Letter to editor: “Vaginal Er:YAG laser application in the menopausal ewe model: a randomised estrogen and sham-controlled trial “Cheng-Yang Hsu1, Ching-Hu Wu1, Cheng-Yu Long1, 21 Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan2 Department of Obstetrics and Gynecology, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, TaiwanRunning head: Two prospective for this promising experimentWords Count: 315Corresponding Author:Dr. Cheng-Yu Long, MD, PhD, Department of Obstetrics and Gynaecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100, Shih-Chuan 1st Rd, Kaohsiung 80708, TaiwanE-mail: urolong@yahoo.com.twDear Editor-in Chief:We read with great interest with recent publication in BJOG by Mackova et al. (1) This study describe effects of non-ablative erbium-doped: yttrium-aluminium-garnet (Er:YAG) laser on vaginal atrophy induced by iatrogenic menopause in the ewe. The ewes were randomized to three groups: vaginal Er:YAG laser application, estrogen replacement, and sham groups.In the estrogen replacement group of ewes, an estrogen implant was inserted under the skin in the inguinal region. The result showed increase in epithelia thickness in vaginal biopsies and it was significantly higher compared with the laser application and sham groups. In all groups, the lamina propria did not showed any significant differences. Also the autopsy showed the uterus of estrogen-exposed ewes weighted more.We would like to humbly comment the vaginal estrogen use and laser application in genitourinary syndrome of menopause.The vaginal estrogen application was given twice a week with the cream in currently practice of female who suffered from genitourinary syndrome of menopause (GSM). Firstly, the vaginal estrogen application was given twice a week with the cream in clinical practice of female who suffered from GSM. The administration showed improvement of the symptoms while no significant change in serum estrogen level. (2) The estrogen implant in the ewe experiment continues to release estrogen and caused sustained estrogen effect in the ewe and caused gaining weight of uterus, which was very different with our clinical practice of intermittent vaginal cream use.Second, the application in this study is Er:YAG laser, with the the lesser wave length: 2940 nm. While the CO2 laser had much longer wave length 10600 nm and had deeper effect in not only vaginal epithelium but also lamina propia. (3) Therefore the vascularization effects of lamina propia may be obvious noticeably.We thought these 2 flaws could be revised to make the ewe experiment more accurate and similar to current management in women with GSM.ReferencesMackova KA-OX, Mazzer AM, Mori Da Cunha MA-O, Hajkova Hympanova LA-O, Urbankova IA-O, Kastelein AA-O, et al. Vaginal Er:YAG laser application in the menopausal ewe model: a randomised estrogen and sham-controlled trial. BJOG . 2021 May;128(6):1087-1096.Long CY, Liu CM, Hsu SC, Wu CH, Wang CL, Tsai EM. A randomized comparative study of the effects of oral and topical estrogen therapy on the vaginal vascularization and sexual function in hysterectomized postmenopausal women. Menopause . Sep-Oct 2006;13(5):737-43.Bhide AA, Khullar V, Swift S, Digesu GA. The use of laser in urogynaecology. Int Urogynecol J . 2019 May;30(5):683-692.

Objective To examine the association of placental and fetal DNA copy number variants (CNVs) with fetal structural malformations (FSMs) in stillborn fetuses. Design A secondary analysis of stillbirth cases in the Stillbirth Collaborative Research Network (SCRN) study. Setting Multicenter, 59 hospitals in 5 geographic regions in the USA. Population 384 stillbirth cases of the SCRN study (2006-2008). Methods FSMs were grouped by anatomic system and specific malformation type (e.g., central nervous system, thoracic, cardiac, gastrointestinal, skeletal, umbilical cord and craniofacial defects). Single-nucleotide polymorphism array detected CNVs of at least 500kb. CNVs were classified into two groups: normal, defined as no CNVs>500kb or benign CNVs, and abnormal, defined as pathogenic or variants of unknown clinical significance. Main outcome measures The proportions of abnormal CNVs and normal CNVs were compared between stillbirth cases with and without FSMs using the Wald Chi-squared test. Results The proportion of stillbirth cases with any FSMs was higher among those with abnormal CNVs compared with those with normal CNVs (46.7% vs. 19.6%; p-value<0.001). The most common organ system-specific FSMs associated with abnormal CNVs were cardiac defects, followed by craniofacial and skeletal defects. A pathogenic deletion of 1q21.1 involving 46 genes (e.g., CHD1L) and a duplication of 21q22.13 involving 4 genes (SIM2, CLDN14, CHAF1B, HLCS) were associated with a skeletal and cardiac defect, respectively. Conclusion Specific CNVs involving several genes were associated with FSMs in stillborn fetuses. The findings warrant further investigation and may inform counseling and care surrounding pregnancies affected by FSMs at risk for stillbirth.

Mini-commentary on BJOG-20-0093.R1: The impact of age and high risk human papillomavirus (hrHPV) status on the prevalence of high grade cervical intra-epithelial neoplasia (CIN2+) in women with persistent hrHPV positive, cytology negative screening samples: a prospective cohort study.

Mini-commentary on BJOG- 19-1590.R1: Obstetric outcomes of twin pregnancies presenting with a complete hydatidiform mole and coexistent normal fetus: A systematic review and meta-analysis

Pelvic dimensions and hypotheses on duration of active second stage of labourTilde Broach OstborgStavanger University HospitalTM EggeboTrondheium University HospitalWe would like to thank Jan Novák and Petr Sedlak for their interest and comments to our manuscript. We found that increasing BMI was associated with shorter estimated median duration of the active second stage of labour.1We could not find any obvious causal mechanism for our findings; but suggested some possible explanations. The shorter active second stage may be related to increased abdominal pressure with increasing BMI, or perhaps increased strength when pushing.2, 3 Increased infiltration of fat in the muscular pelvic floor may decrease its strength and resistance.4 The presence of fat in the birth canal of obese women may delay the urge to bear down, thereby postponing active pushing until the head is lower in the maternal pelvis.Novak et al. measured the bi-ilac and bi-cristal diameters of the greater pelvis and found a broader pelvis in individuals with a history of obesity from adolescence.5 We supposed that there would be an association between the size of the greater pelvis and the size of the birth canal. We agree to the limitations commented by Novák and Sedlak. However, our proposed causal mechanisms are merely hypotheses, and cannot be accepted nor rejected based on current knowledge.1. Ostborg TB, Sande RK, Kessler J, Tappert C, von Brandis P, Eggebo TM. Put your weight behind it-Effect of body mass index on the active second stage of labour: A retrospective cohort study. BJOG. 2022;129:2166-2174.2. Lambert DM, Marceau S, Forse RA. Intra-abdominal pressure in the morbidly obese. Obes Surg. 2005;15:1225-1232.3. Tomlinson DJ, Erskine RM, Morse CI, Winwood K, Onambele-Pearson G. The impact of obesity on skeletal muscle strength and structure through adolescence to old age. Biogerontology. 2016;17:467-483.4. Pomian A, Lisik W, Kosieradzki M, Barcz E. Obesity and Pelvic Floor Disorders: A Review of the Literature. Med Sci Monit. 2016;22:1880-1886.5. Novak JM, Bruzek J, Zamrazilova H, Vankova M, Hill M, Sedlak P. The relationship between adolescent obesity and pelvis dimensions in adulthood: a retrospective longitudinal study. PeerJ. 2020;8:e8951.

Mechanisms of adverse pregnancy outcomes in women with PCOS and ways to prevent these outcomes by knowing more about these mechanismsSedigheh Hantoushzadeh (1), Maasoumeh Saleh* (2), Sepehr Aghajanian (3), Mahboubeh Saleh (4)1-Professor of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Maternal-Fetal Neonatal Research Center, Tehran University of medical sciences, Valiasr Hospital, Tehran, Iran.2-Fellowship of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Tehran University of Medical Sciences, Shariati hospital, Tehran, Iran.3-Department of Community Medicine, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.4-MD, Department of Urogynecology, Fasa University of Medical Sciences, Fars, Iran.Corresponding author*: Maasoumeh Saleh, E-Mail: salehmaasoumeh@yahoo.comDear editor,We have read the study by Valgeirsdottir et al. (1), and wanted to congratulate the authors for this prosperous article on risk of stillbirth in polycystic ovarian syndrome (PCOS) women and make some minor contributions.PCOS is a complex disorder with unclear exact etiology. It involves cardiovascular (CV), metabolic, endocrine, and reproductive system. Several studies have reported an increase in adverse maternal and fetal outcomes for women with PCOS, independent of the use of reproductive technology or body mass index (BMI). PCOS is strongly associated with preeclampsia (PE), gestational diabetes mellitus (GDM), very preterm birth (PTB), large for gestational age fetuses (LGA), and asphyxia during labor (2). In the study by Valgeirsdottir et al. (1), PCOS had a 50% increased risk of stillbirth compared to women without PCOS, especially at term. In this study, the mechanisms of stillbirth are well explained, which include the following: 1-Hyperandrogenism and associated insulin resistance 2-Obesity 3-Hypertensive disorders 4-Placental diseases, fetal anomalies and umbilical cord abnormalities 5-Fetal growth restriction (FGR) 6-Gestational diabetes 7-Chronic inflammation, oxidative state and mitochondrial dysfunction.Serum concentration of homocysteine (Hcy) decreases during pregnancy due to physiologic fall in albumin, as well as folic acid supplementation (3). High serum Hcy level in PCOS women is an independent risk factor for atherosclerotic vascular disease and thromboembolic disorders (4) and it is associated with insulin resistance (5) and adverse pregnancy outcomes, including PE, PTB, and low birth weight (LBW) (6). Elevated C-reactive protein (CRP) levels indicate a low-grade inflammation in PCOS, it is the most sensitive predictor of CV morbidity (7) and also it is associated with adverse pregnancy outcomes (8). These two important mechanisms, including high Hcy serum level and inflammation can play a role in the adverse pregnancy consequences. So, the measurement of serum Hcy level and CRP may be helpful in PCOS patient’s risk stratification for pregnancy complications.Another important issue is to suggest ways to prevent these adverse pregnancy consequences in PCOS patients. Possible options are: 1-Lifestyle modification 2-pharmacological options: metformin, statins, aspirin and high dose folic acid. The possible mechanisms by which aspirin prevents adverse pregnancy outcomes are: 1-improvement in the placentation 2-inhibition of platelet aggregation and its antithrombotic effect 3-antiinflammatory effects and endothelial stabilization (9). Metformin has beneficial effects on endothelial function and improve insulin resistance (10). Statins reverses the pregnancy-specific angiogenic imbalance and improve endothelial function (11). High dosage of folic acid reduces Hcy concentration (12), and through this mechanism may be effective in reducing pregnancy complications. Various studies have been performed with these goals. But in the future, more extensive studies on methods of preventing adverse pregnancy consequences by focusing on their mechanisms are recommended in PCOS women.

Accuracy of outcome definitions in Mendelian randomization of maternal healthQian Yang,1,2 Maria Carolina Borges1,2 1 MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK2 Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UKDear Dr Papageorphiou,We recently read the article by Dr Ardissino and colleagues entitled ‘Genetically predicted body mass index and maternal outcomes of pregnancy: A two-sample Mendelian randomization study’ [1], where 11 outcomes were investigated. To conduct Mendelian randomization (MR) analyses, this study extracted associations of selected genetic variants with those outcomes from publicly available GWAS (genome-wide association study) summary data from FinnGen (the sixth release, total N=147,061 women) – a national-wide network of Finish Biobank [2]. We noticed that “postpartum depression” included in Ardissino et al was inconsistent with the commonly used definition of postnatal depression occurring within a year of delivery [3,4]. FinnGen defined this outcome based on the International Classification of Diseases 10th Revision (ICD-10) codes (ICD-10 F32, F33 and F53.0) among women with at least one episode of delivery (ICD-10 O80-O84), without considering the time interval between delivery and diagnosis of depression. Therefore, cases of “postpartum depression” could be ascertained at any time after giving birth and, therefore, could be unrelated to pregnancy. As a consequence, findings for “postpartum depression” in Ardissino et al should be interpreted with caution due to the unspecific outcome definition.The increasing availability of publicly available or accessible data from GWAS consortia (e.g. Early Growth Genetics) and large biobanks (e.g. UK Biobank and FinnGen), combined with the creation of automated pipelines (e.g. MR-Base [5] used by Ardissino et al), has supported an rapid increase in publications using two-sample MR. Though such a combination has great potential to promote open science and advance health research, including in maternal-child health, we cautioned that detailed understanding of procedures used to generate GWAS summary data underlying MR analyses is of major importance to obtain reliable evidence and interpretable findings.

Objective: To examine whether women with a history of hysteroscopic adhesiolysis (HA)-treated intrauterine adhesions (IUAs) were at higher risk of adverse obstetrical outcomes in subsequent pregnancies. Design: Retrospective cohort study. Setting: A tertiary-care hospital in Shanghai, China. Population: 114,142 pregnant women who were issued an antenatal card and received routine antenatal care in Shanghai First Maternity and Infant Hospital between January 2016 and October 2021. Methods: From the cohort of 114,142 pregnant women, women with history of HA-treated IUAs before this pregnancy (N=780) were compared with 4 women with no history of IUAs (N=3010) matched on propensity score, maternal age and parity, mode of conception, pre-pregnancy BMI and prior history of abortion. Main outcome measures: Pregnancy complications, placental abnormalities, postpartum hemorrhage and adverse birth outcomes. Results : Compared with women with no history of IUAs, women with a history of HA-treated IUAs were at higher risks of preeclampsia (RR=1.69, 95% CI, 1.23, 2.33), placenta accreta spectrum (RR=4.72, 95% CI, 3.9, 5.73) and previa (RR=4.23, 95% CI, 2.85, 6.30), postpartum hemorrhage (RR=2.86, 95% CI, 1.94, 4.23), preterm premature rupture of membranes (RR=3.02, 95% CI, 1.97, 4.64) and iatrogenic preterm birth (RR=2.86, 95% CI, 2.14, 3.81) . Those women were also more likely to receive cervical cerclage (RR=5.63, 95% CI, 3.95, 8.02) during pregnancy and hemostatic therapies after delivery (RR=2.17, 95% CI, 1.75, 2.69). Moreover, we observed that the RRs of those adverse obstetrical outcomes increased with the increasing number of hysteroscopic surgeries. Conclusion: Our findings suggest that pregnant women with a history of HA-treated IUAs, especially those with a history of repeat HAs, are at higher risk of adverse obstetrical outcomes. Key words: hysteroscopic adhesiolysis, obstetrical outcomes, propensity score matching, cohort study

Letter to Editor:

Aortic balloon for the intraoperative management of placenta accreta spectrum: need for standardised methodology and safety dataIn 2003, Bell-Thomas et al (BJOG 2003;110:1120-1122) reported on the emergency use of a transfemoral aortic occlusion catheter to control massive haemorrhage in a case of caesarean hysterectomy for placenta percreta. This was only the second case published in the international literature on the use of an intra-abdominal aortic balloon occlusion (IABO) in the management of placenta accreta spectrum (PAS) (Paull et al. Anesth Intensive Care 1995;23:731-734). A non-exhaustive Pub-Med literature review of articles published in English on this the topic over the last 20 years, identifies 27 articles, 23 of which come from the Peoples Republic of China, where IABO seems to be increasingly popular in the management of PAS.In brief, IABO involves the insertion of a balloon catheter into the infrarenal abdominal aorta above the aortic bifurcation under fluoroscopy guidance. The procedure is performed in a hybrid operating room or interventional radiology (IR) suite with secondary transfer to the operating room. In all but one study (Zhu et al Biomed Res Int.2017:8604849), the balloon was inflated after delivery of the newborn.All publications so far have been retrospective and most are case-control studies, comparing the outcomes of IABO with those of routine surgical techniques with or without additional procedures such as intra-uterine tamponade. Recently, authors have also started to compare IABO with iliac artery balloon occlusion.Overall, these studies have shown that IABO is associated with reduced estimated blood loss and transfusion requirement, ICU admission and hysterectomy and suggested that IABO is more effective than iliac artery balloon occlusion, presumably as arterial occlusion is more effective.However, there is wide variation between studies in prenatal imaging and clinical selection criteria, intraoperative IR methodology and confirmation of the diagnosis of PAS at birth. For example, the pre-operative fluoroscopy time ranges between 2 and 25 minutes with fetal radiation exposure of 4 to 25 mGy; intraoperative balloon inflation/deflation time varies between 5-10/1 minutes and 45-80/10 minutes. The size of the balloon and the need for transfer between the IR room and the operative theatre is rarely described. Most studies lack histopathology confirmation of the diagnosis and/or stratification by PAS grade.Heterogeneity in methodology and design leads to a high risk of confounding, bias or chance. There is also a high risk that the relationship is not causal. One major concern is the risks-benefit ratio of the use of IABO for both mothers and fetuses, in particular if they do not have PAS. The most commonly reported post-operative complication associated with IABO are arterial thrombosis of the external iliac or the femoral artery. There are no data on the long-term follow of the children born after IABO.In 2018, the expert panel of the RCOG green top guidelines 27a (Jauniaux et al., BJOG.2019;126:e1-e48) concluded that larger studies are necessary to determine the safety and efficacy of IR before this technique can be advised in the routine management of PAS. The 10 new studies published in 2019-2010 on the use of IABO in the management of PAS are insufficient to change this statement.Word count: 499

Tweetable abstract: Identical twin pregnancies have more preterm births and other complications than fraternal twin pregnancies.Mini-CommentaryA decade ago, Professor Kypros Nicolaides of Kings’ College opined, “There is NO diagnosis of twins. There are only monochorionic or dichorionic twins. This diagnosis should be written in capital red letters across the top of the patient’s chart.” (Quoted by Moise and Johnson, Am J Obstet Gynecol 2010; 203:1-2.) To make this diagnosis, it is essential to establish chorionicity as early as possible in every twin pregnancy.Monochorionic twin pregnancies have long been known to have higher rates of miscarriage, congenital anomalies, stillbirth, and neonatal death than dichorionic twin pregnancies. Intertwin vascular anastomoses are present in most monochorionic twin placentas, leading to complications such as twin-twin transfusion syndrome (TTTS), twin anemia-polycythemia sequence (TAPS), twin reversed arterial perfusion (TRAP) sequence, and unequal placental sharing (UPS).Monochorionic twins require intensive antenatal surveillance. Because of the increased risk of congenital anomalies, fetal echocardiogram is recommended in addition to routine ultrasound fetal anatomy survey. Because of the risk of TTTS, TAPS, TRAP and UPS, sonographic surveillance is recommended every 2 weeks starting at 16 weeks of gestation. Because of the risk of stillbirth, serial antenatal cardiotocography is recommended. Scheduled delivery is recommended earlier for monochorionic twins than for dichorionic twins (NICE Guideline 137, 2019; ACOG, Obstet Gynecol 2019;133:e151-5; Cheong-See et al, BMJ 2016;354:i4353).Regardless of chorionicity, 60% of twins are born preterm, resulting in substantial perinatal morbidity and mortality. Prevention of preterm birth (PTB) is a major priority for management of twin pregnancy.The systematic review by Marleen and colleagues is the first of several studies planned by the authors to evaluate risk factors for PTB in twin pregnancy. Prior reports have suggested that monochorionic twins have higher rates of PTB than dichorionic twins but, as the authors note, there has been no prior systematic review of this association. It is not surprising that the review shows an increased overall rate of PTB among monochorionic twins in all gestational age ranges, given that complications such as stillbirth, TTTS, TAPS, TRAP, and UPS often result in iatrogenic PTB. Indeed, iatrogenic PTB before 37 weeks of gestation should be routine for monochorionic twins because of the increasing risk of stillbirth past 36+6 weeks cited in the current NICE Guidelines (2019, op. cit .). However, Marleen and colleagues also report that spontaneous PTB at <37 weeks and ≤34 weeks is increased in monochorionic twin pregnancy, which cannot be directly explained by monochorionic placental complications.The overarching goal of Marleen and colleagues is to develop tools to predict which twin pregnancies are at risk of PTB so that preventive measures can be taken. Unfortunately, it is not currently known what preventive measures will reduce the high risk of early spontaneous PTB among monochorionic twin pregnancies. Prophylactic bedrest, hospitalization, uterine activity monitoring, tocolysis, cerclage, cervical pessary, and progestogens have not proven effective for unselected twin pregnancies. Future research will be needed to determine the value of such interventions for women with twin pregnancy plus additional risk factors such as a short cervix, prior PTB, or monochorionicity.Acknowledgements: NoneDisclosure of Interests: C Andrew Combs declares “No relevant or competing interests”Contribution to Authorship: CAC did 100% of the planning, writing, and submission.Details of Ethics Approval : Not applicableFunding: NoneReferences: Cited in-line per instructions for Mini-CommentaryTables/Figures: None

Letter to the Editor, BJOG Title: ESMiE confidential enquiry: Broader view besides focus on errors by birth-attendants.Re: Rowe R, Draper ES, Kenyon S, Bevan C, Dickens J, Forrester M, Scanlan R, Tuffnell D, Kurinczuk JJ. Intrapartum-related perinatal deaths in births planned in midwifery-led settings in Great Britain: findings and recommendations from the ESMiE confidential enquiry. BJOG 2020;127:1665–1675.Author: Mr. Shashikant L SHOLAPURKARMD, DNB, MRCOGDept of Obstetrics & Gynaecology,Royal United Hospital, Bath, BA1 3NG, UKShort running title: ESMiE enquiry: broader viewEmail: s.sholapurkar@nhs.net Tel: 07906620662Word count: 500Corresponding Author: Mr. Shashikant L SHOLAPURKARMD, DNB, MRCOGDept of Obstetrics & Gynaecology,Royal United Hospital, Bath, BA1 3NG, UKStatement of interest: The author has no conflict of interest or funding to declare.

Virtual Reality for Acute Pain in Outpatient Hysteroscopy: A Randomised Controlled Trial We would like to thank E.Mirza and colleagues for their interest in our study, Virtual Reality for acute pain in outpatient hysteroscopy: A randomised controlled trial.We would like to point out that in light of the fact that the sample size was limited to 40 patients, the interpretation of further subgroup analysis is likely to be limited.On further analysing patients we noted that a total of 7/40 (18%) which included 3 in the Standard Procedure (SP) arm and 4 in the Virtual Reality (VR) arm, had had a previous outpatient hysteroscopy. The mean expected pain scores in the VR and SP groups were comparable (VR group was 6.5 and in the SP group was 7) however the perceived average pain scores were 2.25 and 6.3 respectively. This would suggest that VR might have had a beneficial effect despite a previous experience of OPH.We appreciate that patient’s pain thresholds are variable and that it is a very subjective experience. 2 patients in the VR group reported average pain scores of 0 whilst all patients in the SP group experienced some degree of pain. It is difficult to ascertain how much VR contributed to the experience in the context of the patient’s tolerance to pain. We agree that future studies looking into patients with painful hysteroscopies would most benefit from additional pain relief strategies and would be of immense clinical value.Analgesic intake included paracetamol, non steroidal anti-inflammatory drugs, cocodamol either on their own or in combination and the numbers of patients receiving analgesics was comparable across the two groups. However we do not have data on dosages and how long before the procedure the analgesics were taken. We acknowledge that standardisation of analgesics intake would have helped in understanding the actual impact of VR in pain relief.1,2 We agree with these suggestions for future directions of research in this area and the suggested improvements to methodology.Claustrophobia was not an exclusion criterion in our study and hence one patient was recruited but nevertheless only experienced the intervention of a short period of time before she took the VR goggles off. We note recent studies, which have used VR for treatment of claustrophobia.3,4 The outcomes are normally reported taking an Intention to Treat approach. We repeated a regression analysis after removing the patient in question, and the experimental group still reported significantly lower pain and anxiety scores for those patients receiving the VR intervention.Nandita Deo 1,2Khalid Saeed Khan4Jonathan Mak 4John Allotey3Francisoco Jose Gonzalez Carreras 3Gianpaolo Fusari 5Jonathan Benn 6Imperial College London, UK1Whipps Cross University Hospital, London, UK2The London School of Medicine and Dentistry, London, UK3Queen Mary University, London, UK.4Helix Centre, Imperial College London and the Royal College of Art, London, UK 5School of Psychology, University of Leeds, UK6Corresponding Author- Nandita Deo MBBS, MD, FRCOG, MSc (Health Care and Design)Consultant Obstetrician and GynaecologistWhipps Cross University Hospital, Barts Health NHS Trust,Leytonstone, London, E11 1NRTel: 0044 7939360357nandita.deo@gmail.com1. De Silva PM, Mahmud A, Smith PP, Clark TJ. Analgesia for office hysteroscopy: systematic review & meta-analysis. Journal of Minimally Invasive Gynecology. 2020 Jan;S1553465020300467.2. Ghamry NK, Samy A, Abdelhakim AM, Elgebaly A, Ibrahim S, Ahmed AA, et al. Evaluation and ranking of different interventions for pain relief during outpatient hysteroscopy: A systematic review and network meta-analysis. J Obstet Gynaecol Res. 2020 Jun;46(6):807–27.3. Carl E, Stein AT, Levihn-Coon A, Pogue JR, Rothbaum B, Emmelkamp P, et al. Virtual reality exposure therapy for anxiety and related disorders: A meta-analysis of randomized controlled trials. J Anxiety Disord. 2019;61:27–36.4. Rahani VK, Vard A, Najafi M. Claustrophobia Game: Design and Development of a New Virtual Reality Game for Treatment of Claustrophobia. J Med Signals Sens. 2018 Dec;8(4):231–7.

JOURNAL: BJOGDATE 08_25_2022TITLE: Mini commentary on “Familial aggregation of stillbirth: a pedigree analysis of a matched case control study” BJOG_22-0217Author: Matthew A. Shear, MDa,bAuthor Affiliations:a Department of Obstetrics, Gynecology, & Reproductive Sciences, University of California, San Franciscob Division of Medical Genetics, Department of Pediatrics, University of California, San FranciscoDespite advances in genomics, the underlying cause of many stillbirths remains elusive. The emotional toll that a stillbirth takes on families, as well as the providers caring for them, is hard to overstate. Karyotype may identify a causative aneuploidy or large unbalanced translocation, but only in about 6% of stillbirths. Chromosomal microarray is higher yield, but still only identifies pathogenic copy number variants in about 10% of stillbirth cases (Reddy et al. N Engl J Med. 2012). The addition of exome sequencing to microarray only yielded a plausible genetic explanation in 15 out of 246 cases, or about 6% (Stanley et al. N Engl J Med. 2020). This suggested that non-mendelian mechanisms may play a significant role in stillbirth (Wojcik et al N. Engl J Med. 2020), although single gene pathogenic variants are poorly understood at the fetal level relative to the postnatal setting. The non-genetic mechanisms underlying stillbirth are also poorly understood at present, including viral infections, environmental toxins, and comorbid conditions.Workalemahu and their colleagues present a unique analysis suggesting genomic heritability of stillbirth in some families. Using a robust matched case-control study of over 9000 stillbirths and 390 high-risk pedigrees from the Utah Population Database, they calculated the familial standardized incidence ratio and risk of stillbirth among first, second, and third-degree relatives of the pregnant individuals who had experienced stillbirth. In their adjusted model, among all relatives of an individual who experienced stillbirth, there was a relative risk of stillbirth of 1.1 (95% CI 1.00-1.22). This study adds further evidence there are heritable genetic etiologies of stillbirth not yet fully described.Many non-genetic contributors to stillbirth risk may also cluster in families. In the present study, when adjusting for maternal race/ethnicity, socioeconomic status, and education, the elevations in stillbirth risk became attenuated, although this may be due to collinearity among variables used in the model. Health behaviors are informed through regional and family culture, leading to patterns in diet, nutrition, and exercise. These patterns contribute to modifiable health conditions known to impact stillbirth risk, including hypertension, obesity, diabetes, and smoking status. We also know the incidence of stillbirth is higher in lower income versus higher income countries, higher among individuals of lower educational attainment versus higher education, and higher among African American and Black individuals compared to White, likely complicated by the impacts of systemic racism. This is to say nothing of the additional social determinants of health that may impact families across generations.As Workalemahu and colleagues note, there is still much unknown about complex outcomes such as stillbirth. Their findings support that for a patient with a high-risk pedigree, genomic testing may prove informative. Future epigenetic and functional studies may help understand variants at the tissue level, and the impact of comorbidities on gene expression. Together with fetal genome sequencing, previously unexplained cases of stillbirth might be solved, improving patient counseling, and possibly changing clinical management. While genomic testing offers promise to explain a subset of stillbirths, we should not neglect the “non-mendelian” and non-genetic factors that continue to play a significant role in stillbirth risk.

Dear Sir We congratulate Dr Guy and colleagues on their paper1which demonstrates that implementation of combined screening using the FMF algorithm2 is feasible in practice and is better than the existing NICE guidelines in prevention of preeclampsia, especially preterm preeclampsia with delivery before 34 weeks. We hope that this will lead to wider application of combined screening for prediction and prevention of preeclampsia.The authors acknowledge that treatment with aspirin will have led to underestimation of screening performance. We would like to highlight this and emphasise the importance of accounting for the effect of aspirin when assessing predictive performance. To make the point, consider the most extreme case with 100% compliance with a treatment that prevents 100% of cases. In the screen positive group, all cases would be prevented by the treatment and classified as false positives. Adopting the same analysis presented in this paper would result in a detection rate and positive predictive value of zero regardless of performance without treatment.In the data presented in this study, for the FMF algorithm with 99% compliance to aspirin at a dose of 150 mg / day and assuming 62% reduction in risk,3 99%×62% = 61.4% of cases of preterm preeclampsia would be prevented and classed as false positives. The remaining 100-61.4% = 38.6% would be classed as true positives so the 15 cases of preterm preeclampsia which led to the detection rate of 15/27 = 55.6% represent just 38.6% of the cases of preterm preeclampsia detected. An estimate of the number detected, including those prevented by aspirin is, 15/0.386 = 39. The estimated number of cases in total is therefore 39 + 12 = 51, obtained by adding the false negatives 27-15 = 12 to the estimated true positives. This gives a detection rate of 39/51 = 76% compared to the figure of 55.6% given in Table 2. Applying similar calculations to the positive predictive value (i.e. proportion of women in the screen positive group who would, without aspirin, have developed preterm preeclampsia) of 9.8%. This should be compared with the 3.8% presented in the paper. Applying the same arithmetic to the NICE group gives a detection rate of 41.6% and a positive predictive value of 2.4%. These are much closer to the figures in Table 2 of the paper because of the relatively low compliance in the NICE group. Other measures of screening performance presented on this paper including the likelihood ratios, negative predictive value the receiver operating characteristic (ROC) curve analysis are also affected by this problem.The arithmetic presented above is intended for illustration; for the SPREE study4 we applied Markov chain monte carlo (MCMC) methods for inferences about screening performance. These or similar methods should be applied in future studies of screening performance.Dave Wright,1 Kypros Nicolaides2Institute of Health Research, University of Exeter, Exeter, UKHarris Birthright Research Centre for Fetal Medicine, King’s College Hospital, London, UK.

Genital mycoplasma and preterm birth: a difficult puzzle to solve. Letter re: Genital Mycoplasma infection and spontaneous preterm birth outcome: a prospective cohort studySir.In their recent paper, Cunha and colleagues analyzed data from a diverse group of 1349 Brazilian women who participated in a 2011 study evaluating etiological factors associated with preterm birth. 11Cunha GKP, Bastos LB, de Freitas SF, Cavalli RC, Quintana SM. Genital mycoplasma infection and spontaneous preterm birth outcome: a prospective cohort study. BJOG  https://doi-org.uml.idm.oclc.org/10.1111/1471-0528.16949 Women were interviewed and examined at 20-25 weeks’ gestation, and cervicovaginal cultures were taken for mycoplasma, ureaplasma, and bacterial vaginosis. Women were followed until delivery, and clinical associations with preterm birth were evaluated. Positive associations were found for shortened cervix and a history of prior preterm birth. No association was found for infection with mycoplasma, ureaplasma, or bacterial vaginosis. They concluded that “genital mycoplasma infection was not a risk of spontaneous preterm birth, even with other abnormal vaginal microbiota conditions.”There is a flaw in their methodology and conclusion. In the original study, women with a positive culture for ureaplasma or mycoplasma were treated with azithromycin, and those with bacterial vaginosis were treated with oral metronidazole. Treatment would have reduced the presence of these pathogens, limiting their ability to cause preterm birth. Accordingly, this study shows that women with treated mycoplasma, ureaplasma or bacterial vaginosis do not have an increased incidence of preterm birth; however, no comment can be made on whether untreated infection causes preterm birth.Presumably the original investigators who performed the study treated women with genital infection because they believed it might prevent preterm birth; and there lies the rub. An observational study using vaginal culture results unavailable until after birth has shown an association between untreated mycoplasma infection and preterm birth.22Foxman B, Wen A, Srinivasan U, et al. Mycoplasma, bacterial vaginosis, associated bacteria BVAB3, race, and risk of preterm birth in a high-risk cohort. Am J Obstet Gynecol 2014;210:226.e1-7. However, in order to determine whether mycoplasma causes preterm birth and whether treatment prevents it, a randomized trial of treatment or placebo in infected women at elevated risk of preterm birth is needed. This may not be easily feasible. Ethically, investigators may be able to demonstrate research equipoise: that we do not yet know whether treatment reduces preterm birth associated with mycoplasma infection. However, women found to have genital mycoplasma who are at increased risk of preterm birth would need to believe that the benefits and harms of treating or not treating are equal. Given the relative safety of antibiotics and the high morbidity of preterm birth, practically, equipoise may be hard to find.In Northern Canada, with high rates of sexually transmitted infections including mycoplasma, we suspect a causal relationship with preterm birth and late miscarriage. Based on observational studies and anecdotal evidence, our practice is to screen women with a history of prior preterm birth, late miscarriage, or short cervix for ureaplasma, mycoplasma, and bacterial vaginosis in the second trimester and treat those who are positive.2,33Taylor-Robinson D, Lamont R. Mycoplasmas in pregnancy. BJOG 2011;118:164–174.,44Morency AM, Bujold E. The Effect of Second-Trimester Antibiotic Therapy on the Rate of Preterm Birth. J Obstet Gynaecol Can 2007;29(1):35–44 We also test women with threatened preterm labour remote from term and treat those who are positive, sometimes with marked reduction in symptoms. In keeping with Taylor-Robinson’s paper, treatment failures with azithromycin used for Mycoplasma hominis have prompted a switch to Clindamycin, whose activity against both mycoplasma and bacterial vaginosis may explain its better performance than metronidazole in the prevention of preterm birth.3,4 We await better evidence, but are not holding our breath.

Letter to the Editor, BJOG Title:Deceleration Area and Deceleration Capacity: Promising predictors of fetal acidaemia in human labour? Visual versus computerised cardiotocographyRe: Georgieva A, Lear CA, Westgate JA, Kasai M, Miyagi E, Ikeda T, Gunn AJ, Bennet L. Deceleration area and capacity during labour-like umbilical cord occlusions identify evolving hypotension: a controlled study in fetal sheep. BJOG 2021; https://doi.org/10.1111/1471-0528.16638.Author: Mr. Shashikant L SHOLAPURKARMD, DNB, MRCOGDept of Obstetrics & Gynaecology,Royal United Hospital, Bath, BA1 3NG, UKEmail:s.sholapurkar@nhs.net; s.sholapurkar172@gmail.com; Tel: 07906620662Short Running Title: Deceleration area and capacity in labourWord count: 500Corresponding Author: Mr. Shashikant L SHOLAPURKARMD, DNB, MRCOGDept of Obstetrics & Gynaecology,Royal United Hospital, Bath, BA1 3NG, UKStatement of interest: The author has no conflict of interest or funding to declare.

DEATH AND SEVERE MORBIDITY IN ISOLATED PERIVIABLE SMALL-FOR-GESTATIONAL-AGE FETUSESBy Meler et alDescriptive title:Middle cerebral artery Doppler improves risk stratification of SGA babies at a peri-viable gestationMini-commentary by Lawrence ImpeySmall for gestational age (SGA) babies identified before 26 weeks are a heterogenous group but the largest contributor is ‘isolated’ SGA’. Most are ‘constitutionally’ small, but placental issues are common. Traditionally, the ultrasound Doppler parameters used to identify the most at risk are the umbilical artery (UA) and uterine artery (UtA). This paper (Meler et al, BJOG, 2022) challenges the dogma that MCA Doppler in early onset-SGA babies is of limited use, reporting an 87% detection rate for a 14% false positive rate for UA and MCA together in predicting a severe composite adverse outcome (CAO).The analysis uses Doppler findings at referral, thereby reducing but not eliminating the ‘intervention paradox’, common to many analyses, whereby an ‘abnormal’ finding’s association with an outcome is altered because it leads to intervention.The group is defined by local centiles and only comprises those referred but, by including both apparently FGR and SGA babies, is less subject to selection bias. Because of the high risk nature and size of this cohort, the frequency of adverse outcomes is adequate for analysis of a severe CAO (20.4%), of death (15.4%) or long term morbidity that is sufficiently serious and includes postnatal follow up (minimum 9 months).The role of MCA Doppler with placental failure is poorly understood. Near term, as part of the cerebroplacental ratio (CPR), it helps identify the at-risk SGA baby (Veglia et al, UOG, 2018), and even some at-risk normally grown babies. Earlier, however, the role of UA Doppler is clear (Alfirevic et al, Cochrane, 2017). That MCA Doppler adds predictive value at diagnosis is important because it will allow enable more appropriate counselling, follow up and potentially better timing of iatrogenic birth.What does the analysis make of UtA Doppler and the ductus venosus (DV)? It is surprising (Allen et al, UOG 2016) that the former was not predictive, but as its role is well established, this could be the subject of intervention bias. Mild abnormalities (PI>95th c) of the DV were not useful, but severe ones, occurring late in the deterioration in FGR, will still be useful to time iatrogenic birth (Lees et al, Lancet, 2015).MCA Doppler in referred small peri-viable babies improves risk stratification, a process central to maternity care. The ‘checklist’ approach to risk must be replaced by models using continuous variables (as opposed to cut offs of ‘abnormal’) of multiple independent risk factors: as with aneuploidy screening. Only then can we better identify high risk (sensitivity) whilst not over-medicalising pregnancy (specificity). Developing this is complex, not least because of the rarity and gestation-dependence of serious perinatal events and because of the presence of the intervention paradox in large datasets. Nevertheless, the Tommy’s app (https://www.tommys.org/) is a welcome start. Such screening is likely to need to be staged, and this analysis demonstrates one risk factor potentially worth including following a 20 week scan.