Mini-commentary on BJOG-20-1008.R1: Cranial findings detected by second trimester ultrasound in fetuses with myelomeningocele: a systematic review

Mini-commentary on BJOG-20-0442.R2: Impact of hysterectomy on analgesic, psychoactive and neuroactive drug use in women with endometriosis: nationwide cohort study

The American obstetrician, Joseph DeLee, ‘father of modern obstetrics’, founded the Chicago Lying-in Hospital in 1931 with his vision for womens’ health captured in a set of five stone plaques at the top of the cloister of the hospital’s building. Four of the five stone plaques are engraved with the names of pioneering clinicians whose contributions to the field of obstetrics and gynaecology have been seminal: Jan Palfyn (1650-1730), for introducing the obstetric forceps in the 1720s, Hendrik Van Deventer (1651-1724), for discovering obstetric anatomical disorders, William Smellie (1697-1763), for improving the design of the forceps, and Eduardo Porro (1842 –1902), for introducing hysterectomy to stop postpartum haemorrhage. The fifth stone plaque, in the centre, which is still blank today, is reserved for the physician/scientist who discovers the cause and cure of preeclampsia according to legend.That clusters of preeclamsia occur in family units prompted the question whether preecclampsia is an inherited disorder, and if so, what is the mode of inheritance? Familial clustering opened the possibility of deploying genome wide association studies (GWAS) for the identification of candidate genes and susceptibility loci for the development of preeclampsia and researchers have focused on this question since the discovery of DNA. However, till date, there has been no clearly defined causal relationship between a preeclampsia genotype and phenotype except for heterozygous women who are pregnant with long-chain hydroxyacyl-CoA dehydrogenase deficient fetus who have nearly 80% chance of developing HELLP syndrome or acute fatty liver of pregnancy. Defining the genetics and mode of inheritance of preeclampsia is challenged in part by the involvement of two genomes (maternal and fetal), and a wide spectrum of women who meet the diagnostic criteria according to the International Society for the Study of Hypertension in Pregnancy.There is persuasive literature that coexisting maternal medical disorders such as diabetes, chronic hypertension, renal disease, autoimmune disease, antiphospholipid antibody syndrome and other maternal-fetal risk factors including obesity, dyslipidemia, nulliparity, previous/family history of preeclampsia, and multifetal gestation, increase the risk of preeclampsia. In this issue of the Journal, Gray and colleagues (BJOG 2020 xxxx) used single nucleotide polymorphisms (SNPs) for 21 distinct clinical traits for increased risk of preeclampsia within 7 categories (cardiovascular, inflammatory/ autoimmune, insulin resistance, liver, obesity, renal, and thrombophilia) from the European GWAS to test the hypothesis that women with genetic predisposition to these disorders would have increased risk of preeclampsia in a case/control sample of data from the largest known US preeclampsia GWAS. The authors’ findings that; a) risk alleles for raised diastolic blood pressure and increased BMI were strongly associated with preeclampsia risk (more so for the early-onset disease variant), b) risk alleles for raised alkaline phosphatase levels, increased HDL, GFR, and venous thromboembolism were protective, and c) no significant associations for the other traits examined, are consistent with the current status of preeclampsia and HELLP as highly complex disorders with variable clinical presentations depending on pre-pregnancy maternal conditions, fetal/placental genotypes, and maternal adaptation to the challenge of pregnancy.So, preeclampsia is far from a Mendelian inherited type of genetic disease and the search for its cause and cure continues 90 years after DeLee’s vision!Conflict of interest: None. A completed disclosure of interest form is available to view online as supporting information.

Letter to the Editor, BJOG Exchange

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

Debate: The placenta is the villain or victim in the pathogenesis of preeclampsia.

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 7939360357nandita.deo@gmail.com1. 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 tarekeltoukhy@hotmail.com

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