Plexins promote Hedgehog signaling through their cytoplasmic GAP activity.

Hedgehog signaling controls tissue patterning during embryonic and postnatal development and continues to play important roles throughout life. Characterizing the full complement of Hedgehog pathway components is essential to understanding its wide-ranging functions. Previous work has identified neuropilins, established semaphorin receptors, as positive regulators of Hedgehog signaling. Neuropilins require plexin co-receptors to mediate semaphorin signaling, but the role of plexins in Hedgehog signaling has not yet been explored. Here, we provide evidence that multiple plexins promote Hedgehog signaling in NIH/3T3 mouse fibroblasts and that plexin loss of function in these cells results in significantly reduced Hedgehog pathway activity. Catalytic activity of the plexin GTPase-activating protein (GAP) domain is required for Hedgehog signal promotion, and constitutive activation of the GAP domain further amplifies Hedgehog signaling. Additionally, we demonstrate that plexins promote Hedgehog signaling at the level of GLI transcription factors and that this promotion requires intact primary cilia. Finally, we find that plexin loss of function significantly reduces the response to Hedgehog pathway activation in the mouse dentate gyrus. Together, these data identify plexins as novel components of the Hedgehog pathway and provide insight into their mechanism of action.

Obstetric management for stillbirth complicated by a prior cesarean delivery: a cost-effectiveness analysis.

BACKGROUND: The primary concern for a trial of labor after cesarean (TOLAC) is a uterine rupture leading to neonatal injury or mortality and maternal mortality. In individuals who have a term stillbirth, the neonatal concern is absent, yet repeat cesarean delivery remains common in this setting. Given the increased maternal risks from cesarean, it is important to evaluate obstetric management options in the population of women who have a term stillbirth and prior cesarean delivery (CD). OBJECTIVES: To examine the outcomes and costs of a TOLAC via induction of labor verses a repeat CD for cases of stillbirth occurring near term. STUDY DESIGN: A decision-analytic model incorporating the current and a subsequent delivery using TreeAge software was designed to compare outcomes in women induced for a TOLAC to those undergoing repeat CD in the setting of stillbirth at 34-41 weeks' gestation. We used a theoretical cohort of 6000 women, the estimated annual number of women a prior cesarean who experience a stillbirth in the United States. Outcomes included quality-adjusted life years (QALY) for both modes of delivery with consideration of future pregnancy risks. Future pregnancy risks included uterine rupture, hysterectomy, placenta accreta, maternal death, neonatal death, and neonatal neurological deficits. Probabilities were derived from the literature, and a cost-effectiveness threshold was set at $100,000/QALY. RESULTS: In our theoretical cohort of 6000 women with a prior CD and current stillbirth, induction of labor resulted in 4836 fewer cesarean deliveries during stillbirth management, 1040 fewer cesarean deliveries in the subsequent pregnancy, and 14 fewer cases of placenta accreta in the subsequent pregnancy, despite 29 additional uterine ruptures across both pregnancies. Induction of labor was found to be the dominant strategy, resulting in decreased costs and increased QALYs. Univariate sensitivity analyses demonstrated that induction of labor was cost effective until the risk of uterine rupture in the first delivery exceeded 0.83% (baseline estimate: 0.38%). Additional univariate sensitivity analyses found that induction of labor was cost effective until the risk of IOL failure in the first delivery exceeded 64% (baseline estimate: 19%). CONCLUSION: In our theoretical cohort, induction of labor for TOLAC in the setting of a stillbirth with a history of prior CD is cost effective compared to a repeat CD. The results of this analysis demonstrate the benefit of induction of labor among women in this scenario who desire a future pregnancy.

Expectant management of preterm premature rupture of membranes at 34 weeks: a cost effectiveness analysis.

OBJECTIVE: To examine the outcomes and cost effectiveness of expectant management versus immediate delivery of women who experience preterm premature rupture of membranes (PPROM) at 34 weeks. METHODS: A cost-effectiveness model was built using TreeAge software to compare outcomes in a theoretical cohort of 37,455 women with PPROM at 34 weeks undergoing expectant management until 37 weeks versus immediate delivery. Outcomes included fetal death, neonatal sepsis, neonatal death, neonatal neurodevelopmental delay, healthy neonate, maternal sepsis, maternal death, cost, and quality-adjusted life years. Probabilities were derived from the literature, and a cost-effectiveness threshold was set at $100,000 per quality-adjusted life year. RESULTS: In our theoretical cohort of 37,455 women, expectant management yielded 58 fewer neonatal deaths and 164 fewer cases of neonatal neurodevelopmental delay. However, it resulted in 407 more cases of neonatal sepsis and 2.7 more cases of maternal sepsis. Expectant management resulted in 3,531 more quality-adjusted life years and a cost savings of $71.9 million per year, making it a dominant strategy. Univariate sensitivity analysis demonstrated expectant management was cost effective until the weekly cost of antepartum admission exceeded $17,536 (baseline estimate: $12,520) or the risk of maternal sepsis following intraamniotic infection exceeded 20%. CONCLUSION: Our model demonstrated that expectant management of PPROM at 34 weeks yielded better outcomes on balance at a lower cost than immediate delivery. This analysis is important and timely in light of recent studies suggesting improved neonatal outcomes with expectant management. However, individual risks and preferences must be considered in making this clinical decision as expectant management may increase the risk of adverse perinatal outcomes when the risk of puerperal infection increases.

Timing of delivery in women with prior uterine rupture: a decision analysis.

Background: Uterine rupture is an obstetric complication with high rates of associated maternal and neonatal morbidity and mortality. However, limited guidance for the timing of delivery in women with a history of prior uterine rupture exists.Objective: To determine the optimal gestational age of delivery in women with prior uterine rupture.Study design: A decision-analytic model was built using TreeAge software to compare the outcomes of repeat cesarean delivery when performed at 32, 33, 34, 35, or 36 weeks gestation in a theoretical cohort of 1000 women with prior uterine rupture. Strategies involved expectant management until a later gestational age accounting for the risks of spontaneous uterine rupture, spontaneous labor, uterine rupture following spontaneous labor, and stillbirth during each successive week that a woman was still pregnant. Maternal outcomes included uterine rupture, hysterectomy, and death. Neonatal outcomes included hypoxic-ischemic encephalopathy, cerebral palsy, and death. Probabilities were derived from the literature and total quality-adjusted life years (QALYs) were calculated. Sensitivity analyses were used to vary model inputs to investigate the robustness of our baseline assumptions.Results: In our theoretical cohort of 1000 pregnant women with a history of prior uterine rupture, cesarean delivery at 34 weeks maximized maternal and neonatal QALYs. Compared to delivery at 36 weeks, delivery at 34 weeks would prevent 38.6 uterine ruptures, 0.079 maternal deaths, 6.10 hysterectomies, and 12.1 neonatal deaths but results in 4.70 more cases of cerebral palsy. Univariate sensitivity analysis found that repeat cesarean at 34 weeks remained the optimal strategy until the probability of spontaneous repeat uterine rupture (baseline estimate: 0.68%) fell below 0.2% or rose above 0.9%, at which point, a strategy of delivery at 35 or 32 weeks became optimal, respectively. However, Monte Carlo simulation demonstrated that delivery at 35 weeks was the optimal strategy 37% of the time, whereas 34 weeks was the optimal strategy 17% of the time.Conclusion: The optimal time for repeat cesarean delivery in women with prior uterine rupture appears to be between 34-0/7 and 35-6/7 weeks gestation.

Pregnancy in Women With a History of Uterine Rupture.

IMPORTANCE: With increased rates of primary and repeat cesarean deliveries, the potential for uterine rupture and management of women with a history of uterine rupture has also increased. Taking care of a pregnant woman with a prior uterine rupture requires understanding of the risks, the need for additional surveillance, and the limitations of our knowledge about how rupture affects subsequent pregnancies. OBJECTIVE: The aims of this study were to review the literature on pregnancy after uterine rupture and to summarize the evidence to help the obstetrician care for a pregnant woman with a history of uterine rupture. EVIDENCE ACQUISITION: Evidence for this review was acquired using PubMed. CONCLUSIONS: Pregnancy after uterine rupture carries a risk of spontaneous repeat rupture before the onset of labor and of repeat rupture during early labor. Elective cesarean delivery before the onset of labor is the safest strategy to prevent maternal and neonatal morbidity and mortality. However, more research is needed to better inform risk estimates and to guide management of pregnant women with a history of uterine rupture. RELEVANCE: Obstetricians will increasingly be caring for women who have experienced uterine rupture and subsequently become pregnant.