Evaluating Serum HE4: Some Serious ConsiderationsAimen Waqar Khana, Hussain Haider Shahba: Department of Medicine, Jinnah Sindh Medical University, Karachi, Pakistan.b: Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan.Dear Dr Papageorghiou,We have perused with great interest the scholarly article ”Serum HE4 predicts progestin treatment response in endometrial cancer and atypical hyperplasia: A prognostic study” by Chloe Barr et al. [1]. We applaud the authors’ diligent efforts in investigating a biomarker that could independently predict the response to conservative therapy. However, we wish to draw attention to certain noteworthy aspects upon a comprehensive evaluation.Firstly, it is noteworthy that all the women who participated in the study underwent a preliminary endometrial biopsy before the initiation of progestin. However, there is no mention of whether women with relative contraindications such as cervical stenosis, coagulopathy or obstructive cervical lesions were sampled if they were included in the study. It is essential to consider these factors as they can significantly affect the accuracy and reliability of the biopsy results. Furthermore, it is necessary to note that insufficient tissue sampling is a common complication of endometrial biopsy, with an average of 31% of tissues obtained requiring improvement [2]. Considering that this is typically more prevalent in postmenopausal women, and 61% of the participants were 50 years or older, it is crucial to standardize the volume of tissue obtained to ensure fair and precise results. As outlined in the study, the primary form of progestin therapy was levonorgestrel-releasing intrauterine system (LNG-IUS). Still, for women whose devices had been misplaced more than once, an alternative treatment of oral medroxyprogesterone acetate 500mg was administered twice daily. This raises a concern regarding whether these women were closely monitored for compliance with the prescribed treatment regimen. This is particularly important as non-compliance, particularly with extended oral therapies, is a common issue that, if present, could skew the study’s findings. The prognostic potential of pretreatment serum HE4 in predicting therapeutic response has been extensively researched; however, studies have also reported elevated serum HE4 levels in various other cancers, including ovarian, pancreatic, breast, lung, and stomach [3]. Therefore, it is crucial to exclude such patients thoroughly, as their inclusion could lead to inaccurate results by falsely accounting for the non-responder count.Moreover, serum HE4 levels are also known to be influenced by renal function and status, necessitating adjustment [4]. It is, therefore, essential to consider and standardize these factors when analyzing the serum HE4 levels to obtain reliable and valid results. Lastly, it should be noted that a CLEIA technique was employed for analysis, which has been reported to significantly overestimate serum HE4 as compared to EIA [5]. This may raise concerns regarding the validity of the reported findings, and hence, caution must be exercised when interpreting the results.The study focused on endometrial biopsy in women receiving progestin therapy, but potential complications such as insufficient tissue sampling and the inclusion of women with contraindications were not addressed. The study primarily used LNG-IUS but also administered oral medroxyprogesterone acetate, and compliance monitoring was not discussed. Serum HE4 levels were examined, but patients with other cancers or renal issues were not excluded, and the CLEIA technique used for analysis may have overestimated results. Therefore, caution is necessary when interpreting the findings of this study.

Pelvic dimensions and hypotheses on duration of active second stage of labourTilde Broach OstborgStavanger University HospitalTM EggeboTrondheium University HospitalWe would like to thank Jan Novák and Petr Sedlak for their interest and comments to our manuscript. We found that increasing BMI was associated with shorter estimated median duration of the active second stage of labour.1We could not find any obvious causal mechanism for our findings; but suggested some possible explanations. The shorter active second stage may be related to increased abdominal pressure with increasing BMI, or perhaps increased strength when pushing.2, 3 Increased infiltration of fat in the muscular pelvic floor may decrease its strength and resistance.4 The presence of fat in the birth canal of obese women may delay the urge to bear down, thereby postponing active pushing until the head is lower in the maternal pelvis.Novak et al. measured the bi-ilac and bi-cristal diameters of the greater pelvis and found a broader pelvis in individuals with a history of obesity from adolescence.5 We supposed that there would be an association between the size of the greater pelvis and the size of the birth canal. We agree to the limitations commented by Novák and Sedlak. However, our proposed causal mechanisms are merely hypotheses, and cannot be accepted nor rejected based on current knowledge.1. Ostborg TB, Sande RK, Kessler J, Tappert C, von Brandis P, Eggebo TM. Put your weight behind it-Effect of body mass index on the active second stage of labour: A retrospective cohort study. BJOG. 2022;129:2166-2174.2. Lambert DM, Marceau S, Forse RA. Intra-abdominal pressure in the morbidly obese. Obes Surg. 2005;15:1225-1232.3. Tomlinson DJ, Erskine RM, Morse CI, Winwood K, Onambele-Pearson G. The impact of obesity on skeletal muscle strength and structure through adolescence to old age. Biogerontology. 2016;17:467-483.4. Pomian A, Lisik W, Kosieradzki M, Barcz E. Obesity and Pelvic Floor Disorders: A Review of the Literature. Med Sci Monit. 2016;22:1880-1886.5. Novak JM, Bruzek J, Zamrazilova H, Vankova M, Hill M, Sedlak P. The relationship between adolescent obesity and pelvis dimensions in adulthood: a retrospective longitudinal study. PeerJ. 2020;8:e8951.

Symphysis-Fundus Measurement; the Human Factor

BJOG-22-0767.R1 Multimorbidity warrants a proactive management of pregnancy in cancer survivors

BJOG-22-1117.R1: Are Kielland’s Forceps a Safe Option for Birth?Kielland’s rotational forceps deliveries often divide opinion, deriving reactions akin to Marmite, the notorious UK spread. Love or hate them, as many maternity professionals do, what does the current evidence say?The aim of the meta-analysis by Giacchino et al was to estimate the risk of maternal and neonatal complications following Kielland’s births more accurately, when compared with rotational ventouse, non-rotational forceps birth and second stage caesarean section. The authors included 13 observational studies, all published after 2000 to reflect current practice and reported meta-analyses using a random-effects model to allow for clinical heterogeneity.Unsurprisingly, the authors found that Kielland’s births had lower rate of post-partum haemorrhage and of a low 5-minute Apgar score compared to second-stage caesarean. When the cervix is fully dilated, a caesarean has been yet again shown not to be the best ‘way out’, except when it becomes the only ‘way out’ after a failed attempt at instrumental vaginal birth. They also found that babies born by Kielland’s had lower prevalence of significant trauma compared to rotational ventouse, similar to Al-Wattar et al (Curr Opin Obstet Gynaecol 2015;27(6):438-44). This is hardly surprising; despite their notoriety, Kielland’s in the hands of a trained experienced accoucheur can be applied to posterior and transverse malposition, prematurity, face presentation, and in the presence of significant caput. They can also be used for ‘asynclitic occipito-anterior’, a term which has crept into practice in the last couple of decades to describe an occiput more than 45 degrees from the midline where non-rotational forceps could not and should not be used. In observational studies in single centres with expertise, including the papers included in Giacchino et al, Kielland’s are highly effective.Which brings us to key issues not addressed in the review by Giacchino et al. Who is trained nowadays to use Kielland’s safely? And are they safe enough for women’s perineum? In a national UK audit (Tempest et al. Acta Obstet Gynecol Scand 2020;99:537-45) Kiellands were used less often than other methods, particularly for transverse occiput positions. When they were used, the rate of anal sphincter injury was higher with Kielland’s compared to manual rotation.ROTATE, a multicentre RCT in the UK, aims to address these issues with robust methods, and also examine other important outcomes including mental health and continence (https://fundingawards.nihr.ac.uk/award/NIHR127818). Concurrently, innovative research with nano-sensors (Jaufuraully et al, BJOG 2022;129:71) has the potential to make rotational birth techniques safer and more effective regardless of the method used.Such research may take a while before it produces findings applicable to clinical practice. In the meantime, it remains critical to train accoucheurs appropriately, for example with courses such as ROBUST and ART&CRAFT in the UK; but also to propagate good clinical practice beyond isolated silos, before obstetricians become completely deskilled globally. A possible solution would be for centres of excellence in rotational birth to offer apprenticeships to senior obstetricians from other maternity units. Training junior accoucheurs cannot translate into safer practice unless their mentors are also trained and confident to supervise them.

A document by Raymond De Vries. Click on the document to view its contents.

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.

Thorough Assessment of Pain is the key to diagnosis and Management: Letter to Editor

OBJECTIVE To assess the relationship between allostatic load in early pregnancy and CVD, 2 to 7 years postpartum, and potential pathways contributing to racial disparities in CVDs. DESIGN Secondary analysis of an observational cohort study. SETTING nuMom2b Heart Health Study. POPULATION Pregnant individuals. METHODS Our primary exposure was dichotomous high allostatic load in the first trimester, defined as four or more out of 12 biomarkers in the “worst” quartile. The primary outcome was new diagnosis of composite CVD, consisting of HTN and or MD (fasting glucose greater than 100 mg/dL or medication for diabetes). Each outcome and allostatic load component was analyzed secondarily. Multivariable logistic regression was used to test the association between high allostatic load and CVD adjusted for potential confounders. Mediation and moderation analyses assessed the role of high allostatic load in racial disparities of CVD. MAIN OUTCOME MEASURE Composite CVD. RESULTS Among 4,022 individuals, CVD was identified in 1,462 (36.4%); 26.6% had HTN, and had 15.4% MD. High allostatic load was present in 33.0%. After adjustment for covariates, high allostatic load was associated with CVD (aOR 2.0, 1.8-2.3), HTN (2.1, 1.8-2.4), and MD (1.7, 1.5-2.1). There was a reduction in the magnitude of the relationship between race and CVD with the addition of allostatic load. Self-reported race did not significantly moderate the relationship between allostatic load and CVD. CONCLUSION High allostatic load is associated with CVD. Allostatic load was a partial mediator between race and CVD. Race did not moderate the relationship between allostatic load and CVD.

Reduced fetal movements: time to move on?Lawrence Impey, BA, FRCOG. Department of Fetal Medicine, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, and Nuffield Department of Women’s Reproductive Health, John Radcliffe Hospital, Oxford University, Oxford, OX3 9DU, United KingdomNatalia Abadi-Cuchi MD. Servicio de Ginecologia y Obstetricia, Hospital Clinico Unversitario Lozano Blesa, Avda. San Juan Bosco 15, 50009, Zaragoza, SpainCorresponding author:Lawrence ImpeyEmail: lawrence.impey@ouh.nhs.ukTel: +44 1865 851165ORCID 0000-0002-4462-112XRunning title: Reduced fetal movements: time to move on?The authors declare no conflict of interestsBoth authors contributed to the conception and writing up of this commentaryWord count: 1445 words

Objective: To determine SARS-CoV-2 seroprevalence in a UK pregnancy cohort and assess associations with demographic factors and vaccination timing. Design: Observational cohort study. Setting: UK inner-city maternity centre. Sample: 960 pregnant women attending nuchal scans from July 2020-January 2022. Methods: Blood samples were tested for IgG antibodies against SARS-CoV-2 nucleocapsid (N) and spike (S) proteins. Self-reported demographics, vaccination status and previous Covid-19 infection were extracted from health records. Multivariable regression models determined factors associated with seroprevalence and antibody titers. Main outcome measures: IgG N- and S-protein antibody titers. Results: 196/960 (20.4%) women were SARS-CoV-2 seropositive from previous infection. Of these, 70 (35.7%) self-reported previous infection. Amongst unvaccinated women, black women were most likely to be SARS-CoV-2 seropositive (aRR 1.88 [95% CI, 1.35-2.61], P < 0.001). Women from black and mixed ethnic backgrounds were least likely to have a history of vaccination with seropositivity to S-protein (aRR 0.58 [95% CI, 0.40-0.84], P = 0.004 and aRR 0.56 [95% CI, 0.34-0.92], P = 0.021 respectively). Double vaccinated, previously infected women had higher IgG S-protein antibody titers than unvaccinated, previously infected women (mean difference: 4.76, 95% CI = [2.65, 6.86], P < 0.001). Vaccination timing before vs during pregnancy did not significantly affect IgG S antibody titers (F(1, 77) = [0.07], P = 0.785). Conclusions: This inner-city pregnancy cohort demonstrates high rates of asymptomatic SARS-CoV-2 infection with women of black ethnicity having higher infection risk and lower vaccine uptake. SARS-CoV-2 antibody titers were highest among double vaccinated, previously infected women.

Short Commentary: Laser versus Sham for Genitourinary Syndrome of Menopause: a Randomised Controlled Trial

Abstract Objective: To compare rates of urinary retention and postoperative urinary tract infection between women with immediate versus delayed removal of indwelling catheter following benign non-hysterectomy gynecological laparoscopic surgery. Design: This randomized clinical trial was conducted between February 2012 and December 2019, with follow-up to six weeks, in two university-affiliated hospitals in Sydney, Australia. Population: Study participants were 693 women over 18 years of age, undergoing non-hysterectomy laparoscopy for benign gynecological conditions, excluding pelvic floor or concomitant bowel surgery. Methods: 355 participants were randomized to immediate, and 338 to delayed removal of urinary catheter. Main Outcome Measures: The co-primary outcomes were urinary retention (assessed by trial of void and need to re-catheterize) and urinary tract infection. Secondary outcomes included readmission, analgesia requirements, duration of hospitalization and validated bladder function questionnaires. Results: Urinary retention for participants in the immediate removal group was statistically higher at 8.2% (95% CI: 5.7% to 11.4%) vs. 4.2% (95% CI: 2.7% to 7.2%) in the delayed removal group (p=.03). There was no statistically significant difference in the rates of urinary tract infection between the groups at 7.2% (95% CI:4.7% to 10.8%) in the delayed group vs. 4.7% (95% CI: 2.8% to 7.8%) in the immediate group. Conclusions: Rates of urinary retention and urinary tract infection following non-hysterectomy benign gynecological laparoscopy are low. There is a small increased risk of urinary retention with immediate compared with delayed removal of urinary catheter. These findings can be used to counsel patients regarding postoperative bladder care.

Objective Assess whether coronavirus disease 2019 (COVID-19) vaccination impacts menstrual bleeding quantity. Design Retrospective cohort Setting Five global regions Populations Vaccinated and unvaccinated regularly cycling individuals using the digital fertility-awareness application “Natural Cycles”. Methods We used prospectively collected menstrual cycle data and multivariable longitudinal Poisson GEE models, multivariable multinomial logistic regression models, and calculated the adjusted difference between vaccination groups. All regression models were adjusted for confounders. Outcome measures Mean number of heavy bleeding days (fewer, no change, more) and changes in bleeding quantity (less, no change, more) at three time points (first dose, second dose, and post-exposure menses). Results We included 9,555 individuals (7,401 vaccinated, 2,154 unvaccinated). About 2/3 of individuals reported no change in the number of heavy bleeding days regardless of vaccination status. After adjusting for confounders, there were no significant differences in the number of heavy bleeding days by vaccination status. A larger proportion of vaccinated individuals experienced an increase in total bleeding quantity (34.5% unvaccinated, 38.4% vaccinated; 4.0% [0.7, 7.2%] adjusted difference). This translates to an estimated 40 additional people per 1,000 normally cycling individuals who experience more total bleeding quantity following the first vaccine dose due to vaccination. Differences resolved in the cycle post-exposure. Conclusion A small increase in the probability of more total bleeding quantity occurs following the first COVID-19 vaccine dose which resolved the cycle post-vaccination cycle. Total number of heavy bleeding days did not differ by vaccination status. Our findings can reassure the public that any changes are small and transie

JOURNAL: BJOGDATE 08_25_2022TITLE: Mini commentary on “Familial aggregation of stillbirth: a pedigree analysis of a matched case control study” BJOG_22-0217Author: Matthew A. Shear, MDa,bAuthor Affiliations:a Department of Obstetrics, Gynecology, & Reproductive Sciences, University of California, San Franciscob Division of Medical Genetics, Department of Pediatrics, University of California, San FranciscoDespite advances in genomics, the underlying cause of many stillbirths remains elusive. The emotional toll that a stillbirth takes on families, as well as the providers caring for them, is hard to overstate. Karyotype may identify a causative aneuploidy or large unbalanced translocation, but only in about 6% of stillbirths. Chromosomal microarray is higher yield, but still only identifies pathogenic copy number variants in about 10% of stillbirth cases (Reddy et al. N Engl J Med. 2012). The addition of exome sequencing to microarray only yielded a plausible genetic explanation in 15 out of 246 cases, or about 6% (Stanley et al. N Engl J Med. 2020). This suggested that non-mendelian mechanisms may play a significant role in stillbirth (Wojcik et al N. Engl J Med. 2020), although single gene pathogenic variants are poorly understood at the fetal level relative to the postnatal setting. The non-genetic mechanisms underlying stillbirth are also poorly understood at present, including viral infections, environmental toxins, and comorbid conditions.Workalemahu and their colleagues present a unique analysis suggesting genomic heritability of stillbirth in some families. Using a robust matched case-control study of over 9000 stillbirths and 390 high-risk pedigrees from the Utah Population Database, they calculated the familial standardized incidence ratio and risk of stillbirth among first, second, and third-degree relatives of the pregnant individuals who had experienced stillbirth. In their adjusted model, among all relatives of an individual who experienced stillbirth, there was a relative risk of stillbirth of 1.1 (95% CI 1.00-1.22). This study adds further evidence there are heritable genetic etiologies of stillbirth not yet fully described.Many non-genetic contributors to stillbirth risk may also cluster in families. In the present study, when adjusting for maternal race/ethnicity, socioeconomic status, and education, the elevations in stillbirth risk became attenuated, although this may be due to collinearity among variables used in the model. Health behaviors are informed through regional and family culture, leading to patterns in diet, nutrition, and exercise. These patterns contribute to modifiable health conditions known to impact stillbirth risk, including hypertension, obesity, diabetes, and smoking status. We also know the incidence of stillbirth is higher in lower income versus higher income countries, higher among individuals of lower educational attainment versus higher education, and higher among African American and Black individuals compared to White, likely complicated by the impacts of systemic racism. This is to say nothing of the additional social determinants of health that may impact families across generations.As Workalemahu and colleagues note, there is still much unknown about complex outcomes such as stillbirth. Their findings support that for a patient with a high-risk pedigree, genomic testing may prove informative. Future epigenetic and functional studies may help understand variants at the tissue level, and the impact of comorbidities on gene expression. Together with fetal genome sequencing, previously unexplained cases of stillbirth might be solved, improving patient counseling, and possibly changing clinical management. While genomic testing offers promise to explain a subset of stillbirths, we should not neglect the “non-mendelian” and non-genetic factors that continue to play a significant role in stillbirth risk.

BJOG-22-0382.R1: Implementing Effective Investigations for Cause of StillbirthElizabeth M McClure, PhDRobert L Goldenberg, MDRTI International, Durham, NCColumbia University, New York, NYStillbirth is one of the most common adverse pregnancy outcomes in low and middle-income countries (LMICs), with rates in the range of 40 to 50 per thousand births in some regions [1]. International goals aim for no country to have a rate of >10 per thousand births by 2035 [Hug L, et al. Lancet. 2021;398(10302):772-85]. To achieve this, a better understanding of stillbirth causes often requiring additional investigations is critical. For several reasons, including low prioritization, inadequate resources, and hesitancy by families and providers, investigations on stillbirth causes in LMICs have been limited to date.Bedwell et al used a grounded theory approach to explore the views of women, partners, families, health workers and community leaders in Malawi, Tanzania, and Zambia regarding investigations to determine the cause(s) of stillbirth [Bedwell et al, BJOG (in press)]. While most would like more information regarding the stillbirth, the authors noted cultural and religious obstacles to performing the investigations, including preferences for quick burial, reluctance to disfigure the deceased fetus, concerns about blame, as well as costs.One test to inform cause of stillbirths is minimally invasive tissue sampling (MITS), using needle biopsies to obtain internal organ tissue for histological evaluation and microbial analyses. For a study on causes of stillbirth in Pakistan and India, we explored the acceptability of MITS among parents, relatives, religious leaders, and government officials [Feroz A, et al. Reprod Health.2019;16(1):53]. The perceived benefits included knowing the cause of death, and both personal and societal benefits in preventing subsequent stillbirths. Concerns regarded rapid burial and reluctance to disfigure the stillborn. In Pakistan, with some caveats, religious leaders approved, and, when MITS was undertaken, in both Pakistan and India, approximately 50% of the parents consented for the MITS procedure.Because obstacles to testing in general and to MITS specifically relate to time, cost, and disfigurement, we have considered which examinations feasible in LMICs provide the most information at minimal cost. Page et al., in a similar exercise in a US study, noted that the most useful test was placental histology (65%) followed by full autopsy (42%) [Page JM, Obstet Gynecol 2017;129(4):699-706.]. No other tests were useful for >12% of cases. Similar studies have rarely been performed in LMICs. The prevalence of the causes relates to the frequency of tests’ usefulness. In high-income countries where birth asphyxia and infection have been reduced, congenital and genetic anomalies have assumed a larger proportion of stillbirths, and testing for those conditions using karyotyping and other genetic tests become proportionately more important. However, in many LMICs, birth asphyxia remains the major cause of stillbirth and genetic issues play a smaller proportional role.To develop the most effective methodology to determine cause of stillbirth, the prevalent conditions, and the tests’ usefulness to diagnose those conditions should be considered together. Importantly, the community and other stakeholder’s perceived benefits and obstacles to various tests as described in the Bedwell, et al must be considered to ultimately be successful in implementing the necessary investigations.For LMICs, given that asphyxia and infection appear to be major causes of stillbirth, tests to diagnose these conditions will likely be important to implement, including the obstetric history and histological placental evaluation for diagnosing asphyxia and infection. Of potential information gained from MITS, histology of the fetal lung, and bacteriological assessment of the fetal blood and brain/CSF may be the most useful. Thus, by considering the prevalence of the causes of stillbirth, the usefulness of tests to diagnose the prevalent conditions, and importantly addressing the community’s sense of benefit and obstacles, an effective approach to stillbirth cause of death investigation can be developed.Declaration of Interest: The authors declare no conflicts of interest.

Objective: To evaluate the reasons for COVID-19 vaccine hesitancy during pregnancy from first-person reports. Design: We used regular expressions to identify publicly available social media posts from pregnant people expressing at least one reason for their decision not to accept COVID-19 vaccine. Setting: WhatToExpect and Twitter. Sample: 1017 posts from 945 pregnant people in WhatToExpect and 435 tweets from 345 pregnant people in Twitter Methods: Two annotators manually coded posts according to the Scientific Advisory Group for Emergencies (SAGE) working group’s 3Cs model of vaccine hesitancy (confidence, complacency, and convenience barriers). Within each theme we created subthemes which emerged from the data. Results: Confidence barriers were the most common (75%) and were related to safety, waiting until after the 2nd trimester, birth or breastfeeding, efficacy, misinformation or mistrust. Complacency barriers were also common (52%) with people stating that they did not need the vaccine because they were taking other precautions, were not at risk or had already had COVID-19. Convenience barriers were the least common (13%) with most of these related to medical advice or eligibility. Some women gave more than one reason for their hesitancy and many of the reasons were inter-linked. Conclusion: The reasons for COVID-19 vaccine hesitancy during pregnancy give a clear picture of the public health messages required. Concerns around safety should be addressed in a sensitive manner. The relative effectiveness of the vaccine as compared with other precautions could be better promoted as could the high-risk nature of a COVID-19 infection during pregnancy.

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