Oral immunosuppressants improve pregnancy outcomes in women with idiopathic recurrent miscarriage: A meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Reports said immunotherapy is effective for the treatment of idiopathic recurrent miscarriage (RM). Immunotherapy is invasive, and lymphocyte therapy carries some risk of infection. Oral immunosuppressants have the advantages of simple administration and convenience; however, there is no statistical analysis of whether they can improve pregnancy outcomes in patients with idiopathic RM. METHODS: Six databases were searched for studies on oral immunosuppressants and RM; 374 articles were identified. There were two oral immunosuppressants, cyclosporine A and prednisone; two studies were on cyclosporine A and three studies were on prednisone for RM. RESULTS AND DISCUSSION: In total, 554 RM patients were included in this analysis, including 357 patients who received oral immunosuppressive agents and 197 patients who received basic treatment, placebo, or no treatment. Oral administration of cyclosporine A or prednisolone increases live birth rate (OR = 3.6, 95% CI: 2.1-6.15, p < 0.00001) and ongoing pregnancy rate (OR = 8.82, 95% CI: 2.91-26.75, p = 0.0001) in patients with idiopathic RM. Drug use reduced miscarriage rate (OR = 0.21, 95% CI: 0.08-0.52, p = 0.0007); however, there was significant heterogeneity (I2  = 73%) and a moderate-to-severe risk of bias. There was no effect on premature birth rate (OR = 2.26, 95% CI: 0.96-5.31, p = 0.06). This meta-analysis cannot provide a reference for the duration of medication treatment because the selected studies had inconsistent durations. WHAT IS NEW AND CONCLUSION: We did a statistical analysis and found that oral immunosuppressants (including cyclosporine A or prednisolone) can improve pregnancy outcomes in patients with idiopathic RM, increase live birth rate and ongoing pregnancy rate, and reduce miscarriage rate.

Progestogens in the management of miscarriage and preterm birth.

Miscarriage affects up to 20% of pregnant women, resulting in substantial psychological repercussions in addition to inherent problems from bleeding and infection. Preterm births constitute about 7-12% of all births but are over represented in terms of perinatal morbidity and mortality. Despite existing trials examining the use of progestogens in both these conditions, there is a dearth of guidelines for the practicing clinician. A systematic review of the literature was performed by an expert panel formed by the Obstetrical & Gynaecological Society of Malaysia from the inception of the databases searched up to February 2020, without language restrictions. The level of evidence and recommendations was determined by the panel and peer-reviewed by local and international experts. The use of progestogens is recommended in women with threatened miscarriages who have experienced previous miscarriage as luteal phase support in women undergoing assisted reproduction and in women with short cervix of <25mm in the midtrimester. In addition, it can be considered in women with recurrent miscarriage, where no other cause is identified. This article reviews the existing evidence including the guideline above and is intended to aid primary care doctors and obstetricians in their prescribing practices when managing these common conditions.

Management of recurrent miscarriages: an overview of current evidence.

PURPOSE OF REVIEW: Recurrent miscarriage (RM) or recurrent pregnancy loss (RPL) is defined as the consecutive loss of two or more pregnancies before the age of viability. The exact prevalence of RM is unknown, but it has been reported between 1% and 2%. The objective of this review is to provide a critical summary of the latest evidence for the investigation and management of women with RM. RECENT FINDINGS: RMs are associated with multiple factors including increased female age and lifestyle habits, as well as genetic factors, hereditary and acquired thrombophilia and infections. Metabolic and endocrine factors, in addition to anatomical causes such as uterine malformations have also been suggested as a causative factors of RM. SUMMARY: The management of RM would be expected to cause specific, however, in the majority of the cases no cause is identified, and the factors associated with RM may not be causally related with the condition.

Recurrent Massive Perivillous Fibrin Deposition and Chronic Intervillositis Treated With Heparin and Intravenous Immunoglobulin: A Case Report.

BACKGROUND: Massive perivillous fibrin deposition (MPVFD) and chronic intervillositis (CI) are related rare pathological correlates of severe intrauterine growth restriction (IUGR) and fetal loss with high recurrence rates. No standard management has been established. CASE: A patient underwent termination of pregnancy at 21 weeks for severe early onset IUGR. Placental histology showed mixed CI with MPVFD. Several months later, the patient became pregnant and was managed with prednisone and aspirin (ASA) but miscarried at 16 weeks. Placental pathology showed MPVFD and focal CI. For two subsequent pregnancies, she was treated with intravenous immunoglobulin (IVIG), heparin, and ASA. Both pregnancies resulted in healthy near-term deliveries with normal placentas. CONCLUSION: IVIG, heparin, and ASA can be an option in patients with recurrent pregnancy loss due to MPVFD and CI.

Practical Work-up and Management of Recurrent Pregnancy Loss for the Front-Line Clinician.

Only a few so-called etiologies of recurrent pregnancy loss recurrent pregnancy loss in otherwise healthy women are adequately supported by well-designed investigations of association. The majority of proposed "treatments" have not been subjected to rigorous trials. The American Board of Internal Medicine Choosing Wisely initiative urges providers and patients to have constructive dialog aimed at choosing health care that is supported by evidence, not duplicative of other tests or procedures already received, free from harm, and truly necessary. We support the refreshing, objective frankness promoted by this campaign. A version of the Choosing Wisely "Do" and "Don't" format for recurrent pregnancy loss is presented.

Pregnancy morbidity in antiphospholipid syndrome: what is the impact of treatment?

Women with persistently circulating antiphospholipid antibodies (aPL) have a higher incidence of recurrent abortions, fetal losses, pre-eclampsia, and placental insufficiency. Current treatment of patients with antiphospholipid syndrome (APS) during pregnancy with heparin and aspirin can act by preventing clot formation and improving live birth rates, but other obstetric morbidities remain high, especially in patients with a history of thrombotic events. In addition to the classical thrombotic placental events, other factors involving inflammation and complement activation seem to play a role in certain complications. In this article, we will review how medications interfere in the pathogenic mechanisms of APS, discuss the impact of current recommended treatment on pregnancy morbidity, and analyze new promising therapies.

Recurrent miscarriage is a useful and valid clinical concept.

Although epidemiological, clinical and biochemical risk factors are known for recurrent miscarriage (RM), the etiology is mainly unknown. Two main hypotheses dominate: that RM is mainly caused by aneuploid conceptions and other conception errors and that the recurrence rate is explained by the combination of chance and increased risk, or that maternal endocrinological, thrombophilic or immunological abnormalities play a main role in causing loss of euploid conceptions. Believers of the former hypothesis advocate that management of RM should be conservative and that the spontaneous prognosis is very favorable. Believers of the latter hypothesis think that treatments aimed at the woman may improve pregnancy outcome, but that testing of such treatments in randomized controlled trials is needed. In this article in favor of RM being a specific and useful clinical concept, arguments are advanced that a significant subset of RM patients exhibit a poor spontaneous prognosis and should be offered relevant investigations, close surveillance during pregnancy, and treatment, preferably as part of randomized controlled trials.

Recurrent spontaneous abortions, Hashimoto thyroiditis and alopecia totalis: response to anticoagulation and intravenous immunoglobulin therapy.

INTRODUCTION: Although numerous studies indicated a link between antithyroid antibodies and recurrent spontaneous abortions (RSA), consensus on the treatment of this condition is still lacking. CASE REPORT: We present a case of a 35-year-old pregnant woman (gestation week 4) with primary hypothyroidism, total alopecia, high level of positive antithyroid antibodies, and history of two recurrent spontaneous abortions in early pregnancy. Along with L-thyroxin substitution, intravenous human immunoglobulin (IVIg) combined with anticoagulation and antiaggregation therapy was introduced. During pregnancy her scalp hair completely re-grew, and following gestation week 39 she delivered healthy female child. CONCLUSION: Thyroid antibodies could contribute to previous recurrent abortions in our patient. It is suggested that in older primiparas with Hashimoto thyroiditis and history of RSA, a combined treatment with IVIg, anticoagulation and antiaggregation therapy should be considered.

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.

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.

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.

Recurrent miscarriage and thrombophilia: an update.

PURPOSE OF REVIEW: Acquired and inherited thrombophilia is an important research avenue in the recurrent miscarriage field. The optimum treatment for patients with recurrent miscarriage and a confirmed thrombophilia remains a contentious issue. We aim to appraise and explore the latest research in the field of thrombophilia and recurrent miscarriage in this review. RECENT FINDINGS: Antiphospholipid syndrome (APS) is the only proven thrombophilia that is associated with adverse pregnancy outcomes. Research involving inherited thrombophilia and recurrent miscarriage is limited to small observational studies with small and heterogeneous populations. Aspirin and heparin therapy are frequently prescribed for APS, yet there is no robust evidence for the most efficacious regime. The combination of inherited hypercoagulability and environmental factors in association with recurrent miscarriage has recently been explored as an aid to identify high-risk individuals. SUMMARY: The cause of recurrent miscarriage is multifactorial and appropriate treatment continues to be a challenge. Laboratory tests need to be standardized and well designed multicentre research trials are essential to expand on the current knowledge base with the aim to produce strong evidence-based medicine.

Successful pregnancy in a patient suffering from recurrent mid-trimester miscarriage with C9 deficiency after receiving cervical cerclage followed by clindamycin and progesterone: a case report.

Complement component 9 (C9) deficiency is relatively common, especially in Japan. Here we present the case of a 27-year-old Japanese woman whose obstetric history involved three mid-trimester miscarriages (at 22 weeks', 18 weeks' and 21 weeks' gestation) and one early spontaneous miscarriage. Her fifth pregnancy was successfully managed by cervical cerclage at 13 weeks' gestation, followed by clindamycin administration (600 mg/day for 7 days) and progesterone injections (250 mg/week). She gave birth to a healthy 3326-g male infant at 40 weeks and 1 day gestation after natural onset of labor. After delivery, the serum complement components were analyzed. C9 protein and activity were undetectable in the patient's serum. We suggest that an immunologic disorder such as C9 deficiency should be considered as a potential complication of undiagnosed recurrent miscarriages.

Bemiparin versus low dose aspirin for management of recurrent early pregnancy losses due to antiphospholipd antibody syndrome.

STUDY OBJECTIVE: To compare the live birth rate of women presented with recurrent miscarriages in the first trimester due to antiphospholipid antibody syndrome (APS), randomized to either low molecular weight heparin (Bemiparin) or low dose aspirin (LDA) and to determine the maternal and fetal adverse effects in both treatment groups. PATIENTS AND METHODS: A clinical comparative study was conducted in Maternity teaching Hospital, Erbil city, north of Iraq, Kurdistan region from 15th of September 2007 to the 1st of August 2010 on 141 women presented with 2 or more consecutive miscarriages due to APS, the women randomized to receive either prophylactic dose of Bemiparin with the diagnosis of pregnancy or LDA started preconceptioally and until 36 weeks gestation. The primary outcome was live birth rate in both treatment groups, the secondary outcomes were maternal and fetal complications in both trial groups. RESULT: There was no statistically significant difference between the two groups regarding demographic characters (age groups, parity, gestational age and history of previous abortion), and mode of delivery of the viable newborns. There was a statistically significant difference between the two treatment groups regarding live birth rate. The proportions of women who gave birth to a live infant were 72.13% in the LDA group and 86.25% in the Hibor group, the mean difference between the live birth rate in both group was 0.141 (95% Confidence interval of the difference, 0.08, 0.274). The average birth weight for women received LDA was significantly lower than women who received Bemiparin. CONCLUSION: The use of the new second generation LMWH (Bemiparin) in comparison to LDA during pregnancy for prevention of recurrent miscarriage in women with APS is a safe, reliable method with a high live birth rate and no maternal and fetal complications.

Successful prevention of thrombotic thrombocytopenic purpura (TTP) relapse using monthly prophylactic plasma exchanges throughout pregnancy in a patient with systemic lupus erythematosus and a prior history of refractory TTP and recurrent fetal loss.

BACKGROUND: The occurrence of thrombotic thrombocytopenic purpura (TTP) in the setting systemic lupus erythematosus (SLE) is rare. In women of childbearing age, TTP is associated with high rates of recurrence in pregnancy. Furthermore, both TTP and SLE are associated with a significant risk of adverse pregnancy outcomes. CASE PRESENTATION: We describe the case of a 36 year old female in her first trimester of pregnancy with a prior history of SLE-associated severe refractory TTP who was treated with a combination of corticosteroids and prophylactic plasma exchanges (PLEX) throughout pregnancy to prevent TTP recurrence. She delivered a healthy infant at 33 weeks of gestation after the onset of preterm labor. There was no evidence of TTP recurrence in the antepartum or postpartum period in this high risk patient. CONCLUSION: Prophylactic PLEX should be considered as a therapeutic option to prevent recurrent TTP during pregnancy in high risk patients, including patients with previous SLE-associated TTP.

Outcome of pregnancies in women with thrombophilic disorders.

Women with thrombophilic disorders may have pregnancy complications including fetal loss (FL); however, the impact of thromboprophylaxis with low molecular weight heparin (LMWH) and previous obstetric history remains to be clarified. Our aim was to compare the effects of LMWH in three groups of women with thrombophilia who had varying numbers of prior fetal losses. We prospectively investigated the live birth rates in 66 women with thrombophilic conditions, treated with a LMWH (enoxaparin, 40 mg daily). Groups 1, 2 and 3 included patients with 0-1, 2-3 and ≥ 4 pregnancy losses, respectively. Groups 1, 2 and 3 had 90.47%, 83.78% and 50.00% live birth frequencies, respectively. Group 3 had a significantly lower chance of a live birth compared with Group 1, regardless of type of thrombophilic disorder. FL aetiology in thrombophilic patients with multiple miscarriages appears multifactorial, and thromboprophylaxis alone may not be sufficient.

Recurrent pregnancy loss and antiphospholipid syndrome: an overlooked association.

Antiphospholipid Syndrome (APS), a thrombophilic condition, is being increasingly recognised as an important cause of recurrent pregnancy loss, preeclampsia and possible infertility. It could occur as a primary condition or it may be secondary to connective tissue diseases, infections or malignancies. Though recurrent pregnancy loss is a common feature ofAPS, there are other presentations attributable to thrombosis. The mechanism of thrombosis is still not completely understood but there are various suggested mechanisms. Presence of anti-cardiolipin antibodies (aCL) and lupus anticoagulant (LAC) are diagnostic. Management is variously with heparin, aspirin and warfarin, although other treatment modalities are being deployed. A high index of suspicion is needed for this otherwise treatable condition. Management is ideally best done by an obstetrician and a rheumatologist.