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.

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.

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.

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.

Do elevated thyrotropin levels increase the risk of miscarriages: yes or no?

BACKGROUND: To examine correlation between elevated levels of thyrotropin with the frequency of miscarriages. METHODS: A cross-sectional study was conducted on the 380 respondents and it investigated TSH (thyrotropin), thyroid peroxidase antibody(anti-TPO) and free thyroxine (FT4) in pregnant women who had a miscarriage (N = 179) and pregnant women with normal pregnancies (N = 201). RESULTS: The incidence of subclinical hypothyroidism in the miscarriages group was higher than in control group (61.4% vrs 15.79% (p < 0.001). In the miscarriages group with hypothyroidism (first trimester) mean value of TSH was significantly higher 4.31 ± 2.55 mIU/L compared to the control group 1.95 ± 0.86mIU/L (p < 0.001). Logistic multivariate regression revealed that TSH and body mass index (BMI) have a significant influence on the miscarriage; TSH level has a higher odds ratio (OR) 1.47 CI (95% 1.22-1.78) than BMI (OR) 1.14 CI (95% 1.06-1.23)) (p < 0.001). The combination of thyroid autoimmunity and TSH > 2.5mIU/L increase the risk of miscarriage (65.75%) compared to positive anti-TPO antibodies and TSH < 2.5mIU/L(14.15%)(p < 0.001). CONCLUSIONS: Higher TSH levels correspond with obesity during early pregnancy and may be a sign of maternal thyroid dysfunction. Physiological thyroid function in the first trimester of pregnancy is important for perinatal outcome.

Comparison of VEGF-A levels in women with threatened abortion, early pregnancy loss and uncomplicated healthy pregnancies.

INTRODUCTION: To estimate the possible role of VEGF-A in predicting poor early pregnancy outcomes including threatened abortion and early pregnancy loss. METHODS: We conducted a prospective case-control study with three groups of pregnant women diagnosed with threatened abortion, early pregnancy loss, and uncomplicated healthy pregnancies between 01 March 2023 and 15 March 2023. Maternal serum VEGF-A concentration was measured using the Sandwich-ELISA method in accordance to the commercial kit's instructions. There were 30 patients in each 3 group and the gestational age of the patients was between 6 and 14 weeks. The Kruskal-Wallis test was performed for comparing the median values between the groups. Mann-Whitney U test was conducted for pairwise comparisons. RESULTS: VEGF-A levels were compared between 3 groups and a statistically significant difference was found (p = 0.007). There was a moderately significant correlation between VEGF-A levels and poor early pregnancy outcomes. For poor early pregnancy outcomes, the area under the curve (AUC) was 0.75 (95% CI: 0.64-0.85). The best balance of sensitivity/specificity in ROC curves was 0.60 (63.3% sensitivity, 74.3% specificity). DISCUSSION: In conclusion, this study pointed out the increased VEGF concentrations in pregnant women with threatened miscarriage and early pregnancy loss. VEGF-A may be a potential biomarker for the indication of poor early pregnancy outcomes.

Role of the systemic immune-inflammation index in threatened abortion patients and predicting of abortion.

PURPOSE: Our study aimed to compare the systemic immune inflammation index (SII), one of the hematological inflammation parameters, between pregnant women diagnosed with threatened abortion (TA) and healthy pregnant women, and to evaluate the prediction of abortion in pregnant women with TA. METHODS: This retrospective study compared 150 patients with TA group and 150 age- and gestational week-matched healthy pregnant women (control group). Complete blood count parameters were assessed. SII, white blood cells (WBC), neutrophil to lymphocyte ratio (NLR), red cell distribution width (RDW), plateletcrit (PCT), platelet distribution width and monocyte to lymphocyte ratio (MLR) values were calculated. The SII value was calculated as follows: platelet count × (neutrophil/lymphocyte). RESULTS: SII, NLR, MLR, WBC, RDW, and PCT values were significantly higher in the TA group compared to the control group (923 ± 683 vs. 579 ± 364 [p < 0.001], 3.3 ± 2.0 vs. 2.1 ± 1.1 [p < 0.001], 0.3 ± 0.1 vs. 0.2 ± 0.2 [p < 0.001], 9.84 ± 2.87 vs. 8.6 ± 1.6 [p < 0.001], 13.9 ± 1.9 vs. 14.4 ± 2.3 [p = 0.032] and 0.3 ± 0.1 vs. 0.2 ± 0.0 [p < 0.001], respectively). Using receiver operating characteristics curve analysis to predict abortion in AI patients, the highest area under the curve was found for SII (0.727 for SII and 0.666 for NLR). CONCLUSION: SII, NLR, MLR, RDW, and platelet to lymphocyte ratio (PLR) levels were significantly increased in patients with TA. This study supports the idea that several inflammatory pathways may play an important role in the pathogenesis of this disorder. SII may be a much better marker than NLR and PLR for predicting the inflammatory status of the disease and abortion in an ongoing pregnancy.

The expression of anti-protein disulfide isomerase A3 autoantibody is associated with the increased risk of miscarriage in euthyroid women with thyroid autoimmunity.

Miscarriage frequently occurs in euthyroid women with thyroid autoimmunity (TAI), but its mechanisms remain unclear. Our previous study has found that the serum level of anti-protein disulfide isomerase A3 autoantibody (PDIA3Ab) was significantly increased in mice with TAI. This study was aimed to explore whether there could be an association between the expression of PDIA3Ab and the occurrence of miscarriage in euthyroid TAI women. It was found that the serum level of PDIA3Ab was significantly increased in euthyroid TAI women as compared with that of non-TAI controls. Especially, serum PDIA3Ab level was markedly higher in euthyroid TAI women with miscarriage than the ones without miscarriage. Furthermore, binary logistic regression analysis showed that the serum PDIA3Ab level was an independent risk factor for spontaneous abortion in euthyroid TAI women with an odds ratio of 13.457 (95% CI, 2.965-61.078). The receiver operating characteristic (ROC) analysis of serum PDIA3Ab expression for predicting the miscarriage in euthyroid TAI women showed that the area under the curve was 0.707 ± 0.05 (P < 0.001). The optimal cut-off OD450 value of serum PDIA3Ab was 0.7129 with a sensitivity of 52.5% and specificity of 86.3% in euthyroid TAI women. Trend test showed that the prevalence of spontaneous abortion was markedly increased with the rise of serum PDIA3Ab level among TAI women in a titer-dependent manner. In conclusion, serum PDIA3Ab expression may imply an increased risk of spontaneous abortion in euthyroid TAI women, and it can be used as a new predictive bio-marker.

Increased incidence of spontaneous abortions on exposure to cadmium and lead: a systematic review and meta-analysis.

BACKGROUND: Spontaneous abortions are the most severe complication of early pregnancy and are a major reproductive health problem. Although this could be caused due to various cytogenetic, immunological, or endocrinological reasons, role of environmental toxicants cannot be ruled out. In order to explore the role of cadmium and lead in causing spontaneous abortions, current systematic review and meta-analysis had been carried out. METHODOLOGY: Literature search was performed using appropriate keywords in PubMed, Science Direct, Cochrane Library, and Google Scholar databases up to December 25 2020 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA). Metananalysis was carried out with the help of RevMan software (version 5.3). RESULTS: Meta-analysis of nine studies on cadmium concentrations in blood of women with at least one spontaneous abortions and controls revealed standardized mean difference (SMD)=3.39, 95% CI (2.17, 4.61), with p < .05. Similarly, meta-analysis of eight studies on lead concentrations revealed standardized mean difference (SMD)=6.24, 95% CI (4.34, 8.14), with p < .05. CONCLUSION: Populations exposed to heavy metals such as cadmium and lead are at higher risk of pregnancy loss. Therefore, couples experiencing repeated pregnancy losses may be screened for heavy metal load.

Pregnancy and Neonatal Outcomes With Levothyroxine Treatment in Women With Subclinical Hypothyroidism Based on New Diagnostic Criteria: A Systematic Review and Meta-Analysis.

Background: Subclinical hypothyroidism (SCH) during pregnancy has been associated with multiple adverse maternal and neonatal outcomes. However, the potential benefits of levothyroxine (LT4) supplementation remain controversial. Variations across studies in diagnostic criteria for SCH may, in part, explain the divergent findings on the subject. This study aimed to assess the effect of LT4 treatment on pregnancy and neonatal outcomes among pregnant women who were diagnosed as SCH based on the most recent diagnostic criteria. Methods: We conducted a systematic review and meta-analysis of the literature published from inception to January 2020. The search strategy targeted the studies on pregnancy and neonatal outcomes following LT4 treatment in women with SCH based on 2017 American Thyroid Association diagnostic criteria. Pooled effect sizes were estimated using fixed and random effect models, according to the absence or presence of heterogeneity which was assessed using the I-squared statistic. Sources of heterogeneity and the stability of results were evaluated through sensitivity analysis. Results: Of the 2781 identified references, 306 full-text articles were screened for eligibility. Finally, 6 studies including a total of 7955 participants were retained for analysis. Summary effect estimates indicated that pregnant women with SCH treated with LT4 had a lower risk of pregnancy loss [odds ratio (OR) = 0.55, 95% confidence interval (CI): 0.43-0.71], preterm birth (OR=0.63, 95% CI: 0.41-0.98) and gestational hypertension (OR = 0.78, 95% CI: 0.63-0.97) than those in control group. Conclusion: LT4 treatment in pregnant women with SCH may reduce the risk of pregnancy loss, preterm delivery and gestational hypertension.

The RPOC long axis is a simple indicator for predicting the need of invasive strategies for secondary postpartum hemorrhage in either post-abortion or post-partum women: a retrospective case control study.

BACKGROUND: The retained products of conception (RPOC) and related conditions (RPOC-ARC) are the main cause of secondary postpartum hemorrhage (sPPH), but there is no clear consensus for their management. The purpose of this study was to characterize those RPOC-ARC that require invasive treatment and those that could be managed more conservatively. METHODS: We retrospectively analyzed 96 cases of RPOC-ARC that occurred after miscarriage, abortion, or delivery at a gestational age between 12 and 42 completed weeks, that were managed within our institution from May 2015 to August 2020. We reviewed the associations between the occurrence of sPPH requiring invasive treatment with clinical factors such as the maternal background and the characteristics of the lesions. RESULTS: The range of gestational age at delivery in our study was 12-21 weeks in 61 cases, 22-36 in 5, and 37 or later in 30. Among them, nine cases required invasive procedures for treatment. The onset of sPPH was within one month of delivery in all but two cases, with a median of 24 days (range 9-47). We found significant differences between requirements for invasive versus non-invasive strategies according to gestational age at delivery, assisted reproductive technology (ART) pregnancy, amount of blood loss at delivery, and the long axis of the RPOC-ARC lesion (p = 0.028, p = 0.009, p = 0.004, and p = 0.002, respectively). Multivariate analysis showed that only the long axis of the lesion showed a significant difference (p = 0.029). The Receiver Operating Characteristic (ROC) curve for predicting the need for invasive strategies using the long axis of the lesion showed that with a cutoff of 4.4 cm, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) was 87.5, 90.0, 43.8, and 98.7%, respectively. CONCLUSION: The long axis of the RPOC-ARC is a simple indicator for predicting which sPPH will require invasive procedures, which use is rare in cases with lesions less than 4.4 cm or those occurring after the first postpartum month. Conservative management should be considered in such cases.

The effect of A1298c polymorphism of the MTHFR gene on anti-Müllerian hormone levels: experimental and Web-based analysis.

BACKGROUND: The 5,10-methylenetetrahydrofolate reductase (MTHFR) is an important enzyme of folate and methionine metabolism, which is expressed in human oocytes and preimplantation. Due to the involvement of MTHFR in female reproduction, we tend to evaluate the influence of MTHFR A1298C polymorphism on ovarian marker reserves such as serum anti-Müllerian hormone (AMH) levels in women after in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). METHODS: A total of 100 women, who underwent ART treatment due to male factor infertility, were recruited into this study. MTHFR A1298C polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique, and serum AMH concentrations were measured by an ultrasensitive enzyme-linked immunosorbent assay (ELISA). RESULTS: Women with the CC genotype had higher AMH levels (4.15 ± 1.67 ng/ml), albeit not significant, than carriers with other genotypes after ovarian stimulation. No significant differences existed in terms of miscarriage and live birth rates among different genotype groups. CONCLUSION: The presence of the C mutant allele of the 1298 polymorphism in the MTHFR gene led to an increasing trend in serum AMH concentrations; however, the numbers of oocytes retrieved decreased in women with mutated genotypes. The influence of the MTHFR C677T polymorphism on embryo quality and pregnancy rate after ART cycles remains unclear.

Serum calponin 2 is a novel biomarker of tubal ectopic pregnancy.

OBJECTIVE: To evaluate serum protein calponin 2 (CNN2) as a candidate biomarker for tubal ectopic pregnancy (EP). DESIGN: Retrospective study. SETTING: Single University affiliated tertiary hospital. PATIENT(S): Serum samples were obtained from 84 patients with EP, 39 with viable intrauterine pregnancy (vIUP), and 42 with miscarriage. Moreover, 10 fallopian tube and corresponding villous tissue samples from patients with EP, 6 villous tissue samples from patients with vIUP, and 10 villous tissue samples from patients with miscarriage were collected. INTERVENTION(S): Serum CNN2 concentrations were measured using enzyme-linked immunosorbent assay; CNN2 expression in tissues was evaluated via immunohistochemistry and quantitative real-time polymerase chain reaction analysis. MAIN OUTCOME MEASURE(S): The diagnostic performance of serum CNN2 to discriminate an EP from vIUP and miscarriage. RESULT(S): CNN2 was highly expressed in villous stromal cells isolated from patients with EP, and CNN2 messenger ribonucleic acid expression was upregulated in villous tissues from women with EP compared with that in women with vIUPs and miscarriages. Serum CNN2 concentration was higher in women with EP than that in women with vIUP and miscarriage. The serum CNN2 predicted EP from vIUP and miscarriage with areas under the curve (AUCs) of 0.931 (95% confidence interval: 0.889-0.975). For discriminating EP from miscarriage only, the AUC was 0.906 (95% confidence interval: 0.835-0.977). In contrast, the AUCs for serum human chorionic gonadotropin were 0.809 and 0.637, respectively. CONCLUSION(S): Our data highlight the possibility of serum CNN2 as a single biomarker for the diagnosis of EP. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR 1900020483.

Hyperhomocysteinemia and low vitamin B12 are associated with the risk of early pregnancy loss: A clinical study and meta-analyses.

One-carbon metabolism is crucial for the maintenance of healthy pregnancy and alterations in this pathway have been associated with various pregnancy-related complications. Therefore, the present study was conducted to test the hypothesis that the altered folic acid, vitamin B12 and homocysteine levels are associated with the risk of early pregnancy loss (EPL). Plasma folic acid, vitamin B12 and homocysteine levels were analyzed in 83 females with EPL and 70 healthy pregnant females in their first trimester. Further, meta-analyses of folic acid, vitamin B12 and homocysteine were also performed involving various eligible studies. Results from our case-control study and meta-analysis showed that folic acid deficiency is not associated with the risk of EPL. On the other hand, low vitamin B12 and hyperhomocysteinemia were individually found to be significant risk factors for EPL in the present study (P < .01, P < .05, respectively) and meta-analysis as well (P < .001, P < .05, respectively). Vitamin B12 deficiency in combination with hyperhomocysteinemia was a more serious risk factor for EPL (Odds Ratio = 4.98, P = 0.002). Therefore, we conclude that vitamin B12 deficiency and elevated homocysteine levels are independent risk factors for EPL, and of higher risk when combined. The assessment of vitamin B12 and homocysteine levels may serve as a good screening marker for EPL risk.

Monitoring of hemostatic parameters for early prediction of first-trimester miscarriage.

BACKGROUND: Hypercoagulation starts as early as the first-trimester pregnancy and is a risk factor for thromboembolic events which are associated with miscarriage. Our study aimed to investigate coagulation, platelets, and fibrinolysis parameters alteration amongst trimester-specific normal pregnancy and first-trimester miscarriage patients. We also test the accuracy of haemostatic parameters determination for prediction of first-trimester miscarriage. METHODS: Retrospective investigation of 50 women whose most recent pregnancy had ended in the first trimester and 54 age-matched consecutive normal pregnancy between 2016 and 2019. Furthermore, 51 non-pregnant, age-matched women were included in parallel to healthy controls. Twelve screening tests for coagulation and platelet parameters were assessed. RESULTS: We found plasma levels of aPTT, FBG, and TT were significantly prolonged or decreased in miscarriage subjects than the corresponding first phase in normal pregnancies. PT, INR, aPTT, and d-dimer all shift back to normal in miscarriage patients compared with non-pregnant women. Shortened aPTT combined with TT and FBG can predicted the occurrence of first-trimester miscarriage with an AUC of 0.831. CONCLUSIONS: Routine assessment of aPTT combined with TT and FBG is a low-cost, widely available marker for prediction of first-trimester miscarriage.

Economic impact of using maternal plasma cell-free DNA testing to guide further workup in recurrent pregnancy loss.

OBJECTIVE: We have previously demonstrated that maternal-plasma cell-free DNA (cfDNA)-testing can detect chromosomal anomalies in recurrent pregnancy loss (RPL) with 81.8% sensitivity and 90.3% specificity. Here we assess whether this is cost effective in guiding further workup in RPLs. METHOD: A decision-analytic model was developed to compare the cost of various RPL management pathways: (1) current American Society for Reproductive Medicine (ASRM) RPL workup; (2) microarray or karyotyping analysis of products of conception (POCs) and RPL workup only for euploid cases; and (3) cfDNA testing and RPL workup only for euploid cases. Sample accessibility, failure rates, and sensitivity were specified for each test. Costs of sample collection, genetic tests, and RPL workup were considered. Analysis outcomes included detection rate of chromosomal anomaly and cost per patient tested. RESULTS: In comparison to existing cytogenetic testing on POCs, cfDNA testing pathway allowed for better sample accessibility with a lower cost per patient. In addition, using cfDNA to guide further workup significantly increases the number of causative fetal chromosome anomalies detected, reducing the number of patients undergoing unnecessary workup resulting in an overall cost savings. CONCLUSION: Our study showed that inclusion of cfDNA testing is a cost-effective approach to guide RPL workup.

Performance of plasma kisspeptin as a biomarker for miscarriage improves with gestational age during the first trimester.

OBJECTIVE: To compare the performance of kisspeptin and beta human chorionic gonadotropin (ßhCG), both alone and in combination, as biomarkers for miscarriage throughout the first trimester. DESIGN: Prospective, nested case-control study. SETTING: Tertiary Centre, Queen Charlotte Hospital, London, United Kingdom. PATIENT(S): Adult women who had miscarriages (n = 95, 173 samples) and women with healthy pregnancies (n = 265, 557 samples). INTERVENTION(S): The participants underwent serial ultrasound scans and blood sampling for measurement of plasma kisspeptin and ßhCG levels during the first trimester. MAIN OUTCOME MEASURE(S): The ability of plasma kisspeptin and ßhCG levels to distinguish pregnancies complicated by miscarriage from healthy pregnancies unaffected by miscarriage. RESULT(S): Gestation-adjusted levels of circulating kisspeptin and ßhCG were lower in samples from women with miscarriages than in women with healthy pregnancies by 79% and 70%, respectively. The area under the receiver-operating characteristic curve for identifying miscarriage during the first trimester was 0.874 (95% confidence interval [CI] 0.844-0.904) for kisspeptin, 0.859 (95% CI 0.820-0.899) for ßhCG, and 0.916 (95% CI 0.886-0.946) for the sum of the two markers. The performance of kisspeptin in identifying miscarriage improved with increasing length of gestation, whereas that of ßhCG worsened. A decision matrix incorporating kisspeptin, ßhCG, and gestational age had 83% to 87% accuracy for the prediction of miscarriage. CONCLUSION(S): Plasma kisspeptin is a promising biomarker for miscarriage and provides additional value to ßhCG alone, especially during later gestational weeks of the first trimester.

Risk factors for pregnancy morbidity in women with antiphospholipid syndrome.

Antiphospholipid syndrome (APS) increases the risk of obstetric complications, but risk factors for pregnancy morbidity in women with APS remain incompletely characterized. This retrospective study included pregnant women with APS and a control group without APS admitted to Peking University People's Hospital between January 2013 and September 2019. Clinical data were extracted from medical records. Univariate and multivariate logistic regression analyses were used to identify factors associated with adverse pregnancy outcomes (fetal loss, premature birth, fetal growth restriction [FGR], preeclampsia and neonatal death). We included 64 pregnancies in 59 patients with APS (age, 32.3 ± 4.3 years) and 256 pregnancies in 256 women without APS (age, 30.4 ± 3.3 years). Compared with the control group, the APS group had higher incidence rates of preeclampsia (10.9 % vs. 2.3 %, P = 0.002), premature rupture of membranes (17.2 % vs. 3.9 %, P < 0.001), postpartum hemorrhage (23.4 % vs. 4.3 %, P < 0.001), fetal loss (4.7 % vs. 0.8 %, P = 0.024) and premature delivery at ≤34 weeks (7.8 % vs. 2.3 %, P = 0.047). The incidence rates of hypertension during pregnancy, HELLP syndrome, gestational diabetes, oligohydramnios and FGR were similar in both groups. Multivariate logistic regression revealed that three or more prior spontaneous miscarriages (odds ratio [OR], 6.162; 95 % confidence interval [CI], 1.271-29.882; P = 0.024) and double-positivity for antiphospholipid antibodies (OR, 4.024; 95 %CI, 1.025-15.794; P = 0.046) were independently associated with adverse pregnancy outcomes. APS increases the risks of adverse maternal and fetal outcomes during pregnancy. Three or more spontaneous miscarriages and double-positivity for antiphospholipid antibodies are risk factors for adverse pregnancy outcomes in women with APS.

MTHFR (methylenetetrahydrofolate reductase: EC 1.5.1.20) SNPs (single-nucleotide polymorphisms) and homocysteine in patients referred for investigation of fertility.

PURPOSE: MTHFR, one of the major enzymes in the folate cycle, is known to acquire single-nucleotide polymorphisms that significantly reduce its activity, resulting in an increase in circulating homocysteine. Methylation processes are of crucial importance in gametogenesis, involved in the regulation of imprinting and epigenetic tags on DNA and histones. We have retrospectively assessed the prevalence of MTHFR SNPs in a population consulting for infertility according to gender and studied the impact of the mutations on circulating homocysteine levels. METHODS: More than 2900 patients having suffered at least two miscarriages (2 to 9) or two failed IVF/ICSI (2 to 10) attempts were included for analysis of MTHFR SNPs C677T and A1298C. Serum homocysteine levels were measured simultaneously. RESULTS: We observed no difference in the prevalence of different genetic backgrounds between men and women; only 15% of the patients were found to be wild type. More than 40% of the patients are either homozygous for one SNP or compound heterozygous carriers. As expected, the C677T SNP shows the greatest adverse effect on homocysteine accumulation. The impact of MTHFR SNPs on circulating homocysteine is different in men than in women. CONCLUSIONS: Determination of MTHFR SNPs in both men and women must be seriously advocated in the presence of long-standing infertility; male gametes, from MTHFR SNPs carriers, are not exempted from exerting a hazardous impact on fertility. Patients should be informed of the pleiotropic medical implications of these SNPs for their own health, as well as for the health of future children.

Diagnosis and treatment of luteal phase deficiency: a committee opinion.

Luteal phase deficiency (LPD) is a clinical diagnosis associated with an abnormal luteal phase length of ≤10 days. Potential etiologies of LPD include inadequate progesterone duration, inadequate progesterone levels, or endometrial progesterone resistance. LPD has not only been described in association with medical conditions but also in fertile, normally menstruating women. Although progesterone is important for the process of implantation and early embryonic development, LPD has not been proven to be an independent entity causing infertility or recurrent pregnancy loss. Controversy exists regarding the multiple proposed measures for diagnosing LPD and, assuming it can be diagnosed accurately, whether treatment improves outcomes. This document replaces the document entitled "Current clinical irrelevance of luteal phase deficiency: a committee opinion," last published in 2015 (Fertil Steril 2015;103:e27-e32).