Faculty Bibliography

One causal model of preeclampsia (PE) postulates that placental hypoxia alters the production of angiogenic growth effectors (AGEs), causing an imbalance leading to maternal endothelial cell dysfunction. We tested this model using the natural experiment of high-altitude (HA) residence. We hypothesized that in HA pregnancies 1) circulating soluble fms-like tyrosine kinase 1 (sFlt-1) is increased and placental growth factor (PlGF) decreased, and 2) AGE concentrations correlate with measures of hypoxia. A cross-sectional study of healthy pregnancies at low altitude (LA) (400 m) versus HA (3600 m) compared normal (n = 80 at HA, n = 90 at LA) and PE pregnancies (n = 20 PE at HA, n = 19 PE at LA). Blood was collected using standard serum separation and, in parallel, by a method designed to inhibit platelet activation. AGEs were measured by enzyme-linked immunosorbent assays. AGEs did not differ between altitudes in normal or PE pregnancies. AGE concentrations were unrelated to measures of maternal or fetal hypoxia. PlGF was lower and sFlt-1 higher in PE, but overlapped considerably with the range observed in normal samples. PlGF correlated with placental mass in both normal and PE pregnancies. The contribution of peripheral cells to the values measured for AGEs was similar at LA and HA, but was greater in PE than in normotensive women. Hypoxia, across a wide physiological range in pregnancy, does not alter levels of circulating AGEs in otherwise normal pregnancies. Peripheral cell release of AGEs with the hemostasis characteristic of standard blood collection is highly variable and contributes to a doubling of the amount of sFlt-1 measured in PE as compared to normal pregnancies.

Alternative splicing (AS) is a key process underlying the expansion of proteomic diversity and the regulation of gene expression. Here, we identify an evolutionarily conserved embryonic stem cell (ESC)-specific AS event that changes the DNA-binding preference of the forkhead family transcription factor FOXP1. We show that the ESC-specific isoform of FOXP1 stimulates the expression of transcription factor genes required for pluripotency, including OCT4, NANOG, NR5A2, and GDF3, while concomitantly repressing genes required for ESC differentiation. This isoform also promotes the maintenance of ESC pluripotency and contributes to efficient reprogramming of somatic cells into induced pluripotent stem cells. These results reveal a pivotal role for an AS event in the regulation of pluripotency through the control of critical ESC-specific transcriptional programs.

Our objective was to assess the accuracy of ultrasonographic estimation of fetal weight in twins and triplets as compared to singleton pregnancies. Retrospective analysis was undertaken of ultrasound data of all fetuses who underwent an examination within 1 week of delivery (singletons 1832, twins 518, triplets 51). At birth weights below 2500 g, there was a significant overestimation of fetal weight in twins as compared to singletons, but the accuracy of the estimate was the same, except in twins between 1500 and 2499 g, when the weight was based on abdominal circumference and femur length alone. At birth weights of more than 2500 g, no difference was detected between twins and singletons. At all birth weights below 2500 g, the accuracy of weight estimation in triplets was equal to that in singletons and there were no triplets above this weight. We conclude that ultrasonographic estimation of fetal weight is as accurate in twins and triplets as it is in singletons.

The aim of this study was to determine whether preinduction cervical ripening with prostaglandin E2 (PgE2) gel in patients with one previous cesarean section may be used with the same safety and efficacy as in patients without a uterine scar. Primiparous patients (n = 94) with one previous cesarean section were retrospectively compared to nulliparous patients (n = 866). Both groups underwent preinduction cervical ripening with 2 mg intracervical PgE2 gel. Logistic regression was performed to control for confounding factors. Our statistical power was 90% for detecting a doubling of the complication rate, from 10 to 20%. There were no significant differences in the duration of ruptured membranes or length of labor between the two groups. No significant differences were detected in the rate or indications for cesarean section, presence of thick meconium, epidural anesthesia use, amnionitis, or maternal and neonatal morbidity. There were no cases of uterine rupture in either group. PgE2 gel may be used with the same safety and efficacy in patients with previous cesarean section as in nulliparas.

Congenital nephrosis is an autosomal recessive disorder requiring neonatal renal transplant for survival. The postnatal diagnosis rests upon the electron microscopic evaluation of the epithelial foot processes and basal membrane of the glomeruli. The prenatal diagnosis can be suspected in the presence of a positive family history with an amniotic fluid (AF) alpha-fetoprotein level greater than 5 standard deviations (SD) above the population mean accompanied by a negative AF acetylcholinesterase, absent haemoglobin F, and an unremarkable fetal sonographic examination. We reviewed our series of seven cases of congenital nephrosis fulfilling the above criteria; four cases had negative family histories, and in two cases the diagnosis of congenital nephrosis was further supported by the presence of elevated AF albumin concentrations. We conclude that (1) the prenatal diagnosis of congenital nephrosis is feasible in a low-risk population, and (2) an elevated AF albumin concentration may represent an additional marker for the diagnosis of congenital nephrosis, even though false-negative results have been reported.

OBJECTIVE: Our purpose was to determine whether detection of insulin-like growth factor-binding protein-1 in vaginal secretions could be used in the diagnosis of fetal membrane rupture. STUDY DESIGN: Consenting patients (n = 105) with complaints suspicious of membrane rupture between 24 and 42 weeks of gestation who had no evidence of placenta previa were enrolled in the study. The diagnosis of membrane rupture required at least two of the following findings on vaginal examination: pooling of fluid, positive Nitrazine paper (Bristol-Myers Squibb, Cherry Hill, N.J.) test, or microscopic evidence of ferning. A swab of the posterior vaginal fornix was obtained, placed in sample buffer, and analyzed for insulin-like growth factor-binding protein-1 by immunoassay. Data analysis included chi 2 analysis, Student t test, or Mann-Whitney U test and linear regression and receiver operating characteristic curve analysis. RESULTS: A total of 78 (74.3%) patients met the criteria for membrane rupture. There was a highly significant difference in mean vaginal insulin-like growth factor-binding protein-1 concentrations between patients with and without clinical evidence of membrane rupture (553.6 +/- 731.4 micrograms/L vs 3.0 +/- 7.3 micrograms/L, p = 0.0002). Receiver operating characteristic curve analysis demonstrated that the optimal identification of patients with membrane rupture was achieved with an insulin-like growth factor-binding protein-1 value > 3 micrograms/L (sensitivity 74.4%, 95% confidence interval 64.7% to 84.0%; specificity 92.6%, 95% confidence interval 82.7% to 102.5%; positive predictive value 96.7%, 95% confidence interval 92.1% to 101.2%; negative predictive value 55.6%, 95% confidence interval 41.0% to 70.1%). CONCLUSIONS: The presence of vaginal insulin-like growth factor-binding protein-1 is highly predictive of membrane rupture, identifying 74.4% of affected patients with a very low false-positive rate.

OBJECTIVE: To identify risk factors associated with severe preeclampsia and to determine whether these factors are similar in nulliparous and multiparous patients. METHODS: Patients whose pregnancies were complicated by severe preeclampsia (n = 70) were compared retrospectively to 18,964 non-preeclamptic controls. Information on maternal demographic factors; medical, obstetric, and family histories; and neonatal outcome was retrieved and analyzed by univariate and multivariate analysis. RESULTS: By logistic regression, the only risk factors associated with the development of severe preeclampsia were severe obesity in all patients (adjusted odds ratio 3.5, 95% confidence interval [CI] 1.68-7.46) and a history of preeclampsia in multiparous patients (adjusted odds ratio 7.2, 95% CI 2.74-18.74). CONCLUSION: Severe obesity and a history of preeclampsia are the only maternal risk factors identified for the development of severe preeclampsia.

OBJECTIVE: We attempted to test whether antibiotic therapy prolongs pregnancy in preterm premature rupture of membranes, because preterm premature rupture of membranes is frequently associated with chorionic-decidual infection. STUDY DESIGN: Women with preterm premature rupture of membranes and a singleton gestation at 24 to 34 completed weeks were randomized to receive either piperacillin 3 gm or placebo intravenously every 6 hours for 72 hours and were managed conservatively until spontaneous delivery, chorioamnionitis, or fetal distress. RESULTS: Between January 1987 and January 1992, a total of 75 patients were randomized to receive piperacillin (n = 38) or placebo (n = 37). There were no differences between the piperacillin group and the placebo group in mean gestational age at randomization (30.2 +/- 3 vs 30.3 +/- 2.9 weeks). However, a greater number of patients had pregnancy prolonged beyond 7 days (42.1% vs 10.8% p = 0.005) and the mean latency period was significantly prolonged (11.4 +/- 18.8 vs 6.1 +/- 13.6 days, p = 0.001) in the piperacillin group compared with the control groups. CONCLUSIONS: Use of intravenous piperacillin for 72 hours in preterm premature rupture of membranes significantly prolongs the latency period between membrane rupture and delivery.