Unexplained Recurrent Pregnancy Loss Research Articles

Immunohistochemical study of MMP-2, MMP-9, EGFR and IL-8 in decidual and trophoblastic specimens of recurrent pregnancy loss cases

Background and Aim: Unexplained recurrent pregnancy loss has been a a challenging research task to experts since there is no explicit pathophysiological mechanism and therefore, the treatment remains elusive. Immunological imbalance and morphological abnormalities are under investigation. This study aims to evaluate the implication of MMP-2, MMP-9, EGFR, and IL-8 in recurrent pregnancy loss cases. Materials & Methods: The study was carried out through comparison among two groups; the unexplained miscarriage group which consisted of 22 women, and the control group consisted of 18 women, who had electively terminated their pregnancies. Both groups were in the first trimester of gestation. The specimens included the trophoblast, decidua basalis, and decidua parietalis. The study was conducted via immunohistochemical methods. Antibodies were used against MMP-2, MMP-9, EGFR, and IL-8. The results were presented at a contingency table and were statistically analyzed with the Chi-Square Test (X2). Results: There were remarkable disparities in some cases in the comparison of the two groups. MMP-9 was detected significantly high in recurrent pregnancy loss (RPL) cases, both on trophoblastic and decidual specimens (p-value < .00001), MMP-2 displayed no difference among the two groups (mild to moderate detection on trophoblast and almost negative on decidual tissues). EGFR was highly detected in trophoblastic tissue (p-value = .014). IL-8 detection was particularly different in both trophoblast and decidua parietalis of the two groups (p-value < .01). Conclusion: The study revealed both morphological and immunological dysregulations that might participate in the RPL pathogenesis.

High mobility group box 1 in women with unexplained recurrent pregnancy loss.

To investigate whether high mobility group box 1 (HMGB1) is involved in unexplained recurrent pregnancy loss (uRPL). Plasma levels of HMGB1 were measured by ELISAin non-pregnant women with (n=44) and without (n=53 controls) uRPL. Their platelets and plasma-derived microvesicles (MVs) were also assayed for HMGB1. Endometrial biopsies were taken in selected uRPL (n=5) andcontrol women (n=5) and the tissue expression of HMGB1 was determined by western blot and immunohistochemistry (IHC). plasma levels of HMGB1 were significantly higher in women with uRPL than in control women. HMGB1 content in platelets and MVs obtained from women with uRPL was significantly higher than that obtained from control women. HMGB1 expression in endometrium was higher in tissues obtained from women with uRPL than in tissues obtained from control women. IHC analysis revealed that HMGB1 is expressed in endometrium with different patterns between uRPL and control women. HMGB1 could be involved in uRPL.

Thrombophilic gene polymorphisms and recurrent pregnancy loss: a systematic review and meta-analysis.

Recurrent pregnancy loss (RPL) is affecting 1-4% of women who conceive approximately, and no cause could be found in more than 50% of women suffering from RPL. Inherited thrombophilias have got increasing attention in women with unexplained RPL, so we aim to explore the relationship among these most common thrombophilic polymorphisms and RPL through a literature review and meta-analysis. Observational studies from PubMed, Embase, Cochrane, and Web of Science from 1997 to 7 April 2022 were searched. For each genetic variant, a fixed or random-effect model was used according to the heterogeneity test to calculate pooled ORs and 95% CIs for both dominant and recessive genetic models. Egger's line regression test was used to assess publication bias. The quality of the included articles was assessed by the Newcastle Ottawa scale. A total of 124 articles comprising 17,278 RPL patients and 16,021 controls were included. Results showed that hyperhomocysteinemia (MTHFR) C677T (dominant model: OR, 1.43; 95% CI, 1.25-1.64; recessive model: OR, 1.60; 95% CI, 1.36-1.87), MTHFR A1298C (dominant model: OR, 1.66; 95% CI, 1.26-2.18; recessive model: OR, 1.79; 95% CI, 1.42-2.26), PAI-1 4G/5G (dominant model: OR, 1.67; 95% CI, 1.36-2.06; recessive model: OR, 1.80; 95% CI, 1.39-2.32), angiotensin-converting enzyme I/D (OR, 1.23; 95% CI, 1.00-1.53), Factor XIII V34L (OR, 1.38; 95% CI, 1.02-1.87), and β-fibrinogen-455G/A (OR, 1.60; 95% CI, 1.02-2.51) were significantly associated with RPL. This study provides potentially useful clinical markers to evaluate the risk of RPL or to help unexplained RPL patients identify possible causes, which may allow for targeted treatment.

Platelet distribution width and the risk of unexplained recurrent pregnancy loss: a meta-analysis.

Changes of platelet distribution width (PDW) have been observed in women with unexplained recurrent pregnancy loss (URPL). However, relevant previous studies showed inconsistent results. We performed a meta-analysis to comprehensively evaluate the association between PDW and URPL. Observational studies reporting the difference of PDW between women with and without URPL were retrieved by searching PubMed, Embase, Web of Science, Wanfang, and CNKI. A random-effect model was used to pool the results by incorporating potential heterogeneity. Eleven case-control studies with 1847 women with URPL and 2475 healthy women were included. Age was matched for all studies between cases and controls. Pooled results showed women with URPL had significantly increased level of PDW (mean difference [MD]: 1.54%, 95% CI: 1.04 to 2.03, p < 0.05; I2 =77%). Subgroup analysis showed consistent result for URPL defined as ≥ 2 (MD: 1.45%, p = 0.003) and ≥ 3 (MD: 1.61%, p < 0.001) failed clinical pregnancies, and in studies compared to women with normal pregnancy (MD: 2.02%, p < 0.001) and non-pregnant healthy women (MD: 1.34%, p < 0.001). Results of the meta-analysis also showed that increment of PDW was associated with higher odds of URPL (per 1 unit, odds ratio: 1.26, 95% CI: 1.17 to 1.35, p < 0.001; I2 = 0%). Women with URPL had significantly increased levels of PDW compared to healthy women without URPL, which suggest that higher PDW may predict the risk of URPL.

Assessment Of Endometrial Integrin Beta 5 In Women With Unexplained Recurrent Pregnancy Loss.

To examine the relationship between endometrial integrin beta 5 level and risk of recurrent pregnancy loss. The descriptive, prospective, observational, case-controlstudy was conducted at the Kafrelsheikh University Hospital, Egypt, from January to May 2022, and comprised women aged up to 35 years with at least 1 live birth delivery beyond 20-week gestation with normal thyroid and prolactin levels. Age-matched normal fertile women were enrolled as controls. All the participants were subjected to detailed history and complete clinical examination. Endometrial integrin beta 5 was assessed using an antibody sandwich enzyme-linked immunosorbent assay. Data was analysed using SPSS 20. Of the 50 subjects, 25(50%) were cases with a mean age of 26.72±2.64 years, and 25(50%) were controls with a mean age of 25.36±2.16 years. The integrin beta 5 level was significantly lower among the cases than the controls (p<0.05). The best cut-off level of serum integrin beta 5 was ≤2.5765 with area under curve 0.886, sensitivity 88%, specificity 76%, positive predictive value 78.6%, negative predictive value 86.4%, and accuracy 82%. Therewas an inverse correlationbetween endometrial integrinbeta 5 andthe risk ofrecurrentpregnancy loss.

Endogenous retrotransposons cause catastrophic deoxyribonucleic acid damage in human trophoblasts

To determine the mechanistic role of mobile genetic elements in causing widespread DNA damage in primary human trophoblasts. Experimental ex vivo study SETTING: Hospital-affiliated University PATIENT(S): Trophoblasts from a patient with unexplained recurrent pregnancy loss and patients with spontaneous and elective abortions (n=10) INTERVENTION(S): Biochemical and genetic analysis and modification of primary human trophoblasts. To phenotype and systematically evaluate the underlying pathogenic mechanism for elevated DNA damage observed in trophoblasts derived from a patient with unexplained recurrent pregnancy loss, transcervical embryoscopy, G-band karyotyping, RNASeq, qPCR, immunoblotting, biochemical and siRNA assays, and whole-genome sequencing were performed. Transcervical embryoscopy revealed a severely dysmorphic embryo that was euploid on G-band karyotyping. RNASeq was notable for markedly elevated LINE-1 expression, confirmed with qPCR and that resulted in elevated expression of LINE-1-encoded proteins, as shown by Immunoblotting. Immunofluorescence, biochemical and genetic approaches demonstrated that overexpression of LINE-1 caused reversible widespread genomic damage and apoptosis. De-repression of LINE-1 elements in early trophoblasts results in reversible but widespread DNA damage.

The effect of MicroRNAs variants on idiopathic recurrent pregnancy loss.

Although the importance of miRNA variants in female reproductive disorders has been frequently reported, the association between miRNA polymorphisms and recurrent pregnancy loss (RPL) has been poorly studied. In this study, we aimed to assess the correlation of four different miRNA variants to unexplained RPL. The prevalence of four SNPs including miR-21 rs1292037, miR-155-5p rs767649, miR-218-2 rs11134527, and miR-605 rs2043556 in 280 cases with iRPL and 280 controls was performed. The DNA was extracted from all subjects and the SNPs were genotyped using RFLP-PCR methods. The data revealed that rs1292037 and rs767649 were significantly associated with higher rates of iRPL in patients compared with controls while rs11134527 and rs2043556 showed no association with increased rates of iRPL among patients. The haplotypes T-A-G-G and T-A-G-A were the most frequent in both cases and controls. Three haplotypes including T-T-G-A, C-T-G-G, and T-A-A-A showed significantly different frequencies in patients in comparison to healthy females. This study suggests that rs1292037 and rs767649 could be risk factors for increased rates of iRPL.

Effect of low-molecular-weight heparin in women undergoing frozen-thawed embryo transfer cycles: a retrospective cohort study

BackgroundRecurrent pregnancy loss (RPL) and recurrent implantation failure (RIF) during in vitro fertilization (IVF) treatment are still tough problems without effective treatments; thus, they are important research topics. There is controversy on whether low molecular weight heparin (LMWH) improves pregnancy outcomes in women with unexplained RPL and RIF. Moreover, currently, there is a paucity of reports on the role of LMWH in the entire population undergoing frozen-thawed embryo transfer (FET) cycles. This study aimed to estimate the effects of LMWH on pregnancy outcomes in women undergoing FET cycles.MethodsThere were 1881 female patients included in the study. Of the 1881 patients, 107 underwent preimplantation genetic diagnosis cycles, which were analyzed individually. The patients were divided into two groups: the LMWH group received injections of 4100 IU/d LMWH from the day of transfer until 14 ± 2 days posttransplant, the control group was the comparison group (without LMWH use). The baseline characteristics and reproductive outcomes of the patients were reviewed.ResultsOf the 1774 women with normal FET cycles, no significant differences were found in the number of embryos implanted (1.31 ± 0.02 vs. 1.28 ± 0.02), embryo implantation rate, biochemical pregnancy rate, clinical pregnancy rate, live birth rate, late abortion rate, and ectopic pregnancy rate between the two groups. The LMWH group had a higher early abortion (17.8% [76/427] vs. 12.5% [55/439], p = 0.030). In the sub-group analysis, among the patients who underwent more than four transfers, the LMWH group had a lower late abortion rate (1.7% [1/60] vs. 13.2% [7/53], p = 0.043). Similarly, of the 107 women who underwent preimplantation genetic diagnosis cycles, the reproductive outcomes were comparable between the two groups.ConclusionIn the general population and PGD patients, LMWH did not improve pregnancy outcomes. Therefore, the routine use of LMWH is not recommended for early treatment.

Characterization of epidermal growth factor-like domain 7 (EGFL7) expression in normal endometrium and in the endometrium of women with poor reproductive outcomes.

Could epidermal growth factor-like domain 7 (EGFL7) be a factor involved in the preparation of the endometrium for implantation and could its dysregulation be implicated in poor reproductive outcomes? EGFL7 is highly expressed in the endothelium and glandular epithelium throughout the menstrual cycle; it is upregulated by stromal cells in secretory phase and appears strongly reduced in endometrial biopsies and isolated stromal cells of women with unexplained recurrent pregnancy loss (uRPL) and recurrent implantation failure (RIF). The secreted factor EGFL7, originally identified as a gene primarily expressed in endothelial cells, is also expressed by the mouse blastocyst and by mouse and human trophoblast cells. It regulates trophoblast migration and invasion by activating NOTCH1 signaling. NOTCH1 has been demonstrated to play a fundamental role in endometrial receptivity and its dysregulation may be involved in selected pregnancy complications characterized by altered endometrial receptivity, such as uRPL. This is an exploratory study for which 84 endometrial biopsies were collected from normally fertile women, as well as from women with uRPL and RIF. Samples were collected from women in both the proliferative and secretory phases of the menstrual cycle and stratified into three sub-groups according to the patient clinical history: 20 fertile women (8 in proliferative and 12 in secretory phase), 41 women with uRPL (6 in proliferative and 35 in secretory phase), and 27 women with RIF (8 in proliferative and 19 in secretory phase). Immunohistochemistry, real-time PCR, and western blot analyses were performed to study the expression of EGFL7 and NOTCH1, as well as the NOTCH target genes. Analysis of spatial and temporal distribution of EGFL7 in endometrial biopsies from fertile women revealed higher levels of EGFL7 in samples from the secretory phase compared to proliferative phase. The expected expression of EGFL7 in endothelial cells was shown as well as the novel, not previously reported, expression in endometrial glands and stromal cells. EGFL7 was significantly reduced in the endometrium of women with uRPL and RIF in the secretory phases and this was associated with a downregulation of the NOTCH1 signaling pathway. Human recombinant EGFL7 was able to activate the NOTCH1 signaling pathway in endometrial stromal cells (EndSCs) obtained from fertile women but not in cells from uRPL or RIF patients. EndSCs from fertile women and decidualized in vitro for three days showed an upregulation of EGFL7 expression, whereas cells obtained from women with uRPL and RIF and decidualized in vitro did not. This study was conducted with a relatively small number of patient samples. Although results are highly reproducible and consistent, additional observations from multicentric cohorts would strengthen the relevance of the data. Moreover, this is an in vitro study, which might only partially represent the in vivo conditions. Our results demonstrate for the first time that EGFL7 is new player involved in decidualization and provide new insights into the pathophysiology of selected implantation defects and early pregnancy complications. Our studies have revealed that alterations in EGFL7 expression and the consequent dysregulation of NOTCH signaling are potential underlying causes of RIF and uRPL. Our results might have therapeutic relevance, as the EGFL7/NOTCH pathway may represent a potential target for medical intervention. This study has been supported by the Grant for Fertility Innovation 2017 (Merck KGaA). There are no competing interests to disclose. Not applicable.

Rare diagnosis of coexistent antiphospholipid syndrome and systemic lupus erythematosus in a male patient with successful management: a case report.

A 28-year-old male, referred to our hospital for the assessment of chest pain. Past medical history was significant for extensive deep venous thrombosis despite the appropriate management with a therapeutic dose of direct-acting oral anticoagulant. Prolonged partial thromboplastin time was not corrected by mixing study along with positive lupus anticoagulant, anticardiolipin, and B-2 glycoprotein antibodies. In addition, antinuclear antibodies, anti-DNA antibodies, and direct Coombs were positive with decreased levels of C3. The patient was diagnosed with SLE with brain, heart, and kidney involvement in the setting of antiphospholipid antibody syndrome. He was treated successfully with full recovery. SLE and APS both have sneaky ways of manifestation. Ineffective diagnosis and therapy could cause irreversible organ damage. Clinicians should have a high index of suspicion for APS, particularly in young patients who approach with spontaneous or unprovoked thromboses or unexplained recurrent early or late pregnancy loss. Anticoagulation, modifying cardiovascular risk factors, and identifying and treating any underlying inflammatory diseases are all part of the multidisciplinary care that is needed for management. Although male affection is rare, SLE and APS should be considered in male patients as these conditions tend to be more aggressive than in the female.

Cervicovaginal microbiome in patients with recurrent pregnancy loss

There have been few studies concerning an association between unexplained recurrent pregnancy loss (RPL) and the microbiome. A recent study including 67 patients demonstrated that an increase in Ureaplasma species in the endometrium raised the risk of miscarriage with an euploid karyotype. While endometrial sampling is invasive, cervicovaginal sampling is not. We compared vaginal and cervical microbiomes with a 16 S ribosomal RNA sequence between 88 patients with unexplained RPL and 17 healthy women with no history of miscarriage. We prospectively assessed risk factors for maternal colonization at a subsequent miscarriage without an aneuploid karyotype in patients. Cervicovaginal bacteria were dominated by Lactobacillus iners, Gardnerella vaginalis, Atopobium vaginae and Bifidobacterium breve in Japanese population. The proportions of Delftia and unknown bacteria in the cervix were significantly higher in patients with RPL than in controls. Streptococcus, Microbacterium, Delftia, Anaerobacillus and Chloroplast in the cervix were significantly higher in patients with a history of chorioamnionitis compared to the controls. The abundance of Cutibacterium and Anaerobacillus in the cervix was significantly higher in patients who had subsequently miscarried compared to those who gave birth. The miscarriage rate in patients with higher proportions of both Cutibacterium and Anaerobacillus (66.7%, 2/3) was significantly greater than that of patients who lacked these bacteria (9.2%, 6/65, adjusted odds ratio 16.90, 95% confidence interval 1.27–225.47, p = 0.032). The presence of certain bacteria could be a predictor of subsequent miscarriage without an aneuploid karyotype. The cervicovaginal microbiome might be useful for investigating a possible cause of RPL.

The Progress of Research on Genetic Factors of Recurrent Pregnancy Loss.

Recurrent pregnancy loss (RPL) is both mental and physical health problem affecting about 1-5% of women of childbearing age. The etiology of RPL is complex, involving chromosomal abnormalities, autoimmune diseases, metabolic disorders, and endometrial dysfunction. The causes of abortion are still unknown in more than 50% of these cases. With the development of science and technology, an increasing number of scholars focus on this field and find that genetic factors may play an essential role in unexplained RPL, such as embolism-related genes, immune factor-related genes, and chromosomal numeric, and structural variation. This review summarizes the genetic factors associated with RPL, including genetic mutations and genetic polymorphisms, chromosomal variants, and chromosomal polymorphisms. Many related genetic factors have been found to be demographically and geographically relevant, some of which can be used for risk prediction or screening for the etiology of RPL. However, it is difficult to predict and prevent RPL due to uncertain pathogenesis and highly variable clinical presentation. Therefore, the genetic factors of RPL still need plentiful research to obtain a more accurate understanding of its pathogenesis and to provide more detection means for the screening and prevention of RPL.

Growth hormone supplementation ameliorates blastocyst euploidy rates and improves pregnancy outcomes in women undergoing preimplantation genetic testing for aneuploidy cycles.

Growth hormone (GH) supplementation has been shown to improve oocyte quality and live birth, but few studies have examined whether GH can reduce embryonic aneuploidy. Chromosomal abnormalities in preimplantation embryos have been regarded as the principal cause of implantation failure and miscarriage, and an increased percentage of aneuploid embryos has been observed in patient cohorts with unexplained recurrent pregnancy loss (RPL), recurrent implantation failure (RIF), and advanced maternal age. This prospective cohort study was conducted on women whose previous PGT-A cycle ended up with no transferrable blastocysts, or the aneuploidy rate was above 50% and no live birth was acquired. The participants were divided into GH co-treatment and comparison groups according to whether GH was administered in the subsequent PGT-A cycle. In addition, within the GH co-treatment group, the previous failed cycle constituted the self-control group. 208 women were recruited in the study (GH co-treatment group: 96 women, comparison group: 112 women). Compared to the self-control and comparison groups, the rate of euploid blastocysts was significantly higher in the GH co-treatment group (GH vs self-control: 32.00% vs 9.14%, odds ratio [OR]: 4.765, 95% confidence interval [CI]: 2.420-9.385, P < 0.01; GH vs comparison: 32.00% vs. 21.05%, OR: 1.930, 95% CI: 1.106-3.366, P = 0.021), and their frozen embryo transfers resulted in more pregnancies and live births. In the subgroup analysis, for the <35 and 35-40 years groups, the euploidy rate in the GH co-treatment group was significantly higher than those in the self-control and comparison groups, but in the >40 years group, there was no difference in euploidy rate. Our study presents preliminary evidence that GH supplementation may ameliorate blastocyst aneuploidy and improve pregnancy outcomes in women who have previously experienced pregnancy failures along with high aneuploidy rates, particularly in those younger than 40 years. Therefore, the use of GH in such women should be considered. However, considering the limited sample size and mixed indications for PGT-A, further scientific research on the underlying mechanism as well as clinical trials with larger sample sizes are needed to confirm the effects and optimal protocols.

O2-1 - Dysfunction of CCR1+ Decidual Macrophages is a Potential Risk Factor in the Occurrence of Unexplained Recurrent Pregnancy Loss

O2-1 - Dysfunction of CCR1+ Decidual Macrophages is a Potential Risk Factor in the Occurrence of Unexplained Recurrent Pregnancy Loss

O2-2 - Role of PROK1 in decidua of patients with unexplained recurrent pregnancy loss showing insulin hypersecretion

O2-2 - Role of PROK1 in decidua of patients with unexplained recurrent pregnancy loss showing insulin hypersecretion

KISS1 Gene Variations and Susceptibility to Idiopathic Recurrent Pregnancy Loss.

It is widely accepted that kisspeptin plays an integral role in the regulation of reproduction. Genetic variations in the KISS1 gene have been frequently reported to be linked to reproductive diseases, but there is still a lack of data on the association between KISS1 variations and female reproductive disorders. The present study aimed to examine the association of three missense SNPs in the KISS1 gene including rs12998, rs35431622, and rs4889 in association with idiopathic recurrent pregnancy loss (iRPL). A total of 720 individuals were recruited in this study. The DNA from the blood sample was extracted and genotyped using the PCR method. Haplotype and linkage disequilibrium (LD) have also been analyzed. The results of this study suggested that rs12998 G > A and rs4889 C > G had a significant association with iRPL (p < 0.05); while rs35431622 A > G didn't indicate any association with iRPL. A significant association was also found for three haplotypes including C-A-A, G-G-G, and G-G-A in this population. The analysis also showed a significant LD between rs12998 and rs35431622 (P < 0.0005). The rs12998 G > A and rs4889 C > G variants of KISS1 are linked to unexplained recurrent pregnancy loss and may be risk factors for this disease.

ID3 mediates BMP2-induced downregulation of ICAM1 expression in human endometiral stromal cells and decidual cells.

Recurrent pregnancy loss (RPL) remains an unsolved problem in obstetrics and gynecology, and up to 50% of RPL cases are unexplained. Unexplained RPL (uRPL) is widely considered to be related to an aberrant endometrial microenvironment. BMP2 is an important factor involved in endometrial decidualization and embryo implantation, and intercellular adhesion molecule 1 (ICAM1) is a critical inflammatory regulator in the endometrium. In this study, we found that endometrial samples obtained from Unexplained RPL patients have significantly lower BMP2 and higher ICAM1 levels than fertile controls. For further research on the relationship between BMP2 and ICAM1 and the potential molecular mechanisms in Unexplained RPL, immortalized human endometrial stromal cells (HESCs) and primary human decidual stromal cells (HDSCs) were used as study models. Our results showed that BMP2 significantly decreased ICAM1 expression by upregulating DNA-binding protein inhibitor 3 (ID3) in both HESCs and HDSCs. Using kinase receptor inhibitors (dorsomorphin homolog 1 (DMH-1) and dorsomorphin) and siRNA transfection, it has been found that the upregulation of ID3 and the following downregulation of ICAM1 induced by BMP2 is regulated through the ALK3-SMAD4 signaling pathway. This research gives a hint of a novel mechanism by which BMP2 regulates ICAM1 in the human endometrium, which provides insights into potential therapeutics for unexplained RPL.

Whole-genome sequencing analysis in families with recurrent pregnancy loss: A pilot study.

One to two percent of couples suffer recurrent pregnancy loss and over 50% of the cases are unexplained. Whole genome sequencing (WGS) analysis has the potential to identify previously unrecognized causes of pregnancy loss, but few studies have been performed, and none have included DNA from families including parents, losses, and live births. We conducted a pilot WGS study in three families with unexplained recurrent pregnancy loss, including parents, healthy live births, and losses, which included an embryonic loss (<10 weeks' gestation), fetal deaths (10-20 weeks' gestation) and stillbirths (≥ 20 weeks' gestation). We used the Illumina platform for WGS and state-of-the-art protocols to identify single nucleotide variants (SNVs) following various modes of inheritance. We identified 87 SNVs involving 75 genes in embryonic loss (n = 1), 370 SNVs involving 228 genes in fetal death (n = 3), and 122 SNVs involving 122 genes in stillbirth (n = 2). Of these, 22 de novo, 6 inherited autosomal dominant and an X-linked recessive SNVs were pathogenic (probability of being loss-of-function intolerant >0.9), impacting known genes (e.g., DICER1, FBN2, FLT4, HERC1, and TAOK1) involved in embryonic/fetal development and congenital abnormalities. Further, we identified inherited missense compound heterozygous SNVs impacting genes (e.g., VWA5B2) in two fetal death samples. The variants were not identified as compound heterozygous SNVs in live births and population controls, providing evidence for haplosufficient genes relevant to pregnancy loss. In this pilot study, we provide evidence for de novo and inherited SNVs relevant to pregnancy loss. Our findings provide justification for conducting WGS using larger numbers of families and warrant validation by targeted sequencing to ascertain causal variants. Elucidating genes causing pregnancy loss may facilitate the development of risk stratification strategies and novel therapeutics.

Successful Pregnancy and Delivery at Term Following Intravenous Immunoglobulin Therapy with Heparin for Unexplained Recurrent Pregnancy Loss Suspected of Immunological Abnormalities: A Case Report and Brief Literature Review

About 60% of cases of recurrent pregnancy loss have unexplained etiology. Immunotherapy for unexplained recurrent pregnancy loss is still unestablished. A 36-year-old woman, not obese, had a stillbirth at 22 gestational weeks and a spontaneous abortion at 8 weeks. She had been examined for recurrent pregnancy loss at previous clinics with no significant findings. When she visited our clinic, a hematologic test showed a Th1/Th2 ratio imbalance. Ultrasonography, hysteroscopy, and semen analysis showed no abnormalities. She successfully conceived by embryo transfer in hormone replacement therapy cycle. However, she had a miscarriage at 19 weeks. The baby had no deformities, but a chromosomal test was not performed, according to the parents' will. The placenta pathologically suggested hemoperfusion problems. Her and her husband's chromosomal tests showed normal karyotypes. Other examinations revealed a repeated Th1/Th2 ratio imbalance and a high resistance index of uterine radial artery blood flow. She was administered low-dose aspirin, intravenous immunoglobulin, and unfractionated heparin after the second embryo was transferred. Her baby was healthily born by cesarean section at 40 weeks. Intravenous immunoglobulin therapy can be a choice for recurrent miscarriage without risk factors because it has clinically beneficial influences on the patient's immunological aberration.

Anti-Müllerian hormone and live birth in unexplained recurrent pregnancy loss

Research questionIs anti-Müllerian hormone (AMH) associated with live birth rate (LBR) in women with unexplained recurrent pregnancy loss (RPL)? DesignCohort study of women with unexplained RPL attending the RPL Unit, Copenhagen University Hospital, Denmark, between 2015 and 2021. AMH concentration was assessed upon referral, and LBR in the next pregnancy. RPL was defined as three or more consecutive pregnancy losses. Regression analyses were adjusted for age, number of previous losses, body mass index, smoking, treatment with assisted reproductive technology (ART) and RPL treatments. ResultsA total of 629 women were included; 507 (80.6%) became pregnant after referral. Pregnancy rates were similar for women with low and high AMH compared to women with medium AMH (81.9, 80.3 and 79.7%, respectively) (low AMH: adjusted odds ratio [aOR] 1.44, 95% confidence interval [CI] 0.84–2.47, P = 0.18; high AMH: aOR 0.98, 95% CI 0.59–1.64, P = 0.95). AMH concentrations were not associated with live birth. LBR was 59.5% in women with low AMH, 66.1% with medium AMH and 65.1% with high AMH (low AMH: aOR 0.68, 95% CI 0.41–1.11, P = 0.12, high AMH: aOR 0.96, 95% CI 0.59–1.56, P = 0.87). Live birth was lower in ART pregnancies (aOR 0.57, 95% CI 0.33–0.97, P = 0.04) and with higher numbers of previous losses (aOR 0.81, 95% CI 0.68–0.95, P = 0.01). ConclusionIn women with unexplained RPL, AMH was not associated with the chances of live birth in the next pregnancy. Screening for AMH in all women with RPL is not supported by current evidence. The chance of live birth among women with unexplained RPL achieving pregnancy by ART was low and needs to be confirmed and explored in future studies.