Lupus (2014) 23, 1232–1238 http://lup.sagepub.com
SPECIAL ARTICLE
Antiphospholipid antibodies and infertility CB Chighizola1,2 and GR de Jesus3 1
Department of Clinical Sciences and Community Health, University of Milan, Italy; 2Immunorheumatological Research Laboratory, Istituto Auxologico Italiano, Italy; and 3Department of Obstetrics, Universidade do Estado do Rio de Janeiro, Brazil
Since the late 1980s some publications have proposed that antiphospholipid antibodies (aPL) may have some relationship with infertility, considering reported deleterious effects that aPL exert on trophoblast proliferation and growth. Although not included in current classification criteria for antiphospholipid syndrome, many physicians investigate for aPL in patients with a history of infertility, including antibodies not listed in classification criteria, and most of those patients will receive anticoagulant therapy if any of those antibodies have a result considered positive. A review of literature was conducted searching for studies that investigated the association of aPL and infertility and if aPL positivity alters in vitro fertilization (IVF) outcome. The definition of infertility, routine work-up to exclude other causes of infertility, definition of IVF failure as inclusion criteria and control populations were heterogeneous among studies. Most of them enrolled women over 40 years of age, and exclusion of other confounding factors was also inconsistent. Of 29 studies that assessed aPL positivity rates in infertile women, the majority had small sample sizes, implying a lack of power, and 13 (44.8%) reported higher frequency of aPL in infertile patients compared to controls, but most of them investigated a panel of non-criteria aPL tests, whose clinical significance is highly controversial. Only two studies investigated all three criteria tests, and medium-high titer of anticardiolipin cut-off conforming to international guidelines was used in one study. Considering IVF outcome, there was also disparity in this definition: few studies assessed the live birth rate, others the implantation rate. Of 14 publications that addressed the relationship between aPL and IVF outcome, only two described a detrimental effect of these autoantibodies. In conclusion, available data do not support an association between aPL and infertility, and aPL positivity does not seem to influence IVF outcome. Well-designed clinical studies recruiting women with a clear diagnosis of infertility and a high-risk aPL profile should be performed to test whether clinically relevant aPL do—or not—exert an effect on human fertility. Lupus (2014) 23, 1232–1238. Key words: Antiphospholipid antibodies; infertility; in vitro fertilization; anticardiolipin antibodies; lupus anticoagulant; IVF
Introduction Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by vascular thrombosis and/or pregnancy morbidity in the persistent presence of antiphospholipid antibodies (aPL). aPL are currently evaluated by three laboratory tests acknowledged in the revised criteria for APS classification: two solid-phase assays detecting antibodies against beta-2 glycoprotein I (anti-b2GPI
Correspondence to: Cecilia B Chighizola, Immunorheumatological Research Laboratory, Istituto Auxologico Italiano, via Zucchi 18, Cusano, Milanino (Milano), 20095. Italy. Email: [email protected]
antibodies) and against cardiolipin (aCL), plus a functional assay, lupus anticoagulant (LA).1 aPL were initially thought to interfere with pregnancy physiology by inducing placental thrombosis, as they have been shown to disrupt the annexin A5 shield on the trophoblast and to activate monocytes and endothelial cells. However, a non-thrombotic etiology is now regarded as the main pathogenic mechanism induced by aPL during pregnancy. In fact, aPL have been shown to lead to defective placentation by interacting with both sides of the placenta. At the decidual level, aPL induce a proinflammatory phenotype, with neutrophil infiltration, secretion of pro-inflammatory cytokines and complement activation; at a trophoblast level, aPL down-regulate corionic gonadotropin, integrins and cadherins resulting in
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10.1177/0961203314529171
aPL and infertility CB Chighizola and GR de Jesus
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reduced trophoblast proliferation and growth. Such deleterious effects suggested that these autoantibodies might be involved in infertility, a medical condition that affects up to 8% of the population. This hypothesis raised considerable enthusiasm during the 1980s, to such an extent that in 1988 Gleicher and El-Roeiy proposed a novel nosological entity, the reproductive autoimmune syndrome. They suggested that reproductive dysfunction comprising infertility, endometriosis and pregnancy wastage was associated with the polyclonal B cell activation peculiar of autoimmune diseases, resulting in the production of several autoantibodies, including aPL.3 It is not so straightforward to envisage how aPL might affect implantation thus causing infertility, as there is no contact between gametes or pre-implantation embryos with maternal blood. Some experts proposed that aPL may disrupt oocyte development after being secreted into follicular fluid, while others postulated aPL might affect implantation interfering with uterin decidualization. However, most authors believed that the high aPL frequency observed among infertile women undergoing in vitro fertilization (IVF) cycles might be a mere epiphenomenon due to hormonal treatment.4 Over the years, few studies have addressed the relationship between aPL and infertility, focusing on three subgroups of infertile women: those with unexplained infertility, those candidates for IVF and those with IVF failure. An extreme disparity across studies emerged when considering the definition itself of infertility. This is partly ascribable to the fact that the diagnosis of unexplained infertility is of exclusion. Routine female work-up should include hormone profile and evaluation of ovulatory function to rule out ovulatory dysfunction, hysterosalpingography to evaluate uterine cavity anatomy and tubal patency, while laparoscopy may be indicated when there is evidence or strong suspicion of advanced stages of endometriosis, tubal occlusive disease, or signiEcant adnexal adhesions.5 Male investigation is also essential as it may be uniquely responsible for 20% of infertile couples and contributory in another 30%–40%.6 Unfortunately, the exclusion of potential infertility etiologies is never pursued in an identical manner across the studies, varying from rudimentary evaluations to a complete diagnostic process. Similarly, criteria for recruiting women with IVF failure are rather heterogeneous, ranging from one to several failed cycles. An additional confounding factor is provided by the variable exclusion of women with autoimmune conditions, previous thrombosis, and
infectious diseases. Age is another parameter that should be taken into account: the fact many studies enrolled women over 40 years of age may have biased results. There is a wide disparity even in the definition of IVF outcome: few studies assessed the live birth rate, others the implantation rate. In this regard, it should be considered that the likelihood of embryo implantation is lower for IVF than for a physiological cycle, possibly because more than 60% of embryos might be chromosomally abnormal. Moreover, as in fertile women, aPL interfere with pregnancy progression. Similarly, the selection of control populations varies widely, with some studies recruiting healthy women, healthy pregnant women or women with ovulatory or tubal infertility. The pregnant status and the parity of women in the control group are also relevant issues when evaluating aPL prevalence, as pregnancy hormones affect antibody production. In literature, 29 studies have assessed aPL positivity rates in infertile women and control populations. Of these, 13 (44.8%) reported a significant difference between the two groups (Table 1). However, all the three criteria tests were evaluated in two studies only (15.4%), while most studies assessed a panel of non-criteria aPL tests. A medium-high titer aCL cut-off conforming to international guidelines was used in one study, while two studies only confirmed aPL positivity six to 12 weeks apart. Fourteen studies addressed the relationship between aPL and IVF outcome; of these, only two described a detrimental effect of these autoantibodies (Table 1). This observation is consistent with that reported in a meta-analysis published in 2000. These authors concluded that aPL positivity is not associated with a reduced IVF success, as the odds ratios for both clinical pregnancy and live birth in aPL-positive women undergoing IVF compared to those negative for aPL were estimated to be around one.7 Comparable data emerged in a critical review published by the American Society for Reproductive Medicine,8 concluding that assessment of aPL is not recommended among couples undergoing IVF, and therapy is not justified on the basis of existing data. As a whole, some of the available studies observed a higher frequency of positive aPL among infertile women as compared to control women. However, most evidence supporting the role of aPL in infertility comes from studies assessing the non-criteria aPL tests, whose clinical significance is highly controversial. In conclusion, available data do not support an association Lupus
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Number of patients
41
35
21
56
429
65
50
30
538
36
78
42
222
Author, year
Taylor, 19899
Fisch, 199110
Geva, 199411
Birkenfeld, 199412
Sher, 199413
Aoki, 199514
Geva, 199515
Nip, 199516
Balasch, 199617
Ruiz, 199618
Kim, 199619
Kaider, 199620
Kowalik, 199721
Number of controls
80
97
64
14
21
Lupus
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Women non conceiving after IVF
Women with unexplained infertility Women with IVF failure after at least 12 cycles
307
42
91
Women with unexplained 20 infertility Women with unexplained infer- 351 tility (A) and with unexplained IVF failure (B) Women with unexplained 124 infertility
Women with implantation failure Women failing to conceive after one or more ET Women with organic pelvic disease undergoing IVF (A): endometriosis, (B) pelvic inflammatory disease, (C) abdominal/pelvic adhesion, (D) unexplained Women with auto-ab associated infertility Women with 3 or more failed cycles after embryo transfer
Women with unexplained 80 infertility Women undergoing at least two 36 IVF cycles
Study population
LA: 17.8% aCL: 17.8% aCLþaPSþaPGþaPEþaPAþ aPI: (A) 66%, (B) 45%, (C) 58%, (D) 14%
aCL aPS aPC aCL: 14.3%
LAþaCL: 17%
aPL rate in patients
aCL: 0%
LA: 0% aCL: 0%
aCL: 3.1%
LA: 0% aCL: 0% aCLþaPSþaPG þaPEþaPAþaPI
aCL aPS aPC aCL: 0%
LAþaCL: 6%
aPL rate in controls
Healthy women (A) and women LA: 0% LA: 0% with previous infertility aCL: 0% aCL: 0% achieving a livebirth (B) Women with recurrent pregaPE: 18%, aPI 2%, aPA 20%, aPE 5%, aPI 10%, aPA nancy loss aPG 18%, aPS 10% 20%, aPS 12%, aPG 12% Women with ovulatory LA: 2.5% LA: 0% infertility aCL: 9% aCL: 1% Women with successful IVF aCL: 0%, aPE IgG 2.4%, IgM aCL 0%, aPE IgA 4.8%, all others 0% 2.4%, IgA 0%, aPI IgG 2.4%, IgM 4.8%, IgA 0%, aPA IgM 4.8%, IgG 0%, IgA 2.4%, aPG IgG 0%, IgM 4.8%, IgA 0%, aPC IgG 9.5%, IgM 16.6%, IgA 2.4%, aPS IgG 0%, IgM 2.4%, IgA 0% Women undergoing IVF with aCL: 7.2% aCL (A) 0%, (B) 11.4%, (A) biochemical pregnancy, aPS: 10.8% (C) 7.3% (B) with spontaneous misaPS: 2.8% (A), 20% (B), carriage, (C) with ongoing 11.6% (C) pregnancy
Women with no autoimmune aCL: 12.3% infertility Healthy nulligravidas, women LA: 0% who delivered after 3 or less aCL: 6% IVF Healthy non pregnant women aCL: 3.3%
Women who delivered after IVF-ET treatment Women who conceived after ET Infertile women with isolated male factor
Healthy women
Healthy pregnant women
Control population
No
Yes
No
No
No
No
Yes
No
No
Yes
Yes
Yes
Yes
Significant differences between patients and controls
(continued)
No
NA
NA
NA
NA
No
NA
NA
No
NA
NA
NA
NA
Association with IVF outcome
Table 1 Details of studies assessing the aPL positivity rate in infertile women and control population and studies addressing the association between aPL positivity and IVF outcome
aPL and infertility CB Chighizola and GR de Jesus
1234
Number of patients
312
43
191
105
63
219
76
96
234
Author, year
Coulam, 199722
Cubillos, 199723
Kutteh, 199724
Stern, 199825
Azem, 199826
Kaider, 199927
Egbase, 199928
Eldar-Geva, 199929
Martinelli, 200330
Table 1 Continued
Number of controls
200
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45
42
100
54
Women to referred IVF or ICSI 234
Women with unexplained infertility attending IVF program Women with (A) IVF/ET failure and (B) with unexplained unfertility Women with consecutive miscarriages after IVF or ICSI (A) and with primary infertility treated by first IVF or ICSI cycle (B) Women with (A) two or more or (B) with five or more (B) failed IVF cycles
Women enrolled in IVF pro106 gram with > 10 unsuccessful ET
Women undergoing IVF
Women with autoimmune 100 implantation failure Women with primary infertility 35
Study population
Fertile women
Women pregnant after two IVF cycles
Fertile women with 3 or more recurrent miscarriages
Infertile women with tubal factor attending IVF program Healthy women
Fertile women
Healty women
Healthy women with proven fertility and no RPL
Fertile women
Control population aCL: NR aPS: NR LA: 0%, aCL: 2.9%, aPE 8.6%, aPS 5.7%, aPG 11,4%, aPA 5.7%, aPI 5.7% aCLþaPIþaPGþaPSþ aPE 5.5% LA: 0%, aCL IgG 1.9%, aCL IgM 1%, ab2GPI IgG 5.6%, ab2GPI IgM 0%, aPE IgG 5.6%, aPE IgM 1%, aPS IgG 1.8%, aPS IgM 3.8%, aPI IgG 1%, aPI IgM 1.9% aCL: 29.6%
aPL rate in controls
No
Yes
No
Yes
Yes
Yes
Yes
aCL IgG (A) 6%, (B) 7%, aCL aCL IgG 4%, aCL IgM No IgM (A) 4%, (B) 7%, aPE 2%, aPE IgM 11%, IgG (A) IgM 9%, IgG 9%, IgA 13%, IgA 2%, aPI IgM 0%, (B) IgM 7%, IgG 7%, 7%, IgG 9%, IgA 0%, IgA 0%, aPI (A) IgM 9%, aPA IgM 2%, IgG 2%, IgG 6%, IgA 4%, (B) IgM IgA 0, aPG IgG 0%, IgM 14%, IgG 14%, IgA 0%, 7%, IgA 2%, aPS IgM aPA (A) IgM 0%, IgG 0%, 0%, IgG 2%, IgA 0% IgA 0%, (B) IgM 3%, IgG 0%, IgA 3%, aPG (A) IgG 3%, IgM 3%, IgA 0%, (B) IgM 14%, IgG 7%, IgA 10%, aPS (A) IgM 3%, IgG 1%, IgM 0%, (B) IgM 7%, IgG 0%, IgA 0% LA: 0% LA: 0% No aCL: 0% aCL: 0%
(A) aPC 24.6%, aPG 18.5%, NR aPA 15,4%; (B) aPG 25.6%, aPA 23.1%, aPC 20.5% LAþaCL: (A) 25%, (B) 6.6% LAþaCL: 21.4%
aCL: 4% aPS: 5% LA: 0%, aCL: 46.5%, aPE: 25.6%, aPS 32.6%, aPG 27.9%, aPA 20.9 %, aPI 25.6% aCLþaPIþaPGþaPSþaPE: 18.8% LA: 0%, aCL IgG 2.9%, aCL IgM 5.7%, ab2GPI IgG 6.7%, ab2GPI IgM 8.6%, aPE IgG 4.8%, aPE IgM 4.8%, aPS IgG 3.8%, aPS IgM 5.7%, aPI IgG 3.8%, aPI IgM 3.8% aCL: 36.5%
aPL rate in patients
Significant differences between patients and controls
(continued)
NA
No
NA
NA
NA
NA
No
NA
NA
Association with IVF outcome
aPL and infertility CB Chighizola and GR de Jesus
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Lupus
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Radjocic, 200431
Lupus
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101
50 594
26
105 240
793 99
54
76
Sanmarco, 200735
Caccavo, 200736 Steinvil, 201237
El-Roeiy, 198738
Gleicher, 199439 Birdsall, 199640
Denis, 199741 Buckingham, 200642
Lee, 200743
Zhong, 201144
NA NA
NA NA
NA
31 67
160
190
80 391
27
Number of controls
Women undergoing IVF for NA tubal factor aCL þ women undergoing IVF NA for tubal factor
Women undergoing IVF Women undergoing IVF
Women undergoing IVF Women undergoing IVF
Women undergoing IVF
Women undergoing IVF -ET Women undergoing IVF
Women with two unsuccessful IVF-ET
Women with (A) unexplained infertility and (B) with identifiable cause of infertility Women with IVF failure Women (A)after one IVF cycle, (B) after two and more IVF procedures, (C) after three or more pregnancy losses and who had never been pregnant but had a diagnostic laparoscopy Women with 3 or more failed IVF-ET cycles
Study population aCL: 0%
aPL rate in controls Yes
NA
NA
NA NA
NA NA
aCL: 6.4% LAþaCL IgG: (A) 4.7%, (B) 6.3% NA
NA
NA
NA NA
NA NA
NA
No No
Yes LA: 0% aCL, ab2GPI IgA, aPE: NR
LA: (A) 2.2%, (B) 2% aCL: No (A) 2.2%, (B) 3%
LA: 0% aCL: 4.2% LA: 0% aCL: 1.2% No aCL IgG: (A) 19%, (B) 17%, aCL IgG: 1.3% aCL IgM: No (C) 16%, (D) 11.2%; aCL 0.77% ab2GPI IgG: NR IgM: (A) 2%, (B) 6%, (C) 10.5%, (D) 7.3%; ab2GPI IgG: (A) 10%, (B) 12%, (C) 16%, (D) 5.6%
aCL: (A) 21.5%, (B) 23.8%
aPL rate in patients
LA: 8.9% Women with (A) successful pregnancy after first IVF/ET aCL: 10% cycle and (B) fertile women Fertile women LA: 0% aCL: 6% ab2GPI IgA: 75% aPE 67.5% Fertile women aCL: 8% Fertile women (A) and women LAþaCL IgG: 3.3% with history of DVT NA aCL: 34.6% aPS 26.9% NA NR NA aCL IgG: 12.1% aPS: 11.6% NA NR NA aCL IgG: 2%, IgM: 2% ab2GPI G: 10%, M 4% aPS IgG: 4%, IgM: 0% NA LA: 1.8% aCL: 14.8% NA NR
Fertile women Fertile women
Fertile women
Control population
Significant differences between patients and controls
Yes
Yes
No No
No No
No
NA No
No
NA
NA NA
NA
Association with IVF outcome
NA: not assessed; NR: not reported; aPL: anti-phospholipid antibodies; IVF: in vitro fertilization; ET: embryo transfer; LA: lupus anticoagulant; aCL: anti-cardiolipin antibodies; ab2GPI: anti-b2 glycoprotein I antibodies; aPS: anti-phosphatydilserine; aPI: anti-phosphatidylinositol; aPT: anti-prothrombin; aPE: anti-phosphatydilethanolamine; aPA: anti-phosphatidic acid; aPG: antiphosphatidylglycerol; aPC: anti-phosphatidylcholine; DVT: deep venous thromboembolism
90
Qublan, 200634
48 Martinuzzo, 200532 Ulcova-Gallova, 200533 2965
Number of patients
Author, year
Table 1 Continued
aPL and infertility CB Chighizola and GR de Jesus
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aPL and infertility CB Chighizola and GR de Jesus
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between aPL and infertility. It should be considered that the low cut-off used and the frequent testing for clinically irrelevant aPL might have led to an overestimation of aPL rate in control groups. Moreover, the sample sizes were rather small, implying a lack of power of the considered studies. It would be thus interesting to conduct well designed clinical studies recruiting women with a clear diagnosis of infertility and a high-risk aPL profile to test whether clinically relevant aPL do—or not—exert an effect on human fertility.
Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors.
Conflict of interest statement The authors have no conflicts of interest to declare.
References 1 Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4: 295–306. 2 Meroni PL, Borghi MO, Raschi E, Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol 2011; 7: 330–339. 3 Gleicher N, Liu HC, Dudkiewicz A, et al. Autoantibody profiles and immunoglobulin levels as predictors of in vitro fertilization success. Am J Obstet Gynecol 1994; 170: 1145–1149. 4 Buckingham KL, Chamley LW. A critical assessment of the role of antiphospholipid antibodies in infertility. J Reprod Immunol 2009; 80: 132–145. 5 Practice Committee of American Society for Reproductive Medicine. Diagnostic evaluation of the infertile female: A committee opinion. Fertil Steril 2012; 98: 302–307. 6 Male Infertility Best Practice Policy Committee of the American Urological Association; Practice Committee of the American Society for Reproductive Medicine. Report on optimal evaluation of the infertile male. Fertil Steril 2006; 86(5 Suppl 1): S202–S209. 7 Hornstein MD, Davis OK, Massey JB, Paulson RJ, Collins JA. Antiphospholipid antibodies and in vitro fertilization success: A meta-analysis. Fertil Steril 2000; 73: 330–333. 8 Practice Committee of American Society for Reproductive Medicine. Anti-phospholipid antibodies do not affect IVF success. Fertil Steril 2008; 90(5 Suppl): S172–S173. 9 Taylor PV, Campbell JM, Scott JS. Presence of autoantibodies in women with unexplained infertility. Am J Obstet Gynecol 1989; 161: 377–379. 10 Fisch B, Rikover Y, Shohat L, et al. The relationship between in vitro fertilization and naturally occurring antibodies: evidence for increased production of antiphospholipid antibodies. Fertil Steril 1991; 56: 718–724. 11 Geva E, Yaron Y, Lessing J, et al. Circulating autoimmune antibodies may be responsible for implantation failure in in vitro fertilization. Fertil Steril 1994; 62: 802–806.
12 Birkenfeld A, Mukaida T, Minichiello L, Jackson M, Kase NG, Yemini M. Incidence of autoimmune antibodies in failed embryo transfer cycles. Am J Reprod Immunol 1994; 31: 65–68. 13 Sher G, Feinman M, Zouves C, et al. High fecundity rates following in-vitro fertilization and embryo transfer in antiphospholipid antibody seropositive women treated with heparin and aspirin. Hum Reprod 1994; 9: 2278–2283. 14 Aoki K, Dudkiewicz AB, Matsuura E, Novotny M, Kaberlein G, Gleicher N. Clinical significance of b2-glycoprotein I-dependent anticardiolipin antibodies in the reproductive autoimmune failure syndrome: correlation with conventional antibody detection systems. Am J Obstet Gynecol 1995; 172: 926–931. 15 Geva E, Amit A, Lerner-Geva L, Azem F, Yovel I, Lessing JB. Autoimmune disorders: another possible cause for in-vitro fertilization and embryo transfer failure. Hum Reprod 1995; 10: 2560–2563. 16 Nip MMC, Taylor PV, Rutherford AJ, Hancock KW. Autoantibodies and antisperm antibodies in sera and follicular fluids of infertile patients; relation to reproductive outcome after in vitro fertilization. Hum Reprod 1995; 10: 2564–2569. 17 Balasch J, Creus M, Fabregues F, et al. Antiphospholipid antibodies and human reproductive failure. Hum Reprod 1996; 11: 2310–2315. 18 Ruiz AM, Kwak JYH, Kwak FM, Beer AE. Impact of age on reproductive outcome in women with recurrent spontaneous abortions and infertility of immune etiology. Am J Reprod Immunol 1996; 35: 408–414. 19 Kim CK, Cho YK, Mok JE. The efficacy of immunotherapy in patients who underwent superovulation with intrauterine insemination. Fertil Steril 1996; 65: 133–138. 20 Kaider BD, Price DE, Roussev RG, Coulam CB. Antiphospholipid prevalence in patients with IVF failure. Am J Reprod Immunol 1996; 35: 388–393. 21 Kowalik A, Vichinin M, Liu H-C, Branch W, Berkeley AS. Midfollicular anticardiolipi and antiphosphatidylserine antibody titers do not correlate with in vitro fertilization outcome. Fertil Steril 1997; 68: 298–304. 22 Coulam CB, Kaider BD, Kaider AS, Janowicz P, Roussev RG. Antiphospholipid antibodies associated with implantation failure after IVF/ET. J Assist Reprod Gen 1997; 14: 603–608. 23 Cubillos J, Lucena A, Lucena C, et al. Incidence of autoantibodies in the infertile population. Early Pregnancy 1997; 3: 119–124. 24 Kutteh WH, Yetman DL, Chantilis SJ, Crain J. Effect of antiphospholipid antibodies in women undergoing in-vitro fertilization: role of heparin and aspirin. Human Reprod 1997; 12: 1171–1175. 25 Stern C, Chamley L, Hale L, Kloss M, Speirs A, Baker HWG. Antibodies to b2 glycoprotein I are associated with in vitro fertilization implantation failure as well as recurrent miscarriage: results of a prevalence study. Fertil Steril 1998; 70: 938–944. 26 Azem F, Geva E, Amit A, et al. High levels of anticardiolipin antibodies in patients with abnormal morphology who attended an in vitro fertilization program. Am J Reprod Immunol 1998; 39: 161–163. 27 Kaider AS, Kaider BD, Janowicz PB, Roussev RG. Immunodiagnostic evaluation in women with reproductive failure. Am J Reprod Immunol 1999; 42: 335–346. 28 Egbase PE, Al Sharhan M, Diejomaoh M, Grudzinskas JG. Antiphospholipid antibodies in infertile couples with two consecutive miscarriages after in-vitro fertilization and embryo transfer. Human Reprod 1999; 14: 1483–1486. 29 Eldar-Geva T, Wood C, Lolatgis N, et al. Cumulative pregnancy and live birth rates in women with antiphospholipid antibodies undergoing assisted reproduction. Human Reprod 1999; 14: 1461–1466. 30 Martinelli I, Taioli E, Ragni G, et al. Embryo implantation after assisted reproductive procedures and maternal thrombophilia. Haematologica 2003; 88: 789–793. 31 Radjocic L, Marjanovic S, Vicovac L, Kataranovski M. Anticardiolipin antibodies in women with unexplained infertility. Physiol Res 2004; 53: 91–96. 32 Martinuzzo M, Iglesias Varela ML, Adamczuk Y, Broze GJ, Forastiero R. Antiphospholipid antibodies and antibodies to tissue factor pathway inhibitor in women with implantation Lupus
Downloaded from lup.sagepub.com at UCSF LIBRARY & CKM on February 12, 2015
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1238
33
34 35
36 37 38
failures or early and late pregnancy losses. J Thromb Haemost 2005; 3: 2587–2589. Ulcova-Gallova Z, Krauz V, Novakova P, et al. Antiphospholipid antibodies against phosphatidylinositol, and phosphatidylserine are more significant in reproductive failure than antibodies against cardiolipin only. Am J Reprod Immunol 2005; 54: 112–117. Qublan HS, Eid SS, Ababneh HA, et al. Acquired and inherited thrombophilia: implication in recurrent IVF and embryo transfer failure. Hum Reprod 2006; 21: 2694–2698. Sanmarco M, Bardin N, Camoin L, et al. Antigenic profile, prevalence, and clinical significance of antiphospholipid antibodies in women referred for in vitro fertilization. Ann NY Acad Sci 2007; 1108: 457–465. Caccavo D, Pellegrino NM, Lorusso F, et al. Anticardiolipin antibody levels in women undergoing first in vitro fertilization/embryo transfer. Hum Reprod 2007; 22: 2494–2500. Steinvil A, Raz R, Berliner S, et al. Association of common thrombophilias and antiphospholipid antibodies with success rate of in vitro fertilisation. Thromb Haemost 2012; 108: 1192–1197. El-Roeiy A, Gleicher N, Friberg J, Confino E, Dudkiewicz A. Correlation between peripheral blood and folluicular fluid
39 40 41 42
43
44
autoantibodies and impact on in vitro fertilization. Obstet Gynecol 1987; 70: 163–170. Gleicher N, Liu H-C, Dudkiewicz A, et al. Autoantibody profiles and immunoglobulin levels as predictors of in vitro fertilization success. Am J Obstet Gynecol 1994; 170: 1145–1149. Birdsall MA, Lockwood GM, Ledger WL, Johnson PM, Chamley LW. Antiphospholipid antibodies in women having in-vitro fertilization. Hum Reprod 1996; 11: 1185–1189. Denis AL, Guido M, Adler RD, Bergh PA, Brenner C, Scott RT. Antiphospholipid antibodies and pregnancy rates and outcome in vitro fertilization patients. Fertil Steril 1997; 67: 1084–1090. Buckingham KL, Stone PR, Smith JF, Chamley LW. Antiphospholipid antibodies in serum and follicular fluid – is there a correlation with IVF implantation failure? Hum Reprod 2006; 21: 728–734. Lee S-R, Park E-J, Kim S-H, Chae H, Kim C-H, Kang B-M. Influence of antiphospholipid antibodies on pregnancy outcome in women undergoing in vitro fertilization and embryo transfer. Am J Reprod Immunol 2007; 57: 34–39. Zhong Y-P, Ying Y, Wu H-T, et al. Impact of anticardiolipin antibody on the outcome of in vitro fertilization and embryo transfer. Am J Reprod Reprod Immunol 2011; 66: 504–509.
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SPECIAL ARTICLE
Antiphospholipid antibodies and infertility CB Chighizola1,2 and GR de Jesus3 1
Department of Clinical Sciences and Community Health, University of Milan, Italy; 2Immunorheumatological Research Laboratory, Istituto Auxologico Italiano, Italy; and 3Department of Obstetrics, Universidade do Estado do Rio de Janeiro, Brazil
Since the late 1980s some publications have proposed that antiphospholipid antibodies (aPL) may have some relationship with infertility, considering reported deleterious effects that aPL exert on trophoblast proliferation and growth. Although not included in current classification criteria for antiphospholipid syndrome, many physicians investigate for aPL in patients with a history of infertility, including antibodies not listed in classification criteria, and most of those patients will receive anticoagulant therapy if any of those antibodies have a result considered positive. A review of literature was conducted searching for studies that investigated the association of aPL and infertility and if aPL positivity alters in vitro fertilization (IVF) outcome. The definition of infertility, routine work-up to exclude other causes of infertility, definition of IVF failure as inclusion criteria and control populations were heterogeneous among studies. Most of them enrolled women over 40 years of age, and exclusion of other confounding factors was also inconsistent. Of 29 studies that assessed aPL positivity rates in infertile women, the majority had small sample sizes, implying a lack of power, and 13 (44.8%) reported higher frequency of aPL in infertile patients compared to controls, but most of them investigated a panel of non-criteria aPL tests, whose clinical significance is highly controversial. Only two studies investigated all three criteria tests, and medium-high titer of anticardiolipin cut-off conforming to international guidelines was used in one study. Considering IVF outcome, there was also disparity in this definition: few studies assessed the live birth rate, others the implantation rate. Of 14 publications that addressed the relationship between aPL and IVF outcome, only two described a detrimental effect of these autoantibodies. In conclusion, available data do not support an association between aPL and infertility, and aPL positivity does not seem to influence IVF outcome. Well-designed clinical studies recruiting women with a clear diagnosis of infertility and a high-risk aPL profile should be performed to test whether clinically relevant aPL do—or not—exert an effect on human fertility. Lupus (2014) 23, 1232–1238. Key words: Antiphospholipid antibodies; infertility; in vitro fertilization; anticardiolipin antibodies; lupus anticoagulant; IVF
Introduction Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by vascular thrombosis and/or pregnancy morbidity in the persistent presence of antiphospholipid antibodies (aPL). aPL are currently evaluated by three laboratory tests acknowledged in the revised criteria for APS classification: two solid-phase assays detecting antibodies against beta-2 glycoprotein I (anti-b2GPI
Correspondence to: Cecilia B Chighizola, Immunorheumatological Research Laboratory, Istituto Auxologico Italiano, via Zucchi 18, Cusano, Milanino (Milano), 20095. Italy. Email: [email protected]
antibodies) and against cardiolipin (aCL), plus a functional assay, lupus anticoagulant (LA).1 aPL were initially thought to interfere with pregnancy physiology by inducing placental thrombosis, as they have been shown to disrupt the annexin A5 shield on the trophoblast and to activate monocytes and endothelial cells. However, a non-thrombotic etiology is now regarded as the main pathogenic mechanism induced by aPL during pregnancy. In fact, aPL have been shown to lead to defective placentation by interacting with both sides of the placenta. At the decidual level, aPL induce a proinflammatory phenotype, with neutrophil infiltration, secretion of pro-inflammatory cytokines and complement activation; at a trophoblast level, aPL down-regulate corionic gonadotropin, integrins and cadherins resulting in
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10.1177/0961203314529171
aPL and infertility CB Chighizola and GR de Jesus
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reduced trophoblast proliferation and growth. Such deleterious effects suggested that these autoantibodies might be involved in infertility, a medical condition that affects up to 8% of the population. This hypothesis raised considerable enthusiasm during the 1980s, to such an extent that in 1988 Gleicher and El-Roeiy proposed a novel nosological entity, the reproductive autoimmune syndrome. They suggested that reproductive dysfunction comprising infertility, endometriosis and pregnancy wastage was associated with the polyclonal B cell activation peculiar of autoimmune diseases, resulting in the production of several autoantibodies, including aPL.3 It is not so straightforward to envisage how aPL might affect implantation thus causing infertility, as there is no contact between gametes or pre-implantation embryos with maternal blood. Some experts proposed that aPL may disrupt oocyte development after being secreted into follicular fluid, while others postulated aPL might affect implantation interfering with uterin decidualization. However, most authors believed that the high aPL frequency observed among infertile women undergoing in vitro fertilization (IVF) cycles might be a mere epiphenomenon due to hormonal treatment.4 Over the years, few studies have addressed the relationship between aPL and infertility, focusing on three subgroups of infertile women: those with unexplained infertility, those candidates for IVF and those with IVF failure. An extreme disparity across studies emerged when considering the definition itself of infertility. This is partly ascribable to the fact that the diagnosis of unexplained infertility is of exclusion. Routine female work-up should include hormone profile and evaluation of ovulatory function to rule out ovulatory dysfunction, hysterosalpingography to evaluate uterine cavity anatomy and tubal patency, while laparoscopy may be indicated when there is evidence or strong suspicion of advanced stages of endometriosis, tubal occlusive disease, or signiEcant adnexal adhesions.5 Male investigation is also essential as it may be uniquely responsible for 20% of infertile couples and contributory in another 30%–40%.6 Unfortunately, the exclusion of potential infertility etiologies is never pursued in an identical manner across the studies, varying from rudimentary evaluations to a complete diagnostic process. Similarly, criteria for recruiting women with IVF failure are rather heterogeneous, ranging from one to several failed cycles. An additional confounding factor is provided by the variable exclusion of women with autoimmune conditions, previous thrombosis, and
infectious diseases. Age is another parameter that should be taken into account: the fact many studies enrolled women over 40 years of age may have biased results. There is a wide disparity even in the definition of IVF outcome: few studies assessed the live birth rate, others the implantation rate. In this regard, it should be considered that the likelihood of embryo implantation is lower for IVF than for a physiological cycle, possibly because more than 60% of embryos might be chromosomally abnormal. Moreover, as in fertile women, aPL interfere with pregnancy progression. Similarly, the selection of control populations varies widely, with some studies recruiting healthy women, healthy pregnant women or women with ovulatory or tubal infertility. The pregnant status and the parity of women in the control group are also relevant issues when evaluating aPL prevalence, as pregnancy hormones affect antibody production. In literature, 29 studies have assessed aPL positivity rates in infertile women and control populations. Of these, 13 (44.8%) reported a significant difference between the two groups (Table 1). However, all the three criteria tests were evaluated in two studies only (15.4%), while most studies assessed a panel of non-criteria aPL tests. A medium-high titer aCL cut-off conforming to international guidelines was used in one study, while two studies only confirmed aPL positivity six to 12 weeks apart. Fourteen studies addressed the relationship between aPL and IVF outcome; of these, only two described a detrimental effect of these autoantibodies (Table 1). This observation is consistent with that reported in a meta-analysis published in 2000. These authors concluded that aPL positivity is not associated with a reduced IVF success, as the odds ratios for both clinical pregnancy and live birth in aPL-positive women undergoing IVF compared to those negative for aPL were estimated to be around one.7 Comparable data emerged in a critical review published by the American Society for Reproductive Medicine,8 concluding that assessment of aPL is not recommended among couples undergoing IVF, and therapy is not justified on the basis of existing data. As a whole, some of the available studies observed a higher frequency of positive aPL among infertile women as compared to control women. However, most evidence supporting the role of aPL in infertility comes from studies assessing the non-criteria aPL tests, whose clinical significance is highly controversial. In conclusion, available data do not support an association Lupus
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Number of patients
41
35
21
56
429
65
50
30
538
36
78
42
222
Author, year
Taylor, 19899
Fisch, 199110
Geva, 199411
Birkenfeld, 199412
Sher, 199413
Aoki, 199514
Geva, 199515
Nip, 199516
Balasch, 199617
Ruiz, 199618
Kim, 199619
Kaider, 199620
Kowalik, 199721
Number of controls
80
97
64
14
21
Lupus
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Women non conceiving after IVF
Women with unexplained infertility Women with IVF failure after at least 12 cycles
307
42
91
Women with unexplained 20 infertility Women with unexplained infer- 351 tility (A) and with unexplained IVF failure (B) Women with unexplained 124 infertility
Women with implantation failure Women failing to conceive after one or more ET Women with organic pelvic disease undergoing IVF (A): endometriosis, (B) pelvic inflammatory disease, (C) abdominal/pelvic adhesion, (D) unexplained Women with auto-ab associated infertility Women with 3 or more failed cycles after embryo transfer
Women with unexplained 80 infertility Women undergoing at least two 36 IVF cycles
Study population
LA: 17.8% aCL: 17.8% aCLþaPSþaPGþaPEþaPAþ aPI: (A) 66%, (B) 45%, (C) 58%, (D) 14%
aCL aPS aPC aCL: 14.3%
LAþaCL: 17%
aPL rate in patients
aCL: 0%
LA: 0% aCL: 0%
aCL: 3.1%
LA: 0% aCL: 0% aCLþaPSþaPG þaPEþaPAþaPI
aCL aPS aPC aCL: 0%
LAþaCL: 6%
aPL rate in controls
Healthy women (A) and women LA: 0% LA: 0% with previous infertility aCL: 0% aCL: 0% achieving a livebirth (B) Women with recurrent pregaPE: 18%, aPI 2%, aPA 20%, aPE 5%, aPI 10%, aPA nancy loss aPG 18%, aPS 10% 20%, aPS 12%, aPG 12% Women with ovulatory LA: 2.5% LA: 0% infertility aCL: 9% aCL: 1% Women with successful IVF aCL: 0%, aPE IgG 2.4%, IgM aCL 0%, aPE IgA 4.8%, all others 0% 2.4%, IgA 0%, aPI IgG 2.4%, IgM 4.8%, IgA 0%, aPA IgM 4.8%, IgG 0%, IgA 2.4%, aPG IgG 0%, IgM 4.8%, IgA 0%, aPC IgG 9.5%, IgM 16.6%, IgA 2.4%, aPS IgG 0%, IgM 2.4%, IgA 0% Women undergoing IVF with aCL: 7.2% aCL (A) 0%, (B) 11.4%, (A) biochemical pregnancy, aPS: 10.8% (C) 7.3% (B) with spontaneous misaPS: 2.8% (A), 20% (B), carriage, (C) with ongoing 11.6% (C) pregnancy
Women with no autoimmune aCL: 12.3% infertility Healthy nulligravidas, women LA: 0% who delivered after 3 or less aCL: 6% IVF Healthy non pregnant women aCL: 3.3%
Women who delivered after IVF-ET treatment Women who conceived after ET Infertile women with isolated male factor
Healthy women
Healthy pregnant women
Control population
No
Yes
No
No
No
No
Yes
No
No
Yes
Yes
Yes
Yes
Significant differences between patients and controls
(continued)
No
NA
NA
NA
NA
No
NA
NA
No
NA
NA
NA
NA
Association with IVF outcome
Table 1 Details of studies assessing the aPL positivity rate in infertile women and control population and studies addressing the association between aPL positivity and IVF outcome
aPL and infertility CB Chighizola and GR de Jesus
1234
Number of patients
312
43
191
105
63
219
76
96
234
Author, year
Coulam, 199722
Cubillos, 199723
Kutteh, 199724
Stern, 199825
Azem, 199826
Kaider, 199927
Egbase, 199928
Eldar-Geva, 199929
Martinelli, 200330
Table 1 Continued
Number of controls
200
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45
42
100
54
Women to referred IVF or ICSI 234
Women with unexplained infertility attending IVF program Women with (A) IVF/ET failure and (B) with unexplained unfertility Women with consecutive miscarriages after IVF or ICSI (A) and with primary infertility treated by first IVF or ICSI cycle (B) Women with (A) two or more or (B) with five or more (B) failed IVF cycles
Women enrolled in IVF pro106 gram with > 10 unsuccessful ET
Women undergoing IVF
Women with autoimmune 100 implantation failure Women with primary infertility 35
Study population
Fertile women
Women pregnant after two IVF cycles
Fertile women with 3 or more recurrent miscarriages
Infertile women with tubal factor attending IVF program Healthy women
Fertile women
Healty women
Healthy women with proven fertility and no RPL
Fertile women
Control population aCL: NR aPS: NR LA: 0%, aCL: 2.9%, aPE 8.6%, aPS 5.7%, aPG 11,4%, aPA 5.7%, aPI 5.7% aCLþaPIþaPGþaPSþ aPE 5.5% LA: 0%, aCL IgG 1.9%, aCL IgM 1%, ab2GPI IgG 5.6%, ab2GPI IgM 0%, aPE IgG 5.6%, aPE IgM 1%, aPS IgG 1.8%, aPS IgM 3.8%, aPI IgG 1%, aPI IgM 1.9% aCL: 29.6%
aPL rate in controls
No
Yes
No
Yes
Yes
Yes
Yes
aCL IgG (A) 6%, (B) 7%, aCL aCL IgG 4%, aCL IgM No IgM (A) 4%, (B) 7%, aPE 2%, aPE IgM 11%, IgG (A) IgM 9%, IgG 9%, IgA 13%, IgA 2%, aPI IgM 0%, (B) IgM 7%, IgG 7%, 7%, IgG 9%, IgA 0%, IgA 0%, aPI (A) IgM 9%, aPA IgM 2%, IgG 2%, IgG 6%, IgA 4%, (B) IgM IgA 0, aPG IgG 0%, IgM 14%, IgG 14%, IgA 0%, 7%, IgA 2%, aPS IgM aPA (A) IgM 0%, IgG 0%, 0%, IgG 2%, IgA 0% IgA 0%, (B) IgM 3%, IgG 0%, IgA 3%, aPG (A) IgG 3%, IgM 3%, IgA 0%, (B) IgM 14%, IgG 7%, IgA 10%, aPS (A) IgM 3%, IgG 1%, IgM 0%, (B) IgM 7%, IgG 0%, IgA 0% LA: 0% LA: 0% No aCL: 0% aCL: 0%
(A) aPC 24.6%, aPG 18.5%, NR aPA 15,4%; (B) aPG 25.6%, aPA 23.1%, aPC 20.5% LAþaCL: (A) 25%, (B) 6.6% LAþaCL: 21.4%
aCL: 4% aPS: 5% LA: 0%, aCL: 46.5%, aPE: 25.6%, aPS 32.6%, aPG 27.9%, aPA 20.9 %, aPI 25.6% aCLþaPIþaPGþaPSþaPE: 18.8% LA: 0%, aCL IgG 2.9%, aCL IgM 5.7%, ab2GPI IgG 6.7%, ab2GPI IgM 8.6%, aPE IgG 4.8%, aPE IgM 4.8%, aPS IgG 3.8%, aPS IgM 5.7%, aPI IgG 3.8%, aPI IgM 3.8% aCL: 36.5%
aPL rate in patients
Significant differences between patients and controls
(continued)
NA
No
NA
NA
NA
NA
No
NA
NA
Association with IVF outcome
aPL and infertility CB Chighizola and GR de Jesus
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Lupus
65
Radjocic, 200431
Lupus
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101
50 594
26
105 240
793 99
54
76
Sanmarco, 200735
Caccavo, 200736 Steinvil, 201237
El-Roeiy, 198738
Gleicher, 199439 Birdsall, 199640
Denis, 199741 Buckingham, 200642
Lee, 200743
Zhong, 201144
NA NA
NA NA
NA
31 67
160
190
80 391
27
Number of controls
Women undergoing IVF for NA tubal factor aCL þ women undergoing IVF NA for tubal factor
Women undergoing IVF Women undergoing IVF
Women undergoing IVF Women undergoing IVF
Women undergoing IVF
Women undergoing IVF -ET Women undergoing IVF
Women with two unsuccessful IVF-ET
Women with (A) unexplained infertility and (B) with identifiable cause of infertility Women with IVF failure Women (A)after one IVF cycle, (B) after two and more IVF procedures, (C) after three or more pregnancy losses and who had never been pregnant but had a diagnostic laparoscopy Women with 3 or more failed IVF-ET cycles
Study population aCL: 0%
aPL rate in controls Yes
NA
NA
NA NA
NA NA
aCL: 6.4% LAþaCL IgG: (A) 4.7%, (B) 6.3% NA
NA
NA
NA NA
NA NA
NA
No No
Yes LA: 0% aCL, ab2GPI IgA, aPE: NR
LA: (A) 2.2%, (B) 2% aCL: No (A) 2.2%, (B) 3%
LA: 0% aCL: 4.2% LA: 0% aCL: 1.2% No aCL IgG: (A) 19%, (B) 17%, aCL IgG: 1.3% aCL IgM: No (C) 16%, (D) 11.2%; aCL 0.77% ab2GPI IgG: NR IgM: (A) 2%, (B) 6%, (C) 10.5%, (D) 7.3%; ab2GPI IgG: (A) 10%, (B) 12%, (C) 16%, (D) 5.6%
aCL: (A) 21.5%, (B) 23.8%
aPL rate in patients
LA: 8.9% Women with (A) successful pregnancy after first IVF/ET aCL: 10% cycle and (B) fertile women Fertile women LA: 0% aCL: 6% ab2GPI IgA: 75% aPE 67.5% Fertile women aCL: 8% Fertile women (A) and women LAþaCL IgG: 3.3% with history of DVT NA aCL: 34.6% aPS 26.9% NA NR NA aCL IgG: 12.1% aPS: 11.6% NA NR NA aCL IgG: 2%, IgM: 2% ab2GPI G: 10%, M 4% aPS IgG: 4%, IgM: 0% NA LA: 1.8% aCL: 14.8% NA NR
Fertile women Fertile women
Fertile women
Control population
Significant differences between patients and controls
Yes
Yes
No No
No No
No
NA No
No
NA
NA NA
NA
Association with IVF outcome
NA: not assessed; NR: not reported; aPL: anti-phospholipid antibodies; IVF: in vitro fertilization; ET: embryo transfer; LA: lupus anticoagulant; aCL: anti-cardiolipin antibodies; ab2GPI: anti-b2 glycoprotein I antibodies; aPS: anti-phosphatydilserine; aPI: anti-phosphatidylinositol; aPT: anti-prothrombin; aPE: anti-phosphatydilethanolamine; aPA: anti-phosphatidic acid; aPG: antiphosphatidylglycerol; aPC: anti-phosphatidylcholine; DVT: deep venous thromboembolism
90
Qublan, 200634
48 Martinuzzo, 200532 Ulcova-Gallova, 200533 2965
Number of patients
Author, year
Table 1 Continued
aPL and infertility CB Chighizola and GR de Jesus
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aPL and infertility CB Chighizola and GR de Jesus
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between aPL and infertility. It should be considered that the low cut-off used and the frequent testing for clinically irrelevant aPL might have led to an overestimation of aPL rate in control groups. Moreover, the sample sizes were rather small, implying a lack of power of the considered studies. It would be thus interesting to conduct well designed clinical studies recruiting women with a clear diagnosis of infertility and a high-risk aPL profile to test whether clinically relevant aPL do—or not—exert an effect on human fertility.
Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors.
Conflict of interest statement The authors have no conflicts of interest to declare.
References 1 Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4: 295–306. 2 Meroni PL, Borghi MO, Raschi E, Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol 2011; 7: 330–339. 3 Gleicher N, Liu HC, Dudkiewicz A, et al. Autoantibody profiles and immunoglobulin levels as predictors of in vitro fertilization success. Am J Obstet Gynecol 1994; 170: 1145–1149. 4 Buckingham KL, Chamley LW. A critical assessment of the role of antiphospholipid antibodies in infertility. J Reprod Immunol 2009; 80: 132–145. 5 Practice Committee of American Society for Reproductive Medicine. Diagnostic evaluation of the infertile female: A committee opinion. Fertil Steril 2012; 98: 302–307. 6 Male Infertility Best Practice Policy Committee of the American Urological Association; Practice Committee of the American Society for Reproductive Medicine. Report on optimal evaluation of the infertile male. Fertil Steril 2006; 86(5 Suppl 1): S202–S209. 7 Hornstein MD, Davis OK, Massey JB, Paulson RJ, Collins JA. Antiphospholipid antibodies and in vitro fertilization success: A meta-analysis. Fertil Steril 2000; 73: 330–333. 8 Practice Committee of American Society for Reproductive Medicine. Anti-phospholipid antibodies do not affect IVF success. Fertil Steril 2008; 90(5 Suppl): S172–S173. 9 Taylor PV, Campbell JM, Scott JS. Presence of autoantibodies in women with unexplained infertility. Am J Obstet Gynecol 1989; 161: 377–379. 10 Fisch B, Rikover Y, Shohat L, et al. The relationship between in vitro fertilization and naturally occurring antibodies: evidence for increased production of antiphospholipid antibodies. Fertil Steril 1991; 56: 718–724. 11 Geva E, Yaron Y, Lessing J, et al. Circulating autoimmune antibodies may be responsible for implantation failure in in vitro fertilization. Fertil Steril 1994; 62: 802–806.
12 Birkenfeld A, Mukaida T, Minichiello L, Jackson M, Kase NG, Yemini M. Incidence of autoimmune antibodies in failed embryo transfer cycles. Am J Reprod Immunol 1994; 31: 65–68. 13 Sher G, Feinman M, Zouves C, et al. High fecundity rates following in-vitro fertilization and embryo transfer in antiphospholipid antibody seropositive women treated with heparin and aspirin. Hum Reprod 1994; 9: 2278–2283. 14 Aoki K, Dudkiewicz AB, Matsuura E, Novotny M, Kaberlein G, Gleicher N. Clinical significance of b2-glycoprotein I-dependent anticardiolipin antibodies in the reproductive autoimmune failure syndrome: correlation with conventional antibody detection systems. Am J Obstet Gynecol 1995; 172: 926–931. 15 Geva E, Amit A, Lerner-Geva L, Azem F, Yovel I, Lessing JB. Autoimmune disorders: another possible cause for in-vitro fertilization and embryo transfer failure. Hum Reprod 1995; 10: 2560–2563. 16 Nip MMC, Taylor PV, Rutherford AJ, Hancock KW. Autoantibodies and antisperm antibodies in sera and follicular fluids of infertile patients; relation to reproductive outcome after in vitro fertilization. Hum Reprod 1995; 10: 2564–2569. 17 Balasch J, Creus M, Fabregues F, et al. Antiphospholipid antibodies and human reproductive failure. Hum Reprod 1996; 11: 2310–2315. 18 Ruiz AM, Kwak JYH, Kwak FM, Beer AE. Impact of age on reproductive outcome in women with recurrent spontaneous abortions and infertility of immune etiology. Am J Reprod Immunol 1996; 35: 408–414. 19 Kim CK, Cho YK, Mok JE. The efficacy of immunotherapy in patients who underwent superovulation with intrauterine insemination. Fertil Steril 1996; 65: 133–138. 20 Kaider BD, Price DE, Roussev RG, Coulam CB. Antiphospholipid prevalence in patients with IVF failure. Am J Reprod Immunol 1996; 35: 388–393. 21 Kowalik A, Vichinin M, Liu H-C, Branch W, Berkeley AS. Midfollicular anticardiolipi and antiphosphatidylserine antibody titers do not correlate with in vitro fertilization outcome. Fertil Steril 1997; 68: 298–304. 22 Coulam CB, Kaider BD, Kaider AS, Janowicz P, Roussev RG. Antiphospholipid antibodies associated with implantation failure after IVF/ET. J Assist Reprod Gen 1997; 14: 603–608. 23 Cubillos J, Lucena A, Lucena C, et al. Incidence of autoantibodies in the infertile population. Early Pregnancy 1997; 3: 119–124. 24 Kutteh WH, Yetman DL, Chantilis SJ, Crain J. Effect of antiphospholipid antibodies in women undergoing in-vitro fertilization: role of heparin and aspirin. Human Reprod 1997; 12: 1171–1175. 25 Stern C, Chamley L, Hale L, Kloss M, Speirs A, Baker HWG. Antibodies to b2 glycoprotein I are associated with in vitro fertilization implantation failure as well as recurrent miscarriage: results of a prevalence study. Fertil Steril 1998; 70: 938–944. 26 Azem F, Geva E, Amit A, et al. High levels of anticardiolipin antibodies in patients with abnormal morphology who attended an in vitro fertilization program. Am J Reprod Immunol 1998; 39: 161–163. 27 Kaider AS, Kaider BD, Janowicz PB, Roussev RG. Immunodiagnostic evaluation in women with reproductive failure. Am J Reprod Immunol 1999; 42: 335–346. 28 Egbase PE, Al Sharhan M, Diejomaoh M, Grudzinskas JG. Antiphospholipid antibodies in infertile couples with two consecutive miscarriages after in-vitro fertilization and embryo transfer. Human Reprod 1999; 14: 1483–1486. 29 Eldar-Geva T, Wood C, Lolatgis N, et al. Cumulative pregnancy and live birth rates in women with antiphospholipid antibodies undergoing assisted reproduction. Human Reprod 1999; 14: 1461–1466. 30 Martinelli I, Taioli E, Ragni G, et al. Embryo implantation after assisted reproductive procedures and maternal thrombophilia. Haematologica 2003; 88: 789–793. 31 Radjocic L, Marjanovic S, Vicovac L, Kataranovski M. Anticardiolipin antibodies in women with unexplained infertility. Physiol Res 2004; 53: 91–96. 32 Martinuzzo M, Iglesias Varela ML, Adamczuk Y, Broze GJ, Forastiero R. Antiphospholipid antibodies and antibodies to tissue factor pathway inhibitor in women with implantation Lupus
Downloaded from lup.sagepub.com at UCSF LIBRARY & CKM on February 12, 2015
aPL and infertility CB Chighizola and GR de Jesus
1238
33
34 35
36 37 38
failures or early and late pregnancy losses. J Thromb Haemost 2005; 3: 2587–2589. Ulcova-Gallova Z, Krauz V, Novakova P, et al. Antiphospholipid antibodies against phosphatidylinositol, and phosphatidylserine are more significant in reproductive failure than antibodies against cardiolipin only. Am J Reprod Immunol 2005; 54: 112–117. Qublan HS, Eid SS, Ababneh HA, et al. Acquired and inherited thrombophilia: implication in recurrent IVF and embryo transfer failure. Hum Reprod 2006; 21: 2694–2698. Sanmarco M, Bardin N, Camoin L, et al. Antigenic profile, prevalence, and clinical significance of antiphospholipid antibodies in women referred for in vitro fertilization. Ann NY Acad Sci 2007; 1108: 457–465. Caccavo D, Pellegrino NM, Lorusso F, et al. Anticardiolipin antibody levels in women undergoing first in vitro fertilization/embryo transfer. Hum Reprod 2007; 22: 2494–2500. Steinvil A, Raz R, Berliner S, et al. Association of common thrombophilias and antiphospholipid antibodies with success rate of in vitro fertilisation. Thromb Haemost 2012; 108: 1192–1197. El-Roeiy A, Gleicher N, Friberg J, Confino E, Dudkiewicz A. Correlation between peripheral blood and folluicular fluid
39 40 41 42
43
44
autoantibodies and impact on in vitro fertilization. Obstet Gynecol 1987; 70: 163–170. Gleicher N, Liu H-C, Dudkiewicz A, et al. Autoantibody profiles and immunoglobulin levels as predictors of in vitro fertilization success. Am J Obstet Gynecol 1994; 170: 1145–1149. Birdsall MA, Lockwood GM, Ledger WL, Johnson PM, Chamley LW. Antiphospholipid antibodies in women having in-vitro fertilization. Hum Reprod 1996; 11: 1185–1189. Denis AL, Guido M, Adler RD, Bergh PA, Brenner C, Scott RT. Antiphospholipid antibodies and pregnancy rates and outcome in vitro fertilization patients. Fertil Steril 1997; 67: 1084–1090. Buckingham KL, Stone PR, Smith JF, Chamley LW. Antiphospholipid antibodies in serum and follicular fluid – is there a correlation with IVF implantation failure? Hum Reprod 2006; 21: 728–734. Lee S-R, Park E-J, Kim S-H, Chae H, Kim C-H, Kang B-M. Influence of antiphospholipid antibodies on pregnancy outcome in women undergoing in vitro fertilization and embryo transfer. Am J Reprod Immunol 2007; 57: 34–39. Zhong Y-P, Ying Y, Wu H-T, et al. Impact of anticardiolipin antibody on the outcome of in vitro fertilization and embryo transfer. Am J Reprod Reprod Immunol 2011; 66: 504–509.
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