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Prednisolone in ivf treatment.Steroid treatment for IVF problems may do more harm than good
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Eur J Clin Pharmacol. Download references. The authors thank all of the patients for their voluntary participation in this trial and the physicians at all study sites for referring subjects. This research did not receive any internal funding or any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
You can also search for this author in PubMed Google Scholar. YL and YS were involved in the study concept and design and in the drafting of the manuscript. DW and Z-JC contributed to the study design and critical revision of the manuscript. JY and JL contributed to the study design and revision of the manuscript. JT and YH were involved in the study concept and design and in the revision of the manuscript.
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Other studies abound. Research in found benefits in combining Prednisone and low-dose aspirin in IVF protocols, starting three months before ovulation induction. We certainly see this combination regularly in repeat FETs. And a study saw better ongoing pregnancy rates with the use of Prednisone, aspirin, and vitamins B and D.
When prescribed to female fertility patients, Prednisolone is generally used for a short period 6 to 10 weeks. Doses vary, but 5 mg a day is common.
Be wary if your clinic proposes more than 25 mg daily. Prednisolone pills are normally started on embryo transfer day or a few days earlier. But you may be told to start them when you start your stimulating medication. Prednisolone is more often prescribed for donor-egg, donor-embryo and FET cycles. If your HCG blood test is negative, your fertility medication, including Prednisolone, will be stopped. Your dosage may be tapered off in the final week. Like any drug, there are risks involved with taking steroids.
Common side effects of Prednisolone include irritability, anxiety and sleep disturbance. Taking corticosteroids in pregnancy could also affect fetal growth. The question is, are the benefits worth the risk? It could make that crucial difference or be a dead end. Unlike intralipids, with which it is often combined, Prednisolone pills are cheap. Prednisolone can affect your metabolism, increase the risk of diabetes and change your bone structure.
Talk to your fertility clinic about Prednisolone. Until a large-scale, randomised trial is carried out, its true benefits in assisted reproduction are not clear-cut. Hello , i just wondering this is right that doctor after IVF tell me to take 2 time a day prenisolone and how this tablets can effect my pregnacy? Hi Ren, just wondering how are you doing with your IVF? I was not made aware by my gynecologist that this was a steroid nor the side effects until I researched.
I plan on going to another as there has to be a better and safer option. I am currently taking prednisone 20mg tablets. Is this safe? I have been married 16yrs, and we have been trying for 14yrs to conceive, been on numerous cycles of Clomid, had a couple of Hysterosalpingogram done, had my uterus and ovaries checked with ultrasound, every test an procedure I have done have all come back normal.
Only explanation I have been given, unexplainable, but see nothing wrong for us to conceive. In conclusion, can I continue with taking and finishing the prednisone that I am on, and engage in intercourse with my husband? This week I should be ovulating, according to the period diary app I use. I have been trying to conceive for 10 years now, I have pcos, I have never received any fertility treatment, nor have I ever been pregnant, that was until December when I fell pregnant whilst taking prednisone, sadly that pregnancy ended in miscarriage at 8 weeks.
I was only in Prednisone for 10 days for a chest infection so I never expected it would help me get pregnant. I have told my doctor that when I got pregnant I was on prednisone but they refuse to prescribe it me and they are well aware of my struggle to get pregnant.
I have not been able to get pregnant since, no offer of help or any interest from Doctors of my fertility. If ever there comes up any trials to help women get pregnant on prednisone then I would happily put myself forward for it.
I am saving up for surrogacy but if I can get pregnant naturally by taking prednisone then I would happily go for It. Hi pagan, M Dr Devendra from India.
I m a gynecologist.. I want to tell u one thing if u have got pregnant once half d battle u have won…it means there is nothing wrong in d process of fertilization and implantation.. The use of prednisone and baby aspirin and Lovenox has been a game changer for so many women with failed attempts including myself. Hi Jen, I just read your comment.
Did you use all 3 prior to pregnancy — aspirin, prednisone and clovox? Did your gynecologist prescribed them?
Sarah A. Moldenhauer, Michael J. Davies, M. Louise Hull, Robert J. There is ongoing interest in immune-suppressant corticosteroid drugs such as prednisolone to treat infertility in women with repeated IVF failure and recurrent miscarriage. The rationale draws on the pervasive but flawed view that immune activation is inconsistent with normal pregnancy. This ignores clear evidence that controlled inflammation and activation of the immune response is essential for embryo implantation.
Generally, the immune response actively promotes reproductive success — by facilitating endometrial receptivity and tolerance of the foreign embryo, and promoting vascular adaptation to support placental morphogenesis. The peri-conception immune response also establishes developmental trajectories that can impact on fetal growth and gestational age at birth. Here, we describe immune changes accompanying conception that could be impeded by inappropriate corticosteroid administration.
Better diagnostics and more preclinical studies are essential to define patient groups, build evidence for efficacy and fine-tune treatments so as not to inhibit essential actions of immune cells. We argue that unless overt immune pathology is evident, utilization of corticosteroids is not warranted and may be harmful. In most women, perturbing immune adaptation at implantation is expected to adversely influence placental development and impair immune-mediated quality control mechanisms, potentially elevating risk of altered fetal growth and developmental programming, congenital anomalies and preterm birth.
Endometrial receptivity is a key limiting factor underpinning implantation failure after IVF, and recurrent miscarriage Fox et al. The immune system is central to establishing receptivity and initiating pregnancy, with resident immune cells modulating the decidual response, epithelial-embryo attachment, trophoblast invasion, vascular adaptation, immune tolerance and cytokine balance van Mourik et al.
Immune cells also contribute with stromal cells to sensing and elimination of chromosomally abnormal embryos Robertson, ; Macklon and Brosens, Immune events at implantation in turn affect placental morphogenesis, impacting fetal development, gestational disorders, timing of birth and perinatal outcome Redman and Sargent, ; Brosens et al.
Effective therapies for impaired endometrial receptivity are urgently needed. One candidate drug family is the synthetic glucocorticoids, a class of corticosteroid hormones with potent and broad-spectrum anti-inflammatory and immunosuppressive properties Franchimont, ; Rhen and Cidlowski, Prednisolone or related drugs are proposed to improve the embryo implantation rate after IVF and protect against miscarriage, when administered from embryo implantation through the early placentation phase.
Demand for corticosteroids is driven in large part by medical and consumer misunderstanding of immune cells in infertility. A common, but mistaken and out-dated view, is that the immune response is normally inhibited in pregnancy Polak de Fried et al. A common interpretation is that immune function is expendable, so immune suppression by medication must be beneficial and unlikely to cause harm Krigstein and Sacks, This false perception has been encouraged by studies in women with autoimmune disorders.
Success in this patient group has prompted broader use of corticosteroids in patients experiencing repeated IVF failure or recurrent miscarriage in the absence of any overt immune disorder. The rationale for utilizing corticosteroids in women without specific immune dysfunction is dubious.
Protagonists draw comfort in a relatively low incidence of serious adverse outcomes in women who naturally conceive while utilizing corticosteroid therapy for immune disorders, and conclude from analyzes of fetal congenital malformations that corticosteroids do not present a major teratogenic risk Krigstein and Sacks, To date there are no well-controlled, sufficiently powered clinical trial data to allow confident assessment of the effectiveness and safety of corticosteroid therapy in unselected women in early pregnancy.
A recent Cochrane meta-analysis of small studies in IVF patient groups revealed a weakly significant effect on implantation rate but not live birth rate in women conceiving after treatment with peri-implantation glucocorticoids versus no glucocorticoid Boomsma et al. Few studies have followed up the outcomes of corticosteroid use in IVF treatment for infant health, but those that do report perinatal outcomes raise concerns for potential adverse effects on fetal development Motteram et al.
Here we argue for a more rational view, that corticosteroid therapy in the absence of a specific immune indication is at this time, unjustified and potentially risky. However, there may be justification for continued exploratory investigation of prednisolone in fertility disorders with specific and defined immune aetiologies that are demonstrably responsive to corticosteroid therapy.
Initially, corticosteroids were evaluated for their clinical value in women experiencing infertility and testing positive for autoantibodies. Corticosteroids alone or in combination with low-dose aspirin are reported to improve pregnancy rate after IVF in women with anti-nuclear antibodies, anti-cardiolipin antibodies, anti-thyroid antibodies or lupus anticoagulant Hasegawa et al.
Subsequent reports claimed that corticosteroids increase pregnancy rate after IVF, even in women without detectable immune disorders.
One of the first such studies administered high dose corticosteroids 60 mg of methylprednisolone for 4 days, beginning the day of ovum retrieval to IVF patients with tubal factor infertility, reportedly increasing clinical pregnancy and implantation rate Polak de Fried et al.
Additional case studies attribute pregnancy success in women with multiple recurrent miscarriages to preconception corticosteroid therapy Ogasawara and Aoki, ; Quenby et al. Other studies showed no effect of corticosteroids in either high dose 60 mg of methylprednisone for 4 days or low dose prednisolone 10 mg per day on implantation rates in patients receiving routine IVF or ICSI Lee et al. A case-controlled study investigating combined adjuvant co-treatments with prednisolone plus low-dose aspirin and doxycycline in patients showed no significant benefit for implantation or pregnancy rate Motteram et al.
The Cochrane meta-analysis, incorporating 13 trials a total of cyclesconcluded there is no clear evidence that peri-implantation corticosteroid administration improves live birth rates in routine IVF cycles Boomsma et al.
However, the use of corticosteroids in women undergoing standard IVF but not intracytoplasmic sperm injection ICSI was associated with an increased pregnancy rate of borderline statistical significance Boomsma et al. A complicating issue is the variety of different protocols for corticosteroid administration, and the different corticosteroid drugs utilized, ranging from prednisolone, methylprednisolone and dexamethasone to hydrocortisone combined with prednisolone.
The dose schedules and duration of treatment also vary enormously Boomsma et al. Given these inconsistent findings, there is no consensus view on the utility of corticosteroids in assisted reproduction and the possible efficacy of peri-implantation corticosteroid therapy remains controversial in non-selected IVF and ICSI patients. Given the integral role of the immune response at conception and its significance for progression of pregnancy and infant health, there is a risk of harm that reasonably must be taken into account and investigated with transparent information given to patients demanding this treatment.
During conception and early pregnancy, dynamic changes occur in the local immune response of the female reproductive tract and local lymph nodes that influence embryo implantation, progression of pregnancy and its outcome. These changes involve cells and mediators of both the adaptive and the innate immune compartment, and build on the cyclic immune changes that accommodate hormone fluctuations over the course of every menstrual cycle.
In the mid-secretory phase of the cycle, the otherwise hostile endometrial lining becomes transiently accommodating to embryo attachment and invasion Lessey, Through a regulated sequence, with features of a controlled inflammatory response, macrophages, dendritic cells DCs and neutrophils recruited into endometrial tissues over the menstrual cycle are further boosted between conception and implantation, supplementing large populations of uterine NK cells.
This is followed by activation of the adaptive immune compartment, and skewing of the T cell response to generate a specific class of T cells known as regulatory T cells Treg cells. Treg cells exert potent anti-inflammatory effects and these cells are essential in the implantation site to curtail inflammation, assist in vascular remodeling, and suppress immune rejection of the foreign conceptus tissue Guerin et al.
The initial phase of decidualisation, embryo attachment and epithelial breaching is followed by trophoblast invasion through the maternal decidua to commence placental morphogenesis. As placental trophoblasts proliferate and differentiate to form the placental villous structures, extravillous trophoblasts invade deep into the uterine tissue to remodel the maternal spiral arteries. This transformation is required to permit a sufficient maternal blood flow and support optimal placental function and fetal growth in later gestation, and must commence in the early phase of placental development Brosens et al.
Defective deep placentation underlies the great obstetric syndromes preeclampsia, stillbirth and fetal growth restriction Brosens et al. Trophoblast proliferation, differentiation and invasion as well as the accompanying vascular changes are influenced directly and indirectly by uterine leukocytes and cytokines. Leukocytes contributing to early placental development include uterine NK cells, Treg cells, DCs and macrophages Aluvihare et al.
Activated immune cells play a central role particularly in the early events that lead to robust deep placentation Pijnenborg et al. Interventions that suppress or impair immune function in early pregnancy can perturb later placental and fetal development and the health of offspring after birth. Additionally, there is a complex interplay between different leukocytes, explaining why each subset must be present in sufficient abundance and exhibit appropriate activation phenotypes Mor et al. Experimental depletion or perturbation of immune cells in mouse models reveals severe consequences for decidualisation, implantation and placental development, consistent with observations in women with infertility and recurrent miscarriage of altered endometrial leukocyte populations Table I.
Deficiency leads to deficient uterine arterial modification, abnormal uterine blood flow and compromised placentation, in utero growth restriction, altered development in offspring Lima et al. DCs orchestrate and control the adaptive immune compartment and drive the generation of inducible Treg cells to suppress inflammation and mediate immune tolerance of fetal antigens Blois et al. Depletion of uterine DCs results in aberrant decidual vascularization, impaired implantation and anomalies in placental development Plaks et al.
DCs interact with uNK cells to mutually influence phenotype Blois et al. Numbers of endometrial dendritic cells correlate positively with pregnancy success after endometrial biopsy Gnainsky et al. Corticosteroids alter phenotype, inhibit maturation and suppress antigen-presenting function of DCs Andre et al. Corticosteroids impair the ability of DCs to activate T cells and shift the balance of Th1, Th2 and Treg cells induced Franchimont, Numbers of endometrial macrophages correlate positively with pregnancy success after endometrial biopsy Gnainsky et al.
Corticosteroids depress myeloid hemopoiesis, inhibiting macrophage generation and activity Boumpas et al. Corticosteroids shift macrophage phenotype from M1 to M2, promote phagocytosis, inhibit MHC II expression, block synthesis of cytokines, prostaglandins and leukotrienes, and depress tumoricidal and microbicidal activity Franchimont, Treg cells are essential for implantation and successful pregnancy Guerin et al.
Treg cells interact with NK cells and DCs to influence vascular adaptation and placental development Blois et al. Antigen-specific peripheral inducible T cells arise in lymph nodes after immune activation to seminal fluid at coitus Moldenhauer et al. Number and suppressive function of decidual Treg cells is increased by HLA-C mismatch, consistent with requirement for antigen-driven activation Tilburgs et al.
Unexplained infertility and recurrent miscarriage are linked with altered decidual T cells Lachapelle et al. Corticosteroids suppress cellular Th1 immunity and promote humoral Th2 immunity Franchimont, Corticosteroids may favor generation of Treg cells to promote immune tolerance Franchimont, ; Chen et al. Corticosteroid drugs mimic the endogenous glucocorticoid hormone cortisol that is released primarily from the adrenal cortex Rhen and Cidlowski, In general terms, glucocorticoids are stress hormones with a wide range of physiological effects including limiting and resolving inflammation, affecting the generation, differentiation and function of immune cells with profound consequences for tolerance and immunity Franchimont, The importance of glucocorticoid signaling in the uterus is demonstrated in mice with a uterus-specific deficiency in glucocorticoid receptor GRwhich exhibit defective implantation with an exaggerated inflammatory response Whirledge et al.
Glucocorticoid excess in pregnancy causes adverse effects in the placenta, fetal growth restriction and altered fetal development Seckl and Meaney, Leukocytes responsive to cortisol by virtue of GR and mineralocorticoid receptor expression are abundant in the endometrium in the peri-conception phase, and after implantation in the decidua and various compartments of the placenta Bamberger et al.
Implantation requires mild inflammation and activation of a range of types of leukocytes, although the inflammatory events must be tightly controlled and finely orchestrated Sargent et al.
Inflammation elicited at conception recruits immune cells that contribute to the events of trophoblast invasion and early placental development, and allow maternal immune recognition and capacity to respond to paternally-derived major histocompatibility MHC antigens. This active recognition process is required to induce and regulate populations of uterine NK cells and T cells that promote implantation, and persist beyond the first trimester to protect the placenta and fetus from inflammatory injury Table II.
Thus there is a high likelihood that exogenous corticosteroids substantially affect the peri-implantation immune response, impairing the initial phase of immune recognition and responsiveness to the embryo. This would be expected to impact the quality and strength of immune tolerance generated, and capacity to support robust placentation, with consequences for later pregnancy and fetal development.
The known and predicted effects of glucocorticoids on the implantation immune response are summarized below and in Table I. Uterine NK cells are the most prominent immune cells in the decidua at implantation and are key regulators of the vascular changes that accommodate and support placental development.
Their specific phenotype and capacity to secrete angiogenic factors appears more critical than absolute numbers Lima et al. Maternal immune recognition of paternally-derived MHC antigens associated with trophoblasts of the implanting embryo is a determinant of the functional phenotypes and changes in uterine NK cells associated with receptivity to implantation Moffett and Colucci, Others are unable to demonstrate a relationship between uterine NK cells and repeated implantation failures after IVF Matteo et al.
For convenience, it has become increasingly common to examine peripheral blood NK cells in women with sub-fertility or history of recurrent implantation failure, rather than performing an endometrial biopsy Thum et al.
This approach has two main shortcomings. Firstly, uterine NK cells are phenotypically different from those in peripheral blood and there is no strong correlation between them. Recent meta-analyses confirm a lack of robust evidence to support measuring uterine NK cells either in peripheral blood or the uterus as clinically useful in predicting infertility or miscarriage Seshadri and Sunkara, Uterine NK cells express GR, implying that exogenous corticosteroids act directly on this cell population Henderson et al.
Reduced capacity to attenuate cortisol synthesis in decidual stromal cells may contribute to aberrant uterine NK cells Kuroda et al.Participants will be given the treatment of prednisone or placebo from the implantation remains a rate-limiting step in IVF treatment. Prednisolone or related drugs are proposed to improve the embryo implantation rate after IVF and protect against miscarriage, when administered. Participants will be given the treatment of prednisone or placebo from the implantation remains a rate-limiting step in IVF treatment. Prednisolone or related drugs are proposed to improve the embryo implantation rate after IVF and protect against miscarriage, when administered. These patients were treated with prednisone, 10 mg per day, and aspirin, mg per day, starting 4 weeks before induction of ovulation in 52 IVF cycles. Views 48, Helloi just wondering this is right that doctor after IVF tell me to take 2 time a day prenisolone and how this tablets can effect my pregnacy? A complicating issue is the variety of different protocols for corticosteroid administration, and the different corticosteroid drugs utilized, ranging from prednisolone, methylprednisolone and dexamethasone to hydrocortisone combined with prednisolone. My two babies were born healthy. Prednisone pharmacokinetics during pregnancy and lactation. An Australian study used low-dose Prednisolone alongside blood-thinner Clexane to try to suppress natural killer cells in women with recurrent miscarriages.
Trials volume 21 , Article number: Cite this article. Metrics details. Recurrent implantation failure RIF brings great challenges to clinicians and causes deep frustration to patients.
Previous data has suggested that prednisone may play a promising role in the establishment of pregnancy and help improve the pregnancy outcome in women with RIF. But there is insufficient evidence from randomized clinical trials that had adequate power to determine if prednisone can enhance live births as the primary outcome. This trial is a prospective, multicenter, randomized, double-blind, placebo-controlled clinical trial ratio of prednisone versus placebo.
Participants will be given the treatment of prednisone or placebo from the start of endometrial preparation till the end of the first trimester of pregnancy if pregnant. The primary outcome is live birth rate. The results of this study will provide evidence for the effect of prednisone on pregnancy outcomes in patients with RIF. Registered on 9 October Peer Review reports.
In vitro fertilization IVF is widely used and well received in couples with reproductive difficulties. However, despite the optimal use of reproductive technologies such as controlled ovarian hyper-stimulation, assisted hatching, pre-implantation genetic testing, and frozen embryo transfer , implantation remains a rate-limiting step in IVF treatment.
Recurrent implantation failure RIF refers to the clinical condition of failing to achieve a clinical pregnancy after several embryo transfers, which brings great challenges to clinicians and causes deep frustration to patients [ 3 ].
Failure of implantation can be attributed to embryo quality, endometrial receptivity, or both. Thus, many interventions aiming at overcoming decreased endometrial receptivity have been proposed to improve pregnancy outcomes in women with RIF, but only a few are evidence-based [ 8 , 9 ]. Prednisone is a common immunomodulatory agent, which can exert a range of positive effects on the treatment of autoimmune disorders as well as the establishment of early pregnancy [ 1 , 10 ].
Studies have shown that prednisone could not only suppress uterine NK cells cytotoxicity and cytokine secretion in pre-implantation endometrium, but also stimulate the secretion of human chorionic gonadotropin hCG and promote proliferation and invasion of trophoblast [ 1 , 6 ], suggesting that prednisone may have a considerable impact on embryo implantation and IVF outcomes. However, limited clinical trials have focused on the effect of prednisone on pregnancy outcomes.
Also, the trials were either small-sized or non-randomized studies or with combined treatment regimens, which were insufficiently powered to draw a conclusion. Therefore, multiple researchers and clinicians have called for a full-scale and well-designed randomized controlled trial RCT to clarify whether prednisone could improve pregnancy outcomes in women with RIF [ 15 ].
This is a prospective, multicenter, randomized, double-blind, placebo-controlled clinical trial to evaluate whether the administration of prednisone could improve the live birth rate in patients with RIF. Eligible patients will be randomly assigned to the prednisone group or placebo group with a ratio. A flowchart of the study design is illustrated in Fig.
Patients will be recruited from 8 hospitals in China. The study is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The study protocol has been approved by the ethics committees at all hospitals. Infertile women with a history of RIF, which refers to the failure to achieve a clinical pregnancy under one of the following conditions with all embryos transferred being of good quality criteria of good-quality embryos are shown in Table 1 :.
Two embryo transfer cycles where the cumulative number of transferred embryos was no less than three;. Women who are currently receiving any corticosteroid or immunosuppression treatment, such as hydroxychloroquine, cyclosporine, and azathioprine. Two months of washout period will be required prior to screening for patients on these agents;.
Women who have been diagnosed with diseases affecting the uterine cavity, such as uterine malformation and submucous fibroids;. Women or their partner with abnormal chromosome karyotype not including chromosome polymorphisms ;. Women who have experienced recurrent pregnancy loss, defined by two or more failed clinical pregnancies documented by ultrasonography or histopathologic examination;.
According to the meta-analysis published in , the live birth rate was estimated to be In women with 2 or more failed embryo transfer cycles, the live birth rate varied from It is reported that the combined administration of prednisone and low molecular weight heparin or aspirin can improve live birth rate by The ratio between groups will be The minimum sample size will be for each group, for a total of participants.
All eligible subjects will be randomly assigned to one of the two study arms according to a computer-generated randomization sequence generated by the data coordinating center DCC with SAS software version 9.
The randomization will be stratified according to the stage of embryo cleavage embryo or blastocyst. The randomization sequence will be kept strictly confidential by the DCC staff. Therefore, the researchers who are in charge of the enrollment have no access to the list.
Study personnel are all blinded to the upcoming treatment group allocation. The study medication both prednisone and placebo is manufactured by Xianju Pharmaceutical Co. Except for the active ingredients, the rest of the excipient and the appearance and odor are exactly the same as prednisone.
The packaging of study medication both prednisone and placebo is marked according to the randomization sequence. The packaging and tablets of prednisone and the placebo have the same appearance, which cannot be distinguished. Therefore, the participants and all research staff do not know the allocation until the end of the study.
The quality of the placebo, such as contents and bacteria contaminations, was controlled rigorously according to the GMP standard. At the screening visit, patients who have been using corticosteroid or other immunosuppression treatment will be excluded. The trial and study plan will be declared to all participants, and eligible couples who are interested in participating will sign the written informed consent.
The standardized case report forms CRFs are completed to collect current medication status and previous medical history. A physical examination height, body weight, waistline, hipline, blood pressure is performed.
A total of eligible subjects will be enrolled and equally randomized into two parallel treatment arms:. Patients will be instructed to take two tablets for once a day orally in the morning, starting with the hormone replacement regimen for endometrial preparation. Participants will undergo the frozen-thawed embryo transfer FET. If pregnancy is confirmed, the second bottle of corresponding drug will be dispensed on the day of pregnancy test and the medication will be continued till the end of the first trimester of pregnancy.
If the failure of transfer or pregnancy loss occurred, the medication will be discontinued. The remaining tablets will be returned to researchers. The endometrium is prepared with a hormone replacement cycle regimen. One blastocyst or two cleavage embryos will be transferred in each participant. All embryos transferred will be of good quality. The secondary outcomes include biochemical pregnancy, clinical pregnancy, implantation, pregnancy loss, pregnancy and perinatal complication, birth weight, congenital anomalies, and other adverse events.
The first-trimester pregnancy complications including but not limited to miscarriage, ectopic pregnancy, hyperemesis gravidarum, or gestational trophoblastic disease will be evaluated by reviewing medical records or by telephone. The second-trimester pregnancy complications including but not limited to abortion, prenatal test results, gestational diabetes, incompetent cervix, or premature rupture of membrane will be followed up by telephone call.
The fourth follow-up time point will be at delivery. Participants will be required to notify investigators about the time of delivery. Postpartum information regarding complications of the mother including but not limited to infection, postpartum depression, late postpartum hemorrhage or the infant including but not limited to neonatal jaundice, neonatal infection, neonatal respiratory distress syndrome, neonatal hospitalization, and neonatal death will be followed up by telephone or by reviewing medical records.
During the follow-up period, adverse events and concomitant medications will be inquired and recorded every time. Participants who quit or are lost to follow-up will also be recorded.
All AEs will be assessed and recorded in detail. The ethics committee will determine whether the AE or SAE is likely to be associated with the study medication and whether it is necessary to break blinding codes. All of the investigators including physicians, nurses, and research assistants will attend a training workshop before the starting of the trial, to ensure the accuracy of outcome assessments and data collection. A protocol and standard operation procedures will be given to every investigator.
The DCC is responsible for the monitoring tasks of the trial. The DCC and personnel of Ren Ji hospital will check the authenticity, accuracy, and integrity of the data from different sites regularly to ensure the quality of the collected data.
The data will be analyzed by SPSS The analysis will be conducted using intention-to-treat principles. The primary outcome, live birth rate, will be compared between two groups by the Pearson chi-square test. Secondary outcomes, such as rates of pregnancy and implantation, will be analyzed using the Pearson chi-square test.
A per-protocol analysis will be performed according to the actual participants completing the entire trial. As a secondary analysis, we will fit a generalized linear mixed effect model with a logit link to compare the treatment arms with respect to the primary outcome of live birth, and binary secondary outcomes e.
A random intercept will be included to adjust for the correlation among patients within center. We plan to enroll subjects from 8 hospitals in China. The enrollment began in November At the time of manuscript preparation, more than subjects have been enrolled. The result of this multicenter randomized trial will provide valid evidence for the effect of prednisone on pregnancy outcomes in women with RIF. We speculate that the administration of prednisone may improve live birth rate in patients with RIF.
As we all know, there is as yet no universally accepted definition of RIF [ 2 ]. Different descriptions were based on the number of previously failed cycles or the number of embryos transferred or a combination of both. Lukasz et al. It is suggested to define RIF as the absence of implantation after two treatment cycles where the cumulative number of transferred embryos was no less than four for cleavage-stage embryos and no less than two for blastocysts, and all of the embryos transferred should be of good quality [ 4 ].
There are limited clinical trials assessing the efficacy of prednisone in patients with implantation failure. A quasi-randomized, controlled trial conducted in women with previously one or two failed ICSI attempts suggested a combination of prednisolone and low molecular weight heparin LMWH might have a positive effect on pregnancy and implantation rates [ 21 ].
A prospective pilot study confirmed that prednisolone was useful in patients with at least two previous IVF failures and serum antiovarian antibody [ 23 ]. Hence, the effect of prednisone in women with RIF remains controversial. Despite lacking of convincing evidence, prednisone is being used by more and more IVF centers and reproductive physicians all across the world. There is an urgent need for a well-designed, adequately powered RCT to prove the efficacy of prednisone in patients with RIF.