Placenta

Department of Obstetrics and Gynecology
Helsinki University Hospital

University of Helsinki
Finland
PLACENTAL ABRUPTION
STUDIES ON MATERNAL AND OFFSPRING
LONG-TERM MORBIDITY AND MORTALITY
Outi Riihimäki
ACADEMIC DISSERTATION
To be presented by the permission of the Medical Faculty of

the University of Helsinki for public examination in the Seth Wichmann
Auditorium of the Department of Obstetrics and Gynecology, Helsinki
Univeristy Hospital, on November 23rd 2018, at 12 noon.
Helsinki 2018

Supervised by
Adjunct Professor Minna Tikkanen, MD, PhD

Helsinki University Hospital and University of Helsinki
Professor Emeritus, F.A.C.O.G Jorma Paavonen, MD, PhD

Helsinki University Hospital and University of Helsinki
Reviewed by
Professor Leea Keski-Nisula, MD, PhD

Kuopio University Hospital and
University of Eastern Finland
Adjunct Professor Tytti Raudaskoski, MD, PhD

PEDEGO Research Center, University of Oulu
Official opponent
Adjunct Professor Eeva Ekholm, MD, PhD

Turku University Hospital and
University of Turku
Cover design by Saija Hietala and Frida Rundman
ISBN 978-951-51-4630-4 (paperback)

ISBN 978-951-51-4631-1 (PDF)
Unigrafia
Helsinki 2018

To my parents

TABLE OF CONTENTS
LIST OF ORIGINAL PUBLICATIONS ......................................................................... 7

ABBREVIATIONS ................................................................................................... 8
ABSTRACT ............................................................................................................ 9
FINNISH SUMMARY ............................................................................................ 12
INTRODUCTION .................................................................................................. 14
REVIEW OF THE LITERATURE .............................................................................. 16
PLACENTAL DEVELOPMENT ........................................................................................ 16
PLACENTAL ABRUPTION ............................................................................................. 16
Definition ...................................................................................................................... 16
Epidemiology and incidence ..................................................................................... 18
Etiology ........................................................................................................................ 18
Clinical presentation and diagnosis ......................................................................... 19
Risk factors for placental abruption .......................................................................... 22
Sociodemographic and behavioral risk factors ............................................................... 22
Maternal and historical risk factors ................................................................................... 22
Pregnancy-associated risk factors .................................................................................... 23
Recurrence rate of placental abruption ................................................................... 24
MATERNAL SHORT-TERM CONSEQUENCES OF PLACENTAL ABRUPTION ...................... 24
Morbidity due to obstetric hemorrhage .................................................................... 24
Blood transfusions ............................................................................................................... 25
Emergency peripartum hysterectomy ............................................................................... 25
Renal failure ......................................................................................................................... 26
Disseminated Intravascular Coagulopathy ...................................................................... 26
Mental burden ............................................................................................................. 26
Maternal deaths .......................................................................................................... 27
MATERNAL LONG-TERM CONSEQUENCES OF PLACENTAL ABRUPTION ....................... 27
Cardiovascular diseases ........................................................................................... 27
Cancer .......................................................................................................................... 28
Overall mortality .......................................................................................................... 29
PERINATAL AND NEONATAL SHORT-TERM CONSEQUENCES OF PLACENTAL ABRUPTION
................................................................................................................................... 29
Prematurity .................................................................................................................. 29
Asphyxia ....................................................................................................................... 30
Low birthweight and intrauterine growth restriction associated with placental
abruption ...................................................................................................................... 31
Major congenital anomalies associated with placental abruption ........................ 32
Neonatal morbidity ...................................................................................................... 32
Perinatal and neonatal mortality ............................................................................... 34
LONG-TERM OFFSPRING CONSEQUENCES OF PLACENTAL ABRUPTION ....................... 35
Neurological problems ............................................................................................... 35
4
Sudden infant death syndrome ................................................................................. 36
Chronic lung disease .................................................................................................. 37
AIMS OF THE STUDY ........................................................................................... 38

SUBJECTS AND METHODS ................................................................................... 39
SUBJECTS .................................................................................................................... 39
DATA SOURCES ........................................................................................................... 44
The Hospital Discharge Register .............................................................................. 44
The Medical Birth Register ........................................................................................ 44
The Register of Congenital Malformations ............................................................. 45
The Cause-of-Death Register ................................................................................... 45
The Finnish Cancer Register .................................................................................... 45
MATERNAL CHARACTERISTICS .................................................................................... 47
CANCER INCIDENCE AMONG WOMEN WITH A HISTORY OF PLACENTAL ABRUPTION .. 47
DEATHS OF WOMEN WITH OR WITHOUT HISTORY OF PLACENTAL ABRUPTION .......... 47
BIRTH-RELATED CHARACTERISTICS OF THE NEONATES BORN AFTER ABRUPTION–
COMPLICATED OR NONABRUPTION PREGNANCIES ..................................................... 47
CLASSIFICATION OF MAJOR CONGENITAL ANOMALIES ............................................... 48
DEATHS OF CHILDREN BORN AFTER ABRUPTION-COMPLICATED OR NONABRUPTION
PREGNANCIES ............................................................................................................. 48
INTERACTION ANALYSIS ............................................................................................. 48
STATISTICAL METHODS ............................................................................................... 48
Study I .......................................................................................................................... 48
Study II ......................................................................................................................... 49
Study III ........................................................................................................................ 49
Study IV ........................................................................................................................ 50
RESULTS ............................................................................................................. 51
SUBSEQUENT RISK OF CANCER AMONG WOMEN WITH A HISTORY OF PLACENTAL
ABRUPTION (I) ............................................................................................................ 51
MORTALITY AND CAUSES OF DEATH IN WOMEN WITH A HISTORY OF
PLACENTAL ABRUPTION (II) ........................................................................................ 51
MAJOR CONGENITAL ANOMALIES IN BIRTHS WITH PLACENTAL ABRUPTION (III) ..... 54
OVERALL MORTALITY OF CHILDREN BORN AFTER PLACENTAL ABRUPTION (IV) .......... 60
DISCUSSION ....................................................................................................... 68
CANCER MORBIDITY OF WOMEN WITH A HISTORY OF PLACENTAL ABRUPTION ......... 68
OVERALL MORTALITY OF WOMEN WITH A HISTORY OF PLACENTAL ABRUPTION ........ 69
MAJOR CONGENITAL ANOMALIES IN BIRTHS WITH PLACENTAL ABRUPTION .............. 71
OFFSPRING MORTALITY AND PLACENTAL ABRUPTION ................................................ 74
STRENGTHS AND WEAKNESSES OF THE STUDY ........................................................... 76
FUTURE ASPECTS ........................................................................................................ 77
CONCLUSIONS .................................................................................................... 78
ACKNOWLEDGEMENTS ....................................................................................... 79
5
REFERENCES ....................................................................................................... 82
6
LIST OF ORIGINAL PUBLICATIONS
This thesis is based on the following publications:
I Riihimäki O, Tikkanen M, Melin J, Andersson S, Metsaranta M,

Nuutila M, Gissler M, Paavonen J, Pukkala E. Subsequent risk of
cancer among women with a history of placental abruption. Acta
Oncol 2018 Sep 28:1-5. doi: 10.1080/0284186X.2018.1512155.
(Epub ahead of print)
II Riihimäki O, Paavonen J, Luukkaala T, Gissler M, Metsäranta M,

Andersson S, Nuutila M, Pukkala E, Melin J, Tikkanen M.
Mortality and causes of death among women with a history of
placental abruption. Acta Obstet Gynecol Scand 2017; 96:1315–
21.
III Riihimäki O, Metsäranta M, Ritvanen A, Gissler M, Luukkaala

T, Paavonen J, Nuutila M, Andersson S, Tikkanen M Increased
prevalence of major congenital anomalies in births with
placental abruption. Obstet Gynecol 2013; 122:268–74.
IV Riihimäki O, Metsäranta M, Paavonen J, Luukkaala T, Gissler M,

Andersson S, Nuutila M, Tikkanen M. Placental abruption and
child mortality. Pediatrics 2018;142(2): e20173915.
The original publications are reprinted with the permission of their copyright
holders. The publications are referred to in the text by their Roman
numerals.
7
ABBREVIATIONS
AFP alpha-fetoprotein
CDR Cause-of-Death Register
CI confidence interval
CNS central nervous system
CP cerebral palsy
CVD cardiovascular disease
DIC disseminated intravascular coagulopathy
FCR Finnish Cancer Register
HDR Hospital Discharge Register
HR hazard ratio
ICD International Classification of Diseases
ICBDSR International Clearinghouse for Births Defects
Surveillance and Research
IUGR intrauterine growth restriction
LGA large for gestational age
MBR Medical Birth Register
MCA major congenital anomaly
MMR maternal mortality ratio
OR odds ratio
PNM perinatal mortality
PPH postpartum hemorrhage
PPROM preterm prelabor rupture of membranes
RCM Register of Congenital Malformations
RDS respiratory distress syndrome
RR risk ratio
SGA small for gestational age
SIDS sudden infant death syndrome
SIR standardized incidence ratio
SMR standardized mortality ratio
THL National Institute for Health and Welfare
8
ABSTRACT
Placental abruption, defined as a premature separation of the placenta from

the uterine wall before delivery, is a serious obstetric complication with many
potential adverse outcomes for both mother and fetus. The etiology of
abruption is not fully understood, but impaired placentation seems to play an
important role. Smoking, previous abruption and hypertensive disorders are
significant factors in the development of the condition. The classic symptoms
of abruption include vaginal bleeding, abdominal pain, uterine contractions
and tenderness. The immediate maternal risks are related to hemorrhage
caused by placental abruption. Not much is known about maternal longterm
consequences, but impaired placentation and the role of smoking as a
predisposing factor to placental abruption give rise to the hypothesis that
women with a history of placental abruption may be more prone to cancer-
related morbidity and mortality. Children born from pregnancies complicated
by abruption are often premature, present with low birthweight, and they have
an increased risk for hypoxia and asphyxia. They also seem to have congenital
malformations more often than children born from non-abruption
pregnancies. These factors challenge the survival, development and prognosis
of the child. The aim of this thesis was to study the effect of placental abruption
on fetal and maternal morbidity, as well as on overall mortality and causes of
death.
The present study was carried out in the Department of Obstetrics and
Gynecology at Helsinki University Hospital between 2010 and 2018. The
studies were comprised of women who had had placental abruption during the
years 1969–2005 and children born from pregnancies complicated by
placental abruption during 1987–2005. A reference group was comprised of
three women without a history of placental abruption per each abruption,
matched by maternal age at delivery, parity, year of childbirth, and hospital
district area. A control group of children was formed by children born from
the matched non-abruption pregnancies. All women and children were
identified from the Hospital Discharge Registry and the Medical Birth
Registry. Data on major congenital anomalies were retrieved from the Registry
of Congenital Malformations. Data on deaths and causes of death were
retrieved from the Cause-Of-Death Registry and data on cancers from the
Cancer Registry of Finland.
The main outcome measures of studies I–IV included in this thesis were
cancer incidence in women with a history of placental abruption (study I),
overall and cause-specific mortality of women with a history of abruption
(study II), major congenital malformations in births complicated by placental
abruption (study III), and overall and cause-specific mortality of children born
after placental abruption (study IV). In study I, standardized incidence ratios
(SIRs) were calculated for different cancers by dividing the observed numbers
9
of cancers by those expected. The expected numbers were based on national
cancer incidence rates. In studies II and IV, the risk of overall mortality and
different causes of death were estimated by hazard ratios (HRs). In study II, a
standardized mortality ratio (SMR) analysis was also performed to compare
mortality in the index and reference cohorts with mortality in the general
population. In study III, the prevalence of at least one major congenital
anomaly (MCA) in births with and without placental abruption was analyzed
by multivariate logistic regression and the results were shown by odds ratios
(ORs) with 95% confidence intervals (CIs).
No overall increase in risk of cancer was evident among women with a history
of placental abruption (SIR 0.95, 95% CI 0.88–1.02). However, the history of
placental abruption was associated with an increased risk of lung cancer (SIR
1.51, 95% CI 1.05–2.10) and thyroid cancer (SIR 1.47, 95% CI 1.04–2.02). A
decreased risk was found for breast cancer (SIR 0.85, 95% CI 0.75–0.96).
Women with a history of placental abruption had an increased overall
mortality compared with referent women. Their risk of death was increased
due to malignancies of the respiratory tract (HR 1.72, 1.05–2.82), alcohol-
related causes (HR 1.84, 1.25–2.72), and external causes (HR 1.63, 1.19–2.22),
especially suicide (HR 1.71, 1.07–2.74). No difference in mortality from
cardiovascular diseases was evident. These women also tended to die younger
compared with the reference cohort (p<0.001). The SMR was increased in the
index cohort compared with the general Finnish female population (1.13,
1.02–1.24), especially for respiratory tract malignancies (1.79, 1.16–2.64).
There were 4190 children born after placental abruption and 12,570 control
children born after nonabruption pregnancies. Of the neonates, 261 (6.2%)
born after placental abruption and 415 (3.3%) of the controls had at least one
major congenital anomaly. In the adjusted analysis, placental abruption was
associated with an increased prevalence of MCAs (OR 1.92; 95% CI 1.63–2.52;
prevalence 623/10,000 vs. 330/10,000, respectively). After adjusting for
placental abruption, the association was strongest among extremely preterm,
very preterm, and moderately preterm newborns, as well as among newborns
with growth retardation. All larger subgroups of MCAs, except oral clefts and
chromosomal defects, were associated with placental abruption.
Compared with the controls, the overall mortality among children born after
abruption was significantly increased (HR 8.70, 95% CI 6.96–10.90). During
the neonatal period (0–27 days), the mortality was nearly 15-fold (HR 14.8,
95% CI 10.9–20.0), with birth-related asphyxia being the leading cause of
death (HR 108, 95% CI 34–341). Mortality remained high during days 28–365
(HR 10.3, 95% CI 4.83–21.8), and beyond 365 days (HR 1.70, 95% CI 1.03–
2.79). Furthermore, the overall mortality was increased among children born
after abruption at 32–36+6 gestational weeks (HR 2.77, 95% CI 1.54–4.98)
and at ≥37 weeks (HR 4.98, 95% CI 3.54–6.99), and among children born after
abruption with a birthweight of 2500 g or more (HR 5.94, 95% CI 4.33–8.14).
10
In conclusion, the data presented in this thesis provide new information about
the long-term impact of placental abruption on the health of both the woman
and the child. Placental abruption was demonstrated here to be associated
with an increased prevalence of MCAs, the prevalence being nearly double in
births complicated by abruption. Furthermore, placental abruption clearly
influences the long-term mortality of both mothers and their offspring.
Behavioral factors such as smoking and alcohol use are likely to have a crucial
role in mediating an increased risk of death and cancer in women with a
history of abruption. However, placental abruption in itself does not seem to
predispose to cancer. These data provide tools for clinicians for counseling of
patients and families affected by placental abruption.
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FINNISH SUMMARY
Istukan ennenaikainen irtoaminen eli ablaatio tarkoittaa tilannetta, jossa

istukka irtoaa kohdun seinämästä joko osittain tai kokonaan sikiön vielä
ollessa kohdussa. Se on harvinainen, mutta vakava synnytyskomplikaatio,
joka uhkaa sekä syntyvän lapsen että äidin terveyttä ja henkeä. Ablaatioon
johtavia syitä ei varmuudella tiedetä, mutta arvellaan, että istukan
kiinnittyminen on epänormaalia. Äidin tupakointi, edellisessä raskaudessa
tapahtunut ablaatio sekä verenpainetta kohottavat sairaudet ovat
merkityksellisiä ablaation vaaraa lisääviä tekijöitä. Häiriöt istukan
kiinnittymisessä sekä tupakoinnin merkitys ablaatiolle altistavana tekijänä
antavat aiheen olettaa, että ablaation kokeneilla naisilla voi olla myös
suurentunut vaara sairastua syöpään tai sydän- ja verisuonitauteihin.
Ablaatioraskauksista syntyvät lapset ovat usein ennenaikaisia, pienipainoisia
ja heillä on lisääntynyt riski kärsiä istukan heikentyneen verenkierron vuoksi
hapenpuutteesta. Heillä on myös tavallista useammin synnynnäisiä
epämuodostumia verrattuina lapsiin, joiden äidit eivät ole kokeneet istukan
ennenaikaista irtoamista kyseisessä raskaudessa. Nämä seikat tuovat
haastetta ablaatioraskaudesta syntyvän lapsen selviytymismahdollisuuksille
ja hänen kehitykselleen.
Helsingin yliopistollisessa sairaalassa vuosien 2010 ja 2018 välissä

toteuttamissamme tutkimuksissa halusimme selvittää istukan ennenaikaisen
irtoamisen vaikutuksia sekä äidin että syntyvän lapsen sairastuvuuteen että
kuolleisuuteen ja kuolinsyihin. Etsimme hoito-ja poistoilmoitusrekisteristä
sekä syntymärekisteristä ne Suomessa synnyttäneet naiset, joilla oli ollut
ablaatio vuosien 1969 ja 2005 välillä ja lapset, jotka syntyivät
ablaatioraskauksista vuosien 1987 ja 2005 välillä. Näille naisille ja lapsille
valitsimme kullekin kolme verrokkia käyttäen poissulkukriteerinä
ablaatiodiagnoosia. Lisäksi hankimme Epämuodostumarekisteristä tiedot
synnynnäisistä epämuodostumista, kuolintiedot Kuolemansyyrekisteristä ja
syöpäsairastavuutta koskevat tiedot Suomen Syöpärekisteristä.
Tutkimusaineistossa oli yhteensä 7805 naista, joilla oli ollut ablaatio. Näille
naisille olimme hakeneet kolme verrokkia, jotka oli kaltaistettu synnytysiän,
synnytysvuoden, synnyttäneisyyden sekä sairaanhoitopiirin mukaan.
Ablaation sairastaneiden naisten syöpäsairastavuutta käsittelevässä
tutkimuksessa totesimme, että näiden naisten riski sairastua rintasyöpään oli
alentunut, kun taas riski sairastua keuhkosyöpään ja kilpirauhassyöpään oli
lisääntynyt. Ablaation sairastaneiden naisten kuolleisuutta ja kuolinsyitä
käsittelevässä tutkimuksessa totesimme, että ablaation sairastaneiden naisten
kokonaiskuolleisuus oli lisääntynyt verrokeihin nähden. Tämä johtui
lisääntynestä kuolleisuudesta hengitysteiden syöpiin, alkoholisairauksiin sekä
ulkoisista syistä johtuviin kuolemiin, erityisesti itsemurhiin.
12
Tutkimusaineistossa oli yhteensä 4190 ablaatioraskauksista syntynyttä lasta
ja 12570 vertailulasta. Tutkimuksessa tehdyssä monimuuttuja-analyysissä
havaitsimme, että ablaatiolapsilla epämuodostumia esiintyi kaksi kertaa niin
paljon kuin verrokeilla. Yhteys havaittiin lähes kaikkien
epämuodostumatyyppien sekä ablaation välillä.
Ablaatioraskauksista syntyneiden lasten kuolleisuuteen ja kuolinsyihin
keskittyvässä tutkimuksessa totesimme, että näiden lasten
kokonaiskuolleisuus oli huomattavasti lisääntynyt ollen noin 9-kertainen
verrokeihin nähden. Neonataalikaudella kuolleisuus oli lähes 15-kertainen. Yli
vuoden iässä kuolleisuus oli vielä 1,7-kertainen verrokeihin nähden. Asfyksia
oli erittäin merkittävä kuolleisuuden aiheuttaja neonataalikaudella
ablaatioraskauksista syntyneiden lasten keskuudessa.
Yhteenvetona voimme todeta, että ablaatio vaikuttaa niin sen sairastaneiden
naisten kuin näistä raskauksista syntyneiden lastenkin myöhempään
terveyteen. Elintapatekijöillä, kuten tupakoinnilla ja alkoholin käytöllä on
todennäköisesti suuri merkitys ablaatiosta aiheutuvien terveyshaittojen
välittäjinä. Ablaatio ei itsessään vaikuta lisäävän syöpäriskiä.
Tupakoimattomuus vähentää paitsi ablaation riskiä, myös lukuisia muita
terveyshaittoja. Tästä tutkmuksesta saatua uutta tietoa voidaan hyödyntää
ablaation sairastaneiden naisten ja heidän perheidensä neuvonnassa.
13
INTRODUCTION
Placental abruption, defined as complete or partial separation of the placenta

prior to delivery of the fetus, is an infrequent but serious obstetric
complication (1) seen in approximately 0.5–1% of deliveries worldwide (2,3).
Although rare, abruption can cause several severe immediate morbidities or
even death for both mother and fetus. The immediate maternal risks depend
solely on the severity of the abruption and include hypovolemia, disseminated
intravascular coagulopathy (DIC), and emergency hysterectomy because of
bleeding. The risks to the fetus depend on both the severity of the abruption
and the gestational age at the time of the abruption (4). In addition to
prematurity-related problems, surviving newborns have an increased risk for
low birth weight and asphyxia, i.e. low cord pH and base excess values (5).
The risk factors predisposing to placental abruption are well known, the most
important being prior abruption, maternal smoking, and hypertensive
disorders (6). In addition, other known risk factors such as excessive alcohol
consumption and lower social status are related to smoking. Smoking causes
endothelial cell injury and dysfunction leading to defects in the placental
vascular bed (7). Placental infarcts are often detected in the abrupted
placentas of smokers (8). Furthermore, smoking has a major impact on the
later morbidity of both women and children. The effect of smoking on many
cancers is well known. Prenatal and postnatal nicotine exposure may impair
fetal development of the lungs (9) and may later expose the child to sudden
infant death syndrome (SIDS) (10). SIDS occurs more often among children
born after abruption (11,12). Children born from pregnancies complicated by
abruption are likely to have increased risk for congenital anomalies (13–17).
Folate deficiency may also be another risk factor for abruption (18–20), since
it has a major role in preventing major congenital anomalies (21,22).
Later morbidity and mortality of women with a history of placental abruption

has been under scrutiny. Prior abruption has been associated with increased
cardiovascular disease (CVD) mortality in some (23–25), but not all (26,27)
studies. However, little is known about the overall mortality of these women
(23,26), and no systematic studies on causes of death among women with a
history of placental abruption have been reported.
The effect of placental abruption on perinatal and neonatal mortality has been
demonstrated in many previous studies (6,28–32). A significant number of
perinatal deaths caused by abruption involve stillbirth (30,31). Conversely,
surviving children have an increased morbidity because of prematurity and
hypoxia. These morbidities are likely to affect the later survival of the children.
However, the impact of placental abruption on offspring mortality beyond the
perinatal period is not well known.
14
The present study was designed to investigate the long-term impact of
placental abruption on both maternal and offspring morbidity and mortality.
The question was posed regarding whether having a history of placental
abruption affected the subsequent risk of cancer in these women. This study
specifically focused on overall and cause-specific mortality of both women
with a history of placental abruption and children who had primarily survived
after being born from a pregnancy complicated by abruption. The association
between major congenital anomalies and placental abruption was also
explored.
15
REVIEW OF THE LITERATURE
PLACENTAL DEVELOPMENT
The placenta is a unique fetomaternal organ that connects the developing fetus
to the uterine wall and provides oxygen, nourishment, and protection during
pregnancy. The formation of the placenta begins when the zygote transforms
into a morula, which is formed of blastomeres. The morula then further
transforms into a blastocyst. The blastomeres of the blastocyst form an outer
shell of cells, the trophoblast. The inner cell mass is called the embryoblast.
The blastocyst attaches itself tightly to the endometrium. At the site of the
attachment, the trophoblast cells rapidly proliferate and differentiate into an
outer layer of syncytiotrophoblasts and an inner layer mass of
cytotrophoblasts. These trophoblast columns invade the decidualized
endometrium and spiral arteries transforming them into large, inelastic tubes
without vasomotor control (33–35). This remodeling of the spiral arteries is
crucial for the normal function of the placenta (35). The syncytiotrophoblasts
form primary, secondary, and tertiary villi, and cytotrophoblasts form
intervillous space. The placenta is attached to the uterine wall by anchoring
villi. By the end of the fourth month of gestation, the placenta has achieved its
definitive form and no further anatomic modification occurs. Growth,
branching of the villous tree, and formation of fresh villi continues until term
(36).
The placenta normally detaches during the third phase of labor. The
separation process is multiphasic and requires adequate, coordinated changes
and peristalsis in the myometrium after which the placenta expulses and slides
out of the uterine cavity (37,38).
PLACENTAL ABRUPTION
Definition
Placental abruption is a condition in which the whole placenta or part of it

prematurely detaches from the uterine wall (39). There are three categories of
placental abruption, based on the site of the bleeding: a) preplacental or
subamniotic, in which there is blood between the placenta and the amniotic
fluid; b) marginal or subchorionic, in which there is blood between the
placenta and the membranes; and c) retroplacental, in which blood clots
between the placenta and the myometrium (Figure 1). Retroplacental
16
abruptions are the most severe, whereas preplacental abruptions are often of
no clinical importance (39). Most abruptions are partial, with only a small
portion of the placenta detaching from the uterine wall. The less common and
more severe form is total abruption, in which case the entire placenta is
detached. Total abruption often leads to fetal loss (4).
Figure 1. Categories of placental abruption, based on the site of the bleeding.
17
Epidemiology and incidence
The incidence of placental abruption varies between 0.22–1.4 %

(3,18,32,40,41) and seems to be relatively low in the Nordic countries.
Differences in the reported incidences between studied populations may
partly be explained by different inclusion criteria (singleton vs. multiple
pregnancies, gestational age). In the U.S., the incidence of abruption among
African American women is higher than in Caucasians (42). Well known risk
factors for placental abruption, such as hypertensive disease disorders,
smoking, alcohol, and cocaine use are also more common among African
American women (2,18,28).
Studies reporting trend in the incidence of placental abruption are

controversial. An increase in the incidence of abruption was found in an Israeli
population from 0.6 % in 1998 to 0.8% in 2006 (43). Conversly, Tikkanen et
al. performed a large population-based cohort study in Finland and found a
decrease in the incidence of placental abruption from 1980 to 2005 (3). The
trend remained decreased in another Finnish study covering the years from
1991 to 2010 (44). Although many risk factors predisposing to placental
abruption, such as advanced maternal age and prior ceasarean section, are
becoming more frequent, the decrease in incidence may be due to advanced
antenatal clinic care. In addition, an improved overall socioeconomic status of
women results in better health of pregnant women as well (3).
Etiology
Although a number of risk factors leading to placental abruption have been

identified, the exact ethiopathogenesis of this condition remains elusive.
Clinicians often regard abruption as an acute event, though accumulating data
point towards abruption as being the end-result of a chronic process starting
early in pregnancy (45). A defective trophoblastic invasion of the spiral arteries
disturbs the early vascularization of the placenta and is considered the main
mechanism associated with placental abruption (46,47). This results in
placental insuffiency, intrauterine hypoxia, and uteroplacental
underperfusion. Incomplete remodeling of the spiral arteries with retained
contractility leads to maintenance of high uteroplacental vascular resistance,
which may predispose to vascular rupture of a spiral artery in the placental
bed leading to abruption (35,46,48). These changes may be partly genetic (41).
Similar vascular changes are characteristic to pre-eclampsia and intrauterine
growth restriction (IUGR). These three conditions are linked and constitute
the syndrome of ischemic placental disease (49).
Furthermore, folate deficiency and low maternal red blood cell folate levels
could predispose to placental abruption (13,19,20). Folate deficiency is related
18
to hyperhomocysteinemia (50), which, in turn, is associated with placental
abruption (50–52).
In addition to the vascular mechanism, there are two other major pathways
leading to placental abruption: immunological rejection and inflammation
(53). Immunological defects may lead to an adverse maternal inflammatory
response, resulting in a chain of events such as insufficient trophoblast
invasion, defective spiral artery remodeling, placental infarctions, and
thrombosis (54). Placental abruption may also be the result of acute or chronic
inflammation. The observation of placental inflammatory lesions carrying an
increased risk of placental abruption suggests a chronic process rather than
acute event, which may then be the final manifestation of a chronic process
(45,47).
Clinical presentation and diagnosis
The spectrum of the clinical presentation of placental abruption varies from

totally asymptomatic to severe. The classical symptoms of abruption include
vaginal bleeding, abdominal pain and uterine tenderness, backache, and
uterine tetanic contractions (55). Although multiple risk factors of placental
abruption have been identified, most cases occur with no known cause. The
clinical manifestations of abruption include decreased fetal movements, fetal
heart rate abnormalities (bradycardia, repetitive late decelerations, or
decreased beat-to-beat variability) seen in fetal cardiotopography (CTG), a
retroplacental blood clot in the ultrasound, blood clots seen during delivery or
marks of a Couvelaire uterus detected at cesarean section (53). The severity of
the abruption, however, can not be judged by the symptoms and clinical
findings: i.e., a severe abruption may be ”silent”, with no symptoms at all, and
vice versa. In one study, neither bleeding nor pain were present in one fifth of
cases with placental abruption (56). In the same study, a retroplacental blood
clot was detected by ultrasound in only 15% of the cases. Vaginal bleeding was
present in 70%, abdominal pain or uterine tenderness in 51%, fetal heart rate
abnormalities in 69%, and decreased fetal movements in 22% of the cases. The
grading of placental abruption and distribution by severity of cases is
presented in Table 1 (57).
19
Table 1. Grading of placental abruption.
Modified from Potdar, N.; Konje, JC. Antepartum hemorrhage. Best practice in Labour and Delivery. (2009)

There are two basic types of placental abruption: revealed and concealed. In
cases of revealed abruption, blood tracks between the membranes and decidua
and escapes through the cervix into the vagina (Fig. 2A) (1). This subtype is
more common; constituting 65–80% of the abruption cases. In the less
common cases (20–35%) of concealed abruption, blood accumulates behind
the placenta with no visible external bleeding (Fig. 2B) (1). In severe cases,
with a concealed placental abruption, the first clinical sign may be abnormal
bleeding due to disseminated intravascular coagulopathy (DIC) and,
additionally, to maternal hypovolemic shock. Moreover, abruption may be
total, involving the entire placenta, or partial, with only a portion of the
placenta detached from the uterine wall (4). Abruption involving one-half or
more of the placenta is often associated with fetal death (58).
Figure 2. Types of abruption: revealed (A) and concealed (B).
A B
Diagnosis of placental abruption is always clinical. Placental abruption

diagnosed solely on the basis of histopathological examination has been found
in up to 3.8% of consecutively examined placentas, although most findings
were of no clinical significance (34). The use of ultrasonography in diagnostics
is of limited value: it fails to detect at least half of the cases with abruption (4).
21
All other causes for abdominal pain and bleeding, such as placenta previa,
appendicitis, urinary tract infections, preterm labor, fibroid degeneration,
ovarian pathology, and muscular pain must be taken into account in the
differential diagnostics.
Risk factors for placental abruption
At least 50 different risk factors have been identified for placental abruption
(6). However, most cases occur with no known risk factor.
Sociodemographic and behavioral risk factors

The association between smoking during pregnancy and placental abruption
was first described in 1976 (59). Up to 15–25 % of placental abruption episodes
may be attributable to smoking (60). On average, smoking provides a twofold
risk for abruption (6,31,32,56,59). In addition, paternal smoking is an
independent risk factor for abruption, and if both parents smoke, the increase
in risk is nearly fivefold (56). Smoking causes vasoconstriction, which leads to
ischemia and uteroplacental underperfusion. As a result, placental lesions are
formed. Decidual necrosis at the margin of the placenta, placental
microinfarcts, atheromatous or fibrinoid changes, and hypovascular and
atrophic placental villi have been found in the abrupted placentas of smokers
(8). Placental lesions caused by smoking can bring about disruptions in the
placental-uterine interface, leading to abruption (39). The same mechanism
applies to another risk factor, cocaine use (39). Smoking and drug use are
stronger risk factors for severe rather than mild abruptions (61). Excessive
alcohol use also increases the risk for abruption (56).
Other sociodemographic risk factors include advanced maternal age (³35

years) (32,62–64) and multiparity (³3 previous deliveries) (3,32,61,64,65). In
a Finnish study, grand multiparas (4–7 previous deliveries) had a 1.5-fold risk
for abruption compared to parturients with 1–4 previous deliveries (65). Being
black, unmarried, or a single mother also increases the risk for abruption
(32,42,62,66). Interestingly, maternal obesity may protect from placental
abruption. In a cohort study by Salihu et al., obese (prepregnancy body mass
index > 30) women were less likely to have a pregnancy complicated by
placental abruption compared with normal weight women (OR 0.8, 95% CI
0.7–0.9) (67). In another study higher maternal weight in early pregnancy was
associated with a lower risk of abruption or placental infarction (OR 0.81, 95%
CI 0.75–0.91) (68).
Maternal and historical risk factors

Pre-eclampsia is another important risk factor for abruption (6,60,69,70),
severe pre-eclampsia in particular (60,69,71). However, transient
22
hypertension in pregnancy and mild pre-eclampsia have also been linked to
placental abruption in some (66,69), but not all, studies (60,71). The risk for
abruption is further increased among smoking women with a hypertensive
disorder (60,69).
Hyperhomocysteinemia has been linked to placental abruption (50,51,52).
Moreover, smoking increases homocysteine levels in the plasma (50).
Hyperhomocysteinemia can induce endothelial cell injury and dysfunction,
leading to local throm- boembolism and defects within the placental vascular
bed (7). It is also a strong indicator of folate and B12-deficiency, both of which
have been linked to an increased risk of placental abruption (50). Several
studies have suggested that certain major congenital anomalies are more
common in pregnancies with folate deficiency (21,22).
Placental abruption in a previous pregnancy is the most significant risk factor

and the best predictor of abruption (53,63,72–74). The risk estimates range
from 3- to 12-fold (63,73). Other maternal and historical risk factors include
some trombophilias, pregestational diabetes mellitus, hypothyreosis, anemia,
and uterine anomalies. Stillbirth or cesarean section in previous pregnancy
also increase the risk for abruption (6).
Pregnancy-associated risk factors

Chorioamnionitis and preterm prelabor rupture of the membranes (PPROM)
are associated with an increased risk of placental abruption. Approximately 4–
12% of patients with preterm prelabour rupture of the membranes (PPROM)
before 37 weeks of gestation develop placental abruption (75,76). PPROM is
often associated with ascending intrauterine infection. In one study, the rate
of histologically confirmed chorioamnionitis was 30% among women with
placental abruption (77). Disturbances in the amount of amniotic fluid, that is
oligohydramnion and polyhydramnion, increase the risk for abruption
(62,78), as does multiple gestation (4,42). In a multiple pregnancy, the
increased risk may be explained by the sudden decompression of the uterus
following the birth of the first twin (4).
Bleeding in pregnancy carries an increased risk of abruption (45) as do

pregnancies complicated by placenta previa (56). An association between male
fetal sex and increased risk of abruption has been demonstrated in several
studies (5,62,79), however the biological mechanism for this finding is unclear
(5). In pregnancies with a small-for-gestational-age (SGA) fetus (28,32,66,70)
or velamentous umbilical cord insertion (64) the risk of abruption is also
increased. Finally, an increased risk for abruption after assisted reproductive
technology has been found in some (80,81), but not all (82), studies.
23
Recurrence rate of placental abruption
Placental abruption is characterized by substantial recurrence. Increased

recurrence rates of abruption have been reported from many different
countries and populations (40,44,74,83,84). In Finland, a retrospective case-
control study of singleton births from 1991 to 2010 observed a recurrence
rate of 8.6 per 1000 of abruption among women with a history of placental
abruption (44). In two older Finnish studies, abruption recurred in 8.8%
(84) and in 11.9% (72) of women with a previous abruption.
MATERNAL SHORT-TERM CONSEQUENCES OF

PLACENTAL ABRUPTION
Morbidity due to obstetric hemorrhage
Placental abruption is often associated with significant blood loss, especially

in cases of fetal death (85,86). Severe obstetric hemorrhage is suggested to
occur in 25% of cases of placental abruption (57). Blood loss may often be
underestimated since the amount of bleeding into the myometrium is difficult
to quantify in cases of concealed abruption. The situation is also often
accompanied by poor myometrial contractility and atony due to Couvelaire
uterus (57).
Pregnancy provides natural protection against hemorrhage through increased

blood volume and increased level of coagulation factors. However, when
bleeding exceeds 25% of the total blood volume, rapid hemodynamic
deterioration occurs (87). Massive obstetric hemorrhage may result in
hypovolemic shock, which is a clinical condition characterized by tissue
hypoperfusion. Vital signs, urine output, and serum biochemistry are critical
tools in estimating the amount of blood lost as well as in evaluating the
response to treatment. The clinical findings of hypovolemic shock include
tachycardia, hypotonic bloodpressure, tachypnea, altered mental status,
paleness, delayed capillary refill, and decreased urine output. If untreated,
hypovolemic shock can lead to critical underperfusion, acidosis, and thus
ischemic necrosis of target organs (88).
Several studies have observed a significant risk of additional maternal

outcomes as a consequence of postpartum hemorrhage (PPH) in the setting of
abruption (31,83,89–92). Ananth et al. examined outcomes associated with
mild and severe abruption and found an increased risk of several additional
maternal outcomes, such as pulmonary edema, puerperal cerebrovascular
24
disorders, acute heart failure, acute myocardial infarction, cardiomyopathy,
acute respiratory failure, and coma (61). PPH associated with abruption is
likely to explain many of these complications.
Blood transfusions
As an obvious consequence of severe hemorrhage and hypovolemia, women
with placental abruption may require aggressive blood transfusion therapy.
Several studies have found an over 10-fold increased risk for transfusion
(93,94). In cases of massive blood transfusion (10 units or more),
complications often develop, including hyperkalaemia, hypocalcemia,
trombocytopaenia and other clotting disorders (57).
Emergency peripartum hysterectomy

Placental abruption is a distinguished risk factor for emergency peripartum
hysterectomy. Nonetheless, emergency hysterectomy is performed to limit
futher oxygen deprivation to the fetus and to reduce blood loss for the mother.
It may represent a life-saving intervention when other medical and surgical
options in treating massive hemorrhage have failed.
An increased risk of peripartum hysterectomy due to placental abruption was
described in a U.S. study (aOR 3.2, 95% CI 1.8–5.8) (95). Similar results were
obtained in another U.S. study (aRR 2.84; 95% CI 2.52–3.20) (96) and an even
stronger association between placental abruption and peripartum
hysterectomy was found in an Israeli study (OR 7.9, 95% CI 3.4–18.1).
Abruption is also associated with an increased risk of relaparotomy after
delivery by ceasarean section (97,98). Table 2 summarizes these studies.
Table 2. Risk estimates of relaparotomy and hysterectomy in deliveries complicated by

placental abruption.
Hysterectomy
Authors, study Sample size Relaparotomy
aRR/aOR/OR (95%
design (year) (abruptions) aRR/aOR/OR (95% CI)
CI)
Gedikbasi et al.,
28,799 (547) 15.3 (6.9–33.8)
cohort (2008)
Pariente et al.,
185,476 (1,365) 7.9 (3.4–18.1)
cohort (2011)
Friedman et al.,
55 214,208 (573,723) 2.8 (2.5–3.2)
cohort (2016)
Bodelon et al., case-
4,451 (126) 3.2 (1.8–5.8)
control (2009)
Kessous et al., case-
34,469 (1,284) 3.5 (1.8–6.8)
control (2012)
aRR, adjusted risk ratio; aOR, adjusted odds ratio; OR, odds ratio; CI, confidence interval
25
Renal failure
Severe cases of placental abruption can result in renal failure (4), which
develops as a consequence of hypovolemic shock. The loss of 15% to 30% of
the intra-vascular blood volume will result in poor renovascular perfusion,
causing reversible changes in urinary output and blood urea and creatinine
levels. Ongoing blood loss leads to ischemic injury and tubular renal necrosis.
Cortical necrosis can be caused by microvascular clotting. Both renal ischemia
and the obstructive component caused by clotting reduce glomerulal filtration
(99). However, oliguria is commonly seen within the 12 hours following
placental abruption and is not necessarily associated with renal damage. Fluid
replacement and renal fuction should be monitored (57).
Disseminated Intravascular Coagulopathy

Disseminated intravascular coagulation (DIC) is defined as the widespread
activation of intravascular coagulation leading to the deposition of fibrin
within the circulation (99). There are several mechanisms involved in the
complex ethiopathogenesis of DIC: injury to the vascular endothelium, release
of thromboplastic tissue factors, and the production of procoagulant. In many
obstetric complications there may be an interaction between these
mechanisms. In placental abruption, DIC is initiated by tissue factor or
thromboplastin, which is released from trophoblastic or fetal tissue, or from
the maternal decidua or endothelium (100). Tissue factor activates the
coagulation sequence to cause fibrin clotting and its dissolution by the
fibrinolysin system. The result of this process can range from mild, clinically
insignificant laboratory value aberrations to massive uncontrollable
hemorrhage with low fibrinogen and platelet levels.
In severe placental abruption with fetal loss, profound hypofibrinogenemia

has been reported in about one-third of cases. It is much less common if the
fetus is alive (99).
Mental burden
An adverse outcome in birth complicated by placental abruption may

influence the desire for future pregnancies (101). After placental abruption
with perinatal survival in the first delivery, 59% of women had a subsequent
delivery, whereas the rate of subsequent delivery without abruption and
perinatal survival was 71% (p<0.0001). After perinatal loss, the corresponding
rates were 83% and 85%, suggesting that after perinatal survival, the trauma
caused by abruption may discourage women from having future pregnancies.
26
Maternal deaths
Maternal death is the death of a woman while pregnant or within 42 days of

termination of pregnancy, irrespective of the duration and site of pregnancy.
It may be due to any cause related to, or aggravated by, the pregnancy or its
management, but not from accidental or incidental causes (102). The maternal
mortality ratio (MMR) is defined as the number of female deaths per 100,000
live births (103).
The role of placental abruption in maternal deaths was assessed in a Finnish

study by Tikkanen et al. (104). There were 2,104,436 live births during the
study period, 1987–2005. The number of maternal deaths during this period
of time was 121, of which three were caused by placental abruption. The overall
MMR was 5.7 per 100,000 and that of direct maternal deaths was 5.6 per
100,000. The placental abruption-associated MMR was considerably higher,
38.8/100,000. Despite the rarity of a maternal death caused by placental
abruption, maternal mortality associated with abruption was seven times
higher than the overall maternal mortality rate (104). In a more recent study
between 2006 and 2010 in the U.S., placental abruption was found to be the
direct cause of maternal mortality in 1.1% of pregnancy-related deaths (105).
Maternal mortality associated with placental abruption decreased from 8% in

1919 to less than 1% in 1995 (1). Many advances in the treatment of severe
obstetric hemorrhage and atony have taken place during the last few decades,
such as routinely administered oxytocin and the established use of B-Lynch
surgical technique and intrauterine balloon tamponade (104,106). These
advances may have decreased maternal deaths caused by placental abruption
and other obsterical emergencies attributable to obstetric hemorrhage
(104,106).
MATERNAL LONG-TERM CONSEQUENCES OF PLACENTAL

ABRUPTION
Cardiovascular diseases
Obstetrical complications, such as placental abruption, preeclampsia, and

intrauterine growth restriction share one common feature: uteroplacental
ischemia (107). A history of preeclampsia is associated with increased risk of
both CVD-related morbidity (108–111) and mortality (26,112,113) later in life.
Given the histopathological similarities of placental abruption and
preeclampsia, abruption might also have an impact on later CVD morbidity
and mortality. Furthermore, there are other factors that support this
27
assumption. Smoking is a strong risk factor for both abruption and CVD.
Moreover, vaginal bleeding caused by placental abruption is associated with a
high risk of preterm delivery (114), which, in turn, is associated with increased
risk of maternal CVD (115,116). Given this background, several studies have
assessed the association between a history of placental abruption and CVD-
related morbidity and mortality later in life. These studies are presented in
Table 3.
Table 3. Summary of studies on the association between cardiovascular disease (CVD)

morbidity/mortality and placental abruption.
Association with
Authors (year) Outcome of the study placental abruption HR (95% CI)
yes/no
Ray et al. (2005) CVD morbidity Yes 1.7 (1.3–2.2)
Prevalence of CVD risk

Veerbeek et al. (2013) Yes* NA
factors after pregnancy
Cain et al. (2016) CVD morbidity No 1.1 (0.8–1.6)
Lykke et al. (2010) CVD mortality No 1.2 (0.8–1.9)
CVD mortality (first

Pariente et al. (2014) Yes 4.8 (1.1–20.1)
CVD hospitalization)
DeRoo et al. (2016) CVD mortality Yes 1.8 (1.3–2.4)
Ananth et al. (2017) CVD mortality Yes 2.7 (1.5–5.0)
CVD, cardiovascular disease; HR, hazard ratio; CI, confidence interval; NA, not available. *) All following factors
were increased (p<0.05): blood pressure, BMI, fasting blood glucose, total cholesterol, and LDL-cholesterol
Cancer
Both abruption and cancer are conditions in which extensive cell proliferation
and neovascularization take place. Moreover, excessive alcohol consumption
and smoking increase the risk of placental abruption and they also expose to
cancer. Nevertheless, there are little data on placental abruption and
subsequent risk of cancer.
Innes et al. reported an association between breast cancer and previous
placental abruption (OR 1.8, 95% CI 1.1–3.0) (117). They evaluated first
pregnancy characteristics in women with a subsequent breast cancer diagnosis
at least a year after the pregnancy. DeRoo et al. executed a large register-based
study and evaluated cancer-related mortality in a small subset of 34 women
28
with a history of recurrent placental abruption. Cancer-related deaths were
not increased among these women (23).
Overall mortality
The increased CVD morbidity and mortality of women with a history of

placental abruption gives rise to the assumption that the overall mortality of
these women may be increased as well. In addition, the overall mortality of
women with a history of preeclampsia, a placental pathology sharing similar
features with placental abruption, is increased.
Two previous studies have evaluated the overall mortality of women with a
history of placental abruption. Lykke et al. investigated the effects of
pregnancy complications on early maternal death among primiparous women
with a singleton delivery. Placental abruption was associated with death from
all causes (HR 1.41, 95% CI 1.2–1.67) (26). A more recent study, based on
combined analysis of data from the Medical Birth Registries of Sweden and
Norway, found an increased overall mortality among women with a history of
abruption (HR 1.3, 95% CI 1.1–1.4) (23). The main focus in both of these
studies was the relation of placental abruption to CVD mortality. There are no
studies that would have investigated the cause-specific mortality of women
with a history of placental abruption.
PERINATAL AND NEONATAL SHORT-TERM

CONSEQUENCES OF PLACENTAL ABRUPTION
Prematurity
Preterm birth, defined as birth occurring before 37 weeks of gestation, is the

most significant contributor to perinatal and neonatal mortality and morbidity
in births complicated by placental abruption (3,28–31,43,47,118–120). There
are sub-categories of preterm birth, based on gestational age, which are
outlined in Table 4.
29
Table 4. Classification of prematurity by gestational age.
Extremely preterm <28+0
Very preterm 28+0-31+6
Moderately preterm 32+0-36+6
Although placental abruption is an important cause of spontaneous preterm

birth, it also causes iatrogenic preterm delivery (28). Approximately 5% of all
preterm births are associated with abruption (121). Nearly half of the births
complicated by abruption occur before 37 gestational weeks (3) and
approximately 14% of them occur before 32 weeks of gestation (28).
In a study by Ananth et. al of over 50,000 singleton births, the risk of preterm
birth among women with and without placental abruption was 39.6% and
9.1%, respectively, yielding an aRR of 3.9 (95% CI 3.5–4.4) (28). The
association was much stronger for very preterm births (aRR 10.6, 95% CI 8.4–
13.2) than for moderately preterm births (aRR 3.4, 95% CI 2.9–3.9). The
median gestational age of births complicated by abruption was 36.5 weeks,
and on average, these children were born two weeks earlier than the controls.
In another US study, preterm placental abruptions were estimated to be 9
times more common than term abruptions (47).
Räisänen et al. analyzed all singleton births in Finland in 1987–2010 and

reported placental abruption as a significant risk factor for prematurity, the
ORs ranging from 12.18 (95% CI 11.04–13.44) for moderately preterm to 23.41
(95% CI 18.87-29.04) for extremely preterm, and 31.69 (95% CI 29.92–37.32)
for very preterm babies (120). Recently, Downes et al. found that 53% of
children born after abruption were delivered prematurely, on average three
weeks earlier than children born from non-abruption pregnancies (122). In a
study by Tikkanen et al., births with placental abruption occurred
approximately two weeks earlier compared with nonabruption births (37.7
gestational weeks vs. 40 gestational weeks) (5).
Asphyxia
Abruption increases the risk of birth asphyxia by depriving the fetus of oxygen.
If severe, asphyxia can cause permanent damage in the brain and lead to long-
term consequences (123). It manifests in low Apgar scores, umbilical cord
30
blood pH, and base excess values. The risk of adverse neurological outcomes
starts to rise below a pH of 7.10. Despite this, the risk rises sharply only below
pH 7.00 (124). In addition, decreased variability and pathological
decelerations may be present in fetal cardiotocography during labor as
markers of asphyxia (57).
In a Finnish study, placental abruption was an independent risk factor for

intrapartum asphyxia (umbilical artery base deficit > 12mmol/l) (OR 3.74,
95% CI 2.15–6.51) (125). A large, population-based study of U.S. women
reported a strong association between abruption and neonatal asphyxia
(diagnosis of asphyxia based on medical records) (RR 8.5, 99% CI 5.7-11.3)
(122). In another Finnish study, children born after abruption had a
significantly lower 1-minute Apgar score and lower umbilical cord pH
compared with controls without abruption (p<0.001). Altogether, 15% of them
were asphyctic (pH 7.05 or less) compared with 1.5% of children born from
non-abruption pregnancies (5). The association of abruption with low Apgar
scores has also been found in several other studies (31,43,126) as well as the
association with low umbilical cord artery pH (31,127).
Low birthweight and intrauterine growth restriction associated with

placental abruption
The association between placental abruption and fetal growth restriction is

strong, and growth restriction alone could be used as a risk marker for
abruption (41). This association is likely the result of underlying chronic
placental ischemic disease, which leads to oxygen and nutrient deprivation of
the fetus and suppresses fetal growth (92).
Children born from pregnancies complicated by abruption have been

described to have lower birthweight and are more often SGA than controls
without abruption (9.4% vs. 2.3%, p>0.001) (3).
Another Finnish study found that 6% of births with placental abruption were
growth restricted (≤ -2 SD) compared with 1% in nonabruption births. Of the
babies born after abruption, 10.5% weighed <1500 g compared with 0.5% of
the controls. For babies weighing 1500–2499 g, the percentages were 22.5 %
vs. 2.4 % (5). A strong association between placental abruption and low
birthweight was found in a case-control study by Nath et al. (OR 13.7, 95% CI
7.4–25.2) (128). This association was largely mediated through preterm birth.
Two other older studies by Kramer et al. and Ananth et al. also reported an
association between fetal growth restriction and placental abruption (28,66).
In the latter study, neonates born to women with abruption also weighed, on
average, 494 grams less than those born to women without abruption (28).
31
Major congenital anomalies associated with placental abruption
MCAs have been linked to placental abruption. The first study reporting an
increased prevalence of MCAs in births with placental abruption was
published in 1966 by Hibbard and Jeffocate (13). There were 16 newborns with
a congenital malformation among 506 births complicated by placental
abruption. The observed prevalence of 310/10,000 was significantly higher
compared with that of the whole hospital population at that time
(130/10,000). Over a decade later in 1979, Paterson reported exactly the same
prevalence as Hibbard and Jeffocate (15) based on a study sample including
193 abruption cases. The majority of MCAs reported in these two studies were
central nervous system (CNS) defects. In 1986, Kåregård and Gennser
executed the first large register-based study and reported a prevalence of
350/10,000, which was twice the prevalence among the general population
(14). A later study by Raymond and Mills provided stronger evidence (RR 2.57,
95% CI 1.48–4.44) on the association of placental abruption and MCA (16).
This association was almost entirely due to a nearly 5-fold increase in
congenital heart defects. Nevertheless, the study was also relatively small, with
a total of 13 children with a MCA among 307 births complicated by abruption.
Wyszynski and Wu investigated maternal morbid conditions of women
carrying offspring with oral clefts and found that these mothers were at
increased risk for placental abruption (17). Pariente et al. reported that
congenital malformations were more common in births complicated by
abruption (OR 3.4, 95% CI 3.3–4.4), but failed to specify what kind of
malformations were included (43). The reason that children born after
placental abruption seem to have congenital malformations more often than
children born from non-abruption pregnancies is unknown, but plausible
explanations may include the role of folic acid and anomaly-associated
polyhydramnions.
Neonatal morbidity
Placental abruption predisposes the surviving newborn to several morbidities,

including respiratory distress syndrome (RDS), apnea, intraventricular
hemorrhage, anemia, cystic periventricular leucomalasia, necrotizing
enterocolitis, acute kidney injury, and nosocomial infections. Of these,
intraventricular hemorrhage, cystic periventricular leucomalasia, RDS,
necrotizing enterocolitis, and acute kidney injury are largely due to the
association between placental abruption and preterm birth, as well as asphyxia
(129).
Gouyon et al. studied babies born early term (at 37–38 weeks of gestational
age) and compared those with severe respiratory disorders to those without.
In multivariate analysis, placental abruption was identified an independent
32
risk factor for severe respiratory disorder (OR 5.0, 95% CI 1.2–20.5) (130).
Downes et al. reported that neonates born after abruption had a 6.5-fold risk
for RDS (RR 6.5, 95% CI 5.9–7.1) and an elevated risk for apnea (RR 5.8, 99%
CI 5.1–6.5) compared with children born from nonabruption pregnancies. The
increase in risk was seen in both term and preterm babies born after abruption
(122).
In a study with preterm infants, placental abruption was associated with

severe intraventricular hemorrhage (grades III and IV, OR 4.3, 95% CI 1.1–
16.6 and OR 4.4, 95% CI 1.1–18.1, respectively) when compared with infants
born under placental vascular disease conditions (maternal hypertension,
preeclampsia, eclampsia, and HELLP syndrome) (131). A case-control study
of 29 neonates delivered after abruption at a median gestational age of 29
weeks found that 34% of them developed cystic periventricular leucomalacia,
a 10-fold increase over controls that were matched with cases by gestational
age. Similarly, the rate of intraventricular hemorrhage among the abruption
cases was higher than that of controls (72% vs. 48%, p<0.05) (132).
Infants born after placental abruption may be anemic due to severe

fetomaternal hemorrhage. Hurd et al. reported infants born after abruption to
be anemic more often than all other liveborn infants delivered during the study
period (20% vs. 4.4%, p<0.001) (133). In a more recent study, placental
abruption was observed in 3.3% of cases with fetomaternal hemorrhage,
making abruption a significant predictor of fetomaternal hemorrhage (OR
9.77, 95% CI 7.18–13.31) (134).
In babies born at less than 32 weeks of gestation, placental abruption was

independently associated with increased odds for necrotizing enterocolitis
(OR 2.20, 95% CI 1.39–3.50, p=0.001). This can likely be explained by
compromised oxygenation or blood flow to the splanchnic circulation (135). In
a study of extremely low birthweight children, those with acute kidney injury
had a stronger association with abruption than the controls (54.1% vs. 34.3%)
(136). Abruption was also associated with an increased risk of nosocomial
infections (p< 0.01; OR 2.73, 95% CI 1.38–5.40) (137).
Finally, babies born from pregnancies with placental abruption are more likely
to need medical interventions immediately after birth (31,122,138). In a large
U.S. multisite cohort study, neonates born from pregnancies complicated by
abruption were more likely to need resuscitation in the delivery room (RR 1.5,
99% CI 1.5-1.6) and to be admitted to the neonatal intensive care unit (NICU)
(RR 3.4, 99% CI 3.2–3.6) than neonates born from non-abruption
pregnancies. Among the neonates admitted to the NICU, abruption was also
associated with a length of stay nearly twice as long (incidence rate ratio 2.0,
99% CI 1.9–2.2) (122). A large register-based Finnish study reported that
neonates born after placental abruption needed special care and respirator
treatment after birth significantly more often than control neonates born from
33
non-abruption pregnancies (50% vs 10.5%, p<0.001 and 17.5% vs. 1%,
p<0.001, respectively). Furthermore, their need for IV antimicrobial
treatment and phototherapy was significantly increased compared with
controls (21.5% vs. 3%, p<0.001 and 21% vs 5.5%, p<0.001, respectively) (5).
Perinatal and neonatal mortality
The terminology concerning perinatal and neonatal mortality is heterogenous.

In some studies, neonatal mortality has been classified as a subgroup of
perinatal mortality (PNM). The other studies report stillbirths as one entity
and all remaining deaths up to 28 days of life as neonatal mortality (31,122).
This heterogenous terminology makes the comparision of the studies difficult.
According to the World Health Organization, PNM includes all deaths
occurring in utero after 22 completed weeks of pregnancy (stillbirths) and
during the first seven days of life. Neonatal mortality covers all deaths of
neonates born alive up to 28 days of life (139).
Placental abruption is associated with substantial risks for both perinatal and
neonatal mortality, which in turn are closely related to gestational age at birth.
A high PNM rate related to abruption is indeed strongly linked to preterm
delivery. However, even term babies with normal birthweight born after
abruption have a 25-fold higher mortality compared with term babies born out
of nonabruption pregnancies (41).
In addition to prematurity, placental abruption is associated with birth

asphyxia, congenital malformations, low birthweight, and IUGR, which
decline the neonatal survival of liveborn babies (1). Older studies from the 20th
century have reported PNM rates as high as 47% among children born after
placental abruption (140). However, in most recent studies the rates have been
substantially lower, around 10-15% (29–32).
Tikkanen et al. performed a large population-based cohort study and found
that PNM associated with placental abruption was 19-fold compared with non-
abruption births. Stillbirths accounted for 77% of perinatal deaths associated
with abruption. Furthermore, 7% of all PNM was attributable to abruption.
The trend in placental abruption-related PNM in Finland from 1987 to 2005
was decreasing (30). Downes et al. evaluated the neonatal outcomes after
placental abruption in a retrospective observational study of more than
223,000 singleton deliveries in 2002–2008 and discovered a 6.3-fold risk of
stillbirth and a 7.6-fold risk of neonatal mortality among children born after
abruption (3,619 deliveries) compared with non-abruption deliveries (122).
34
LONG-TERM OFFSPRING CONSEQUENCES OF PLACENTAL
ABRUPTION
The neonates who primarily survive after placental abruption have an

increased risk of developing long-term consequences, most of which are likely
to result from in utero exposure to hypoxia or birth-related asphyxia. Table 5
summarizes the long-term morbidities associated with placental abruption.
Table 5. Associations between selected offspring morbidities and placental

abruption based on published data. Odds ratios (OR) or risk ratios (RR)
provided if available.
Morbidity OR/RR Reference number
Cerebral palsy 8.0–20.9 129–132

SIDS 1.6–7.9 11, 12, 134, 135
Epilepsy 4.6 144
Chronic lung disease 125, 145
Congnitive defects
Psychomotor 2.4 146
Mental 2.0 146
Neurological problems
Cerebral palsy (CP) is a life-long syndrome of motor impairment that results

from non-progressive disturbances occuring in the developing fetal or infant
brain. Severity, patterns of motor involvement, and other associated
impairments vary to a great extent (141). The diagnosis can often be made
before 5 months of age (142).
The clinical picture can range from mild spasticity and contracture in the arm
and leg of one side of the body to a complex mixture of spasticity and
dyskinesia involving all four limbs, accompanied by severe learning
difficulties, cortical visual impairment and vulnerability to chest infections
(141).
The risk of CP increases with decreasing gestational age and birthweight.
However, 70% of children with CP are born at term (142). Several predisposing
risk factors for CP in children born at term have been identified, i.e. placental
abnormalities, birth asphyxia, and meconium aspiration (143). One of the
most important risk factors are placental abnormalities, placental abruption
in particular (144–147).
35
In a case-control study based on the Swedish Medical Birth Register,
Thorngren-Jerneck et al. found placental abruption to be highly associated
with CP (OR 8.58, 95% CI 5.63–13.3) (146). Another Swedish study by Hjern
et al. investigated the socioeconomic differences in CP incidence in the
presence of perinatal indicators. They also found a strong association between
abruption and CP (OR 10.9, 95% CI 8.4–14.1) (144).
Tronnes et al. performed a cohort study utilizing Medical Birth Registry
(MBR) data from Norway. They found that CP was associated with placental
abruption (aOR 8.0, 95% CI 6.6–9.6). The strength of the association
increased with advancing gestational age (147). In Japan, Hasegawa et al.
found a strong association between abruption and CP (aRR 20.9, 95% CI 11.8–
36.9), although the study sample was relatively small with only 175 CP cases
(145).
Epilepsy is one of the most common neurological disorders of childhood.

Bleeding in the prenatal period is among the most important events associated
with epilepsy (148,149,150,151). However, none of these studies specified the
underlying reasons for the bleeding. In a population-based cohort study by
Whitehead et al. in 2006, a significant association between placental
abruption and childhood epilepsy was found (152). This association is likely
explained by fetal hypoxia or anoxia caused by placental abruption.
Only one study has evaluated the neurodevelopmental outcome in children

born after placental abruption (153). In this cohort study by Ananth et al.,
cognitive development was evaluated based on the Bayley scale at 8 months
(mental and motor Scores), and intelligent quotient (IQ) based on the
Stanford–Binet scale at 4 years and the Wechsler Intelligence Scale for
Children at 7 years. Placental abruption was associated with psychomotor and
mental deficits at the age of 8 months. At 4 years of age, the association
attenuated and resolved at 7 years of age. Preterm delivery seems to play a
major role in mediating the consequences of abruption on the child’s
neurodevelopmental outcome.
Sudden infant death syndrome
Sudden infant death syndrome (SIDS) is characterized by the sudden,

unexplained death of a seemingly healthy infant with the cause of death
remaining unknown despite a thorough investigation including a review of the
clinical history, an examination of the death scene, and a complete autopsy.
Most SIDS deaths occur during the first 6 months, the peak being between 2
and 4 months of age (154). In Finland, eight children died of SIDS in 2016
(155).
Children born after placental abruption have an increased risk of SIDS as
36
shown in several studies (11,12,156,157). Prenatal exposure to tobacco smoke
in particular puts infants at increased risk because it alters recovery from
hypoxia, results in impaired arousal patterns, and disrupts both autonomic
function and cardiovascular reflexes (158,159). Maternal smoking is
associated with a significantly increased risk for SIDS (160,161). Knowing that
maternal smoking is one of the most established risk factors for placental
abruption, the association between SIDS and placental abruption seems
plausible. Furthermore, Downes et al. recently reported that neonates in
pregnancies complicated by abruption are vulnerable beyond the immediate
perinatal time period. Their discovery of children born after placental
abruption having an increased risk of neonatal apnea may partly explain the
mechanism behind the association between abruption and SIDS (122).
Chronic lung disease
Two studies have explored the association between the placental

abruption/chronic abruption-oligohydramnios sequence and subsequent
chronic lung disease of the neonate (138,162). Data presented in these studies
suggest that the incidence of chronic lung disease is increased in children born
extremely and moderately preterm after placental abruption. However, the
results should be interpreted with caution due to small sample sizes and
inadequate study designs.
37
AIMS OF THE STUDY
The present study was designed to investigate later morbidity and mortality of
women and children affected by placental abruption. The specific aims were:
I To examine the cancer incidence among women with a history of

placental abruption.
II To examine the overall and cause-specific mortality among

women with a history of placental abruption, specifically focusing
on cancer and CVD mortality.
III To examine the association between births with placental

abruption and major congenital anomalies of the newborn.
IV To examine the overall and cause-specific mortality of children

born after placental abruption.
38
SUBJECTS AND METHODS
SUBJECTS
The studies included in this thesis were carried out in the Department of
Obstetrics and Gynecology at Helsinki University Hospital between 2010 and
2018, with permission from the National Institute for Health and Welfare
(THL, the register keeper) (1372/900/2006; 1202/5.05.00/2013).
Statistics Finland authorized the use of cause-of-death register data (TK-53-
1035-13).
All study protocols were approved by the Helsinki and Uusimaa Hospital
District Ethics Committee for Obstetrics and Gynecology, Pediatrics, and
Psychiatry (permission number 334/13/03/03/2013).
Women with a history of placental abruption were identified on the Hospital

Discharge Register (HDR) (since 1967) and the Medical Birth Register (MBR)
(since 1987) maintained by the National Institute for Health and Welfare
(THL) by using International Classification of Diseases (ICD) codes (ICD-8
codes 632.1, 632.4 and 632.2 for 1969–1986, ICD-9 codes 641.20, 641.21, and
641.23 for 1987–1995, and ICD-10 codes O45.0, O45.8, and O45.9 from 1996
onwards) in the HDR and a check-mark for placental abruption (yes/no) in
the MBR (October 1990–2005). Three control women were identified for each
abruption from the same registers, matched by maternal age, parity,
multiplicity, year of childbirth, and hospital district area. If a sufficient
number of controls were not found, the age criteria were loosened by +/- 1 year
to attain three controls for each case. In study I, women with a history of
placental abruption were linked with the records of the Finnish Cancer
Register (FCM) up to the end of 2013 to identify all cancer cases in the cohort.
In studies II and IV, the study data were linked with Cause-of-Death Register
(CDR) records up to the end of 2013. For studies III and IV, the hospital
discharge data were linked to the MBR using the mother’s unique personal
identification number to identify the births of women with placental abruption
and their controls. In study III, the study data were further linked with the
Register of Congenital Malformations (RCM) to identify all births with at least
one major congenital anomaly.
The characteristics of studies I-IV are presented in Figures 3-6.
39
Figure 3. Characteristics of data collection for study I.
HDR; Hospital Discharge Register, MBR; Medical Birth Register, FCR;

Finnish Cancer Register

Figure 4. Characteristics of data collection for study II.
HDR; Hospital Discharge Register, MBR; Medical Birth Register, CDR;

Cause-of-Death Register

Figure 5. Characteristics of data collection for study III.
HDR; Hospital Discharge Register, MBR; Medical Birth Register, RCM;

Register of Congenital Malformations

Figure 6. Characteristics of data collection for study IV.
HDR; Hospital Discharge Register, MBR; Medical Birth Register, CDR;

Cause-of-Death Register

DATA SOURCES
All studies presented in this thesis are based on validated register data. The
quality of register data has been proven to be excellent (163,164). A summary
of the registers used is presented in Table 6.
Table 6. The nationwide registers employed in studies I–IV.

Complete nationwide
Register Register Keeper Used in Studies
data available from
National Institute for
Cancer Register I
Health and Welfare 1953
Cause-of-Death Register Statistics Finland II, IV 1936
Hospital Discharge National Institute for

I, II, III, IV 1967
Register Health and Welfare
National Institute for
Medical Birth Register I, II, III, IV 1987
Health and Welfare
Register for Congenital National Institute for
III 1963
Malformations Health and Welfare

The Hospital Discharge Register
The HDR has recorded data for all inpatient diagnoses since 1967 and for
outpatient diagnoses from public hospitals since 1998. No diagnoses made in
primary care or in private outpatient units are included. In the HDR, the
diagnoses are classified according to ICD-8 (1969–1986), ICD-9 (1987–1995),
and ICD-10 (1996–present). The register also contains information on
admission and discharge dates.
The Medical Birth Register
Baseline data on interventions that mothers receive during pregnancy and

delivery and on the newborn’s outcome during the first 7 days are collected
in the MBR from all delivery units (since 1987). All live births and stillbirths
with either a gestational age of at least 22 completed weeks (≥154 days) or a
birthweight of ≥500 g are registered in the MBR. The data are compiled at
the time of birth using the mother’s maternity records. Less than 0.1% of all
births are missing from the MBR.
44
The Register of Congenital Malformations
The RCM is maintained by the National Institute for Health and Welfare. It
includes information on live births, stillbirths, and elective terminations of
pregnancy for severe fetal anomalies, all with at least one detected major
congenital anomaly, including major structural anomalies and chromosomal
defects classified and coded according to an extended version of the ICD-9-
Clinical modification. Minor anomalies are principally excluded according to
the exclusion system of the European Surveillance of Congenital Anomalies
(165). In the case of severe fetal major congenital anomalies or disease,
permission for elective termination of pregnancy for serious fetal anomalies
may be granted at the woman’s request by a National Board at the National
Supervisory Authority for Welfare and Health up to the 24th completed
gestational week but not later. Terminated pregnancies were excluded from
the data, however. The RCM receives and actively collects data nationwide
from several sources, including hospitals, health care professionals, and
cytogenetic laboratories as well as from other national health registers and
authorities. The coverage and quality of data of the RCM data have been
proven to be excellent (166,167,168).
The Cause-of-Death Register
The Cause-of-Death Register (CDR) is maintained by Statistics Finland.

Causes of death are obtained from death certificates. The determination of
the cause of death is based on medical or forensic evidence required for the
death certificate. A forensic cause of death assignment may be necessary if
death is not the result of an illness, i.e. if it was accidental or violent, or
caused by a treatment procedure or an occupational disease (169). Data on
underlying causes of death have been collected in a computerized database
since 1969. Coverage of the CDR is 99.9%, and coding is by the International
Classification of Diseases. Furthermore, in order to improve comparability of
cause-of-death data from different years, Statistics Finland has made a time
series classification to allow a comparable national time series for 53 cause-
of-death categories from 1969 onwards (170).
The Finnish Cancer Register
The Finnish Cancer Register (FCR) includes information on cancers diagnosed

in Finland since 1953. For decades, more than 99% of cancers have been
reported in the Register (171). The cancers are classified according to the ICD-
45
O-3 system.
The study populations, study designs, lengths of follow-ups, and registers used
in the studies I–IV are summarized in Table 7.
Table 7. The stdy populations, study design, follow-up, and registers used in studies I-IV.
Study Design Study Subjects Follow- Excluded Registers used

period up
I Cohort 1971– Women with 1969– Medical Birth
2005 placental 2013 Register,
abruption Hospital
Discharge
Register, Cancer
Register
II Cohort 1969– Index cohort: 1969– Medical Birth
2005 7,805 women 2013 Register,
with placental Hospital
abruption; Discharge
Reference Register, Cause-
cohort: 23,523 of-Death Register
women without
abruption
III Case- 1987– Cases: 4,190 1987– Multiple Register for
control 2005 children born 2005 pregnancies Congenital
after placental Malformations,
abruption; Medical Birth
Controls: 12,570 Register,
children born Hospital
after Discharge
nonabruption Register
pregnancies
IV Case- 1987– Cases: 3,888 1987– Stillbirths Medical Birth
control 2005 children born 2013 Multiple Register,
after placental pregnancies Hospital
abruption; Discharge
Controls: 12,530 Register, Cause-
children born of-Death Register
after non-
abruption
pregnancies
46

MATERNAL CHARACTERISTICS
Data on maternal age, parity, maternal education level, marital status, and
smoking during pregnancy were collected from HDR and MBR. Women who
smoked at least one cigarrette per day during the whole pregnancy were
defined as smokers. Data on smoking and socioeconomic factors were
available from 1987 onward; thus, these data were not available for all study
participants in studies II and IV.
CANCER INCIDENCE AMONG WOMEN WITH A HISTORY OF

PLACENTAL ABRUPTION
The numbers of observed cancers and person-years at risk among women

with a history of placental abruption were calculated by 5-year age groups, by
calendar periods, and by follow-up periods (<5 months, 5 months–5 years,
5–15 years, and ≥15 years since the abruption). The numbers of expected
cancers were calculated by multiplying the number of person-years in each
stratum by the corresponding cancer incidence rate among women in
Finland.
DEATHS OF WOMEN WITH OR WITHOUT HISTORY OF

PLACENTAL ABRUPTION
Mortality in the cohort of women with a history of placental abruption was

compared with mortality in the reference cohort consisting of parous women
without abruption. Mortality of both cohorts was also compared with
mortality in the general Finnish female population. These comparisons were
performed for all-cause mortality and the 53 specific cause-of-death categories
included in the Statistics Finland data (170). The follow-up periods began at
the relevant delivery and ended at death or at study termination on 31
December 2013.
BIRTH-RELATED CHARACTERISTICS OF THE NEONATES

BORN AFTER ABRUPTION–COMPLICATED OR
NONABRUPTION PREGNANCIES
Sex, gestational age at birth, and standardized birth weight were studied. The
duration of gestation calculated from the last menstrual period was confirmed
or corrected by ultrasonographic screening examinations at 11–13 weeks or
47
18–20 weeks of gestation. Small-for-gestational-age newborns were defined
by birth weight -2 standard deviations or less, and large-for-gestational-age
newborns as +2 or more standard deviations of the national sex-specific
standard (172). Extremely preterm newborns were born before 28 weeks of
gestation, very preterm from 28+0 weeks to 31+6 weeks of gestation, and
moderately preterm from 32+0 weeks to 36+6 weeks of gestation.
CLASSIFICATION OF MAJOR CONGENITAL ANOMALIES
In study I, the extended ICD-9-Clinical Modification classification system

used by the RCM and the definitions used by the International Clearinghouse
for Birth Defects Surveillance and Research (ICBDSR) for the surveillance of
selected major congenital anomalies (http://www.icbdsr.org/) were applied to
classify the observed major congenital anomalies.
DEATHS OF CHILDREN BORN AFTER ABRUPTION-

COMPLICATED OR NONABRUPTION PREGNANCIES
In study III, the causes of death were grouped by accounting for both the
main and underlying causes of death. All deaths of the included individuals
were manually double-checked by two authors (OR and MT) in order to
confirm the accurate cause of death.
INTERACTION ANALYSIS
An interaction analysis was performed if a compound effect between

variables was suspected (study III).
STATISTICAL METHODS
Study I
To compare the cancer incidence among women with a history of placental

abruption and that in the general Finnish female population, standardized
incidence ratios (SIRs) were calculated as the ratios of observed to expected
numbers of cancers. The 95% confidence intervals (CIs) for the SIRs were
based on the presumption that the number of observed cases followed a
Poisson distribution.
48
Study II
Crude death rates/100,000 person-years were calculated for both cohorts.

Age-adjusted hazard ratios (HR) with 95% confidence intervals (CI) were
calculated for index and reference cohorts by the Cox hazard regression
method. The expected number of deaths was calculated by multiplying the
age- and calendar period-specific numbers of person-years by the respective
mortality rates in the general Finnish female population obtained from
Statistics Finland. When comparing the mortality of a cohort to that in the
general Finnish female population, standardized mortality ratios (SMR) were
calculated as the ratio of observed to expected number of deaths, and the 95%
CI were defined assuming Poisson distribution of the observed number of
deaths.
HRs were calculated by age at delivery and at 5-year periods since delivery. A
p-value <0.05 was considered to be significant. The HR analyses were
performed by IBM SPSS STATISTICS version 23 (IBM Corp., Armonk, NY,
USA).
Study III
Prevalence of at least one major congenital anomaly was analyzed by

multivariate logistic regression analysis and the results were shown by odds
ratios (ORs) with 95% confidence intervals (CIs). All models were adjusted by
selected baseline characteristics or birth-related characteristics of the women
with placental abruption and control participants without abruption. Missing
data were recorded as an unknown category and included in the analyses.
Births with selected major congenital anomalies according to the definitions
by the ICBDSR among pregnancies with and without abruptions were studied
by logistic regression adjusting models by selected baseline characteristics.
Statistical analyses were performed by IBM SPSS Statistics 19.0 release
19.0.02. Statistical significance was defined as p-value <0.05. To avoid
problems with multiple testing, a stricter limit for statistical significance (p-
value <0.01) was applied for comparisons of selected major congenital
anomalies according to the definitions by the ICBDSR. All births with major
congenital anomalies were also divided into subgroups according to the MCA
pattern (isolated, multiple, or syndrome). Multiple anomalies were defined as
having at least two major unrelated congenital anomalies according to the
ICBDSR (173).
49

Study IV
The Cox proportional hazard regression method was used to compare the
children born after abruption-complicated pregnancies with children born
from nonabruption pregnancies. The results were shown as age-adjusted
hazard ratios (HRs) with 95% confidence intervals (CIs). P-values <0.05 were
considered to be statistically significant. The analyses were performed by IBM
SPSS Statistics version 23 (IBM Corp., Armonk, NY, USA). The trend of infant
mortality during the follow-up was tested as two-sided by the Cochran-
Armitage trend test using StatXact version 4.0.1.
50
RESULTS
SUBSEQUENT RISK OF CANCER AMONG WOMEN WITH A

HISTORY OF PLACENTAL ABRUPTION (I)
There were 597 cancer cases detected in the study cohort by the end of the
follow-up (31 Dec. 2013). The expected number was 628, giving a SIR for all
cancers of 0.95 (95% CI 0.88–1.02). An increased risk for cancers of the lung
and trachea was found (SIR 1.51, 95% CI 1.05–2.10), which was greatest 5–15
years after placental abruption (SIR 2.44, 95% CI 0.98–5.03).
The risk for breast cancer was decreased among women with a history of
placental abruption (SIR 0.85, 95% CI 0.75–0.96). The risk was reduced for
ductal (SIR 0.80, 95% CI 0.69–0.93) but not for lobular (SIR1.07, 95% CI
0.78–1.42) cancers of the breast. No difference was seen between pre- and
post-menopausal ages.
An increased risk for thyroid cancer was observed (SIR 1.47, 95% CI 1.04–
2.02). The vast majority of cases (35 out of 37 cases) consisted of the papillary
subtype of thyroid cancer (SIR 1.62, 95% CI 1.13–2.25).
The risk of rectal cancer was reduced, although the decrease was not
statistically significant because of small numbers (SIR 0.49, 95% CI 0.20–
1.01).
The incidence of other cancers did not differ from that in the reference
population.
MORTALITY AND CAUSES OF DEATH IN WOMEN WITH A

HISTORY OF PLACENTAL ABRUPTION (II)
When comparing the index cohort of women with a history of placental

abruption and the reference cohort consisting of matched referent women
without abruption, an increased overall mortality was observed among the
index cohort (Table 8). No increase in mortality was seen for all malignant
neoplasms (consisting of 18 different subgroups). In the subgroup analysis,
mortality from malignancies of the larynx, trachea, bronchus, and lung
(pulmonary tissue) was increased, but no significant differences in mortality
were observed in the other cancer subgroups. Suicides were more common in
the index compared with the reference cohort. Mortality due to alcohol-
related causes was also increased. For ischemic and cerebrovascular diseases,
there were no differences in mortality between the cohorts (Table 8).
51
Table 8. Observed numbers of deaths among the index and reference
cohorts.
Index cohort (n=7,805) Reference cohort (n=23,523) HR

Cause of death Deaths (n) Deaths (n) (95% CI)
All deaths 395* 863* 1.39 (1.24−1.57)
Malignant neoplasms 147 411 1.09 (0.90−1.31)
Larynx, trachea, bronchus, and lung 25 44 1.72 (1.05−2.82)
Breast cancer 36 123 0.89 (0.61−1.29)
Gynecological cancers** 18 41 1.35 (0.77−2.35)
Ischemic heart disease 21 66 0.95 (0.58−1.55)
Cerebrovascular disease 26 62 1.27 (0.80−2.01)
Other diseases of circulatory system 7 16 1.34 (0.55−3.26)
Alcohol-related 41 68 1.84 (1.25−2.72)
External causes 61 114 1.63 (1.19−2.22)
Accidents 26 58 1.36 (0.86−2.17)
Suicides 27 48 1.71 (1.07−2.74)
Homicides 3 6 1.52 (0.38−6.08)
SMR analysis was used to compare the index cohort and the reference cohort
with the general Finnish female population. In this analysis, an increased
overall mortality in the index cohort and a decreased overall mortality in the
reference cohort were seen (Table 9). The women in the index cohort had an
excess mortality risk in malignancies of larynx, trachea, bronchus, and lung.
Mortality in the reference cohort was decreased for alcohol-related causes, and
external causes, particularly suicides (Table 9).
52
Table 9. Observed numbers of deaths and standardized mortality ratios (SMRs) among women with a history of placental
abruption (index cohort) and matched controls (reference cohort).
Index cohort Reference cohort

(n=7,805) SMR 95% CI (n=23,523) SMR 95% CI
Cause of death Deaths (n) Deaths (n)
All deaths 395* 1.13 1.02–1.24 863* 0.81 0.76–0.86
Malignant neoplasms 147 1.10 0.93–1.28 411 1 0.90–1.09
Larynx, trachea, bronchus
and lung 25 1.79 1.16–2.64 44 1.03 0.75–1.38
Breast cancer 36 0.98 0.68–1.35 123 1.08 0.90–1.28
Gynecological cancers** 18 1.16 0.69–1.83 41 0.8 0.62–1.17
Ischemic heart disease 21 0.91 0.56–1.38 66 0.97 0.75–1.23
Cerebrovascular disease 26 1.19 0.78–1.75 62 0.92 0.70–1.18
Other diseases of
circulatory system 7 0.88 0.35–1.80 16 0.67 0.38–1.08
Alcohol-related 41 1.30 0.93–1.75 68 0.7 0.54–0.88
External causes 61 1.06 0.81–1.36 114 0.63 0.52–0.75
Accidents 26 1.03 0.67–1.50 58 0.74 0.56–0.95
Suicides 27 1.03 0.68–1.49 48 0.58 0.42–0.76
Homicides 3 0.76 0.16–2.21 6 0.50 0.18–1.08
HR; hazard ratio, CI; confidence interval. * In both cohorts, there were five women whose cause of death was unknown; these women died abroad. There were
87 deaths in the index cohort and 121 deaths in the reference cohort due to other diseases and medical conditions were divided into several subgroups:
infectious and parasitic diseases endocrine, nutritional, and metabolic diseases dementia, Alzheimer’s disease and other diseases of the nervous system and
sense organs; diseases of the respiratory, digestive, and genitourinary systems; congenital malformations and chromosomal abnormalities; maternal deaths;
other diseases, symptoms, and signs not classified elsewhere. **Including malignancies of cervix uteri, uterus and ovary.
53
The cumulative hazard of death in the index cohort was higher than in the
reference cohort (p < 0.001), suggesting that women with a history of placental
abruption tend to die younger (Figure 7).
Figure 7. Cumulative hazard for all-cause mortality for women with a history
of placental abruption (index cohort) and matched controls (reference
cohort).
By permission from Acta Obstetricia et Gynecologica Scandinavica.
MAJOR CONGENITAL ANOMALIES IN BIRTHS WITH

PLACENTAL ABRUPTION (III)
During the study period (1987-2005), there were 4190 women with a singleton
birth and placental abruption and 12,570 matched control participants
without abruption that were included in the study. In total, 261 women with
abruption (6.2%) and 415 control participants (3.3%) had a birth with at least
54
one major congenital anomaly.
Table 10 presents the multivariate logistic regression analysis of the

prevalence of at least one MCA among singleton births of women with
placental abruption and their control participants. After adjusting by maternal
age, parity, socioeconomic status, and smoking during pregnancy, placental
abruption was associated with increased prevalence of MCAs. Maternal age,
parity, socioeconomic status, and smoking during pregnancy were not
associated with increased prevalence of congenital anomalies (Table 10).
55
Table 10. Prevalence of at least one major congenital anomaly (MCA) by multivariate logistic regression analysis among
singleton births of women with placental abruption and control participants from 1987 to 2005.

Abruption Non-abruption
All MCA All MCA Adjusted* prevalence
(N=4,190) (N=261) (N=12,570) (N=415) of MCA
n n per 10,000 n n per 10,000 OR 95% CI

Abruption vs. non-abruption 4,190 261 623 12,570 415 330 1.92 (1.63–2.52)
Age, years
<25 720 43 597 2,160 67 310 1.00
25–34 2,516 149 592 7,538 248 329 1.10 (0.88–1.40)
≥35 954 69 723 2,872 100 348 1.28 (0.97–1.69)
Parity
0 1,642 100 609 4,635 153 330 1.00
1–2 1,894 120 634 6,020 192 319 0.96 (0.81–1.15)
≥ 3 608 40 658 1,773 60 338 0.97 (0.75–1.26)
Unknown 46 1 217 142 10 704
Socio-economic status
Upper white collar worker 457 30 656 1,611 39 242 1.00
Lower white collar worker 1,370 65 474 4,186 128 306 1.05 (0.79–1.39)
Blue collar worker 682 40 587 1,709 59 345 1.24 (0.90–1.72)
Other 539 31 575 1,693 55 325 1.21 (0.86–1.69)
Unknown 1,142 95 832 3,371 134 398
Smoking during pregnancy

No 3,001 189 630 10,212 325 318 1.00
Yes 956 55 575 1,950 68 349 1.00 (0.81–1.23)
Unknown 233 17 730 408 22 539

*All variables shown in the model were included in the model.
56
After adjusting with placental abruption in the multivariable model, extremely
preterm, very preterm, and moderately preterm newborns were nearly twice
as likely to have a major congenital anomaly compared with those born at
term. Also, SGA newborns had a significant association with major congenital
anomalies compared with AGA newborns. After adjusting with birth-related
characteristics, the association between placental abruption and MCAs was
attenuated but remained increased (Table 11).
Table 11. Prevalence of at least one major congenital anomaly (MCA) during years 1987–2005 among
singleton births was analyzed by logistic regression methods as univariable and backward stepwise
multivariable model. Results shown by odds ratios (OR) with 95% confidence intervals (CI).

Major Congenital Anomaly
Univariable Multivariable
OR (95% CI) OR (95% CI)

Abruption
No 1.00 1.00
Yes 1.95 (1.66-2.28) 1.36 (1.12-1.65)
Gestational age (weeks)
Unknown 1.34 (0.65-2.73) 3.48 (0.69-17.7)
<28 2.28 (1.46-3.55) 1.92 (1.19-3.12)
28–31+6 3.05 (2.20-4.23) 2.19 (1.53-3.13)
32–36+6 2.34 (1.91-2.85) 1.84 (1.46-2.31)
≥ 37 1.00 1.00
Birth weight (grams)
Unknown 0.97 (0.39-2.37)
<1500 2.77 (2.08-3.69)
1500–2499 2.37 (1.90-2.95)
≥ 2500 1.00
Standardized birth weight
AGA 1.00 1.00
SGA (≤ -2SD) 2.76 (2.10-3.63) 1.89 (1.42-2.52)
LGA (≥ +2SD) 1.00 (0.65-1.55) 0.98 (0.63-1.51)
Unknown 1.00 (0.53-1.90) 0.32 (0.07-1.38)
Offspring sex
Male 1.00
Female 0.88 (0.75-1.03)

AGA= appropriate for gestational age, SGA= small for gestational age, LGA= large for gestational age. Also
age, parity, socio-economic status and smoking were included into the multivariable model. Their
univariable odds ratios were very similar to those shown in Table 10.

A significant association was found between placental abruption and all other
major congenital anomalies grouped by organ systems, except for oral clefts
and chromosomal defects (Table 12).
57
Table 12. Births with selected major congenital anomalies by organ group (modified from the ICD-9 classification system)
among pregnancies with and without placental abruption from 1987 to 2005.
Central Cleft
nervous Anomalies Cardio- palate Gastro- Genito- Musculo- Anomalies Chromo- Other
system of eyes vascular Respiratory and/or intestinal urinary skeletal of somal congenital
anomalies and ears anomalies anomalies cleft clip anomalies anomalies anomalies integument defects anomalies
Abruption

(N=4,190)
MCA
(n=261)
n 20 23 77 13 18 33 49 69 8 9 14
per 10,000 50 55 184 31 43 79 117 167 19 22 33

Non-abruption
(N=12,570)
MCA
(n=415)
n 25 37 131 11 36 26 58 125 7 29 20
per 10,000 20 29 104 9 29 21 46 99 6 23 16
Abruption vs
non-abruption
OR* 2.3 1.8 1.8 3.5 1.4 3.8 2.5 1.7 3.3 0.8 2.1
(95% CI) (1.3–4.2) (1.1–3.1) (1.3–2.4) (1.6–7.9) (0.8–2.4) (2.3–6.4) (1.7–3.7) (1.2–2.2) (1.2–9.0) (0.4–1.9) (1.1–4.2)

Note: The same newborn can be included in several different extended ICD-9 groups, however, the newborn can appear only once within each group.
*Adjusted by maternal age, parity, socioeconomic status, and smoking during pregnancy.
Associations between births with and without abruption and selected major congenital anomalies were analyzed by multivariate logistic regression
enter method, results shown by odds ratios (OR) with 95% confidence intervals (CIs).
58
A significant association with major congenital anomalies among births with
placental abruption was found for hydrocephaly, esophageal atresia or
stenosis, duodenal atresia, anorectal atresia or stenosis, diaphragmatic hernia,
and hypospadias. Otherwise, the groups did not differ (Table 13).
Table 13. Analyses of selected major congenital anomalies (as defined by the
International Clearinghouse for Birth Defects Surveillance and Research)
between births with and without abruption.
Births with Nonabruption Adjusted

Abruption Births
Selected major congenital
N
anomaly N OR 95% CI
Anencephaly 2 1 3.57 (0.54–66.19)
Spina bifida 1 3 0.85 (0.10–9.62)
Encephalocele 1 0 NA NA
Microcephaly 1 4 0.62 (0.08–6.71)
Holoprosencephaly 0 2 NA NA
Hydrocephaly 10 4 7.16 (2.35–23.93)
Transposition of great vessels 3 5 1.91 (0.43–7.54)
Tetralogy of Fallot 5 5 3.06 (0.87–10.37)
Hypoplastic left heart syndrome 2 4 1.34 (0.27–8.19)
Coarctation of the aorta 5 12 1.33 (0.44–3.55)
Anophthalmos/microphthalmos 1 0 NA NA
Anotia/microtia 2 5 1.15 (0.23–6.19)
Choanal atresia, bilateral 0 2 NA NA
Cleft palate without cleft lip 7 18 1.08 (0.49–2.80)
Cleft lip with or without cleft
11
palate 18 1.69 (0.87–3.88)
Esophageal atresia/stenosis 14 9 4.92 (2.02–10.79)
Duodenal atresia 4 2 6.84 (1.10–32.77)
Small intestine atresia/stenosis 1 1 3.17 (0.19–47.98)
Anorectal atresia/stenosis 7 6 3.06 (1.18–10.42)
Diaphragmatic hernia 5 1 16.03 (1.75–128.43)
Omphalocele 3 4 2.12 (0.50–10.06)
Gastroschisis 1 2 1.45 (0.14–16.55)
Prune belly sequence 1 0 NA NA
Renal agenesis 2 1 6.08 (0.54–66.19)
Cystic kidney 6 6 2.79 (0.97–9.31)
Bladder exstrophy 2 1 5.37 (0.54–66.19)
Hypospadias 11 5 7.14 (2.29–19.01)
Indeterminate sex 1 1 1.81 (0.19–47.98)
Polydactyly, preaxial 2 4 1.77 (0.27–8.19)
Limb reduction defects 5 9 1.95 (0.56–4.98)
Trisomy 13 1 0 NA NA
Trisomy 18 3 7 1.27 0.33–4.97)
Trisomy 21 3 15 0.58 0.17–2.07)
NA, not applicable
59
All births with a major congenital anomaly in this study were also divided into
subgroups according to the pattern of major congenital anomalies (isolated,
multiple, or syndrome). Multiple anomalies were more common among
neonates born from abruption pregnancies compared with neonates born
from nonabruption pregnancies (OR 1.69, 95% CI 1.05–2.73, data not shown).
OVERALL MORTALITY OF CHILDREN BORN AFTER

PLACENTAL ABRUPTION (IV)
A total of 280 deaths were observed among children born after abruption
(index children) and 107 deaths among referent children born from
nonabruption pregnancies during follow-up extended to the end of 2013. The
median follow-up time after birth was 18 years (range 0–27).
The results revealed an increased overall mortality among children born after
placental abruption. The cumulative hazard of death among the index children
was higher compared with the referent children. The difference was already
evident in the early postnatal period and increased during longer duration of
follow-up (Figure 8). The trend of infant mortality among both index and
referent children was decreasing during the study period (p<0.001) (Figure
9).
60
Figure 8. Cumulative hazard for all-cause mortality of children born after
placental abruption (index children) and referent children born after non-
abruption deliveries during 1987-2013.
By permission from Pediatrics.
61
Figure 9. Infant mortality as a 2-year moving average by year of birth during
1987-2005.
By permission from Pediatrics.
The interaction of placental abruption, maternal smoking, and offspring

mortality were studied in four different subgroups. Non-abruption, non-
smoking mothers were set as the reference group. Smoking increased overall
offspring mortality and mortality in all age groups among mothers with and
without abruption. The impact of abruption attenuated after the first year, but
reached a significant increase in mortality combined with maternal smoking.
The strongest increase in offspring mortality throughout all age groups,
however, was seen among smoking mothers with abruption (Table 14).
62
Table 14. Interaction between smoking, placental abruption and offspring mortality.
Mortality at 0-27 days Mortality at 28-365 days Mortality at >365 days

Overall mortality (n=387)
(n=281) (n=36) (n=70)
p-value HR 95% CI p-value HR 95% CI p-value HR 95% CI p-value HR 95% CI
Placental <0.001 <0.001 <0.001 0.003

abruption
and maternal
smoking
interaction
Non-abruption, 1.00 1.00 1.00 1.00
non-smoking
Non-abruption, <0.001 2.55 1.66−3.90 0.019 2.23 1.14−4.36 0.026 4.46 1.19−16.67 0.005 2.43 1.31−4.51
smoking
Abruption, non- <0.001 9.53 7.19−12.64 <0.001 17.33 11.69−25.69 <0.001 13.60 5.05−36.63 0.273 1.45 0.75−2.81
smoking
Abruption,
<0.001 14.90 10.74−20.67 <0.001 26.49 17.11−41.0 <0.001 21.59 7.04−66.17 0.004 3.1 1.43−6.74
smoking
Footnote: Altogether 856 (22.0%) mothers of index children and 1946 (15.5%) mothers of referent children smoked during pregnancy. Non-smokers included
women who had stopped smoking during pregnancy. Smoking data were not available for 199 mothers of index children and 396 mothers of referent children.
The reference group was adjusted by maternal age.
63
Mortality after placental abruption was increased in all age groups: during the
neonatal period (less than 28 days), at the age of 28–365 days, and at more
than one year of age. The major causes of death in both groups are listed in
Table 15. The strongest increase in neonatal mortality was observed in birth-
related asphyxia. Mortality was also increased due to prematurity,
intracerebral hemorrhage, respiratory distress syndrome (RDS) or other
respiratory disorders, anomaly, infection, and other causes. Other causes
included birth injury to spine and spinal cord, unspecified cardiomyopathy,
cerebral edema due to birth injury, unspecified conditions originating in the
perinatal period, congenital anemia, missing death certificate, disorders of
glysine metabolism, disorders of tyrosine metabolism, fetal adrenal
hemorrhage, hydrops fetalis not due to isoimmunization, massive aspiration
syndrome, unspecified metabolism disorders, neuronal seroid lipofuscinosis,
other and unspecified cirrhosis of liver, and other cardiovascular disorders
originating in the perinatal period.
At the age of 28–365 days, mortality among the index children was
singinifantly increased, being over 10-fold compared with the referent
children. Among index children, there were 4 deaths due to SIDS, and none
among the referent children. Beyond one year of age, the increase in mortality
was 1.7-fold among index children compared with referent children. For the
index children, the median of age at death in this age group was 12.86 years
(range 1.64–24.05) and for the referent children, 15.13 years (range 1.50–
24.23). Nearly half of all deaths of the referent children were due to external
causes, whereas for the index children, these causes covered only a quarter of
all deaths. Deaths due to cancer were also more common among referent
children than among index children.
64
Table 15. Observed numbers of deaths and major causes of death among
singleton children born alive after placental abruption (index children) and
singleton referent children born alive after nonabruption deliveries.
Index Referent
children children Age–adjusted
n=3,888 n=12,530
Deaths Deaths HR (95% CI)
All deaths 280 107 8.70 (6.96–10.9)
Cause of death at age of 0–27 230 51 14.8 (10.9–20.0)

days
Birth-related asphyxia 100 3 108 (34–341)
Prematurity 32 6 17.5 (7.21–41.8)
Intracerebral hemorrhage 11 1 36.9 (4.76–286)
RDS/Breathing problem 35 4 29.0 (10.3–81.7)
Anomaly 28 24 3.83 (2.22–6.61)
Infection 15 7 7.04 (2.87–17.3)
Other cause 9 6 4.90 (1.74–13.8)
Cause of death at age of 28–365 27 9 10.3 (4.83–21.8)

days
Cerebral palsy 3 0
Birth-related asphyxia 3 0
Prematurity 5 0
Intracerebral hemorrhage 0 1
RDS/Breathing problem 4 0
Anomaly 3 4
Infection 1 1
Sudden infant death 4 0
syndrome
External cause 0 2
Other cause 4 1
Cause of death at >365 days 23 47 1.70 (1.03–2.79)

Cerebral palsy 6 0
Birth-related asphyxia 2 1
Cancer 1 11
External cause 6 24
Anomaly 3 1
Infection 2 5
Other cause 3 5
There were no significant differences in mortality among very preterm and

extremely preterm children of the index and referent groups. However, index
children who were born moderately preterm, term, or with birthweight equal
to or greater than 2500 g had increased overall mortality (HR 2.77, 95% CI
1.54–4.98 and HR 4.98, 95% CI 3.54–6.99, and 5.94, 95% CI 4.33–8.14,
respectively) compared with the referent children. Index children, who were
65
born at term or with birthweight equal to or more that 2500 g, had increased
age-specific mortality up to the age of one year compared with the referent
children. For SGA index infants, the mortality was increased during the
neonatal period and not later, whereas for LGA-index children, both the
neonatal and overall mortality were increased compared with the referent
children. Among index children, only boys had increased mortality after the
first year (Table 16).
66
Table 16. Baseline characteristics and mortality of singleton index children born after placental abruption and referent children born after non-abruption deliveries.

Index children Referent children Adjusted mortality
Total Deaths (%) Total Total (%) Overall At age of 0–27 days At age of 28–365 At age of ˃ 365 days
(n) (n) (n) (n) days
HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI)

Sex
Girls 1,761 105 (6.0) 6047 46 (0.8) 8.03 (5.68–11.4) 16.9 (10.2–28.1) 13.2 (3.69–47.5) 0.88 (0.36–2.14)
Boys 2,127 175 (8.2) 6483 61 (0.9) 9.07 (6.77–12.1) 13.4 (9.17–19.6) 8.70 (3.40–22.2) 2.56 (1.36–4.82)
Gestational age, weeks
<28 187 97 (51.9) 32 15 (46.9) 1.12 (0.64–1.93) 1.08 (0.61–1.90) * ***
28–31+6 348 38 (10.9) 48 8 (16.7) 0.66 (0.31–1.43) 0.55 (0.25–1.20) * *
32–36+6 1,172 80 (6.8) 514 13 (2.5) 2.77 (1.54–4.98) 3.48 (1.66–7.27) 3.28 (0.40–26.7) 1.29 (0.41–2.06)
≥37 2,138 63 (2.9) 11801 71 (0.6) 4.98 (3.54–6.99) 12.4 (7.41–20.7) 4.95 (1.79–13.6) 1.22 (0.59–2.50)
Birth weight, grams
<1,500 434 127 (29.3) 72 22 (30.6) 0.97 (0.61–1.52) 0.91 (0.57–1.44) * 0.18 (0.01–2.94)
1,500–2,499 882 65 (7.4) 307 15 (4.9) 1.55 (0.88–2.71) 1.57 (0.81–3.03) 2.89 (0.36–23.1) 1.09 (0.29–4.02)
≥2,500 2,536 86 (3.4) 12042 70 (0.6) 5.94 (4.33–8.14) 16.8 (10.1–28.0) 4.26 (1.54–11.7) 1.37 (0.72–2.61)
Standardized birth weight
SGA (≤ – 2SD) 334 41 (12.3) 243 18 (7.4) 1.72 (0.98–2.99) 2.02 (1.07–3.82) ** 0.64 (0.17–2.40)
LGA (≥ + 2SD) 109 9 (8.3) 459 5 (1.1) 7.78 (2.61–23.2) 8.57 (2.58–28.5) ** 4.50 (0.28–72.2)

*no deaths among the referent children **no deaths among the index children ***nine deaths among referent children, all appropriate for gestational age
67
DISCUSSION
CANCER MORBIDITY OF WOMEN WITH A HISTORY OF

PLACENTAL ABRUPTION
The main findings were that women with a history of abruption were a
decreased risk for breast cancer and an increased risk for lung and thyroid
cancers (study IV). Previous studies evaluating the risk of cancer among
women with abruption do not exist. A single American case-control study (117)
including 2,522 breast-cancer cases reported an association between breast
cancer and placental abruption (OR 1.8, 95% CI 1.1–3.0). In this study, cases
were defined retrospectively as breast-cancer patients who had experienced
their first delivery at least one year prior to being diagnosed with cancer. The
result of this reported study with an increased risk of breast cancer is
contradictory to the current finding of a reduced breast cancer risk among
women with a history of placental abruption. However, the study designs
differed, as their cases were women with a diagnosis of breast cancer and the
current index cohort was comprised of women with a history of placental
abruption. Thus, these two reports cannot be considered to be directly
comparable. While data on the association of placental abruption and
subsequent cancer morbidity is limited, the link between cancer and other
placental syndromes, such as pre-eclampsia, has been extensively studied. A
reduced risk for breast cancer among women with a history of pre-eclampsia
has been observed in several studies (174–178). The explanation for this
association is unclear, but maternal metabolic factors, such as obesity, may
play an important role (175). Furthermore, some biological mechanisms, such
as differences in hormone profiles and antiangiogenic factors have been
suggested to mediate the risk reduction, but these warrant further
investigation (178).
Parity and breast cancer risk are inversely associated, where each additional
pregnancy provides additional protection. This effect may be due to the
repeated exposure to pregnancy hormones (179). According to a study of the
Finnish Maternity Cohort, the incidence of breast cancer in women with at
least three children is about one-tenth below the rate of all Finnish women
(180). In breast cancer the risk increases transiently after childbirth but
reduces in later years (181). Multiparity (three or more previous deliveries)
increases the risk for placental abruption (3), which may partly explain the
decreased breast cancer risk among women with a history of abruption.
Moreover, breastfeeding is protective against breast cancer (182), but data on
68

breastfeeding by the women in the current study sample were unavailable, so
this remains speculative. High gestational levels of alpha-fetoprotein (AFP)
present another potential explanation for the association between placental
abruption and subsequent decreased risk for breast cancer. They may protect
against subsequent development of breast cancer (183). On the other hand,
high gestational levels of AFP are also associated with an increased risk of
placental abruption (184–187). Thus, elevated maternal serum AFP could, to
some extent, explain the decreased risk of subsequent breast cancer in women
with a history of abruption. However, further research is needed to confirm
the association between placental abruption and reduced breast cancer risk
and whether this association can be attributed to pregnancy-specific events or
to underlying biological factors.
The observed increased lung cancer risk among women with earlier placental
abruption is expected, since smoking is a significant risk factor for both
abruption (6,63,188) and lung cancer (189). In addition, women with a history
of abruption were previously shown to have increased mortality of respiratory
tract malignancies.
An increased risk of papillary thyroid cancer was observed among women with
a history of abruption. Hypothyroidism is a risk factor for placental abruption
(190,191). Hence women who have had placental abruption may undergo
evaluation of the thyroid gland, which in turn may result in detection bias.
Nonetheless, this may also be a chance finding.
OVERALL MORTALITY OF WOMEN WITH A HISTORY OF

PLACENTAL ABRUPTION
An increased overall mortality was observed among women with a history of

placental abruption. This result was in line with two previous studies
performed in Danish and Swedish-Norwegian populations (HRs 1.41, 95% CI
1.20–1.67 and 1.3, 95% CI 1.1–1.4, respectively) (23,26).
The results suggest that women with a history of abruption have increased
mortality from respiratory tract cancer. Smoking during pregnancy is a
consistently reported risk factor for abruption (6,63,188), making this finding
plausible. Furthermore, it has been previously demonstrated that smoking
women with subsequent placental abruption have higher median levels of
serum cotinine compared with smoking control women. This suggests that
women with placental abruption smoke more heavily during pregnancy
compared with control women (192). The underlying mechanisms of the
association between smoking and placental abruption are most likely related
to underperfusion of the uterus, which may lead to lesions (i.e., decidual
necrosis, placental microinfarcts, fibroid changes, and atrophic placental villi)
69

that are consistent with chronic hypoxic changes in the placenta. Increased
fragility might result in arterial rupture leading ultimately to placental
abruption (192). Although it is unclear how many of the smokers continue to
smoke after pregnancy where they have experienced abruption, the results
concerning respiratory tract malignancies suggest that a notable number of
women do. However, smoking is a strong risk factor for CVD morbidity and
mortality as well. Surprisingly, the results of two previous studies reporting an
increased CVD mortality among women with a history of abruption were
unable to be confirmed (23,25). On the other hand, no increase in CVD
mortality was found by Lykke et al. and Cain et al. (26,27). This may partly be
explained by lack of power in study sample sizes to detect an association
between placental abruption and CVD mortality. In the study of Cain and
colleagues there were 3,037 cases with placental abruption, which is notably
less than in other studies. In comparison, Lykke and colleagues had a larger
study sample which was similar to that reported here (n=7,684 and n=7,805,
respectively) but clearly smaller than in the studies by DeRoo et al. (n=10,981)
and Ananth et al. (n=9,495).
Unlike previous studies, this study compared the mortality of women with a
history of placental abruption with that of matched referent women without
abruption but also with mortality in the general Finnish female population.
Compared with the general population, the mortality among the referent
women was decreased in most cause-of-death categories. This could partly be
due to the healthy-pregnant-women effect, according to which the risk of a
medical-condition-related death within the first year after delivery is lower
than the risk among non-pregnant women in the same age group (193). The
results of this investigation show that this effect may last for years.
Furthermore, when women with a previous abruption are compared with a
reference group consisting of other parous women, the mortality rates differ
from those in the general population, and the relative risk estimates may thus
appear higher.
The recurrence rate of placental abruption is approximately 10% (40,72).

Rasmussen and colleagues found that 59% of women who experienced
abruption with perinatal survival had a subsequent pregnancy, whereas the
rate was 83% for those who had abruption and perinatal loss (101). This
suggests that women with placental abruption and perinatal survival are less
willing to have more children, which of course reduces the possibility of
recurrence of abruption. Information was lacking on the subsequent
pregnancies of women who had experienced placental abruption. Those with
a recurrent abruption within the study period were identified, but the numbers
were small and were not analyzed as a separate entity. Similarly, no
information was available regarding concomitant ischemic placental disease,
such as pre-eclampsia. It has been suggested that placental abruption and pre-
eclampsia have a common etiology, i.e., failed placentation in early pregnancy
70

(194), possibly leading to placental dysfunction and further increasing the risk
of placental abruption in women with pre-eclampsia.
In the study by DeRoo et al., women with both placental abruption and pre-
eclampsia in the same pregnancy, had a significantly increased CVD mortality
later after pregnancy (HR 3.0, 95% CI 1.9–4.8) (23). Their overall mortality
was (HR 1.3, 95% CI 1.1–1.7), however, similar to women with a history of only
one abruption. In the same study there were only five CVD-related deaths
among women with a recurrent abruption, and this difference was not
statistically significant (HR 2.2, 95% CI 0.8–6.0). Mortality of non-CVD
causes was somewhat higher among women with a recurrent abruption (HR
1.6, 95% CI 1.1–2.5) than among all women with a history of abruption.
The results revealed that deaths due to alcohol-related causes and external
causes like suicides were increased among women with a history of abruption.
Similar results were obtained in the study by DeRoo et al. (23), although in a
small subset of women with recurrent abruption. Alcohol and drug abuse are
factors related to an increased risk of abruption (56), and this is likely reflected
in the causes of deaths as well. On the other hand, placental abruption as such,
and especially if accompanied by fetal loss, may be devastating for the mother,
which could eventually result in an increased number of alcohol-related deaths
and suicides. However, as with smoking, information was lacking on alcohol
or drug use after the index pregnancy.
MAJOR CONGENITAL ANOMALIES IN BIRTHS WITH

PLACENTAL ABRUPTION
The results suggest that neonates born after placental abruption are twice as
likely to have an MCA compared with those born after non-abruption
pregnancies. The observed prevalence for MCAs among births with abruption
was 623 per 10,000, while the prevalence in non-abruption births was 330 per
10,000. The total birth prevalence of MCAs in Finland was 356 per 10,000 in
1993–2010 (195), which is in acccordance with the prevalence of MCAs among
control participants in our study.
Several previous studies have implicated that the rate of congenital anomalies
is increased among children born from pregnancies complicated by placental
abruption (13–17). The earliest studies from 1966 and 1979 (13,15) reported an
increased prevalence of MCAs among births with abruption compared to the
general prevalence of MCAs. In these studies, the majority of reported
anomalies were CNS defects. A Swedish study reported a MCA prevalence of
350 per 10,000 among births with abruption which was twice the prevalence
of MCAs in the general population (14). Raymond and Mills reported a relative
risk of 2.57 for MCAs and 4.67 for congenital heart defects among births with
abruption in 1993 (16). Another study evaluated the obstetrical features of
71

mothers carrying offspring with an oral cleft and found that these mothers had
an increased risk of placental abruption. The majority of these previous studies
evaluating placental abruption and MCAs are old and lack power and
systematics, and they have focused on single or only a few entities of
anomalies. Therefore, study III presents a novel and thorough evaluation of
the association between abruption and a spectrum of different major
congenital anomalies. However, our study has many similarities with the
previous ones. The early observations of an increased prevalence of MCAs of
CNS and the cardiovascular system were confirmed. In addition, an
association was shown between placental abruption and a number of other
anomalies, such as genitourinary, gastrointestinal, and musculoskeletal
anomalies. In contrast to an earlier study by Wyszynski and Wu (17), no
association between abruption and oral clefts was found.
After adjusting with placental abruption, the prevalence of MCAs was

strongest for extremely preterm, very preterm and moderately preterm babies,
as well as for those that were growth restricted. Placental abruption and
intrauterine growth restriction, together with pre-eclampsia, constitute the
syndrome of ischemic placental disease (49). Nearly half of medically
indicated preterm births are attributable to ischemic placental disease (49).
IUGR may partly be due to poor placentation, which further predisposes to
placental abruption. Furthermore, impaired placentation and subsequent
maternal vascular underperfusion and reduced oxygen supply to the fetus
could affect organogenesis and thus predispose to development of congenital
anomalies (196). The observations of study III were in line with the reults from
study IV, where neonatal mortality due to congenital anomalies in births with
placental abruption was shown to be four-fold higher compared with
nonabruption births.
Previous studies have provided no explanation as to why MCAs are more

common among births complicated by abruption. Although it is challenging to
explain the relation between MCAs and abruption, there are several biological
explanations for the association.
It is possible that deficient folic acid supply is one of the links to this
association. Previous studies have suggested that folic acid deficiency and low
red blood cell folate levels could predispose to placental abruption (13,18,50).
According to a Cochrane review, the use of folic acid prevents neural tube
defects (21). Although data concerning the prevention of other MCAs are less
evident, maternal use of folic acid has been suggested to reduce structural
heart defects, obstructive urinary tract anomalies, limb deficiencies,
congenital hypertrophic pyloric stenosis, and some facial clefts (18,22).
Periconceptional folic acid supplementation is advised for all women. In
Finland, the women at higher risk, such as those with type I diabetes mellitus
or those with a history of a neural tube defect, are recommended an elevated
72

daily dose of folic acid, while in normal pregnancies the recommended dose is
400 micrograms per day (197).
In line with these assumptions, hyperhomocysteinemia, a strong indicator of
folate deficiency, has been linked to an increased risk of both abruption and
congenital developmental defects (50–52,198,199). A 677C → T
polymorphism in the methylenetetrahydrofolate reductase gene, which is
involved in the metabolism of folate and homocysteine, has been associated
with an elevated risk for placental abruption in one study (199). However, this
association was not found in the Finnish population (200).
Smoking increases the levels of homocysteine as well as it is also a significant

risk factor for abruption and predisposes the fetus to several major birth
defects (201). Up to 15–25% of placental abruption episodes are attributable
to smoking (60). Fifteen percent of pregnant women smoked during the study
period in Finland (202). Surprisingly, in our study smoking did not increase
the prevalence of MCAs among births of women with abruption. In fact, 5.7 %
of smoking mothers with abruption had a birth with at least one MCA
compared to 6.3% of nonsmoking mothers with abruption. In births of women
without abruption, 3.5% of smokers and 3.2% of nonsmokers had a birth with
at least one MCA.
Other explanations for the association between MCAs and placental abruption
include abnormalities of the amount of amniotic fluid, i.e. oligohydramnion
and polyhydramnion. Both clinical situations are associated with a higher
prevalence of congenital anomalies, and at the same time increase the risk for
abruption. Further, oligohydramnion may be due to uteroplacental insuffiency
(203), thus predisposing to placental abruption. In cases of polyhydramnios,
sudden uterine decompression resulting from membrane rupture may lead to
placental abruption (4). Furthermore, both oligo- and polyhydramnion have
been associated with MCAs of the gastrointestinal and genitourinary systems.
No data on abnormalities of the amniotic fluid was available for subjects in
this thesis study.
There may also be other predisposing causes between MCAs and placental
abruption. Maternal pregestational diabetes is a known risk factor for
congenital anomalies (204). It is known that good metabolic control in the
preconceptional period decreases the risk of congenital anomalies (205–207).
In some studies, the incidence of placental abruption has been increased
among mothers with pregestational diabetes (32). However, in this study, data
on maternal pregestational diabetes were omitted, unfortunately.
73

OFFSPRING MORTALITY AND PLACENTAL ABRUPTION
Overall child mortality was observed to increase after placental abruption

(study IV). Evidence regarding the association of placental abruption and its
association with preterm birth and PNM is strong, but little is known of other
neonatal morbidities associated with abruption or associated overall offspring
mortality. As shown in study IV, the burden of increased neonatal morbidity
in births complicated by placental abruption results in increased overall
mortality, which extends far beyond the neonatal period. After one year-of-age
the increase in mortality among children born after abruption was attenuated,
although still present, but mainly for boys and children born to smoking
mothers with or without abruption.
The results suggest that the combination of maternal smoking and placental
abruption has an additive effect on infant mortality. Although smoking also
increased infant mortality among children of nonabruption mothers, the
highest overall offspring mortality was found with abruption and maternal
smoking. In offspring deaths that occurred at the age of one year or more, the
role of maternal smoking was particularly interesting. Mortality in children of
smoking nonabruption mothers was increased whereas the mortality of
children of nonsmoking mothers with abruption was not statistically
significant. Nevertheless, when maternal smoking was added to abruption, the
impact in offspring mortality was strongest. Deaths due to SIDS were also
found to be more common among children born after placental abruption
compared with the expected number of cases in the general population (169).
Maternal smoking may be a common factor explaining this (3,6,60). Prenatal
and postnatal tobacco smoke, or nicotine exposure, affects fetal development
of the lungs, including growth, structure and function (208) and may later
increase the child’s risk for SIDS (10). Furthermore, children who have
survived placental abruption may have suffered from birth-related hypoxia,
thereby compromising subsequent growth and development which in turn
may predispose to SIDS (12). In a recent study, neonates surviving abruption
had an elevated risk for neonatal apnea (122), which may further explain the
association between placental abruption and SIDS. The exact mechanism by
which maternal smoking adds to the risk of infant mortality among children
born after abruption is not clear, but the vulnerability of these children is likely
to be high.
In this study, prematurity and several associated morbidities displayed a
significant role in the increased mortality of children born after abruption.
However, there were no significant differences between extremely and very
preterm babies born after abruption or non-abruption pregnancies. The
probable reason for this is that there is no excess risk from abruption among
very preterm births, and it is likely that the harm to newborns from abruption
is no worse than the harm already done by other pathological causes of
prematurity. Regarding the increased mortality with abruption, it is
74

impossible to estimate what proportion of the increased mortality with
abruption is attributable to the accompanying increase in preterm birth. Thus,
one needs to be cautious when interpreting the results and causality between
placental abruption and increased mortality among babies born before 32
gestational weeks. On the other hand, the overall mortality among moderately
preterm babies and babies born at term was significantly increased in births
with abruption compared with nonabruption births. This highlights the
possible causal relation between placental abruption and subsequent
increased offspring mortality when the effect of prematurity as such
attenuates. It is possible that neonates in pregnancies complicated by
placental abruption experience chronic hypoxia, which leads to
underdevelopment even among term children, and it may also undermine the
ultimate postnatal outcome also in the absence of prematurity. Furthermore,
according to previous reports, children born at term after placental abruption
had an elevated risk of RDS (130) and apnea (122). These findings suggest that
placental abruption may have a negative impact on the neonate in general,
which is not yet well recognized (122).
In deaths that occurred at the age of one year or later, the mortality of male
index children was increased compared with male referent children, but for
females there was no difference between the two groups. Male fetal sex is more
common in pregnancies complicated by placental abruption (5,62,79).
According to several studies, male fetal sex is associated with adverse
pregnancy and perinatal outcomes (209–211). However, studies assessing
placental abruption and fetal survival or perinatal outcome in relation to fetal
gender have found no differences between sexes. Therefore, the observed
increase of mortality of male index children aged one year or more is probably
due to factors other than placental abruption. The results revealed that the role
of asphyxia in the deaths of children born after placental abruption was
outstanding, with a HR of 108 (95% CI 34–341) during the neonatal period. In
a previous Finnish study, 15% of children born after placental abruption had
asphyxia at birth (pH 7.05 or less) compared with 1.5% of children from non-
abruption pregnancies. In a recent U.S. study by Downes et al., abruption was
associated with a 8.5-fold risk of neonatal asphyxia. In the same study, the risk
for neonatal mortality among children born after abruption was 7.6-fold, while
in this study it was nearly twice as high (HR 14.8). The difference may be
explained by the fact that the current study period was longer (1987–2005)
and that it started earlier than the U.S. study (2002–2008). Furthermore,
deaths due to CP were more common among children born after abruption
than among nonabruption births (3/3,888 vs. 0/12,530 at 28–365 days and
6/3,888 vs. 0/12530 at > 365 days). This observation is in accordance with
existing research, since several studies have confirmed a strong association
between CP and placental abruption (144–147). On the other hand, this
association may partly be due to confounding by prematurity, which increases
the risk of CP (147).
75

Due to small numbers of deaths in children aged one year or more, the number
of deaths by causes of deaths could not be compared reliably between index
and referent children. However, deaths due to CP and birth-related asphyxia
among index children counted for nearly 35% of all deaths in this age group
compared with 2% among the referent children. Cancer and external causes
were the most common causes of death among 1–14 year old children in
Finland in 2013 (212), which is well reflected in the causes of deaths of referent
children in this thesis study. However, to be able to draw further conclusions
of the effect of placental abruption on causes of death after first year, an even
larger study sample with a longer follow-up period would be needed.
STRENGTHS AND WEAKNESSES OF THE STUDY
All studies included in this thesis were large, population-based and well
executed, using properly validated health registers. The results of all four
studies are novel. No other studies evaluating cancer incidence of women with
a history of placental abruption, as in study I, have been published. Study III
is, to date, the only known comprehensive, systematic study performed to
investigate the association between placental abruption and major congenital
anomalies. Furthermore, study IV is so far the only one that assesses the
impact of placental abruption on overall mortality of children born after
abruption.
One limitation of study I was the relatively small number of detected cancers
among women with a history of placental abruption. The same limitation was
present also in studies II and IV, concerning the actual number of deaths,
although the amount of subjects included in all studies was large. Limitations
for study III were that data on maternal use of folic acid are not gathered in
the national health registers. Similarly, no information was available
regarding possible co-existing oligo- or polyhydramnios among the studied
births. Moreover, infants born from pregnancies complicated by abruption
were possibly examined more carefully than those born from uncomplicated
pregnancies, which might have led to more precise detection of major
congenital anomalies among births complicated by abruption. In study II,
baseline characteristics, including smoking, were unavailable prior to 1987,
and in study I, this data was not available at all. No data on severity of
abruption were available in any of the studies, but this was a relevant
limitation only for study IV. Finally, all studies included in this thesis are
single-country studies, which may limit the generalizability of the results on a
global scale.
76

FUTURE ASPECTS
The characteristics of Finnish parturients are changing. The mean maternal

age at birth (30.7 years) and the mean maternal age at first birth (29.0 years)
are higher than ever before (213). Although the mean rates of cesarean
sections have remained quite stable during recent years, the rates are higher
among older parturients (213). Smoking during pregnancy is slightly
decreasing but still high, as 14.2% of parturients smoked in 2016 (213). Based
on these facts, the rate of placental abruption may increase in the future, as
advanced maternal age, previous caesarean section and smoking during
pregnancy are associated with an increasing risk of placental abruption (2,3).
Nevertheless, the result of the most recent study evaluating trends in the
incidence of placental abruption in the Finnish population disagreed with this
hypothesis. The factors explaining the decreasing trend of placental abruption
are less evident. Regular antenatal clinic care for all pregnant women,
improved care of high-risk pregnancies, generally improved socioeconomic
status and generalized use of folate supplementation already in the planning
stage of pregnancy may explain the decrease to some extent (3,214).
Pregnancy outcomes are increasingly being recognized as predictors of long-

term health in women. Women with pregnancy-related hypertension are at
higher risk for hypertension and metabolic abnormalities in long-term follow-
up (215,216). Gestational diabetes markedly increases the risk of developing
diabetes later in life (217–219). Placental syndromes offer a window for both
health and disease of the mother and the developing fetus. The data presented
in this thesis have addressed the role and impact of placental abruption in the
future health of women who have experienced the condition and of the
children born from these pregnancies. Clinicians should pay more attention to
the obstetrical history of women as it may provide useful information and
insight to future health outcomes.
77

CONCLUSIONS
1. The overall cancer incidence among women with a history of placental

abruption was not increased. However, the risk of breast cancer was decreased
and the risk of respiratory tract and thyroid cancers was increased among
these women. These observations may be due to behavioral factors and parity.
Placental abruption as such seems to have no effect on future cancer risk.
2. The overall mortality of women with a history of placental abruption is
increased. The increased risk is related to excess deaths due to respiratory
tract cancer.
3. Placental abruption is associated with increased prevalence of major
congenital anomalies, which are due to defects in several different organ
systems.
4. The overall mortality of children born from pregnancies complicated by
placental abruption is increased, and this increase extends far beyond the
perinatal period. Asphyxia has a major role as a cause of death.
78

ACKNOWLEDGEMENTS
This study was carried out at the Department of Obstetrics and Gynecology,
Helsinki University Hospital, University of Helsinki between 2010 and 2018.
I wish to express my gratitude to the administrative Head of our Institution,
Professor Seppo Heinonen, as well as to the academic Head of our
Department, Professor Juha Tapanainen, for creating a motivating
environment and for providing excellent working facilities. I also address my
sincere thanks to the other chiefs of our clinic: Professor Aila Tiitinen,
Professor Oskari Heikinheimo, Professor Juha Räsänen, Adjunct Professor
Aydin Tekay, Adjunct Professor Veli-Matti Ulander and Adjunct Professor Jari
Sjöberg, for providing the opportunity to do research along with clinical work.
My deepest gratitude belongs to my supervisors, Adjunct Professor Minna

Tikkanen and Professor emeritus Jorma Paavonen. Minna introduced me to
the world of obstetrics – first “hands-on” and then via research. Her sharp and
broad knowledge on placental abruption and perinatology in general together
with her patience and kindness made her the best supervisor I could ever hope
for. I also want to thank my other supervisor, Jorma Paavonen, for his positive
and encouraging attitude and wisdom as a supervisor and his excellent skills
in scientific writing, which I truly admire.
My warmest appreciation goes to Professor Leea Keski-Nisula and Adjunct

Professor Tytti Raudaskoski, the official reviewers of my thesis. Their
constructive and critical comments and advice greatly improved this study.
It has been a priviledge to work in the placental abruption group with

internationally acknowledged experts of their own branch. I owe my sincere
gratitude to MSc. Tiina Luukkaala, for all her statistical work, help and
guidance during this long project, all the way to the very end! I am grateful to
M.D. Annukka Ritvanen, whose exquisite expertise on birth defects is
admirable. I want to thank and warmly acknowledge Professor Mika Gissler
and Professor Eero Pukkala for their wide expertise and their exceptionally
fast replies to my whatever questions and requests. Adjunct Professor Mika
Nuutila, thank you for all your support, encouragement and help during these
years. Professor Sture Andersson and Adjunct Professor Marjo Metsäranta,
thank you for your hard work, positive energy and always helpful attitude
towards me and this project. M.D. Johanna Melin is also warmly thanked for
her co-work.
I want to thank the members of my thesis follow-up group, Professor Seppo

Heinonen and Adjunct Professor Mikko Loukovaara. You were there when you
79

were needed – thank you for your support, advice and interest towards my
work.
Pia Nevalainen and Nina Nyholm are warmly thanked for their always friendly
and generous assistance with practical issues. I sincerely thank Saija Hietala
for her beautiful illustrations for this thesis, and Frida Rundman, who together
with Saija designed the cover of the thesis book.
I warmly thank all my collagues in Helsinki University Hospital with whom I

have the priviledge to work with. Professor Juha Tapanainen is warmly
thanked for his advice, support and encouragement, starting already in Oulu
University Hospital with my previous research project twenty years ago.
Adjunct Professor Maija Jakobsson has not only been a friend but also
someone I could consult with my research issues. Kristiina Rönö, M.D., thank
you for your friendship and numerous times you have helped me with my
computer and especially with the tables! Mari Kiviharju, M.D., Johanna
Hautala, M.D., Outi Äyräs; M.D., Ph.D., and Anni Ellenberg, M.D.: thank you
for your friendship and for sharing the sometimes quite bumpy road of
specialization and research.
I want to thank Merli Kuustik and Mervi Sallinen for taking such good care of
my children hundreds of hours that I’ve spent working on my thesis. I also
want to thank my mother-in-law Liisa Riihimäki for her help during these busy
years of building a family, specializing and doing research simultaneously.
My dearest friend Sannamari Lepojärvi is thanked for all the support she has
given me during this work and my whole life since 1997. I couldn’t wish for a
better soulmate! I also want to thank Samppa Lepojärvi, Jonna Jansson, Hiski
and Tiina Kopponen, Ulla and Iikka Lantto, Hanna and Kalle Lindroth, Antti
and Lili Luusuaniemi, Pekka Nikumatti, Eija and Ville Suorsa and Elli
Turjanmaa. You are all very dear to me. Thank you for all the support and
encouragement especially at the end of this project, when everything seemed
devastating. You lifted my spirit numerous times with your messages, phone
calls, bad jokes and hugs.
I wish to express my love and gratitude to my extended childhood family – my

mother Kati, my father Martti, my dear sister Katri and her husband Erland
and their lovely daughters Anni and Elsa, and my dear brother Antti with his
charming sons Santeri, Anton and Sauli and my sweet little brother Felix.
Antti, thank you for your sense of humour and your support. Katri, thank you
for your endless compassion and for always being on my side. Erland, thank
you for the many nice discussions on various matters concerning research. You
80

were always ready and interested to hear about my projects and even read my
manuscripts, which I truly appreciate!
My parents: Thank you for always being there for me, and believing in me -
both on the good days and the bad days of my research path. Thank you for
supporting me in all that I’ve done. A heartfelt thanks to my father for his love
and enthusiasm towards my research which have given me special strength to
go further. My mother is the most positive and loving human being that I know
– I thank her for helping me see the hope and positive side even in the most
hopeless-feeling situations. And thank you mom for all the help with taking
care of our children and preparing food for us. It is an honour to dedicate this
thesis to parents like you.
Finally, I want to thank the love of my life, my dear husband Vellu, and our
georgeus children. I am forever grateful to life that I’ve been given all you five.
Kalle, Ronja, Lotta and Urho: Nothing makes me more proud than to be a
mom to such great kids as you are. I love you all more than anything.
This study was financially supported by Helsinki University Hospital Research

grant (TYH2014237), the Finnish Medical Foundation, the Finnish Cultural
Foundation and the Finnish-Norwegian Medical Foundation.
Lauttasaari, Helsinki, October 2018
Outi Riihimäki
81

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Department of Obstetrics and Gynecology

Helsinki University Hospital

STUDIES ON MATERNAL AND OFFSPRING

LONG-TERM MORBIDITY AND MORTALITY

To be presented by the permission of the Medical Faculty of

Adjunct Professor Minna Tikkanen, MD, PhD

Professor Emeritus, F.A.C.O.G Jorma Paavonen, MD, PhD

Professor Leea Keski-Nisula, MD, PhD

Adjunct Professor Tytti Raudaskoski, MD, PhD

Adjunct Professor Eeva Ekholm, MD, PhD

Cover design by Saija Hietala and Frida Rundman

ISBN 978-951-51-4630-4 (paperback)

LIST OF ORIGINAL PUBLICATIONS ......................................................................... 7

AIMS OF THE STUDY ........................................................................................... 38

This thesis is based on the following publications:

I Riihimäki O, Tikkanen M, Melin J, Andersson S, Metsaranta M,

II Riihimäki O, Paavonen J, Luukkaala T, Gissler M, Metsäranta M,

III Riihimäki O, Metsäranta M, Ritvanen A, Gissler M, Luukkaala

IV Riihimäki O, Metsäranta M, Paavonen J, Luukkaala T, Gissler M,

Placental abruption, defined as a premature separation of the placenta from

Istukan ennenaikainen irtoaminen eli ablaatio tarkoittaa tilannetta, jossa

Helsingin yliopistollisessa sairaalassa vuosien 2010 ja 2018 välissä

Placental abruption, defined as complete or partial separation of the placenta

Later morbidity and mortality of women with a history of placental abruption

Placental abruption is a condition in which the whole placenta or part of it

Figure 1. Categories of placental abruption, based on the site of the bleeding.

The incidence of placental abruption varies between 0.22–1.4 %

Studies reporting trend in the incidence of placental abruption are

Although a number of risk factors leading to placental abruption have been

Clinical presentation and diagnosis

The spectrum of the clinical presentation of placental abruption varies from

Figure 2. Types of abruption: revealed (A) and concealed (B).

Diagnosis of placental abruption is always clinical. Placental abruption

Risk factors for placental abruption

Sociodemographic and behavioral risk factors

Other sociodemographic risk factors include advanced maternal age (³35

Maternal and historical risk factors

Placental abruption in a previous pregnancy is the most significant risk factor

Pregnancy-associated risk factors

Bleeding in pregnancy carries an increased risk of abruption (45) as do

Placental abruption is characterized by substantial recurrence. Increased

MATERNAL SHORT-TERM CONSEQUENCES OF

Morbidity due to obstetric hemorrhage

Placental abruption is often associated with significant blood loss, especially

Pregnancy provides natural protection against hemorrhage through increased

Several studies have observed a significant risk of additional maternal

Emergency peripartum hysterectomy

Table 2. Risk estimates of relaparotomy and hysterectomy in deliveries complicated by

Disseminated Intravascular Coagulopathy

In severe placental abruption with fetal loss, profound hypofibrinogenemia

An adverse outcome in birth complicated by placental abruption may

Maternal death is the death of a woman while pregnant or within 42 days of

The role of placental abruption in maternal deaths was assessed in a Finnish

Maternal mortality associated with placental abruption decreased from 8% in

MATERNAL LONG-TERM CONSEQUENCES OF PLACENTAL

Obstetrical complications, such as placental abruption, preeclampsia, and

Table 3. Summary of studies on the association between cardiovascular disease (CVD)

Ray et al. (2005) CVD morbidity Yes 1.7 (1.3–2.2)

Prevalence of CVD risk

Lykke et al. (2010) CVD mortality No 1.2 (0.8–1.9)

CVD mortality (first

Ananth et al. (2017) CVD mortality Yes 2.7 (1.5–5.0)

The increased CVD morbidity and mortality of women with a history of

PERINATAL AND NEONATAL SHORT-TERM