Specific plasma microRNA profiles could be potential non-invasive biomarkers for biochemical pregnancy loss following embryo transfer.

BACKGROUND: Plasma microRNAs act as biomarkers for predicting and diagnosing diseases. Reliable non-invasive biomarkers for biochemical pregnancy loss have not been established. We aim to analyze the dynamic microRNA profiles during the peri-implantation period and investigate if plasma microRNAs could be non-invasive biomarkers predicting BPL. METHODS: In this study, we collected plasma samples from patients undergoing embryo transfer (ET) on ET day (ET0), 11 days after ET (ET11), and 14 days after ET (ET14). Patients were divided into the NP (negative pregnancy), BPL (biochemical pregnancy loss), and CP (clinical pregnancy) groups according to serum hCG levels at day11~14 and ultrasound at day28~35 following ET. MicroRNA profiles at different time-points were detected by miRNA-sequencing. We analyzed plasma microRNA signatures for BPL at the peri-implantation stage, we characterized the dynamic microRNA changes during the implantation period, constructed a microRNA co-expression network, and established predictive models for BPL. Finally, the sequencing results were confirmed by Taqman RT-qPCR. RESULTS: BPL patients have distinct plasma microRNA profiles compared to CP patients at multiple time-points during the peri-implantation period. Machine learning models revealed that plasma microRNAs could predict BPL. RT-qPCR confirmed that miR-181a-2-3p, miR-9-5p, miR-150-3p, miR-150-5p, and miR-98-5p, miR-363-3p were significantly differentially expressed between patients with different reproductive outcomes. CONCLUSION: Our study highlights the non-invasive value of plasma microRNAs in predicting BPL.

Can single progesterone concentration predict miscarriage in early pregnant women with threatened miscarriage: a systematic review and meta-analysis.

BACKGROUND: About 25% of pregnant women experience bleeding in the early stage, and half of them eventually progress to pregnancy loss. Progesterone serves as a useful biomarker to predict miscarriage in threatened miscarriage, yet its performance is still debated. AIM: To evaluate the performance of single serum progesterone predicting miscarriage in early pregnant patients with threatened miscarriage. METHOD: The online database was searched to yield the literature using the terms of 'Abortion', 'Miscarriage', and 'serum Progesterone', including PubMed, Scopus, Embase, Cochrane library, and China national knowledge infrastructure. Receiver operating characteristic (ROC) curve, likelihood ratio (LLR) and diagnostic odds ratio (DOR) and 95% confidence interval (CI) were computed. Publication bias was assessed by the deeks funnel plot asymmetry test. Subgroup analyses were conducted according to the progesterone level (< 12 ng/mL), recruited location and region, progesterone measurement method, exogenous progesterone supplement and follow up. RESULTS: In total, 12 studies were eligible to be included in this study, with sample sizes ranging from 76 to 1087. The included patients' gestational age was between 4 and 12 weeks. No significant publication bias was detected from all included studies. The threshold of progesterone reported ranged from 8 to 30 ng/ml. The synthesized area under the ROC curve (0.85, 95% CI 0.81 to 0.88), positive LLR (6.2, 4.0 to 9.7) and DOR (18, 12 to 27) of single progesterone measurement distinguishing miscarriage were relatively good in early pregnant patients with threatened miscarriage. When the threshold of < 12 ng/mL was adapted, the progesterone provided a higher area under the ROC curve (0.90 vs. 0.78), positive LLR (8.3 vs. 3.8) and DOR (22 vs.12) than its counterpart (12 to 30 ng/mL). CONCLUSION: Single progesterone measurement can act as a biomarker of miscarriage in early pregnant patients with threatened miscarriage, and it has a better performance when the concentration is <12 ng/mL. TRIAL REGISTRATION: PROSPERO (CRD42021255382).

EARLY PREGNANCY LOSS: INVESTIGATING THE ROLE OF PROGESTERONE-INDUCED BLOCKING FACTOR.

Aim of the study - the assessment of the diagnostic value of Progesterone-Induced Blocking Factor (PIBF) in Early Pregnancy Loss (EPL), in naturally conceived women and in women who underwent In Vitro Fertilization (IVF). In the prospective and retrospective study 50 naturally conceived women were divided into three groups: Group I - patients with progressive pregnancy; Group II- patients with EPL; Group III - patients with biochemical pregnancy (BP). 36 pregnant women after IVF were divided into three groups: Group IV - patients with progressive pregnancy, Group V - patients with EPL, and Group VI - patients with BP. ß human Chorionic Gonadotropin (ßhCG), PIBF and Progesterone (PG) were assessed in the women conceived naturally and after IVF on the 12th to 14th day after ovulation and embryo transfer (ET), respectively. PG and PIBF levels were significantly higher in the progressive and significantly lower in the biochemical pregnancy groups as in the naturally conceived women, so after IVF. PIBF was not significantly different in EPL and BP groups of naturally conceived and IVF pregnant, opposite to the PG, which was significantly lower in the BP group. Thus, PIBF is more informative in the prognosis of EPL and PG - in the diagnosis of clinical pregnancy. PIBF emerges as a prognostic indicator for early pregnancy loss, encompassing even its preclinical stage.

Association Between Anti-Müllerian Hormone and Early Spontaneous Abortion in Assisted Reproduction Treatment: A Case-Control Study Integrated with Biological Evidence.

Early spontaneous abortion (ESA) is a common adverse pregnancy outcome mainly attributed to embryo chromosomal abnormalities. However, as a quantitative marker, whether the anti-Müllerian hormone (AMH) can reflect oocyte quality is still controversial. By integrating biological evidence and adjusting many cofounders, this study aimed to clarify the controversies about the association between AMH and ESA caused by embryo aneuploidy during assisted reproductive technology (ART) treatment. We strictly preselected 988 patients receiving first ART treatment for analyzing clinical data, while 55 of them acquired chorionic villi karyotype results. In addition, 373 biopsied embryos from 126 patients receiving preimplantation genetic diagnosis (PGT) were tracked to compare embryo karyotypes. Univariate and multiple factor regressions were applied to analyze the risk factors leading to ESA. As covariates unadjusted, AMH (odds ratio 0.87, 95% CI 0.82-0.93) was the significant variable contributing to ESA. However, AMH played no significant role in the following regression models after age was adjusted. Also, AMH had no significant association with ESA in most age-adjusted subgroups, except in the male factors engaged subgroup. Additionally, compared to the patients with euploid chorionic villi karyotypes, those with aneuploid karyotypes were older and acquired fewer oocytes, yet their AMH levels were not significantly different. Furthermore, the embryo aneuploidy was independent of AMH while associated with maternal age, retrieved oocyte number, and embryo quality. This study suggested that AMH was unassociated with the ESA caused by embryo aneuploidy in ART therapy. As a critical cofounder, age remains the variable closely related to ESA.

Systemic Inflammation Response Index and Systemic Immune-inflammation Index for Prediction of Pregnancy Loss: a Case-control Study.

The systemic inflammation response index (SIRI) and systemic immune inflammation index (SII) have recently been investigated as new prognostic markers for obstetric morbidities. However, there are few studies on their predictive role in patients with pregnancy loss. Predicting miscarriages may be useful to support and prevent selected cases.The aim of this study was to investigate the role of SIRI and SII in the prediction of pregnancy loss. A total of 800 patients were included in the retrospective case-control study at a tertiary hospital.Group 1 consisted of 200 patients who had a pregnancy loss for the first time; group 2 consisted of 200 patients with recurrent pregnancy loss; the control group consisted of 400 patients who had a healthy pregnancy. The groups were compared in terms of maternal characteristics, SIRI and SII. Receiver operating characteristic analysis was performed to determine optimal cut-off values for SIRI and SII in predicting pregnancy loss. SIRI and SII were higher in the group with recurrent pregnancy loss than in the control group (p < 0.001).SIRI was higher in the first pregnancy loss group than in the control group (p < 0.001).To predict recurrent pregnancy loss, optimal cut-off values were 1.57 (80% sensitivity, 70% specificity) and 924.12 (74% sensitivity, 57% specificity) for SIRI and SII, respectively. For first pregnancy loss prediction, the optimal cut-off value was 1.38 for SIRI, with 75% sensitivity and 60% specificity. SIRI and SII may be used as inflammatory markers to predict recurrent pregnancy loss. High SIRI values can also help to predict first pregnancy loss.

Diagnostic utility of clinicodemographic, biochemical and metabolite variables to identify viable pregnancies in a symptomatic cohort during early gestation.

A significant number of pregnancies are lost in the first trimester and 1-2% are ectopic pregnancies (EPs). Early pregnancy loss in general can cause significant morbidity with bleeding or infection, while EPs are the leading cause of maternal mortality in the first trimester. Symptoms of pregnancy loss and EP are very similar (including pain and bleeding); however, these symptoms are also common in live normally sited pregnancies (LNSP). To date, no biomarkers have been identified to differentiate LNSP from pregnancies that will not progress beyond early gestation (non-viable or EPs), defined together as combined adverse outcomes (CAO). In this study, we present a novel machine learning pipeline to create prediction models that identify a composite biomarker to differentiate LNSP from CAO in symptomatic women. This prospective cohort study included 370 participants. A single blood sample was prospectively collected from participants on first emergency presentation prior to final clinical diagnosis of pregnancy outcome: LNSP, miscarriage, pregnancy of unknown location (PUL) or tubal EP (tEP). Miscarriage, PUL and tEP were grouped together into a CAO group. Human chorionic gonadotrophin ß (ß-hCG) and progesterone concentrations were measured in plasma. Serum samples were subjected to untargeted metabolomic profiling. The cohort was randomly split into train and validation data sets, with the train data set subjected to variable selection. Nine metabolite signals were identified as key discriminators of LNSP versus CAO. Random forest models were constructed using stable metabolite signals alone, or in combination with plasma hormone concentrations and demographic data. When comparing LNSP with CAO, a model with stable metabolite signals only demonstrated a modest predictive accuracy (0.68), which was comparable to a model of ß-hCG and progesterone (0.71). The best model for LNSP prediction comprised stable metabolite signals and hormone concentrations (accuracy = 0.79). In conclusion, serum metabolite levels and biochemical markers from a single blood sample possess modest predictive utility in differentiating LNSP from CAO pregnancies upon first presentation, which is improved by variable selection and combination using machine learning. A diagnostic test to confirm LNSP and thus exclude pregnancies affecting maternal morbidity and potentially life-threatening outcomes would be invaluable in emergency situations.

Diagnostic value of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio to predict recurrent pregnancy loss and abortion; a systematic review and meta-analysis.

OBJECTIVE: This systematic review and meta-analysis aimed to evaluate the diagnostic value of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in women with a history of abortion (missed and threatened) and recurrent pregnancy loss (RPL) in comparison with healthy pregnancies. METHODS: Electronic databases including MEDLINE, Scopus, Web of Science, Embase, and Cochrane Library were searched for NLR and PLR in women who experienced early pregnancy loss up to January 1, 2023 with a combination of proper keywords. Meta-analysis was done for comparison with three or more studies and summary estimates were measured. RESULTS: A total of 390 citations were retrieved initially, and after screening, 16 articles were deemed eligible for the final review. Among these, 14 studies underwent meta-analysis. The meta-analysis revealed that the standard mean of the NLR was significantly higher in abortion cases compared to the control group. However, there was no significant difference in the PLR between the pregnancy loss group and the control group. CONCLUSION: NLR was significantly higher among RPL patients compared to the control group, according to these data, NLR may be capable of being used in the diagnosis of RPL as an easy, cheap, and accessible modality. Further studies, which take these variables into account, will need to be undertaken to determine the diagnostic value of NLR and PLR in early pregnancy loss.

Exploring the association of hyperhomocysteinemia with early pregnancy losses: A retrospective case-control study in a tertiary clinic in Türkiye.

A disturbance in the metabolism of homocysteine in both the mother and the fetus has been implicated in several placental vasculopathy-related disorders, including pregnancy loss. This study aimed to provide insights into the potential role of homocysteine, Vitamin B12, and folic acid in early pregnancy losses, with a specific focus on the Turkish population. The results of 93 pregnant women who experienced miscarriage between 5 and 14 gestational weeks and 93 healthy pregnant women at the same gestational weeks were compared. The demographic and pregnancy characteristics of all pregnant women were recorded. Vitamin B12, folic acid, and homocysteine levels were measured in serum samples obtained from the groups at similar gestational weeks. In addition, any associations between these biomarkers and different types of pregnancy loss, such as spontaneous abortion and missed abortion, were evaluated. Vitamin B12 and folic acid serum levels were significantly lower in women with miscarriages (P = .019, P < .001, respectively). Homocysteine levels were higher in the patient group (P < .001). Logistic regression analysis showed that a higher homocysteine level was the only predictive factor of miscarriage (P = .001, odds ratio = 0.596); however, folic acid and Vitamin B12 were not predictive factors. There was no significant difference in homocysteine and micronutrient levels between women with missed abortions and women with spontaneous abortions (P > .05). Our results support the continuing evidence of a link between maternal homocysteine levels and fetal loss. However, in exploring the shared pathways in the underlying mechanisms causing the 2 forms of pregnancy loss, maternal blood analysis showed no relationship.

Inflammatory markers in systemic immune-inflammatory index and inflammatory response index to predict early pregnancy loss.

OBJECTIVES: To uncover the predictive value of systemic immune-inflammatory index (SII) and systemic inflammatory response index (SIRI) on early pregnancy loss. METHODS: A total of 535 individuals were enrolled in this retrospective analysis. The early pregnancy losses (EPL) group included patients between 18-35 years old who experienced EPL. The control group comprised healthy pregnant women who gave birth at ≥37 weeks. RESULTS: The EPL group had significantly lower plateletcrit (p=0.04), platelet distribution width (PDW, p<0.0001), and RDW (p<0.0001) and higher monocyte (p<0.0001) and SIRI (p<0.0001) values than the control group. The hemoglobin, white blood cells, platelet count, neutrophil count, lymphocyte count, mean platelet volume, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and SII values were not significantly different between the EPL and control groups (p>0.05). The cut-off value for the SIRI that offers the best sensitivity/specificity balance was 1.48 (sensitivity of 63%; specificity of 63%) in the receiver operating characteristics curve. Among the inflammatory parameters for predicting EPL, PDW had highest specificity (84%), and RDW had the highest sensitivity (80%). CONCLUSION: This study provides compelling evidence that various inflammatory pathways may significantly contribute to EPL pathogenesis. Moreover, our findings suggest that SIRI could be a more effective marker than NLR, PLR, MLR, and SII in predicting EPL in an ongoing pregnancy, thereby potentially revolutionizing early pregnancy loss diagnostics.

Infeccoes de transmissao vertical em material abortivo e sangue com enfase em Toxoplasmose gondii / Vertical transmission from abortive material and blood with emphasis on Toxoplasma gondii

OBJETIVO: Analisar os resultados sorológicos, anatomopatológicos e parasitológicos de material abortivo para infecções com risco de transmissão vertical, com ênfase na toxoplasmose. MÉTODOS: Foi realizado um estudo coorte-transversal tratando da prevalência das doenças infectoparasitárias. Participaram da pesquisa 105 mulheres que sofreram aborto espontâneo completo e/ou incompleto; elas foram entrevistadas por meio de um questionário, e foram coletadas amostras de sangue e material abortivo. Foram realizados testes imunológicos para toxoplasmose, doença de Chagas, rubéola, citomegalovírus e sífilis e análise anatomopatológica nos restos ovulares. RESULTADOS: 55% das mulheres tinham entre 20 e 30 anos de idade. A maioria (68%) apresentou idade gestacional entre a 7ª e a 14ª semanas. 54,3% das mulheres tinham o ensino médio completo ou incompleto. Pela análise da sorologia, a infecção com risco de transmissão vertical mais frequente foi o citomegalovírus (CMV) com 97,1% de positividade, e em seguida a rubéola, com 95,2%. A toxoplasmose teve um percentual de 54,3%, a doença de Chagas, de 1,9% e a sífilis, de 0,95%. A análise dos laudos de biópsia demonstrou que 63,1% apresentaram inflamação e 34%, ausência de inflamação. Das análises sorológica, anatomopatológica e parasitológica das 105 mulheres, 57 foram soropositivas para T. gondii, e nenhuma teve resultado positivo para a Reação em Cadeia da Polimerase (PCR) e para inoculação em camundongos. CONCLUSÕES: A prevalência de doenças com risco de transmissão congênita nas mulheres com abortamento espontâneo é importante, sendo necessárias pesquisas visando esclarecer a etiologia do aborto. .

PURPOSE: To analyze the serological, anatomopathological and parasitological results obtained from abortive material in order to detect infections with the risk of vertical transmission, with emphasis on toxoplasmosis. METHODS: A cross-sectional cohort study was conducted in order to determine the prevalence of infectoparasitic diseases. A total of 105 women who suffered spontaneous complete or incomplete abortion participated in the study. The women were interviewed, answered a questionnaire and had their blood and abortive material collected. Immunological tests were carried out in order to detect toxoplasmosis, Chagas disease, rubeola, cytomegalovirus and syphilis, and anatomopathological analysis of the ovular remains was performed. RESULTS: 55% of the women studied were 20 to 30 years old. Most of them (68%) presented a gestational age between the 7th and 14th week. 54.3% of the women had complete or incomplete high school education. Serological analysis showed cytomegalovirus (CMV) as the most common vertically transmitted infection with 97.1% positivity, followed by rubeola with 95.2%. Toxoplasmosis showed 54.3% positivity, Chagas disease 1.9% and syphilis 0.95%. Anatomopathological analysis showed inflammation in 63.1% of the cases and absence of inflammation in 34%. The results of the serological, anatomopathological and parasitological analysis of the 105 participants showed that 57 women were T. gondii positive. However, none showed positivity in the polymerase chain reaction (PCR) or in mouse inoculation. CONCLUSIONS: The prevalence of diseases with the risk of vertical transmission is important in women with spontaneous abortion, indicating the need for more research in order to investigate the etiology of abortion. .

Manual "Código Rojo" para el manejo de la hemorragia obstétrica / Manual "Red Code" for the management of obstetric hemorrhage

El manual, corresponde a una estrategia para reducir la tasa de mortalidad materna en relación a la hemorragia obstétrica y como indica el documento: "El comportamiento de la morbi-mortalidad materna en los últimos diez años, ha situado a la hemorragia obstétrica en el primer lugar del país. Por lo anterior se priorizan las acciones que impacten en la reducción de la muerte materna implementando la estrategia de "Código Rojo", la cual estandariza los lineamientos técnicos, normativos y clínicos para la prevención y manejo de la hemorragia obstétrica y choque hipovolémico, respondiendo así al derecho reproductivo que establece que ninguna mujer debe morir por causas relacionadas al embarazo, parto y post parto." Código rojo

Niveles de estradiol plasmático como índice pronóstico en la gestación inicial / Plasma estradiol levels as a predictive pronostic of the early pregnancy

Las autores estudian el valor de los niveles plasmáticos de Estradiol como predictores de aborto en la gestación inicial. Para ello miden semanalmente estos niveles en 82 gestantes dentro de las 10 semanas de gestación. Se observa el comportamiento individual de la curva descrita por estas determinaciones a través del cálculo de su pendiente. 24 embarazadas normales constituyen el grupo control. Las 58 restantes habían recibido previamente tratamiento por esterilidad de diversas etiologías. De acuerdo al destino final de la gestación se estableció 2 categorías de pacientes: No abortadoras (44) y abortadoras(14). Estas últimas cursaron sus primeras semanas de embarazo con niveles de estradiol significativamente menores al comparar sus pendientes con las del grupo no abortadoras y las del grupo control. Se observó un valor predictivo de un 91% para una pendiente positiva de la curva de estradiol y de un 66% para una pendiente negativa