Abnormal Early Pregnancy Research Articles

Biochemistry in diagnosis and management of abnormal early pregnancy.

This review examines the biochemical parameters of early pregnancy failure and the role that biochemical markers have to play in the selection of patients for expectant management. Earlier studies have concentrated on the role that human chorionic gonadotrophin and progesterone have to play in early pregnancy failure. Recent studies, however, have explored newer markers such as the inhibins and insulin growth factor binding proteins. Diagnostic models have now been created incorporating demographic, morphological, and biochemical parameters for the prediction of successful expectant management of early pregnancy failure. Examining the role of newer biochemical markers in early pregnancy failure has led to an improved understanding of the mechanisms behind it. Incorporation of these newer markers into diagnostic models has aided selection of patients for whom expectant management is appropriate.

Comparison of ultrasonographic and Doppler mapping of the intervillous circulation in normal and abnormal early pregnancies

Objective To assess the value of ultrasonography and Doppler imaging in characterizing the intervillous circulation in normal and abnormal early pregnancy. Design Cross-sectional study. Setting Tertiary care academic hospital. Patient(s) Eighty-five normal pregnancies and 125 missed miscarriages at 7 to 13 weeks of gestation. Intervention(s) Grey-scale ultrasonography was used to evaluate the placental anatomy and detect moving echoes inside the intervillous space, and color power Doppler imaging was used to detect continuous venous-like flow in the placental tissue. Main outcome measure(s) Degree of agreement between two investigators for use of grey-scale imaging, comparison of detection of moving echoes in normal and abnormal pregnancies, and comparison of detection of intervillous circulation with grey-scale and color Doppler imaging in abnormal pregnancies. Result(s) The overall degree of agreement between the two investigators was good. A significantly different distribution of blood flow was found between normal and abnormal pregnancies at 7 to 9 weeks and 10 to 11 weeks but not at 12 to 13 weeks. Intervillous moving echoes were detected by grey-scale imaging significantly more frequently than an intervillous blood flow was detected with color Doppler imaging. Conclusion(s) In early pregnancy failure, there is a premature and diffuse onset of intervillous blood flow that can be detected by grey-scale imaging. This abnormal blood flow pattern may increase the oxidative stress on the early placental tissue and subsequently impair placental development.

Trophoblastic Oxidative Stress in Relation to Temporal and Regional Differences in Maternal Placental Blood Flow in Normal and Abnormal Early Pregnancies

Onset of the maternal-placental circulation was studied by Doppler ultrasonography in 65 pairs of age-matched normal and abnormal pregnancies. In normal pregnancies intervillous blood flow increased with gestational age, being detected in 9 of 25 cases at 8 to 9 weeks but in 18 of 20 at 12 to 13 weeks (P = 0.001). By contrast, in abnormal pregnancies flow was detected in nearly all cases (22 of 25) at 8 to 9 weeks (P < 0.001). In addition, regional differences were observed between the groups. Early flow was restricted to the peripheral regions of most normal placentas (P < 0.001), whereas in missed miscarriages it was most common in central regions or throughout the placenta (P < 0.05 and P < 0.001, respectively). Immunoreactivity for heat shock protein 70 and nitrotyrosine residues was greater in samples from peripheral than from central regions of normal placentas (P = 0.028 and P = 0.019, respectively), and from missed miscarriages compared to controls (P = 0.005 and P = 0.001, respectively). Our results indicate that oxidative damage to the trophoblast, induced by premature and widespread onset of the maternal placental circulation secondary to shallow trophoblast invasion, is a key factor in early pregnancy loss. High oxygen concentrations in the periphery of normal early placentas may similarly induce local regression of the villi, leading to formation of the chorion laeve.

GROSSESSE HÉTÉROTOPIQUE DE DÉCOUVERTE PRÉ-OPÉRATOIRE

Simultaneous presence of intrauterine and ectopic pregnancy in the same patient is called heterotopic pregnancy. Preoperative diagnosis of such case is in frequent. A new case is reported in a 22 years old patient in whom the preoperative diagnosis was suspected by ultra sonic examination. Laparotomy confirmed the diagnosis and radical treatment of the ectopic pregnancy. Spontaneous expulsion of intrauterine pregnancy occurred 48 hours in the postoperative period. Anatomopathologic findings confirmed the intrauterine . In front of every case of abnormal early pregnancy, we have to think of the possibility of heterotopic pregnancy especially with the highly developed techniques of medically assisted production.

How to discriminate between normal and abnormal early pregnancy

Early fetal growth delay and early oligohydramnios have been suspected as signs of embryonal jeopardy. Sonographic examinations of 100 early pregnancies between the sixth and ninth gestational week were performed to investigate predictable sonographic findings of early abortion. Sonographic measurements of the gestational sac (G‐SAC), Crown‐rump length (CRL) and fetal heart rate (FHR) were performed using a transvaginal transducer with Doppler. All measurement of 11 early abortions were compared to those of 89 normal pregnancies to investigate the objective rules for the screening of early abortion. Most of the early aborted pregnancies were classified correctly by discriminant analysis with G‐SAC and CRL (G‐SAC = 0.5222 × CRL + 14.6673 = 0.5 × CRL + 15). In conclusion, early fetal growth retardation and oligohydramnios could discriminate the poor prognosis of early pregnancies.

The expression of killer cell inhibitory receptors on natural killer cells and activation status of CD4 + and CD8 + T cells in the decidua of normal and abnormal early pregnancies

The establishment of the human placenta in early pregnancy is characterized by the presence of large numbers of natural killer cells within the maternal decidua. These NK cells have an unusual phenotype, CD3 −CD16 −CD56 bright, distinguishing them from peripheral blood NK cells. They may control trophoblast migration and placentation. Using a panel of monoclonal antibodies to several members of the KIR family and flow cytometry, we found that KIRs are expressed on decidual NK cells. There is variation in both the percentage of cells expressing a particular receptor and the density of receptor expression between decidual NK cells from different individuals. In anembryonic pregnancy, the proportions of decidual NK cells with a particular KIRs (GL183 and EB6) decreased significantly when compared with normal pregnancy ( p = 0.01 and 0.01, respectively), raising the possibility that these NK receptors may be involved in recognition of the allogeneic fetus by the mother at the implantation site. In the decidua, more CD4 + and CD8 + T cells expressed CD69 and HLA-DR than in blood, indicating that T cells are regionally activated during early pregnancy. When compared with normal pregnancy, decidual HLA-DR +CD4 +CD3 +, CD69 +CD8 +CD3 + and HLA-DR +CD8 +CD3 + T lymphocytes are significantly increased in anembryonic pregnancy. The over-activation of decidual T cells during anembryonic pregnancy may thus contribute to the increased NK cytotoxicity activity.

Chromosomally abnormal early ongoing pregnancies: Correlation of ultrasound and placental histological findings

The pathophysiology of placental microscopic changes in chromosomally abnormal pregnancies remains poorly understood. We have reviewed the relationship between ultrasound findings and villous histological features in a group of 25 ongoing pregnancies presenting with fetal aneuploidy at 11 to 15 weeks of gestation. The chromosomal abnormalities were diagnosed by chorion villous sampling, and the data were compared with those of a group of 25 chromosomally normal pregnancies undergoing surgical termination and matched for gestational age. The aneuploid group included 10 pregnancies with trisomy 21, nine with trisomy 18, three with triploidy, two with monosomy X, and one with trisomy 13. The overall degree of agreement between the two investigators for the histological diagnosis was good (kappa, 0.64), and the sensitivity of histology ranged between 72.0% and 80.0%. Fetal and placental edema was observed on scan in 10 and 7 cases, respectively, of the aneuploid group and was systematically associated with trophoblastic hypoplasia, stromal edema, or cavitation, reduced vascularization, and ramification of the main villous trunks. Fetoplacental hydrops was not observed in the euploid group. These findings indicate that histological changes observed in the placenta of fetuses from ongoing pregnancies presenting with aneuploidy can be linked with early fetal hydrops. The villous features in these cases are probably secondary to a reduction in the villous circulation due to a cardiovascular defect and leading to generalized stromal edema. The reduced villous branching and trophoblastic hypoplasia could be secondary to the enlargement of all villous types or to a basic defect in placental development.

Evaluation of maternal plasma creatine kinase activity as a marker of abnormal early pregnancy.

We have tested the value of maternal plasma creatine kinase activity for diagnosing ectopic pregnancies obtained after in-vitro fertilization and embryo transfer. Plasma creatine kinase was assayed in 57 patients: 20 normal, 23 miscarriages and 14 ectopic pregnancies, for a total of 240 samples. All values were in the lower part of the normal range except only one in a miscarrying patient. A statistically significant difference was observed for a cut-off value of 45 IU/l between normal and ectopic pregnancies. However, for this cut-off point, the measurement of plasma creatine kinase activity had a sensitivity of 0.50 and a specificity of 0.76 for the diagnosis of ectopic pregnancy. The positive predictive value was 0.69. Creatine kinase activity measurements are thus of no practical value in this particular population, in which an early and specific marker of ectopic implantation would be of paramount interest. The association of human chorionic gonadotrophin (HCG) determinations and ultrasound scanning of the pelvis still remain the best paraclinical support for an early diagnosis of ectopic implantation.

Doppler assessment of the intervillous blood flow in normal and abnormal early pregnancy

To compare resistance index (RI) and pulsatility index (PI) in the spiral and intervillous arteries, and peak systolic velocity of the continuous intervillous flow in normal and abnormal first-trimester pregnancy. Transvaginal color and pulsed Doppler were used in a prospective analysis of 60 normal (controls) and 54 abnormal (30 missed abortions and 24 anembryonic) pregnancies (6-12 weeks' gestation). Repeated-measures analysis of variance was used for comparison between groups. A gradual decrease in spiral artery RI and PI was found in women with anembryonic pregnancies. No difference in spiral artery impedance was noted in women with normal pregnancies, but there was a progressive increase in spiral artery RI and PI in women with missed abortion. A significant increase in continuous intervillous blood flow velocity was noted from the 11th week onward in the normal pregnancy group (8.0 +/- 0.9 versus 12.2 +/- 1.4 cm/second). Intervillous arterial blood flow signals did not demonstrate any difference in RI and PI with advancing gestational duration. Significantly lower PI values were obtained from the intervillous arteries in women with anembryonic pregnancy (PI 0.54 +/- 0.04) than in controls (PI 0.80 +/- 0.04) and those with missed abortions (PI 0.75 +/- 0.04). However, there was no statistically significant difference in the intervillous RI between subgroups. The new generation of sensitive Doppler units can detect intervillous flow as a continuous progressive process during the first trimester of normal and abnormal pregnancy. There is a significant difference in intervillous artery vascular impedance between normal and anembryonic pregnancies.

Absence of innervation of the uteroplacental arteries in normal and abnormal human pregnancies.

The spiral arteries of the human uterus are considerably remodeled structurally during pregnancy to facilitate an increase in blood flow. An immunohistochemical study was undertaken to determine whether the spiral arteries were innervated and, if so, whether they were denervated in the process of the physiologic vascular changes of normal pregnancy or, conversely, remained innervated in the absence of physiologic changes in abnormal pregnancy. Uterine tissues from nonpregnant nulliparous women, from normal early pregnancy, from normal late pregnancy, from abnormal early pregnancy (i.e. spontaneous abortions), and from abnormal late pregnancy (i.e. preeclampsia and intrauterine growth retardation) were subjected to immunohistochemistry using a panel of neuron-associated antibodies (neurofilament, neuron-specific enolase, S100 protein, protein gene product 9.5). All sections of the nonpregnant uterus showed an abundance of nerves deep in the myometrium, some of which were associated with radial and arcuate arteries. Very few nerves were demonstrated at the endomyometrial junction and no nerves were seen accompanying the intramyometrial spiral arteries. In both normal and abnormal pregnancy, nerves were not detected in the decidua or accompanying intradecidual spiral arteries, whether they were physiologically altered or not. Nerves were seen in the myometrium in 7 of 10 normal and in 1 of the 8 third-trimester abnormal placental beds, but none were seen accompanying intramyometrial spiral arteries, whether showing physiological changes or not. The lack of innervation of the spiral arteries in the nonpregnant state as well as in normal and abnormal pregnancy suggests that nonneurogenic mechanisms control blood flow at the spiral-arterial level.

Corpus luteum blood flow in abnormal early pregnancy.

Thirty-eight consecutive patients with the diagnosis of abnormal early singleton pregnancy were studied with transvaginal color velocity imaging and pulsed Doppler ultrasonography to assess corpus luteum blood flow. Mean gestational age was 8.5 weeks (range, 6 to 12 weeks). Patients' mean age was 30.9 years (range, 24 to 43 years). There were 19 (50%) threatened abortions, 13 (34.2%) missed abortions, and six (15.8%) anembryonic pregnancies. Blood flow impedance in the corpus luteum was estimated by calculating the resistive index. The results of this study group were compared with those obtained in a series of 85 normal singleton early pregnancies used as controls. Overall, detection of corpus luteum blood flow was 78.9% in study group and 76.4% in control group (P = 0.51). Mean resistive index +/- standard deviation in the control group was 0.50 +/- 0.10; the corresponding values in threatened abortion, anembryonic pregnancy, and missed abortion were 0.52 +/- 0.10, 0.42 +/- 0.06, and 0.57 +/- 0.05, respectively. No statistical. differences in mean resistive index were found among threatened abortion and anembryonic pregnancy with respect to control group. A higher mean resistive index was observed in missed abortion than in control group (P < 0.01). In conclusion, our data show that luteal vascularization might be decreased in missed abortion but not in threatened abortion and anembryonic pregnancy.

Activation status of T and NK cells in the endometrium throughout menstrual cycle and normal and abnormal early pregnancy

Endometrial lymphocytes were studied at all stages throughout the menstrual cycle and early pregnancy by flow cytometry to examine different lymphocyte subpopulations and the expression of the T- and NK-cell activation markers. After pregnancy, CD8 +CD3 + lymphocytes were decreased in the decidua. In both endometrium and decidua, more T cells expressed CD69, CD71, HLA-DR, and CD38 antigens than in peripheral blood. After pregnancy, CD71 +CD3 + lymphocytes were further increased. CD25 +CD3 + lymphocytes decreased significantly in the endometrium and decidua of ectopic pregnancies, but not in the decidua of normal pregnancies. These findings indicate that T cells are regionally activated in the first trimester, and it may be the result of the stimulation by fetal antigens. NK cells were the most abundant cell type in the decidua, which expressed the phenotype CD16 − CD56 +, and CD57 −CD56 +. The proportion of activated decidual NK cells was increased in anembryonic pregnancies more than in normal pregnancies, although the total NK subpopulation was similar in both groups. This might result in increased NK cytotoxicity in anembryonic pregnancies. In conclusion, T cells are activated, but NK cytotoxicity is decreased in the decidua of early normal pregnancies. This might be important in the control of trophoblast growth and placental development.

The activation status of T and NK cells in the endometrium throughout menstrual cycle, normal and abnormal early pregnancy

The activation status of T and NK cells in the endometrium throughout menstrual cycle, normal and abnormal early pregnancy

Value of serum placental protein 14 determination in differential diagnosis of abnormal early pregnancy

Single measurements of hCG and placental protein 14 were carried out in 32 patients with tubal pregnancies, in 38 patients with spontaneous abortion and 28 women with normal intrauterine pregnancies from the 5th to the 7th week of pregnancy. HCG-measurement could only show significant differences between normal and abnormal early pregnancies. PP 14-measurements showed significant differences between all groups. Low concentrations of serum PP 14 point to an ectopic pregnancy.

Serum progesterone predicts abnormal gestations in clomiphene citrate conception cycles as well as in spontaneous conception cycles

To determine if a "discriminatory" P concentration could be established that predicted abnormal early pregnancies in clomiphene citrate (CC)-conceived cycles. Progesterone concentrations of gestations between 28 and 49 days from last menstrual period in both spontaneously conceived and CC-stimulated cycles were analyzed using a relative-operating characteristic (ROC) curve. Serum P concentrations were measured in 222 pregnant patients from the first 49 days of gestation. One hundred sixteen patients conceived in a spontaneous cycle and 106 patients conceived in CC-treated cycles. Two by two contingency tables were used to calculate the true-positive (sensitivity) and false-positive rates at 20 specific P at 20 specific P concentrations. A ROC curve was then generated by plotting the sensitivity of the test against the percent of normal patients incorrectly classified (false positive) at each P level. The best discriminatory value was estimated in each curve at a point of high sensitivity associated with a minimal false-positive value. The areas under the curve and SE were calculated for each group and compared by the critical ratio z-test. The best discriminatory P concentration was 10 ng/mL (32 nmol/L) for spontaneously conceived pregnancies and 30 ng/mL (95 nmol/L) for CC-treated pregnancies. The area under each ROC curve was significantly predictive. Comparison of the two curves indicated that the ability of P measurements to predict gestational complications was independent of follicular stimulation. Follicular stimulation with CC increases the discriminatory P value that predicts gestational normalcy but does not alter the clinical utility of the test.

Transvaginal color and pulsed Doppler study of uterine blood flow in the first and early second trimesters of pregnancy: normal versus abnormal.

Transvaginal color Doppler ultrasonography was used to study 131 normal early pregnancies, 30 molar pregnancies, 20 threatened abortions, two blighted ova, and five pregnancies with intramural myoma. Four separate parts of the maternal circulation were studied: uterine, arcuate, radial, and spiral arteries. There was statistical difference in the RI and PI among uterine, arcuate, radial, and spiral arteries (P < 0.001) in all observed groups of patients except those with intramural myoma. When the same part of the maternal circulation was compared among different groups of patients, the following results reached statistical significance: uterine artery in normal and molar pregnancy (P < 0.001); arcuate artery in normal and molar pregnancy (P < 0.001); radial artery in normal and molar pregnancy (P < 0.001) and in normal pregnancy and threatened abortion (P < 0.01); spiral artery in normal and molar pregnancy (P < 0.001), in normal pregnancy and threatened abortion (P < 0.01), and in molar pregnancy and threatened abortion (P < 0.01). The standard values of blood flow are different in normal and in some cases of abnormal early pregnancy (molar pregnancy, threatened abortion).

Transvaginal color doppler assessment of uteroplacental circulation in normal and abnormal early pregnancy

Transvaginal color Doppler offers the potential to study uteroplacental circulation in early normal pregnancies and pregnancies associated with intrautine fibroids. A total of 62 patients (30 early pregnancies complicated by myoma and 32 normal pregnancies representing the control group) whose gestational age ranged from the 6th to the 14th week were examined. The equipment used was an Aloka color Doppler SSD-680 with 5.0 MHz curve-linear transvaginal transducer. The main uterine, radial and spiral arteries were identified in all patients. Peak systolic velocity and resistance index were measured and automatically calculated. Statistical analysis used was Student t-test. This study documents a physiological decrease in impedance in the uteroplacental circulation in pregnancy associated with fibroids, while the blood velocity of the radial arteries showed a significant increase between the 10th and 14th week of gestation.

Receiver-operator characteristic, efficiency analysis, and predictive value of serum progesterone concentration as a test for abnormal gestations

Our objective was to determine if a discriminatory progesterone concentration could be established that confidently predicted abnormal early gestations. We analyzed differences in progesterone concentrations between normal (n = 40) and abnormal (n = 34) pregnancies during the first 49 days of gestation. The receiver-operator characteristic curve, test efficiency, and predictive value of serum progesterone to discriminate between an abnormal and normal first-trimester gestation were calculated for progesterone concentrations between 5 and 25 ng/ml. Receiver-operator characteristic curve analysis indicated that the best discriminatory progesterone concentration was 10 ng/ml. Test efficiency was maximum between serum progesterone concentration of 9 to 14 ng/ml (80%). When progesterone was less than 10 ng/ml, the predictive value of the abnormal test result was greater than 90%. Receiver-operator characteristic analysis, test efficiency, and the predictive value of an abnormal test result suggest that the best progesterone cut off point that predicts abnormal early pregnancies is 10 ng/ml.

Recurrent spontaneous abortion

Recurrent pregnancy loss is a condition with many different etiologies. The proper evaluation and care of couples suffering from this form of reproductive failure requires that the clinician be well versed in many aspects of the physiology of normal and abnormal early pregnancy. Topics relevant to the subject of recurrent spontaneous abortion, with special attention to recent advances, are examined in this review.

Development of the early human placenta: A morphometric study

The placentae of 46 normal pregnancies artificially terminated between 6 and 15 weeks ofgestation were investigated morphologically to provide trends in early villous development. Study of the specimens included phase contrast microscopic examination and histomorphometric investigation in all cases, and scanning electron microscopy in ten cases. Histomorphometric measurements included the villous barrier thickness, i. e. the distance between the intervillous space and the villous capillary lumen, the trophoblastic layer thickness and the volume fraction of each villous constituents, i. e. trophoblast, stroma and capillaries. Significant negative correlations were observed between gestational age and the villous barrier and trophoblastic thickness. The data obtained were separated into two groups, embryonic (5–10 weeks) and fetal (11–15 weeks) groups, and compared. The mean barrier thickness, the mean trophoblastic thickness, the mean volume fraction for trophoblast and the sprouting-villous index were significantly greater during the embryonic period compared with the fetal period. The mean volume fraction for the stroma and for the fetal capillaries, and the mean number of capillary profiles per villous profile were significantly smaller during the embryonic period than during the fetal period. The comparison of placental histomorphometric data obtained in cases of normal early pregnancies with those observed in cases of abnormal early pregnancies could help us to elucidate the origin ofanatomical and biological changes in these cases.