Anatomy and physiology of the uterine cervix.

The human uterine cervix undergoes extensive changes during pregnancy. Collagen is reorganized and consolidated early in gestation with proliferation and hyperplasia of the cellular component. As term approaches, multiple factors work together in complex interactions that cause collagen dispersion and the cervix to ripen (clinically become softer). Increases in decorin levels, hyaluronic acid, and physiologic cell death are in part responsible for this remodeling process. As the collagen bundles disperse and lose strength, cytokines, hyaluronic acid, collagenases, and elastase possibly work together to allow effacement. Then, the mechanical forces of uterine contractions extend the elastin and allow dilatation. During dilation, levels of cytokines and hyaluronic acid begin to decrease, which may serve to decrease collagenolytic activity and allow the cervix to begin the process of repairing itself. Despite this advance knowledge of cervical ripening, the signals responsible for the initiation of these changes remain to be elucidated. If we can understand the exact mechanisms that affect these changes, then we may be better able to address such complex issues as cervical incompetence, preterm delivery, postterm delivery, and proper "ripening" of the cervix to avoid surgical delivery for arrest disorders of the active phase.

Can antenatal clinical and biochemical markers predict the development of severe preeclampsia?

OBJECTIVE: This study was undertaken to develop a multivariable clinical predictive rule for severe preeclampsia using second-trimester clinical factors and biochemical markers. STUDY DESIGN: We performed a retrospective cohort study of all pregnant patients with single gestations from 1995 through 1997 for whom we had complete follow-up data. Through medical record review we determined whether patients had severe preeclampsia develop according to American College of Obstetricians and Gynecologists criteria. Case patients with severe preeclampsia were compared with control subjects with respect to clinical data and multiple-marker screening test results. With potential predictive factors identified in the bivariate and stratified analyses both an explanatory logistic regression model and a clinical prediction rule were created. Patients were assigned a predictive score according to the presence or absence of predictive factors, and receiver operating characteristic analysis was used to determine the optimal score cutoff point for prediction of severe preeclampsia with maximal sensitivity. RESULTS: Among the 1998 patients we found 49 patients with severe preeclampsia (prevalence, 2.5%). After we controlled for confounding variables, case patients and control subjects had similar human chorionic gonadotropin and alpha-fetoprotein levels, and the only variables that remained significantly associated with severe preeclampsia were nulliparity (relative risk, 3.8; 95% confidence interval, 1.7-8.3), history of preeclampsia (relative risk, 5.0; 95% confidence interval, 1.7-17.2), elevated screening mean arterial pressure (relative risk, 3.5; 95% confidence interval, 1.7-7.2), and low unconjugated estriol concentration (relative risk, 1.7; 95% confidence interval, 0.9-3.4). Our predictive model for severe preeclampsia, which included only these 4 variables, had a sensitivity of 76% and a specificity of 46%. CONCLUSION: Even after incorporation of the strongest risk factors, our predictive model had only modest sensitivity and specificity for discrimination of patients at risk for development of severe preeclampsia. The addition of the human chorionic gonadotropin and alpha-fetoprotein biochemical markers did not enhance the model's predictive value for severe preeclampsia.

Ultrasonographic prediction of fetal macrosomia. Association with cesarean delivery.

OBJECTIVE: To investigate whether the incorrect ultrasonographic prediction of macrosomia affects the cesarean delivery rate among nonmacrosomic neonates. STUDY DESIGN: For this retrospective, cohort study, comprehensive ultrasonographic records were reviewed at two centers. Patients with singleton, nonanomalous gestations whose ultrasonography predicted an estimated fetal weight > or = 4,000 g composed one cohort (n = 135), while the other cohort (n = 129) consisted of patients whose ultrasonography predicted an estimated fetal weight between 3,000 and 3,999 g. We compared the cesarean delivery rate in neonates falsely diagnosed with macrosomia (false positives) with the rate in those correctly diagnosed as nonmacrosomic (true negatives). RESULTS: The rate of cesarean delivery was significantly higher among those falsely diagnosed by ultrasonography with a macrosomic fetus as compared to those with a fetus truly diagnosed as nonmacrosomic (42.3% vs. 24.3%, relative risk = 1.74, 95% confidence interval 1.09-2.78). Subgroup analyses excluding diabetic mothers and multiparous women and comparing false positives with true negatives with neonatal birth weights between 3,500 and 4,000 g (birth weights similar to false positives) demonstrated significantly increased cesarean delivery rates among false positives. CONCLUSION: Even in nonmacrosomic neonates, the antenatal ultrasonographic diagnosis of suspected macrosomia is associated with a significant increase in cesarean delivery rates.

Predictive factors for neonatal morbidity in neonates with an umbilical arterial cord pH less than 7.00.

OBJECTIVE: Fewer than 50% of neonates with an umbilical arterial pH < 7.00 have neonatal complications. Our objective was to identify clinical predictive factors for adverse outcomes in this group of neonates. STUDY DESIGN: In this case-control study both cases and controls had an umbilical arterial cord pH < 7.00. Cases were defined as those neonates who had seizures, grade 3 to 4 intraventricular hemorrhage, gastrointestinal dysfunction, respiratory distress syndrome requiring intubation, sepsis, or death. Controls had an umbilical arterial cord pH < 7.00 and no complications. A multivariable prediction model was created, with variables having an association with adverse outcome by bivariate analyses, attempting to predict which neonates in this umbilical arterial pH range are at greatest risk for adverse outcomes. RESULTS: We identified 73 of 10,705 neonates born between July 1992 and October 1996 with an umbilical arterial cord pH < 7.00. Thirty-five neonates met our case definition, and the remaining 38 composed the control group. Cases had significantly lower arterial pH values and 1- and 5-minute Apgar scores, greater arterial base deficit values, and a higher incidence of abruptio placentae and maternal cocaine use. More cases were delivered before 34 weeks. There were three neonatal deaths, two cases of grade 3 or 4 intraventricular hemorrhage, five cases of gastrointestinal dysfunction, and four cases of neonatal seizures. In our predictive model for adverse neonatal outcome, an arterial base deficit > or = 16 mmol/L and a 5-minute Apgar score < 7 had a sensitivity and a specificity of 79% and 80.8%, respectively. CONCLUSION: Neonatal morbidity in neonates with an umbilical arterial cord pH < 7.00 can be predicted by a high arterial base deficit value and low 5-minute Apgar score.

The association between maternal cocaine use and placenta previa.

OBJECTIVE: Our aim was to determine whether maternal cocaine exposure is a risk factor for placenta previa. STUDY DESIGN: In this case-control study, cases of placenta previa confirmed at delivery (ascertained by International Classification of Diseases, ninth revision, Clinical Modification, code-based search, N = 40) were compared with a random sample of patients without placenta previa (N = 80) in a ratio of two controls per case. Data on antecedent maternal cocaine use, as well as other potential risk factors for placenta previa, were obtained from a review of the prenatal chart and the hospital record. Categorization of cocaine use was based on either patient self-report or urine toxicologic testing, or both. Multiple logistic regression was performed to assess the association between cocaine and placenta previa while we controlled for other variables. RESULTS: After the effects of other variables were adjusted for, maternal cocaine use was an independent risk factor for placenta previa (adjusted odds ratio = 4.39, 95% confidence interval 1.17 to 16.4). Other significant risk factors included a history of cesarean section and prior elective abortion. CONCLUSION: These results suggest that cocaine use, as well as prior cesarean section, prior elective abortion, and parity, are associated with placenta previa.

Evidence for magnesium sulfate as a tocolytic agent.

The objective of our study is to quantitatively examine the available evidence regarding the efficacy and side effects of magnesium sulfate for acute tocolysis (from randomized trials) compared with placebo and beta-agonist agents. Randomized trials comparing magnesium sulfate with placebo or beta-agonists for tocolysis were identified with a MEDLINE-based search and was supplemented by a search of obstetrical textbooks and bibliographies. Trials underwent quality evaluation and data abstraction by two independent, blinded investigators. Outcomes evaluated included delivery delay of various durations as well as the frequency of major and minor side effects. Summary odds ratios and 95 percent confidence intervals for dichotomous outcomes were calculated using a random effects model. Interstudy heterogeneity for these outcomes was assessed with a Q statistic. We identified 12 randomized controlled trials of magnesium sulfate for acute tocolysis. Four studies were excluded because of either lack of comparison of magnesium sulfate to either placebo or beta-agonists or lack of reporting clinical outcomes of interest. The eight remaining randomized trials comparing magnesium sulfate with placebo or beta-agonists were included in this analysis. There was no significant difference between MgSO4 and placebo for any of the measured outcomes for delay in delivery. Comparing magnesium sulfate to ritodrine or beta-agonists did not demonstrate any differences between the agents in achieving clinically significant tocolysis. There was a significant difference between MgSO4 and beta-agonists in the frequency of medication discontinuation because of side effects, but not in the frequency of major adverse drug events. There are few data comparing magnesium sulfate with a placebo for acute tocolysis. Magnesium sulfate seems to be comparable to ritodrine and beta-agonists, although the available data are not sufficient for a rational choice between these agents.

E-cadherin expression during the differentiation of human trophoblasts.

The morphologic and functional differentiation of human trophoblast cells culminates in the formation of the terminally differentiated multinucleated syncytial trophoblast. In culture, isolated mononuclear cytotrophoblasts aggregate and then fuse to form syncytia, recapitulating the in vivo process. In the present studies, we investigated the expression of the Ca(2+)-dependent cell adhesion molecule (CAM), E-cadherin, during the morphologic differentiation of trophoblastic cells. Cytotrophoblasts were isolated from human chorionic villi, and JEG-3 and BeWo choriocarcinoma cells, cytotrophoblastic cell lines which under standard culture conditions are not fusion competent, were obtained by dispersion of ongoing cultures. Cultures were terminated at timed intervals and E-cadherin was analyzed by immunocytochemistry and electron microscopy using specific antibodies. In addition, E-cadherin expression was investigated by western and northern blotting. During the aggregation of cytotrophoblasts, E-cadherin was localized on the cell surface at points of cell-cell contact and could not be demonstrated following cellular fusion. In contrast, it remained on the surface of aggregated JEG-3 and BeWo cells throughout the duration of culture. Western blot analysis revealed a time-dependent increase in E-cadherin (120 x 10(3) Mr) which coincided with maximal aggregate formation at 24 h in both normal cytotrophoblasts and JEG-3 cells. A marked reduction of E-cadherin in fusing cytotrophoblasts was subsequently observed as syncytial trophoblasts became the predominant cellular form in culture. In agreement with the immunohistochemical observations, there was no change in E-cadherin levels in the non-fusing JEG-3 cells. Northern blotting demonstrated a significant reduction in the 4.5 kb transcript in fusion-competent cells over the 96 h of culture. Exposure of the normally non-fusing BeWo cells to 1.5 mM 8-bromo cyclic AMP induced cellular fusion and syncytium formation. This process was accompanied by a disappearance of E-cadherin from the cell surface as assessed by immunocytochemistry and western blotting and a parallel reduction in the abundance of the E-cadherin mRNA. Immunoneutralization experiments using an antiserum directed against the extracellular domain of cadherins inhibited syncytium formation in normal trophoblasts compared to an antiserum against the E-cadherin cytoplasmic tail, which had no effect upon aggregation and fusion of these cells. We conclude that E-cadherin exists in a dynamic state in fusion-competent cytotrophoblasts and that down regulation of its gene expression coincides with cellular fusion. In addition, this process appears to be cyclic AMP-mediated in BeWo choriocarcinoma cells.(ABSTRACT TRUNCATED AT 400 WORDS)