Retained Products of Conception as an Etiology for EndometritisPietro Bortoletto, MD1, Phillip A. Romanski, MD1, Nina Schatz-Siemers, DO2, Steven D. Spandorfer, MD11 The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical College, 1305 York Ave, 7th Floor, New York, NY 10021, USA.2 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, NY 10021, USA.

A document by Blair Wylie. Click on the document to view its contents.

Objective: To estimate the association between maternal origin and obstetric anal sphincter injury (OASI), and assess if associations differed by length of residence. Design: Population-based cohort study. Setting: The Medical Birth Registry of Norway. Population: Primiparous women with vaginal livebirth of a singleton cephalic fetus between 2008 and 2017 (n=188 658). Methods: Multivariable logistic regression models estimated aORs for OASI with 95% CI by maternal region of origin and birthplace. We stratified models on length of residence and paternal birthplace. Main outcome measures: OASI. Results: Overall 6 373 cases of OASI were identified (3.4% of total cohort). Women from South Asia were most likely to experience OASI (6.2%; aOR 2.24, 95% CI 1.93–2.60), followed by those from Southeast/East Asian/Pacific (5.7%; 1.83, 1.64–2.04), and Sub-Saharan Africa (5.2%; 1.97, 1.72–2.26), compared to women originating from Norway. Among women born in the same region, those with short length of residence in Norway (0–4 years), showed higher odds of OASI. Migrant women across most regions of origin had reduced risk of OASI if they had a Norwegian compared to foreign-born partner. Conclusions: Primiparous women from Asian regions and Sub-Saharan Africa had up to two-fold risk of OASI, compared to women originating from Norway. Migrants with short residence and those with a foreign-born partner had higher risk of OASI, implying that some of the risk differential is due to sociocultural factors. Some migrants, especially new arrivals, may benefit from special attention during labour to reduce morbidity and achieve equitable outcomes.

Objective To estimate the pregnancy rates and outcomes for women with cystic fibrosis (wwCF) in the UK compared to the general population and to explore the impact of the introduction of disease modifying treatments on pregnancy rates. Design A population-based cross-sectional study. Setting Electronic records of UK CF Registry Data (~99% of all CF), and conceptions data for England and Wales (E&W). Population All women aged 15-44 years who were pregnant between 2003-2017. Methods We calculated 3-yearly crude and age-specific pregnancy rates per 1,000 women years (wys), pregnancy rates for wwCF with a G551D mutation before and after Ivacaftor was introduced in 2012 and compared live birth rates. Main outcome measures Crude rates, age specific fertility, and maternal morbidity. Results The overall pregnancy rate was 23.5 (95% CI 21.9-25.3) per 1,000 wys, ~3.4fold difference to E&W women (77.7). This pattern was evident in the age specific rates, except for those aged 40-44 years where the difference in rates was much less (wwCF 8.2 per 1,000 wys vs. 13.3 in E&W). LB rate differences mirrored pregnancy rates (wwCF 17.4 per 1000 wys vs. 61.4 E&W women). Following the introduction of Ivacaftor, pregnancy rates in wwCF with G551D increased from 29.5 to 56.9 per 1000wys (2012-2014 to 2015-2017). Conclusions Pregnancy rates in wwCF are about a third of the rates in the general population but on the rise following the introduction of Ivacaftor. There is no indication that there is a reduced chance of a live birth in wwCF who become pregnant.

BJOG commentary for BJOG-21-0466 A core outcome set for the treatment of pregnant women with pregestational diabetes: an international consensus study

Mini-Commentary on Manuscript # BJOG-20-2493A Biomarker for Amniotic Fluid Embolism: The Search ContinuesWord count: 495Research into the pregnancy associated cytokine storm-like condition historically known as amniotic fluid embolism (AFE) has been hampered by a lack of unique diagnostic criteria. In its classic form, the clinical presentation of this condition is unmistakable. In less classic presentations, each of the clinical hallmarks of AFE (depressed ventricular function, lung injury and coagulopathy) may, in isolation, be seen in other obstetric conditions. Indeed, much of the confusion arising from previously published case series purporting to describe women with AFE appears to be the result of the inclusion of patients with other conditions. (Clark SL et al Obstet Gynecol 2014:123: 337-48) Identification of a reliable, objective biomarker specific to AFE is badly needed.It is against this background that the work of Bouvet et al is especially welcome. These investigators examined the use of insulin-like growth factor binding protein -1, a protein found in high concentration in amniotic fluid, as a potential biomarker of AFE in women suspected to have this condition. Unfortunately, the results were negative, leading the authors to question the usefulness of this assay.Although the results were negative, the major importance of this study may be as an example of how to properly conduct a search for AFE biomarkers. These authors avoided several pitfalls that have invalidated most previous biomarker publications. First, they used 2 objective, internationally recognized clinical criteria sets for identifying women with AFE. Their finding that only about half of women suspected to have AFE actually had the condition based on either of the identified criteria sets emphasizes the importance of insisting on inclusion criteria more stringent than “someone thought the patient had AFE,” so common in current literature. Secondly, in their use of women with suspected AFE these investigators avoided another common pitfall in biomarker research, namely the use of normal pregnant women, rather than critically ill women as controls. Presumably the women without AFE had some other form of critical illness. This distinction is particularly important in investigating the potential of various inflammatory mediators as specific markers for AFE.Finally, the authors’ data support 2 additional important conclusions beyond the original intent of the paper. The finding that 100% of AFE patients identified by the SMFM criteria also met the UK diagnostic criteria serve as additional validation of the ability of the former criteria to reliably identify a group of women who, for research purposes, do have the disease, while excluding some others with less typical forms of AFE. (Clark et al, Am J Obstet Gynecol 2016:408-12.) Secondly, the authors’ findings of no difference in levels of ILGFBP-1 in women with and without clinical AFE, despite high levels of this protein in amniotic fluid, supports the current belief that amniotic fluid per se is unrelated to the condition known as amniotic fluid embolism.It is generally accepted by the scientific community that AFE is unpreventable. It is hoped that additional quality research such as that of Bouvet et al may someday change this unfortunate fact.

Professor PEP Petros DSc DS (UWA) PhD (Uppsala) MB BS MD (Syd) FRCOG (Lond)31/93 Elizabeth Bay Rd, Elizabeth Bay NSW 2011 AUSTRALIAReconstructive Pelvic Floor Surgeon and Certified Urogynaecologist (retired)Formerly University of NSW Professorial Dept of Surgery, St Vincent’s Hospital Sydney (retired)Adjunct Professor, University of Western Australia School of Mechanical and Chemical Engineering, Perth WA (current)Tel 61 2 9361 3853 Cellphone (AUST) 61 411 181 731Email [email protected] website www.integraltheory.org

Objective: to evaluate current practice and outcomes of pregnancy in women previously diagnosed with Budd-Chiari syndrome and/or portal vein thrombosis, with and without concomitant portal hypertension. Design and setting: multicentre retrospective cohort study between 2008-2021 Population: Women who conceived in the predefined period after the diagnosis of Budd-Chiari syndrome and/or portal vein thrombosis Methods and main outcome measures: We collected data on diagnosis and clinical features. The primary outcomes were maternal mortality and live birth rate. Secondary outcomes included maternal, neonatal and obstetric complications. Results: Forty-five women (12 Budd-Chiari syndrome, 33 portal vein thrombosis; 76 pregnancies) were included. Underlying prothrombotic disorders were present in 23 of 45 women (51%). Thirty-eight women (84%) received low-molecular-weight heparin during pregnancy. Of 45 first pregnancies, 11 (24%) ended in pregnancy loss and 34 (76%) resulted in live birth of which 27 at term age (79% of live births and 60% of pregnancies). No maternal deaths were observed, one woman developed pulmonary embolism during pregnancy and two women (4%) had variceal bleeding requiring intervention. Conclusions: The high number of term live births (79%) and lower than expected risk of pregnancy-related maternal and neonatal morbidity in our cohort suggest that Budd-Chiari syndrome and/or portal vein thrombosis should not be considered as an absolute contra-indication for pregnancy. Individualized, nuanced counselling and a multidisciplinary pregnancy surveillance approach are essential in this patient population.

BJOG-20-2353.R2 What should we believe when systematic reviews disagree?For many years, uterine balloon tamponade (UBT) has been used to treat severe postpartum haemorrhage (PPH), despite a lack of randomised trials to demonstrate its effectiveness. With commercial devices being expensive, clinicians in low resource settings have made their own using 2 low-cost, widely available items (Foley catheters and condoms). Public health experts have been so confident of their benefit that large programmes have been set up to disseminate the necessary skills worldwide.Recently, however, the global maternal health community has been thrown into disarray when not one, but two randomised controlled efficacy trials suggested that outcomes with condom catheter UBTs were actuallyworse than normal care in low resource settings. The Cochrane meta-analysis concluded that “in [low resource] settings, balloon tamponade [should be] only introduced alongside multi‐system improvements in PPH care” (Kellie et al. Cochrane Database of Systematic Reviews 2020(7): CD013663).Systematic reviews may be the pinnacle of evidence-based medicine, but even they can differ in how to interpret evidence. And so, proponents of the condom catheter conducted their own systematic review with far wider inclusion criteria – they not only included the randomised trials but examined success rates from 15 non-randomised trials and 69 case series (Suarez et al. Am J Obstet Gynecol 2020;222(4):293.e1–e52). Furthermore, the primary outcome was the success rate of the technique (overall 86%) rather than the risk of morbidity and mortality compared to controls, as used in the Cochrane review. This is problematic, as reported ‘success rates’ without controls can be very difficult to interpret: in initial case series misoprostol showed similar success rates against life-threatening haemorrhage before RCTs eventually showed it to be less effective than oxytocin.A third version of the same review is published today by a WHO team (Pingray et al. BJOG 2021;XXX,XXX). This time they include only 4 high quality studies in which UBT was compared to standard care. With a composite maternal morbidity / mortality outcome, they found no evidence of benefit and concluded that “the effect … is unclear, as is the role of the type of device and the setting”. WHO studies are now underway to address this uncertainty.But why is this all so important? The difficulty comes because the World Health Organisation has been updating its guidance on PPH management, and had to declare a position on UBT. The recently-published guideline, drawn up by independent experts, accepts the validity of the RCTs but recognises that there is wide acceptability of the technique and that the evidence of harm is only for condom catheters and onlyin resource-poor settings. They put a high emphasis on minimising harm and conclude that UBTs should only be used in settings where there is already a good standard of care, including recourse to blood transfusion and surgery if needed (WHO. Geneva: World Health Organization; 2021).Until further studies are published, the debate will continue. But this episode shows how the choice of inclusion criteria and outcomes in systematic reviews are critical, both for their conclusions, and for global policy.

Is the patient choice the best choice?

Aortic balloon for the intraoperative management of placenta accreta spectrum: need for standardised methodology and safety dataIn 2003, Bell-Thomas et al (BJOG 2003;110:1120-1122) reported on the emergency use of a transfemoral aortic occlusion catheter to control massive haemorrhage in a case of caesarean hysterectomy for placenta percreta. This was only the second case published in the international literature on the use of an intra-abdominal aortic balloon occlusion (IABO) in the management of placenta accreta spectrum (PAS) (Paull et al. Anesth Intensive Care 1995;23:731-734). A non-exhaustive Pub-Med literature review of articles published in English on this the topic over the last 20 years, identifies 27 articles, 23 of which come from the Peoples Republic of China, where IABO seems to be increasingly popular in the management of PAS.In brief, IABO involves the insertion of a balloon catheter into the infrarenal abdominal aorta above the aortic bifurcation under fluoroscopy guidance. The procedure is performed in a hybrid operating room or interventional radiology (IR) suite with secondary transfer to the operating room. In all but one study (Zhu et al Biomed Res Int.2017:8604849), the balloon was inflated after delivery of the newborn.All publications so far have been retrospective and most are case-control studies, comparing the outcomes of IABO with those of routine surgical techniques with or without additional procedures such as intra-uterine tamponade. Recently, authors have also started to compare IABO with iliac artery balloon occlusion.Overall, these studies have shown that IABO is associated with reduced estimated blood loss and transfusion requirement, ICU admission and hysterectomy and suggested that IABO is more effective than iliac artery balloon occlusion, presumably as arterial occlusion is more effective.However, there is wide variation between studies in prenatal imaging and clinical selection criteria, intraoperative IR methodology and confirmation of the diagnosis of PAS at birth. For example, the pre-operative fluoroscopy time ranges between 2 and 25 minutes with fetal radiation exposure of 4 to 25 mGy; intraoperative balloon inflation/deflation time varies between 5-10/1 minutes and 45-80/10 minutes. The size of the balloon and the need for transfer between the IR room and the operative theatre is rarely described. Most studies lack histopathology confirmation of the diagnosis and/or stratification by PAS grade.Heterogeneity in methodology and design leads to a high risk of confounding, bias or chance. There is also a high risk that the relationship is not causal. One major concern is the risks-benefit ratio of the use of IABO for both mothers and fetuses, in particular if they do not have PAS. The most commonly reported post-operative complication associated with IABO are arterial thrombosis of the external iliac or the femoral artery. There are no data on the long-term follow of the children born after IABO.In 2018, the expert panel of the RCOG green top guidelines 27a (Jauniaux et al., BJOG.2019;126:e1-e48) concluded that larger studies are necessary to determine the safety and efficacy of IR before this technique can be advised in the routine management of PAS. The 10 new studies published in 2019-2010 on the use of IABO in the management of PAS are insufficient to change this statement.Word count: 499

New insights in diagnostic thresholds for total serum bile acid (TSBA) in intrahepatic cholestasis of pregnancy (ICP)

A document by Shashikant Sholapurkar. Click on the document to view its contents.

Background Guidelines standardise high-quality evidence-based management strategies for clinicians. Uterine fibroids are a highly prevalent condition and may exert significant morbidity. Objectives The purpose of this study was to appraise national and international uterine fibroid guidelines using the validated AGREE-II instrument. Selection Strategy An electronic database search of PubMed and EMBASE from inception to October 2020 for all published English-language uterine fibroid clinical practice guidelines was undertaken. Data Collection and Analysis 939 abstracts were screened for eligibility by two reviewers independently. Three reviewers used the AGREE-II instrument to assess guideline quality in six domains (scope and purpose, stakeholder involvement, rigour of development, clarity of presentation, applicability, and editorial independence). Recommendations were mapped to allow a narrative synthesis regarding areas of consensus and disagreement. Main Results Eight national (AAGL, SOGC 2014, ACOG, ACR, SOGC 2019, CNGOF, ASRM, and SOGC 2015) and one international guideline (RANZOG) were appraised. The highest scoring guideline was RANZOG 2001(score 56.5%). None of the guidelines met the a priori criteria for being high-quality overall (score >= 66%). There were 166 recommendations across guidelines. There were several areas of disagreement and uncertainty. Conclusions There is a need for high-quality fibroid guidelines given heterogeneity across individuals and a large range of treatment modalities available. There are also areas of controversy in the management of fibroids (e.g. Ulipristal acetate, power morcellation) which also should be addressed in any guidelines. Future guidelines should be methodologically robust to allow high-quality decision-making regarding fibroid treatments.

Mini Commentary – BJOG

Anaemia in pregnancy remains a global health problem In this issue of BJOG Hull et al …… et al report on an important study from South Africa regarding anaemia in pregnancy and the response to iron therapy. They report that in HIV-positive women the response was slower than in HIV-negative women. The underlying causes of anaemia varied and included iron deficiency (as assessed by ferritin levels) as well as concurrent infections (urinary tract infections and tuberculosis)Anaemia in pregnancy (blood haemoglobin Hb<11.0g/dl) occurs in > 40% of women living in low- and middle-income countries (LMIC) and in some settings in Asia prevalence is >60%. (McCauley et al, BMJ Global Health, 2018; 3(3):e000625) The latest WHO recommendations on antenatal care consider anaemia as the world’s second leading cause of disability and one of the most serious global public health problems (WHO Geneva 2016 ) .Although globally the focus has largely been on anaemia in pregnancy resulting from either iron deficiency or malaria, this is an incomplete approach at best. Iron deficiency is hard to measure and confirm as; i) this requires a functioning laboratory to be in place, ii) indicators for iron deficiency are influenced by the presence of concurrent infection, or, iii) repeated measures of Hb are needed to check whether the anaemia is responsive to treatment with iron. By contrast, malaria is relatively easy to diagnose via rapid diagnostic tests or microscopic examination of a stained blood smear slide. The handful of studies which have comprehensively assessed aetiology of anaemia in pregnant women demonstrate that anaemia is most commonly the result of complex multiple underlying factors including nutritional deficiencies as well as infectious diseases. Both nutritional deficiency and other infections (malaria, tuberculosis) are more likely with HIV-infection which itself can lead to anaemia probably through direct suppression of erythropoiesis.Hull et al show what was possible in a real-life clinical practice setting. This example of integration of research into clinical practice is laudable and is illustrative of how such integration could result in better services being made available for women in LMIC where burden of disease is high, but diagnostic tests are largely unavailable. It is sobering to realise that the majority of women world-wide will still only be screened for anaemia during pregnancy using ‘conjunctival inspection’ which is highly inaccurate. (van den Broek et al. Bull WHO 1999; 77(1):15-21) Rapid diagnostic tests are available for Hb, malaria, syphilis, HIV and, more recently, for tuberculosis. We are doing women a dis-service if we cannot offer at least these basic diagnostic tests as part of antenatal care.To prevent anaemia during pregnancy, the ‘fall-back’ position is to offer all women daily iron prophylaxis (30-60mg elemental iron) - with luck tablets are available that include folic acid (0.4mg) - along with presumptive treatment of malaria (various regimes) in endemic areas. Multi-micronutrients (including the required amount of iron and folic acid) might actually be better but cannot be recommended because of lack of evidence and they are still three times as expensive as iron and folic acid supplementation alone (3$ vs 1$ approximately).WHO recently recommended a better understanding of the aetiology of anaemia. A search on PubMed shows a clear lack of papers on the topic and more good research is needed. Investment in the antenatal care package offered to women is also much needed if we are aiming for a global ‘Health for All’.

Background: Normal mature sperm have a considerably reduced number of mitochondria which provide the energy required for progressive sperm motility. Literature suggests that disorders of sperm motility may be linked to abnormal sperm mitochondrial number and function. Objectives: To summarise the evidence from literature regarding the association of mitochondrial DNA copy numbers and semen quality with a particular emphasis on the spermatozoa motility. Search strategy: Standard methodology recommended by Cochrane. Selection criteria: All published primary research reporting on differences in mitochondrial DNA copy numbers between the sperm of males with a normal and abnormal semen analysis. Data collection and analysis: Using standard methodology recommended by Cochrane we pooled results using a random effects model and the findings were reported as a standardised mean difference. Main results: We included 10 trials. The primary outcome was sperm mitochondrial DNA copy numbers. A meta-analysis including five studies showed significantly higher mitochondrial DNA copy numbers in abnormal semen analysis as compared to normal semen analysis(SMD 1.08, 95% CI 0.74-1.43). Three other studies not included in the meta-analysis showed a significant negative correlation between mitochondrial DNA copy numbers and semen parameters. The quality of evidence was assessed as good to very good in 60% of studies. Conclusions: Our review demonstrates significantly higher mitochondrial DNA in human sperm cells of men with abnormal semen analysis in comparison to men with normal semen analysis. PROSPERO registration: CRD42019118841 Funding None received

A document by David Savitz. Click on the document to view its contents.