A rapid improvement event: progesterone prescribing in prevention of miscarriage.

A rapid improvement event (RIE) is a standard operational excellence technique that uses team-based problem solving to improve processes. In this study, a RIE was undertaken to improve progesterone prescribing rates for those with a history of miscarriage experiencing vaginal bleeding in early pregnancy. This was on the basis of a recent change in guidelines regarding prescribing in these instances. NICE guidelines changed in November 2021 after Cochrane meta-analysis and the PRISM (Progesterone in Spontaneous Miscarriage) randomised control trial demonstrated a higher incidence of live births in those prescribed vaginal micronised progesterone for threatened miscarriage, when compared with those not prescribed it.A RIE involves a team approach and a standard sequence of events allowing analysis and improvement of a process. Analysis in the form of audit revealed a low progesterone prescribing rate for eligible patients in our unit. Dissection of this problem into its elements revealed a low level of staff knowledge regarding the change in guidelines and a lack of confidence in prescription of progesterone. A plan of actionable events to improve prescribing rates was devised. The updated guidance and local recommendations on appropriate micronised progesterone formulations were presented at hospital Grand Rounds with multidisciplinary attendance. Infographics were displayed in areas visible to stakeholders within the hospital and on the hospital's social media pages. The validity of these educational measures to improve the process was reaudited after 3 months.Progesterone prescribing improved by 48%. Those comfortable with prescribing as per the new guidelines improved from 43% to 78%. A RIE proved to be an effective and efficient approach to collaboration, decision-making and action.

Progesterone in Pregnancy: Evidence-Based Strategies to Reduce Miscarriage and Enhance Assisted Reproductive Technology.

The incidence of miscarriage in early pregnancy, between 5-20 weeks, is common, with a prevalence of between 5-22% of all pregnancies. Miscarriage can have physical, social, and mental health impacts on women and their families. In societies such as Taiwan, where the birth rate is falling and life expectancy is increasing, there is concern that factors that reduce birth rates will have detrimental economic and societal effects. Progesterone has a significant role in maintaining early and successful pregnancy to term. Evidence from preclinical and clinical research on the roles of progesterone has supported recent clinical guidelines in obstetrics and gynecology to reduce rates of early miscarriage and improve methods of assisted reproductive technology (ART). This article aims to present an evidence-based review of current recommendations for the use of progesterone in early pregnancy to reduce miscarriage rates and in luteal phase support for ART, including embryo transfer.

A randomized, controlled clinical study of low-molecular-weight heparin improving pregnancy outcomes in PCOS women undergoing IVF: study protocol.

BACKGROUND: Polycystic ovary syndrome (PCOS), an incidence of 10-15% in women of reproductive age, shows sex hormone disorders, luteal insufficiency, and the tendency of placental villus space thrombus. The incidence of early pregnancy loss in women with PCOS is three to eight times higher than that in non-PCOS women. PCOS women were reported in a pre-thrombotic state, which was manifested by accelerated thrombin production, increased PAI-1 activity, and fibrinogen. Other research also found an over-activated state of women with PCOS in immune system. Therefore, changing the prethrombotic state of PCOS through anticoagulation may be a new way to improve the adverse pregnancy outcome of PCOS. Low-molecular-weight heparin (LMWH) is the most common used anticoagulant drug in pregnancy, and it also was proposed for the prevention of recurrent abortion, although the application of LMWH in PCOS population during early pregnancy has not been reported. The objective of this study is to investigate the effect of LMWH on pregnancy outcomes after invitro fertilization-frozen embryo transfer (IVF-FET) in patients with polycystic ovary syndrome. METHODS: A total of 356 PCOS women aged between 20 and 38 years which prepared for IVF followed with FET will be enrolled in the study. The patients, from four different hospitals stratified by age and body mass index (BMI), will be randomly divided into the study group who will be treated with LMWH started on the day of progesterone transformation (hormone therapy) during FET cycle and the control group without additional medicine. Serum or urine hCG test will be given 14 days after embryo transfer to confirm biochemical pregnancy. If pregnancy is positive, LMWH+ hormone therapy/hormone therapy will be continued for another 2 weeks. Transvaginal ultrasonography will be performed 14 days later to confirm intrauterine pregnancy. The primary outcome is the ongoing pregnancy, which is defined as intrauterine live fetus with ultrasound after 12 weeks of gestation. DISCUSSION: This is the first study protocol to investigate the efficacy of LMWH as an adjuvant drug for IVF-FET outcomes in PCOS women, by comparing differences in ongoing pregnancy rate, clinical pregnancy rate, live birth rate, and early pregnancy loss rate between LMWH group and the control group. TRIAL REGISTRATION: ClinicalTrials.gov ChiCTR2000036527. Registered on August 24, 2020.

Jianpi Antai formula prevents miscarriage by repressing M1 polarization of decidual macrophages through ubiquitination of NLRP3 mediated by MARCH7.

ETHNOPHARMACOLOGICAL RELEVANCE: Jianpi Antai Formula (JAF) is an ancient formula from He's gynecology, which has been used clinically for more than 30 years and has significant therapeutic effects on spontaneous abortion (SA). Both macrophage polarization and NLRP3 inflammasome correlate with the occurrence of SA in women with recurrent or threatened miscarriage. Whether JAF prevent SA via mediating activation of decidual macrophage (dMφ) and ubiquitination-associated degradation of NLRP3 remains uncertain. AIM OF THE STUDY: This study aimed to clarify the effects of JAF on pregnancy outcomes and dMφ polarization at the maternal-fetal interface in an SA mouse model, and use in vivo and invitro methods to explore whether JAF can inhibit M1 polarization of dMφ by up-regulating MARCH7-mediated NLRP3 ubiquitination, thereby preventing SA. MATERIALS AND METHODS: The CBA/J × DBA/2 mating method was used to establish an SA model and the dMφs of SA mice were isolated and cultured. Th1-, Th2-, Th17- and Treg-related cytokine levels were evaluated using ELISA. qRT-PCR was used to detect the levels of M1/M2 macrophage-related cytokine mRNA in the decidua, and western blotting was used to detect the expression of NLRP3 inflammasome-related proteins in the decidua and placenta. The expression of M1/M2 markers of dMφ was detected using flow cytometry, ASC speck formation was observed using immunofluorescence, and the ubiquitination level of MARCH7-NLRP3 was detected using co-immunoprecipitation. RESULTS: JAF increased the survival rate of fetuses and the levels of estradiol and progesterone in SA model mice. It also reduced the serum Th1 and Th17-associated cytokine levels and decidual M1 macrophage-associated cytokine levels, while elevating the M2 macrophages in SA mice. NLRP3, caspase-1, ASC, and IL-1ß protein expression in the decidua and placenta were also reduced. si-MARCH7 transfection reversed the effect of JAF on inhibiting the formation of the NLRP3 inflammasome and the activation of macrophages in dMφs of SA mice. CONCLUSION: JAF could effectively prevent and treat SA by repressing M1 polarization of dMφs through NLRP3 ubiquitination and pyroptosis inhibition, which were mediated by MARCH7.

[90 years of recurrent miscarriage]. / 90 jaar herhaalde miskraam.

The author comments on a report in The Lancet of a conference in London in 2019 regarding miscarriages. Key-message of the meeting: "There is no high-quality evidence for any treatment to prevent miscarriages in women at high risk of miscarriage"Thisstatement seems to mark the end of an era.Around 1930 estrogenes and progesteron were isolated. Both were recognized as extremely important in pregnancy, and therefore used as a treatment for "Habitual Abortion", or "Recurrent Miscarriage". Numerous attempts with very different treatments followed. None of these, however, produced reliable positive results. Although most research focussed on treatment of the woman, over 90% of the miscarriages is caused by abnormalities of the embryo: anembryonic amnionsacs, aneuploidy, closuredefects of the cerebrospinal system, etc. Malformed embryos, however, should not be included in trials. Live-birth-rates in women continuing their attempts are high. Providing these people with moral support including the right information is preferable over accelerating on a dead end.

Long Non-Coding RNA ZEB2-AS1 Augments Activity of Trophoblast Cells and Prevents the Development of Recurrent Spontaneous Abortion in Mice Through EZH2-Mediated CST3 Inhibition.

Recurrent spontaneous abortion (RSA) is the most common complication of pregnancy where reduced invasion of trophoblasts plays a major role. This work aimed to explore the effect of abnormally expressed long non-coding RNA (lncRNA) ZEB2-AS1 on the occurrence of RSA. Differentially expressed lncRNAs in trophoblast cells between healthy controls and patients with RSA were screened using the GEO database. Female CBA/J mice were allowed to mate with male DBA/2 mice to establish inbred mice with RSA. ZEB2-AS1 was poorly expressed in placental tissues and trophoblast cells in the condition of RSA. ZEB2-AS1 upregulation augmented proliferation, migration, and invasion of trophoblast cells in vitro. ZEB2-AS1 negatively regulated cystatin C (CST3) expression. Further overexpression of CST3 blocked the activity of trophoblast cells. ZEB2-AS1 recruited enhancer of EZH2 to the promoter region of CST3, which increased H3K27me3 modification to suppress CST3 expression. In vivo, overexpression of ZEB2-AS1 reduced embryo resorption rate and increased the weights of fetuses and placentas in mice with RSA. However, the protective roles of ZEB2-AS1 were blocked upon artificial silencing of EZH2 or upregulation of CST3. Taken together, this study demonstrates that ZEB2-AS1 enhances activity of trophoblast cells and prevents RSA development through reducing CST3 expression in an EZH2-dependent manner.

A pairwise and network meta-analysis comparing the efficacy and safety of progestogens in threatened abortion.

BACKGROUND: Progesterone is widely used to prevent threatened miscarriage. OBJECTIVE: To determine the efficacy and safety of progestogens in the treatment of threatened miscarriage. SEARCH STRATEGY: PubMed, Cochrane Library, EMBASE, CNKI, CBM, and WanFang databases were searched for randomized controlled trials (RCTs) published from the date of inception of the database to August 2020. The search terms included "abortion, threatened," "progesterone," and "progestogens." SELECTION CRITERIA: A network meta-analysis was conducted of all the RCTs on threatened abortion so far to compare the efficacy and safety of different progestogens in the treatment of threatened abortion. DATA COLLECTION AND ANALYSIS: Odds ratios for dichotomous data with 95% confidence intervals were calculated and the data were pooled using a random-effects model. The surface under the cumulative ranking area (SUCRA) was calculated for efficacy and safety with different interventions. MAIN RESULTS: A total of 59 RCTs with 10 424 participants were included. Oral dydrogesterone (DYD) had the lowest risk of miscarriage (SUCRA 100.0%), followed by vaginal progesterone (SUCRA 67.9%). Oral micronized progesterone had the highest risk of miscarriage (SUCRA 15.7%). CONCLUSION: Oral DYD is effective in the treatment of threatened miscarriage. The results of the present study can help patients make informed decisions about treatment options for threatened miscarriage.

Diet Supplementation with Pomegranate Peel Improves Embryonic Survival in a Mouse Model of Early Pregnancy Loss.

The peel of pomegranate fruit is a rich source of polyphenolic compounds with powerful antioxidant properties. We evaluated the therapeutic potential of pomegranate peel (PP) in the prevention of early pregnancy loss in a mouse model of embryonic mortality and abortion (female CBA/J x male DBA/2). CBA/J mice were divided into 3 groups: mice in control group (CONT group) were fed a standard diet, whereas mice in groups 2 and 3 were fed a standard diet supplemented with 1% PP (PP1% group) and 5% PP (PP5% group), respectively. All the mice were fed their diets for 10 days before mating and continued with the same diets for a further 14 days after mating. At day 14 of pregnancy the female mice were sacrificed and the placentas and maternal livers were harvested for measurement of the content of thiols and thiobarbituric acid reactive substances (TBARS), as biomarkers of oxidative stress, and the enzymatic activities of total superoxide dismutase (TSOD), copper/zinc SOD (SOD1), manganese SOD (SOD2), selenium glutathione peroxidase (GPX) and glutathione reductase (GR). Diet supplemented with 5% PP improved embryonic survival and reduced embryonic mortality from 28.2% (CONT) to 8.5% (PP5%). This was accompanied by increased activities of placental TSOD, SOD1 and SOD2, and thiol content. Diet supplemented with 5% PP also reduced placental oxidative stress as demonstrated by a decrease of placental TBARS content. This study highlights the potential of interventions with PP-supplemented diet before and during early pregnancy, in order to ameliorate embryonic survival and prevent early pregnancy loss.

Pharmacological activation of rev-erbα suppresses LPS-induced macrophage M1 polarization and prevents pregnancy loss.

BACKGROUND: Circadian rhythm is an important player for reproduction. Rev-erbα, a significant clock gene, is involved in regulating cell differentiation, inflammation and metabolism. Macrophage polarization plays crucial roles in immune tolerance at the maternal-fetus interface, which also modulates the initiation and resolution of inflammation. Alteration of macrophage polarization induces adverse pregnancy outcomes such as infertility, recurrent spontaneous abortion and preterm labor. RESULTS: Decidual macrophages from LPS-induced mice abortion model displayed M1-like bias, accompanied by decreased expression of Rev-erbα. SR9009, an agonist of Rev-erbα, may reduce lipopolysaccharide (LPS)-induced M1 polarization of macrophages via activation of PI3K but not NF-κB signaling pathway. Furthermore, SR9009 could reduce M1-like polarization of decidual macrophages induced by LPS and attenuate LPS-induced resorption rates in mice model. CONCLUSIONS: Both in vivo and in vitro experiments demonstrated that the pharmacological activation of Rev-erbα using SR9009 could attenuate the effect of LPS on macrophage polarization and protect pregnancy. This study may provide a potential therapeutic strategy for miscarriage induced by inflammation.

Protopanaxadiol improves endometriosis associated infertility and miscarriage in sex hormones receptors-dependent and independent manners.

Background: Patients with endometriosis (EMs) have high risks of infertility and spontaneous abortion. How to remodel the fertility of patients with EMs has always been the hot spot and difficulty in the field of reproductive medicine. As an aglycone of ginsenosides, protopanaxadiol (PPD) possesses pleiotropic biological functions and has high medicinal values. We aimed to investigate the effect and potential mechanism of PPD in the treatment of EMs-associated infertility and spontaneous abortion. Methods: The EMs mice models were constructed by allotransplantation. The pregnancy rates, embryo implantation numbers and embryo resorption rates of control and EMs were counted. RNA sequencing, qRT-PCR, enzyme linked immunosorbent assay (ELISA) and FCM analysis were performed to screen and confirm the expression of endometrial receptivity/decidualization-related molecules, inflammation cytokines and NK cell function-related molecules in vitro and/or in vivo. The SWISS Target Prediction, STRING and Cytoscape were carried out to predict the potential cellular sensory proteins, the protein-protein interaction (PPI) network between sensory proteins and fertility-related molecules, respectively. Micro-CT detection, liver and kidney function tests were used to evaluate the safety. Results: Here, we observe that PPD significantly up-regulates endometrial receptivity-related molecules (e.g., Lif, Igfbp1, Mmps, collagens) and restricts pelvic inflammatory response (low levels of IL-12 and IFN-γ) of macrophage, and further remodel and improve the fertility of EMs mice. Additionally, PPD increases the expression of decidualization-related genes and Collagens, and promotes the proliferation, residence, immune tolerance and anagogic functions of decidual NK cells (low levels of CD16 and NKp30, high levels of Ki67, VEGF, TGF-ß) in pregnant EMs mice, and further triggers decidualization, decidual NK cell-mediated maternal-fetal immune tolerance and angiogenesis, preventing pregnant EMs mice from miscarriage. Mechanically, these effects should be dependent on ESRs, PGR and other sensory proteins (e.g., AR). Compared with GnRHa (the clinic first-line drug for EMs), PPD does not lead to the decline of serum estrogen and bone loss. Conclusion: These data suggest that PPD prevents EMs-associated infertility and miscarriage in sex hormones receptors-dependent and independent manners possibly, and provides a potential therapeutic strategy with high efficiency and low side effects to remodels the fertility of patients with EMs.

Primary hyperparathyroidism presenting as a brown tumor with hypercalcemia crisis in a second-trimester pregnant woman: A case report.

INTRODUCTION: Primary hyperparathyroidism (PHPT) in pregnancy is rare and unrecognized because the maternal physiological adaptations blurs the symptoms. There is no standard treatment strategy for maternal PHPT. Early diagnosis and interventions can prevent catastrophic consequences to the mother and fetus. PATIENT CONCERNS: A 31-year-old Chinese woman was admitted, due to a lump on the left lower leg for 4 months. The patient complained of mild pain in the left lower leg following exercise that could be relieved after a short rest. The patient was at 18 weeks of gestation, and the growth of the fetus was normal. The patient has a 3-year history of hypercalcemia and a 2-year history of nephrolithiasis. No family history of hypercalcemia and endocrine tumors were present. DIAGNOSIS: Laboratory tests demonstrated high serum calcium level of 3.84 mmol/L, parathyroid hormone 1393 pg/mL, alkaline phosphatase 488 µ/L. Ultrasound showed a 22.4 mm × 7.8 mm solid nodule in the left lower lobe of the thyroid gland. Based on these findings, the patient was diagnosed with PHPT. INTERVENTIONS: The patient accepted continuous renal replacement to reduce ironized calcium level. Parathyroidectomy was performed at the 19th week of gestation. Threatened abortion occurred 2 days after the surgery, and magnesium sulfate was used to prevent the abortion. Calcium gluconate, calcium carbonate and vitamin D3 were used to treat the hypocalcemia that occurred 5 days after the surgery. OUTCOMES: Pathology examination demonstrated the parathyroid adenoma. Abortion was prevented using magnesium sulfate and hypocalcemia was cured with calcium gluconate, calcium carbonate and vitamin D3. At 38-week of gestation, the patient (ionized calcium level: 2.16 mmol/L) delivered a healthy female baby weighing 2700 g with 10/10 Apgar. Till now, both the mother and infant showed no complications. CONCLUSION: Maternal PHPT is rare and challenging to diagnose, causing life-threatening complications to mother and fetus. Any decision regarding surgery for a pregnant woman with primary hyperparathyroidism is more complex than in men or nonpregnant women. The decision should be made based on the severity of hypercalcemia and symptoms.

Progestogens for preventing miscarriage: a network meta-analysis.

BACKGROUND: Miscarriage, defined as the spontaneous loss of a pregnancy before 24 weeks' gestation, is common with approximately 25% of women experiencing a miscarriage in their lifetime, and 15% to 20% of pregnancies ending in a miscarriage. Progesterone has an important role in maintaining a pregnancy, and supplementation with different progestogens in early pregnancy has been attempted to rescue a pregnancy in women with early pregnancy bleeding (threatened miscarriage), and to prevent miscarriages in asymptomatic women who have a history of three or more previous miscarriages (recurrent miscarriage). OBJECTIVES: To estimate the relative effectiveness and safety profiles for the different progestogen treatments for threatened and recurrent miscarriage, and provide rankings of the available treatments according to their effectiveness, safety, and side-effect profile. SEARCH METHODS: We searched the following databases up to 15 December 2020: Cochrane Central Register of Controlled Trials, Ovid MEDLINE(R), ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP), and reference lists of retrieved studies. SELECTION CRITERIA: We included all randomised controlled trials assessing the effectiveness or safety of progestogen treatment for the prevention of miscarriage. Cluster-randomised trials were eligible for inclusion. Randomised trials published only as abstracts were eligible if sufficient information could be retrieved. We excluded quasi- and non-randomised trials. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed the trials for inclusion and risk of bias, extracted data and checked them for accuracy. We performed pairwise meta-analyses and indirect comparisons, where possible, to determine the relative effects of all available treatments, but due to the limited number of included studies only direct or indirect comparisons were possible. We estimated the relative effects for the primary outcome of live birth and the secondary outcomes including miscarriage (< 24 weeks of gestation), preterm birth (< 37 weeks of gestation), stillbirth, ectopic pregnancy, congenital abnormalities, and adverse drug events. Relative effects for all outcomes are reported separately by the type of miscarriage (threatened and recurrent miscarriage). We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: Our meta-analysis included seven randomised trials involving 5,682 women, and all provided data for meta-analysis. All trials were conducted in hospital settings. Across seven trials (14 treatment arms), the following treatments were used: three arms (21%) used vaginal micronized progesterone; three arms (21%) used dydrogesterone; one arm (7%) used oral micronized progesterone; one arm (7%) used 17-α-hydroxyprogesterone, and six arms (43%) used placebo. Women with threatened miscarriage Based on the relative effects from the pairwise meta-analysis, vaginal micronized progesterone (two trials, 4090 women, risk ratio (RR) 1.03, 95% confidence interval (CI) 1.00 to 1.07, high-certainty evidence), and dydrogesterone (one trial, 406 women, RR 0.98, 95% CI 0.89 to 1.07, moderate-certainty evidence) probably make little or no difference to the live birth rate when compared with placebo for women with threatened miscarriage. No data are available to assess the effectiveness of 17-α-hydroxyprogesterone or oral micronized progesterone for the outcome of live birth in women with threatened miscarriage. The pre-specified subgroup analysis by number of previous miscarriages is only possible for vaginal micronized progesterone in women with threatened miscarriage. In women with no previous miscarriages and early pregnancy bleeding, there is probably little or no improvement in the live birth rate (RR 0.99, 95% CI 0.95 to 1.04, high-certainty evidence) when treated with vaginal micronized progesterone compared to placebo. However, for women with one or more previous miscarriages and early pregnancy bleeding, vaginal micronized progesterone increases the live birth rate compared to placebo (RR 1.08, 95% CI 1.02 to 1.15, high-certainty evidence). Women with recurrent miscarriage Based on the results from one trial (826 women) vaginal micronized progesterone (RR 1.04, 95% CI 0.95 to 1.15, high-certainty evidence) probably makes little or no difference to the live birth rate when compared with placebo for women with recurrent miscarriage. The evidence for dydrogesterone compared with placebo for women with recurrent miscarriage is of very low-certainty evidence, therefore the effects remain unclear. No data are available to assess the effectiveness of 17-α-hydroxyprogesterone or oral micronized progesterone for the outcome of live birth in women with recurrent miscarriage. Additional outcomes All progestogen treatments have a wide range of effects on the other pre-specified outcomes (miscarriage (< 24 weeks of gestation), preterm birth (< 37 weeks of gestation), stillbirth, ectopic pregnancy) in comparison to placebo for both threatened and recurrent miscarriage. Moderate- and low-certainty evidence with a wide range of effects suggests that there is probably no difference in congenital abnormalities and adverse drug events with vaginal micronized progesterone for threatened (congenital abnormalities RR 1.00, 95% CI 0.68 to 1.46, moderate-certainty evidence; adverse drug events RR 1.07 95% CI 0.81 to 1.39, moderate-certainty evidence) or recurrent miscarriage (congenital abnormalities 0.75, 95% CI 0.31 to 1.85, low-certainty evidence; adverse drug events RR 1.46, 95% CI 0.93 to 2.29, moderate-certainty evidence) compared with placebo. There are limited data and very low-certainty evidence on congenital abnormalities and adverse drug events for the other progestogens. AUTHORS' CONCLUSIONS: The overall available evidence suggests that progestogens probably make little or no difference to live birth rate for women with threatened or recurrent miscarriage. However, vaginal micronized progesterone may increase the live birth rate for women with a history of one or more previous miscarriages and early pregnancy bleeding, with likely no difference in adverse events. There is still uncertainty over the effectiveness and safety of alternative progestogen treatments for threatened and recurrent miscarriage.

Diagnosis and treatment of luteal phase deficiency: a committee opinion.

Luteal phase deficiency (LPD) is a clinical diagnosis associated with an abnormal luteal phase length of ≤10 days. Potential etiologies of LPD include inadequate progesterone duration, inadequate progesterone levels, or endometrial progesterone resistance. LPD has not only been described in association with medical conditions but also in fertile, normally menstruating women. Although progesterone is important for the process of implantation and early embryonic development, LPD has not been proven to be an independent entity causing infertility or recurrent pregnancy loss. Controversy exists regarding the multiple proposed measures for diagnosing LPD and, assuming it can be diagnosed accurately, whether treatment improves outcomes. This document replaces the document entitled "Current clinical irrelevance of luteal phase deficiency: a committee opinion," last published in 2015 (Fertil Steril 2015;103:e27-e32).

Myeloproliferative neoplasms and pregnancy: Overview and practice recommendations.

Pregnancy in the context of myeloproliferative neoplasms (MPN) poses unique fetal and maternal challenges. Current literature in this regard mostly involves essential thrombocythemia (ET) and less so polycythemia vera (PV) or myelofibrosis. In ET, live birth rate is estimated at 70% with first trimester fetal loss (˜ 30%) as the major complication. Risk of pregnancy-associated complications is higher in PV, thus mandating a more aggressive treatment approach. Herein, we appraise the relevant literature, share our own experience and propose management recommendations. Aspirin therapy may offer protection against fetal loss; however the additive benefit of systemic anticoagulation or cytoreductive therapy, in the absence of high risk disease, is unclear. We recommend cytoreductive therapy in the form of interferon alpha in all high risk and select low-risk ET and PV patients with history of recurrent fetal loss, prominent splenomegaly or suboptimal hematocrit control with phlebotomy. In addition, all women with PV should maintain strict hematocrit control <45% with the aid of phlebotomy. Systemic anticoagulation with low molecular weight heparin is advised in patients with history of venous thrombosis. Further clarification awaits prospective clinical trials that implement risk adapted therapeutic interventions.

Interferon alpha for essential thrombocythemia during 34 high-risk pregnancies: outcome and safety.

PURPOSE: Pregnancies in women with essential thrombocythemia (ET) are at a higher risk for obstetrical complications. Acetylsalicylic acid (ASA) and low-molecular weight heparin (LMWH) are common options to prevent miscarriages and maternal complications, whereas interferon alpha (IFN) seems to be the cytoreductive therapy of choice. This retrospective study analyzes the largest number of IFN pregnancies to date in terms of outcome and safety. METHODS: Data of 34 high-risk pregnancies in 23 women presenting at the University hospitals of Minden and Jena from 01-Jun-2007 to 01-Jun-2020 were collected. Reasons defining high-risk ET pregnancy in all 23 patients were: Thrombosis (n = 9) or severe hemorrhage (n = 2) in history, platelet count ≥ 1500 × 103/µl (n = 8) or severe microcirculatory disturbances not completely responding to ASA (n = 4). RESULTS: Without the use of IFN, live birth rate was 60% (6/10), however, after the use of IFN live birth rate increased to 73.5% (25/34 pregnancies). Nine pregnancies ended in miscarriages (9/34; 26.5%); all of them spontaneous abortions. Live birth rate significantly improved with ASA (90% versus 50%, p = 0.0168), however, if ASA and LMWH was added (n = 14), live birth rate was 100%. IFN compound (PEGylated versus standard IFN) and JAK2-driver mutation had no impact on pregnancy outcome. One major maternal complication occurred as a major peripartal bleeding after abortion curettage. CONCLUSION: IFN was associated with an encouraging live birth rate of 73.5% with no fatal maternal events and manageable side effects.

Adoptive cell therapy with induced regulatory T cells normalises the abortion rate in abortion-prone mice.

Ovarian hormones drive invivo generation of regulatory T cells (Tregs) during pregnancy. Little is known about the therapeutic potential of invitro hormone-derived Tregs in pregnancy loss. We investigated the effects of hormone-induced Tregs in a murine model of abortion. CD4+CD25- T cells were isolated from the spleens of CBA/J mice and stimulated with either 17ß-oestradiol (E2), progesterone (P4) or transforming growth factor-ß1 (TGFB1) plus retinoic acid (RA) for 4 days to generate induced Tregs (iTregs). On Days 1-4 of gestation, DBA/2-mated pregnant CBA/J female mice (abortion prone) were injected intravenously with iTregs or Tregs isolated from normal BALB/c-mated pregnant CBA/J mice (np-Tregs). On Day 14, the number of resorbed fetuses was assessed. Serum interferon (IFN)-γ and uterine forkhead box p3 (Foxp3) expression was analysed by ELISA and immunohistochemistry respectively. Using a 3H-thymidine incorporation assay, isolated CD4+CD25+ Tregs induced by the different treatments suppressed the proliferation of CD4+CD25- T cells. Adoptive transfer of iTregs (from all induction groups) significantly decreased fetal resorption in abortion-prone mice. There were no significant changes in serum IFN-γ concentrations after the adoptive transfer of iTregs or np-Tregs. Immunohistochemistry revealed significantly higher Foxp3 expression in gravid uteri from mice injected with np-Tregs and P4-induced iTregs than in the phosphate-buffered saline-treated group. The findings of this study indicate a potential therapeutic benefit of invitro-induced Tregs in patients with recurrent abortion.

Adoptive transfer of Tregs: A novel strategy for cell-based immunotherapy in spontaneous abortion: Lessons from experimental models.

Since half of the genes are inherited from the paternal side, the maternal immune system has to tolerate the presence of foreign paternal antigens. Regulatory T cells facilitate the development and maintenance of peripheral tissue tolerance of the fetus during pregnancy. Reduction in regulatory T cells is associated with complications of pregnancy, including spontaneous abortion. Recent studies in mouse models have shown that the adoptive transfer of Tregs can prevent spontaneous abortion in mouse models through improving maternal tolerance. Thus, adoptive cell therapy using autologous Tregs could potentially be a novel therapeutic approach for cell-based immunotherapy in women with unexplained spontaneous abortion. Besides, strategies for activating and expanding antigen-specific Tregs ex vivo and in vivo based on pharmacological agents can pave the foundation for an approach incorporating immunotherapy and pharmacotherapy. This review aims to elaborate on the current understanding of the therapeutic potential of the adoptive transfer of Tregs in the treatment of spontaneous abortion disease.

Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome.

BACKGROUND: The use of insulin-sensitising agents, such as metformin, in women with polycystic ovary syndrome (PCOS) who are undergoing ovulation induction or in vitro fertilisation (IVF) cycles has been widely studied. Metformin reduces hyperinsulinaemia and suppresses the excessive ovarian production of androgens. It is suggested that as a consequence metformin could improve assisted reproductive techniques (ART) outcomes, such as ovarian hyperstimulation syndrome (OHSS), pregnancy, and live birth rates. OBJECTIVES: To determine the effectiveness and safety of metformin as a co-treatment during IVF or intracytoplasmic sperm injection (ICSI) in achieving pregnancy or live birth in women with PCOS. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL via the Cochrane Register of Studies Online (CRSO), MEDLINE, Embase, PsycINFO, LILACS, the trial registries for ongoing trials, and reference lists of articles (from inception to 13 February 2020). SELECTION CRITERIA: Types of studies: randomised controlled trials (RCTs) comparing metformin treatment with placebo or no treatment in women with PCOS who underwent IVF or ICSI treatment. TYPES OF PARTICIPANTS: women of reproductive age with anovulation due to PCOS with or without co-existing infertility factors. Types of interventions: metformin administered before and during IVF or ICSI treatment. PRIMARY OUTCOME MEASURES: live birth rate, incidence of ovarian hyperstimulation syndrome. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the studies, extracted the data according to the protocol, and assessed study quality. We assessed the overall quality of the evidence using the GRADE approach. MAIN RESULTS: This updated review includes 13 RCTs involving a total of 1132 women with PCOS undergoing IVF/ICSI treatments. We stratified the analysis by type of ovarian stimulation protocol used (long gonadotrophin-releasing hormone agonist (GnRH-agonist) or short gonadotrophin-releasing hormone antagonist (GnRH-antagonist)) to determine whether the type of stimulation used influenced the outcomes. We did not perform meta-analysis on the overall (both ovarian stimulation protocols combined) data for the outcomes of live birth and clinical pregnancy rates per woman because of substantial heterogeneity. In the long protocol GnRH-agonist subgroup, the pooled evidence showed that we are uncertain of the effect of metformin on live birth rate per woman when compared with placebo/no treatment (risk ratio (RR) 1.30, 95% confidence interval (CI) 0.94 to 1.79; 6 RCTs; 651 women; I2 = 47%; low-quality evidence). This suggests that if the chance for live birth following placebo/no treatment is 28%, the chance following metformin would be between 27% and 51%. Only one study used short protocol GnRH-antagonist and reported live birth rate. Metformin may reduce live birth rate compared with placebo/no treatment (RR 0.48, 95% CI 0.29 to 0.79; 1 RCT; 153 women; low-quality evidence). This suggests that if the chance for live birth following placebo/no treatment is 43%, the chance following metformin would be between 13% and 34% (short GnRH-antagonist protocol). We found that metformin may reduce the incidence of OHSS (RR 0.46, 95% CI 0.29 to 0.72; 11 RCTs; 1091 women; I2 = 38%; low-quality evidence). This suggests that for a woman with a 20% risk of OHSS without metformin, the corresponding risk using metformin would be between 6% and 14%. Using long protocol GnRH-agonist stimulation, metformin may increase clinical pregnancy rate per woman compared with placebo/no treatment (RR 1.32, 95% CI 1.08 to 1.63; 10 RCTs; 915 women; I2 = 13%; low-quality evidence). Using short protocol GnRH-antagonist, we are uncertain of the effect of metformin on clinical pregnancy rate per woman compared with placebo/no treatment (RR 1.38, 95% CI 0.21 to 9.14; 2 RCTs; 177 women; I2 = 87%; very low-quality evidence). We are uncertain of the effect of metformin on miscarriage rate per woman when compared with placebo/no treatment (RR 0.86, 95% CI 0.56 to 1.32; 8 RCTs; 821 women; I2 = 0%; low-quality evidence). Metformin may result in an increase in side effects compared with placebo/no treatment (RR 3.35, 95% CI 2.34 to 4.79; 8 RCTs; 748 women; I2 = 0%; low-quality evidence). The overall quality of evidence ranged from very low to low. The main limitations were inconsistency, risk of bias, and imprecision. AUTHORS' CONCLUSIONS: This updated review on metformin versus placebo/no treatment before or during IVF/ICSI treatment in women with PCOS found no conclusive evidence that metformin improves live birth rates. In a long GnRH-agonist protocol, we are uncertain whether metformin improves live birth rates, but metformin may increase the clinical pregnancy rate. In a short GnRH-antagonist protocol, metformin may reduce live birth rates, although we are uncertain about the effect of metformin on clinical pregnancy rate. Metformin may reduce the incidence of OHSS but may result in a higher incidence of side effects. We are uncertain of the effect of metformin on miscarriage rate per woman.

[MAVRIC study: when abdominal cerclage is preferable to vaginal cerclage]. / Étude MAVRIC: quand le cerclage par voie abdominale est préférable à la voie vaginale.

Vaginal cerclage can be used to treat cervical incompetence, thus reducing the risk of an unfavourable outcome. However, in some cases, it can be ineffective. One of the challenges for the gynaecologist-obstetrician is how to deal with a subsequent pregnancy after a failure of vaginal cerclage. The recently published MAVRIC study shows that performing abdominal cerclage prior or at the beginning of pregnancy reduces the rate of late miscarriage and premature delivery compared to vaginal cerclage. This implies a birth by caesarean section, and therefore a second surgery for the woman. However, it remains to determine the best surgical technique for abdominal cerclage. In the MAVIRC study, cerclage was done by laparotomy. It shall be elucidated whether this technique is superior to laparoscopy.

Le cerclage par voie vaginale permet de pallier une incompétence cervicale, diminuant ainsi le risque d'issues défavorables. Néanmoins, il peut s'avérer inefficace. Un des enjeux pour le gynécologue-obstétricien est de savoir quelle attitude adopter lors d'une grossesse suivante après échec de cerclage vaginal. L'étude MAVRIC, publiée récemment, apporte la preuve que la réalisation d'un cerclage par voie abdominale avant ou en début de grossesse permet une diminution du taux de fausse couche tardive et d'accouchement prématuré par rapport à la voie vaginale. Ceci implique une naissance par césarienne, et donc une deuxième intervention pour la femme. Il reste encore à déterminer le choix de la technique chirurgicale du cerclage abdominal. L'abord par laparotomie ayant été utilisé pour l'étude MAVRIC, il reste à montrer si cette approche est supérieure à la laparoscopie.