Measurement of maternal serum soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF), and the ratio between the two, has been shown to predict preeclampsia. In women with suspected preeclampsia, an sFlt-1: PlGF ratio below 38 rules out the need for delivery in the subsequent week with a negative predictive value of 99.3% (95% CI 97.9 to 99.9%) (Zeisler H et al. , N Engl J Med 2016;374:13-22). This test may be of particular benefit for women at low risk of developing the disease in the short term, as it may reduce unnecessary follow-up, investigations and admissions (Cerdeira ASet al. , Hypertension 2019;74:983–990).But do these biomarkers have a potential use in women after preeclampsia is diagnosed? This has not been studied extensively. In this issue of BJOG, Peguero and colleagues report the results of a study in which the changes in sFlt-1 and PlGF levels were examined in 63 women with early-onset preeclampsia from diagnosis to delivery (Peguero A et al. , BJOG 2020). Whilst no association between the change in PlGF levels and the development of adverse outcomes was evident, changes in sFlt-1 levels were significantly more pronounced in women who later developed complications and negatively associated with interval to delivery. This change (i.e., the delta sFlt-1) also outperformed a previously published risk score and the use of sFlt-1 at admission only.Because prevention is better than cure, identifying high-risk women early and modifying their risk is desirable. Prediction of preeclampsia can now be achieved at 11 to 14 weeks of gestational age by calculation of individual patient risk. The risk calculation is based on a combined screening test that incorporates maternal characteristics, medical history and biomarkers (mean arterial pressure, uterine artery Doppler and PlGF) alongside first trimester combined screening for fetal aneuploidy. This test is particularly accurate for predicting early-onset preeclampsia, identifying nine out of ten of these severe cases (O’Gorman N et al. , Am J Obstet Gynecol. 2016;214(1):103 e1- e12). More importantly, when this high-risk group is given prophylaxis using aspirin 150 mg from the first trimester to 36 weeks, the rate of preeclampsia before 37 and before 32 weeks is reduced by more than 60% and 90%, respectively (Rolnik DL et al. , N Engl J Med. 2017;377(7):613-22). A recent implementation study demonstrated that early screening is not only feasible in a public health care setting, but is also associated with a significant reduction in the rate of preterm preeclampsia and nearly total physician compliance of aspirin use (29% with usual care versus 99% when combined screening is used) (Guy GP et al. , BJOG 2020).Nevertheless, not all women will undergo such early screening, and not all cases will be avoided by aspirin: some women will still develop preeclampsia, and early-onset disease will remain a significant cause of morbidity and mortality, disproportionally driving the disease burden. Hence, the findings of Peguero and colleagues are important and suggest that serial sFlt-1 measurements following a diagnosis of early-onset preeclampsia can still allow risk stratification – identifying women at lower risk of complications who may be eligible for expectant management, and those at higher risk who require prompt administration of steroids and timely transfer to tertiary health care facilities.No disclosures: Completed disclosure of interest forms are available to view online as supporting information.

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.

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.

Minimally invasive surgery has been widely adopted in gynaecologic oncology with a significant surge the past decade associated with the introduction of robot-assisted surgery. Up until 2018, virtually all testimonials of minimally invasive surgery for cervical cancer indicated equal oncologic outcomes compared to laparotomy. The unexpected results from the only randomised controlled trial (Ramirez PT et al, N Engl J Med, 2018;379:1895-1904) seriously challenge the use of minimally invasive surgery for cervical cancer. However, the lack of plausible explanations for the inferior survival has made it hard for many gynaecologic oncologists to accept the results at face value. Suggested causes such as the use of intrauterine manipulators and intracorporeal colpotomy may to some extent account for the detrimental outcomes but as practice differs widely worldwide, none of these factors seem convincing. In the current paper by Baeten et al, a different aspect of novel surgical technologies has been explored (BJOG 2020 xxxx). The adoption of any new modality/technology is clearly associated with a learning curve and it is well known from surgery that procedural outcomes such as operative time improves with increasing case numbers. However, the potential impact of learning curve on “hard outcomes” such as survival has scarcely been reported before. Baeten et al convincingly demonstrate that a substantial number of robot-assisted radical hysterectomies is required to overcome an initial harm. The authors point out that the learning curve should be considered institutional; suggesting that an individual learning-curve may benefit from previous experiences at the specific institution. Intriguingly, similar data has not been presented for endometrial cancer which may be related to the higher complexity of radical hysterectomy for cervical cancer. Although no specific changes were made over time in the current study, a learning curve may include modifications of surgical routines based on early experiences. Which specific improvements during the learning-curve that accounts for the increased survival is unclear but reducing complications that could delay adjuvant treatment may be one. The data presented by Baeten et al signifies a solid effort to elucidate the underlying cause of the outcomes from the LACC-trial, especially since the trial was launched at a time when most surgeons had limited experience from laparoscopic/robotic radical hysterectomy. The study should raise the awareness of surgical learning curve in the context of survival in oncologic surgery. It also brings us to the most important question – how do we avoid harming our patients when novel technologies are adopted? The authors suggest that centralisation and structured training represents two of the most important strategies to mitigate the effects of early errors. Interestingly, recent population-based studies from countries with high levels of centralisation do not corroborate the findings from the LACC-trial (Alfonzo E et al, Eur J Cancer, 2019;29:1072-1076, Jensen et al, Eur J Cancer 2020;128:47-56). Although the current study may reopen the door for robotic surgery in the management of cervical cancer, prospective randomised trials are needed to ensure its safety. The impact of surgical learning curve should be considered in any future trial exploring oncologic safety for procedural interventions.Conflict of interest: H.F is a proctor for Intuitive Surgical Inc. A completed disclosure of interest form is available to view online as supporting information.

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

A document by Karl Oláh (BJOG DEBATES ONLY). Click on the document to view its contents.

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.

Letter to Editor:

We are all likely to need a blood test, a biopsy or wind up on the wrong end of an endoscope. We know that the experience is not going to be pleasant. Many of us will revert to techniques to divert attention away from painful stimuli, such as counting forwards or backwards in our heads, deep breathing, imagining tranquil places or listening to music. But the paper published in this issue of BJOG by (Neo D et al, BJOG 2020; xxxx) shows us how we can distract patients in a more sophisticated way, using virtual reality (VR) technology. The procedure the research groups chose to investigate was outpatient hysteroscopy.Outpatient hysteroscopy is a key part of contemporary gynaecological practice. The procedure is acceptable to the vast majority of women, but most will experience some pain and, in a small proportion of women, this can be severe (Smith P, et al, BJOG 2019;126:891-899). Thus, outpatient hysteroscopy, being common and potentially painful, is a good health technology to evaluate the impact of VR technology on patient experienceDeo N et al, conducted a randomised trial of 40 women undergoing outpatient hysteroscopy for a variety of indications and simple therapeutic procedures were allowed such as biopsy, polypectomy and insertion of a Mirena® device. Women were allocated to standard care or “immersive and interactive video content using a portable, standalone VR headset”. The latter delivered a “guided relaxation experience” which included viewing an 8-minute, narrated video depicting “a calming rainforest and lake setting with animated wildlife, which could be explored by using the “head-tracker”.The preliminary results are impressive. Reduction in peri-procedural pain was statistically significant but more importantly the effect size of a 2cm (20%) difference on a 10cm visual analogue scale must be clinically significant. Reduction in anxiety scores were of a similar magnitude. However, the average hysteroscopy procedure duration was less than 4 minutes, which begs the question, is the cost, time and hassle of setting up and using VR technology worth it? Moreover, 16% of eligible women did not want to use the VR technology because of prior adverse experiences, anxiety or state a preference to see the procedure or use their own distraction media.No-one is going to change clinical practice on a sample of 40, but many practitioners will be energised to conduct larger scale trials to confirm these provisional results and to analyse more deeply the impact of immersive VR technology on reducing pain and anxiety associated with outpatient hysteroscopy. Future work should look at the type of VR technology, the context where it is deployed for what kind of procedure. The optimal VR programme may vary according to patient characteristics, the type of surgery and its duration. VR technology should be tested in more painful gynaecological interventions such as endometrial ablation, cervical biopsy and transvaginal egg collection. Moreover, the prospective benefit of VR need not be restricted to gynaecological practice but should be evaluated in a whole host of ambulatory procedures involving conscious patients.No disclosures: A completed disclosure of interest form is available to view online as supporting information.

Mini commentary on BJOG-21-0823: Pregnancy outcomes in women with Budd-Chiari syndrome or portal vein thrombosis - A multicentre retrospective cohort study.Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT) are rare thrombotic disorders which can affect females of reproductive age. Physiological changes in pregnancy may result in or exacerbate pre-existing known portal hypertension related issues associated with these conditions. These conditions may also present de-novo in pregnancy with acute onset ascites or variceal haemorrhage. Both in pregnancy and in the non-pregnant state, in those with established disease, in general, the overall balance of risk, favours continued anticoagulation.The study by Wiegers et al. has shown favourable maternal and foetal outcomes once greater than 20 weeks gestation is reached in patients with BCS and/or PVT. However, the risk of preterm birth and early pregnancy loss remains. These results are in keeping with the recent study by Andrade et al. (Journal of Hepatology 2018; 69: 1242-1249) looking at pregnancy outcomes from 24 pregnancies in 16 women with idiopathic non-cirrhotic portal hypertension (INCPH). Rautou et al. (Journal of Hepatology 2009; 51: 47-54) reviewed 24 pregnancies in 16 women with BCS and also reported similar findings. Taken as a whole, these results support the concept that patients with vascular liver disease can achieve favourable pregnancy outcomes but warrant careful consideration in pregnancy.Preconception counselling is a crucial opportunity to optimise patients with vascular liver disease who are considering pregnancy. This can be achieved in a multidisciplinary forum with input from obstetricians, haematologists and hepatologists. It is useful to identify those women with significant portal hypertension and varices before pregnancy so that appropriate surveillance and eradication with endoscopic band ligation and/or prophylaxis with beta blockers is undertaken. If pregnancy is achieved before surveillance, then a second trimester endoscopy for those with significant portal hypertension should be performed. In patients with portal and mesenteric vein thrombosis, magnetic resonance imaging of the pelvis may be needed to assess for the presence of abdominal wall/pelvic varices. This stratifies the risk of a variceal bleed and allows planning of the mode of delivery (caesarean, vaginal or assisted vaginal delivery). Wiegers et al. reported 2 variceal bleeds in pregnancy but did not find a significant association with adverse maternal outcomes, though this may be related to the low number of patients. Andrade et al. also reported 2 variceal bleeds including 1 patient with PVT without adequate endoscopic prophylaxis who required a portosystemic shunt. This outlines the need for appropriate screening and portal hypertension management according to findings.The majority of patients with BCS and PVT have an underlying pro-thrombotic tendency and the intra-partum and the post-partum periods are associated with thrombotic events. Vitamin K antagonists are historically the commonest anticoagulation used in BCS and PVT which should be switched to low molecular heparin ideally before conception. The use of anticoagulation is more common in patients with BCS and PVT than in INCPH (38/45 women in BCS and/or PVT compared to 4/16 in INCPH). 4 out of 6 women with BCS and/or PVT who experienced post-partum haemorrhage (PPH) were on anticoagulation. 2 patients with INCPH had PPH whilst on anticoagulation which may be confounded by the thrombocytopenia and type-2 error. In the study by Rautou et al., 17/24 pregnancies received anticoagulation and the 4 women who experienced post-partum bleeding (vaginal or intrauterine/parietal haematoma) were on anticoagulation which includes one woman with an ectopic pregnancy. No maternal deaths were reported in the three studies and the continued use of anticoagulation when indicated is safe and appropriate.The mode of delivery did not affect the risk of PPH in the three studies. The mode of delivery should be decided based on the individual risk profile taking into account the severity of portal hypertension, distribution of venous thrombosis, presence of coagulopathy and thrombocytopenia, obstetric indications and the presence of oesophageal or abdominal wall/pelvic varices.The live birth rates may be lower in patients with BCS compared to PVT (75% versus 82% after excluding first trimester pregnancy loss) but due to the low number of patients it remains difficult to interpret the results in this study. In the study by Andrade et al., all 18 pregnancies reaching 20 weeks gestation were delivered with 2 infant deaths (both preterm births). Rautou et al. reported 16/17 live births in pregnancies reaching 20 weeks gestation.To conclude, patients with BCS and PVT after 20 weeks gestation and appropriate planning can have a reasonable expectation for delivery and successful outcomes. Preconception counselling and antenatal care with multidisciplinary input is key to achieving this goal.

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.

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.

Objective: To investigate reliable biomarkers for predicting histological chorioamnionitis (HCA). Design: In this retrospective study, PPROM mothers were treated with a course of dexamethasone. Blood tests for serum indictors were conducted continuously after first injection. Setting: One Shanghai hospital Population: PPROM mothers before 34 0/7 weeks of gestation Methods: Data were compared by General Linear Model analysis. The diagnostic accuracy in predicting HCA were evaluated with ROC curve. Main Outcome Measures: The response of infectious indictors to dexamethasone treatment; the diagnostic accuracy for CRP and PCT in predicting HCA. Results： We found 98 HCA women (62.42%) and 59 CON women (37.58%) in 157 PPROM mothers. WBC and neutrophil significantly increased 24 hours after the first injection in both groups, followed by a decrease at 72 hours post first injection (P<0.05). No significances were found between two groups in WBC, neutrophil and lymphocyte. Both CRP and PCT were significantly higher in the HCA group after first injection. PCT had both high specificity and sensitivity, especially at the baseline (cutoff, 0.031 ng/ml). Furthermore, the positive predictive values (PPV) of PCT were respectively 0.946 and 0.960 at 48 (cutoff, 0.049 ng/ml) and 72 (cutoff, 0.051 ng/ml) hours, which were better than the corresponding PPV of CRP. Conclusion: The response of WBC, neutrophil and lymphocyte to dexamethasone could be differentiated from uterine infection; PCT could be a reliable biomarker for early diagnosis of HCA. Funding: Shanghai Municipal Commission of Health and Family Planning (GWIV-26, 202040128); Pudong Commission of Health and Family Planning (PW2019D-13).

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

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.

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.

Objective: To investigate programming effects of maternal testosterone on offspring birth anthropometrics. Design: Population-based prospective cohort study. Setting: University Hospital. Population: 1,486 mother-child dyads from Odense Child Cohort. Methods: Maternal blood samples were collected at gestational week 27-30 and free testosterone (FT) levels were calculated using the Vermeulen equation from total testosterone (TT) analyzed by mass spectrometry and sex hormone binding globulin (SHBG). Associations between FT or TT levels and birth anthropometrics were analyzed with multiple linear regression models according to offspring sex with adjustment for maternal age, parity, smoking and educational level. Analyses were repeated with polycystic ovary syndrome (PCOS) as exposure for offspring birth anthropometrics. Main outcome measures: Offspring birth weight (BW), birth length, abdominal- and head circumferences. Results: Maternal mean (SD) age was 30.2 (4.5) years and pre-pregnancy body mass index (BMI) was 23.5 (5.3) kg/m2. In boys (n=787), higher FT was associated with lower BW (adjusted doubling constant=-65.53, p=0.010), shorter birth length (adjusted doubling constant=-0.43, p<0.001), and lower abdominal circumference (adjusted doubling constant=-0.39, p<0.001); Higher TT was associated with lower abdominal circumference (adjusted doubling constant=-0.25, p=0.028). In girls, no associations were found between maternal FT or TT and offspring anthropometrics. Conclusions: Higher maternal free testosterone exposure was linked to reduced birth weight, length and abdominal circumference in boys, whereas girls were not susceptible to maternal testosterone exposure.