Marcilly En Villette, France

Diamine Oxidase and Adverse Pregnancy Outcomes

Aspirin for the Prevention of Preeclampsia and Pregnancy Outcomes After Assisted Reproductive Technology

Preeclampsia (PE) affects 2% of pregnancies in France and is an important cause of maternal and perinatal mortality and morbidity. Aspirin is currently the only prophylactic therapy for PE in high-risk women when initiated before 16 weeks of gestation and at a daily dose of 100-160 mg, with a reduction in the incidence of preterm preeclampsia of 60-70% in recent meta-analysis. Latest data also demonstrate a potential beneficial effect of aspirin on spontaneous preterm birth. A major challenge in modern obstetrics is early identification of pregnant women at high-risk of PE who could benefit from aspirin treatment. In France, the College National des Gynécologues et Obstétriciens Français and the Société Française d'HyperTension Artérielle have restrictive recommendation of aspirin to be prescribed only to women with a history of PE or vascular intra-uterine growth restriction, thus leaving out all nulliparous women (including those with multiple risk factors). Other countries (USA, United Kingdom (UK), Canada) have much broader recommendations with aspirin prescription for patients with one high or 2 moderate risk factors, but exposing nearly 30% of pregnant women to aspirin (leading to unnecessary exposure to treatment). The Fetal Medicine Foundation provides a screening test combining clinical parameters, uterine artery Doppler, and biomarkers; but this strategy has high false-positive rate and the reproducibility needs to be confirmed in clinical practice. It seems necessary to be able to better target women at risk, especially in nulliparous women. Nulliparity and assisted reproductive technology (ART) are independent risk factors for PE. Currently the proportion of pregnancy after ART in France is roughly 6.9% and is rising. Nulliparous ART pregnant women have a higher risk of PE and preterm birth. Indeed, they commonly cumulate risk factors including age>35years in association with nulliparity and ART. The rate of PE in this population can rise up to 10%. Our hypothesis is that nulliparous pregnant women after ART are at high risk of preeclampsia and perinatal complications and represent a subgroup for which aspirin prophylaxis during pregnancy may be effective in the prevention of preterm preeclampsia and other perinatal adverse outcomes.

Comparative Effects of Jacobson's Relaxation Techniques and Stretching Exercises in Preeclampsia

The effectiveness of Jacobson's progressive muscle relaxation technique on maternal, fetal, and neonatal outcomes in women with non-severe preeclampsiain have been studied in an RCT study. Pregnant women who use this technique experience reduced muscle tension and a sense of calm. in one of the study The Effect of Relaxation Techniques on Blood Pressure and Stress Among Pregnant Women with Mild Pregnancy Induced Hypertension were investigated in which Women with mild pregnancy-induced hypertension who used relaxation techniques saw significant improvements in their knowledge, physiological parameters, and blood pressure as well as a reduction in stress. To the best of the researcher's knowledge, no comparative study has been done to yet to evaluate the efficacy of relaxation and stretching exercise. There is not enough data to determine whether Jacobson's relaxation techniques and stretching exercise reduce preeclampsia in pregnant women. As a result, this study will contribute to the expanding body of knowledge about which approach should be used as an alternative if results from other procedures are comparable

Efficacy of Hydrogen Peroxide ( H2O2) in Controlling Placental Site Bleeding in Caesarian Delivery for Placenta Previa / Accreta Spectrum ( PAS)

- Population of study: A total of 84 pregnant patients with placenta previa / Accreta spectrum. - Study location: Obstetrics and Gynecology Kasr Al-Ainy Hospital , Faculty of Medicine , Cairo University. The aim of the study is to evaluate the efficacy of hydrogen peroxide for controlling bleeding from placental bed in caesarian section for placenta previa/ Accreta spectrum (PAS). • This is a randomized controlled trial including a total number of 84 patients representing study group , randomized in 2 equal groups , using computer generated randomization sheet on (Medcalc ®) . Group A : hydrogen peroxide group (n=42) Group B : control group (normal Saline solution) (n=42) .

Topical Adrenaline Versus Warm Saline Solution for Minimizing Intraperitoneal Bleeding During Caesarian Delivery for Placenta Previa / Accreta Spectrum ( PAS)

- Population of study: A total of 84 pregnant patients with placenta previa / Accreta spectrum. - Study location: Obstetrics and Gynecology Kasr Al-Ainy Hospital , Faculty of Medicine , Cairo University. This is a randomized controlled trial including a total number of 84 patients representing study group , randomized in 2 equal groups , using computer generated randomization sheet on (Medcalc ®) . Group A : Topical adrenaline group (n=42) Group B : Warm saline Group (control) (n=42) The aim of the study is to evaluate the efficacy of topical adrenaline for decreasing intraperitoneal bleeding during caesarian section for placenta previa/ Accreta spectrum (PAS).

Effect of Foot Reflexology on Preeclampsia

Preeclampsia is defined as arterial hypertension identified for the first time after the 20th week associated with proteinuria. It affects 5% to 7% of all pregnant women. It is more common in primigravida women, women with previous early onset preeclampsia, in age greater than 40 years, previous history of preeclampsia, pre-pregnancy obesity, women who become pregnant with donor eggs, embryo donation and donor insemination. It is responsible for over 70 000 maternal deaths and 500 000 fetal deaths worldwide every year. There are many risk factors for it as: Hypertension, diabetes mellitus, proteinuria, obesity, family history, null parity, multiple pregnancies, use of contraception, older women conception (> 40) and thrombotic vascular disease,edema, renal failure, liver failure and hellp syndrome.Complementary therapies such as massage and foot reflexology are used with patients of preeclampsia, it is to normalize the body's function, break down tension, alleviate stress, improve nerve function and blood supply throughout the body. this trial has two groups; one will receive anti-hypertensive drugs and the second will receive anti-hypertensive drugs+foot reflexology sessions for 8 weeks (30 min, 2 session/ week).

The Microbiome in (Non-) Obese Pregnancy and Pregnancy Outcomes

With the increasing global prevalence of obesity, pregnancy problems related to maternal obesity are increasingly occurring. Microbial gut symbiosis plays an important role in health, with dysbiosis being associated with diseases such as obesity. Of interest are pregnancy, dietary patterns and pre- or probiotics that affect the composition of the gut microbiome. The microbiome itself can influence many physiological processes, such as immune responses (production of microbial products) and the nutrient-dependent one-carbon metabolism. It is hypothesized that gut dysbiosis, due to maternal obesity, during pregnancy can be considered an endogenous chronic stressor causing impaired immune response and carbon metabolism. Both processes result in excessive oxidative stress, detrimental to cell replication, differentiation and epigenetic programming of maternal and infant tissues. Together, these biological disturbances contribute to placental and vascular dysfunction, leading to an increased risk of preeclampsia or gestational diabetes mellitus. Vertical (during pregnancy) and horizontal (during delivery) transmission of gut dysbiosis from mother to newborn and epigenetic placental and foetal changes may ultimately lead to macrosomia and obesity in children. Therefore, the differences between the gut and vaginal microbiome, maternal and fetal immune responses and one-carbon metabolism in obese versus normal-weight pregnant women will be analysed.

At High-risk for Pre-eclampsia After Assisted Reproductive Technology

Background: Pre-eclampsia (PE) is a multisystemic syndrome occurring in 4-5% of pregnant women. It is defined by a new-onset hypertension (HT) developing after 20 weeks of gestation in combination with one of the following entities: proteinuria, maternal organ dysfunction and/or uteroplacental insufficiency. The vicious circle of the syndrome can end up in life-threatening complications for mother and child and, today, the only treatment of cure is the induction of delivery. Furthermore, besides the problems in the acute phase of the disease, women who experienced PE have been shown to have an increased lifetime risk of developing cardiovascular disease (CVD) and chronic kidney disease, while the children carry the consequences of their prematurity and, often following intra-uterine growth restriction, also seem to be more prone to develop metabolic disturbances like diabetes, HT and CVD later in life. Research, including data publishes by my own research group, shows that the risk of PE development in subfertile patients undergoing assisted reproductive technology (ART), is more than doubled, with incidences between 8-12%. ART includes in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), using autologous or heterologous gametes, followed by fresh or frozen embryo transfer. The increased risk of PE within this population has mainly been attributed to known maternal PE risk factors associated with ART like increased maternal age, nulliparity and metabolic disturbances e.g. in patients with polycystic ovary syndrome (PCOS). Recent studies however have shown that ART is an independent risk factor of PE. More specifically, a higher PE incidence is consistently observed when patients have a frozen embryo transfer (FET) in an artificially prepared cycle. Unlike in a natural cycle in which ovulation occurs, an artificial cycle is characterized by the absence of ovulation as the luteal phase is induced by exogenous progesterone administration. It has been put forward that the absence of the corpus luteum, producing vasoactive and angiogenic substances (e.g. VEG-F, relaxin) and thereby orchestrating a correct placental development, could be held responsible for this observation. Other high risk ART patients are recipients of heterologous oocytes (i.e. oocyte recipients) potentially due to immunological conflicts. In 2016, the ASPRE trial published their results evaluating a new first trimester screening tool developed by the fetal medicine foundation (FMF). This algorithm takes into account a limited number of anamnestic maternal characteristics, maternal blood pressure, the measurement of placental growth factor (PlGF) as a serum biomarker and the ultrasonographic measurement of the pulsatility index of the uterine artery. When an increased risk of PE had been detected (>1/100), aspirin daily is given, starting before 16 weeks' of gestation. As of May 2021, the FMF first trimester screening for PE is offered in the Brussels IVF fertility clinic to all the above-described high-risk patients pregnant following ART (PCOS and oocyte recipients included). Preliminary data confirm a high incidence of positive screening with an overall risk of 18%, reaching upto 27% in oocyte recipients (compared to the reported 10% in the general population following spontaneous conception). To the best of our knowledge, the applicability of the screening tool and aspirin administration for PE prevention has never been specifically evaluated post-ART. PE etiopathogenesis is complex and the exact molecular causative processes are still being unraveled. PE has a wide range of clinical presentations and it is currently unknown what drives these differences. Of critical importance for instance is the difference between early onset pre-eclampsia (EOPE), defined as PE occurring before 34 weeks of gestation and late onset pre-eclampsia (LOPE), defined as PE occurring at or after 34 weeks of gestation. In EOPE, which is mainly a placental disease, the impaired invasion of the spiral arteries by the extravillous cytotrofoblast cells has been put forward as the key pathophysiological component. This in contrary to LOPE, which is seen as a maternal disease, where there is a discrepancy between fetal growth, aging of the placenta an the maternal supply and cardiovascular reserve. Further, single-cell RNA sequencing on placentas confirmed the extensive different expressed genes between EOPE and LOPE. Also, the role of different serum markers (PlGF, sFLT-1, VEGF, leptin, annexin…) have been studied, but their contribution to EOPE and LOPE still remains unclear. Lastly, very limited but intriguing research data suggest that the preconceptional endometrium could be implicated in PE development during pregnancy, with the focus on impaired decidualization and its role in PE origin. Given the differences in patient characteristics between the above-mentioned ART subgroups at risk for PE, our research team expects their PE-etiopathogenesis to be diverse. Though the multidisciplinary approach of this project, both on a clinical and fundamental research level, we hope to unravel pre-eclampsia, a multifactorial disease, and this in specific relation to different ART high-risk groups. This way, ultimately, the results will point towards targets for prevention and treatment of PE following ART and will contribute to a decrease in the morbidity and mortality associated with this devastating disease, for which, currently, no cure but termination of the pregnancy is available. Hypothesis: Work package 1a: there is a significant difference in preconceptional maternal characteristics between ART patients screening positive/developing PE and ART patients screening negative/not developing PE and these identified risk factors are specific for each ART subgroup. Work package 1b: preconceptionally harvested endometrial tissue/stromal cells/organoids harbor significant differences in function of the subsequent (i.e. during pregnancy) negative or positive PE screening, PE development and specific high-risk ART group. Work package 2a: the incidence of a positive screening/PE development (EOPE vs. LOPE) differs significantly among different ART groups. Work package 2b: parameters during the pregnancy (blood pressure, biomarkers in the blood, ultrasound, nutritional and cardiac parameters) are significantly different between ART patients screening positive/developing PE and these identified parameters are specific for each ART subgroup. Work package 3: placental tissue, membranes, cord tissue and cord blood harbor significant differences in expressed molecular pathways depending on negative or positive PE screening, PE development or not and are specific for the high-risk ART group. Experimental design: Prospective interventional cohort study without the use of a product nor medical device. Methodology: The study population will be subdivided into two different patient groups. Patients will be asked to participate to the study when they are planning to undergo ART and are (already prior to the start of their treatment) suspected to be at higher risk for the development PE after achieving pregnancy: - Group 1 will include oocyte recipients as the use of donor oocytes predisposes them to a potential immunological conflict during pregnancy contributing to PE development - Group 2 will include PCOS patients as endocrine and metabolic abnormalities predispose them to an abnormal trophoblast invasion contributing to PE development Work package 1a: evaluation of maternal baseline characteristics, laboratory studies, ultrasound examination, cardiac and nutritional work-up. Work package 1b: harvesting and biobanking of preconceptional endometrium during the luteal phase of a preparative non-conceptional test-ART cycle (MOCK cycle). Depending on the outcome of the pregnancy, tissue can be thawed and used for basic research experiments (stromal cell lines, organoids, decidualization experiments, implantation experiments). Work package 2a: patients are screened between 11- and 14-weeks' gestation using the FMF PE screening algorithm (routine care at our center). When patients are determined to be at high-risk of PE development (>1/100), they are advised to take aspirin (160 mg daily) until 36 weeks' gestation. Work package 2b: patients will be followed up at different time points during their pregnancy (7, 12, 20, 28, 36 weeks' gestation) using urine sampling, blood analysis, blood pressure measurement, cardiac and nutritional work-up and ultrasound evaluation. Work package 3: collection of placental tissue, membranes, umbilical cord tissue and cord blood at time of delivery for basic research analysis. Evaluation of different molecular pathways and expressed genes between no PE, EOPE and LOPE and this in specific relation to the different high-risk groups.

Relugolix Pregnancy Registry: An Observational Study of the Safety of Relugolix-Containing Therapy Exposure in Pregnant Women and Their Offspring

The outcomes of interest include major congenital malformation (MCM; primary outcome), minor congenital malformation, spontaneous abortion (SAB), stillbirth, elective termination, small for gestational age (SGA), preterm birth, postnatal growth deficiency, and infant developmental deficiency. Pregnancy outcomes will be assessed throughout pregnancy, with data collection occurring at enrollment, the end of the second trimester, and pregnancy outcome. Infant outcomes will be assessed throughout the infant's first year of life, with active data collection by the registry occurring at 4 and 12 months after delivery. Enrolled pregnant women and the healthcare providers (HCPs) involved in their care or the care of their infants, if applicable, will serve as data reporters to the registry. The registry is strictly observational; the schedule of office visits and all treatment regimens will be determined by HCPs. Only data that are documented in patients' medical records during the course of medical care will be collected. No additional laboratory tests or HCP assessments will be required as part of this registry.

Point-of-care Ultrasound Abnormalities in Eclampsia

Preeclampsia is a life-threatening hypertensive disorder involving the heart and vasculature affecting 5-8% of pregnancies. Untreated, 2-10% of women develop eclampsia, defined as new onset of seizures in the setting of preeclampsia. Eclamptic seizures are estimated to occur in 2-8 per 10.000 deliveries in high-income countries (HIC) and with a higher prevalence of up to 16-69 per 10.000 deliveries in low-income countries (LIC). Eclampsia is associated with significant maternal and neonatal morbidity, with a case fatality rate as high as 25-50 % in LIC, and associated with a 16-26 fold odds of death in HIC. Associated maternal complications include intracranial hemorrhage (ICH), cerebral edema, acute kidney injury, acute respiratory syndrome (ARDS), cardiac failure, coagulopathy and postpartum hemorrhage. Obstetric and medical management include seizure prophylaxis and control, aggressive blood pressure management and the urgent delivery of the baby. Anesthesia management can be challenging and has to be tailored to the clinical condition of the eclamptic woman. Unless the usual contraindications to regional anesthesia (RA) apply, spinal anesthesia (SPA) has been described as the method of choice in parturients in whom the Glasgow Coma Scale (GCS) is ≥ 14, and cardiac failure is absent. For patients with persistent decreased level of consciousness, general anesthesia (GA) is recommended. However, in eclamptic women both anesthesia techniques may be associated with significant complications. Raised intracranial pressure (ICP) present in eclamptic women raises the possibility of cerebellar tonsillar herniation in association with SPA. Cardiac diastolic dysfunction, with or without preserved ejection fraction, has been described in preeclamptic women. With preserved ejection fraction, induction of RA or GA is generally hemodynamically well tolerated. However, in women with decreased systolic function, induction of anesthesia can lead to life-threatening cardiovascular collapse, which may only be prevented by cautious titration of anesthesia agents. This might be in conflict with the need to administer high dosages of induction agents to blunt the hypertensive response to tracheal intubation that, if untreated, may lead to life-threatening ICH and pulmonary edema. Consequently, early detection of increased ICP and knowledge of cardiopulmonary function in the individual case are essential to the obstetric anesthetist to guide appropriate management. Cardiopulmonary and optic nerve sheath point-of-care ultrasound (POCUS) protocols might be particularly suitable for this purpose. These involve a defined bedside ultrasound examination to identify critical cardiopulmonary pathophysiology, which may remain undetected by clinical examination alone. The identification of increased optic nerve sheath diameter (ONSD) on ultrasound may suggest raised ICP. It is further well documented that the serum brain natriuretic peptide (BNP) level, a marker of cardiac dysfunction, is increased in preeclampsia. However, no data is available to confirm that elevated BNP levels identify those eclamptic women at risk for cardiopulmonary abnormalities. Therefore, this study is planned to describe the prevalence and severity of cardiac, lung and ONS US abnormalities in women with eclampsia.