The Diagnosis, Treatment, And Follow-up of Cesarean Scar Pregnancy

Research www.AJOG.org

OBSTETRICS

The diagnosis, treatment, and follow-upof cesarean scar pregnancyIlan E. Timor-Tritsch, MD; Ana Monteagudo, MD; Rosalba Santos, RDMS;Tanya Tsymbal, RDMS; Grace Pineda, RDMS; Alan A. Arslan, MD

OBJECTIVE: The diagnosis and treatment of cesarean scar pregnancy(CSP) is challenging. The objective of this study was to evaluate the di-agnostic method, treatments, and long-term follow-up of CSP.

STUDY DESIGN: This is a retrospective case series of 26 patients be-tween 6-14 postmenstrual weeks suspected to have CSP who were re-ferred for diagnosis and treatment. The diagnosis was confirmed withtransvaginal ultrasound. In 19 of the 26 patients the gestational sac wasinjected with 50 mg of methotrexate: 25 mg into the area of the embryo/fetus and 25 mg into the placental area; and an additional 25 mg wasadministered intramuscularly. Serial serum human chorionic gonado-tropin determinations were obtained. Gestational sac volumes and vas-cularization were assessed by 3-dimensional ultrasound and used to
monitor resolution of the injected site and outcome.
2012;207:44.e1-13.

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44.e1 American Journal of Obstetrics & Gynecology JULY 2012

RESULTS: The 19 treated pregnancies were followed for 24-177 days.No complications were observed. After the treatment, typically, therewas an initial increase in the human chorionic gonadotropin serum con-centrations as well as in the volume of the gestational sac and their vas-cularization. After a variable time period mentioned elsewhere the val-ues decreased, as expected.

CONCLUSION: Combined intramuscular and intragestational metho-trexate injection treatment was successful in treating these CSP.

Key words: accreta, cesarean section, cesarean section scarpregnancy, ectopic pregnancy, methotrexate, minimally invasive
procedure, placenta, pregnancy, punctures, ultrasound
Cite this article as: Timor-Tritsch IE, Monteagudo A, Santos R, et al. The diagnosis, treatment, and follow-up of cesarean scar pregnancy. Am J Obstet Gynecol

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S ince 1996, the cesarean delivery(CD) rate in the United States has

increased by approximately 40%, and in2007, the rate was 31.8%.1 This is largelyattributed to a rise in primary CD (from

From the Department of Obstetrics andGynecology, NYU School of Medicine, NewYork, NY.

Received December 16, 2011; revised March16, 2012; accepted April 9, 2012.

The authors report no conflict of interest.

Reprints: Ilan E. Timor-Tritsch, MD,Department of Obstetrics and Gynecology,NYU School of Medicine, 550 First Ave., NBV-9N1, New York, NY [email protected].

0002-9378/free© 2012 Mosby, Inc. All rights reserved.http://dx.doi.org/10.1016/j.ajog.2012.04.018

For Editors’ Commentary, seeContents

See related article, page 14

VIDEOClick Supplementary Content underthe title of this article in theonline Table of Contents

12.6-20.6%) and a decline in vaginal de-liveries after CD (28-9.2%).1,2 The rate

f repeat CD is now about 91%.2 Thetrend toward an increasing rate of CDhas been reported in other countries.3,4

A previous CD increases the risk for apathologically adherent placenta (ac-creta, increta, and percreta) and themagnitude of risk increases with each ad-ditional CD. Similar risks were reportedfor cesarean scar pregnancy (CSP).3,5-11

A particular complication of a preg-nancy after CD is the implantation of thegestational sac in the hysterotomy scar,known as a “cesarean scar pregnancy”(CSP).10 This condition is referred to us-ng several terms including “cesarean ec-opic pregnancy” or simply “cesareancar ectopic.”3,12-30 Some other terms in-

clude the word “ectopic.” The term “ce-sarean delivery scar pregnancy” has alsobeen used.31,32 Since the majority of re-

orts use “cesarean scar pregnancy,”CSP)10,11,32-57 we will use this term in

the article. CSP are not ectopic gestationsby definition (even though no official

has been agreed t

upon) since the bulk of the gestation in-cluding the placenta are in the niche or inthe scar facing the uterine cavity and arepart of it.

The incidence of CSP has been esti-mated to range from 1/1800 –1/2500 ofall CD performed.3,42,43,58 The diagnosisis often difficult, and a false-negativediagnosis may result in major compli-cations, including a hysterectomy. Thediagnosis is based on finding a gesta-tional sac at the site of the previous CDin the presence of an empty uterinecavity and cervix, as well as a thin myo-metrium adjacent to the bladder. Dif-ferent diagnostic, radiological imagingmethods, and management options havebeen proposed. However, the optimalmanagement remains to be determined. Ifthe patient presents with a uterine ruptureor major bleeding, surgery is unavoidable.Management of diagnosed but stable pa-tients represent a challenge (the reader isreferred to a recent review for details).4 Inhis article, we describe the use of intrages-ational sac injection of methotrexateMTX) as a simple and effective office-ased treatment. The follow-up of the pa-
ients is described.
mailto:[email protected]

http://dx.doi.org/10.1016/j.ajog.2012.04.018

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www.AJOG.org Obstetrics Research

MATERIALS AND METHODS

This is a retrospective case series of 26patients between 6-14 weeks postmen-strual age referred to NYU LangoneMedical Center over a period of 3 years(2009 through 2011 and evaluated in2011) with diagnosed or suspected CSP.The diagnosis, treatment, and follow-upof all patients were performed in the ul-trasound facility without anesthesia.Twenty-two of the 26 patients had de-monstrable fetal heart activity at the timeof ultrasound examination in our insti-tution. One patient was referred after shehad undergone elective termination of a7-week pregnancy. However, we subse-quently diagnosed that the pregnancyhad not been located within the uterinecavity and was located in the hysterot-omy scar. One patient was referred be-cause of an arteriovenous (A-V) malfor-mation in the scar of a CD. Two patientspresented with CSP with embryos/fe-tuses without heart activity. Two pa-tients were referred for a second opinion.Twelve women had been treated withvarious doses (25-50 mg) of intramuscu-lar MTX prior to referral to our institu-tion. Since MTX was not effective incausing cessation of fetal heart activity inthese patients they were referred for ad-ditional treatment.

In the presence of a positive pregnancytest, a CSP was diagnosed by transvaginalultrasound using the following criteria:1. Visualization of an empty uterine

cavity as well as an empty endocervi-cal canal (Figure 1, A and B).

2. Detection of the placenta and/or agestational sac embedded in the hys-terotomy scar (Figure 1, C).

3. In early gestations (�8 weeks), a tri-angular gestational sac that fills theniche of the scar (Figure 1, D); at �8postmenstrual weeks this shape maybecome rounded or even oval.

. A thin (1-3 mm) or absent myome-trial layer between the gestational sacand the bladder (Figure 1, C).

. A closed and empty cervical canal.

. The presence of embryonic/fetal poleand/or yolk sac with or without heartactivity.

. The presence of a prominent and at
times rich vascular pattern at or in the r
area of a CD scar in the presence of apositive pregnancy test (Figure 1,E-G).

All these criteria had to be present todiagnose CSP. Some of the above criteriawere derived from the literature (items 1,4, and 5)59,60 or generated and modified

y our group (items 2, 3, 6, and 7).Sonographic diagnosis and a baseline

erum human chorionic gonadotropinhCG) concentration were determined.n addition, 3-dimensional (3D) ultra-ound data sets using a 4- to 8-MHzransvaginal probe (Voluson 730; Gen-ral Electric Medical Systems, Milwau-ee, WI) were obtained. Volume of thehorionic sac site and power Doppleras used serially after the injection ofTX and compared to baseline infor-ation obtained before the local injec-

ion of MTX. Power Doppler settingsere 0.9 kHz pulse repetition frequency

nd 200 MHz filter (standardized for allxaminations). Chorionic sac volumend vascularization were analyzed of-ine using a software system (4DView;eneral Electric Medical Systems). Thelacenta/gestational sac complex vol-me (mL) was calculated using the man-al segmentation procedure (Virtual Or-an Computer-aided Analysis [VOCAL]DView; General Electric Medical Sys-ems) (Figure 2, A). The outer boundar-es of the segmentation, or in otherords the perimeter of the gestational

ac, were followed to define the sac size.his area/volume also included the vas-ular “ring.” Six rotational steps (60 de-rees apart) were used to define sac vol-me. The sensitivity for defining theascularization index (VI) was men-ioned above. The VI was calculated us-ng the same software (Figure 2, B). TheI is the number of color flow– contain-

ng voxels divided by the total number ofoxels contained within the volume ex-ressed as a percent value (Figure 2, C).he mean VI for patients undergoingysterectomies was compared to thoseho were not treated by hysterectomy.onographic examinations were re-eated for 3 weeks at weekly intervals atrst, and subsequently, bimonthly, until

he site of the sac was barely visible andhe VI declined (usually �3%). We also
equired that the area of the gestational
JULY 2012 Ameri

ac site did not show any more coloroppler signals with a pulse repetition

requency as low as 0.3 kHz.Patients were counseled about the

isks of the condition and managementlternatives, including potential benefitsnd risks (known and unknown). Theeed to adhere to a follow-up period waspecified. Patients signed a written in-ormed consent for treatment.

If interventional treatment was rec-mmended as an option, this consistedf a real-time, transvaginal ultrasound-uided puncture and MTX injection intohe chorionic sac. An automated, spring-oaded device (Labotect Co, Göttingen,ermany) was attached to the transvag-

nal transducer (SL400; Siemens, Erlan-en, Germany). The procedure repre-ented a slight modification of theuncture injection approach previouslyeported by the authors.61-64 We used

a 20-gauge needle. Under ultrasoundguidance, the area of the embryonic/fetalheart was identified for the placement ofthe tip of the needle.

After confirming the placement of theneedle, 25 mg of MTX in 1 mL of solu-tion was injected slowly. The intragesta-tional sac dose administered was 25 mg,and an additional 25 mg was injectedoutside the gestational sac as the needlewas withdrawn, preferably the placentalsite if that area was in the needle tract.

The patient underwent another sono-graphic examination 60-90 minutes afterthe procedure to confirm cessation of fe-tal heart activity and to identify localbleeding. The patient also received anadditional intramuscular injection of 25mg MTX (for a total, combined dose of75 mg) before discharge from our unit.Patients were asked to return in 24-48hours for a follow-up scan. As for thenumber of CD before the CSP, of the 26patients, 15 had 1, 9 had 2, and 2 had3 CD.

One patient had 2 chorionic sacs (twingestation) in the scar, but only 1 gesta-tional sac had detectable embryonicheart activity (an intragestational sac in-jection was performed in the sac withcardiac activity) since the other sac didnot contain viable embryo. One patient
had 3 consecutive CSP. All 3 were treated
can Journal of Obstetrics & Gynecology 44.e2

Research Obstetrics www.AJOG.org

FIGURE 1Transvaginal sonographic criteria for diagnosis of cesarean scar pregnancy

A B

C

E

F G

D

A, Empty uterine cavity with gestational sac (arrow) between cavity and cervix (Cx). B, Power Doppler of blood vessels surrounding gestational sac. C,Gestational sac embedded in scar. Thin (1-3 mm) or lack of myometrium (arrow) between sac and bladder. D, Triangular shape of sac (on sagittal plane)assuming shape of niche. E-G, Prominent, richly vascular area in site of previous cesarean delivery scar highlighted by power Doppler in patient presentingwith bleeding and positive serum human chorionic gonadotropin test. Arrows point to vascular malformation.Timor-Tritsch. Diagnosis and treatment of cesarean scar pregnancy. Am J Obstet Gynecol 2012.

44.e3 American Journal of Obstetrics & Gynecology JULY 2012

owTadipr

fts

hobTwiianww

t


according to the same protocol andcounted as 3 separate cases.

The protocol for follow-up includedevaluation of the outcome: (1) a weeklyserum hCG determination for 3 consec-utive weeks, and 1 determination bi-monthly until this hormone was unde-tectable; and (2) determination of thegestational sac volume and the area vas-cularization at the above intervals usingthe previously described techniques. Pa-tients were asked not to have vaginalintercourse until the resolution of theCSP. This was judged by sonographicexamination.

Analysis of the data was as follows: val-ues of the serum hCG, sac volume, and

FIGURE 2Evaluation of volume and vascular

A

B

Evaluation used 3-dimensional (3D) transvaginaSystems, Milwaukee, WI). A, 3D segmentation ofrendering of vascularization around gestational saunits (voxels) over outlined grayscale units.Timor-Tritsch. Diagnosis and treatment of cesarean scar preg

VI were tabulated for each patient enter- p

ing them into an Excel spreadsheet (Mi-crosoft, Redmond, WA) on the day theywere obtained. These values were used togenerate graphic representation, as afunction of the days following treatment.

RESULTSClinical details of the patients are sum-marized in Table 1. Of the 26 patients, 2

f them (patients 4 and 15 in Table 1)ere referred to us for a second opinion.hey each had 1 prior CD and presentedt 9 and 14 weeks, respectively. After theiagnosis of CSP (Figure 3) and counsel-

ng, both patients opted to continue theirregnancies (after being informed of theisk of a possible placenta accreta). Both

pply of cesarean scar pregnancy

trasound with Virtual Organ Computer-aided Anperimeter drawn around outer boundaries of co, 3D angiographic measurement of vascularizat

cy. Am J Obstet Gynecol 2012.

atients had uterine rupture with pro- a

JULY 2012 Ameri

use bleeding at 15 and 17 weeks, respec-ively, requiring massive blood transfu-ions and hysterectomies.

Patient 10 in Table 1 was scheduled toave intragestational sac MTX injectionf a CSP at 6 weeks and 1 day, but slightlyled prior to the scheduled procedure.he patient was treated by tamponadeith a 5-mL balloon catheter inserted

nto the cervix and inflated until bleed-ng ceased. The next morning, there wasbsence of detectable fetal heart rate, ando additional treatment was given. Sixeeks later, involution of the scar siteas noted.On the day of referral, 2 patients (pa-

ients 23 and 24 in Table 1) had detect-

C

sis (VOCAL) software (General Electric Medicalring resulting in sac volume. B, 3D angiographicndex representing percent blood flow containing

su

l ul alysac lorc. C ion i

nan

ble embryonic/fetal cardiac activity and


pregn


were scheduled for treatment, but thefollowing day (when the procedure wasscheduled), fetal cardiac activity hadceased. No treatment was administered.Patient 23 received intramuscular MTXprior to referral, while for patient 24, thefetal cardiac activity ceased without MTX

TABLE 1Cesarean scar pregnancies with anintragestational MTX injections

Patient GA, wks

Pretreatment

hCG, mIU/mL Sac v

With MTX...................................................................................................................

1 7 2/7 46,300 14.1..........................................................................................................

2 10 3/7 101,000 119.9..........................................................................................................

3 6 1/7 37,200 10.6..........................................................................................................

5 7 0/7 2640 6.6..........................................................................................................

6 8 1/7 100,010 44.9..........................................................................................................

7 7 3/7 7600 8.3..........................................................................................................

8 8 2/7 2950 21.1..........................................................................................................

11 7 0/7 43,341 11.4..........................................................................................................

12 6 1/7 13,076 3.6..........................................................................................................

13 6 6/7 1976 28.7..........................................................................................................

14 6 2/7 8518 2.9..........................................................................................................

16 8 0/7 2717 14.3..........................................................................................................

17 6 2/7 5469 4.1..........................................................................................................

18 6 2/7 4673 17.0..........................................................................................................

19 6 4/7 2870 1.3..........................................................................................................

20 6 1/7 1340 2.1..........................................................................................................

21 7 2/7 2100 3.1..........................................................................................................

22 7 6/7 12,657 1.7..........................................................................................................

25 5 6/7 8550 3.2

...................................................................................................................

Without MTX..........................................................................................................

4 9 1/7 Unavailable 59.9..........................................................................................................

9 7 6/7 55 53.6

..........................................................................................................

10 6 0/7 59 2.6..........................................................................................................

15 14 0/7 Unavailable 35.0..........................................................................................................

23 6 0/7 6081 3.1..........................................................................................................

24 6 4/7 8868 4.0..........................................................................................................

26 Unavailable 0 —...................................................................................................................

A-V, arteriovenous; FHR, fetal heart rate; GA, gestational age;VI, vascularization index.

Timor-Tritsch. Diagnosis and treatment of cesarean scar

administration. These patients were fol-

44.e5 American Journal of Obstetrics & Gynecolog

lowed up according to the protocol de-scribed above.

Patient 9 in Table 1 had a complexclinical course. This 33-year-old patienthad 6 pregnancies, 4 deliveries, and 1abortion, and presented to the emer-gency room with vaginal bleeding 67

without

Days to resolution

Tme, mL VI, % hCG Sac volume VI

.........................................................................................................................

7.3 88 133 133 L.........................................................................................................................

25.5 63 150 150 L.........................................................................................................................

34.6 125 125 L.........................................................................................................................

24.5 68 57 57 L.........................................................................................................................

27.5 64 177 177 L.........................................................................................................................

37.1 95 140 140 L.........................................................................................................................

6.4 63 93 93 L.........................................................................................................................

12.2 35 44 44 L.........................................................................................................................

23.1 98 133 133 L.........................................................................................................................

24.1 89 110 110 L.........................................................................................................................

4.5 60 60 60 L.........................................................................................................................

9.3 24 76 72 L.........................................................................................................................

7.9 33 109 109 L.........................................................................................................................

43.0 63 22 63 L.........................................................................................................................

4.7 61 62 48 L.........................................................................................................................

6.1 63 63 63 L.........................................................................................................................

16.4 41 41 41 L.........................................................................................................................

15.2 54 61 61 L.........................................................................................................................

3.9 26 26 26 L

.........................................................................................................................

.........................................................................................................................

39.7 — — — D.........................................................................................................................

71 — — — U

.........................................................................................................................

7.8 39 39 39 B.........................................................................................................................

48.5 — — — D.........................................................................................................................

4.1 58 65 65 N.........................................................................................................................

4.0 42 42 42 N.........................................................................................................................

65.0 — — — E.........................................................................................................................

human chorionic gonadotropin; L, local; MTX, methotrexate; S, sy

ancy. Am J Obstet Gynecol 2012.

days after an attempted elective termina-

y JULY 2012

tion of pregnancy at 7 weeks of gestationat another institution (the pathology re-port described the presence of chorionicvilli). The patient had 2 previous CD and2 normal vaginal deliveries at term. Atpresentation, the serum hCG was 55mIU/mL, and sonographic examination

tment Observations

..................................................................................................................

MTX..................................................................................................................

MTX..................................................................................................................

MTX..................................................................................................................

MTX..................................................................................................................

MTX..................................................................................................................

MTX..................................................................................................................

MTX..................................................................................................................

MTX..................................................................................................................

MTX..................................................................................................................

MTX..................................................................................................................

MTX..................................................................................................................

MTX..................................................................................................................

MTX..................................................................................................................

MTX..................................................................................................................

MTX..................................................................................................................

MTX..................................................................................................................

MTX..................................................................................................................

MTX..................................................................................................................

MTX Clots from cavityaspirated on d 26

..................................................................................................................

..................................................................................................................

lined Bled at 15 wk, TAH..................................................................................................................

mbolization A-V malformation; TAH(Table 2)

..................................................................................................................

d: balloon catheter Resolved..................................................................................................................

lined Rupture at 18 wk, TAH..................................................................................................................

HR Resolved..................................................................................................................

HR Resolved..................................................................................................................

olization A-V malformation..................................................................................................................

ic; TAH, total abdominal hysterectomy; UA, uterine artery;

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at our center revealed an empty uterine

w


cavity, a clearly imaged hysterotomy scarniche (Figure 4, A), and a richly vascu-larized anterior uterine wall (which wasdouble in thickness compared to theposterior wall) (Figure 4, B). We consid-ered that the images were consistent withthe diagnosis of placenta accreta or per-creta that was left untouched during thetermination procedure. The pregnancywas in close proximity to the hysterot-omy scar. We managed this condition byadministering intramuscular MTX (80mg) on day 81 after her initial dilatationand curettage (D&C) on the first day un-der our care. This injection was admin-istered with the suspicion that the pa-tient may have had residual gestationaltrophoblastic disease. On follow-up thehCG serum concentration became non-detectable 2 weeks (on the 100th day)from the time of the initial surgical inter-vention. The VI and placental volumeshowed a decrease in magnitude on the105th day. However, the patient devel-oped severe vaginal bleeding. A hysterec-tomy and uterine artery embolizationwere offered, but declined by the patient.A repeat sonographic examination dem-onstrated an increase in the VI. The ultra-

FIGURE 3Two untreated CSPs with subseque

A

A, 3-Dimensional power Doppler angiogram at 9eeks of patient 15 in Table 1.

CSP, cesarean scar pregnancy cases.

Timor-Tritsch. Diagnosis and treatment of cesarean scar preg

sound image was suspicious for the pres-

ence of an A-V malformation (Video Clips1 and 2). Vaginal bleeding persisted, andon the 155th day bilateral uterine arteryembolization was performed. Vaginalbleeding decreased, but there was persis-tence of the prominent vessel in the loweranterior uterine wall (Figure 4, C). Thepeak systolic velocity within the vascularstructure was 45.3 cm/s, consistent with anA-V vascular malformation (Figure 4, D).Five days later, the patient underwent ahysterectomy with an uneventful recovery.The sequence of events is illustrated inTable 2.

Patient 26 in Table 1 was referred to usfor vaginal bleeding and a positive preg-nancy test. On transvaginal ultrasoundan A-V malformation was seen at the siteof her previous CD scar (Figure 1, E-G).This patient did not have any surgical in-tervention for this pregnancy and waspromptly treated by emergency uterineartery embolization to stop the bleeding.Two other patients had no demonstrableembryonic/fetal cardiac activity on theday of their scheduled MTX injectionthus were not treated at all.

In only 1 patient (patient 3 in Table 1)was the CSP the result of in vitro fertil-

uterine rupture and hysterectomy

B

eks of patient 4 in Table 1. B, 2-Dimensional c


ization and transfer of 2 embryos. Nine-

JULY 2012 Ameri

teen patients (6-9 weeks of gestation)underwent successful local injection of50 mg of MTX and all showed evidenceof embryonic/fetal cardiac activity. Onepatient had 3 prior CD. Typically, pa-tients had prolonged, intermittent vagi-nal spotting for 2-3 weeks following theprocedure. During the follow-up period,most women resumed menses beforeresolution of the gestational sac volumeand vascularization. No side effects wereseen related to the MTX treatments.

Of interest, 1 patient with 2 previous CDunderwent intragestational sac MTX in-jection of 50 mg at 7 postmenstrual weeksfor a CSP, and subsequently returned 10weeks later with a second CSP at 6 post-menstrual weeks. She underwent again in-tragestational sac MTX injection. It isnoteworthy that the first CSP was a dicho-rionic twin gestation with 1 empty sac(blighted ovum?), and an additional gesta-tional sac containing an embryo. Thissame patient returned again, 4 months af-ter her second CSP similarly treated with athird CSP at 5 postmenstrual weeks and 6days. She was treated again as per our de-scribed protocol with good outcome.

A small number of clots from the uter-

Doppler ultrasound image at 14 postmenstrual

nt

we olor

nan

ine cavity were aspirated on day 26 in


pg


patient 25 after continuous spotting wasreported.

The following observations were notedregarding the hCG serum concentrations,the gestational sac volume, and the VI:1. Serum hCG: in 13 of the 19 injected

cases after an initial plateau or a smalltemporary increase in the serum hCGconcentrations, the values decreasedslowly and became nondetectable(cutoff was �3 mIU/L) 41-100 daysfollowing MTX injection (Figure 5).

2. Gestational sac volume: in 12 of thecases the gestational sac volume in-creased or plateaued after MTX injec-tion, and this was followed by a slowdecrease in volumes (Figure 6). How-ever, the area of involution was visibleeven �5 months’ posttreatment.

3. VI: in 14 of the cases after an initial in-crease or brief plateau in the VI, a slowbut steady decline was observed to whatwas considered to be minimal values(�3%). Color Doppler did not demon-strate vascularization 30-140 days fromthe MTX injection (Figure 7).

The interquartile ranges for the serumhCG concentrations, the sac volumes,and VI are presented in Table 3.

COMMENTPrincipal findings of this studyFirst, an early diagnosis of CSP is possi-ble using the criteria proposed in this ar-ticle. Second, treatment is possible usinga combination of systemic and intrages-tational sac injection with MTX. Third,the local injection of MTX into the ges-tational sac is simple to perform underultrasound guidance using a needleguide, and in this report, was done trans-vaginally. Lastly, the natural history ofhCG serum concentrations, gestationalsac volume, and the VI after systemic andlocal MTX treatment is described. An in-crease in both serum hCG and gesta-tional sac volume was consistently ob-served immediately after treatment, andwas followed by a progressive decline un-til hCG became nondetectable and thegestational sac involuted. The optimalmanagement of CSP continues to repre-
sent a challenge.4

The clinical challenge of a cesareansection pregnancyThis pregnancy complication can pres-ent broadly in 2 ways: (1) as an acuteemergency in which the patient hasbleeding, or an acute abdomen due to

FIGURE 4Placenta percreta in case no. 9 from

A

C

, Sagittal section of uterus. Anatomy is outlinedocation, cesarean section (C/S) niche, empty uower Doppler image of vascularization. C, Afte

nlay represents color flow of vessel. D, Peak sysimor-Tritsch. Diagnosis and treatment of cesarean scar preg

TABLE 2Clinical and laboratory data of pati

Events Date Days post D&C Volum

1 10/17/09 0 Unavai...................................................................................................................

2 01/04/10 81 48...................................................................................................................

3 02/03/10 100 53.6...................................................................................................................

4 02/05/10 102 60...................................................................................................................

5 02/08/10 105 25...................................................................................................................

6 02/24/10 121 34.4...................................................................................................................

7 03/15/10 140 35...................................................................................................................

8 03/19/10 144 Bleeds...................................................................................................................

9 03/26/10 155 Emboli...................................................................................................................

10 04/02/10 160 Hystere...................................................................................................................

D&C, dilatation and curettage; hCG, human chorionic gonadot

Timor-Tritsch. Diagnosis and treatment of cesarean scar pregn

y JULY 2012

a uterine rupture–in both, emergencysurgery or uterine artery embolizationby interventional radiology are re-quired36,65-68; and (2) at sonography in a

atient with a history of CD, who under-oes an ultrasound examination.

able 1

dotted lines and annotations indicate placentale cavity, and cervical canal. B, 3-Dimensional0-144 days large dilated blood vessel is seen.velocity of 45.3 cm/s was measured in vessel.


9 from Table 1

L VI, % hCG, mIU/mL MTX, mg

e Unavailable Unavailable —..................................................................................................................

66 16 100..................................................................................................................

71 �2 —..................................................................................................................

42 �2 —..................................................................................................................

15.1 �2 —..................................................................................................................

52.6 Bleeding..................................................................................................................

76.7 — —..................................................................................................................

in..................................................................................................................

on..................................................................................................................

my..................................................................................................................

; MTX, methotrexate; VI, vascularization index.

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The optimal treatment of the patientin the first trimester of pregnancy with asonographic diagnosis of suspected CSPremains uncertain. The list of proposedtreatment modalities is long and in-volves among other one main treatmentalone or its combination with othertreatment modalities:

FIGURE 5Graph of serum hCG as function of

After initial increase most levels dropped to undehCG, human chorionic gonadotropin.


FIGURE 6Graph of gestational sac volumes a


a. Curettage4,10,11,13-15,22,24,25,31,32,36,37,39,43,

45,48,49,53,68-83

b. Hysteroscopy12,17,24,54,55,84-86

c. Systemic MTX alone10,14,17,18,21,26-28,32,

33,35,40,41,47,50,52,56,69,76,87-98

d. Laparotomy21,51,77,84,86,99-102

e. Uterine artery embolization34,38,44,56,57,

86,93,96,103,104

ys post injection

table levels by day 40-60.


function of days post injection


c

JULY 2012 Ameri

In general, these procedures can beperformed by obstetricians and gynecol-ogists with expertise in ultrasound. Someprocedures require involvement of theradiology department.

Diagnosis of CSPA recent literature search4 identified 751ases of CSP. Of interest is that 13.6%107/751) had been misdiagnosed as cer-ical pregnancies, spontaneous abor-ions in progress (on its way to expul-ion), or low intrauterine pregnancies.iven the potential serious complica-

ions of a CSP, reliable diagnostic criteriare required for the differential diag-osis. The primary scanning route usedas transvaginal using frequencies of-12 MHz. Transabdominal probes maylso be used. However, due to the loweresolution ability of transabdominalrobes, fine details of placental implan-ation site, definition of embryonic/fetals well as extraembryonic structures areeen better using the transvaginal ultra-ound probes. Another reason for usingransvaginal probes was that the viewingoint and viewing angle of the probe was

dentical both at the diagnosis as well ast the time of the injection. The diagnos-ic criteria used in this study includedere mentioned in the “Materials andethods” section.While the presence of embryonic/fetal

ardiac activity facilitates the diagnosisf CSP, its absence does not exclude theiagnosis, since in many cases there maye cessation of cardiac activity, and thisoes not eliminate the complications de-ived from CSP. Another considerations that patients may have been previouslyreated with intramuscular MTX andome to the attention of the ultrasoundnit after fetal demise has already oc-urred. Since the exact time and amountss well as, in certain cases, the intervals be-ween multiple administrations were un-eliable and inaccurate, we can only sayhat these data could not be analyzed in a

eaningful way. The precise sensitivity,pecificity, and predictive values of theseriteria would need to be tested prospec-ively. However, we have proposed theseriteria after considerable experience inur unit and welcome evaluation of their

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Treatment of an earlydiagnosis of CSPTreatment of CSP carried a significantcomplication rate. Of the 751 cases, 331(44.1%) ended up with complications.As a result, 36 hysterectomies, 40 lapa-rotomies, and 21 uterine artery emboliza-tions were performed as emergency mea-sures to treat complications. Treatments,such as systemic MTX, D&C, and uterineartery embolization carried the highestnumber of complications (62.1%, 61.9%,and 46.9%, respectively).4

Mean vascularity indices for the 3 pa-tients undergoing hysterectomy in ourseries was 63.1% while for the 16 patientswithout hysterectomy the mean VI was17.8% (P � .05). The lowest complica-ion rates were achieved by using localntragestational injection of MTX or ka-ium chloride as well as hysteroscopy9.6% and 18.4%, respectively).4 In

treating our patients with local intrages-tational MTX injection we applied thelessons learned from reviewing the entireavailable literature on CSP. In all but oneof the referred patients intramuscularMTX injections by the primary provid-ers failed to stop the heart activity. All ofour injected cases were successfullytreated (ie, the heartbeats were stopped)and yielded the expected results (ie, nocomplications were noted). CSP compli-cation can present in 2 ways: (1) as anacute emergency in which the patient isbleeding, or has an acute abdomen due touterine rupture–in both, emergency sur-gery or uterine artery embolization by in-terventional radiology are required; and(2) at sonography in a patient with a his-tory of CD, who undergoes ultrasoundexamination.

Our expectations of the treatmentwere based upon our previously re-ported results of injecting various ecto-pic pregnancies61-64 as well as the first in-tragestational sac injection cases byGodin et al.105 In the advanced case (pa-ient 9 in Table 2) where D&C was used,ot only did the procedure fail to provide

he expected and final treatment, but itay have led to the development of an-V malformation. In the same case, as

n some cases reported in the literature,
mbolization of the uterine artery was

ot fully effective leading to hysterec-omy.4 It is important to mention thathe patient who presented with heavyleeding to our emergency departmentpatient 26 in Table 1) was promptly di-gnosed with an A-V malformationithin the CD and in this case the pa-

hologies were successfully treated bymergency embolization of the uterinertery.

Since real-time transvaginal (or transab-ominal) ultrasound-guided intragesta-ional sac injections can be performed inn outpatient office setting, no anesthesias required. None of our 19 patients hadnesthesia. To perform the intragesta-ional sac injection we used an automated,pring-loaded device mated to the trans-

FIGURE 7VI as function of time after intragesac injection of methotrexate

I increased after injection and steadily droppedI, vascularization index.

imor-Tritsch. Diagnosis and treatment of cesarean scar preg

TABLE 3Mean, SE, and interquartile range fvolume of gestational sac, and VI

Measure Mean

hCG, mIU/mL 4334.6...................................................................................................................

Volume, mL 18.1...................................................................................................................

VI 18.9...................................................................................................................

hCG, human chorionic gonadotropin; VI, vascularization index.

Timor-Tritsch. Diagnosis and treatment of cesarean scar pregn

y JULY 2012

aginal ultrasound probe.61-64 The tech-nique we used is not the only one to beused for such a treatment. The fact is, al-most all manufacturers enable a needleguide to be attached to their transvaginalprobe. They also feature an electronic on-screen needle path with depth markings.Given the above, the technique of trans-vaginal (or for that matter, transabdomi-nal) ultrasound-guided puncture and in-jection is widely available. Oocyte retrievalrelies on similar needle insertion tech-niques for years.106,107 A considerable ad-antage of ultrasound-guided intragesta-ional sac injection is that it can beerformed as an office procedure. This is

n contrast to most surgical treatment ap-roaches, which are performed under an-

tional

reafter.


serum hCG,

SE 25-75% range

1114.1 9.0–4677.0..................................................................................................................

3.1 2.4–24.6..................................................................................................................

2.1 7.0–26.4..................................................................................................................

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esthesia, therefore, one has to also considerthis as an additional source of risk, mini-mal as it may be. All our locally injectedcases provided adequate final treatmentwith no resulting complications.

We have to address the issue of treat-ment with MTX by the referring siteprior to our intervention. To our knowl-edge, patients were injected with lowdoses of MTX (25-50 mg) and were re-ferred to our care 7-10 days later whenthe serum hCG levels failed to drop andthe heart activity was still present. Wesuggest that waiting in excess of 3-4 daysfor the trophoblast to cease its functionand result in declining hCG productioncausing the heart activity to stop endan-gers the patient. During this period ofwaiting for results, the gestation is grow-ing and its vascularization is increasing,presenting a more challenging manage-ment problem. Our approach treatingpregnancies by injecting MTX is that thisshould be done as early as possible for theaforementioned reasons.

Follow-up and resolutionAs to the resolution of the CSP after itslocal treatment, it should be clear thatthis is a long process measured in manyweeks or months. The mean time of res-olution of the 22 patients who did nothave hysterectomy or embolization was88.6 days (range, 26 –177). The literatureacknowledges this as well as the initialincrease of the serum hCG, the sac vol-ume, and its vascularity before theirslow resolution.10,18,32,48,52,89,96,108-110

The reasons for the initial increase of theserum hCG are unclear. More impor-tantly, in the case reports many of thesecondary treatments (laparoscopy, hys-teroscopy, laparotomy, and emboliza-tion) were not triggered by bleeding, butby the observation of the posttreatmentincrease in serum hCG, as well as the sizeand blood supply of the treated site.

Follow-up after intragestationaland intramuscular local MTXinjection of CSPOurapproachhasincluded3parameters:(1)serial serum hCG determinations; (2) vol-ume of the gestational sac; and (3) the degreeof vascularization. The rationale for selecting
this combination is that hCG is a marker of
trophoblast viability. Serum concentrationsof hCG are used to follow up patients withectopic pregnancies treated with MTX, andalso, gestational trophoblastic disease. Thefinding of a nondetectable hCG concentra-tion in serum is widely accepted as evidencethat no trophoblast is viable. This is a reason-able indication that treatment of MTX injec-tionoftheintragestationalsacwassuccessful.However, we (and others) have observedcomplications of ectopic pregnancy in pa-tients with a nondetectable hCG.111 Suchomplications often result from the detach-entofthegestationalsacfromthematernal

issues.111 For this reason, we incorporatedhe other 2 sonographic parameters: volumestimation of the gestational sac and the de-ree of vascularization. The expectationouldbethatsuccessful treatmentwouldre-

ultinareductioninthesizeofthegestationalac and decrease of the VI.

A fact is worth mentioning: the mean VIn the 3 patients treated by hysterectomyas higher than the 23 patients who didot have their uteri removed (68.1% vs7.8%). This may imply that a high VI atresentation may be a predictor of compli-ations. Even though patient 26 with an-V malformation did not undergo surgi-al treatment her VI was high (65%) andhe had uterine artery embolization.

An interesting observation of ourtudy is that, after the treatment regimenas instituted, hCG concentrations ini-

ially increased, the volume of the gesta-ional sac went up, and the VI also rose.imilar observations have been made bythers.10,32,48,52,89,96,108-110 One possible

explanation for this is that, after MTXadministration, trophoblast cells un-dergo necrosis. Stored hCG within tro-phoblast cells may be released into thecirculation, and hence, the apparent in-crease in hCG serum concentration. Ne-crosis of trophoblasts may lead to a localperitrophoblastic inflammatory reac-tion: this may explain the transient in-crease in volume observed with 3D ultra-sound and the increase in VI. After theinitial inflammatory reaction subsidesand the CSP is in the process of resolu-tion, volume and VI decrease. It is note-worthy that the mass may persist in somepatients for months– clinicians shouldbe aware of this particular observation,
and if such a transient increase is ob-
JULY 2012 Americ

served, we recommend expectant man-agement, which has been successful inthe cases presented in this series.

We have used 3D ultrasound tomonitor the effect of treatment onCSP. The rationale for this is that theVOCAL software allows calculation ofthe volume of the mass, and that the VIis an index of the degree of vasculariza-tion based upon power angiographywith 3D ultrasound. Whether thesemodalities are superior to 2-dimen-sional ultrasound and simple color andpower Doppler remains to be deter-mined. A comparison of the 2 was notthe purpose of this study. Subjectiveobservation and follow-up of vesseldensity in the injected area shouldguide those who do not use the 3D ul-trasound angiographic techniques.

ConclusionCSP represents a diagnostic and thera-peutic challenge. Its frequency is increas-ing as more CD are performed. We haveused a set of diagnostic criteria as well asa management and follow-up programfor the minimally invasive treatment ofthis complication of pregnancy. Thecombination of systemic and intragesta-tional sac administration of MTX is rel-atively simple, can be performed as anoffice procedure, and has been highlysuccessful in the treatment of CSP in thiscase series. Recent articles suggest thattransvaginal ultrasound can be usedto examine the first-trimester uterinescar112 and the likelihood of placenta ac-reta in the first trimester.113 f

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The Diagnosis, Treatment, And Follow-up of Cesarean Scar Pregnancy

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