The Prediction of Fetal Death with a Simple Maternal Blood Test (2): Fetal death affects more than 3 million pregnancies worldwide annually during the 3rd trimester of pregnancy, and there is no method to assess risk. Unexplained fetal deaths are characterized by an anti-angiogenic profile low concentrations of placental growth factor (PlGF) and high concentrations of soluble vascular endothelial growth factor (sVEGFR)-1 at the time of diagnosis, and before fetal death. Therefore, we conducted a study including all cases from a cohort of 4006 women to assess the risk of fetal death at 24-28 weeks of gestation. We found that, at 24-28 weeks, maternal plasma Angiogenic Index-1 (PlGF /sVEGFR-1) had a sensitivity of 88%, specificity of 96.5%, and a LR of 29 to identify fetal death with placental lesions consistent with maternal vascular malperfusion (MVU). Importantly, 61% of women with an apparent false-positive test subsequently experienced adverse pregnancy outcomes, such as preeclampsia, SGA, and spontaneous preterm labor/delivery. This is the first test for the assessment of risk of fetal death based on a simple measurement of two proteins in maternal blood, for which we have filed a patent application (NIH/WSU). The implications of this are that: 1) mothers who had a fetal death can now be assessed for risk of recurrence in subsequent pregnancies; and 2) interventions, such as pravastatin, may be considered in the context of a randomized clinical trial for patients at risk Vaginal Progesterone for Preventing Preterm Birth and Adverse Perinatal Outcomes in Singleton Gestations (3): This meta-analysis of individual patient data was conducted to evaluate the efficacy of vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a sonographic short cervix in the midtrimester including the data of the OPPTIMUM study. Trials comparing vaginal progesterone vs placebo/no treatment in women with a singleton gestation and a midtrimester sonographic cervical length 25 mm were included in this study. The primary outcome was preterm birth <33 weeks of gestation. Secondary outcomes included adverse perinatal outcomes and neurodevelopmental and health outcomes at 2 years of age. Data were available from 974 women (498 allocated to vaginal progesterone, 476 allocated to placebo) with a cervical length 25 mm participating in 5 high-quality trials. Vaginal progesterone was associated with a significant reduction in the risk of preterm birth <33 weeks of gestation (relative risk, 0.62; 95% confidence interval, 0.47-0.81; P = .0006; high-quality evidence). Moreover, vaginal progesterone significantly decreased the risk of preterm birth at <36, <35, <34, <32, <30, and <28 weeks of gestation; spontaneous preterm birth <33 and <34 weeks of gestation; respiratory distress syndrome; composite neonatal morbidity and mortality; birthweight <1500 and <2500 g; and admission to the neonatal intensive care unit (relative risks from 0.47-0.82; high-quality evidence for all). There were 7 (1.4%) neonatal deaths in the vaginal progesterone group and 15 (3.2%) in the placebo group (relative risk, 0.44; 95% confidence interval, 0.18-1.07; P = .07; low-quality evidence). Maternal adverse events, congenital anomalies, and adverse neurodevelopmental and health outcomes at 2 years of age did not differ between groups. In summary, vaginal progesterone decreases the risk of preterm birth and improves perinatal outcomes in singleton gestations with a midtrimester sonographic short cervix, without any demonstrable harmful effects on childhood neurodevelopment. Vaginal Progesterone is as Effective as Cervical Cerclage to Prevent Preterm Birth in Women with a Singleton Gestation (11): This is an indirect comparison meta-analysis of individual patient data which compared the efficacy of vaginal progesterone and cerclage in preventing preterm birth and adverse perinatal outcomes in women with a singleton gestation, previous spontaneous preterm birth, and a midtrimester sonographic short cervix. Both vaginal progesterone and cerclage, compared to placebo/no cerclage, significantly reduced the risk of preterm birth <35 and <32 weeks of gestation and composite perinatal morbidity/mortality. Adjusted indirect comparison meta-analyses did not show statistically significant differences between vaginal progesterone and cerclage in the reduction of preterm birth or adverse perinatal outcomes. In conclusion, vaginal progesterone and cerclage are equally effective for preventing preterm birth and improving perinatal outcomes in women with a singleton gestation, previous spontaneous preterm birth, and a midtrimester sonographic short cervix. Alloreactive Fetal T Cells Promote Uterine Contractility in Preterm Labor (13): Pregnancy is considered as a successful form of immune tolerance in which the mother accepts the semi-allogeneic fetus. Given that a breakdown of such tolerance is considered a mechanism for disease, several studies have focused on the mechanisms whereby the maternal immune system rejects the fetus. However, the fetal immune system has been somewhat disregarded. Herein, we hypothesized that the fetal immune system must also tolerate the mother and that a breakdown of such tolerance may likewise lead to pregnancy complications. Therefore, we investigated whether maternal antigen-specific activated fetal T cells contribute to the pathogenesis of spontaneous preterm labor. We first demonstrated that antigen-presenting cells are activated in the umbilical cord blood of preterm neonates which was accompanied by an increased proportion of pro-inflammatory memory CD4+ T cells together with a corresponding decrease in nave CD4+ T cells. These results establish that preterm neonates possess a distinct population of activated pro-inflammatory memory CD4+ T cells. Maternal cells can be present in the fetal circulation during pregnancy where they promote the generation of fetal regulatory T cells in order to suppress fetal immune responses. However, the number of maternal cells present in the fetal circulation can increase in women with pregnancy complications. We, therefore, determined whether changes in these maternal cells in the cord blood are associated with preterm labor. We found that maternal cells were increased in the circulation of preterm neonates. CD4+ and CD8+ T cells from preterm neonates underwent increased proliferation when presented with maternal antigens compared to those from term neonates; moreover, this response was specific to the mother since proliferation was not observed in response to antigens from third-party donors. Finally, using a mouse model of in utero adoptive transfer, we established that the presence of activated T cells in mouse fetuses in mid-pregnancy can result in pregnancy loss. Collectively, these findings demonstrate that fetal anti-maternal rejection is a novel mechanism for spontaneous preterm labor. This is the first demonstration that the fetal immune system can reject the mother leading to pregnancy termination.
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