New approaches suggest term and preterm human fetal membranes may have distinct biomechanical properties

Preterm prelabour rupture of membranes is the leading cause of preterm birth and its associated infant mortality and morbidity. However, its underlying mechanism remains unknown. We utilized two novel biomechanical assessment techniques, ball indentation and Optical Coherence Elastography (OCE), to compare the mechanical properties and behaviours of term (≥ 37 weeks) and preterm (33-36 weeks) human fetal membranes from ruptured and non-ruptured regions. We defined the expression levels of collagen, sulfated glycosaminoglycans (sGAG), matrix metalloproteinase (MMP-9, MMP-13), fibronectin, and interleukin-1β (IL-1β) within membranes by biochemical analysis, immunohistochemical staining and Western blotting, both with and without simulated fetal movement forces on membrane rupture with a new loading system. Preterm membranes showed greater heterogeneity in mechanical properties/behaviours between ruptured and non-ruptured regions compared with their term counterparts (displacement rate: 36% vs. 15%; modulus: 125% vs. 34%; thickness: 93% vs. 30%; collagen content: 98% vs. 29%; sGAG: 85% vs 25%). Furthermore, simulated fetal movement forces triggered higher MMP-9, MMP-13 and IL-1β expression in preterm than term membranes, while nifedipine attenuated the observed increases in expression. In conclusion, the distinct biomechanical profiles of term and preterm membranes and the abnormal biochemical expression and activation by external forces in preterm membranes may provide insights into mechanisms of preterm rupture of membranes

Investigation of polycystic ovarian syndrome: variation in practice and impact on the speed of diagnosis

Objective Accurate diagnosis of polycystic ovarian syndrome (PCOS) enables clinical interventions/cardiometabolic risk factor management. Diagnosis can take over 2 years and multiple clinician contacts. We examined patterns of PCOS-associated biochemical investigations following initial consultation prior to pelvic ultrasound scan (USS). Methods We determined in 206 women (i) the range of different biochemical test panels used in the diagnosis of PCOS in primary/secondary care prior to USS relative to national guidance in the UK and (ii) the relation between testing patterns and time to USS to highlight potential delays introduced by inappropriate testing. Results In these 206 women, 47 different test combinations were requested at initial venepuncture; only 7 (3%) had the test panel suggested in UK guidance (follicle-stimulating hormone/luteinizing hormone/testosterone/sex hormone-binding globulin/prolactin). The number of tests performed prior to USS varied from one test to all seven tests. There was an inverse relation between the number of biochemistry tests requested at initial venepuncture episode and ‘time to scan’. Those who had <3 tests had a significantly longer time from first request to USS (median 70 days) than those with 3–7 tests (median 40 days; P = 0.002). One venepuncture episode prior to USS was associated with shorter ‘time to scan’ (median 29 days) than those with 2–4 episodes (median 255 days; P < 0.001). Conclusion There was no identifiable pattern to biochemical investigations requested as part of the initial diagnostic evaluation in women with suspected PCOS. We recommend standardization of the initial biochemical panel of analytes for PCOS workup, with incorporation into hospital/general practice ordering software systems

Temporal trends in pregnancy-associated stroke and its outcomes among women with hypertensive disorders of pregnancy

Funding PW is funded by a NIHR Transitional Research Fellowship. CCG is part-funded by West Midlands ARC. LCC is funded by a NIHR Professorship (RP-2014-05-019). This paper presents independent research funded by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. The funders had no involvement in the conduct of this research.Peer reviewedPublisher PD

Preeclampsia and Future Cardiovascular Health

Background—Preeclampsia is a pregnancy-specific disorder resulting in hypertension and multiorgan dysfunction. There is growing evidence that these effects persist after pregnancy. We aimed to systematically evaluate and quantify the evidence on the relationship between preeclampsia and the future risk of cardiovascular diseases.Methods and Results—We studied the future risk of heart failure, coronary heart disease, composite cardiovascular disease, death because of coronary heart or cardiovascular disease, stroke, and stroke death after preeclampsia. A systematic search of MEDLINE and EMBASE was performed to identify relevant studies. We used random-effects meta-analysis to determine the risk. Twenty-two studies were identified with >6.4 million women including >258?000 women with preeclampsia. Meta-analysis of studies that adjusted for potential confounders demonstrated that preeclampsia was independently associated with an increased risk of future heart failure (risk ratio [RR], 4.19; 95% confidence interval [CI], 2.09–8.38), coronary heart disease (RR, 2.50; 95% CI, 1.43–4.37), cardiovascular disease death (RR, 2.21; 95% CI, 1.83–2.66), and stroke (RR, 1.81; 95% CI, 1.29–2.55). Sensitivity analyses showed that preeclampsia continued to be associated with an increased risk of future coronary heart disease, heart failure, and stroke after adjusting for age (RR, 3.89; 95% CI, 1.83–8.26), body mass index (RR, 3.16; 95% CI, 1.41–7.07), and diabetes mellitus (RR, 4.19; 95% CI, 2.09–8.38).Conclusions—Preeclampsia is associated with a 4-fold increase in future incident heart failure and a 2-fold increased risk in coronary heart disease, stroke, and death because of coronary heart or cardiovascular disease. Our study highlights the importance of lifelong monitoring of cardiovascular risk factors in women with a history of preeclampsia

Pregnancy and neonatal outcomes of COVID-19: The PAN-COVID study

Objective To assess perinatal outcomes for pregnancies affected by suspected or confirmed SARS-CoV-2 infection. Methods Prospective, web-based registry. Pregnant women were invited to participate if they had suspected or confirmed SARS-CoV-2 infection between 1st January 2020 and 31st March 2021 to assess the impact of infection on maternal and perinatal outcomes including miscarriage, stillbirth, fetal growth restriction, pre-term birth and transmission to the infant. Results Between April 2020 and March 2021, the study recruited 8239 participants who had suspected or confirmed SARs-CoV-2 infection episodes in pregnancy between January 2020 and March 2021. Maternal death affected 14/8197 (0.2%) participants, 176/8187 (2.2%) of participants required ventilatory support. Pre-eclampsia affected 389/8189 (4.8%) participants, eclampsia was reported in 40/ 8024 (0.5%) of all participants. Stillbirth affected 35/8187 (0.4 %) participants. In participants delivering within 2 weeks of delivery 21/2686 (0.8 %) were affected by stillbirth compared with 8/4596 (0.2 %) delivering ≥ 2 weeks after infection (95 % CI 0.3–1.0). SGA affected 744/7696 (9.3 %) of livebirths, FGR affected 360/8175 (4.4 %) of all pregnancies. Pre-term birth occurred in 922/8066 (11.5%), the majority of these were indicated pre-term births, 220/7987 (2.8%) participants experienced spontaneous pre-term births. Early neonatal deaths affected 11/8050 livebirths. Of all neonates, 80/7993 (1.0%) tested positive for SARS-CoV-2. Conclusions Infection was associated with indicated pre-term birth, most commonly for fetal compromise. The overall proportions of women affected by SGA and FGR were not higher than expected, however there was the proportion affected by stillbirth in participants delivering within 2 weeks of infection was significantly higher than those delivering ≥ 2 weeks after infection. We suggest that clinicians’ threshold for delivery should be low if there are concerns with fetal movements or fetal heart rate monitoring in the time around infection

Fetal tissue engineering: Regenerative capacity of fetal stem cells

Considerable debate has focused on the contrasting merits of embryonic and adult stem cells. Fetal stem cells represent an intermediate cell type in this controversy. Adult stem cells have limited capacity to differentiate into fully functioning mature cell types of their tissue of origin (multipotent), whereas embryonic stem cells (ESCs) have the advantageous capacity to develop into all tissue types (pluripotent), including trophoblasts (totipotent). However, ESC research has been hampered by both safety concerns and ethical reservations due to requisite destruction of the blastocyst during harvesting. Transplantation of ESCs is almost invariably followed by the development of embryonal teratomas, precluding cell transplantation. On the other hand, adult stem cells have the advantage of greater accessibility, but the disadvantage of more limited proliferative capacity and restricted plasticity. Nevertheless, adult mesenchymal stem cells (MSCs) can differentiate into a range of mesoderm-derived tissues such as bone, fat and cartilage, while adult haemopoietic stem cells (HSCs) can reconstitute the haemopoietic system. The plasticity of ESC might seem to give them a therapeutic advantage over adult stem cells, whereas, in effect, this limits potential therapeutic application as a result of oncogenicity. So it is adult stem cells that hold promise for cell transplantation, while the eventual clinical use for ESCs is likely to be in tissue engineering applications

Muscular dystrophy cell therapy : an in utero approach using human fetal mesenchymal stem cells

Duchenne muscular dystrophy (DMD) is the most prevalent genetic neuromuscular disorder and affects 1 in 3,500 live male births. Lack of the protein dystrophin in muscle fibres causes permanent muscle damage, is lethal and despite various potential therapeutic strategies aimed at restoring dystrophin expression, has no cure. As DMD affects all skeletal muscles as well as the heart, a systemic treatment would be necessary and in utero stem cell transplantation is a promising way of achieving this. The identification of human fetal mesenchymal stem cells (hfMSC) in early gestation fetal blood offers the prospect of allogeneic or autologous cell therapy, while intrauterine administration would capitalise on ontological opportunities unique to the developing fetus. The aim of the study was to improve hfMSC engraftment and contribution to skeletal muscle fibres following intrauterine transplantation (IUT) in a mouse model of DMD. My project demonstrated that hfMSCs are easily isolated and expandable with the ability to undergo myogenesis in vitro. HfMSCs differentiated into mature myotubes following exposure to galectin-1 conditioned medium, while galectin-1 transduced hfMSCs showed significantly higher expression of myogenic markers compared to non-transduced hfMSCs. Co-culture experiments provided an in vitro model to explore the underlying mechanism for muscle differentiation of hfMSCs following IUT. HfMSCs were able to form chimeric myotubes by fusing with myoblasts isolated from E15 mouse embryos, evidence that they should be able to fuse with developing muscle fibres in vivo. Engraftment and differentiation into muscle fibres of hfMSCs injected intra-peritoneally into E15 mouse embryos in vivo was enhanced by using immunodeficient dystrophic host mice, postnatal muscle injury and additional neonatal hfMSC transplantation following IUT. In conclusion, my thesis supports the use of hfMSC as an attractive source for cell therapy and provides the background for further studies to optimise their engraftment and differentiation to underpin future clinical applications.EThOS - Electronic Theses Online ServiceWellbeing of Women and Institute of Obstetrics and Gynaecology TrustGBUnited Kingdo

Adverse pregnancy outcomes in pregnant women with chronic kidney disease: A systematic review and meta‐analysis

Background: Chronic kidney disease (CKD) is associated with an increased risk of adverse pregnancy outcomes, but the risk at different stages of CKD (defined by estimated glomerular filtration rate, eGFR) compared with women without CKD has not been quantified in large cohorts. Objectives: To quantify the association between CKD and adverse pregnancy outcomes according to CKD definition, CKD stage and presence or absence of diabetes. Search strategy: A systematic search of EMBASE and MEDLINE from inception to 5 January 2023. Selection criteria: English‐language randomised controlled trials as well as cohort and case–control studies investigating adverse pregnancy outcomes in pregnant women with CKD. Data collection and analysis: Two reviewers conducted independent data extractions. A random‐effects model was used to estimate risk. Main results: We included 19 studies with 3 251 902 women. Defining CKD using eGFR or serum creatinine produced results with greater effect size but wider confidence intervals. Compared with CKD stages 1–2, women with CKD stages 3–5 have a greater risk, but also greater imprecision in the risk estimate, of the following outcomes: pre‐eclampsia (OR 55.18, 95% CI 2.63–1157.68, vs OR 24.74, 95% CI 1.75–348.70), preterm birth (OR 20.24, 95% CI 2.85–143.75, vs OR 8.18, 95% CI 1.54–43.46) and neonatal intensive care unit admission (OR 19.32, 95% CI 3.07–121.68, vs OR 9.77, 95% CI 2.49–38.39). Women with diabetic kidney disease, compared with women without diabetic kidney disease, have higher risks of maternal mortality, small‐for‐gestational‐age neonates, pre‐eclampsia and gestational hypertension. Conclusions: There is heterogeneity in the definition of CKD in pregnancy. Future studies should consider ways to standardise its definition and measurement in pregnancy

Temporal Changes in Hypertensive Disorders of Pregnancy and Impact on Cardiovascular and Obstetric Outcomes

Hypertensive disorders of pregnancy (HDP) are a major cause of maternal morbidity. However, short-term outcomes of HDP subgroups remain unknown. Using National Inpatient Sample database, all delivery hospitalizations between 2004 and 2014 with or without HDP (preeclampsia/eclampsia, chronic hypertension, superimposed preeclampsia on chronic hypertension, and gestational hypertension) were analyzed to examine the association between HDP and adverse in-hospital outcomes. We identified >44 million delivery hospitalizations, within which the prevalence of HDP increased from 8% to 11% over a decade with increasing comorbidity burden. Women with chronic hypertension have higher risks of myocardial infarction, peripartum cardiomyopathy, arrhythmia, and stillbirth compared to women with preeclampsia. Out of all HDP subgroups, the superimposed preeclampsia population had the highest risk of stroke (odds ratio [OR] 7.83, 95% confidence interval [CI] 6.25 to 9.80), myocardial infarction (OR 5.20, 95% CI 3.11 to 8.69), peripartum cardiomyopathy (OR 4.37, 95% CI 3.64 to 5.26), preterm birth (OR 4.65, 95% CI 4.48 to 4.83), placental abruption (OR 2.22, 95% CI 2.09 to 2.36), and stillbirth (OR 1.78, 95% CI 1.66 to 1.92) compared to women without HDP. In conclusion, we are the first to evaluate chronic systemic hypertension without superimposed preeclampsia as a distinct subgroup in HDP and show that women with chronic systemic hypertension are at even higher risk of some adverse outcomes compared to women with preeclampsia. In conclusion, the chronic hypertension population, with and without superimposed preeclampsia, is a particularly high-risk group and may benefit from increased antenatal surveillance and the use of a prognostic risk assessment model incorporating HDP to stratify intrapartum care

Pregnancy-Associated Cancer: A Systematic Review and Meta-Analysis

This study aimed to systematically evaluate and quantify the risk of adverse maternal and neonatal outcomes in patients with pregnancy-associated cancer (PAC). This study was conducted from February 13, 2021, through July 24, 2023. A systematic search of MEDLINE, Embase, Web of Science Core Collection, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials was conducted to identify studies reporting outcomes for patients with PAC. The study was registered on PROSPERO. Two reviewers independently conducted screening, data extraction, and quality assessment. The associations were quantified using random-effects meta-analysis. The initial search produced 29,401 titles and abstracts, after which 147 unique full-text articles were screened, of which 22 articles with 59,190 pregnancies with PAC from 70,097,167 births were included in the meta-analysis. Women with PAC were at significantly increased risk of cesarean deliveries (risk ratio [RR], 1.58; 95% CI, 1.31-1.89), preterm birth (RR, 3.07; 95% CI, 2.37-3.98), venous thromboembolism (RR, 6.76; 95% CI, 5.08-8.99), and maternal death (RR, 41.58; 95% CI, 20.38-84.83). The only outcome with reduced risk was instrumental mode of delivery (RR, 0.67; 95% CI, 0.52-0.87). Pregnancy-associated cancer increases risk of adverse outcomes, including a 7-fold risk of venous thromboembolism and a 42-fold risk of maternal death. Further research is required to better understand the mechanisms leading to these adverse outcomes, especially for women who are not diagnosed until the postpartum period. Affected women should have counseling regarding their increased risk of adverse outcomes