Glucocorticoids Improves Pregnancy Rate and Outcome in Woman With Unexplained Positive Autoantibody: a Systematic Review and Meta-analysis

Glucocorticoids Improves Pregnancy Rate and Outcome in Woman With Unexplained Positive Autoantibody: a Systematic Review and Meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Glucocorticoids Improves Pregnancy Rate and Outcome in Woman With Unexplained Positive Autoantibody: a Systematic Review and Meta-analysis Ting Li, Yilin Yuan, Huixin Liu, Qun Lu, Rong Mu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-147807/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: The effect of glucocorticoids (GCs) therapy for women with unexplained positive autoantibody is under debate. This systematic review and meta-analysis was performed to evaluate whether GCs administration can improve the pregnancy outcome of this population. Methods: A meta-analysis based on a systematic review of PubMed, Embase, EBSCO, and the Cochrane Central Register of Controlled Trials, until January 2021, was used to evaluate pregnancy outcome of GCs treatment for women with unexplained recurrent fetal loss or infertility whose autoantibody positive, but does not meet any classification criteria for autoimmune diseases. Results: We found GCs treatment improved clinical pregnancy rate (RR 2.19, 95% CI 1.64 to 2.92) and live birth rate (RR 1.92, 95% CI 1.17 to 3.16), especially when started GCs administration before pregnancy (clinical pregnancy rate: RR 2.30, 95% CI 1.58 to 3.34; live birth rate: RR 2.30, 95% CI 1.58 to 3.34). However, no effect of GCs on miscarriage rate was found (RR 0.75, 95% CI 0.55 to 1.02) regardless of time of drug administration. Conclusions: Our systematic review and meta-analysis surports the rational use of GCs in women with unexplained positive autoantibody. Rheumatology GCs unexplained positive autoantibody pregnancy outcome meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Introduction Human fertility is declining globally. The global infertility rate is about 14% and miscarrage rate is up to 10%-15% [ 1 , 2 ] . Infertility or miscarriage, in broad sense, is the result of failed establishment or maintenance of pregnancy. Although advancement have been achieved in technology, such as in vitro fertilization-embryo transfer (IVF-ET), nearly half patients undergoing IVF-ET can not gain a successful pregnancy [ 3 ] which is frustrating experience for both patients and clinicians. To improve pregnancy outcome is of great importance. Maternal immune tolerance to the placenta and the fetus is one of the key factors in establishing and maintaining pregnancy. Immunological abnormality was reported to account for 27.88% of fetal loss, include overproduction of autoantibodies and proinflammatory cytokines, and imbalance of immune cells ect [ 4 , 5 ] .Women with autoantibody-positive can be divided into two groups based on whether they are diagnosed with autoimmune diseases. The chance of a live birth was significantly reduced in women with rheumatoid arthritis receiving ART treatment, relative to women without rheumatoid arthritis [ 6 ] . Antiphospholipid syndrome accounts for ~ 3.2% recurrent pregnancy loss in the first trimester [ 7 ] . However, those diseases only account for a small proportion of all immune factors affecting obstetrics. When it comes to more often cases, autoantibody positive women with recurrent fetal loss or a history of recurrent implantation failure who cannot be classified into any known autoimmune disease, guidelines are insufficient. It remains marginalized in terms of improving pregnancy outcome of this population. For infertile women with unexplained positive autoantibody, empirical treatment takes a mainstay possession. Several therapies have been proposed in daily practice [ 8 ] , among which glucocorticoids (GCs) are a group of classic drugs for autoimmune diseases. However, the effect of GCs in improving pregnancy outcome in women with unexplained positive autoantibody is controversial. Furthermore, dispute of GCs treatment remains in matters of drug selection, initial treatment time, dosage of GCs, and period of treatment. It’s demanding to determine whether GCs treatment is beneficial to pregnancy outcome in women with unexplained positive autoantibody, as the treatment regimen is quite arbitrary and confusing in daily practice. Therefore, we reviewed clinical research content, and did systematic review and meta-analysis around treatment effect of GCs on this populationsystematic review, in hoping to provide evidence for rational drug use in women with unexplained positive autoantibody. Methods Search strategy and selection criteria This study has been registered with PROSPERO (the registration number: CRD42019124442), and was conducted and reported according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement [ 9 ] . We conducted a systematic search both in English and Chinese in Pubmed, Embase, EBSCO, and the Cochrane Central Register of Controlled Trials. For comprehensive literature search, a string made up of relevant keywords was utilized: ("glucocorticoids” or "steroid" or "prednisone" or "prednisolone" or "methylprednisolone" or "dexamethasone") and ("recurrent fetal loss" or "recurrent pregnancy loss" or "recurrent spontaneous miscarriage" or "infertility" or "assisted reproductive technique" or "IVF-ET" or "recurrent implantation failure") and ("autoimmune" or "autoantibody"). The time of publication was not limited. Two independent reviewers (Yilin Yuan and Ting Li) reviewed titles and abstracts for basic relevance, followed by a full-text examination using the following inclusion and exclusion criteria. Only Randomized controlled trials (RCT) and cohort study investigating the use of GCs in women with unexplained positive autoantibody undergoing pregnancy were assessed based on full text. Any discordant findings between the two independent reviewers were adjudicated by a third reviewer. The inclusion criteria are as follows: unexplained recurrent fetal loss or infertility; with autoantibody positive, but does not meet any classification criteria for autoimmune diseases; intervention group treated with GCs and control group given placebo or untreated. The exclusion criteria includes repeated data, being diagnosed with specific autoimmune disease, lack of positive autoantibodies, lack of GCs administration, and risk of confounding factors such as thyroid function anomaly. Quality assessment RCTs were quality assessed based on the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Retrospective cohort studies were quality assessed based on the New Castle-Ottawa Quality Assessment Scale-Cohort Studies. Two authors independently assessed every paper. Data extraction and analysis The following data were extracted: the number of enrolled patients, status of autoantibodies, the type of GCs, initial GCs treatment time, dosage of GCs, period of treatment, combination therapy, the number of clinical pregnancy, live birth, and miscarriage (per pregnancy). The primary outcome in our study is relative risk (RR) of establishment of clinical pregnancy comparing GCs-treatment and non-GCs-treatment group. The secondary outcomes in our study are: 1) RR of live birth rate (per couple) comparing GCs-treatment and non-GCs-treatment group; 2) RR of miscarriage rate (per pregnancy) comparing GCs-treatment and non-GCs-treatment group. We examined the heterogeneity (variations) between the results of different studies by checking the results of the chi-squared Cochran’s Q statistic and I 2 statistics. I 2 > 50% represent statistical significance for heterogeneity, random-effects models were used if heterogeneity presents. All analysis were conducted by Cochrane Collaboration’ Review Manger 5.3 software package. Results Using the keywords and database listed above, 7 studies were identified for inclusion. During the initial search, we identified a total of 114 studies by searching strategy in all four databases. After eliminating 57 duplicate records and 29 studies not relevant to our research question, 28 studies remained suitable for following screening. Among these, we excluded 21 studies [ 10 – 30 ] (see supplementary table 1 for studies excluded and reason for exclusion). 7 studies meet the inclusion criteria with no reason for exclusion, providing data comparing peri-implantation GCs versus placebo (or untreated). Full agreement existed between the two review authors concerning inclusion or exclusion trials. Among the 7 studies identified, 5 studies were parallel-design RCT, 2 studies were cohort studies. All were single center studies. The risk of bias is listed in supplementary table 2 and 3. Participants 681 participants were included from 7 independent studies. Among these studies, one study further divided their participants into subgroups with positive ANA or APL [ 31 ] (Table 1 ). 3 studies included women who are positive for one of the autoantibodies, including antinuclear antibody (ANA), anti-DNA (anti-dsDNA by Geva et al ., anti-ssDNA and anti-dsDNA by Ando et al . and Laskin et al .), anticardiolipin antibody (ACL), lupus anticoagulant (LAC), antilymphocyte antibody [ 31 – 33 ] , 2 studies included only women with positive ANA [ 34 , 35 ] , one study included only women with positive antiphospholipid antibody (APL). [ 36 ] One study included women whom had thyroid peroxidase antibodies (TPO-Abs) with normal thyroid function [ 37 ] . Table 1 Characteristics of participants of included studies. Study Age Indication for treatment Autoantibody profile GCs use Adjuvant therapy Fan, 2016 [ 35 ] 31.1 ± 4.2 IVF-ET failure Positive for ANA Prednisone: 10 mg/d Started 3 months before COH Stopped if confirmation of clinical pregnancy Aspirin: 100 mg/d Administered simultaneously with GCs Turi, 2010 [ 37 ] 34.4 ± 3.8 Infertilty Positive for antithyroid antibody Prednisone: 10 mg/d*1 week, 5 mg/d*1 week, 2.5 mg/d*1 week, and 2.5 mg/d * 3 times Started 4 weeks before IUI Stopped just before IUI Geva, 1998 [ 32 ] n.d. IVF-ET failure Positive for ANA, anti-ds DNA, ACL or LAC Prednisone: 10 mg/d Started 4 weeks before induction of ovulation Stopped at 18th week of gestation, IVF-ET failure or fetal loss Aspirin: 100 mg/d Started simultaneously with GCs Stopped 6 weeks’ postpartum, IVF-ET failure or fetal loss Laskin, 1997 [ 33 ] 3 ± 3.8 RPL Positive for ANA, anti-ds DNA, ACL, LAC or anti-lymphocyte Prednisone: 0.8 mg/kg/d* 4 weeks (maximum, 60 mg), 0.5 mg/kg/d (maximum, 40 mg) Started since confirmation of pregnancy Stopped at delivery or fetal loss Aspirin: 100 mg/d Started simultaneously with GCs Stopped at 36th week of gestation or shortly before delivery Ando, 1996 † [ 31 ] 32.8 ± 3.4 n.d. Positive for ANA, anti-DNA or LAC Prednisolone 5 mg/d Or dexamethasone 0.5 mg/day, changed into prednisolone after confirmation of pregnancy Started with IVF cycle Stopped according to autoantibody titers Aspirin: 81 mg/d Administered simultaneously with GCs Zhu, 2013 [ 34 ] 32.33 ± 4.25 Infertility Positive for ANA Prednisone: 10 mg/d Up to 3 months before IVF/ICSI cycle Aspirin: 100 mg/d Administered simultaneously with GCs Ying, 2012 [ 36 ] 32.1 ± 4.0 Infertility Positive for ACL Methylprednisolone: 8 mg/d Up to 3 months before IVF cycle Aspirin: 50 mg/d Administered simultaneously with GCs Abbreviations: RPL = recurrent pregnancy loss, ANA = antinuclear antibody, ACL = anticardiolipin antibody, LAC = lupus anticoagulant, APL = antiphospholipid antibody, COH = controlled ovarian hyperstimulation, IUI = intrauterine insemination, IVF-ET = in vitro fertilization-embryo transplantation, ICSI = intracytoplasmic sperm injection, n.d. = not defined. †Further divided into subgroups according to autoantibodies, including ANA(+) and LAC(+) ‡Further divided into 2 subgroups according to autoantibodies, including ANA(+)/APL(-) and ANA(+)/APL(-) Intervention A variety of different protocols for GCs administration were used. The type of GCs were prednisone [ 32 – 35 , 37 ] , methylprednisolone [ 36 ] , prednisolone [ 31 ] , and dexamethasone [ 31 ] . Among these studies, most of them used only one particular GCs, except that Ando et al . prescribed 2 types of GCs, either dexamethasone or prednisolone, with no explanation of the basis for choosing which one to give [ 31 ] . GCs were mostly used in low dose. However, the dose schedules and length of treatment were variable (table 2). Methylprednisolone was used in a dose of 8 mg/d by Ying et al . [ 36 ] . Prednisone was used in a dose of 10 mg/d by Zhu et al ., Geva et al . and Fan et al . [ 32 , 34 , 35 ] . Turi et al . started prednisone administration at the dose of 10 mg/d in the 1st week then gradually reduced the dosage until complete withdrawal [ 37 ] . Laskin et al . prescribed prednisone 0.8 mg/kg/d for four weeks (maximum, 60 mg/d) from confirmation of pregnancy by ultrasonography, followed by 0.5 mg/kg/d (maximum 40 mg/d) until delivery or fetal loss [ 33 ] . Ando et al . prescribed prednisolone 5 mg/d or dexamethasone 0.5 mg/d during the entire IVF cycle, and changed into prednisolone 5 mg/d after confirmation of pregnancy [ 31 ] . All studies use only oral regimens. 6 studies included involved ART. Among them, the assisted reproductive technique differed. Most assisted reproductive technology (ART) conducted was IVF-ET [ 31 , 32 , 34 – 36 ] , except for one study used IUI [ 37 ] , 1 study did not mention whether ART was used [ 33 ] . In the 6 studies, treatment initation was related with ART cycle, GCs were provided consecutively during both luteal phase and follicular phase. GCs were administered either up to 3 months before IVF/ICSI cycle [ 34 , 36 ] and induction of ovulation [ 35 ] , or 4 weeks before induction of ovulation [ 32 ] or intrauterine insemination (IUI) [ 37 ] . Ando et al . [ 31 ] administered GCs from IVF cycle. In 1 study without ART, GCs were provided from the confirmation of pregnancy [ 33 ] . Additional aspirin 100 mg/d [ 32 – 35 ] , 81 mg/d [ 31 ] , or 50 mg/d [ 36 ] was provided as adjuvant in most included studies except the one by Turi et al . [ 37 ] . Outcome Six studies reported clinical pregnancy rate [ 31 , 32 , 34 – 37 ] . Live birth rate is obtained from six studies [ 31 – 33 , 35 – 37 ] . In one study, the clinical observation stopped after the first trimester, so we classified those who did not miscarry by the end of the study as ongoing pregnancy [ 34 ] . With regard to miscarriage rate, 6 studies reported total miscarriage rate [ 31 – 33 , 35 – 37 ] . Geva et al . and Zhu et al . reported early miscarriage as well [ 32 , 34 ] . Other incidences in pregnancy were also recorded in some studies, including preterm birth, intrauterine death, neonatal death, ectopic pregnancy, hypertension (HTN) and gestational diabetes mellitus (GDM) [ 32 , 33 ] . Effects of interventions Clinical pregnancy rate per couple In six studies reported clinical pregnancy rate per couple, the result favors GCs use on improving clinical pregnancy rate (RR 2.19, 95% CI 1.64 to 2.92, P < 0.00001, 6 cohort studies, 479 women, I 2 = 39%; Fig. 2 ). We further conducted subgroup analysis for women with positive ANA and positive APL, and found that ANA-positive subgroup favors GC therapy (RR 2.54, 95% CI 1.09 to 5.89, P = 0.03, 3 cohort studies, 213 women, I 2 = 51%) while APL-positive subgroup does not (RR 2.73, 95% CI 0.41 to 18.27, P = 0.30, 2 cohort studies, 176 women, I 2 = 72%; Fig. 3 ). Live birth rate per couple A total of 6 studies provided live birth rate as evaluating the effect of GCs administration, in which 2 studies supported GCs use and 4 studies showed no significant difference between GCs and control groups. Meta-analysis concluded that it favors peri-implantation GCs compared to no GCs (RR 1.92, 95% CI 1.17 to 3.16, P = 0.009, 6 cohort studies, 644 women, I 2 = 64%; Fig. 4 ). We then conducted subgroup analysis based on autoantibodies. It showed that GCs could improve the live birth rate in women with positive ANA (RR 2.45, 95% CI 1.47 to 4.09, P = 0.0006, 2 cohort studies, 167 women, I 2 = 0%, Fig. 5 ). However, in women with positive APL, the result remained controversial (RR 2.22, 95% CI 0.66 to 7.45, P = 0.20, 2 cohort studies, 176 women, I 2 = 40%; Fig. 5 ). To further understand the effect of GCs, we divided the studies into two subgroups according to initial time of treatment. 5 studies initiated GCs treatment before confirmation of pregnancy, 1 study after confirmation of pregnancy. The former favors GCs use (RR 2.30, 95% CI 1.58 to 3.34, P < 0.0001, 5 cohort studies, 442 women, I 2 = 0%; Fig. 6 ), while the latter did not (RR 1.16, 95% CI 0.93 to 1.45, P = 0.20, 1 cohort study, 202 women; Fig. 6 ). Miscarriage rate per pregnancy The use of peri-implantation GCs on miscarriage rate per couple showed no statistical significance compared to no GCs (RR 0.75, 95% CI 0.55 to 1.02, P = 0.06, 6 cohort studies, 340 women, I 2 = 0%; Fig. 7 ). After dividing the studies according to initial treatment time, same result showed in both pre-pregnancy GCs group and post-pregnancy GCs group (GCs before pregnancy: RR 0.58, 95% CI 0.31 to 1.07, P = 0.08, 5 cohort studies, 138 women, I 2 = 22%; GCs after pregnancy: RR 0.80, 95% CI 0.56 to 1.13, P = 0.20, 1 cohort study, 202 women; Fig. 8 ). Discussion There is a lack of consensus in the treatment of infertile women with unexplained positive autoantibody. For better understanding the effect of a commonly used drug, GCs, in this population, we conducted this systematic review and meta-analysis, and the major finding of our study is that GCs use has positive effect on improving clinical pregnancy rate and live birth rate in women with unexplained autoantibodies. Clinical pregnancy rate and live birth rate were improved only in ANA positive women without specific autoimmune disorder, but not in those with positive ACL. In addition, the effect on live birth rate is significant when GCs are administered before confirmation of pregnancy rather than after pregnancy. 4 RCTs and 2 cohort studies provided data on clinical pregnancy rate, in which 4 independent studies favored GCs use. Our systematic review and meta-analysis based on current studies confirmed the efficiency of GCs administration in improving clinical pregnancy rate in ANA but not APL positive women, which implies the different pathogenetic roles of diverse autoantibodies in establishing or maintening pregnancy. However, for subgroup with APL, we find data extracted from 2 studies are heterogenous and the sample size is small. Thus, examining whether GCs use can improve clinical pregnancy rate in APL-positive women needs further research. The analysis based on 5 studies providing live birth rate shows the same results that GCs use has a positive effect in increasing live birth rate only in ANA positive patients, but not in APL. These results indicate that patients with different autoantibodies may also have different immunologic characteristics and clinical outcomes, thus showed different responses to GCs. Additional subgroup analysis was added to help determine the best time to start GCs therapy, and showed that preconception use of GCs improved live birth rate, while post-conception GCs administration did not. A meta-analysis conducted by Dan et al . showed that women experiencing unexplained recurrent miscarriage benefit significantly from prednisolone treatment after confirmation of pregnancy in terms of an increased live birth rate compared with placebo [ 38 ] . However, the population in the studies included in their meta-analysis was different from ours. They used high uterine natural killer cell density (> 5%), a test that is not popular in daily practice, as inclusion criteria, and known cause for recurrent miscarriage as exclusion criteria, but no mention of autoantibodies [ 39 , 40 ] . Therefore, difference in target population of the two studies may underlie the inconsistency in terms of the efficacy of GCs treatment. Furthermore, no effect in post-conception GCs treatment may also indicate risk in fetal exposure to exogenous GCs. A prospective controlled study collected and followed 311 pregnancies with systemic use of GCs in the first trimester. Higher rates of miscarriage (11.5% versus 7.0%, P = 0.013) and preterm birth (22.7% versus 10.8%, P < 0.001) were observed in GCs exposed group compared to the controls [ 41 ] . To date, prednisolone maintains a Category D rating with the Food and Drug Administration in the USA, indicating routine administration is not recommended. Therefore, further well-designed studies are needed to determine the best initial time and length of GCs therapy. Miscarriage rate is not improved by GCs administration in neither 6 studies included nor our systematic review and meta-analysis. Same result is obtained from further subgroup analysis concerning the initiation time of GCs treatment. The miscarriage rate in subgroup “GCs administration before pregnancy” in our study is 9.4%, which is comparable to 13.5% reported by Anderson et al . [ 42 ] . Only 1 study is included in post-conception GCs administration subgroup, and the miscarriage rate is lower than control group without statistical significance. As discussed before, early fetal exposure to exogenous GCs may cause risk in miscarriage. Therefore, identifying the optimal indication for GCs use after confirmation of pregnancy warrant further well-designed study with large sample size. Our study has several limitations that have to be considered when it comes to interpretation of the data. First, as mentioned before, our meta-analysis included only seven studies due to lack of related studies. However, because the question is so important and sample size is small in each study, and couldn’t give clinicians effective guidance, so it is necessary to have meta-analysis and systematic review to help us get more comprehensive information. Although several borderline effects needs to be confirmed by larger sample size, our study still provides preliminary information that is important for further studies. Second, the dosage, type and the therapeutic course of GCs among included trials were of a great discrepancy. Using placebo or not is also inconsistent between studies. Third, the type and dose of adjuvant therapy varies in studies included, and the effect of these therapies, such as oral aspirin, on changing pregnancy outcome are not clear [ 43 – 45 ] . The effect of GCs use in women with unexplained positive autoantibody needs further investigations of high quality to confirm. To gain better understanding of this therapy, well-designed prospective, randomized, controlled clinical trials must be proposed. Based on our finding, the recommendations for future study design are listed below. First, the type of GCs should not be long acting GCs including dexamethasone or betamethasone, for they can pass through placenta and cause adverse effects such as fetal malformation. Second, the dose is not necessarily high, 10 mg/d prednisone/prednisolone or less is possibly enough to have positive effect. Third, the therapeutic course covering 1–3 months before confirmation of pregnancy or controlled ovarian hyperstimulation is recommended, although the effect of post-conception GCs therapy initiation needs further understanding. Adjuvant therapy such as anticoagulants can be added, but should be comparable in both control and GCs groups. Forth, patients should be divided into different subgroups according to their type of autoantibodies. Conclusion our systemic review and meta-analysis report improvement in clinical pregnancy rate and live birth rate of GCs use in women with unexplained positive autoantibody. Further investigation is required to ascertain its efficacy. Declarations Ethical Approval and Consent to participate: Not needed in meta-analysis. Consent for publication: Yes. Availability of supporting data: All data generated or analysed during this study are included in this published article. Competing interests: The authors declare that they have no competing interests. Funding: This work is not funded by any organization. Acknowledgements: The authors wish to thank all researchers of the included studies who provided additional data. Authors' information: Nothing to report. Authors' contributions: Ting Li, Yilin Yuan, Rong Mu and Qun Lu conceived and designed the study. Ting Li and Yilin Yuan performed the literature search, data extraction, and assessed the risk of bias and overall quality of evidence. Rong Mu resolved disagreement between Ting Li and Yilin Yuan. Ting Li, Yilin Yuan and Huixin Liu performed and interpreted the data analysis. Ting Li and Yilin Yuan drafted the manuscript. Rong Mu revised the manuscript. All authors read and approved the final manuscript. References Haas, D.M., T.J. Hathaway, and P.S. Ramsey, Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiology. Cochrane Database Syst Rev, 2018. 10 : p. Cd003511. Ramos-Ibeas, P., et al., Senescence and Apoptosis During in vitro Embryo Development in a Bovine Model. Front Cell Dev Biol, 2020. 8 : p. 619902. Graham, M.C., K.M. Hoeger, and W.R. Phipps, Initial IVF-ET experience with assisted hatching performed 3 days after retrieval followed by day 5 embryo transfer. Fertil Steril, 2000. 74 (4): p. 668-71. Wang, N.F., et al., Immunologic Abnormalities, Treatments, and Recurrent Pregnancy Loss: What Is Real and What Is Not? Clinical obstetrics and gynecology, 2016. 59 (3): p. 509-523. Vander Borght, M. and C. Wyns, Fertility and infertility: Definition and epidemiology. Clin Biochem, 2018. 62 : p. 2-10. Norgard, B.M., et al., Decreased chance of a live born child in women with rheumatoid arthritis after assisted reproduction treatment: a nationwide cohort study. Ann Rheum Dis, 2019. 78 (3): p. 328-334. Schreiber, K., et al., Antiphospholipid syndrome. Nature Reviews Disease Primers, 2018. 4 : p. 17103. Shetty, S. and K. Ghosh, Anti-phospholipid antibodies and other immunological causes of recurrent foetal loss--a review of literature of various therapeutic protocols. American journal of reproductive immunology (New York, N.Y. : 1989), 2009. 62 (1): p. 9-24. Moher, D., et al., Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med, 2009. 6 (7): p. e1000097. Geva, E., et al., Prednisone and aspirin improve pregnancy rate in patients with reproductive failure and autoimmune antibodies: a prospective study. American journal of reproductive immunology (New York, N.Y. : 1989), 2000. 43 (1): p. 36-40. Ordi, J., et al., Fetal loss treatment in patients with antiphospholipid antibodies. Annals of the rheumatic diseases, 1989. 48 (10): p. 798-802. Vaquero, E., et al., Pregnancy outcome in recurrent spontaneous abortion associated with antiphospholipid antibodies: a comparative study of intravenous immunoglobulin versus prednisone plus low-dose aspirin. American journal of reproductive immunology (New York, N.Y. : 1989), 2001. 45 (3): p. 174-179. Ye, S.-L., et al., Efficacy of Different Treatment Regimens for Antiphospholipid Syndrome-related Recurrent Spontaneous Abortion. Chinese medical journal, 2017. 130 (12): p. 1395-1399. Hasegawa, I., et al., Effectiveness of prednisolone/aspirin therapy for recurrent aborters with antiphospholipid antibody. Human reproduction (Oxford, England), 1992. 7 (2): p. 203-207. Hasegawa, I., et al., Prednisolone plus low-dose aspirin improves the implantation rate in women with autoimmune conditions who are undergoing in vitro fertilization. Fertility and sterility, 1998. 70 (6): p. 1044-1048. Moradan, S. and R. Ghorbani, Dexamethasone in unexplained infertility. Saudi medical journal, 2009. 30 (8): p. 1034-1036. Siristatidis, C., et al., Addition of prednisolone and heparin in patients with failed IVF/ICSI cycles: a preliminary report of a clinical trial. Human fertility (Cambridge, England), 2013. 16 (3): p. 207-210. Ou, H. and Q. Yu, [Effects of combination therapy with aspirin, prednisone, and Elevit in patients with unexplained recurrent early pregnancy loss]. Zhonghua yi xue za zhi, 2017. 97 (41): p. 3250-3254. Siristatidis, C., et al., Administration of prednisolone and low molecular weight heparin in patients with repeated implantation failures: a cohort study. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology, 2018. 34 (2): p. 136-139. Moffitt, D., et al., Low-dose glucocorticoids after in vitro fertilization and embryo transfer have no significant effect on pregnancy rate. Fertility and sterility, 1995. 63 (3): p. 571-577. Ubaldi, F., et al., Low dose prednisolone administration in routine ICSI patients does not improve pregnancy and implantation rates. Human reproduction (Oxford, England), 2002. 17 (6): p. 1544-1547. Duvan, C.I., et al., Does addition of low-dose aspirin and/or steroid as a standard treatment in nonselected intracytoplasmic sperm injection cycles improve in vitro fertilization success? A randomized, prospective, placebo-controlled study. Journal of assisted reproduction and genetics, 2006. 23 (1): p. 15-21. Fawzy, M., et al., Treatment options and pregnancy outcome in women with idiopathic recurrent miscarriage: a randomized placebo-controlled study. Archives of gynecology and obstetrics, 2008. 278 (1): p. 33-38. Kilic, S., et al., The effect of anti-thyroid antibodies on endometrial volume, embryo grade and IVF outcome. Gynecol Endocrinol, 2008. 24 (11): p. 649-55. Revelli, A., et al., Low-dose acetylsalicylic acid plus prednisolone as an adjuvant treatment in IVF: a prospective, randomized study. Fertil Steril, 2008. 90 (5): p. 1685-91. Tang, A.-W., et al., A feasibility trial of screening women with idiopathic recurrent miscarriage for high uterine natural killer cell density and randomizing to prednisolone or placebo when pregnant. Human reproduction (Oxford, England), 2013. 28 (7): p. 1743-1752. Fawzy, M. and A.-A.A. El-Refaeey, Does combined prednisolone and low molecular weight heparin have a role in unexplained implantation failure? Archives of gynecology and obstetrics, 2014. 289 (3): p. 677-680. Gomaa, M.F., et al., Combined oral prednisolone and heparin versus heparin: the effect on peripheral NK cells and clinical outcome in patients with unexplained recurrent miscarriage. A double-blind placebo randomized controlled trial. Archives of gynecology and obstetrics, 2014. 290 (4): p. 757-762. Litwicka, K., et al., In women with thyroid autoimmunity, does low-dose prednisolone administration, compared with no adjuvant therapy, improve in vitro fertilization clinical results? The journal of obstetrics and gynaecology research, 2015. 41 (5): p. 722-728. Stern, C., et al., A randomized, double-blind, placebo-controlled trial of heparin and aspirin for women with in vitro fertilization implantation failure and antiphospholipid or antinuclear antibodies. Fertility and Sterility, 2003. 80 (2): p. 376-383. Ando, T., et al., Successful glucocorticoid treatment for patients with abnormal autoimmunity on in vitro fertilization and embryo transfer. J Assist Reprod Genet, 1996. 13 (10): p. 776-81. Geva, E., et al., Prevention of early pregnancy loss in autoantibody seropositive women. Lancet (London, England), 1998. 351 (9095): p. 34-35. Laskin, C.A., et al., Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss. The New England journal of medicine, 1997. 337 (3): p. 148-153. Zhu, Q., et al., A retrospective study on IVF/ICSI outcome in patients with anti-nuclear antibodies: the effects of prednisone plus low-dose aspirin adjuvant treatment. Reproductive biology and endocrinology : RB&E, 2013. 11 : p. 98. Fan, J., Y. Zhong, and C. Chen, Combined treatment of prednisone and aspirin, starting before ovulation induction, may improve reproductive outcomes in ANA-positive patients. American journal of reproductive immunology (New York, N.Y. : 1989), 2016. 76 (5): p. 391-395. Ying, Y., et al., A retrospective study on IVF outcome in patients with anticardiolipin antibody: effects of methylprednisolone plus low-dose aspirin adjuvant treatment. Journal of reproductive immunology, 2012. 94 (2): p. 196-201. Turi, A., et al., Preconception steroid treatment in infertile women with antithyroid autoimmunity undergoing ovarian stimulation and intrauterine insemination: a double-blind, randomized, prospective cohort study. Clin Ther, 2010. 32 (14): p. 2415-21. Dan, S., et al., Effect of Prednisolone Administration on Patients with Unexplained Recurrent Miscarriage and in Routine Intracytoplasmic Sperm Injection: A Meta-Analysis. American journal of reproductive immunology (New York, N.Y. : 1989), 2015. 74 (1): p. 89-97. Tang, A.W., et al., Prednisolone Trial: Study protocol for a randomised controlled trial of prednisolone for women with idiopathic recurrent miscarriage and raised levels of uterine natural killer (uNK) cells in the endometrium. Trials,10,1(2009-11-10), 2009. 10 (1): p. 102-102. Ai-Wei, T., et al., A feasibility trial of screening women with idiopathic recurrent miscarriage for high uterine natural killer cell density and randomizing to prednisolone or placebo when pregnant. Human Reproduction, 2013. 28 (7): p. 1743-1752. Gur, C., et al., Pregnancy outcome after first trimester exposure to corticosteroids: a prospective controlled study. Reproductive Toxicology, 2004. 18 (1): p. 93-101. Andersen, A.-M.N., et al., Maternal age and fetal loss: population based register linkage study. BMJ : British Medical Journal, 2000. 320 (7251): p. 1708-1712. Rai, R., et al., Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). Bmj British Medical Journal, 1997. 314 (7076): p. 253-257. Dendrinos, S., E. Sakkas, and E. Makrakis, Low-molecular-weight heparin versus intravenous immunoglobulin for recurrent abortion associated with antiphospholipid antibody syndrome. International Journal of Gynecology & Obstetrics, 2009. 104 (3): p. 223-225. Schisterman, E.F., et al., Preconception low-dose aspirin and pregnancy outcomes: results from the EAGeR randomised trial. Lancet, 2014. 384 (9937): p. 29-36. Table Table 2 is not available with this version. Supplementary Files SupplmentryTables.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-147807","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":8248379,"identity":"09b7667d-f0e2-428d-a649-5f3fe47970bd","order_by":0,"name":"Ting Li","email":"","orcid":"https://orcid.org/0000-0002-2950-614X","institution":"Peking University Third Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ting","middleName":"","lastName":"Li","suffix":""},{"id":8248380,"identity":"b806b9be-a814-4163-a318-76753fd647f7","order_by":1,"name":"Yilin Yuan","email":"","orcid":"","institution":"Peking University Sixth Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yilin","middleName":"","lastName":"Yuan","suffix":""},{"id":8248381,"identity":"d770a0e9-1369-46ce-b677-80a9cc072faf","order_by":2,"name":"Huixin Liu","email":"","orcid":"","institution":"Peking University People's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Huixin","middleName":"","lastName":"Liu","suffix":""},{"id":8248382,"identity":"3048155e-214b-47d7-802f-5ccbb96c4f8c","order_by":3,"name":"Qun Lu","email":"","orcid":"","institution":"Peking University People's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Qun","middleName":"","lastName":"Lu","suffix":""},{"id":8248383,"identity":"c4dd6c2b-0c40-48b6-b158-99767dc1aa1b","order_by":4,"name":"Rong Mu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxklEQVRIiWNgGAWjYPACGwYJBgY2IIOZaC1ppGs5TIIW3Rm5Dx8X/DqfJzkj99gDhgrrxAb2swfwajG7kW5sPLPvdrG0RF66AcOZ9MQGnrwEAlrS2KR5e24nzpPIMZNgbDuc2CDBY0CMlnNQLf+I1cLz40DibLCWBmK0nHnGbMzbkFws2fMuTSLhWLpxG08OAS3H0xgf8/yxy5M4nntM4kONtWw/+xn8WsCAsY0hgYGBhwFEgmOHCPAHqmUUjIJRMApGATYAAHF8QUHc67fHAAAAAElFTkSuQmCC","orcid":"","institution":"Department of Rheumatology and Immunology, Peking University Third Hospital ","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Rong","middleName":"","lastName":"Mu","suffix":""}],"badges":[],"createdAt":"2021-01-14 20:22:45","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-147807/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-147807/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":5089861,"identity":"24815fe3-6a1a-42dc-8308-035b87625802","added_by":"auto","created_at":"2021-01-19 16:46:06","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":46696,"visible":true,"origin":"","legend":"The process of finding studies.","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-147807/v1/1c1ee353c28f7f71cdd08fa2.jpg"},{"id":5089867,"identity":"408846f2-1337-487b-ba8d-f99b1fab181e","added_by":"auto","created_at":"2021-01-19 16:46:07","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":57160,"visible":true,"origin":"","legend":"Forrest plot for comparison: GCs versus no GCs/placebo, outcome: I.I Clinical pregnancy rate per couple. 6 studies reported clinical pregnancy rate per couple. The result favors GCs use on improving clinical pregnancy rate (RR 2.19, 95% CI 1.64 to 2.92, P\u003c0.00001, 6 cohort studies, 479 women, I2 = 39%).","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-147807/v1/fb0887b60e066f8caf97d3f9.jpg"},{"id":5089862,"identity":"223009f8-5de1-4609-8da3-ee76555ca7cb","added_by":"auto","created_at":"2021-01-19 16:46:06","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":93614,"visible":true,"origin":"","legend":"Forrest plot comparison: GCs versus no GCs/placebo, outcome: I.II Clinical pregnancy rate per couple in subgroups by autoantibody. ANA-positive subgroup favors GC therapy while APL-positive subgroup does not (ANA: RR 2.54, 95% CI 1.09 to 5.89, P = 0.03 , 3 cohort studies, 213 women, I2 = 51%; APL: RR 2.73, 95% CI 0.41 to 18.27, P = 0.30, 2 cohort studies, 176 women, I2 = 72%).","description":"","filename":"Fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-147807/v1/d1e6cebd820b0f02b2d83463.jpg"},{"id":5090119,"identity":"93938960-9967-4121-9a0c-9a853ac3c893","added_by":"auto","created_at":"2021-01-19 16:49:07","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":59250,"visible":true,"origin":"","legend":"Forrest plot for comparison: GCs versus no GCs/placebo, outcome: II.I Live birth rate per couple. A total of 7 studies provided live birth rate as evaluating the effect of GCs administration. Meta-analysis concluded that it favors peri-implantation GCs compared to no GCs (RR 1.92, 95% CI 1.17 to 3.16, P = 0.009, 6 cohort studies, 644 women, I2 = 64%).","description":"","filename":"Fig4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-147807/v1/2f79576a5ee4f4b9919b8143.jpg"},{"id":5089869,"identity":"dacd7d64-44fa-4db1-a079-9537463ac6a9","added_by":"auto","created_at":"2021-01-19 16:46:07","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":87930,"visible":true,"origin":"","legend":"Forrest plot for comparison: GCs versus no GCs/placebo, outcome: II.II Live birth rate per couple in subgroups by autoantibody. GCs could improve the live birth rate in women with positive ANA (RR 2.45, 95% CI 1.47 to 4.09, P = 0.0006, 2 cohort studies, 167 women, I2 = 0%). However, in women with positive APL, the result remained controversial (RR 2.22, 95% CI 0.66 to 7.45, P = 0.20, 2 cohort studies, 176 women, I2 = 40%)","description":"","filename":"Fig5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-147807/v1/32ed4d990dfc15020669be90.jpg"},{"id":5090118,"identity":"ae9e0c00-cbb4-4129-914c-fa9821a3bde7","added_by":"auto","created_at":"2021-01-19 16:49:06","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":99801,"visible":true,"origin":"","legend":"Forrest plot for comparison: GCs versus no GCs/placebo, outcome: II.III Live birth rate per couple in subgroups by time of treatment. 5 studies initiated GCs treatment before confirmation of pregnancy, 1 study after confirmation of pregnancy. The former favors GCs use (RR 2.30, 95% CI 1.58 to 3.34, P \u003c 0.0001, 5 cohort studies, 442 women, I2 = 0%), while the latter did not (RR 1.16, 95% CI 0.93 to 1.45, P = 0.20, 1 cohort study, 202 women)","description":"","filename":"Fig6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-147807/v1/3a36c60eb5ddf262e6224e39.jpg"},{"id":5090117,"identity":"536111b1-9d29-4aa6-a970-2fa1c0986c9e","added_by":"auto","created_at":"2021-01-19 16:49:06","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":56506,"visible":true,"origin":"","legend":"Forrest plot for comparison: GCs versus no GCs/placebo, outcome: III.I Miscarriage rate per clinical pregnancy. The use of peri-implantation GCs on miscarriage rate per couple showed no statistical significance compared to no GCs (RR 0.75, 95% CI 0.55 to 1.02, P = 0.06, 6 cohort studies, 340 women, I2 = 0%). ","description":"","filename":"Fig7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-147807/v1/54c2f4225e16104f0b61966f.jpg"},{"id":5089870,"identity":"aa1118d9-2240-4471-8266-89c9ea8891ea","added_by":"auto","created_at":"2021-01-19 16:46:07","extension":"jpg","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":96928,"visible":true,"origin":"","legend":"Forrest plot for comparison: GCs versus no GCs/placebo, outcome: III.II Miscarriage rate per clnical pregnancy in subgroups by time of treatment. 6 studies were divided into 2 subgroups according to initial treatment time, same result showed for both pre-pregnancy GCs use and post-pregnancy GCs use (GCs before pregnancy: RR 0.58, 95% CI 0.31 to 1.07, P = 0.08, 5 cohort studies, 138 women, I2 = 22%; GCs after pregnancy: RR 0.80, 95% CI 0.56 to 1.13, P = 0.20, 1 cohort study, 202 women).","description":"","filename":"Fig8.jpg","url":"https://assets-eu.researchsquare.com/files/rs-147807/v1/87f7b73be6628466aeff92ec.jpg"},{"id":13648432,"identity":"ea2674db-51bd-4c90-8475-741e4a01f5c9","added_by":"auto","created_at":"2021-09-17 09:32:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":799293,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-147807/v1/2197afdf-22d3-40f3-a4da-7bbbbc367b98.pdf"},{"id":5089868,"identity":"d99b519c-b8c3-46a3-9faa-3e64f89c76b0","added_by":"auto","created_at":"2021-01-19 16:46:07","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":44089,"visible":true,"origin":"","legend":"","description":"","filename":"SupplmentryTables.docx","url":"https://assets-eu.researchsquare.com/files/rs-147807/v1/f7eb57be1bb449d86f27225f.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eGlucocorticoids Improves Pregnancy Rate and Outcome in Woman With Unexplained Positive Autoantibody: a Systematic Review and Meta-analysis\u003c/p\u003e","fulltext":[{"header":"Introduction","content":" \u003cp\u003eHuman fertility is declining globally. The global infertility rate is about 14% and miscarrage rate is up to 10%-15%\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Infertility or miscarriage, in broad sense, is the result of failed establishment or maintenance of pregnancy. Although advancement have been achieved in technology, such as in vitro fertilization-embryo transfer (IVF-ET), nearly half patients undergoing IVF-ET can not gain a successful pregnancy \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e which is frustrating experience for both patients and clinicians. To improve pregnancy outcome is of great importance. Maternal immune tolerance to the placenta and the fetus is one of the key factors in establishing and maintaining pregnancy. Immunological abnormality was reported to account for 27.88% of fetal loss, include overproduction of autoantibodies and proinflammatory cytokines, and imbalance of immune cells \u003cem\u003eect\u003c/em\u003e \u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e.Women with autoantibody-positive can be divided into two groups based on whether they are diagnosed with autoimmune diseases. The chance of a live birth was significantly reduced in women with rheumatoid arthritis receiving ART treatment, relative to women without rheumatoid arthritis\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Antiphospholipid syndrome accounts for ~\u0026thinsp;3.2% recurrent pregnancy loss in the first trimester \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. However, those diseases only account for a small proportion of all immune factors affecting obstetrics. When it comes to more often cases, autoantibody positive women with recurrent fetal loss or a history of recurrent implantation failure who cannot be classified into any known autoimmune disease, guidelines are insufficient. It remains marginalized in terms of improving pregnancy outcome of this population.\u003c/p\u003e \u003cp\u003eFor infertile women with unexplained positive autoantibody, empirical treatment takes a mainstay possession. Several therapies have been proposed in daily practice \u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e, among which glucocorticoids (GCs) are a group of classic drugs for autoimmune diseases. However, the effect of GCs in improving pregnancy outcome in women with unexplained positive autoantibody is controversial. Furthermore, dispute of GCs treatment remains in matters of drug selection, initial treatment time, dosage of GCs, and period of treatment. It\u0026rsquo;s demanding to determine whether GCs treatment is beneficial to pregnancy outcome in women with unexplained positive autoantibody, as the treatment regimen is quite arbitrary and confusing in daily practice. Therefore, we reviewed clinical research content, and did systematic review and meta-analysis around treatment effect of GCs on this populationsystematic review, in hoping to provide evidence for rational drug use in women with unexplained positive autoantibody.\u003c/p\u003e "},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003eSearch strategy and selection criteria\u003c/h2\u003e\n\u003cp\u003eThis study has been registered with PROSPERO (the registration number: CRD42019124442), and was conducted and reported according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. We conducted a systematic search both in English and Chinese in Pubmed, Embase, EBSCO, and the Cochrane Central Register of Controlled Trials. For comprehensive literature search, a string made up of relevant keywords was utilized: (\"glucocorticoids\u0026rdquo; or \"steroid\" or \"prednisone\" or \"prednisolone\" or \"methylprednisolone\" or \"dexamethasone\") and (\"recurrent fetal loss\" or \"recurrent pregnancy loss\" or \"recurrent spontaneous miscarriage\" or \"infertility\" or \"assisted reproductive technique\" or \"IVF-ET\" or \"recurrent implantation failure\") and (\"autoimmune\" or \"autoantibody\"). The time of publication was not limited.\u003c/p\u003e\n\u003cp\u003eTwo independent reviewers (Yilin Yuan and Ting Li) reviewed titles and abstracts for basic relevance, followed by a full-text examination using the following inclusion and exclusion criteria. Only Randomized controlled trials (RCT) and cohort study investigating the use of GCs in women with unexplained positive autoantibody undergoing pregnancy were assessed based on full text. Any discordant findings between the two independent reviewers were adjudicated by a third reviewer.\u003c/p\u003e\n\u003cp\u003eThe inclusion criteria are as follows: unexplained recurrent fetal loss or infertility; with autoantibody positive, but does not meet any classification criteria for autoimmune diseases; intervention group treated with GCs and control group given placebo or untreated.\u003c/p\u003e\n\u003cp\u003eThe exclusion criteria includes repeated data, being diagnosed with specific autoimmune disease, lack of positive autoantibodies, lack of GCs administration, and risk of confounding factors such as thyroid function anomaly.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n\u003ch2\u003eQuality assessment\u003c/h2\u003e\n\u003cp\u003eRCTs were quality assessed based on the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Retrospective cohort studies were quality assessed based on the New Castle-Ottawa Quality Assessment Scale-Cohort Studies. Two authors independently assessed every paper.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003ch2\u003eData extraction and analysis\u003c/h2\u003e\n\u003cp\u003eThe following data were extracted: the number of enrolled patients, status of autoantibodies, the type of GCs, initial GCs treatment time, dosage of GCs, period of treatment, combination therapy, the number of clinical pregnancy, live birth, and miscarriage (per pregnancy).\u003c/p\u003e\n\u003cp\u003eThe primary outcome in our study is relative risk (RR) of establishment of clinical pregnancy comparing GCs-treatment and non-GCs-treatment group.\u003c/p\u003e\n\u003cp\u003eThe secondary outcomes in our study are: 1) RR of live birth rate (per couple) comparing GCs-treatment and non-GCs-treatment group; 2) RR of miscarriage rate (per pregnancy) comparing GCs-treatment and non-GCs-treatment group.\u003c/p\u003e\n\u003cp\u003eWe examined the heterogeneity (variations) between the results of different studies by checking the results of the chi-squared Cochran\u0026rsquo;s Q statistic and I\u003csup\u003e2\u003c/sup\u003e statistics. I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026gt;\u0026thinsp;50% represent statistical significance for heterogeneity, random-effects models were used if heterogeneity presents. All analysis were conducted by Cochrane Collaboration\u0026rsquo; Review Manger 5.3 software package.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eUsing the keywords and database listed above, 7 studies were identified for inclusion. During the initial search, we identified a total of 114 studies by searching strategy in all four databases. After eliminating 57 duplicate records and 29 studies not relevant to our research question, 28 studies remained suitable for following screening. Among these, we excluded 21 studies \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e (see supplementary table 1 for studies excluded and reason for exclusion). 7 studies meet the inclusion criteria with no reason for exclusion, providing data comparing peri-implantation GCs versus placebo (or untreated). Full agreement existed between the two review authors concerning inclusion or exclusion trials.\u003c/p\u003e\n\u003cp\u003eAmong the 7 studies identified, 5 studies were parallel-design RCT, 2 studies were cohort studies. All were single center studies. The risk of bias is listed in supplementary table 2 and 3.\u003c/p\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003ch2\u003eParticipants\u003c/h2\u003e\n\u003cp\u003e681 participants were included from 7 independent studies. Among these studies, one study further divided their participants into subgroups with positive ANA or APL \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). 3 studies included women who are positive for one of the autoantibodies, including antinuclear antibody (ANA), anti-DNA (anti-dsDNA by Geva \u003cem\u003eet al\u003c/em\u003e., anti-ssDNA and anti-dsDNA by Ando \u003cem\u003eet al\u003c/em\u003e. and Laskin \u003cem\u003eet al\u003c/em\u003e.), anticardiolipin antibody (ACL), lupus anticoagulant (LAC), antilymphocyte antibody \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e, 2 studies included only women with positive ANA \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e, one study included only women with positive antiphospholipid antibody (APL). \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e One study included women whom had thyroid peroxidase antibodies (TPO-Abs) with normal thyroid function \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eCharacteristics of participants of included studies.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eStudy\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAge\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eIndication for treatment\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAutoantibody profile\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eGCs use\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAdjuvant therapy\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eFan, 2016\u003c/strong\u003e\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e31.1\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIVF-ET failure\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePositive for ANA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePrednisone: 10\u0026nbsp;mg/d\u003c/p\u003e\n\u003cp\u003eStarted 3 months before COH\u003c/p\u003e\n\u003cp\u003eStopped if confirmation of clinical pregnancy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAspirin: 100\u0026nbsp;mg/d\u003c/p\u003e\n\u003cp\u003eAdministered simultaneously with GCs\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eTuri, 2010\u003c/strong\u003e\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInfertilty\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePositive for antithyroid antibody\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePrednisone: 10\u0026nbsp;mg/d*1 week, 5\u0026nbsp;mg/d*1 week, 2.5\u0026nbsp;mg/d*1 week, and 2.5\u0026nbsp;mg/d * 3 times\u003c/p\u003e\n\u003cp\u003eStarted 4 weeks before IUI\u003c/p\u003e\n\u003cp\u003eStopped just before IUI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eGeva, 1998\u003c/strong\u003e\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003en.d.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIVF-ET failure\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePositive for ANA, anti-ds DNA, ACL or LAC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePrednisone: 10\u0026nbsp;mg/d\u003c/p\u003e\n\u003cp\u003eStarted 4 weeks before induction of ovulation\u003c/p\u003e\n\u003cp\u003eStopped at 18th week of gestation, IVF-ET failure or fetal loss\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAspirin: 100\u0026nbsp;mg/d\u003c/p\u003e\n\u003cp\u003eStarted simultaneously with GCs\u003c/p\u003e\n\u003cp\u003eStopped 6 weeks\u0026rsquo; postpartum, IVF-ET failure or fetal loss\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLaskin, 1997\u003c/strong\u003e\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRPL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePositive for ANA, anti-ds DNA, ACL, LAC or anti-lymphocyte\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePrednisone: 0.8\u0026nbsp;mg/kg/d* 4 weeks (maximum, 60\u0026nbsp;mg), 0.5\u0026nbsp;mg/kg/d (maximum, 40\u0026nbsp;mg)\u003c/p\u003e\n\u003cp\u003eStarted since confirmation of pregnancy\u003c/p\u003e\n\u003cp\u003eStopped at delivery or fetal loss\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAspirin: 100\u0026nbsp;mg/d\u003c/p\u003e\n\u003cp\u003eStarted simultaneously with GCs\u003c/p\u003e\n\u003cp\u003eStopped at 36th week of gestation or shortly before delivery\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAndo, 1996\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e\u0026dagger;\u003c/strong\u003e[\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003en.d.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePositive for ANA, anti-DNA or LAC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePrednisolone 5\u0026nbsp;mg/d\u003c/p\u003e\n\u003cp\u003eOr dexamethasone 0.5\u0026nbsp;mg/day, changed into prednisolone after confirmation of pregnancy\u003c/p\u003e\n\u003cp\u003eStarted with IVF cycle\u003c/p\u003e\n\u003cp\u003eStopped according to autoantibody titers\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAspirin: 81\u0026nbsp;mg/d\u003c/p\u003e\n\u003cp\u003eAdministered simultaneously with GCs\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eZhu, 2013\u003c/strong\u003e\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32.33\u0026thinsp;\u0026plusmn;\u0026thinsp;4.25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInfertility\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePositive for ANA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePrednisone: 10\u0026nbsp;mg/d\u003c/p\u003e\n\u003cp\u003eUp to 3 months before IVF/ICSI cycle\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAspirin: 100\u0026nbsp;mg/d\u003c/p\u003e\n\u003cp\u003eAdministered simultaneously with GCs\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eYing, 2012\u003c/strong\u003e\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32.1\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInfertility\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePositive for ACL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMethylprednisolone: 8\u0026nbsp;mg/d\u003c/p\u003e\n\u003cp\u003eUp to 3 months before IVF cycle\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAspirin: 50\u0026nbsp;mg/d\u003c/p\u003e\n\u003cp\u003eAdministered simultaneously with GCs\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"6\"\u003eAbbreviations: RPL\u0026thinsp;=\u0026thinsp;recurrent pregnancy loss, ANA\u0026thinsp;=\u0026thinsp;antinuclear antibody, ACL\u0026thinsp;=\u0026thinsp;anticardiolipin antibody, LAC\u0026thinsp;=\u0026thinsp;lupus anticoagulant, APL\u0026thinsp;=\u0026thinsp;antiphospholipid antibody, COH\u0026thinsp;=\u0026thinsp;controlled ovarian hyperstimulation, IUI\u0026thinsp;=\u0026thinsp;intrauterine insemination, IVF-ET\u0026thinsp;=\u0026thinsp;in vitro fertilization-embryo transplantation, ICSI\u0026thinsp;=\u0026thinsp;intracytoplasmic sperm injection, n.d. = not defined.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"6\"\u003e\u0026dagger;Further divided into subgroups according to autoantibodies, including ANA(+) and LAC(+)\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"6\"\u003e\u0026Dagger;Further divided into 2 subgroups according to autoantibodies, including ANA(+)/APL(-) and ANA(+)/APL(-)\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003eIntervention\u003c/h2\u003e\n\u003cp\u003eA variety of different protocols for GCs administration were used. The type of GCs were prednisone \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e, methylprednisolone \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e, prednisolone \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e, and dexamethasone \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. Among these studies, most of them used only one particular GCs, except that Ando \u003cem\u003eet al\u003c/em\u003e. prescribed 2 types of GCs, either dexamethasone or prednisolone, with no explanation of the basis for choosing which one to give \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eGCs were mostly used in low dose. However, the dose schedules and length of treatment were variable (table 2). Methylprednisolone was used in a dose of 8\u0026nbsp;mg/d by Ying \u003cem\u003eet al\u003c/em\u003e. \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e. Prednisone was used in a dose of 10\u0026nbsp;mg/d by Zhu \u003cem\u003eet al\u003c/em\u003e., Geva \u003cem\u003eet al\u003c/em\u003e. and Fan \u003cem\u003eet al\u003c/em\u003e. \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e. Turi \u003cem\u003eet al\u003c/em\u003e. started prednisone administration at the dose of 10\u0026nbsp;mg/d in the 1st week then gradually reduced the dosage until complete withdrawal \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e. Laskin \u003cem\u003eet al\u003c/em\u003e. prescribed prednisone 0.8\u0026nbsp;mg/kg/d for four weeks (maximum, 60\u0026nbsp;mg/d) from confirmation of pregnancy by ultrasonography, followed by 0.5\u0026nbsp;mg/kg/d (maximum 40\u0026nbsp;mg/d) until delivery or fetal loss \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e. Ando \u003cem\u003eet al\u003c/em\u003e. prescribed prednisolone 5\u0026nbsp;mg/d or dexamethasone 0.5\u0026nbsp;mg/d during the entire IVF cycle, and changed into prednisolone 5\u0026nbsp;mg/d after confirmation of pregnancy \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. All studies use only oral regimens.\u003c/p\u003e\n\u003cp\u003e6 studies included involved ART. Among them, the assisted reproductive technique differed. Most assisted reproductive technology (ART) conducted was IVF-ET \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e, except for one study used IUI \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e, 1 study did not mention whether ART was used \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e. In the 6 studies, treatment initation was related with ART cycle, GCs were provided consecutively during both luteal phase and follicular phase. GCs were administered either up to 3 months before IVF/ICSI cycle \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e and induction of ovulation \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e, or 4 weeks before induction of ovulation \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e or intrauterine insemination (IUI) \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e. Ando \u003cem\u003eet al\u003c/em\u003e. \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e administered GCs from IVF cycle. In 1 study without ART, GCs were provided from the confirmation of pregnancy \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eAdditional aspirin 100\u0026nbsp;mg/d \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e, 81\u0026nbsp;mg/d \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e, or 50\u0026nbsp;mg/d \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e was provided as adjuvant in most included studies except the one by Turi \u003cem\u003eet al\u003c/em\u003e. \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n\u003ch2\u003eOutcome\u003c/h2\u003e\n\u003cp\u003eSix studies reported clinical pregnancy rate \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e. Live birth rate is obtained from six studies \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e. In one study, the clinical observation stopped after the first trimester, so we classified those who did not miscarry by the end of the study as ongoing pregnancy \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e. With regard to miscarriage rate, 6 studies reported total miscarriage rate \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e. Geva \u003cem\u003eet al\u003c/em\u003e. and Zhu \u003cem\u003eet al\u003c/em\u003e. reported early miscarriage as well \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e. Other incidences in pregnancy were also recorded in some studies, including preterm birth, intrauterine death, neonatal death, ectopic pregnancy, hypertension (HTN) and gestational diabetes mellitus (GDM) \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n\u003ch2\u003eEffects of interventions\u003c/h2\u003e\n\u003cdiv id=\"Sec11\" class=\"Section3\"\u003e\n\u003ch2\u003eClinical pregnancy rate per couple\u003c/h2\u003e\n\u003cp\u003eIn six studies reported clinical pregnancy rate per couple, the result favors GCs use on improving clinical pregnancy rate (RR 2.19, 95% CI 1.64 to 2.92, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.00001, 6 cohort studies, 479 women, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;39%; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eWe further conducted subgroup analysis for women with positive ANA and positive APL, and found that ANA-positive subgroup favors GC therapy (RR 2.54, 95% CI 1.09 to 5.89, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03, 3 cohort studies, 213 women, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;51%) while APL-positive subgroup does not (RR 2.73, 95% CI 0.41 to 18.27, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.30, 2 cohort studies, 176 women, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;72%; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section3\"\u003e\n\u003ch2\u003eLive birth rate per couple\u003c/h2\u003e\n\u003cp\u003eA total of 6 studies provided live birth rate as evaluating the effect of GCs administration, in which 2 studies supported GCs use and 4 studies showed no significant difference between GCs and control groups. Meta-analysis concluded that it favors peri-implantation GCs compared to no GCs (RR 1.92, 95% CI 1.17 to 3.16, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009, 6 cohort studies, 644 women, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;64%; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eWe then conducted subgroup analysis based on autoantibodies. It showed that GCs could improve the live birth rate in women with positive ANA (RR 2.45, 95% CI 1.47 to 4.09, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0006, 2 cohort studies, 167 women, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e). However, in women with positive APL, the result remained controversial (RR 2.22, 95% CI 0.66 to 7.45, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.20, 2 cohort studies, 176 women, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;40%; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eTo further understand the effect of GCs, we divided the studies into two subgroups according to initial time of treatment. 5 studies initiated GCs treatment before confirmation of pregnancy, 1 study after confirmation of pregnancy. The former favors GCs use (RR 2.30, 95% CI 1.58 to 3.34, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, 5 cohort studies, 442 women, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e), while the latter did not (RR 1.16, 95% CI 0.93 to 1.45, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.20, 1 cohort study, 202 women; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section3\"\u003e\n\u003ch2\u003eMiscarriage rate per pregnancy\u003c/h2\u003e\n\u003cp\u003eThe use of peri-implantation GCs on miscarriage rate per couple showed no statistical significance compared to no GCs (RR 0.75, 95% CI 0.55 to 1.02, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.06, 6 cohort studies, 340 women, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eAfter dividing the studies according to initial treatment time, same result showed in both pre-pregnancy GCs group and post-pregnancy GCs group (GCs before pregnancy: RR 0.58, 95% CI 0.31 to 1.07, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.08, 5 cohort studies, 138 women, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;22%; GCs after pregnancy: RR 0.80, 95% CI 0.56 to 1.13, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.20, 1 cohort study, 202 women; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":" \u003cp\u003eThere is a lack of consensus in the treatment of infertile women with unexplained positive autoantibody. For better understanding the effect of a commonly used drug, GCs, in this population, we conducted this systematic review and meta-analysis, and the major finding of our study is that GCs use has positive effect on improving clinical pregnancy rate and live birth rate in women with unexplained autoantibodies. Clinical pregnancy rate and live birth rate were improved only in ANA positive women without specific autoimmune disorder, but not in those with positive ACL. In addition, the effect on live birth rate is significant when GCs are administered before confirmation of pregnancy rather than after pregnancy.\u003c/p\u003e \u003cp\u003e4 RCTs and 2 cohort studies provided data on clinical pregnancy rate, in which 4 independent studies favored GCs use. Our systematic review and meta-analysis based on current studies confirmed the efficiency of GCs administration in improving clinical pregnancy rate in ANA but not APL positive women, which implies the different pathogenetic roles of diverse autoantibodies in establishing or maintening pregnancy. However, for subgroup with APL, we find data extracted from 2 studies are heterogenous and the sample size is small. Thus, examining whether GCs use can improve clinical pregnancy rate in APL-positive women needs further research.\u003c/p\u003e \u003cp\u003eThe analysis based on 5 studies providing live birth rate shows the same results that GCs use has a positive effect in increasing live birth rate only in ANA positive patients, but not in APL. These results indicate that patients with different autoantibodies may also have different immunologic characteristics and clinical outcomes, thus showed different responses to GCs.\u003c/p\u003e \u003cp\u003eAdditional subgroup analysis was added to help determine the best time to start GCs therapy, and showed that preconception use of GCs improved live birth rate, while post-conception GCs administration did not. A meta-analysis conducted by Dan \u003cem\u003eet al\u003c/em\u003e. showed that women experiencing unexplained recurrent miscarriage benefit significantly from prednisolone treatment after confirmation of pregnancy in terms of an increased live birth rate compared with placebo \u003csup\u003e[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/sup\u003e. However, the population in the studies included in their meta-analysis was different from ours. They used high uterine natural killer cell density (\u0026gt;\u0026thinsp;5%), a test that is not popular in daily practice, as inclusion criteria, and known cause for recurrent miscarriage as exclusion criteria, but no mention of autoantibodies \u003csup\u003e[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/sup\u003e. Therefore, difference in target population of the two studies may underlie the inconsistency in terms of the efficacy of GCs treatment. Furthermore, no effect in post-conception GCs treatment may also indicate risk in fetal exposure to exogenous GCs. A prospective controlled study collected and followed 311 pregnancies with systemic use of GCs in the first trimester. Higher rates of miscarriage (11.5% versus 7.0%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013) and preterm birth (22.7% versus 10.8%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were observed in GCs exposed group compared to the controls \u003csup\u003e[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/sup\u003e. To date, prednisolone maintains a Category D rating with the Food and Drug Administration in the USA, indicating routine administration is not recommended. Therefore, further well-designed studies are needed to determine the best initial time and length of GCs therapy.\u003c/p\u003e \u003cp\u003eMiscarriage rate is not improved by GCs administration in neither 6 studies included nor our systematic review and meta-analysis. Same result is obtained from further subgroup analysis concerning the initiation time of GCs treatment. The miscarriage rate in subgroup \u0026ldquo;GCs administration before pregnancy\u0026rdquo; in our study is 9.4%, which is comparable to 13.5% reported by Anderson \u003cem\u003eet al\u003c/em\u003e. \u003csup\u003e[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]\u003c/sup\u003e. Only 1 study is included in post-conception GCs administration subgroup, and the miscarriage rate is lower than control group without statistical significance. As discussed before, early fetal exposure to exogenous GCs may cause risk in miscarriage. Therefore, identifying the optimal indication for GCs use after confirmation of pregnancy warrant further well-designed study with large sample size.\u003c/p\u003e \u003cp\u003eOur study has several limitations that have to be considered when it comes to interpretation of the data. First, as mentioned before, our meta-analysis included only seven studies due to lack of related studies. However, because the question is so important and sample size is small in each study, and couldn\u0026rsquo;t give clinicians effective guidance, so it is necessary to have meta-analysis and systematic review to help us get more comprehensive information. Although several borderline effects needs to be confirmed by larger sample size, our study still provides preliminary information that is important for further studies. Second, the dosage, type and the therapeutic course of GCs among included trials were of a great discrepancy. Using placebo or not is also inconsistent between studies. Third, the type and dose of adjuvant therapy varies in studies included, and the effect of these therapies, such as oral aspirin, on changing pregnancy outcome are not clear\u003csup\u003e[\u003cspan additionalcitationids=\"CR44\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]\u003c/sup\u003e. The effect of GCs use in women with unexplained positive autoantibody needs further investigations of high quality to confirm. To gain better understanding of this therapy, well-designed prospective, randomized, controlled clinical trials must be proposed.\u003c/p\u003e \u003cp\u003eBased on our finding, the recommendations for future study design are listed below. First, the type of GCs should not be long acting GCs including dexamethasone or betamethasone, for they can pass through placenta and cause adverse effects such as fetal malformation. Second, the dose is not necessarily high, 10\u0026nbsp;mg/d prednisone/prednisolone or less is possibly enough to have positive effect. Third, the therapeutic course covering 1\u0026ndash;3 months before confirmation of pregnancy or controlled ovarian hyperstimulation is recommended, although the effect of post-conception GCs therapy initiation needs further understanding. Adjuvant therapy such as anticoagulants can be added, but should be comparable in both control and GCs groups. Forth, patients should be divided into different subgroups according to their type of autoantibodies.\u003c/p\u003e "},{"header":"Conclusion","content":" \u003cp\u003eour systemic review and meta-analysis report improvement in clinical pregnancy rate and live birth rate of GCs use in women with unexplained positive autoantibody. Further investigation is required to ascertain its efficacy.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Approval and Consent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot needed in meta-analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of supporting data:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work is not funded by any organization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors wish to thank all researchers of the included studies who provided additional data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' information:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNothing to report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTing Li, Yilin Yuan, Rong Mu and Qun Lu conceived and designed the study. Ting Li and Yilin Yuan performed the literature search, data extraction, and assessed the risk of bias and overall quality of evidence. Rong Mu resolved disagreement between Ting Li and Yilin Yuan. Ting Li, Yilin Yuan and Huixin Liu performed and interpreted the data analysis. Ting Li and Yilin Yuan drafted the manuscript. Rong Mu revised the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHaas, D.M., T.J. Hathaway, and P.S. Ramsey, \u003cem\u003eProgestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiology.\u003c/em\u003e Cochrane Database Syst Rev, 2018. \u003cstrong\u003e10\u003c/strong\u003e: p. Cd003511.\u003c/li\u003e\n\u003cli\u003eRamos-Ibeas, P., et al., \u003cem\u003eSenescence and Apoptosis During in vitro Embryo Development in a Bovine Model.\u003c/em\u003e Front Cell Dev Biol, 2020. \u003cstrong\u003e8\u003c/strong\u003e: p. 619902.\u003c/li\u003e\n\u003cli\u003eGraham, M.C., K.M. Hoeger, and W.R. Phipps, \u003cem\u003eInitial IVF-ET experience with assisted hatching performed 3 days after retrieval followed by day 5 embryo transfer.\u003c/em\u003e Fertil Steril, 2000. \u003cstrong\u003e74\u003c/strong\u003e(4): p. 668-71.\u003c/li\u003e\n\u003cli\u003eWang, N.F., et al., \u003cem\u003eImmunologic Abnormalities, Treatments, and Recurrent Pregnancy Loss: What Is Real and What Is Not?\u003c/em\u003e Clinical obstetrics and gynecology, 2016. \u003cstrong\u003e59\u003c/strong\u003e(3): p. 509-523.\u003c/li\u003e\n\u003cli\u003eVander Borght, M. and C. Wyns, \u003cem\u003eFertility and infertility: Definition and epidemiology.\u003c/em\u003e Clin Biochem, 2018. \u003cstrong\u003e62\u003c/strong\u003e: p. 2-10.\u003c/li\u003e\n\u003cli\u003eNorgard, B.M., et al., \u003cem\u003eDecreased chance of a live born child in women with rheumatoid arthritis after assisted reproduction treatment: a nationwide cohort study.\u003c/em\u003e Ann Rheum Dis, 2019. \u003cstrong\u003e78\u003c/strong\u003e(3): p. 328-334.\u003c/li\u003e\n\u003cli\u003eSchreiber, K., et al., \u003cem\u003eAntiphospholipid syndrome.\u003c/em\u003e Nature Reviews Disease Primers, 2018. \u003cstrong\u003e4\u003c/strong\u003e: p. 17103.\u003c/li\u003e\n\u003cli\u003eShetty, S. and K. Ghosh, \u003cem\u003eAnti-phospholipid antibodies and other immunological causes of recurrent foetal loss--a review of literature of various therapeutic protocols.\u003c/em\u003e American journal of reproductive immunology (New York, N.Y. : 1989), 2009. \u003cstrong\u003e62\u003c/strong\u003e(1): p. 9-24.\u003c/li\u003e\n\u003cli\u003eMoher, D., et al., \u003cem\u003ePreferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.\u003c/em\u003e PLoS Med, 2009. \u003cstrong\u003e6\u003c/strong\u003e(7): p. e1000097.\u003c/li\u003e\n\u003cli\u003eGeva, E., et al., \u003cem\u003ePrednisone and aspirin improve pregnancy rate in patients with reproductive failure and autoimmune antibodies: a prospective study.\u003c/em\u003e American journal of reproductive immunology (New York, N.Y. : 1989), 2000. \u003cstrong\u003e43\u003c/strong\u003e(1): p. 36-40.\u003c/li\u003e\n\u003cli\u003eOrdi, J., et al., \u003cem\u003eFetal loss treatment in patients with antiphospholipid antibodies.\u003c/em\u003e Annals of the rheumatic diseases, 1989. \u003cstrong\u003e48\u003c/strong\u003e(10): p. 798-802.\u003c/li\u003e\n\u003cli\u003eVaquero, E., et al., \u003cem\u003ePregnancy outcome in recurrent spontaneous abortion associated with antiphospholipid antibodies: a comparative study of intravenous immunoglobulin versus prednisone plus low-dose aspirin.\u003c/em\u003e American journal of reproductive immunology (New York, N.Y. : 1989), 2001. \u003cstrong\u003e45\u003c/strong\u003e(3): p. 174-179.\u003c/li\u003e\n\u003cli\u003eYe, S.-L., et al., \u003cem\u003eEfficacy of Different Treatment Regimens for Antiphospholipid Syndrome-related Recurrent Spontaneous Abortion.\u003c/em\u003e Chinese medical journal, 2017. \u003cstrong\u003e130\u003c/strong\u003e(12): p. 1395-1399.\u003c/li\u003e\n\u003cli\u003eHasegawa, I., et al., \u003cem\u003eEffectiveness of prednisolone/aspirin therapy for recurrent aborters with antiphospholipid antibody.\u003c/em\u003e Human reproduction (Oxford, England), 1992. \u003cstrong\u003e7\u003c/strong\u003e(2): p. 203-207.\u003c/li\u003e\n\u003cli\u003eHasegawa, I., et al., \u003cem\u003ePrednisolone plus low-dose aspirin improves the implantation rate in women with autoimmune conditions who are undergoing in vitro fertilization.\u003c/em\u003e Fertility and sterility, 1998. \u003cstrong\u003e70\u003c/strong\u003e(6): p. 1044-1048.\u003c/li\u003e\n\u003cli\u003eMoradan, S. and R. Ghorbani, \u003cem\u003eDexamethasone in unexplained infertility.\u003c/em\u003e Saudi medical journal, 2009. \u003cstrong\u003e30\u003c/strong\u003e(8): p. 1034-1036.\u003c/li\u003e\n\u003cli\u003eSiristatidis, C., et al., \u003cem\u003eAddition of prednisolone and heparin in patients with failed IVF/ICSI cycles: a preliminary report of a clinical trial.\u003c/em\u003e Human fertility (Cambridge, England), 2013. \u003cstrong\u003e16\u003c/strong\u003e(3): p. 207-210.\u003c/li\u003e\n\u003cli\u003eOu, H. and Q. Yu, \u003cem\u003e[Effects of combination therapy with aspirin, prednisone, and Elevit in patients with unexplained recurrent early pregnancy loss].\u003c/em\u003e Zhonghua yi xue za zhi, 2017. \u003cstrong\u003e97\u003c/strong\u003e(41): p. 3250-3254.\u003c/li\u003e\n\u003cli\u003eSiristatidis, C., et al., \u003cem\u003eAdministration of prednisolone and low molecular weight heparin in patients with repeated implantation failures: a cohort study.\u003c/em\u003e Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology, 2018. \u003cstrong\u003e34\u003c/strong\u003e(2): p. 136-139.\u003c/li\u003e\n\u003cli\u003eMoffitt, D., et al., \u003cem\u003eLow-dose glucocorticoids after in vitro fertilization and embryo transfer have no significant effect on pregnancy rate.\u003c/em\u003e Fertility and sterility, 1995. \u003cstrong\u003e63\u003c/strong\u003e(3): p. 571-577.\u003c/li\u003e\n\u003cli\u003eUbaldi, F., et al., \u003cem\u003eLow dose prednisolone administration in routine ICSI patients does not improve pregnancy and implantation rates.\u003c/em\u003e Human reproduction (Oxford, England), 2002. \u003cstrong\u003e17\u003c/strong\u003e(6): p. 1544-1547.\u003c/li\u003e\n\u003cli\u003eDuvan, C.I., et al., \u003cem\u003eDoes addition of low-dose aspirin and/or steroid as a standard treatment in nonselected intracytoplasmic sperm injection cycles improve in vitro fertilization success? A randomized, prospective, placebo-controlled study.\u003c/em\u003e Journal of assisted reproduction and genetics, 2006. \u003cstrong\u003e23\u003c/strong\u003e(1): p. 15-21.\u003c/li\u003e\n\u003cli\u003eFawzy, M., et al., \u003cem\u003eTreatment options and pregnancy outcome in women with idiopathic recurrent miscarriage: a randomized placebo-controlled study.\u003c/em\u003e Archives of gynecology and obstetrics, 2008. \u003cstrong\u003e278\u003c/strong\u003e(1): p. 33-38.\u003c/li\u003e\n\u003cli\u003eKilic, S., et al., \u003cem\u003eThe effect of anti-thyroid antibodies on endometrial volume, embryo grade and IVF outcome.\u003c/em\u003e Gynecol Endocrinol, 2008. \u003cstrong\u003e24\u003c/strong\u003e(11): p. 649-55.\u003c/li\u003e\n\u003cli\u003eRevelli, A., et al., \u003cem\u003eLow-dose acetylsalicylic acid plus prednisolone as an adjuvant treatment in IVF: a prospective, randomized study.\u003c/em\u003e Fertil Steril, 2008. \u003cstrong\u003e90\u003c/strong\u003e(5): p. 1685-91.\u003c/li\u003e\n\u003cli\u003eTang, A.-W., et al., \u003cem\u003eA feasibility trial of screening women with idiopathic recurrent miscarriage for high uterine natural killer cell density and randomizing to prednisolone or placebo when pregnant.\u003c/em\u003e Human reproduction (Oxford, England), 2013. \u003cstrong\u003e28\u003c/strong\u003e(7): p. 1743-1752.\u003c/li\u003e\n\u003cli\u003eFawzy, M. and A.-A.A. El-Refaeey, \u003cem\u003eDoes combined prednisolone and low molecular weight heparin have a role in unexplained implantation failure?\u003c/em\u003e Archives of gynecology and obstetrics, 2014. \u003cstrong\u003e289\u003c/strong\u003e(3): p. 677-680.\u003c/li\u003e\n\u003cli\u003eGomaa, M.F., et al., \u003cem\u003eCombined oral prednisolone and heparin versus heparin: the effect on peripheral NK cells and clinical outcome in patients with unexplained recurrent miscarriage. A double-blind placebo randomized controlled trial.\u003c/em\u003e Archives of gynecology and obstetrics, 2014. \u003cstrong\u003e290\u003c/strong\u003e(4): p. 757-762.\u003c/li\u003e\n\u003cli\u003eLitwicka, K., et al., \u003cem\u003eIn women with thyroid autoimmunity, does low-dose prednisolone administration, compared with no adjuvant therapy, improve in vitro fertilization clinical results?\u003c/em\u003e The journal of obstetrics and gynaecology research, 2015. \u003cstrong\u003e41\u003c/strong\u003e(5): p. 722-728.\u003c/li\u003e\n\u003cli\u003eStern, C., et al., \u003cem\u003eA randomized, double-blind, placebo-controlled trial of heparin and aspirin for women with in vitro fertilization implantation failure and antiphospholipid or antinuclear antibodies.\u003c/em\u003e Fertility and Sterility, 2003. \u003cstrong\u003e80\u003c/strong\u003e(2): p. 376-383.\u003c/li\u003e\n\u003cli\u003eAndo, T., et al., \u003cem\u003eSuccessful glucocorticoid treatment for patients with abnormal autoimmunity on in vitro fertilization and embryo transfer.\u003c/em\u003e J Assist Reprod Genet, 1996. \u003cstrong\u003e13\u003c/strong\u003e(10): p. 776-81.\u003c/li\u003e\n\u003cli\u003eGeva, E., et al., \u003cem\u003ePrevention of early pregnancy loss in autoantibody seropositive women.\u003c/em\u003e Lancet (London, England), 1998. \u003cstrong\u003e351\u003c/strong\u003e(9095): p. 34-35.\u003c/li\u003e\n\u003cli\u003eLaskin, C.A., et al., \u003cem\u003ePrednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss.\u003c/em\u003e The New England journal of medicine, 1997. \u003cstrong\u003e337\u003c/strong\u003e(3): p. 148-153.\u003c/li\u003e\n\u003cli\u003eZhu, Q., et al., \u003cem\u003eA retrospective study on IVF/ICSI outcome in patients with anti-nuclear antibodies: the effects of prednisone plus low-dose aspirin adjuvant treatment.\u003c/em\u003e Reproductive biology and endocrinology : RB\u0026amp;E, 2013. \u003cstrong\u003e11\u003c/strong\u003e: p. 98.\u003c/li\u003e\n\u003cli\u003eFan, J., Y. Zhong, and C. Chen, \u003cem\u003eCombined treatment of prednisone and aspirin, starting before ovulation induction, may improve reproductive outcomes in ANA-positive patients.\u003c/em\u003e American journal of reproductive immunology (New York, N.Y. : 1989), 2016. \u003cstrong\u003e76\u003c/strong\u003e(5): p. 391-395.\u003c/li\u003e\n\u003cli\u003eYing, Y., et al., \u003cem\u003eA retrospective study on IVF outcome in patients with anticardiolipin antibody: effects of methylprednisolone plus low-dose aspirin adjuvant treatment.\u003c/em\u003e Journal of reproductive immunology, 2012. \u003cstrong\u003e94\u003c/strong\u003e(2): p. 196-201.\u003c/li\u003e\n\u003cli\u003eTuri, A., et al., \u003cem\u003ePreconception steroid treatment in infertile women with antithyroid autoimmunity undergoing ovarian stimulation and intrauterine insemination: a double-blind, randomized, prospective cohort study.\u003c/em\u003e Clin Ther, 2010. \u003cstrong\u003e32\u003c/strong\u003e(14): p. 2415-21.\u003c/li\u003e\n\u003cli\u003eDan, S., et al., \u003cem\u003eEffect of Prednisolone Administration on Patients with Unexplained Recurrent Miscarriage and in Routine Intracytoplasmic Sperm Injection: A Meta-Analysis.\u003c/em\u003e American journal of reproductive immunology (New York, N.Y. : 1989), 2015. \u003cstrong\u003e74\u003c/strong\u003e(1): p. 89-97.\u003c/li\u003e\n\u003cli\u003eTang, A.W., et al., \u003cem\u003ePrednisolone Trial: Study protocol for a randomised controlled trial of prednisolone for women with idiopathic recurrent miscarriage and raised levels of uterine natural killer (uNK) cells in the endometrium.\u003c/em\u003e Trials,10,1(2009-11-10), 2009. \u003cstrong\u003e10\u003c/strong\u003e(1): p. 102-102.\u003c/li\u003e\n\u003cli\u003eAi-Wei, T., et al., \u003cem\u003eA feasibility trial of screening women with idiopathic recurrent miscarriage for high uterine natural killer cell density and randomizing to prednisolone or placebo when pregnant.\u003c/em\u003e Human Reproduction, 2013. \u003cstrong\u003e28\u003c/strong\u003e(7): p. 1743-1752.\u003c/li\u003e\n\u003cli\u003eGur, C., et al., \u003cem\u003ePregnancy outcome after first trimester exposure to corticosteroids: a prospective controlled study.\u003c/em\u003e Reproductive Toxicology, 2004. \u003cstrong\u003e18\u003c/strong\u003e(1): p. 93-101.\u003c/li\u003e\n\u003cli\u003eAndersen, A.-M.N., et al., \u003cem\u003eMaternal age and fetal loss: population based register linkage study.\u003c/em\u003e BMJ : British Medical Journal, 2000. \u003cstrong\u003e320\u003c/strong\u003e(7251): p. 1708-1712.\u003c/li\u003e\n\u003cli\u003eRai, R., et al., \u003cem\u003eRandomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies).\u003c/em\u003e Bmj British Medical Journal, 1997. \u003cstrong\u003e314\u003c/strong\u003e(7076): p. 253-257.\u003c/li\u003e\n\u003cli\u003eDendrinos, S., E. Sakkas, and E. Makrakis, \u003cem\u003eLow-molecular-weight heparin versus intravenous immunoglobulin for recurrent abortion associated with antiphospholipid antibody syndrome.\u003c/em\u003e International Journal of Gynecology \u0026amp; Obstetrics, 2009. \u003cstrong\u003e104\u003c/strong\u003e(3): p. 223-225.\u003c/li\u003e\n\u003cli\u003eSchisterman, E.F., et al., \u003cem\u003ePreconception low-dose aspirin and pregnancy outcomes: results from the EAGeR randomised trial.\u003c/em\u003e Lancet, 2014. \u003cstrong\u003e384\u003c/strong\u003e(9937): p. 29-36.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 2 is not available with this version.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"GCs, unexplained positive autoantibody, pregnancy outcome, meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-147807/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-147807/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: The effect of glucocorticoids\u003cstrong\u003e \u003c/strong\u003e(GCs) therapy for women with unexplained positive autoantibody is under debate. This systematic review and meta-analysis was performed to evaluate whether GCs administration can improve the pregnancy outcome of this population.\u003c/p\u003e\u003cp\u003eMethods: A meta-analysis based on a systematic review of PubMed, Embase, EBSCO, and the Cochrane Central Register of Controlled Trials, until January 2021, was used to evaluate pregnancy outcome of GCs treatment for women with unexplained recurrent fetal loss or infertility whose autoantibody positive, but does not meet any classification criteria for autoimmune diseases.\u003c/p\u003e\u003cp\u003eResults: We found GCs treatment improved clinical pregnancy rate (RR 2.19, 95% CI 1.64 to 2.92) and live birth rate (RR 1.92, 95% CI 1.17 to 3.16), especially when started GCs administration before pregnancy (clinical pregnancy rate: RR 2.30, 95% CI 1.58 to 3.34; live birth rate: RR 2.30, 95% CI 1.58 to 3.34). However, no effect of GCs on miscarriage rate was found (RR 0.75, 95% CI 0.55 to 1.02) regardless of time of drug administration.\u003c/p\u003e\u003cp\u003eConclusions: Our systematic review and meta-analysis surports the rational use of GCs in women with unexplained positive autoantibody.\u003c/p\u003e","manuscriptTitle":"Glucocorticoids Improves Pregnancy Rate and Outcome in Woman With Unexplained Positive Autoantibody: a Systematic Review and Meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-01-19 16:46:04","doi":"10.21203/rs.3.rs-147807/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a53205d4-1473-4435-8989-46ca1978c019","owner":[],"postedDate":"January 19th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":1962829,"name":"Rheumatology"}],"tags":[],"updatedAt":"2021-03-12T17:30:17+00:00","versionOfRecord":[],"versionCreatedAt":"2021-01-19 16:46:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-147807","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-147807","identity":"rs-147807","version":["v1"]},"buildId":"369fNeqWncA4NS6XSWjrt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}