Mini-commentary on BJOG-19-1802.R1 & BJOG-19-1803.R1Title: To be decodedZarko Alfirevic,Department of Women’s and Children’s Health, University of LiverpoolSimon GatesCancer Research UK Clinical Trials Unit, University of BirminghamEmail contact: Zarko Alfirevic, Zarko@liverpool.ac.ukRandomised trials remain gold standard for evaluation of effectiveness of medical interventions. However, they are expensive, time consuming and demand huge efforts from participants, researchers and clinical services that facilitate them. Even when trials are successfully completed, peer reviewers often find them wanting. One of the most common criticisms is a ‘lack of power’ to tackle clinically important outcomes. Why is this happening time and again?When an important clinical question creates an equipoise, trialists are faced with difficult choices. If they design a trial to tackle the most important (often rare) outcomes aiming to detect modest, but plausible, risk reductions from a proposed intervention, such studies are rarely feasible and very expensive forcing most funders to simply walk away. Common ‘remedies’ are to change the outcome to something more common and less important (often composite), or to propose an unrealistic risk reduction, sometimes in excess of 50%. Trials of magnesium sulphate for neuroprotection included in the seminal Cochrane review (Doyle LW et al. DOI: 10.1002/14651858.CD004661.pub3) that triggered changes in numerous guidelines world-wide were not an exception (Table 1).Cerebral palsy is a rare, but devastating complication of prematurity and even a very modest reduction would, surely, be worth detecting. The problem is that even in the most ‘at risk’ groups, the incidence of cerebral palsy will not exceed 10%. A conventional sample size calculation estimates that to detect a ‘massive’ 25% risk reduction in cerebral palsy, in excess of 5,000 women would have to be randomised.Interestingly, such a priori sample size calculations are not a feature of most published meta-analyses. Step forward Trial Sequential Analysis (TSA). The TSA is a deceptively simple concept; meta-analysis sample size needs to be increased to allow not only for the heterogeneity of included studies, but also for repeated testing when meta-analyses are being updated and therefore subjected to repeated significance testing. Interested readers can find out more from the Copenhagen Trial Unit’s website - vocal proponents of this methodology (www.ctu.dk/tsa).In their two sister papers, Wolf et al have, quite ingeniously, used TSA to determine the size of their randomised trial and, by doing so, avoided the risk of their randomised trial and updated meta analysis being criticised as ‘underpowered’ (Wolf H et al. BJOG 2020 xxxx (RCT); Wolf H et al. (BJOG 2020 xxxx (SR & MA). Could this concept be a methodological ‘game changer’ in perinatal trials?The concept of TSA has been widely criticised, and a Cochrane Collaboration expert panel recommended against its use (https://methods.cochrane.org/sites/default/files/public/uploads/tsa_expert_panel_guidance_and_recommendation_final.pdf). Key criticisms are, first, that decision-makers require a summary of the currently available evidence and this should not depend on past and future updates. Second, TSA focuses only on statistical significance. Interpretation of meta-analysis should be based on the estimates of the treatment effect and its uncertainty, rather than whether an arbitrary significance threshold is passed. Third, the ways that evidence accumulates in systematic reviews and individual trials are fundamentally different. Review updates are not equivalent to trial interim analyses; updates are not pre-planned and their number cannot be determined in advance. Furthermore, reviews address multiple clinically-relevant effects on several outcomes or subgroup analyses, which need to be integrated into an overall conclusion. The Cochrane expert panel concluded: “Any sequential adjustment procedure is necessarily based on a particular instance of the evolution of evidence that applies to a limited context and cannot satisfy the requirements of all decision makers.”Table 1. Key features of randomised trials of MgSO4given to pregnant women for prevention of cerebral palsy in infants born preterm
Objective. To externally validate five approaches to predict ectopic pregnancy (EP) in pregnancies of unknown location (PUL): the M6P and M6NP risk models, the two-step triage strategy (2ST, which incorporates M6P), the M4 risk model, and beta human chorionic gonadotropin ratio cut-offs (BhCG-RC). Design. Secondary analysis of a prospective cohort study.Setting. Eight UK early pregnancy assessment units.Population. Women presenting with a PUL and BhCG >25 IU/L.Methods. Women were managed using the 2ST protocol: PUL were classified as low risk of EP if presenting progesterone ≤2 nmol/L; the remaining cases returned two days later for triage based on M6P. EP risk ≥5% was used to classify PUL as high risk. Missing values were imputed, and predictions for the five approaches were calculated post hoc. We meta-analysed centre-specific results. Main outcome measures. Discrimination, calibration and clinical utility (decision curve analysis) for predicting EP.Results. Of 2899 eligible women, the primary analysis excluded 297 (10%) women who were lost to follow-up. The area under the ROC curve for EP was 0.89 (95% confidence interval 0.86-0.91) for M6P, 0.88 (0.86-0.90) for 2ST, 0.86 (0.83-0.88) for M6NP, and 0.82 (0.78-0.85) for M4. Sensitivities for EP were 96% (M6P), 94% (2ST), 92% (N6NP), 80% (M4), and 58% (BhCG-RC); false positive rates were 35%, 33%, 39%, 24%, and 13%. M6P and 2ST had the best clinical utility and good overall calibration, with modest variability between centres.Conclusions. 2ST and M6P performed best to predict and triage PUL.Funding. Research Foundation – Flanders (FWO; G0B4716N), Internal Funds KU Leuven (C24/15/037), NIHR Collaboration for Leadership in Applied Health Research & Care, NorthWest London (RDIP033), NIHR Biomedical Research Centre based at Imperial College Healthcare NHS Trust. Keywords Pregnancy of unknown location, ectopic pregnancy, beta human chorionic gonadotrophin (BhCG) ratio, progesterone, prediction model, prediction model validation
Specific therapies in pregnant women are discussedThe health crisis caused by the novel SARS-cov-2 (2019-nCoV) related pandemic requires urgent and necessary therapeutic response. Pregnant women are just as exposed as the general population and should not be excluded, because of their status, from discussions on effective and well tolerated candidate treatments. While in countries that have opted for national containment, daily non-emergency medical and surgical activities are suspended, obstetric services continue to operate relentlessly and are experiencing a surge in so-called ”at-risk” pregnancies. Some countries have now recommended routine screening of all pregnant women 1 but the low availability and performance of the current tests limits their use. Management of an infected pregnant women is essentially conditioned by maternal symptomatology. Women with little or no symptoms do not require routine treatment or in-patient care and simply need to be monitored for up to 15 days for evidence of respiratory deterioration. In the absence of validated specific treatment, the primary approach to therapy is mainly symptomatic and delivery is considered in the event of critical respiratory distress in order to maximize oxygenation and lung capacity2–4 . However, it has been reported that women with respiratory signs may be given antiviral treatment to improve their clinical condition 2,4To date, there is no proven effective strategy, although many teams are working tirelessly to identify an effective treatment. Four molecules are leading in this race:1) Remdesivir is a novel nucleotide analogue prodrug which incorporates into nascent viral RNA chains and results in pre-mature termination. Its effectiveness has been already demonstrated against others coronaviruses such as SARS-Cov and MERS-Cov5, and it has proven to be highly effective on in vitro 2019-nCoV infection6. Compassionate use in human were also reported 7 and phase 3 studies are currently underway.2) (Hydroxy)chloroquine has been known for years because of its effectiveness in the treatment of inflammatory diseases and against malaria. Recent studies have shown antiviral effects of chloroquine and in vitro studies concluded that it was highly effective in the control of 2019-nCoV 6,8. Elevation of endosomal pH and interference with terminal glycosylation of the cellular receptor, angiotensin-converting enzyme 2 conduct to block virus infection. (Hydroxy)chloroquine has been used in 2019-nCoV infected humans with highly controversial restuls9,10 and well-designed randomized studies should be available soon.3) Lopinavir, a viral protease inhibitor, with its pharmacological booster Ritonavir (LPV/R) are commonly used in HIV positive patients. It has already been used for SARS-Cov. Some countries such as China and India approved its use in symptomatic infected patients although a first randomized, controlled, open-label trial showed no benefit of LPV/R over standard care in patients with severe 2019-nCoV disease11.4) Ribavirin, is a guanosine analog that interferes with the replication of RNA and DNA viruses. It has been used for years in the treatment of chronic hepatitis C. Based on its direct anti‐viral activity against 2019‐nCoV in vitro and some evidence for its potential efficacity during the prior SARS-Cov and MERS-Cov outbreaks, it has been suggested as a potential candidate for the treatment of 2019-nCoV diease12. 2019-nCoV infected patients treated with Ribavirin have been reported by Chinese studies4,13but its exact benefit remains to be demonstrated in well designed randomized studies as well.To date, all four drugs are being independently tested in Phase 3 studies, mostly national, to investigate their efficacy and safety in the management of 2019-nCoV disease. Several European countries have also set up, as a result of joint efforts since mid-March, a randomized, multicentre, open-label trial to evaluate and compare the efficacy and toxicity of the first three treatments mentioned above.14With regard to the possibility of treating pregnant patients with these molecules, few data are available for Remdesivir. Only one study reports its use in six pregnant women in a randomized trial during Ebola epidemics. The authors reported no adverse effect15.Many more pharmacological studies on maternal-fetal tolerance of Hydroxy(chloroquine), Lopinavir and Ribavirin are available. The historical use of (hydroxy)chloroquine in antimalarial treatment, but also in connective tissue diseases, has resulted in a well-documented safety and tolerance profile in pregnant women16. Animal studies, undertaken during the Zika virus epidemic, have also suggested that chloroquine may also reduce the risk of viral transplacental transmission to the fetus17. The optimal dosage to be used in pregnant women will have to be specified, but it appears that there is no pharmacokinetic difference between chloroquine and its major metabolite between pregnant and non-pregnant women18. With respect to the use of protease inhibitors during pregnancy, such as Lopinavir, some teams have reported an increased risk of preterm delivery. However, a specific analysis of more than 4,000 pregnant women found a similar incidence and rate of adverse pregnancy outcomes than in controls at all three trimesters of pregnancy, including preterm birth, low birth weight and birth defects19. Significant teratogenic effects have been demonstrated in all animal species exposed to Ribavirin, it is therefore currently contraindicated in pregnant women and in their male sexual partners, although the ribavirin pregnancy registry did not bring evidence of teratogenicity in humans20.The use of antiviral therapy in infected pregnant patients should follow the same indication as in the general population, but some obstetric specificities should be emphasized.1) The main goal should be to slow down and at best stop the clinical progression of the disease, i.e to remain asymptomatic and to avoid progression to acute respiratory distress syndrome in symptomatic cases. In the latter, the obstetrician is often called on to perform an emergency delivery and thus to induce extreme prematurity. Expert consensus provided obstetric guidance, but the management of cases at between 25 and 32 weeks’ remains challenging in the absence of effective antiviral treatment1.2) The second objective would be to rapidly decrease viral load and duration of contagiousness in infected pregnant women. The majority of them are doing well, but the infection can disrupt their obstetrical calendar. Some procedures need to be performed at a specific age, such as first trimester serum markers, ultrasound examinations, chorionic villi sampling (CVS). The same applies to access to termination of pregnancy. All such procedures may indeed be delayed, either to limit contagion, to limit the burden on the health care team (due to reinforced barrier measures…) or in the particular case of CVS/amniocentesis, to limit the theoretical risk of fetal transmission.3) Finally, the third advantage could be to introduce preventive treatment in case of maternal contact with an infected person, similar to what is done for seasonal influenza and oseltamivir21.The use of immunotherapy such as Tocilizumab, plasma of recovered coronavirus patient, Interferons, were not discussed here as they are currently understudy only for critically ill COVID-19 patients. No place for these treatments in a patient who is still pregnant should be considered for the time being, since if the pregnant woman presents a very severe form, the birth will be considered as a priority.The results of the Phase 3 therapeutic studies should be available soon. However, it is unfortunate that infected pregnant women are not included in any appropriate research protocols. Consequently, in this period of pandemic, mutual exchanges of experience between all countries’ maternity hospitals must be carried out in order to ensure the best possible management of infected pregnant women.
Objectives: To investigate the mental status of pregnant women and to describe their obstetrical choices during the outbreak of COVID-19. Design: A cross-sectional study. Setting: Wuhan and Chongqing, two different epidemic areas. Population: A total of 1947 valid questionnaires were received. Methods: We collected information on demographic, pregnancy, and epidemic, along with their attitudes towards the epidemic, anxiety status and obstetrical choices. We described and compared the city-based distribution of all above factors, aiming to explain how anxiety and obstetrical choices existed and differed. Main Outcome Measures: To explore why differences existed, we estimated the impact of the epidemic on women’s anxiety by multivariable analysis. Results: Distribution differences could be seen between cities in employment status, household income, gestational age, fetal number, and exposure history. Women’s attitudes towards COVID-19 in Wuhan were more extreme than that in Chongqing. The anxiety rate was more than double in Wuhan (24.47%) compared to that in Chongqing (10.44%). Generally speaking, obstetrical choices were similar among the 1947 participants, but more obvious in Wuhan. Conclusions: Our study found that the outbreak aggravated prenatal anxiety, and the influence factors could be targets of mental care. Synchronously, vital obstetrical choices changed, followed by pertinent professional advice to prevent irreversible adverse pregnancy outcomes. Online platforms may play crucial roles to address patients’ needs in future PHEs. Funding: National Natural Science Foundation of China (No. 81771614 and No. 81771613), and the National Key Research and Development Program of China (No. 2016YFC1000407). Keywords: COVID-19; Pregnancy; Prenatal Anxiety; Obstetrical Choices.
Dear Editor,We read the letter from colleagues Dr. Seedat and Dr. Marshall, commenting on our article, with great interest (1, 2). Their clarifications on the UK National Screening Committee (UK NSC) position are very clear. The UK NSC decided against a general screening since they cannot assess the benefits and harms in the patient populations of women (3) but they could indeed in newborns. The on-going clinical trial (GBS3 Trial; ISRCTN49639731) in the UK will compare the current risk-based strategy to two different screening tests. A lab based culture test at 3 to 5 weeks before anticipated delivery date will use an established microbiological technique [Enriched Culture Medium Testing] to reduce false-negative results and a molecular point of care test at the onset of labour. The latter test reduces the time period between screening and the start of labour. The predictive value of antenatal GBS cultures decreases if the interval between culture and delivery is longer than 5 weeks. The results of the trial will help to determine the appropriate screening technique and the rational use of antibiotics for the prevention of early onset GBS sepsis in newborn babies.Perinatal empirical therapy of newborns at risk for or with suspected EOS represents the main contributor to the use of antibiotics in early life (4). There is growing concern about the effects that unnecessary exposure to antibiotics in the perinatal period may have on the future health of these children (5, 6). Antibiotic-related alterations in the microbiome may have downstream effects on the developing immune system and may increase the risk of allergic, autoimmune, and metabolic diseases (5, 6).Seedat and Marshall state that according to another study, the use of IAP would indeed increase if screening were implemented, and that the portion of women receiving IAP would be ‘low risk women’ who… ‘would not have a neonate with EOGBS in the absence of IAP’ (1). In this statement is embedded the assumption that the currently established risk factors are indeed a good prediction of EOGBS transmission. However, 50% of neonates with early onset sepsis with GBS did not have risk factors. To the contrary, we confirm in our meta-analysis and systematic review that universal screening lowered the incidence of early onset GBS sepsis in newborn whereas risk-based approaches did not (2). This might indicate that although screening is imperfect, risk factors might be worse in predicting EOGBS outcomes.Besides, we found no evidence that the rate of intrapartum antibiotic treatment was different in risk-based screening than in universal screening. Administration of antibiotics in risk-based policies was in our study neither lower nor associated with a reduction in the burden of disease in early onset GBS sepsis (2). We are looking forward to the results of the GBS3 trial since there is a need for unbiased evidence on the appropriate policy. A trial comparing screening with risk-factor based intrapartum antibiotic prophylaxis is hard to conduct in areas that currently have a screening policy. Recruitment of participants is very challenging and a premature stop for futility is very likely. A lot of women might not want a risk-based protocol if screening is already the standard of care or easily available. Therefore, the UK data will be very helpful in guiding the future way.References1. Seedat F, Marshall J. Re: Universal screening versus risk-based protocols for antibiotic prophylaxis during childbirth to prevent early-onset Group B streptococcal disease: A systematic review and meta-analysis. (First comment letter. Reference to be added). BJOG. 2020.2. Hasperhoven GF, Al-Nasiry S, Bekker V, Villamor E, Kramer B. Universal screening versus risk-based protocols for antibiotic prophylaxis during childbirth to prevent early-onset Group B streptococcal disease: a systematic review and meta-analysis. BJOG. 2020. https://doi.org/10.1111/1471-0528.160853. Seedat F, Geppert J, Stinton C, Patterson J, Freeman K, Johnson SA, et al. Universal antenatal screening for group B streptococcus may cause more harm than good. BMJ. 2019;364:l463.4. Achten NB, Klingenberg C, Benitz WE, Stocker M, Schlapbach LJ, Giannoni E, et al. Association of Use of the Neonatal Early-Onset Sepsis Calculator With Reduction in Antibiotic Therapy and Safety: A Systematic Review and Meta-analysis. JAMA Pediatr. 2019.5. Cotten CM. Adverse consequences of neonatal antibiotic exposure. Curr Opin Pediatr. 2016;28(2):141-9.6. Esaiassen E, Fjalstad JW, Juvet LK, van den Anker JN, Klingenberg C. Antibiotic exposure in neonates and early adverse outcomes: a systematic review and meta-analysis. J Antimicrob Chemother. 2017;72(7):1858-70.
Dear Editor,Thank you for the opportunity to respond to Dr Sahu’s letter1. We would like to thank Dr Sahu and his team for their valuable points and ourselves recognise and acknowledge the gaps in our early commentary2 which reflected on the early practice at our hospital, with an aim to help fellow obstetricians with the management of COVID-19 at the start of the outbreak. Since then, more literature has been published providing us with greater knowledge regarding this new infection. Guidance from the Royal College of Obstetricians and Gynaecologists (RCOG)3 and International Society of Ultrasound in Obstetrics and Gynaecology (ISUOG)4 amongst others help us streamline management of COVID-19 in pregnant patients.Both guidelines concur that radiographic investigations should be performed in pregnant patients – protecting the fetus by using a radiation shield over the gravid uterus. Chest CT has high sensitivity up to 97% for diagnosis of COVID-19 and may be considered as primary tool for COVID-19 detection.Both guidelines recommend the use of antenatal corticosteroids (ANC) for the usual indications but cautions use in critically ill women with COVID-19 infection as it may worsen their clinical condition. Importantly, urgent deliveries should not be delayed for the administration of ANC.Li et al5 compared clinical characteristics, maternal and neonatal outcomes of pregnant women with and without COVID-19. They found that COVID-19 infection generally causes mild respiratory symptoms in pregnant women, with no deaths or severe respiratory complications requiring critical care. They observed a higher rate of preterm deliveries in confirmed cases (33.3%) compared to control groups (¬5%). This study included two patients who had vaginal deliveries prior to COVID-19 diagnosis. Their newborns did not show any respiratory symptoms.New reports of SARS-COV-2 IgM in infants6 at birth suggest possibility of vertical transmission although COVID-19 infection in newborns is more commonly likely due to neonatal transmission.During breastfeeding, the main risk for infants lies in their close contact with mothers and transmission of infective respiratory droplets. Infected mothers wishing to breastfeed should do so with precautions such as wearing surgical masks, practising good hand hygiene and thorough cleaning of equipment after use. While the decision for separation of mother and baby has serious consequences on bonding and mental health, we continue to advise separation of baby from mothers infected with COVID-19 due to risk of neonatal transmission.Current data suggests that the adverse effects of COVID-19 in pregnancy are less severe than those of SARS-CoV and MERS-CoV. All presently reported patients were diagnosed in the third trimester and the potential effects of COVID-19 infections in the first and second trimesters remain to be investigated.As Dr Sahu mentioned, comparative studies are scarce. Establishment of international registries will improve our understanding of COVID-19 in pregnancy. Meanwhile, we shall continue to support one another and work together in the fight against this pandemic.We would like to thank the all departments from the Division of Obstetrics and Gynaecology, Infectious Diseases Department and all staff in KK Womens’ and Children’s Hospital for leading the COVID-19 fight locally.Monica Shi Qi Chua1, Jill Cheng Sim Lee2, Suzanna Sulaiman1, Hak Koon Tan31Department of Obstetrics and Gynaecology,2Department of Urogynaecology,3Division of Obstetrics and GynaecologyKK Women’s and Children’s Hospital, Singapore
Background: Maternal levels of angiogenic factors are promising prognostic parameters in patients with suspected preeclampsia, but in women with confirmed preeclampsia this performance has been less explored. Objective: To assess in women with early-onset severe preeclampsia whether longitudinal changes in angiogenic factors improve the prediction of adverse outcome. Study design: A cohort was created of consecutive women admitted for early-onset severe preeclampsia with no indication for immediate delivery. Levels of placental growth factor [PlGF], soluble fms-like tyrosine kinase [sFlt-1] and sFlt-1/PlGF ratio were measured at admission and before delivery; and average daily change was calculated. The association of longitudinal changes of angiogenic factors with maternal complications and with the time interval to delivery was evaluated by logistic and Cox regression. Results: Sixty-three women were analyzed, of which 23 (36.5%) had a complication. Longitudinal changes of sFlt-1 were more pronounce in complicated pregnancies (median: 1079.5 vs. 343.7 pg/mL/day; p=0.04). On the multivariate analysis, the baseline model (clinical risk score and sFlt-1 at admission) explained a 6.6% of the uncertainty for complication (R2-Naegelkerke). The addition of sFlt-1 longitudinal changes improved this performance to 23.2% (p=0.004). The median time from admission to delivery was 3 days (95% confidence interval: 1.9-4.05) in those in the highest quartile of sFlt-1 longitudinal changes vs. 10 days (95% confidence interval: 8.1-11.9) in the remaining women (Log-rank test p<0.001). Conclusions: Longitudinal changes in sFlt-1 maternal levels from admission for confirmed early-onset severe preeclampsia add to baseline characteristics in the prediction of maternal complications.
Objective To compare the safety and efficacy of Veregen® ointment against placebo in the treatment of usual type vulvar intraepithelial neoplasia (uVIN). Design A Phase II randomised control trial. Setting A tertiary gynaecological oncology referral center. Population All women diagnosed with primary and recurrence uVIN. Methods Eligible patients were randomised to receive either Veregen® or placebo ointment (applied 3 times daily for 16 weeks), and were followed up at 2, 4, 8, 16, 32 and 52 weeks. Main outcome measures Outcome measures, recorded at 16 and 32 weeks, were histological (HR) and clinical (CR) response (as measured by ≥30% reduction in the sum of the longest diameter of all lesions when compared to baseline), toxicity and changes in quality of life and pain scores. Results 26 patients were randomised and all 13 patients who received Veregen® showed either complete (n=5) or partial (n=8) CR with a trend towards an improvement in baseline symptoms. In placebo group, 3 patients had complete CR, 2 had partial CR and 6 had stable disease. Patients in the Veregen® group showed a significant improvement in CR as compared to the placebo group (P=0.0026). There was no evidence of difference in HR and toxicity reported in both groups. Conclusion Our study indicates that Veregen application is safe and leads to at least a partial clinical resolution of uVIN lesions and symptoms improvement, thus warranting a phase III multi-centre RCT.
Background: Postpartum haemorrhage (PPH) rates are increasing in developed countries. A reliable prognostic tool for PPH has potential to aid prevention efforts. Objective: To systematically identify and appraise prognostic modelling studies for prediction of PPH. Search strategy: MEDLINE, Embase, CINAHL and the Cochrane Library were searched using a combination of terms and synonyms including ‘prediction tool’, ‘risk score’ and ‘postpartum haemorrhage’. Selection criteria: Any observational or experimental study developing a prognostic model for women’s risk of PPH. English language publications. Data collection and analysis: Predesigned data extraction form to record: data source; participant criteria; outcome; candidate predictors; actual predictors; sample size; missing data; model development; model performance; model evaluation; interpretation. Main Results: Of 1723 citations screened, 10 studies were eligible for inclusion. An additional paper was published and identified following completion of the search. Studies addressed populations of women who experienced; placenta praevia; vaginal births; caesarean birth; and the general obstetric population. Primary study authors deemed four models to be confirmatory. There was a high risk of bias across all studies due to a combination of retrospective selection of women, low sample size, no internal validation, suboptimal external validation and no reporting of missing data. Conclusion: Of eleven prognostic models for PPH risk, one developed for women undergoing caesarean section is deemed suitable for external validation. Future research requires robust internal and external validation of existing tools and development of a model that can be used to predict PPH in the general obstetric population. Protocol registration number: PROSPERO 95587