Mini-commentary on BJOG-19-1876.R1: Glycosylated fibronectin point-of-care test for diagnosis of preeclampsia in a low-resource setting: a prospective Southeast Asian population study

Endometriosis is often described as a chronic condition. Surgical or medical treatment approaches do not cure it, and recurrence of the disease or its symptoms is common. Medical treatment is usually used to achieve symptomatic control whilst surgery aims to eliminate the visible lesions. However, recurrence is frequently seen even after very radical surgery.Endometriomas are frequently used for diagnosis and as a marker of recurrence due their easy recognition on imaging. In this issue of BJOG, Wattanayingcharoenchai et al (BJOG 2020 xxxx) present their systematic review and network metaanalysis (NMA) on the efficacy of postoperative medical therapies in reducing endometrioma recurrence with some mixed messages. They conclude that evidence from randomised controlled trials (RCTs) do not support the use of postoperative hormonal therapies, whereas data from cohort studies indicate a significant protective effect of levonorgestrel intrauterine system (LNG-IUS) followed by dienogest, gonadotrophin releasing hormone agonists (GnRHa) + LNG-IUS, continuous and cyclical oral contraceptives (OC). The most effective postoperative therapy (although non-significant) was GnRHa+LNG-IUS, followed by continuous OC and GnRHa based on RCTs.Direct meta-analysis of RCTs in the Wattanayingcharoenchai et al. article indicate an approximately 40-50% reduction with OCs but this remained statistically non-significant. This finding is in contrast to an earlier meta-analysis (Vercellini et al. Acta Obstet Gynecol Scand. 2013;92:8-16) which concluded that the postoperative OC use dramatically reduced the risk of endometrioma recurrence and international guidelines that recommend use of hormonal contraceptives for the secondary prevention of endometrioma (Dunselman et al. Hum Reprod. 2014;29:400-12). So what are we to believe and what should we advise women affected by endometriosis to do?There is a wide variation in the design of studies on which metaanalyses and the current NMA are based on in terms of inclusion criteria, duration of treatment and definition of recurrence. Some studies allocate the participants on the basis of their disease stage without taking the preoperative cyst size and bilaterality into account. The definition of a ‘recurrent cyst’ varies from ‘no definition’ to endometrioma of > 1 cm or >3 cm. These introduce significant heterogeneity which potentially compromise the validity of any meta-analysis. Furthermore, there is also a conceptual difference between using medical treatment (e.g. GnRHa) for 3-6 months postoperatively and continuing with therapy (e.g. hormonal contraceptives) in the long term and assessing the recurrence rates at 1-5 years. In fact the ESHRE guideline (Dunselman et al.) proposed distinguishing postoperative adjunctive treatment of < 6 months that aims to improve the outcome of surgery and longer treatments with the intention to reduce recurrences (secondary prevention). The former may have a significant side effect profile whereas the latter has a good safety record.It is very plausible that suppression of ovulation and reducing/eliminating menstrual flow in the long term would reduce recurrences. The current literature is too heterogeneous and fragmented to confirm or refute this. Properly designed large scale studies with the required power are still required. The Pre-Empt trial which is currently ongoing in United Kingdom may give some of the answers.Disclosure of interest: None. A completed disclosure of interest form is available to view online as supporting information.

Uterine rupture is the feared complication when a uterus scarred by a caesarean section (CS) is labouring. The increased awareness of uterine rupture and its dramatic consequences of perinatal asphyxia has lead to guidelines dictating safe circumstances when undertaking a trial of labour after caesarean section (TOLAC). This complication occurs in an estimated 35 per 10 000 women with a previous CS undergoing labour (INOSS study of uterine rupture, BJOG 2019;126:370–381), but is extremely rare before the onset of labour and in the unscarred uterus. Our knowledge of prelabour uterine ruptures is confined merely to a small number of published case reports and case series in the literature.In this issue of BJOG, Al-Zirqi and colleagues present the results of a retrospective population-based study during 41 years (1967-2008) in Norway describing the characteristics and outcomes of complete uterine rupture before the onset of labour in 8 unscarrred and 22 scarred uteri, besides another 45 partial ruptures in scarred uteri (BJOG 2020 xxxx). The authors point out that complete ruptures before onset of labour are absolutely rare, but result in a higher number of perinatal deaths. In the unscarred uterus, complete ruptures before onset of labour were related to trauma (n=3), abnormal invasive placenta (n=2) and congenital uterine malformations (n=2) and were unavoidable in most cases. In the scarred uterus, complete ruptures before onset of labour were related to abnormally invasive placenta (n=4), previous complete uterine rupture (n=3) and scars outside the lower uterine segment (n=17). These scars were caused by classical CS (n=9), myomectomy (n=5), tubo-uterine surgery (n=3), uterine septal operation (n=1) and perforation during endometrial ablations (n=3). Classical CS by vertical incision has become rare, while laparoscopic and hysteroscopic uterine surgery increase in frequency. A systematic review by Gambacorti-Passerini et al. (Acta Obstetricia et Gynecologica Scandinavica 2016;95:724-734) revealed that the majority of uterine ruptures after prior myomectomy occurred before 36 weeks and before labour (5/330, 1.5%), while only 0.47% (2/426) in women undergoing a trial of labour after myomectomy (TOLAM). The researchers could not reveal any riskfactor (surgical approach, type of myoma, type of hemostasis, suture layers) keeping the risk of uterine rupture following prior myomectomy largely unpredictable. Only case reports and small case series report on uterine ruptures following operative hysteroscopy or tubo-uterine surgery, where perforation is considered a risk factor (Sentilhes et al. Gynecol Obstet Fertil 2006;34(11):1064-70), similar to the 3 cases of endometrial ablation with perforation in the study of Al-Zirqi et al. More large scale studies like this retrospective analysis are needed to understand to what extent uterine surgical procedures contribute to uterine ruptures, during or before onset of labour. In this regard, we expect a report of the International Network of Obstetric Survey Systems (INOSS) who analysed complete uterine ruptures in 10 countries, including 215 uterine ruptures before onset of labour.This study advocates a higher level of alertness for uterine rupture when taking care for women with congenital uterine abnormalities, with suspected AIP and with prior uterine surgery.No disclosures: A completed disclosure of interest form is available to view online as supporting information.

Mini-commentary on BJOG-19-1883.R1: A core outcome set for pre-eclampsia research: An international consensus development study

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) in China at the end of 2019 brought with it uncertainty as to whether it would bring an increase in maternal, fetal and neonatal morbidity and mortality. This uncertainty drove fear; understandable given the high case fatality rate associated with previous severe respiratory illness causing coronaviruses.Given the novel nature of SARS-CoV-2, clinicians and women and their families rely primarily on limited information from case reports and case series to inform their decisions about pregnancy management. Early evidence from these sources demonstrated a tendency toward preterm delivery mainly as a consequence of elective interventions (Della Gatta et al. Am J Obstet Gynecol, 2020, Vol.223, p36-41), which are likely to have been exacerbated by the uncertainty of COVID-19 on pregnancy and neonatal outcomes.The reliance on research reports, case series and case reports continues. However, such reports are at higher risk of bias, including publication bias. Concerns have also been expressed about the potential of reporting of same people with COVID-19 across different reports (Bauchner et al. JAMA, 2020, Vol.323, p1256). Such reporting leads to inaccurate estimates of the impact of the disease on outcomes, which is aggravated when an evidence base is relatively small, evolving and critical to informing good care decisions.In this issue, Thornton et al. report a review of case reports and case series of the risk of the neonate becoming infected with SARS-COV-2 by mode of birth, type of infant feeding and mother-infant interaction (BJOG 2020 xxxx). Their findings lead them to conclude that vaginal delivery, breast and are safe in the context of COVID-19 disease. But, what interests me equally in this paper is their approach to reducing the risk of duplicate reports in estimating disease impact.First, their data sources included a daily PubMed search supplemented by alerts from experts on social media; daily searches of three electronic databases including the Maternity and Infant Care Database and citation tracking. Second, geo-coding of data to unique distinct locations. Here, in response to reviewer feedback, which the authors refreshingly acknowledge, the team invited a native speaker of Chinese familiar with health institutes in Wuhan to provide contextual information to maximise the likelihood of correct site identification (which did result in some geo-coding revisions). Third, they attempted to identify sites unnamed in reports using author affiliations, which ultimately did not provide the assurances they needed to be confident in retaining some reports.The accuracy of inferences drawn from research reports, case series and case reports is enhanced when authors report clearly if and when any patients are reported in other reports and when processes to minimise erroneous repeated inclusion of the same patients. Thornton et al.’s paper is informative clinically but is equally interesting in its flexing of methods to iteratively address an evolving evidence base and minimise uncertainty. Such approaches may lack the sophistication of techniques applied to larger evidence bases yet are critical to informing decisions early in an evolving evidence base. Further development of the processes may inform future pandemic readiness.No disclosures: A completed disclosure of interest form is available to view online as supporting information.

Dear editor, we have read with interest the study by Deo et al.published in BJOG: An International Journal of Obstetrics and Gynaecology 1. We have noted that although the control and VR group were ‘comparable’ regarding previous hysteroscopies, differences in baseline pain expectation scores between patients with a previous hysteroscopy and those without were not given. Each patient has an individual pain experience during hysteroscopy, some may not experience any pain at all, whereas others feel pain during cervical manipulation, distension of the uterus, during pipelle biopsy or delayed pain due to the release of prostaglandins2. Therefore, it could be possible the VR group has patients who do not experience any pain at all. It would be beneficial to know if there was any difference in pain expectation scores between those with prior experience of hysteroscopy and those without. A further study with a group known to have painful hysteroscopies could be of immense clinical value, as this group of patients may experience the greatest benefit.Furthermore, it is mentioned that ‘patients were instructed to self administer analgesics prior to the procedure (either paracetamol or non steroidal anti-inflammatory drugs)’ . It would be useful to ask the patients which specific analgesic they took, the dosage and how long before the procedure they took the medication. As use of analgesia prior to the procedure could potentially affect the pain perceived and therefore the pain scores in both groups; potentially being a confounding factor. Having more information about analgesia used prior to the procedure could allow clinicians to identify significant differences between cohorts with regards to analgesia use and signify a possible correlation to pain scores.Finally, it is mentioned that one patient in the VR group had a previous history of claustrophobia and decided to remove the headset when the procedure started as she felt claustrophobic. Therefore, the patient would not have experienced VR throughout the procedure, rather only for a small period of time, potentially effecting the reported pain score for that patient and the larger results as study populations were only 20 patients per cohort. To avoid this, the patient could have perhaps not been included in the results.Disclosure of Interests: No conflicts to declare.Contribution to Authorship: All authors were involved in the conception, analysis, drafting of intellectual content and final approval of this correspondence letter. All authors are also in agreement to be accountable for all aspects of work in this correspondence letter.Details of Ethics Approval: No ethics approval required.Funding : No funding.

Leiomyomata are common benign pelvic masses that occur in up to 77% of reproductive aged women (Flyckt et al Clin Obstet Gynecol 2017;60(2):252-272). Myomectomies are frequently performed for symptomatic leiomyoma unresponsive to non-surgical treatments and can be performed via laparotomy (open) or minimally invasive approaches. Open myomectomies are often performed because of lack of access to or training with minimally invasive approaches, or secondary to concerns surrounding morcellation.Misoprostol is a relatively inexpensive readily accessible uterotonic and vasoconstrictive medication. Based on mechanism of action, misoprostol is often used at the time of myomectomy to decrease blood loss. This led Wali et al. (Wali et al BJOG 2020 xxxx) to perform a systematic review on the effectiveness of preoperative misoprostol specifically at the time of open myomectomy. Eight randomized-controlled trials met inclusion criteria and were included in this systematic review with a total of 385 participants, 192 in the misoprostol group 193 in the control group.These studies provide moderate to high quality evidence on the following six outcomes: 1) estimated blood loss, 2) drop in haemoglobin, 3) need for blood transfusion, 4) operative time, 5) post-operative fever, and 6) length of hospital stay. The specific findings for those six outcomes are as follows. Compared to placebo, misoprostol significantly reduced estimated blood loss by a mean of 170cc with an associated haemoglobin decrease of 0.48 g/dL. Perhaps the most clinically significant finding was that preoperative misoprostol led to a three-fold lower risk of blood transfusion with an odds-ratio of 0.31. The use of preoperative misoprostol also led to a decreased operative time of 11 minutes, which is probably clinically significant based on the relative low expense of misoprostol and relative high cost of time in the operating theater. There was no statistically significant difference in the rates of postoperative fever or length of hospital stay. Patients in the misoprostol group were discharged an average of 3.5 hours earlier than the placebo group which is probably not clinically significant.Based on the overall risk-benefit profile identified in this study, it would seem that preoperative misoprostol should be recommended for most patients prior to open myomectomy. The findings from this systematic review are particularly important for low-resource settings where access to minimally invasive approaches and the availability of blood for possible transfusion are limited. Although there was variability in the timing and the dose of preoperative misoprostol, Wali et al (Wali et al BJOG 2020 xxxx) suggest the evidence supports a single dose of 400μg of misoprostol 30 to 60 minutes prior to surgery, or two doses 3 hours apart. A protocol of one dose of misoprostol 30 minutes prior to taking a patient to the operating theater could be implemented as part of a standard preoperative order set and administered in the pre-anesthesia care unit. This study highlights a simple, low-cost intervention that can significantly improve patient outcomes.Disclosure of interest: None to declare. A completed disclosure of interest form is available to view online as supporting information.

Vasomotor symptoms (VMS), namely hot flashes and night sweats, are the key symptoms of menopause. Women frequently seek healthcare interventions for these bothersome symptoms. Early menarche ≤11 years has been associated with an earlier onset of menopause (Mishra et al.Hum Reprod 2017;32:679-86), that may subsequently exert a negative impact on fat distribution and glucose homeostasis (Mauvais-Jarvis et al. Endocr Rev 2017;38:173-88). To date, the relationship between early menarche and the frequency/severity of VMS, and if it is modified by obesity, is unclear.In this issue of BJOG , Chung et al. put into context the complex interplay of several factors that contributed to a higher frequency or severity of VMS by harmonising individual-level data of six cohort studies involving 18,555 women (median age 48 years; 91.2% White, 4.6% African Americans and 4.2% Asians) (Chung et al. BJOG 2020). Compared with women with age at menarche ≥14 years, women with early menarche ≤11 years were at increased risk for frequent hot flashes and night sweats, showing a relative risk (RR) of 1.48 (95% confidence interval [CI] 1.24-1.76) and 1.59 (95% CI 1.49-1.70), respectively. The corresponding RRs for severe hot flashes and night sweats were 1.16 (95% CI 0.94-1.42) and 1.27 (95% CI 1.01-1.58). When adjusting for body mass index (BMI) in midlife, the associations were attenuated but remained significant (except for severe hot flashes). Compared with women with age at menarche ≥14 years and midlife BMI<25 kg/m2, women with early menarche ≤11 years had an RR of 2.36 (95% CI 2.17-2.57) when BMI was 25-29.9 kg/m2, and 2.87 (95% CI 2.79-2.95) when BMI ≥30 kg/m2 for frequent hot flashes, suggestive of a dose-response relationship. Despite these encouraging results, the majority of studies involved the White populations, which might limit the generalisability of the results to other populations.Given the increasing burden of obesity in childhood/adolescence and women (Afshin et al. N Engl J Med 2017;377:13-27), the results have important clinical implications. We now have stronger evidence to not only suggest that early menarche contributes to increased risk of frequent and/or severe VMS, but also having a higher midlife BMI can potentially exacerbate the condition. For example, a woman who attained menarche at an age younger than 11, irrespective of prior genetic and/or environmental influences, is more likely to experience frequent and/or severe VMS. The good news is that she may at least halve the risk by striving to maintain a normal BMI in midlife.These results will add strength to the recommendation of weight reduction as one of the effective non-pharmacological approaches to relieve VMS (Menopause 2015;22:1155-74). The impact of weight reduction will likely extend beyond management of VMS, to also reduce the incidence of non-communicable diseases in perimenopausal women. While questions regarding the risks and benefits of menopausal hormonal therapy on cardiovascular and cancer outcomes remain (The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. Menopause2017;24:728-53), an emphasis for the role of non-pharmacological management of VMS may be pertinent now more than ever.Disclosure of Interests: LLL has received research grants and/or speaker honoraria from AstraZeneca, Boehringer Ingelheim, Merck Serono, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, Procter & Gamble Health, Sanofi and Servier outside of this work. QHL declared no potential conflict of interest.

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.

Ultrasound-detected structural anomalies have an impact on fetal mortality and morbidity. Prenatal Exome Sequencing is incorporated into clinical care pathways for paediatric populations but maybe used to delineate the prognosis of fetal structural anomalies. This paper reviews the literature defining the clinical utility of prenatal ES and discusses the potential promise and challenges for implementation of this technology into clinical practice. Prospective case selection with accurate and informative pre-test counselling by multidisciplinary, clinical genetic-led teams is imperative. Robust, regulated laboratory sequencing, informative bioinformatic pathways with variant identification and conservative matching with the phenotype (within clinical review panels) is also important.

With no end in sight to the convergence of COVID-19, countries are struggling with strategies to halt the “second wave” and mitigate economic decline. Estimated to account for around half of the infections, asymptomatic transmission of SARS-CoV-2 has been hampering the containment of the virus. A positive case rate of 10% was reported by Prabhu et al. among 625 pregnant women who were universally screened for SARS-CoV-2 on the day of admission for delivery at 3 institutions in New York City, of which 80% were asymptomatic at the time of testing including pre- and post-symptomatic patients. As evidence shows that virus sheds before symptoms appear and even after their cessation, these populations may have increased the chances of COVID-19 outbreak in the hospitals. Utilization of testing results for isolation practices was not mentioned in the report, possibly given the long turnaround time for the testing platforms at the time.While the risk of nosocomial transmission is affected by clinical settings, the intimate and prolonged nature of childbirth elevates the risk of cross-infection between midwives and women. The role of nosocomial transmission has been increasingly recognized, and its severity risk may be greater than those of community-acquired infections. A recent report has suggested facilities to consider testing pregnant women for SARS-CoV-2 at the time of admission (Rasmussen SA, et al. JAMA. 2020). International Confederation of Midwives has also called for governments to prioritize testing for all pregnant women and their care providers. Identification of infectious women prior to delivery could contribute to prevention of further transmission to patients and healthcare workers. Importance should also be emphasized on evaluating contact history due to the nature of false-negative PCR results (Woloshin S, et al. NEJM. 2020).Another significance of performing testing for SARS-CoV-2 on pregnant women is for the adequate medical management of the women and the fetuses. While outcome for mothers and neonates seems generally favorable, data suggest that pregnancy can be associated with increased risk for severity, including intensive care unit admission and receipt of mechanical ventilation (Ellington S, et al., MMWR Morb Mortal Wkly Rep 2020;69:769–775). Furthermore, a recent article has raised concerns over transplacental transmission of SARS-CoV-2 to the fetus (Vivanti AJ, et al. Nat Commun. 2020;11:3572). Collection of longitudinal data is crucial to understand the effects of SARS-CoV-2 infection on maternal and neonatal outcomes. Results of large-scale prospective cohort studies, such as INTERCOVID study, are expected to add high-quality evidence on the effects of COVID-19 in pregnancy on the health of the mothers, fetuses, and newborns.Screening a maternity population under a pandemic can be a way to provide a glimpse of the distribution of the population, since capacity constraints still impede widespread testing in many countries. Recent development of faster diagnostic testing could bring improvement, but test sensitivity will remain a challenge. Fundamental preventive measures and clinical management should be continued; that is, hygiene and social distancing practices for women themselves, and careful evaluation of each mother and fetus for care providers.

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.

Dear editor/Sir,We thank Song et al. for their insightful comments (1) on our article (2) and commend them for their study about human papillomavirus (HPV)-genotyping on self-samples and their analysis on different triage strategies for detecting cervical intraepithelial neoplasia grade 2 or worse (CIN2+) (3). They report that cytology on physician-sampled material has a sensitivity of 74.8% for detecting CIN2+, while HPV-genotyping for 16/18 has a sensitivity of 52.6% for detecting CIN2+. This means that HPV-genotyping in their hands, is still inferior to cytology testing and cannot fully replace this triage strategy. However, adding HPV-genotyping to cytology testing could increase the sensitivity, as has been described by others as well. While our study shows that reflex cytology on self-samples cannot replace triage with regular cytology for HPV-positive women, because of the low sensitivity of 29.4% for detecting CIN2+, it is valuable as an additional method for triage (2). With a positive predictive value (PPV) of 68.1% for detecting CIN2+ it is effective to refer HPV-positive women with abnormal cytology on self-sampling directly for colposcopic evaluation without the requirement of an extra visit to the general practitioner. A PPV of 21.2% for HPV-genotyping for 16/18 on self-samples for detecting CIN2+ is not enough to refer these women directly for colposcopy. We agree that cost-effectiveness is important. It is not sure if 15% of direct referral will completely cover the costs for 85% of double cytology testing. As the collection in PreservCyt (Cytyc Corporation, Boxborough, MA, USA) has already been performed for HPV-testing on the self-samples, extra costs will include the use of ThinPrep slides (Hologic Inc, Marlborough, MA, USA) and cytotechnicians’ time for analysing the slides. On the other hand, there will be a reduction in costs for consulting the general practitioner and for regular cytology testing, including material costs (Cervex brush (Rovers® Medical Devices B.V., Oss, the Netherlands), PreservCyt jar, ThinPrep slide), transportation costs, and cytotechnicians’ time for analysing the slides. However, besides cost-effectiveness, patient comfort is at least as important, as well as reduction in loss-to-follow-up and diagnostic delay, in which the latter also positively influences the costs. It remains a challenge to find a triage method on HPV-positive self-samples which could fully replace regular cytology. Molecular tests, such as methylation markers and microRNA detection, are promising future triage methods (4, 5). They are more objective than cytology testing and highly reproducible, however not ready yet for full implementation in cervical cancer screening. Further research on self-samples is warranted to find an optimal triage strategy. Until then, reflex cytology on self-samples could be easily implemented in the current screening programme and improve cervical cancer prevention.Diede L Loopik 1; Willem JG Melchers 2; Judith EM Vedder 3; Adriaan JC van den Brule4; Leon FAG Massuger 1; Ruud LM Bekkers5; Albert G Siebers 3,61 Department of Obstetrics and Gynaecology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, PO Box 9101, 6500HB, Nijmegen, the Netherlands;2 Department of Medical Microbiology, Radboud university medical center, PO Box 9101, 6500HB, Nijmegen, the Netherlands;3 Department of Pathology, Radboud university medical center, PO Box 9101, 6500HB, Nijmegen, the Netherlands;4 Department of Pathology, Lab for Molecular Diagnostics, Pathologie-DNA, Jeroen Bosch Hospital, PO Box 90153, 5200ME,‘s-Hertogenbosch, the Netherlands; 5 Department of Obstetrics and Gynaecology, Catharina Hospital, PO Box 1350, 5602ZA, Eindhoven, the Netherlands; 6 PALGA, the nationwide network and registry of histo- and cytopathology, Randhoeve 225a, 3995 GA, Houten, the NetherlandsPresent address Ruud LM Bekkers: GROW, School for Oncology & Developmental Biology, Maastricht University Medical Centre, PO Box 616, 6200MD, Maastricht, the Netherlands

A document by Jan Willem de Leeuw. Click on the document to view its contents.

A document by Birgit Arabin. Click on the document to view its contents.

Endometriosis is a common health condition affecting women of reproductive age who often present with chronic pelvic pain and/or infertility. There is wide variation in the estimates of endometriosis prevalence. Accurate reporting of the disease prevalence is hampered by multiple factors including long delay in diagnosis due to natural fluctuation in symptoms severity, lack of a reliable non-surgical diagnostic tool, polymorphic appearance of endometriosis lesions at laparoscopy, inability to achieve histological confirmation is all suspected cases and tendency for disease recurrence. Therefore, a longitudinal, rather than cross-sectional, cohort study design spanning an extended follow-up period is better suited to assess endometriosis prevalence. In this issue of BJOG, Rowlands and colleagues (2020) linked longitudinal survey data to three administrative health databases to identify the prevalence of endometriosis among 13,508 young Australian women followed up for nearly 20 years. The study reported a 6% cumulative prevalence of clinically-confirmed endometriosis and an additional 5.4% of clinically-suspected endometriosis. If these figures reflect the true prevalence of endometriosis, then one in nine women will be diagnosed with endometriosis at some point during their reproductive years up to the age of 44 with a peak at 30-34 years, thus underscoring the significant impact of the disease on the well-being and quality of life in young women and the enormous burden on healthcare resources needed to diagnose and treat endometriosis and its sequelae.The data presented in the study of Rowlands and colleagues (BJOG 2020) included patients who could have been diagnosed with adenomyosis but their condition was coded as endometriosis. This is unlikely to have significantly over-estimated the prevalence of endometriosis as recent evidence suggests adenomyosis prevalence to be only 1% with a considerable proportion of those patients having co-existing endometriosis (Yu et al, Am J Obstet Gynecol 2020; 223: 94.e1-10). The same can not be said about the 5.4% of clinically-suspected endometriosis cases. Symptoms review, clinical examination and various imaging modalities, including ultrasound scanning and magnetic resonance imaging, represent the cornerstone of non-invasive diagnosis of endometriosis. Current evidence suggests that the predictive accuracy of those non-invasive methods in the diagnosis of endometriosis compared to laparoscopy and histological confirmation is modest (Nisenblat et al, Cochrane Database Syst Rev, 2016 (2): CD009591) and depends on the combination of diagnostic tools used as well as the site and extent of the endometriosis lesions (Reid et al, Eur J Obstet Gynecol Reprod Biol 2019; 234: 171-178). These data are not provided in the study of Rowlands and colleagues. It is therefore difficult to accurately estimate the prevalence of endometriosis whether it’s the 6% clinically-confirmed rate or the full 11.4% confirmed and suspected rate. The truth probably lies somewhere in the middle! Future epidemiological studies should endeavour to elucidate on the distinction between the different methods used in the diagnosis of endometriosis with reference to the predictive accuracy of each diagnostic modality to help advance our understanding of the incidence and risk factors associated with this debilitating gynaecological condition.Mr. Tarek A El-ToukhyAssisted Conception Unit, Guys and St. Thomas Hospital NHS Trust11th Floor, Tower Wing,Guys Hospital,St. Thomas Street [email protected]

Epidemiologic studies performed in the Melbourne Sexual Health Center over several years have explored and emphasized the role of sexual transmission in the pathogenesis of sporadic bacterial vaginosis (BV) as well as recurrent BV (Fethers KA., et al. Infect. Dis. 2008; 47: 1426-1435). Some of the most definitive studies documenting details of heterosexual sexual transmission followed. There can be little doubt as to the causal role of sexual transmission in BV particularly with regard to the initial episode (Cherpes, TL., et al. Sex. Transm. Dis 2008; 35: 78-83). The present study adds solid molecular data to their previous epidemiologic data that recurrent BV is more likely to occur in a heterosexual woman with a single regular male partner (Ratten L., et al BJOG 2020 xxxx): Moreover, the risk is mitigated by use of an oral contraceptive and barrier contraceptives. Specifically, Ratten et al conclude that sex is associated with persistence of non-optimal, BV-associated vaginal dysbiosis following appropriate antimicrobial treatment for BV in a cohort followed prospectively, likely the result of sexual transmission from a regular partner. The key term used in the title of the study is persistence, which implies that the non-optimal vaginal microbiota fails to resolve, as opposed to future reintroduction from the same guilty partner. Persistence in this context, unfortunately, also indirectly suggests that inadequate antimicrobial treatment is currently prescribed to women, perhaps sufficient to relieve symptoms and meet diagnostic criteria of satisfactory response, but insufficient to eradicate BV pathogens. The author emphasizes needed improvement in the, so far, futile male partner therapy to prevent female reinfection, a goal that has repeatedly eluded experts to date.The unanswered question facing patients and clinicians alike is the role of sexual reinfection as opposed to vaginal relapse in the causation and likelihood of BV recurrence. The tone of the article would indicate that reinfection is the more likely causal mechanism of BV recurrence, by emphasizing “persistence” and outweighing the role of unexplained relapse. In dealing with a symptomatic patient suffering from an episode of recurrent BV, it is currently not possible to differentiate relapse from reinfection unless the patient declares herself to be celibate, ergo relapse is the cause of recurrence. The clinical picture is identical as are Amsel or Nugent criteria. Unfortunately, molecular microbiome studies have not revealed significant differences between sequential episodes regardless of causation. We lack a “unique fingerprint” to differentiate cause or nature of the recurrent episode. Even with reinfection, sexual or otherwise, details of pathogenesis are still lacking. We know too that coitus can elicit symptoms of BV (post coital malodor) even with use of a condom. The role of receptive oral-vulvovaginal sex is also undetermined, as is the role of penile – anorectal penetration although the latter was found to be minimal in the latest study by Ratten L., et al. (BJOG 2020 xxxx): Moreover, not all longitudinal studies have revealed that heterosexual sex is a major factor in recurrence (Sobel J.D., et al. Infect. Drug Resist. 2019: 12; 2297-2307).The role of sex and reinfection in causation of RBV will depend significantly upon the population studied, including biologic and behavioral differences. Determination of causation of BV recurrence in different patient populations should be personalized and acknowledged as we admit our current limitations. Will more effective male treatment help reduce BV recurrence? Hopefully but still unknown. Determining all the causes of vaginal microbiota persistence, including the role of biofilm, remains a challenge.No disclosures: A completed disclosure of interest form is available to view online as supporting information.

Risk assessment to target aspirin is accurate but not universalLow dose aspirin, for the prevention of early onset pre-eclampsia is an established antenatal intervention; it is safe, effective, cheap and accessible in many health care settings.Optimal implementation strategies including dose, timing and screening are currently debated. The evidence supports starting aspirin early (before 16 weeks), prescribe at night, give up to 150mg and continue until at least 36 weeks gestation ((Poon et al. Int J Gynaecol Obstet. 2019 May;145 Suppl 1(Suppl 1):1-33). From the women’s perspective, many may not be happy to routinely medicate an apparently normal pregnancy, to prevent an unknown or unfamiliar disease.Despite campaigns by APEC and others, too many women only hear of pre-eclampsia when it affects them. Generally, as perceived risks escalate the acceptance of taking aspirin is greater which improves compliance by both physicians prescribing, and by pregnant women. Any strategy that allows targeting of aspirin is likely to prevent unnecessary treatment and would be welcomed. It should be noted that the MBRAACE Report (Knight et al. University of Oxford 2019. ISBN: 978-0-9956854-8-2) called for a national patient direction for midwives to prescribe aspirin which has not yet happened.This current analysis compared two such strategies to target antenatal aspirin NICE guidance uses history to establish risk (Guy et al. BJOG 2020 xxxx). It is relatively simple, requiring either a combination of minor risk factors or a single major risk factor to dictate the need for aspirin. The FMF algorithm uses a combination of tests, including scans, blood pressure and blood markers to dictate risk; this requires skill and more resource which may not be consistently available in lower income settings.When compared in a real-world setting, in a London teaching hospital, the FMF algorithm had a screen positive rate that was half that of NICE, while aspirin was given to far more high-risk women. The FMF algorithm was changed to suit local circumstances, including details of the tests used (PAPPA, rather than PLGF) and thresholds adopted for treatment, but the real-world findings are impressive.The dosage of aspirin was higher in the FMF group, (150mg vs 75mg) which could explain some of the additional clinical benefit. Aspirin has recently been shown to impact on preterm birth when given routinely to all women who have never given birth in a low resource setting. In these settings, the cost and practicalities of implementing the algorithm maybe prohibitive. However, elements of the algorithm such as blood pressure measurement are simple and potentially more generalisable.It is exciting we have an intervention that can impact on one of the world’s most significant pregnancy disorders; but if resources allow, we clearly now have the tools to predict risk and improve outcomes. The challenge is how to deliver this to the global south, where most of pre-eclampsia occurs.At Action on Pre-Eclampsia, in the UK, we will continue to push for easy availability of aspirin. This paper is a welcome piece of the jigsaw and we hope it offers further tools in the armoury to defeat pre-eclampsia.No disclosures: Completed disclosure of interest forms are available to view online as supporting information.