Epidemiology

DOI: 10.1111/1471-0528.12752
www.bjog.org

Retained placenta is associated with

pre-eclampsia, stillbirth, giving birth
to a small-for-gestational-age infant,
and spontaneous preterm birth: a national
register-based study
M Endler,a S Saltvedt,b S Cnattingius,c O Stephansson,b,c A-K Wikstromc,d
a

Department of Clincal Science and Education, Division of Obstetrics and Gynaecology, Karolinska Institutet, S
odersjukhuset, Stockholm,
Sweden b Department of Womens and Childrens Health, Division of Obstetrics and Gynaecology, Karolinska University Hospital, Stockholm,
Sweden c Department of Medicine, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden d Department of Womens and
Childrens Health, Uppsala University, Uppsala, Sweden
Correspondence: Dr M Endler, Division of Obstetrics and Gynaecology, Department of Clincal Science and Education, Karolinska Institutet,
S
odersjukhuset, 118 83 Stockholm, Sweden. Email margit.endler@sodersjukhuset.se
Accepted 8 February 2014. Published Online 7 April 2014.

Objective To evaluate whether defective placentation disorders, i.e.

pre-eclampsia, stillbirth, small for gestational age (SGA), and

spontaneous preterm birth, are associated with risk of retained
placenta.
Design Population-based cohort study.
Setting Sweden.
Population Primiparous women in Sweden with singleton vaginal

deliveries between 1997 and 2009 at 3241 weeks of gestation

(n = 386 607), without placental abruption or infants with
congenital malformations.
Methods Risks were calculated as odds ratios (ORs) by

unconditional logistic regression with 95% confidence intervals

(95% CIs) after adjustments for maternal, delivery, and infant
characteristics.
Main outcome measure Retained placenta, defined by the

presence of both a diagnostic code (of retained placenta) and a

procedure code (for the manual removal of the placenta).

Results The overall rate of retained placenta was 2.17%. The risk
of retained placenta was increased for women with pre-eclampsia
(adjusted OR, aOR, 1.37, 95% CI 1.211.54), stillbirth (aOR 1.71,
95% CI 1.282.29), SGA birth (aOR 1.47, 95% CI 1.281.70), and
spontaneous preterm birth (3234 weeks of gestation, aOR 2.35,
95% CI 1.972.81; 3536 weeks of gestation, aOR 1.55, 95% CI
1.371.75). The risk was further increased for women with
preterm pre-eclampsia (aOR 1.69, 95% CI 1.252.28) and preterm
SGA birth (aOR 2.19, 95% CI 1.423.38). There was no
association between preterm stillbirth (aOR 1.10, 95% CI 0.63
1.92) and retained placenta, but the exposed group comprised
only 15 cases.
Conclusions Defective placentation disorders are associated with

an increased risk of retained placenta. Whether these relationships

indicate a common pathophysiology remains to be investigated.
Keywords Postpartum haemorrhage, pre-eclampsia, preterm
birth, retained placenta, small for gestational age, stillbirth.

Please cite this paper as: Endler M, Saltvedt S, Cnattingius S, Stephansson O, Wikstr
om A-K. Retained placenta is associated with pre-eclampsia, stillbirth,
giving birth to a small-for-gestational-age infant, and spontaneous preterm birth: a national register-based study. BJOG 2014;121:14621470.

Introduction
Retained placenta, which complicates approximately 3% of
vaginal deliveries,1 is associated with severe blood loss after
delivery.2,3 Irrespective of access to emergency obstetric
care, retained placenta is the second leading cause of postpartum haemorrhage after uterine atony.4 The manual

1462

removal of the placenta further involves risks associated

with anaesthesia and an increased risk of postpartum endometritis.5,6 Despite this, very little is known of the etiology
or pathophysiology behind the disorder.
Previous studies have indicated that retained placenta is
associated with pre-eclampsia and preterm birth.2,3,7,8
These conditions are, together with fetal growth restriction

2014 Royal College of Obstetricians and Gynaecologists

Retained placenta and defective placentation disorders

and intrauterine death, considered part of a larger spectrum of disorders of defective or impaired deep placentation.9 These disorders are known to be associated with
enhanced oxidative stress and apoptosis in the placenta.10,11
Several studies within the field of veterinary medicine have
shown that oxidative stress and apoptosis is increased in
the placenta of dairy cattle with retained placenta.12,13
Based on this evidence, we used a nationwide Swedish
cohort to study the associations between defective placentation disorders, i.e. pre-eclampsia, stillbirth, small-for-gestational-age (SGA) birth, and spontaneous preterm birth,
and risk of retained placenta.

Methods
The population-based Swedish Medical Birth Register
includes nationwide information on live births (from 22
completed weeks of gestation and onwards) and stillbirths
(from 28 completed weeks of gestation and onwards). In
Sweden 99.7% of births take place in public hospitals, and
antenatal and obstetric care is free of charge, with standardized management routines.14 Active management of
the third stage of labour, including the administration of
oxytocin after delivery, has been part of normal practice
since 2001, but was widely used prior to that.15 The birth
register includes data on more than 98% of deliveries,
including demographic data, information on reproductive
history, and complications that occur during pregnancy,
delivery, and the neonatal period.16 Since 1997, complications during pregnancy and delivery have been classified
according to the the tenth version of the International
Classification of Diseases (ICD-10), noted at discharge
from hospital after delivery. Information on each pregnancy and delivery is forwarded to the birth register
through copies of standardized antenatal, obstetric, and
paediatric records. Individual record linkage between the
birth register and other registries are possible through each
individuals unique personal registration number, assigned
to each Swedish resident.17

was defined as fetal death at 28 weeks of gestation or later.

Analysis of stillbirth was therefore restricted to births at
28 weeks of gestation or later. Both antepartal and intrapartal stillbirths were included based on the premise that
intrapartal death can also reflect placental insufficiency
caused by defective placentation.
The birth of an SGA infant was used as a proxy for fetal
growth restriction. We defined SGA as a birthweight of
more than two standard deviations below the mean weight
for gestational age, according to the Swedish sex-specific
fetal growth curve.19 Gestational age was generally based on
ultrasound assessment at 1820 weeks of gestation. In Sweden, a routine early ultrasonic scan is offered to all women,
and 97% accept this offer.20 If information about ultrasound was unavailable, gestational age was based on the
date of the last menstrual period. In the SGA analyses, we
excluded women with stillbirths. We also excluded pregnancies complicated by pre-eclampsia because pre-eclampsia has a strong association with SGA birth.
Spontaneous preterm birth was defined as a spontaneous
onset of labour with subsequent vaginal delivery prior to
37 completed weeks of gestation. These deliveries were
identified through the delivery record, where labour initation is classified as either spontaneous or medically indicated. In the analysis of spontaneous preterm birth, we
only included deliveries with spontaneous onset of labour
and excluded women with pre-eclampsia, stillbirths, or
SGA births. These disorders are foremost associated with
medically indicated preterm delivery, but also with spontaneous preterm birth.21 Our aim was to study preterm birth
irrespective of underlying disorders.

Outcome
Retained placenta was defined as a diagnosis of retained
placenta (ICD-10 codes O720, O722, O730, or O731) combined with a procedure code for the manual removal of the
placenta, according to the Swedish National Procedure
Code (MBA30).

Covariates
Exposures
Our exposure variables were pre-eclampsia, stillbirth, SGA
birth, and spontaneous preterm birth.
Pre-eclampsia (including eclampsia) was identified by
the ICD-10 codes O14 and O15. During the study period
pre-eclampsia was defined as a blood pressure of 140/
90 mmHg, combined with proteinuria (0.3 g in 24 hours)
occurring after 20 weeks of gestation. The quality of this
diagnosis in the birth register has been validated, with a
93% congruity between registry data and individual patient
records.18
Stillbirths are registered in the birth register. During
most of the study period (before 1 July 2008), stillbirth

2014 Royal College of Obstetricians and Gynaecologists

Potential confounding factors were chosen based on biological plausibility and on results from previous studies. Information on maternal body mass index (BMI), smoking
habits, number of previous miscarriages, and use of assisted
reproductive technology was retrieved from the records of
the first antenatal visit, usually taking place at the end of
the first trimester.22 In the interests of privacy, the medical
birth register does not include data on previous terminations of pregnancy. Data on maternal age, chronic diseases
(such as diabetes or hypertension), and delivery-related
variables (such as premature rupture of membranes, induction of labour, epidural analgesia, labour dystocia, instrumental delivery, as well as gestational length and infant

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Endler et al.

birthweight) were collected after delivery. Pregnancy and

delivery-related conditions and interventions were identified and defined according to their ICD-10 diagnostic
codes or the Nordic Classification of Interventions in
Health Care diagnostic code (Appendix S1). Information
on the mothers educational level was obtained from the
education register of 2010. The Register of Population and

Population Changes provided information on the mothers

country of birth. Variables were categorised according to
Tables 1 and 2.

Study population
During the study period (19972009), 550 263 primiparous
women gave birth to a singleton infant (Figure 1). We only

Table 1. Rates and unadjusted risk of retained placenta according to maternal characteristics among 386 607 singleton births at 3241 weeks of
gestation in primiparous women in Sweden between 1997 and 2009
Total number
of deliveries

Total population
Maternal characteristics
Age (years)
<20
2024
2529
3034
35
Missing data
BMI in early pregnancy
18.4
18.524.9
2529.9
30
Missing data
Smoking in early pregnancy pregnancy
No
Yes
Missing data
Country of birth
Nordic
Non-Nordic
Missing data
Education (years)
12
>12
Missing data
Previous miscarriages
None
12
2
Assisted reproductive technology
No
Yes
Chronic hypertension
No
Yes
Diabetes
No
Gestational
Pre-gestational

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Retained placenta
Rate%

Number

Crude odds ratio

(95% CI)

386 607

2.17

8389

16 274
87 499
146 818
103 304
31 637
1075

0.90
1.19
1.92
2.98
4.11
1.58

147
1044
2819
3080
1301
17

0.75
Ref.
1.59
2.52
3.54

10
229
71
25
49

663
491
724
336
393

1.67
2.09
2.36
2.63
2.19

178
4788
1693
667
1082

0.81 (0.690.95)
Ref.
1.13 (1.071.21)
1.28 (1.161.40)

353 667
32 940
23 984

2.20
1.94
2.24

7770
638
537

Ref.
0.86 (0.780.94)

314 777
59 685
12 145

2.29
1.67
1.64

7215
994
199

Ref.
0.72 (0.670.77)

186 078
186 234
14 295

1.96
2.44
1.49

3655
4540
213

0.80 (0.760.84)
Ref.

337 056
47 500
2051

2.02
3.15
5.27

6805
1495
108

Ref.
1.59 (1.501.69)
2.72 (2.183.40)

377 318
9289

2.13
3.82

8053
355

Ref.
1.80 (1.602.04)

384 970
1637

2.17
3.67

8348
60

Ref.
1.72 (1.332.22)

374 704
2545
950

2.17
2.45
2.16

8323
64
21

Ref.
1.13 (0.881.45)
1.00 (0.651.53)

(0.620.91)
(1.471.72)
(2.332.72)
(3.233.87)

2014 Royal College of Obstetricians and Gynaecologists

Retained placenta and defective placentation disorders

Table 2. Rates and unadjusted risk of retained placenta according to delivery characteristics among 386 607 singleton births at 3241 weeks of
gestation in primiparous women in Sweden between 1997 and 2009
Total number
of deliveries

Total population
Delivery characteristics
Gestational age (weeks)
3741 weeks
3536 weeks
3234 weeks
Premature rupture of membranes
No
Yes
Induction of labour
No
Yes
Missing
Epidural analgesia
No
Yes
Labour dystocia
No
Yes
Instrumental vaginal delivery
No
Yes
Birthweight*
Appropriate
Small
Large
Missing data

Retained placenta
Rate (%)

Number

Crude odds ratio

(95% CI)

386 607

2.17

8389

367 851
14 057
4699

2.10
3.16
4.94

7732
444
232

Ref.
1.52 (1.381.67)
2.42 (2.122.77)

348 906
37 701

2.08
3.03

7266
1142

Ref.
1.44 (1.331.55)

353 333
30 470
2804

2.08
3.34
1.21

7355
1019
34

Ref.
1.63 (1.521.74)

216 414
170 193

1.97
2.43

4273
4135

Ref.
1.21 (1.151.27)

320 216
66 391

2.03
2.86

6506
1902

Ref.
1.47 (1.391.55)

326 154
60 453

2.01
3.08

6548
1860

Ref.
1.54 (1.451.63)

370 189
9258
5952
1208

2.14
3.12
3.13
1.74

7912
186
289
21

Ref.
1.48 (1.311.66)
1.48 (1.271.71)

*Small and large for gestational age were defined as two standard deviations below or above the mean birthweight for gestational age,
according to the sex-specific Swedish fetal growth curve, respectively.

included primiparous women because a history of retained

placenta is strongly associated with the recurrence of
retained placenta.2,8,23 We excluded women delivered by
caesarean section and women diagnosed with placental
abruption. We also excluded women who gave birth to an
infant with congenital malformations, as our interest was
to study stillbirth and SGA birth resulting from placental
insufficiency. Amongst women with suspected retained placenta, we excluded those who did not have both an
ICD-10 diagnostic code and a procedure code for the manual removal of the placenta recorded (n = 6436). Furthermore, we excluded deliveries of less than 32 weeks of
gestation, as pregnancies diagnosed with pre-eclampsia or
fetal growth restriction prior to this week of pregnancy are
usually delivered by caesarean section, thereby precluding
the possibility of studying the relationship between retained
placenta and these conditions in early gestation. Post-term

2014 Royal College of Obstetricians and Gynaecologists

deliveries (at 42 weeks of gestation) were also excluded.

We assessed that the exclusion of post-term deliveries
would add to the homogeneity of the study population and
decrease confounding. The final study cohort consisted of
386 607 women (Figure 1).

Statistical analysis
We estimated the association between retained placenta
and pre-eclampsia, stillbirth, SGA birth, and spontaneous
preterm birth by calculating odds ratios (ORs) with 95%
confidence intervals (95% CIs) using unconditional logistic
regression analysis. First, we assessed the associations
between retained placenta and pre-eclampsia, stillbirth,
SGA birth, and spontaneous preterm birth, as well as each
covariate listed in Tables 1 and 2, using univariate logistic
regression. Confounding variables that were significant in
univariate analysis were entered into multivariate models in

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Endler et al.

Singleton deliveries primiparous

women 19972009
N = 550 263

Exclude congenital
malformations

Exclude cesarean section

N = 100 766

N = 18 449

Exclude cases of retained

placenta with ICD diagnosis
without prodecure code or vice
versa

Exclude placental abruption

N = 228

N = 6436

N = 424 384

Exclude gestational age < 32+0

weeks

Exclude gestational age 42+0

N = 1945

N = 35 832

Final study cohort

N = 386 607

Figure 1. Stepwise inclusion and exclusion steps in the assembly of the

study cohort.

order of strength (combined assessment of ORs and

95% CIs). Variables that lost significance in the multivariate analysis were excluded from the model. The confounding factors adjusted for in each model are specified in the
footnotes to Tables 3 and 4. Thereafter, we stratified deliveries into preterm (3236 weeks of gestation) and term
(3741 weeks of gestation), and re-evaluated the risk of
retained placenta for each exposure through the same process as described above. Data were analysed using SAS 9.3
(SAS Institute Inc., Cary, NC, USA).

Results
The overall rate of retained placenta was 2.17% (Table 1).
Compared with women with spontaneous placental expul-

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sion, those with retained placenta were on average older,

more educated, had a somewhat higher BMI, and were less
likely to smoke. Women with retained placenta were also
more likely to have been born in a Nordic country, to have
had previous miscarriages, to have a current pregnancy
after assisted reproductive technology, and to have chronic
hypertension. Women with retained placenta were more
likely to deliver preterm, to have premature rupture of
membranes (PROM), induced labour, use epidural analgesia, develop labour dystocia, have instrumental vaginal
delivery, and give birth to SGA or large-for-gestational-age
(LGA) infants (Tables 1 and 2).
Pregnancies complicated by pre-eclampsia, stillbirth,
SGA birth, and spontaneous preterm birth had higher risks
of retained placenta compared with women without these
disorders, even after adjusting for possible confounding factors (Table 3). Compared with women with term births
(3741 weeks of gestation), the risk of retained placenta
increased with decreasing gestational age (3536 weeks of
gestation, aOR 1.55, 95% CI 1.371.75; 3234 weeks of
gestation: aOR 2.35, 95% CI 1.972.81).
In the adjusted analyses, maternal age remained as an
independent risk factor for retained placenta with an
increasing risk according to increasing age. Compared with
women aged 2024 years, women over 34 years of age had
aORs between 2.98 and 3.05, depending on the exposure
studied. A history of previous miscarriage was also an
independent risk factor for retained placenta (one previous
miscarriage, aOR 1.381.44; two or more previous miscarriages, aOR 2.082.21, depending on the exposure studied).
Giving birth to a large for gestational age infant (>2 SD)
was an independent risk factor in term models, with aORs
ranging from 1.40 to 1.51. All of the other variables
adjusted for were only marginally associated with retained
placenta (adjusted aORs 1.30).
When deliveries were subdivided by gestational age, the
association between pre-eclampsia and SGA birth and risk
of retained placenta appeared stronger in preterm than
term deliveries (OR 1.69, 95% CI 1.252.28, versus
OR 1.32, 95% CI 1.161.50, for pre-eclampsia, respectively;
OR 2.19, 95%CI 1.423.38, versus OR 1.43, 95% CI 1.23
1.66, for SGA birth, respectively). Stillbirth was only associated with retained placenta in the term subcohort; however,
the preterm cohort only included 15 stillbirths (Table 4).

Discussion
Main findings
We found that defective placentation disorders, i.e.
pre-eclampsia, stillbirth, SGA, and spontaneous preterm
birth, were all associated with an increased risk of retained
placenta. The association was stronger for preterm
pre-eclampsia and preterm SGA birth.

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Retained placenta and defective placentation disorders

Table 3. Risk of retained placenta associated with disorders of defective placentation

Retained placenta
Number

Pre-eclampsia**
No
7982
Yes
426
Stillbirth**
No
8340
Yes
68
Small for gestational age***
No
7456
Yes
247
Spontaneous preterm birth****
No
6467
3536 weeks
336
3234 weeks
182

Rate (%)

Crude OR
(95% CI)

aOR (95% CI)*

2.13
3.55

Ref.
1.69 (1.531.87)

Ref.
1.37 (1.211.54)

2.16
5.80

Ref.
2.79 (2.183.56)

Ref.
1.71 (1.282.29)

2.08
3.01

Ref.
1.46 (1.281.66)

Ref.
1.47 (1.281.70)

1.97
2.90
4.60

Ref.
1.49 (1.331.66)
2.41 (2.072.80)

Ref.
1.55 (1.371.75)
2.35 (1.972.81)

*All models were adjusted for maternal age, body mass index, country of birth, previous miscarriages, year of delivery, gestational age, epidural
analgesia, labour dystocia, instrumental vaginal delivery, and large-for-gestational-age birthweight. Pre-eclampsia was additionally adjusted for
premature rupture of membranes and induction of labour. Stillbirth was additionally adjusted for induction of labour. SGA was additionally
adjusted for induction of labour. Spontaneous preterm labour was additionally adjusted for premature rupture of membranes.
**In the analyses of pre-eclampsia and stillbirth, the total number of births were 386 607.
***Analysis only includes live births. Pregnancies with pre-eclampsia were excluded, and 1164 pregnancies with missing data on birthweight
were not included in the analysis. The total number of births in this analysis was 373 466.
****Analysis only includes live births. Pregnancies with pre-eclampsia, SGA infant, or induction of labour were excluded. The total number of
births in this analysis was 344 307.

Table 4. Risk of retained placenta stratified into preterm (<37 weeks of gestation) and term (37 weeks of gestation) delivery
Retained placenta
Preterm delivery
Numbers
Pre-eclampsia
No
1064
Yes
54
Stillbirth
No
351
Yes
15
Small for gestational age***
No
366
Yes
25

Term delivery

aOR (95% CI)*

Number

aOR (95% CI)**

3.53
4.83

Ref.
1.69 (1.252.28)

10 509
372

2.06
3.42

Ref.
1.32 (1.161.50)

3.59
4.10

Ref.
1.10 (0.631.92)

753
53

2.09
6.58

Ref.
2.36 (1.713.27)

3.46
6.39

Ref.
2.19 (1.423.38)

7605
222

2.02
3.11

Ref.
1.43 (1.231.66)

*Adjusted for maternal age, country of birth, previous miscarriages, year of delivery, gestational age, premature rupture of membranes and
instrumental vaginal delivery. In analyses of pre-eclampsia and stillbirth, the total number of births was 18 756. In the analysis of SGA, the total
number of births was 17 291.
**Adjusted for maternal age, body mass index, country of birth, previous miscarriages, year of delivery, gestational age, induction of labour,
epidural analgesia, labour dystocia, instrumental vaginal delivery, and LGA birthweight. In analyses of pre-eclampsia and stillbirth, the total
number of births was 367 851. In the analysis of SGA, the total number of births was 356 175.
***Defined as a liveborn infant with a birthweight of more than two standard deviations below the mean birth weight for gestational age
according to the sex-specific Swedish fetal growth curve. Pregnancies with pre-eclampsia and those missing data on birthweight were
excluded.

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Endler et al.

Strenghts and limitations

The strenghts of this study include its large size and the
population-based design using prospectively collected data
on maternal exposures. The large cohort enables research of
rare exposures and outcomes. The rate of retained placenta
in the study population was 2.17%, which is somewhat
lower than the average incidence of approximately 3% in
the western hemisphere.1 The reliability of the diagnosis of
retained placenta has not been validated in the birth register; however, by including only cases registered with both
the diagnostic code for retained placenta and the procedure
code for manual removal of the placenta, we believe that
we have increased the specificity of the outcome. Our exposures of interest had incidences that were closely comparable with other studies in similar populations.2426 Another
strength is that we included only primiparous women in
our analysis, and therefore precluded the influence of
obstetric history related to previous childbirth on our risk
assessments. We do not have access to histologically confirmed diagnosis of infection in the medical birth register.
Although retained placenta per se is not known to be associated with prepartal infection,3 this variable may have been
relevant to consider in our analysis, particularly in investigating the association with preterm birth and stillbirth.

Interpretation
In accordance with some previous studies,2,3 we found that
pre-eclampsia was associated with an increased risk of
retained placenta; however, we are unaware of any previous
study that has investigated associations between SGA birth
or fetal growth restriction and risk of retained placenta, or
has performed analyses of any of these variables stratified
by gestational age. Compared with term pre-eclampsia and
fetal growth restriction, preterm pre-eclampsia and fetal
growth restriction are regarded as more representative of
underlying defective placentation. The presence of histological and biochemical signs of oxidative stress and apoptosis
in placental tissue are indicators of inbalanced hypoperfusion/reperfusion, and are more pronounced in early
compared with late disease onset.2733 Furthermore,
high-resistance uterine artery doppler velocimetry, as a
measurement of defective placentation, is more strongly
associated with early-onset pre-eclampsia and fetal growth
restriction than late-onset disease.34,35 The fact that preterm
pre-eclampsia and preterm SGA birth were more strongly
associated with retained placenta than term disorders is
therefore compatible with our research hypothesis of a link
between defective placentation and retained placenta.
Spontaneous preterm birth also increased the risk of
retained placenta, and we found that the risk increased by
decreasing gestational age: in the early preterm delivery
group (3234 weeks of gestation), the risk of retained pla-

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centa was more than doubled. Preterm birth has been indicated as a risk factor for retained placenta in several
previous studies,2,3,7,8 but we are unaware of any study distinguishing between medically indicated and spontaneous
preterm birth. By excluding stillbirths, SGA births, deliveries with pre-eclampsia, and deliveries occurring after
induced labour, as well as adjusting for PROM (as an indicator of infection), we strove to study a non-iatrogenic and
more idiopathic form of spontaneous preterm labour. The
positive association suggests that retained placenta is
related to the phenomenon of spontaneous preterm labour.
To our knowledge, we are the first to report an association
between stillbirth and retained placenta; however, we could
not show an association between preterm stillbirth and
retained placenta. This is not consistent with our hypothesis,
as preterm stillbirth has, like pre-eclampsia and fetal growth
restriction, been associated with an increased degree of
uteroplacental insufficiency.36 Given that only 15 preterm
stillbirths were included, the power to show an association
between preterm stillbirth and retained placenta may have
been limited. Moreover, stillbirth is of multifactorial etiology, potentially involving both fetal and maternal factors.
Recurrent miscarriage is suggested to be an extreme form
of defective placentation.37 Although it was not a primary
exposure in our study, we found that a history of two or
more previous miscarriages was associated with a more than
two-fold increase in risk for retained placenta in all our exposure models. This adds support to the association between
retained placenta and defective placentation disorders.
Our results fulfill several of Hills criteria of causation as
interpreted by the GRADE approach,38 and therefore we suggest a causality between defective placentation disorders and
retained placenta. There were significant associations with all
defective placentation disorders studied and, with the exception of preterm stillbirths in the preterm cohort, the results
were consistent across all exposures, supporting the analogy
criterion. The outcomes occur after the stipulated cause. Furthermore, we suggest a doseresponse or, in this context, a
temporalresponse relationship, as we found increasing risk
for retained placenta with decreasing gestational age of
pre-eclampsia. Given the current lack of understanding of
the pathophysiology of retained placenta, we may only speculate about the biological plausibility of the findings. The link
between defective placentation disorders and retained placenta could imply a common pathophysiological mechanism.
It is also plausible that these disorders render the placenta
either more vulnerable to the mechanism that causes retained
placenta or more resistent to a stimulus that normally
orchestrates the spontaneous release of the placenta.
Defective placentation disorders are associated with incomplete or shallow placentation in early pregnancy.10 Shallow
placentation with incomplete spiral artery remodelling results

2014 Royal College of Obstetricians and Gynaecologists

Retained placenta and defective placentation disorders

in an imbalanced hypoperfusion/reperfusion, which in turn

increases oxidative stress and cell apoptosis.9,10 This is
hypothesized to lead to the spectrum of clinical obstetric
disorders that we have studied. The pathophysiology of the
human retained placenta is, however, mostly unknown.
Animal studies suggest a complex etiology behind retained
placenta, with disrupted placental maturation and separation influenced by oxidative stress, an inbalanced prostaglandin E2/F2 alpha ratio, and decreased steroid hormone
receptor status, which in turn increases the rate of apoptosis in the chorionic epithelium before delivery.39

Conclusion
Excessive blood loss after delivery is the main cause of
maternal mortality globally, accounting for a quarter of all
deaths during pregnancy and childbirth.40 Knowledge of
mothers at risk of retained placenta and subsequent haemorrhage can increase preparedness to intervene in time to
limit complications. A further understanding of the pathophysiology of this disorder is mandated in order to pursue
a possible prevention or treatment. Although defective placentation disorders may be associated with an increased
risk of retained placenta, it remains to be investigated
whether this relationship is indicative of a common pathophysiology.

Disclosure of interests
All authors report no conflict of interests.

Contribution to authorship
ME and SS had the original idea for the study. OS and SC
contributed with database management and expertise in
epidemiology. A-KW and ME contributed to the design of
the study. ME performed the analyses and wrote the first
draft of the article. A-KW, SS, OS, and SC made substantial contributions to the interpretation of results and to
revising the article.

Details of ethics approval

The study was approved by the research ethics committee
at Karolinska Institutet (2012/1250-31/4).

Funding
The research was funded by the Division of Obstetrics and
Gynaecology, S
odersjukhuset, affiliated to the Department
of Clinical Science and Education, Karolinska Institutet.

Supporting Information
Additional Supporting Information may be found in the
online version of this article:

2014 Royal College of Obstetricians and Gynaecologists

Appendix S1. Diagnostic codes used to identify and

define covariates adjusted for in the multivariate logistic
regression models of the study. &

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2014 Royal College of Obstetricians and Gynaecologists