Dear Editor,We read the letter from colleagues Dr. Seedat and Dr. Marshall, commenting on our article, with great interest (1, 2). Their clarifications on the UK National Screening Committee (UK NSC) position are very clear. The UK NSC decided against a general screening since they cannot assess the benefits and harms in the patient populations of women (3) but they could indeed in newborns. The on-going clinical trial (GBS3 Trial; ISRCTN49639731) in the UK will compare the current risk-based strategy to two different screening tests. A lab based culture test at 3 to 5 weeks before anticipated delivery date will use an established microbiological technique [Enriched Culture Medium Testing] to reduce false-negative results and a molecular point of care test at the onset of labour. The latter test reduces the time period between screening and the start of labour. The predictive value of antenatal GBS cultures decreases if the interval between culture and delivery is longer than 5 weeks. The results of the trial will help to determine the appropriate screening technique and the rational use of antibiotics for the prevention of early onset GBS sepsis in newborn babies.Perinatal empirical therapy of newborns at risk for or with suspected EOS represents the main contributor to the use of antibiotics in early life (4). There is growing concern about the effects that unnecessary exposure to antibiotics in the perinatal period may have on the future health of these children (5, 6). Antibiotic-related alterations in the microbiome may have downstream effects on the developing immune system and may increase the risk of allergic, autoimmune, and metabolic diseases (5, 6).Seedat and Marshall state that according to another study, the use of IAP would indeed increase if screening were implemented, and that the portion of women receiving IAP would be ‘low risk women’ who… ‘would not have a neonate with EOGBS in the absence of IAP’ (1). In this statement is embedded the assumption that the currently established risk factors are indeed a good prediction of EOGBS transmission. However, 50% of neonates with early onset sepsis with GBS did not have risk factors. To the contrary, we confirm in our meta-analysis and systematic review that universal screening lowered the incidence of early onset GBS sepsis in newborn whereas risk-based approaches did not (2). This might indicate that although screening is imperfect, risk factors might be worse in predicting EOGBS outcomes.Besides, we found no evidence that the rate of intrapartum antibiotic treatment was different in risk-based screening than in universal screening. Administration of antibiotics in risk-based policies was in our study neither lower nor associated with a reduction in the burden of disease in early onset GBS sepsis (2). We are looking forward to the results of the GBS3 trial since there is a need for unbiased evidence on the appropriate policy. A trial comparing screening with risk-factor based intrapartum antibiotic prophylaxis is hard to conduct in areas that currently have a screening policy. Recruitment of participants is very challenging and a premature stop for futility is very likely. A lot of women might not want a risk-based protocol if screening is already the standard of care or easily available. Therefore, the UK data will be very helpful in guiding the future way.References1. Seedat F, Marshall J. Re: Universal screening versus risk-based protocols for antibiotic prophylaxis during childbirth to prevent early-onset Group B streptococcal disease: A systematic review and meta-analysis. (First comment letter. Reference to be added). BJOG. 2020.2. Hasperhoven GF, Al-Nasiry S, Bekker V, Villamor E, Kramer B. Universal screening versus risk-based protocols for antibiotic prophylaxis during childbirth to prevent early-onset Group B streptococcal disease: a systematic review and meta-analysis. BJOG. 2020. https://doi.org/10.1111/1471-0528.160853. Seedat F, Geppert J, Stinton C, Patterson J, Freeman K, Johnson SA, et al. Universal antenatal screening for group B streptococcus may cause more harm than good. BMJ. 2019;364:l463.4. Achten NB, Klingenberg C, Benitz WE, Stocker M, Schlapbach LJ, Giannoni E, et al. Association of Use of the Neonatal Early-Onset Sepsis Calculator With Reduction in Antibiotic Therapy and Safety: A Systematic Review and Meta-analysis. JAMA Pediatr. 2019.5. Cotten CM. Adverse consequences of neonatal antibiotic exposure. Curr Opin Pediatr. 2016;28(2):141-9.6. Esaiassen E, Fjalstad JW, Juvet LK, van den Anker JN, Klingenberg C. Antibiotic exposure in neonates and early adverse outcomes: a systematic review and meta-analysis. J Antimicrob Chemother. 2017;72(7):1858-70.

Dear Editor,Thank you for the opportunity to respond to Dr Sahu’s letter1. We would like to thank Dr Sahu and his team for their valuable points and ourselves recognise and acknowledge the gaps in our early commentary2 which reflected on the early practice at our hospital, with an aim to help fellow obstetricians with the management of COVID-19 at the start of the outbreak. Since then, more literature has been published providing us with greater knowledge regarding this new infection. Guidance from the Royal College of Obstetricians and Gynaecologists (RCOG)3 and International Society of Ultrasound in Obstetrics and Gynaecology (ISUOG)4 amongst others help us streamline management of COVID-19 in pregnant patients.Both guidelines concur that radiographic investigations should be performed in pregnant patients – protecting the fetus by using a radiation shield over the gravid uterus. Chest CT has high sensitivity up to 97% for diagnosis of COVID-19 and may be considered as primary tool for COVID-19 detection.Both guidelines recommend the use of antenatal corticosteroids (ANC) for the usual indications but cautions use in critically ill women with COVID-19 infection as it may worsen their clinical condition. Importantly, urgent deliveries should not be delayed for the administration of ANC.Li et al5 compared clinical characteristics, maternal and neonatal outcomes of pregnant women with and without COVID-19. They found that COVID-19 infection generally causes mild respiratory symptoms in pregnant women, with no deaths or severe respiratory complications requiring critical care. They observed a higher rate of preterm deliveries in confirmed cases (33.3%) compared to control groups (¬5%). This study included two patients who had vaginal deliveries prior to COVID-19 diagnosis. Their newborns did not show any respiratory symptoms.New reports of SARS-COV-2 IgM in infants6 at birth suggest possibility of vertical transmission although COVID-19 infection in newborns is more commonly likely due to neonatal transmission.During breastfeeding, the main risk for infants lies in their close contact with mothers and transmission of infective respiratory droplets. Infected mothers wishing to breastfeed should do so with precautions such as wearing surgical masks, practising good hand hygiene and thorough cleaning of equipment after use. While the decision for separation of mother and baby has serious consequences on bonding and mental health, we continue to advise separation of baby from mothers infected with COVID-19 due to risk of neonatal transmission.Current data suggests that the adverse effects of COVID-19 in pregnancy are less severe than those of SARS-CoV and MERS-CoV. All presently reported patients were diagnosed in the third trimester and the potential effects of COVID-19 infections in the first and second trimesters remain to be investigated.As Dr Sahu mentioned, comparative studies are scarce. Establishment of international registries will improve our understanding of COVID-19 in pregnancy. Meanwhile, we shall continue to support one another and work together in the fight against this pandemic.We would like to thank the all departments from the Division of Obstetrics and Gynaecology, Infectious Diseases Department and all staff in KK Womens’ and Children’s Hospital for leading the COVID-19 fight locally.Monica Shi Qi Chua1, Jill Cheng Sim Lee2, Suzanna Sulaiman1, Hak Koon Tan31Department of Obstetrics and Gynaecology,2Department of Urogynaecology,3Division of Obstetrics and GynaecologyKK Women’s and Children’s Hospital, Singapore

Letter to the Editor, BJOG Exchange

Background: Maternal levels of angiogenic factors are promising prognostic parameters in patients with suspected preeclampsia, but in women with confirmed preeclampsia this performance has been less explored. Objective: To assess in women with early-onset severe preeclampsia whether longitudinal changes in angiogenic factors improve the prediction of adverse outcome. Study design: A cohort was created of consecutive women admitted for early-onset severe preeclampsia with no indication for immediate delivery. Levels of placental growth factor [PlGF], soluble fms-like tyrosine kinase [sFlt-1] and sFlt-1/PlGF ratio were measured at admission and before delivery; and average daily change was calculated. The association of longitudinal changes of angiogenic factors with maternal complications and with the time interval to delivery was evaluated by logistic and Cox regression. Results: Sixty-three women were analyzed, of which 23 (36.5%) had a complication. Longitudinal changes of sFlt-1 were more pronounce in complicated pregnancies (median: 1079.5 vs. 343.7 pg/mL/day; p=0.04). On the multivariate analysis, the baseline model (clinical risk score and sFlt-1 at admission) explained a 6.6% of the uncertainty for complication (R2-Naegelkerke). The addition of sFlt-1 longitudinal changes improved this performance to 23.2% (p=0.004). The median time from admission to delivery was 3 days (95% confidence interval: 1.9-4.05) in those in the highest quartile of sFlt-1 longitudinal changes vs. 10 days (95% confidence interval: 8.1-11.9) in the remaining women (Log-rank test p<0.001). Conclusions: Longitudinal changes in sFlt-1 maternal levels from admission for confirmed early-onset severe preeclampsia add to baseline characteristics in the prediction of maternal complications.

Objective To compare the safety and efficacy of Veregen® ointment against placebo in the treatment of usual type vulvar intraepithelial neoplasia (uVIN). Design A Phase II randomised control trial. Setting A tertiary gynaecological oncology referral center. Population All women diagnosed with primary and recurrence uVIN. Methods Eligible patients were randomised to receive either Veregen® or placebo ointment (applied 3 times daily for 16 weeks), and were followed up at 2, 4, 8, 16, 32 and 52 weeks. Main outcome measures Outcome measures, recorded at 16 and 32 weeks, were histological (HR) and clinical (CR) response (as measured by ≥30% reduction in the sum of the longest diameter of all lesions when compared to baseline), toxicity and changes in quality of life and pain scores. Results 26 patients were randomised and all 13 patients who received Veregen® showed either complete (n=5) or partial (n=8) CR with a trend towards an improvement in baseline symptoms. In placebo group, 3 patients had complete CR, 2 had partial CR and 6 had stable disease. Patients in the Veregen® group showed a significant improvement in CR as compared to the placebo group (P=0.0026). There was no evidence of difference in HR and toxicity reported in both groups. Conclusion Our study indicates that Veregen application is safe and leads to at least a partial clinical resolution of uVIN lesions and symptoms improvement, thus warranting a phase III multi-centre RCT.

Mini-commentary on BJOG-19-1139.R1: Mesh inlay, mesh kit or native tissue repair for women having repeat anterior or posterior prolapse surgery: randomised controlled trial (PROSPECT)

Mini-commentary on BJOG-19-1824.R1: Demographics, Natural History and Treatment Outcomes of Non-Molar Gestational Choriocarcinoma; A UK population study

Background: Postpartum haemorrhage (PPH) rates are increasing in developed countries. A reliable prognostic tool for PPH has potential to aid prevention efforts. Objective: To systematically identify and appraise prognostic modelling studies for prediction of PPH. Search strategy: MEDLINE, Embase, CINAHL and the Cochrane Library were searched using a combination of terms and synonyms including ‘prediction tool’, ‘risk score’ and ‘postpartum haemorrhage’. Selection criteria: Any observational or experimental study developing a prognostic model for women’s risk of PPH. English language publications. Data collection and analysis: Predesigned data extraction form to record: data source; participant criteria; outcome; candidate predictors; actual predictors; sample size; missing data; model development; model performance; model evaluation; interpretation. Main Results: Of 1723 citations screened, 10 studies were eligible for inclusion. An additional paper was published and identified following completion of the search. Studies addressed populations of women who experienced; placenta praevia; vaginal births; caesarean birth; and the general obstetric population. Primary study authors deemed four models to be confirmatory. There was a high risk of bias across all studies due to a combination of retrospective selection of women, low sample size, no internal validation, suboptimal external validation and no reporting of missing data. Conclusion: Of eleven prognostic models for PPH risk, one developed for women undergoing caesarean section is deemed suitable for external validation. Future research requires robust internal and external validation of existing tools and development of a model that can be used to predict PPH in the general obstetric population. Protocol registration number: PROSPERO 95587

A document by Russell Kirby. Click on the document to view its contents.

Despite extensive research, the pathophysiology and prevention of pre-eclampsia remain elusive, diagnosis is challenging, and pre-eclampsia remains associated with adverse maternal and perinatal outcomes. Angiogenic biomarkers, including placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1), have been identified as valuable biomarkers for preterm pre-eclampsia, accelerating diagnosis and reducing maternal adverse outcomes by risk stratification, with enhanced surveillance for high-risk women. PlGF-based testing is increasingly being implemented into clinical practice in several countries. This review provides healthcare providers with an understanding of the evidence for PlGF-based testing and describes the practicalities and challenges to implementation.

Mini-commentary on BJOG-19-1677.R1: Risk-factors for second-line dactinomycin failure after methotrexate treatment for low-risk gestational trophoblastic neoplasia: a retrospective study

Abstract Objective To evaluate the clinical diagnostic validity of carbon nanoparticle suspension (CNS) in sentinel lymph node biopsy (SLNB) for assessing lymphatic spread of early-stage cervical cancer. Design A prospective study. Setting and population 356 cases. Methods We enrolled 356 stage Ia2-IIa2 cervical cancer patients to undergo SLNB using CNS followed by systematic pelvic lymphadenectomy. All lymph node specimens were assessed using conventional histopathologic ± pathologic ultrastaging analyses. Main outcome measures SLN detection rate (DR), clinical diagnostic validity, and various related factors were analysed. Results CNS identified 1456 SLNs in 325 patients. The overall SLN DR was 91.29%. A significantly higher DR was found for patients with tumours <20 mm (97.75% vs. 71.91%; p = 0.000). Two patients had false-negative results, accounting for 0.615% of patients who had successful SLN detection. SLNB with CNS had sensitivity of 92.86%, false-negative rate (FNR) of 7.14%, and negative predictive value (NPV) of 99.29%. Importantly, sensitivity (100%), NPV (100%), and FNR (0%) were improved when testing the subgroup of patients with tumours <20 mm (267 cases). There were no observed differences in DR based on pathologic type or grade, stage, depth of stromal invasion, surgical approach, menopausal status, or prior treatment with chemotherapy (p > 0.05). Conclusions SLNB with CNS results in favourable DR, sensitivity, and NPV for women with early-stage cervical cancer with small tumour sizes. SLNB with CNS is safe, feasible, and relatively effective for guiding precise surgical treatment of early-stage cervical cancer. Keywords SLNB, CNS, early-stage cervical cancer

Objective: To evaluate the effectiveness of virtual reality as a distraction technique in the management of acute pain and anxiety during outpatient hysteroscopy. Methods: A parallel group, prospective randomised controlled trial was conducted at a UK University Hospital (August to October 2018) (ClinicalTrials.gov Id: NCT03699280). Forty consenting, eligible women were randomised to virtual reality intervention (immersive video content as a distraction method) or standard care during outpatient hysteroscopy. Pain and anxiety outcomes were measured as a numeric rating score (scale of 0-10). Results: Compared to standard care, women with virtual reality intervention experienced less average pain (score 6.0 vs 3.7, mean difference 2.3, 95% CI 0.61-3.99, p=0.009) and anxiety (score 5.45 vs 3.3, mean difference 2.15, 95% CI 0.38-3.92, p=0.02). Conclusion: Virtual Reality was effective in reducing pain and anxiety during outpatient hysteroscopy in a pilot trial. Its wide potential role in ambulatory gynaecologic procedures needs further evaluation.

Letter to the Editor, BJOG Exchange

Objective: To determine whether planned cesarean section (CS) for a second delivery protects anal continence in women with obstetrical anal sphincter lesions. Design: Randomized trial. Setting: 6 maternity units in the Paris area. Sample : Women at high risk of sphincter lesions (first delivery with 3d degree laceration and/or forceps) but no symptomatic anal incontinence. Methods : Endoanal ultrasound was performed in the third trimester of the second pregnancy. Women with sphincter lesions were randomized to planned CS or vaginal delivery (VD). Main outcome measures : Anal continence at 6 months post-partum. Secondary outcomes were urinary continence, sexual morbidity, maternal and neonatal morbidities and worsening of external sphincter lesions. Results : Anal sphincter lesions were detected by ultrasound in 264/434 women enrolled (60.8%) ; 112 were randomized to planned VD and 110 to planned CS. At 6-8 weeks after delivery, there was no significant difference in anal continence between the 2 groups. At 6 months after delivery, median Vaizey scores of anal continence were 1 [IQR 0-4] in the CS group and 1 [IQR 0-3] in the VD group (p = 0.34). There were no significant differences for urinary continence, sexual functions or for other maternal and neonatal morbidities. Conclusions : In women with asymptomatic obstetrical anal sphincter lesions diagnosed by ultrasound, planning a CS had no significant impact on anal continence 6 months after the second delivery. These results do not support advising systematic CS for this indication.

Letter to the Editor, BJOG Exchange

Since December 2019, a new coronavirus (COVID-19) infection has rapidly become prevalent in central China [1]. On the basis of knowledge obtained from a previous coronavirus outbreak [2], pregnant women are believed to be susceptible to this virus. Once a maternal infection of 2019-nCoV is suspected or confirmed, childbirth becomes complicated and challenging. Efficient obstetric treatment is required, and is key to optimizing the prognosis for both mother and child. Care should be taken in determination of the timing of delivery, assessment of the indications for caesarean section, preparation of the delivery room to prevent infection, choice of the type of anesthesia, and newborn management.

Letter to the Editor, BJOG Exchange