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

Dear Sir We congratulate Dr Guy and colleagues on their paper1which demonstrates that implementation of combined screening using the FMF algorithm2 is feasible in practice and is better than the existing NICE guidelines in prevention of preeclampsia, especially preterm preeclampsia with delivery before 34 weeks. We hope that this will lead to wider application of combined screening for prediction and prevention of preeclampsia.The authors acknowledge that treatment with aspirin will have led to underestimation of screening performance. We would like to highlight this and emphasise the importance of accounting for the effect of aspirin when assessing predictive performance. To make the point, consider the most extreme case with 100% compliance with a treatment that prevents 100% of cases. In the screen positive group, all cases would be prevented by the treatment and classified as false positives. Adopting the same analysis presented in this paper would result in a detection rate and positive predictive value of zero regardless of performance without treatment.In the data presented in this study, for the FMF algorithm with 99% compliance to aspirin at a dose of 150 mg / day and assuming 62% reduction in risk,3 99%×62% = 61.4% of cases of preterm preeclampsia would be prevented and classed as false positives. The remaining 100-61.4% = 38.6% would be classed as true positives so the 15 cases of preterm preeclampsia which led to the detection rate of 15/27 = 55.6% represent just 38.6% of the cases of preterm preeclampsia detected. An estimate of the number detected, including those prevented by aspirin is, 15/0.386 = 39. The estimated number of cases in total is therefore 39 + 12 = 51, obtained by adding the false negatives 27-15 = 12 to the estimated true positives. This gives a detection rate of 39/51 = 76% compared to the figure of 55.6% given in Table 2. Applying similar calculations to the positive predictive value (i.e. proportion of women in the screen positive group who would, without aspirin, have developed preterm preeclampsia) of 9.8%. This should be compared with the 3.8% presented in the paper. Applying the same arithmetic to the NICE group gives a detection rate of 41.6% and a positive predictive value of 2.4%. These are much closer to the figures in Table 2 of the paper because of the relatively low compliance in the NICE group. Other measures of screening performance presented on this paper including the likelihood ratios, negative predictive value the receiver operating characteristic (ROC) curve analysis are also affected by this problem.The arithmetic presented above is intended for illustration; for the SPREE study4 we applied Markov chain monte carlo (MCMC) methods for inferences about screening performance. These or similar methods should be applied in future studies of screening performance.Dave Wright,1 Kypros Nicolaides2Institute of Health Research, University of Exeter, Exeter, UKHarris Birthright Research Centre for Fetal Medicine, King’s College Hospital, London, UK.

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

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

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

Minimally invasive surgery has been widely adopted in gynaecologic oncology with a significant surge the past decade associated with the introduction of robot-assisted surgery. Up until 2018, virtually all testimonials of minimally invasive surgery for cervical cancer indicated equal oncologic outcomes compared to laparotomy. The unexpected results from the only randomised controlled trial (Ramirez PT et al, N Engl J Med, 2018;379:1895-1904) seriously challenge the use of minimally invasive surgery for cervical cancer. However, the lack of plausible explanations for the inferior survival has made it hard for many gynaecologic oncologists to accept the results at face value. Suggested causes such as the use of intrauterine manipulators and intracorporeal colpotomy may to some extent account for the detrimental outcomes but as practice differs widely worldwide, none of these factors seem convincing. In the current paper by Baeten et al, a different aspect of novel surgical technologies has been explored (BJOG 2020 xxxx). The adoption of any new modality/technology is clearly associated with a learning curve and it is well known from surgery that procedural outcomes such as operative time improves with increasing case numbers. However, the potential impact of learning curve on “hard outcomes” such as survival has scarcely been reported before. Baeten et al convincingly demonstrate that a substantial number of robot-assisted radical hysterectomies is required to overcome an initial harm. The authors point out that the learning curve should be considered institutional; suggesting that an individual learning-curve may benefit from previous experiences at the specific institution. Intriguingly, similar data has not been presented for endometrial cancer which may be related to the higher complexity of radical hysterectomy for cervical cancer. Although no specific changes were made over time in the current study, a learning curve may include modifications of surgical routines based on early experiences. Which specific improvements during the learning-curve that accounts for the increased survival is unclear but reducing complications that could delay adjuvant treatment may be one. The data presented by Baeten et al signifies a solid effort to elucidate the underlying cause of the outcomes from the LACC-trial, especially since the trial was launched at a time when most surgeons had limited experience from laparoscopic/robotic radical hysterectomy. The study should raise the awareness of surgical learning curve in the context of survival in oncologic surgery. It also brings us to the most important question – how do we avoid harming our patients when novel technologies are adopted? The authors suggest that centralisation and structured training represents two of the most important strategies to mitigate the effects of early errors. Interestingly, recent population-based studies from countries with high levels of centralisation do not corroborate the findings from the LACC-trial (Alfonzo E et al, Eur J Cancer, 2019;29:1072-1076, Jensen et al, Eur J Cancer 2020;128:47-56). Although the current study may reopen the door for robotic surgery in the management of cervical cancer, prospective randomised trials are needed to ensure its safety. The impact of surgical learning curve should be considered in any future trial exploring oncologic safety for procedural interventions.Conflict of interest: H.F is a proctor for Intuitive Surgical Inc. A completed disclosure of interest form is available to view online as supporting information.

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.

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.