasound and the diagnosis
(hemoglobin < 8 g/dL),

Copyright 2011 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2011; 37: 328–334.
Preterm placental calcification and pregnancy outcome 331

of pregnancy-induced hypertension, pre-eclampsia and above – 63 women in Group 1, 192 in Group 2 and 521 in
gestational diabetes were made on subsequent visits at 12 – 28 Group 3. The demographic characteristics of the women are
weeks’ gestation. We recorded the condition of participants shown in Table 1. The total numbers of divorced and widowed
and newborns at delivery, and followed the infants for 3 women were both less than 10, and both were included in the
months after delivery. The study was approved by the ethics married category. There were no significant differences in
committee of Tzu-Chi General Hospital, Taipei, Taiwan. maternal age, body mass index, economic status, marital
status, parity and type of delivery among the three groups. In
all three groups, the majority of women were married and
Data analysis nulliparous at presentation, had a vaginal delivery and, with
regard to economic status, were classified as ‘nonpoor’. In all
Data were collected and analyzed using SPSS 12.0 (SPSS
three groups the average maternal age was around 26 years
Inc., Chicago, IL, USA). The statistics used in this study
included descriptive statistics, chi-square test, loglinear and the average body mass index was around 21 kg/m2.
analysis (for expected numbers < 5) and ANOVA to compare
the differences in personal characteristics and the differences There were notable differences in the distribution of Apgar
in pregnancy outcome between the three groups. We score at delivery (P < 0.01), gestational age at delivery (P <
performed logistic regression analysis to estimate the risks of 0.001) and neonatal birth weight (P < 0.01) among the three
adverse pregnancy outcomes associated with early and with groups. The mean gestational age at delivery was 37.2, 38.6
late preterm placental calcification in comparison with the and 38.6 weeks in Groups 1, 2 and 3, respectively, and the
control group. The odds ratios (OR) with the 95% CIs for each mean birth weight was 3019.4, 3218.1 and 3198.6 g,
group were calculated and presented after adjusting for the respectively. Posthoc examination of one-way analysis of
effects of maternal age, body mass index, economic status, variance showed that fetuses of women in Group 1 had a
marital status, parity and type of delivery, on maternal and lower gestational age at delivery and a lower birth weight than
fetal outcomes. those in Groups 2 and 3.

Outcome
RESULTS
Pregnancy outcomes in the three groups are listed in Table 2.
Characteristics of participants
Maternal and fetal outcomes were compared by chi-square test
Seven hundred and seventy-six participants were enrolled in and loglinear analysis. Among these three groups, significant
the study, divided into the three groups mentioned differences were noted in

Table 1 Characteristics of the women in the three study groups

Group 1 Group 2 Group 3


Characteristic (n = 63) (n = 192) (n = 521) P

Economic status 0.233


Poor 12 (19.0) 32 (16.7) 67 (12.9)
Non-poor 51 (81.0) 160 (83.3) 454 (87.1)
Marital status 0.602
Unmarried 6 (9.5) 16 (8.3) 35 (6.7)
Married† 57 (90.5) 176 (91.7) 486 (93.3)
Parity 0.955
0 35 (55.6) 105 (54.7) 283 (54.3)
1 21 (33.3) 62 (32.3) 163 (31.3)
≥2 7 (11.1) 25 (13.0) 75 (14.4)
Type of delivery 0.657
Vaginal 41 (65.1) 127 (66.1) 360 (69.1)
Cesarean section 22 (34.9) 65 (33.9) 161 (30.9)
Apgar score at 5 min 0.001*
7 –10 57 (90.5) 189 (98.4) 513 (98.5)
4 –6 4 (6.3) 2 (1.0) 6 (1.2)
0 –3 2 (3.2) 1 (0.5) 2 (0.4)
Maternal age (years) 2 26.24 ± 2.23 26.78 ± 2.04 26.89 ± 2.03 0.060
Body mass index (kg/m ) 21.89 ± 1.54 21.58 ± 1.19 21.53 ± 1.09 0.063
Gestational age at delivery (weeks) 37.23 ± 1.93 38.57 ± 1.21 38.56 ± 1.19 < 0.001**
Birth weight (g) 3019.36 ± 577.39 3218.08 ± 418.45 3198.61 ± 431.08 0.006*
Data presented as n (%) or mean ± SD. Group 1, women with early preterm placental calcification (noted at 28–32 weeks’ gestation); Group 2, women
with late preterm placental calcification (noted at 32–36 weeks’ gestation); Group 3, controls, i.e. women with no placental calcification noted on
ultrasound at 28–36 weeks’ gestation. *P < 0.01, **P < 0.001: chi-square test for categorical factors of expected numbers > 5, loglinear analysis for
categorical factors of expected numbers < 5 and one-way analysis of variance for continuous factors. †Including divorced and widowed.

Copyright 2011 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2011; 37: 328–334.
332 Chen et al.

maternal outcomes including postpartum hemorrhage (P < parity (Table 3). The risks of adverse maternal outcome were
0.05), placental abruption (P < 0.01) and maternal transfer to much greater in Group 1 than in Group 3. These adverse
the intensive care unit (ICU) (P < 0.01). Significant outcomes included postpartum hemorrhage (OR, 3.43; 95%
differences were also noted in fetal outcomes including CI, 1.251 – 9.388), placental abruption (OR,
preterm birth (P < 0.01), low birth weight (P < 0.001), low 6.52; 95% CI, 1.356 – 31.382) and maternal transfer to the
Apgar score (P < 0.01) and neonatal death (P < 0.05). ICU (OR, 9.76; 95% CI, 1.826 – 52.195). Similarly, the risks
of adverse fetal outcome, including preterm birth (OR, 4.20;
Further analysis was performed by logistic regression to 95% CI, 1.775 – 9.940), low birth weight (OR, 4.58; 95% CI,
compare the differences in pregnancy outcomes among the 2.201 – 9.522), low Apgar score (OR, 6.53; 95% CI, 2.116 –
three groups, adjusted by maternal age, body mass index, 20.142) and neonatal death (OR, 9.04; 95% CI, 1.722 –
economic status, marital status, type of delivery and 47.411) were also greater in Group 1. In

Table 2 Pregnancy outcomes of the women in the three study groups

Outcome Group 1 Group 2 Group 3 P

Maternal outcome
Postpartum hemorrhage 0.047*
Yes 6 (9.5) 5 (2.6) 15 (2.9)
No 57 (90.5) 187 (97.4) 506 (97.1)
Placental abruption 0.007**
Yes 4 (6.3) 1 (0.5) 3 (0.6)
No 59 (93.7) 191 (99.5) 518 (99.4)
Maternal transfer to ICU 0.004**
Yes 4 (6.3) 1 (0.5) 2 (0.4)
No 59 (93.7) 191 (99.5) 519 (99.6)
Fetal outcome
Preterm birth 0.007**
Yes 9 (14.3) 7 (3.6) 20 (3.8)
No 54 (85.7) 185 (96.4) 501 (96.2)
Low birth weight < 0.001***
Yes 14 (22.2) 9 (4.7) 30 (5.8)
No 49 (77.8) 183 (95.3) 491 (94.2)
Low Apgar score† 0.006**
Yes 6 (9.5) 3 (1.6) 8 (1.5)
No 57 (90.5) 189 (98.4) 513 (98.5)
Neonatal death 0.024*
Yes 3 (4.8) 1 (0.5) 2 (0.4)
No 60 (95.2) 191 (99.5) 519 (99.6)

Data presented as n (%). Group 1, women with early preterm placental calcification (noted at 28–32 weeks’ gestation); Group 2, women with late
preterm placental calcification (noted at 32–36 weeks’ gestation); Group 3, controls, i.e. women with no placental calcification noted on ultrasound at
28–36 weeks’ gestation. *P < 0.05, **P < 0.01, ***P < 0.001: chi-square test for categorical factors of expected numbers > 5, loglinear analysis for
categorical factors of expected numbers < 5. †Score < 7 at 5 min. ICU, intensive care unit.

Table 3 Odds ratios for comparison of adverse pregnancy outcome in the study groups

Odds ratio (95% CI)

Outcome Group 1 Group 2

Maternal outcome
Postpartum hemorrhage 3.43 (1.251–9.388)* 0.90 (0.322 –2.514)
Placental abruption 6.52 (1.356–31.382)** 0.72 (0.078 –6.511)
Maternal transfer to ICU 9.76 (1.826–52.195)** 0.96 (0.098 –9.341)
Fetal outcome
Preterm birth 4.20 (1.775–9.940)** 0.95 (0.392 –2.290)
Low birth weight 4.58 (2.201–9.522)*** 0.80 (0.371 –1.735)
Low Apgar score† 6.53 (2.116–20.142)** 1.02 (0.200 –3.915)
Neonatal death 9.04 (1.722–47.411)** 1.87 (0.308 –11.396)

Group 1, women with early preterm placental calcification (noted at 28–32 weeks’ gestation); Group 2, women with late preterm placental calcification
(noted at 32–36 weeks’ gestation). Odds ratios compared to control group (women with no placental calcification noted on ultrasound at 28–36 weeks’
gestation), calculated by logistic regression analysis and adjusted by maternal age, body mass index, economic status, marital status, type of delivery and
parity. *P < 0.05, **P < 0.01, ***P < 0.001. †Score < 7 at 5 min. ICU, intensive care unit.

Copyright 2011 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2011; 37: 328–334.
Preterm placental calcification and pregnancy outcome 333

contrast, there were no statistically significant differences in action appears to be time-dependent because late preterm
adverse maternal or fetal outcomes between Groups 2 and 3. placental calcification is not related to adverse pregnancy
outcome. Hence, placental calcification is not only an aging
progress, but is also a reflection of underlying placental
dysfunction when it is noted in earlier stages of pregnancy.
DISCUSSION
More attention should be paid to women with early preterm
The results of this study reveal that pregnant women with placental calcification even if the pregnancy is regarded as
early preterm placental calcification (noted before 32 weeks’ normal, in the absence of risk factors such as smoking, alcohol
gestation) had a higher incidence of adverse maternal outcome consumption, hypertension or diabetes. In these women with
including postpartum hemorrhage, placental abruption and early preterm placental calcification, closer antepartum
maternal transfer to the ICU, and a higher incidence of surveillance may be considered for the evaluation of fetal
adverse fetal outcome including preterm birth, low birth wellbeing. In addition, these women should be closely
weight, low Apgar score and neonatal death. In contrast, the monitored and well prepared during delivery because of their
incidence of adverse maternal and fetal outcomes was no increased risk for maternal complications.
greater in the group with late preterm placental calcification
(noted between 32 and 36 weeks’ gestation) than in the Our study has some limitations. First, we recruited
control group. In other words, isolated early preterm placental participants who received care in a large hospital. Applying
calcification noted on ultrasound is a risk factor for adverse the conclusions to small hospitals or local clinics is not
pregnancy outcome, even in the absence of other risk factors necessarily valid because of questionable external validity.
such as cigarette smoking, alcohol consumption, diabetes or Second, some characteristics of the pregnant women,
hypertension. Conversely, women with late preterm placental including race and educational status, were not considered in
calcification are not at greater risk for adverse maternal and our study. These factors may affect the results. Finally,
fetal outcomes. These findings may help to identify the at-risk because this was a longitudinal study, we could not
pregnancy and to provide information for counseling. completely control for changes in medical policies and some
Pregnant women with early preterm placental calcification factors that vary with time. A longer follow-up investigation
may be warned about the greater risk to both mother and fetus, may overcome this problem and provide more reliable results.
and may require closer surveillance for fetal wellbeing.

ACKNOWLEDGMENTS
Vintzileos and Tsapanos28 proposed adding placental
grading as a component of the biophysical profile for the We are particularly grateful to the postpartum women who
evaluation of fetal wellbeing. In their scoring system, a participated in the study. This research was supported by a
finding of Grade III placenta would have the lowest score (0). grant from Buddhist Tzu Chi General Hospital, Taipei Branch,
This is equivocal since many researchers regard placental Taiwan (TCRD-TPE-96-35).
calcification as an aging process rather than a pathological
change. Our results also indicate that only ‘isolated early
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