Mini-commentary on BJOG-20-0442.R2: Impact of hysterectomy on analgesic, psychoactive and neuroactive drug use in women with endometriosis: nationwide cohort study

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.

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

BJOG-21-0667.R1: Our Guidelines Are Not Good EnoughAlexandra Wojtaszewskaa, Martin HirschbaWatford General Hospital, Watford, United KingdombOxford Endometriosis CaRe Centre, Nuffield Department of Women’s & Reproductive Health, University of Oxford, Oxford, United Kingdom.Declarations of interest: noneFinancial support received: noneBJOG-21-0667.R1: Our Guidelines Are Not Good EnoughAmoah et al. highlight the lack of high-quality fibroid guidelines in their appraisal of uterine fibroid management guidelines. This paper sheds light on the association between low quality research informing low quality clinical guidance. The authors included nine national and international guidelines on fibroid management in their analysis and screened 189 recommendations and statements made across these documents. Guideline quality was assessed using the AGREE-II instrument and no high-quality guidelines were identified. No guidelines reported involvement of patients with fibroids in their development and across all guidelines consensus was reached on only three (1.6%) of 189 statements. The authors explored the quality of evidence base behind the recommendations concluding that 25.3% were developed from good-quality evidence while 27.7% were based on lowest quality evidence (expert opinion or clinical consensus).These findings of poor quality and high discrepancy between guideline recommendations for fibroids are not unique to the condition. Other systematic reviews found similar results when analysing guidelines for management of endometriosis (Hirsch et al. BJOG 2018;125:556-564) and uncomplicated birth (Zhao et al. BJOG 2020;127:789-797).When writing or updating guidelines, locally or nationally, authors must consider how to ensure highest possible quality. There are several validated tools for quality assessment available (including AGREE II, ADAPTE, AMTAR and INAHTA and iCAHE Guideline Quality Checklists).The landscape for guideline development is changing. The rapid development of novel technologies requires a prompt response and evaluation of not only efficacy but the wider environmental impact and health economic assessment. The current system of laborious static single point assessments of evidence-based medicine producing clinical guidelines every few years is no longer appropriate. The National Institute for Health and Care Excellence (NICE) acknowledge the need for proactive, fluid, and flexible processes to enable the digitalisation of health systems to inform practice through real-world evidence (NICE 2021, The NICE Strategy 2021 to 2026 ). Guidelines will respond in a dynamic manner to population changes using contemporaneous evaluation of clinical data available from digitalised care systems. We look forward to integrated care systems delivering population-based healthcare on a regional basis. Guidelines will extend across health, social care, and public health focusing on health prevention, reducing health inequality, and delivering those interventions that offer the greatest benefit.As highlighted by this study, the development of guidelines without standardised methods is commonplace. This may lead to exclusion of beneficial treatments, a paucity of comparable recommendations, recommendations based on poor quality data, and poor patient outcomes. Looking to the future we do not see the need to fix a fractured guideline development system but rather build a new one. We must adapt and adopt the integration of digitalised real-world health system data to facilitate rapid and robust clinical decisions on a regional or national basis.

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

Letter to the Editor, BJOG Exchange

Time for action- oxytocin & uterotonics are life-saving AND dangerous: a commentaryDeborah ArmbrusterUnited States Agency for International DevelopmentWashington, DC (currently based in Indonesia)Global Health Bureau/Maternal, Child and Nutrition Office/Maternal and Newborn Division+1 202 [email protected]

Letter to the Editor, BJOG Exchange

A document by Becky Liu. Click on the document to view its contents.

Letter to the Editor, BJOG Exchange

Objective: To assess psychosexual distress among women receiving different human papillomavirus (HPV) and cytology results in the context of the English HPV primary screening pilot, shortly after women received their results and 6 and 12-months later. Design: Longitudinal, between-groups study. Setting: Five sites in England where primary HPV testing was piloted. Population: Women aged 24-65 years (n=1133) who had taken part in the NHS Cervical Screening Programme. Methods: Women were sent a postal questionnaire soon after receiving their screening results and 6 and 12-months later. Data were analysed using linear regression models to compare psychosexual outcomes between groups receiving six possible screening results. Main Outcome Measures: Psychosexual distress, assessed using six items from the Psychosocial Effects of Abnormal Pap Smears Questionnaire (PEAPS-Q). Results: At all three time-points, there was an association between screening result and overall psychosexual distress (all p<0.001). At baseline, psychosexual distress was significantly higher among women with HPV and normal cytology (B=1.15, 95% CI:0.961-1.337), HPV and abnormal cytology (B=1.02, 95% CI:0.783-1.266) and persistent HPV (B=0.90, 95% CI:0.703-1.102) compared with the control group (all p<0.001). At 6 and 12-month follow-up the pattern of results was similar, but coefficients were smaller. Conclusions: Our findings suggest that while simply participating in HPV testing does not appear to cause psychosexual distress, receiving an HPV-positive result does, particularly in the short-term. Developing interventions to minimise the psychosexual burden of testing HPV-positive will be essential to avoiding unnecessary harm to the millions of women taking part in cervical screening.

Time to move on from the hCG hypothesis regarding nausea and vomiting of pregnancy and hyperemesis gravidarumMarlena S. Fejzo, PhDKeck School of Medicine, University of Southern California, Department of Maternal-FetalMedicine, Los Angeles, CA 90033, United StatesThank you for your letter1 highlighting our study that implicates GDF15 and does not support a direct causal role for hCG in Hyperemesis Gravidarum (HG).2 Both GDF15 and hCG are expressed in blastocysts and increase in the 1st trimester,2 so any association between the two hormones in early pregnancy is not surprising and does not imply one controls expression of the other. While it is possible hCG plays a secondary role contributing to GDF15 levels, it is unlikely to be important for HG for the following reasons:From Deruelle and Tranchant‘s letter,1 “nausea and vomiting are not common side-effects of hCG,” but are for GDF15.Circulating hCG reaches its peak at 9-10 weeks,3 while GDF15 levels and HG symptoms do not.4While the Petry et al. study mentioned by Deruelle and Tranchant shows GDF15 and hCG concentrations correlate, they failed to mention Petry also found that only GDF15 levels, and not hCG levels correlated with maternal antiemetic use and second trimester vomiting. Similarly, our study comparing GDF15 and hCG levels in pregnant patients hospitalized with HG compared to healthy pregnant controls also found an association with GDF15 levels, but not hCG.4At least 14 studies, one including 4,372 pregnancies found no association between hCG and HG.4 While other studies find an association, continuing to spend limited resources attempting to prove an association, or a secondary relationship, while interesting, is unlikely to provide any clinically relevant finding regarding hCG and HG.We recently presented a multi-ancestry meta-analysis of 7,197 HG cases and 178,953 controls that confirmed GDF15 as the greatest genetic risk factor, but also replicated associations with placental genes insulin-like growth factor-binding protein 7 (IGFBP7 ) and progesterone receptor (PGR ).5 Therefore, resources would be better spent determining whether IGFBP7 and PGR alter GDF15 levels, and if not, elucidating their etiological role.Both GDF15 and hCG are present in pregnancy directly because of the placental genes that code for them, and yet while the GDF15gene was the most significant locus in 4 individual GWASes,5 none identified any association with genes encoding hCG. If hCG plays a secondary role in HG through upregulating GDF15, genetic variation causing higher levels or overactive hCG should show up in larger GWASes -so far it has not. The theory that hCG causes NVP and HG was a good one, and the lack of a genetic association was surprising. But the fascinating association with the nausea and vomiting hormone GDF15, a hormone highly expressed by the placenta, and the discovery of a mutation in GDF15resulting in > 10-fold increased risk for HG, strongly implicates GDF15 as a causal factor.2 This discovery leads to a potentially clinically relevant pathway for treatment of HG. Drugs that disrupt this pathway are currently in clinical trials to treat nausea and vomiting associated with cancer, and if safe in pregnancy, may be a game changer for HG. It is time to move on from hCG and focus on GDF15.Deruelle and Tranchant‘s letter, in press.Fejzo, M. S., MacGibbon, K. W., First, O., Quan, C., & Mullin, P. M. (2022). Whole-exome sequencing uncovers new variants in GDF15 associated with hyperemesis gravidarum. BJOG : an international journal of obstetrics and gynaecology , 129 (11), 1845–1852. https://doi.org/10.1111/1471-0528.17129Rull, K., & Laan, M. (2005). Expression of beta-subunit of HCG genes during normal and failed pregnancy. Human reproduction (Oxford, England) , 20 (12), 3360–3368. https://doi.org/10.1093/humrep/dei261Fejzo, M. S., Trovik, J., Grooten, I. J., Sridharan, K., Roseboom, T. J., Vikanes, Å., Painter, R. C., & Mullin, P. M. (2019). Nausea and vomiting of pregnancy and hyperemesis gravidarum. Nature reviews. Disease primers , 5 (1), 62. https://doi.org/10.1038/s41572-019-0110-3Fejzo M., Mulin P., Pujol Gualdo N., Laisk T., E. Biobank Research Team, MacGibbon K.W., Wang X., Mancuso N. (2022). Large-scale genome-wide association study meta-analysis of Hyperemesis Gravidarum confirms the nausea and vomiting hormonegene GDF15 is the greatest genetic risk factor and identifies additional risk loci. ASHG, Los Angeles, CA.

BJOG perspectives

Sexual Minority Individuals and Pregnancy Outcomes: A CommentaryJulie Croll, MPHa,b; Laura Sanapo, MD, MSHS, RDMSa,c; Ghada Bourjeily, MD, FCCPa,caWomen’s Medicine Collaborative at Lifespan, The Miriam Hospital, 146 West River Street, Providence, RI 02904, USAbRCSI University of Medicine and Health Sciences, School of Medicine, 123 St Stephen’s Green, Dublin 2, IrelandcWarren Alpert Medical School of Brown University, Department of Medicine, 222 Richmond Street, Providence, RI, USA

Mini-commentary on BJOG-19-1824.R1: Demographics, Natural History and Treatment Outcomes of Non-Molar Gestational Choriocarcinoma; A UK population study

Objective: Observational studies have described associations between obesity and adverse outcomes of pregnancy. Mendelian randomization (MR) takes advantage of the ‘natural’ genetic randomization to risk of an exposure such as body mass index (BMI) to study the effects of the exposure on outcomes. Similar to randomization in a clinical trial, this limits the potential for confounding and bias. Design: A two-sample MR study. Setting: Summary statistics from published genome wide association studies (GWAS) in European ancestry populations. Population or Sample: Instrumental variants for body mass index (BMI) were obtained from a study on 434,794 females. Female-specific genetic association estimates for outcomes were extracted from the sixth round of analysis of the FINNGEN cohort data. Methods: Inverse-variance weighted MR was used to assess the association between BMI and all outcomes. Sensitivity analyses with weighted median and MR-Egger were also performed. Results: A 1-SD increase in BMI was associated with higher risk of pre-eclampsia (OR 1.68, 95%CI 1.46-1.94, p=8.74x10-13), gestational diabetes (OR 1.67, 95%CI 1.46-1.92, p=5.35x10-14), polyhydramnios (OR 1.40, 95%CI 1.00-1.96, p=0.049). There was evidence suggestive of a potential association with higher risk of premature rupture of membranes (OR 1.16, 95%CI 1.00-1.36, p=0.050) and postpartum depression (OR 1.12, 95%CI 0.99-1.27, p=0.062). Conclusions: Higher maternal BMI is associated with marked increase in risk of pre-eclampsia, gestational diabetes and polyhydramnios. The relationship between BMI and premature rupture of membranes and postpartum depression should be assessed in further studies. Our study supports efforts to target BMI as a cardinal risk factor for maternal morbidity.

Covariate analysis query: Hospital surgical volume-outcome relationship in caesarean hysterectomy for placenta accreta spectrumOguljemal Redjepovaa, Jack Lowe-Zinolab, Christopher Griffinc

Objective To investigate associations of early and middle adulthood physical activity (PA) with symptoms of pelvic floor disorders (PFD), i.e. stress urinary incontinence (SUI), urge urinary incontinence (UUI), fecal incontinence (FI), constipation or defecation difficulties (CDD), and feeling of pelvic organ prolapse (POP) among middle-aged women. Design A cross-sectional, observational study with retrospective physical activity assessment. Setting University Research Laboratory. Sample A random population sample of 1098 47-to-55-year-old Finnish women. Methods PA history, current PA, and demographical and gynaecological variables were assessed using self-report questionnaires. Logistic regression analyses were applied to study associations of past and current PA with PFDs. Associations of demographical and gynaecological variables with PFDs were studied and their potential confounding effect was controlled in multiple logistic regression models. Main outcome measures Structured questionnaire-assessed retrospective physical activity history at the age of 17–29, current physical activity at middle age, and prevalence of SUI, UUI, FI, CDD and POP. Results Current PA was not independently associated with the occurrence of the PFDs. Middle-aged women with early adulthood history of competitive sports were more likely to experience UUI (OR 2.161, 95% CI 1.102–4.237, p=0.025) but not SUI, FI or POP, while women with history of regular PA were more likely to experience FI (OR 4.405, 95% CI 1.049–18.493, p=0.043) but not other PFDs. Conclusions Competitive sports during early adulthood may increase the risk of UUI at middle age. The history of regular PA may increase the risk of FI. Keywords Pelvic floor function, exercise, menopausal women