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ORIGINAL ARTICLE
Year : 2021  |  Volume : 5  |  Issue : 3  |  Page : 161-173

Role of autoantibodies in infertility, miscarriage, and assisted reproductive technology outcomes


1 Laboratory for Reproductive Immunology, Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, China
2 Laboratory for Reproductive Immunology, Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China

Date of Submission15-Oct-2020
Date of Decision07-Jan-2021
Date of Acceptance09-Mar-2021
Date of Web Publication30-Jul-2021

Correspondence Address:
Ming-Qing Li
Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, No. 1326, Pingliang Road, Shanghai 200080
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2096-2924.322829

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  Abstract 


Although considerable advances have been made in the field of assisted reproductive technology (ART), millions of couples still suffer from infertility and miscarriage. In a large number of cases, the etiology of these common reproductive failures remains unknown. However, the significance of autoantibodies in infertility and miscarriage has sparked extensive interest because of their pleiotropic roles in disrupting normal pregnancy. This review discusses the pleiotropic roles of a series of autoantibodies in infertility and miscarriage. A brief recapitulation of how the autoantibodies interfere with ART outcomes and treatments for this type of idiopathic infertility or miscarriage is also provided. While several disputes remain to be resolved, further studies employing better designs and larger sample sizes are required in view of the therapeutic potential of autoantibody inhibitors and the future of contraceptive vaccines.

Keywords: Antiphospholipid Antibody; In Vitro Fertilization; Oocyte; Sperm; Zona Pellucida


How to cite this article:
Shen HH, Lai ZZ, Yang HL, Shi JW, Li MQ. Role of autoantibodies in infertility, miscarriage, and assisted reproductive technology outcomes. Reprod Dev Med 2021;5:161-73

How to cite this URL:
Shen HH, Lai ZZ, Yang HL, Shi JW, Li MQ. Role of autoantibodies in infertility, miscarriage, and assisted reproductive technology outcomes. Reprod Dev Med [serial online] 2021 [cited 2021 Dec 8];5:161-73. Available from: https://www.repdevmed.org/text.asp?2021/5/3/161/322829




  Introduction Top


Infertility refers to the failure to conceive despite at least 1 year of regular sexual intercourse without contraception, affecting approximately 50–70 million couples worldwide.[1] The problem is difficult to definitively diagnose and treat, since many patients are labeled as having “idiopathic infertility.” With advances in clinical and laboratory tests, recent studies have demonstrated that autoantibodies play an active role in infertility. Increased levels of autoantibodies are observed in women with infertility, and such elevated levels are considered to be indicative in the diagnosis of infertility and in monitoring treatment progress.[2]

Miscarriage can be divided into spontaneous abortion and recurrent pregnancy loss (RPL). The former refers to pregnancy loss before 28 weeks of gestational age, while the latter remains under debate. Some clinicians insist on three or more spontaneous and consecutive gestational losses, while a more accepted definition is the occurrence of more than two successive pregnancy losses.[3] Although this disorder is multifactorial, there is sufficient evidence that immunologic idiosyncrasies are major mediators in RPL. Previous studies have confirmed that the immune milieu in late-stage miscarriage is completely different from that in a first-trimester miscarriage, and the presence of a wide spectrum of autoantibodies is correlated with this disturbance. Pathogenic autoantibodies trigger a proinflammatory state in antiphospholipid syndrome (APS) and preeclampsia pregnancy, as neutrophils have been shown to release excessive neutrophil extracellular traps into the placental intervillous space, which results in endothelial dysfunction and vascular damage.[4] Similarly, when pregnant mice were administered murine and human monoclonal antiphospholipid (APL) antibodies, they exhibited fetal loss and growth restriction.[5] Concomitantly, treatment targeting these autoantibodies improves pregnancy outcome.[6]

However, many questions remain unaddressed. Why does the apparently high prevalence of autoantibodies interfere with the normal process of pregnancy? Is there a necessity to assess these autoantibodies in affected couples? In this review, we objectively examine the evidence surrounding associations involving autoantibodies and unexplained infertility (UI) and miscarriage [Figure 1] and [Table 1]. In addition, we discuss the potential use of autoantibodies as prognostic markers for pregnancy outcomes based on their roles in successful assisted reproduction cycles.
Figure 1: Potential adverse ripple effects during pregnancy arising from autoantibodies. (a) Normal pregnancy events encompass the development and maturation of sperm and oocytes, fertilization, receptivity, implantation, placentation, and fetal development. Defective early pregnancy events induced by autoantibodies (ASA, AEA, AOA, APL, ATA and ANA) veer the remainder of pregnancy off course, leading to adverse outcomes (e.g., infertility and miscarriage). (b) Adverse pregnancy events stemming from abnormally high levels of autoantibodies in preceding stages. Defective sperm and oocyte maturation and development and gamete fusion (left two stages) induced by autoantibodies (e.g., ASA, AZPA, anti-FSH, anti-hCG, ATA, and ANA) result in fertilization failure. Suboptimal receptivity/decidualization (third stage) and blastocyst attachment and implantation (fourth stage) triggered by autoantibodies (e.g., AEA, ASA, AZPA, anti-FSH, anti-hCG, and APL) can lead to implantation failure. In addition, autoantibodies (e.g., APL, ATA, AEA, ANA, and anti-hCG) can lead to miscarriage through defective trophoblast function, placentation, and/or fetal development (right stage). ASAs: Antisperm antibodies; AEAs: Antiendometrial antibodies; AOAs: Antiovary antibodies; AZPAs: Anti-zona pellucida antibodies; anti-FSH: Antibody against follicle-stimulating hormone; anti-hCG: Antibody against human chorionic gonadotropin; APL antibodies: Antiphospholipid antibodies; ATAs: Antithyroid antibodies; ANAs: Antinuclear antibodies.

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Table 1: Summary of common autoantibodies in human infertility and miscarriage

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  Antisperm Antibodies Top


The concentration of antisperm antibodies (ASAs) in infertile groups has been reported to be markedly higher than that in fertile groups,[7] and ASA titers in primary infertility are higher than those in secondary infertility.[8] When sperm antigens are exposed to the female immune system, an analogic inflammatory reaction and ASAs are produced. As shown in [Figure 2], ASAs have a negative effect on sperm capacitation and acrosome reaction, on their ability to pass through female genital secretions, and on gamete fusion, as well as in the initial stages of embryo development.[9],[10] Although the presence of ASAs does not affect sperm volume, viability, progressive motility, and sperm morphology, it significantly reduces the sperm liquefaction and sperm motility.[2] In addition, antibody-coated spermatozoa are susceptible to the deleterious effects of complement activation when entering the female genital tract, which interferes with sperm migration in the fallopian tubes.[11]
Figure 2: Pleiotropic roles of autoantibodies in key biological events during pregnancy. (1) Autoantibodies (e.g., ASA and anti-FSH) can impair spermatogenesis, sperm motility, the ability to penetrate cervical mucus, and capacitation; (2) Autoantibodies (e.g., ASA, AZPA, anti-FSH, anti-hCG, ATA, and AEA) can suppress oocyte development and result in anovulation and luteal phase deficiency; (3) Autoantibodies (e.g., ASA, AZPA, anti-FSH, and ATA) are involved in defective gamete fusion; (4) Hormones and trophoblast cells participate in the process of receptivity and decidualization. AEA can result in defective endometrial receptivity, decidualization disorders, and inflammatory responses by endometrial tissue; (5) Autoantibodies (e.g., ASA, AEA, APL, AZPA, anti-FSH, and anti-hCG) restrict blastocyst implantation, possibly through inhibiting trophoblast invasion and interactions between blastocysts and endometrium; (6) Autoantibodies (e.g., ASA, AEA, APL, AZPA, anti-FSH, and anti-hCG) can lead to impaired placentation and fetal development. Of note, increased inflammatory responses and thrombosis, defective trophoblast differentiation and invasion, spiral artery remodeling, and fetal growth are involved in these pathological events. CM: Cervical mucus. ASAs: Antisperm antibodies; AEAs: Antiendometrial antibodies; AOAs: Antiovary antibodies; AZPAs: Anti-zona pellucida antibodies; anti-FSH: Antibody against follicle-stimulating hormone; anti-hCG: Antibody against human chorionic gonadotropin; APL antibodies: Antiphospholipid antibodies; ATAs: Antithyroid antibodies; ANAs: Antinuclear antibodies.

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The effects of ASAs on the outcome of in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) are inconsistent. This discrepancy may result from different specimen preparations and test interpretations, owing to the lack of well-proven ASA test thresholds and natural biologic variation. In addition, the use of different testing methodologies for the detection of ASAs applied to different body materials (serum, seminal plasma, and sperm) precludes a uniform evaluation of the problem. Some authors believe that outcomes following IVF are affected, as the rate of fertilization and early human embryonic cleavage notably reduced in patients with high levels of surface-bound ASAs.[12] ART may reduce the inhibitory effects of ASAs bound to spermatozoa; other studies have shown that fertilization and clinical pregnancy rates in ASA-positive and -negative patient groups are comparable.[13],[14],[15] In contrast to natural and intrauterine insemination (IUI) pregnancy, a systemic review (10 IVF and 6 ICSI) reported that ASA levels had no measurable relationship with IVF and ICSI pregnancy rates, suggesting that ART remains a viable initial treatment for couples with semen ASA.[16] Of note, ASAs are too sticky to knock off sperm so that they may interfere with IVF. The number of included studies may not achieve statistical significance due to heterogeneity. Given the possible harmful effects of ASAs on embryo development and IVF outcomes, ASA detection should be implemented as a routine measure in fertility screening.

In terms of mechanisms underlying the effects of ASAs, infertility instead of recurrent abortion is more likely.[17] However, increased miscarriage rates in women with ASAs have also been reported in some cases.[18] The manner in which ASAs interfere with pregnancy, resulting in miscarriage, remains inconclusive, owing to the lack of adequate research involving their weak effects on miscarriage.

There are various treatment options for female patients with infertility who exhibit ASAs; these options include immunosuppressive drugs such as corticosteroids,[19] gamete intrafallopian transfer, sperm washing (alone or combined with intrauterine insemination),[20] and ICSI. Although sperm washing reduces the combination of sperm and ASAs, it disrupts embryo development and causes irreversible loss of sperm motility.[20] IVF is successful only when antibodies are located at the sperm tail. Thus, ICSI appears to be the optimal treatment for those with severe sperm autoimmunity, such as low sperm counts or sperm motility;[12],[21] however, this is not the case in normospermia.[22]


  Antiendometrial Antibodies Top


Antiendometrial antibodies (AEAs), closely associated with endometriosis,[23] have been extensively researched as a possible marker for endometriosis and reproductive failure.[24],[25] The mechanisms underlying AEA interference in reproduction can be diverse, and AEAs have been detected in patients with ovulatory disorders and tubal obstructions, as well as in patients with decreased endometrial receptivity and recurrent implantation failure. Generally, once AEA binding to specific antigens in the endometrium that are responsible for components in the implantation process, the embryo cannot survive at the implantation process because subsequent activation of the complement cascade may result in cellular damage to the embryo and endometrium.[26] Furthermore, abnormal autoimmunity can affect the reproductive process at various stages. AEA triggered by an inflammatory response in the female genital tract, such as the fallopian tube and the ovary, contributes to immunological infertility.[27]

First, establishing a successful pregnancy relies on implantation to build a bridge between the endometrium and the blastocyst. One significant reason for abnormal implantation and endometriosis-associated infertility is endometrial receptivity, which is necessary for the attachment, invasion, and development of embryos.[28] However, there is a discordant note regarding certain antigens associated with positive immune responses that are involved in endometrial receptivity, owing to the genetic background, various test methods, and the complexity of human endometrial proteins that fluctuate during menstrual cycles. Mathur et al.[29] and Rajkumar et al.[30] demonstrated the reactivity of AEAs against endometrial antigens with a molecular weight (MW) of 26 and 34 kDa through immunoblotting, whereas Switchenko et al. failed to demonstrate the presence of AEAs using this approach.[31] Unlike the study by Mathur et al., which reported that the 64 kDa endometrial antigens were only detected in patients with endometriosis,[32] in Gorai et al.'s western blot analysis, antibodies in the peritoneal fluid (PF) from endometriosis patients reacted against endometrial antigens with MWs of 26, 34, 38, 42, and 64 kDa and those from normal controls against 38, 42, and 64 kDa antigens.[33] In addition, immunoblotting studies revealed that two endometrial antigens of 60 and 66 kDa were recognized by more than half of patient sera positive for AEAs and that their expression was not dependent on the phase of the menstrual cycle.[34] Although multiple endometrial antigens were targeted in the work reported by Gajbhiye et al., 30 and 45 kDa antigens seemed to be predominant.[35] Meanwhile, when those authors chose immunohistochemistry to determine the antigenic endometrial cell types involved, more intense fluorescence staining was noted in the glandular luminal (epithelial) and glandular (epithelial) cells than in the stromal component of the normal endometrium.[35] Specifically, elevated levels of endometrial transferrin and alpha 2-HS glycoprotein were reported in the PF of patients.[36],[37] It is hypothesized that autoimmunity to transferrin causes ovarian dysfunction in these patients, involving anovulation, menorrhagia, and luteal phase deficiency. In experimental models, alpha 2-HS glycoprotein in the follicular fluid (FF) induced polyspermy by inhibiting the maturation-associated transformation of mouse zona pellucida (ZP) protein ZP3 to ZP3f.[38] Antibodies against transferrin and alpha 2-HS glycoprotein also hamper in vitro sperm motility.[36]

Inflammatory responses resulting from the combination of AEAs and endometrial antigens have caught the attention of investigators. The resulting reactive oxygen species contribute to the etiology of endometriosis-associated infertility.[39] Likewise, AEAs can recognize new oxidized protein epitopes generated due to oxidative stress in the endometrial cells.[24] The concentration of peritoneal macrophages is higher in women with infertility and endometriosis than in those with no endometriosis. Studies have also revealed that patients with infertility and endometriosis have significantly higher stem cell growth factor (SCGF)-β, interleukin 8 (IL-8), hepatocyte growth factor (HGF) and monocyte chemotactic protein-1 (MCP-1) levels than controls, in addition to abundant PF leukocyte populations and an increased percentage of cells positive for macrophage markers.[40] Regrettably, how AEAs lead to infertility and miscarriage remains poorly understood.

Some clinicians believe that patients with endometriosis and tubal factor infertility undergoing IVF can greatly benefit from the determination of AEA status to predict their pregnancy outcome.[41] Unlike CA125 testing, which has low sensitivity and specificity, especially in the early stages, the AEA assay shows remarkable sensitivity and specificity.[42] Hence, the AEA assay is expected to be a novel and noninvasive method for diagnosing and monitoring endometriosis[43],[44] as there can be a significant delay of more than a decade in the diagnosis of endometriosis.


  Antiovarian Antibodies Top


Various components of the ovary can be the targets of antiovarian antibodies (AOAs). Thus, antioocyte antibodies, anti-zona pellucida antibodies (AZPAs), antibodies against follicle-stimulating hormone (anti-FSH), antibodies against luteinizing hormone, and antibodies against human chorionic gonadotropin (anti-hCG), all belong to the family of AOAs.[45] It has been speculated that coating eggs with AOAs may affect oocyte and embryo development, prevent embryonic attachment to the endometrium, or prevent embryos from escaping from the ZP, thereby inhibiting implantation. Serum AOAs can be detected in premature ovarian failure (POF), systemic lupus erythematosus (SLE), polycystic ovary syndrome (PCOS), and autoimmune thyroid disease and may also be present after laparoscopic abdominal surgery, collection of oocytes for ART, and oophoritis. Among them, POF is the most studied and occurs in women aged ≠40 years, who present with amenorrhea, hypergonadotropic hypogonadism, and infertility.[46]

In animal studies, passive immunization with adsorbed antiovary serum or ovarian antigens produces ovary-reactive antibodies, resulting in a reduction in litter size and the appearance of infertile cycles.[47] Increased AOA levels were detected in patients with ovarian dysfunction.[48],[49] The association between POF and AZPAs has been extensively explored.[50],[51] ZP is primarily composed of three glycoproteins, ZP1, ZP2, and ZP3, which form sperm receptors throughout the ZP. ZP3, a self-antigen, plays a critical role in oocyte and gamete development. Immunization with ZP3 induces a strong immune response and the production of AZPAs. Therefore, ZP3 could be used as a potential antigen for developing contraceptive vaccines because of its inhibitory effect on sperm attachment and penetration through the ZP.[52] A substantial number of studies have confirmed the vital role of AZPAs in idiopathic infertility,[53],[54] and AZPAs may induce a diminished ovarian response in IVF cycles via immune responses.[55] Furthermore, AZPAs were harmful to the normal development of follicles and oocytes because they disrupted gap junctions between oocyte and granulosa cells.[55]

ART provides an opportunity to use human ovarian antigens for AOA detection assays. Several investigators have reported that high levels of these antibodies are correlated with a lower number of embryos and failed IVF cycles.[56] Those who experienced long-term infertility and repeated ovulation induction procedures without IVF were more likely to have high levels of AOAs.[57],[58],[59] Zou et al. suggested that anti-hCG treatment may cause miscarriage in women with infertility undergoing IVF and that this is correlated with decreased ongoing pregnancy rates.[60] Another member of AOA, anti-FSH, shares a relationship with FSH levels in women with male factor and tubal factor infertility. The concentration of anti-FSH is significantly elevated in women with infertility who exhibit disordered immune responses and repeatedly perform IVF;[61] anti-FSH levels have also been reported to be higher in patients with oligozoospermia and/or asthenozoospermia than in individuals with normal sperm count and motility. Therefore, the presence of anti-FSH is indicative of the number and quality of sperm in idiopathic male infertility.[62] In addition, Haller et al. found that circulating anti-FSH prevents ovarian responses to FSH stimulation during IVF.[63] Therefore, it will be helpful to assess the AOA levels before initiation of the IVF and embryo transfer (IVF–ET) program for the evaluation of ovarian responsiveness, and patients could further benefit from treatment with such antibodies.


  Antiphospholipid Antibodies Top


Brief introduction to antiphospholipid antibodies

APL antibodies, commonly referred to anticardiolipin (aCL) antibodies, including lupus anticoagulant (LA), and anti-beta-2-glycoprotein I (anti-β2GPI) antibodies, are a family of heterogeneous antibodies that are associated with thrombosis and a range of pregnancy failures, including UI, RPL, and implantation failure after IVF–ET.[64],[65] The targets of these antibodies range from phospholipids and certain blood proteins that bind to phospholipids to the complexes formed when proteins and phospholipids interact. Therefore, antibodies directed against plasma proteins such as prothrombin (PT), protein C, protein S, and annexin V also belong to this family.

In autoimmune diseases, to stabilize the antigenic conformation of cardiolipin, β2GPI is required for the recognition of aCL. Thus, aCL represents a mixture of antibodies against β2GPI and antibodies directed to phospholipid epitopes stabilized by interactions with β2GPI. β2GPI can inhibit thrombase activity, adenosine diphosphate (ADP)-activated platelet activation, and formation of platelet factor IX.[66],[67] Individuals suffering from complications from APL are diagnosed with APS, whose hallmark is pregnancy complications, including unexplained recurrent early pregnancy loss, fetal death, and premature birth.[68] In some cases, patients with RPL may be negative for aCL or LA but positive for other APL antibodies. Thus, to recognize patients with APL-associated pregnancy loss, other antibodies except LA and aCL are indispensable, such as anti-phosphatidylserine, anti-phosphatidyl ethanolamine, anti-phosphatidylcholine, anti-phosphatidyl glycerol, and anti-phosphatidylinositol.[69],[70],[71],[72]

Overview of associations with infertility, miscarriage, and assisted reproductive technology outcomes

Several studies have confirmed that the most common consequence of the presence of APL antibodies is miscarriage.[73],[74],[75] During pregnancy, the maternal immune system is faced with semi-allogenic antigens. To ensure the survival of the fetus, tolerance to fetal alloantigens must be induced and the degree of inflammation must be restricted by regulating Treg function.[76] Treg cells are vital for inducing tolerance to fetal alloantigens and limiting the intensity of immune responses. Depletion of Treg cells leads to embryo implantation failure and increases the production of proinflammatory cytokines.[77] In comparison with healthy women, patients with APL in circulation exhibit lower numbers of Treg cells and higher numbers of activated T- and pathogenic B-cells.[78],[79] NK cells are involved in trophoblast invasion and spiral artery remodeling. APL-positive women with infertility exhibit significantly lower levels of NK and NK T-cells than healthy women.[79] Thus, the abnormal immune status in these patients accounts for insufficient decidualization of the endometrium for embryo invasion.

Women with infertility are commonly screened for APL. Most studies suggest an association between infertility and anti-β2GPI antibodies and almost all noncriteria APL. However, the association rate was found to be below 50% for LA and aCL.[80] The relationship between APL and IVF outcomes remains controversial. Patients with aCL who did not receive any adjuvant treatment showed a significantly lower fertilization rate, fewer high-quality embryos, and markedly lower pregnancy and implantation rates than controls.[81] Similarly, a large cohort study suggested that the presence of aCL-immunoglobulin (Ig) G, aCL-IgM, and β2GPI-IgG might exert a detrimental effect in terms of IVF/ICSI outcomes.[82] However, a recent systematic review incorporated seven prospective studies and concluded that no relation existed between ART outcomes in terms of the number of clinical pregnancies and live births and the presence of APL.[83] Another review evinced 5 of 18 studies reported a detrimental effect of APL on ART outcomes.[80] Because of the lack of a definite causative link, some researchers thought that APL should not be included in the diagnostic panel for women with infertility.[84]

Collectively, the wide variability between study populations may contribute to different results. Although the recognition of cryptic epitopes by APL antibodies sheds light on APS heterogeneity, variations in study design and selection of controls may also be responsible for such discrepancies. The definition of RPL between studies also varies. Another concern is that assays for APL antibodies, other than those for aCL, are nonstandardized. Heterogeneity among the assays used further explains the inconsistent results observed. In the future, we need to conduct well-designed clinical studies with uniform positive values of APL antibodies, standardization methods for APL assays, and patients with a high-risk APL profile to better understand the effects of APL on fertility.

Potential role in diagnostic work-up

Given the above, should we encourage routine APL testing in all cases with implantation failure? Could high titers of APL be regarded as a temporary contraindication for undertaking IVF? Some obstetricians think that routine APL screening means little clinically and increases unnecessary anxiety and stress for both clinicians and patients. Moreover, despite the strong association with pregnancy loss, the presence of APL alone does not imply APS. It should be noted that women with APL antibodies have a greater risk of IVF failure or subfertility due to vascular impairment and insufficient decidualization of the endometrium before implantation.[85] It will miss almost 90% of APL-positive women if they are only tested for aCL.[86] Therefore, currently, women planning pregnancy via ART at the initiation of IVF should be tested for APL antibodies, usually in a “panel” assay containing at least five APL antibodies because of the risk conferred to a fetus and to expand treatment options.[87] Furthermore, they are required to receive anticoagulant therapy from the 1st day of the hormonal protocol to reduce thromboembolic complications. Therapy could be tailored for individuals to improve the outcomes of IVF programs.[84]

Mechanisms of action in “in vitro” and “in vivo” findings

The pathological processes that occur in pregnancies affected by APL involve placental infarction, impaired spiral artery remodeling, decidual inflammation, increased syncytial knots, decreased vasculosyncytial membranes, and deposition of cleaved complement product C4d.[88] APL antibodies impede oocyte development after their secretion into FF, interfere with endometrial decidualization, and negatively affect trophoblast proliferation.[89] APL antibodies can also inhibit the production of hCG and other hormones secreted by trophoblasts, as well as reduce the ability of extravillous trophoblasts to invade the maternal decidua.[90] The placenta is another target of APL antibody because it expresses phospholipids on the surface of villi, which are involved in the transfer of nutrients and oxygen from maternal blood.

Further, potential pathogenic effects on the placenta include activating the complement cascade through the classical innate pathway such that certain anaphylatoxins and mediators of effector cell activation are generated in large quantities.[91] Experimental data identified complement deposition at the decidual.[92] Meanwhile, complement activation triggers neutrophil recruitment, resulting in the release of proinflammatory cytokines.[93] According to recent research, defective decidual endovascular trophoblast invasion is the most common histological abnormality in APS-associated early pregnancy loss, rather than excessive intervillous thrombosis.[80] Collectively, the presence of APL antibodies suppresses trophoblast viability and invasion, increases trophoblast death, and reduces syncytialization.[90]

Treatment of patients with antiphospholipid

Overall, APLs either present in patients without previous thrombosis (primary thromboprophylaxis) or patients with APS who have already had a thrombotic event (secondary thromboprophylaxis). For primary thromboprophylaxis, low-dose aspirin and hydroxychloroquine (HCQ) are commonly prescribed.[94] Low-dose aspirin inhibits APL antibody binding to trophoblast cells and promotes implantation in early pregnancy.[95] However, HCQ works on platelet inhibition, reduction of β2GPI complexes binding to phospholipid surfaces, and reduction of APL titers.[96] For patients with definite APS, unfractioned heparin or low-molecular-weight heparin followed by long-term oral anticoagulation therapy is the most commonly treatment.[97] Guerin et al. demonstrated that heparin exerts beneficial effects in APS patients because it prevents the binding of β2GPI to phospholipids and potentiates the production of an inactive form of β2GPI by plasmin.[98] In addition to its anticoagulant effects, heparin has been shown to prevent trophoblast apoptosis.[99] Over the past decade, statins, rituximab, belimumab, eculizumab, sirolimus, defibrotide, and peptide therapy are considered as promising treatment options, which also effectively reduced the APL titers.[100] However, controlled trials are badly needed for each of these novel therapies.


  Antithyroid Antibodies Top


Role in miscarriage and infertility pathogenesis

Thyroid autoimmunity (TAI) is the most common autoimmune disorder in childbearing women, affecting 5%–20% of the female population. It refers to the presence of autoantibodies against thyroid peroxidase (TPOAb), thyroglobulin, and/or thyroid-stimulating hormone (TSH) receptor. With some exceptions,[101],[102] most studies support the notion that TAI is associated with miscarriage.[103],[104] Similarly, previous studies evaluating the clinical efficacy of levothyroxine in decreasing the miscarriage rate in euthyroid and ATA-positive women reported a decreased miscarriage rate, indicating their association.[103],[105]

TAI is also associated with infertility, which manifests as disturbed folliculogenesis, lower fertilization rates, and poorer embryo quality.[106],[107] Induced animal models showed that TPOAb positivity is correlated with poor fecundity and higher incidence of pregnancy loss by affecting postimplantation embryo development.[108] Although one study found that the antithyroid antibody (ATA) levels in UI and early pregnancy loss groups were similar to those in a control group,[109] most studies suggest that euthyroid women who are ATA+ have a higher prevalence of infertility and preterm delivery.[110] Furthermore, TPOAb positivity is associated with depressed antral follicle counts in women with diminished ovarian reserves or UI.[111] A recent study included 529 patients with normal thyroid function, suggesting that TPOAb positivity may be associated with PCOS and endometriosis.[112]

Women with ATAs are likely to develop subclinical hypothyroidism (SCH) or overt hypothyroidism.[113] SCH, characterized by elevated TSH concentrations accompanied by normal fT4 levels, has a higher prevalence than overt clinical hypothyroidism, especially at reproductive age.[114] A prospective cohort study in 3,315 women suggested that those with SCH and TAI were at an increased risk of miscarriage[115] and early intervention may avoid adverse pregnancy outcomes and complications.[116]

Relationship with assisted reproductive technology outcomes

The impacts of ATAs on pregnancy outcomes following IVF–ET are inconsistent. Some studies revealed that they were detrimental to the pregnancy outcomes.[117],[118] Other studies present the opposite results.[119],[120],[121] Litwicka et al. verified a strong association between ATAs and unsatisfactory IVF outcomes; prednisolone treatment could improve the pregnancy rate and reduce miscarriage frequency after IVF in women affected by TAI.[122] Moreover, oocyte fertilization, incidence of grade A embryos, implantation, and pregnancy rates in ATA+ women are lower than those in ATA controls.[123],[124] However, TAI in euthyroid women does not seem to impair ART outcomes.[125],[123],[127] A recent meta-analysis showed that the presence of ATA did not affect the rates of fertilization and implantation. However, it may have a detrimental effect on the course of a pregnancy, influencing miscarriage and live birth rates.[128]

Mechanisms of action in “in vitro” and “in vivo” findings

It has been suggested that women with ATA show abnormal T-cell function, hyperactive polyclonal B-cells, and a lack of Vitamin D.[107] Further, ATA may directly interfere with trophoblast differentiation and proliferation by targeting ZP, hCG receptors, and other placental antigens.[129],[130] TPOAb can be transferred to the baby via the placenta and TPOAb-positive euthyroid women were more likely to have elevated TSH. Ab-mediated thyroid hypofunction, cross-reactivity of ATA with hCG receptors on the ZP, and increased levels of endometrial cytokines in women with TAI all contribute to the pregnancy loss or infertility.[129] Another explanation proposes that reproductive problems in those with high titers of autoantibodies exist in an attempt to protect the next generation from the transmission of autoimmune genes.[131] The interplay between the hypothalamic–pituitary–thyroid axis and the hypothalamic–pituitary–ovarian axis may also be responsible.

Therapeutic applications and clinical trials

Generally, screening for thyroid autoimmunity should be performed as part of the work-up for women with infertility or miscarriage. Many trials have been conducted to evaluate the efficacy of levothyroxine treatment in reducing obstetric risk. Negro et al. found that the miscarriage rate and poorer delivery rate were higher in a TPOAb+ group than in a TPOAb− group, whereas the pregnancy rate was unaffected by the presence of TPOAb or treatment with levothyroxine.[132] Another prospective trial performed in women with infertility and SCH revealed that the rates of pregnancy and delivery were significantly increased and the miscarriage rate was reduced in a levothyroxine treatment group compared with those in a placebo cohort.[133] Therefore, it is suggested that women of childbearing age with SCH should be administered levothyroxine to achieve successful pregnancy outcomes.[134] However, a recent study recruited 600 TPOAb-positive women with normal thyroid function to determine the effectiveness of levothyroxine in miscarriage. Surprisingly, both miscarriage and live birth rates were comparable between the groups with and without levothyroxine, and levothyroxine did not improve pregnancy outcomes.[135] This discrepancy may result from placebo effects and/or ethnic differences. Furthermore, the levothyroxine dosage employed was relatively low, which might have diminished the effects of levothyroxine. A recent guideline for the management of TAI during pregnancy does not recommend intravenous Ig treatment of euthyroid women with a history of RPL. Given its potential benefits, administration of LT4 to TPOAb-positive euthyroid pregnant women with previous miscarriage is weakly recommended, while SCH infertile women and those undergoing IVF or ICSI should be treated with LT4.[104] For overt hypothyroidism, if it was diagnosed for the first time in pregnancy, it is better to start a weight-based dose of 2 mcg/kg a day.[136]


  Antinuclear Antibodies Top


Brief introduction to antinuclear antibodies

The term antinuclear antibodies (ANAs) refer to a wide spectrum of nonorgan-specific autoantibodies targeting the contents of the cell nucleus, including anti-dsDNA, anti-RNA, and extractable nuclear antigen (ENA) antibodies. High titers of ANAs are often used as biomarkers for autoimmune diseases, including SLE and rheumatoid arthritis, while low titers can sometimes be detected in healthy individuals. However, it is unclear whether these ANA levels reflect abnormal immune reactions in these patients or if they may have direct harmful effects.[137]

Role in infertility and reproductive failure pathogenesis

ANAs can impair oocyte quality and embryo development, leading to reduced pregnancy and implantation rates.[138] Anticentromere antibodies not only hinder oocyte maturation from MI to MII but also interfere with embryo cleavage.[139],[140] Similar findings were reported by Ying et al. They identified that the number of available high-quality embryos, proportion of MII oocytes and two pronuclear zygotes, and cleavage rates in an ANA+ group were markedly lower than in an ANA− group.[141]

At present, concentrated efforts have centered on the importance of ANAs in IVF implantation failure. Kikuchi et al. found that the presence of ANA reduced pregnancy and implantation success in the first IVF–ET or ICSI–ET cycles.[142] Their ANA+group also exhibited significantly lower MII oocyte rates, normal fertilization, and pregnancy and implantation rates, as well as remarkably higher levels of abnormal fertilization and early miscarriage rates.[143] In addition, ANA concentrations are inversely correlated to the number of good-quality embryos obtained.[144]

RPL patients also have highly elevated ANA levels.[145],[146],[147] The presence of anti-Ro (SSA) and anti-La antibodies[148],[149] may increase the risk of fetal wastage due to congenital heart block caused by the binding of anti-Ro/SSA antibodies to cardiac conductive tissue and to the consequent inflammatory/fibroid reactions.[150],[151] Moreover, anti-Rib-p, anti-Jo-1, and anti-dsDNA antibodies are also associated with a higher risk of fetal loss[152] because they can enter living cells and induce apoptosis. In addition, anti-dsDNA and ENA antibody positivity may cause immunologic inflammation in the placenta and thereby affect pregnancy outcomes.[153]

Treatment for women with ANAs is inconsistent. Although some studies have confirmed the efficacy of therapeutic drugs such as glucocorticoids alone[154] or glucocorticoids combined with aspirin,[155] there are various viewpoints regarding the drug selection, initial treatment time, dosage of drug, and period of treatment. Other studies revealed that the absence of therapeutic intervention in ANA+ patients can also help achieve normal pregnancy outcomes and that the cumulative pregnancy rates in ANA+ and ANA− groups are similar.[142] Thus, it is unclear whether ANA+ patients should be treated. Since cross-sectional studies cannot prove causation, prospective studies with large sample sizes are needed to demonstrate the significance of ANA positivity in pregnancy and the underlying pathogenic mechanisms involved.


  Conclusions and Future Perspectives Top


Here, we reviewed the spectrum of autoantibodies that may be responsible for conditions involving several stages in the reproductive process, including fertilization, implantation, and placental development. It is difficult to determine whether these autoantibodies are produced by stimulated immune system activation, abnormal hormone responses, or mechanical stress induced by improper medical practice. A battery of treatments for women with autoimmune antibodies has been applied in clinical practice; however, the validity and efficacy of these therapeutic interventions remain unclear owing to various methodological and design drawbacks involving previous data. Future studies will be undertaken to provide more accurate information regarding the antibodies that should be measured and those that are suitable for clinical evaluation.

Evaluating autoantibody abnormalities in all suspected cases of autoantibody-associated reproductive failure is worthwhile as a result of improved clinical care for affected patients. By identifying the causes of IVF failure and selecting suitable therapeutic strategies for individuals, significant improvements in IVF outcomes can be achieved. As such autoantibodies play a critical role in UI, miscarriage, and repeated IVF failure, the development of autoantibody inhibitors and contraceptive vaccines might prove to be valuable in the treatment of numerous patients.

Financial support and sponsorship

This study was supported by the National Natural Science Foundation of China (NSFC) (Nos. 31970798, 31671200, the Innovation-oriented Science and Technology Grant from the NPFPC Key Laboratory of Reproduction Regulation (CX2017-2), the Program for Zhuoxue of Fudan University, (JIF157602) and the Support Project for Original Personalized Research of Fudan University.

Conflicts of interest

There are no conflicts of interest.



 
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