The decision to implement screening for infections during pregnancy depends upon epidemiological, economic, therapeutic and test performance criteria. It therefore varies with public health priorities from country to country. When screening is implemented, first trimester has become the best time slot to build individual care pathways also in this field. This is most relevant for evaluating the risk of embryonic consequences, plan diagnostic testing, initiate primary or secondary prevention and increase the accuracy of ultrasound follow-up. This is a critical appraisal of epidemiological data and current international screening recommendations for infections in pregnancy.

Sir,We read with great interest the recent study by Misra et al.evaluating different surgical interventions for the treatment of pain associated with endometriosis.1 We understand the importance of this research to inform our clinical practice and extend our gratitude to the researchers, the women who participated in the study, and the research funder.BJOG: An International Journal of Obstetrics and Gynaecology has been at the forefront of reducing research waste by implementing several important interventions including the requirement to prospectively register randomised trials, implementing the Consolidated Standards of Reporting Trials (CONSORT) statement, and mandating the reporting of core outcome sets.2Reflecting upon this recent study presents an opportunity to consider the impact of implementing such initiatives on selective outcome reporting. The authors prospectively registered their trial (ISRCTN50928834) and reported their pre-specified primary outcome as pelvic pain. This differs from the primary outcome reported in the final publication. A secondary outcome, dyspareunia, reported in the final publication, was not prospectively registered. The CONSORT statement commits researchers to report all prespecified primary and secondary outcomes. When new outcomes are added this should be made clear in the final publication and a comprehensive explanation provided. It would be useful for the authors to clarify the discrepancies between the prospective registry record and the published trial report.Core outcomes aim to address the challenges of poorly selected, collected, and reporting outcomes, including tackling outcome reporting bias.3 We are grateful to the authors for acknowledging the development of a core outcome set for endometriosis research within their study report. The core outcome set for endometriosis has recently been published and was developed using formal consensus methods involving 116 healthcare professionals, 32 researchers, and 206 women with endometriosis from 29 countries.4 The core outcomes include overall pain, improvement in most troublesome symptom, quality of life, adverse events, and patient satisfaction with treatment. It would be useful for the authors to clarify if the core outcomes had been collected as part of the trial and report available data.Over eight speciality journals, including the Cochrane Gynaecology and Fertility Group, have committed to supporting the development, dissemination, and implementation of the core outcome set for endometriosis. The collaboration who have developed the core outcome set for endometriosis are now assisting with implementation and are systematically examining published endometriosis trials. Where inconsistencies between the trial registry record and the outcomes reported in the published trial report are identified or when the core outcome set has not been fully reported we are writing to the authors seeking clarification. Our progress can be followed at https://twitter.com/EndoOutcomes where we will be posting the prospective registry record, final publication, and response to this letter.

Pregnancy provides optimal opportunities for health promotion and disease prevention. Smoking before and during pregnancy is one of the largest modifiable risk factors for a range of adverse pregnancy outcomes. Concerns over the risks of smoking motivate many pregnant smokers to quit. However, most of their partners continue to smoke throughout pregnancy. More than one-third (35%) of men in the world smoke, and just over 6% of women do (Ritchie et al. Published online at OurWorldInData.org 2020). The impact of paternal smoking, second-hand or third-hand smoking on the perinatal health is largely overlooked. Given the vast majority of studies focusing on the pregnant smokers, less is known about paternal smoking on their future children.In this paper (Zhou et al. BJOG 2020), using a large national prepregnancy registry database, Zhou et al. found that paternal smoking may be associated with birth defects such as congenital heart diseases, limb abnormalities and neural tube defects in the offspring. The result was consistent with previous retrospective studies, but a medium to large effect size was seen. All of the odd ratios exceeded 2.5, with one even over 20 (congenital heart diseases OR=2.51, 95%CI 1.04-6.05; limb abnormalities OR=20.64 95%CI 6.46-68.02; digestive tract anomalies OR=3.67 95%CI 1.44-9.37; neural tube defect OR=4.87,95%CI 1.66-14.28). Such difference might be partially explained by potential confounding factors. For example, the extent of tobacco exposure, in the National Birth Defects Prevention Study (Malik et al. Pediatrics 2008; 121: e810), compared with light smoking exposure (<14 cigarettes per day), heavy smoking women (≥25 cigarettes per day) were more likely to have infants with septal defects (OR 2.06; 95%CI: 1.20-3.54), suggesting a dose-dependent relationship between tobacco exposure and birth defects.In addition, a reduced risk of birth defects after changing smoking behaviors was found in Zhou’s paper. It is no surprise that paternal smoking cessation could improve the adverse outcomes. Limited evidences address whether there is a critical window period by which smoking must be stopped to prevent subsequent adverse perinatal outcomes. Results from a retrospective case-control study indicated that the risk of fetal congenital heart diseases increased as women smoked during the first trimester (Sullivan et al. J Pediatr; 2015; 166:978). In a prospective cohort study (McCowan et al. BMJ 2009; 338: b1081), the authors concluded that stopping smoking early in pregnancy, and certainly by 15-16 weeks’ gestation, may minimize the adverse effects of smoking on late pregnancy complications and should be an important goal for pregnant smokers. Yet, such critical time for paternal smoking cessation remains unknown.Tobacco smoke is also a human germ cell mutagen. It is estimated that with even a modest 25% increase in sperm mutation frequency caused by smoke-exposure, for each generation across the global population there will be millions of smoking-induced de novo mutations transmitted from father to offspring (Beal et al. Mutation Research;2017; 773:26).Therefore, it is strongly recommended that women and men should immediately stop smoking in advance of reproduction.No disclosures: A completed disclosure of interest form is available to view online as supporting information.

The interesting article published on this issue by Helen Perry et al (BJOG 2020 xxxx) is an important contribution to the idea demonstrated several years ago with echocardiographic evaluation of maternal central parameters, that the blood pressure value alone is not useful to understand the degree of compromise of the maternal condition in the evaluation of gestational hypertension and Preeclampsia (Valensise H et al. BJOG. 2006 Sep;113(9):1044-52. Epub 2006 Jul 7). The authors present an elegant study in which the evaluation of the maternal cardiovascular parameters obtained through non-invasive methods (Continuous Waveform Doppler USCOM) show major differences in cardiac output, systemic vascular resistances and heart rate in those patients with the diagnosis of Preeclampsia with a reduced fetal growth.These findings open two lines of research that needs to be implemented on the future: the first is linked to the possibility to identify ‘personal targeted therapy’ according to the parameters found to ameliorate the placental perfusion and fetal growth increasing the heart rate when below the normal values, reducing the systemic vascular resistances and increasing the plasma volume so as to try to bring back to normal the cardiocirculatory conditions (Valensise H et al. Ultrasound Obstet Gynecol. 2008 Jan;31(1):55-64).The second most important research line has to concentrate to the maternal circulatory condition before pregnancy (Vasapollo B et al. Am J Obstet Gynecol. 2020 Mar 3. pii: S0002-9378(20)30234-9. doi: 10.1016/j.ajog.2020.02.043) that in high risk pregnancies might induce not only an automatic passive calculation of the risk factors, but an active therapy based on the modifications of the maternal cardiac parameters to bring them back to normal as much as possible to PREVENT the appearance of the abnormal adaptation to pregnancy.In the future maternal health control in pregnancy will not be possible without the knowledge of maternal cardiac hemodynamics before pregnancy, in the first and second trimester, and at the appearance of hypertension or signs of fetal growth restriction. For this reason the implementation of clinical research with the use of non-invasive devices accessible to any doctor need to be recommended.No disclosures: A completed disclosure of interest form is available to view online as supporting information.

Mini-commentary on BJOG- 19-1590.R1: Obstetric outcomes of twin pregnancies presenting with a complete hydatidiform mole and coexistent normal fetus: A systematic review and meta-analysis

Dear Editor, We would like to thank Dr. Lamont and colleagues for their interesting commentary.1 The authors point out very pressing topics that deserve more attention than we could provide in the original manuscript.They expressed concerns in their letter towards the heterogeneity of the data that were used in our meta-analysis. If incidences differ between regions and populations, absolute numbers on colonisation and neonatal infections might not be comparable. However, new policies were implemented in various settings, where differences in outcomes were measured under the same local circumstances. So as rightly mentioned by Lamont et al, data from the US cannot and should not be used as a blueprint for other parts of the world.1 Yet the general trend in developed countries that we observed, might shed some new light on the respective effectiveness of the strategies currently available.

Mini-commentary on BJOG-20-0063.R1: Association of maternal attention deficit hyperactivity disorder and preterm birth: a cohort study

I moved out of our shared bedroom of nearly 10 years on 3/22/2020. It was not a difficult decision as we have two young children and wondered what would happen if both of us became ill at the same time. As a Maternal-Fetal medicine physician in New York City, I was acutely aware of the coming COVID-19 crisis, and its potential ramifications on the health of my family, friends, patients and community. I am trained to function well in emergencies, and in this case, it was a quick and seemingly logical next-step to sleep separately.This decision also comes along with an already in place full-scale decontamination effort that begins as soon as I enter our home. This involves minimizing what jewelry, clothing, food and bags go back and forth between the hospital and my home, 3-shoe changes, stripping off my clothing and placing everything into the wash, and then running to the shower. None of these choices were rooted in years of medical science, given the novelty of the virus, and paucity of data on the SARS-CoV-2 (COVID-19). I used early data regarding transmission as well as anecdotal reports from friends in Asia who seemed to suggest that it was highly contagious and highly transmissible. Thus, when I recently learned that there is a science and a history surrounding how pathogens have shaped human psychological adaptations. As we are forced to confront the longstanding evolutionary pressure of pathogen avoidance regarding what to eat, and touch and who to be intimate with, it no longer feels theoretical.1Looking back at what I’ve gained and what I’m missing over this last month, I am acutely aware of how much less we are touching as a family and in my medical practice, and I miss it. As I say goodnight to my family and retreat to our windowless den, I am both thankful for a place to sleep that is near enough to be able to peek at their beautiful sleeping faces, while sad that I feel less at ease hugging or kissing them. While every health care worker on the front-line of this crisis has drawn different boundaries (some more or less extreme), my decision to sleep in a separate room, create a decontamination routine, and be less physically affectionate with my children was the only way I could feel in control in an uncontrollable situation.Medical professionals know that touch, rooted in the amygdala of the brain, cannot be separated from the expression of empathy and solidarity that it provides.2 In medicine, touch has long been hypothesized to have an impact on health and development over our lifespan. Dr. Cascio and her team at the Vanderbilt Kennedy Center for Human Development describe social touch as “a powerful force in human development, shaping social reward, attachment, cognitive, communication, and emotional regulation from infancy and throughout life.3” Many of the babies of the mothers I care for will begin their lives in the Neonatal Intensive Care Unit where the science surrounding touch as part of healthcare is widely accepted and engrained in the culture. Skin-to-skin and kangaroo care, the act of carrying your child in a pouch-like device, have been shown to improve breastfeeding, bonding, and neurocognitive development4,5 In fact, the World Health Organization currently has an ongoing international trial looking at the benefits of survival on low-birthweight infants of kangaroo care initiated immediately after birth on survival of low birth weight infants.6 Later in life, touch, relationship quality and intimacy continue to drive good health and have been associated with improved cognitive function in the Rotterdam Study7,8and improved cardiovascular outcomes in the National Social Life Health and Aging Project.8 Their findings suggest physical touch may have positive health implications for older adults.Prior to the pandemic, physicians were already sounding alarms about the loss of medical touch in modern medicine. In a 2011 TED talk with over 1.7 million views, renowned author and physician Abraham Verghese discussed the power of physician touch and the physical exam as he tried to revive the culture of bedside medicine.9 With this pandemic all of that has changed. We are all exceedingly careful to prevent transmission and yet try to provide care and solace in new ways. At the bedside, a gloved hand continues to provide care and comfort. I am happily finding ways to connect with patients through smiling eyes behind a mask, and jokes or phrases that now replace touch. I find myself more commonly expressing words of empathy in telemedicine visits to fill in for the gaps that touch might have provided before. I ask many, many questions to understand symptoms if I cannot see the patient in person. Due to the surrounding events, I am undertaking the fulfilling process of learning a new skill in medicine, to express my emotions on a screen and affect patients’ lives in ways similar to that of an in-person visit.As we raise our family in this time of pandemic, I am thankful that my husband is doing “double-duty” in the realm of hugging and kissing, and has always been a physically affectionate father to our children. I try to tell them how much I love them with greater frequency and despite the concerted effort there are days it’s almost impossible to share our apartment without being physically close. The psychological impact this crisis will have on them is yet to be determined. I hope time will find them healthy, more resilient and grateful at the end of this journey.But tonight, as they sleep soundly in their beds for another night, I am still saddened that I’m not doing the usual kissing and hugging as I tuck them into bed, and it feels like a true loss, among the many others. I am not sleeping as soundly these days for a multitude of reasons including the guest bed, the strangeness of being alone after so many years, and the exponential rise in screen time for work and media consumption. I am truly hopeful we will return to a time when we can more freely touch and care for the people we love and the patients we value so much. In the simplest of internet searches, touch has so many definitions. Touch can mean to be in close contact, but it can also mean to affect.10 COVID-19 has affected us in innumerable ways, and as healthcare workers navigate a post-COVID landscape, I’m hopeful we can continue to innovate and find safe ways to incorporate medical touch into a practice that will be forever changed.Acknowledgements : I would like to acknowledge our patients for their immense flexibility in this changing landscape, the support of my division and department, and my family. I’d like to thank Dr. Gwendolyn Quinn and my husband David Lee, for their significant editorial assistance.

Ultrasound-detected structural anomalies have an impact on fetal mortality and morbidity. Prenatal Exome Sequencing is incorporated into clinical care pathways for paediatric populations but maybe used to delineate the prognosis of fetal structural anomalies. This paper reviews the literature defining the clinical utility of prenatal ES and discusses the potential promise and challenges for implementation of this technology into clinical practice. Prospective case selection with accurate and informative pre-test counselling by multidisciplinary, clinical genetic-led teams is imperative. Robust, regulated laboratory sequencing, informative bioinformatic pathways with variant identification and conservative matching with the phenotype (within clinical review panels) is also important.

Mini-commentary on BJOG-20-0076.R1: Differences in fetal fractional limb volume changes in normal and gestational diabetic pregnancies: an exploratory observational study

Two papers in this issue, on births to Covid-19 infected mothers, are important additions to this rapidly evolving literature. They are both broadly reassuring.The paper from Lombardy, the epicentre of the pandemic in Italy, is the first detailed report of pregnancies from this large region (Ferrazzi et al. BJOG 2020 xxxx). Among 42 affected women, 19 developed pneumonia, of whom seven required oxygen and four critical care. Eighteen babies were delivered by Caesarean, although in eight the indication was unrelated to Covid-19. Three babies tested positive for SARS-COV-2. Two to women who had developed Covid-19 postnatally and had breast-fed without a mask; the presumed source was the mother. One baby who delivered vaginally and did not breast-feed, developed respiratory symptoms requiring one day’s ventilation and tested positive. No mothers or babies died.The paper from China reports SARS-COV-2 viral tests in a range of body fluids from mothers and babies with COVID-19, cared for at Renmin Hospital of Wuhan University (RHWU) (Yanting Wu et al. BJOG 2020 xxxx). This hospital appears on the Global Research Identifier Database (GRID) here https://grid.ac/institutes/grid.412632.0. Readers should know that the GRID database reports that RHWU has the following English aliases “People’s Hospital of Wuhan University”, “Hubei Provincial People’s Hospital”, “First Affiliated Hospital of Wuhan University”, “Wuhan University Renmin Hospital” and “Hubei General Hospital”. This raises the possibility that some or all of the cases may have been reported previously.With this proviso, the detailed information that 1/9 stool samples, 0/13 vaginal samples, and 1/3 breast milk samples were positive is important. Of the five babies who have delivered, none tested positive for Covid-19, although two, both preterm, had pneumonia diagnosed on chest x ray. Apart from one biochemical pregnancy in the first trimester in which a serum human chorionic gonadotrophin of 25.9 IU/L reverted to negative, no mothers or babies died.Taken together with other accumulating data, it is already clear that Covid-19 is less severe in pregnancy than the two previous coronavirus infections, Severe Acute Respiratory Syndrome-related coronavirus (SARS) and Middle East Respiratory Syndrome-related coronavirus (MERS). Nevertheless, four of the mothers from Lombardy required critical care, and there have been other reports of both mother and baby deaths in association with Covid-19. It remains an important disease in pregnancy, which should be taken seriously.No disclosures. A completed disclosure of interest form is available to view online as supporting information.

Mini-commentary on BJOG-19-1550.R1: Effect of Progestogen for Women with Threatened Miscarriage: A Systematic Review and Meta-analysis

Letter to the Editor, BJOG Exchange

Mini-commentary on BJOG-19-0970.R4: External validation of a simple risk score based on the ASPRE trial algorithm for preterm preeclampsia considering maternal characteristics in nulliparous pregnant women: a multicentric retrospective cohort study

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, [email protected] 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

Letter to the Editor, BJOG Exchange

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 

Mini-commentary on BJOG-20-0093.R1: The impact of age and high risk human papillomavirus (hrHPV) status on the prevalence of high grade cervical intra-epithelial neoplasia (CIN2+) in women with persistent hrHPV positive, cytology negative screening samples: a prospective cohort study.