Objective: To assess the benefits and safety of early human fibrinogen concentrate (FC) in postpartum haemorrhage (PPH) management. Design: Multicentre, double-blind, randomized placebo-controlled trial. Setting:30 French hospitals. Population: patients with persistent PPH after vaginal delivery requiring a switch from oxytocin to prostaglandins. Methods: Within 30 min after introduction of prostaglandins, patients received either 3 g FC or placebo. Main outcome measures: Failure as composite primary efficacy endpoint: at least 4 g/dL of haemoglobin decrease and/or transfusion of at least 2 units of packed red blood cells within 48h following investigational medicinal product administration. Secondary endpoints: PPH evolution, need for haemostatic procedures, and maternal morbidity-mortality within 6±2 weeks after delivery. Results: the intention-to-treat analysis included 437 patients of which 224 received FC and 213 placebo. At inclusion, blood loss (877 ± 346mL) and plasma fibrinogen (FG) (4.1 ± 0.9g/L) were similar in both groups (mean ± SD). Failure rates were 40.0% and 42.4% in the FC and placebo groups, respectively (OR=0.99) after adjustment on centre and baseline FG; (95%CI: [0.66;1.47]; p=0.96). No significant differences in secondary efficacy outcomes were observed. The mean plasma FG was unchanged after 2 hours in the FC group and decreased by 0.56 g/L in the placebo group. No thromboembolic or other relevant adverse effects were reported in the FC group, versus two in the placebo group. Conclusions: Early and systematic administration of 3 g fibrinogen concentrate did not reduce blood loss, transfusion needs, and postpartum anaemia, but prevented plasma fibrinogen decrease without any subsequent thromboembolic events.

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

The paper by Mulder et al. addresses the effect of pregnancy prolongation on maternal and fetal outcomes in women with early-onset pre-eclampsia diagnosed after 24 weeks of gestation (Mulder et al., BJOG 2020 xxxx). They report that pregnancy prolongation - from the time of pre-eclampsia diagnosis to delivery - is associated with improved offspring outcome and survival, without adverse consequences on short-term maternal cardiovascular and metabolic function. The maternal findings are apparently at odds with another recent study from New York (Rosenbloom et al. Obstet Gynecol 2020;135:27-35) which observed an increased risk of maternal cardiovascular events after pregnancy, in case of an interval of more than 7 days between the diagnosis of any hypertensive disorders of pregnancy and delivery.Some issues should be pointed out in order to avoid misunderstandings about these findings. Being Mulder et al.’s an observational study, readers cannot infer causality because women were not randomized to the length of pregnancy prolongation. Data are spread over a significant time period (from 1996 to 2017), and this aspect could be another confounder. Pre-eclampsia is a multi-organ syndrome based on chronic inflammation, oxidative stress and endothelial dysfunction leading to a persistent subclinical cardiovascular impairment and an increased risk of adverse events later in life (Sciatti et al., Eur J Prev Cardiol 2020 doi: 10.1177/2047487320925646), similarly to what happens in cases with heart failure with preserved ejection fraction. Myocardial geometry and ejection fraction are not sensitive enough to be altered by just a few days of pregnancy prolongation, and to forecast cardiovascular consequences. Only innovative techniques such as speckle-tracking imaging may document an impairment in myocardial contractility and relaxation in former pre-eclamptics, even if ejection fraction is normal.Pre-eclampsia is currently defined as new-onset hypertension combined with de-novo proteinuria and/or “adverse conditions” or “severe maternal/fetal complications” (Magee et al., Pregnancy Hypertens 2014;4:105-145). International guidelines recommend that women with severe forms of pre-eclampsia should be delivered immediately regardless of gestational age, while an expectant management should be considered for women with non-severe pre-eclampsia before term (Magee et al., Pregnancy Hypertens 2014;4:105-145; NICE guideline no. 133, 2019). Delaying delivery is expected to benefit newborn’s health, which is well exemplified by Mulder et al.’s findings. However, the fetus is often the protagonist of adverse conditions, and severe complications such as fetal growth restriction, often co-exist with early-onset pre-eclampsia, requiring longitudinal monitoring with Doppler ultrasound and cardiotocography. The timing of delivery depends on both maternal and fetal conditions. The lack of data about fetal growth and Doppler and cardiotocography findings (in cases with growth restricted babies) limits the generalisability of the results by Mulder et al. One would expect that a longer delay before delivery can be attained only in fetuses and mothers with milder clinical manifestations of disease.Word count: 455

Mini-commentary on BJOG-20-0320.R1: Cesarean section in the second delivery to prevent anal incontinence after asymptomatic obstetrical anal sphincter injury: the EPIC multicenter randomized trialAn obstetric anal sphincter injury poses an important clinical dilemma for subsequent vaginal deliveries, which may be complicated by recurrent obstetric anal sphincter injury and / or worsening or de novo anal incontinence.Recurrent obstetric anal sphincter injury has a similar incidence to primary obstetric anal sphincter injury (6.3% vs 5.7%), and similar associated risk factors including instrumental delivery with either forceps [OR 3.12, 95% confidence interval (CI) 2.42-4.01) or ventouse (OR 2.44, 95%CI 1.83-3.25), birth weight ≥4 kg (OR 2.29, 95%CI 2.06-2.54) and previous fourth-degree tear (OR 1.7, 95%CI 1.24-2.36) (Jha S, Parker V: Int Urogynecol J. 2016 Jun;27(6):849-57).The risk of long-term anal incontinence is also related to the degree of sphincter tear. Women with a fourth-degree sphincter injury in the first delivery are at higher risk for anal incontinence compared to women with a third-degree injury (58.8% vs. 41.0%). (Jangö H et al. 2018 Feb;218(2):232.e1-232.e10. Am J Obstet Gynecol). Although primary caesarean may be protective against anal incontinence, the previous observational evidence is consistent in finding that adjusted odds of long-term anal incontinence do not differ significantly by mode of second delivery after obstetric anal sphincter injury, and specifically that subsequent elective cesarean delivery is not protective (Jangö H et al, Am J Obstet Gynecol. 2016;214(6):733.e1-733.e13.) However, previous observational studies may suffer from confounding by indication, due to widespread adoption of planned caesarean for subsequent deliveries in women with incontinence symptoms or persistent sphincter defectsThere have been no previous randomised trials to test whether anal incontinence could be prevented by planned cesarean section for the second delivery. Abramowitz and colleagues’ (Abramowitz L et al. BJOG 2020) RCT provides us with a better understanding of the role of caesarean in women with asymptomatic third degree anal sphincter injury. There was limited cross-over between groups: of the 112 women randomized to the vaginal delivery group, 17 (15.6%) had a caesarean section for obstetric indications. For those randomized to the planned cesarean section, 18 (16.58%) delivered vaginally. One fifth of the randomized women did not complete the post-partum follow-up, but their characteristics did not differ between the two study groups. In this RCT, planned cesarean section in the second delivery was unequivocally not protective against anal incontinence at 8 months post-partum, with low rates of symptoms in both groups (Vaizey score 1/24 vs. 1/24 p=0.34). As rates of incontinence were lower than expected, the trial may have been underpowered for a clinically relevant difference between groups. In an unplanned analysis, there was however, an interaction between baseline Vaizey score, and worsening symptoms after vaginal delivery, with significantly worse symptoms after vaginal delivery for women with pre-existing mild symptoms.The authors rightly suggest that the findings are useful when counseling women about risks and benefits of caesarean at their second delivery. These results do not support advising systematic cesarean after asymptomatic third degree obstetric anal sphincter injury. The medicalization of pregnancy associated with planned caesarean is undesirable from both individual and societal perspectives, and cesarean delivery is associated with a number of health risks when compared to vaginal delivery (NICE Clinical Guideline CG132, https://www.nice.org.uk/guidance/cg132/). Important questions remain for future work whether subsequent cesarean section may be useful in the long term, among women with mildly symptomatic anal incontinence, or for women with asymptomatic fourth degree obstetric anal sphincter injury.Disclosure of interests: Tähtinen declares honoraria from Olympus. Cartwright declares no conflicts of interest. Completed disclosure of interest forms are available to view online as supporting information.

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.

Objective To examine early and late pregnancy loss in women with and without polycystic ovary syndrome (PCOS) undergoing IVF/ICSI transfers. Design Retrospective cohort study. Setting Reproductive medicine center at a tertiary hospital. Population Records were reviewed for women with a positive β-hCG after IVF/ICSI treatment from May 2014 to April 2019. Methods Odds ratios (ORs) for early (13 ≤weeks) and late (13-24 weeks) pregnancy loss were calculated among women with and without PCOS for plurality of the pregnancy with adjustment for confounding factors. Main outcomes measures Early and late pregnancy loss. Results A total of 21,820 charts identified with a positive β-hCG, 2,357 (10.8%) subjects had PCOS, and 19,463 (89.2%) controls did not. Early pregnancy loss occurred in 12.4% of women with PCOS versus 12.8% in women with non-PCOS. Women with PCOS demonstrated a higher rate of late pregnancy loss (5.4% in PCOS vs 3.1% in non-PCOS, OR 1.79, 95%CI, 1.46-2.19, P<.001), regardless of the plurality of the pregnancy (one gestational sac: 4.1 vs. 2.7 percent, OR 1.56, 95%CI,1.18-2.05; ≥ two gestational sacs: 8.1 vs. 4.1 percent, OR 2.08, 95%CI,1.54-2.82, PCOS vs. Non-PCOS, respectively). Potential negative impact of PCOS was reduced to marginal level once BMI were taken into account (aOR 1.42, 95% CI, .99-2.03). BMI and maternal comorbidities were independently associated with late pregnancy loss (aOR 1.65, 95%CI, 1.26-2.17 and aOR 2.07,95%CI,1.43-3.00). Conclusions PCOS women with overweight and preexisting comorbidities would benefit from lifestyle intervention and close surveillance throughout the whole pregnancy.

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

Having lived through the havoc of COVID-19 in a hospital situated in one of the hardest hit zip codes in the United States, the thought that another wave could loom in the fall is bracing. Obstetricians at our institution have cared for well over 200 COVID-19-infected pregnant women, and are acutely aware of the herculean effort it took to reorganize the service to accommodate the needs of women infected with this new pathogen.1 Many institutions, including ours, modified the frequency of prenatal visits, among other measures, to minimize in-person contacts, in an effort to reduce the likelihood of viral spread. However, it is those changes, along with our prior experience of treating women unimmunized against influenza that leads to our concern that a singular focus on COVID-19 could leave pregnant women at risk from a more familiar threat.While COVID-19 is a threat to the health of individuals and society, its effect on pregnancy is less clear. Thus far, few COVID-19-infected pregnant women have required ICU care, and to date three maternal deaths has been reported in the United States.2-4 The toll of influenza in pregnancy is more clearly documented and is more severe.5Now that the first wave is ebbing in New York, we are seeing fewer and fewer cases but still diagnose about 15 infections per week in our hospital. That pattern is the converse of what is being seen in large swaths of the country. Despite the higher prevalence seen earlier in the epidemic in New York, and the fact that many of those women needed respiratory support, only two women in our hospital required admission to the intensive care unit (ICU), and only one needed ventilator support. Mercifully, none died. During the preceding influenza season, whose end overlapped with the start of the COVID-19 pandemic, we treated six women with influenza who required admission to the ICU, only one of whom had been vaccinated against influenza. As opposed to our COVID-19 cases (putting aside the more rigorous application of social distancing), there were clearly missed opportunities to have prevented some of the morbid events caused by influenza.Admittedly, the higher admission rate to the ICU may be misleading. It is certainly possible that criteria for admission to ICUs, like almost all other aspects of care, evolved during the COVID-19 crisis. There was such a rapid and dramatic increase in the need for ICU beds in our hospital (from a baseline of 40 mid-March, 2020 to a peak of 140 mid-April; 2020, internal data) that more stringent criteria for admission may have been applied and some of our COVID-19 patients that were cared for on the wards, may have been cared for in an ICU in less harrowing times. But even given that possibility, the fact that a similar number of women were extremely ill with influenza raises grave concerns going forward.In the first instance, co-infection with COVID-19 and influenza, as well as other viruses, has been reported.6 Co-infection events will make diagnosis of either entity more difficult, and could potentially increase morbidity. Thus, both because of the risks of co-infection, and the known risks of influenza in pregnancy, providers can’t afford to take their “eye off the ball,” and become less vigilant about vaccinating patients, even if some of the new protocols for fewer visits or telehealth visits remain in place. With fewer visits comes the risk of missing both the vaccination “window” and the opportunity to incorporate vaccination as an essential component of health maintenance. In addition, obstetricians’ performance as vaccinators has been less than ideal as only approximately half of pregnant women get influenza vaccines.7In addition to vaccination, obstetricians must remain vigilant in order to prevent progression of disease among those who get infected. Oseltamivir provides the opportunity for secondary prevention.8 It has been shown to reduce maternal ICU admission and mortality.9 Yet, as with vaccination, even before the COVID-19 epidemic, it was underutilized.10Beyond committing to better use of medical interventions for influenza, obstetricians have to assure that just because they have lived through COVID-19, and the world’s attention remains fixed on COVID-19, they don’t become so COVID-19-focused, that they fail to include influenza in the differential diagnosis of women reporting respiratory symptoms in the fall. Every fever and ache will not be COVID-19. If we delay consideration of the diagnosis of influenza, we will lose the opportunity to use Oseltamivir before the window of eligibility closes. In the post-pandemic world, it will be hard to avoid cognitive biases, such as the availability heuristic (a strategy for making judgments about likelihood of occurrence based on the salience of the information) and confirmation bias (the tendency to gather evidence that confirms preexisting expectations, typically by emphasizing or pursuing supporting evidence while dismissing or failing to seek contradictory evidence). These can result in physicians being hammers and every respiratory symptom, a COVID-19 nail; especially when rapid COVID-19 tests are not uniformly available and don’t yet have uniformly high quality. This is the reverse of one of the most cited examples of the availability heuristic, “In influenza season, it is tempting to consider all patients with fever and myalgias as having influenza.”11 An enhanced situational awareness, i.e., recognizing the influence of recent diagnoses on your diagnostic proclivities, will become an ever more crucial antidote to the hard earned reflex response to fevers and aches that developed during the first wave of COVID-19.We know from history that influenza recurs both in epidemic and pandemic forms, and that an initial wave can be a “herald wave” for the following one.12 Hence, it is our responsibility not to let the current COVID pandemic prevent us from properly dealing with the possibility of overlapping epidemics (seasonal influenza and COVID) in the fall. Vaccination, rapid recourse to antivirals (e.g., Oseltamivir), and community mitigation measures will be more important than ever. COVID-19 can kill, but so can influenza, and if we do our jobs, we can reduce that toll.

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]

The prenatal diagnosis of fetal anomalies started with the development of X-ray. In 1943, Hartley and Burnet, Radiologists in Manchester (J Obstet Gynaecol Brit Empire,1943;50:1-12), reported a series of 11 cases of “croaniolacunia” or lacunar skull, a condition often associated at births with spina bifida or encephalocele. These cases were all diagnosed in the third trimester of pregnancy and the radiograph features believed to be due to the effect of increased intracranial pressure on the fetal skull of hydrocephaly. Until the end of the 1960s, radiography remained the main technique to diagnose congenital abnormalities. In 1969, Russell (J Obstet Gynaecol Br Commonw,1969;76:345-50), also a consultant radiologist from Manchester, compared the accuracy of antenatal radiology examinations with paediatric reports in the diagnosis of anencephaly and other major neural tube defects, skeletal abnormalities such as achondroplasia and severe exomphalos when associated with rib deformities. Overall, the accuracy of the radiological diagnosis was considered as “strikingly” accurate for neural tube defects with 88 out of 113 cases of anencephaly diagnosed before delivery. Although, the author did not provide the gestational age at diagnosis, the images included in the article indicate that these were obtained in the third trimester. As neonatal care and surgery were in their infancy at the time, the main objective in diagnosing these anomalies was not the fetus but the need to identify antenatally mothers at risk of obstructed labour.Not surprisingly, some of the first publications by the team of Ian Donald in Glasgow were on the antenatal use of ultrasound imaging in the evaluation of the size of the fetal head (Willocks et al., J Obstet Gynaecol Br Commonw,1964;71:11-20). The fetal head was the only structure that could be measured and biparietal diameter the only measurement that could be obtained with the “ultrasound beam” of the first ultrasound machine (Figure). The technique called “cephalometry” was used at the end of the third trimester to assess “growth and maturity” of the fetus and “disproportion” and was found to be more reliable with ultrasound than X-ray. It would be another decade, before ultrasound imaging could reliably identify fetal anomalies such as spina-bifida in the second trimester of pregnancy (Campbell et al., Lancet,1975;1(7920):1336-7). However, the use of ultrasound imaging in the mid-seventies to search for major neural tube defects was always triggered by high levels of maternal serum alpha-fetoprotein. As there were few ultrasound equipment available and few trained operators, this biomarker was to remain for two decades the first line of action in the antenatal screening strategy for spina-bifida. The advent of high-resolution imaging, access low-cost and mobile ultrasound equipment and the training of more specialists and sonographers has moved the antenatal screening and diagnosis of many fetal anomalies to 11-14 weeks of gestation (Ushakov et al., UOG,2019;54:740-5).The systematic review by Drukker et al. (BJOG 2020) brings the focus back to late pregnancy: even in our exciting modern era of early anomaly scanning, a fetal abnormality will still be found in about 1 in 300 women scanned in the third trimester.Word count: 500BJOG since 1902 Perspectives on BJOG-20-0525R1

OBJECTIVE: To demonstrate that delayed cord clamping (DCC) is safe in mothers with confirmed SARS-CoV-2 infection. DESIGN, SETTING, AND PARTICIPANTS: Prospective, observational study involving epidemiological information from 403 pregnant women with SARS-CoV-2 between March 1st and May 31st, 2020. Data were collected from 70 centers that participate in the Spanish Registry of COVID-19. MAIN OUTCOMES AND MEASURES: The rate of perinatal transmission of SARS-CoV-2 and development of COVID-19 disease in neonates at day 14 of the delivery. RESULTS: The Early cord clamping (ECC) group consisted of 231 infants (57.3%), whereas the DCC group consisted of 172 infants (42.7%). A total of 5 positive cases (1.7% of total tests performed) were identified with the nasopharyngeal PCR tests, 2 from the ECC group (1.7%) and 3 from the DCC group (3.6%). No significant differences between groups were found regarding neonatal tests for COVID-19. No confirmed cases of vertical transmission were detected. The percentage of mothers who made skin-to-skin contact within the first 24 hours after delivery was significantly higher in the DCC group (84.3% versus 45.9%). Breastfeeding in the immediate postpartum period was also significantly higher in the DCC group (77.3% versus 50.2%). CONCLUSIONS: The results of our study have been similar to early cord clamping practices, no skin-to-skin contact, and suppression or delay of breastfeeding. FUNDING: This study was fully funded with public funds from the Institute of Health Carlos III and co-financed with FEDER funds. KEYWORDS: COVID-19, umbilical cord clamping, skin-to-skin, breastfeeding, vertical transmission, safety.

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

Objective: To assess whether folic acid supplementation ameliorates hot flushes. Design: Double-blind, placebo-controlled randomised trial. Setting: Nine hospitals in England. Population: Postmenopausal women experiencing ≥50 hot flushes weekly. Methods: Women (n=164) were randomly assigned in a 1:1 ratio to receive folic acid 5mg tablet or placebo daily for 12 weeks. Participants recorded frequency and severity of hot flushes in Sloan Diary daily and completed Greene Climacteric and Utian Quality of Life (UQoL) Scales at 4-weekly intervals. Main Outcome Measures: The change in daily Hot Flush Score at week-12 from randomisation based on Sloan Diary Composite Score B calculation. Results: Data of 143 (87%) women was available for the primary outcome. The mean change (SD) in Hot Flush Score at week-12 was -6.98 (10.30) and -4.57 (9.46) for folic acid and placebo group, respectively. The difference between groups in the mean change was -2.41 (95% CI: -5.68, 0.87), p=0.149 and in the adjusted mean change was -2.61 (95% CI: -5.72, 0.49) with p=0.098. There was an increased benefit in the folic acid group regarding changes in total and emotional UQoL scores at week-8 when compared with placebo. The difference in the mean change from baseline was 5.22 (95% CI: 1.16, 9.28) and 1.88 (95% CI: 0.23, 3.52) for total and emotional score, respectively. Conclusions: Folic acid had a greater benefit in reducing Hot Flush Score over 12 weeks in postmenopausal women when compared with placebo; however, the difference did not reach statistical significance. Definitive evidence of benefit requires a larger study.

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.

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.

Objective: To elucidate the correlation between sleep disturbances and blood pressure during pregnancy in women with no pre-existing hypertension. Design: Prospective cohort study. Setting: Outpatient specialist clinics at KK Women’s and Children’s Hospital, Singapore. Population: Women with viable singleton pregnancies confirmed by ultrasonography at less than 14 weeks of amenorrhea at first visit. Methods: 926 subjects were recruited for this study in the outpatient specialist clinics at KK Women’s and Children’s Hospital, Singapore, between September 1, 2010, and August 31, 2014. They were followed up throughout pregnancy with sleep quality, blood pressure and uterine artery doppler assessed at each visit. Main outcome measures: sleep quality, blood pressure and uterine artery doppler. Results: Sleep progressively worsened as pregnancy advances. Shorter sleep duration and poorer sleep efficiency were associated with higher blood pressure, especially in the first trimester. Mixed model analysis demonstrated overall positive correlation between sleep quality represented by Pittsburgh Sleep Quality Index (PSQI) score and diastolic blood pressure (DBP) (p<0.001) and mean arterial pressure (MAP) (p=0.005) during pregnancy after considering all trimesters. Sleep duration was found to be negatively correlated with both systolic blood pressure (SBP) (p=0.029) and DBP (p=0.002) while sleep efficiency is negatively correlated with DBP (p=0.002) only. Overall poor sleep during pregnancy was also found to be correlated to higher uterine artery pulsatility index. Conclusion: Our prospective study demonstrated that sleep quality is significantly correlated with blood pressure during pregnancy with most prominent effect in the first trimester.

Authors’ reply re: ’Maternal transmission of SARS-COV-2 to the neonate, and possible routes for such transmission: A systematic review and critical analysis (Response to BJOG-20-1416)Kate F Walker1, Keelin O’Donoghue2, Nicky Grace3, Jon Dorling4, Jeannette L Comeau4, Wentao Li5 Jim G Thornton11Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham2The Irish Centre for Maternal and Child Health, University College Cork, Cork University Maternity Hospital, Cork, Ireland3 School of English, University of Nottingham4Department of Pediatrics, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada5Department of Obstetrics and Gynaecology, Monash University, Clayton, AustraliaThank you for the opportunity to comment on the letter by Dr Xue from Shanghai Jiao Tong University. We agree there are many weaknesses in the data we reviewed. Dr Xue has identified one. Others are the incomplete reporting of infant feeding and mother-child interactions, and the frequent lack of infant testing to confirm or refute the possibility of vertical transmission of COVID-19. Finally, although we simply provided summary totals, it would be statistically preferable to combine series using the Mantel-Haenszel method and calculate a relative risk. We judged that doing this in light of the uncertainties around the data which Dr Xue has identified, might give a spurious precision to our results. As he says, more work is needed. For now we think it remains reasonable to not regard COVID-19 in itself, as an indication for Caesarean, artificial feeding or separation, in the mother and baby’s interest.

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.