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Recurrent Pregnancy Loss (RPL): Clinical Presentations, Diagnosis, and Management

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Obstetrics & Gynecology".

Deadline for manuscript submissions: closed (29 February 2024) | Viewed by 20464

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Special Issue Editor

Prof. Dr. Asher Bashiri

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Guest Editor

1. Recurrent Pregnancy Loss Preventive Clinic, Department of Obstetrics and Gynecology, Soroka University Medical Center, Beer-Sheva, Israel
2. Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Interests: recurrent pregnancy loss (RPL); miscarriage; fetal loss; genetics; maternal–fetal medicine; lifestyle; obesity; maternal age; prognosis; thrombophilia; immunology treatment; hypothyroidism

Special Issue Information

Dear Colleagues,

Recurrent pregnancy loss (RPL) has become a central subject at the forefront of the clinical and research stages in the fields of obstetrics, gynecology, and fertility. Current guidelines have been published in recent years, including by ESHRE, Israel, and more. As we deepen the knowledge and research on the subject, we will be able to offer innovative evidence-based treatments and thus allow more couples to become parents and/or have more children.

Active research collaborations between medical centers and the increase in multicenter retrospective research are key points in understanding the mechanisms that cause RPL and, at the same time, for the development of innovative treatments.

Aspects related to the genetic component, immunological treatments, congenital hypercoagulability, endoscopy, and emotional as well as mental support are only some of the issues that medicine focuses on in couples with RPL.

Prof. Dr. Asher Bashiri
Guest Editor

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Keywords

recurrent pregnancy loss (RPL)
miscarriage
fetal loss
genetics
maternal–fetal medicine
lifestyle
obesity
maternal age
prognosis
thrombophilia
immunology treatment
hypothyroidism

Published Papers (9 papers)

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Research

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10 pages, 249 KiB

Open AccessFeature PaperArticle

Seminal Oxidative Stress and Sperm DNA Fragmentation in Men from Couples with Infertility or Unexplained Recurrent Pregnancy Loss

by Johanne Mejlholm Kold Rasmussen, Maya Isabella Riise Dalgaard, Hiva Alipour, Fereshteh Dardmeh and Ole Bjarne Christiansen

J. Clin. Med. 2024, 13(3), 833; https://doi.org/10.3390/jcm13030833 - 31 Jan 2024

Cited by 1 | Viewed by 962

Abstract

(1) Background: This case–control study examined whether men from couples with unexplained recurrent pregnancy loss (RPL) or infertility exhibited higher seminal oxidative stress (OS) and sperm DNA fragmentation (SDF) compared to fertile controls. (2) Methods: The study included 30 participants from each group: unexplained RPL, unexplained infertility, and proven fertility. Data were collected at Aalborg University Hospital tertiary RPL and fertility treatment clinics (Aalborg, Denmark), excluding couples with mixed conditions for homogeneity. Semen samples were analyzed using computer-aided sperm analysis (CASA) for concentration, motility, and morphology. SDF was assessed via a CASA-based sperm chromatin dispersion test. OS was measured as static oxidation-reduction potential (sORP). (3) Results: The results showed no significant OS differences between groups. The RPL group had significantly lower SDF levels than the control group. A significant positive correlation between SDF and OS was observed in the infertility group. Overall, this study did not find significant differences in OS levels between men from couples with unexplained RPL or infertility and fertile controls, while SDF levels were lower in the RPL group compared to controls. (4) Conclusion: In conclusion, despite the existing literature suggesting that OS and SDF are negative prognostic factors, our findings suggest they may not be reliable diagnostic markers for RPL and infertility. Full article

(This article belongs to the Special Issue Recurrent Pregnancy Loss (RPL): Clinical Presentations, Diagnosis, and Management)

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9 pages, 511 KiB

Open AccessArticle

To Test or Not to Test: Routine Thrombophilia Diagnostic Screening of Women with Reproductive Failures

by Urszula Wysocka, Kinga Sałacińska, Iwona Pinkier, Łukasz Kępczyński, Wojciech Ałaszewski, Lech Dudarewicz and Agnieszka Gach

J. Clin. Med. 2023, 12(24), 7527; https://doi.org/10.3390/jcm12247527 - 6 Dec 2023

Cited by 1 | Viewed by 1021

Abstract

Background: Recurrent reproductive failure is a global health issue affecting a significant number of women. Thrombophilias have been implicated as a possible cause. Inherited thrombophilias include a single nucleotide variant on factor V Leiden and prothrombin. Objective: The aim of this study was to evaluate the association between the following single nucleotide variants: factor V Leiden (c.1601G>A), the prothrombin gene (c.*97G>A) and the reproductive failure in the Polish population. Methods: The study was conducted in a group of 545 patients with recurrent pregnancy loss, RPL (≥2 miscarriages), and in a group of 641 patients with infertility. The distribution of genotypes for the selected variants were determined by RFLP-PCR and by the real-time PCR method. Results: A variant of the F5 gene was found in 5.14% of patients with RPL and in 6.08% of infertile women. A variant of the F2 gene was identified in 0.73% of patients with RPL and in 2.03% of women with infertility. The frequency in the study groups did not differ from that in the general population. No association between the studied variants of the F5 gene or the F2 gene and the predisposition to reproductive wastage was found. Conclusions: Recommendations for routine thrombophilia testing in women with recurrent miscarriages should be revisited. The decision regarding testing should be made individually depending on additional factors indicating an increased risk of venous thromboembolism. Full article

(This article belongs to the Special Issue Recurrent Pregnancy Loss (RPL): Clinical Presentations, Diagnosis, and Management)

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12 pages, 2807 KiB

Open AccessArticle

NK and T Cell Subtypes in the Endometrium of Patients with Recurrent Pregnancy Loss and Recurrent Implantation Failure: Implications for Pregnancy Success

by Anne-Sophie Braun, Kilian Vomstein, Elisabeth Reiser, Susanne Tollinger, Christiana Kyvelidou, Katharina Feil and Bettina Toth

J. Clin. Med. 2023, 12(17), 5585; https://doi.org/10.3390/jcm12175585 - 27 Aug 2023

Cited by 1 | Viewed by 1395

Abstract

Background: RPL and RIF are challenges in reproductive medicine. The immune system plays a pivotal role in endometrial receptivity, successful implantation, and pregnancy complications. Immunological changes have been associated with RPL and RIF. Understanding immune dysregulation especially in NK and T cell subtypes may lead to better diagnostic concepts and treatments. From July 2019 to August 2020 patients with RPL and RIF underwent a standardized diagnostic procedure including endometrial biopsies. Immune cell analysis was performed using flow cytometry. Patients were contacted in March 2023 and interviewed concerning their pregnancy outcomes following diagnostics. Results: Out of 68 patients undergoing endometrial biopsies, 49 patients were finally included. Live birth rates were high with 72% in RPL and 86% in RIF. Immune cell analysis revealed that patients with RPL had more cytotoxic CD56^dimCD16^high cells, while RIF patients had more CD56⁺ uNK cells. RPL patients with pregnancy complications showed increased NKT cell percentages. Conclusion: Our findings suggest specific immune changes in RPL and RIF patients, offering potential therapeutic targets. Tailored immunotherapy based on endometrial immunophenotyping might be an option, but further research is needed. Full article

(This article belongs to the Special Issue Recurrent Pregnancy Loss (RPL): Clinical Presentations, Diagnosis, and Management)

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11 pages, 444 KiB

Open AccessArticle

Investigating the “Fetal Side” in Recurrent Pregnancy Loss: Reliability of Cell-Free DNA Testing in Detecting Chromosomal Abnormalities of Miscarriage Tissue

by Silvia D’Ippolito, Giuliana Longo, Daniela Orteschi, Andrea Busnelli, Nicoletta Di Simone, Eleonora Pulcinelli, Giorgia Schettini, Giovanni Scambia and Marcella Zollino

J. Clin. Med. 2023, 12(12), 3898; https://doi.org/10.3390/jcm12123898 - 7 Jun 2023

Cited by 2 | Viewed by 1523

Abstract

(1) Background: The aim of our study is to evaluate whether cell-free DNA testing can overlap the genetic testing of miscarriage tissue in women with early pregnancy loss (EPL) and length of recurrent pregnancy loss (RPL); (2) Methods: We conducted a prospective cohort study at the Pregnancy Loss Unit of the Fondazione Policlinico Universitario A. Gemelli (IRCCS), Rome, Italy between May 2021 and March 2022. We included women with EPL and length of RPL. Gestational age was >9 weeks + 2 days and <12 weeks + 0 days of gestation corresponding to a crown rump length measurement of >25 and <54 mm. Women underwent both dilation and curettage for the collection of miscarriage tissue and for blood sample collection. Chromosomal microarray analysis (CMA) on miscarriage tissues was performed by oligo-nucleotide- and single nucleotide polymorphisms (SNP)-based comparative genomic hybridization (CGH+SNP). Maternal blood samples were analyzed by Illumina VeriSeq non-invasive prenatal testing (NIPT) to evaluate the cell-free fetal DNA (cfDNA) and the corresponding fetal fraction and the presence of genetic abnormalities; (3) Results: CMA on miscarriage tissues revealed chromosome aneuploidies in 6/10 cases (60%), consisting of trisomy 21 (5 cases) and monosomy X (one case). cfDNA analysis was able to identify all cases of trisomy 21. It failed to detect monosomy X. A large 7p14.1p12.2 deletion concomitant to trisomy 21 was, in one case, detected by cfDNA analysis but it was not confirmed by CMA on miscarriage tissue. (4) Conclusions: cfDNA largely reproduces the chromosomal abnormalities underlying spontaneous miscarriages. However, diagnostic sensitivity of cfDNA analysis is lower with respect to the CMA of miscarriage tissues. In considering the limitations when obtaining biological samples from aborted fetuses suitable for CMA or standard chromosome analysis, cfDNA analysis is a useful, although not exhaustive, tool for the chromosome diagnosis of both early and recurrent pregnancy loss. Full article

(This article belongs to the Special Issue Recurrent Pregnancy Loss (RPL): Clinical Presentations, Diagnosis, and Management)

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9 pages, 231 KiB

Open AccessArticle

Increased Live Birth Rate with Dydrogesterone among Patients with Recurrent Pregnancy Loss Regardless of Other Treatments

by Asher Bashiri, Gabi Galperin, Atif Zeadna, Yael Baumfeld and Tamar Wainstock

J. Clin. Med. 2023, 12(5), 1967; https://doi.org/10.3390/jcm12051967 - 2 Mar 2023

Cited by 4 | Viewed by 2552

Abstract

Background: Recurrent pregnancy loss (RPL) is defined as the loss of two or more pregnancies. Several treatment options are available, including progesterone, which is one of the few treatments that improve live birth rates in RPL patients. Objective: To compare the live birth rates, medical and obstetric characteristics, and RPL evaluation results of women with and without progesterone treatment. These women attended the RPL clinic at Soroka University Medical Center. Methods: A retrospective cohort study based on 866 patients was conducted. The patients were divided into two groups and examined: the dydrogesterone treatment group consisting of 509 women and a group of 357 patients who did not receive the treatment. All the patients had a subsequent (index) pregnancy. Results: The two groups were not statistically different in terms of their demographic and clinical characteristics or evaluation results. In a univariate analysis, no statistically significant differences were found between the groups in terms of live birth rates (80.6% vs. 84%; p-value = 0.209). In a multivariate logistic analysis adjusted for maternal age, the ratio of pregnancy losses to the number of pregnancies, other administered treatments, antiphospholipid syndrome, and body mass index, dydrogesterone treatment was found to be independently associated with a higher rate of live births than the control group (adjusted OR = 1.592; CI 95% 1.051–2.413; p-value = 0.028). Conclusions: Progesterone treatment is associated with an increased live birth rate in RPL patients. Studies with larger sample sizes are recommended to strengthen these results. Full article

(This article belongs to the Special Issue Recurrent Pregnancy Loss (RPL): Clinical Presentations, Diagnosis, and Management)

11 pages, 278 KiB

Open AccessArticle

Depression, Anxiety, and Stress in Kazakhstani Women with Recurrent Pregnancy Loss: A Case–Control Study

by Assylzhan Issakhanova, Alpamys Issanov, Talshyn Ukybassova, Lyazzat Kaldygulova, Aizada Marat, Balkenzhe Imankulova, Nazira Kamzayeva, Wassim Y. Almawi and Gulzhanat Aimagambetova

J. Clin. Med. 2023, 12(2), 658; https://doi.org/10.3390/jcm12020658 - 13 Jan 2023

Cited by 6 | Viewed by 2545

Abstract

Background: Recurrent pregnancy loss (RPL) is associated with increased incidence and severity of depression, anxiety, and stress, and screening for these comorbidities following miscarriages is beneficial for women with RPL who are planning future pregnancies. This study aims to investigate depression, anxiety, and stress among Kazakhstani women with RPL. Methods: This was a case–control study involving 70 women with confirmed RPL and 78 ethnically matched control women. Depression, anxiety, and stress were evaluated using the Depression Anxiety Stress Scales (DASS)-21 instrument. Linear regression and correlation analysis were used in assessing the association of RPL with symptoms of depression, and/or anxiety, and/or stress, after adjusting for key covariates. Results: Women with RPL were found to have significantly higher mean scores for depression (p < 0.001), anxiety (p < 0.001), and stress (p < 0.001) symptoms. Mild–moderate stress and mild–moderate and severe–extreme depression and anxiety symptoms were more frequent in the RPL group than in the control group. Regression analysis demonstrated that RPL was the only significant variable associated with anxiety, depression, and stress symptoms. Conclusion: The results of this study suggest that women with RPL are more likely to experience heightened symptoms of depression, anxiety, and stress. Proper psychological counseling is recommended for women with RPL, as well as their spouses. Full article

(This article belongs to the Special Issue Recurrent Pregnancy Loss (RPL): Clinical Presentations, Diagnosis, and Management)

Review

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22 pages, 1619 KiB

Open AccessReview

Maternal–Fetal Compatibility in Recurrent Pregnancy Loss

by Isabel Cuadrado-Torroglosa, Juan A. García-Velasco and Diana Alecsandru

J. Clin. Med. 2024, 13(8), 2379; https://doi.org/10.3390/jcm13082379 - 19 Apr 2024

Viewed by 986

Abstract

Nowadays, recurrent pregnancy loss (RPL) is an undesirable condition suffered by many patients of reproductive age. In this scenario, certain immune cell populations and molecules, involved in maternal–fetal compatibility, have emerged as factors related with the pathogenesis of RPL. Among them, uterine Natural Killer cells (uNKs) appear to be of great relevance. These cells are involved in numerous processes during pregnancy, such as the remodeling of uterine spiral arteries or the control of trophoblast invasion. These functions are regulated by the interactions that these cells establish with the extravillous trophoblast, mainly through their Killer Immunoglobulin-like Receptors (KIRs) and the Human Leukocyte Antigen-C (HLA-C) molecules expressed by the embryo. A high level of polymorphism has been reported for both molecules involved in this interaction, with some of the possible KIR–HLA-C combinations being associated with an increased risk of RPL. However, the complexity of the maternal–fetal interface goes beyond this, as other HLA molecules also appear to be related to this reproductive pathology. In this review, we will discuss the role of uNKs in pregnancy, as well as the polymorphisms and clinical implications of KIR–HLA-C binding. We will also address the involvement of other, different HLA molecules in RPL, and the current advice on the appropriate management of patients with ‘immunological mismatch’, thus covering the main aspects regarding the involvement of maternal–fetal compatibility in RPL. Full article

(This article belongs to the Special Issue Recurrent Pregnancy Loss (RPL): Clinical Presentations, Diagnosis, and Management)

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21 pages, 683 KiB

Open AccessReview

Prevention of Pregnancy Loss: Combining Progestogen Treatment and Psychological Support

by Nana Tetruashvili, Alice Domar and Asher Bashiri

J. Clin. Med. 2023, 12(5), 1827; https://doi.org/10.3390/jcm12051827 - 24 Feb 2023

Cited by 6 | Viewed by 4559

Abstract

Pregnancy loss can be defined as a loss before either 20 or 24 weeks of gestation (based on the first day of the last menstrual period) or the loss of an embryo or fetus less than 400 g in weight if the gestation age is unknown. Approximately 23 million pregnancy losses occur worldwide every year, equating to 15–20% of all clinically recognized pregnancies. A pregnancy loss is usually associated with physical consequences, such as early pregnancy bleeding ranging in severity from spotting to hemorrhage. However, it can also be associated with profound psychological distress, which can be felt by both partners and may include feelings of denial, shock, anxiety, depression, post-traumatic stress disorder, and suicide. Progesterone plays a key part in the maintenance of a pregnancy, and progesterone supplementation has been assessed as a preventative measure in patients at increased risk of experiencing a pregnancy loss. The primary objective of this piece is to assess the evidence for various progestogen formulations in the treatment of threatened and recurrent pregnancy loss, postulating that an optimal treatment plan would preferably include a validated psychological support tool as an adjunct to appropriate pharmacological treatment. Full article

(This article belongs to the Special Issue Recurrent Pregnancy Loss (RPL): Clinical Presentations, Diagnosis, and Management)

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Other

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6 pages, 494 KiB

Open AccessCase Report

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

by Junichiro Mitsui, Kuniaki Ota, Yuko Takayanagi, Yurie Nako, Makiko Tajima, Atsushi Fukui and Kiyotaka Kawai

J. Clin. Med. 2023, 12(4), 1250; https://doi.org/10.3390/jcm12041250 - 4 Feb 2023

Cited by 1 | Viewed by 3467

Abstract

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. Full article

(This article belongs to the Special Issue Recurrent Pregnancy Loss (RPL): Clinical Presentations, Diagnosis, and Management)

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