Incidence and outcomes of vasa praevia in the United Kingdom

Keywords: Vasa praevia, incidence, outcomes, perinatal mortality, velamentous cord insertion, pregnancy, surveillance, UK Obstetric Surveillance System ALL Metrics - Views Downloads How to cite this article Attilakos G, David AL, Tunn R et al. Incidence and outcomes of vasa praevia in the United Kingdom [version 2; peer review: 3 approved, 2 approved with reservations, 1 not approved]. NIHR Open Res 2024, 4:49 (https://doi.org/10.3310/nihropenres.13696.2) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente Select a format first ▬ ✚ Research Article Revised Incidence and outcomes of vasa praevia in the United Kingdom [version 2; peer review: 3 approved, 2 approved with reservations, 1 not approved] George Attilakos https://orcid.org/0000-0001-9757-952X 1, Anna L David2,3, Ruth Tunn https://orcid.org/0000-0003-1187-1808 4, Marian Knight https://orcid.org/0000-0002-1984-4575 4, Peter Brocklehurst5George Attilakos https://orcid.org/0000-0001-9757-952X 1, Anna L David2,3, [...] Ruth Tunn https://orcid.org/0000-0003-1187-1808 4, Marian Knight https://orcid.org/0000-0002-1984-4575 4, Peter Brocklehurst5 PUBLISHED 05 Dec 2024 Author details Author details 1 Fetal Medicine Unit, University College London Hospitals NHS Foundation Trust, 235 Euston Road, London, NW1 2BU, UK 2 Elizabeth Garrett Anderson Institute for Women’s Health, University College London, Medical School Building, Huntley Street, London, WC1E 6AU, UK 3 NIHR University College London Hospitals Biomedical Research Centre, 149 Tottenham Court Road, London, W1T 7DN, UK 4 National Perinatal Epidemiology Unit, University of Oxford, Old Road Campus, Headington, Oxford, OX3 7LF, UK 5 Birmingham Clinical Trials Unit, Institute of Applied Health Research, University of Birmingham, Room 106, Public Health Building, Edgbaston, Birmingham, B15 2TT, UK 2 Elizabeth Garrett Anderson Institute for Women’s Health, University College London, Medical School Building, Huntley Street, London, WC1E 6AU, UK 3 NIHR University College London Hospitals Biomedical Research Centre, 149 Tottenham Court Road, London, W1T 7DN, UK 4 National Perinatal Epidemiology Unit, University of Oxford, Old Road Campus, Headington, Oxford, OX3 7LF, UK 5 Birmingham Clinical Trials Unit, Institute of Applied Health Research, University of Birmingham, Room 106, Public Health Building, Edgbaston, Birmingham, B15 2TT, UK George Attilakos Roles: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Writing – Original Draft Preparation Roles: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Writing – Original Draft Preparation Anna L David Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Writing – Review & Editing Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Writing – Review & Editing Ruth Tunn Roles: Validation, Writing – Review & Editing Roles: Validation, Writing – Review & Editing Marian Knight Roles: Conceptualization, Formal Analysis, Investigation, Methodology, Writing – Review & Editing Roles: Conceptualization, Formal Analysis, Investigation, Methodology, Writing – Review & Editing Peter Brocklehurst Roles: Conceptualization, Formal Analysis, Investigation, Writing – Review & Editing Roles: Conceptualization, Formal Analysis, Investigation, Writing – Review & Editing OPEN PEER REVIEW REVIEWER STATUS Vasa praevia is an obstetric condition in which the fetal vessels run through the membrane over the internal cervical os, unprotected by the placenta or umbilical cord. It is associated with perinatal mortality if not diagnosed antenatally. We estimated the incidence and investigated outcomes of vasa praevia in the UK. We conducted a population-based descriptive study using the UK Obstetric Surveillance System (UKOSS). Cases were identified prospectively through monthly UKOSS submissions from all UK hospitals with obstetrician-led maternity units. All women diagnosed with vasa praevia who gave birth between 1st December 2014 and 30th November 2015 were included. The main outcome was estimated incidence of vasa praevia with 95% confidence intervals, using 2015 maternities as the denominator. Fifty-one women met the case definition. The estimated incidence of diagnosed vasa praevia was 6.64 per 100,000 maternities (95% CI 5.05-8.73). Of 198 units, 10 (5%) had a vasa praevia screening programme; one of these 10 units identified 25% of the antenatally diagnosed cases. Among women who had vasa praevia diagnosed or suspected antenatally (n=28, 55%), there were no perinatal deaths or hypoxic ischaemic encephalopathy (HIE). Twenty-four women with antenatal diagnosis were hospitalised at a median 32 weeks’ gestation and caesarean section was scheduled at a median 36 weeks’ gestation. When vasa praevia was diagnosed peripartum (n=23, 45%), the perinatal mortality rate was 37.5% and 47% of survivors developed HIE. The incidence of diagnosed vasa praevia was lower than anticipated. There was high perinatal mortality and morbidity for cases not diagnosed antenatally. The incidence of antenatally identified cases was much higher in the few centres that actively screened for this condition, and the perinatal outcomes were better. However, this group were all delivered by caesarean section and may include women who would not have experienced any adverse perinatal outcome. Vasa praevia is a pregnancy complication in which the blood vessels that connect the mother and fetus run across the opening of the womb, without protection from the placenta or umbilical cord. During birth, the vessels can tear. This can result in rapid blood loss from the baby and in some cases, death of the baby. We investigated how common vasa praevia is in the UK, and how women with the condition and their babies fared. The UK Obstetric Surveillance System (UKOSS) collects anonymous information from all maternity units in the UK about pregnant women who have certain medical conditions. UKOSS reporters provided information about all women with vasa praevia who gave birth between December 2014 and November 2015. We identified 51 women with vasa praevia, meaning vasa praevia was diagnosed less often in the UK than we had expected based on studies from other countries. Twenty-eight women were diagnosed during the antenatal period, while 23 were diagnosed during labour or after giving birth. Pregnant women in the UK are not screened for vasa praevia as standard, and some women may have had vasa praevia that was not diagnosed. A small number (5%) of maternity units in our study did offer screening for vasa praevia in their pregnant population. One of these units identified a quarter of all the women who had vasa praevia diagnosed during pregnancy. Babies born to women whose vasa praevia was diagnosed during pregnancy had good outcomes. All of these women gave birth by planned caesarean section, and they and their babies survived. Babies born to women whose vasa praevia was suspected or diagnosed during labour or after birth had worse outcomes. Around 40% were stillborn or died shortly after birth, and about half of those who survived had brain damage caused by lack of oxygen.

Vasa praevia, incidence, outcomes, perinatal mortality, velamentous cord insertion, pregnancy, surveillance, UK Obstetric Surveillance System Corresponding Author(s) George Attilakos ([email protected]) Grant information: This project is part-funded by the National Institute for Health and Care Research (NIHR) under its University College London Hospitals NHS Foundation Trust Research Capability Fund (Grant Reference Number RCF68/PB/2014 5990), which was used to cover the UKOSS fee for a year. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. No other funding or financial support was obtained for the study. MK is an NIHR Senior Investigator; award reference NIHR303806. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2024 Attilakos G 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 work is properly cited. How to cite: Attilakos G, David AL, Tunn R et al. Incidence and outcomes of vasa praevia in the United Kingdom [version 2; peer review: 3 approved, 2 approved with reservations, 1 not approved]. NIHR Open Res 2024, 4:49 (https://doi.org/10.3310/nihropenres.13696.2) First published: 03 Sep 2024, 4:49 (https://doi.org/10.3310/nihropenres.13696.1) Latest published: 05 Dec 2024, 4:49 (https://doi.org/10.3310/nihropenres.13696.2) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. In the revised version, we have: 1. Added a link to the original data collection form used in the study. 2. Added information about reasons for antenatal hospital admission for women whose vasa praevia was diagnosed perinatally. 3. Added details of the categories used for classifying the urgency of Caesarean section. 4. Clarified the difference between cases of vasa praevia and reports that did not meet the case definition, by revising the terminology used in Figure 1 and the text. 5. Mentioned the existence of a third type of vasa praevia, first described in 2019. 6. Expanded the discussion of recommendations around targeted screening. 7. Clarified throughout that the incidence figure is an estimate. 8. Implemented minor clarifications and corrections of typos requested by the reviewers. In the revised version, we have: 1. Added a link to the original data collection form used in the study. 2. Added information about reasons for antenatal hospital admission for women whose vasa praevia was diagnosed perinatally. 3. Added details of the categories used for classifying the urgency of Caesarean section. 4. Clarified the difference between cases of vasa praevia and reports that did not meet the case definition, by revising the terminology used in Figure 1 and the text. 5. Mentioned the existence of a third type of vasa praevia, first described in 2019. 6. Expanded the discussion of recommendations around targeted screening. 7. Clarified throughout that the incidence figure is an estimate. 8. Implemented minor clarifications and corrections of typos requested by the reviewers. 1. Added a link to the original data collection form used in the study. 2. Added information about reasons for antenatal hospital admission for women whose vasa praevia was diagnosed perinatally. 3. Added details of the categories used for classifying the urgency of Caesarean section. 4. Clarified the difference between cases of vasa praevia and reports that did not meet the case definition, by revising the terminology used in Figure 1 and the text. 5. Mentioned the existence of a third type of vasa praevia, first described in 2019. 6. Expanded the discussion of recommendations around targeted screening. 7. Clarified throughout that the incidence figure is an estimate. 8. Implemented minor clarifications and corrections of typos requested by the reviewers. See the authors' detailed response to the review by Paolo Ivo Cavoretto See the authors' detailed response to the review by Antonios Siargkas See the authors' detailed response to the review by Ramesha Papanna and Neha Agarwal See the authors' detailed response to the review by Cristina Trilla Vasa praevia is a rare obstetric complication which is defined as fetal vessels coursing through the membranes over the internal cervical os and below the fetal presenting part, unprotected by placental tissue or the umbilical cord1. This can be secondary to a velamentous cord insertion (vasa praevia type 1) or to fetal vessels running between lobes of a placenta with one or more accessory lobes (vasa praevia type 2)1. A third type, first described in 2019, involves vessels that leave then re-enter the placenta in a “boomerang” path (vasa praevia type 3)2. Rupture of the vessels during labour can lead to rapid fetal exsanguination and fetal death. Vasa praevia can be associated with high perinatal mortality if it is not diagnosed antenatally3,4. Although antenatal screening is possible, a suspicion of vasa praevia usually leads to caesarean section before labour, avoiding the chance of fetal vessel rupture during birth. However, the rarity of the condition; the possibly high false positive rate of antenatal diagnosis; the potential harms of iatrogenic late preterm delivery, such as neurodevelopmental issues5; and the inability of antenatal diagnosis to predict which cases of vasa praevia will rupture and bleed during labour means that antenatal screening has the potential for greater harm than benefit. Consequently, routine screening for vasa praevia is not advised by Royal College of Obstetricians and Gynaecologists guidelines6 or the National Screening Committee (NSC)7,8, although both organisations indicate a paucity of evidence on which to base a recommendation. Conversely, a recent international expert consensus statement supported routine screening because of the potential reduction in preventable perinatal mortality9. A recent systematic review of 24 studies suggested a mean incidence of vasa praevia of 7.9 (95% CI 5.9–10.1) per 10,000 pregnancies10. The majority of the included studies were retrospective, single-centre investigations and ultrasound protocols for antenatal detection of vasa praevia varied between studies. Two included prospective studies were small (4 and 11 cases of vasa praevia) and each based in two institutions11,12. Two large population-based studies were identified: a retrospective study of the California birth cohort from 2007 to 2012 found an incidence of 2 per 10,000 live singleton births13, while a prospective study using the Australasian Maternity Outcomes Surveillance System (AMOSS) showed a similar incidence of 2.1 per 10,000 women giving birth1. Data from the UK are limited; a retrospective study of data from a prospective vasa praevia screening programme in a single UK fetal medicine unit estimated an incidence of 8 per 10,000 singleton pregnancies, in a study population of 26,83014, while a 5-year historical cohort study at a single UK hospital with a screening program estimated a similar incidence of 7.7 per 10,000 births15. However, no study has investigated the population incidence of vasa praevia in the UK prospectively or using nationwide data. We used the United Kingdom Obstetric Surveillance System (UKOSS) to prospectively estimate the incidence and investigate outcomes of vasa praevia in the UK. We also surveyed all UKOSS reporting centres about vasa praevia antenatal screening practices. Patients were not directly involved in the design of the study. Two members of the public were indirectly involved in the design of the study via representatives on the UKOSS Steering Committee, which reviews, comments on, and approves all studies to be run through UKOSS. This is a population-based descriptive study using the UK Obstetric Surveillance System (UKOSS). UKOSS was established to study rare pregnancy disorders through routine monthly reporting from all UK maternity units. The UKOSS methodology has been previously described16. In summary, nominated reporting clinicians (midwives, obstetricians and/or obstetric anaesthetists) in each hospital were sent a card each month, which included a simple tick-box to indicate a case of vasa praevia (along with other conditions studied). When a case was reported, a data collection form was sent to the reporting clinician to collect details on demographics, pregnancy risk factors, ultrasound diagnosis, antenatal and intrapartum management, delivery and neonatal outcome. We asked about the following risk factors for vasa praevia: IVF conception, low lying placenta, marginal or velamentous cord insertion, and bilobed or succenturiate lobed placentation. The full data collection form for this study can be found here: https://www.npeu.ox.ac.uk/assets/downloads/ukoss/forms/UKOSS-Vasa-Praevia-V1.pdf. We used a robust case definition where each case was required to meet at least one clinical criterion and at least one postnatal confirmation criterion (Table 1). Cases were confirmed against the case definition. The woman’s year of birth, hospital and estimated date of delivery were used to exclude duplicate cases. We collected data for vasa praevia cases in births occurring between 1st December 2014 and 30th November 2015. To establish the existence of screening programmes for vasa praevia, we asked each reporting centre the following question: “Between the 1st of December 2014 and the 30th of November 2015 was there a formal screening programme for vasa praevia at your hospital/centre?”. Estimated incidence with 95% confidence intervals was calculated using the number of maternities for 2015 as denominator, using published data from the Office for National Statistics (England and Wales)17, National Records of Scotland18 and the Northern Ireland Statistics and Research Agency19. For the purpose of the analyses, those cases diagnosed or suspected in the antenatal period were labelled as “antenatal”. Those cases not suspected/diagnosed in the antenatal period, but identified either during labour/delivery or after birth we labelled as “peripartum”. We used chi-square test, Fisher exact test, t-test and Mann-Whitney U tests as appropriate for statistical comparisons. We used SPSS 22.0 (IBM Corp., Armonk, NY, USA) for statistical analyses. The UK Obstetric Surveillance System general methodology was approved by the London Multi-Centre Research Ethics Committee (04/ MRE02/45; 24 September 2004) and this study was approved by the Proportionate Review Sub-committee of the East Midlands-Derby NRES Committee (14/EM/1237; 10 November 2014). Consent was not required for the collection of anonymous routine data. Following exclusion of duplicates, UKOSS received reports of 73 women with vasa praevia. However, only 51 met the case definition (details of excluded reports are in Figure 1). Most excluded reports did not meet the placental confirmation criteria of our case definition: 10 had planned caesarean section for suspected vasa praevia but there was no documentation of the placenta being examined or sent to histopathology after birth, so there was no confirmation of vasa praevia; 7 did not have vasa praevia (2 had cord prolapse, 2 had placenta praevia, 3 others had suspected vasa praevia but no evidence of vasa praevia on postnatal examination of the placenta and membranes); and for 4 others, vasa praevia was not confirmed on histopathology despite suspicious delivery events or outcomes. The total number of maternities for 2015 was 768,161. Therefore, we calculated the estimated incidence of vasa praevia in the UK as 6.64 per 100,000 maternities (95% CI 5.05–8.73). This equates to approximately 1 case for every 15,062 maternities. Of the 51 cases included, 28 cases (55%) were antenatal (diagnosed or suspected in the antenatal period). The remaining 23 cases (45%) were peripartum (not suspected/diagnosed in the antenatal period). All but one of these 23 cases were associated with bleeding during labour or during induction of labour. Demographic data and pregnancy characteristics are summarised in Table 2. A low placenta or a succenturiate lobe were more likely to have been identified in the antenatally diagnosed cases. Otherwise, there were no differences between the two groups. It is notable that all cases had at least one risk factor for vasa praevia. | Characteristics | Total (n=51) | Antenatal (n=28) | Peripartum (n=23) | p* | |---|---|---|---|---| | Maternal age (years) | 32.7 (4.5) | 33.3 (4.4) | 31.9 (4.7) | 0.29 | | Body Mass Index | 25.2 (4.5) | 24.4 (3.3) | 26.0 (5.7) | 0.22 | | Ethnic group | 0.27 | ||| | Any white background | 41 (80) | 20 (71) | 21 (91) | | | Other | 10 (20) | 8 (29) | 2 (9) | | | Nulliparous | 25 (49) | 16 (57) | 9 (39) | 0.34 | | Smoking during pregnancy | 7 (14) | 3 (11) | 4 (17) | 0.25 | | Risk factors for VP | |||| | Low lying placenta | 34 (67) | 24 (86) | 10 (43) | 0.001 | | Velamentous cord insertion | 25 (49) | 15 (54) | 10 (43) | 0.26 | | Bilobed placenta | 5 (10) | 2 (7) | 3 (13) | 0.75 | | Succenturiate lobe | 13 (25) | 10 (36) | 3 (13) | 0.07 | | Marginal cord insertion | 3 (6) | 1 (4) | 2 (9) | 0.21 | | IVF conception | 8 (16) | 6 (21) | 2 (9) | 0.26 | | At least one risk factor | 51 (100) | 28 (100) | 23 (100) | The clinical presentation and management are summarised in Table 3. Of the 11 women in the peripartum diagnosis group admitted to hospital antenatally, three were admitted for reasons relating to the position or movement of the fetus; four for maternal indications unrelated to vasa praevia, such as elevated blood pressure; and two for antepartum haemorrhage that progressed to birth. Notably, two women were admitted for antepartum bleeding earlier in the pregnancy, which could indicate a missed opportunity for vasa praevia diagnosis. | Antenatal diagnosis n=28 | Peripartum diagnosis n=23 | p | | |---|---|---|---| | Number of scans after 17 weeks of gestation | 0.03 | || | 1 | 0 (0) | 4 (17) | | | 2 | 2 (7) | 5 (22) | | | 3 | 5 (18) | 10 (43) | | | 4 | 10 (36) | 2 (9) | | | 5 or more | 11 (39) | 2 (9) | | | Antenatal bleeding | 0 (0) | 10 (43) | <0.0001 | | Bleeding during labour | 0 (0) | 8 (35) | 0.002 | | Bleeding at membrane rupture | 0 (0) | 13 (57) | <0.0001 | | Antenatal hospital admission | 24 (86) | 11 (48) | 0.006 | | Cervical length measured | 10 (36) | 0 (0) | 0.001 | | Cervical length used in decision to admit | 3 (11) | 0 (0) | 0.006 | | Fetal fibronectin testing | 1 (4) | 0 (0) | | | Fetal fibronectin used in decision to admit | 0 (0) | 0 (0) | | | Antenatal steroids | 25 (89) | 2 (9) | <0.0001 | | CTG classification (where used) | <0.0001 | || | Normal | 7 (25) | 4 (17) | | | Suspicious | 0 (0) | 3 (13) | | | Pathological | 1 (4) | 11 (48) | | | Delivery by CS | 28 (100) | 22 (96) | 0.45 | | Planned CS | 28 (100) | 3 (13) | <0.0001 | | Gestation of planned CS | 36.7 (34.2–39.0) | 37.7 (37.7–37.7) (1 case) | 1.000 | | Gestation at delivery | 36.4 (31.3–39.6) | 38 (36.1 – 39.9) | <0.0001 | | Urgency category* | <0.0001 | || | Category 1 | 0 (0) | 19 (83) | | | Category 2 | 6 (21) | 1 (4) | | | Category 3 | 3 (11) | 2 (9) | | | Category 4 | 19 (68) | 0 (0) | | | Anaesthesia method | ||| | Regional | 25 (89) | 7 (30) | <0.0001 | | General | 3 (11) | 15 (65) | 1000 ml | 3 (11) | 1 (4) | 0.38 | | Placenta examined | 28 (100) | 21 (91) | 0.28 | | Placenta to pathology | 9 (32) | 15 (65) | 0.03 | Data are presented as n (%) or median (range). *Urgency classification: 1- Immediate threat to life of woman or fetus; 2 – Maternal or fetal compromise which is not immediately life threatening; 3 – needing early delivery but no maternal or fetal compromise; 4 – At a time to suit the woman and maternity team. CTG: cardiotocography; CS, caesarean section; PPH, postpartum haemorrhage Most peripartum-diagnosed cases presented with bleeding and this bleeding was at membrane rupture for 13 (57%) of these cases. Of the 23 women diagnosed peripartum, 22 (96%) delivered by caesarean section, of which 83% were category 1 surgeries; 15 women (65%) had general anaesthesia. There was one vaginal birth of a stillborn baby in this group. Of the 23 peripartum-diagnosed cases, 20 (87%) were born after 37 weeks and all after 36 weeks. Only 14% (n=4) of antenatally diagnosed cases were not admitted to hospital prior to delivery. The cervical length was measured in 10 (36%) of the antenatally diagnosed cases but it was used as a factor in the decision to admit for only 3 (11%) cases. Fetal fibronectin was measured in only one case and it was not a factor in the decision to admit. The median gestation at diagnosis was 29 weeks, with the earliest at 17 and the latest at 36 weeks. The earliest admission for antenatally diagnosed vasa praevia was at 21 weeks. This woman had 4 admissions for a total of 73 days. Only 3 other women with an antenatal diagnosis of vasa praevia were admitted to hospital prior to 30 weeks (two of them because of vaginal bleeding). The median gestation at admission was 32.6 weeks with the latest admission at 36.5 weeks. The median duration of admission was 6 days (range 1–73). Seventeen (61%) women with antenatal diagnosis stayed in hospital for more than 10 days. The 4 women who were not admitted had planned caesarean sections at 38–39 weeks. All antenatally diagnosed cases were scheduled for a caesarean section, with the majority scheduled between 36 and 37 weeks. The earliest scheduled caesarean section was at 34 weeks (n=4) and the latest at 39 weeks (n=2). However, 9 (32%) of these women had a category 2 or 3 caesarean section earlier than planned. The earliest caesarean birth was at 31 weeks (n=1) because of recurrent antepartum bleeding. Only one other woman was delivered before 34 weeks, because of threatened preterm labour. Of the prenatally diagnosed cases, 25 (89%) had regional anaesthesia. The perinatal outcomes are summarised in Table 4. There was a multiple pregnancy in the peripartum diagnosis group, so the outcomes refer to 52 fetuses. There were 4 stillbirths and 5 neonatal deaths in the peripartum group, making the perinatal mortality rate 37.5% for this group. The overall perinatal mortality rate was 17%. Almost 50% (7 of 15) of the surviving babies in the peripartum group had hypoxic ischaemic encephalopathy (HIE). In the group with peripartum diagnosis, 11 (46%) of babies had a blood transfusion for anaemia. There were no stillbirths, neonatal deaths or HIE cases in the antenatally diagnosed group but 2 babies in this group developed respiratory distress syndrome after delivery at 35–36 weeks. | Antenatal diagnosis (n=28) | Peripartum diagnosis (n=24*) | p | | |---|---|---|---| | Gender | 0.58 | || | Male | 13 (46) | 13 (54) | | | Female | 15 (54) | 11 (46) | | | Birthweight (g) | 2685 (±488) | 3126 (±378) | 0.001 | | Stillbirth | 0 (0) | 4 (17) | 0.04 | | Neonatal death | 0 (0) | 5 (21) | 0.002 | | NICU admission | 10 (36) | 15 (62) | 0.006 | | Anaemia | 0 (0) | 9 (37) | <0.0001 | | Blood transfusion | 0 (0) | 11 (46) | <0.0001 | | Hypoxic ischaemic encephalopathy | 0 (0) | 7 (29) | 0.002 | | Seizures | 0 (0) | 6 (25) | 0.007 | | Renal failure | 0 (0) | 4 (17) | 0.04 | Of the 198 reporting centres, 174 (88%) replied to our question: “Between the 1st of December 2014 and the 30th of November 2015 was there a formal screening programme for vasa praevia at your hospital/centre?”. Only 10 hospitals (6% of respondents) declared they had a formal screening programme for vasa praevia during the time of the study. Fifteen replies (9%) were “unknown”. One of the 10 hospitals with screening programmes reported 7 cases, all antenatally diagnosed (14% of all cases and 25% of all antenatally diagnosed cases). The other 9 hospitals did not report any cases. This difference in antenatally diagnosed cases between screening and non-screening hospitals was statistically significant (Table 5). This prospective population-based study estimated a lower than anticipated incidence of vasa praevia in the UK: 6.64 per 100,000 maternities, or 1 case for every 15,062 maternities. There was high perinatal mortality and morbidity with peripartum diagnosis. The estimated incidence of antenatally identified cases in the few centres that actively screened for this condition was much higher, and the perinatal outcomes were better. However, this group were all delivered by caesarean section and some infants had respiratory morbidity as a consequence of elective preterm delivery. A significant strength of our study is its prospective population-based design, which does not rely on routinely coded data to ascertain cases. This is a national study, conducted at all obstetric units in the UK and therefore covering the whole of the pregnant population. UKOSS is a well-established and validated system for identifying cases of uncommon pregnancy complications and, because it covers all obstetric units, is not subject to the usual biases of single-centre studies. While we cannot exclude the possibility that there may have been a few cases that were diagnosed but not reported, we have no reason to suspect substantial under-ascertainment or bias in reporting. This study therefore represents a true snapshot of the current number of diagnosed cases in the UK pregnant population, with the caveat that only a small number of centres are actively screening for vasa praevia. We used a robust case definition in order to accurately capture clinically diagnosed and confirmed cases. However, this strict definition was a potential weakness, as demonstrated by the 10 antenatally suspected cases who could not be included as there was no evidence of examination (histopathological or not) of the placenta after birth. Photographic documentation during caesarean birth could have been considered as an alternative means of confirming the diagnosis. Although we had multiple reporters in each hospital, we cannot be certain all cases were identified. In particular, the diagnosis may never have been considered as there is a possibility that ruptured vasa praevia mimics other conditions (e.g., abruption) and there is no “gold” standard to confirm the diagnosis after birth if the vessels are not ruptured. There are guidelines about the diagnosis and management of vasa praevia in the UK, USA, Canada and Australia highlighting the importance of the condition. These were compared in a recent publication20. All guidelines agree that colour and pulsed Doppler transvaginal ultrasound should be used in mid-trimester to diagnose the condition, but third trimester confirmation is also needed. Universal screening is not recommended but rather targeted screening for women with risk factors, such as low placenta, is advocated in the U.S.A, Canada and Australia21–23. The UK’s Royal College of Obstetricians and Gynaecologists and National Screening Committee advise that further research into the balance of benefit and harm of targeted screening is needed before a recommendation can be made6,24. Antenatal steroids are to be considered from 28–32 weeks and hospitalisation from 30–32 weeks. All four guidelines agree the optimal timing of birth is unknown, but they recommend birth by caesarean section at 34–37 weeks. A recent expert consensus statement recommended caesarean birth at 35–37 weeks, but advocated second-trimester screening as routine for all pregnancies, via transabdominal ultrasound with colour Doppler sweep over the cervix, followed by third-trimester confirmation of the diagnosis by transvaginal ultrasound9. Our study demonstrates that vasa praevia diagnosis in the UK is less common than anticipated, with a lower estimated incidence of vasa praevia than found in previous studies1,10,13. Even if the 10 planned caesarean sections with no postnatal confirmation were included, the estimated incidence would still be relatively low at 7.94 per 100,000 maternities (1 case for every 12,593 maternities). Although our strict case definition may be partially responsible, the AMOSS study in Australia demonstrated about 2–3 times higher incidence (21 per 100,000) using an almost identical case definition. However, in the Australian study, 92% of cases were identified antenatally with only 5 cases being identified peripartum. Peripartum cases might be considered to represent the true incidence of ruptured vasa praevia; the incidence of peripartum vasa praevia in Australia was 1.7 per 100,000, and in the UK it was 3 per 100,000. The differing thresholds and screening protocols for detecting vasa praevia antenatally are likely to explain these apparent differences in the overall reported incidence between the two countries. Other possible reasons include cases not being reported or not recognised during the study period; women with undiagnosed vasa praevia having pre-labour caesarean section for other indications (especially low lying placenta); and some cases with poor outcome could have been attributed to other causes, such as abruption, or ruptured fetal vessels on placental histopathology being attributed to “snapped” cord during continuous cord traction at delivery, which is more likely to occur with velamentous cord insertion. Our study found very different outcomes in those cases that were identified antenatally compared with those diagnosed intrapartum or postnatally. In cases not diagnosed antenatally there was an almost 40% perinatal mortality. This high perinatal mortality is remarkably similar to that observed in a retrospective study (44%)3 and in the prospective AMOSS study (40%)1 and confirms the high fatality rate of vasa praevia when it is not suspected or diagnosed before labour. Our study also found that almost half of the survivors in cases with no antenatal diagnosis had hypoxic ischaemic encephalopathy, although the grade and consequences of this are unknown; in contrast, none of the infants in cases with antenatal diagnosis had hypoxic ischaemic encephalopathy. This is in keeping with the findings of a recent systematic review, which found that 58% of surviving neonates in cases of vasa praevia without antenatal diagnosis displayed hypoxic morbidity, compared with only 2.7% in cases with antenatal diagnosis4. Most previous studies25 demonstrated the presence of risk factors in most vasa praevia cases; in our study all cases had at least one risk factor. This might suggest that targeted screening for cases with risk factors, particularly low placenta and velamentous cord insertion, might be useful as one or both of these were present in almost half of the cases in our study. This would be consistent with current US, Canadian and Australian guidelines, all of which recommend targeted screening20. Ten maternity units declared they had a formal screening programme for vasa praevia. Of these, only one centre reported any cases of antenatally detected vasa praevia during the study period. Table 5 illustrates that the number of reported cases of vasa praevia was substantially higher if there was antenatal screening. Large, well-designed prospective screening studies may elucidate this observation further; our study was not designed to evaluate screening efficiency or accuracy. A historical cohort study of a screening program in a single UK institution reported 100% sensitivity and 99.78% specificity, but a perinatal mortality of 5% (one death in 19 confirmed cases of vasa praevia)15. Evaluation of accuracy of screening methods for vasa praevia is difficult because of the absence of a diagnostic “gold standard”. Once the placenta is delivered, velamentous cord insertion or bilobed placenta can be confirmed but it is impossible to know what the proximity of the vasa praevia to the cervix was. Inspection during the caesarean section is often difficult because of bleeding from the uterine incision and the placental bed. In addition, there is no clear definition of vasa praevia as there is no evidence about a “safe” distance from the internal os. A distance of 2 cm between the fetal vessels and the internal os has been proposed21,26 but it is not based on robust evidence. It is likely that many clinicians would find it difficult to recommend expectant management and normal birth to a woman with fetal vessels at e.g. 2.3 cm from the cervix. Indeed, a recent expert consensus process failed to reach agreement on the fetal vessel-internal os distance that should be used to define vasa praevia, but concluded that it should not be limited to 2 cm9, and a recently registered clinical trial of fetoscopic laser photocoagulation in management of vasa praevia (https://clinicaltrials.gov/study/NCT06290232) will use a 5-cm threshold for diagnosis. A UK single-institution study of a two-stage screening strategy for vasa praevia used a diagnostic threshold of 5 cm and estimated an incidence of 8 per 10,000 singleton pregnancies14. If reporting centres in our study were using more restrictive criteria, this may go some way to explaining the much lower incidence that we observed. The Royal College of Obstetricians and Gynaecologists6 recommends consideration of prophylactic hospitalisation for confirmed vasa praevia after 30–32 weeks. Our study showed a wide variation in practice with most women with an antenatal diagnosis of vasa praevia being admitted after 30 weeks, at a median gestation of 32–33 weeks. Although most women spent up to 18 days in hospital in the antenatal period, there were 2 women who were admitted for over 2 months. The 4 women who did not have antenatal hospital admission had later planned caesarean sections at 38–39 weeks, suggesting the absence of any episodes of antepartum bleeding, no risk factors for early labour or even perhaps maternal preference. Our data showed that most caesarean sections for the antenatally diagnosed cases were scheduled for 36–37 weeks and some up to 39 weeks. In about one third of these cases the caesarean section had to be brought forward, usually because of episodes of bleeding or threatened preterm labour. Only 2 caesarean sections (7%) were performed before 34 weeks. Within the antenatally diagnosed group there were only 2 cases of respiratory distress syndrome but 10 (36%) babies were admitted to a neonatal unit. Given the recently recognised additional risks of late preterm birth5,27, it would seem sensible to aim for delivery at 36–37 weeks and perform earlier caesarean sections for cases with episodes of vaginal bleeding or other risk factors. Clinicians can also consider using cervical length and/or fetal fibronectin or other cervicovaginal biochemical swab tests to stratify further the risk of preterm labour before 35 weeks of gestation although there is no current evidence to support this approach28. Of course, maternal anxiety cannot be underestimated in these circumstances29 and can be a significant factor in birth timing. This prospective national study estimated a lower than anticipated incidence of vasa praevia, and a very low population incidence of poor perinatal outcome after vasa praevia. However, peripartum diagnosis was associated with an almost 40% perinatal mortality and about 50% risk of HIE in the surviving neonates. Antenatal diagnosis led to planned caesarean section for the majority of infants at 36–37 weeks with no observed deaths or cases of HIE, but some infants had respiratory morbidity. Our study could not address screening efficacy or the optimal screening method, but showed that a screening programme was associated with an increased number of vasa praevia diagnoses and no perinatal deaths, although the difference on the latter metric between maternity units with and without a screening program did not reach statistical significance. Data cannot be shared because of confidentiality issues and potential identifiability of sensitive data as identified in the Research Ethics Committee approval. Requests to access the data can be made by contacting the National Perinatal Epidemiology Unit data access committee via [email protected]. The estimated response time for requests is 4 weeks. Data sharing outside the UK or the European Union may require consultation with the UK Health Research Authority. For more information, please refer to the National Perinatal Epidemiology Unit Data Sharing Policy available at: https://www.npeu.ox.ac.uk/assets/downloads/npeu/policies/Data_Sharing_Policy.pdf The authors would like to thank the UK Obstetric Surveillance System (UKOSS) reporting clinicians who notified cases and completed the data-collection forms. They would also like to thank the UKOSS staff who enable these studies to be completed. Preliminary study results were presented at the British Maternal and Fetal Medicine Society meeting in Amsterdam, March 2017. Faculty Opinions recommendedReferences - 1. Sullivan EA, Javid N, Duncombe G, et al.: Vasa previa diagnosis, clinical practice, and outcomes in Australia. Obstet Gynecol. 2017; 130(3): 591–8. PubMed Abstract | Publisher Full Text - 2. Suekane T, Tachibana D, Pooh RK, et al.: Type-3 vasa previa: normal umbilical cord insertion cannot exclude vasa previa in cases with abnormal placental location. Ultrasound Obstet Gynecol. 2020; 55(4): 556–557. PubMed Abstract | Publisher Full Text - 3. Oyelese Y, Catanzarite V, Prefumo F, et al.: Vasa previa: the impact of prenatal diagnosis on outcomes. Obstet Gynecol. 2004; 103(5 Pt 1): 937–42. PubMed Abstract | Publisher Full Text - 4. Zhang W, Geris S, Al-Emara N, et al.: Perinatal outcome of pregnancies with prenatal diagnosis of vasa previa: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2021; 57(5): 710–9. PubMed Abstract | Publisher Full Text - 5. Mitha A, Chen R, Razaz N, et al.: Neurological development in children born moderately or late preterm: national cohort study. BMJ. 2024; 384: e075630. PubMed Abstract | Publisher Full Text - 6. Jauniaux E, Alfirevic Z, Bhide A, et al.: Vasa praevia: diagnosis and management: green-top guideline no. 27b. BJOG. 2019; 126(1): e49–e61. PubMed Abstract | Publisher Full Text - 7. UK National Screening Committee: Screening for vasa praevia in the second trimester of pregnancy: external review against programme appraisal criteria for the UK National Screening Committee (UK NSC). 2017; [accessed 02 May 2024]. Reference Source - 8. UK National Screening Committee: Screening for Vasa Praevia: an evidence map to outline the volume and type of evidence related to screening for vasa praevia for the UK National Screening Committee. 2023; [accessed 30 April 2024]. Reference Source - 9. Oyelese Y, Javinani A, Gudanowski B, et al.: Vasa previa in singleton pregnancies: diagnosis and clinical management based on an international expert consensus. Am J Obstet Gynecol. 2024; 231(6): 638.e1–638.e24. PubMed Abstract | Publisher Full Text - 10. Zhang W, Giacchino T, Chanyarungrojn PA, et al.: Incidence of vasa praevia: a systematic review and meta-analysis. BMJ Open. 2023; 13(9): e075245. PubMed Abstract | Publisher Full Text | Free Full Text - 11. Derisbourg S, Boulay A, Lamy C, et al.: First trimester ultrasound prediction of velamentous cord insertions: a prospective study. J Matern Fetal Neonatal Med. 2021; 34(16): 2642–8. PubMed Abstract | Publisher Full Text - 12. Catanzarite V, Maida C, Thomas W, et al.: Prenatal sonographic diagnosis of vasa previa: ultrasound findings and obstetric outcome in ten cases. Ultrasound Obstet Gynecol. 2001; 18(2): 109–15. PubMed Abstract | Publisher Full Text - 13. Yeaton-Massey A, Girsen AI, Mayo JA, et al.: Vasa previa and extreme prematurity: a population-based study. J Perinatol. 2019; 39(3): 475–80. PubMed Abstract | Publisher Full Text - 14. Zhang W, Geris S, Beta J, et al.: Prevention of stillbirth: impact of two-stage screening for vasa previa. Ultrasound Obstet Gynecol. 2020; 55(5): 605–12. PubMed Abstract | Publisher Full Text - 15. Nwandison M, Daly-Jones E, Drought A, et al.: Incorporation of vasa previa screening into a routine anomaly scan: a single center cohort study. Acta Obstet Gynecol Scand. 2024; 103(7): 1466–73. PubMed Abstract | Publisher Full Text | Free Full Text - 16. Knight M, Kurinczuk JJ, Tuffnell D, et al.: The UK Obstetric Surveillance System for rare disorders of pregnancy. BJOG. 2005; 112(3): 263–5. PubMed Abstract | Publisher Full Text - 17. Office for National Statistics: Births in England and Wales: summary tables. 2015 edition of this dataset. 2016; [accessed 2 May 2024]. Reference Source - 18. National Records of Scotland: Vital events reference tables 2015. Section 3: Births. Table 3.11: Live births, stillbirths and maternities, by sex of child, marital status of parents and age of mother, Scotland, 2015; [accessed 2 May 2024]. Reference Source - 19. The Northern Ireland Statistics and Research Agency: Registrar general Northern Ireland: annual report 2015. 2016; [accessed 2 May 2024]. Reference Source - 20. Tsakiridis I, Mamopoulos A, Athanasiadis A, et al.: Diagnosis and management of vasa previa: a comparison of 4 national guidelines. Obstet Gynecol Surv. 2019; 74(7): 436–42. PubMed Abstract | Publisher Full Text - 21. Sinkey RG, Odibo AO, Dashe JS: #37: diagnosis and management of vasa previa. Am J Obstet Gynecol. 2015; 213(5): 615–9. PubMed Abstract | Publisher Full Text - 22. Jain V, Gagnon R: Guideline no. 439: diagnosis and management of vasa previa. J Obstet Gynaecol Can. 2023; 45(7): 506–518. PubMed Abstract | Publisher Full Text - 23. The Royal Australian and New Zealand College of Obstetricians and Gynaecologists: Vasa praevia. 2019; [accessed 30 Oct 2024]. Reference Source - 24. UK National Screening Committee: Antenatal screening programme: vasa praevia. 2023; [accessed 30 Oct 2024]. Reference Source - 25. Ruiter L, Kok N, Limpens J, et al.: Incidence of and risk indicators for vasa praevia: a systematic review. BJOG. 2016; 123(8): 1278–87. PubMed Abstract | Publisher Full Text - 26. Oyelese Y, Smulian JC: Placenta previa, placenta accreta, and vasa previa. Obstet Gynecol. 2006; 107(4): 927–41. PubMed Abstract | Publisher Full Text - 27. Chan E, Leong P, Malouf R, et al.: Long-term cognitive and school outcomes of late-preterm and early-term births: a systematic review. Child Care Health Dev. 2016; 42(3): 297–312. PubMed Abstract | Publisher Full Text - 28. Hezelgrave NL, Shennan AH, David AL: Tests to predict imminent delivery in threatened preterm labour. BMJ. 2015; 350: h2183. PubMed Abstract | Publisher Full Text - 29. Javid N, Sullivan EA, Halliday LE, et al.: "Wrapping myself in cotton wool": Australian women's experience of being diagnosed with vasa praevia. BMC Pregnancy Childbirth. 2014; 14: 318. PubMed Abstract | Publisher Full Text | Free Full Text Author details Author details 1 Fetal Medicine Unit, University College London Hospitals NHS Foundation Trust, 235 Euston Road, London, NW1 2BU, UK 2 Elizabeth Garrett Anderson Institute for Women’s Health, University College London, Medical School Building, Huntley Street, London, WC1E 6AU, UK 3 NIHR University College London Hospitals Biomedical Research Centre, 149 Tottenham Court Road, London, W1T 7DN, UK 4 National Perinatal Epidemiology Unit, University of Oxford, Old Road Campus, Headington, Oxford, OX3 7LF, UK 5 Birmingham Clinical Trials Unit, Institute of Applied Health Research, University of Birmingham, Room 106, Public Health Building, Edgbaston, Birmingham, B15 2TT, UK 2 Elizabeth Garrett Anderson Institute for Women’s Health, University College London, Medical School Building, Huntley Street, London, WC1E 6AU, UK 3 NIHR University College London Hospitals Biomedical Research Centre, 149 Tottenham Court Road, London, W1T 7DN, UK 4 National Perinatal Epidemiology Unit, University of Oxford, Old Road Campus, Headington, Oxford, OX3 7LF, UK 5 Birmingham Clinical Trials Unit, Institute of Applied Health Research, University of Birmingham, Room 106, Public Health Building, Edgbaston, Birmingham, B15 2TT, UK George Attilakos Roles: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Writing – Original Draft Preparation Roles: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Writing – Original Draft Preparation Anna L David Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Writing – Review & Editing Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Writing – Review & Editing Ruth Tunn Roles: Validation, Writing – Review & Editing Roles: Validation, Writing – Review & Editing Marian Knight Roles: Conceptualization, Formal Analysis, Investigation, Methodology, Writing – Review & Editing Roles: Conceptualization, Formal Analysis, Investigation, Methodology, Writing – Review & Editing Peter Brocklehurst Roles: Conceptualization, Formal Analysis, Investigation, Writing – Review & Editing Roles: Conceptualization, Formal Analysis, Investigation, Writing – Review & Editing Competing interests George Attilakos has received travel expenses from Ferring UK to present at national and international meetings. Anna David: Member of Hologic UK Perinatal Advisory Board 2017–2018 and received honorarium to present about preterm birth at British Maternal Fetal Medicine Society conference in 2018. Peter Brocklehurst has received consultancy fees from Biotest AG. Ruth Tunn: No competing interests were disclosed. Marian Knight: No competing interests were disclosed. Grant information This project is part-funded by the National Institute for Health and Care Research (NIHR) under its University College London Hospitals NHS Foundation Trust Research Capability Fund (Grant Reference Number RCF68/PB/2014 5990), which was used to cover the UKOSS fee for a year. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. No other funding or financial support was obtained for the study. MK is an NIHR Senior Investigator; award reference NIHR303806. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (2) Copyright © 2024 Attilakos G 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 work is properly cited. metrics VIEWS $counts.viewCount downloads Citations CITE how to cite this article Attilakos G, David AL, Tunn R et al. Incidence and outcomes of vasa praevia in the United Kingdom [version 2; peer review: 3 approved, 2 approved with reservations, 1 not approved]. NIHR Open Res 2024, 4:49 (https://doi.org/10.3310/nihropenres.13696.2) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. track receive updates on this article Track an article to receive email alerts on any updates to this article. Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions Version 2 VERSION 2 PUBLISHED 05 Dec 2024 Revised Views 0 How to cite this report: Abdalla M. Reviewer Report For: Incidence and outcomes of vasa praevia in the United Kingdom [version 2; peer review: 3 approved, 2 approved with reservations, 1 not approved]. NIHR Open Res 2024, 4:49 (https://doi.org/10.3310/nihropenres.14995.r34164) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-49/v2#referee-response-34164 https://openresearch.nihr.ac.uk/articles/4-49/v2#referee-response-34164 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 17 Jan 2025 Approved with Reservations VIEWS 0 This study provides valuable insights into the incidence and outcomes of vasa praevia using prospective, population-based data from the UK Obstetric Surveillance System (UKOSS). The study highlights a high perinatal mortality rate (37.5%) in undiagnosed cases and the absence of ... Continue reading I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close This study provides valuable insights into the incidence and outcomes of vasa praevia using prospective, population-based data from the UK Obstetric Surveillance System (UKOSS). The study highlights a high perinatal mortality rate (37.5%) in undiagnosed cases and the absence of perinatal deaths in antenatally diagnosed cases, emphasizing the importance of early detection. Major Concerns: 1- The study states that 10 hospitals (5%) had a formal screening program, but it is unclear whether these programs were universal or risk-based. Given that screening approaches can significantly influence detection rates, the authors should: 2- A significant number of suspected cases (22 out of 73, or 30%) were excluded due to lack of histopathological confirmation. Given that: Vasa praevia is difficult to confirm postpartum, even with placental examination. The authors should: 3- The rising use of ART is an important contributor to vasa praevia risk, yet it is only briefly mentioned. Given that ART pregnancies have a 10-20x higher risk of vasa praevia, the discussion should: 4- While the antenatal diagnosis group had no perinatal deaths, the conclusion that screening reduces mortality is not fully supported because: · Only 10 hospitals had screening programs, and 9 reported no cases · The statistical significance of screening impact is unclear · Some pregnancies diagnosed antenatally may never have resulted in adverse outcomes, even without screening The authors should: Minor Concerns: In the discussion; discuss the potential role of cervical length measurement in guiding timing of delivery? Add a section for limitations. Fix minor spelling and grammatical errors ("form" instead of "from" in Methods section of the abstract) Major Concerns: 1- The study states that 10 hospitals (5%) had a formal screening program, but it is unclear whether these programs were universal or risk-based. Given that screening approaches can significantly influence detection rates, the authors should: - Specify how these screening programs operated - Discuss whether screening was transvaginal or transabdominal ultrasound-based - Clarify how screening influenced antenatal detection rates 2- A significant number of suspected cases (22 out of 73, or 30%) were excluded due to lack of histopathological confirmation. Given that: Vasa praevia is difficult to confirm postpartum, even with placental examination. The authors should: - Provide more details on why these cases were excluded - Consider whether photographic or intraoperative documentation could be used as an alternative to histopathology 3- The rising use of ART is an important contributor to vasa praevia risk, yet it is only briefly mentioned. Given that ART pregnancies have a 10-20x higher risk of vasa praevia, the discussion should: - Expand on how increasing ART usage may impact future incidence rates - Discuss whether targeted screening for ART pregnancies should be considered 4- While the antenatal diagnosis group had no perinatal deaths, the conclusion that screening reduces mortality is not fully supported because: · Only 10 hospitals had screening programs, and 9 reported no cases · The statistical significance of screening impact is unclear · Some pregnancies diagnosed antenatally may never have resulted in adverse outcomes, even without screening The authors should: - Clarify that the impact of screening on perinatal outcomes remains uncertain - Emphasize the need for larger, well-designed studies to evaluate screening efficacy Minor Concerns: In the discussion; discuss the potential role of cervical length measurement in guiding timing of delivery? Add a section for limitations. Fix minor spelling and grammatical errors ("form" instead of "from" in Methods section of the abstract) - Is the work clearly and accurately presented and does it cite the current literature? Yes - Is the study design appropriate and is the work technically sound? Yes - Are sufficient details of methods and analysis provided to allow replication by others? Yes - If applicable, is the statistical analysis and its interpretation appropriate? Yes - Are all the source data underlying the results available to ensure full reproducibility? Yes - Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Obstetrics and Gynaecology, fetal medicine, high risk obstetrics, maternal medicine. CITE HOW TO CITE THIS REPORT Abdalla M. Reviewer Report For: Incidence and outcomes of vasa praevia in the United Kingdom [version 2; peer review: 3 approved, 2 approved with reservations, 1 not approved]. NIHR Open Res 2024, 4:49 (https://doi.org/10.3310/nihropenres.14995.r34164) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-49/v2#referee-response-34164 https://openresearch.nihr.ac.uk/articles/4-49/v2#referee-response-34164 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. Views 0 How to cite this report: Libretti A. Reviewer Report For: Incidence and outcomes of vasa praevia in the United Kingdom [version 2; peer review: 3 approved, 2 approved with reservations, 1 not approved]. NIHR Open Res 2024, 4:49 (https://doi.org/10.3310/nihropenres.14995.r33986) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-49/v2#referee-response-33986 https://openresearch.nihr.ac.uk/articles/4-49/v2#referee-response-33986 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 19 Dec 2024 Approved VIEWS 0 Review of the Article: Incidence and Outcomes of Vasa Praevia in the United Kingdom This study provides valuable insights into the incidence and outcomes of vasa praevia using robust, population-based data from UKOSS. It highlights the significant ... Continue reading I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close This study provides valuable insights into the incidence and outcomes of vasa praevia using robust, population-based data from UKOSS. It highlights the significant ... Continue reading Review of the Article: Incidence and Outcomes of Vasa Praevia in the United Kingdom This study provides valuable insights into the incidence and outcomes of vasa praevia using robust, population-based data from UKOSS. It highlights the significant perinatal mortality (37.5%) in undiagnosed cases and the absence of deaths with antenatal diagnosis, emphasizing the importance of early detection. Strengths: This study underscores the critical role of antenatal diagnosis but raises questions about the low incidence and limited screening uptake. Clarifying screening approaches and international comparisons would enhance its clinical impact. This study provides valuable insights into the incidence and outcomes of vasa praevia using robust, population-based data from UKOSS. It highlights the significant perinatal mortality (37.5%) in undiagnosed cases and the absence of deaths with antenatal diagnosis, emphasizing the importance of early detection. Strengths: - Study Design: National, prospective data with rigorous case definitions ensure reliable results. - Clinical Relevance: Clear evidence of improved outcomes with antenatal diagnosis supports the value of targeted screening. - Low Incidence: The reported rate (6.64 per 100,000) is lower than international studies. The authors should expand on potential factors, including stringent criteria and underreporting. - Screening Programs: More details are needed on the nature of screening protocols (universal vs. risk-based) in the few units reporting success. - Broader Context: Discuss the rising use of ART and its impact on future incidence and screening needs. This study underscores the critical role of antenatal diagnosis but raises questions about the low incidence and limited screening uptake. Clarifying screening approaches and international comparisons would enhance its clinical impact. - Is the work clearly and accurately presented and does it cite the current literature? Yes - Is the study design appropriate and is the work technically sound? Yes - Are sufficient details of methods and analysis provided to allow replication by others? Yes - If applicable, is the statistical analysis and its interpretation appropriate? Yes - Are all the source data underlying the results available to ensure full reproducibility? Yes - Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Fetal medicine, ultrasound, prenatal diagnosis, obstetrics CITE HOW TO CITE THIS REPORT Libretti A. Reviewer Report For: Incidence and outcomes of vasa praevia in the United Kingdom [version 2; peer review: 3 approved, 2 approved with reservations, 1 not approved]. NIHR Open Res 2024, 4:49 (https://doi.org/10.3310/nihropenres.14995.r33986) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-49/v2#referee-response-33986 https://openresearch.nihr.ac.uk/articles/4-49/v2#referee-response-33986 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. Version 1 VERSION 1 PUBLISHED 03 Sep 2024 Views 0 How to cite this report: Trilla C. Reviewer Report For: Incidence and outcomes of vasa praevia in the United Kingdom [version 2; peer review: 3 approved, 2 approved with reservations, 1 not approved]. NIHR Open Res 2024, 4:49 (https://doi.org/10.3310/nihropenres.14872.r32820) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-49/v1#referee-response-32820 https://openresearch.nihr.ac.uk/articles/4-49/v1#referee-response-32820 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 30 Sep 2024 Cristina Trilla, Department of Obstetrics and Gynaecology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Catalonia, Spain Approved with Reservations VIEWS 0 Attilakos and co-authors present a comprehensive study on the incidence of vasa previa in the UK. From their results, it is clear that a prenatal diagnosis is critical for a good neonatal oucome. The authors used a prospective, population-based study ... Continue reading I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close Attilakos and co-authors present a comprehensive study on the incidence of vasa previa in the UK. From their results, it is clear that a prenatal diagnosis is critical for a good neonatal oucome. The authors used a prospective, population-based study design using the UK Obstetric Surveillance System (UKOSS), which should ensure a correct national representation. However, I am concerned by the very low incidence of vasa previa the authors report and by the potential impact this may have on local policies regarding screening and management of the condition. This is why I would recommend a more cautious discussion on their findings. My main concerns are presented below: My minor concerns are presented below: My main concerns are presented below: - Methods: the authors describe a screening program for vasa previa in some of the institutions involved in this survey. Please, provide more accurate information on these screening programs (universal? Risk-based?), as this could significantly affect prenatal diagnosis. - The definition criteria and confirmation criteria for vasa previa was very strict. Sometimes vasa previa is difficult to diagnose post-partum, even with a careful examination of the placenta and the cord. This could explain the unexpected low rate of vasa previa in the study. The authors have included this as a limitation of the study, but I would ask the authors to elaborate more regarding the added value of this research considering this limitation. I understand that the aim of the study was to provide accurate information on vasa previa incidence in the UK, but these results are not concordant with previous research on the topic in other countries, and there is no clear explanation for this very low incidence in the UK. In any case, vasa previa incidence should be increasing, mainly due to the increase of ART among other risk factors. This should be mentioned and discussed more clearly in the manuscript, as such data may impact management policies for the condition if the incidence is really this low. - Many cases were excluded (22 out of 73, which represents 30% of the suspected cases). I do not clearly understand the exclusion criteria for these, and I would suggest revising this, as I believe it has greatly affected the final numbers. Examination of the placenta was apparently a requirement for diagnosis, but how often is this really performed? - Please, provide accurate definition for urgency categories for CS in methods. - If I understand correctly, 2015 maternity centers participated in the study. As such, many maternity centers did not report any cases of vasa previa. Did the number of deliveries per maternity center correlate with the number of vasa previa diagnosed (either antenatally or postnatally)? Please, provide more data regarding the number the deliveries per center and the number of cases diagnosed. - I believe one of the main conclusions should be that a more clear definition of vasa previa and its diagnosis is needed, rather than that its incidence in the UK is lower than in other countries. My minor concerns are presented below: - Introduction: the authors are only referring to vasa previa type 1 and 2, but a third type has been described. This should be mentioned in the introduction - Underreporting of vasa previa: They state there is no reason to believe there were any underreported cases, but this is impossible to ascertain and should be listed as a limitation for the study. - Minor spelling error in the Methods section of the abstract: “form” should be spelled “from”. I did not find any other spelling concerns. - Is the work clearly and accurately presented and does it cite the current literature? Yes - Is the study design appropriate and is the work technically sound? Partly - Are sufficient details of methods and analysis provided to allow replication by others? Yes - If applicable, is the statistical analysis and its interpretation appropriate? Yes - Are all the source data underlying the results available to ensure full reproducibility? Yes - Are the conclusions drawn adequately supported by the results? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: Prenatal diagnosis, placenta previa and vasa previa. Pregnancy loss. CITE HOW TO CITE THIS REPORT Trilla C. Reviewer Report For: Incidence and outcomes of vasa praevia in the United Kingdom [version 2; peer review: 3 approved, 2 approved with reservations, 1 not approved]. NIHR Open Res 2024, 4:49 (https://doi.org/10.3310/nihropenres.14872.r32820) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-49/v1#referee-response-32820 https://openresearch.nihr.ac.uk/articles/4-49/v1#referee-response-32820 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. - Author Response 09 Dec 2024Ruth Tunn, National Perinatal Epidemiology Unit, University of Oxford, Old Road Campus, Headington, OX3 7LF, UK09 Dec 2024Author ResponseReviewer Comments:

the authors describe a screening program for vasa previa in some of the institutions involved in this survey. Please, provide more accurate information on these screening programs ... Continue reading Reviewer Comments:

the authors describe a screening program for vasa previa in some of the institutions involved in this survey. Please, provide more accurate information on these screening programs (universal? Risk-based?), as this could significantly affect prenatal diagnosis. Author Response: Unfortunately, we do not have further details of the screening protocols used at the centres in question at the time of the study. UKOSS reporting operates on a volunteer basis, and to avoid overburdening reporters and maximise return rates, we limit the amount of information requested. This study did not have evaluation of screening as a main objective, so we limited data collection about screening programmes to the simple yes/no question described in the methods. We present data about screening programmes in relation to diagnosis in Table 5 to encourage and inform future research into this important issue, but do not seek to draw recommendations from the limited information collected. ------------- Reviewer Comments: The definition criteria and confirmation criteria for vasa previa was very strict. Sometimes vasa previa is difficult to diagnose post-partum, even with a careful examination of the placenta and the cord. This could explain the unexpected low rate of vasa previa in the study. The authors have included this as a limitation of the study, but I would ask the authors to elaborate more regarding the added value of this research considering this limitation. I understand that the aim of the study was to provide accurate information on vasa previa incidence in the UK, but these results are not concordant with previous research on the topic in other countries, and there is no clear explanation for this very low incidence in the UK. In any case, vasa previa incidence should be increasing, mainly due to the increase of ART among other risk factors. This should be mentioned and discussed more clearly in the manuscript, as such data may impact management policies for the condition if the incidence is really this low. Author Response: As we note in the discussion, the clearly defined criteria we used meant that suspected cases diagnosed following screening could not be included if there was no postnatal examination of the placenta and membranes to confirm an abnormal vessel. As we describe in our response to reviewer 2 concerning incidence, the important point to note is the difference between diagnosed VP based on screening, and diagnosed VP based on adverse outcome. As few hospitals in the UK have VP screening programmes, the estimate of incidence is more reflective of the latter, which may partly explain why it is lower than some other estimates, although notably similar to studies using similar methodology (Sullivan EA, Javid N, Duncombe G, Li Z, Safi N, Cincotta R, et al. Vasa previa diagnosis, clinical practice, and outcomes in Australia. Obstetrics & Gynecology. 2017;130(3):591-8). Both our study and the AMOSS study are nationwide population studies in contrast to single centre VP screening studies, which report higher incidence. ------------- Reviewer Comments: Many cases were excluded (22 out of 73, which represents 30% of the suspected cases). I do not clearly understand the exclusion criteria for these, and I would suggest revising this, as I believe it has greatly affected the final numbers. Examination of the placenta was apparently a requirement for diagnosis, but how often is this really performed? Author Response: UKOSS collects data prospectively, meaning clinicians are asked to be alert to cases of the specified conditions being studied at any given time and to report them. This potentially increased the frequency of confirmatory examination of the placenta beyond that seen in normal clinical practice, helping to ensure cases were captured. As indicated in Table 3, the placenta was examined in 100% of antenatally diagnosed cases and 91% of peripartum-diagnosed cases; it was sent to pathology for further examination in 32% of antenatally diagnosed cases and 65% of peripartum-diagnosed cases. We provide additional information about the excluded “cases” in Figure 1. Of the 22 reports of apparent cases that were excluded, one fell outside the study period and seven were found when reviewed to not meet the case definition (two were cases of cord prolapse, two were placenta praevia, and three were other non-vasa praevia reports). It would therefore be inappropriate to consider these in calculation of vasa praevia incidence. Of the remaining fourteen reports received but not confirmed as vasa praevia, four were of women who had antepartum haemorrhage, fetal anaemia, or other poor outcomes. These outcomes are sometimes associated with vasa praevia but could be due to a range of other causes, and there was no indication that vasa praevia was suspected antenatally. Because UKOSS reporters are asked to identify and report all cases of the condition in question, they will sometimes err on the side of caution and include reports of observations that might be of interest, “just in case”, to allow the UKOSS researchers on the specific study to make the final adjudication. However, there was little evidence in these cases to suspect vasa praevia specifically. The remaining ten excluded reports were of women in whom vasa praevia was suspected antenatally and who underwent caesarean section indicated by vasa praevia, but there was no documented confirmation of the condition. We could therefore not include these under our case definition in the primary estimate of incidence; however, we do discuss the possible impact of their exclusion in the Discussion: “Even if the 10 planned caesarean sections with no postnatal confirmation were included, the estimated incidence would still be relatively low at 7.94 per 100,000 maternities (1 case for every 12,593 maternities).” We have expanded on the reasons for exclusion in Figure 1 and changed the terminology of unconfirmed “cases” to “reports” in the text for clarity. ------------- Reviewer Comments: Please, provide accurate definition for urgency categories for CS in methods. Author Response: We have added a link to the full data collection form in the Methods, which includes the classification of urgency as provided to the reporting clinicians, in the “Definitions” section. We have also provided the definitions in the footnote to Table 3. ------------- Reviewer Comments: If I understand correctly, 2015 maternity centers participated in the study. As such, many maternity centers did not report any cases of vasa previa. Did the number of deliveries per maternity center correlate with the number of vasa previa diagnosed (either antenatally or postnatally)? Please, provide more data regarding the number the deliveries per center and the number of cases diagnosed. Author Response: We apologise for any confusion. In total, there are 193 consultant-led maternity units in the UK, all of which participate in UKOSS. The 2015 annual statistics for the constituent countries of the UK were used as the denominator for the incidence calculation, rather than data on the number of deliveries per individual maternity centre being collected in this study. Examining case distribution by centre would risk identification of sensitive information given the small numbers involved, and would be unlikely to be informative given the very limited statistical power of this analysis. ------------- Reviewer Comments: I believe one of the main conclusions should be that a more clear definition of vasa previa and its diagnosis is needed, rather than that its incidence in the UK is lower than in other countries. Author Response: We state in the Discussion that differing thresholds and screening protocols for detecting vasa praevia antenatally are likely to explain the apparent differences in the overall reported incidence between countries. For example, a variable distance of 2-5 cm from the internal cervical os is used to diagnose vasa praevia in ultrasound screening. We also discuss other possible reasons for the apparent differences between countries (under-diagnosis, underreporting, mis-diagnosis). ------------- Reviewer Comments: My minor concerns are presented below:

the authors are only referring to vasa previa type 1 and 2, but a third type has been described. This should be mentioned in the introduction Author Response: When this study was designed and conducted (2014–2015), type III vasa praevia had not been described as a distinct subtype. It was therefore not explicitly considered as a sub-type in the case definition or eligibility criteria. However, cases of VP of this type would have been captured by the case definition. We have added a mention of type III vasa praevia to the Introduction. ------------- Reviewer Comments: Underreporting of vasa previa: They state there is no reason to believe there were any underreported cases, but this is impossible to ascertain and should be listed as a limitation for the study. Author Response: We state in the Discussion section: “Although we had multiple reporters in each hospital, we cannot be certain all cases were identified. In particular, the diagnosis may never have been considered as there is a possibility that ruptured vasa praevia mimics other conditions (e.g., abruption) and there is no “gold” standard to confirm the diagnosis after birth if the vessels are not ruptured.” We also mention that misattribution of cases to other causes, and cases not being reported or not recognised during the study period, are possible reasons for the lower-than-expected estimate of incidence. As mentioned above, the important point to note is the difference between diagnosed vasa praevia based on screening, and diagnosed vasa praevia based on adverse outcome. As few hospitals in the UK have vasa praevia screening programmes, the estimate of incidence is more reflective of the latter. ------------- Reviewer Comments: Minor spelling error in the Methods section of the abstract: “form” should be spelled “from”. I did not find any other spelling concerns. Author Response: Thank you, we have corrected this error.Reviewer Comments:Competing Interests: No competing interests were disclosed. Close

the authors describe a screening program for vasa previa in some of the institutions involved in this survey. Please, provide more accurate information on these screening programs (universal? Risk-based?), as this could significantly affect prenatal diagnosis. Author Response: Unfortunately, we do not have further details of the screening protocols used at the centres in question at the time of the study. UKOSS reporting operates on a volunteer basis, and to avoid overburdening reporters and maximise return rates, we limit the amount of information requested. This study did not have evaluation of screening as a main objective, so we limited data collection about screening programmes to the simple yes/no question described in the methods. We present data about screening programmes in relation to diagnosis in Table 5 to encourage and inform future research into this important issue, but do not seek to draw recommendations from the limited information collected. ------------- Reviewer Comments: The definition criteria and confirmation criteria for vasa previa was very strict. Sometimes vasa previa is difficult to diagnose post-partum, even with a careful examination of the placenta and the cord. This could explain the unexpected low rate of vasa previa in the study. The authors have included this as a limitation of the study, but I would ask the authors to elaborate more regarding the added value of this research considering this limitation. I understand that the aim of the study was to provide accurate information on vasa previa incidence in the UK, but these results are not concordant with previous research on the topic in other countries, and there is no clear explanation for this very low incidence in the UK. In any case, vasa previa incidence should be increasing, mainly due to the increase of ART among other risk factors. This should be mentioned and discussed more clearly in the manuscript, as such data may impact management policies for the condition if the incidence is really this low. Author Response: As we note in the discussion, the clearly defined criteria we used meant that suspected cases diagnosed following screening could not be included if there was no postnatal examination of the placenta and membranes to confirm an abnormal vessel. As we describe in our response to reviewer 2 concerning incidence, the important point to note is the difference between diagnosed VP based on screening, and diagnosed VP based on adverse outcome. As few hospitals in the UK have VP screening programmes, the estimate of incidence is more reflective of the latter, which may partly explain why it is lower than some other estimates, although notably similar to studies using similar methodology (Sullivan EA, Javid N, Duncombe G, Li Z, Safi N, Cincotta R, et al. Vasa previa diagnosis, clinical practice, and outcomes in Australia. Obstetrics & Gynecology. 2017;130(3):591-8). Both our study and the AMOSS study are nationwide population studies in contrast to single centre VP screening studies, which report higher incidence. ------------- Reviewer Comments: Many cases were excluded (22 out of 73, which represents 30% of the suspected cases). I do not clearly understand the exclusion criteria for these, and I would suggest revising this, as I believe it has greatly affected the final numbers. Examination of the placenta was apparently a requirement for diagnosis, but how often is this really performed? Author Response: UKOSS collects data prospectively, meaning clinicians are asked to be alert to cases of the specified conditions being studied at any given time and to report them. This potentially increased the frequency of confirmatory examination of the placenta beyond that seen in normal clinical practice, helping to ensure cases were captured. As indicated in Table 3, the placenta was examined in 100% of antenatally diagnosed cases and 91% of peripartum-diagnosed cases; it was sent to pathology for further examination in 32% of antenatally diagnosed cases and 65% of peripartum-diagnosed cases. We provide additional information about the excluded “cases” in Figure 1. Of the 22 reports of apparent cases that were excluded, one fell outside the study period and seven were found when reviewed to not meet the case definition (two were cases of cord prolapse, two were placenta praevia, and three were other non-vasa praevia reports). It would therefore be inappropriate to consider these in calculation of vasa praevia incidence. Of the remaining fourteen reports received but not confirmed as vasa praevia, four were of women who had antepartum haemorrhage, fetal anaemia, or other poor outcomes. These outcomes are sometimes associated with vasa praevia but could be due to a range of other causes, and there was no indication that vasa praevia was suspected antenatally. Because UKOSS reporters are asked to identify and report all cases of the condition in question, they will sometimes err on the side of caution and include reports of observations that might be of interest, “just in case”, to allow the UKOSS researchers on the specific study to make the final adjudication. However, there was little evidence in these cases to suspect vasa praevia specifically. The remaining ten excluded reports were of women in whom vasa praevia was suspected antenatally and who underwent caesarean section indicated by vasa praevia, but there was no documented confirmation of the condition. We could therefore not include these under our case definition in the primary estimate of incidence; however, we do discuss the possible impact of their exclusion in the Discussion: “Even if the 10 planned caesarean sections with no postnatal confirmation were included, the estimated incidence would still be relatively low at 7.94 per 100,000 maternities (1 case for every 12,593 maternities).” We have expanded on the reasons for exclusion in Figure 1 and changed the terminology of unconfirmed “cases” to “reports” in the text for clarity. ------------- Reviewer Comments: Please, provide accurate definition for urgency categories for CS in methods. Author Response: We have added a link to the full data collection form in the Methods, which includes the classification of urgency as provided to the reporting clinicians, in the “Definitions” section. We have also provided the definitions in the footnote to Table 3. ------------- Reviewer Comments: If I understand correctly, 2015 maternity centers participated in the study. As such, many maternity centers did not report any cases of vasa previa. Did the number of deliveries per maternity center correlate with the number of vasa previa diagnosed (either antenatally or postnatally)? Please, provide more data regarding the number the deliveries per center and the number of cases diagnosed. Author Response: We apologise for any confusion. In total, there are 193 consultant-led maternity units in the UK, all of which participate in UKOSS. The 2015 annual statistics for the constituent countries of the UK were used as the denominator for the incidence calculation, rather than data on the number of deliveries per individual maternity centre being collected in this study. Examining case distribution by centre would risk identification of sensitive information given the small numbers involved, and would be unlikely to be informative given the very limited statistical power of this analysis. ------------- Reviewer Comments: I believe one of the main conclusions should be that a more clear definition of vasa previa and its diagnosis is needed, rather than that its incidence in the UK is lower than in other countries. Author Response: We state in the Discussion that differing thresholds and screening protocols for detecting vasa praevia antenatally are likely to explain the apparent differences in the overall reported incidence between countries. For example, a variable distance of 2-5 cm from the internal cervical os is used to diagnose vasa praevia in ultrasound screening. We also discuss other possible reasons for the apparent differences between countries (under-diagnosis, underreporting, mis-diagnosis). ------------- Reviewer Comments: My minor concerns are presented below:

the authors are only referring to vasa previa type 1 and 2, but a third type has been described. This should be mentioned in the introduction Author Response: When this study was designed and conducted (2014–2015), type III vasa praevia had not been described as a distinct subtype. It was therefore not explicitly considered as a sub-type in the case definition or eligibility criteria. However, cases of VP of this type would have been captured by the case definition. We have added a mention of type III vasa praevia to the Introduction. ------------- Reviewer Comments: Underreporting of vasa previa: They state there is no reason to believe there were any underreported cases, but this is impossible to ascertain and should be listed as a limitation for the study. Author Response: We state in the Discussion section: “Although we had multiple reporters in each hospital, we cannot be certain all cases were identified. In particular, the diagnosis may never have been considered as there is a possibility that ruptured vasa praevia mimics other conditions (e.g., abruption) and there is no “gold” standard to confirm the diagnosis after birth if the vessels are not ruptured.” We also mention that misattribution of cases to other causes, and cases not being reported or not recognised during the study period, are possible reasons for the lower-than-expected estimate of incidence. As mentioned above, the important point to note is the difference between diagnosed vasa praevia based on screening, and diagnosed vasa praevia based on adverse outcome. As few hospitals in the UK have vasa praevia screening programmes, the estimate of incidence is more reflective of the latter. ------------- Reviewer Comments: Minor spelling error in the Methods section of the abstract: “form” should be spelled “from”. I did not find any other spelling concerns. Author Response: Thank you, we have corrected this error. COMMENTS ON THIS REPORT - Author Response 09 Dec 2024Ruth Tunn, National Perinatal Epidemiology Unit, University of Oxford, Old Road Campus, Headington, OX3 7LF, UK09 Dec 2024Author ResponseReviewer Comments:

the authors describe a screening program for vasa previa in some of the institutions involved in this survey. Please, provide more accurate information on these screening programs ... Continue reading Reviewer Comments:

the authors describe a screening program for vasa previa in some of the institutions involved in this survey. Please, provide more accurate information on these screening programs (universal? Risk-based?), as this could significantly affect prenatal diagnosis. Author Response: Unfortunately, we do not have further details of the screening protocols used at the centres in question at the time of the study. UKOSS reporting operates on a volunteer basis, and to avoid overburdening reporters and maximise return rates, we limit the amount of information requested. This study did not have evaluation of screening as a main objective, so we limited data collection about screening programmes to the simple yes/no question described in the methods. We present data about screening programmes in relation to diagnosis in Table 5 to encourage and inform future research into this important issue, but do not seek to draw recommendations from the limited information collected. ------------- Reviewer Comments: The definition criteria and confirmation criteria for vasa previa was very strict. Sometimes vasa previa is difficult to diagnose post-partum, even with a careful examination of the placenta and the cord. This could explain the unexpected low rate of vasa previa in the study. The authors have included this as a limitation of the study, but I would ask the authors to elaborate more regarding the added value of this research considering this limitation. I understand that the aim of the study was to provide accurate information on vasa previa incidence in the UK, but these results are not concordant with previous research on the topic in other countries, and there is no clear explanation for this very low incidence in the UK. In any case, vasa previa incidence should be increasing, mainly due to the increase of ART among other risk factors. This should be mentioned and discussed more clearly in the manuscript, as such data may impact management policies for the condition if the incidence is really this low. Author Response: As we note in the discussion, the clearly defined criteria we used meant that suspected cases diagnosed following screening could not be included if there was no postnatal examination of the placenta and membranes to confirm an abnormal vessel. As we describe in our response to reviewer 2 concerning incidence, the important point to note is the difference between diagnosed VP based on screening, and diagnosed VP based on adverse outcome. As few hospitals in the UK have VP screening programmes, the estimate of incidence is more reflective of the latter, which may partly explain why it is lower than some other estimates, although notably similar to studies using similar methodology (Sullivan EA, Javid N, Duncombe G, Li Z, Safi N, Cincotta R, et al. Vasa previa diagnosis, clinical practice, and outcomes in Australia. Obstetrics & Gynecology. 2017;130(3):591-8). Both our study and the AMOSS study are nationwide population studies in contrast to single centre VP screening studies, which report higher incidence. ------------- Reviewer Comments: Many cases were excluded (22 out of 73, which represents 30% of the suspected cases). I do not clearly understand the exclusion criteria for these, and I would suggest revising this, as I believe it has greatly affected the final numbers. Examination of the placenta was apparently a requirement for diagnosis, but how often is this really performed? Author Response: UKOSS collects data prospectively, meaning clinicians are asked to be alert to cases of the specified conditions being studied at any given time and to report them. This potentially increased the frequency of confirmatory examination of the placenta beyond that seen in normal clinical practice, helping to ensure cases were captured. As indicated in Table 3, the placenta was examined in 100% of antenatally diagnosed cases and 91% of peripartum-diagnosed cases; it was sent to pathology for further examination in 32% of antenatally diagnosed cases and 65% of peripartum-diagnosed cases. We provide additional information about the excluded “cases” in Figure 1. Of the 22 reports of apparent cases that were excluded, one fell outside the study period and seven were found when reviewed to not meet the case definition (two were cases of cord prolapse, two were placenta praevia, and three were other non-vasa praevia reports). It would therefore be inappropriate to consider these in calculation of vasa praevia incidence. Of the remaining fourteen reports received but not confirmed as vasa praevia, four were of women who had antepartum haemorrhage, fetal anaemia, or other poor outcomes. These outcomes are sometimes associated with vasa praevia but could be due to a range of other causes, and there was no indication that vasa praevia was suspected antenatally. Because UKOSS reporters are asked to identify and report all cases of the condition in question, they will sometimes err on the side of caution and include reports of observations that might be of interest, “just in case”, to allow the UKOSS researchers on the specific study to make the final adjudication. However, there was little evidence in these cases to suspect vasa praevia specifically. The remaining ten excluded reports were of women in whom vasa praevia was suspected antenatally and who underwent caesarean section indicated by vasa praevia, but there was no documented confirmation of the condition. We could therefore not include these under our case definition in the primary estimate of incidence; however, we do discuss the possible impact of their exclusion in the Discussion: “Even if the 10 planned caesarean sections with no postnatal confirmation were included, the estimated incidence would still be relatively low at 7.94 per 100,000 maternities (1 case for every 12,593 maternities).” We have expanded on the reasons for exclusion in Figure 1 and changed the terminology of unconfirmed “cases” to “reports” in the text for clarity. ------------- Reviewer Comments: Please, provide accurate definition for urgency categories for CS in methods. Author Response: We have added a link to the full data collection form in the Methods, which includes the classification of urgency as provided to the reporting clinicians, in the “Definitions” section. We have also provided the definitions in the footnote to Table 3. ------------- Reviewer Comments: If I understand correctly, 2015 maternity centers participated in the study. As such, many maternity centers did not report any cases of vasa previa. Did the number of deliveries per maternity center correlate with the number of vasa previa diagnosed (either antenatally or postnatally)? Please, provide more data regarding the number the deliveries per center and the number of cases diagnosed. Author Response: We apologise for any confusion. In total, there are 193 consultant-led maternity units in the UK, all of which participate in UKOSS. The 2015 annual statistics for the constituent countries of the UK were used as the denominator for the incidence calculation, rather than data on the number of deliveries per individual maternity centre being collected in this study. Examining case distribution by centre would risk identification of sensitive information given the small numbers involved, and would be unlikely to be informative given the very limited statistical power of this analysis. ------------- Reviewer Comments: I believe one of the main conclusions should be that a more clear definition of vasa previa and its diagnosis is needed, rather than that its incidence in the UK is lower than in other countries. Author Response: We state in the Discussion that differing thresholds and screening protocols for detecting vasa praevia antenatally are likely to explain the apparent differences in the overall reported incidence between countries. For example, a variable distance of 2-5 cm from the internal cervical os is used to diagnose vasa praevia in ultrasound screening. We also discuss other possible reasons for the apparent differences between countries (under-diagnosis, underreporting, mis-diagnosis). ------------- Reviewer Comments: My minor concerns are presented below:

the authors are only referring to vasa previa type 1 and 2, but a third type has been described. This should be mentioned in the introduction Author Response: When this study was designed and conducted (2014–2015), type III vasa praevia had not been described as a distinct subtype. It was therefore not explicitly considered as a sub-type in the case definition or eligibility criteria. However, cases of VP of this type would have been captured by the case definition. We have added a mention of type III vasa praevia to the Introduction. ------------- Reviewer Comments: Underreporting of vasa previa: They state there is no reason to believe there were any underreported cases, but this is impossible to ascertain and should be listed as a limitation for the study. Author Response: We state in the Discussion section: “Although we had multiple reporters in each hospital, we cannot be certain all cases were identified. In particular, the diagnosis may never have been considered as there is a possibility that ruptured vasa praevia mimics other conditions (e.g., abruption) and there is no “gold” standard to confirm the diagnosis after birth if the vessels are not ruptured.” We also mention that misattribution of cases to other causes, and cases not being reported or not recognised during the study period, are possible reasons for the lower-than-expected estimate of incidence. As mentioned above, the important point to note is the difference between diagnosed vasa praevia based on screening, and diagnosed vasa praevia based on adverse outcome. As few hospitals in the UK have vasa praevia screening programmes, the estimate of incidence is more reflective of the latter. ------------- Reviewer Comments: Minor spelling error in the Methods section of the abstract: “form” should be spelled “from”. I did not find any other spelling concerns. Author Response: Thank you, we have corrected this error.Reviewer Comments:Competing Interests: No competing interests were disclosed. Close

the authors describe a screening program for vasa previa in some of the institutions involved in this survey. Please, provide more accurate information on these screening programs (universal? Risk-based?), as this could significantly affect prenatal diagnosis. Author Response: Unfortunately, we do not have further details of the screening protocols used at the centres in question at the time of the study. UKOSS reporting operates on a volunteer basis, and to avoid overburdening reporters and maximise return rates, we limit the amount of information requested. This study did not have evaluation of screening as a main objective, so we limited data collection about screening programmes to the simple yes/no question described in the methods. We present data about screening programmes in relation to diagnosis in Table 5 to encourage and inform future research into this important issue, but do not seek to draw recommendations from the limited information collected. ------------- Reviewer Comments: The definition criteria and confirmation criteria for vasa previa was very strict. Sometimes vasa previa is difficult to diagnose post-partum, even with a careful examination of the placenta and the cord. This could explain the unexpected low rate of vasa previa in the study. The authors have included this as a limitation of the study, but I would ask the authors to elaborate more regarding the added value of this research considering this limitation. I understand that the aim of the study was to provide accurate information on vasa previa incidence in the UK, but these results are not concordant with previous research on the topic in other countries, and there is no clear explanation for this very low incidence in the UK. In any case, vasa previa incidence should be increasing, mainly due to the increase of ART among other risk factors. This should be mentioned and discussed more clearly in the manuscript, as such data may impact management policies for the condition if the incidence is really this low. Author Response: As we note in the discussion, the clearly defined criteria we used meant that suspected cases diagnosed following screening could not be included if there was no postnatal examination of the placenta and membranes to confirm an abnormal vessel. As we describe in our response to reviewer 2 concerning incidence, the important point to note is the difference between diagnosed VP based on screening, and diagnosed VP based on adverse outcome. As few hospitals in the UK have VP screening programmes, the estimate of incidence is more reflective of the latter, which may partly explain why it is lower than some other estimates, although notably similar to studies using similar methodology (Sullivan EA, Javid N, Duncombe G, Li Z, Safi N, Cincotta R, et al. Vasa previa diagnosis, clinical practice, and outcomes in Australia. Obstetrics & Gynecology. 2017;130(3):591-8). Both our study and the AMOSS study are nationwide population studies in contrast to single centre VP screening studies, which report higher incidence. ------------- Reviewer Comments: Many cases were excluded (22 out of 73, which represents 30% of the suspected cases). I do not clearly understand the exclusion criteria for these, and I would suggest revising this, as I believe it has greatly affected the final numbers. Examination of the placenta was apparently a requirement for diagnosis, but how often is this really performed? Author Response: UKOSS collects data prospectively, meaning clinicians are asked to be alert to cases of the specified conditions being studied at any given time and to report them. This potentially increased the frequency of confirmatory examination of the placenta beyond that seen in normal clinical practice, helping to ensure cases were captured. As indicated in Table 3, the placenta was examined in 100% of antenatally diagnosed cases and 91% of peripartum-diagnosed cases; it was sent to pathology for further examination in 32% of antenatally diagnosed cases and 65% of peripartum-diagnosed cases. We provide additional information about the excluded “cases” in Figure 1. Of the 22 reports of apparent cases that were excluded, one fell outside the study period and seven were found when reviewed to not meet the case definition (two were cases of cord prolapse, two were placenta praevia, and three were other non-vasa praevia reports). It would therefore be inappropriate to consider these in calculation of vasa praevia incidence. Of the remaining fourteen reports received but not confirmed as vasa praevia, four were of women who had antepartum haemorrhage, fetal anaemia, or other poor outcomes. These outcomes are sometimes associated with vasa praevia but could be due to a range of other causes, and there was no indication that vasa praevia was suspected antenatally. Because UKOSS reporters are asked to identify and report all cases of the condition in question, they will sometimes err on the side of caution and include reports of observations that might be of interest, “just in case”, to allow the UKOSS researchers on the specific study to make the final adjudication. However, there was little evidence in these cases to suspect vasa praevia specifically. The remaining ten excluded reports were of women in whom vasa praevia was suspected antenatally and who underwent caesarean section indicated by vasa praevia, but there was no documented confirmation of the condition. We could therefore not include these under our case definition in the primary estimate of incidence; however, we do discuss the possible impact of their exclusion in the Discussion: “Even if the 10 planned caesarean sections with no postnatal confirmation were included, the estimated incidence would still be relatively low at 7.94 per 100,000 maternities (1 case for every 12,593 maternities).” We have expanded on the reasons for exclusion in Figure 1 and changed the terminology of unconfirmed “cases” to “reports” in the text for clarity. ------------- Reviewer Comments: Please, provide accurate definition for urgency categories for CS in methods. Author Response: We have added a link to the full data collection form in the Methods, which includes the classification of urgency as provided to the reporting clinicians, in the “Definitions” section. We have also provided the definitions in the footnote to Table 3. ------------- Reviewer Comments: If I understand correctly, 2015 maternity centers participated in the study. As such, many maternity centers did not report any cases of vasa previa. Did the number of deliveries per maternity center correlate with the number of vasa previa diagnosed (either antenatally or postnatally)? Please, provide more data regarding the number the deliveries per center and the number of cases diagnosed. Author Response: We apologise for any confusion. In total, there are 193 consultant-led maternity units in the UK, all of which participate in UKOSS. The 2015 annual statistics for the constituent countries of the UK were used as the denominator for the incidence calculation, rather than data on the number of deliveries per individual maternity centre being collected in this study. Examining case distribution by centre would risk identification of sensitive information given the small numbers involved, and would be unlikely to be informative given the very limited statistical power of this analysis. ------------- Reviewer Comments: I believe one of the main conclusions should be that a more clear definition of vasa previa and its diagnosis is needed, rather than that its incidence in the UK is lower than in other countries. Author Response: We state in the Discussion that differing thresholds and screening protocols for detecting vasa praevia antenatally are likely to explain the apparent differences in the overall reported incidence between countries. For example, a variable distance of 2-5 cm from the internal cervical os is used to diagnose vasa praevia in ultrasound screening. We also discuss other possible reasons for the apparent differences between countries (under-diagnosis, underreporting, mis-diagnosis). ------------- Reviewer Comments: My minor concerns are presented below:

the authors are only referring to vasa previa type 1 and 2, but a third type has been described. This should be mentioned in the introduction Author Response: When this study was designed and conducted (2014–2015), type III vasa praevia had not been described as a distinct subtype. It was therefore not explicitly considered as a sub-type in the case definition or eligibility criteria. However, cases of VP of this type would have been captured by the case definition. We have added a mention of type III vasa praevia to the Introduction. ------------- Reviewer Comments: Underreporting of vasa previa: They state there is no reason to believe there were any underreported cases, but this is impossible to ascertain and should be listed as a limitation for the study. Author Response: We state in the Discussion section: “Although we had multiple reporters in each hospital, we cannot be certain all cases were identified. In particular, the diagnosis may never have been considered as there is a possibility that ruptured vasa praevia mimics other conditions (e.g., abruption) and there is no “gold” standard to confirm the diagnosis after birth if the vessels are not ruptured.” We also mention that misattribution of cases to other causes, and cases not being reported or not recognised during the study period, are possible reasons for the lower-than-expected estimate of incidence. As mentioned above, the important point to note is the difference between diagnosed vasa praevia based on screening, and diagnosed vasa praevia based on adverse outcome. As few hospitals in the UK have vasa praevia screening programmes, the estimate of incidence is more reflective of the latter. ------------- Reviewer Comments: Minor spelling error in the Methods section of the abstract: “form” should be spelled “from”. I did not find any other spelling concerns. Author Response: Thank you, we have corrected this error. Views 0 How to cite this report: Ivo Cavoretto P. Reviewer Report For: Incidence and outcomes of vasa praevia in the United Kingdom [version 2; peer review: 3 approved, 2 approved with reservations, 1 not approved]. NIHR Open Res 2024, 4:49 (https://doi.org/10.3310/nihropenres.14872.r32941) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-49/v1#referee-response-32941 https://openresearch.nihr.ac.uk/articles/4-49/v1#referee-response-32941 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 30 Sep 2024 Approved VIEWS 0 This is a very good study from a known research group in the UK, presenting a compelling study topic and aim, adequate rationale and methodology and acceptable conclusions. I have few remarks and recommendations to improve this interesting paper: ... Continue reading I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close ... Continue reading This is a very good study from a known research group in the UK, presenting a compelling study topic and aim, adequate rationale and methodology and acceptable conclusions. I have few remarks and recommendations to improve this interesting paper: 1. Type III vasa previa was not considered enough by the authors and this in an important reticence to be corrected. Type III vasa previa is a rare form of VP, not necessarily associated with other placental or vascular anomalies, in which aberrant vessels run from the placenta to the amniotic membranes, near the internal cervical os, before returning to the placenta. It was object of a recent systematic review published in UOG that should be considered by the authors (ref 1). Were type III VP accounted for? Were they excluded from the study? This is very interesting to be added for readers. A wide dissemination on knowledge around type III vasa previa is required as this is not yet a well-known topic. 2. The authors state that in 10 cases "no documentation of the placenta being examined or sent to histopathology after birth, so there was no confirmation of vasa praevia". However I am afraid that anatomopatological diagnosis simply cannot rule out or rule in vasa previa, as the relationship with the uterine structures is only available as an intraoperative surgical macroscopic diagnosis. This diagnosis can be documented with pictures and videos or with clinical diagnosis during delivery Anatomopatologists can only diagnose velamentous cord insertion, bilobate/succenturiate or type III extraplacental aberrant vessels as well as placental structural or morpholigcal aberrations associated (but not patognominic) to vasa previa. This comment is not against the authors findings but instead it may be useful to reinforce their message (there is an extent of wrong prenatal diagnosis but this risk in expert hands is very low). 3. Methods. Among risk factors for VP multiple pregnancies should be included. 4. The issue of cervical screening for cervical lenght, to be used to screen also for vasa previa screening may be considered and mentioned with pros and cons. I congratulate with the authors for this brilliant work. 1. Type III vasa previa was not considered enough by the authors and this in an important reticence to be corrected. Type III vasa previa is a rare form of VP, not necessarily associated with other placental or vascular anomalies, in which aberrant vessels run from the placenta to the amniotic membranes, near the internal cervical os, before returning to the placenta. It was object of a recent systematic review published in UOG that should be considered by the authors (ref 1). Were type III VP accounted for? Were they excluded from the study? This is very interesting to be added for readers. A wide dissemination on knowledge around type III vasa previa is required as this is not yet a well-known topic. 2. The authors state that in 10 cases "no documentation of the placenta being examined or sent to histopathology after birth, so there was no confirmation of vasa praevia". However I am afraid that anatomopatological diagnosis simply cannot rule out or rule in vasa previa, as the relationship with the uterine structures is only available as an intraoperative surgical macroscopic diagnosis. This diagnosis can be documented with pictures and videos or with clinical diagnosis during delivery Anatomopatologists can only diagnose velamentous cord insertion, bilobate/succenturiate or type III extraplacental aberrant vessels as well as placental structural or morpholigcal aberrations associated (but not patognominic) to vasa previa. This comment is not against the authors findings but instead it may be useful to reinforce their message (there is an extent of wrong prenatal diagnosis but this risk in expert hands is very low). 3. Methods. Among risk factors for VP multiple pregnancies should be included. 4. The issue of cervical screening for cervical lenght, to be used to screen also for vasa previa screening may be considered and mentioned with pros and cons. I congratulate with the authors for this brilliant work. - Is the work clearly and accurately presented and does it cite the current literature? Partly - Is the study design appropriate and is the work technically sound? Yes - Are sufficient details of methods and analysis provided to allow replication by others? Yes - If applicable, is the statistical analysis and its interpretation appropriate? Yes - Are all the source data underlying the results available to ensure full reproducibility? Yes - Are the conclusions drawn adequately supported by the results? Yes

1. Pozzoni M, Sammaria C, Villanacci R, Borgese C, et al.: Prenatal diagnosis and postnatal outcome of Type-III vasa previa: systematic review of literature.Ultrasound Obstet Gynecol. 2024; 63 (1): 24-33 PubMed Abstract | Publisher Full TextCompeting Interests: No competing interests were disclosed. Reviewer Expertise: I am expert in maternal fetal medicine and obstetrics and I did previous research on the topic. I feel comfortable in providing a review on the paper. in object. CITE HOW TO CITE THIS REPORT Ivo Cavoretto P. Reviewer Report For: Incidence and outcomes of vasa praevia in the United Kingdom [version 2; peer review: 3 approved, 2 approved with reservations, 1 not approved]. NIHR Open Res 2024, 4:49 (https://doi.org/10.3310/nihropenres.14872.r32941) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-49/v1#referee-response-32941 https://openresearch.nihr.ac.uk/articles/4-49/v1#referee-response-32941 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. - Author Response 05 Dec 2024Ruth Tunn, National Perinatal Epidemiology Unit, University of Oxford, Old Road Campus, Headington, OX3 7LF, UK05 Dec 2024Author Response1. Type III vasa previa was not considered enough by the authors and this in an important reticence to be corrected. Type III vasa previa is a rare form of ... Continue reading 1. Type III vasa previa was not considered enough by the authors and this in an important reticence to be corrected. Type III vasa previa is a rare form of VP, not necessarily associated with other placental or vascular anomalies, in which aberrant vessels run from the placenta to the amniotic membranes, near the internal cervical os, before returning to the placenta. It was object of a recent systematic review published in UOG that should be considered by the authors (ref 1). Were type III VP accounted for? Were they excluded from the study? This is very interesting to be added for readers. A wide dissemination on knowledge around type III vasa previa is required as this is not yet a well-known topic. Response: When this study was designed and conducted (2014–2015), type III vasa praevia had not been described as a distinct subtype. It was therefore not explicitly considered as a sub-type in the case definition or eligibility criteria. However, cases of VP of this type would have been captured by the case definition. Indeed, in some scientific presentations before 2014, the term "type III vasa praevia” was used to describe vasa praevia of a second twin when its membranes were presenting after the birth of the first twin. This type of vasa praevia would also have been captured by the case definition. We have added a mention of type III vasa praevia to the Introduction. 2. The authors state that in 10 cases "no documentation of the placenta being examined or sent to histopathology after birth, so there was no confirmation of vasa praevia". However I am afraid that anatomopatological diagnosis simply cannot rule out or rule in vasa previa, as the relationship with the uterine structures is only available as an intraoperative surgical macroscopic diagnosis. This diagnosis can be documented with pictures and videos or with clinical diagnosis during delivery Anatomopatologists can only diagnose velamentous cord insertion, bilobate/succenturiate or type III extraplacental aberrant vessels as well as placental structural or morpholigcal aberrations associated (but not patognominic) to vasa previa. This comment is not against the authors findings but instead it may be useful to reinforce their message (there is an extent of wrong prenatal diagnosis but this risk in expert hands is very low). Response: Thank you, we have added to the discussion the consideration of the potential value of intra-operative photographic documentation. 3. Methods. Among risk factors for VP multiple pregnancies should be included. Response: Data were collected on multiple pregnancies, but numbers were too small to be meaningfully analysed as only one woman with a multiple pregnancy was affected. We have added a link to the full data collection form for the study. Furthermore, in the meta-analysis by Ruiter et al, multiple pregnancy was not found to be a statistically significant risk factor. 4. The issue of cervical screening for cervical length, to be used to screen also for vasa previa screening may be considered and mentioned with pros and cons. Response: As indicated in Table 3, cervical length was measured in 36% of antenatally diagnosed cases but used in the decision to admit the woman to hospital in only 11%. Cervical length was not measured in any of the peripartum-diagnosed women.1. Type III vasa previa was not considered enough by the authors and this in an important reticence to be corrected. Type III vasa previa is a rare form of VP, not necessarily associated with other placental or vascular anomalies, in which aberrant vessels run from the placenta to the amniotic membranes, near the internal cervical os, before returning to the placenta. It was object of a recent systematic review published in UOG that should be considered by the authors (ref 1).Competing Interests: No competing interests were disclosed. Close Were type III VP accounted for? Were they excluded from the study? This is very interesting to be added for readers. A wide dissemination on knowledge around type III vasa previa is required as this is not yet a well-known topic. Response: When this study was designed and conducted (2014–2015), type III vasa praevia had not been described as a distinct subtype. It was therefore not explicitly considered as a sub-type in the case definition or eligibility criteria. However, cases of VP of this type would have been captured by the case definition. Indeed, in some scientific presentations before 2014, the term "type III vasa praevia” was used to describe vasa praevia of a second twin when its membranes were presenting after the birth of the first twin. This type of vasa praevia would also have been captured by the case definition. We have added a mention of type III vasa praevia to the Introduction. 2. The authors state that in 10 cases "no documentation of the placenta being examined or sent to histopathology after birth, so there was no confirmation of vasa praevia". However I am afraid that anatomopatological diagnosis simply cannot rule out or rule in vasa previa, as the relationship with the uterine structures is only available as an intraoperative surgical macroscopic diagnosis. This diagnosis can be documented with pictures and videos or with clinical diagnosis during delivery Anatomopatologists can only diagnose velamentous cord insertion, bilobate/succenturiate or type III extraplacental aberrant vessels as well as placental structural or morpholigcal aberrations associated (but not patognominic) to vasa previa. This comment is not against the authors findings but instead it may be useful to reinforce their message (there is an extent of wrong prenatal diagnosis but this risk in expert hands is very low). Response: Thank you, we have added to the discussion the consideration of the potential value of intra-operative photographic documentation. 3. Methods. Among risk factors for VP multiple pregnancies should be included. Response: Data were collected on multiple pregnancies, but numbers were too small to be meaningfully analysed as only one woman with a multiple pregnancy was affected. We have added a link to the full data collection form for the study. Furthermore, in the meta-analysis by Ruiter et al, multiple pregnancy was not found to be a statistically significant risk factor. 4. The issue of cervical screening for cervical length, to be used to screen also for vasa previa screening may be considered and mentioned with pros and cons. Response: As indicated in Table 3, cervical length was measured in 36% of antenatally diagnosed cases but used in the decision to admit the woman to hospital in only 11%. Cervical length was not measured in any of the peripartum-diagnosed women. COMMENTS ON THIS REPORT - Author Response 05 Dec 2024Ruth Tunn, National Perinatal Epidemiology Unit, University of Oxford, Old Road Campus, Headington, OX3 7LF, UK05 Dec 2024Author Response1. Type III vasa previa was not considered enough by the authors and this in an important reticence to be corrected. Type III vasa previa is a rare form of ... Continue reading 1. Type III vasa previa was not considered enough by the authors and this in an important reticence to be corrected. Type III vasa previa is a rare form of VP, not necessarily associated with other placental or vascular anomalies, in which aberrant vessels run from the placenta to the amniotic membranes, near the internal cervical os, before returning to the placenta. It was object of a recent systematic review published in UOG that should be considered by the authors (ref 1). Were type III VP accounted for? Were they excluded from the study? This is very interesting to be added for readers. A wide dissemination on knowledge around type III vasa previa is required as this is not yet a well-known topic. Response: When this study was designed and conducted (2014–2015), type III vasa praevia had not been described as a distinct subtype. It was therefore not explicitly considered as a sub-type in the case definition or eligibility criteria. However, cases of VP of this type would have been captured by the case definition. Indeed, in some scientific presentations before 2014, the term "type III vasa praevia” was used to describe vasa praevia of a second twin when its membranes were presenting after the birth of the first twin. This type of vasa praevia would also have been captured by the case definition. We have added a mention of type III vasa praevia to the Introduction. 2. The authors state that in 10 cases "no documentation of the placenta being examined or sent to histopathology after birth, so there was no confirmation of vasa praevia". However I am afraid that anatomopatological diagnosis simply cannot rule out or rule in vasa previa, as the relationship with the uterine structures is only available as an intraoperative surgical macroscopic diagnosis. This diagnosis can be documented with pictures and videos or with clinical diagnosis during delivery Anatomopatologists can only diagnose velamentous cord insertion, bilobate/succenturiate or type III extraplacental aberrant vessels as well as placental structural or morpholigcal aberrations associated (but not patognominic) to vasa previa. This comment is not against the authors findings but instead it may be useful to reinforce their message (there is an extent of wrong prenatal diagnosis but this risk in expert hands is very low). Response: Thank you, we have added to the discussion the consideration of the potential value of intra-operative photographic documentation. 3. Methods. Among risk factors for VP multiple pregnancies should be included. Response: Data were collected on multiple pregnancies, but numbers were too small to be meaningfully analysed as only one woman with a multiple pregnancy was affected. We have added a link to the full data collection form for the study. Furthermore, in the meta-analysis by Ruiter et al, multiple pregnancy was not found to be a statistically significant risk factor. 4. The issue of cervical screening for cervical length, to be used to screen also for vasa previa screening may be considered and mentioned with pros and cons. Response: As indicated in Table 3, cervical length was measured in 36% of antenatally diagnosed cases but used in the decision to admit the woman to hospital in only 11%. Cervical length was not measured in any of the peripartum-diagnosed women.1. Type III vasa previa was not considered enough by the authors and this in an important reticence to be corrected. Type III vasa previa is a rare form of VP, not necessarily associated with other placental or vascular anomalies, in which aberrant vessels run from the placenta to the amniotic membranes, near the internal cervical os, before returning to the placenta. It was object of a recent systematic review published in UOG that should be considered by the authors (ref 1).Competing Interests: No competing interests were disclosed. Close Were type III VP accounted for? Were they excluded from the study? This is very interesting to be added for readers. A wide dissemination on knowledge around type III vasa previa is required as this is not yet a well-known topic. Response: When this study was designed and conducted (2014–2015), type III vasa praevia had not been described as a distinct subtype. It was therefore not explicitly considered as a sub-type in the case definition or eligibility criteria. However, cases of VP of this type would have been captured by the case definition. Indeed, in some scientific presentations before 2014, the term "type III vasa praevia” was used to describe vasa praevia of a second twin when its membranes were presenting after the birth of the first twin. This type of vasa praevia would also have been captured by the case definition. We have added a mention of type III vasa praevia to the Introduction. 2. The authors state that in 10 cases "no documentation of the placenta being examined or sent to histopathology after birth, so there was no confirmation of vasa praevia". However I am afraid that anatomopatological diagnosis simply cannot rule out or rule in vasa previa, as the relationship with the uterine structures is only available as an intraoperative surgical macroscopic diagnosis. This diagnosis can be documented with pictures and videos or with clinical diagnosis during delivery Anatomopatologists can only diagnose velamentous cord insertion, bilobate/succenturiate or type III extraplacental aberrant vessels as well as placental structural or morpholigcal aberrations associated (but not patognominic) to vasa previa. This comment is not against the authors findings but instead it may be useful to reinforce their message (there is an extent of wrong prenatal diagnosis but this risk in expert hands is very low). Response: Thank you, we have added to the discussion the consideration of the potential value of intra-operative photographic documentation. 3. Methods. Among risk factors for VP multiple pregnancies should be included. Response: Data were collected on multiple pregnancies, but numbers were too small to be meaningfully analysed as only one woman with a multiple pregnancy was affected. We have added a link to the full data collection form for the study. Furthermore, in the meta-analysis by Ruiter et al, multiple pregnancy was not found to be a statistically significant risk factor. 4. The issue of cervical screening for cervical length, to be used to screen also for vasa previa screening may be considered and mentioned with pros and cons. Response: As indicated in Table 3, cervical length was measured in 36% of antenatally diagnosed cases but used in the decision to admit the woman to hospital in only 11%. Cervical length was not measured in any of the peripartum-diagnosed women. Views 0 How to cite this report: Papanna R and Agarwal N. Reviewer Report For: Incidence and outcomes of vasa praevia in the United Kingdom [version 2; peer review: 3 approved, 2 approved with reservations, 1 not approved]. NIHR Open Res 2024, 4:49 (https://doi.org/10.3310/nihropenres.14872.r32819) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-49/v1#referee-response-32819 https://openresearch.nihr.ac.uk/articles/4-49/v1#referee-response-32819 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 27 Sep 2024 Ramesha Papanna, Department of Obstetrics, Gynecology and Reproductive Sciences, McGovern Medical School, The University of Texas, Houston, TX, USA Neha Agarwal, Obstetrics and Gynecology, The University of Texas Health Science Center at Houston John P and Katherine G McGovern Medical School, Houston, Texas, USA Not Approved VIEWS 0 Attilakos et al are presenting a population based prospective study of vasa previa in UK to demonstrate registered incidence of vasa previa and its outcomes. The study confirms the well-known knowledge of antenatal diagnosis is critical in reducing perinatal mortality ... Continue reading We confirm that we have read this submission and believe that we have an appropriate level of expertise to state that we do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close Attilakos et al are presenting a population based prospective study of vasa previa in UK to demonstrate registered incidence of vasa previa and its outcomes. The study confirms the well-known knowledge of antenatal diagnosis is critical in reducing perinatal mortality and morbidity of vasa previa. It also reflects upon the effect of lack of screening policy for vasa previa and its impact on the perinatal outcomes. Below are the major concerns of the article: Below are the major concerns of the article: - Limited Scope of Screening Analysis: While the article mentions that only 5% of obstetric units in the UK had screening programs for vasa previa, it does not provide sufficient detail about the methods or criteria used for these screenings. Although there are significant differences in outcomes between hospitals with and without screening programs, the study lacks a detailed exploration of the specific screening strategies that could help reduce perinatal mortality and morbidity. A more in-depth investigation into the screening protocols used by the 10 units with programs would be beneficial. This additional detail could help inform future recommendations for the implementation of nationwide screening programs. - Exclusion of cases in antepartum vs postpartum: Need this distinction made to help improve the clarity of case selection. Of those 22 excluded cases are from antenatal diagnosis group, due to lack of sufficient details, it would help to make a better determination of the incidence. - Underestimation of the vasa previa. As authors acknowledge in the weakness of the study, there is high probability of underestimation of vasa previa due to nature of reporting in this large-scale study. There is lack of rigorous methods to determine the true incidence of vasa previa. Consider avoiding “incidence” in the title, objective, and use “estimates” . - Confirmation of vasa previa: Lack of details in the diagnosis of vasa previa including exposed fetal vessels on clinical examination. How often is clinical examination performed of the placenta? Is this universal? Are there standard protocols that require post-delivery placental evaluation to ensure optimal case capture? - Confirmation of pathologic examination of the placenta” How many in this cohort? How can you confirm that without information on placental orientation within the uterine environment? - It is recommended that for the authors to estimates of effect of universal screening for vasa previa similar to 6% of hospitals on the obstetrical outcomes- number of c-sections to prevent one perinatal death and hypoxic ischemic encephalopathy. Does this justify the national guidelines for universal screening for vasa previa. - In the Methods section of the abstract, there is a spelling error in line 3. The word "form" should be corrected to "from." - 48% of the cases of peripartum identification had an antepartum admission. What were the indications for admission? Was this preterm labor? Vaginal bleeding? Unrelated medical indications (e.g., preeclampsia)? - Irrespective of universal screening recommendation, are there recommendations for screening among those with risk factors considering 43% of the cases with peripartum identification had low-lying placenta and/or velamentous cord insertion and 100% had at least 1 risk factor. - In the 7th paragraph of the Results section, why term “no antenatal diagnosis” rather than “peripartum” as is otherwise used throughout the article? - Is the work clearly and accurately presented and does it cite the current literature? Yes - Is the study design appropriate and is the work technically sound? No - Are sufficient details of methods and analysis provided to allow replication by others? Yes - If applicable, is the statistical analysis and its interpretation appropriate? Partly - Are all the source data underlying the results available to ensure full reproducibility? Yes - Are the conclusions drawn adequately supported by the results? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: Vasa previa, placenta accreta and fetal surgery CITE HOW TO CITE THIS REPORT Papanna R and Agarwal N. Reviewer Report For: Incidence and outcomes of vasa praevia in the United Kingdom [version 2; peer review: 3 approved, 2 approved with reservations, 1 not approved]. NIHR Open Res 2024, 4:49 (https://doi.org/10.3310/nihropenres.14872.r32819) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-49/v1#referee-response-32819 https://openresearch.nihr.ac.uk/articles/4-49/v1#referee-response-32819 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. - Author Response 05 Dec 2024Ruth Tunn, National Perinatal Epidemiology Unit, University of Oxford, Old Road Campus, Headington, OX3 7LF, UK05 Dec 2024Author Response1. Limited Scope of Screening Analysis: While the article mentions that only 5% of obstetric units in the UK had screening programs for vasa previa, it does not provide sufficient ... Continue reading 1. Limited Scope of Screening Analysis: While the article mentions that only 5% of obstetric units in the UK had screening programs for vasa previa, it does not provide sufficient detail about the methods or criteria used for these screenings. Although there are significant differences in outcomes between hospitals with and without screening programs, the study lacks a detailed exploration of the specific screening strategies that could help reduce perinatal mortality and morbidity. A more in-depth investigation into the screening protocols used by the 10 units with programs would be beneficial. This additional detail could help inform future recommendations for the implementation of nationwide screening programs. Response: Unfortunately, we do not have further details of the screening protocols used at the centres in question at the time of the study. UKOSS reporting operates on a volunteer basis, and to avoid overburdening reporters and maximise return rates, we limit the amount of information requested. This study did not have evaluation of screening as a main objective, so we limited data collection about screening programmes to the simple yes/no question described in the methods. We present data about screening programmes in relation to diagnosis in Table 5 to encourage and inform future research into this important issue, but do not seek to draw recommendations from the limited information collected. 2. Exclusion of cases in antepartum vs postpartum: Need this distinction made to help improve the clarity of case selection. Of those 22 excluded cases are from antenatal diagnosis group, due to lack of sufficient details, it would help to make a better determination of the incidence. Response: We provide additional information about the excluded “cases” in Figure 1. Of the 22 reports of apparent cases that were excluded, one fell outside the study period and seven were found when reviewed to not meet the case definition (two were cases of cord prolapse, two were placenta praevia, and three were other non-vasa praevia reports). It would therefore be inappropriate to consider these in calculation of vasa praevia incidence. Of the remaining fourteen reports received but not confirmed as vasa praevia, four were of women who had antepartum haemorrhage, fetal anaemia, or other poor outcomes. These outcomes are sometimes associated with vasa praevia but could be due to a range of other causes, and there was no indication that vasa praevia was suspected antenatally. Because UKOSS reporters are asked to identify and report all cases of the condition in question, they will sometimes err on the side of caution and include reports of observations that might be of interest, “just in case”, to allow the UKOSS researchers on the specific study to make the final adjudication. However, there was insufficient evidence in these cases to suspect vasa praevia specifically. The remaining ten excluded reports were of women in whom vasa praevia was suspected antenatally and who underwent planned caesarean section because of this suspicion, but there was no documented confirmation of the condition after women gave birth. We could therefore not include these under our case definition in the primary estimate of incidence; however, we do discuss the possible impact of their exclusion in the Discussion: “Even if the 10 planned caesarean sections with no postnatal confirmation were included, the estimated incidence would still be relatively low at 7.94 per 100,000 maternities (1 case for every 12,593 maternities).” We have expanded on the reasons for exclusion in Figure 1 and changed the terminology of unconfirmed “cases” to “reports” in the text for clarity. 3. Underestimation of the vasa previa. As authors acknowledge in the weakness of the study, there is high probability of underestimation of vasa previa due to nature of reporting in this large-scale study. There is lack of rigorous methods to determine the true incidence of vasa previa. Consider avoiding “incidence” in the title, objective, and use “estimates” . Response: We have retained the term “incidence”, as this was the metric that the study was designed to investigate, but have added “estimated” at relevant points in the text to reflect the uncertainty arising from the acknowledged limitations. The important point to note is the difference between diagnosed vasa praevia based on screening, and diagnosed vasa praevia based on adverse outcome. As few hospitals in the UK have vasa praevia screening programmes, the estimate of incidence is more reflective of the latter. 4. Confirmation of vasa previa: Lack of details in the diagnosis of vasa previa including exposed fetal vessels on clinical examination. How often is clinical examination performed of the placenta? Is this universal? Are there standard protocols that require post-delivery placental evaluation to ensure optimal case capture? 5. Confirmation of pathologic examination of the placenta” How many in this cohort? How can you confirm that without information on placental orientation within the uterine environment? Response: Visual examination of all placentas post-birth is standard practice in the UK, to ensure completeness as well as to identify abnormal vessels. As indicated in Table 3, the placenta was examined in 100% of antenatally diagnosed cases (noting that this was required to establish the case definition) and 91% of peripartum-diagnosed cases; it was sent to pathology for further examination in 32% of antenatally diagnosed cases and 65% of peripartum-diagnosed cases. As the reviewer notes, in placentas of women who have had no suspicion of vasa praevia antenatally and no adverse outcome, the observation of fetal vessels in the membranes postnatally cannot be used to confirm vasa praevia as it would be unknown as to whether those vessels crossed the cervix, although the position of membrane rupture may be an indication. However, ruptured fetal vessels are readily detectable and, in women with antenatal suspicion in whom the orientation will have been confirmed on scan, fetal vessels running through the membranes can be confirmed postnatally. 6. It is recommended that for the authors to estimates of effect of universal screening for vasa previa similar to 6% of hospitals on the obstetrical outcomes- number of c-sections to prevent one perinatal death and hypoxic ischemic encephalopathy. Does this justify the national guidelines for universal screening for vasa previa. Response: We agree that this would be useful information to have. However, we do not think that our study design and the limited amount of data from the few centres with screening programmes can support such analyses or would yield robust conclusions/recommendations. The numbers involved are small, association between screening and antenatal diagnosis was not consistent across centres with programmes and, and as you identified in a previous comment, we have limited details of the exact composition of the screening programmes that the screening centres had in place at the time of the study, so a recommendation would lack necessary details of any advocated intervention. We say in the discussion, “Table 5 illustrates that the number of reported cases of vasa praevia was substantially higher if there was antenatal screening. Large, well-designed prospective screening studies may elucidate this observation further; our study was not designed to evaluate screening efficiency or accuracy”. We agree that future studies should investigate screening in more depth to be able to provide guidance on this issue. Below are the minor concerns of the article: 1. In the Methods section of the abstract, there is a spelling error in line 3. The word "form" should be corrected to "from." Response: Thank you, we have corrected this error. 2. 48% of the cases of peripartum identification had an antepartum admission. What were the indications for admission? Was this preterm labor? Vaginal bleeding? Unrelated medical indications (e.g., preeclampsia)? Response: Of the 11 women in the peripartum diagnosis group admitted to hospital antenatally, three were admitted for reasons relating to the position or movement of the fetus; four for maternal indications unrelated to vasa praevia, such as elevated blood pressure; and two for antepartum haemorrhage that progressed to birth. Notably, two women were admitted for antepartum bleeding earlier in the pregnancy, which could indicate a missed opportunity for vasa praevia diagnosis. We have added this information to the manuscript. 3. Irrespective of universal screening recommendation, are there recommendations for screening among those with risk factors considering 43% of the cases with peripartum identification had low-lying placenta and/or velamentous cord insertion and 100% had at least 1 risk factor. Response: Our study suggests that targeted screening may be appropriate, although we are cautious about making firm recommendations on the basis of this evidence alone. National guidelines in the US, Canada and Australia all advocate targeted screening for women with risk factors for vasa praevia. We mentioned these guidelines in broader terms in the fourth paragraph of the Discussion, but have now emphasised the relevant recommendations again where we reflect on risk factors in the cases in our study, by adding the sentence in bold below: “Most previous studies (20) demonstrated the presence of risk factors in most vasa praevia cases; in our study all cases had at least one risk factor. This might suggest that targeted screening for cases with risk factors, particularly low placenta and velamentous cord insertion, might be useful as one or both of these were present in almost half of the cases in our study. This would be consistent with current US, Canadian and Australian guidelines, all of which recommend targeted screening (19).” 19. Tsakiridis I, Mamopoulos A, Athanasiadis A, Dagklis T. Diagnosis and Management of Vasa previa: a comparison of 4 national guidelines. Obstetrical & Gynecological Survey. 2019;74(7):436-42. 4. In the 7th paragraph of the Results section, why term “no antenatal diagnosis” rather than “peripartum” as is otherwise used throughout the article? Response: Thank you for pointing this out, we have made the terminology consistent.1. Limited Scope of Screening Analysis: While the article mentions that only 5% of obstetric units in the UK had screening programs for vasa previa, it does not provide sufficient detail about the methods or criteria used for these screenings. Although there are significant differences in outcomes between hospitals with and without screening programs, the study lacks a detailed exploration of the specific screening strategies that could help reduce perinatal mortality and morbidity. A more in-depth investigation into the screening protocols used by the 10 units with programs would be beneficial. This additional detail could help inform future recommendations for the implementation of nationwide screening programs.Competing Interests: No competing interests were disclosed. Close Response: Unfortunately, we do not have further details of the screening protocols used at the centres in question at the time of the study. UKOSS reporting operates on a volunteer basis, and to avoid overburdening reporters and maximise return rates, we limit the amount of information requested. This study did not have evaluation of screening as a main objective, so we limited data collection about screening programmes to the simple yes/no question described in the methods. We present data about screening programmes in relation to diagnosis in Table 5 to encourage and inform future research into this important issue, but do not seek to draw recommendations from the limited information collected. 2. Exclusion of cases in antepartum vs postpartum: Need this distinction made to help improve the clarity of case selection. Of those 22 excluded cases are from antenatal diagnosis group, due to lack of sufficient details, it would help to make a better determination of the incidence. Response: We provide additional information about the excluded “cases” in Figure 1. Of the 22 reports of apparent cases that were excluded, one fell outside the study period and seven were found when reviewed to not meet the case definition (two were cases of cord prolapse, two were placenta praevia, and three were other non-vasa praevia reports). It would therefore be inappropriate to consider these in calculation of vasa praevia incidence. Of the remaining fourteen reports received but not confirmed as vasa praevia, four were of women who had antepartum haemorrhage, fetal anaemia, or other poor outcomes. These outcomes are sometimes associated with vasa praevia but could be due to a range of other causes, and there was no indication that vasa praevia was suspected antenatally. Because UKOSS reporters are asked to identify and report all cases of the condition in question, they will sometimes err on the side of caution and include reports of observations that might be of interest, “just in case”, to allow the UKOSS researchers on the specific study to make the final adjudication. However, there was insufficient evidence in these cases to suspect vasa praevia specifically. The remaining ten excluded reports were of women in whom vasa praevia was suspected antenatally and who underwent planned caesarean section because of this suspicion, but there was no documented confirmation of the condition after women gave birth. We could therefore not include these under our case definition in the primary estimate of incidence; however, we do discuss the possible impact of their exclusion in the Discussion: “Even if the 10 planned caesarean sections with no postnatal confirmation were included, the estimated incidence would still be relatively low at 7.94 per 100,000 maternities (1 case for every 12,593 maternities).” We have expanded on the reasons for exclusion in Figure 1 and changed the terminology of unconfirmed “cases” to “reports” in the text for clarity. 3. Underestimation of the vasa previa. As authors acknowledge in the weakness of the study, there is high probability of underestimation of vasa previa due to nature of reporting in this large-scale study. There is lack of rigorous methods to determine the true incidence of vasa previa. Consider avoiding “incidence” in the title, objective, and use “estimates” . Response: We have retained the term “incidence”, as this was the metric that the study was designed to investigate, but have added “estimated” at relevant points in the text to reflect the uncertainty arising from the acknowledged limitations. The important point to note is the difference between diagnosed vasa praevia based on screening, and diagnosed vasa praevia based on adverse outcome. As few hospitals in the UK have vasa praevia screening programmes, the estimate of incidence is more reflective of the latter. 4. Confirmation of vasa previa: Lack of details in the diagnosis of vasa previa including exposed fetal vessels on clinical examination. How often is clinical examination performed of the placenta? Is this universal? Are there standard protocols that require post-delivery placental evaluation to ensure optimal case capture? 5. Confirmation of pathologic examination of the placenta” How many in this cohort? How can you confirm that without information on placental orientation within the uterine environment? Response: Visual examination of all placentas post-birth is standard practice in the UK, to ensure completeness as well as to identify abnormal vessels. As indicated in Table 3, the placenta was examined in 100% of antenatally diagnosed cases (noting that this was required to establish the case definition) and 91% of peripartum-diagnosed cases; it was sent to pathology for further examination in 32% of antenatally diagnosed cases and 65% of peripartum-diagnosed cases. As the reviewer notes, in placentas of women who have had no suspicion of vasa praevia antenatally and no adverse outcome, the observation of fetal vessels in the membranes postnatally cannot be used to confirm vasa praevia as it would be unknown as to whether those vessels crossed the cervix, although the position of membrane rupture may be an indication. However, ruptured fetal vessels are readily detectable and, in women with antenatal suspicion in whom the orientation will have been confirmed on scan, fetal vessels running through the membranes can be confirmed postnatally. 6. It is recommended that for the authors to estimates of effect of universal screening for vasa previa similar to 6% of hospitals on the obstetrical outcomes- number of c-sections to prevent one perinatal death and hypoxic ischemic encephalopathy. Does this justify the national guidelines for universal screening for vasa previa. Response: We agree that this would be useful information to have. However, we do not think that our study design and the limited amount of data from the few centres with screening programmes can support such analyses or would yield robust conclusions/recommendations. The numbers involved are small, association between screening and antenatal diagnosis was not consistent across centres with programmes and, and as you identified in a previous comment, we have limited details of the exact composition of the screening programmes that the screening centres had in place at the time of the study, so a recommendation would lack necessary details of any advocated intervention. We say in the discussion, “Table 5 illustrates that the number of reported cases of vasa praevia was substantially higher if there was antenatal screening. Large, well-designed prospective screening studies may elucidate this observation further; our study was not designed to evaluate screening efficiency or accuracy”. We agree that future studies should investigate screening in more depth to be able to provide guidance on this issue. Below are the minor concerns of the article: 1. In the Methods section of the abstract, there is a spelling error in line 3. The word "form" should be corrected to "from." Response: Thank you, we have corrected this error. 2. 48% of the cases of peripartum identification had an antepartum admission. What were the indications for admission? Was this preterm labor? Vaginal bleeding? Unrelated medical indications (e.g., preeclampsia)? Response: Of the 11 women in the peripartum diagnosis group admitted to hospital antenatally, three were admitted for reasons relating to the position or movement of the fetus; four for maternal indications unrelated to vasa praevia, such as elevated blood pressure; and two for antepartum haemorrhage that progressed to birth. Notably, two women were admitted for antepartum bleeding earlier in the pregnancy, which could indicate a missed opportunity for vasa praevia diagnosis. We have added this information to the manuscript. 3. Irrespective of universal screening recommendation, are there recommendations for screening among those with risk factors considering 43% of the cases with peripartum identification had low-lying placenta and/or velamentous cord insertion and 100% had at least 1 risk factor. Response: Our study suggests that targeted screening may be appropriate, although we are cautious about making firm recommendations on the basis of this evidence alone. National guidelines in the US, Canada and Australia all advocate targeted screening for women with risk factors for vasa praevia. We mentioned these guidelines in broader terms in the fourth paragraph of the Discussion, but have now emphasised the relevant recommendations again where we reflect on risk factors in the cases in our study, by adding the sentence in bold below: “Most previous studies (20) demonstrated the presence of risk factors in most vasa praevia cases; in our study all cases had at least one risk factor. This might suggest that targeted screening for cases with risk factors, particularly low placenta and velamentous cord insertion, might be useful as one or both of these were present in almost half of the cases in our study. This would be consistent with current US, Canadian and Australian guidelines, all of which recommend targeted screening (19).” 19. Tsakiridis I, Mamopoulos A, Athanasiadis A, Dagklis T. Diagnosis and Management of Vasa previa: a comparison of 4 national guidelines. Obstetrical & Gynecological Survey. 2019;74(7):436-42. 4. In the 7th paragraph of the Results section, why term “no antenatal diagnosis” rather than “peripartum” as is otherwise used throughout the article? Response: Thank you for pointing this out, we have made the terminology consistent. COMMENTS ON THIS REPORT - Author Response 05 Dec 2024Ruth Tunn, National Perinatal Epidemiology Unit, University of Oxford, Old Road Campus, Headington, OX3 7LF, UK05 Dec 2024Author Response1. Limited Scope of Screening Analysis: While the article mentions that only 5% of obstetric units in the UK had screening programs for vasa previa, it does not provide sufficient ... Continue reading 1. Limited Scope of Screening Analysis: While the article mentions that only 5% of obstetric units in the UK had screening programs for vasa previa, it does not provide sufficient detail about the methods or criteria used for these screenings. Although there are significant differences in outcomes between hospitals with and without screening programs, the study lacks a detailed exploration of the specific screening strategies that could help reduce perinatal mortality and morbidity. A more in-depth investigation into the screening protocols used by the 10 units with programs would be beneficial. This additional detail could help inform future recommendations for the implementation of nationwide screening programs. Response: Unfortunately, we do not have further details of the screening protocols used at the centres in question at the time of the study. UKOSS reporting operates on a volunteer basis, and to avoid overburdening reporters and maximise return rates, we limit the amount of information requested. This study did not have evaluation of screening as a main objective, so we limited data collection about screening programmes to the simple yes/no question described in the methods. We present data about screening programmes in relation to diagnosis in Table 5 to encourage and inform future research into this important issue, but do not seek to draw recommendations from the limited information collected. 2. Exclusion of cases in antepartum vs postpartum: Need this distinction made to help improve the clarity of case selection. Of those 22 excluded cases are from antenatal diagnosis group, due to lack of sufficient details, it would help to make a better determination of the incidence. Response: We provide additional information about the excluded “cases” in Figure 1. Of the 22 reports of apparent cases that were excluded, one fell outside the study period and seven were found when reviewed to not meet the case definition (two were cases of cord prolapse, two were placenta praevia, and three were other non-vasa praevia reports). It would therefore be inappropriate to consider these in calculation of vasa praevia incidence. Of the remaining fourteen reports received but not confirmed as vasa praevia, four were of women who had antepartum haemorrhage, fetal anaemia, or other poor outcomes. These outcomes are sometimes associated with vasa praevia but could be due to a range of other causes, and there was no indication that vasa praevia was suspected antenatally. Because UKOSS reporters are asked to identify and report all cases of the condition in question, they will sometimes err on the side of caution and include reports of observations that might be of interest, “just in case”, to allow the UKOSS researchers on the specific study to make the final adjudication. However, there was insufficient evidence in these cases to suspect vasa praevia specifically. The remaining ten excluded reports were of women in whom vasa praevia was suspected antenatally and who underwent planned caesarean section because of this suspicion, but there was no documented confirmation of the condition after women gave birth. We could therefore not include these under our case definition in the primary estimate of incidence; however, we do discuss the possible impact of their exclusion in the Discussion: “Even if the 10 planned caesarean sections with no postnatal confirmation were included, the estimated incidence would still be relatively low at 7.94 per 100,000 maternities (1 case for every 12,593 maternities).” We have expanded on the reasons for exclusion in Figure 1 and changed the terminology of unconfirmed “cases” to “reports” in the text for clarity. 3. Underestimation of the vasa previa. As authors acknowledge in the weakness of the study, there is high probability of underestimation of vasa previa due to nature of reporting in this large-scale study. There is lack of rigorous methods to determine the true incidence of vasa previa. Consider avoiding “incidence” in the title, objective, and use “estimates” . Response: We have retained the term “incidence”, as this was the metric that the study was designed to investigate, but have added “estimated” at relevant points in the text to reflect the uncertainty arising from the acknowledged limitations. The important point to note is the difference between diagnosed vasa praevia based on screening, and diagnosed vasa praevia based on adverse outcome. As few hospitals in the UK have vasa praevia screening programmes, the estimate of incidence is more reflective of the latter. 4. Confirmation of vasa previa: Lack of details in the diagnosis of vasa previa including exposed fetal vessels on clinical examination. How often is clinical examination performed of the placenta? Is this universal? Are there standard protocols that require post-delivery placental evaluation to ensure optimal case capture? 5. Confirmation of pathologic examination of the placenta” How many in this cohort? How can you confirm that without information on placental orientation within the uterine environment? Response: Visual examination of all placentas post-birth is standard practice in the UK, to ensure completeness as well as to identify abnormal vessels. As indicated in Table 3, the placenta was examined in 100% of antenatally diagnosed cases (noting that this was required to establish the case definition) and 91% of peripartum-diagnosed cases; it was sent to pathology for further examination in 32% of antenatally diagnosed cases and 65% of peripartum-diagnosed cases. As the reviewer notes, in placentas of women who have had no suspicion of vasa praevia antenatally and no adverse outcome, the observation of fetal vessels in the membranes postnatally cannot be used to confirm vasa praevia as it would be unknown as to whether those vessels crossed the cervix, although the position of membrane rupture may be an indication. However, ruptured fetal vessels are readily detectable and, in women with antenatal suspicion in whom the orientation will have been confirmed on scan, fetal vessels running through the membranes can be confirmed postnatally. 6. It is recommended that for the authors to estimates of effect of universal screening for vasa previa similar to 6% of hospitals on the obstetrical outcomes- number of c-sections to prevent one perinatal death and hypoxic ischemic encephalopathy. Does this justify the national guidelines for universal screening for vasa previa. Response: We agree that this would be useful information to have. However, we do not think that our study design and the limited amount of data from the few centres with screening programmes can support such analyses or would yield robust conclusions/recommendations. The numbers involved are small, association between screening and antenatal diagnosis was not consistent across centres with programmes and, and as you identified in a previous comment, we have limited details of the exact composition of the screening programmes that the screening centres had in place at the time of the study, so a recommendation would lack necessary details of any advocated intervention. We say in the discussion, “Table 5 illustrates that the number of reported cases of vasa praevia was substantially higher if there was antenatal screening. Large, well-designed prospective screening studies may elucidate this observation further; our study was not designed to evaluate screening efficiency or accuracy”. We agree that future studies should investigate screening in more depth to be able to provide guidance on this issue. Below are the minor concerns of the article: 1. In the Methods section of the abstract, there is a spelling error in line 3. The word "form" should be corrected to "from." Response: Thank you, we have corrected this error. 2. 48% of the cases of peripartum identification had an antepartum admission. What were the indications for admission? Was this preterm labor? Vaginal bleeding? Unrelated medical indications (e.g., preeclampsia)? Response: Of the 11 women in the peripartum diagnosis group admitted to hospital antenatally, three were admitted for reasons relating to the position or movement of the fetus; four for maternal indications unrelated to vasa praevia, such as elevated blood pressure; and two for antepartum haemorrhage that progressed to birth. Notably, two women were admitted for antepartum bleeding earlier in the pregnancy, which could indicate a missed opportunity for vasa praevia diagnosis. We have added this information to the manuscript. 3. Irrespective of universal screening recommendation, are there recommendations for screening among those with risk factors considering 43% of the cases with peripartum identification had low-lying placenta and/or velamentous cord insertion and 100% had at least 1 risk factor. Response: Our study suggests that targeted screening may be appropriate, although we are cautious about making firm recommendations on the basis of this evidence alone. National guidelines in the US, Canada and Australia all advocate targeted screening for women with risk factors for vasa praevia. We mentioned these guidelines in broader terms in the fourth paragraph of the Discussion, but have now emphasised the relevant recommendations again where we reflect on risk factors in the cases in our study, by adding the sentence in bold below: “Most previous studies (20) demonstrated the presence of risk factors in most vasa praevia cases; in our study all cases had at least one risk factor. This might suggest that targeted screening for cases with risk factors, particularly low placenta and velamentous cord insertion, might be useful as one or both of these were present in almost half of the cases in our study. This would be consistent with current US, Canadian and Australian guidelines, all of which recommend targeted screening (19).” 19. Tsakiridis I, Mamopoulos A, Athanasiadis A, Dagklis T. Diagnosis and Management of Vasa previa: a comparison of 4 national guidelines. Obstetrical & Gynecological Survey. 2019;74(7):436-42. 4. In the 7th paragraph of the Results section, why term “no antenatal diagnosis” rather than “peripartum” as is otherwise used throughout the article? Response: Thank you for pointing this out, we have made the terminology consistent.1. Limited Scope of Screening Analysis: While the article mentions that only 5% of obstetric units in the UK had screening programs for vasa previa, it does not provide sufficient detail about the methods or criteria used for these screenings. Although there are significant differences in outcomes between hospitals with and without screening programs, the study lacks a detailed exploration of the specific screening strategies that could help reduce perinatal mortality and morbidity. A more in-depth investigation into the screening protocols used by the 10 units with programs would be beneficial. This additional detail could help inform future recommendations for the implementation of nationwide screening programs.Competing Interests: No competing interests were disclosed. Close Response: Unfortunately, we do not have further details of the screening protocols used at the centres in question at the time of the study. UKOSS reporting operates on a volunteer basis, and to avoid overburdening reporters and maximise return rates, we limit the amount of information requested. This study did not have evaluation of screening as a main objective, so we limited data collection about screening programmes to the simple yes/no question described in the methods. We present data about screening programmes in relation to diagnosis in Table 5 to encourage and inform future research into this important issue, but do not seek to draw recommendations from the limited information collected. 2. Exclusion of cases in antepartum vs postpartum: Need this distinction made to help improve the clarity of case selection. Of those 22 excluded cases are from antenatal diagnosis group, due to lack of sufficient details, it would help to make a better determination of the incidence. Response: We provide additional information about the excluded “cases” in Figure 1. Of the 22 reports of apparent cases that were excluded, one fell outside the study period and seven were found when reviewed to not meet the case definition (two were cases of cord prolapse, two were placenta praevia, and three were other non-vasa praevia reports). It would therefore be inappropriate to consider these in calculation of vasa praevia incidence. Of the remaining fourteen reports received but not confirmed as vasa praevia, four were of women who had antepartum haemorrhage, fetal anaemia, or other poor outcomes. These outcomes are sometimes associated with vasa praevia but could be due to a range of other causes, and there was no indication that vasa praevia was suspected antenatally. Because UKOSS reporters are asked to identify and report all cases of the condition in question, they will sometimes err on the side of caution and include reports of observations that might be of interest, “just in case”, to allow the UKOSS researchers on the specific study to make the final adjudication. However, there was insufficient evidence in these cases to suspect vasa praevia specifically. The remaining ten excluded reports were of women in whom vasa praevia was suspected antenatally and who underwent planned caesarean section because of this suspicion, but there was no documented confirmation of the condition after women gave birth. We could therefore not include these under our case definition in the primary estimate of incidence; however, we do discuss the possible impact of their exclusion in the Discussion: “Even if the 10 planned caesarean sections with no postnatal confirmation were included, the estimated incidence would still be relatively low at 7.94 per 100,000 maternities (1 case for every 12,593 maternities).” We have expanded on the reasons for exclusion in Figure 1 and changed the terminology of unconfirmed “cases” to “reports” in the text for clarity. 3. Underestimation of the vasa previa. As authors acknowledge in the weakness of the study, there is high probability of underestimation of vasa previa due to nature of reporting in this large-scale study. There is lack of rigorous methods to determine the true incidence of vasa previa. Consider avoiding “incidence” in the title, objective, and use “estimates” . Response: We have retained the term “incidence”, as this was the metric that the study was designed to investigate, but have added “estimated” at relevant points in the text to reflect the uncertainty arising from the acknowledged limitations. The important point to note is the difference between diagnosed vasa praevia based on screening, and diagnosed vasa praevia based on adverse outcome. As few hospitals in the UK have vasa praevia screening programmes, the estimate of incidence is more reflective of the latter. 4. Confirmation of vasa previa: Lack of details in the diagnosis of vasa previa including exposed fetal vessels on clinical examination. How often is clinical examination performed of the placenta? Is this universal? Are there standard protocols that require post-delivery placental evaluation to ensure optimal case capture? 5. Confirmation of pathologic examination of the placenta” How many in this cohort? How can you confirm that without information on placental orientation within the uterine environment? Response: Visual examination of all placentas post-birth is standard practice in the UK, to ensure completeness as well as to identify abnormal vessels. As indicated in Table 3, the placenta was examined in 100% of antenatally diagnosed cases (noting that this was required to establish the case definition) and 91% of peripartum-diagnosed cases; it was sent to pathology for further examination in 32% of antenatally diagnosed cases and 65% of peripartum-diagnosed cases. As the reviewer notes, in placentas of women who have had no suspicion of vasa praevia antenatally and no adverse outcome, the observation of fetal vessels in the membranes postnatally cannot be used to confirm vasa praevia as it would be unknown as to whether those vessels crossed the cervix, although the position of membrane rupture may be an indication. However, ruptured fetal vessels are readily detectable and, in women with antenatal suspicion in whom the orientation will have been confirmed on scan, fetal vessels running through the membranes can be confirmed postnatally. 6. It is recommended that for the authors to estimates of effect of universal screening for vasa previa similar to 6% of hospitals on the obstetrical outcomes- number of c-sections to prevent one perinatal death and hypoxic ischemic encephalopathy. Does this justify the national guidelines for universal screening for vasa previa. Response: We agree that this would be useful information to have. However, we do not think that our study design and the limited amount of data from the few centres with screening programmes can support such analyses or would yield robust conclusions/recommendations. The numbers involved are small, association between screening and antenatal diagnosis was not consistent across centres with programmes and, and as you identified in a previous comment, we have limited details of the exact composition of the screening programmes that the screening centres had in place at the time of the study, so a recommendation would lack necessary details of any advocated intervention. We say in the discussion, “Table 5 illustrates that the number of reported cases of vasa praevia was substantially higher if there was antenatal screening. Large, well-designed prospective screening studies may elucidate this observation further; our study was not designed to evaluate screening efficiency or accuracy”. We agree that future studies should investigate screening in more depth to be able to provide guidance on this issue. Below are the minor concerns of the article: 1. In the Methods section of the abstract, there is a spelling error in line 3. The word "form" should be corrected to "from." Response: Thank you, we have corrected this error. 2. 48% of the cases of peripartum identification had an antepartum admission. What were the indications for admission? Was this preterm labor? Vaginal bleeding? Unrelated medical indications (e.g., preeclampsia)? Response: Of the 11 women in the peripartum diagnosis group admitted to hospital antenatally, three were admitted for reasons relating to the position or movement of the fetus; four for maternal indications unrelated to vasa praevia, such as elevated blood pressure; and two for antepartum haemorrhage that progressed to birth. Notably, two women were admitted for antepartum bleeding earlier in the pregnancy, which could indicate a missed opportunity for vasa praevia diagnosis. We have added this information to the manuscript. 3. Irrespective of universal screening recommendation, are there recommendations for screening among those with risk factors considering 43% of the cases with peripartum identification had low-lying placenta and/or velamentous cord insertion and 100% had at least 1 risk factor. Response: Our study suggests that targeted screening may be appropriate, although we are cautious about making firm recommendations on the basis of this evidence alone. National guidelines in the US, Canada and Australia all advocate targeted screening for women with risk factors for vasa praevia. We mentioned these guidelines in broader terms in the fourth paragraph of the Discussion, but have now emphasised the relevant recommendations again where we reflect on risk factors in the cases in our study, by adding the sentence in bold below: “Most previous studies (20) demonstrated the presence of risk factors in most vasa praevia cases; in our study all cases had at least one risk factor. This might suggest that targeted screening for cases with risk factors, particularly low placenta and velamentous cord insertion, might be useful as one or both of these were present in almost half of the cases in our study. This would be consistent with current US, Canadian and Australian guidelines, all of which recommend targeted screening (19).” 19. Tsakiridis I, Mamopoulos A, Athanasiadis A, Dagklis T. Diagnosis and Management of Vasa previa: a comparison of 4 national guidelines. Obstetrical & Gynecological Survey. 2019;74(7):436-42. 4. In the 7th paragraph of the Results section, why term “no antenatal diagnosis” rather than “peripartum” as is otherwise used throughout the article? Response: Thank you for pointing this out, we have made the terminology consistent. Views 0 How to cite this report: Siargkas A. Reviewer Report For: Incidence and outcomes of vasa praevia in the United Kingdom [version 2; peer review: 3 approved, 2 approved with reservations, 1 not approved]. NIHR Open Res 2024, 4:49 (https://doi.org/10.3310/nihropenres.14872.r32946) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-49/v1#referee-response-32946 https://openresearch.nihr.ac.uk/articles/4-49/v1#referee-response-32946 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 18 Sep 2024 Approved VIEWS 0 "Incidence and Outcomes of Vasa Praevia in the United Kingdom" by Attilakos et al. is an excellent and comprehensive study that sheds light on the rare but critical obstetric condition of vasa praevia. The authors have executed a robust, prospective, ... Continue reading I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close "Incidence and Outcomes of Vasa Praevia in the United Kingdom" by Attilakos et al. is an excellent and comprehensive study that sheds light on the rare but critical obstetric condition of vasa praevia. The authors have executed a robust, prospective, population-based study using the UK Obstetric Surveillance System (UKOSS), ensuring a sound methodology and national representation. They provided a clear definition of vasa praevia and meticulously described the case reporting process by nominated clinicians across all UK hospitals with obstetrician-led maternity units. This approach ensured that specific risk factors—such as IVF conception, low-lying placenta, marginal or velamentous cord insertion, and bilobed or succenturiate lobed placentation—were thoroughly reported and analyzed. The statistical analysis was appropriately conducted and clearly presented, offering valuable insights into this rare pathological entity. The results were particularly interesting, revealing an incidence of diagnosed vasa praevia at 6.64 per 100,000 maternities, which is lower than anticipated. This equates to approximately one case per 15,062 maternities. The study highlighted significant differences in outcomes between antenatally diagnosed cases and those diagnosed peripartum. In the peripartum diagnosis group, there were four stillbirths and five neonatal deaths, resulting in a perinatal mortality rate of 37.5% for this group. The overall perinatal mortality rate was 17%. Moreover, almost 50% (seven out of 15) of the surviving babies in this group developed hypoxic ischaemic encephalopathy (HIE), and 46% required blood transfusions due to anaemia. In stark contrast, the antenatal diagnosis group reported no severe adverse outcomes, aside from a 36% admission rate to the neonatal intensive care unit (NICU), likely due to preterm delivery from planned caesarean sections. The discussion was highly informative and thoroughly covered the key points of the study. One of the main findings was the high perinatal mortality and morbidity associated with peripartum diagnosis of vasa praevia. The authors used a robust case definition to accurately capture clinically diagnosed and confirmed cases. However, they acknowledged that this strict definition might have been a potential weakness, as it excluded ten antenatally suspected cases without postnatal confirmation due to the lack of examination of the placenta after birth. This exclusion could have led to an underestimation of the true incidence, but the authors transparently discussed this limitation and provided relevant data. The study also reviewed relevant guidelines, noting that routine screening for vasa praevia is not currently advised. However, given that all cases in their study had at least one risk factor, the authors proposed that targeted screening for pregnancies with specific risk factors—particularly low-lying placenta and velamentous cord insertion—might be beneficial. This suggestion is compelling, as one or both of these risk factors were present in almost half of the cases. Such targeted screening could improve early detection without the drawbacks associated with universal screening. Interestingly, only ten hospitals (6% of respondents) had a formal screening programme for vasa praevia during the study period. One of these hospitals identified 25% of the antenatally diagnosed cases, indicating that formal screening programmes in high-risk populations can significantly enhance detection rates and improve outcomes. In conclusion, this study offers valuable insights into the incidence and outcomes of vasa praevia in the UK, highlighting the critical importance of antenatal diagnosis in improving perinatal outcomes. The authors have provided a well-structured and detailed analysis, with sound methodology and comprehensive reporting. Their proposal for targeted screening based on specific risk factors is particularly noteworthy and could inform future guidelines and clinical practice. Overall, this research represents a significant contribution to obstetric literature and has important implications for the management of pregnancies at risk of vasa praevia. Upon carefully reading the article, I found no mistakes or issues that require correction. The statistical analysis was appropriately conducted and clearly presented, offering valuable insights into this rare pathological entity. The results were particularly interesting, revealing an incidence of diagnosed vasa praevia at 6.64 per 100,000 maternities, which is lower than anticipated. This equates to approximately one case per 15,062 maternities. The study highlighted significant differences in outcomes between antenatally diagnosed cases and those diagnosed peripartum. In the peripartum diagnosis group, there were four stillbirths and five neonatal deaths, resulting in a perinatal mortality rate of 37.5% for this group. The overall perinatal mortality rate was 17%. Moreover, almost 50% (seven out of 15) of the surviving babies in this group developed hypoxic ischaemic encephalopathy (HIE), and 46% required blood transfusions due to anaemia. In stark contrast, the antenatal diagnosis group reported no severe adverse outcomes, aside from a 36% admission rate to the neonatal intensive care unit (NICU), likely due to preterm delivery from planned caesarean sections. The discussion was highly informative and thoroughly covered the key points of the study. One of the main findings was the high perinatal mortality and morbidity associated with peripartum diagnosis of vasa praevia. The authors used a robust case definition to accurately capture clinically diagnosed and confirmed cases. However, they acknowledged that this strict definition might have been a potential weakness, as it excluded ten antenatally suspected cases without postnatal confirmation due to the lack of examination of the placenta after birth. This exclusion could have led to an underestimation of the true incidence, but the authors transparently discussed this limitation and provided relevant data. The study also reviewed relevant guidelines, noting that routine screening for vasa praevia is not currently advised. However, given that all cases in their study had at least one risk factor, the authors proposed that targeted screening for pregnancies with specific risk factors—particularly low-lying placenta and velamentous cord insertion—might be beneficial. This suggestion is compelling, as one or both of these risk factors were present in almost half of the cases. Such targeted screening could improve early detection without the drawbacks associated with universal screening. Interestingly, only ten hospitals (6% of respondents) had a formal screening programme for vasa praevia during the study period. One of these hospitals identified 25% of the antenatally diagnosed cases, indicating that formal screening programmes in high-risk populations can significantly enhance detection rates and improve outcomes. In conclusion, this study offers valuable insights into the incidence and outcomes of vasa praevia in the UK, highlighting the critical importance of antenatal diagnosis in improving perinatal outcomes. The authors have provided a well-structured and detailed analysis, with sound methodology and comprehensive reporting. Their proposal for targeted screening based on specific risk factors is particularly noteworthy and could inform future guidelines and clinical practice. Overall, this research represents a significant contribution to obstetric literature and has important implications for the management of pregnancies at risk of vasa praevia. Upon carefully reading the article, I found no mistakes or issues that require correction. - Is the work clearly and accurately presented and does it cite the current literature? Yes - Is the study design appropriate and is the work technically sound? Yes - Are sufficient details of methods and analysis provided to allow replication by others? Yes - If applicable, is the statistical analysis and its interpretation appropriate? Yes - Are all the source data underlying the results available to ensure full reproducibility? Yes - Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Maternal Fetal Medicine, placenta, umbilical cord, high risk pregnancies CITE HOW TO CITE THIS REPORT Siargkas A. Reviewer Report For: Incidence and outcomes of vasa praevia in the United Kingdom [version 2; peer review: 3 approved, 2 approved with reservations, 1 not approved]. NIHR Open Res 2024, 4:49 (https://doi.org/10.3310/nihropenres.14872.r32946) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-49/v1#referee-response-32946 https://openresearch.nihr.ac.uk/articles/4-49/v1#referee-response-32946 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. - Author Response 28 Nov 2024Ruth Tunn, National Perinatal Epidemiology Unit, University of Oxford, Old Road Campus, Headington, OX3 7LF, UK28 Nov 2024Author ResponseThank you for your supportive comments.Competing Interests: No competing interests were disclosed.Thank you for your supportive comments.Thank you for your supportive comments.Competing Interests: No competing interests were disclosed. Close COMMENTS ON THIS REPORT - Author Response 28 Nov 2024Ruth Tunn, National Perinatal Epidemiology Unit, University of Oxford, Old Road Campus, Headington, OX3 7LF, UK28 Nov 2024Author ResponseThank you for your supportive comments.Competing Interests: No competing interests were disclosed.Thank you for your supportive comments.Thank you for your supportive comments.Competing Interests: No competing interests were disclosed. Close Alongside their report, reviewers assign a status to the article: - Approved - Approved with reservations - Not approved | Invited Reviewers | |||||| |---|---|---|---|---|---|---| | 1 | 2 | 3 | 4 | 5 | 6 | | | Version 2 (revision) 05 Dec 24 | read | read | |||| | Version 1 03 Sep 24 | read | read | read | read | - Neha Agarwal, The University of Texas Health Science Center at Houston John P and Katherine G McGovern Medical School, Houston, USA - Cristina Trilla, Autonomous University of Barcelona, Barcelona, Spain Sign up for content alerts You are now signed up to receive this alert Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. 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