Serum biomarkers may help predict successful misoprostol management of early pregnancy failure.

In order to simplify management of early pregnancy loss, our goal was to elucidate predictors of successful medical management of miscarriage with a single dose of misoprostol. In this secondary analysis of data from a multicenter randomized controlled trial, candidate biomarkers were compared between 49 women with missed abortion who succeeded in passing their pregnancy with a single dose of misoprostol and 46 women who did not pass their pregnancy with a misoprostol single dose. We computed the precision of trophoblastic protein and hormone concentrations to discriminate between women who succeed or fail single dose misoprostol management. We also included demographic factors in our analyses. We found overlap in the concentrations of the individual markers between women who succeeded and failed single-dose misoprostol. However, hCG levels ≥ 4000 mIU/mL and ADAM-12 levels ≥ 2500 pg/mL were independently associated with complete uterine expulsion after one dose of misoprostol in our population. A multivariable logistic model for success included non-Hispanic ethnicity and parity <2 in addition to hCG ≥ 4000 mIU/mL and ADAM-12 ≥ 2500 pg/mL and had an area under the receiver operating characteristic (ROC) of 0.81 (95% confidence interval: 72-90%). Categorizing women with a predicted probability of ≥ 0.65 resulted in a sensitivity of 75.0%, specificity 77.1% and positive predictive value of 81.8%. While preliminary, our data suggest that serum biomarkers, especially when combined with demographic characteristics, may be helpful in guiding patient decision-making regarding the management of early pregnancy failure (EPF). Further study is warranted.

Coelomic cells show apoptosis via Fas/FasL system: a comparative study between healthy human pregnancies and missed miscarriages.

BACKGROUND: The Fas/Fas ligand (FasL) system represents one of the main apoptotic pathways controlling placental apoptosis throughout gestation. In the current study, we have examined the Fas/FasL protein expression and the apoptotic incidents of coelomic cells, amniotic cells and trophoblastic tissue in first trimester human pregnancies and missed miscarriages (MM). METHODS: Protein expression was determined by immunofluoresence, western blotting analysis, immunohistochemistry and indirectly by RT-PCR, whereas apoptotic cell death was assessed by in situ DNA fragmentation analysis. RESULTS: Coelomic cells express Fas/FasL proteins, can undergo apoptosis and were the only cells in which apoptosis, Fas protein expression and FasL protein expression were accordingly increased along with gestational age (P = 0.001, P = 0.008; P = 0.012, respectively). In contrast, amniotic cells and trophoblast showed a consistency in the expression levels of Fas/FasL proteins in healthy pregnancies. MM were accompanied by increased Fas/FasL protein expression in all examined samples (P < 0.001). The increase of Fas/FasL protein expression was accompanied by proportional increase of apoptotic incidents among the coelomic cell population (P = 0.023, P = 0.009, respectively), whereas amniotic cells and trophoblast appeared to be resistant to Fas-induced apoptosis. The lowest expression of Fas/FasL proteins and the minimum occurrence of apoptotic incidents were detected in the trophoblast. CONCLUSIONS: These data suggest that there is a different regulation and function of the Fas/FasL system in early human pregnancies. Aberration of the Fas-mediated apoptosis may represent one of the execution-step necessary for pregnancy loss in MM cases.

Comparison of glycosylation patterns of placental proteins between normal pregnancy and missed abortion.

Contemporary understanding of missed abortion, as the case of spontaneous abortion where embryo is retained in uterus for four-weeks or more after its death, is very poor. Aiming to improve the level of knowledge about this process, we have compared glycosylation patterns of placental proteins in normal pregnancy and missed abortion. Oligosaccharide branches were detected by Western-blot using SNA, DBA and PHA-E lectins. The comparison of samples of the same gestational age enabled identification of changes in protein glycosylation between normal and pathological placentas. Lectin DBA detects in normal placenta the glycoprotein GP 105 during the eleventh week, which is absent in missed abortion. PHA-E identifies GP 71 during fourteenth week only in normal placenta. However GP 25 recognized by SNA in missed abortion was not found in normal pregnancy at tenth week. These results indicate that abnormal placental development is associated with changes in glycoprotein structures, and that glycoconjugates might have an important role in placental development.

Uteroplacental circulation during the first trimester of normal and abnormal pregnancy.

The aim of this study was to evaluate the uteroplacental vascular characteristics during the first trimester of normal and failed pregnancies. A clinical descriptive study was conducted using colour Doppler ultrasound in 45 women with normal pregnancies (group A) and 44 with non-embryonic sac or missed abortions (group B). The mean gestational age in these two groups was 9.3 and 7.6 weeks respectively (P < 0.01). The number of myometrial blood vessels (arteries and veins identified by power Doppler mapping), the quantity of intervillous flow, the resistance index (RI) for the arterial system, and the pulsatility index (PI) of the myometrial arteries were evaluated. The number of myometrial blood vessels in group A was lower than that in group B. The intervillous flow was observed in some cases from early pregnancy and more often after 10 weeks. This characteristic was observed significantly more frequently in group B than in group A. The RI and PI in the uterine arteries were significantly higher in group A than in group B. The RI and the PI of the uterine arteries decreased with the advance of gestational age in both groups. Colour Doppler ultrasound provides information about uteroplacental circulation during the first trimester and indicates early development of intervillous circulation. Although a greater uteroplacental blood circulation was observed in failed pregnancies, the overlapping between groups severely limits the application of this characteristic in clinical practice.

Parallel Doppler assessment of yolk sac and intervillous circulation in normal pregnancy and missed abortion.

This study assessed yolk sac morphology and vascularity and intervillous blood flow in normal early pregnancy and missed abortion. Transvaginal colour and pulsed Doppler were used in a prospective analysis of 87 normal pregnancies and 48 missed abortions between 6 and 12 weeks gestation. The Kruskal-Wallis rank test was used to calculate the difference in yolk sac diameter and vascularity visualization rate between gestational weeks. Repeated measures analysis of variance was used for comparison of the intervillous circulation between groups. The growth of the yolk sac was considered statistically significant between gestational weeks 6 and 9, being most prominent between 9 and 10 weeks of gestation. Vascularity of the yolk sac, characterized by low velocity and absence of diastolic flow, was demonstrated in 67 per cent of normal pregnancies. Yolk sac blood flow was detected in 19 per cent of the patients with missed abortion. Doppler analysis of the intervillous circulation demonstrated decreased peak velocity of the continuous flow in patients with missed abortion for gestational weeks 11 and 12. It is concluded that progressive decrease of yolk sac vascularity coincides with visualization of more prominent colour-coded areas within the intervillous space. In patients with missed abortion, such changes do not occur.

Intervillous blood flow in patients with missed abortion.

AIM: Analysis of the color Doppler features of intervillous flow in cases of missed abortion, and their comparison with the findings in normal pregnancy. METHODS: Transvaginal color and pulsed Doppler was used in the analysis of 38 patients with missed abortion and 40 patients with normal pregnancy. The gestational age ranged from 6 to 11 weeks. Repeated analysis of variance was used to compare the groups. RESULTS: Two types of Doppler signals were detected in the intervillous space: pulsatile and continuous. Impedance in the intervillous space of both groups did not change significantly with the gestational age. For the group with missed abortion, the mean resistance index (RI) was 0.37 +/- 0.03 and pulsatility index (PI) 0.75 +/- 0.07. For the control group, the mean RI was 0.36 +/- 0.02 and PI 0. 72 +/- 0.04. The differences in RI and PI for all gestational age groups and between the two patient groups were not statistically significant. With advancing gestation, continuous, venous-like signal became stronger and randomly dispersed throughout the placenta. Peak flow velocity values obtained from both groups did not change significantly with gestational age, nor between the two groups. Conclusion. The new generation of sensitive Doppler units can detect the intervillous flow as a continuous progressive process at 6-11 weeks of gestation. The vascular resistance in the intervillous space does not change in cases of missed abortion.

Gonadotropin-releasing hormone increases serum human chorionic gonadotropin in pregnant women.

Hypothalamic decapeptide, gonadotropin-releasing hormone (GnRH) has been found to stimulate human chronic gonadotropin (hCG) secretion by trophoblast cells in vitro. To determine the biological effect of GnRH on the release of hCG in vivo, we studied the effect of the administration of GnRH on the serum levels of human chronic gonadotropin (hCG) during pregnancy. Serum hCG levels were measured before and 15, 30, and 60 min after the intravenous administration of 100 micrograms of GnRH to 22 volunteers with normal pregnancy. Nine of the 12 (75%) women responded to GnRH in the first trimester, while only 1 of the 5 women (20%) responded to GnRH in the second trimester. None of the 5 women tested in the third trimester showed a significant response of hCG to the injection of GnRH. The average increase in hCG during the first, second and third trimester was 160.7 +/- 13.5%, 111.0 +/- 7.4% and 95.0 +/- 2.3%, respectively (mean +/- SEM). Whereas the pregnant courses of all the cases were uneventful and normal, other abnormal pregnancies were also investigated with informed consents. Three patients with missed abortions also showed a significant response of hCG to GnRH (increase: 136.7 +/- 8.5%) when GnRH was administered before curettage of the uterine cavity. However, 4 patients with unruptured ectopic pregnancies did not respond to GnRH stimulation. These findings indicate that GnRH can stimulate the release of hCG by the placenta in vivo, consistent with the previous in vitro study, while the responsiveness depend on gestational age and the implantation site.

Spontaneous abortion.

Spontaneous abortion, or the early termination of pregnancy without outside interference, may be caused by fetal, maternal or external factors. In many cases, a specific etiology may never be identified. A variety of clinical presentations are possible, ranging from imperceptible loss to profound life-threatening shock. Physicians should be able to diagnose and manage the six recognized types of spontaneous abortion: threatened, inevitable, incomplete, complete, missed and septic. In all cases, uterine evacuation, avoidance of complications and psychologic support of the family are important. The prognosis for a subsequent successful pregnancy is good, except in cases of habitual abortion.

Role of maternal prolactin in early pregnancy failure.

To study the significance of maternal prolactin (PRL) secretion in early pregnancy failures, intravenous thyrotropin-releasing hormone (TRH) stimulation tests were carried out in 39 women with normal or doomed early pregnancy, as verified by ultrasound examination, before the onset of clinical symptoms of abortion. The basal PRL levels did not differ between the women with normal early pregnancy (N = 15), blighted ovum (N = 13), or with missed abortion (N = 11). Thyrotropin-releasing hormone injection stimulated PRL secretion in all cases, but the response was smaller (P less than .01) in women with early pregnancy failure. It is concluded that PRL is not significant in the etiology or course of early pregnancy wastage and that its basal or stimulated measurement is of limited value in the prediction of pregnancy outcome.

Correlation of human chorionic gonadotropin secretion in early pregnancy failure with size of gestational sac and placental histology.

The relationships between maternal plasma human chorionic gonadotropin (hCG) levels, the gestational sac diameter, and histopathologic findings in the placenta were studied in 99 cases of bleeding during the sixth to 15th weeks of pregnancy. In cases of threatened abortion with a successful outcome of pregnancy, the maternal hCG levels and gestational sac diameter were normal, the correlation being significant during weeks seven to ten. In cases of blighted ovum and missed abortion, both the hCG concentration and gestational sac diameter were usually normal during the sixth to eighth weeks of pregnancy. After the ninth week nearly all gestational sac diameters were under the normal range, whereas normal plasma hCG levels were detected occasionally until the 14th week in these doomed pregnancies. Villous structures were histologically normal in ten of the 31 cases of blighted ovum and missed abortion. However, only two of these ten cases showed normal hCG levels and only one had a normal gestational sac diameter immediately before abortion. The results suggest a correlation between the hCG secretion of the trophoblast and gestational sac diameter in cases of bleeding during the early weeks of pregnancy, both in successful and unsuccessful outcome. Normal hCG levels in maternal plasma and nonpathologic histologic findings in the placental tissue often appear to be present in cases of blighted ovum and missed abortion until the second trimester without any mutual correlation.

The effect of missed abortion and spontaneous abortion on the fate of subsequent pregnancies.

Sixty-two patients with spontaneous abortion and 58 with missed abortion were all promptly treated with curettage. The reproductive performance and the subsequent fertility of both groups during a five year period before and after the abortion were compared. To our suprise, no significant differences were found between the two groups.

Missed abortion and uterine contractility.

In missed abortion myometrial contractility is thought to be suppressed. However, such a simple procedure as sweeping of the fetal membranes by physiologic saline solution was found to provoke abortion within 24 hours in 10 of 12 cases of missed abortion, but not in any of 10 women admitted for therapeutic abortion. Myometrial contractility thus seems not to be diminished in missed abortion.

Human decidua and uterine contractility.

Physiological saline solution injected into the uterus by the extraamniotic route was found to damage the decidua and rupture its lysosomes. The mechanism by which this procedure provokes abortion may be through the release of lysosomal phospholipase A2 (EC 3.1.1.4), an enzyme thought to regulate the formation of polyunsaturated fatty acids utilized for prostaglandin synthesis. A similar sequence of events may be involved in the initiation of spontaneous labour, since decidual cells obtained at elective Caesarean section at term exhibited degenerative changes and signs of release of a lysosomal marker enzyme. The cause of this release is unknown.