Copy number variation sequencing for the products of conception: What is the optimal testing strategy.

BACKGROUND: Copy number variation sequencing (CNV-seq) is crucial in prenatal diagnosis, but its limitations in detecting polyploidy, maternal cell contamination (MCC), and uniparental disomy (UPD) restrict its application in the analysis of products of conception (POCs). This study aimed to investigate an optimal genetic testing strategy for POCs in the era of CNV-seq. METHODS: CNV-seq and quantitative fluorescent polymerase chain reaction (QF-PCR) were performed in all 4,211 spontaneous miscarriage cases. Different testing strategies were compared and the optimal testing strategies were proposed. RESULTS: Of the 4,211 cases, 2561 (60.82%) exhibited clinically significant chromosomal abnormalities. CNV-seq alone, without QF-PCR, might misdiagnose 311 (7.39%) cases, including 278 polyploidy, 13 UPD, and 20 MCC. In 20 MCC cases identified by QF-PCR, CNV-seq successfully pinpointed the cause of miscarriage in 13 cases. Furthermore, in cases where QF-PCR suggested polyploidy, CNV-seq improved the diagnostic accuracy in 54 (1.28%) hypo/hypertriploidy cases. After comparing four different strategies, the sequential approach (initiating with CNV-seq followed by QF-PCR if necessary) emerged as advantageous, reducing approximately 70% of the cost associated with QF-PCR while maintaining result accuracy. CONCLUSIONS: We propose an initial CNV-seq followed by QF-PCR if needed-an efficient and cost-effective strategy for the genetic analysis of POCs.

Expression and clinical significance of miR-141-5p as a biomarker in the serum of patients with early spontaneous abortion.

AIM: miR-141-5p expression in patients with Early Spontaneous Abortion (ESA) and its correlation with hormone levels during pregnancy were investigated. METHODS: A total of 70 pregnant women with ESA were selected as the research group, and 70 normal pregnant women who chose abortion for non-medical reasons were selected as the Con group. Serum ß-HCG, Progesterone (P), and Estrogen (E2) were detected by enzyme-linked immunosorbent assay. Differentially expressed miRNAs were screened by miRNA microarray analysis. miR-141-5p expression was detected by RT-qPCR, and its correlation with serum ß-HCG, P, and E2 levels was analyzed. The diagnostic value of miR-141-5p for ESA was evaluated by the ROC curve. RESULTS: Serum ß-HCG, P, and E2 were decreased and serum miR-141-5p was increased in patients with ESA. Pearson correlation analysis showed that serum ß-HCG, P, and E2 levels were negatively correlated with miR-141-5p expression levels. ROC curve showed that miR-141-5p had a diagnostic value for ESA. CONCLUSIONS: miR-141-5p is related to hormone levels during pregnancy and is expected to become a new candidate diagnostic marker for ESA.

Frozen embryo transfer outcomes decline with increasing female body mass index in female but not male factor infertility: analysis of 56,564 euploid blastocyst transfers.

OBJECTIVE: To evaluate the association of body mass index (BMI) with cycle outcomes after euploid frozen blastocyst transfer. DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): A total of 56,564 first single autologous euploid frozen embryo transfers from the 2016-2019 Society for Assisted Reproductive Technology database were analyzed using BMI and using World Health Organization BMI cohorts. Subanalyses were performed on cycles among patients with a sole diagnosis of polycystic ovary syndrome (PCOS) (n = 4,626) and among patients with only a male factor (n = 10,854). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Clinical pregnancy, pregnancy loss, and live birth (LB). RESULT(S): Success rates and adjusted odds ratios (aORs) with 95% confidence intervals (CIs) for all outcomes were most favorable among those with normal BMI and progressively worsened with increasing BMI. These trends persisted among patients with PCOS for clinical pregnancy (aOR, 0.99; 95% CI, 0.98-0.997), pregnancy loss (aOR, 1.02; 95% CI, 1.01-1.04), and LB (aOR, 0.98; 95% CI, 0.97-0.99), but not among patients with a male factor only for clinical pregnancy (aOR, 1.00; 95% CI, 0.99-1.01), pregnancy loss (aOR, 1.01; 95% CI, 0.99-1.03), or LB (aOR, 0.99; 95% CI, 0.98-1.00). CONCLUSION(S): In the largest cohort to date, increasing BMI was associated with decreased pregnancy and LB and increased pregnancy loss after euploid frozen embryo transfers among the entire cohort and among patients with a sole diagnosis of PCOS; however, these results were attenuated among patients with a sole diagnosis of male factor infertility, suggesting that associated female infertility diagnoses and not BMI alone may underlie this trend.

A prospective study to evaluate whether serum kisspeptin is a marker predictive of the first-trimester miscarriage of women who conceive in IVF.

PURPOSE: Kisspeptin is an emerging biomarker for the discrimination of viable pregnancy. The aim of the study is to determine whether serum kisspeptin can predict the first-trimester miscarriage and compare it with serum HCG in the prediction of the first-trimester miscarriage. METHODS: This study is a prospective case-control design including 178 women who had experienced early miscarriage (n = 21) and viable single pregnancy (n = 157), following frozen-thawed embryo transfer (FET) from May to December 2019. Serum samples on 14 days, 21 days, and 28 days after FET were collected for kisspeptin and HCG detection. TRIAL REGISTRATION NUMBER: NCT03940495. RESULTS: On day 21 after FET, serum kisspeptin levels were significantly lower in the early miscarriage group [0.260 (0.185-0.375)] vs in the viable single-pregnancy group [0.370 (0.280-0.495)] (p = 0.005). Similar results were shown on day 28 after FET, the serum kisspeptin levels were significantly lower in the early miscarriage group [0.270 (0.200-0.330)] vs in the viable single pregnancy group [0.670 (0.455-1.235)] (p < 0.001). But on day 14 after FET, serum kisspeptin levels were comparable in the early miscarriage group [0.260 (0.210-0.325)] and in the viable single-pregnancy group [0.280 (0.215-0.340)] (p = 0.551). Serum kisspeptin levels on days 21 and 28 have a poor predictive value of miscarriage compared with serum HCG levels. [Day 21: AUC = 0.687 (kisspeptin) and 0.816 (HCG); Day 28: AUC = 0.896 (kisspeptin) and 0.909 (HCG)]. CONCLUSIONS: Serum kisspeptin on day 14 failed to discriminate between miscarriage and ongoing pregnancies, and days 21 and 28 had poor predictive values of miscarriage.

Double Trisomy 16 and 22 Clinically Mimic Partial Hydatidiform Mole in a Case of Subsequent Pregnancy Loss.

A case of double trisomy 16 and 22 in the second pregnancy loss is presented. DNA analyses (short tandem repeats genotyping) of miscarriage specimen was indicated because of ultrasound suspicion of partial hydatidiform mole. After the partial hydatidiform mole exclusion, further DNA analyses focused on the most common aneuploidies causing pregnancy loss, detected double trisomy 16 and 22 in the product of conception. The couple was referred to clinical genetic consultation and normal parental karyotypes were proved. For further explanatory purposes, archived material from the first pregnancy loss was analyzed and trisomy of chromosome 18 was detected. By comparison of allelic profiles of the mother, father, and both losses, the maternal origin of all aneuploidies was proven what can be attributed to frequent meiosis errors, probably due to advanced maternal age (44 years at the first loss and 45 years at the second loss). In conclusion, aneuploidies can mimic partial hydatidiform mole. Genetic analysis is helpful on the one hand to rule out partial hydatidiform mole and on the other hand to identify aneuploidies and in this way to determine the cause of miscarriage.

Euploid programmed frozen embryo transfer cycles are associated with a higher live birth rate when estradiol levels more closely mimic physiology.

OBJECTIVE: To determine whether peak estradiol (E2) levels above the usual physiologic range (300-500 pg/mL) will impact programmed frozen embryo transfer (FET) outcomes in an ideal study population of those using good-quality single euploid blastocysts. DESIGN: Retrospective cohort study. SETTING: University-based clinic. PATIENTS: Single euploid-programmed FET done at a single academic institution from January 2016 to December 2019. The population was divided into three groups on the basis of peak serum E2 levels during endometrial preparation: group A (E2 <300 pg/mL), group B (300-500 pg/mL), and group C (>500 pg/mL). Group B was used as the reference range for statistical analysis. INTERVENTION: Frozen embryo transfer cycles. MAIN OUTCOME MEASURES: The primary outcome was the live birth rate (LBR). Secondary outcomes included implantation, biochemical, ectopic, and miscarriage rates. RESULTS: A total of 750 FET cycles were included in this study. Poisson regression analysis showed a negative impact of higher peak E2 on the LBR. A decrease in LBR was noted between group C and referent group B (50.2% vs. 63.4%, risk ratio 0.79 [0.68-0.91]) and group A and referent group B (42.5% vs. 63.4%, risk ratio 0.67 [0.46-0.98]). Secondary outcomes were notable for a lower implantation rate when groups A and C were compared with group B and a higher biochemical rate between group C and group B. There was no notable difference between groups in ectopic or miscarriage rates. CONCLUSION: Limiting peak serum E2 levels to 300-500 pg/mL during programmed FET cycles is associated with improved LBRs compared with cycles with peak E2 levels of <300 pg/mL or >500 pg/mL in an ideal study population.

Molecular diagnosis of complete and partial hydatidiform moles.

Complete and partial hydatidiform moles are abnormal products of conception that can be identified by clinical, ultrasonographic, morphologic, histologic, and genetic methods. The diagnosis is usually confirmed only by histological examination. However, accurate diagnosis based on morphological criteria is difficult and some studies have shown that misclassifications are common, even when analysed by highly experienced pathologists. Misdiagnosis may mean that women are either not included in adequate ß-hCG follow-up with the risk that the hydatidiform mole progresses to choriocarcinoma or, conversely, are included in follow-up unnecessarily. A reliable complementary method to pathological interpretation may be genetic analysis of the conceptus to eliminate the diagnostic dilemma by distinguishing non-molar spontaneous abortions from hydatidiform moles and defining the type of hydatidiform mole. The aim of our short paper is to introduce the routine molecular analysis used in our laboratory to a wider range of clinical pathologists.

Biomarkers at 6 weeks' gestation in the prediction of early miscarriage in pregnancy following assisted reproductive technology.

INTRODUCTION: Miscarriage is a major concern in early pregnancy among women having conceived with assisted reproductive treatments. This study aimed to examine potential miscarriage-related biophysical and biochemical markers at 6 weeks' gestation among women with confirmed clinical pregnancy following in vitro fertilization (IVF)/embryo transfer (ET) and evaluate the performance of a model combining maternal factors, biophysical and biochemical markers at 6 weeks' gestation in the prediction of first trimester miscarriage among singleton pregnancies following IVF/ET. MATERIAL AND METHODS: A prospective cohort study was conducted in a teaching hospital between December 2017 and January 2020 including women who conceived through IVF/ET. Maternal mean arterial pressure, ultrasound markers including mean gestational sac diameter, fetal heart activity, crown rump length and mean uterine artery pulsatility index (mUTPI) and biochemical biomarkers including maternal serum soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), kisspeptin and glycodelin-A were measured at 6 weeks' gestation. Logistic regression analysis was carried out to determine significant predictors of miscarriage prior to 13 weeks' gestation and performance of screening was estimated by receiver-operating characteristics curve analysis. RESULTS: Among 169 included pregnancies, 145 (85.8%) pregnancies progressed to beyond 13 weeks' gestation and had live births whereas 24 (14.2%) pregnancies resulted in a miscarriage during the first trimester. In the miscarriage group, compared to the live birth group, maternal age, body mass index, and mean arterial pressure were significantly increased; mean gestational sac diameter, crown rump length, mUTPI, serum sFlt-1, glycodelin-A, and the rate of positive fetal heart activity were significantly decreased, while no significant differences were detected in PlGF and kisspeptin. Significant prediction for miscarriage before 13 weeks' gestation was provided by maternal age, fetal heart activity, mUTPI, and serum glycodelin-A. The combination of maternal age, ultrasound (fetal heart activity and mUTPI), and biochemical (glycodelin-A) markers achieved the highest area under the curve (AUC: 0.918, 95% CI 0.866-0.955), with estimated detection rates of 54.2% and 70.8% for miscarriage before 13 weeks' gestation, at fixed false positive rates of 5% and 10%, respectively. CONCLUSIONS: A combination of maternal age, fetal heart activity, mUTPI, and serum glycodelin-A at 6 weeks' gestation could effectively identify IVF/ET pregnancies at risk of first trimester miscarriage.

Elevated serum progesterone levels before frozen embryo transfer do not negatively impact reproductive outcomes: a large retrospective cohort study.

OBJECTIVE: To evaluate whether patients with high-serum progesterone levels before frozen embryo transfer (FET) under hormonal replacement therapy present with worse reproductive outcomes. DESIGN: A cohort retrospective study. SETTING: A university-affiliated fertility center. PATIENT(S): A total of 3,183 FET cycles in patients receiving hormonal replacement therapy between March 2009 and December 2020 were included. The luteal phase was covered with 200 mg per 8 hours of vaginal micronized progesterone either alone or in combination with a daily subcutaneous injection of 25 mg of progesterone. A total of 1,360 cycles corresponded to frozen homologous embryo transfer (ET) (hom-FET), 1,024 were euploid ET (eu-FET) after preimplantation genetic testing for aneuploidies, and 799 cycles were frozen heterologous ET (het-FET). All patients had adequate serum progesterone levels (≥10.6 ng/mL) before the procedure. INTERVENTION(S): Frozen embryo transfer cycles. MAIN OUTCOME MEASURE(S): Clinical pregnancy, miscarriage, and live birth rates (LBRs). RESULTS: Median (P25; P75) serum progesterone level before FET was 14.39 (12.43-17.49) ng/mL. Progesterone levels were significantly higher in the group under vaginal plus subcutaneous progesterone (15.96 [13.74-21.60] vs. 14.09 [12.19-16.95]). No differences in clinical pregnancy, miscarriage, and LBR were observed based on the use of vaginal or vaginal plus subcutaneous progesterone for each of the groups (hom-FET, eu-FET, and het-FET). Live birth rates were comparable among patients in the highest centile of serum progesterone levels (≥p90) (22.33 ng/mL) and the rest of the patients (p<90) (43.9% vs. 41.3%). Patients with progesterone levels ≥p90 presented lower body mass index than those in the lower centiles (

Serum Cu, Zn and IL-1ß Levels May Predict Fetal Miscarriage Risk After IVF Cycles: A Nested Case-Control Study.

To explore the association between serum-related indicators (levels of inflammatory cytokines and essential trace elements) and miscarriage risk among infertile women undergoing assisted reproductive techniques (ART) on the 14th day after embryo transfer, and to develop and establish a multivariable algorithm model that might predict pregnancy outcome. According to a nested case-control study design, a total of 100 miscarriage cases and 100 live birth controls were included in this study, and women in both groups were infertile and have underwent in vitro fertilization (IVF). Pregnancy tests were performed and serum levels of five essential trace elements (vanadium (V), copper (Cu), zinc (Zn), selenium (Se) and molybdenum (Mo)) and five inflammatory cytokines (interleukin-1ß (IL-1ß), IL-6, IL-8, IL-10 and tumor necrosis factor-α (TNF-α)) of the participants were measured on the 14th day after embryo transfer. The serum levels of five inflammatory cytokines were determined by multiple magnetic bead enzyme immunity analyzer; and the serum concentrations of five elements were determined simultaneously by inductively coupled plasma‒mass spectrometry (ICP ‒ MS). The logistic regression was used to evaluate the relationship between these serum indices and miscarriage risk among women undergoing ART, and a predictive model of pregnancy outcome based on these indices was established. The levels of IL-10, IL-1ß and TNF-α of infertile women in the live birth group were significantly higher than those in the miscarriage group (p = 0.009, p < 0.001, p = 0.006), and the levels of V, Cu, Zn and Se of infertile women in the live birth group were also significantly higher than those in the miscarriage group (all p < 0.001). Through logistic regression analyses, we found that serum levels of IL-1ß, TNF-α, V, Cu, Zn and Se were significantly and negatively associated with miscarriage risk. Different combination prediction models were generated according to the results of logistic regression analyses, and the combination of IL-1ß, Cu and Zn had the best prediction performance. The area under the curve (AUC) was 0.776, the sensitivity of the model was 60% and the specificity was 84%. In conclusion, the serum-related indicators of women undergoing ART on the 14th day after embryo transfer, including the inflammatory cytokines such as IL-1ß and TNF-α and the essential trace metal elements such as V, Cu, Zn and Se, were negatively correlated with miscarriage risk. A multivariate algorithm model to predict pregnancy outcome among women undergoing ART was established, which showed that IL-1ß, Cu and Zn might synergistically predict pregnancy outcome.

Hystero-embryoscopy: evaluation and evacuation of spontaneous missed abortions.

OBJECTIVE: To demonstrate the steps for hystero-embryoscopic evaluation of a 7-week spontaneous missed abortion and evacuation of the products of conception. Illustrate the surgical technique and highlight its advantages in improving the evaluation of spontaneous missed abortions. DESIGN: Video case presentation and demonstration of surgical technique. SETTING: Tertiary referral center. PATIENT(S): The patient provided consent for the video and its publication. INTERVENTION(S): Following vaginoscopy, the cervix was approached without prior blind cervical dilation. Navigation from the endocervix to the endometrial cavity was performed using a 2.9-mm diameter hysteroscope. The endometrial cavity was thoroughly inspected revealing an intact gestational sac and submucosal fibroids. An operative grasper was introduced, the chorion and amnion were penetrated, and embryoscopy was performed. In-flow was reduced for external morphological inspection of the embryo, which was then grasped and retrieved. The procedure was continued by introducing of a 26-french bipolar resectoscope, after which the products of conception were excised without electricity and sent for histologic and genetic analyses. MAIN OUTCOME MEASURE(S): This procedure allowed for proper embryonic evaluation and hysteroscopic evacuation of products of conception was successfully performed. RESULT(S): Cytogenic analysis of this case revealed a female embryo with trisomy 15. No maternal and fetal cell admixture was noted in the analysis, allowing a precise diagnosis. CONCLUSION(S): Hystero-embryoscopy is a valuable diagnostic and therapeutic procedure for cases of missed abortion. It may reveal embryonic morphological abnormalities, expand the diagnostic spectrum in the evaluation of pregnancy loss, and avoid potential complications from blind curettage.

Performance of single serum progesterone in the evaluation of symptomatic first-trimester pregnant patients: a systematic review and meta-analysis.

OBJECTIVES: Pain and bleeding complicate 30% of pregnancies, raising concerns for viability. The objective is to evaluate the diagnostic characteristics of a single serum progesterone level in assessing pregnancy viability among symptomatic patients. METHODS: We conducted a predefined literature search in MEDLINE, Embase (OVID), CINAHL and Cochrane databases for studies that enrolled patients in first trimester with miscarriage symptoms, measured progesterone and reported pregnancy viability, from inception to July 2020. We extracted data for 2 × 2 tables, progesterone threshold levels and viability. We obtained summary estimates of sensitivity, specificity, Diagnostic Odds Ratio (DOR), and predictive values at given prevalence rates. RESULTS: We identified 54 publications. There was a total of 15,878 patients enrolled, of whom 7864 patients (49.5%) were confirmed to have a viable pregnancy and 8014 patients (50.5%) were confirmed to have a non-viable pregnancy. The cut-off value of progesterone ranged from 3.2 to 25 ng/mL (20.034-79.5 nmol/L). We evaluated the performance of the following progesterone cut-off categories: < 6.3, 6.3-12.6, 12.7-19.9, and 20-25 ng/mL. To detect non-viable pregnancy, progesterone with cut-off < 6.3 ng/mL had sensitivity 73.1%, specificity 99.2% and DOR 322.0 (PPV 0.91, 0.97 and 0.99 at prevalences 0.1, 0.25, 0.5, respectively, indicating higher likelihood of non-viable pregnancy), and cut-off category 20-25 ng/mL had sensitivity 91.3%, specificity 75% and DOR 31.4 (NPV 0.99, 0.96 and 0.89 at the prevalences above indicating higher likelihood of viable pregnancy). CONCLUSION: A single progesterone level provides a clinically useful prognostic information on pregnancy viability. More than nine out of ten patients with a level < 6.3 ng/mL (< 20.034 nmol/L) will be diagnosed with a non-viable pregnancy, and more than 90% of patients with a level ≥ 20-25 ng/mL (63.6-79.5 nmol/L) will have a viable pregnancy confirmed.

RéSUMé: OBJECTIVES: La douleur et les saignements compliquent 30% des grossesses, ce qui soulève des inquiétudes quant à la viabilité. L'objectif est d'évaluer les caractéristiques diagnostiques d'un seul taux sérique de progestérone dans l'évaluation de la viabilité de la grossesse chez les patientes symptomatiques. MéTHODES: Nous avons effectué une recherche littérature prédéfinie dans les bases de données MEDLINE, Embase (OVID), CINAHL et Cochrane pour des études qui ont recruté des patientes au cours du premier trimestre présentant des symptômes de fausse couche, mesuré la progestérone et signalé la viabilité de la grossesse, du début à juillet 2020. Nous avons extrait les données pour les tableaux 2 × 2, les niveaux de seuil de progestérone et la viabilité. Nous avons obtenu des estimations sommaires de la sensibilité, de la spécificité, du rapport de cotes diagnostiques (DOR) et des valeurs prédictives à des taux de prévalence donnés. RéSULTATS: On a identifié 54 publications. Il y avait un total de 15 878 patientes recrutées, dont 7864 patientes (49.5%) ont été confirmées comme ayant une grossesse viable et 8014 patientes (50,5%) ont été confirmées comme ayant une grossesse non viable. La valeur seuil de la progestérone variait de 3.2 ­ 25 ng/mL (20.034 ­ 79.5 nmol/L). Nous avons évalué les performances des catégories de seuil de progestérone suivantes: < 6.3, 6.3­12.6, 12.7­19.9 et 20­25 ng/mL. Pour détecter une grossesse non viable, la progestérone avec seuil < 6.3 ng/mL avait une sensibilité de 73.1%, une spécificité de 99.2% et une DOR 322.0 (PPV 0.91, 0.97 et 0.99 à des prévalences de 0.1, 0.25, 0.5 respectivement indiquant une probabilité plus élevée de grossesse non viable), et la catégorie de coupure 20­25 ng/mL avait une sensibilité de 91,3%, une spécificité de 75% et une DOR 31,4 (NPV 0.99, 0.96 et 0.89 aux prévalences ci-dessus indiquant une probabilité plus élevée de grossesse viable). CONCLUSION: Un seul niveau de progestérone fournit une information pronostique cliniquement utile sur la viabilité de la grossesse. Plus de neuf patientes sur dix avec un niveau < 6.3 ng/mL (< 20.034 nmol/L) sera diagnostiqué de grossesse non viable, et plus de 90% des patientes ayant un niveau ≥ 20­25 ng/mL (63.6­79.5 nmol/L) auront une grossesse viable confirmée.

A mathematical model to predict the probability of a successful pregnancy.

AIM: To develop a scoring system for the prediction of a successful pregnancy. METHODS: Data were collected prospectively from women diagnosed with pregnancy from January 1, 2015, to December 31, 2018. Pregnant days, hormone levels, and gestational sac diameters were recorded. Relationships among the pregnancy days, hormones, and gestational sac were analyzed by Spearman correlation analysis. A scoring system was established and stratified by the 5th, 50th, and 95th percentile of hormone levels and gestational sac diameters on different pregnancy days. Pregnancy outcomes were predicted by the scores using quadratic polynomial regression analyses. A portable desktop analyzer was developed and the performance was evaluated by receiver operating characteristic (ROC) curve. RESULTS: In 273 successful pregnancy cases, the length of gestational days was significantly correlated to beta-human chorionic gonadotropin (ß-hCG) (r = 0.74, p < 0.001) and E2 (r = 0.79, p < 0.001) levels, and the size of the gestational sac (r = 0.88, p < 0.001). Meanwhile, the size of gestational sac was positively correlated with ß-hCG (r = 0.93, p < 0.001) and E2 (r = 0.55, p < 0.001). For 273 delivery and 103 miscarriage cases included in this study, our scoring-based prediction model rendered an area under the ROC curve (AUC) of 0.86 with the sensitivity of 78.31% and the specificity of 80.83%. CONCLUSIONS: We successfully developed a scoring-based analyzer to evaluate the viability of embryos at different gestation stages and to predict the probability of a successful delivery, which would provide a reference for clinicians in postpregnancy management.

Diagnostic Value of Kisspeptin Levels on Early Pregnancy Outcome: a Systematic Review and Meta-analysis.

The objective of this study is to investigate whether kisspeptin levels in early pregnancy have a better diagnostic value on early pregnancy outcome as compared with human chorionic gonadotropin (hCG). This study was a systematic review and meta-analysis aiming to investigate the diagnostic value of kisspeptin levels on early pregnancy outcome. The primary outcome was miscarriage or viable intrauterine pregnancy. Five studies were included for systematic review, and three studies were included for meta-analysis. Meta-analysis showed kisspeptin levels had a good diagnostic value with the area under the curve (AUC) 0.902 (0.866, 0.937) when kisspeptin was measured after 6 weeks of gestation. Sensitivity analysis demonstrated kisspeptin levels had a diagnostic value with AUC = 0.881 (0.855, 0.906). hCG levels had a diagnostic value with AUC = 0.834 (0.785, 0.883), which was inferior to the diagnostic value of kisspeptin (mean difference = 0.09 (0.02, 0.16)). Kisspeptin measurement has a potential for comparable or even higher accuracy than hCG in differentiating between miscarriage and viable intrauterine pregnancy after 6 weeks of gestation.

Prediction of miscarriage in first trimester by serum estradiol, progesterone and ß-human chorionic gonadotropin within 9 weeks of gestation.

PURPOSE: To predict miscarriage outcome within 12 weeks of gestational age by evaluating values of serum estradiol, progesterone and ß-human chorionic gonadotropin (ß-HCG) within 9 weeks of gestation. METHODS: One hundred sixty-five women with singleton pregnancies were retrospectively studied. Estradiol, progesterone and ß-HCG levels were measured at 5-6 weeks of gestation and the measurements were repeated at 7-9 weeks. According to pregnancy outcome at 12 weeks of gestation, 71 cases were categorized into miscarriage group, and 94 cases into group of normal pregnancy. Each group was further divided into 5-6 and 7-9 weeks of gestation sub-group. Predictive values of estradiol, progesterone and ß- HCG levels at 5-6 weeks and 7-9 weeks of gestation were analyzed with receiver operating characteristic (ROC) curves and logistic regression. RESULTS: Serum levels of estradiol at 7-9 weeks identified miscarriage with an area under the ROC curve (AUC) of 0.866 (95% CI 0. 793 ~ 0.938, P = 0.000), diagnostic cutoff value of 576 pg/ml, sensitivity of 0.804, and specificity of 0.829 respectively at the optimal threshold, according to Youden index. Progesterone levels at 7-9 weeks were with AUC of 0.766 (95% CI 0. 672 ~ 0.861, P = 0.000), cutoff value of 15.27 ng/ml, sensitivity of 0.921, and specificity of 0.558, respectively; Estradiol at 5-6 weeks were with AUC of 0.709 (95% CI 0. 616 ~ 0.801, P < 0.001), the diagnostic cutoff value of 320 pg/ml, sensitivity of 0.800, and specificity of 0.574, respectively. The performance of the dual markers of estradiol and progesterone analysis (AUC 0.871, CI 0.793-0.950), three-markers analysis (AUC 0.869, CI 0.759-0.980)were slightly better than the single marker at 7-9 weeks. ß-HCG or progesterone provide additional utility of estradiol prediction at 5-6 weeks with AUC 0.770 (0.672-0.869) for ß-HCG and estradiol, AUC0.768(CI 0.670-0.866) for ß-HCG, estradiol and progesterone and AUC 0.739 (CI 0.651-0.827) for progesterone and estradiol. CONCLUSIONS: Low serum levels such as dual of estradiol and progesterone or estradiol alone at 7-9 weeks, ß-HCG or progesterone combing estradiol at 5-6 weeks of gestation can be used better to predict miscarriage in first trimester.

Serum kisspeptin, to discriminate between ectopic pregnancy, miscarriage and first trimester pregnancy.

The present study aimed to determine serum kisspeptin levels which is an emergent marker regarding trophoblastic invasion, in patients with different types of early pregnancy. We also aimed to investigate whether kisspeptin can be used for differential diagnosis of ectopic pregnancy or miscarriage from early pregnancy. This was a prospective case-control study that was conducted at a tertiary centre of obstetrics and gynaecology. Four groups of women (81 patients) enrolled in the study: group 1, women with ectopic pregnancy (n = 17); group 2, women with miscarriage (n = 23); group 3, women with healthy pregnancy at first trimester (n = 21); and group 4, healthy non-pregnant women (n = 18). Serum kisspeptin levels were found as 0.30 (0.22-0.40), 0.11 (0.08-0.16), 1.48 (1.29-1.80), and 0.03 (0.01-0.04) ng/mL in ectopic, miscarriage, healthy pregnancy and non-pregnant groups, respectively (p< .001). A moderate correlation was seen between serum kisspeptin levels and human chorionic gonadotropin (ß-hCG) (r= 0.51, p< .001). Our data showed that for the first time that a single serum kisspeptin level may be used to discriminate ectopic pregnancy or miscarriage from healthy pregnancy at early weeks' gestation. In addition, serum kisspeptin levels of the patients with ectopic pregnancy were found higher significantly than the patients with miscarriage.Impact StatementWhat is already known on this subject? Definite diagnosis of abnormal or abnormal pregnancies at first trimester is based on hCG levels and ultrasonography. Kisspeptin, a neuropeptide was investigated in normal pregnancies and found to be increased in trophoblastic invasion.What do the results of this study add? Serum kisspeptin levels in patients with normal pregnancy were found more higher than patients with ectopic or miscarriage at early weeks of gestation (p < .001). The women with ectopic pregnancy have higher kisspeptin levels than the women with miscarriage (p < .001).What are the implications of these findings for clinical practice and/or further research? These findings can be used to make differential diagnosis between abnormal and normal early pregnancies. In future studies with more sample size, serum or plasma kisspeptin levels in early weeks of gestation can be investigated.

Association between gestational trophoblastic disease (GTD) history and clinical outcomes in in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles.

BACKGROUND: Gestational trophoblastic disease (GTD) usually affects young women of childbearing age. After treatment for GTD, 86% of women wish to achieve pregnancy. On account of the impacts of GTD and treatments as well as patient anxiety, large numbers of couples turn to assisted reproductive technology (ART), especially in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). But few studies have investigated whether a history of GTD affects the outcomes of IVF/ICSI in secondary infertile patients and how it occurs. We investigate whether a history of GTD affects the IVF/ICSI outcomes and the live birth rates in women with secondary infertility. METHODS: This retrospective cohort study enrolled 176 women with secondary infertility who underwent IVF/ICSI treatment at the reproductive medical center of Nanjing Drum Tower Hospital from January 1, 2016, to December 31, 2020. Participants were divided into the GTD group (44 women with GTD history) and control group (132 women without GTD history matched from 8318 secondary infertile women). The control group and the study group were matched at a ratio of 3:1 according to patient age, infertility duration, number of cycles and body mass index (BMI). We assessed retrieved oocytes and high-grade embryos, biochemical pregnancy, miscarriage, ectopic pregnancy, gestational age at delivery, delivery mode and live birth rates. RESULT(S): We found a significantly reduced live-birth rate (34.1% vs 66.7%) associated with IVF/ICSI cycles in patients with a GTD history compared to those without a GTD history. The biochemical pregnancy and miscarriage rates of the GTD group were slightly higher than those of the control group. In addition, there was a difference in gestational age at delivery between the GTD and control groups (p < 0.001) but no differences in the mode of delivery (p = 0.267). Furthermore, the number of abandoned embryos in the GTD group was greater than that in the control group (p = 0.018), and the number of good-quality embryos was less than that in the control group (p = 0.019). The endometrial thickness was thinner (p < 0.001) in the GTD group. Immunohistochemistry (IHC) showed abnormal endometrial receptivity in the GTD group. CONCLUSION(S): The GTD history of patients undergoing IVF/ICSI cycles had an impact on the live-birth rate and gestational age at delivery, which might result from the thinner endometrium and abnormal endometrial receptivity before embryo transfer.