The safety and efficacy of tumor necrosis factor-alpha inhibitor on pregnancy outcomes in patients with unexplained recurrent miscarriage.

OBJECTIVES: Although tumor necrosis factor-alpha inhibitor (TNFi) treatment may improve pregnancy outcomes in unexplained recurrent miscarriage (URM) patients, evidence for its efficacy and safety is still insufficient. The goal of this study was to evaluate the efficacy and safety of TNFi on pregnancy outcomes in patients with URM. METHODS: This retrospective study was conducted at a single institution in China, involving 121 patients treated with TNFi for URM from 2019 to 2022. Patients enrolled were divided into treatment group (receiving TNFi and heparin therapy) and control group (receiving heparin therapy). The outcome variables were the 24-week live birth rate, miscarriage rate, ectopic pregnancy rate, neonatal outcomes, and adverse events. RESULTS: In our study, patients receiving TNFi treatment exhibited a significant increase in live birth rates, achieving 71.2 % compared to the 50.9 % observed in the control group (OR 2.507, 95 % CI: 1.127-5.579). Concurrently, there was a discernible reduction in the miscarriage rate within the TNFi-treated group, marking 24.2 %, in contrast to 43.6 % in the control group (OR 0.387, 95 % CI: 0.170-0.884). Subgroup analyses further illuminated that those under the age of 35 benefitted remarkably from TNFi treatment, with live birth rates soaring to 62.5 % (OR 2.525, 95 % CI: 1.041-6.125). For patients with a history of two miscarriages, the TNFi regimen significantly augmented the live birth rate to 58.9 % (OR 3.044, 95 % CI: 1.039-8.921). Patients with a normal weight range registered a 58.4 % live birth rate post-TNFi treatment (OR 4.261, 95 % CI: 1.539-11.397). Notably, an evident interaction between BMI and TNFi treatment was identified, suggesting a potential modulatory role of BMI on the therapeutic efficacy of TNFi. About safety assessments, neither the TNFi-treated group nor the control manifested any significant disparities in liver function abnormalities, platelet count anomalies, or other pregnancy-related complications. CONCLUSIONS: TNFi, alongside basic therapy, notably enhances the live birth rate in URM patients under 35, with two prior miscarriages or a normal BMI, without increasing adverse event risk. Further prospective studies are essential to validate these observations.

Robotic-assisted single-site abdominal cerclage in the bicornuate uterus patient with cervical insufficiency.

OBJECTIVE: To demonstrate the surgical techniques for improving safety in robotic-assisted abdominal cerclage in patients with bicornuate uteri complicated by recurrent pregnancy loss and cervical insufficiency. DESIGN: Stepwise demonstration with narrated video footage. SETTING: An academic tertiary care hospital. PATIENTS: Our patient is a 22-year-old G2P0020 with a history of recurrent pregnancy loss. During her first pregnancy, she was asymptomatic until 19 weeks and delivered because of a preterm premature rupture of membranes. A transvaginal cerclage was performed for her second pregnancy at 14 weeks, which ended at 16 weeks because of preterm premature rupture of membranes. The final magnetic resonance imaging report noted a "bicorporeal uterus with duplication of the uterine body, resulting in two markedly divergent uterine horns that are fused at the isthmus... unlike a typical didelphic uterus, a single, non septated cervix is noted, which shows normal appearances, measuring 3.8 cm in length." Given her history of a uterine anomaly and recurrent pregnancy loss in the absence of other biochemical factors, her maternal-fetal medicine specialist referred her to us as the patient strongly desired future viable pregnancies. The patient was counseled on multiple alternatives, including different methods of performing the cerclage, and ultimately decided on the robotic-assisted (Da Vinci Xi) prophylactic abdominal cerclage. INTERVENTIONS: The bicornuate uterus is a rare class IV mullerian duct anomaly caused by the impaired fusion of the mullerian ducts in the uterus, classically appearing in imaging studies as a heart-shaped uterus. This patient demographic reports a high incidence of obstetric complications. Pregnancy in such a uterus causes complications like first- and second-trimester pregnancy loss, preterm labor, low-birthweight infants, and malpresentation at delivery.1 Researchers have postulated that there is an abnormal ratio of muscle fibers to connective tissue in a congenitally abnormal cervix. During pregnancy, an inadequate uterine volume may lead to increased intrauterine pressure and stress on the lower uterine segment, which can lead to cervical incompetence.2 To address cervical incompetence, cervical cerclages are a commonly utilized procedure, as recent studies demonstrate that the incidence of term pregnancies in the group with documented cervical incompetence treated with cerclage placement increased from 26% to 63%.3 One observational study noted improved obstetrical outcomes occurred with interval placement, a cerclage placed in between pregnancies in the nongravid uterus, compared with cerclage placement between 9 and 10 weeks gestation, with the mean gestational age for delivery at 32.9 weeks and 34.5 weeks when a cerclage was placed in gravid and nongravid women, respectively.4 In addition, another retrospective study was done, which demonstrated a lower incidence of neonatal death with prophylactic cerclages.5 Operating on a nonpregnant uterus offers several benefits, including its reduced size, fewer and smaller blood vessels, and simplified handling. Moreover, there are clearly no concerns regarding the fetus. In the decision to use a robotic-assisted platform vs. laparoscopic, a systematic review showed the rates of third-trimester delivery and live birth (LB) using laparoscopy during pregnancy were found to be 70% and 70%-100%, respectively. The same review demonstrated slightly improved outcomes via the robotic route regarding gestational age at delivery (median, 37 weeks), rates of LB (90%), and third-trimester delivery (90%).6 Additional factors contributing to the preference for robotics in surgical procedures include incorporating advanced tools, which can enhance the robotic system's advantages compared with traditional laparoscopy. An invaluable tool in this context is the simultaneous utilization of Firefly mode, which employs a near-infrared camera system, achieved through injecting indocyanine green dye or integrating other light sources concurrently. The intravenous administration of indocyanine green is acknowledged widely for its safety and efficacy as a contrast agent in the evaluation of microvascular circulation and organ vascularization. This property equips surgeons with heightened precision when guiding the needle, proving especially advantageous when faced with challenges in visualizing vascular anatomy. In our specific case, we harnessed the capabilities of Firefly mode in conjunction with hysteroscopic light, enabling us to vividly illustrate the contours of a bicornuate uterus from both external and internal perspectives. We demonstrate a simplified technique of the abdominal cerclage, one cerclage around the internal cervical os of the uterus, using a robotic-assisted platform in a nongravid patient. The surgery began with the eversion of the umbilicus, and a 15-mm skin incision was made in the umbilicus. A Gelpoint mini advanced access site laparoscopy device was inserted into the incision, and CO2 was allowed to insufflate the abdominal cavity with careful attention given to intraabdominal pressure. Once the DaVinci was docked, the surgeon began the creation of a bladder flap. The bladder was carefully dissected from the lower uterine segment and both uteri using monopolar scissors. The anatomical differences of a bicornuate uterus prompted the surgeon to dissect a wider circumference for safety reasons, where a wider dissection offers a better view of the uterine vessels and ease of introducing the Mersilene tape later on. Bilateral uterine vessels were further skeletonized and exposed anteriorly using blunt dissection and monopolar scissors. After further dissection and lateralization, the final result creates a landmark medial to the right uterine vessels at the level of the internal cervical os with which the needle of the Mersilene tape will be able to pass through. The Mersilene tape was guided from anterior to posterior via a previously straightened needle. Similarly, a landmark was created on the left, and the Mersilene tape was directed from anterior to posterior. The Mersilene tape was placed circumferentially around the internal cervical os of the bicornuate uterus, medial to the uterine vessels. Both ends of the Mersilene tape were then gently pulled, ensuring that the tape was lying flat on the anterior of the internal cervical os with no bowels or uterine vessels within it. The tape was then tied posteriorly at the 6 o'clock position with appropriate tension. A 2-0 silk was then sutured to the tails of the tape using the purse-string technique to ensure that it would remain securely tied and in the correct position. Hemostasis was assured. Both a hysteroscopy and a cystoscopy were done after the completion of the cerclage to ensure that no tape or sutures were seen within the cervical canal or the uterine cavity. None were observed. MAIN OUTCOMES MEASURES: The success criteria for the surgery were identified as the patient's ability to attain a viable pregnancy after the cerclage placement, along with achieving LB. RESULTS: Subsequently, a spontaneous pregnancy was achieved. An infant weighing 3 pounds and 16 ounces was delivered by cesarean section at 36 weeks because of an oligohydramnios. The infant is currently healthy at 13 pounds. CONCLUSION: Robotic-assisted abdominal cerclage around the internal cervical os in a bicornuate uterus offers a possibly feasible and straightforward technique for surgeons seeking to reduce risks, although further research is needed.

Treatment with plasma exchange of a pregnant woman with anti-PP1Pk alloimmunization: A case report.

The histo-blood group antigens P, P1 and Pk are a closely related set of glycosphingolipid structures expressed by red blood cells and other tissues. None of these three characters is expressed on p cells, a null phenotype that arises in the context of homozygous mutation of the A4GALT gene. Subjects with p phenotype spontaneously develop a natural alloantibody named anti-PP1Pk, which is a mixture of IgG and IgM against P1, P and Pk. While anti-P1 is a weak cold antibody with poor clinical significance, anti-P and anti-Pk antibodies are potent haemolysins responsible for severe hemolytic transfusion reactions. The rare anti-PP1Pk alloantibodies are associated with recurrent spontaneous abortion in the first trimester of gestation. P and Pk antigens are expressed at high levels on the placenta and antibodies directed against both these structures are deleterious to placental trophoblasts. Here we describe the use of plasma exchange (PEX) in a nulliparous 39-year-old woman with anti-PP1Pk antibodies and a history of repeated spontaneous early abortions and hypofertility. The patient underwent apheresis starting from the third week throughout the pregnancy and a healthy child was delivered by cesarean section at 35 WG. The newborn required only phototherapy within a few days of life. We can state that an early treatment with the only PEX has proven to be effective and safe in the management of a fetomaternal P-incompatibility caused by a high anti-PP1Pk titer (256).

Evaluation of Recurrent Pregnancy Loss.

Recurrent pregnancy loss (RPL) affects approximately 5% of couples. Although RPL definitions vary across professional societies, an evaluation after a second clinically recognized first-trimester pregnancy loss is recommended. Good quality evidence links parental chromosomal rearrangements, uterine anomalies, and antiphospholipid syndrome (APS) to RPL. In contrast, the relationship between RPL and other endocrine, hematologic, and immunologic disorders or environmental exposures is less clear. Anticoagulant therapy and low-dose aspirin are recommended for patients with RPL who have also been diagnosed with APS. Vaginal progesterone supplementation may be considered in patients experiencing vaginal bleeding during the first trimester. Surgical correction may be considered for patients with RPL in whom a uterine anomaly is identified. Evaluation and management of additional comorbidities should be guided by the patient's history rather than solely based on the diagnosis of RPL, with the goal of improving overall health to reduce complications in the event of pregnancy. Most people with RPL, including those without identifiable risk factors, are expected to achieve a live birth within 5 years from the initial evaluation. Nevertheless, clinicians should be sensitive to the psychological needs of individuals with this condition and provide compassionate and supportive care across all stages.

Adverse outcomes in subsequent pregnancies in women with history of recurrent spontaneous abortion: A meta-analysis.

OBJECTIVE: This study aimed to investigate the association between a history of recurrent spontaneous abortion (RSA) and adverse outcomes in women with spontaneous conception. METHODS: A search strategy from the inception to March 3, 2023 was run in PubMed, Embase, Cochrane Library, and Web of Science databases. The odds ratio (OR), and the 95% confidence interval (CI) or point estimation were used as the evaluation indexes. Each outcome measure tested was assessed for heterogeneity using the Cochran Q test. Sensitivity analyses were performed to test the credibility of the meta-analysis results. RESULTS: Fifteen studies involving 1 475 389 pregnant women were included. A history of RSA was associated with gestational diabetes (OR: 2.21, 95% CI: 1.70-2.87, p < 0.001), preeclampsia (OR: 2.06, 95% CI: 1.49-2.86, p < 0.001), placenta previa (OR: 1.82, 95% CI: 1.09-3.02, p = 0.021), placental abruption (OR: 1.67, 95% CI: 1.36-2.06, p < 0.001), miscarriage (OR: 6.37, 95% CI: 3.83-10.57, p < 0.001), preterm birth (OR: 1.80, 95% CI: 1.36-2.37, p < 0.001), cesarean section (OR: 1.47, 95% CI: (1.13-1.91, p = 0.004), perinatal death (OR: 2.24, 95% CI: 1.39-3.60, p = 0.001), and neonatal intensive care unit admission (OR: 1.39, 95% CI: 1.01-1.92, p = 0.047). However, the associations of a history of RSA with gestational hypertension, small for gestational age, fetal anomalies, fetal growth restriction, and postpartum hemorrhage were not observed. CONCLUSION: This meta-analysis indicates a history of RSA was associated with increased risks of several adverse outcomes in pregnant women with spontaneous conception.

Massive perivillous fibrin deposition: Diagnosis, obstetrical features, and treatment.

MPVFD (Massive perivillous fibrin deposition) is placental lesion characterized by extensive massive deposits of fibrin in the intervillous space, extending over at least 25 % of the placental volume. Currently, this pathology can only be detected through histopathological examination of the placenta after a pregnancy has ended. The underlying mechanisms are poorly studied, there is no biomarker available for the diagnosis of MPVFD and treatment protocols are experimental and still lacking. The objective of this study is to systematically review the literature on the associated clinicopathologic features, treatment, and prognosis of MPVFD. We ended up with 17 studies, of these 12 studies were considered relevant for this article and included in the final analysis. All studies reporting MPVFD are retrospective. MPVFD is associated with recurrent miscarriage, intra uterine fetal death (IUFD), intra uterine growth restriction (IUGR) and preterm delivery. The prevalence in pregnancies with a delivery after 22 weeks of gestation was at 1.1 % and even higher to 2.7 % in recurrent early miscarriages. The reported risk of fetal death in MPVFD ranges mainly from 15 to 80 %. Preterm delivery is spontaneous in 50 to 70 % of cases and induced by of a severe intrauterine growth restriction (IUGR) in 30 to 50 % of cases depending on the study. Its causes and treatment are still poorly understood, although several avenues have been explored. This review summarizes current understanding of the prevalence, diagnostic features, clinical consequences, immune pathology, and potential prophylaxis against recurrence in this chronic inflammatory placental syndrome.

Preconceptual administration of doxycycline in women with recurrent miscarriage and chronic endometritis: protocol for the Chronic Endometritis and Recurrent Miscarriage (CERM) trial, a multicentre, double-blind, placebo-controlled, adaptive randomised trial with an embedded translational substudy.

INTRODUCTION: Recurrent miscarriage is a common condition with a substantial associated morbidity. A hypothesised cause of recurrent miscarriage is chronic endometritis (CE). The aetiology of CE remains uncertain. An association between CE and recurrent miscarriage has been shown. This study will aim to determine if preconceptual administration of doxycycline, in women with recurrent miscarriages, and CE, reduces first trimester miscarriages, increasing live births. METHODS AND ANALYSIS: Chronic Endometritis and Recurrent Miscarriage is a multicentre, double-blind adaptive trial with an embedded translational substudy. Women with a history of two or more consecutive first trimester losses with evidence of CE on endometrial biopsy (defined as ≥5 CD138 positive cells per 10 mm2) will be randomised to oral doxycycline or placebo for 14 days. A subset will be recruited to a mechanistic substudy in which microbial swabs and preintervention/postintervention endometrial samples will be collected. Up to 3062 women recruited from 29 National Health Service (NHS) hospital sites across the UK are expected to be screened with up to 1500 women randomised in a 1:1 ratio. Women with a negative endometrial biopsy (defined as <5 CD138 positive cells per 10 mm2) will also be followed up to test validity of the tool. The primary outcome is live births plus pregnancies ≥24 + 0 weeks gestation at the end of the trial, in the first or subsequent pregnancy. Secondary clinical outcomes will also be assessed. Exploratory outcomes will assess the effect of doxycycline treatment on the endometrial microbiota, the differentiation capacity of the endometrium and the senescent profile of the endometrium with CE. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the NHS Research Ethics Committee Northwest-Haydock (19/NW/0462). Written informed consent will be gained from all participants. The results will be published in an open-access peer-reviewed journal and reported in the National Institute for Health and Care Research journals library. TRIAL REGISTRATION NUMBER: ISRCTN23947730.

Future risk of metabolic syndrome after recurrent pregnancy loss: a cohort study using UK Biobank.

OBJECTIVE: To evaluate the risk of metabolic syndrome (MS) after recurrent pregnancy loss (RPL) using UK Biobank data. A history of pregnancy loss is associated with the development of cardiovascular diseases in the future. However, the association between RPL and subsequent MS is poorly understood. Therefore, we aimed to check the risk of MS after RPL. DESIGN: The study population was divided into 2 groups according to reproductive history: women with a history of RPL and women without a history of RPL. Recurrent pregnancy loss was defined as 2 or more spontaneous miscarriages, and MS was defined as at least 3 of the following: abdominal obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol levels, high-blood pressure, and hyperglycemia. SETTING: UK Biobank resource. PATIENTS: The UK Biobank is a prospective cohort study that enrolled individuals aged between 40 and 69 years whose medical and reproductive histories were retrieved at enrollment. In this cohort, only women with a history of at least one pregnancy were selected. INTERVENTIONS: Recurrent pregnancy loss. MAIN OUTCOME MEASURES: The primary outcome was the prevalence of MS. The secondary outcomes were 5 diagnostic components of MS. RESULTS: We analyzed 228,674 women, including 15,702 with a history of RPL and 212,972 without a history of RPL. Women with a history of RPL have a higher prevalence of MS between the ages of 40 and 60 years (33.0% vs. 31.5%). After adjusting for covariates (age, race, number of live births, early menopause, smoking, alcohol consumption, and physical activity), the increased risk of MS after RPL remained significant (adjusted odds ratio, 1.10; 95% confidence interval, 1.06-1.15). Furthermore, in the analysis of the 5 diagnostic components of MS, a history of RPL significantly increased the risk of abdominal obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol levels, and hyperglycemia. CONCLUSION: Middle-aged women with a history of RPL have an increased risk of MS.

Polycystic ovary syndrome and recurrent pregnancy loss, a review of literature.

Objective: PCOS is a syndrome of ovarian dysfunction associated with recurrent pregnancy loss. Several correlating factors have been investigated that influence the risk of pregnancy loss in PCOS. However, uncertainty remains about their contribution to pregnancy loss and prognosis. This review of literature aims to identify what is known and what requires further investigation on the relationship between PCOS and recurrent pregnancy loss, to guide future research and optimize medical guidance throughout pregnancy. Study design: a review of literature was performed on several search engines using the following terms; polycystic ovarian syndrome, PCOS, recurrent pregnancy loss, recurrent miscarriage, RPL, aborted fetus, abortus provocatus, miscarriage and habitual abortion. Results: 37 articles were included; 3 systematic reviews, 1 meta-analysis, 2 randomized controlled trials, 6 prospective cohort studies, 22 case-control studies and 3 case series. The main objectives investigated by studies were pregnancy complications, pregnancy loss and live birth in the PCOS population. Conclusion: Studies that investigated the relationship between PCOS and recurrent pregnancy loss are few and inconsistent and warrant further research. Factors apt for further investigation include the extent to which PCOS phenotypes, BMI, obesity, insulin resistance, hyperandrogenemia, SHBG, hs-CRP, CTRP6, adiponectin, plasma leptin, homocysteine, AMH and thrombophilia contribute to further risk of miscarriage. Other factors requiring further exploration in relation to risk for miscarriage in PCOS patient with RPL include sOB-R, PAI-Fx and the Factor-V-Leiden mutations.

Lupus and recurrent pregnancy loss: the role of female sex hormones and B cells.

Systemic lupus erythematosus is a debilitating autoimmune disease characterized by uncontrolled activation of adaptive immunity, particularly B cells, which predominantly affects women in a 9 to 1 ratio compared to men. This stark sex disparity strongly suggests a role for female sex hormones in the disease's onset and progression. Indeed, it is widely recognized that estradiol not only enhances the survival of autoreactive B cells but also stimulates the production of autoantibodies associated with systemic lupus erythematosus, such as anti-nuclear antibodies and anti-dsDNA antibodies. Clinical manifestations of systemic lupus erythematosus typically emerge after puberty and persist throughout reproductive life. Furthermore, symptoms often exacerbate during the premenstrual period and pregnancy, as increased levels of estradiol can contribute to disease flares. Despite being fertile, women with lupus face a heightened risk of pregnancy-related complications, including pregnancy loss and stillbirth, which significantly surpass the rates observed in the healthy population. Therefore, this review aims to summarize and discuss the existing literature on the influence of female sex hormones on B-cell activation in patients with systemic lupus erythematosus, with a particular emphasis on their impact on pregnancy loss.

[Hematological workup in cases of recurrent early miscarriages: what evidences?] / Bilan hématologique en cas de fausses couches précoces à répétition : quelles évidences ?

Recurrent miscarriages have a major psychological and somatic impact, as well as a significant economic burden. An etiological work-up should be offered after two or three miscarriages, the threshold varying from one scientific society to another. However, the proposed biological work-up must be justified by scientific evidence. A simple blood count, basic coagulation tests including fibrinogen assay and anti-phospholipid antibodies testing should be performed initially. Hereditary thrombophilia testing should only be carried out if there is a history of maternal thrombosis. In the event of an abnormality, management should be multidisciplinary, and the prescription of medication should follow recommended guidelines. Prophylactic treatment is not justified in the absence of a known etiology.

Les fausses couches précoces (FCP) à répétition ont un impact psychologique et somatique important, ainsi qu'un poids économique non négligeable. Un bilan étiologique devrait être proposé à partir de deux ou trois fausses couches, le seuil variant selon les sociétés savantes. Cependant, le bilan biologique doit être justifié par des évidences scientifiques. Une formule sanguine simple, des tests de coagulation de base avec le dosage du fibrinogène et une recherche d'anticorps anti-phospholipides devraient être réalisés en première intention. Une recherche de thrombophilie héréditaire ne devrait être effectuée qu'en cas d'antécédent thrombotique maternel. En cas d'anomalie, la prise en charge doit être multidisciplinaire et la prescription de médicaments doit suivre les recommandations. Un traitement prophylactique n'est pas justifié en l'absence d'étiologie retrouvée.

Diagnostic workup of endocrine dysfunction in recurrent pregnancy loss: a cross-sectional study in Northeast China.

Objective: To evaluate the prevalence of abnormal endocrine dysfunction for recurrent pregnancy loss (RPL) amongst patients with two versus three or more pregnancy losses. Methods: This cross-sectional study retrospectively collected pre-pregnancy data of 537 women diagnosed with RPL in Shengjing Hospital of China Medical University from 2017 to 2022, including the baseline data of patients and the test results of endocrine factors. Several endocrine dysfunction included in this study were: thyroid dysfunction, obesity, hyperprolactinemia, polycystic ovary syndrome and blood glucose abnormality. Furthermore, vitamin D level were collected to study its relationship with endocrine dysfunction. Finally, we subdivided the patients according to the number of previous pregnancy loss and compared the prevalence of endocrine dysfunction between subgroups. Results: Among 537 RPL patients, 278 (51.8%) patients had abnormal endocrine test results. The highest incidence of endocrine dysfunction was thyroid dysfunction (24.39%, 131/537), followed by hyperprolactinemia (17.34%, 85/490), obesity (10.8%, 58/537), polycystic ovary syndrome (10.50%, 56/533), and abnormal blood glucose (5.29%, 27/510). Only 2.47%(13/527) of patients have vitamin D level that reach the standard. After subdividing the population according to the number of pregnancy loss, we did not find that the incidence of endocrine dysfunction (P=0.813), thyroid dysfunction (P=0.905), hyperprolactinemia (P=0.265), polycystic ovary syndrome (P=0.638), blood glucose abnormality (P=0.616) and vitamin D deficiency (P=0.908) were different among patients with two versus three or more pregnancy losses. However, obesity (P=0.003) was found more frequently observed in patients with more times of pregnancy loss. Conclusion: The prevalence of endocrine dysfunction in RPL population is high. There is no difference in the prevalence of endocrine dysfunction, except for obesity, among patients with two or more pregnancy losses, which may suggest investigations of endocrine dysfunction when patients have two pregnancy losses.

Series of overviews on miscarriage and recurrent miscarriage.

Miscarriage is a relatively common occurrence with many knowns and unknowns and a profound psychological impact on individuals and couples. The editors felt it was time to publish a series of overviews for Views and Reviews on both sporadic miscarriage and recurrent miscarriage. The series starts with the prevalence of miscarriage and recurrent miscarriage and subsequently describes the psychological impact, what we know of the genetics, whether uterine natural killer cells may play a role, the association with infections, and potential interventions.

Identifying discrepancies between clinical practice and evidence-based guideline in recurrent pregnancy loss care, a tool for clinical guideline implementation.

BACKGROUND: Practice variation in recurrent pregnancy loss (RPL) care is common. International guidelines vary in their recommendations for the management of RPL couples, which could lead to an increase of cross border reproductive care. Currently, the Dutch RPL guideline is being adapted from the European Society for Human Reproduction and Embryology (ESHRE) guideline. We aim to identify discrepancies between RPL guidelines and RPL practice. These discrepancies could be considered in the development of a new guideline and implementation strategies to promote adherence to new recommendations. METHODS: A nationwide survey on the management of RPL patients was conducted across all 107 hospital-based obstetrics and gynaecology practices in the Netherlands. The survey was sent via the Dutch Society for Obstetricians and Gynaecologists to all affiliated clinicians. The questionnaire consisted of 36 questions divided in four sections: clinician's demographics, RPL definition, investigations and therapy. The data were compared to the recommendations given by the Dutch national guideline and the most recent guideline of the ESHRE. RESULTS: All hospital-based practices (100%; n = 107) filled in the online questionnaire. The majority of respondents defined RPL similarly, as two or more pregnancy losses (87.4%), not obligatory consecutive (93.1%). More than half of respondents routinely perform thrombophilia screening ( 58%), although not advised by the ESHRE, while thyroid function (57%), thyroid auto-immunity (27%) and ß2-glycoprotein antibodies (42%) in the context of antiphospholipid syndrome (APS) are recommended but investigated less often. Regarding parental karyotyping, 20% of respondents stated they always perform parental karyotyping, without prior risk assessment. because of RPL. Treatment for hereditary thrombophilia was frequently (43.8% (n = 137)) prescribed although not recommended. And finally, a considerable part (12-16%) of respondents prescribe medication in case of unexplained RPL. CONCLUSION: While many clinicians perform investigations recommended by the ESHRE, there is a considerable variation of RPL practice in the Netherlands. We identified discrepancies between RPL guidelines and RPL practice, providing possibilities to focus on multifaceted implementation strategies, such as educational intervention, local consensus processes and auditing and feedback. This will improve the quality of care provided to RPL patients and may diminish the necessity felt by patients to turn to multiple opinions or cross border reproductive care.

Early pregnancy complications including recurrent pregnancy loss and obesity.

This review on early pregnancy complications and obesity will focus on the known pregnancy complications such as miscarriage (whether spontaneous or after fertility treatment), polycystic ovaries and risk of miscarriage, recurrent pregnancy loss, ectopic pregnancy, hyperemesis gravidarum and birth defects. Evidence will be assessed and mechanistic pathways for the outcomes will be described. We know that obesity is now a pandemic and has an impact on early pregnancy complications. The evidence has been summarised to provide the reader with a comprehensive overview and advice for pregnant women with obesity in early pregnancy.

Uterine Septum and Other Müllerian Anomalies in a Recurrent Pregnancy Loss Population: Impact on Reproductive Outcomes.

STUDY OBJECTIVE: To study the impact of Müllerian anomalies on reproductive outcomes in a recurrent pregnancy loss (RPL) population and to evaluate the effect of surgical correction of uterine septum on the odds of achieving live birth in RPL patients with a septate uterus. DESIGN: A retrospective cohort study. SETTING: A specialized RPL clinic at a tertiary center. PATIENTS: RPL patients with ≥ 2 pregnancy losses before 20 weeks' gestation who attended a specialized RPL clinic. INTERVENTION: We aimed to assess the association between a possible risk factor (Müllerian anomalies) and reproductive outcomes and that between having surgery for septate uterus and achieving a live birth. MEASUREMENTS AND MAIN RESULTS: The primary outcome is live birth rate in RPL patients with Müllerian anomalies compared with those without; secondary outcome measures include rates of full-term live birth, preterm live birth, first and second trimester pregnancy loss, and stillbirth. After adjusting for patient age at the initial RPL visit, the number of pregnancy losses, and the presence of any other abnormal RPL investigation, the odds of achieving live birth were on average 49.4% lower for patients with a septate uterus than those without Müllerian anomalies (odds ratio, 0.51; 95% confidence interval, 0.30-0.86) in the studied cohort (n = 377). A subanalysis of 72 patients with septate uterus demonstrated a higher likelihood of live birth in those who underwent septum resection (46/72; 63.9%) than those who elected to go for expectant management (26/72; 36.1%), yet this study was underpowered to establish a significant difference (52.2% vs 34.6%; p = .22). CONCLUSION: In RPL patients, having a septate uterus significantly decreased the chances of achieving live birth. Patients with septate uterus who received hysteroscopic septum division had a higher tendency to achieve more live births than those who elected expectant management. However, our study was underpowered to detect a statistically significant difference.

Evaluation of platelet parameters, coagulation markers, antiphospholipid syndrome, and thyroid function in palestinian women with recurrent pregnancy loss.

BACKGROUND: Multiple etiologies contribute to recurrent pregnancy loss (RPL) including immunological, endocrine, anatomical, genetic and infection but more than 50% of cases remain unexplained. Evidences of thrombotic and inflammatory processes were observed at maternal-fetal interface and considered pathological findings in most RPL cases including unexplained cases. This study aimed to evaluate the association between RPL and several risk factors: platelet parameters, coagulation factors, antiphospholipid syndrome, and thyroid function. METHODS: This is an unmatched case-control study that included 100 RPL and 100 control women. Anthropometric and health data were collected and a gynecologist examined participants to assure fitting the inclusion criteria. Platelet parameters [including Mean Platelet Mass (MPM), Concentration (MPC) and Volume (MPV)] and ratios (MPV/Platelet, MPC/Platelet, MPM/Platelet, Platelet/Mononuclear cells), coagulation markers [Protein C (PC), Protein S (PS), Antithrombin III, D-dimer], antiphospholipid antibodies [Anti-phospholipid (APA), Anti-cardiolipin (ACA) and anti-B2-glycoprotein 1], Lupus anticoagulant, Antinuclear antibodies, and thyroid function (Thyroid stimulating hormone and anti-thyroid peroxidase) were measured. RESULTS: Mean ages of cases and controls at marriage were 22.5 years for both, and their current ages were 29.4 and 33.0, respectively. 92% of cases and 99% of controls aged blow 30 years at marriage. 75% of cases have 3-4 miscarriages and 9% have ≥ 7 miscarriages. Our results indicated significantly lower male/female age ratio (p = .019), PC (p = .036) and PS (p = .025) in cases compared to controls. Plasma D-dimer (p = .020) and antiphospholipid antibodies [ACA (IgM and IgG), APA (IgM)] were significantly higher in cases compared to controls. No significant differences were observed between cases and controls concerning APA (IgG), anti-B2-glycoprotein 1 (IgM and IgG), Lupus anticoagulant, Antinuclear antibodies, platelet parameters, thyroid markers, family history of miscarriage, consanguineous marriage, and other health data. CONCLUSIONS: This is the first study that investigated the association between platelet, coagulation, antiphospholipid, autoimmune and thyroid parameters, and RPL in Palestinian women. Significant associations between male/female age ratio, PC, PS, D-dimer, ACA (IgM, IgG), APA (IgM) and RPL were observed. These markers could be used in evaluating RPL. These findings confirm the heterogeneous nature of RPL and emphasize the need for further studies to find out risk factors for RPL.

Investigation and Management of Recurrent Pregnancy Loss: A Comprehensive Review of Guidelines.

Importance: Recurrent pregnancy loss (RPL) is one of the most frustrating clinical entities in reproductive medicine requiring not only diagnostic investigation and therapeutic intervention, but also evaluation of the risk for recurrence. Objective: The aim of this study was to review and compare the most recently published major guidelines on investigation and management of RPL. Evidence Acquisition: A descriptive review of guidelines from the Royal College of Obstetricians and Gynaecologists, the European Society of Human Reproduction and Embryology, the American Society for Reproductive Medicine, the French College of Gynecologists and Obstetricians, and the German, Austrian, and Swiss Society of Gynecology and Obstetrics on RPL was carried out. Results: There is consensus among the reviewed guidelines that the mainstays of RPL investigation are a detailed personal history and screening for antiphospholipid syndrome and anatomical abnormalities of the uterus. In contrast, inherited thrombophilias, vaginal infections, and immunological and male factors of infertility are not recommended as part of a routine RPL investigation. Several differences exist regarding the necessity of the cytogenetic analysis of the products of conception, parental peripheral blood karyotyping, ovarian reserve testing, screening for thyroid disorders, diabetes or hyperhomocysteinemia, measurement of prolactin levels, and performing endometrial biopsy. Regarding the management of RPL, low-dose aspirin plus heparin is indicated for the treatment of antiphospholipid syndrome and levothyroxine for overt hypothyroidism. Genetic counseling is required in case of abnormal parental karyotype. The Royal College of Obstetricians and Gynaecologists, the European Society of Human Reproduction and Embryology, and the French College of Gynecologists and Obstetricians guidelines provide recommendations that are similar on the management of cervical insufficiency based on the previous reproductive history. However, there is no common pathway regarding the management of subclinical hypothyroidism and the surgical repair of congenital and acquired uterine anomalies. Use of heparin for inherited thrombophilias and immunotherapy and anticoagulants for unexplained RPL are not recommended, although progesterone supplementation is suggested by the American Society for Reproductive Medicine and the German, Austrian, and Swiss Society of Gynecology and Obstetrics. Conclusions: Recurrent pregnancy loss is a devastating condition for couples. Thus, it seems of paramount importance to develop consistent international practice protocols for cost-effective investigation and management of this early pregnancy complication, with the aim to improve live birth rates.