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 Department of Obstetrics and Gynecology
Helsinki University Hospital and University of Helsinki
Professor Emeritus, F.A.C.O.G Jorma Paavonen, MD, PhD Department of Obstetrics and Gynecology
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 Department of Obstetrics and Gynecology 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
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
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
REFERENCES ... 82
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.
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
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
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
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.
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
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.
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.
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.
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
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.
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
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).
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).
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).
A B
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),
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.
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
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.
28,799 (547)
Bodelon et al., case- control (2009)
Table 2. Risk estimates of relaparotomy and hysterectomy in deliveries complicated by placental abruption.
4,451 (126) 3.2 (1.8–5.8)
Friedman et al.,
cohort (2016) 55 214,208 (573,723) 2.8 (2.5–3.2)
34,469 (1,284) 3.5 (1.8–6.8) Pariente et al.,
cohort (2011) 185,476 (1,365) 7.9 (3.4–18.1)
Kessous et al., case- control (2012) Authors, study
design (year) Sample size
(abruptions) Relaparotomy aRR/aOR/OR (95% CI)
Hysterectomy aRR/aOR/OR (95%
CI) Gedikbasi et al.,
cohort (2008) 15.3 (6.9–33.8)
aRR, adjusted risk ratio; aOR, adjusted odds ratio; OR, odds ratio; CI, confidence interval
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.
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
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.
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
No
Yes
1.2 (0.8–1.9) NA
4.8 (1.1–20.1) 1.8 (1.3–2.4) 1.1 (0.8–1.6)
2.7 (1.5–5.0) No
Yes*
Ananth et al. (2017)
CVD morbidity
CVD mortality Prevalence of CVD risk factors after pregnancy
CVD mortality (first CVD hospitalization)
CVD mortality CVD morbidity
CVD mortality Lykke et al. (2010)
Veerbeek et al. (2013)
Pariente et al. (2014) DeRoo et al. (2016)
Ray et al. (2005)
Table 3. Summary of studies on the association between cardiovascular disease (CVD) morbidity/mortality and placental abruption.
Cain et al. (2016)
Authors (year) Outcome of the study
Association with placental abruption
yes/no
HR (95% CI)
Yes Yes
Yes 1.7 (1.3–2.2)
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
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.
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-
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).
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.
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
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).
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).
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).
