retained placenta and postpartum haemorrhage

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ACTA UNIVERSITATIS UPSALIENSIS UPPSALA 2015 Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1077 Retained Placenta and Postpartum Haemorrhage JOHANNA BELACHEW ISSN 1651-6206 ISBN 978-91-554-9182-6 urn:nbn:se:uu:diva-246185

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Page 1: Retained Placenta and Postpartum Haemorrhage

ACTAUNIVERSITATIS

UPSALIENSISUPPSALA

2015

Digital Comprehensive Summaries of Uppsala Dissertationsfrom the Faculty of Medicine 1077

Retained Placenta and PostpartumHaemorrhage

JOHANNA BELACHEW

ISSN 1651-6206ISBN 978-91-554-9182-6urn:nbn:se:uu:diva-246185

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Dissertation presented at Uppsala University to be publicly examined in Rosénsalen, Ing95/96, Akademiska sjukhuset, Uppsala, Thursday, 23 April 2015 at 13:15 for the degree ofDoctor of Philosophy (Faculty of Medicine). The examination will be conducted in Swedish.Faculty examiner: Professor Kjell Å Salvesen (Lunds Universitet).

AbstractBelachew, J. 2015. Retained Placenta and Postpartum Haemorrhage. Digital ComprehensiveSummaries of Uppsala Dissertations from the Faculty of Medicine 1077. 59 pp. Uppsala: ActaUniversitatis Upsaliensis. ISBN 978-91-554-9182-6.

The aim was to explore the possibility to diagnose retained placental tissue and other placentalcomplications with 3D ultrasound and to investigate the impact of previous caesarean sectionon placentation in forthcoming pregnancies.

3D ultrasound was used to measure the volumes of the uterine body and cavity in 50women with uncomplicated deliveries throughout the postpartum period. These volumes werethen used as reference, to diagnose retained placental tissue in 25 women with secondarypostpartum haemorrhage. All but three of the 25 women had retained placental tissue confirmedat histopathology. The volume of the uterine cavity in women with retained placental tissue waslarger than the reference in most cases, but even cavities with no retained placental tissue wereenlarged (Studies I and II).

Women with their first and second birth, recorded in the Swedish medical birth register, werestudied in order to find an association between previous caesarean section and retained placenta.The risk of retained placenta with heavy bleeding (>1,000 mL) and normal bleeding (≤1,000mL) was estimated for 19,459 women with first caesarean section delivery, using 239,150women with first vaginal delivery as controls. There was an increased risk of retained placentawith heavy bleeding in women with previous caesarean section (adjusted OR 1.61; 95% CI1.44-1.79). There was no increased risk of retained placenta with normal bleeding (Study III).

Placental location, myometrial thickness and Vascularisation Index were recorded on 400women previously delivered by caesarean section. The outcome was retained placenta andpostpartum haemorrhage (≥1,000 mL). There was a trend towards increased risk of postpartumhaemorrhage for women with anterior placentae. Women with placenta praevia had an increasedrisk of retained placenta and postpartum haemorrhage. Vascularisation Index and myometrialthickness did not associate (Study IV).

In conclusion: 3D ultrasound can be used to measure the volume of the uterine body and cavitypostpartum, but does not increase the diagnostic accuracy of retained placental tissue. Previouscaesarean section increases the risk of retained placenta in subsequent pregnancy, and placentapraevia in women with previous caesarean section increases the risk for retained placenta andpostpartum haemorrhage.

Keywords: postpartum haemorrhage, retained placenta, secondary postpartum haemorrhage,retained placental tissue, threedimensional ultrasound, previous caesarean section

Johanna Belachew, Department of Women's and Children's Health, Akademiska sjukhuset,Uppsala University, SE-75185 Uppsala, Sweden.

© Johanna Belachew 2015

ISSN 1651-6206ISBN 978-91-554-9182-6urn:nbn:se:uu:diva-246185 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-246185)

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To Yosef

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List of Papers

This thesis is based on the following papers, which are referred to in the text by their Roman numerals.

I Belachew J, Axelsson O, Mulic-Lutvica A, Eurenius K. Longitudinal study of the uterine body and cavity with three-dimensional ultrasonography in the puerperium. Acta Obstet Gynecol Scand. 2012 Oct; 91:1184-90.

II Belachew J, Axelsson O, Eurenius K, Mulic-Lutvica A. Three-dimensional ultrasound does not improve diagnosis of retained placental tissue compared to two-dimensional ultrasound. Acta Obstet Gynecol Scand. 2015 Jan; 94:112-6.

III Belachew J, Cnattingius S, Mulic-Lutvica A, Eurenius K, Axelsson O, Wikström AK. Risk of retained placenta in women previously delivered by ceasarean section: A population-based cohort study. BJOG. 2014 Jan;121(2):224-9.

IV Belachew J, Eurenius K, Mulic-Lutvica A, Axelsson O. Placental location, postpartum haemorrhage and retained placenta in women previously delivered by caesarean section: a prospective cohort study. Submitted.

Reprints are made with permission from the respective publishers.

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Contents

Abbreviations .................................................................................................. 9

Introduction ................................................................................................... 11 Postpartum period and uterine involution ................................................ 11 Secondary postpartum haemorrhage and retained placental tissue .......... 11 Ultrasound postpartum ............................................................................. 12 3D ultrasound ........................................................................................... 12 Caesarean section ..................................................................................... 13 Complications following caesarean section in previous pregnancy ......... 14 Postpartum haemorrhage .......................................................................... 14 Retained placenta ..................................................................................... 15 Abnormal invasive placentation ............................................................... 16 Ultrasound and abnormal invasive placenta ............................................. 16

Aims of the studies........................................................................................ 18 General aim .............................................................................................. 18 Specific aims ............................................................................................ 18

Study I .................................................................................................. 18 Study II ................................................................................................ 18 Study III ............................................................................................... 18 Study IV ............................................................................................... 18

Material and methods .................................................................................... 19 Study populations and settings ................................................................. 19

Studies I and II ..................................................................................... 19 Study III ............................................................................................... 20 Study IV ............................................................................................... 20

Methods .................................................................................................... 21 Studies I and II ..................................................................................... 21 Study III ............................................................................................... 21 Study IV ............................................................................................... 24

Statistical analysis .................................................................................... 26 Studies I and II ..................................................................................... 26 Study III ............................................................................................... 26 Study IV ............................................................................................... 27

Ethical considerations .............................................................................. 27

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Results ........................................................................................................... 28 Studies I and II ......................................................................................... 28 Study III ................................................................................................... 34 Study IV ................................................................................................... 35

Discussion ..................................................................................................... 39 Studies I and II ......................................................................................... 39 Studies III and IV ..................................................................................... 41 Strengths and limitations .......................................................................... 43 Clinical implications ................................................................................ 44

Conclusions ................................................................................................... 46

Future studies ................................................................................................ 47

Sammanfattning på svenska – Summary in Swedish .................................... 48 Studie I och II ........................................................................................... 49 Studie III ................................................................................................... 49 Studie IV .................................................................................................. 50

Acknowledgements ....................................................................................... 51

References ..................................................................................................... 53

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Abbreviations

PPH Postpartum haemorrhage 2D Two-dimensional 3D Three-dimensional VI Vascularisation Index FI Flow Index VFI Vascularisation Flow Index MRI Magnetic Resonance Imaging OR Odds Ratio aOR adjusted Odds Ratio CI Confidence Interval BMI Body Mass Index IQ Interquartile vol. volume ref. reference

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Introduction

Postpartum period and uterine involution The postpartum period is associated with great physiological changes for the mother. After delivery of the child, the uterus contracts again in order to detach the placenta from the uterine wall and deliver the placenta and membranes (1). The myometrium is composed of a network of muscle fibers and the blood vessels supplying the placental bed travel within this network. The muscular contraction after delivery is a prerequisite for preventing ecsessive, life-threatening bleeding from the placental bed by constricting the otherwise open blood vessels (2). These physiological changes continue throughout the postpartum period of 6-8 weeks and the uterus undergoes a substantial involution process. Right after delivery the uterus has an estimated weight of around 1,000 g and can be easily palpated at the level of the umbilicus. Six weeks later the uterus is back to its non-pregnant state and weighs less than 100 g (3).

Secondary postpartum haemorrhage and retained placental tissue Excessive bleeding occurring more than 24 hours after delivery is referred to as secondary postpartum haemorrhage (PPH) (4). In developed countries it affects 0.5 to 2% of mothers and is associated with severe maternal morbidity (5). Secondary PPH is also associated with maternal mortality and accounts for half of the maternal deaths caused by PPH (6). The reason for the secondary PPH is an inadequate contraction of the uterus caused by either intrauterine infection (7) or retained placental tissue (8). If there is a suspicion of retained products, the treatment is either medical with the use of uterotonics or surgical curettage (5). The latter is used in around half of the cases with suspected retained placental tissue (9). There is, however, no consensus regarding treatment of choice as no randomised controlled trials have been conducted on the management of women with secondary PPH (10). Moreover, the surgical intervention can be complicated by infection or perforation and, in severe cases, may result in Asherman’s syndrome, which is associated with intrauterine adhesions and infertility (11). These potential

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risks enhance the importance of accurate diagnosis of retained placental tissue.

Ultrasound postpartum The uterus was one of the first organs examined by ultrasound (12) and the postpartum uterus was described as early as in the 1970s (13-15). The involution of the postpartum uterus has been described further (16, 17), and in 2001, Mulic-Lutvica et al (18) conducted a prospective, longitudinal study of the uterine involution in women with normal deliveries and postpartum periods . They measured the anteroposterior diameter of the uterine body and cavity, and described the intrauterine content. The uterus was found to be retroverted and empty on the first day postpartum, and after one and two weeks, the cavity was filled with fluid with a mixed echogenic pattern. In late puerperium the uterus was anteroverted and the cavity was empty.

Ultrasound has been used for several years in the diagnosis of secondary PPH. The presence of a uterine mass detected by two-dimensional (2D) ultrasound in women with secondary PPH has been found to associate with retained placental tissue (19, 20). The accuracy of 2D ultrasound as a diagnostic tool to diagnose retained placental tissue has, however, been questioned, and it has been suggested that retained placental tissue is over-diagnosed, leading to unnecessary surgical interventions (21).

In spite of previous research, many clinicians today still find it difficult to interpret the ultrasound image in women with secondary PPH with such certainty that they can verify or rule out the presence of retained placental tissue.

3D ultrasound During the last decades, three-dimensional (3D) ultrasound has been introduced and with that the possibility to measure volumes (22). In the obstetric and gynaecologic field this technique has been used when measuring, for example, the ovaries (23), cervix (24) and foetal renal pelvis (25). The commonly used program, the virtual organ computer-aided analysis (VOCAL), has proven good reliability and valildity for volume measurements (23, 24, 26-28). When measuring the volume of a non-pregnant uterus, the 3D ultrasound has shown higher accuracy than the two-dimensional (2D) ultrasound (29).

Before the introduction of 3D ultrasound, volume measurements were made by 2D measurements in different planes and the use of mathematic formulas, such as in ovarian volumes where the prolate ellipsoid formula (L x H x W x 0.523) was used (30). This method relies on regularity in shape of

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the organ examined while 3D ultrasound can be used successfully for more irregular shapes (28).

3D power Doppler has been used to investigate blood flow and vascular-ity in different organs (31, 32). The placental vascular tree has been exam-ined in that way, but only in the first trimester, as it is not possible to picture the whole placenta in one volume later in pregnancy (33). With this back-ground, a method has been developed where a part of the placenta, or a “bi-opsy”, is measured and, in that biopsy, the vascularity is assessed as the Vascularisation Index (VI), Flow Index (FI) or Vascularisation-flow Index (VFI). VI measures the amount of blood vessels within a tissue as a percent-age, FI measures the average blood flow intensity and VFI represents both blood flow and vascularity (34). These indices have been used in studies on placental vascularisation in growth-restricted foetuses (35).

During the years of ultrasound scanning for foetal monitoring, the issue of safety regarding the use of energy with potential bioeffects has been dis-cussed. Although there are no proven harmful effects on humans (36, 37), the whole truth on the safety of ultrasound has not yet been clarified. How-ever, regarding 3D ultrasound, it seems that it is not any more harmful than 2D ultrasound because the energy effects, measured as the Thermal Index (TI), are comparable to those of 2D ultrasound (38).

Caesarean section During the last decades, the caesarean section rates reported worldwide have increased substantially (39). In the United States, the caesarean section rate reported in 2010 was 30.5% (40) and in New South Wales, Australia, 29.5% (41). Some industrialised countries have doubled their caesarean delivery rate between 1992 and 2007 (42). On the other hand, in developing countries, the overall rate is low (39), but there are large regional differences. A study from a University hospital in Tanzania has reported a ceasarean section rate of 49% (43).

The guidelines from the World Health Organisation supporting a caesarean delivery rate of no more than 15% (44) have not only been exceeded, but also questioned (45). The reasons for the increasing caesarean section rates are not fully understood but it seems that there are no changes in maternal characteristics that can explain the rising trend (46). It is most likely that the attitudes and expectations of the mothers, as well as those of the physicians, play a major role (47-49) in this increase.

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Complications following caesarean section in previous pregnancy Alongside the rising trends in caesarean section delivery, the associated complications affecting the mother and infant need to be addressed. Immediate complications reported are, for example, severe bleeding and infection for the mother and respiratory distress for the infant (50). Concerning the mother, it is, however, not only the direct complications during and shortly after surgery that are the only concerns, but also the increased risk of long-term complications affecting the mother in subsequent pregnancies. Such complications are uterine rupture (51), PPH (52), placenta praevia and placenta accreta (53). A slight risk increase has also been shown for preeclampsia and for pregnancies with foetuses that are small for gestatinal age (54).

A woman previously delivered by caesarean section is also more likely to be delivered by caesarean section in subsequent pregnancies and after two caesarean section deliveries, most women are advised against any trial of vaginal birth (55). Consequently, women with a first caesarean delivery are at risk of beeing delivered by caesarean section multiple times. Reports show that, in women with placenta praevia, the risk of abnormal invasive placenta increases with the number of previous caesarean sections (56). The risks following repeat caesarean sections are found to exceed the risks associated with vaginal birth after previous caesarean section (57).

Postpartum haemorrhage PPH is the most common cause of maternal mortality worldwide (58). It accounts for almost one-quarter of all maternal deaths (59) and one-third of the maternal deaths in Africa and Asia (60). PPH is defined as blood loss exceeding 500 mL within 24 hours after delivery (61). This definition has been questioned as a blood loss of more than 500 mL is common in many uncomplicated deliveries (59) and blood loss of up to 1,000 mL would probably have no clinical impact on healthy women (62). More recent con-sensus has stated that severe PPH is defined as blood loss more than 1,000 mL (63). This level is used in Sweden when diagnosing PPH according to the International Classification of Disease, Clinical Modification (ICD-10). However, in low resource settings where more women already suffer from anaemia (64) or are immunocompromised as a result of HIV or malaria, 500 mL bleeding can be life-threatening (62).

Estimating blood loss during delivery is difficult (65) and often underes-timated (66). Most records on PPH are received from medical charts where the amount of blood has been estimated by midwives or obstetricians and where reliability is uncertain. Therefore, it is suggested that PPH should be

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defined on a clinical basis as hematocrit falls or when there is a need for blood transfusion (67). However, the incidence of PPH has increased over the last years (52, 68-70). According to Bateman et al, this is due to an in-crease in uterine atony (52) and not to changes in risk factors (68). Risk fac-tors mentioned in the literature for PPH are maternal age, multiparity, prior caesarean section, preeclampsia, retained placenta, placenta praevia and accreta, gestational age, foetal macrosomia, polyhydramnios and delivery by caesarean section or instrumental vaginal delivery (52, 59, 68, 71).

Retained placenta Retained placenta is associated with both maternal morbidity and mortality. In the industrial world, the mortality rates from retained placenta have de-creased substantially. In the UK, for example, the maternal deaths from re-tained placenta in the 1920s were the same as all maternal deaths today; 7.5 per 100,000 live births (72). In developing countries, however, the case fatal-ity rate from retained placenta is high (73, 74) due to its strong relation to PPH. In these settings, the mothers are, to a higher degree, exposed to anae-mia and malnutrition before delivery and, with lack of efficient transporta-tion to health centres, home deliveries contribute to the severe outcomes (73). Retained placenta is the second most common cause of PPH after uter-ine atony and it is the most common indication for blood transfusion post-partum (52).

The definition of retained placenta and time for manual removal of the placenta varies between and within countries (72). The optimum time period between delivery of the infant until delivery of the placenta varies between European countries, from less than 30 to more than 60 minutes (75). Studies have shown an increased risk of PPH after 18 minutes (76) and after 30 min-utes (77). This ought to be weighed against the chance of spontaneous deliv-ery of the placenta (78) and the risk of complications caused by manual re-moval (79, 80). In Sweden, the clinical practice is to perform manual re-moval of the placenta within 30-60 minutes after delivery, according to the National Institute for Health and Clinical Excellence (NICE) guidelines de-veloped in the UK (81).

There has been a general increase in incidence of retained placenta and manual removal of the placenta which can be explained by the aetiology and risk factors of retained placenta (82). Factors known to increase the risk are, among others; high maternal age, previous retained placenta and premature delivery (83-86). However, the results are contradictory. There are studies showing an increased risk of retained placenta in women with high BMI (87), whereas others do not (88). Previous abortion was found to increase the risk of retained placenta in one study (89) but not in another (90). A potential risk factor for retained placenta is a previous delivery by caesarean section.

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This finding has been investigated in previous studies but with varying re-sults. Some studies state that previous caesarean section increases the risk of retained placenta (86, 91), while others could not show such an association (85, 92, 93). None of these studies have distinguished between retained pla-centa with normal bleeding and retained placenta with heavy bleeding.

Abnormal invasive placentation Alongside the rising trends of caesarean section deliveries, placental compli-cations such as placenta praevia and placenta accreta increase as a result of the strong association between these conditions and previous caesarean sec-tion (56). These abnormal invasive placentae are fortunately rare events, but are still important because of the severity of the outcome for affected women (94). The prevalence of placenta accreta differs between studies. One per 500 has been reported from Thailand (95), one per 4,000 in the US (96) and 1.7 per 10,000 in the UK (97). In 2002, the American Congress of Obstetri-cians and Gynecologists reported a 10-fold increase over 50 years to an inci-dence of 1 in 2,500 deliveries (98). These differences can be explained by variations in clinicopathological definitions. According to a report by Sol-heim et al (99), there will be a substantial increase in incidence of placenta praevia, placenta accreta and maternal mortality in the US if the caesarean section rate continues to increase at the same rate as today. They predict, using a decision-analytic model, a caesarean section rate of 56.2% and 130 maternal deaths yearly in the US by 2020.

The mechanism behind the abnormal placentation is not yet fully under-stood and there are different theories explaining the pathology that also ex-plain the association with the scarred uterine wall (56). The first theory sug-gested a primary defect of trophoblastic function leading to invasive placen-tation (100). Tantbirojn et al (101) proposed that the absence of decidua at the site of the uterine scar allows the abnormal trophoblastic invasion in the myometrium. The latest theory is that localised hypoxia in the scarred uter-ine wall leads to a defective decidualisation and trophoblastic invasion (102).

The abnormal invasive placenta can cause severe maternal outcome, but it has been shown that if women with placenta accreta are delivered by a mul-tidisciplinary care team instead of standard obstetric care, maternal morbidi-ty is reduced (103). This finding emphasises the importance of prenatal, correct diagnosis of the abnormal invasive placenta.

Ultrasound and abnormal invasive placenta The two major diagnostic modalities used to attempt a prenatal diagnosis of abnormal invasive placenta are ultrasound and magnetic resonance imaging

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(MRI). MRI has been difficult to evaluate because of the low number of women examined and the different study designs used (104). One pilot study could, however, show that the volume of dark placental bands seen on MRI was the most predictive finding in cases of abnormal invasive placenta (105). They found that MRI could correctly identify 78% of the placentae accreta compared to 67% by ultrasound. Because MRI is a much more ex-pensive and time-consuming test than ultrasound, it is important to know when it can contribute to additional information.

Ultrasound has been used in all trimesters to diagnose abnormal invasive placenta. Cases with excessive bleeding, presenting as first trimester abor-tions, have confirmed that invasive placentae can even occur in early preg-nancy (106, 107). Studies have shown that early pregnancy invasive placenta can be identified by ultrasound as it will reveal if the gestational sac is im-planted in the anterior lower uterine segment (108). This condition is mainly linked to women with previous caesarean section (109). Comstock and Bronsteen suggest in a review article that an early ultrasound scan (before 10 weeks) on women with previous caesarean section could identify those with high risk of abnormal invasion and those who are unlikely to develop an abnormal invasive placenta (104).

In the second and third trimester, different ultrasonic findings are used to diagnose abnormal invasive placenta. One is the absence of a clear space; a hypoechogenic space between the placenta and myometrium. This finding is also present in many normal placentations and hence accounts for many false positive diagnoses (110). The presence of a clear space can, however, almost rule out a placenta accreta. Another sign with high positive predictive value, is the interruption of the bladder and uterus interface, which is normally seen as a continuous white line (111) on 2D ultrasound. The presence and amount of lacunae in cases with abnormal invasive placenta varies greatly between reports (104). A myometrial thickness of less than 1 mm has been found to predict abnormal invasive placenta (110). 2D colour and power Doppler have also been used as diagnostic tools, where the increased vascularity in the placenta and myometrium predicts not only placenta accreta but can also distinguish placenta accreta between increta and percreta (112).

Concerning 3D ultrasound, this has been used to complement 2D colour and power Doppler in the diagnosis of the hypervascularity between uterus and placenta (110). Studies have shown that 3D colour power Doppler shows an increased vascularity at the uterine bladder interface and irregular intraplacental vascularisation, distinguishing placenta percreta from accreta and increta (111).

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Aims of the studies

General aim The overall aim of this thesis is to explore the possibility to diagnose re-tained placental tissue and other placental complications with 3D ultrasound and to investigate the impact of previous caesarean section on placentation in forthcoming pregnancies.

Specific aims Study I To create reference data on uterine body and cavity volumes postpartum using 3D ultrasound.

Study II To improve the diagnosis of retained placental tissue by measuring the uter-ine body and cavity volumes using 3D ultrasound.

Study III To evaluate if women with a caesarean section at their first delivery have an increased risk of retained placenta at their second delivery.

Study IV To determine if placental location, myometrial thickness, and VI influenced the risk of PPH and retained placenta in women previously delivered by caesarean section.

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Material and methods

Table 1. Overview of the studies.

Study Study design Subjects Variables studied

I Longitudinal, prospective, descriptive

50 women with normal deliveries and postpartum periods

Uterine body and cavity volumes measured by 3D ultrasound

II Prospective,

comparative, descriptive

25 women with suspected retained placental tissue

Uterine body and cavity volumes measured by 3D ultrasound

III Population-based

cohort 258,608 women with first and se-cond singleton deliveries

Retained placenta with normal (<1,000 mL) and heavy (>1,000 mL) bleeding in women with pre-vious caesarean section compared to women with previous vaginal delivery

IV Prospective cohort

400 women with previous caesarean section delivery

Placental location, myometrial thickness, VI, PPH and retained placenta

Study populations and settings Studies I and II These studies were conducted at the Department of Obstetrics and Gynae-cology, Uppsala University Hospital, between 2009 and 2012. Uppsala Uni-versity Hospital is a tertiary referral centre with approximately 4,000 deliver-ies per year. In the first study, 63 healthy women with uncomplicated preg-nancies, term (gestational week 39-42) deliveries and uneventful postpartum periods were recruited. Thirteen women did not complete the examinations because of social reasons or endometritis and one woman was diagnosed with retained placental tissue and thereby included in Study II.

In the second study, 25 women with secondary PPH who were to undergo surgical curettage on suspicion of retained placental tissue were recruited.

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Only women for whom the clinician had already decided on uterine explora-tion participated. This decision was based on clinical evaluation and 2D ul-trasound findings of a hyperechogenic intrauterine mass. The intrauterine mass was defined as a well-circumscribed mass, without any fluid compo-nents, as described earlier by Lutvica et al (19). One woman did not have an echogenic mass but a mixed echo-pattern in the uterus. Women with heavy bleeding that needed emergency uterine evacuation were excluded in order not to delay necessary medical intervention.

Study III Data were obtained from the Swedish Medical Birth Register which is a large national population-based database established in 1973. It includes information on more than 98% of all births in Sweden, such as demographic data, reproductive history, pregnancy complications, delivery and neonatal characteristics (113). During 1994-2006, approximately 1.3 million births were recorded in the register and data were used from all women who had their first and second consecutive singleton pregnancy resulting in birth after 22 weeks’ gestation. This cohort included 296,251 women. Of these, 37,643 women who had a caesarean section or a placental abruption in their second delivery were excluded because they could not be diagnosed with retained placenta. Thus, the final study population was made up of 258,608 women.

Study IV The study was conducted at the Department of Obstetrics and Gynaecology, Uppsala University Hospital, between 2010 and 2013. During the study pe-riod the caesarean section rate at the department was 16%. All women with singleton pregnancies who had been delivered by caesarean section in at least one previous pregnancy could be included. The women were asked to participate by the midwives or a research-nurse when conducting the routine ultrasound scan at 18 weeks of gestation. Out of 529 women asked, seven women were excluded; five due to premature delivery and two who moved away before examination. One hundred and twenty-two women chose not to participate and their reasons for not participating were not recorded. Thus, 400 women constituted the study group.

A power calculation was completed, presuming an incidence of 10% for PPH. To detect an increase to 20% in women with anterior placenta with a two-sided alfa of 0.05 and a beta of 0.20, at least 398 women had to be in-cluded.

During the study period, about 900 women who previously had been de-livered by caesarean section had their routine ultrasound scan at the depart-ment. Recruitment to the study was not entirely continuous as it was periodi-

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cally interrupted due to the necessity of sick-leave for a research nurse and the heavy workload of the midwives.

Methods Studies I and II The volumes of the uterine body and cavity were measured using 3D ultra-sound. The examinations before Day 28 were done transabdominally and from Day 28, transvaginally. Ultrasound scans were done between uterine contractions and with a moderately filled bladder. After visualising the uterus in the sagittal 2D plane, the 3D mode was activated and the volume box was placed over the uterus, excluding the cervix. The angle between the uterine body and cervix was used as a landmark to separate the cervix from the uterine body. Volume assessment was based on manual delineation of the contour of the body and cavity. A rotation step of 30 degrees was used, resulting in the definition of 6 contours. Plane A (sagittal view) was used as the reference plane. The acquired volume dataset was analysed using the VOCAL imaging program, integrated in the Voluson E8 ultrasound system.

The volume and shape of the uterine body and cavity, as well as the 2D description of the intrauterine content, was analysed. Data on age, parity, birth weight, gestational week at delivery, smoking habits, breast-feeding, mode of delivery and blood loss during delivery were recorded for all women.

In the first study the 50 women were examined on day 1, 7, 14, 28 and 56 postpartum to show the involution process by volume decrease in normal puerperium.

In the second study, women with suspected retained placental tissue were examined as described above, before surgical evacuation of the uterus. Re-tained products from the evacuation were then sent for histological examina-tion to verify or rule out retained placental tissue. Hereafter the volumes of the uterine body and cavity in women with retained placental tissue were compared to the volumes from women with uncomplicated puerperium in Study I. Comparisons were made with reference values from Day 1, 7, 14, 28 or 56, the day closest to the actual day for examination, which were on the same day the woman attended the clinic because of secondary PPH. If the woman presented on Day 4, 21 or 42, we chose to compare with Day 7, 28 and 56 postpartum, respectively.

Study III Mode of delivery is recorded in the Swedish Medical Birth register and cae-sarean section delivery in first pregnancy was used as a measure of exposure.

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Controls were determined as those women who delivered vaginally in the first pregnancy.

The outcome was a second vaginal delivery complicated by retained pla-centa and this was identified by the ICD-9 codes 666A and 667A and the ICD-10 codes O720 and O730. Additionally, retained placenta was separated in those with normal bleeding (<1,000 mL) as opposed to heavy bleeding (>1,000 mL) by separating ICD-9 code 667A and ICD-10 code O730 (nor-mal bleeding) from ICD-9 code 666A and ICD-10 code O720 (heavy bleed-ing).

Several covariates were considered and maternal reproductive history, so-ciodemographic and anthropometric characteristics, as well as delivery and infant characteristics, were accounted for as possible confounders. From the first antenatal visit in the second pregnancy, data on BMI, height, smoking habits, cohabitation with the infant’s father, number of previous miscarriages and in vitro fertilisation in present pregnancy were obtained. Data on previ-ous termination of pregnancy are not included in Swedish registers. At de-livery, information on maternal age, premature rupture of membranes, labour dystocia, mode of delivery as well as gestational length, infant birth weight and sex was collected. The women’s educational level was obtained from the Education Registry from 2005 and the mother’s country of birth from the Registry of Population and Population Changes. All variables were catego-rised according to Table 2.

Table 2. Rates and risk of retained placenta according to maternal, delivery and infant characteristics at second delivery

MATERNAL CHARACTERISTICS

Number of births

Rate (%)

Crude OR (95% CI)

Caesarean section first delivery No 239,150 1.96 Reference Yes 19,458 3.44 1.45 (1.32-1.59) Maternal age (years) < 25.0 31,091 1.44 0.81 (0.73-0.90) 25.0-29.9 91,166 1.78 Reference 30.0-34.9 100,040 2.27 1.28 (1.20-1.36) > 35.0 36,311 2.79 1.59 (1.47-1.72) Maternal height (cm) < 162 70,906 1.85 0.90 (0.84-0.96) 162-171 126,619 2.06 Reference > 172 42,867 2.41 1.17 (1.09-1.26) Smoking habits Yes 19,087 2.37 1.18 (1.06-1.30) No 222,421 2.03 Reference Mother’s country of birth Nordic 225,840 2.13 Reference Non-Nordic 31,642 1.68 0.79 (0.72-0.86) Previous miscarriages 0 206,339 1.92 Reference 1-2 49,479 2.62 1.38 (1.29-1.47) > 3 2790 3.48 1.84 (1.50-2.26)

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Table 2 (Continued)

Number of births

Rate (%)

Crude OR (95% CI)

In vitro fertilisation Yes 2056 3.36 1.65 (1.30-2.10) No 256,552 2.06 Reference Interpregnancy interval < 1.0 years 47,962 1.98 0.97 (0.91-1.04) 1.0-3.9 years 183,350 2.04 Reference 4.0-6.9 years 22,071 2.32 1.14 (1.04-1.26) > 7.0 years 4763 2.88 1.42 (1.20-1.69) DELIVERY AND INFANT CHARACTERISTICS

Premature rupture of membranes

Yes 2,046 4.89 2.46 (2.01-3.01) No 256,562 2.05 Reference Induction of labour Yes 20,138 3.45 1.79 (1.65-1.94) No 236,439 1.96 Reference Labour dystocia Yes 14,266 3.29 1.67 (1.52-1.84) No 244,342 2.00 Reference Instrumental vaginal delivery

Yes 9,180 3.37 1.69 (1.50-1.90) No 249,428 2.02 Reference Epidural Yes 46,017 2.77 1.46 (1.37-1.56) No 212,591 1.92 Reference Gestational length (weeks) < 31 603 9.45 5.33 (4.05-7.01) 32-36 6,913 3.79 2.01 (1.77-2.28) 37-41 217,898 1.92 Reference > 42 32,868 2.53 1.33 (1.23-1.43) Infant weight (gram) < 2,000 907 7.83 4.48 (3.50-5.72) 2,000-2,999 19,994 2.56 1.97 (1.26-1.52) 3,000-3,999 174,082 1.86 Reference 4,000-4,999 61,418 2.38 1.29 (1.21-1.37) > 5,000 1,419 3.66 2.01 (1.52-2.65) Infant sex Boy 132,723 1.89 Reference Girl 125,885 2.25 1.19 (1.13-1.26)

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Study IV The 400 women constituting the study group were examined with ultrasound at gestational week 28-30. A Voluson E8, GE Medical Systems ultrasound machine was used. The location of the placenta was recorded as anterior, low-anterior, posterior, low-posterior, fundal or placenta praevia. Low-anterior or low-posterior was diagnosed when placenta was close to but not covering the internal cervical os. Praevia was diagnosed only when the pla-centa was covering the cervical os and could be either anterior or posterior praevia. The thickness of the myometrium was measured in mm (Fig 1). 3D ultrasound power Doppler was used to measure VI, which was obtained from a preset sonobiopsy in the midsection of the placenta and uterine wall (Fig 2 and 3).

Figure 1. Ultrasound image of an anterior placenta and myometrium.

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Figure 2. 3D ultrasound image of a sonobiopsy in the midsection of the placenta and myometrium.

Figure 3. Histogram from the 3D volume calculating VI.

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Maternal characteristics such as age, BMI, smoking, parity, number of pre-vious caesarean sections and placental location at the second trimester rou-tine ultrasound were recorded, as were delivery and infant characteristics, induction, mode of delivery, use of oxytocin to promote labour, gestational age at delivery, infant birth weight, retained placenta and PPH. These char-acteristics were obtained for all 522 women, both participating and non-participating.

The main outcomes were PPH defined as blood loss ≥ 1,000 mL and re-tained placenta. Retained placenta was diagnosed when the placenta had to be removed manually after vaginal delivery or was difficult to remove dur-ing Caesarean section.

Statistical analysis Studies I and II The demographics of the participants are presented descriptively, with means and ranges. Uterine body and cavity volumes are presented as medi-ans, ranges and interquartile ranges. The proportion of women with intrau-terine content at various time points is presented as percentages. Postpartum changes in uterine body and cavity volumes are presented as graphs showing data from all women over time. Quantitative values from the 25 studied women with suspected retained placental tissue are plotted in the reference box plot graph. Calculations were done in R version 2.12 (http://www.r-project.org/).

Study III The risk of retained placenta at second delivery was calculated for women with a first caesarean section delivery, using women with a first vaginal de-livery as a reference. Unconditional logistic regression analysis was used to calculate risk as odds ratio with a 95% confidence interval. Maternal charac-teristics, including age, height, smoking habits, country of birth, previous miscarriages, in vitro fertilisation, years of interpregnancy interval, maternal BMI, cohabitation with the infant’s father and years of formal education were recognised as possible confounders (Table 2). The last three variables were not associated with our outcome in univariate analyses and were there-fore not adjusted for in further analyses. Because of the large number of confounding factors, maternal characteristics were analysed separately from infant and delivery characteristics by calculating the risk in two models. In a first multiple logistic model, we calculated risk of retained placenta adjusted for maternal characteristics and thereafter we created a second multiple lo-gistic model by adding delivery and infant characteristics, such as premature

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rupture of membranes, induction of labour, labour dystocia, instrumental vaginal delivery, use of epidural anaesthesia, gestational length at delivery, infant birth weight and infant sex. All analyses were performed using the Statistical Analysis Software version 9.1 (SAS Institute, Inc, Cary, NC).

Study IV For PPH and retained placenta as the outcome variables, Chi square and Fisher’s exact test were used to calculate the association with placental loca-tion. A p-value of less than 0.05 was considered statistically significant. Spearman’s correlation coefficient was used to calculate associations be-tween maternal characteristics and PPH. When calculating the association between VI and PPH, the Pearson correlation coefficient was used. All sta-tistical analyses were performed using SPSS statistical software, version 19.

Ethical considerations The Regional Ethical Board at the medical faculty, Uppsala University, Sweden, approved studies I, II and IV. Informed consent was obtained from all participating women. All women were informed that their participation in the studies was voluntary and would not influence their medical care. They could withdraw from the study at any time without needing to explain the reason for not participating. In Study II the decision on surgical intervention was taken by the clinician and was not influenced by the study.

The Regional Ethical Board at Karolinska Institutet, Stockholm, Sweden approved Study III.

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Results

Studies I and II Demographic data from the two studies are shown in Table 3.

Table 3. Demographic data Studies I and II

Study I Study II

Age (years)

32 (30-38) 37 (30-42)

Nullipara (%)

68 64

Smoking (n)

0 1

Gestational age at delivery (week)

40 (38-42) 37 (30-42)

Blood loss (mL)

377 (150-930) 1,052 (300-4,500)

Caesarean section (n)

0 3

Birth weight (g)

3,720 (2,450-5,040) 3,182 (1,480-4,620)

Brest feeding (%) 96 85

In the first study, all but 13 (94.8%) of the 250 planned examinations were performed and the measurements were done as planned, except on Day 1, because the uterus then was too large for the screen in 26 cases. For these women, part of the contours had to be estimated and they all had a uterine body volume larger than 800 cm3.

The median uterine body and cavity volumes from women with uncom-plicated puerperium are shown with ranges and interquartile ranges in Table 4. The presence of uterine content or not is shown in percentages.

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Table 4. Uterine cavity and body volumes (medians, interquartile ranges and ranges) and percentage of women with cavity contents

Day postpartum (n)

Uterine volume (cm3) Median (IQ range)

Range

Cavity volume (cm3) Median (IQ range)

Range

Cavity content (%)

1 (50) 756 (662-899) 443-1480

22 (16-36) 9-113

36

7 (46) 440 (385-499) 286-667

18 (11-26) 5-43

93

14 (45) 253 (227-298) 138-413

6 (4-10) 0-29

87

28 (48) 125 (108-156) 59-252

1 (0-2) 0-6

28

56 (48) 68 (56-81) 39-129

0 0

Figure 4 shows all uterine body volumes where the individual variations are most pronounced on day 1, ranging from 443 to 1,480 cm3. The median uter-ine volume decreased from 756 cm3 on day 1 postpartum to 68 cm3 on day 56. The variations between women decreased over time and on day 56 the volume ranged from 39 to 129 cm3 (Table 4, Fig 4). In a great majority the uterine body shape resembled that of an ellipsoid (Fig 6). The median cavity volumes shown in Table 4 decreased from 22 cm3 on day 1 to 1 cm3 on day 28 with a large individual variation on day 1. This variation decreased over time (Fig 5).

Figure 4. Individual uterine body volumes in women with uncomplicated delivery and postpartum periods

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Figure 5. Individual uterine cavity volumes in women with uncomplicated delivery and postpartum periods.

Intrauterine content (non-echogenic and echogenic) was found in 36, 95 and 87% of the women on Days 1, 7 and 14, respectively (Table 4). On Day 28, only a thin echo-free line was observed in 28% of the women and on Day 56 the cavity was empty in all women.

The uterine involution is shown as 3D volumes taken from one woman in the first study on Days 1 to 56 (Fig. 6).

Figure 6. 3D ultrasound images of uterine body volumes from one woman with normal postpartum period.

The volumes of the uterine body and cavity of all 25 women with suspected retained placental tissue in Study II are shown in Table 5, together with reference values from Study I.

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Table 5. 3D ultrasound volumes of the uterine body and cavity of the 25 women when they presented with secondary PPH and reference volumes from study I.

Case Day Day + Uterine body vol.

cm3

Uterine body ref. vol.

median cm3 (IQ-range)

range

Uterine cavity vol.

cm3

Uterine cavity ref. vol.

median cm3 (IQ-range)

range

Histological confirmation

1 62 56 62 68 (56-81) 39-129

5 0 yes

2 9 7 404 440 (385-499) 286-667

42 18 (11-26) 5-43

yes

3 21 28 468 125 (108-156) 59-252

96 1 (0-2) 0-6

yes

4 13 14 307 253 (227-298) 138-413

32 6 (4-10) 0-29

yes

5 63 56 105 68 (56-81) 39-129

18 0 no

6 14 14 247 253 (227-298) 138-413

12 6 (4-10) 0-29

yes

7 19 14 191 253 (227-298) 138-413

13 6 (4-10) 0-29

no

8 48 56 155 68 (56-81) 39-129

38 0 yes

9 4 7 433 440 (385-499) 286-667

37 18 (11-26) 5-43

yes

10 58 56 262 68 (56-81) 39-129

110 0 yes

11 42 56 79 68 (56-81) 39-129

9 0 yes

12 47 56 60 68 (56-81) 39-129

4 0 yes

13 1 1 778 756 (662-899) 443-1480

232 22 (16-36) 9-113

yes

14 50 56 72 68 (56-81) 39-129

4 0 yes

15 70 56 60 68 (56-81) 39-129

5 0 yes

16 52 56 59 68 (56-81) 39-129

7 0 yes

17 46 56 58 68 (56-81) 39-129

4 0 yes

18 10 7 252 440 (385-499) 286-667

8 18 (11-26) 5-43

yes

19 12 14 253 (227-298) 138-413

23 6 (4-10) 0-29

no

20 56 56 81 68 (56-81) 39-129

2 0 yes

21 30 28 208 125 (108-156) 59-252

21 1 (0-2) 0-6

yes

22 6 7 620 440 (385-499) 286-667

47 18 (11-26) 5-43

no

23 24 28 249 125 (108-156) 59-252

19 1 (0-2) 0-6

yes

24 28 28 135 125 (108-156) 59-252

29 1 (0-2) 0-6

yes

25 9 7 335 440 (385-499) 286-667

55 18 (11-26) 5-43

yes

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Twenty-one of the 25 examined women in the second study were diagnosed with histologically verified retained placental tissue. Two of those were delivered by caesarean section. One of the four women who did not have verified retained placental tissue was treated with surgical curettage despite that the clinician had not found an echogenic mass on 2D ultrasound. She had a uterine body volume below the normal range and a cavity volume exceeding the interquartile range. Among the other three women without verified retained placental tissue, two had uterine body volumes above the interquartile range. All three women had uterine cavity volumes exceeding the interquartile range whereof two had larger cavity volumes than any reference value. One of them was later diagnosed with a uterine cavity myoma that had been misinterpreted as retained placental tissue but remained as an echogenic mass on ultrasound after surgical evacuation.

The volumes of the uterine body and cavity of the 25 women with secon-dary postpartum haemorrhage are shown as red dots in box plot graphs of the reference volumes from the first study (Figs 7 and 8).

Figure 7. Uterine body volumes from women with normal postpartum period (box plot with medians, ranges and IQ ranges). Volumes of the 25 women with secondary postpartum haemorrhage as red dots if placental tissue and triangles if no placental tissue present.

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Figure 8. Uterine cavity volumes from women with normal postpartum period (box plot with medians, ranges and IQ ranges). Volumes of the 25 women with secondary postpartum haemorrhage as red dots if placental tissue and triangles if no placental tissue present.

Of the 21 women with histologically confirmed retained placental tissue, 6 had a uterine body volume larger than the interquartile range and 3 had vol-umes exceeding any reference value (Table 5, Fig 7). Twenty of the 21 women with retained placental tissue had cavity volumes larger than inter-quartile range and 17 had volumes larger than any reference volume (Table 5, Fig 8). In all 14 cases examined 28 days or more after delivery, the uterine cavity volume exceeded the largest volume observed in the normal postpar-tum period.

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Figure 9. 3D ultrasound images of uterine body and cavity volumes in one woman with normal puerperium, 7 days postpartum.

Figure 10. 3D ultrasound images of uterine body and cavity volumes in one woman with retained placental tissue, 7 days postpartum.

Study III In the study population of 258,608 women, 2.07% were diagnosed with re-tained placenta. The risk of retained placenta according to maternal, delivery and infant characteristics is shown in Table 2. The highest OR values for retained placenta were shown for preterm delivery and low infant birth weight.

The crude OR for retained placenta was 1.79 (95% CI: 1.65-1.94) for women with a previous caesarean section delivery compared to women with a first vaginal delivery. When adjusting for maternal characteristics this as-sociation did not change substantially but when adjusting for infant and de-livery characteristics the risk attenuated to some extent (Table 6).

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Table 6. Rates and risk of retained placenta at second delivery by caesarean section at first delivery.

Retained placenta at second delivery

Odds Ratio (95% CI)CS first delivery

Total

N. Rates Crude Adjusted model 1 Adjusted model 2

No 239,150

4,680 1.96% Ref. Ref. Ref.

Yes

19,458

670

3.44%

1.79 (1.65-1.94)

1.75 (1.61-1.91)

1.45 (1.32-1.59)

Separate analyses of retained placenta with normal or heavy bleeding are shown in Table 7. A previous caesarean section was only associated with retained placenta and heavy bleeding; adjusted OR: 1.61 (95% CI: 1.44-1.79).

Table 7. Rates and risk of retained placenta with heavy (>1,000 mL) or normal (< 1,000 mL) bleeding at second delivery by caesarean section at first delivery.

Retained placenta at second delivery

Heavy bleeding Normal bleeding

Odds Ratio (95% CI) Odds Ratio (95% CI) CS first delivery N Rates Crude Adj. N Rates Crude Adj. No 3,294 1.4% Ref. Ref. 1,386 0.6% Ref. Ref. Yes

493

2.5%

1.87 (1.70-2.06)

1.61 (1.44-1.79)

177

0.9%

1.59 (1.36-1.87)

1.11 (0.92-1.33)

Study IV Maternal, delivery and infant characteristics are shown in Table 8. Non-participating women were more often multipara, smokers and had fewer inductions. Otherwise, there were minor or no differences.

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Table 8. Maternal, delivery and infant characteristics among participants and non-participants (Missing values between 1-4)

Participants n = 400

Non-participants n = 129

Age (years) 22-29 75 (18.8%) 28 (21.7%) 30-39 288 (72.0%) 90 (69.8%) 40-49 37 (9.2%) 11 (8.5%) Parity (para) 1 272 (68.3%) 75 (58.1%) >1 126 (31.7%) 54 (41.9%) Previous CS 1 337 (85.1%) 102 (79.0%) >1 59 (14.9%) 27 (21.0%) Body Mass Index 18-25 233 (58.8%) 77 (63.1%) 26-30 109 (27.6%) 27 (22.1%) 31-53 54 (13.6%) 18 (14.8%) Smoking Yes 15 (3.8%) 8 (6.3%) Preeclampsia Yes 10 (2.5%) 1 (0.8%) Gestational week 31-36 22 (5.5%) 10 (8.1%) at delivery 37-42 376 (94.5%) 113 (91.9%) Mode of delivery Vaginal 179 (44.8%) 58 (45.3%) non-instrumental 145 (36.3%) 50 (39.0%) vacuum extraction 34 (8.5%) 8 (6.3%) Caesarean section 221 (55.2%) 70 (54.7%) Induction Yes 66 (16.7%) 11 (8.7%) Use of Oxytocin Yes 125 (31.4%) 34 (26.6%) Birth weight (g) Mean 3,723 3,589 Range 1,687-5,090 2,010-4,840

Myometrial Mean 5.5 thickness (mm) Range 3.0-10.5 Vascularisation Mean 25.8 Index (%) Range 2.5-63.0 Postpartum < 1,000 352 (88.9%) 107 (85.6%) haemorrhage (mL) ≥ 1,000 44 (11.1%) 18 (14.4%) Retained placenta Yes 14 (3.5%) 6 (4.7%)

No significant differences concerning demographics were found between women with PPH and others, thus only univariate statistical analyses were performed. Placental location is shown in Table 9.

Table 9. Placenta location at 28 weeks (n=400)

Placenta location n percent

Anterior 195 48.7% Low anterior 17 4.3% Posterior 152 38.0% Low posterior 7 1.7% Fundal 21 5.3% Anterior praevia 6 1.5% Posterior praevia 2 0.5% Total 400 100%

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Between the routine ultrasound at 18 weeks and the 28 week examination, 23 (62.2%) of the low-lying placentae had migrated to an anterior or poste-rior position. On the other hand, five women who were diagnosed with low-lying placenta had a confirmed placenta praevia at 28 weeks. There were 8 (2%) placenta praevia in the study group; 6 anterior and 2 posterior. One of the anterior placenta praevia was a placenta accreta. Two women had a hys-terectomy because of excessive bleeding and placenta praevia. They were clinically diagnosed as placenta accreta but this could not be confirmed his-tologically. Four women (1.0%) were diagnosed with uterine rupture.

The risk for PPH and retained placenta in women with anterior placenta compared to others is shown in Table 10. There was an increase in PPH with anteriorly located placenta; 29 women (13.6%) compared to 15 (8.3%), but this difference was not significant. Among the women with retained placen-tae, six (2.8%) were anterior and eight (4.4%) localised elsewhere. There was, however, a significant increased risk for women with low-lying anterior placentae; 6 (26.1%) compared to 38 (10.3%) with other placental locations (p=0.032). Among women with retained placentae, three (13.0%) had low lying anterior placentae and 11 (2.9%) other locations (p=0.040). All but one of the six cases with low-lying anterior placentae and PPH and all with re-tained placenta were placenta praevia. When excluding women with placenta praevia, no significant differences remained between low anterior and other placental locations concerning PPH and retained placenta (Table 10).

Table 10. Risk of postpartum haemorrhage (PPH ≥1,000 mL) and retained placenta correlated to placental location.

PPH Retained placenta

Placenta location N Percent

(%) p-value N Percent (%) p-value

Anterior 29 13.60.098

6 2.80.367

Others 15 8.3 8 4.4Anterior (excl. praevia) 24 11.6

0,154 3 1.4

0.197 Others (excl. praevia) 13 7.3 7 3.9Low anterior 6 26.1

0.032 3 13.0

0.040 Others 38 10.3 11 2.9Low-anterior (excl. praevia) 1 5.9

1.000 0

1.000 Others (excl. praevia) 36 9.8 10 2.7

VI was not associated with PPH or retained placenta. Mean VI was 25.8% with a range from 2.5 to 63.0% and did not differ between anterior or other placental locations. It was, however, easier to access the 3D volumes in ante-rior placentae and measure the VI correctly.

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Mean myometrial thickness was 5.5 mm with a range from 3.0 to 10.5 mm. The myometrium was more easily visualised on the anterior uterine wall, resulting in a more exact measurement. Myometrial thickness did not correlate with PPH or retained placenta.

A sub-analysis was done for PPH, excluding all women who were deliv-ered by caesarean section in the present pregnancy. Results were not signifi-cant with PPH in 9.3% of women with anterior placenta compared to 5.7% with other locations (p=0.364).

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Discussion

Studies I and II The use of 3D ultrasound as a tool to measure the volume of the uterine body and cavity postpartum was found to be successful. 3D ultrasound is, in a historical view, a new diagnostic tool, where not all areas of possible use are investigated. Against this background, our findings add another important piece of knowledge to the 3D ultrasound field.

In the first weeks postpartum we used the abdominal ultrasound probe to estimate the volumes, as the uterus was too large for the vaginal approach. It has been shown earlier that the vaginal approach can only measure volumes up to 220 cm3 (29).. Moreover, the vaginal approach is probably more dis-comforting for the mother this soon after delivery. On the first day postpar-tum the uterus was sometimes too large for the screen, so the delineation of the uterine body contour had to be estimated. It is therefore recommended that the abdominal approach is used in the early postpartum period.

Concerning the method used to calculate the volumes, we used a rotation step of 30 degrees, altering delineation of the contours in six different planes. A previous study has investigated 3D volume calculations in an in-vitro setting and compared the accuracy between different degrees of rota-tion (27). They found, not surprisingly, that the six degrees rotation steps had the best reliability. Despite that knowledge, we used the 30 degrees steps to make the method applicable to a daily, clinical setting. The six degrees rota-tion step would alter 30 different delineations of the contours which would be too time-consuming and not possible for the clinician to perform. More-over, the volume of the non-pregnant uterus has been measured with 30 de-grees rotation and this method has shown sufficient accuracy (29).

The uterine involution was clearly shown by decreasing volumes, al-though the individual variations were substantial. It is however, perhaps not the uterine body size that is important when finding the cause of secondary PPH, but rather, the uterine cavity. The cavity volumes were, in most cases, enlarged by the intrauterine content, supporting the diagnosis of retained placental tissue demonstrated by 2D ultrasound. On the other hand, in those cases that did not have histologically confirmed retained placental tissue, the cavity volumes were still large. Hence, 3D ultrasound could not rule out these false positive cases.

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After one and two weeks postpartum, the volume of the cavity is large and contains a mixed echo pattern seen by ultrasound. This observation can be mistaken as retained placental tissue, if one is not aware that a mixed echo-pattern with both hypo- and hyper-echogenic components are a com-mon finding in this postpartum period, as shown here and in previous studies (18). King et al (8) stated that most complications concerning secondary PPH appear in the early postpartum period, making the ultrasound findings during this period of utmost clinical importance. This is, however, not the case in our report, where 60% of the women with secondary PPH presented after four weeks or more (Table 5). At that time, in women with a normal postpartum period, the cavity was always empty or only seen as a thin line of fluid. It should therefore be easy to verify or rule out retained placental tis-sue at this time postpartum. Thus, any volume of the cavity, if it is able to be measured by 3D ultrasound, more than one month after delivery, is patho-logical and most probably a sign of retained placental tissue.

We could confirm that a finding of an echogenic mass, as reported in pre-vious studies (19, 114), is the most predictive sign of retained placental tis-sue. On the other hand, Carlan et al (114) found an echogenic mass in only 25% of the cases with retained placental tissue. This is probably explained by the fact that they examined the uterus on every woman shortly after pla-cental delivery and not only those affected with secondary PPH. They found a 19% incidence of women with retained placental tissue after normal vagi-nal delivery, which probably has no clinic implication in most cases where the content of the uterus is expelled physiologically, without intervention.

The accuracy of ultrasound postpartum has been questioned earlier. Neill et al (115) showed limited accuracy when ultrasound findings were not agreeing with clinical assessments of women with secondary PPH. They found high sensitivity (93%) but low specificity (62%) for the presence of an echogenic focus as a sign of retained placental tissue. They did not, however, define the echogenic mass, which makes it difficult to compare their findings with ours. Moreover, Neill and Thornton (21) stated in a review that ultra-sound scans before seven days postpartum are not useful because of blood clots in the uterine cavity. In our report, all six women with secondary PPH before seven days postpartum, had findings of an echogenic mass on 2D ultrasound and five of them had histological confirmation of retained placen-tal tissue. Hoveyda et al (116) found retained placental tissue in only 37% of women undergoing surgical curettage and an ultrasound scan before surgery in around half of these cases did not provide better diagnostic accuracy com-pared to clinical evaluation.

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Studies III and IV Women with previous caesarean section deliveries were found to have an increased risk of retained placenta in a subsequent pregnancy. The risk was most pronounced for retained placenta with heavy bleeding. Women with a previous caesarean section had no increased risk of retained placenta with normal bleeding. Several confounding factors were identified, but the in-creased risk remained after adjustment.

Women with previous caesarean section and placenta praevia had an in-creased risk of PPH and retained placenta. The women with anteriorly-located placentae had an increased risk of PPH but this association was not statistically significant. Five of eight women with placenta praevia were not diagnosed as such, at the routine abdominal ultrasound scan at 18 weeks of gestation.

Many maternal, delivery and infant characteristics influenced the risk of retained placenta (Table 2). Older, taller, smoking women and women who originated from the Nordic countries had a higher risk of retained placenta. In vitro fertilisation and previous miscarriages were other maternal risk fac-tors. We chose to adjust for confounders in two steps, beginning with the maternal characteristics. This had only a minor effect on the OR; crude OR 1.79 to adjusted OR 1.75 (Table 6). When we then adjusted for delivery and infant characteristics, the OR became 1.45. This result is probably explained by premature delivery, which, in itself, increases the risk of retained placenta with an OR of 5.33 (Table 2).

When separating retained placenta with normal and heavy bleeding, it was only the latter that was associated with previous caesarean section. Per-haps these are two different conditions, where the retained placenta with normal bleeding is not caused by an abnormal placentation, but rather a trapped placenta behind a closed cervix (72). In our population-based study, we could not, however, distinguish between different types of retained pla-centa because this is not recorded in the birth register. For the same reason, we excluded cases in our third study; those who delivered by caesarean sec-tion in their second delivery. We assumed that the diagnosis of retained pla-centa (ICD-9 code 666A and 667A and ICD-10 code O720 and O730) would not be registered at caesarean section even though the placenta had to be removed manually. Consequently, no women with placenta praevia were included in our third study, as they were delivered by caesarean section in their second pregnancy. In our fourth study, all medical records were re-viewed, and those delivered by caesarean section where the surgeon reported that the placenta had to be removed manually for being attached to the uter-ine wall, retained placenta was recorded.

Because caesarean section delivery is a risk factor for PPH, we also made a sub-analysis, comparing the risk of PPH in women with anterior placenta and others, in women with vaginal delivery. The trend towards increased risk

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of PPH in those with anterior placentae was, though, the same as that seen for the whole study group.

Results from previous studies, investigating the association between pre-vious caesarean section and retained placenta, are contradictory. Three stud-ies, including 687 cases of retained placenta, did not find an association with previous caesarean section (85, 92, 93). The reason for such results could be that previous caesarean section was not the main and only exposure. More-over, the sample sizes were small, which could have concealed a real differ-ence. On the contrary, Taylor et al (91), who used linked population data-bases including 136,401 women, did find an increased risk of manual re-moval of the placenta (aOR 1.3), which is in line with our results.

If retained placenta with heavy bleeding shares the same mechanism as abnormal invasive placenta, one could assume that the placental location in the uterus matters. The scar from a previous caesarean section only affects the anterior uterine wall, which should lead to an increased risk with the placenta localised anteriorly. Our results do show that women with placenta praevia, attached to the scarred uterine wall, have a significant increased risk for PPH and retained placenta. For women with other anterior placentae, the increased risk was non-significant.

In our cohort, six of the eight (75%) placentae praevia were anterior. Pre-vious studies on women with placenta praevia, regardless of previous cae-sarean section, report on only 30% on the anterior wall (117, 118). This might indicate that a scar in the uterine wall affects the placentation site. In our study, 55.5% of the women had an anterior-located placenta (low ante-rior and anterior praevia included) compared to 44% in a general population (119). On the contrary, a previous study by Naji et al (120) reported an inci-dence of 46.8% anterior-located placentae in women with previous caesar-ean section. They even found more posterior placentae in the previous cae-sarean section group than others and the same amount of low-anterior pla-centae in both groups. A major difference from our study was that they as-sessed placental location with abdominal ultrasound at 11-14 weeks and only the low-lying placentae were examined further in weeks 20 and 34. Migra-tion from low-lying to anterior or posterior location occurred in 62-64%, with no difference between those with previous caesarean section and others. This percentage of placental migration is well in line with our finding (62%) and with the report by Lal et al (119). Lal et al did, however, show a com-plete resolution of placenta praevia in 90% of the women without previous caesarean section, thus favouring the hypothesis on the influence of caesar-ean scar on placental location.

In study IV, we did not find any association between VI and myometrial thickness, and PPH or retained placenta. The hypothesis was that these diag-nostic signs of invasive placentation might also be affected in less severe events such as PPH or retained placenta.

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Myometrial thickness of less than 1 mm, as described by Wong et al (110) in cases of placenta accreta, is probably describing the absence of myometrium caused by placental invasion. Such an invasion was not seen in any of our cases.

VI varied with a range from 2.5 to 63.0% and we could not find an in-creased VI in cases with PPH or retained placenta. We found it more diffi-cult to assess the VI on the posterior uterine wall, because images of the myometrium and placental interface were disturbed by echoes from the foe-tus and the longer distance from the ultrasound probe. Therefore, it is proba-bly preferable to measure VI on anterior placentae only. This was done by Lai et al (121) who studied the perfusion and vascularity in different regions of the third trimester placenta, including only women with anterior placen-tae. They found insufficient reliability and reproducibility of VI as a tool to measure placental perfusion and vascularity; findings well in line with ours.

Strengths and limitations The major strengths of these studies are the prospective, longitudinal de-signs. In studies I, II and IV, all examinations were done by the authors and at one department with the same equipment. All women were examined, treated or delivered at the same department which optimised reliability of the data. The study population in study I was well defined and with very few dropouts. In study II, only women who underwent surgical curettage, where histopathology could confirm the presence of retained placental tissue, were included, making interpretation more correct.

In study III, the large population-based design was a major strength, with all the data on maternal, delivery and infant characteristics available. More-over, the data were prospectively collected, which limited the risk of recall bias. Furthermore, the data collection comprised several confounding fac-tors that could affect the studied association. Another strength was that we separated the outcome as retained placenta with heavy bleeding and retained placenta with normal bleeding, a determination which has not been studied before.

Limitations in studies I, II and IV are the sample sizes, where clinical and practical feasibility downsized the number of women examined. In study IV, a larger sample size may have been able to show an association between anterior located placentae and PPH in women with previous caesarean sec-tion.

One limitation in studies III and IV concerns the definition of PPH or heavy bleeding. It is well known that estimating blood loss is difficult and associated with both over- and under-estimation. This should, however, not affect the results in study III, because the possible misclassification should be non-differential. In study IV, the clinical practice at the department is that

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when PPH is estimated to be more severe than normal, the midwives at the delivery ward are obliged to weigh all tissues with blood, in order to esti-mate the blood loss as exactly as possible. Thus, an estimation of blood loss of 1,000 mL or more is probably correct.

In Sweden, data on termination of pregnancy are not available in the reg-isters. This is a limitation in study III, as previous surgical termination of pregnancy has been found to increase the risk of retained placenta (89). However, a majority of terminations in Sweden are medical and not surgical, and medical terminations have not been found to be associated with retained placenta (90).

Clinical implications Surgical evacuation of the uterus postpartum is associated with risks of in-fection, blood loss and perforation (122), which enhances the need of a cor-rect diagnosis of retained placental tissue, in order to avoid unnecessary in-terventions. Because the volume of the uterus and uterine cavity, measured by 3D ultrasound, only supports but does not verify or rule out the presence of retained placental tissue, this method has limited clinical significance. The most important ultrasound sign is, as previously shown, a hyperechogenic mass in the uterine cavity and should always be used as a complement to clinical evaluation. Because the individual variations of uterine body and cavity volumes are large, especially in the early postpartum period, there is no need for routine ultrasound scans postpartum, as has been suggested (9). Such a policy might lead to an erroneous diagnosis (114).

As retained placenta is associated with maternal morbidity and mortality, the findings of increased risk for women with previous CS need to be con-sidered in the risk assessment of a pregnant woman. An increased risk of retained placenta from 1.96% for women with previous vaginal delivery to 3.44% for women with previous caesarean section might be seen as a minor risk increase. However, as an addition to other risks following previous cae-sarean section it ought to be considered. When counselling women concern-ing preferred mode of delivery, all risks, both immediate and long-term, need to be taken into account. Therefore, it is important to know that a deliv-ery by caesarean section increases the risk for retained placenta with heavy bleeding in a forthcoming pregnancy. It is also important to know, before delivery, if a woman is at increased risk of retained placenta with heavy bleeding, so that proper preparations can be made in order to prevent PPH.

Because reports indicate that the rising caesarean section trend also af-fects parts of the developing world, the risks following caesarean section need to be considered in the low resource context as well. This is particularly stressed by the fact that complications such as PPH and retained placenta

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have a much more severe impact on women who are already suffering from anaemia and a lack of proper health care.

In light of the severity of PPH and abnormal invasive placentae, the ante-natal diagnosis is of utmost importance. Diagnosing placenta praevia before delivery is important and especially in women who have had a previous cae-sarean section. Because not all cases of placenta praevia are diagnosed at the routine 18 weeks ultrasound, it might be advisable that all women with pre-vious caesarean section and low-lying placenta are examined again later in pregnancy, in order to verify or rule out placenta praevia. As an extra pre-cautionary measure, all women with previous caesarean section might bene-fit from additional ultrasound in the third trimester, so as not to risk missing a case of placenta praevia.

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Conclusions

• 3D ultrasound can easily be used to measure the volume of the uterine body and cavity in women throughout the postpartum period.

• The volumes of the uterine body and cavity decrease substantially during the postpartum period, but the individual variations, especially in early postpartum period, are extensive.

• The uterine cavity is always empty two months postpartum.

• Large uterine cavity volumes, measured by 3D ultrasound, support the presence of retained placental tissue. However, 3D ultrasound adds no diagnostic accuracy above 2D ultrasound, as it is still the presence of an intrauterine echogenic mass, revealed by 2D ultrasound, which is most predictive of retained placental tissue.

• Women delivered by caesarean section have a higher risk of retained placenta in subsequent pregnancy, compared to women with previous vaginal delivery. This risk is highest for retained placenta with heavy bleeding.

• Women previously delivered by caesarean section with placenta praevia, have an increased risk of retained placenta and PPH. All women with anteriorly-located placentae might have an increased risk of PPH.

• VI and myometrial thickness is not associated to PPH or retained pla-centa.

• Abdominal ultrasound at 18 weeks of gestation is not sufficient to diag-nose placenta praevia.

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Future studies

The correct diagnosis and best treatment of choice for secondary PPH is not yet agreed upon. 3D ultrasound can confirm the diagnosis demonstrated by 2D ultrasound, but cannot rule out the false positive cases, thus may not prevent unnecessary interventions. Future studies on the management and treatment of secondary PPH should include large samples that probably would need a multicentre approach. Women with suspected retained placen-tal tissue should be randomised to expectancy with uterotonics or surgical curettage. A diagnostic ultrasound with thorough measurements of size, vol-umes and intrauterine content should be performed before intervention. Ad-ditionally, a 3D power Doppler of the uterus could measure the VI and FI, to evaluate the diagnostic value. In cases of surgical curettage, intrauterine content would be sent for histological examination and, in cases of expec-tancy, follow-up ultrasound and clinical assessments should be performed to evaluate the optimum treatment to choose.

More effort ought to be used to identify women antenatally, to determine who is likely to suffer from retained placenta and PPH. Today, most studies focus on antenatal diagnostic of abnormal invasive placentae. However, in our study, two women had major PPH leading to hysterectomy without his-tological confirmation of placenta accreta. Future studies could perhaps find a significant association between placental location and PPH. Other ultra-sound findings might also be associated with PPH and ought to be investi-gated.

Concerning the Swedish population, where mothers are routinely exam-ined by ultrasound only at gestational week 18, a concern must be raised about how accurate the abdominal second trimester ultrasound is in deter-mining placental location. Our study showed that a substantial amount of women were diagnosed differently at week 28. The accuracy of placental location determination at the routine ultrasound scan in Sweden ought to be studied further to evaluate guidelines concerning which women need addi-tional ultrasound scans, and these should be optimised in order to predict PPH.

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Sammanfattning på svenska – Summary in Swedish

Efter förlossningen drar livmodern ihop sig kraftigt för att strypa de blodkärl som tidigare har försörjt moderkakan. Om detta inte sker riskerar kvinnan att förblöda. Veckorna efter förlossningen fortsätter sedan livmodern att dra ihop sig och minska i storlek för att återgå till den storlek den hade före gra-viditeten. Detta tar 6-8 veckor. När kvinnor drabbas av rikliga blödningar mer än 24 timmar efter förlossningen, kallas detta sekundära postpartum-blödningar. Dessa kan bero på infektion eller kvarvarande rester av moder-kakan i livmodern.

För att ställa rätt diagnos vid sekundära postpartumblödningar används idag ultraljud. Det är dock fortfarande oklart för många kliniker hur livmo-dern ska se ut vid olika tidpunkter efter förlossningen och det är då svårt att veta om ultraljudsbilden är normal eller visar tecken på kvarvarande rester av moderkakan.

Andelen kejsarsnitt har ökat avsevärt i världen under de senaste åren. Det-ta för med sig en ökning av komplikationer associerade till kejsarsnitt. Det gäller inte bara de komplikationer som uppstår direkt i samband med kejsar-snittet utan även, och kanske främst, de komplikationer som uppstår i näst-kommande graviditet hos kvinnor som tidigare förlösts med kejsarsnitt. Så-dana komplikationer är bl. a uterusruptur, föreliggande moderkaka (placenta praevia) och onormal inväxt av moderkakan i livmoderväggen (placenta accreta). Man vet också att risken för stor blödning i samband med förloss-ningen ökar. Det som däremot har varit oklart är huruvida risken för kvarva-rande moderkaka som behöver uthämtas manuellt; placentaretention, ökar hos kvinnor som tidigare förlösts med kejsarsnitt.

Teorierna bakom den ökade risken för placenta accreta och stor postpar-tumblödning är att moderkakan fäster djupare in i livmoderväggen pga ärr-vävnaden efter tidigare kejsarsnitt. I så fall borde det ha betydelse var i liv-modern moderkakan sitter; om den sitter på bakväggen eller på framväggen där ärret efter tidigare kejsarsnitt finns.

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Studie I och II Till den första studien rekryterades 50 kvinnor med normala graviditeter, förlossningar och postpartumperioder. De undersöktes med tredimensionellt ultraljud för att mäta volymen av livmodern och livmoderkaviteten på dag 1, 7, 14, 28 och 56 efter förlossningen. Volymerna användes sedan som refe-rens vid bedömning av kvinnor med sekundära postpartumblödningar.

Tjugofem kvinnor som sökte vård p.g.a. sekundära postpartumblödningar och där klinikern tagit beslut om kirurgisk evakuering av livmodern på miss-tanke om kvarvarande placentarester, inkluderades i studie II. De undersök-tes på samma sätt som kvinnorna i studie I och volymerna av livmodern och livmoderkaviteten jämfördes med referensmaterialet. Det som skrapades ut skickades sedan för histologisk undersökning för att säkerställa om kvarva-rande placentarester förelåg eller ej.

Volymen av livmodern och livmoderkaviteten minskade avsevärt men med stora variationer mellan individerna. De individuella skillnaderna mins-kade med tiden. Två månader efter förlossningen var livmodern alltid tom. Kvinnorna med kvarvarande placentarester hade ofta större volym på livmo-derkaviteten än normalmaterialet. Majoriteten av kvinnorna där man med tvådimensionellt ultraljud misstänkt placentarester hade sådana verifierade histologiskt. De fall som inte diagnostiserades med kvarvarande placentares-ter hade också större volymer av kaviteten mätt med tredimensionellt ultra-ljud. Således kunde tredimensionellt ultraljud bekräfta fyndet vid tvådimen-sionellt ultraljud men inte tillföra något i diagnostiken av kvarvarande pla-centarester.

Studie III Syftet med den tredje studien var att ta reda på om kvinnor som tidigare för-lösts med kejsarsnitt har en ökad risk för placentaretention i nästföljande graviditet. Uppgifter om 258 608 kvinnor som fött ett första och andra barn hämtades ur medicinska födelseregistret. 19 458 kvinnor som var förlösta med kejsarsnitt i sin första graviditet jämfördes mot 239 150 kvinnor som tidigare var vaginalförlösta. Utfallet som mättes var placentaretention med stor blödning och placentaretention med normal blödning. Flertalet faktorer som påverkade både risken för kejsarsnitt och risken för placentaretention justerades för.

Kvinnor som tidigare förlösts med kejsarsnitt hade en ökad risk för pla-centaretention (OR 1,45, 95 % CI 1,32–1,59). Den risken var störst för pla-centaretention med stor blödning (OR 1,61, 95 % CI, 1,44–1,79).

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Studie IV Syftet med studie IV var att undersöka om moderkakans läge i livmodern påverkade risken för placentaretention och stor blödning för kvinnor som tidigare förlösts med kejsarsnitt. 400 kvinnor som tidigare förlösts med kej-sarsnitt undersöktes i graviditetsvecka 28 med ultraljud. Moderkakans läge i livmodern samt livmoderväggens tjocklek och blodflödet i livmoderväggen och moderkakan undersöktes. Utfallet var stor blödning och placentareten-tion.

Kvinnor med föreliggande moderkaka, i framväggen över ärret efter tidi-gare kejsarsnitt, hade ökad risk för stor blödning och placentaretention. Det fanns en tendens mot ökad risk för stor blödning hos alla med moderkakan i framväggen men denna skillnad var ej signifikant. Livmoderväggens tjock-lek och blodflödet i livmoderväggen och moderkakan påverkade ej risken för stor blödning eller placentaretention.

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Acknowledgements

Without the support and help from so many, this thesis would not have been written. I especially want to thank: All women who patiently participated in the ultrasound examinations, without them, none of this would have been possible. Ove Axelsson, my main supervisor, who has encouraged me and patiently taught me everything I know about scientific writing. I admire the way you integrate your outstanding clinical understanding in your scientific work. Most of all, I love your excellent, dry humor, with which you have shown me the exciting and bright side of research life. Ajlana-Mulic Lutvica, my supervisor, both in doctorial studies and clinical education. When I needed it the most, your support has been life saving. You have always contributed with the finishing touch that brought our manu-scripts to the next level. You are a role model as a clinician and as a re-searcher. Karin Eurenius, my supervisor and mentor, within my research work as well as clinical work. With your excitement and enthusiasm concerning my work and our studies, you always encouraged me to continue and believe in myself. It is a great privilege to have you as a colleague and friend. Anna-Karin Wikström, my co-author and supervisor in the third paper. I learned so much from writing with you and admire your brilliance as a re-searcher and clinician. All midwives and staff at the fetal medicine unit, who helped me recruit women to participate in the studies. Helena Holmgren, who with enthusiasm and great professional skills, intro-duced me to and helped me with ultrasound techniques and examinations. Fredrik Granström, who with a great portion of patience helped me with the statistics.

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Martin Selinus and all administrative staff at the Department of Wom-en’s and Children’s Health in Uppsala, for kind support and help. All my wonderful friends and colleagues at the Department of Obstet-rics and Gynaecology, for clinical advises, fruitful discussions and an in-spiring working environment. Eva for introducing me to fetal medicine and Christopher for “fika” brakes and concert tickets. Lena and Mariella, my beautiful sisters in arms, for massive support, end-less laughs and talks about life, work, summer schedules and purse shop-ping. Ulf Högberg, professor and head of our obstetric research group for kind support and encouragement. Masoumeh Rezapour, head of our department and Gunilla Hallberg, head of the obstetric division for giving me the time and support for my research. In memory of my mother Kerstin, for endless, unconditional love and love and love. My colleague, mentor, therapist, friend, cooking specialist and winter-hating father Anders, who always has believed in me more than I´ve ever de-served. My big sister Maria, who became my best friend and always has been the second brightest brain I know, for endless support and life-coaching. My little brother Mattias, the brightest brain I know, who with the best sense of humor has shown me different perspectives of life. Esther, Aron and Lilly, my brilliant, beautiful children, my greatest pride, for making me laugh and reminding me on the real important things in life. Yosef, the love of my life, for being my technical advisor, proofreader, IT support and personal shopper, without never, ever complaining about my working hours or occupational addiction. The best I’ve done so far in life would certainly not have been, without you.

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