The autoimmune bases of infertility and repeated implantation … YANG.pdf · At the meantime, with...
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The autoimmune bases of infertility and repeated
implantation failure after IVF/ICSI-ET
Dongzi Yang, M.D., Ph.D. Professor, Chief Physician
Medical center of Human Reproduction, Dept. Ob/Gyn
Memorial Hospital, Sun Yat-Sen University,
Guangzhou, China
The maternal immune system at the time of implantation is characterized by significant immunological changes which play a critical role in successful implantation.
There is a growing interest in using immune-modulating treatments in women with RIF and RPL to correct potential immune imbalances. However, the nature of immune alterations in RIF and RPL remains ill-defined with limited evidence for suitable immune biomarkers to identify patients that may be suited for such immune-modulating treatment.
At the meantime, with few exceptions such as SLE or APS, the impact of autoimmune diseases on reproductive health variables is largely overlooked in clinical practice and in research. the contribution of autoimmunity to impaired fertility remains controversial..
The autoimmune disorders and infertility and RIF
Howard JA Carp, Carlo Selmi, Yehuda Shoenfeld: J Autoimmunity, 2012, 38:J266-J274 Chelsea Fox, Scott Morin, et al: Fertil Steril, 2016, 105(4):873-884
Xian Chen, Yong Zeng, et al: J Reproductive Immunology 2017, 122:14-20 Syed B Ali, Yogesh Jeelall, Graig E Pennell, et al: Am J Ewprod Immunol, 2017, e12784
The key pathophysiological features of Systemic lupus erythematosus (SLE) are the generation of autoantibodies and the deposition of antibody-
antigen complexes in the basal membranes of the organs where they evoke inflammatory responses and injury.
Anti-phospholipid antibodies (aPL) are the serological markers of the anti-phospholipid syndrome (APS), a systemic autoimmune condition characterized by vascular thrombosis and/or pregnancy morbidity.
SLE/APS has been well realized and there has been the guideline for management of SLE/APS patients during their peri-pregnancy.
SLE and APS
Andreoli L, et al. Ann Rheum Dis 2016;0:1–10.
C.B. Chighizola et al. : Autoimmunity Reviews 15 (2016) 493–500
The autoimmune disorders and ART
ARTs are generally safe for SLE/APS patients if the patient has quiescent disease
In women with APS (primary or SLE-APS), risk factors include high-risk aPL profile (lupus anticoagulant, multiple aPL, moderate to high titre aPL) (1/A), coexisting SLE (2/B), history of vascular/thrombotic APS (2/B) and of previous adverse pregnancy complications (2/B).
Appropriate antithrombotic treatment if aPL positive, some general measures for prophylaxis such as the type(low-dose aspirin (LDA); low molecular weight heparin(LMWH)) and dosage (prophylactic vs full anticoagulant) of antithrombotic treatment in aPL-positive women undergoing ovarian stimulation has been suggested.
Andreoli L, et al. Ann Rheum Dis 2016;0:1–10.
Howard JA Carp, Carlo Selmi, Yehuda Shoenfeld: J Autoimmunity, 2012, 38:J266-J274
Chelsea Fox, Scott Morin, et al: Fertil Steril, 2016, 105(4):873-884
Xian Chen, Yong Zeng, et al: J Reproductive Immunology 2017, 122:14-20
Numerous autoimmune diseases, including but not limited to SLE and APS, may be associated with infertility and pregnancy loss
The process involve microvascular pathology, prethrombotic state, inflammation and immune reaction in endometrium, villus and deciduas.
The normal condition
Positive auto
antibodies
Symptom and sign of connective
tissue disease
Undifferent-iated
connective tissue
disease(UCTD)
Connective tissue
disease (SLE,APS)
The progression of autoimmune diseases
Outline
The role of auto antibody mediated
autoimmune disorders in infertility and RIF.
Immune modulation treatments in ART and RIF
Outline
The role of auto antibody mediated
autoimmune disorders in infertility and RIF.
Immune modulation treatments in RIF
Autoimmune diseases may be associated with infertility and pregnancy loss through different putative mechanisms.
First, serum autoantibodies such as anti-phospholipid(aPL), anti-thyroid, or antinuclear antibodies(ANA) may be directly associated with infertility, regardless of the presence of a clinically overt autoimmune disease.
Second, autoimmunity may affect all stages of fertility, via ovarian failure, testicular failure, implantation failure, and pregnancy loss.
Third, infertility may also be secondary to vasculitis associated
with other conditions such as SLE and diabetes mellitus
The autoimmune disorders and infertility and RIF
Howard J.A. Carp , Carlo Selmi , Yehuda Shoenfeld: Journal of Autoimmunity 38 (2012) J266eJ274
Khaled M. Zohni, Itai GAT, Clifford Librach, Minerva Ginecologica, 2016,Decem. 68(6):653-67
Auto-immune disease is one of the factors of RIF
Evidence-base investigations for patients with RIF
Immunological Screening Proposal
Mekinian A, et al. Am J Reprod Immunol. 2016;76(1):8-28.
There are few studies demonstrating a physiopathological implication of these detectable autoantibodies, but their presence could help the physician to discuss the need for immunomodulatory strategy.
Pregnancy test results
Viable pregnancy
Case control studies on APS and ART outcome
Di Nisio M, et al. Blood. 2011;118(10):2670-2678.
The relationship between ART failure and thrombophilia remains largely inconclusive. But all the studies were with small number of patients.
Live birth
Di Nisio M, et al. Blood. 2011;118(10):2670-2678.
Case control studies on APS and ART outcome
Chighizola CB, et al. Autoimmun Rev. 2016;15(6):493-500.
Meta analysis of APS and ART outcome
Chighizola CB, et al. Autoimmun Rev. 2016;15(6):493-500.
Anti-phospholipid syndrome and ART outcome
Conclusions:
No association between anti-phospholipid antibodies (aPL)
positivity and ART outcome in the majority of studies.
aPL should not be included in the investigation of women
undergoing ART.
Inclusion of healthy controls and spontaneous pregnancy could have led to a biased comparison.
APA positivity can occur as a transient epiphenomenon during ovarian stimulation for ART(false positive).
The lack of confirmation of persistence of APAs can be regarded a serious limitation of all these studies, leading to overestimation of an effect of APAs on ART outcome.
Possible explanations
Ata B, et al. J Assist Reprod Genet. 2016;33(10):1305-1310.
Anti-phospholipid syndrome and ART outcome
APA testing should be standardized, with regard to both APAs to be tested and cut-off levels for positivity.
Study populations should be standardized, e.g., women undergoing
ART versus women with recurrent implantation failure. APA positivity should be confirmed on two separate occasions as
suggested in the Sapporo criteria. APA testing should be required 6~12 weeks before ovarian
stimulation.
Future studies
Ata B, et al. J Assist Reprod Genet. 2016;33(10):1305-1310.
Anti-phospholipid syndrome and ART outcome
Signs and symptoms suggestive of a rheumatic disorder, but that do not fulfill the established criteria for a rheumatic disease;
The presence of antinuclear antibodies (ANA) at a titer ≥1:80
The definition
● Undifferentiated connective tissue diseases (UCTD) are probably relatively common among women of reproductive age and can be frequently encountered by obstetricians both before and during pregnancy.
Spinillo A, et al. Am J Reprod Immunol. 2017 Dec;78(6).
Undifferentiated connective tissue disease (UCTD)
Spinillo A, et al. Am J Reprod Immunol. 2017 Dec;78(6).
Biological mechanisms causing poor reproductive outcome in UCTD
the auto-antibodies increase thrombosis of placental vessels, defective placentation, defective trophoblast invasion.
The term defines any condition associated with an increased risk of thrombosis.
Microvascular occlusion at the decidua due to thrombophilia has
been suggested as a potential cause of implantation failure in ART cycles.
The changes in ovarian stimulation for ART increase the risk for
thrombosis and thromboembolism. Damage of decidual or chorionic vessels, or reduction of trophoblast
invasiveness, could prevent embryo implantation.
Ata B, et al. J Assist Reprod Genet. 2016;33(10):1305-1310.
Thrombophilia
Zohni KM. Minerva Ginecol. 2016;68(6):653-667.
Thrombophilia and RIF
The association between trombophilia and RIF were uncertain
Most were case-control studies.
The overall methodologic quality was poor.
Only a few of the case-control studies used a representative control.
Bates SM. Hematology Am Soc Hematol Educ Program. 2014;2014(1):379-386.
The research of Thrombophilia and RIF
A prospective cohort analysis of the association between Individual and cumulative thrombophilic single nucleotide polymorphisms and IVF outcome .
1717 patients, 4169 embryos, the first fresh cycle of IVF
Patounakis G, et al. J Assist Reprod Genet. 2016;33(1):67-73.
Thrombophilic genotypes and IVF outcome
● Individual and cumulative thrombophilic single nucleotide polymorphisms do not affect IVF outcomes.
The relationship of congenital thrombophilia with ART outcome is dubious.
Testing for and treatment of congenital thrombophilia are not indicated in patients undergoing ART in the absence of a personal or family history of venous thromboembolism.
Current evidence does not support routinely testing or treatment for thrombophilia in the setting of ART nor in couples with implantation failure.
Ata B, et al. J Assist Reprod Genet. 2016;33(10):1305-1310.
Thrombophilia and ART outcome
A prospective cohort study, first IVF/ICSI treatment
Chen X, et al. J Reprod Immunol. 2017;122:14-20.
A prospective cohort study of auto-antibodies
The presence of aCL-IgG, aCL-IgM and aβ2GPI-IgG might exert a
detrimental effect on IVF/ICSI outcomes.
Chen X, et al. J Reprod Immunol. 2017;122:14-20.
A prospective cohort study of autoantibodies
Percentage of abnormally elevated antiphospholipid antibody serum concentrations including anticardiolipin antibodies (CL,ACA),antiphospatidylethanolamine (PE), antiphosphatidylinositol, antiphosphatidic acid (PA), antiphosphatidylglycerol (PG), antiphopatidylcholine(PC), and antiphosphatidylserine (PS) among groups.
A =IgG, B =IgM, and C =IgA
Sauer. Correspondence. Fertil Steril 2010.
676
789
1,325
205
Age (years) 36.46±4.64
BMI (kg/m2) 21.91±2.95
FSH (IU/L) 9.68±5.13
LH (IU/L) 4.68±3.54
AMH (μg/L) 3.02±3.65
Duration of infertility (years) 6.81±3.91
Total cycles 4.61±2.22
Unpublished data from Sun Yat-Sen Memorial Hospital,Sun Yat-Sen University, 2015-2018
Baseline condition of 337 RIF patients in our center
Recurrent implantation failure refers to failure to achieve a clinical pregnancy after transfer of at least four good-quality embryos in a minimum of three fresh or frozen cycles in a woman under the age of 40 years . C Coughlan, et al: Reproductive BioMedicine Online (2014) 28, 14– 38
74.06%
61.07%
25.86%
25.29%
18.48%
12.43%
11.72%
11.11%
8.13%
7.81%
6.59%
6.38%
6.31%
5.56%
2.20%
0.00% 10.00% 20.00% 30.00% 40.00% 50.00% 60.00% 70.00% 80.00%
Natural killer cell↑
Platelet aggregation function↑
Anti-thyroglobulin antibody↑
Anti-thyroid peroxidase antibody↑
Antinuclear antibody(+)
Anti-β2-glycoprotein1 antibody(+)
D-Dimer↑
Protein C↓
Antithrombin III activity↓
Protein S↓
Anti-dsDNA antibody(+)
Anti-a-Fodrin A antibody(+)
Anticardiolipin IgG antibody(+)
Anti-C1q antibody (+)
Anti-nucleosome antibody(+)
Abnormity rate
Immunological and coagulation function of 337 patients with RIF from 2015-2018
Unpublished data from Sun Yat-Sen Memorial Hospital,Sun Yat-Sen University, 2015-2018
For those RIF patients with positive auto-antibodies without typical symptoms and signs of autoimmune diseases, the immune modulating treatment remains uncertainty and controversy.
The normal condition
Positive auto
antibodies
Symptom and sign of connective
tissue disease
Undifferent-iated
connective tissue
disease(UCTD)
Connective tissue
disease (SLE,APS)
The progression of autoimmune diseases
Outline
The role of auto antibody mediated
autoimmune disorders in infertility and RIF.
Immune modulation treatments in ART and RIF
Antirheumatic drugs
Intravenous immunoglobulin (IVIg)
Corticosteroids
Low dose of Aspirin (LDA)
Low molecular weight heparin(LMWH)
Immune modulation treatments
EULAR (european league against rhumatism) recommendations for SLE/APS
Andreoli L, et al. Ann Rheum Dis. 2017;76(3):476-485.
EULAR recommendations for ART in SLE/APS patients
Pregnancy rate is comparable with that in the general population (up to 30%).
Assisted reproduction techniques are generally safe if the patient
has quiescent disease and is on appropriate antithrombotic treatment if antiphospholipid antibodies positive.
The type (low-dose aspirin (LDA); low molecular weight heparin (LMWH) and dosage (prophylactic vs full anticoagulant) of antithrombotic treatment should be recommended as during pregnancy according to the individual risk profile.
Assisted reproduction techniques
Andreoli L, et al. Ann Rheum Dis. 2017;76(3):476-485.
EULAR recommendations for antithrombotic treatment during ART in SLE/APS patients
LDA should be stopped three days before egg retrieval and resumed the following day.
Patients taking LMWH should stop it at least 12 hours prior to the procedure and resume it the very same day as long as there is no bleeding.
Patients with positive antiphospholipid antibodies who are not taking LDA during the ovarian stimulation period should start LDA on the day of the embryo transfer, usually in combination with LMWH (which will be continued during pregnancy).
The antithrombotic treatment
Andreoli L, et al. Ann Rheum Dis. 2017;76(3):476-485.
ART outcome in SLE/APS patients
18 cases,8 of them got live birth after ART. One of them tried 4 cycles of IVF-ET . All took antirheumatic drugs, LDA and LMWH during ART.
age obstetrical history
AMH(ng/ml)
Immune antibody
diagnosis COH Protoc
ol
No. egg
No.Availble
embryos
ET pregnancy
outcome
others
30 G0P0 补体C3 1180mg/L 补体C4 165mg/L ESR 50↑mm/h
ANA 1.51 抗dsDNA 0.845
Infertility, SLE, PCOS, MS Long protocol INF
10 7 2 No pregnancy
SLE flair
32 G0P0 2.12 未查及检查报告 Infertility, SLE, EM Long protocol IVF
14 12 2
Live birth single
32 G2A2,自然流产2次
1.52 ANA+阳性斑点型 抗dsDNA 弱阳性 炎症TNFa 9.44↑
Infertility, SLE, RSA, IR 双侧输卵管炎
OI IVF 4 3 取消鲜胚移植宫腔因素 (内膜薄)
2015-11 NC+FET2个
Live birth twin
33 G0P0 3.82 ANA++阳性斑点型 抗dsDNA 弱阳性 ESR 40mm/h炎症
ANA 3.328 ↑ 抗dsDNA 3.159↑
Infertility, SLE Antagonist protocol IVF
12 取消移植宫腔因素 (内膜薄)
2016-3 NC+FET 2个
Clinical pregnancy
Spontaneous
abortion
35 G0P0 1.04 补体C3 669mg/L 补体C4 72↓mg/L
ESR 20mm/h ANA 3.572↑
抗dsDNA 2.007↑
Infertility, SLE 盆腔粘连(松解术后)
双侧输卵管阻塞 多发性子宫内膜息肉(电切术
后) 不完全子宫中隔(电切术后)
CIN III(锥切术后)
子宫腺肌症
Antagonist protocol IVF
4 取消移植珍贵胚胎 2016-3 促排周期
FET3个
Clinical pregnancy
Spontaneous
abortion
SLE flair
32 G1A1,自然流产1次
0.57 未查及检查报告 Infertility, POI SLE
Mild stimulation IVF+ICSI
5 2 2 Biochemical
pregnancy
37 Infertility, POI SLE
Mild stimulation ICSI
2 2 2 Live birth single
24 G3A1E2,人流1次,异位妊娠2
次
3.5 补体C3 626↓mg/L 补体C4 57↓mg/L
ESR 15mm/h ANA 4.52↑
抗dsDNA 2.23↑
双侧输卵管缺如(切除术后) 宫颈轻度鳞状上皮不典型增生
SLE
Long protocol IVF
14 12 2 Live birth single
ART outcome of SLE/APS patients in our clinic
Averag age of 32 year,clinical pregnancy rate 75%, live birth rate 50%,SLE flare in 2 cases during ART
Unpublished data from Sun Yat-Sen Memorial Hospital,Sun Yat-Sen University, 2015-2018
The challenges of the diagnosis and interventions of undifferentiated autoimmune disorders
For those atypical autoimmune disorders with infertility, their diagnosis is still not well defined and the evidence for the management is weak
The normal condition
Positive auto
antibodies
Symptom and sign of connective
tissue disease
Undifferent-iated
connective tissue
disease(UCTD)
Connective tissue
disease (SLE,APS)
Khaled M. Zohni, Itai GAT, Clifford Librach, Minerva Ginecologica, 2016,Decem. 68(6):653-67
Identifying the patients for proper interventions
Interventions for RIF and their benefit
Zohni KM. Minerva Ginecol. 2016;68(6):653-667.
Immune modulation treatments
indications
Treatment of UCTD with infertility
Spinillo A, et al. Am J Reprod Immunol. 2017 Dec;78(6).
All types of studies investigating the effects of IVIG
alone or in conjunction with heparin or aspirin on IVF
or ICSI outcomes were included. The use of IVIG was
in the random effects model in comparison with placebo
or no treatment.
Li J, et al. Am J Reprod Immunol. 2013;70(6):434-447.
IVIg in RIF and ART outcome
Am J Reprod Immunol 2013; 70: 434–447
IVIg in RIF and ART outcome Implantation rate
Live birth rate
Clinical pregnancy rate
Miscarriage rate
IVIg in RIF and ART outcome
Am J Reprod Immunol 2013; 70: 434–447
IVIG is a useful treatment option for women undergoing repeated IVF failure.
Li J, et al. Am J Reprod Immunol. 2013;70(6):434-447.
IVIg in RIF and ART outcome
Am J Reprod Immunol 2013; 70: 434–447
The use of IVIG was associated with a significantly higher implantation rate, and the RR was 2.708 (95%CI: 1.302–5.629, I2 = 65.0%) in the random effects model in comparison with placebo or no treatment.
The use of IVIG was associated with a significantly higher pregnancy rate, and the RR was 1.475 (95%CI: 1.191–1.825, I2 = 65.7%) in the random effects model.
The use of IVIG was effective in increasing the rate of live birth compared with placebo or no treatment, and the pooled RR was 1.616 (95%CI: 1.243–2.101, I2 = 58.2%) in the random effects model.
The use of IVIG was effective in decreasing the rate of miscarriage compared with placebo or no treatment
Nardo LG, et al. Hum Fertil (Camb). 2015;18(1):2-15.
Guidance and recommendations
Increased number of peripheral natural killer cells or cytotoxicity Abnormal T helper (Th)1:Th2 ratio Positive anti-thyroid antibody or anti-phospholipid antibody (APL)
test Increased TNF-α level or human leukocyte antigen (HLA) antigens
similarity
Indications for Intravenous immunoglobulin(IVIG)
Nardo LG, et al. Hum Fertil (Camb). 2015;18(1):2-15.
Guidance and recommendations
Nardo LG, et al. Hum Fertil (Camb). 2015;18(1):2-15.
Elevated NK cells Presence of auto-antibodies including ACA, anti-thyroid, ANA and
anti-ovarian antibodies
There is a lack of robust evidence to support the routine use of corticosteroids empirically as an adjuvant in IVF cycles.
There is limited evidence that corticosteroids may improve pregnancy rates in women undergoing conventional IVF and in the subgroup of women with auto-immunity or unexplained implantation failure.
Corticosteroids
Recommendation
Nardo LG, et al. Hum Fertil (Camb). 2015;18(1):2-15.
Guidance and recommendations
Various studies and seven meta-analyses have provided conflicting evidence.
There is lack of proven efficacy for routine use of aspirin as an adjuvant in IVF cycles.
Aspirin
Recommendation
Nardo LG, et al. Hum Fertil (Camb). 2015;18(1):2-15.
Guidance and recommendations
Three meta-analyses evaluating the efficacy of heparin in women undergoing IVF treatment cycles, albeit having a different objective, gave similar results.
Evidence for the efficacy of LMWH is weak such that its routine use in the wide population of women undergoing IVF treatment is not warranted. However, it should be carefully considered in women with thrombophilia.
Heparin
Recommendation
Nardo LG, et al. Hum Fertil (Camb). 2015;18(1):2-15.
Guidance and recommendations
Sung N, et al. Clin Exp Reprod Med. 2017;44(1):1-7.
Guidelines for IVIG from Korean
Clin Exp Reprod Med 2017;44(1):1-7
Sung N, et al. Clin Exp Reprod Med. 2017;44(1):1-7.
Guidelines of IVIG
Clin Exp Reprod Med 2017;44(1):1-7
400 mg/kg per each treatment Every 3 to 4 weeks from the early stage of pregnancy in
women with RPL or from the beginning of the IVF cycle for RIF patients (evidence level C).
● The end-point of IVIG treatment and the need for further laboratory tests can be determined by the clinician’s decision, depending on the patient’s state.
Sung N, et al. Clin Exp Reprod Med. 2017;44(1):1-7.
Clin Exp Reprod Med 2017;44(1):1-7
The recommended protocol for IVIG
Prior to IVIG infusion in all patients, the blood level of immunoglobulin A must be determined and renal function tests are required.
Mild side effects: fever, malaise, myalgia, and headache. Severe side effects: myocardial infarction, renal failure,
alopecia, aseptic meningitis, and renal necrosis. With the proper regimen of IVIG in well-selected patients, the
occurrence of side effects is very rare. There is no report of significant side effects in neonates.
Sung N, et al. Clin Exp Reprod Med. 2017;44(1):1-7.
The safety of IVIG therapy
Clin Exp Reprod Med 2017;44(1):1-7
Boomsma CM, et al. Cochrane Database Syst Rev. 2012;(6):CD005996.
Cochrane Database of Systematic Reviews Corticosteroids
Cochrane Database of Systematic Reviews 2017, Issue 3. Art. No.: CD004752. DOI: 10.1002/14651858.CD004752.pub2
Kalampokas T, et al. Cochrane Database Syst Rev. 2017;3:CD004752.
There is insufficient evidence to determine the effectiveness of glucocorticoid administration in women undergoing IVF/ICSIcycle.
Corticosteroids
Cochrane Database of Systematic Reviews 2017, Issue 3. Art. No.: CD004752. DOI: 10.1002/14651858.CD004752.pub2
Robertson SA, et al. Hum Reprod. 2016;31(10):2164-2173.
Human Reproduction, Vol.31, No.10 pp. 2164–2173, 2016
Corticosteroids
Population: 2653 women with subfertility Intervention: Low-dose aspirin Comparison: Placebo or no treatment. An identical dose of the intervention was administered in most of the
studies and most reported a similar timing of the initiation of aspirin intake.
The duration of trial varied across the studies, but was sufficient to
provide data on the reported outcomes.
Siristatidis CS, et al. Cochrane Database Syst Rev. 2016;11:CD004832.
Key results: There was no evidence of a difference between
the groups in rates of live birth, clinical pregnancy, ectopic
pregnancy, multiple pregnancy, miscarriage or vaginal bleeding.
Conclusion: There is no evidence to support the use of LDA
treatment in order to improve pregnancy rates for a general
IVF population.
Low Dose Aspirin (LDA)
Cochrane Database of Systematic Reviews 2016, Issue 11. Art.
No.: CD004832.DOI: 10.1002/14651858.CD004832.pub4.
Hviid MM, et al. Fertil Steril. 2017;107(6):1284-1293.
differ significantly in design, participants, intervention, and outcome measures
Hviid MM, et al. Fertil Steril. 2017;107(6):1284-1293.
Overview of RCT’s testing Aspirin intervention
Treatment with low-dose aspirin does not improve pregnancy
outcome in terms of implantation, clinical pregnancy, ongoing
pregnancy, or live-birth rates in an unselected population of
women undergoing IVF or ICSI.
The available studies differ significantly in design, participants,
intervention, and outcome measures, making the conclusions
drawn from these studies hard to interpret.
Hviid MM, et al. Fertil Steril. 2017;107(6):1284-1293.
Low Dose Aspirin (LDA)
Potdar N, et al. Hum Reprod Update. 2013;19(6):674-684.
A significant improvement in the LBR and a reduction in the miscarriage rate in RIF patients with LMWH compared with controls.
Low molecular weight heparin(LMWH)
Conclusion: In women with ≥3 RIF, the use of adjunct LMWH significantly improves LBR by 79% compared with the control group.
This is to be considered with caution, since the overall number of
participants in the studies was small. Further evidence from adequately powered multi-centered RCTs is
required prior to recommending LMWH for routine clinical use.
Potdar N, et al. Hum Reprod Update. 2013;19(6):674-684.
Low molecular weight heparin(LMWH)
Hviid MM, et al. Fertil Steril. 2017;107(6):1284-1293.
Low molecular weight heparin(LMWH)
The evidence supporting the value of heparin as a putative
effective immuno modulating treatment in IVF is weak.
There may be some support for its use in a younger group of
women with three or more failed attempts and at least one
thrombophilia disorder, but further high-quality trials are required
before this can be advocated.
Hviid MM, et al. Fertil Steril. 2017;107(6):1284-1293.
Low molecular weight heparin(LMWH)
A six-center two-arm retrospective cohort study, but still small sample size.
The addition of LMWH at the day of ET until the β-HCG test
Siristatidis C, et al. Gynecol Endocrinol. 2018 Feb 21:1-5.
Different voice about LMWH
There is no evidence to
support the standard
addition of LMWH in
patients with two or more
unsuccessful IVF/ICSI
cycles.
Siristatidis C, et al. Gynecol Endocrinol. 2018 Feb 21:1-5.
Given the lack of evidence to support improved IVF outcomes,
there is good evidence to recommend against the routine use of low-dose aspirin to improve the outcome of live birth in ART cycles in the general population.(Grade A). There is good evidence to recommend against the routine use of corticosteroids during stimulation to improve the outcome of live birth in ART cycles in the general population.(Grade A). There is good evidence to recommend against the routine use of corticosteroids during the implantation window to improve the outcome of live birth in ART cycles in the general population.(Grade A). There is insufficient evidence to recommend for or against local G-CSF to improve endometrial thickness in women with thin endometrium or clinical pregnancy rates with IVF (Grade C). There is insufficient evidence to recommend for or against G-CSF or GM-CSF administered locally or systemically to improve IVF outcomes. (Grade C). There is insufficient evidence to routinely recommend intravenous fat emulsions for infertile women pursuing IVF. (Grade C). There is insufficient evidence to recommend IVIG administration as part of IVF to improve IVF outcomes. (Grade C).
Practice Committee of the American Society for Reproductive Medicine: Fertil Steril 2018;110:387–400
Agaist the routine use immunotheapy in unselected population
The role of immunotherapy in in vitro fertilization: a guideline of ASRM
Conclusions The role of auto antibody mediated autoimmune diseases in infertility and
RIF remains an area of active investigation. The impact of autoimmune diseases on ART outcome, the testing evaluation, as well as the intervention remains controversial.
In women with autoimmune diseases such as SLE/APS, UCTD, the thrombophilia may be the potential cause of adverse fertility outcome. Antithrombotic treatment is recommeded in those patients undergoing ovarian stimulation. The routine use of immuno-therapy in unselected population has been against .
Evidence for the Immunological Screening in RIF needed further reseach. The study in this field should be standardized in the perspectives of antibody testing,cut-off levels for positivity, study populations .
Well designed large sample RCT is needed for the evidence-base of immunotheapy.
My colleagues and postgraduates Perticularly to:
Professor Dai Lie, Dr. Pan Ping, Dr.Liang Zhu
Thanks
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University