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.

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

In November 2019, section 4.6 of the ondansetron Summary of Product Characteristics (SmPC) was revised by the European Medicines Agency (EMA). It explicitly states, “ondansetron should not be used during the first trimester of pregnancy” (Ondansetron, SmPC[cited 2020 July 08]. Available from: https://www.medicines.org.uk/emc/). Ondansetron is an effective antiemetic drug commonly prescribed as a second-line treatment for severe Nausea and Vomiting of Pregnancy (NVP) (Fiaschi L et al,BJOG 2019;126:1201–11; Oliviera L et al. Obstet Gynecol2014;124:735-42). We do not believe that the underlying evidence supports a strong regulatory discouragement.Tightening of the SmPC on the use during pregnancy follows EMA assessment of two large pharmacoepidemiological studies, each comprising more than 80,000 first trimester pregnancy exposed liveborn children.In a methodologically meticulous pharmacoepidemiological study, Huybrechts et al. studied malformation outcomes among 88,000 liveborn children exposed to ondansetron in the first trimester. Comparing to 1,727,000 unexposed liveborn, they used comprehensive propensity score adjustments for their inferential analysis. Adjusted relative risks were 1.01 (95% CI 0.98-1.05) for any malformation, 0.99 (95% CI 0.93-1.06) for cardiac malformations and 1.24 (95% CI 1.03-1.48) for oral clefts (Huybrechts et al. JAMA 2018;320:2429–37).Subject to substantial academic controversy, Zambelli-Weiner et al. reported data on 82,000 liveborn children exposed to ondansetron in the first trimester (Zambelli-Weiner et al. Reprod Toxicol2019;83:14–20). Overall, they reported a small excess risk of cardiac malformations with an adjusted odds-ratio (aOR) of 1.04 (95% CI 1.00-1.08) and a weak association with orofacial clefts, aOR 1.12 (95% CI: 0.95-1.33). When restricting exposure to about 5,500 women who were administered ondansetron in a hospital setting, the vast majority of which comprised a single intravenous dose, aOR was 1.43 (95% CI 1.28-1.61) for cardiac malformations and 1.30 (95% CI: 0.75-2.25) for orofacial clefts. This study is substantially flawed and we argue it should not be considered when weighing the totality of evidence on the safety of ondansetron in pregnancy due to: 1) strong selection bias 2) poor external validity (the cardiac malformation rate of 3.7% was extraordinarily high among 780,000 unexposed controls) 3) inadequate adjustment for confounders and covariates and, importantly, 4) serious conflict of interest (Schachtman Law. Re: Zambelli-Weiner [cited 2020 July 8]. Available from: http://schachtmanlaw.com/litigation-science-in-re-zambelli-weiner/ )In summary, robust clinical data suggest 1) no overall increased risk of major malformations 2) no increased risk of cardiac malformations 3) a small excess risk of oral clefts corresponding to three additional cases of oral cleft for every 10,000 liveborn children exposed to ondansetron in the first trimester of pregnancy (figure 1).NVP causes significant physical and psychological morbidity to the degree that some women contemplate termination of pregnancy. Denying such patients effective and low-risk treatment is inappropriate. We are confident that women suffering from severe NVP can comprehend the small excess risk of oral clefts in making an informed decision. The statement “ondansetron should never be used in pregnancy” is: 1) misconceived 2) insufficiently substantiated by evidence and 3) not in the best interest of pregnant women.

Letter to the Editor, BJOG Exchange

Objective: To evaluate whether a particular group of women with intrahepatic cholestasis of pregnancy would benefit from treatment with ursodeoxycholic acid. Design: Secondary analysis of the PITCHES trial (ISRCTN91918806). Setting: United Kingdom. Population or Sample: Women with intrahepatic cholestasis of pregnancy. Methods: Subgroup analyses were performed to determine whether baseline bile acid concentrations or baseline itch scores moderated a woman’s response to treatment with ursodeoxycholic acid. Main Outcome Measures: Bile acid concentration and itch score. Results: In women with baseline bile acid concentrations less than 40 μmol/L, treatment with UDCA resulted in increased post-randomisation bile acid concentrations (geometric mean ratio 1.19, 95% CI 1.99 to 1.41, p = 0.048). A test of interaction showed no significance (p = 0.647). A small, clinically insignificant difference was seen in itch response in women with a high baseline itch score (–6.0 mm, 95% CI –11.80 to –0.21, p = 0.042), with a test of interaction not showing significance (p = 0.640). Further subgroup analyses showed no significance. Across all women there was a weak relationship between bile acid concentrations and itch severity. Conclusions: There was no subgroup of women with intrahepatic cholestasis of pregnancy in whom a beneficial effect of treatment with ursodeoxycholic acid on bile acid concentration or itch score could be identified. This confirms that its routine use in women with this condition for improvement of bile acid concentration or itch score should be reconsidered. Funding: NIHR Efficacy and Mechanism Evaluation Programme 12/164/16. Keywords: Cholestasis, Pregnancy, Ursodeoxycholic acid, Perinatal, Stillbirth.

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

Objective To compare rates of vaginal delivery and adverse outcomes of instrumental delivery trials in obstetric theatre compared to primary emergency full dilatation Caesarean section Design Retrospective cohort study Setting University teaching hospital Population Women with singleton, non-anomalous, pregnancy undergoing instrumental delivery trial in obstetric theatre Methods Data was collected from consecutive cases during 2014 until 2018 using clinical records. Multivariate regression analysis was used comparing groups per first delivery attempt. Main Outcome Measures Primary outcome was completion of vaginal delivery between all methods of instrumental delivery. Secondary outcome was a composite of immediate perinatal adverse outcomes for instrumental delivery modes and primary full dilatation Caesarean section. Results From 971 deliveries analysed: ventouse delivery was significantly less likely to achieve vaginal delivery compared to Keilland’s forceps delivery (OR 0.42, 95%CI 0.22-0.79). Once confounding factors were adjusted for, adverse outcome rates were less frequent in the Keilland’s forceps group compared with primary full dilatation Caesarean section (OR 0.37, 95% CI: 0.16-0.81), however the receiver operating characteristic curve produced from this model demonstrated low predictive value (AUC 0.64). Conclusions Attempting instrumental delivery in delivery suite theatre, as an alternative to primary emergency full dilatation Caesarean section, is both reasonable and safe. Ventouse delivery in this situation may be associated with a higher chance of failure than other modes of instrumental delivery, thus making appropriate choice of delivery method of paramount importance according to each clinical situation. Funding None Keywords Caesarean section, Keilland’s forceps, ventouse, trial of instrumental delivery

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

Sir, We read with interests the article by Kate F Walker and colleagues, entitled ”Maternal transmission of SARS-COV-2 to the neonate, and possible routes for such transmission: A systematic review and critical analysis”. In the article, the authors systematically analyzed the mode of delivery on the infection rates of COVID-19 in the newborn. Despite the limitations, especially the retrospective nature of studies examined, this study provided important information about the selection of mode of delivery of women with COVID-19. It suggests that neonatal infection rates are not different after Caesarean birth or vaginal delivery. However, the severity of the COVID-19 infection of the mothers was not considered. Clinically, pregnant women with the more severe COVID-19 infection appear to prefer delivery by Caesarean delivery rather than vaginal birth. Therefore, it is possible that any beneficial effects of Caesarean birth in reducing transmission of COVID-19 might not be apparent because the severity of COVID-19 infection was greater in these women. This selective bias would weaken the conclusions of current studies. We feel that prospective evaluation the safety of mode of delivery with COVID-19 is required.Rui-hong Xue11Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

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

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

We are all likely to need a blood test, a biopsy or wind up on the wrong end of an endoscope. We know that the experience is not going to be pleasant. Many of us will revert to techniques to divert attention away from painful stimuli, such as counting forwards or backwards in our heads, deep breathing, imagining tranquil places or listening to music. But the paper published in this issue of BJOG by (Neo D et al, BJOG 2020; xxxx) shows us how we can distract patients in a more sophisticated way, using virtual reality (VR) technology. The procedure the research groups chose to investigate was outpatient hysteroscopy.Outpatient hysteroscopy is a key part of contemporary gynaecological practice. The procedure is acceptable to the vast majority of women, but most will experience some pain and, in a small proportion of women, this can be severe (Smith P, et al, BJOG 2019;126:891-899). Thus, outpatient hysteroscopy, being common and potentially painful, is a good health technology to evaluate the impact of VR technology on patient experienceDeo N et al, conducted a randomised trial of 40 women undergoing outpatient hysteroscopy for a variety of indications and simple therapeutic procedures were allowed such as biopsy, polypectomy and insertion of a Mirena® device. Women were allocated to standard care or “immersive and interactive video content using a portable, standalone VR headset”. The latter delivered a “guided relaxation experience” which included viewing an 8-minute, narrated video depicting “a calming rainforest and lake setting with animated wildlife, which could be explored by using the “head-tracker”.The preliminary results are impressive. Reduction in peri-procedural pain was statistically significant but more importantly the effect size of a 2cm (20%) difference on a 10cm visual analogue scale must be clinically significant. Reduction in anxiety scores were of a similar magnitude. However, the average hysteroscopy procedure duration was less than 4 minutes, which begs the question, is the cost, time and hassle of setting up and using VR technology worth it? Moreover, 16% of eligible women did not want to use the VR technology because of prior adverse experiences, anxiety or state a preference to see the procedure or use their own distraction media.No-one is going to change clinical practice on a sample of 40, but many practitioners will be energised to conduct larger scale trials to confirm these provisional results and to analyse more deeply the impact of immersive VR technology on reducing pain and anxiety associated with outpatient hysteroscopy. Future work should look at the type of VR technology, the context where it is deployed for what kind of procedure. The optimal VR programme may vary according to patient characteristics, the type of surgery and its duration. VR technology should be tested in more painful gynaecological interventions such as endometrial ablation, cervical biopsy and transvaginal egg collection. Moreover, the prospective benefit of VR need not be restricted to gynaecological practice but should be evaluated in a whole host of ambulatory procedures involving conscious patients.No disclosures: A completed disclosure of interest form is available to view online as supporting information.

Global estimates for 2017 indicated that there were 295,000 maternal deaths, 35 per cent lower than in 2000 with a decline in global maternal mortality ratio from 342 to 211 deaths per 100,000 live births (World Health Organization (WHO) 2019). Maternal hemorrhage is the leading direct cause of maternal death worldwide, representing 27% (20-36) of maternal deaths ( Say L, et al. Lancet 2014).Multiple large retrospective population cohorts have identified risk factors invariably associated with maternal hemorrhage including mode of delivery, prolonged labor, chorioamnionitis, and twins among others (Briley A, et al. BJOG 2014). Factors such as maternal BMI, race or ethnicity, pregnancy induced hypertension, and maternal age have not been consistently associated with increased PPH and require more research, especially given the relationship between maternal obesity, gestational diabetes, pregnancy induced hypertension and PPH.Over 80% of cases of primary PPH are preventable and are due to uterine atony. Active management of the third stage is the gold standard for prevention of PPH. Among women at low risk it is not clear whether active management provides benefit, as with women at mixed risk or at high risk for PPH (RR 0.34, 0.14-0.87) (Begley CM, et.al. Cochrane 2019). The WHO has published evidence-based recommendations for management of PPH and have included use of an effective uterotonic with oxytocin being the preferred agent with alternatives used in specific circumstances when oxytocin is not available (Who, 2018). Most recently, use of tranexamic acid has been introduced for prevention and treatment of PPH with a potential to reduce risk of severe PPH by 50% and maternal death by 20%. (Shakir H, et. al. Lancet 2017). These evidence based interventions have been endorsed by professional organizations and the WHO, and have contributed to a progressive decrease in maternal mortality secondary to hemorrhage.Assessment of risk for hemorrhage incorporates risk factors and appropriate protocols according to risk, implementing preventive measures on an individualized basis. It has been demonstrated that successful implementation requires more than identifying risk factors and their interdependence. Attention to organizational context, involvement of entire health care team, and increased recognition of the role of organizational leadership have been identified as basic components (Main EK, et al. AJOG 2017).In this issue of BJOG, Neary et. al. (BJOG 2020 xxxx) address the important aspect of quality and clinical applicability of risk assessment tools using a structured review that included systematic assessment for bias, sample size and both internal and external validation following a standardized methodology established by PRISMA and CHARMS. The authors concluded that current risk assessment protocols have deficiencies related to general obstetrical applicability and lack of external validation. They recommend development of more broadly applicable and appropriately validated risk assessment protocols that would applicable to the general obstetrical population.Evidenced based risk assessment and corresponding protocols during the antepartum, intrapartum and most importantly immediately after delivery, has the potential of contributing to the prevention of over 80% of maternal deaths attributable to maternal hemorrhage.No disclosures: A completed disclosure of interest form is available to view online as supporting information.

Sir ,We read with great interest the study by Zhou et al.1, where the authors demonstrated a significant association between preconception paternal smoking and birth defects in the offspring. The study is timely given the increasing recognition of the role that paternal factors play in pregnancy outcomes. The authors must be congratulated on performing a large scale, nationwide study, in which a potential link between preconception paternal smoking and birth defects in offspring was made.A salient point discussed by Zhou and colleagues is the difficulty in estimating the effect of paternal smoking as an independent variable on the risk of birth defects due to a myriad of confounding factors. Although the authors had adequately adjusted for maternal biological, environmental and behavioural factors, as well as paternal alcohol consumption, it may be prudent to note that paternal age could be a potentially significant confounder in this relationship.Advanced paternal age has shown robust links with increases in sperm DNA fragmentation.2 DNA damage is attributed to environmental, hormonal and degenerative changes.2Over time, multiple cycles of mitotic replications generate greater stress on the DNA repair mechanisms.2 The failure to control the DNA repair mechanisms invariably amounts to ejaculated spermatozoa containing a higher proportion of abnormal paternal DNA.2 In the same vein, children born to fathers of advanced age are at a slightly increased risk of birth defects including cardiac, respiratory, gastrointestinal tract and musculoskeletal abnormalities.3 It has been speculated that mutations accumulate over repeated spermatogenesis, subsequently increasing the number of birth defects in the offspring.3 At the opposite end of the age spectrum, young paternal age has also been associated with a slight increased risk of selected birth defects.3At large, prenatal smoke exposure has unfavourable effects on pregnancies. Effects of maternal smoking has been comprehensively studied and is associated with fetal and developmental conditions. Harmful substances in tobacco smoke such as nicotine, carbon monoxide and polycyclic aromatic hydrocarbons are able to cross the placenta and negatively affect the fetal development.4 On the other hand, the extent of paternal smoking has not been well-established. Exposure to cigarette smoke has been found to affect sperm parameters, as well as increase sperm chromatin structural abnormalities and DNA damage.5 Infant low birth weight, increased obesity risk in childhood and high blood pressure have been identified as potential complications of paternal smoking.4 This study provides new evidence that birth defects are also complications of paternal smoking.In conclusion, Zhou et al. have accomplished a tremendous job of investigating the effects of paternal smoking on birth defects. The current study has laid the groundwork for future research to be built upon and to elucidate the true effects of paternal smoking during pregnancy. As exposure to first or second-hand smoke poses a major risk to pregnancies, it might be worthwhile to recommend smoking cessation in both parents during preconception counselling.Jania J. Y. Wu1, Kyla Ng Yin2, Keng Siang Lee3, John J. Y. Zhang11Yong Loo Lin School of Medicine, National University of Singapore, Singapore2Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK3Bristol Medical School, Faculty of Health Sciences, University of Bristol, Bristol, UK

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

Objective: To investigate hair cortisol concentrations (HCC) monthly in pregnant women and to explore the effect of parity. Design: Prospective cohort study from gestational week (GW) 26, at childbirth and postpartum. Setting: An antenatal care clinic in southeast Sweden. Sample: 390 pregnant women. Methods: Cortisol was measured using radioimmunoassay in methanol extracts of ground hair samples. Main outcome measures: Hair cortisol concentrations Results: Both primi- and multiparae exhibited an increase in HCC throughout pregnancy. Primiparae had significantly higher HCC in the latter part of the last trimester compared to multiparae (one month p=0.003 and two months p=0.038). The use of psychotropic medication in the first trimester correlated to HCC postpartum (p<0.001). HCC in GW 14-17 were associated with HCC in GWs 18-21 (primiparae and multiparae, p<0.001), GW 22-25 (primiparae p=0.036 and multiparae p=0.033), and two months postpartum (primiparae p=0.049). HCC in GW 18-21 was associated with GW 22-25 among both primiparae (p<0.001) and multiparae (p<0.001) as well as two months prior to childbirth among primiparae (<0.037). In general, all estimates of HCC in pregnancy and postpartum showed a significant association between HCC for a specific month and the HCC in the previous month (all p<0.001), except for the association of HCC among primiparae in GW 22-25 and three months prior to childbirth. Conclusions: Increased cortisol concentrations in hair were observed during pregnancy, which decreased three months prior to childbirth in multiparae. The results indicate a quicker suppression of the hypothalamic CRH production by placenta CRH in multiparous women.

Effective Cervical screening involves a complex sequence of interactions between women, clinical staff and systems. Even in well organised screening programmes, achieving high population coverage is challenging. The transition to using Human Papilloma Virus (HPV) testing as the primary screening modality, rather than cytology, has introduced the possibility of using a self-collected sample for the primary HPV test. This has been shown to be a reliable method of detecting CIN2+ (Polman et al, Lancet Oncology 2019;20(2):229-38).Regardless of the way the sample is collected, the low specificity of a positive HPV test means that positive results must be triaged. In all cases where self-sampling has been integrated into a cervical screening programme to date, this triage is by cytology on a subsequent, clinician taken sample. Other molecular tests which can be performed on the original sample may in the future be an alternative, but are not yet fully evaluated.It has generally been assumed that a self-collected sample would not be suitable for cytology because the cervix is unlikely to be thoroughly (if at all) sampled.However, the authors have shown that using a well-established self-sampling device, 95.8% samples had at least 5000 cells, the usual threshold for adequacy for cytology. (ThinPrep LBC method). Results were highly specific, and in fact the positive predictive value (PPV) for high grade disease was higher on the self-collected specimens than on the subsequent professionally taken samples (Loopik et al. BJOG 2020 xxxx).As expected, the sensitivity of the test was lower than for a professionally taken sample, but it still detected 29.4 % of CIN2+. In this study, an impressive 91.9% of women returned for their reflex cytology test. This is higher than in other studies, possibly because the study was not focussed on women who have previously not responded to invitation.It is likely that a significant proportion of women needing treatment could be reliably identified by self-sampling alone by this method.It is worth noting that despite implementation in several organised screening programmes, self-sampling tests for HPV have yet to achieve regulatory approval, and the process for doing so for cytology from self-collected samples is likely to require studies with more extended monitoring of clinical outcomes.Self-sampling is not yet widely implemented internationally and the pathways can be challenging. There is a concern about how to address loss to follow up, design of multistep pathways for management, and potential delays in diagnosis. A pathway which could reliably prioritise women for referral for immediate colposcopy, with a high PPV for CIN2+, without requiring a face to face clinical interaction would be extremely valuable. This is potentially even more topical in the post COVID-19 world where there are new challenges in risks of consultations and in capacity of health care delivery.No disclosures: A completed disclosure of interest form is available to view online as supporting information.

The development of clear approaches to the assessment, resuscitation, treatment and monitoring of the four case scenarios are presented as algorithms, based on available evidence. They need to be field tested, and adapted for Artificial intelligence and different settings. Further research is needed around multimodal sequential care package of care for PPH, conservative surgical measures, resuscitation in LMICs, and the psychological impact of PPH on women.