How should recurrent implantation failure (RIF) in patients undergoing ART be defined and managed?

Recurrent pregnancy loss is a distressing pregnancy disorder experienced by ~2.5% of women trying to conceive. Recurrent pregnancy loss is defined as the failure of two or more clinically recognized pregnancies before 20-24 weeks of gestation and includes embryonic and fetal losses. The diagnosis of an early pregnancy loss is relatively straightforward, although progress in predicting and preventing recurrent pregnancy loss has been hampered by a lack of standardized definitions, the uncertainties surrounding the pathogenesis and the highly variable clinical presentation. The prognosis for couples with recurrent pregnancy loss is generally good, although the likelihood of a successful pregnancy depends on maternal age and the number of previous losses. Recurrent pregnancy loss can be caused by chromosomal errors, anatomical uterine defects, autoimmune disorders and endometrial dysfunction. Available treatments target the putative risk factors of pregnancy loss, although the effectiveness of many medical interventions is controversial. Regardless of the underlying aetiology, couples require accurate information on their chances of having a baby and appropriate support should be offered to reduce the psychological burden associated with multiple miscarriages. Future research must investigate the pathogenesis of recurrent pregnancy loss and evaluate novel diagnostic tests and treatments in adequately powered clinical trials.

At implantation, the embryo expresses paternally derived alloantigens and evokes inflammation that can threaten reproductive success. To ensure a robust placenta and sustainable pregnancy, an active state of maternal immune tolerance mediated by CD4+ regulatory T cells (Tregs) is essential. Tregs operate to inhibit effector immunity, contain inflammation, and support maternal vascular adaptations, thereby facilitating trophoblast invasion and placental access to the maternal blood supply. Insufficient Treg numbers or inadequate functional competence are implicated in idiopathic infertility and recurrent miscarriage as well as later-onset pregnancy complications stemming from placental insufficiency, including preeclampsia and fetal growth restriction. In this Review, we summarize the mechanisms acting in the conception environment to drive the Treg response and discuss prospects for targeting the T cell compartment to alleviate immune-based reproductive disorders.

Certain miscarriages result from immunologic factors, but there is no clear identification of the precise causes of recurrent pregnancy loss (RPL). Miscarriages and RPL can arise from a disruption of maternal-fetal immune homeostasis. Remodeling of the maternal uterine spiral arteries is one of the key steps for normal growth and development of the fetus. An adequate oxygen supply is necessary for correct placentation, and it is accomplished by proper vascular changes. The development of fetal tissues creates a potential immunologic problem since the fetus can express paternal antigens and, in some cases, antigens of a gamete donor. The maternal immune system actively responds to fetal antigens, and dysregulation of this crosstalk could partly explain pregnancy complications such as miscarriages and RPL. RPL resulting from thrombophilia is primarily due to acquired thrombophilia, and therefore screening and treatment should be focused on antiphospholipid antibody syndrome.Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

In the present manuscript, we review the recent research investigating the pathogenic association between most studied autoantibodies and recurrent pregnancy loss. Pregnancy loss represents a common obstetric complication occurring in about 15%‐25% of all clinically recognized pregnancies. The recurrence of pregnancy loss identifies a distinct clinical entity, that is recurrent pregnancy loss (RPL), affecting about 2%‐4% of couples. Several factors, including age, chromosomal abnormalities, uterine anomalies, thrombophilic disorders, endocrinopathies, hormonal and metabolic disorders, infections, sperm quality, and lifestyle issues, are involved in RPL. The role of autoantibodies in RPL is only partially determined. In some cases (antiphospholipid antibodies [aPL]), their involvement is well established. In other cases (anti‐thyroid autoantibodies, antinuclear, anti‐transglutaminase, and anti‐endomysial antibodies), it is still debated, despite multiple, although not fully conclusive, evidences strongly suggest a possible involvement in RPL. Further extensive research is needed to definitively confirm or exclude their actual role.

Pregnancy complications might lead to the development of autoimmune diseases in women. This review aims to summarise studies evaluating the association between pregnancy complications and the development of autoimmune diseases in women.

It is becoming clear that during each developmental stage of pregnancy, different immunological conditions exist and may even be necessary for success. The widely accepted T helper (Th) 1 and 2 concept has some limitations if applied to the various developmental stages of pregnancy. During the implantation period, a multidirectional cytokine network is necessary with the blastocyst producing cytokines and other factors and the endometrium synthesizing factors necessary for the embryonic development. Improper immune responses and an unbalanced cytokine network may be related to implantation failures, pregnancy losses and obstetrical complications. A propensity to Th1 immune responses has been reported in these conditions systemically or locally. The presence of elevated Th1:Th2 cell ratios, high concentration of Th1 cytokines secreted by peripheral blood mononuclear cells, elevated NK cell cytotoxicity and levels, and emergence of various autoantibodies are the supporting evidence. The underlying immunopathology for the preponderance of Th1 is unknown. Genetic, environmental, and hormonal etiologies need to be explored further in the future. The purpose of this review is to give an overview of what is known about the immune response in women with reproductive failures and provide an update of some of the most recent findings in this field.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by inflammation and immune-mediated injury to multiple organ systems, including the mucocutaneous, musculoskeletal, hematologic, and kidney systems. Approximately 3.4 million people worldwide have received a diagnosis of SLE.

One of the most important reasons of infertility and human reproductive failure is related to uncontrolled immunological response of maternal immune system to early embryo or fetus, that cause rejection of this semi-allograft. Therefore, a tolerance in the immune system is essential to modulate the reactions against the fetus to avoid rejection. The immune system imbalance during implantation or pregnancy may lead to implantation failure or miscarriage. So, use of immunosuppressive or immunomodulator agents can be helpful to prevent immunological attack. Initially, there was a focus on steroids like prednisolone or intralipids in treatment of miscarriage that suppressed the activity of most immune cells, Intravenous Immunoglobulin (IVIG) was then introduced with various mechanisms. Nowadays, novel and specific strategies are established such as monoclonal antibodies and cytokines. More recently, Tacrolimus and Cyclosporine, which were utilized in prevention of transplantation reject, are used as immunosuppressive factors in modulation of immune responses against the fetus. This review is focused on the main immunotherapeutic methods of infertility treatment.Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Problem  The purpose of this study was to investigate whether treatment with TNF‐α inhibitors and/or intravenous immunoglobulin (IVIG) increases in vitro fertilization (IVF) success rates among young (<38 years) women with infertility and T helper 1/T helper 2 cytokine elevation.

Maternal-fetal immune dysregulation is one of the risk factors that increases the probability of embryo rejection and reproductive failure. The stimulation of immunological tolerance and suppression of immunological rejection are prerequisites for protecting embryos and preventing immunological attacks. Hence, it appears that immunomodulatory and immunosuppressive therapies can manage reproductive failures by controlling immune cells. The current medical literature has shown that immunotherapy approaches and cell therapy have promising results in improving pregnancy outcomes and live birth rates. These outcomes are obtained by regulating maternal immune responses, and exerting positive effects on human reproductive processes.Copyright © 2021 Elsevier Ltd. All rights reserved.

To investigate the therapeutic effect of co‐administration of tacrolimus (TAC) and low‐molecular‐weight heparin (LMWH) or LMWH only on pregnancy outcomes in the female with a history of implantation failure and elevated peripheral blood natural killer (pNK) cell proportion in frozen‐thawed embryo transfer cycles.

Recurrent pregnancy loss (RPL) is a one of the most common obstetrical complications. Since, the successful pregnancy occurs in T helper 2 (Th2)-dominant situation and since, Th1 type immunity is related to pregnancy failure, we investigated the effects of cyclosporine on Th1 and Th2 cells in RPL women. Totally, 76 RPL patients (38 women as treated group and 38 as control group) were included in this study. Flow cytometry was utilized to analyze the frequency of Th1 and Th2 in blood samples. Also, real-time polymerase chain reaction was carried out to assess the messenger RNA (mRNA) expression of transcription factors and enzyme-linked immunosorbent assay was used to evaluate Th1 and Th2 related cytokines. Significant decrease in Th1 frequency (p = 0.0004), Th1/Th2 ratio (p < 0.0001), T-bet mRNA expression (p < 0.0001), interferon-γ (p = 0.0007), and tumor necrosis factor α (p = 0.0002) secretion level were observed in cyclosporine group. Moreover, significant increase in Th2 frequency (p < 0.0001), mRNA expression of GATA binding protein 3 (p = 0.0001), and interleukin 10 secretion level (p = 0.0027) was also evident in treated group. At the end of the investigation, 31 (81.5%) patients in cyclosporine-treated group had successful childbirth when compared with 16 (42.1%) women in control group (p = 0.0001). Given this, cyclosporine treatment for RPL patients with elevated Th1/Th2 ratio can result in improved pregnancy outcome.© 2019 Wiley Periodicals, Inc.

There are few treatments for patients with recurrent pregnancy loss (RPL) or recurrent implantation failure (RIF). Women with RPL and unexplained infertility have lower T regulatory cell (T) expression when compared to fertile controls. A murine model has been developed with depletion of regulatory T cells (DEREG) after administration of diphtheria toxin (DT), resulting in smaller litter sizes, secondary to embryo implantation failure. Numerous murine studies have shown that adoptive transfer of CD4CD25FoxP3 T from donors improves litter sizes in DEREG mice with depleted T. Our hypothesis is that DEREG mice treated with a single dose of DT will deplete T and subsequently decrease litter sizes and that treatment with rapamycin (sirolimus; Pfizer) during the time of embryo implantation will increase T and restore litter sizes nearly back to normal levels. Syngeneic mating of DEREG mice after depletion of T resulted in smaller litter sizes and this defect was reversed when these DEREG mice were treated with rapamycin at the time of embryo implantation. The importance of T at the time of embryo implantation has been well established and immunotherapy treatments, such as rapamycin (mammalian target of rapamycin inhibitor), may prove to be an effective treatment for patients with RPL, RIF, or unexplained infertility with low T.

Pregnant patients are often on immunosuppressant medications, most commonly to manage transplantation or autoimmune disorders. Most immunosuppressant agents, including tacrolimus, corticosteroids, azathioprine, and calcineurin inhibitors, are safe during pregnancy and lactation. However, mycophenolic acid is associated with higher risks of birth defects and should be avoided in pregnancy. Tacrolimus, the commonly used drug in transplantation medicine and autoimmune disorders, requires monitoring of serum levels for dose adjustment, particularly during pregnancy. Although no pregnancy-specific therapeutic range exists, the general target range is 5-15 ng/mL, and pregnant patients may require higher doses to achieve therapeutic levels. Adherence to prescribed immunosuppressive regimens is crucial to prevent graft rejection and autoimmune disorder flare-ups. This review aims to provide essential information about the use of immunosuppressant medications in pregnant individuals. With a rising number of pregnant patients undergoing organ transplantations or having autoimmune disorders, it is important to understand the implications of the use of these medications during pregnancy.Copyright © 2024 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.

Tumor necrosis factor-alpha (TNF-α) is a multifunctional Th1 cytokine and one of the most important inflammatory cytokines. In pregnancy, TNF-α influences hormone synthesis, placental architecture, and embryonic development. It was also shown that increased levels of TNF-α are associated with pregnancy loss and preeclampsia. Increased TNF-α levels in complicated pregnancy draw attention to trophoblast biology, especially migratory activity, syncytialisation, and endocrine function. Additionally, elevated TNF-α levels may affect the maternal-fetal relationship by altering the secretory profile of placental immunomodulatory factors, which in turn affects maternal immune cells. There is growing evidence that metabolic/pro-inflammatory cytokines can program early placental functions and growth in the first trimester of pregnancy. Furthermore, early pregnancy placenta has a direct impact on fetal development and maternal immune system diseases that release inflammatory (e.g., TNF-α) and immunomodulatory factors, such as chronic inflammatory rheumatic, gastroenterological, or dermatological diseases, and may result in an abnormal release of cytokines and chemokines in syncytiotrophoblasts. Pregnancy poses a challenge in the treatment of chronic disease in patients who plan to have children. The activity of the disease, the impact of pregnancy on the course of the disease, and the safety of pharmacotherapy, including anti-rheumatic agents, in pregnancy should be considered.

The aim of this study was to evaluate whether certolizumab pegol, a tumour necrosis factor α inhibitor with little or no transport across the placenta, added to standard treatment with low molecular weight heparin plus low dose aspirin, reduces rates of adverse pregnancy outcome (APO) in high-risk pregnancies with antiphospholipid syndrome (APS).We assessed treatment with certolizumab in pregnant patients with APS and lupus anticoagulant, administered gestational weeks 8 through 28, in addition to standard treatment. The primary APO was a composite of fetal death ≥10 weeks' gestation or pre-eclampsia with severe features or placental insufficiency requiring delivery <34 weeks' gestation. Target sample size was 45 with expected APO rate of 20% with certolizumab versus 40% in historical controls from a prospectively observed population of similarly managed APS pregnancies.Fifty-one patients were enrolled, and 9 had primary APO (17.6%; 95% CI, 8.4%-30.9%). Excluding 6 patients who had a pregnancy loss <10 weeks' gestation or fetal loss due to genetic abnormalities, primary APO occurred in 9 of the 45 patients (20%; 95% CI, 9.6%-34.6%), meeting predetermined criteria for efficacy of certolizumab and significantly lower than rates in historical controls. Median gestational age at delivery in certolizumab-treated patients was 36.5 weeks and was after 30 weeks in those who met the primary outcome of pre-eclampsia. Neonatal survival to hospital discharge was 93%. There were no serious infections and no new cases or severe flares of lupus.Certolizumab appears effective in preventing placenta-mediated adverse outcomes in high-risk patients with APS.Copyright © 2025 European Alliance of Associations for Rheumatology (EULAR). Published by Elsevier B.V. All rights reserved.

The aim of the study was to assess the granulocyte-colony stimulating factor (G-CSF) effect on unresponsive thin (<7 mm) endometrium in women undergoing frozen-thawed embryo transfer at the blastocyst stage. A total of 62 women with thin unresponsive endometrium were included in the study, of which, 29 received a G-CSF infusion and 33 who opted out of the study served as controls. Patients in both groups had similar endometrial thickness at the time of the initial evaluation: 6.50 mm (5.50-6.80) in the G-CSF and 6.40 mm (5.50-7.0) in the control group. However, after the infusion endometrial thickness increased significantly in the G-CSF group in comparison with the controls (p=0.01), (Δ) 0.5 (0.02-1.2) (p=0.005). In the G-CSF group endometrium expanded to 7.90 mm (6.58-8.70) while in the control group to 6.90 mm (6.0-7.75). Five women in each group conceived. The clinical pregnancy rate was 5/29 (17.24%) in the G-CSF treated group and 5/33 (15.15%) in the control group (p>0.05). The live birth rate was 2/29 (6.89%) in the G-CSF group and 2/33 (6.06%) in the control group (p>0.05). We concluded that G-CSF infusion leads to an improvement in endometrium thickness but not to any improvement in the clinical pregnancy and live birth rates. Until more data is available G-CSF treatment should be considered to be of limited value in increasing pregnancy rate.G-CSF: granulocyte colony-stimulating factor; M-CSF: macrophagecolony-stimulating factor; GM-CSF: granulocyte-macrophage colony-stimulating factor; FET: frozen embryo transfer; IVF: in vitro fertilization.

\n To describe and analyze the benefit of immunomodulatory drugs for recurrent miscarriages and implantation failures. The literature research was conducted in Medline, Embase and Cochrane Library concerning recurrent miscarriages and implantation failures and steroids, progesterone, intralipids,\n TNF\n ‐α antagonists, G‐\n CSF\n, hydroxychloroquine, intravenous immunoglobulins, endometrial scratching. Using meta‐analysis, modest benefit was found for progesterone to obtain a live birth, with odds ratio at 1.38 (95%\n CI\n : 1.07–1.77) and significant heterogeneity (\n P\n = 0.01,\n I\n 2\n = 78%). In early ≥3 miscarriages, patients treated by\n TNF\n ‐α antagonists (adalimumab or etanercept;\n n\n = 17) combined with low‐dose aspirin, heparin and intravenous immunoglobulins have a live births of 71% (12/17), vs 19% with aspirin+heparin (4/21) (\n P\n = 0.0026). Sixty‐eight patients with unexplained recurrent miscarriage were randomized to receive either G‐\n CSF\n (filgastrim, Neupogen, 1 μ/kg/day\n SC\n,\n n\n = 35) after the ovulation until the 9th weeks of gestation or placebo (\n n\n = 33). Among patients treated with G‐\n CSF\n, 29/35 (82.8%) have live birth and 16/33 (48.5%) of controls (\n P\n = 0.006). Among 200 women with recurrent miscarriages and implantation failure treated with intralipids, the pregnancy rate was 52%, with pregnancy ongoing/live birth rate at 91%. The physiopathological rational for immunotolerance failure in this topic raise the need to demonstrate the efficacy of immunomodulatory drugs, define the patients subsets and develop treatment strategies.\n

Systemic lupus erythematosus (SLE) often affects females of reproductive age and Cyclophosphamide, an alkylating agent leading to premature ovarian insufficiency (POF) and labelled category D for pregnancy is used as induction therapy for severe manifestations of lupus. There have been multiple case series reflecting variable outcomes of pregnancies after cyclophosphamide use for cancers and autoimmune diseases. With increasing maternal age, we have an increasing population of lupus patients who may wish to conceive after having received cyclophosphamide therapy. The objective of our study was to improve our understanding of the impact of cyclophosphamide exposure on fertility and pregnancy outcomes in patients with SLE.

High‐dose methotrexate (MTX) exposure during pregnancy is associated with embryopathy. The teratogenic potential of MTX at dosages typically used in the treatment of rheumatic diseases remains uncertain. The aim of this study was to evaluate the risk of spontaneous abortion, major birth defects, elective termination of pregnancy, shortened gestational age at delivery, and reduced birth weight in women exposed to MTX.

Mycophenolate mofetil (MMF) is probably the most common employed immunosuppressant drug in recipients of solid organ transplant and in many autoimmune diseases. In vitro studies, a significant number of single clinical observations and a recent study from a group of different European teratogen information services, have provided very consistent data supporting the existence of a specific MMF embryopathy. The typical malformative pattern of MMF embryopathy includes external ear anomalies ranging from hypoplastic pinna (microtia) to complete absence of pinna (anotia); cleft lip, with or without cleft palate, and ocular anomalies as iris or chorioretinal coloboma and anophthalmia/microphthalmia. Other less frequent features are congenital heart defects, distal limbs anomalies, esophageal atresia, vertebral malformations, diaphragmatic hernia, and kidney and central nervous system anomalies. Neurodevelopmental outcome seems favorable in the small number of patients where information about this issue is available, but neurological deficits have been documented. Physicians in charge of women under MMF therapy should be aware of the potential risk of this drug to cause a specific embryopathy and the need of interrupting the treatment at least six weeks before becoming pregnant.Copyright © 2016 Elsevier Masson SAS. All rights reserved.

The objective of this study was to assess pregnancy outcome in women with a history of refractory antiphospholipid antibody-associated pregnancy loss(es) who were treated with early low-dose prednisolone in addition to aspirin and heparin. Eighteen women with antiphospholipid antibodies who had refractory pregnancy loss(es) were given prednisolone (10 mg) from the time of their positive pregnancy test to 14 weeks' gestation. Before low-dose prednisolone was given as treatment, 4 (4%) of 97 pregnancies had resulted in live births. Among 23 pregnancies supplemented with prednisolone, 9 women had 14 live births (61%), including 8 uncomplicated pregnancies. The remainder were complicated by preterm delivery, preeclampsia, and/or small-for-gestational-age infants. There were 8 first-trimester miscarriages and 1 ectopic pregnancy. There were no fetal deaths after 10 weeks' gestation and no evidence of maternal morbidity. The addition of first-trimester low-dose prednisolone to conventional treatment is worthy of further assessment in the management of refractory antiphospholipid antibody-related pregnancy loss(es), although complications remain elevated.

Recurrent pregnancy loss (RPL) is defined as the occurrence of two or more consecutive pregnancy losses before 24 weeks of gestation. It affects 3–5% of women who are attempting to conceive. RPL can stem from a variety of causes and is frequently associated with psychological distress and a diminished quality of life. By contrast, recurrent implantation failure (RIF) refers to the inability to achieve a successful pregnancy after three or more high-quality embryo transfers or at least two instances of egg donation. RIF shares several causative factors with RPL. The immunological underpinnings of these conditions involve alterations in uterine NK cells, reductions in M2 macrophages and myeloid-derived suppressor cells, an increased Th1/Th2 ratio, a decreased Treg/Th17 ratio, the presence of shared ≥3 HLA alleles between partners, and autoimmune disorders. Various therapeutic approaches have been employed to address these immunological concerns, achieving varying degrees of success, although some therapies remain contentious within the medical community. This review intends to explore the immunological factors implicated in RPL and RIF and to analyze the immunological treatments employed for these conditions, which may include steroids, intravenous immunoglobulins, calcineurin inhibitors, anti-TNF antibodies, intralipid infusions, granulocyte colony-stimulating factor, and lymphocyte immunotherapy.

Previously, we reported the clinical efficacy of tacrolimus in women with repeated implantation failures (RIF) of immune etiologies. Safety of tacrolimus in pregnant women has been reported in women with organ transplantations. However, the safety of tacrolimus for women with RIF undergoing assisted reproductive technology cycles and their babies has not been reported prior.

To evaluate the effectiveness of etanercept in the treatment of refractory recurrent spontaneous abortion with innate immune disorders.A randomized controlled trial in patients with refractory innate immune RSA was conducted in our hospital. 188 patients were selected, all with at least 4 consecutive miscarriages and caused by innate immunity disorders. Patients were randomly allocated into 2 groups. One group (n = 95) used etanercept 25 mg per week starting from the first day after menstruation, while the other (n = 93) with placebo. Delivery of a healthy baby without malformations was regarded as the primary outcome.In etanercept group, 85 (89.47%) patients delivered a healthy baby, while in placebo group, this number was only 67 (72.04%) [P = 0.01, OR = 3.30; 95% CI(1.49～7.32)]. Significantly lower levels of TNF-α and NK cell activity were observed in gestation weeks 4-10 in etanercept group versus placebo group (P < 0.05).The results provide a proof of principle that etanercept can be an attractive therapeutic strategy for refractory innate immune RSA.Copyright © 2019. Published by Elsevier B.V.