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First-trimester screening for placenta accreta spectrum

Pe’er Dar , Georgios Doulaveris

PII: S2589-9333(24)00055-7
DOI: https://doi.org/10.1016/j.ajogmf.2024.101329
Reference: AJOGMF 101329

To appear in: American Journal of Obstetrics & Gynecology MFM

Received date: 28 November 2023

Revised date: 2 February 2024
Accepted date: 27 February 2024

Please cite this article as: Pe’er Dar , Georgios Doulaveris , First-trimester screening for pla-
centa accreta spectrum, American Journal of Obstetrics & Gynecology MFM (2024), doi:
https://doi.org/10.1016/j.ajogmf.2024.101329

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© 2024 Published by Elsevier Inc.

Title: First-trimester screening for placenta accreta spectrum

Pe’er Dar, Georgios Doulaveris

Obstetrics, Gynecology and Women’s Health, Division of Fetal Medicine and Ultrasound,

Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, United States.

Corresponding author:

Pe’er Dar, MD

1695 Eastchester Rd, Suite L4, Bronx, NY 10461

Phone: 718-405-8218

Fax: 718-405-8024

Email: peerdar@gmail.com

Conflict of interest

The authors report no conflict of interest.

Illustrations included in the manuscript are subject to copyright and cannot be used without

permission from the primary author Dr. Pe'er Dar.

Short title: First trimester screening for placenta accreta

Word count:

Abstract: 143, Main text: 3,377

Condensation: Screening for placenta accreta spectrum is feasible in the early or late first-

trimester.

Short title: First-trimester screening for placenta accreta spectrum

Blinded Conflict of Interest Statement

The authors report no conflict of interest.

Keywords:

Placenta accreta, first trimester, ultrasound, screening

Abstract

In recent years, there has been a significant rise in cases of placenta accreta spectrum (PAS), a

group of life-threatening placental disorders that can arise during childbirth. Early detection

plays a crucial role in facilitating meticulous delivery planning, ultimately leading to a reduction

in mortality and morbidity rates and improved overall outcomes. While third-trimester

ultrasound has traditionally been the primary method for prenatal screening for PAS, it often

falls short in identifying cases or diagnosis is too late for optimal delivery planning.

Emerging evidence has highlighted the option of early detection of PAS indicators during the

first trimester of pregnancy. This comprehensive review delves into our current knowledge of

sonographic assessment of the uterine cervico-isthmical complex in the first trimester, examining

the location and appearance of cesarean scars and exploring first-trimester screening strategies,

ultimately paving the way for improved maternal and neonatal outcomes.
 1. Introduction

Placenta accreta spectrum (PAS), also referred to as morbidly adherent placenta or abnormally

invasive placenta, includes a range of serious, potentially life-threatening pregnancy

complications related to abnormal placentation. PAS typically occurs when a trophoblast

abnormally adheres to a uterine defect, most often a previous cesarean scar, leading to

progressive invasion of the uterine scar niche and related morbidity.1,2 The incidence of PAS has

risen in conjunction with the higher rates of cesarean deliveries over recent decades,3,4 becoming

a leading cause of severe maternal and neonatal complications.4-7 Early prenatal diagnosis of

PAS is crucial; it enables detailed planning for delivery, which involves transferring patient care

to a PAS-specialized tertiary facility, scheduling delivery, typically before 37 weeks, and

developing a thorough pre-surgical strategy. Such proactive planning and the establishment of

specialized PAS centers have successfully resulted in halving morbidity rates and enhanced

patient outcomes.5, 8–13

Currently, screening for PAS is predominantly conducted by ultrasound during the third

trimester and, to a lesser extent, the second trimester.14,15 Ultrasound-based diagnosis of PAS can

be challenging, even to experienced providers, leading to the occasional use of magnetic

resonance imaging (MRI) to confirm or exclude the diagnosis. However, the effectiveness and

advantage of MRI over ultrasound in this context remain subjects of debate.16,17 Regardless of

the screening modality, a diagnosis of PAS in the third trimester is suboptimal with many cases

remaining undetected until delivery. Moreover, a late suspicion might leave insufficient time for

surgical planning or for transferring patients to a facility with the necessary expertise.
Recently, mounting evidence suggests that sonographic indicators of PAS can be detectable as

early as the first trimester. Cesarean scar pregnancy (CSP) has been recognized as a precursor to

PAS, underscoring the early initiation of abnormal placental adherence to the uterine scar.18,19

Consequently, research has been directed toward predicting PAS in the first trimester. Currently,

two primary screening approaches have emerged: one focuses on screening for CSP early in the

first trimester, between 5-8 weeks, and the other screens for PAS between 11-14 weeks,

coinciding with the routine nuchal translucency scan. This review delves into our current

understanding of sonographic evaluations of the uterine isthmus and cesarean scar during the

first trimester, as well as the evaluation of low placentation and the identification of scar

pregnancies. It then further elaborates on the two screening strategies for PAS in the first

trimester based on various sonographic markers that can be identified in different gestational

ages (early first trimester, 5–8 weeks, and at the time of the routine translucency scan, 11–14

weeks).

2. Sonographic assessment of the uterine cervico-isthmical complex and cesarean scar

2.1 First-trimester assessment of the cervico-isthmical complex

An in-depth understanding of the utero-cervical anatomy and the cervico-isthmical complex

(CIC) as visualized on transvaginal sonography (TVS) earlier in pregnancy, is paramount to

the proper evaluation of placentation in the setting of a prior cesarean delivery, as well as to

an early diagnosis of a scar pregnancy and associated risk of PAS. The CIC is a

sonographically virtual structure, comprising the cervix and the uterine isthmus, the lowest

part of the uterine corpus that evolves into the lower uterine segment as the pregnancy

advances (Figure 1).

The anatomy of the cervical canal gained significant attention following the report by Iams et

al on the association between cervical length and the risk of preterm birth.20 Nevertheless, an

accurate delineation of the boundaries of the cervical canal and particularly of the location of

the internal os, originally described as a V-shaped notch juxtaposed with the sac,21,22 were

only later thoroughly assessed and clarified.23,24 Although a few authors noted a common

finding of a “closed”, or contracted, uterine isthmus, in continuation with the cervical

canal,21,25,26 the concept of a CIC was first employed in 2011 by Greco et al.27

The cervical canal can be identified as a thin, usually echoic line surrounded by hypoechoic

cervical mucosa. The internal os is identified at the end of the cervical canal and in most cases

is seen perpendicular to the lower end of the bladder. The isthmical segment of the CIC begins

at the internal os at one end and ends at the gestational sac at the other. The virtual isthmical

canal is not clearly defined as the cervical canal. One notable marker is the lack of the

hypoechoic glandular tissue that is seen around the cervical canal. In many instances, it is also

possible to differentiate the echogenicity of the isthmic myometrium from that of the cervical

stroma. This distinction becomes evident as circular echogenic structures appear in each

section of the isthmus, potentially indicative of a muscular ring in this specific region (Figure

1). As pregnancy progresses, the isthmical myometrium becomes thinner, allowing the

gestational sac to occupy the space between its walls, and eventually be in direct contact with

the internal cervical os. In some pregnancies, this process continues throughout the second

trimester (Figure 2). In addition to the significant implication of the CIC in the assessment of

the actual length of the cervical canal, as is now well described by the Fetal Medicine

Foundation,28 it is crucial to the identification of a cesarean scar, as cesarean hysterotomies

are expected to be done at the low uterine segment. Figure 3A depicts the cesarean scar as
seen early in the first trimester in a normal intrauterine pregnancy. The scar can be located

within the CIC and therefore away from the placenta (Figure 3B) and gestational sac, or

outside the CIC (Figure 3C). Most of the scars are identified in the isthmical section of the

CIC close to the internal cervical os, just under the lower edge of the bladder wall. We

speculate that hysterotomies that were done after dissecting down the bladder flap on a

developed, thin, low uterine segment, result in a scar seen in the CIC. Conversely,

hysterotomies that were done without dissecting down the bladder or when the low uterine

segment is thick and cannot be clearly identified, as seen in preterm deliveries, may result in

higher scars outside the CIC. In cases with more than one prior cesarean section, a

combination of scar locations, in and outside the CIC, can be seen that may suggest a more

cephalad hysterotomy in repeat surgeries. Furthermore, scar niches can appear different in

width, and while the reason behind these differences is unclear, a wider niche may be related

to inadequate scar healing. In some cases, with more than a single prior cesarean delivery,

what appears to be a single wide scar on ultrasound may represent more than one

hysterotomies, thereby, limiting the overall number of scar niches seen in those cases.

2.2 Sonographic assessment of low placentation and diagnosis of a cesarean scar

pregnancy

A low implantation of a gestational sac is suggested when the sac is seen in the lower half of the

uterine corpus in close proximity to the internal cervical os, rather than in a normal eccentric

position near the uterine fundus.29 In the setting of a prior cesarean scar, the pathogenesis of CSP

involves the implantation of a blastocyst in the niche of the cesarean scar in the low uterine

segment.30,31 This abnormal trophoblastic attachment leads to abnormal angiogenesis and

vascular remodeling that in turn leads to progressive uterine scar dehiscence.2 The diagnosis of

CSP can therefore be made by a systematic examination of the CIC by transvaginal ultrasound in

the first trimester, optimally at 5-7 weeks. Transvaginal ultrasound is the preferred diagnostic

modality in the first trimester due to the optimal image resolution and the good agreement

between sonographers.32 The position of the gestational sac relative to the scar niche and the

uterine cavity is the most important parameter in the early diagnosis of CSP. In a recent Delphi

consensus, most ultrasound experts agreed that a CSP can be defined as a pregnancy in which

either the largest portion of a low implanted gestational sac is outside the uterine cavity, is

embedded in the myometrium, or crosses the serosal line herniating anteriorly towards the

bladder.33 Figure 4A depicts an early first-trimester pregnancy in which the gestational sac is

implanted inside the niche of the previous cesarean scar. By using transvaginal ultrasound, the

gestational sac can be seen penetrating the niche (Figure 4B). When applying color Doppler,

significant vascularity can be seen surrounding the sac, mostly in the fundal side of the scar

niche (Figure 4C). On the other hand, a pregnancy that is implanted below the cesarean scar

niche but not penetrating it, is not considered a CSP and should be described as a low-implanted

pregnancy (Figures 5A and 5B).33 Moreover, caution should also be exercised to distinguish a

CSP from a cervical ectopic pregnancy, where the gestational sac's blood supply originates

directly from the cervical canal. This is also true for differentiating a CSP from an ongoing

spontaneous miscarriage, which is characterized by a gestational sac present in the cervical canal

without a detectable blood supply. Consequently, a referral to a specialized center with expertise

in CSP diagnosis and treatment is warranted to confirm the diagnosis and expedite treatment.

3. First-trimester screening strategies for PAS

 3.1 Screening for PAS in the early first-trimester (5-8 weeks)

Currently, there is no widely established screening protocol for PAS in the early first trimester.

Pregnancies that progress to develop PAS in the second and third trimesters, demonstrate

sonographic features during the early first trimester that are comparable to those observed in

cases of CSP (Table 1). Moreover, the histopathological features of CSP and PAS are

indistinguishable, suggesting that they may be distinct stages in the same disease continuum with

the CSP being a precursor of PAS.17,18 In a recent systematic review and meta-analysis

evaluating the outcome in patients with CSP managed expectantly, 74.8% of patients had a

surgical or pathological diagnosis of PAS at delivery, with 69.7% of them diagnosed with

placenta percreta.34 As such, screening for PAS in the early first trimester at less than 8

gestational weeks should aim at diagnosis of CSP, and an initial finding of a gestational sac that

is located low and anteriorly with close proximity to the cesarean scar should warrant further

investigation with transvaginal and transabdominal ultrasound.35 Furthermore, Screening at this

time provides the opportunity for offering minimally invasive pregnancy termination and

avoidance of the significant sequelae expected later in pregnancy.

In a study of 68 patients with PAS confirmed at delivery, all (100%) were found to have low

implantation of the gestational sac, below the uterine midline, by transvaginal ultrasound

performed between 6 and 8 gestational weeks.35 Given the potential variability in the positioning

of the gestational sac relative to the scar niche (including the different positions of the gestational

seen between Figures 4A and 5A), the researchers of this cohort also have proposed the

"crossover sign" (COS) as a tool to more accurately determine the sac's location early in the first

trimester. The COS is defined as the gestational sac position relative to an imaginary line

connecting the internal cervical os and the uterine fundus. A gestational sac that is above and
towards the anterior uterine wall near the cesarean scar, was considered as a positive COS and

was found to be helpful in stratifying patients at increased risk for intraoperative or postoperative

complications.36 It is important to note, however, that while the COS is readily identifiable in an

anteflexed uterus, it can be more challenging to discern in a retroflexed uterus, which is

commonly observed in patients with a previous cesarean section. Furthermore, the COS is also

more readily discernible at 5-6 weeks, but as the gestational sac enlarges, it may become less

effective as a diagnostic tool. Using a different, more subjective terminology, differentiation of

CSP implanting “on the scar” versus implanting inside the scar niche (“in the niche”) has been

described in a small retrospective study of 17 patients diagnosed with CSP at less than 9

gestational weeks.37 A finding of a CSP growing “in the niche” was significantly associated with

PAS at delivery with most cases being on the severe end of the spectrum (increta or percreta)

requiring hysterectomy at delivery. On the contrary, pregnancies implanted “on the scar”

appeared to have more favorable outcomes with lower rates of cesarean hysterectomy.37 When

assessing these three early first trimester signs of PAS (low implantation below uterine midline,

COS, and pregnancy implantation “in the niche”) at less than 8 gestational weeks, they all have

high predictive accuracy for the most severe form of PAS in the third trimester [AUC 0.92, (95%

CI, 0.88 – 0.96) for low implantation, 0.94, (95% CI, 0.91 – 0.97) for COS and 0.92 (95% CI,

0.89 – 0.96) for implantation “in the niche”].38

Other sonographic markers to detect CSP in the early first trimester have also been described

including a thin or absent myometrial layer under the gestational sac (between the sac and the

bladder), presence of placenta lacunae, and increased or chaotic vascularity surrounding the

gestational sac.13,29,39–42 In over half of the cases, there is myometrial thinning between the

gestational sac and the bladder, defined by the authors as residual myometrial thickness of less
than 2mm and about two out of three cases of CSP between 6 and 10 gestational weeks exhibit

moderate or high blood flow using color Doppler imaging and.41 In a systematic review and

meta-analysis examining first trimester sonographic signs of PAS, when assessing only patients

in the early first trimester, at least one sonographic sign concerning for PAS was present in

95.1% of cases with low implantation of the sac being the most common.42

3.2 Screening for PAS in late first-trimester (11-14 weeks)

Routine ultrasound between 11 and 14 weeks is advocated by both national and international

guidelines to screen for chromosomal anomalies and structural malformations.43 Yet, similar to

the early first trimester, a standardized screening protocol for PAS has not been established.

Though identifying low implantation of the gestational sac is straightforward early in the first

trimester, it becomes more complex as the pregnancy advances. By 11 to 14 weeks, the

gestational sac enlarges considerably, occupying the entirety of the uterine cavity towards its

fundus, complicating the assessment of the initial implantation site. Consequently, during this

period, only 28% of patients with PAS could have a low gestational sac implantation identified.34

However, while the sac grows towards the fundus, the placenta and its associated vascularity

remain in close proximity to the previous cesarean scar in cases with PAS, and imaging in the

late first trimester with transvaginal and transabdominal ultrasound should shift focus from the

location of the gestational sac to the assessment of the placenta and its relationship to the

cesarean scar.

Stirnemann et al were the first to assess the feasibility of first trimester screening for PAS. In

their study, they examined prospectively 105 patients with a history of cesarean delivery and

were able to detect one case of PAS out of six patients that were considered high-risk by
transvaginal ultrasound at 11 to 14 weeks.44 Our group, examined retrospectively 467 patients

who underwent transvaginal ultrasound at 11 to 14 weeks assessing the relationship between the

placenta and the cesarean scar.45 Cases were graded as “no suspicion” for PAS if the placenta

was not next to the scar; “intermediate suspicion” if the placenta was next or on the scar but not

inside the niche (Figures 6A and 6B); and “high suspicion” if the placenta was inside the scar

niche (Figures 7A and 7B). Using this grading system, we identified at least three out of four

cases of PAS and found that placenta implanting inside the scar niche had a high positive

predictive value for PAS.45 Interestingly, 87.5% of the patients in this cohort who had a

transvaginal ultrasound to assess the placental location in the first trimester had a timely planned

delivery compared to 50% in those who had a routine third trimester screening for PAS, during

the same period. An assessment of the low uterine segment in 535 women in the late first

trimester by Bhatia et al, yielded similar results with a high negative predictive value for a

finding of placental implantation over an exposed scar.46 A two-stage approach for screening

PAS in early pregnancy has also been described.47 The first screening by ultrasound at 11-13

weeks was carried out in 22,604 singleton pregnancies, out of which 1298 (6%) were considered

to be at high risk of PAS based on a history of uterine surgery and low-lying placenta. These

patients underwent two more specialized scans in the second and third trimesters, and eventually,

the diagnosis of PAS was suspected in 14 cases, and confirmed at delivery in 13, for a positive

predictive value of 92.8% in the third trimester.

Other sonographic markers that have traditionally been associated with PAS in the second and

third trimester, such as the presence of placental lacunae, myometrial thinning, loss of

retroplacental clear zone, uterine-bladder interface abnormalities, and uterovesical

hypervascularity have also been examined in the late first-trimester and have been variably
associated with PAS. The development of these sonographic markers is closely linked to

gestational age. Although they can manifest early in pregnancy, they typically become more

prominent with time, making them more detectable in the later stages of gestation. From our

observations, the placenta's position relative to the cesarean scar serves as the most consistent

marker for PAS during the 11-14 week period. The presence of these markers, in conjunction

with the placental location, could potentially increase the performance of early screening for

PAS. In a study of 105 gestations with PAS examined at different intervals in the first, second,

and third trimester, the presence of these classical third trimester markers increased, as expected,

from the early first trimester onwards with many identified during the 11 to 14 week scan.34 In

the study by Jauniaux et al that examined 27 women with CSP who elected for conservative

management, even though there was no difference in subplacental hypervascularity between PAS

and controls at 11 to 14 weeks, placental lacunae were significantly more commonly seen in

women with PAS.41 Similarly, in the study of Abinader et al, placental lacunae were significantly

larger, more numerous (three or more), and with turbulent high-velocity flow in PAS

pregnancies compared with controls.48 In the same study, abnormal uteroplacental interface and

lower uterine segment hypervascularity were also more commonly seen in cases with PAS.48 In a

prospective study by Yule et al, color Doppler mapping during the late first trimester revealed a

significant increase in color Doppler pixel area at the bladder-uterine serosal interface in patients

who were subsequently diagnosed with PAS demonstrating the significant neovascularization

occurring with the abnormal placentation.49 Myometrial thinning (<2mm), assessed by

examining the narrowest myometrial thickness between the anterior trophoblast border and the

uterine serosa in the sagittal plane, has also been described as a predictive marker for PAS50,51 as

has loss of the retroplacental clear zone that can be especially helpful in assessing the severity of
disease, with a sensitivity of 84.3% for all PAS cases and 92.1% for cases with confirmed

placenta percreta at delivery.39 Finally, as with cases in the second and third trimester, the

presence of multiple sonographic markers in the late first trimester is associated with

significantly higher diagnostic accuracy as compared to a single marker.39,42,47

4. Conclusion

In conclusion, PAS poses a growing global threat due to rising cesarean delivery rates,

underscoring the need for early diagnosis to improve maternal and neonatal outcomes. For

individuals with a history of cesarean section, early first-trimester care should involve a

transvaginal ultrasound at 5-7 weeks to assess the gestational sac's location and rule out a CSP.

Timely referral to specialists experienced in CSP diagnosis and treatment is crucial to confirm

the findings and discuss management options. For patients with a prior cesarean delivery who

present late in the first trimester for sonographic assessment of the nuchal translucency at 11-14

weeks, we recommend a standardized examination of the CIC, the cesarean scar and placental

location by transvaginal ultrasound. A finding of the placenta under or within the scar niche

should prompt further assessment at a PAS-specialized center. It is important to communicate the

possibility of both false positive and false negative results during screening and the need for

additional assessments. Large and prospective studies are warranted to assess the efficacy and

cost-effectiveness of the different screening approaches for PAS in the first trimester.

Data availability statement

Data sharing is not applicable to this article as no new data were generated or analyzed for the

current study.
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Table 1. Sonographic markers seen in patients with placenta accreta spectrum in early and

late first trimester

Rate of sonographic
Gestational age Anatomic sonographic finding
marker
Low gestational sac29 68-100% 35,38

Crossover (COS-1) sign36 50-79% 38

Implantation “in the niche”37 67-94% 38

5 to 8 weeks
Myometrial thinning 56%% 41

Hypervascularity surrounding the gestational sac 0-43% 35,41

Low gestational sac 28% 35

Placenta penetrating the scar niche45 75% 45

Placenta overlying an exposed scar45,46 88-100% 45,46

Placenta lacunae 40-85% 39,41,48

11 to 14 weeks
Myometrial thinning 77% 39,48

Hypervascularity of the vesicouterine interface 51-100% 39,41,48

Loss of retroplacental clear zone 84% 39

Figure Legend

Figure 1. The cervicoisthmical complex (CIC) is a transient sonographic structure that is seen in

most cases of early pregnancy ultrasounds. It encompasses both the isthmus, the lowest part of

the uterine body which later transforms into the lower uterine segment, and the cervix. The

cervical canal is discerned as a thin echoic line enveloped by a hypoechoic layer, representing

the cervical mucosa. Notably, the internal os is located at the internal canal's end (small arrow),

typically seen perpendicular to the bladder's lower end. The isthmical portion of the CIC is

situated between the internal os and the gestational sac. The distinction between the echogenicity

of the isthmus and the cervical stroma becomes evident as circular echogenic structures appear in
each section of the isthmus, potentially indicative of a muscular ring in this specific region

(asterisk). The cesarean scar here can be seen within the CIC (large arrow).

Figure 2. A cervicoisthmical complex that persists in the second trimester of the pregnancy. The

isthmus or low uterine segment (LUS) can be identified separately from the cervix. Similar to the

first trimester, the circular echogenic structures in the LUS are helpful in differentiating the

isthmus from the cervical canal.

A
B

C
Figure 3. The cesarean scar as seen in the early first trimester in a normal pregnancy (Figure

3A). By using transvaginal ultrasonography, the scar (arrows) can be seen within the

cervicoisthmical complex (CIC) and therefore hidden from the gestational sac and placenta

(Figure 3B). In Figure 3C the cesarean scar is identified outside the CIC, exposed to the

gestational sac in this case. The internal cervical os can be identified by the curved arrow in

Figures 3B and 3C.

A
B

Figure 4. A cesarean scar pregnancy, in which the gestational sac is implanted in the niche of the

previous cesarean scar, as seen in the early first trimester (Figure 4A). Transvaginal ultrasound

(Figure 4B) reveals low implantation of the gestational sac (asterisk), inside the niche of the

cesarean scar (arrows). The gestational sac is seen above the endometrial line and towards the

anterior uterine wall (crossover sign, COS-1). In Figure 4C, examination of a cesarean scar
pregnancy by application of Color Doppler in the early first trimester reveals hypervascularity

surrounding the gestational sac, mostly in the fundal side of the scar niche.

A
B

Figure 5. A low implanted pregnancy, in which the gestational sac can be seen under the

previous cesarean scar but not penetrating the scar niche (Figure 5A). Figure 5B depicts a low

implanted gestational sac (asterisk) that is implanted below the cesarean scar (arrows) but not

penetrating. This is not considered a CSP and should be described as a low-implanted pregnancy.
A
B

Figure 6. The relationship between the placenta and the cesarean scar in the cervicoisthmical

complex, as examined in the late first trimester at 11-14 weeks in “intermediate suspicion” cases

(Figure 6A; illustration, Figure 6B; sonographic image). The placenta can be seen overlying an

exposed scar (arrows) but not penetrating the scar niche.

A
B

Figure 7. The relationship between the placenta and the cesarean scar in the cervicoisthmical

complex, as examined in the late first trimester at 11-14 weeks in “high suspicion” cases (Figure

7A; illustration and Figure 7B; sonographic image). The placenta appears to penetrate inside the

cesarean scar niche (arrows), completely replacing the anterior portion of the isthmus.