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eNatural history of caesarean scar pregnancy on prenatal ultrasound:

the cross-over sign

Giuseppe Cali1, Francesco Forlani1, Ilan Timor-Trisch2, Jose Palacios-Jaraquemada3, Gabriella Minneci1, Francesco D’Antonio4

1: Department of Obstetrics and Gynaecology, Arnas Civico Hospital, Palermo, Italy

2: Department of Obstetrics and Gynaecology, Division of Maternal-Fetal Medicine, New York University SOM, New York, NY, USA

3: Centre for Medical Education and Clinical Research (CEMIC), University Hospital, Buenos Aires, Argentina

4: Department of Clinical Medicine, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway

Corresponding Author: Francesco D’Antonio, MD, PhD, Women's Health and Perinatology Research Group Department of Obstetrics and Gynaecology Department of Clinical Medicine Faculty of Health Sciences, UiT - The Arctic University of Norway Hansine Hansens veg 18 9019 Tromsø, Norway francesco.dantonio@uit.no

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This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/uog.16216

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eABSTRACT

Objective: Advances in prenatal imaging techniques have led to an increase in the diagnosis of

caesareans scar pregnancy (CSP). However, antenatal counselling when CSP is diagnosed is

challenging and the current evidence mainly derived from small series reporting high rates of

adverse maternal outcomes. The aim of this study was to ascertain the performance of prenatal

ultrasound in anticipating the natural history of CSP introducing a new sonographic sign, the cross-

over sign (COS).

Methods: Retrospective analysis of early first trimester (6-8 weeks of gestation) ultrasound images

of women with morbidly adherent placenta (MAP) treated in the third trimester of pregnancy. We

tested the hypothesis the relationship between the gestational sac of the CSP, anterior uterine wall

and previous caesarean scar (COS insertion) can be used to predict the evolution of these cases. The

odd ratios (OR) and logistic regression analysis were carried out in order to ascertain the association

between different types of COS insertion and the occurrence of MAP.

Results: Sixty-eight pregnancies were included in the study. The risk of placenta percreta was

significantly higher in pregnancies with COS1 compared to COS2 insertion (OR: 6.67, 95% CI 1.3-

33.3; p= 0.001); There was a significant difference in the occurrence of placenta percreta between

COS1 and COS 2+ (10/12 vs 18/39, p= 0.04), with an OR of 5.83, 95% CI 1.1-30.2 (p=0.036);

furthermore, this risk was even higher when comparing cases with COS1 with COS2- (OR: 12.0,

95% CI 1.9-75.7; p= 0.003). Women with COS2- had a lower risk of developing placenta percreta

compared to those with COS1 (OR: 0.069, 95% CI 0.01-0.4). Logistic regression analysis showed

that COS1 insertion was independently associated with the occurrence of severe forms of MAP

such as placenta percreta and increta (OR: 12.85, 95% CI 2.0-84.0), while COS2+ insertion was

associated independently associated with the occurrence of placenta accreta (OR: 4.37, 95% CI 1.1-

17.0).

Conclusion: Ultrasound assessment of the relationship between the ectopic gestational sac and the

endometrial line (COS insertion) may anticipate the natural history of CSP. CSP may theoretically

progress towards less severe forms of MAP amenable of post-natal treatment and successful

pregnancy outcome. Large prospective studies are needed in order to confirm these finding and to

elucidate the natural history of this disease.

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eINTRODUCTION

Morbidly adherent placenta (MAP) encompasses a spectrum of conditions characterized by an

abnormal adherence of the placenta to the implantation site. MAP is one of the major cause of

maternal mortality and morbidity worldwide and is associated with the occurrence of several major

complications such as severe maternal hemorrhage, need for blood transfusion, peri-partum

hysterectomy, damage to adjacent organs and post-operative complications1.

Placenta previa and previous uterine surgery represent the main risk factors for the occurrence of

this condition and the incidence of MAP has been shown to rise in the last decade most likely as the

consequence of the increase in caesarean section rate2-4.

Despite this, the underlying mechanisms leading to MAP are not well understood yet. A defective

development of the decidua basalis allowing the invasion of the myometrium by the trophoblastic

tissue constitutes the pathophysiological explanation for the occurrence of invasive placentation2-4.

Recent evidences pose peculiar attention on caesarean scar pregnancy (CSP) as the precursor of

MAP. CSP5-8. Timor-Tritsch et al evaluated the natural history of CSP in 10 cases diagnosed before

10 weeks of gestation, whose parents opted to continue pregnancy. All cases had sonographic signs

suggestive of MAP in the second trimester and all underwent hysterectomy at the time of CD.

Histopathological diagnoses confirmed placenta percreta in all 10 cases6.

Advances in prenatal imaging technique has led to an increase in the diagnosis of CSP7-9. However,

antenatal counselling once CSP is diagnosed is challenging10-12. The association between CPS and

MAP poses the prognostic dilemma of how women with a prenatal diagnosis of CPS should be

counselled and whether termination of pregnancy should be the only therapeutic option offered to

these women. Although evolution towards early severe haemorrhage or uterine rupture may seem

the most likely scenario, the reported association with MAP raises doubts about the proportion of

CSP progressing to viability and how to identify those cases amenable of post-natal treatment and

successful pregnancy outcome.

The aim of this study was to ascertain the performance of prenatal ultrasound in predicting the

natural history of CSP introducing a new sonographic sign, the cross-over sign (COS).

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eMETHODS

This is a retrospective case series of all women referred to our centre for the ultrasound suspicion of

MAP, from January 2007 to December 2015. These women were identified from an electronic

database of the fetal medicine unit. The delivery details were retrieved from hospital maternity

records. Operative notes were checked for details of operative findings and interventions performed.

All cases underwent pathology examination to confirm the presence and the degree of placental

invasion.

Early first trimester ultrasound images from 6 to 8 weeks of gestations were retrieved from the

computerized databases of each referring hospital. All the stored images showed the gestational sac

or trophoblast within the previous caesarean section scar and thus were labelled as CSP13. Other

ultrasound criteria used to confirm the diagnosis were:

• Visualization of an empty uterine cavity as well as an empty endocervical canal.

• A closed and empty cervical canal.

• The presence of embryonic/fetal pole and/or yolk sac with or without heart activity.

• The presence of a prominent and at times rich vascular pattern at or in the area of a scar in

the

We tested the hypothesis the relationship between the gestational sac of the CSP, previous

caesarean scar and the anterior uterine wall can be used to predict the evolution of these cases. In

order to do this, we propose a new sonographic sign, the cross-over sign (COS).

Briefly, in a sagittal view of the uterus, a straight longitudinal line was drawn connecting the

internal cervical os and the uterine fundus trough the endometrium (endometrial line) (Figure 1).

Then the gestational sac was identified and its superior-inferior (S-I) diameter perpendicular to the

endometrial line traced. According to the relationship between the endometrial line and the S-I

diameter of the ectopic sac, we divided the patients into two different groups:

1. COS1 insertion: when the gestational sac was implanted within the previous CS and ≥ two

thirds of the S-I diameter of the gestational sac was above the endometrial line towards the

anterior uterine wall (Figures 1,2)

2. COS2 insertion: when the gestational sac was implanted within the previous CS and < two

thirds of the S-I diameter of the gestational sac was above the endometrial line. Furthermore,

these cases were divided into two different categories according to the presence (COS2+) or

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enot (COS2-) of an intersection between the S-I diameter of the ectopic sac and the

endometrial line (Figure 1,2).

Two examiners, blinded to pregnancy outcome and pathology reports, analysed all the images

independently and labelled them according to their COS insertion.

Furthermore, COS was ascertained in stored pictures from 38 consecutive patients referred to our

centre with a prenatal diagnosis of CSP ended in abortion or termination of pregnancy.

Final diagnosis of the type of MAP was made after surgery and hysterectomy on the basis of the

pathological examination of the removed uterus. Placenta accreta when diagnosed when anchoring

placental villi were attached to myometrium rather than decidua, but without completely invading

it.

Placenta increta when diagnosed when chorionic villi penetrate into the myometrium, while

placenta percreta when chorionic villi penetrate through the myometrium to the uterine serosa or

adjacent organs)14.

Study groups were compared using Student’s t-test for normally distributed continuous variables or

the Mann–Whitney U-test for non-normally distributed continuous variables, and the chi-square or

Fisher’s exact test (for expected cell size less than five) for dichotomous variables. The odd ratios

(OR) and 95% CI for the occurrence of MAP in each group were calculated. Furthermore, logistic

regression analysis was carried out in order to look for maternal, pregnancy or ultrasound

characteristics, including the type of COS insertion, independently associated with the occurrence

of different types of MAP.

The statistical analysis was performed using Stat Direct (StatsDirect statistical software,

http://www.statsdirect.com; England: StatsDirect Ltd. 2013) and SPSS version 15.0 (SPSS Inc.,

Chicago, IL, USA). Statistical significance was set at p<0.05. All p values were two-tailed.

STROBE guidelines were followed15.

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eRESULTS

During the study period, 102 women with a prenatal diagnosis of MAP confirmed at

histopathological examination were referred to our center. Early first trimester ultrasound images

were retrieved from the local computerized databases in 68 cases.

At histopathological analysis, 34 cases were diagnosed as placenta percreta, 13 increta and 21

accreta.

General characteristics of the women included in the study are reported in Table. The two groups

did not show any significantly difference as regard for maternal age, parity and number of previous

cesarean section. Gestational age at birth was significantly higher in COS2 and this was due to the

higher number of placenta percreta cases in COS1 group. There was full agreement in the labelling

of all CPS images as regard for the type of COS sign between the two researchers.

The proportion of cases with placenta percreta was significantly higher in COS1 compared to COS2

group (83.3% vs 42.9%; p= 0.002); all pregnancies with COS1 implantation resulted in severe

forms of MAP, such as placenta increta or percreta, while there was no case of placenta accreta in

this group.

COS2 cases were then subdivided into two different categories on the basis of the intersection (39)

or no intersection (17) with the endometrial line (Figures 1,2). The risk of placenta percreta was

significantly higher in pregnancies with COS1 compared to COS2 insertion (OR: 6.67, 95% CI 1.3-

33.3; p= 0.001); furthermore, there was a significant difference in the occurrence of placenta

percreta between COS1 and COS 2+ (10/12 vs 18/39, p= 0.04), with an OR of 5.83, 95% CI 1.1-

30.2 (p=0.036). Finally, the risk of placenta percreta was even higher when comparing cases with

COS1 with COS2- (OR: 12.0, 95% CI 1.9-75.7; p= 0.003). COS2- cases had significantly more

cases of less severe forms of MAP (placenta accreta) compared to COS2+ (64.71% vs 28.21%; p=

0.017) and had a significantly lower risk of developing placenta percreta compared to those with

COS1 (OR: 0.069, 95% CI 0.01-0.4). Logistic regression analysis showed that COS1 insertion was

independently associated with the occurrence of severe forms of MAP such as placenta percreta and

increta (OR: 12.85, 95% CI 2.0-84.0), while COS2+ insertion was independently associated with

the occurrence of placenta accreta (OR: 4.37, 95% CI 1.1-17.0).

Ultrasound images of 38 cases of CSP referred to our centre in the same time period and which

underwent termination of pregnancy were evaluated for the presence of COS; assessment of this

ultrasound sign was possible in all cases; 79.0% (95% CI 62.7-90.4; 30/38) showed COS1 and

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e21.1% (95% CI 9.6-37.3; 8/68) COS2+, while there was no case of COS2- in this sub-group of

patients.

DISCUSSION

The findings from this study showed that the assessment of the relationships between the ectopic

gestational sac, previous caesarean scar and anterior uterine wall (COS insertion) may represent a

reliable tool able to stratify the obstetric risk of women with a first trimester diagnosis of CSP. The

risk of placenta percreta was significantly higher in pregnancy with COS1 compared to COS 2+

(OR: 5.83, 95% CI 1.1-30.2). Furthermore, women with COS2- insertion had a significantly lower

risk of developing placenta percreta compared to those with COS1 (OR: 0.069, 95% CI 0.01-0.4).

Finally, COS1 insertion was an independent risk factor for placenta percreta.

Antenatal counselling of women with a prenatal diagnosis of CSP is challenging, especially in

asymptomatic cases. The current evidence is sparse and mainly derived from small retrospective

series including only highly symptomatic patients which report high rates of adverse maternal

outcomes such as profuse bleeding, uterine rupture and need for hysterectomy16. This has led in turn

to the common practice of offering termination of pregnancy to all this women10-12.

Evaluation of gestational sac implantation using COS criteria is a simple a reproducible tool to

ascertain the relationship between the ectopic sac, caesarean scar and anterior uterine wall. In the

present series, all cases with COS1 implantation ended in severe variants of MAP such as placenta

percreta or increta, while there was no case of placenta accreta in this group. It might be speculated

that COS1 implantation represents the most severe variant of CSP characterized by the implantation

of the ectopic sac within the previous caesarean scar and close to the anterior uterine wall, thus

potentially resulting in higher risk of bladder or parametrial invasion, massive haemorrhage and

intra-surgical complications.

The findings from this study highlight the fact that the relationship between the previous caesarean

scar and the ectopic gestational sac are not the only determinants in predicting the natural history of

CSP; the distance between the upper pole of the ectopic sac and the anterior uterine wall may

determine whether CSP will evolve towards anterior invasion eventually ending in acute symptoms

before viability or less severe form amenable of elective post-natal treatment.

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eThe majority of MAP included in the present study showed COS2+ implantation at first trimester

ultrasound; furthermore, when looking at the ultrasound images of the 38 cases with CPS which

ended in termination of pregnancy, there was no case of COS2- implantation. COS2- implantation

may represent the milder variant of CPS which does not completely fit the classical proposed

ultrasound criteria for CSP; in this scenario, the implantation of the upper pole of ectopic

gestational sac relatively away from the uterine wall might result in a lower risk of further placental

invasion, with a reduced risk of developing severe types of MAP. Furthermore, the peculiar

insertion of COS2- cases relatively away from the anterior uterine wall, might contribute to the high

rates of false negative diagnoses during the early first trimester of pregnancy. At the time of the 11-

14 weeks’ scan, the relative migration of the uterine sac towards the uterine cavity, would make this

sub-type of CSP difficult to differentiate from a normal intra-uterine pregnancy. On the other hand,

insertion of the ectopic sac in close proximity to the anterior uterine wall, such as in case of COS1

and COS2+, would make CPS easier to diagnosis.

It might be speculated that the high rates of adverse maternal outcomes reported in women with

CSP, would be the results of COS1 implantation, which is relatively easy to diagnose, while most of

the COS2- cases will be missed at the scan, thus potentially leading to over-estimate the burden of

co-morbidities associated with this anomaly.

In the present series, a significant proportion of CSPs with COS2 implantation ended in milder

forms of MAP such as placenta accreta; furthermore, although the majority of CPS cases terminated

during the first trimester had COS1 implantation, almost one third (28%) had COS2+ insertion.

These findings raise doubts about whether women with CSP showing the implantation of the

ectopic sac away from the anterior uterine wall (COS2) should be offered termination of

pregnancies as the only available therapeutic option. It might be speculated that at least a small

proportion of these cases may progress towards milder forms of MAP which can be successfully

identified and treated. This concept should be mentioned during parental counselling, pointing out,

on the other hand, that the most likely evolution of CSP is towards severe invasion eventually

ending in acute life-threatening symptoms requiring immediate surgical intervention.

The small number of included cases, retrospective design of the study are the main limitations of

this study. Another limitation was the lack of information about the evolution of CPS cases

diagnosed in the first trimester which ended in termination of pregnancy.

Large multicentre studies prospectively looking at women with previous caesarean section from the

early first trimester onwards are needed in order to quantify the actual incidence and the evolution

of CSP in order to more appropriately counsel patients with a prenatal diagnosis of this anomaly.

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eREFERENCES

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in management. Ultrasound Obstet Gynecol 2004; 23: 247-253.

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12. Timor-Tritsch IE, Cali G, Monteagudo A, Khatib N, Berg RE, Forlani F, Avizova E. Foley

balloon catheter to prevent or manage bleeding during treatment for cervical and Cesarean scar

pregnancy. Ultrasound Obstet Gynecol 2015; 46: 118-123.

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e13. Timor-Tritsch IE, Monteagudo A, Santos R, Tsymbal T, Pineda G, Arslan AA. The diagnosis,

treatment, and follow-up of cesarean scar pregnancy. Am J Obstet Gynecol 2012; 207: 44.e1-13.

14. Benirschke K, Kaufmann P, Baergen RN. Pathology of the human placenta. 5th ed. New York:

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pregnancy. Ultrasound Obstet Gynecol 2015; 46: 118-123.

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eTable 1: general characteristics of the population analysed in the study.

Characteristics Overall population (n=68) COS 1 (n=12) COS 2 (n=56) p-value Maternal age 34.32±4.24 34.50±3.32 34.29±4.44 0.877 GA at delivery 34.6±2.06 31.86±2.37 35.18±1.43 0.0001 Parity 2 (1-3) 3 2 (2-3) 0.629 Previous CS 2 (1-2) 2 2 (1-2) 0.826 Histopathology

Placenta accreta Placenta increta Placenta percreta

33 13 34

0 (0)

2 (16.7) 10 (83.3)

21 (37.5) 11 (19.6) 24 (42.9)

0.012

1 0.02

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eFIGURE LEGEND

Normal COS1

COS2-COS2+

a) b)

c) d)

Figure 1 (a-d). Diagrammatic representation showing the relationships between ectopic gestational

sac, previous CS and anterior uterine wall (COS insertion). In a sagittal view of the uterus, a straight

longitudinal line is drawn connecting the internal cervical os and the uterine fundus trough the

endometrium (endometrial line) (yellow line). Then the gestational sac is identified and its S-I

diameter perpendicular to the endometrial line traced. According to the relationship between the

endometrial line and the S-I diameter of the ectopic sac, patients can be divided into two different

groups: normal pregnancy (a), the gestational sac implant away from the CS, in close proximity to

the uterine fundus; COS1 insertion (b), gestational sac is implanted within the previous CS and ≥

two thirds of the S-I diameter of the gestational sac was above the endometrial line towards the

anterior uterine wall; COS2+ insertion (c), gestational sac is implanted within the previous CS and

< two thirds of the S-I diameter of the gestational sac is above the endometrial line; COS2- insertion

(d), gestational sac is implanted within the previous CS, < two thirds of the S-I diameter of the

gestational sac is above the endometrial line but there is no intersection between the S-I diameter of

the ectopic sac and the endometrial line.

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eCS

B

GS

EL

E

A Ut W

Ut F

CSO12a

C

2b CSO2+ CSO2-2c

A Ut WC

EL

Ut F

CS

GS CS

Ut F

EL

GS

CA Ut W

Figure 2 (a-c). Ultrasound images showing the different types of COS insertion (A. Ut. W: anterior

uterine wall; B: bladder; C: cervix, CS: caesarean scar; E: endometrium; EL: endometrial line; GS:

gestational sac; S-I d: superior-inferior diameter; Ut. F: uterine fundus).

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