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