OBJECTIVE: We aimed to perform a systematic review and meta-analysis addressing the efficacy of levothyroxine therapy in pregnant women with subclinical hypothyroidism considering most recent evidence and subgroups of interest for clinical practice.
METHODS: PubMed, Embase, and Cochrane Central were searched from inception for randomized controlled trials (RCTs) comparing levothyroxine with placebo or no intervention in pregnant women with subclinical hypothyroidism. We used a random-effects model and conducted subgroup analyses based on thyroid peroxidase antibody status, thyroid stimulating hormone levels, fertility treatment, and recurrent miscarriage.
RESULTS: We included 11 RCTs comprising 2,749 pregnant women with subclinical hypothyroidism. Patients treated with levothyroxine (1,439; 52.3%) had significantly lower risk of pregnancy loss (risk ratio 0.69; 95% confidence interval 0.52-0.91; p < 0.01; 6 studies). However, there was no significant association between levothyroxine and live birth (risk ratio 1.01; 95% confidence interval 0.99-1.03; p = 0.29; 8 studies). No statistically significant interaction was observed across subgroups (p > 0.05).
CONCLUSIONS: Levothyroxine replacement therapy for subclinical hypothyroidism during pregnancy may decrease pregnancy loss when early prescribed. Nevertheless, further investigation is needed in patients with thyroid stimulating hormone above four milliunits per liter, especially when associated with recurrent miscarriage or infertility.

OBJECTIVE: Is exposure to dydrogesterone a risk factor for congenital anomalies when given in the first trimester for recurrent/threatened pregnancy loss or as luteal support in assisted reproductive technology (ART)?
CONCLUSIONS: Dydrogesterone, when given in the first trimester for recurrent/threatened pregnancy loss or as luteal support in ART, is not a relevant additional risk factor for congenital anomalies.
BACKGROUND: Despite large clinical trials and meta-analyses that show no association between dydrogesterone and congenital anomalies, some recently retracted publications have postulated an association with teratogenicity. Dydrogesterone is also often rated as less safe than bioidentical progestins.
UNASSIGNED: A systematic review was conducted according to a pre-specified protocol with searches on Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Clinicaltrials.gov. The search was limited to human studies, with no restrictions on language, geographical region, or date. The search algorithm used a PICO (Population, Intervention, Comparison, Outcome)-style approach combining both simple search terms and medical subject heading terms. As congenital anomalies are mostly reported as secondary outcomes, the search term \'safety\' was added.
METHODS: Interventional study and observational study (OS) designs were eligible for inclusion. Inclusion criteria were: women >17 years old treated for threatened miscarriage, recurrent pregnancy loss, and/or ART; the use of dydrogesterone in the first trimester compared with placebo, no treatment or other interventions; and reporting of congenital anomalies in newborns or infants ≤12 months old (primary outcome). Two authors (A.K., M.R.N.) independently extracted the following data: general study information, study population details, intervention and comparator(s), and frequencies of congenital anomalies (classification, time of determination, and type). Risk of bias focused on the reporting of congenital malformations and was assessed using the Cochrane Risk of Bias Tool Version 2 or the ROBINS-I tool. The GRADEproGDT platform was used to generate the GRADE summary of findings table.
RESULTS: Of the 897 records retrieved during the literature search, 47 were assessed for eligibility. Nine studies were included in the final analysis: six randomized controlled trials (RCTs) and three OSs. Among the RCTs, three had a low risk and three a high risk of bias. Two of the OSs were considered to have a serious risk of bias and one with critical risk of bias and was excluded for the evidence syntheses. The eight remaining studies included a total of 5070 participants and 2680 live births from 16 countries. In the meta-analysis of RCTs only, the overall risk ratio (RR) was 0.92 [95% CI 0.55; 1.55] with low certainty. When the two OSs were included, the overall RR was 1.11 [95% CI 0.73; 1.68] with low certainty.
CONCLUSIONS: The studies included in the analysis do not report congenital anomalies as the primary outcome; reporting of congenital anomalies was often not standardized.
CONCLUSIONS: This systematic literature review and meta-analysis provide clear reassurance to both clinicians and patients that dydrogesterone is not associated with congenital anomalies above the rate that might be expected due to environmental and genetic factors. The results of this work represent the highest current level of evidence for the question of congenital anomalies, which removes the existing uncertainty caused by poor quality and retracted studies.
BACKGROUND: Editorial support was provided by Highfield Communication Consultancy, Oxford, UK, sponsored by Abbott Products Operations AG, Allschwil, Switzerland. A.K., J.A.G.-V., L.P.S., J.N.v.d.A., and J.F.S. received honoraria from Abbott for preparation and participation in an advisory board. J.A.G.-V. received grants and lecture fees from Merck, Organon, Ferring, Gedeon Richter, and Theramex. M.R.N. has no conflicts of interest. J.N.v.d.A. and J.A.G.-V. have no other conflicts of interest. A.K. received payment from Abbott for a talk at the IVF Worldwide congress on 22 September 2023. J.F.S. has received grants from the National Institutes of Health, royalties/licences from Elsevier and Prescient Medicine (SOLVD Health), consulting fees from Burroughs Wellcome Fund (BWF) and Bayer, honoraria from Magee Women\'s Research Institute, Wisconsin National Primate Research Centre, University of Kansas and Oakridge National Research Laboratory, Agile, Daiichi Sankyo/American Regent, and Bayer, and travel support to attend meetings for the International Academy of Human Reproduction (IAHR). J.F.S. has patents related to diagnosis and treatment of PCOS and prediction of preterm birth. J.F.S. participates on advisory boards for SOLVD Health, Wisconsin National Primate Research Centre, and FHI360, was the past President board member of the Society for Reproductive Investigation, has a leadership role for the following organizations: Scientific Advisory Board, SOLVD Health, EAB Chair for contraceptive technology initiative, FHI360, EAB member, Wisconsin National Primate Research Centre, Advisory Board for MWRI Summit, Chair of BWF NextGen Pregnancy Research Panel, Medical Executive Committee at the Howard, and Georgeanna Jones Foundation, and is Vice President, IAHR. L.P.S. has received consulting fees from Shield Pharmaceuticals, Scynexis, Organon, Natera, Celula China, AiVF, Agile, Daiichi Sankyo, American Regent, and Medicem, honoraria from Agile, Daiichi Sankyo/American Regent, and Bayer, and travel support from BD Diagnostics. L.P.S. participates on the data safety monitoring board for Astellas and is a Chair of DSMB for fezolinetant. Abbott played no role in the funding of the study or in study design, data collection, data analysis, data interpretation, or writing of the report.
BACKGROUND: PROSPERO 2022 CRD42022356977.

UNASSIGNED: Recurrent miscarriage is defined as 2 or more failed clinical pregnancies, typically known as repeated pregnancy loss, occurring before 20 gestational weeks, and further categorized into primary and secondary types. It represents a common and distressing condition to deal with in the field of reproductive medicine, usually affecting <5% of couples, with up to 50% of cases lacking a clearly defined aetiology. The epidemiology also varies depending on maternal age. Remarkably, the situation significantly afflicts expecting parents, whereas maternal factors, such as age and previous pregnancy loss rate, are commonly reported as risk factors. Although previously underestimated, existing evidence suggests the male factor is a possible cause of recurrent pregnancy loss.
UNASSIGNED: A non-systematic literature review was conducted in the PubMed and Scopus databases for articles written in English investigating the possible association of the male factor in recurrent pregnancy loss. The eligible studies were synthesized in a narrative review format upon discussion and consensus among the authors after being previously independently assessed and selected.
UNASSIGNED: Lifestyle, obesity, genetic predisposition, chromosomal anomalies, endocrine dysfunction, anatomical abnormalities, immunological factors, infections, and oxidative stress can result in poor embryo development and recurrent miscarriage. Although professional organizations currently recognize male gender as a possible risk factor, specific recommendations on the diagnostic and therapeutic field are still lacking, and the condition necessitates a high level of suspicion and case-by-case management.
UNASSIGNED: In this review, we delve deeper into the contribution of the male factor in the concept of recurrent miscarriage.

Recurrent miscarriage (RM) is a condition defined as having three or more consecutive pregnancy losses before the 20 weeks of pregnancy. The present study was undertaken to investigate association of Interleukin-17A (IL-17A) rs2275913 polymorphism with RM. To this end, we searched the international databases (Web of Science, PubMed, Embase, and Scopus) and extracted studies investigating the association of IL-17A rs2275913 polymorphism with RM using the appropriate keywords. The collected data were analyzed with the random-effects model and STATA (version 14). A total of five studies met the eligibility criteria, and total sample size was 998 subjects. Mean age of the cases and controls were 31.41 ± 4.16 and 30.56 ± 3.5 years, respectively. Our results disclosed a significant relationship of the IL-17A rs2275913 AA genotype [odds ratio (OR)=1.68; 95% confidence interval (CI)=1.16- 2.43; I2=19; P=0.294) with RM. There was no statistically significant correlation between IL-17Ars2275913 GG genotype (OR=1.04; 95% CI=0.64-1.7; I2=59.5; P=0.042) and GA genotype (OR=0.85; 95% CI=0.65-1.12; I2=19.1; P=0.293) with RM. Our findings revealed that the IL-17A rs2275913 polymorphism is associated with RM, and the AA genotype of this polymorphism increased possibility of being involved in RM.

PCOS is a syndrome of ovarian dysfunction associated with recurrent pregnancy loss. Several correlating factors have been investigated that influence the risk of pregnancy loss in PCOS. However, uncertainty remains about their contribution to pregnancy loss and prognosis. This review of literature aims to identify what is known and what requires further investigation on the relationship between PCOS and recurrent pregnancy loss, to guide future research and optimize medical guidance throughout pregnancy.
a review of literature was performed on several search engines using the following terms; polycystic ovarian syndrome, PCOS, recurrent pregnancy loss, recurrent miscarriage, RPL, aborted fetus, abortus provocatus, miscarriage and habitual abortion.
37 articles were included; 3 systematic reviews, 1 meta-analysis, 2 randomized controlled trials, 6 prospective cohort studies, 22 case-control studies and 3 case series. The main objectives investigated by studies were pregnancy complications, pregnancy loss and live birth in the PCOS population.
Studies that investigated the relationship between PCOS and recurrent pregnancy loss are few and inconsistent and warrant further research. Factors apt for further investigation include the extent to which PCOS phenotypes, BMI, obesity, insulin resistance, hyperandrogenemia, SHBG, hs-CRP, CTRP6, adiponectin, plasma leptin, homocysteine, AMH and thrombophilia contribute to further risk of miscarriage. Other factors requiring further exploration in relation to risk for miscarriage in PCOS patient with RPL include sOB-R, PAI-Fx and the Factor-V-Leiden mutations.

Recurrent pregnancy loss (RPL), defined as two or more failed clinical pregnancies, affects 1%-3% of couples trying to conceive. Nowadays up to 50% of cases remain idiopathic. In this context, paternal factors evaluation is still very limited. The aim is to address the topic of the male factor in RPL with a broad approach, analyzing collectively data on sperm DNA fragmentation (SDF) and semen parameters. We systematically searched in Pubmed/MEDLINE and Google Scholar from inception to February 2023. A protocol has been registered on PROSPERO (ID number CRD42022278616). PRISMA guidelines were followed.
Pooled results from 20 studies revealed a higher DNA fragmentation rate in the RPL group compared to controls (mean difference [MD] 9.21, 95% CI 5.58-12.85, p < 0.00001, I2 98%). Age, body mass index (BMI), smoking, and alcohol intake were not associated with DNA fragmentation. Subgroup analysis by different SDF assays (TUNEL and COMET at a neutral pH vs. indirect assessment with other assays) and ethnicity did not highlight different results (p = 0.25 and 0.44).
Results pooled from 25 studies showed a significant difference comparing RPL and control groups regarding ejaculation volume (MD -0.24, 95% CI -0.43; -0.06, p 0.01, I2 66%), total sperm number (MD -10.03, 95% CI -14.65; -5.41, p < 0.0001, I2 76%), total sperm motility (MD -11.20, 95% CI -16.15; -6.25, p < 0.0001, I2 96%), progressive sperm motility (MD -7.34, 95% CI -10.87; -3.80, p < 0.0001, I2 97%), and normal sperm morphology (MD -5.99, 95% CI -9.08; -2.90, p 0.0001, I2 98%). A sub-analysis revealed that Asian and Africans, but not white-European RPL men had lower progressive sperm motility compared to controls.
In conclusion, current review and meta-analysis findings suggested that SDF and some specific semen parameters were associated with RPL in a multi-ethnic evaluation. This effort opens future direction on a growing awareness of, first, how the male factor plays a key role and, second, how appropriate would be to establish a direct dialogue between the gynecologist and the urologist.
We performed a systematic review and meta-analysis on the male component of RPL. We found that sperm DNA fragmentation and some specific sperm parameters are significantly associated with RPL.

Recurrent miscarriage is classically defined as three or more consecutive pregnancy losses in about 1-5% of couples trying to conceive. However, several researchers have amended this to two or more because of the recent increase in childless miscarriages. Recurrent miscarriage is a clinical challenge for clinicians because there are many possible causes, and diagnostic testing is expensive and time-consuming. Established causes of recurrent miscarriage are antiphospholipid antibodies, uterine anomalies, and abnormal chromosomes in either partner, particularly translocations. Uterine anatomical abnormalities, endocrine abnormalities, infections, immunologic factors, environmental factors, metabolic or hormonal disorders, sperm quality, and maternal and paternal age have each been linked. Among them, the genetic factor plays a significant role in recurrent miscarriage. Approximately 70% of miscarriage conceptions with sporadic spontaneous miscarriage reveal some chromosome abnormality. Specifically, recurrent miscarriage can be caused by a structural or numerical defect in the parents\' or fetus\' chromosomes. Recurrent miscarriage has been linked to several genes, including those involved in oxidative stress, angiogenesis, clotting, and inflammation. Despite several well-known etiologic factors, the etiology of recurrent miscarriage is unknown in over half of all instances. The current review aims to analyse the role of the genetic basis of recurrent miscarriages.

Recurrent pregnancy loss (RPL) or recurrent miscarriage is the failure of pregnancy before 20-24 weeks that influences around 2-5% of couples. Several genetic, immunological, environmental and physical factors may influence RPL. Although various traditional methods have been used to treat post-implantation failures, identifying the mechanisms underlying RPL may improve an effective treatment. Recent evidence suggested that gene expression alterations presented essential roles in the occurrence of RPL. It has been found that long non-coding RNAs (lncRNAs) play functional roles in pregnancy pathologies, such as recurrent miscarriage. lncRNAs can function as dynamic scaffolds, modulate chromatin function, guide and bind to microRNAs (miRNAs) or transcription factors. lncRNAs, by targeting various miRNAs and mRNAs, play essential roles in the progression or suppression of RPL. Therefore, targeting lncRNAs and their downstream targets might be a suitable strategy for diagnosis and treatment of RPL. In this review, we summarized emerging roles of several lncRNAs in stimulation or suppression of RPL.

Recurrent miscarriage (RM) is a complex reproductive medicine disease that affects many families. The cause of RM is unclear at this time; however, lifestyle and genetic variables may influence the process. The slight alteration in miRNA expression has enormous consequences for a variety of difficulties, one of which may be RM. The target of this systematic study was to provide a framework of the dysregulated miRNAs in RM. The Prisma guidelines were applied to perform current systematic review pertaining to articles in the seven databases. Thirty-nine papers out of 245 received fulfilled all inclusion requirements. From all the mentioned miRNAs, 40 were up-regulated (65.57 %), whereas 21 were down-regulated (34.43 %). These dysregulated miRNAs contributed to the pathophysiology of RM by influencing key pathways and processes such as apoptosis, angiogenesis, epithelial-mesenchymal transition, and the immune system. Understanding the dysregulation of miRNAs, as well as the pathways and processes that engage these miRNAs and impact disease pathogenesis, may aid in clarifying the unknown underlying mechanisms of RM and the development of novel molecular therapeutic targets and medical domains.

There is significant variation in practice when managing couples with recurrent miscarriage (RM), with guidelines differing on the definition of RM, recommended investigations, and treatment options. In the absence of evidence-based guidance, and following on from a paper by the authors-FIGO Good Practice Recommendations on the use of progesterone in the management of recurrent first-trimester miscarriage-this narrative review aims to propose a global holistic approach. We present graded recommendations based on best available evidence.