The relationship between thyroid autoantibodies and X chromosome monosomy in the chorionic tissue of patients with missed miscarriage.

OBJECTIVE: The aim of this study was to investigate the relationship between thyroid autoantibodies (TGAb and TPOAb) and X chromosome monosomy in the chorionic tissue of patients with missed early miscarriage. METHODS: The baseline data, thyroid function, thyroid antibody and the chromosomes from the chorionic tissue of 228 patients with missed early miscarriage were examined. RESULTS: (1) Among the 228 patients, 121 had a normal chromosome number, and 107 had an abnormal chromosome number. The majority of them were autosomal trisomy, of which trisomy 16 (40.19%) was predominant. Sex chromosome monosomy (28.04%) was secondary. (2) Among the 228 patients, 208 patients in this study had normal thyroid function (including 134 cases of negative thyroid antibodies and 74 cases of positive thyroid antibodies alone); 6 patients had abnormal thyroid function (including 2 cases of clinical hyperthyroidism, 3 cases of subclinical hypothyroidism, 1 case of hypothyroxinemia); and 14 patients had normal TSH and elevated T4 alone.(3) After exclusion of patients with thyroid function abnormalities, there were no significant differences in baseline data between the normal chromosome group and the abnormal chromosome group (P > 0.05). However, there was a significant difference in TGAb and TPOAb between the normal chromosome and abnormal chromosome group with 45, X karyotype, with a higher proportion of TGAb and/or TPOAb positivity in the 45, X karyotype group (P < 0.05). Additionally, compared to TGAb and/or TPOAb-positive patients, the risk of X chromosome monosomy was significantly reduced in TGAb and TPOAb-negative patients (P < 0.05). Moreover, both TGAb and TPOAb titer values in the X chromosome monosomy group were higher than those in the chromosomally normal group (P < 0.05). CONCLUSION: There is a correlation between TGAb, TPOAb and X chromosome monosomy in the chorionic tissue of patients with missed early miscarriage, although the mechanism remains to be further investigated.

Using liquid chromatography and mass spectrometry to predict potential biomarkers for missed miscarriage and its metabolic pathways in a tertiary center: A cross-sectional analytic study.

OBJECTIVE: To determine and compare the serum metabolites in missed abortion versus normal early pregnancy using ultra-high-performance liquid chromatography and tandem time-of-flight mass spectrometry, and to determine how these metabolites can be used to predict the potential biomarkers and possible metabolic pathways of a missed abortion. METHODS: The serum of patients with a missed abortion was used as the experimental group and the serum of patients with an induced abortion during normal early pregnancy was used as the control group. Principal component analysis and orthogonal partial least square discriminant analysis were additionally used to observe the difference in metabolite distribution between the two groups. A variable weight value (variable importance in the projection; VIP) obtained from the orthogonal partial least squares discriminant analysis model more than 1 and P less than 0.05 were taken to indicate significant differences in metabolite screening. After this, enrichment analysis of the metabolic pathways of these metabolites was conducted using Fisher precise test in order to find the metabolic pathway with the highest correlation with the differential metabolites. RESULTS: In total, 30 patients were included in the experimental group, with 30 patients in the control group. Fifty-five metabolites (VIP > 1, P < 0.05) with significant differences related to missed abortion were selected, among which 35 metabolites increased and 20 decreased in patients with a missed abortion. KEGG pathway enrichment analysis showed that the four metabolic pathways with the highest correlation were cholesterol metabolism, arginine biosynthesis, cell apoptosis, and the FoxO signaling pathway. CONCLUSION: The missed abortion serum metabolites and changes in related metabolic pathways reported in this study provide a basis for the early prediction and diagnosis of a missed abortion.

Circulating fibroblast growth factor 21 as a potential biomarker for missed abortion in humans.

OBJECTIVE: To investigate whether serum levels of fibroblast growth factor 21 (FGF21) and fatty acid-binding protein-4 (FABP4) are associated with missed abortion (MA) in humans. DESIGN: Cross-sectional study. SETTING: University-affiliated hospital. PATIENT(S): Patients with MA at 8-12 weeks of gestation. INTERVENTION(S): None. MAIN OUTCOME MEASURES(S): Serum levels of FGF21 and FABP4 were tested by enzyme-linked immunosorbent assay. Placental samples were collected during dilation and curettage surgery, and the expression of FGF21 and its related genes were measured using quantitative polymerase chain reaction. RESULT(S): In the discovery cohort, 78 patients with MA and 79 healthy pregnant women matched for maternal age and body mass index were nested from a prospective cohort. Circulating levels of FGF21 and FABP4 were significantly and independently elevated in patients with MA relative to the levels in the healthy controls. A single measurement of FGF21 serum level effectively discriminated MA with an area under the receiver operating characteristics curve of 0.80 (95% confidence interval: 0.73-0.87). Importantly, in our external validation cohort that comprised subjects with MA (n = 34) or induced abortion (n = 27), the FGF21 serum levels achieved an area under the receiver operating characteristics curve of 0.85 (95% confidence interval: 0.75-0.96) when identifying those with MA. Nevertheless, expression of FGF21 in the placenta was not associated with its serum concentration. Placental tissues from patients with MA exhibited impaired FGF21 signaling. CONCLUSION(S): Our results suggested that serum levels of FGF21 and FABP4 were associated with MA. Circulating FGF21 may serve as a potential biomarker for the recognition of MA.

Serum Levels of Collectins Are Sustained During Pregnancy: Surfactant Protein D Levels Are Dysregulated Prior to Missed Abortion.

About 15% of pregnant women undergo missed abortion (MA), wherein women do not experience cramping and vaginal bleeding. Dysregulation of the immune molecules and steroid hormones contribute to early pregnancy loss. Collectins- surfactant protein A (SP-A), surfactant protein D (SP-D), and mannose-binding lectin (MBL) are a group of innate immune molecules regulated by the steroid hormones. Reduced levels of SP-A and SP-D during the early gestation exhibited a significant association with the severe early onset preeclampsia. In order to determine the serum profile of collectins throughout the normal pregnancy and explore their predictive potential during the 8-12 weeks of gestation for MA, we examined a prospective cohort of pregnant women (n = 221). The serum levels of SP-A and SP-D were significantly downregulated in the normal pregnant women in all the three trimesters (n = 30) compared with the non-pregnant women (n = 20) and were not significantly different across the three trimesters. Fourteen of the women from the cohort underwent MA during the 14-20 weeks of gestation and exhibited a significant downregulation in the serum levels of SP-D during 8-12 weeks of gestation. A significant inhibition of the HTR-8/SVneo cell proliferation and migration in the presence of a recombinant fragment of human SP-D suggested the relevance of SP-D in placental development. We report here that the serum levels of SP-A, SP-D, and MBL are consistently maintained during pregnancy in the Indian cohort. Dysregulated serum levels of SP-D and P4/E2 ratio during the early first trimester may predict occurrence of MA.

Platelet to Lymphocyte Ratio and Neutrophil to Lymphocyte Ratio in Missed Abortion.

OBJECTIVE: Missed abortion occurs in ∼ 15% of all clinical pregnancies. The pathogenesis is not clearly known. However, defective placentation resulting in maternal systemic inflammatory response is considered responsible for missed abortion. Platelet lymphocyte ratio (PLR) and neutrophil lymphocyte ratio (NLR) are increasingly cited parameters of inflammation in the literature. However, no study evaluated the PLR and NLR rates in missed abortions so far. The aim of the present study is to investigate whether complete blood count (CBC) inflammatory parameters such as NLR and PLR are increased in patients with missed abortion. METHODS: Medical records of 40 pregnant women whose gestation ended in missed abortion at between 6 and14 weeks of gestation and of 40 healthy pregnant women were collected and compared retrospectively. The groups were compared regarding hemoglobin, hematocrit, platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW), PLR and NLR. RESULTS: Platelet distribution width, NLR and PLR values were higher in the missed abortion group compared with the healthy pregnant women group (rates are p = 0.043; p = 0.038; and p = 0.010, respectively). Hematocrit, MPV, and lymphocyte values were found to be lower in the missed abortion group compared with the healthy pregnant women group (p = 0.027, p = 0.044 and p = 0.025, respectively). CONCLUSION: The PDW, NLR and PLR values of the missed abortion group were reported high; and MPV values were reported low in the present study. These findings may help to speculate a defective placentation in the pathogenesis of missed abortion.

Platelet to lymphocyte ratio and neutrophil to lymphocyte ratio in missed abortion

Abstract Objective Missed abortion occurs in ~ 15% of all clinical pregnancies. The pathogenesis is not clearly known. However, defective placentation resulting in maternal systemic inflammatory response is considered responsible for missed abortion. Platelet lymphocyte ratio (PLR) and neutrophil lymphocyte ratio (NLR) are increasingly cited parameters of inflammation in the literature. However, no study evaluated the PLR and NLR rates in missed abortions so far. The aim of the present study is to investigate whether complete blood count (CBC) inflammatory parameters such as NLR and PLR are increased in patients with missed abortion. Methods Medical records of 40 pregnant women whose gestation ended in missed abortion at between 6 and14 weeks of gestation and of 40 healthy pregnant women were collected and compared retrospectively. The groups were compared regarding hemoglobin, hematocrit, platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW), PLR and NLR. Results Platelet distribution width, NLR and PLR values were higher in the missed abortion group compared with the healthy pregnant women group (rates are p = 0.043; p = 0.038; and p = 0.010, respectively). Hematocrit, MPV, and lymphocyte values were found to be lower in the missed abortion group compared with the healthy pregnant women group (p = 0.027, p = 0.044 and p = 0.025, respectively). Conclusion The PDW, NLR and PLR values of the missed abortion group were reported high; and MPV values were reported low in the present study. These findings may help to speculate a defective placentation in the pathogenesis of missed abortion.

Serum progesterone levels could predict diagnosis, completion and complications of miscarriage.

BACKGROUND: Low serum progesterone levels were strongly correlated with miscarriages in several publications and with completion of miscarriage in one paper. This study evaluated several parameters, predominantly serum progesterone, as predictors for miscarriages, their swift non-surgical completion and their complications. BASIC PROCEDURES: Suspected or confirmed non-viable pregnancies with available concomitant serum progesterone measurements were retrospectively reviewed. The performance of serum progesterone, either alone or combined with other parameters, to predict viability, surgical removal and delay of non-surgical evacuation of non-viable pregnancy and complications, was analysed by logistic regression combined with Akaike and Bayesian information criteria, likelihood, receiver operated characteristic (ROC) curves, Mann-Whitney test and Fisher's exact test. MAIN FINDINGS: From 151 included pregnancies, 104 (68.9 %) were non-viable with 91 completions of miscarriage without surgery. The probability of viability was correlated linearly and curvilinearly with serum progesterone (p < 0.001). The probability of surgical removal, and the delay before non-surgical evacuation, showed a linear relationship with progesterone. No complication occurred when progesterone levels remained below 10 µg/L, while its rates were 9.5 % of non-viable pregnancies with progesterone levels between 10 and 20 µg/L and 26.7 % of cases with progesterone levels above 20 µg/L. Combined with progesterone, either "parity" or "history of miscarriage" improved the prediction of viability, "history of supra-isthmic uterine surgery" improved the prediction of surgery and "history of miscarriage" improved the prediction of delayed non-surgical evacuations. CONCLUSION: Serum progesterone can probably predict the odds of miscarriages, surgical removal, delayed non-surgical evacuation and complications, with potential improvements when different predictors are combined.

Expression of vitamin D and vitamin D receptor in chorionic villous in missed abortion.

The contemporary world despite its enough developed medicine and generally highly enlightened population faces a great problem of vitamin, micro-element and nutrient deficiency turning to become the XXI century pandemic. Along with that significant growth of interest can be seen towards vitamin D importance for reproductive physiology. The fact is that vitamin D receptors (VDR) have been detected in women's ovarium tissue, fallopian tubes, decidua and placenta. Some recent years studies have proven that vitamin D may act as immune regulator during implantation. During early pregnancy the trophoblast release vitamin D, which produces anti-inflammatory reaction and also induce decidual tissue growth for successive pregnancy. It was a comparison between the expression of Vitamin D and VDR in chorionic villous in cases of normal pregnancy and missed abortion groups. 64 samples of chorionic villous were taken: 32 from missed abortion and 32 from the induced abortion group. Abortive material was taken from two groups of women residing in North-West region of Russia: missed abortion and pregnancy terminated at woman's wish (induced abortion); 6-12 weeks of gestation, singleton pregnancy. Immune histochemical examination showed homogenous distribution of vitamin D and VDR expression in syncytiotrophoblasts, cytotrophoblasts and chorion villus stroma.Vitamin D expression relative area was 10,3% which is statistically different from the induced abortion group - 15,4% (p<0,01). VDR expression analysis showed its homogenous distribution in chorionic villus structures in both groups. High VDR expression was detected in chorion villus stromal components. In missed abortion group, the morphometry results showed distinctly lower relative area of vitamin D expression against the comparison group (35,9 ± 1,8; 56,1 ± 2,4 p < 0,01). Also in missed abortion group, positively significant correlation has been determined between the level of vitamin D in blood and VDR relative area expression (r = 0,412). In missed abortion group, definite vitamin D and VDR expression decrease was detected compared to the induced abortion group. The results witness vitamin D importance for pregnancy progress.

Biochemical clinical factors associated with missed abortion independent of maternal age: A retrospective study of 795 cases with missed abortion and 694 cases with normal pregnancy.

The incidence of fertile women with missed abortion dramatically increased in recent years, while very few serum indices have been identified for the diagnosis of missed abortion. The aim of this study was to identify related factors for missed abortion through a retrospective study of serum indices.A total of 795 cases of women with missed abortion and 694 cases of women with normal pregnancy between March 2014 and March 2017 were included in the present study. The diagnosis of missed abortion was based on clinical history, clinical examination, and transvaginal ultrasound findings. The final diagnosis of missed abortion was based on assessment of pregnancy structures (i.e., a gestational sac without fetal heart rate) via transvaginal ultrasound. We evaluated the clinical values of 4 serum indices and their relationship to missed abortion: gamma-glutamyltransferase (GGT), lactate dehydrogenase (LDH), adenosine deaminase (ADA), and fibrinogen (FIB).The serum levels of GGT, ADA, and FIB showed statistically significant differences comparing women who experienced missed abortion with women who had normal pregnancies (controls). Among women with missed abortion, the levels of GGT and ADA were dramatically increased (GGT: P < .0001; ADA: P = .0459), while FIB levels were slightly lower (P = .0084) compared to controls. The LDH levels exhibited a non-significant trend toward lower levels in the missed abortion group (P = .3951). Interestingly, the observed significant increase in serum GTT levels among women with missed abortion was not affected by maternal age.This study found that GTT may be a useful marker which was associated with missed abortion, indicating its potential clinical roles in missed abortion.

Evaluation of thiol/disulphide homeostasis as a novel predictor testing tool of early pregnancy viability.

OBJECTIVE: To evaluate serum dynamic thiol/disulphide concentrations in patients with suspected missed abortion (MA) and to determine whether this ratio has a predictive role in the viability in these pregnancies. MATERIALS AND METHODS: In this prospective cohort study, 48 out of 120 recruited pregnant patients were confirmed MA in the study group. Following the recommended waiting time (7-10 days), the remaining 72 viable pregnancies that met the inclusion criteria were categorized as the control group. A novel, automated, and spectrophotometric assay, which can measure both sides of the thiol/disulphide balance, was used. The cut-off values were used for the ROC curve. RESULTS: There were no statistically significant differences between the groups (MA and control) regarding maternal obstetric and demographic features. Significantly reduced levels of Total Thiol and Native Thiol were shown in patients with MA compared to the control group (p = 0.016 and p = 0.001, respectively). Serum levels of disulphide was significantly increased in the MA group (23.4 ± 7.8 µmol/l vs. 17.9 ± 4.99 µmol/l, p < 0.0001). Disulphide values of less than 17.68 predicted 80.8% of the viable pregnancies. CONCLUSION: Significantly increased serum disulphide levels, one of the oxidative stress markers, and decreased antioxidant levels (total and native thiol) were found in patients with MA. Increased oxidative stress status is thought to play a role in the etiology of MA. Serum dynamic thiol/disulphide homeostasis may serve as a promising testing tool to rule out subsequent diagnosis of MA and may benefit as an early pre-treatment testing tool for viability.

NMR-based serum metabolomics study reveals a innovative diagnostic model for missed abortion.

A missed abortion (MA) is an in-utero death of the embryo or fetus before the 20th week of gestation with retained products of conception. In order to discover novel biomarkers for MA, a 1H NMR spectroscopy-based metabolomics approach was applied to detect human MA serum metabolic profiles. Serum samples were obtained from patients with MA (n = 15) and healthy controls (n = 9) for study. The NOESYPR1D spectrum combined with multi-variate pattern recognition analysis was used to cluster the groups and establish a disease-specific metabolites phenotype. Principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA) models were capable of distinguishing MA patients from healthy subjects. The results revealed that 24 metabolites altered in MA patients compared with the control population. Metabolomic pathway analysis demonstrated that alanine, aspartate and glutamate metabolism, citrate cycle (TCA cycle), taurine and hypotaurine metabolism were significantly altered in MA. The results indicated that serum NMR-based metabolomic profiling method is sensitive and specific enough to distinguish MA and from healthy controls, this method could be developed as a clinically useful diagnostic tool for MA. The finding from the MA serum metabolic profiling shed a new light on further understanding of MA disease mechanisms.

The decreased expression of TIPE2 protein in the decidua of patients with missed abortion and possible significance.

BACKGROUND: Missed abortion is a common occurrence for otherwise healthy women. Immunological factor is one of the most important reasons. Tumor necrosis factor-α-induced protein-8 like-2 (TIPE2) is a novel negative immune regulator related to several human diseases. However, the expression level and clinical significance of TIPE2 in missed abortion remain unclear. METHODS: The expression of TIPE2 mRNA and protein in decidua and chorion from 36 missed abortion patients and 36 healthy controls was detected using quantitative real-time PCR, western blot and immunohistochemistry. In addition, serum TNF-ɑ and IL-10 levels were measured using flow cytometry. Serum estradiol and progesterone levels were measured by radioimmunoassay test. The correlations of TIPE2 protein levels with TNF-ɑ, IL-10, estradiol and progesterone were further analyzed. RESULTS: TIPE2 protein levels were significantly lower in decidual tissues of missed abortion patients than those in healthy controls. The patients with missed abortion had significantly higher levels of serum TNF-ɑ, and lower levels of serum IL-10, estradiol and progesterone compared with healthy controls. The TIPE2 protein levels were positively related to serum IL-10 levels. CONCLUSION: Our data indicate TIPE2 could play important roles in maintaining the maternal-fetal tolerance and decreased TIPE2 expression in the decidua may be related to the development of missed abortion.

Utility of ßhCG monitoring in the follow-up of medical management of miscarriage.

OBJECTIVE: To evaluate the percentage change in total ßeta-unit human chorionic gonadotropin (ßhCG) levels (%ΔßhCG) in the prediction of treatment outcomes following intravaginal misoprostol for missed miscarriage before 13 weeks. METHODS: A secondary analysis of a randomised controlled study of medical management of miscarriage was performed. Total ßhCG levels were collected before misoprostol (baseline) and after a planned seven day interval (follow-up), when a transvaginal ultrasound (TVUS) reported a gestational sac as present or not. If no sac at TVUS, surgery was indicated on clinical criteria. %ΔßhCG ((baseline ßhCG - follow-up ßhCG)/baseline ßhCG × 100) was evaluated in the prediction of a sac at TVUS and surgery on clinical criteria. RESULTS: %ΔßhCG was calculated for cases with ßhCG levels within two days of misoprostol and TVUS; calculation interval determined case number. The median %ΔßhCG for 24 cases with a persistent sac (6-9 day interval) was significantly lower than for 145 with no sac (58.75% (interquartile range (IQR): 37.59-76.69; maximum 86.54) vs 97.65% (IQR: 95.44-98.43); P < 0.0001). The median %ΔßhCG for eight cases needing surgery on clinical criteria (5-9 day interval) was significantly lower than for 140 cases with no sac not needing surgery (79.68% (IQR: 64.63-91.15; maximum 94.06) vs 97.68% (IQR: 95.61-98.50); P < 0.0001). The area under the receiver-operator curve was 0.975 for prediction of a persistent sac and 0.944 for prediction of surgery on clinical criteria, respectively. %ΔßhCG > 87% predicted no sac at TVUS. %ΔßhCG > 94.5% predicted no surgery on clinical criteria. CONCLUSION: %ΔßhCG calculation over one week reliably predicted treatment outcomes after medical management of missed miscarriage.

Maternal serum markers in predicting successful outcome in expectant management of missed miscarriage.

The aim of this study was to evaluate the use of biological serum markers, available routinely in most hospital clinical laboratories, in predicting successful outcomes of expectant management in women presenting with a missed miscarriage. This is a single centre observational prospective study over a 16-month period. Among the 490 women who consented to the study protocol, 83 presented with missed miscarriage during the first trimester of pregnancy and opted for expectant management. The mean gestation sac diameter and volume of the gestation sac were recorded during ultrasound examination. Maternal serum samples were obtained in each case and assayed for human chorionic gonadotrophin, progesterone, pregnancy associated plasma protein A (PAPP-A) and high-sensitivity C-reactive protein using commercial assays. When examined individually, maternal age (P = 0.01), progesterone (P = 0.03) and PAPP-A (P = 0.02) were all significantly associated with successful expectant management. Increased maternal age was associated with an increased chance of success with the odds of success increased by around 75% for a 5-year increase in age. Higher values of progesterone and PAPP-A were associated with a reduced chance of successful management. Low maternal serum progesterone concentration was the strongest parameter associated with a successful spontaneous completion of miscarriage.

Use of cell-free DNA in the investigation of intrauterine fetal demise and miscarriage.

OBJECTIVE: To estimate whether cell-free DNA is present in nonviable pregnancies and thus can be used in diagnostic evaluation in this setting. METHODS: We conducted a prospective cohort study of 50 participants at MedStar Washington Hospital Center, Washington, DC, between June 2013 and January 2014. Included were women with pregnancies complicated by missed abortion or fetal demise. All gestational ages were considered for study participation. Participants with fetal demise were offered the standard workup for fetal death per the American College of Obstetricians and Gynecologists. Maternal blood samples were processed to determine the presence of cell-free DNA, the corresponding fetal fractions, and genetic abnormalities. RESULTS: Fifty samples from nonviable pregnancies were analyzed. The average clinical gestational age was 16.9 weeks (standard deviation 9.2). The mean maternal body mass index was 30.3 (standard deviation 9.1). Seventy-six percent (38/50) of samples yielded cell-free DNA results, that is, had fetal fractions within the detectable range of 3.7-65%. Among the 38, 76% (29) were classified as euploid, 21% (8) as trisomies, and 3% (1) as microdeletion. A cell-free DNA result was obtained more frequently at ultrasonographic gestational ages of 8 weeks or greater compared with less than 8 weeks (87.9% [n=29/33, 95% confidence interval (CI) 72.7-95.2; and 52.9%, n=9/17, 95% CI 31.0-73.8] of the time, respectively, P=.012). Time from demise was not associated with obtaining a result. CONCLUSION: Among nonviable pregnancies, cell-free DNA is present in the maternal plasma with fetal fractions greater than 3.7% in more than three fourths of cases after an ultrasonographic gestational age of 8 weeks. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01916928. LEVEL OF EVIDENCE: III.

Placental growth factor, soluble fms-like tyrosine kinase 1 and progesterone as diagnostic biomarkers for ectopic pregnancy and missed abortion.

OBJECTIVE: The aim of this study is to investigate if progesterone, placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt1) serum levels are useful markers to differentiate between ectopic pregnancy (EP), missed abortion (MA) and viable intrauterine implantation pregnancy (IUP). METHODS: We designed a retrospective case-control study which included 100 pregnant women (50 EP and 50 MA) at 6-8 weeks of gestation with ßhCG serum levels between 800 and 3500 UI/L and a viable IUP group. Progesterone, PlGF and sFlt-1 levels were measured with an electrochemiluminescence assay (Roche Diagnostics, Manheim, Alemania). A non parametric test was used to compare the markers in the different groups and we used receiver operating characteristic (ROC) curve analysis to calculate the area under the curve (AUC). RESULTS: When we compared the EP group with the MA group, we didn't find significant differences for PlGF (15.1[13.2-17.4]/16.7[12.8-18.7] pg/mL) (p=0.275). We only obtained significant differences for progesterone (9.1[3.1-16.8]/2.6[1.3-6.1] ng/mL) (p<0.001) and sFlt-1 (84[65-96]/126[94-256] pg/mL) (p<0.001). The AUC for progesterone was 0.756 and the cutoff point with better sensitivity and lower false positive rate was 6 ng/mL (sensitivity=60%, specificity=72.7%). The AUC for sFlt-1 was 0.842 and the cutoff point was 93 pg/mL (sensitivity=84.5%, specificity=86.3%). The combination of both markers allowed us to increase the AUC to 0.910. CONCLUSIONS: In conclusion, the present study suggests that sFlt-1 could be a useful marker to differentiate between an EP or a MA when ßhCG levels are similar in both groups. The combination of sFlt-1 with progesterone helps to increase the diagnostic performance.

Common stress and serum cortisol and IL-12 levels in missed abortion.

To investigate stress levels, serum cortisol levels, and changes in IL-12 concentration in patients with missed abortion. Patients with missed abortion (n = 48) were age and gestational age-matched with normal early pregnancy cases (n = 48). All subjects completed a stress evaluation survey questionnaire about common stressors. Venous blood samples were collected at 07.00 hours, and serum cortisol and IL-12 concentrations were measured by electrochemiluminescence immunoassay and ELISA methods, respectively. Missed abortion patients demonstrated a significantly higher number of common stressors and higher serum cortisol levels compared to controls (both p < 0.05). Dilation and curettage did not lead to significant differences in serum cortisol and IL-12 levels (p > 0.05). Stress and immunity alterations of the immune system may contribute to the aetiology of missed abortion.

Activin A and follistatin as biomarkers for ectopic pregnancy and missed abortion.

Activin A as a predictor of pregnancy failure has been the focus of heated debate, but the value of a combined activin A and follistatin (FS) measurement in serum to predict pregnancy failure has not been reported yet. We assessed whether a single serum measurement of the two physiological antagonists at 6-8 weeks gestation could differentiate ectopic pregnancies (EP) or missed abortions (MA) from healthy intrauterine pregnancies (IUP). activin A concentrations were significantly lower in women with EP (n = 30, median value of 264 pg/mL) and women with MA (n = 30, median value of 350 pg/mL) compared to IUP (n = 33, median value of 788 pg/mL); P < 0.001. At a threshold value of 505 pg/mL, activin A had 87.9% sensitivity and 100% specificity and negative predictive value of 0.974 for discriminating an ectopic pregnancy from viable pregnancies. FS was able to discriminate IUP from EP (ROC curve P < 0.001) as was their ratio (ROC curve P = 0.008), but was unable to discriminate a MA from an EP. In EP, activin A did not correlate with beta HCG levels. The present findings support the thesis that activin A or FS could be considered promising biomarkers for the discrimination between an IUP and a failed pregnancy (MA or EP).

The association between serum progesterone and outcome of medical management of early fetal demise: a pilot study.

The study objective was to determine the relationship between serum progesterone level and the outcome of mifepristone-misoprostol regimen for medical management of missed miscarriage up to 12 weeks. A blood sample was collected just before mifepristone administration for serum progesterone assay. After 48 h, misoprostol 800 µg was administered vaginally; further 400 µg was administered 4 h later if necessary. Treatment was classed as a success if retained tissues were expelled within 72 h (Group 1), and a failure if this did not occur (Group 2). Of 52 analysed cases, complete medical evacuation occurred within 72 h in 40 (76.9%) women (serum progesterone ranged 13-90 nmol/l). Serum progesterone between the two groups were statistically significant (p < 0.001), by Mann-Whitney test. Of the 12 patients who did not respond, nine (75%) women had serum progesterone < 10 nmol/l. We found mifepristone-misoprostol regimen is less effective in missed miscarriage when serum progesterone is < 10 nmol/l.

Angiopoietin-1 and angiopoietin-2 as serum biomarkers for ectopic pregnancy and missed abortion: a case-control study.

BACKGROUND: A case-control study to evaluate whether a single serum measurement of angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2) at 6-8 weeks gestation can differentiate failed pregnancies, whether ectopic pregnancies (EP) or missed abortions (MA), from healthy intrauterine pregnancies (IUP). INTERVENTION(S): Serum and tissue mRNA determination of ANG-1 and ANG-2 levels by ELISA and RTPCR, from 60 (30 EP and 30 MA) patients with failed early pregnancy and 33 IUPs. RESULTS: ANG-1 and ANG-2 concentrations and their ratio are lower in EP (median, 689 and 302 pg/ml, respectively) and MA cases (median, 810 and 402 pg/ml, respectively) compared to IUP (median, 963 and 1477 pg/ml, respectively) (p<0.05, for all). Unlike ANG-2, serum ANG-1 discriminates an EP from a MA (p=0.011). Trophoblastic ANG-1 mRNA expression levels are lower in EP compared to MA and IUP (p<0.05), while ANG-2 mRNA is higher in EP and MA than in IUP (p<0.05). CONCLUSIONS: A single measurement of serum ANG-1 and ANG-2 at 6-8 weeks of gestation designate the outcome of a pregnancy, as their levels are significantly decreased in failed than normal pregnancies. Serum ANG-1 showed potential to discriminate MA from EP.