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RESEARCH ARTICLE
The impact of ultrasound-based antenatal
screening strategies to detect vasa praevia in
the United Kingdom: An exploratory study
using decision analytic modelling methods
Benjamin Ruban-FellID
1
, George Attilakos
2
, Tao Haskins-Coulter
1
, Christopher Hyde
3
,
Jeanette Kusel
1
, Anne Mackie
4
, Oliver Rivero-Arias
5
, Basky Thilaganathan
6
,
Nigel Thomson
7
, Cristina Visintin
8
, John Marshall
8
*
1Costello Medical, London, United Kingdom, 2Fetal Medicine Unit, University College London Hospital,
London, United Kingdom, 3Exeter Test Group, Institute of Health Research, College of Medicine and Health,
University of Exeter, St. Luke’s Campus, Exeter, United Kingdom, 4National Screening Committee, Public
Health England, London, United Kingdom, 5National Perinatal Epidemiology Unit, Nuffield Department of
Population Health, University of Oxford, Oxford, United Kingdom, 6Fetal Medicine Unit, St George’s
University Hospital NHS Foundation Trust and Molecular & Clinical Sciences Research Institute, St George’s
University of London, London, United Kingdom, 7The Society and College of Radiographers, London, United
Kingdom, 8UK National Screening Committee, London, United Kingdom
*john.marshall@dhsc.gov.uk
Abstract
The objective of this exploratory modelling study was to estimate the effects of second-tri-
mester, ultrasound-based antenatal detection strategies for vasa praevia (VP) in a hypothet-
ical cohort of pregnant women. For this, a decision-analytic tree model was developed
covering four discrete detection pathways/strategies: no screening; screening targeted at
women undergoing in-vitro fertilisation (IVF); screening targeted at women with low-lying
placentas (LLP); screening targeted at women with velamentous cord insertion (VCI) or a
bilobed or succenturiate (BL/S) placenta. Main outcome measures were the number of
referrals to transvaginal sonography (TVS), diagnosed and undiagnosed cases of VP, over-
detected cases of VCI, and VP-associated perinatal mortality. The greatest number of refer-
rals to TVS occurred in the LLP-based (2,083) and VCI-based screening (1,319) pathways.
These two pathways also led to the highest proportions of pregnancies diagnosed with VP
(VCI-based screening: 552 [78.9% of all pregnancies]; LLP-based: 371 [53.5%]) and the
lowest proportions of VP leading to perinatal death (VCI-based screening: 100 [14.2%];
LLP-based: 196 [28.0%]). In contrast, the IVF-based pathway resulted in 66 TVS referrals,
50 VP diagnoses (7.1% of all VP pregnancies), and 368 (52.6%) VP-associated perinatal
deaths which was comparable to the no screening pathway (380 [54.3%]). The VCI-based
pathway resulted in the greatest detection of VCI (14,238 [99.1%]), followed by the IVF-
based pathway (443 [3.1%]); no VCI detection occurred in the LLP-based or no screening
pathways. In conclusion, the model results suggest that a targeted LLP-based approach
could detect a substantial proportion of VP cases, while avoiding VCI overdetection and
requiring minimal changes to current clinical practice. High-quality data is required to
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OPEN ACCESS
Citation: Ruban-Fell B, Attilakos G, Haskins-Coulter
T, Hyde C, Kusel J, Mackie A, et al. (2022) The
impact of ultrasound-based antenatal screening
strategies to detect vasa praevia in the United
Kingdom: An exploratory study using decision
analytic modelling methods. PLoS ONE 17(12):
e0279229. https://doi.org/10.1371/journal.
pone.0279229
Editor: Yinka Oyelese, Beth Israel Deaconess
Medical Center, UNITED STATES
Received: August 18, 2021
Accepted: December 2, 2022
Published: December 20, 2022
Peer Review History: PLOS recognizes the
benefits of transparency in the peer review
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all of the content of peer review and author
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editorial history of this article is available here:
https://doi.org/10.1371/journal.pone.0279229
Copyright: ©2022 Ruban-Fell et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
explore the clinical and cost-effectiveness of this and other detection strategies further. This
is necessary to provide a robust basis for future discussion about routine screening for VP.
Introduction
Vasa praevia (VP) is a rare condition whereby fetal blood vessels run across or close to the cer-
vical opening during labour [1]. Without antenatal detection and intervention through
planned Caesarean section, fatal exsanguination of the fetus may occur [2]. Type I VP arises
from velamentous cord insertion (VCI) and Type II arises as a consequence of a bilobed or
succenturiate (BL/S) placenta [3–5]. A third type has recently been described in cases with
abnormal placental location [6].
The development of guidelines for antenatal detection of VP is dependent on a limited evi-
dence base and diagnostic criteria continue to evolve [5,7]. Strategies vary, but most rely on
detecting predisposing risk factors such as low-lying placenta (LLP), BL/S placenta, VCI or,
less frequently, marginal cord insertion (MCI) via transabdominal sonography (TAS) in the
second trimester, with the presence of VP (and the need for a Caesarean section) confirmed
with further TAS and/or transvaginal sonography (TVS) [7–11].
In the UK there is no nationally recommended strategy for antenatal detection and man-
agement of VP from clinical guideline bodies [5,12]. The UK National Screening Committee
(UK NSC) does not recommend universal screening for VP. This is based on a review which
identified a weak evidence base relating to screening for VP and concerns regarding unneces-
sary Caesarean sections and VCI overdetection [1].
Systematic detection of VCI, for example as part of a screening strategy for VP, would rep-
resent a departure from UK clinical practice as this and other cord anomalies are not included
in the panel of mid trimester screening targets [13]. Though VCI has a demonstrated high
prevalence in cases with VP [14], and many women with VP will therefore have VCI, only
around 2% of women with VCI will also have VP. This suggests a possibly high rate of VCI
overdetection if this marker is used to identify a group of women who would be offered further
testing for VP. At the same time VCI itself is reported to have an association with a number of
adverse perinatal outcomes, albeit weak-to-moderate [15]. Management pathways for VCI
based on enhanced monitoring are beginning to be described in guidelines outside the UK
[10,16], which may indicate a growing awareness of this association. However, test accuracy
studies are limited and there is an absence of evidence-based interventions for VCI and related
anomalies such as MCI [15].
Antenatal VP detection practice and awareness of risk factors have been reported to vary
across UK maternity units [17]. While interest in this area is increasing in the UK, a very lim-
ited body of UK-based research is available to inform discussion or quantify outcomes from
screening strategies [18–20].
The concept of ‘screening’ is centrally concerned with the early detection of a disease, or
risk of disease, in whole populations in which the prevalence of the condition in question is
low. The aim of this strategy is to improve outcomes while minimising any screening-related
harms from, for example, false positive results, findings of uncertain clinical significance, over-
diagnosis or unnecessary interventions. Guidance on VP by the Royal Australian and New
Zealand College of Obstetricians and Gynaecologists (RANZCOG) characterises TAS-based
screening for VCI as universal, or population, screening strategy [9]. In this screening
approach, all pregnant women would be offered TAS for VCI in order to establish the risk of
VP. Where the presence of VP is confirmed by TVS diagnosis, women could be offered Cae-
sarean section to prevent the adverse consequences with this condition.
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Data Availability Statement: All relevant data are
included within the paper and supplementary
information.
Funding: This study was funded by the UK NSC.
The views and opinions expressed by the authors
in this publication are not necessarily those of the
UK NSC.
Competing interests: All authors have completed
the ICJME uniform disclosure form at www.icmje.
org/coi_disclosure.pdf (available on request from
the corresponding author) and declare: no support
from any organisation for the submitted work other
than that described above; JM, CV, and AM are
employees of the UK NSC secretariat which funded
the submitted work; CH is a member of the UK
NSC; BT and ORA are members of the Fetal,
Maternal and Child Health Group (FMCH) of the UK
NSC; GA is a Council member of the Royal College
of Obstetricians and Gynaecologists and a Steering
Committee member of the UK Obstetric
Surveillance System; BRF, JK and THC are, or were
formerly, employed by Costello Medical which was
commissioned for the model development and
supportive work by the UK NSC; no other
relationships or activities that could appear to have
influenced the submitted work. The above
statement does not alter our adherence to PLOS
ONE policies on sharing data and materials.
However, discussion of the concept of screening has also identified alternative approaches
such as ‘targeted screening’ [21,22]. This might be described as a testing intervention which is
proactively offered to a group of people identified as being at elevated risk of a condition com-
pared to the general population; an important consequence of this approach is a lower number
needing to be screened to detect a case of disease compared to universal (population) screening
[23,24]. LLP stands out as a candidate for such an approach, where placental localisation at
mid-term to establish risk of placenta praevia has been embedded in antenatal care for many
years and LLP is detected in approximately 10% of pregnancies [13]. Detection and manage-
ment are well served by guidelines from national bodies, recommending that women with LLP
at mid-term should be recalled for further scanning in the third trimester and offered caesar-
ean section where indicated [5,12].
Given the limited availability of UK evidence on VP, its detection and management, a
screening impact model was developed within an expert group. Rather than providing a defini-
tive analysis of all possible pathways based on all possible combinations of risk factors, the aim
of this exploratory study was to use decision analytic modelling techniques to develop a series
of screening pathways based on discrete risk factors relevant to the UK setting in order to
explore the evidence base and to compare the potential impact of each pathway on key out-
comes relating to VP. The overall purpose of this work was to make a practical contribution to
the evolving discussion about the antenatal detection of VP in the UK; this was achieved by
presenting here an analysis of four possible detection pathways for VP which increase in scale
and by highlighting the need for high-quality data in order to fully explore the clinical and
cost-effectiveness of potential detection strategies in the UK setting.
Methods
Model structure
The VP screening model was programmed in Microsoft Excel and used a decision-analytic
tree structure to explore the effects of four potential detection pathways in a hypothetical one-
year UK pregnancy cohort. Decision trees are appropriate for modelling the short-term out-
comes of antenatal screening programmes when these outcomes are based on well-defined
processes, such as those assessed in this study [25,26]. Decision tree structures have been used
in previously published VP screening models and in other models of antenatal screening sce-
narios in a UK population [27–29]. The structure of the modelled decision tree is outlined in
Table 1 and S1 Fig.
As part of this exploratory model, each detection pathway was assessed as a discrete deci-
sion alternative. During the first stage of the decision tree, the hypothetical pregnancy cohort
entered one of four alternative detection pathways; these were designed through expert discus-
sion during two independent workshops and consultation of existing guidelines for VP detec-
tion in the US, Australia, New Zealand and Canada [8–10,30]. The pathways, considered to be
of most interest in this exploratory analysis, were: no screening, in-vitro fertilisation (IVF)-
based screening, LLP-based screening or VCI-based screening. An overview diagram compar-
ing the different pathways (and their hypothetical integration into clinical practice) is provided
in Fig 1, with all four pathways including the recommended 18
+0
to 20
+6
week fetal anomaly
scan as a first step. The no screening pathway was designed to provide an approximation of
VP detection in current routine clinical practice (in the absence of a nationally recommended
VP detection strategy). In this pathway, it was assumed that only pregnancies in which VP was
incidentally detected during the 18
+0
to 20
+6
week fetal anomaly scan, as the main component
of this pathway, were referred to TVS for VP for confirmation. In all four pathways it was
assumed that all pregnancies were examined for LLP during the 18
+0
to 20
+6
week scan, and
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women with LLP were offered a follow-up examination at 32 weeks, in keeping with currently
recommended good clinical practice [13]. However, only in the LLP-based pathway was detec-
tion of LLP at 18
+0
to 20
+6
weeks followed up with an additional TAS specifically for VP at 32
weeks (representing a targeted screening strategy in which VP is actively sought only in
women who have a risk factor routinely detected in current practice to prevent adverse out-
comes from placenta praevia). In the VCI-based pathway, additional testing for VCI and BL/S
placenta specifically aimed at establishing the risk of VP would be performed during the 18
+0
to 20
+6
week scan, with positive detection prompting a recall at 32 weeks to perform further
TAS to confirm the presence of VP (representing a population screening strategy based on a
risk factor which is sought for the sole purpose of identifying and preventing adverse outcomes
from VP, and which is not currently reported in UK practice). The same strategy was followed
for the IVF-based pathway, except that this was applied only to women with pregnancies
resulting from IVF; as this is a predisposing factor associated with VP in a very small popula-
tion subgroup, this was used to represent risk assessment in routine clinical care [4]. All detec-
tion pathways focused only on singleton pregnancies, a simplifying assumption based on
findings indicating that there is no independently significant association between multiple
pregnancies and VP incidence [1,4]. In all pathways, pregnancies that underwent TAS at 32
weeks were also followed-up by TVS for VP, if VP was suspected. Incidental detection of VP
across all pregnancies was also accounted for in all four pathways.
Data sources
The majority of model inputs were derived from published sources identified through the pre-
viously conducted UK NSC review of VP screening [1], targeted literature searches, a system-
atic literature review (SLR) and meta-analysis (MA) of adverse outcomes associated with (un-)
diagnosed VP, as well as normal pregnancies and pregnancies with VCI (S1 File). Quality
assessments were conducted for all published sources included in the base case model using
the Joanna Briggs Institute Critical Appraisal Checklist for Studies Reporting Prevalence Data
for epidemiological studies [31], Centre for Evidence Based Medicine Prognostic Studies
Table 1. Branches of the VP screening model.
Section Description
Detection pathways (as the
decision alternatives)
One of the four detection pathways is selected at the initial stage
Test eligible groups (as per
detection pathway)
The group of pregnancies eligible for testing for VP and therefore entering the
respective screening pathway are identified at this stage (e.g. the number/
proportion of pregnancies with LLP, IVF or the whole cohort)
True (biological) health state This represents the underlying biological health state of each pregnancy,
irrespective of the eventual diagnosis (VCI, VP or uncomplicated pregnancy)
Screening result This segment determines whether VP is diagnosed by TVS or not (and
whether a woman is referred to TVS, not referred to TVS or opts out of testing
completely). Women may also be re-scanned where TVS is indeterminate for
VP diagnosis. Women in the not screened arm may also be diagnosed with VP
via TVS, accounting for any incidental diagnoses
Birth method This stage determines whether the birth is planned vaginal or via planned
Caesarean section, followed by whether the birth happened as planned or if an
emergency Caesarean section was required
Survival of the baby This considers the risk of death at any point in the perinatal period
Abbreviations: IVF, in vitro fertilisation; LLP, low-lying placenta; TVS, transvaginal sonography; VCI, velamentous
cord insertion; VP, vasa praevia.
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Critical Appraisal Worksheet for prognostic studies [32], the Quality Assessment of Diagnostic
Accuracy Studies (QUADAS-2) tool for diagnostic studies [33], or the Drummond checklist for
economic evaluations (S2 File) [34]. Literature-derived inputs were validated through expert opin-
ion during two workshops involving six UK clinical experts (GA, BT, NT, AM, EDJ, HG) and two
modelling experts (CH, ORA); these workshops were also used to inform inputs in the absence of
published data. Workshop participants were selected based on their relevant roles and expertise
within the UK NSC structures and/or involvement in previous UK NSC consultations.
Table 2 lists the key model inputs; a full list of all model inputs is provided in the S1 Table.
Model outputs
In order to understand the potential impact of the different detection pathways, with regards
to the outcomes in VP pregnancies as well as possible resource implications and trade-offs, a
variety of outputs were modelled. These were the number of additional TAS scans and referrals
Fig 1. Modelled detection pathways. �Women with LLP defined by a placental edge that is 2 cm or less from the internal cervical opening. Abbreviations:
BL/S, bilobed/succenturiate; IVF, in vitro fertilisation; LLP, low-lying placenta; TAS, transabdominal scan; TVS, transvaginal scan; VCI, velamentous cord
insertion; VP, vasa praevia.
https://doi.org/10.1371/journal.pone.0279229.g001
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to TVS (as a direct outcome of the modelled pathways, i.e. not including referrals as part of cur-
rent clinical practice), diagnosed and undiagnosed cases of VP, detected cases of VCI, the pro-
portion of emergency Caesarean sections for VP pregnancies, and the number of VP-associated
perinatal deaths. The ratio of additional TAS scans or referrals to TVS to the number of diag-
nosed VP cases was included as a simplified estimate of efficiency for each of the pathways.
The two outputs considered as main outcomes of interest for additional sensitivity analyses
(see below for more details) were the proportion of diagnosed VP pregnancies, due to this
being a key step towards the comparison of clinical outcomes, and number of referrals to TVS,
as an important indicator of possible resource implications.
Sensitivity and scenario analyses
In order to identify key drivers for the two main outcomes of interest in the model (diagnosed
VP pregnancies and referrals to TVS), a deterministic sensitivity analysis (DSA) was
Table 2. Key model inputs.
Input Value Rationale Reference
Overall model population
The total number of pregnancies in the
UK population per year
862,785 Official UK statistics, providing accurate, population-level data ONS [35]
Proportion of women entering the VP screening pathway
No screening 0.00% Assumption that no women are tested as part of the no screening pathway Assumed
VCI-based 100.00% Assumption that all pregnant women in the UK are initially tested for VCI (and
BL/S placenta) as part of the VCI-based pathway
Assumed
IVF-based 1.60% Based on the prevalence of IVF-based pregnancies (see S1 Table) Ebbing 2013
[36]
LLP-based 10.00% Based on the prevalence of LLP pregnancies (see S1 Table) Expert opinion
Incidence of VCI
General population 1.50% Appropriate literature value (based on applicability and quality of the study)
identified through targeted searches
Ebbing 2013
[36]
IVF pregnancies 3.70% Appropriate literature value (based on applicability and quality of the study)
identified through targeted searches
Ebbing 2013
[36]
LLP pregnancies 2.80% Appropriate literature value (based on applicability and quality of the study)
identified through targeted searches
Suzuki 2015 [37]
Incidence of VP
General population 0.03% Average value identified in the UK NSC review, in alignment with expert opinion UK NSC 2017
[1]
IVF pregnancies 0.34% Appropriate literature value (based on applicability and quality of the study)
identified through targeted searches
Schachter 2002
[38]
LLP pregnancies 0.52% Appropriate literature value (based on applicability and quality of the study)
identified through targeted searches
Rosenberg 2011
[39]
Diagnostic test accuracy
Sensitivity of TAS for VCI 99.00% Appropriate literature value (based on applicability and quality of the study)
identified through targeted searches
Sepulveda 2003
[40]
Sensitivity of TAS for BL/S placenta 75.00% (range:
65.00–85.00)
Appropriate literature value (based on applicability and quality of the study)
identified through targeted searches
Cipriano 2010
[27]
Sensitivity of TAS for VP 87.00% Appropriate literature value (based on applicability and quality of the study)
identified through targeted searches
Catanzarite 2001
[3]
Sensitivity of TVS for VP 96.60% Appropriate literature value (based on applicability and quality of the study)
identified through targeted searches
Bronsteen 2013
[41]
Abbreviations: BL/S, bilobed or succenturiate; IVF, in vitro fertilisation; LLP, low-lying placenta; TAS, transabdominal sonography; TVS, transvaginal sonography; UK
NSC, United Kingdom National Screening Committee; VCI, velamentous cord insertion; VP, vasa praevia.
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conducted to evaluate the impact of each model parameter on the difference in these outcomes
between each pathway and no screening. Where possible, published variance data (e.g. confi-
dence intervals [CI]) were used to perform the DSA; in the absence of published data, approxi-
mate 95% CIs were calculated from the base case values using the Wilson score interval
method for binomial probabilities [42].
A probabilistic sensitivity analysis (PSA) was carried out to evaluate the joint parameter
uncertainty across model inputs on the two main outcomes of interest. Input values were var-
ied stochastically based on published variance data where possible, or calculated Wilson score
intervals where required in the absence of published data, and using beta distributions (as all
included inputs were binomial probabilities) [43]. Each new combination of input values was
tested in turn during 1,000 iterative simulations, and a plot was generated showing the mean
average difference (and associated non-parametric 95% CI) between each pathway and no
screening with regards to the number of referrals to TVS and diagnosed VP pregnancies.
Scenario analyses were run to explore both uncertainties associated with model inputs and
structural assumptions concerning the detection pathways. To explore uncertainty in the
model inputs, a set of alternative literature values for key model inputs (Alternative Inputs Sce-
nario) were used simultaneously. The key model inputs were informed by the inputs that were
found to have the greatest impact on the proportion of diagnosed VP in the DSA (these inputs,
and the alternative values used, are summarised in S2 Table). To account for the assumption
that accuracy of diagnostic testing for VP may improve over time, based on likely evolving
technology and clinical practice, an additional scenario analysis was based on the inclusion of
higher sensitivity inputs for TVS for VP (100%; based on Ruiter et al.) [44] and for TAS for VP
(98%; assumed to be slightly lower than TVS).
To explore structural assumptions, two Structural Scenarios were developed. In Structural
Scenario 1, the TAS for VP step at 32 weeks was removed from all pathways. Structural Sce-
nario 2 included a combined IVF- and LLP-based pathway in which pregnancies resulting
from IVF and/or with LLP were considered eligible for TAS at 32 weeks. For this scenario,
published odds ratios for the occurrence of LLP in IVF pregnancies were used to calculate the
combined IVF/LLP cohort, and VCI and VP incidence values in either IVF (for VCI) or LLP
(for VP) pregnancies were conservatively assumed for this cohort. All scenario analyses were
decided through discussion with clinical experts during two independent workshops, taking
into account alternative scenarios that were deemed plausible in clinical practice and of the
most interest for this exploratory analysis.
Results
Base case
In the no screening pathway, no pregnancies were actively tested for VP. However, 0.003% (27
pregnancies) of all pregnancies were incidentally diagnosed as VP at 18
+0
to 20
+6
weeks and
directly referred to confirmatory TVS. 14,126 pregnancies in the IVF-based pathway under-
went TAS specifically for VCI and BL/S placenta at 18
+0
to 20
+6
weeks; for the VCI-based path-
way, all of the 862,785 pregnancies that occurred within the modelled one-year UK pregnancy
cohort underwent TAS for VCI and BL/S placenta in addition to the routine fetal anomaly
scan at 18
+0
to 20
+6
weeks. In the LLP-based pathway 10.0% (86,270 pregnancies) of all preg-
nancies had LLP, with 85,407 (99.0%) of these being detected as part of the routine fetal anom-
aly scan at 18
+0
to 20
+6
weeks and referred to follow-up examinations, with TAS for VP added
to current practice, at 32 weeks accordingly (Table 3).
Correspondingly, the LLP-based pathway resulted in the highest number of referrals to
32-week TAS and subsequent referrals to TVS (85,407 and 2,083 referrals, respectively),
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followed by VCI-based screening (38,028 and 1,319 referrals, respectively). While a higher
number of referrals may appear counterintuitive for a more targeted screening approach, this
is in keeping with the higher incidence of LLP in the general population (10.0%) compared to
VCI (1.5%) and BL/S placenta (3.1%) (see S1 Table), and should also be regarded in the overall
context of fewer additional TAS scans being performed at 18
+0
to 20
+6
weeks as part of this tar-
geted approach when compared with VCI-based screening (Table 3). The IVF-based pathway
resulted in substantially fewer TAS and TVS referrals (834 and 66 respectively), and only 27
referrals to TVS due to incidental detection occurred in the no screening pathway (Table 3).
At 32 weeks, the rate of false positive VP diagnoses was very low in all pathways, with two false
positives in the LLP-based pathway and one false positive in the VCI-based pathway. VCI-
based screening diagnosed the highest proportion of VP pregnancies (78.9%, 552 pregnancies)
Table 3. Base case results for demographic and screening outcomes.
No screening IVF-based pathway LLP-based pathway VCI-based pathway
VP pregnancies, n [difference vs no screening pathway]
Within the affected population entering the pathway 0 62 448 700
[+62] [+448] [+700]
Within the affected population not entering the pathway 700 638 252 0
[–62] [–448] [–700]
Total 700 700 700 700
[0] [0] [0]
VCI pregnancies, n [difference vs no screening pathway]
Within the affected population entering the pathway 0 447 2,397 14,361
[+447] [+2,397] [+14,361]
Within the affected population not entering the pathway 14,361 13,914 11,964 0
[–447] [–2,397] [–14,361]
Total 14,361 14,361 14,361 14,361
[0] [0] [0]
Number of scans, n [difference vs no screening pathway]
Additional TAS scans at 18
+0
to 20
+6
weeks
a
0 14,126 0 862,785
[+14,126] [+862,785]
Referrals to 32-week TAS 0 834 85,407 38,028
[+834] [+85,407] [+38,028]
TVS scans for VP 27 66 2,083 1,319
[+39] [+2,056] [+1,292]
Screening outcomes
VCI detected, n (% of all VCI pregnancies) [difference vs no screening pathway] 0 (0) 443 (3.1) 0 (0) 14,238 (99.1)
[+443 (+3.1)] [0] [+14,238 (+99.1)]
VP diagnosed, n (% of all VP pregnancies) [difference vs no screening pathway] 27 (3.9) 50 (7.1) 371 (53.5) 552 (78.9)
[+23 (+3.2)] [+344 (+49.6)] [+525 (+75.0)]
TAS scans per VP diagnosed, n [difference vs no screening pathway]
b
0 299 230 1,632
[+299] [+230] [+1,631]
TVS scans per VP diagnosed, n [difference vs no screening pathway] 1.0 1.3 5.6 2.4
[+0.3] [+4.6] [+1.4]
a
TAS scans (for VCI) performed in addition to the routine fetal anomaly TAS at 18+0 to 20+6 weeks b Including additional TAS for VCI at 18+0 to 20+6 weeks (for the
IVF- and VCI-base pathways) and TAS for VP at 32 weeks (for the IVF-, LLP- and VCI-based pathways)
Abbreviations: IVF, in vitro fertilisation; LLP, low-lying placenta; TAS, transabdominal sonography; TVS, transvaginal sonography; VCI, velamentous cord insertion;
VP, vasa praevia.
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followed by the LLP-based pathway (53.5%, 371 pregnancies). 50 VP pregnancies (7.0%) were
identified in the IVF-based pathway, and the no screening pathway led to the incidental detec-
tion of only 27 VP pregnancies (3.9%; Table 3). When considering a simplified measure of effi-
ciency, the LLP-based pathway resulted in the lowest number of additional TAS scans (for
VCI or VP) for each diagnosed case of VP (230 TAS scans) but also the highest number of
TVS scans per diagnosed VP (5.6 TVS scans), when compared with the IVF-based (299 TAS
and 1.3 TVS scans per diagnosed VP) and VCI-based (1,632 TAS and 2.4 TVS scans per diag-
nosed VP) pathways (Table 3). These results should however also be regarded in the context of
the actual detection algorithms and rates for each pathway, as exemplified by the no screening
pathway resulting in a seemingly perfect ratio of 1.0 TVS scan per diagnosed case of VP based
on the incidental detection (and direct referral to confirmatory TVS) of 27 VP pregnancies
during the 18
+0
to 20
+6
weeks routine scan.
Despite the overall incidence of VCI being equal across all four pathways, it was assumed
that no VCI pregnancies were detected in the LLP-based or no screening pathways, due to
VCI not being actively tested for or considered as part of the respective detection strategies in
these two pathways (Table 3). 443 VCI pregnancies (3.1%) were detected in the IVF-based
pathway, while 14,238 VCI pregnancies (99.1%) were detected under VCI-based screening.
For the VCI-based pathway, it should also be noted that this number is considerably smaller
than the 38,028 pregnancies that were referred to 32-week TAS for VP due to the false positive
detection of VCI at 18
+0
to 20
+6
weeks.
The pathways with higher proportions of diagnosed VP cases also resulted in a higher pro-
portion of VP pregnancies being delivered via planned Caesarean section (Table 4). In the
VCI-based and LLP-based pathways, 61.6% and 42.6% of all VP pregnancies were delivered
via planned Caesarean section, respectively, compared with 9.0% and 6.6% of all VP pregnan-
cies in the IVF-based and no screening pathways. A higher proportion of VP pregnancies were
therefore delivered via emergency Caesarean section (64.9% and 66.3% of all VP pregnancies,
respectively) or vaginal births (26.1% and 27.1%) in the IVF-based and no screening pathways,
compared to the VCI-based and LLP-based pathways (emergency Caesarean section: 32.5%
and 44.1%; vaginal delivery: 5.9% and 13.3%, respectively). In line with the increased propor-
tion of planned Caesarean sections versus vaginal births for VP pregnancies in the VCI-based
and LLP-based pathways, the proportion of VP pregnancies resulting in perinatal death was
substantially lower in these pathways compared to the no screening and IVF-based pathways
(Table 4). The VCI-based pathway resulted in 100 perinatal deaths in VP pregnancies (14.2%
of all VP pregnancies), and the LLP-based pathway resulted in 196 perinatal deaths (28.0%).
Table 4. Base case results for birth method and perinatal outcomes.
No
screening
IVF-based
pathway
LLP-based
pathway
VCI-based
pathway
Planned Caesarean Sections for VP pregnancies, n (% of all VP pregnancies) [difference vs
no screening pathway]
46 (6.6) 63 (9.0) 298 (42.6) 431 (61.6)
[+17 (+2.4)] [+252 (36.0)] [+385 (+55)]
Emergency Caesarean Sections for VP pregnancies, n (% of all VP pregnancies) [difference vs
no screening pathway]
464 (66.3) 454 (64.9) 309 (44.1) 227 (32.5)
[-10 (-1.4)] [-155 (-22.2)] [-237 (-33.8)]
Vaginal deliveries for VP pregnancies, (% of all VP pregnancies) [difference vs no screening
pathway]
190 (27.1) 183 (26.1) 93 (13.3) 42 (5.9)
[-7 (-1.0)] [-97 (-13.8)] [-148 (21.2)]
Perinatal deaths in VP pregnancies, n (% of VP pregnancies) [difference vs no screening
pathway]
380 (54.3) 368 (52.6) 196 (28.0) 100 (14.2)
[-12 (-1.7)] [-184 (-26.3)] [280 (-40.0)]
Abbreviations: IVF, in vitro fertilisation; LLP, low-lying placenta; VCI, velamentous cord insertion; VP, vasa praevia.
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Meanwhile, the IVF-based pathway resulted in 368 deaths (52.6%) and no screening resulted
in 380 deaths (54.3%).
Sensitivity analyses
The results of the DSA display the impact of the key model drivers on the difference between
no screening and each of the IVF-based, LLP-based and VCI-based detection pathways for the
number of referrals to TVS (Fig 2) and diagnosed VP cases (Fig 3). For both of these outcomes,
the results of the PSA further demonstrate that joint parameter uncertainty across model
inputs led to some variation in the difference between no screening and the LLP-based and
Fig 2. Results of the DSA for the number of referrals to TVS. Upper estimate demonstrates the impact on the difference between each pathway and the no
screening pathway in terms of referrals to TVS by increasing the variable; lower estimate demonstrates the impact on the referrals to TVS by decreasing the
variable. Asymmetric bars are indicative of input values already being close to the ceiling value for the input type (for example, a probability of 0.9) and
therefore being unable to be increased to the full extent. Abbreviations: BL/S, bilobed or succenturiate; DSA, deterministic sensitivity analysis; IVF, in vitro
fertilisation; LLP, low-lying placenta; TAS, transabdominal sonography; TVS, transvaginalsonography; VCI, velamentous cord insertion; VP, vasa praevia.
https://doi.org/10.1371/journal.pone.0279229.g002
Fig 3. Results of the DSA for the number of diagnosed VP cases. Upper estimate demonstrates the impact on the difference between each pathway and the
no screening pathway in terms of diagnosed VP pregnancies by increasing the variable; lower estimate demonstrates the impact on the number of diagnosed
VP pregnancies by decreasing the variable. Asymmetric bars are indicative of input values already being close to the ceiling value for the input type (for
example, a probability of 0.9) and therefore being unable to be increased to the full extent. Abbreviations: BL/S, bilobed or succenturiate; DSA, deterministic
sensitivity analysis; IVF, in vitro fertilisation; LLP, low-lying placenta; TAS, transabdominal sonography; TVS, transvaginal sonography; VCI, velamentous cord
insertion; VP, vasa praevia.
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VCI-based pathways in particular (Fig 4). Here, a noticeable overlap between these two path-
ways was observed with regards to the mean average difference versus no screening for refer-
rals to TVS (LLP-based: 2,075 [95% CI: 391, 5,750]; VCI-based: 1,301 [95% CI: 409, 2,920])
and the number of diagnosed VP cases (LLP-based: 336 [95% CI: 70, 788]; VCI-based: 521
[95% CI: 172, 1,041]).
Scenario analyses
The results of all scenario analyses are presented in Fig 5. The simultaneous incorporation of
alternative literature values for ten key inputs in the Alternative Inputs Scenario resulted in a
substantial decrease in both the proportion of diagnosed VP and detected VCI pregnancies in
the VCI-based pathway, accompanied by a corresponding increase in the proportion of peri-
natal death in VP pregnancies; this was also observed, to a lesser degree, for the LLP-based
pathway. A substantial increase in the proportion of detected VCI pregnancies was also
observed in the IVF-based pathway. The proportion of diagnosed VP and perinatal death in
VP pregnancies in the no screening pathway, as well as the number of referrals to TVS in all
four pathways, remained comparatively unchanged.
The increase of test sensitivity for TAS and TVS for VP resulted in a substantially increased
proportion of diagnosed VP cases for the LLP-based (62%) and VCI-based (92%) pathways in
particular, with correspondingly lower proportions of perinatal death in VP pregnancies (23%
and 7% in the LLP-based and VCI-based pathway, respectively).
Removal of TAS for VP at 32 weeks in Structural Scenario 1 resulted in a substantially
increased number of referrals to TVS in the LLP-based, VCI-based, and IVF-based pathways,
with correspondingly increased rates of VP detection in the VCI-based and LLP-based path-
ways, in particular. In Structural Scenario 2, combining the IVF- and LLP-based pathways gen-
erated very similar results to the LLP-based pathway.
Fig 4. Results of the PSA for the difference versus no screening (number of referrals to TVS and numberof diagnosed VP cases). Upper estimate
demonstrates the impact on the difference between each pathway and the no screening pathway in terms of diagnosed VP pregnancies by increasing the
variable; lower estimate demonstrates the impact on the number of diagnosed VP pregnancies by decreasing the variable. Asymmetric bars are indicative of
input values already being close to the ceiling value for the input type (for example, a probability of 0.9) and therefore being unable to be increased to the full
extent. Abbreviations: BL/S, bilobed or succenturiate; DSA, deterministic sensitivity analysis; IVF, in vitro fertilisation; LLP, low-lying placenta; TAS,
transabdominal sonography; TVS, transvaginal sonography; VCI, velamentous cord insertion; VP, vasa praevia.
https://doi.org/10.1371/journal.pone.0279229.g004
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Fig 5. Results of scenario analyses. Alternative Inputs Scenario: Incorporation of alternative inputs based on alternate literature values. VP
Test Accuracy Scenario: Higher test sensitivity for TAS and TVS for VP. Structural Scenario 1: Removal of TAS for VP at 32 weeks.
Structural Scenario 2: Combined IVF- and LLP-based pathway. Abbreviations: BL/S, bilobed or succenturiate; IVF, in vitro fertilisation; LLP,
low-lying placenta; TAS, transabdominal sonography; TVS, transvaginal sonography; UKOSS, UK Obstetric Surveillance System; VCI,
velamentous cord insertion; VP, vasa praevia.
https://doi.org/10.1371/journal.pone.0279229.g005
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Discussion
The base case results of this exploratory study showed that the modelled VCI-based and LLP-
based pathways led to the detection of a greater proportion of VP pregnancies and a higher
number of referrals to TVS than the no screening or IVF-based pathways. These higher VP
detection rates also led to a correspondingly lower proportion of VP pregnancies resulting in
perinatal death. The VCI-based pathway resulted in the highest VP detection rate (78.9%) and
lowest proportion of perinatal death in VP pregnancies (14.2%); however, it also resulted in
the detection of almost all VCI pregnancies, compared to minimal detection of VCI in the
other pathways, and required a substantially higher number of additional TAS scans which,
currently, are rarely recommended in practice. In contrast, the LLP-based pathway diagnosed
a lower proportion of VP (53.5%) but required significantly fewer additional TAS scans; this
pathway also did not include the detection of VCI as part of its screening algorithm.
The major limitation of this modelling study is the considerable uncertainty associated with
many of the model inputs due to the lack of consistent high-quality data. The evidence base
available for prevalence estimates of VP and corresponding risk factors, as well as diagnostic
test accuracy, is generally characterised by a high degree of heterogeneity and mixed quality of
reporting [4,14,44]. Formal quality appraisals also indicated that available studies used to
inform model parameters were generally of low or moderate quality. This applied to key
parameters such as test accuracy and the incidence and impact of both VP and VCI. Therefore,
an Alternative Inputs Scenario analysis was used to explore this uncertainty by applying alter-
native literature-derived inputs. This resulted in a pronounced decrease in the detection of VP
in the VCI-based pathway below the rate of detection in the LLP-based pathway, likely driven
by the considerably lower scenario input for VCI test sensitivity. This finding is further sup-
ported by the results of the PSA, which demonstrated a noticeable overlap in the number of
referrals to TVS and detected VP cases for the VCI-based and LLP-based pathways. Collec-
tively, the results of the sensitivity and scenario analyses indicate that the relative benefits of
individual pathways, and especially VCI-based screening, remain uncertain to some degree
and the general lack of high-quality evidence should prompt caution when interpreting the
results of this exploratory analysis.
Reduction of VP-related mortality is directly linked to the VP detection rate and is therefore
also impacted by the uncertainty of this latter outcome, with this also being supported by the
results of a scenario analysis which applied a higher VP diagnostic test sensitivity and resulted
in noticeably lower numbers of perinatal deaths in VP pregnancies. Similarly, while an inter-
mediate measure of screening efficiency was based on VP detection as the more immediate
key outcome in the model, the observed trends with regards to the number needed to screen
for detecting VP in each pathway would also apply to VP-related deaths prevented, which
would be the ultimate aim of any VP screening strategy.
Additional uncertainty surrounds the mortality associated with ultrasound-detected VP
compared to clinically presenting VP at birth. The model base case estimated that 380 (54.3%)
of 700 cases of VP would result in perinatal death without antenatal ultrasound screening. This
case-fatality rate is informed by the literature on clinically presenting VP and is also aligned
with the conclusions made from a UK single-centre study by Zhang et al. where the authors
estimated that around half of the 21 ultrasound-detected cases of VP (in a cohort of 26,830
pregnancies) would have resulted in stillbirth if they had not been diagnosed prenatally [2,20].
However, these estimates of VP-related mortality contrast with a 2017 national clinical surveil-
lance study conducted in the UK where, in a cohort of approximately 750,000 pregnancies in a
setting in which screening for VP is not recommended in national guidance, six deaths to VP
were reported as part of the currently available preliminary results [19,45]. Whilst the
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potential impact of under-reporting in this surveillance study may require further consider-
ation, any large difference between the assumed and observed number of perinatal deaths may
also be explained by the different diagnostic criteria for ultrasound-detected VP, with Zhang
et al. having applied a definition based on vessels within 5 cm of the internal os as diagnostic
criterion for VP [20]. This broadened diagnostic definition of VP may not correlate with VP
which presents clinically in labour and a lower mortality per case detected might therefore be
expected in screen detected VP. This would also impact any estimates of the number needed
to screen to prevent VP-related mortality. When estimating the impact of antenatal detection
strategies on VP-related mortality, caution should therefore be exercised when extrapolating
outcomes from clinically presenting VP to ultrasound-detected VP.
This exploratory model is also consistent with two other, Canadian and US-based, model-
ling studies which investigate the cost-effectiveness of VP screening [27,28]. Although the
exploratory model presented here does not consider cost-effectiveness, the results align with
these published studies with respect to the proportion of diagnosed VP under the VCI-based
(as approximate to population screening) and LLP-based pathways.
One finding of the model was that the modelled LLP-based pathway resulted in a substan-
tially higher number of referrals to TAS at 32 weeks compared to the VCI-based pathway. This
should, however, also be interpreted in the context of current clinical practice. As LLP is rou-
tinely detected at the 18
+0
to 20
+6
week scan and women with LLP are usually re-scanned at 32
weeks [13], this already existing rate of LLP-related referrals would thus be present in any
potential detection strategy in practice. Therefore, the LLP-based pathway would require only
minimal additional TAS resource overall specifically for the detection of VP compared to cur-
rent practice. In contrast, the VCI-based pathway would require additional screening for VCI
and BL/S placenta in all pregnancies undergoing the routine fetal anomaly scan at 18
+0
to 20
+6
weeks. It should however be noted that this may overestimate the number of additionally
required scans, as reporting of placental cord insertion during the 18
+0
to 20
+6
week scan may
already be routinely practiced in some UK centres. Irrespective, the referral of all pregnancies
with detected VCI would always result in the additional recall of large numbers of women
(38,028 in the base case) with positive screening results to TAS for VP at 32 weeks and subse-
quent referral to TVS where indicated.
Crucially, a high proportion of the VCI pregnancies detected as part of this pathway would
not be affected by VP and a substantial number of VCI pregnancies diagnosed at 18
+0
to 20
+6
weeks would actually be false positives (around 24,000 in the base case). The situation relating
to VCI is therefore complicated, and it has also been noted that VCI, and cord anomalies more
generally, currently represent an area of obstetrics which has not been well studied [46]. At the
same time, some evidence points towards a small absolute increase in the risk of adverse preg-
nancy outcomes for VCI pregnancies [1,46,47], but no evidence-based interventions or man-
agement pathways are available to reduce such risks. Overdetection and false positive test
results may cause unnecessary anxiety and, with a limited evidence base it may be challenging
to develop high quality information to mitigate this. So while the association between VP and
VCI has led to some guidelines recommending that all women are screened for VCI [9,10],
this would be a departure from current UK practice and the uncertainties relating to key ele-
ments of a screening and management pathway for such cord anomalies have been highlighted
[46]. As such, there is uncertainty about the balance of clinical benefit and harm that may
result from screen detection of VCI, particularly in the absence of VP. In contrast, adding the
offer of testing for VP alongside already performed scans for placenta praevia in late pregnancy
in a limited number of women may represent a more targeted approach compared to a VCI-
based pathway in areas, like the UK, where there is no nationally recommended strategy for
detection of VP or cord anomalies.
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However, given the exploratory nature of the reported analyses and the considerable uncer-
tainty associated with many of the model inputs, further investigation is required regarding
the potential effect of the different detection strategies and there is a need for high-quality data
to inform discussions about VP screening in the UK.
In conclusion, the results of this modelling exercise suggest that a targeted LLP-based
approach could detect a substantial proportion of VP cases while avoiding the potential com-
plications from the detection of VCI and requiring minimal changes to current clinical prac-
tice. However, without further research, future discussions about screening for VP will
continue to be constrained by the lack of high-quality data encountered in this exploratory
study.
Supporting information
S1 Fig. Structure of the VP screening model.
(TIF)
S1 Table. Full list of inputs, including rationale and references.
(DOCX)
S2 Table. Alternative inputs used in the Alternative Inputs scenario analysis.
(DOCX)
S1 File. SLR and MA on adverse perinatal outcomes.
(DOCX)
S2 File. Quality assessment results.
(DOCX)
S3 File. Glossary.
(DOCX)
S4 File. Model spreadsheet.
(XLSX)
Acknowledgments
The authors acknowledge Elizabeth Daly-Jones, Lead Sonographer at Imperial NHS Trust,
and Hilary Goodman, Operational Manager–Antenatal Services/Screening at Hampshire Hos-
pitals NHS Foundation Trust, for substantial contributions to study design. The authors also
acknowledge Helen Bewicke-Copley MSc, Kate Hanman MSc, Hattie Cant BSc, Ania
Bobrowska PhD and Annabel Griffiths PhD from Costello Medical, UK, for medical writing
and editorial assistance in preparing this manuscript for publication, based on the authors’
input and direction.
Author Contributions
Conceptualization: Benjamin Ruban-Fell, George Attilakos, Tao Haskins-Coulter, Christo-
pher Hyde, Jeanette Kusel, Anne Mackie, Oliver Rivero-Arias, Basky Thilaganathan, Nigel
Thomson, Cristina Visintin, John Marshall.
Formal analysis: Benjamin Ruban-Fell.
Methodology: Benjamin Ruban-Fell, George Attilakos, Tao Haskins-Coulter, Christopher
Hyde, Jeanette Kusel, Anne Mackie, Oliver Rivero-Arias, Basky Thilaganathan, Nigel
Thomson, Cristina Visintin, John Marshall.
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Validation: Benjamin Ruban-Fell, George Attilakos, Tao Haskins-Coulter, Christopher Hyde,
Jeanette Kusel, Anne Mackie, Oliver Rivero-Arias, Basky Thilaganathan, Nigel Thomson,
Cristina Visintin, John Marshall.
Writing – original draft: Benjamin Ruban-Fell, John Marshall.
Writing – review & editing: Benjamin Ruban-Fell, George Attilakos, Tao Haskins-Coulter,
Christopher Hyde, Jeanette Kusel, Anne Mackie, Oliver Rivero-Arias, Basky Thilaganathan,
Nigel Thomson, Cristina Visintin, John Marshall.
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