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ORIGINAL ARTICLE: EARLY PREGNANCY

Cesarean scar pregnancy: a


systematic review of
treatment studies
Kathrine Birch Petersen, Ph.D.,a Elise Hoffmann, M.D.,b Christian Rifbjerg Larsen, M.D., Ph.D.,c
and Henriette Svarre Nielsen, M.D., D.M.Sci.a
a
Fertility Clinic 4071, Copenhagen University Hospital, Rigshospitalet, Copenhagen; b Department of Obstetrics and
Gynaecology, Copenhagen University Hospital, Roskilde Sygehus, Roskilde; and c Centre for Minimal Invasive and
Robotic Surgery Research, Departments of Gynecology, General Surgery, and Urology, Copenhagen University Hospital,
Herlev Hospital, Herlev, Denmark

Objective: To study treatment modalities for cesarean scar pregnancies (CSPs), focusing on efcacy and complications in relation to
study quality.
Design: Systematic review.
Setting: Not applicable.
Patient(s): A total of 2,037 women with CSP.
Intervention(s): Review of MEDLINE, EMBASE, and Cochrane Library to nd studies including ve or more women. Data were ex-
tracted on primary treatment modality/efcacy, complications, and future fertility. The level of evidence was categorized according
to Oxford Centre for Evidence-based Medicine guidelines. Quality was assessed using The Cochrane Collaboration's Risk of Bias
Tools for Randomized Controlled Trials and the modied Delphi techniques for case series. Meta-analysis was impossible owing to
multifarious treatments.
Main Outcome Measure(s): Successful rst-line treatment. Complications were hysterectomy, laparotomy, bleeding >1,000 mL, or
blood transfusion.
Result(s): Fifty-two studies were included: four randomized, controlled trials and 48 case series. Fifteen of the 52 analyzed studies were
scored as high quality. Treatment modalities were condensed to 14 different approaches. Combining study quality, level of evidence,
efcacy, and safety, ve approaches for treating CSP are recommended, depending on availability, severity of patient symptoms,
and surgical skills: [1] resection through a transvaginal approach, [2] laparoscopy, [3] uterine artery embolization in combination
with dilatation and curettage and hysteroscopy, [4] uterine artery embolization in combination with dilatation and curettage, and
[5] hysteroscopy.
Conclusion(s): This review recommends treatment options for CSP in clinical practice, based on efcacy and safety. The literature sup-
ports an interventional rather than medical approach. Present recommendations are primarily based on case series. Multicenter, well-
designed studies are needed to draw denite conclusions on how to treat CSP. (Fertil Steril
2016;-:--. 2016 by American Society for Reproductive Medicine.) Use your smartphone
Key Words: Cesarean scar pregnancy, early pregnancy complications, ectopic pregnancy, to scan this QR code
hysteroscopy methotrexate and connect to the
discussion forum for
this article now.*
Discuss: You can discuss this article with its authors and with other ASRM members at http://
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T
he frequency of cesarean section Brazil in front with a rate of 46% (3). In placenta accreta/percreta, postpartum
(CS) is increasing worldwide recent years there has been augmented hysterectomy, and ectopic pregnancy
(1, 2) (Supplemental Table 1, focus on the complications seen in in a cesarean scar (cesarean scar
available online). In 2008, 15 countries subsequent pregnancies, of which the pregnancy [CSP]) (4, 5). Cesarean scar
worldwide had CS rates over 30%, with more serious include uterine rupture, pregnancy is characterized by an
empty uterus and cervical canal, a
Received October 5, 2015; revised November 30, 2015; accepted December 22, 2015.
gestational sac (GS) located in the
K.B.P. has nothing to disclose. E.H. has nothing to disclose. C.R.L. has nothing to disclose. H.S.N. has anterior uterine wall with diminished
nothing to disclose. myometrium between the sac and the
Reprint requests: Kathrine Birch Petersen, Ph.D., Fertility Clinic 4071, Copenhagen University Hospital,
Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen , Denmark (E-mail: kbirch@dadlnet.dk). bladder, and a discontinuity in the
anterior wall of the uterus adjacent to
Fertility and Sterility Vol. -, No. -, - 2016 0015-0282/$36.00
Copyright 2016 American Society for Reproductive Medicine, Published by Elsevier Inc.
the GS (6). Cesarean scar pregnancy
http://dx.doi.org/10.1016/j.fertnstert.2015.12.130 can cause severe maternal morbidity

VOL. - NO. - / - 2016 1


ORIGINAL ARTICLE: EARLY PREGNANCY

and mortality (7, 8). Cesarean scar pregnancy was rst CSP; [2] exclusion of background and review articles; [3]
described in 1978, and until 2001 only 19 cases were reported primary/rst-line treatment and if necessary secondary treat-
(9). Since then the frequency of reported cases has ment sufciently described; and [4] treatment success and
dramatically increased (10). It was recently estimated that 1 in complications sufciently described.
531 women with a cesarean scar will have a CSP and that We chose an arbitrary threshold of ve women in criteria
4.2% of ectopic pregnancies are CSP (11). During the last two 1 to reduce heterogeneity in extremely small reports and sin-
decades ultrasonography and diagnostics have improved (12 gle cases. The study designs were divided in accordance with
14), and the techniques for uterine surgery have changed (8, the Oxford Center for Evidence-based Medicine (19). All four
11). Today the uterus is often closed in one layer, compared authors extracted data regarding study design, efcacy, and
with the previous two-layer technique (15, 16). All factors complication rates in the 52 selected studies (Table 1 and
may play a role in the increasing prevalence of CSP (10, 14). Supplemental Table 2), and we divided treatment modalities
Today, more than 30 CSP treatment regimens have been into 14 categories (Table 2).
published, and the majority of recommendations are based on
case series rather than randomized controlled trials (RCTs). Study Outcomes
This systematic review aimed to collect and condense
published literature on CSP treatment. It is based on a The success rate (as a percentage) was dened as the efcacy
predened protocol and reports according to the PRISMA of rst-line treatment. Major complications were dened as
(Preferred Reporting Items for Systematic Reviews and Meta- hysterectomy and/or hemorrhage R1,000 mL and/or blood
Analyses) and MOOSE (Meta-analysis Of Observational Studies transfusion (Table 1 and Supplemental Table 2).
in Epidemiology) guidelines (17, 18). We present the largest
number of CSP cases to date and evaluate the evidence level Study Quality Assessment
and study quality of eligible studies to address and All authors assessed selected articles for the level of evidence
recommend future treatment modalities. The lack of high- according to study design, on the basis of Oxford Centre for
level evidence encouraged us to develop a one-page registration Evidence-based Medicine guidelines (19). Methodologic qual-
chart for CPS cases to be included in local and national guide- ity, including risk of bias in individual studies, was assessed in
lines to increase awareness, support coherent evaluation, and as accordance with The Cochrane Collaboration's Risk of Bias
an optimal basis for future treatment trials. Tools for RCTs and a modied Delphi technique for case series
We aimed to investigate and dene the most efcient and (2022).
safe treatment for women with CSP. Randomized, controlled trials (2326) were assessed in
relation to random sequence generation, allocation
MATERIALS AND METHODS concealment, blinding of participants and personnel,
blinding of outcome assessment, incomplete outcome
Sources
data, selective reporting, and other bias such as selection
We searched MEDLINE, EMBASE, and the Cochrane Library bias.
for relevant articles from inception until June 2015 using Case studies (6, 2774) were evaluated with regard to
the following search string combining MeSH key words: ((ce- assessment of exposure, valid and reliable diagnostic
sarean scar pregnancy OR (cesarean scar AND ectopic preg- procedures in relation to outcome of interest, and sufcient
nancy) OR cesarean scar ectopic pregnancy OR (cesarean selection of cases.
scar complications AND pregnancy) OR (previous cesarean
scar AND pregnancy))) OR (cesarean scar pregnancy OR (ce-
Clinical Chart for CSP
sarean scar AND ectopic pregnancy) OR cesarean scar ectopic
pregnancy OR (cesarean scar complications AND pregnancy) The selected studies were also used to develop a clinical one-
OR (previous cesarean scar AND pregnancy)). Additional re- page chart for symptoms, treatment, and outcomes, to stan-
cords were identied by reference lists in retrieved articles. dardize the reporting with the aim of structured comparison
The search was primarily performed by K.B.P., E.H., and and assessment in future studies (Supplemental Appendix 1,
H.S.N., in collaboration with librarian Sussi Andersen. The available online).
retrieved articles were compared and discussed in plenum,
and a dedicated EndNote database (version X7; Thomson Statistics
Reuters) was established. Frequency statistics were calculated by Microsoft Ofce Excel
2010 (version 2.13.2).
Study Selection
Eligible articles were published in peer-reviewed journals and Description of CSP Treatments
written in English. Duplicates, articles in languages other than Medical treatment by systemic methotrexate. Systemic
English, and articles in which title and abstract did not report methotrexate (MTX) for CSP (single-dose 50 mg administered
on CSP treatment were excluded (PRISMA chart; Fig. 1). Full- IM) is used in hemodynamically stable patients without pain,
text articles were screened (n 198). Final inclusion or exclu- with a gestation age <8 weeks, myometrium thickness
sion decisions were made after examination according to the <2 mm between the pregnancy and the bladder, serum hCG
following criteria: [1] studies with ve or more women with <5,000 IU/L, GS %2.5 cm, and/or a fetus without heart action

2 VOL. - NO. - / - 2016


Fertility and Sterility

FIGURE 1

PRISMA Flow Diagram: Cesarean Scar Pregnancies

Idenficaon

Records idenfied through Addional records idenfied


database searching through other sources
(Cochrane+ Embase+Pubmed) (n = 17)

Records aer duplicates were removed


(n = 1492)
Screening

Records excluded on basis


Records screened of tle and abstract: Did
(n=1492) not report on CSP
treatment, no English text
available, methodological
or diagnosc manuscripts
(n=1294)
Full-text arcles assessed
for eligibility
Eligibility

Case reports of < 5 cases


(n=198) Review
No informaon on
treatment regimen,
success or complicaon
Studies included in rates
qualitave synthesis Double publicaons
(n=52) (n=146)
Included

Meta-analysis
is not possible

A PRISMA ow chart of the 52 included studies.


Birch Petersen. Treating cesarean scar pregnancy. Fertil Steril 2016.

(23, 36). If the serum hCG does not decrease sufciently dilatation and curettage (D&C) can be performed blind or as-
additional MTX may be administered (26). Citrovorum sisted by a perioperative transabdominal/transrectal ultra-
rescue can be considered. sound scan under general anesthesia (63).
Medical treatment by systemic and local MTX. Local injec- Hysteroscopy. The procedure can be used for CSP with pro-
tion of MTX (up to 50 mg) can be performed transabdominally gression toward the uterine cavity or the bladder. The gesta-
or transvaginally (40). A 2022-G needle is used; both proce- tional sac is dissected free of the uterine wall through a
dures are performed under local analgesia. Local injection of natural entrance, and hemostasis can be achieved with
MTX results in a higher MTX concentration at the CSP and a electro-coagulation using a wire-loop or roller-ball. Hyster-
more rapid termination of the pregnancy (42). oscopy is a minimally invasive technique and is conducted
Treatment by needle aspiration and local MTX. General under direct observation or abdominal ultrasound (51). A
anesthesia is usually considered in relation to this procedure balloon catheter can be placed postoperatively for compres-
owing to needle size (16-G double-canal IVF needle). The sion hemostasis and wound surface drainage (39).
gestational sac is aspirated transvaginally by ultrasound Resection of CSP through a transvaginal approach. The
guidance (38). bladder is dissected away through an incision in the anterior
Uterine curettage. A curette is inserted into the uterus cervico-vaginal junction, and the CSP is identied in the
through the dilated cervix. The curette is used to scrape the anterior part of the lower uterine segment. The ectopic preg-
lining of the uterus and remove the pregnancy tissue. Uterine nancy tissue is removed through a transverse incision, and

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ORIGINAL ARTICLE: EARLY PREGNANCY

TABLE 1

Included RCTs.
Severe
Author, year Study Inclusion Gestational Success complication
(reference) type period n (FHR) Primary treatment age (wk) rate Complications rate (%)
Peng et al., RCT 20082013 104 Systemic MTX (50 mg/ 8.0  3.2 35/52 UAE D&C (n 17) 5.8
2015 (23) (FHR n/a) m2) Laparotomy due to
(n 52) bleeding (n 3)
Local MTX (50 mg/m2) 7.9 2.9 36/52 UAE D&C (n 16) 1.9
(n 52) Laparotomy due to
bleeding (n 1)
Zhuang et al., RCT 20032007 72 UAE D&C (n 37) 7.3  0.2 35/37 Iodoform meche (n 1) 0
2009 (24) (FHR n/a) Readmitted due to
bleeding (n 2)
Systemic MTX 7.4  0.4 33/35 Iodoform meche (n 4) 5.7
(50 mg/m2) Hysterectomy (n 2)
D&C (n 35)
Qian et al., RCT 20082013 66 UAE D&C (n 33) 7.31.1 33/33 None 0
2015 (25) (FHR 37) UAE D&C 7.41.6 30/33 Hysterectomy (n 1) 3
hysteroscopy (n 33)

Li C et al., RCT 20022009 44 Systemic MTX (50 mg/ 9.7  2.5 10/13 Hysterectomy (n 3) 54
2011 (26) (FHR 2) m2) Severe bleeding 500
D&C (n 13) 1,500 mL (n 4)
UAE with MTX (40 mg) 9.8  7.25 13/15 Bleeding <110 mL 0
and gelatin sponge (n 2)
D&C (n 15) UAE (n 3)
UAE with MTX (40 mg) 10.3  1.8 16/16 None 0
and polyvinyl alcohol
D&C (n 16)
Note: Success rate: No additional treatment needed. Severe complications: hysterectomy, laparotomy, bleeding >1,000 ml or blood transfusions. (1): Based on Oxford Centre for Evidence based
medicine guidelines. (2): Quality was assessed using The Cochrane Collaboration's Risk of Bias Tools for RCTs and the modied Delphi techniques for case series. FHR fetal heart rate; GW
gestational weeks; TAS transabdominal sonography; TVS transvaginal sonography.
Birch Petersen. Treating cesarean scar pregnancy. Fertil Steril 2016.

suction curettage through the incision on the uterus can be oscopic D&C (44, 68). The initial procedure is performed under
performed. Finally, the myometrial and vaginal defects are re- conscious sedation. A transducer produces the therapeutic
paired (56). energy required. Real-time ultrasound is used to target the
Uterine artery embolization. Interventional radiologists area of the GS and monitor the response. Additional D&C is
perform the procedure under local anesthesia. Catheterization performed in general anesthesia.
of the uterine arteries is carried out through a transfemoral
approach. If embolization is combined with a dose of MTX RESULTS
it is split between the two uterine arteries and infused via Fifty-two studies out of 1,492 initially identied met our pre-
the arterial catheter (69). Finally, both uterine arteries are em- dened criteria to be included in this systematic review, of
bolized with gelatin sponge particles (0.51.0 mm in diam- which 4 were RCTs and 48 case series and with a total of
eter). Subsequently, postembolization angiography can be 2,037 women diagnosed with CSP (Fig. 1, PRISMA ow
performed to validate the obstruction of the arteries. Gelatin chart). Accordingly, the vast majority of the studies had a
sponge plugs can be replaced with polyvinyl alcohol (26). low level of evidence (4). Chinese publications comprised
Laparoscopy. This procedure is performed under general 77% of the seven contributing countries. Details and assess-
anesthesia and has been used in CSP with progression toward ments of the included studies are described in Table 1 and
the bladder. The bladder is dissected free of the front of the Supplemental Table 2. Success and complication rates are
uterus, and excision is performed of the uterine scar that con- listed in Table 2. Contribution by country is listed in
tains the ectopic pregnancy, with subsequent repair of the Supplemental Table 3.
defect in the uterus (39). A Frey catheter can be used for intra-
uterine drainage (39). To avoid heavy perioperative bleeding, Treatment Modality 1: Expectant Management
bilateral ligation of the uterine arteries may be performed (71). This treatment modality was described in ve case series with
High-intensity focused ultrasound. The procedure can be 41 women (42, 47, 53, 55, 73). The efcacy was low (41.5%),
performed with ablation alone or in combination with hyster- and the complication rate was high (53.7%). The quality of the

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Fertility and Sterility

TABLE 1

Continued.
Author Country
Fertility (menstruation, Author's comments and Conclusion of the Level of quality of Journal title,
pregnancy, birth) concerns present study evidence (1) assessment (2) origin impact factor
No follow-up Well-designed study, Systemic and local MTX 1b M China Therapeutics and
but relevant outcome injections are equally Clinical Risk
data are missing. No effective. Management,
follow-up. 1.5

No follow-up Randomization via sealed UAE followed by suction 1b M China American Journal of
envelopes and a curettage seems to Obstetrics and
table. No blinding of have more advantage Gynecology, 4.0
patients and health than systemic MTX
care providers. No treatment and may
follow-up. be a priority option.
UAE/D&C: Three Computerized No signicant difference 1b H China Archives of
pregnancies randomization. Well between the two Gynecology and
(two CS at 38 GW, conducted study. treatment regimens. Obstetrics, 1.4
one ongoing)
UAE/D&C/HYST: Four
pregnancies (CS at 37
and 38 GW, one
ongoing, one
recurrent CSP)
No follow-up Randomization via an Arterial 1b L China International
open table. No chemoembolization Journal of
blinding of patients with MTX was more Gynecology and
and health care effective than Obstetrics, 1.6
providers. No follow- systemic MTX
up treatment for
termination of CSP.

Birch Petersen. Treating cesarean scar pregnancy. Fertil Steril 2016.

studies was assessed as medium and high (Table 2 and the quality was assessed as primarily medium. Dilatation
Supplemental Table 2). and curettage as treatment modality for CSP is
characterized by a high complication rate of 21%, and
Treatment Modality 2: Systemic MTX additional treatment was needed in 52% of the cases.
This is the second most elaborated modality, reported for 339
women in 3 RCTs and 18 case series (23, 24, 26, 29, 31, 33, 36,
Treatment Modality 5: Hysteroscopy
4042, 47, 48, 50, 51, 53, 54, 60, 65, 70, 71, 75). Additional
treatment was necessary in one-fourth of the cases, and se- Hysteroscopy was described as primary treatment in 95
vere complications were seen in 13%. The design the quality women reported in seven case series (29, 33, 39, 51, 52, 64,
of the RCTs was only medium to low, primarily owing to sub- 76). Only 3.2% experienced major complications, but 17%
optimal randomization and blinding procedures (Table 1). needed additional treatment. The 11 women included in the
Le et al. study (52) all received preoperative systemic MTX.
Treatment Modality 3: Needle Aspiration and MTX
This modality was described in six studies of 148 women (32, 38, Treatment Modality 6: Resection of CSP through a
40, 53, 54, 74); 71 women were from one study of medium Transvaginal Approach
quality (38). Major complications were present in 13.5%, and
additional treatment was required in 15.5% (Table 2). This modality is a novel approach and was recently reported
as primary treatment in 118 women in six studies (6, 30, 34,
52, 56, 58), of which 63% were high-quality cases. Twelve
Treatment Modality 4: Uterine Curettage (D&C) women had MTX preoperatively in one study (30). The
This treatment modality was described in 21 studies with a to- complication rate was very low (0.9%); only one woman
tal of 243 women (29, 31, 33, 4143, 4547, 49, 51, 53, 55, had a hysterectomy, and none of the remaining 117 women
5961, 63, 66, 69, 71, 75). All studies were case series, and required additional treatment.

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ORIGINAL ARTICLE: EARLY PREGNANCY


TABLE 2

Treatment modalities.
Severe
Success complication Hysterectomy Bleeding >1,000 mL Laparotomy H M L H M L
Treatment modality Cases (n) rate (%) rate (%) (n) or blood transfusion (n) (n) studies studies studies cases cases cases
Expectant managementa 41 41.5 53.7 17 5 0 2 3 0 20 21 0
Systemic medical 339 75.2 13.0 10 25 9 2 14 5 20 240 79
treatment MTXb
Needle aspiration 148 84.5 13.5 9 9 2 2 2 2 16 82 50
MTX/KClc
Uterine curettage (D&C)d 243 48.1 21.0 11 37 3 5 13 3 49 160 34
Hysteroscopye 95 83.2 3.2 1 0 2 1 5 1 39 39 17
Resection of CSP through 118 99.2 0.9 1 0 0 3 3 0 74 44 0
transvaginal approachf
Selective UAE without MTXg 295 93.6 3.4 6 4 0 1 6 0 33 262 0
UAE D&CHysteroscopyh 85 95.4 1.2 1 0 0 2 0 0 85 0 0
UAE MTXi 427 68.6 2.8 2 8 2 4 7 3 251 99 77
Local systemic MTXj 34 76.5 2.3 1 0 0 0 2 0 0 34 0
Laparoscopyk 69 97.1 0 0 0 0 2 5 0 33 36 0
Local MTXl 74 64.9 4.1 0 0 3 0 3 0 0 74 0
Repeated high-intensity 16 100 0 0 0 0 1 0 0 16 0 0
focused ultrasound
ablationm
High-intensity focused 53 100 0 0 0 0 1 0 0 53 0 0
ultrasound
hysteroscopic suction
curettagen
Total 2,037 59 88 21 26 63 14 689 1,091 257
Note: Success rate: no additional treatment needed. Severe complications: hysterectomy, laparotomy, bleeding >1,000 mL or blood transfusions. Quality assessed by The Cochrane Collaboration's Risk of Bias Tools for RCTs and the modied Delphi techniques for case
series. H high quality; L low quality; M medium quality.
a
References (42, 47, 53, 55, and 73).
b
References (23, 24, 26, 29, 31, 33, 36, 4042, 47, 48, 50, 51, 53, 54, 60, 65, 70, 71, and 75).
c
References (32, 38, 40, 53, 54, and 74).
d
References (29, 31, 33, 4143, 4547, 49, 51, 53, 55, 5961, 63, 66, 69, 71, and 75).
e
References (29, 33, 39, 51, 52, 64, and 76).
f
References (6, 30, 34, 52, 56, and 58).
g
References (24, 25, 33, 36, 37, 42, and 46).
h
References (25 and 43).
i
References (26, 28, 33, 35, 41, 45, 46, 48, 49, 52, 54, 57, 66, and 69).
j
References (29 and 42).
k
References (31, 39, 47, 52, 53, 62, and 71).
VOL. - NO. - / - 2016

l
References (23, 59, and 67).
m
Reference (68).
n
Reference (44).
Birch Petersen. Treating cesarean scar pregnancy. Fertil Steril 2016.
Fertility and Sterility

Treatment Modality 7: Uterine Artery Treatment Modality 13: Repeated High-intensity


Embolization in Combination with D&C, without Focused Ultrasound Ablation
MTX This novel treatment modality was only described in one
Uterine artery embolization (UAE) combined with D&C was high-quality case series of 16 women (68). None of the women
reported in 295 women distributed in two RCTs and ve required additional treatment or reported severe
case series (24, 25, 33, 36, 37, 42, 46). The RCT by Qian complications.
et al. (25) was rated high quality (n 33), and the
remaining studies medium quality. Overall this treatment
Treatment Modality 14: Repeated High-intensity
modality was efcient in relation to additional treatment
Focused Ultrasound D Hysteroscopic Suction
needed (only 6.4%) and severe complications (3.4%, six
hysterectomies and four bleeding episodes). Curettage
Similarly, this novel modality was described in another high-
quality case series of 53 women (44), with a success rate of
Treatment Modality 8: UAE D D&C D 100% and no complications.
Hysteroscopy
Although only described in one recent RCT (n 33) and one DISCUSSION
case series (n 52) (25, 43), both studies were of high quality. The consequences of the increasing prevalence of CSs in terms
Furthermore, the modality has a high success rate of 95.4% of CSP are escalating. Half of the reported CSP cases have
and a very low complication rate of 1.2% (one hysterectomy). been published within the last year, primarily from China.
This bias in contribution by country is most likely explained
by the high frequency of CS rates (two to four million per
Treatment Modality 9: UAE in Combination D&C, year) (3, 77). Combined with the large-scale tertiary hospitals
with MTX in China, this induces the possibility to perform RCTs and
cohort studies. Cesarean scar pregnancy is still a rare diag-
This was the most numerous treatment modality described, in
nosis, and the available literature regarding CSP is mostly
14 studies with a total of 427 women (one RCT and 13 case
observational or casuistic, with an unclear denition of the
series) (26, 28, 33, 35, 41, 45, 46, 48, 49, 52, 54, 57, 66, 69).
recruited populations. Treatment of CSP should be evidence
The majority of the cases were high quality (58.8%). All
based and focus on prevention of severe complications and
women received D&C in relation to the procedure, but
conservation of fertility. This review is the rst to collect,
additional treatment was needed in 31.4 % because of
condense, evaluate, and recommend treatment options for
treatment failure. Eight women experienced bleeding
CSP to clinical practice using existing guidelines and vali-
exceeding 1,000 mL, two required laparotomy, and two a
dated assessment tools for the reporting of systematic reviews
hysterectomy (2.8%).
(2022). We have performed an extensive literature search
and present the largest number of CSP cases to date. It was
not possible to perform meta-analysis on the available data
Treatment Modality 10: Local and Systemic MTX owing to the large proportion of different treatments. The
Two case series (29, 42) described this treatment modality, treatment recommendations were based on quality assess-
primarily in the study by Timor-Tritsch et al. including 33 ment of the 52 studies which, despite validated tools, can be
women of 34 in total. The quality assessment of this study subjectively biased by the interpretation of the authors. A
was medium. Almost one-fourth of the women required addi- recent article from Timor-Tritsch and Monteagudo (78) iden-
tional treatment, and the complication rate was 2.3% (one tied 31 different primary treatment options in 751 women
hysterectomy). with CSP, whereas we chose to condense and simplify the
treatment modalities into 14 approaches. This implies a risk
of missing a possibly valid procedure. That the majority of
Treatment Modality 11: Laparoscopy included studies are case reports is the main limitation of
the conclusions. Furthermore, only few of the studies
Seven case series of 69 women described laparoscopy as rst-
described the localization of the CSP (i.e., endogenous
line treatment (31, 39, 47, 52, 53, 62, 71). Two studies were
[growth toward the uterine cavity] or exogenous [growth to-
assessed as high quality (n 33) and the remaining ve as
ward the myometrium and uterine serosal layer], the latter be-
medium (n 36). The success rate was very high (97.1%),
ing more prone to cause uterine rupture and severe
and there were no reported severe complications.
hemorrhage [79]). We found no consensus on treatment strat-
egy in relation to CSP type or thickness of the myometrium
between the bladder and gestational sac. Early detection by
Treatment Modality 12: Local MTX ultrasonography or MRI to determine the localization of the
One RCT and two case series (23, 59, 67) assessed as medium CSP is essential when deciding on the optimal approach.
quality comprised a total of 74 women describing primary We recommend ve treatment modalities. The following
treatment with local MTX. The success rate was one of the reect these limitations in relation to each of the ve sug-
lowest (64.9%), with a complication rate of 4.1%. gested treatments. A similar discussion is available in the

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ORIGINAL ARTICLE: EARLY PREGNANCY

supplemental le on the treatments not recommended increasing accessibility. No major complications occurred,
(Supplemental Appendix 2). although additional treatment was required in 17%. The
Resection of CSP through a transvaginal approach is a quality of the studies varied substantially. The 2014 study
promising novel and efcient treatment with a low complica- by Wang G et al. (39) was of high quality, despite the fact
tion rate. It is only reported in case series, which enhances the the patients chose their own treatment in relation to risk
risk of selection bias. The 23 women described by Wang et al. and costs. The patient selection and subsequent clustering
(6) apparently chose their own treatment, and the type of in- in the study from Yang et al. (51) with 23 women was
formation was not described, which furthermore enhances the inhomogeneous and not comparable. Because of the diverse
risk of bias. A major limitation of this modality is the depen- quality of the studies and the low number of patients, the
dence on specic surgical skills, which calls for centralization full potential of hysteroscopy is not fully explored at the
and could make the procedure less accessible. Equally does present.
the severity of the diagnosis CSP support centralized and Repeated high-intensity focused ultrasound is a prom-
highly specialized treatment. Again, well-designed and ising novel approach, but the published literature on the sub-
adequately powered studies are needed to draw a nal ject is still too insufcient for further recommendations. The
conclusion. remaining eight treatment modalities cannot be recommen-
Laparoscopy as an image-guided minimal invasive tech- ded on the basis of the combined approach of study outcome
nique is superior to laparotomy owing to the low risk of with evaluation of study quality and level of evidence. Further
bleeding. Using laparoscopy, the bladder is dissected free in details are listed in Supplemental Appendix 2. In general,
front of the uterus, and excision is performed of the CSP medical compared with surgical treatments have disadvan-
with subsequent repair of the defect in the uterus. Hence, tages in terms of slow resolution, persisting risk of uterine
the procedure is preferable in CSPs with progression toward rupture and hemorrhage, need for additional treatment, and
the uterine serosal surface, thus this modality could be the uncertainty for the women (59).
treatment of choice in selected cases initially assessed by ul- In conclusion, cesarean scar pregnancy is an increasing
trasound. However, similar concerns apply for laparoscopy as challenge worldwide. The most safe and efcient clinical
for the transvaginal approach with regard to the need of approach to CSP is yet to be determined, but ve approaches
specialized surgical skills. depending on availability, severity of patient symptoms, and
Uterine artery embolization plus D&C and hysteroscopy surgical skills are recommended. The literature supports an
as a treatment modality has only been described in two interventional rather than medical approach.
studies of 85 women, which may impair the validity of the re- We suggest a prospective, multicenter RCT aiming to
sults. Yet the two studies have been published within the last evaluate and compare minimally invasive surgery with UAE
year, and the quality of the RCT and the case series was high. and medical treatment with MTX. The study should involve
Furthermore, subsequent pregnancies in the follow-up period organizations conducting high-quality studies of these un-
were thoroughly described, in contrast to the majority of pub- common disorders on a regional, national, and international
lications on CSP. Dilatation and curettage as well as hysteros- basis, with the objective of improving the quality of care for
copy are usually easily accessible, but UAE requires an women. To facilitate this, we developed a one-page registra-
interventional radiologist, which may limit the availability tion chart to optimize future treatment trials. We are con-
of the treatment. cerned that recommendations for treatment and
Uterine artery embolization combined with D&C without management of CSP would otherwise continue to be based
MTX has a low risk of heavy bleeding and hysterectomy. A on case reports and cohort studies with a limited number of
recent review by Timor-Tritsch and Monteagudo (78) reported patients and varying validity.
relatively higher rates of less-severe complications: fever,
mild pains from the abdomen or the pelvisoverall a compli- Acknowledgments: The authors thank research librarian
cation rate of 46.9%. In our review only 5% of the patients Sussi Andersen for her assistance in relation to the search
required additional treatment such as repeated UAE, hysteros- string and literature search.
copy, or laparotomy. Although UAE combined with D&C is
found to have signicantly better results compared with sys-
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