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Recurrent pregnancy loss, one of the crucial reproductive health concerns affecting 6% of couples. Clinically recognized pregnancy loss is familiar, occurring in approximately 15–25% cases of pregnancy. The most common cause of recurrent pregnancy loss is cytogenetic anomaly, antiphospholipid antibody, metabolic and hormonal disorders. However, approximately 50% cases of recurrent pregnancy loss remain unexplored. Recurrent pregnancy loss is correlated with specificity of antiphospholipid like anti-β2-glycoprotein-I antibodies, lupus anticoagulant, anti-cardiolipin antibodies, and anti-phosphatidylserine. aPL inhibits the release of human chorionic gonadotropin (HCG) hormone from placenta, trophoblast growth, migration, and cell adhesion while induce the inflammatory response in earlier pregnancy. Some clinical studies reported that occurrence of antiphospholipid during recurrent pregnancy loss is uncommon. In this time line article, we are focusing on the role of antiphospholipid in the recurrent pregnancy loss and clinico-diagnostic against recurrent pregnancy loss.
*Address all correspondence to: nilam2711@gmail.com
1. Introduction
Premature loss of pregnancy referred to spontaneous abortion or miscarriage is described as loss of clinical pregnancy after the 18 weeks of fertilization (gestational age-20 weeks). Guidelines from ESHRE (the European Society of Human Reproduction and Embryology) and ASRM (the American Society for Reproductive Medicine) interpret recurrent pregnancy loss or miscarriage was traditionally described as consecutive loss of 3 or more pregnancy [1, 2] prior to 24 weeks of gestational age and molar (characterized by superfluous placental growth owing to an atypical fertilization of egg) and ectopic (implantation of embryo outward the uterine cavity) pregnancies are not incorporated in definition set by ESHRE and ASRM. It is a frequent obstetric complication prevailing in approximately 15–25% of clinically recognized pregnancy [2] which is confirmed by histopathology or ultrasonography. Moreover, epidemiological studies have shown that the frequency of succeeding loss of pregnancy is 24% post 2 pregnancy losses while it is 30% and 40% after 3 and 4 subsequent pregnancy losses respectively [3, 4]. The prevalence of obstetric complications increases with maternal age (Figure 1) [5]. The patho-physiology of recurrent miscarriage differs according to age of gestation and maternal, however several mechanisms may merged at some points that induces the loss of pregnancy. The most familiar mechanisms are chromosomal abnormalities in the conceptus which inhibit the further development and disintegrate the interface between the fetus and maternal resulting in cramping, bleeding, and miscarriage. Several etiological factors have been associated with recurrent miscarriage but they influence only few cases of pregnancies which is still not clear. Approximately in case of more than 50% of women, the risk factor is not determined for pregnancy loss [6, 7]. Incidence of premature pregnancy loss is depending upon the method used by clinician to recognize the pregnancy. Approximately 50% of all conceptions are found to lost at pre-clinical stages due to failure of implantation or biochemical loss [1, 2, 8, 9] while clinically recognized pregnancies loss are reported in 9–20% of cases [9, 10], especially during 1st trimester (gestational age: 5–12 weeks) [11]. Week by week, the rate of miscarriage is varied during early pregnancy. One of the studies showed a sharp decline in the incidence rate by ~1% post twelve weeks of gestation [11] suggesting that in most of the cases the loss of pregnancy takes place shortly after implantation. Diagnosis of miscarriage is depend upon self-reporting (delayed menstrual cycle and pregnancy test at home) and clinical testing including histopathology, trans-vaginal ultrasonography and declining level of serum human chorionic gonadotrophin (hCG). Distinction must be made between embryonic, fetal losses and biochemicals because pregnancy loss is varied according to gestational age. Nonetheless, the prognostic utility of staging 1st trimester pregnancy losses on the basis of gestational age is not clear, hence it is not reported in the studies. Basically, discrimination between the 1st and 2nd trimester pregnancy loss is usually done in clinical practice. In most of the cases, risk factor (etiology) is not clear but several studies recognized the risk factors including uterine anatomic and chromosomal anomalies, endocrine anomalies, infections of endometrial, alloimmune causes, inherited thrombophilias, stress factors, exposure to environmental factors, genetic factors and antiphospholipid syndrome (Figure 2) [4, 12, 13, 14]. Several studies focused on the relationship between the presence of antiphospholipid and recurrent pregnancy loss and they reported the positive relationship [15, 16, 17]. A study conducted by Rai et al., [18] showed that fetal loss (≥10 weeks of gestation) is robustly linked with antiphospholipid in contrast to earlier pregnancy losses. In this review, we will discuss the clinic-pathological approach and analysis of the pathogenic association between recurrent pregnancy loss and antiphospholipid.
Figure 1.
Prevalence of recurrent pregnancy loss increases with age.
Antiphospholipid triggers the obstetric complications (or thrombosis) by influencing the functional aspect of various cells including monocytes, platelets and endothelial cells on the vascular side, decidual and trophoblast cells and neutrophils during the 1st trimester of pregnancy. Antiphospholipid interacts with these targets through multiple receptors including Toll-like Receptor (TLR)-9, TLR2, TLR4, heparan-sulphate, Annexin A2, glycoprotein (GP)-Iba and apolipoprotein E (APOE) receptor-20. On interaction with receptor, antiphospholipid activates the multiple intracellular mediators like PI3K (phosphatidylinositol 3-kinase)-AKT pathway, p38-MAPK (mitogen-activated protein kinase), NFk-B (nuclear factor k-B) resulting in the recruitment of mTOR and NLRP3 as well as Caspase-1 by the activation of NOX-2 (endosomal NADPHoxidase) [19]. Eventually, these signaling events induce the overexpression of various pro-inflammatory molecules (TNFα, IL-6, IL-8 and tissue factor). In spite of this, antiphospholipid interacts with various soluble molecules of coagulation and also activates the complement system. One of the in vivo studies showed that antiphospholipid induces the pro-thrombotic pathogenic potential in animals that are earlier challenged with lipopolysaccharide (LPS) or mechanical or photochemical trauma [20]. Antiphospholipid IgG is efficient to trigger the fetal loss in mice with pregnancy without 2nd hit which is necessary for occurrence of blood clotting for thrombophilic condition [20]. This might be owing to high expression of β2-glycoprotein-I (β2-GPI) at the physiological level. Decidual and trophoblast cells express anionic phospholipid on the cell membrane like phosphatidylserine which acts as an anchor for β2-GPI [20, 21]. An in vitro study conducted by Poulton et al., [22] showed that immunoglobulins from obstetric and thrombotic APS patients elicit different biological response because immunoglobulins extracted from obstetric patients impede the invasion of trophoblast in contrast to immunoglobulins extracted from non-obstetric patients. Antiphospholipid inhibits the progress of pregnancy by damaging the both ends of tissue: (1) Embryo side: Antiphospholipid disrupts this end by various ways; (a) impaired the trophoblast invasion through inducing the inhibitors of MMP (matrix metalloproteinase) resulting in down-regulation of MMP; (b) affect the differentiation of trophoblast by reducing the secretion of β-hCG; (c) promotes the apoptosis of trophoblast; (d) activation of conventional complement system that leads to synthesis of TNF-α culminating with recruitment of inflammatory molecules [20, 23, 24]. (2) Maternal side: impaired the endometrial angiogenesis by disrupting the ratio of angiogenic factors. Hence, there are 3 key mechanisms associated with pathogenesis of obstetric APS i.e. inflammation, complement activation and placental thrombosis. Antiphospholipid triggers the focal thrombosis at the terminal end of uteroplacental vascularization which culminates with placental infarction and impaired the blood exchange between maternal and fetus. In spite of this, antiphospholipid induces the placental thrombosis by disturbing the Annexin on epithelial and trophoblast cells that acts as A5 anticoagulant shield. One of the studies performed on antiphospholipid-positive placenta showed the decreased dispersion of Annexin A5 on the surface of intervillous [25]. Placental infarction occurs chiefly owing to an intra-luminal thrombus that occludes the spiral artery and it is a familiar histo-pathological manifestation in obstetric APS. Although few studies demonstrated that spiral artery thrombosis or placental infarction is not observed in the placenta isolated from 1st trimester abortions [26, 27] and suggested that placental infarction or spiral artery thrombosis might be implicated only for complications that occur during the late stage of gestational period [21] (Figure 3).
Antiphospholipid syndrome (APS), an autoimmune disorder in which auto-antibodies are developed against self molecules in the individuals such as in case of APS, auto-antibodies (antiphospholipid) binds with phospholipid binding proteins. APS is a causative agent of recurrent pregnancy loss [28] and a main clinical manifestation is thrombosis or recurrent pregnancy loss. In spite of this, renal impairment, thrombocytopenia, livedo reticularis and vulvular heart diseases. Approximately 10–15% of women with recurrent pregnancy loss are detected with APS [29, 30]. One of the studies showed that it occurs in approximately 38.6% of European women with APS [31]. van Dijk et al., [7] demonstrated that similar prevalence is found in both APS and women with 2 or women with 3 or more losses. The precise mechanism of recurrent pregnancy loss associated with APS is not clear. Several lines of evidence suggested that detrimental inflammatory response by autoantbodies on endothelial cells and placenta in contrast to thrombosis which is initially assumed for recurrent pregnancy loss [32, 33, 34]. Some of the studies based on humans demonstrated that excessive complement activation is responsible for early pregnancy loss [35]. Preclinical studies showed that antiphospholipid activates the complement resulting in recurrent pregnancy loss [36]. Another study supports this hypothesis as treatment with anti-C5 antibody prevents the fetal loss in pregnant mice injected with antiphospholipid antibody [37]. Thrombosis and recurrent pregnancy loss are
Thrombosis: It is the formation of blood clots inside the blood vessels which may be micro-vascular, venous and artery; may be all of these present in the same patients.
Recurrent Pregnancy Loss: Recurrent pregnancy loss is described as loss of 3 or more pregnancy. It excludes the ectopic and molar pregnancy and is the main feature in case of obstetrics.
The preliminary role of this approach is diagnosis and treatment of disease in individuals.
4.1 Diagnosis
Assessment and management of recurrent miscarriage must include the recognition of modifiable risk factor and avoid the invasive testing for perceived risk factor [38]. Multinational prospective studies are needed to improve the potency of diagnostic test especially in case of live birth rates in women with recurrent miscarriage.
4.1.1 Diagnosis: pregnancy loss
Reduction in the level of hCG hormone in the 1st trimester is indication of pregnancy loss, but further additional examination is required like histo-pathological examination (identification of placental villi). ELISA (enzyme linked immunosorbent assay) used to determine antiphospholipid and it is a popular method for detection of antiphospholipid by using purified antigens. ELISA is useful in evaluating the recurrent pregnancy loss by determining the antinuclear positive antibodies, especially to prevent the recurrent pregnancy loss during the 1st trimester. Basically, a solid phase Immunoassay is carried out on cardiolipin-coated plate (different coating for o detect the different antibody) usually in the presence of blocking agent (fetal calf or bovine serum) that consists of β2-glycoprotein-I which acts as antigenic epitope to anti-cardiolipin antibody and eventually leads to detection of antibody [39]. In spite of this, other diagnostic method include screening of POC (products of conception) and ultrasonography [1]. Trans-vaginal ultrasonography is considered as a gold standard for the testing of pregnancy loss (Table 1) while the exact diagnostic criteria are still under debate [40]. Obstetricians and Gynecologists of different countries have different setting associated with mean sac diameter (MSD) like in the USA; they consider the bare gestation sac with ≥16 mm MSD or CRL (crown rump length) with ≥5 mm and absence of heartbeat while MSD with ≥20 mm or CRL with 6 mm in the UK for diagnosis of pregnancy loss [41, 42]. False positive diagnosis may occur during the test of pregnancy due to this variability; hence, a strict criterion has been developed by the international committee of Obstetricians and Gynecologists i.e. MSD with ≥25 mm or CRL with ≥7 mm and absence of heartbeat [43]. This criterion has been confirmed by large multicentre prospective observational studies and also set criteria for follow up scan to verify the pregnancy loss like absence of heartbeat after 7 days of 1st scan of embryo with ≤7 mm CRL and failing to attain the doubled size in ≥14 days for vacant gestational sac with <12 mm MSD. In spite of this, estimation of concentration of progesterone hormone provides more information regarding the pregnancy loss [43]. Less than 10 μg/l concentration of progesterone hormone represents the robust indication of pregnancy loss [44]. In 2012, ASRM recommended the guidelines for absolute assessment of pregnancy loss in women having 2 clinically recognized pregnancy losses including evaluation of uterine anatomy, karyotyping of both parents, assessment of prolactin and thyroid hormone abnormalities and APS. ESHRE provide more extensive guidelines with a graded system for diagnosis of pregnancy loss that includes evaluation of the uterine cavity, APS and screening of thyroid. They also recommend the conditional guidelines for parental karyotyping and prolactin anomalies. Karyotyping diagnosis is used when couples were having enhanced risk of aneuploidy or couples having family history for abnormal translocation of chromosome or in case of congenital anomalies [1]. Contrarily, diagnostic test for prolactin anomalies are used when women possess manifestation of hyperprolactinaemia incuding women with amenorrhoea or oligomenorrhoea [1]. Both ESHRE and ASRM did not recommend the screening of thrombophilia and recommend thrombophilia screening only in case of individuals having family history of thrombophilia [1, 2]. Additionally, ESHRE did not also recommend the routine testing of chronic endometritis, POC, ovarian reserve and luteal insufficiency [1].
Screening of APS: Clinical guidelines recommended the identification of antiphospholipid antibodies including IgM & IgG anti-β2-glycoprotein-I, lupus anticoagulant and IgM & IgG anti-cardiolipin for the detection of APS in women with recurrent miscarriage (Table 1). Screening of anti-β2-glycoprotein-I is not performed in some countries including UK because weak association has been reported between anti-β2-glycoprotein-I and recurrent pregnancy loss as well as it provides less predictive outcomes [45]. APS is manifested by the existence of one laboratory and one clinical criterion:
Laboratory (replicated at the minimum of 2 times, >12 weeks apart);
+ve plasma level (high to medium) of anti-cardiolipin
+ve plasma level of lupus anti-coagulant
Clinical;
More than one established episodes of vascular thrombosis (Arterial, Venous and small vessel)
Obstetric complications including 3 or more subsequent loss of pregnancy at <10 weeks of gestational age, more than one fetal demise at >10 weeks of gestational age or premature birth at <34 weeks owing to placental insufficiency or dreadful pre-eclampsia
Parental karyotyping and cytogenetic analysis of POC: Reason behind the conducting the regular parental karyotyping owing to existence of a Robertsian translocation (chromosomal inversion, supernumerary chromosome or sex chromosome aneuploidy) or balanced reciprocal translocation which is accounts for 2–5% of couples with recurrent miscarriage (Table 1) [46, 47, 48]. According to ASRM guidelines, parental karyotyping provides valuable information about prognosis of succeeding pregnancies [10]. ESHRE clinical guidelines underline the successful collective live births even they have chromosomal anomalies, hence probability of recurrent miscarriage are greater but the probability of live birth is very low when the fetus have balanced translocation [1, 49]. ASRM notified the barrier associated with G-banding karyotyping examination i. e. adulteration of maternal tissue like in case of cell culture based analysis of G-banding karyotyping where probability of maternal contamination is high including selective expansion of mosaic cells or adulteration of 46XX embryos [50, 51]. Issues with adulteration of maternal tissue can be overcome CMA (24-chromosomal microarray) diagnostic testing of maternal blood. Although assays having greater sensitivity may recognize variants which have no impact on pregnancy loss or recognize the mosaicism that are restricted to placental cells [10, 52]. Hence, CMA is considered as gold standard test for the genetic evaluation of POC [51, 53]. One of the studies conducted on 22,451 miscarriage samples showed that approximately 59% of miscarriage samples possess chromosomal anomalies [51]. Additionally, CMA test has some limitations including detection of lesser number of mosaicism (<10–15%) and unable to identify the balanced structural rearrangement of chromosome that may promote the early pregnancy loss [54, 55]. A prospective study conducted on 100 women by using both CMA test and ASRM guidelines observed the probable clarification of pregnancy loss in approximately of 90% of women [56, 57]. Although, genetic testing of POC is not promising in case of outcomes in women with recurrent miscarriage while it only provide the reason for the pregnancy loss. Future numerous studies are needed to verify that regular genetic testing associated with POC must be an intrinsic part of psychological and clinical management of women with recurrent miscarriage.
Diagnostic Test for hormone anomalies: Assessment of prolactin in serum is not recommended for women with recurrent miscarriage except they possess the clinical symptoms for hyper-pro-lactinaemia [1, 10]. Screening and testing of thyroid function for the existence of thyroid peroxidase antibodies and TSH (thyroid stimulating hormone) are recommended for women who have recurrent miscarriage [1].
Evaluation of the uterine cavity: Estimation of the uterine cavity for acquired and congenital abnormalities is basically performed by using 3D-ultrasonography (Table 1) [1, 10]. MRI, saline-infused sonography or hysteroscopy can also be utilized particularly in case of unavailability of 3D-ultrasonography.
Investigation
Rational
Antiphospholipid antibodies (lupus anticoagulant & IgM and IgG anti-cardiolipin)
Approximately 15% of women have APS (antiphospholipid syndrome). Treatment with low dose aspirin and low molecular weight heparin significantly improves the outcomes of live-birth rate.
Parental karyotyping where testing POC (products of conception) which reports an unbalanced chromosomal anomaly
Whenever parental karyotype is unusual, there is a stronger prognosis for the following pregnancy. If unbalanced chromosomal abnormality perform parental karyotypes. Approximately 4% of couples have an unusual karyotype. Recommend for genetic counseling.
Trans-vaginal pelvic ultrasound scan
To determine ovarian morphology and uterine anatomy. Suspected uterine abnormalities may need further examination by using laparoscopy, hysteroscopy or 3D-pelvic ultrasound.
Table 1.
Diagnosis of recurrent pregnancy loss.
4.1.2 Diagnostic test
There are two broad tests to diagnose the APS (antiphospholipid antibodies):
ELISA: This is a biochemical assay to detect the ligand (more commonly protein) and it is employed to determine the antiphospholipid antibodies. Two different ELISAs (anti-2GPI and the anti-cardiolipin) are employed to diagnose the APS [57]. In this method, ELISA plate is coated with either the anionic phospholipid cardiolipin or 2GPI followed by adding the pre-specified diluted (1:50) serum of the patient. Further, add the secondary labeled antibody which helps to quantify the bound IgM or IgG isotypes [58]. The anti-cardiolipin ELISA recognizes the antibody that specifically binds to cardiolipin as well as other anionic phospholipids. Anti-2GPI ELISA recognizes the antibody that interacts with 2GPI which is coated on the surface on anionic phospholipid [59]. The anti-cardiolipin ELISA is less specific in contrast to anti-2GPI ELISA to diagnose the APS as it also detects non-specific antibodies present in the serum due to various infections [60]. To overcome this problem, retesting is recommended for antiphospholipid antibodies after 12 weeks of initial tests [57] and acts as a safety precaution against false positive readings. The advantages of ELISA to determine the antiphospholipid antibody are as follows: (1) Several samples can be analyzed at the same time, (2) It is independent of anticoagulant treatment and coagulation confounding factors.
4.1.3 Principle
In the standard for aCL or β2GPI ELISA, polystyrene plate is coated with cardiolipin/β2GPI in ethanol, and then dried the plate through evaporation of ethanol by placing the plate to air. Plate is blocked with a blocking agent (10% fetal calf serum, or 1% BSA) for 1–2 hours after washing the plate with PBS. Plate is again washed with PBS and then adds the patient’s sample at the dilution of 1/50–1/100. Sufficient number of standards must be taken to generate the standard calibration plot / curve. Microtitre plate is incubated for 2 to 3 hours; after incubation, the plate is washed again with PBS. Labeled (alkaline phosphatase) anti-human IgM or IgG is added to the plate at the appropriate dilution followed by incubation 1to 2 hours. The substrate (p-nitrophenyl phosphate) is added. 3 N NaOH is employed to prevent the reactions especially when standard calibration curve is reached to pre-determined OD (optical density). The estimation of aCL/β2GPI levels is determined from the standard calibration curve [61].
Lupus anticoagulant assay (LAC): There are several assays to perform the LAC assay in laboratories to detect the LAC including dRVVT (dilute Russell Viper Venom Test), dPT (dilute Prothrombin Time), STACLOT-LA (Hexagonal Phase Phospholipid Neutralization), KCT (Kaolin Clotting time), SCT (Silica Clotting Time), Tissue Thromboplastin Inhibition, and Platelet Neutralization Procedure. There are two other less commonly employed assays i. e. the Textarin:Ecarin Ratio and Taipan Venom Time [62]. Single assay is not enough to identify the all LAC antibody owing to the heterogeneity nature of LAC antibody. Hence, it is recommended that laboratories should be performing at least two assays to test the LAC antibody. LAC assay is based on coagulation and measures the in vitro clotting time of the plasma of a patient with respect to control samples which is called a screening test. Two further diagnosing test performed after prolongation time for clotting is noted: (1) To estimate the prolonged time for clotting is reversed after mixing (1:1 ratio) the plasma of patient with pooled plasma from normal healthy controls, (2) To estimate the prolongation of clotting time (observed in screening test) is reversed after the inclusion of surplus amount of anionic phospho-lipid. It is considered a confirmatory test. These tests are collectively known as LAC assays. Plasma sample is considered as positive (+) for LAC when prolonged coagulation time is not reversed after the mixing anionic phospho-lipid while it is reversed after addition of excess phospho-lipid [63]. Venom extracted from Russel viper is employed in the dRVVT assay in combination with dilute phosphor-lipids to trigger the activation of factor X. KCT, aPTT, and SCT assays stimulate the contact activation and they are compatible with automated analyzers [64].
4.2 Treatment: women possess +ve antiphospholipid
Identification of antiphospholipid has been progressively carried out in asymptomatic women, particularly for obstetrical reasons. In parallel, low titer detection of antiphospholipid is very common-the concurrence benchmark for APS do not comprise sero-positive anti-β2-GPI and anti-cardiolipin beneath the 99%-in patients with obstetric characteristics. Hence, it is not uncommon to grasp the authority to recommend treatment throughout the gestation period in healthy women with antiphospholipid.
Low dose of aspirin (LDASA): LDASA is a primary prophylaxis drug for the obstetric and also advisable in case of women without antiphospholipid to prevent the pre-eclampsia [58]. Several physicians are utilizing this drug to control the pregnant carriers of antiphospholipid especially in patients who have earlier experienced the 1 or 2 fetal loss or in case of coexistence of maternal risk factors like obesity, arterial hypertension, and age [59]. A macro-scale retrospective observational study demonstrated that outcomes of pregnancy may be beneficial without LDASA particularly in case of patients carrying low-risk antiphospholipid profile [60]. Another large cohort study performed on 73 pregnant antiphospholipid carriers (largely isolated lupus anticoagulant), LDASA treatment yielded a favorable pregnancy outcome which was equivalent to the control population [61]. A study carried out at multicenter by collecting 200 women carrying +ve antiphospholipid during pregnancy showed that approximately 18% of antiphospholipid carriers have adverse pregnancy outcome, similarly in case of thrombotic APS (24%) and obstetric APS (18%) [62]. Triple antiphospholipid sero-positivity is the only risk factor for adverse outcomes associated with pregnancy [62]. Further studies suggested that additional treatments (low molecular weight heparin or immunemodulatory treatment) are beneficial for patients with triple sero-positivity antiphospholipid carriers.
Low dose aspirin with low molecular weight heparin (LMWH): Patients with obstetric morbidness not fulfilling benchmark for APS have similar pregnancy outcomes to those patients with obstetric manifestations and shows beneficial outcomes after treatment with LDASA in combination with LMWH [63].
Hydroxychloroquine (HCQ): HCQ possesses the immunomodulatory properties and have been advised to be useful for pregnant women with antiphospholipid [64, 65]. Several lines of evidence based on experimental and animal studies showed that it is capable of antagonizing the antiphospholipid mediated inhibition of formation of trophoblast [64, 66, 67]. A retrospective study based on clinical studies validated the potency of HCQ in obstetric APS which is unmanageable with conventional treatment [68, 69, 70]. A randomized, placebo-controlled clinical trial (HYPATIA) proved the effectiveness of HCQ in treatment of pregnant antiphospholipid carriers [71]. Another concern about antiphospholipid sero-positive patients is the puerperium which is a high risk time-period for thrombosis.
Recurrent pregnancy loss is a crucial reproductive health problem globally. Several risk factors have been reported in the studies and effective treatment strategies are developed. True prevalence of recurrent miscarriage must be reported globally. Multicentre and international clinical trial studies must be carried out to identify the subgroups that get benefit from treatment. Further, unveiling the mechanism behind endometrial homeostasis and inter-cycle variability during decidual responses regarding recurrent miscarriage as well as determining whether the pregnancy loss itself impacts succeeding endometrial remodeling and placental function may enhance the understanding about endometrial homeostasis. Additionally, the prospective case–control studies are required in which individuals tested +ve for anti-β2GPI antibody to confirm that it can act as a most frequently detected biomarker in association with anti-HLA-DR for recurrent pregnancy loss.
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Written By
Nilam Bhasker
Submitted: 28 July 2021Reviewed: 25 August 2021Published: 23 June 2022
Open access peer-reviewed chapter
