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Multiple factors contribute to recurrent pregnancy loss (RPL). This review highlights the latest international guidelines for RPL workup, including immunological testing, by the American Society for Reproductive Medicine (ASRM), the European Society of Human Reproduction and Embryology (ESHRE), and the Royal College of Obstetricians and Gynaecologists (RCOG). These three societies recommend testing for antiphospholipid syndrome. ESHRE and RCOG also recommend thyroid peroxidase antibody testing, whereas ASRM does not. All guidelines advise against testing of natural killer cells, cytokines, antinuclear antibodies, human leukocyte antigen (HLA) compatibility, anti-HLA antibodies, and anti-sperm antibodies. However, when following ASRM, ESHRE or RCOG diagnostic guidelines, over 50% of cases have no identifiable cause. Genetic testing of products of conception (POC) can improve our understanding of unexplained RPL as aneuploidy is a common cause of RPL. Based on studies reporting results from chromosomal microarray analysis (CMA) of POC, we propose a novel algorithm for RPL evaluation. The algorithm involves following evidence-based societal guidelines (published by ASRM, ESHRE, or RCOG), excluding parental karyotyping, in combination with CMA testing of miscarriage tissue. When utilizing this new evaluation algorithm, the number of unexplained cases of RPL decreases from over 50% to less than 10%. As a result, most patients are provided an explanation for their loss and healthcare costs are potentially reduced. Patients with an otherwise negative workup with euploid POC, are classified as "truly unexplained RPL". These patients are excellent candidates for enrollment in randomized, controlled trials examining novel immunological testing and treatment protocols., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The purpose of this study was to determine the efficacy of intestinal tract immunization in the induction of specific antibodies in human female genital tract secretions. Live attenuated typhoid vaccine Ty 21a was administered to three groups of healthy female volunteers, who were not using hormonal contraceptives. Group 1 included 15 women vaccinated orally. Group 2 included seven of the same women, who were vaccinated rectally 6 months later. Group 3 included 11 volunteers, who were vaccinated rectally. Salmonella-specific antibodies of IgG and IgA were measured in vaginal lavage and cervical mucus after oral or rectal primary vaccination. Salmonella-specific antibodies measured 1 month after rectal booster vaccination demonstrated significant increases in vaginal fluids and cervical mucus and were dominated by IgA. These results indicate that specific antibodies in the human female genital tract induced by primary vaccination can be enhanced by subsequent rectal administration of vaccines.

Mucosal immunity in the female reproductive tract is influenced by immunoglobulins (Igs), cytokines, and reproductive hormones. Previous studies of reproductive-aged women demonstrated that IgA and IgG increases in cervical mucus corresponded to elevated levels of IL-1beta which occurred 1 day before the peak of endogenous estradiol production prior to ovulation. We sought to determine the effect of exogenous hormones on reproductive tract immunity in women on oral contraceptive pills (OCPs) and to compare the results with respect to naturally cycling women. Twelve women of reproductive age who had negative cervical cultures, a normal pap smear, and agreed to abstain from sexual intercourse during the study initiated OCPs. Cervical mucus and vaginal washes were collected at six intervals (2-3 days apart) throughout the treatment cycle. Fifteen naturally cycling women had similar samples collected prior to, during, and subsequent to ovulation. Cervical mucus samples were assayed for IgA, IgG, IL-1beta, IL-6, and IL-10 by enzyme-linked immunosorbent assay (ELISA). IgA, IgG and IL-1beta levels in women on OCPs paralleled increasing levels of norethindrone. Mean values of IgA increased from a low of 14.4+/-3.1 to 41.1+/-9.4 mg/dl and decreased significantly after the cessation of the pills (P < 0.001). In naturally cycling women, the largest quantities of Igs were detected prior to ovulation. By comparison, mean values of IgA in the cervical mucus of women on OCPs (24.4 mg/dl) exceeded peak levels of IgA in the cervical mucus of naturally cycling women (14.6 mg/dl). IgA was the predominant Ig detected in cervical mucus of women on OCPs. Both immunoglobulins in each group exhibited changes relative to their hormonal status. The increased levels of IgA in the cervical mucus of women on OCPs may explain the clinical observation of a lower incidence of sexually transmitted diseases.

The antiphospholipid antibodies (APA) are acquired antibodies against a phospholipid which has been associated with slow progressive thrombosis and infarction in the placenta. Clinical features (venous or arterial thrombosis, recurrent fetal loss, thrombocytopenia) in conjunction with positive laboratory findings (positive IgG or IgM anticardiolipin antibodies, or positive lupus anticoagulant tests) will satisfy criteria for diagnosis of the antiphospholipid antibody syndrome (APS). A number of studies report the incidence of antiphospholipid antibodies in different patient populations: normal obstetrical patients (5.3% of 7278 women), women with recurrent pregnancy loss (20% of 2226 women), women with systemic lupus erythematosus (37% of 1579 women) and, more recently, women undergoing in vitro fertilization (24% of 3343 women). As in all autoimmune syndromes it is possible that APA are secondary to some underlying disease or that they are instrumental in the pathogenesis of the various manifestations. The most commonly proposed mechanisms of antiphospholipid antibody induced thrombosis include decreased prostacycline production by endothelial cells, increased thromboxane production by platelets, and decreased protein C activation. More recently it has been demonstrated that certain phospholipids are exposed on the endothelial surface and may alter implantation during in vitro fertilization. Treatment with subcutaneous heparin and aspirin has been shown to benefit women with recurrent pregnancy loss and APA resulting in successfully deliveries of approximately 75%. Several trials of treatment with heparin and aspirin in women with positive APA undergoing IVF have been completed. Although none of the studies were randomized, prospective, blinded trials there does not appear to be a significant difference in implantation rate, pregnancy rate, or ongoing pregnancy rate. This subject remains, however, an area of active investigation as antiphospholipid antibodies have been shown to interact with syncytiotrophoblast and cytotrophoblast layers and could theoretically affect implantation.

Several laboratories currently offer panels of serum autoantibody assays to screen women with unexplained infertility and those undergoing in vitro fertilization (IVF). Offering these tests implies that they have predictive value for the outcome of proposed infertility treatments such that the results of the testing would alter clinical management. Because screening for antiphospholipid antibodies adds expense to already costly procedures, it is an appropriate time to review the justification for the use of these panels.

The goal was to determine what proportion of pregnant women with unexplained elevations of maternal serum alpha-fetoprotein (MSAFP) have increased levels of anticardiolipin antibodies (ACA), and if this might explain the increased prevalence of adverse pregnancy outcomes. Maternal serum alpha-fetoprotein levels of 12,295 pregnant women were evaluated at 15-19.5 gestational weeks. Elevated readings (> 2.5 MOM) were identified in 190 women (1.5%) and 86 (0.7%) of these had unexplained causes. Specimens (80) were recovered and ACA levels for cardiolipin were determined using enzyme-linked immunosorbant assay. Positive IgG ACA were identified in 10 out of 80 cases (12.5%) of elevated MSAFP; 3 out of 80 cases (3.8%) had positive IgM ACA. The control women with normal MSAFP levels had positive IgG ACA in 3 of 86 cases (3.5%) and 1 of 86 cases (1.2%) for IgM. Women with increased MSAFP and positive ACA had infants with an average birth weight of 2684 +/- 889 g compared to 2793 +/- 847 g in women with increased MSAFP and normal ACA. No significant differences in IgG ACA were found in pregnant women with unexplained elevated MSAFP (10/80, 12.5%) compared to women with normal MSAFP (3/86, 3.5%). As expected, lower birth weight was identified in women who had elevated MSAFP (2738 +/- 868 g) vs. women with normal MSAFP 3181 +/- 1082 g (P = 0.004), independent of ACA positivity.