Vaginal progesterone to reduce preterm birth <34 weeks in women with singletons and a short cervix an updated meta-analysis including data from the OPPTIMUM study (1): Preterm birth is the leading cause of perinatal morbidity and mortality worldwide, and is attributable to multiple pathological processes. In 2012, we published an individual patient data meta-analysis evaluating the efficacy and safety of vaginal progesterone administration for the prevention of preterm birth in women with a short cervix. Recently, the OPPTIMUM study created confusion as to the efficacy of vaginal progesterone in these women. Therefore, we updated the previous systematic review and meta-analysis to include all relevant patient data, including those from the OPPTIMUM trial, to quantify the efficacy of this natural hormone in preventing preterm birth and perinatal morbidity and mortality in asymptomatic women with a singleton gestation and a midtrimester sonographic cervical length <25mm. Five trials (974 women) were included. Results showed that vaginal progesterone significantly decreased the risk of preterm birth <34 weeks gestation or fetal death compared to placebo. Meta-analyses of data from four trials (723 women) showed that vaginal progesterone administration was associated with a statistically significant reduction in the risk of preterm birth <28 to <36 weeks of gestation, respiratory distress syndrome, composite neonatal morbidity and mortality, birth weight <1500g, and admission to the neonatal intensive care unit. Our updated systematic review and meta-analysis reaffirmed that vaginal progesterone reduces the risk of preterm birth and neonatal morbidity and mortality in women with a singleton gestation and a midtrimester cervical length <25mm, without any deleterious effects on neurodevelopmental outcome. Weak functional connectivity in the human fetal brain prior to preterm birth (2): Neurological problems are significantly more common in children born preterm such children are three times more likely to develop autism, attention deficit/hyperactivity disorders, and emotional disorders; five times more likely to manifest neurological abnormalities; and three to four times more likely to experience school failure. It has been suggested that such neurological problems are expressed prior to birth, but due to technical limitations, testing this in humans has been difficult. We utilized resting-state functional magnetic resonance imaging (rs-fMRI) to measure neural connectivity in utero in 32 human fetuses, 14 of which were subsequently born preterm. An intrinsic connectivity distribution analysis of rs-fMRI data to map synchrony in MRI signals over time across the fetal brain was employed, followed by post-hoc seed analysis, in order to explore regions in which specific connections were most responsible for changes in intrinsic connectivity distribution value differences between preterm and full-term groups. Novel rs-fMRI was applied in utero in 32 fetuses we found that systems-level neural functional connectivity was diminished in those who would subsequently be born preterm. Neural connectivity was reduced in a left-hemisphere pre-language region, and the degree to which connectivity of this region extended to right-hemisphere homologs was positively associated with the time elapsed between fMRI assessment and delivery. These results show that altered functional connectivity in the preterm brain is identifiable before birth, and that neurodevelopmental disorders associated with preterm birth may result from neurological insults that begin in utero. Fetal/placental Type I IFN can affect maternal survival and fetal viral load during viral infection (3): The reason why pregnant women have greater mortality and complications associated with viral infections compared to the general population is not well-defined. We hypothesized that the loss of placental interferon (IFN) affects the regulation of the maternal immune system, therefore resulting in the differential response to infections observed in pregnancy. We compared disease severity between pregnant and nonpregnant mice without the type I IFN receptor to determine whether IFN contributes to pregnancy-specific mortality during viral infections. Furthermore, we investigated viral replication and the severity of the maternal and fetal response to viral infections by manipulating embryonic-placental IFN, and demonstrated that the loss of fetal-derived type I IFN, specifically, contributes to fetal viremia, and fetal-placental IFN signaling can affect maternal mortality. In summary, this study demonstrated that placental/fetal IFN signaling regulates fetal viral transmission and has the potential to modulate maternal viral infection. Neutrophil extracellular traps in the amniotic cavity of women with intra-amniotic infection: a new mechanism of host defense (4): Intra-amniotic inflammation can be due to microorganisms (i.e. intra-amniotic infection) or danger signals derived from necrosis and cellular stress. Neutrophils are the first line of defense against invading pathogens and possess an arsenal of weapons utilized in the elimination of microbes. Neutrophils can also undergo a specialized cell death termed neutrophil extracellular traps (NETs), which represents the final containment effort of a neutrophil to lyse pathogens.
The aim of this study was to investigate whether neutrophils in the amniotic cavity of women with intra-amniotic infection are capable of forming NETs. Amniotic fluid samples from women with intra-amniotic infection were stained for bacteria; amniotic fluid neutrophils were purified by filtration. Different stages of NET formation were visualized using antibodies against elastase and histone H3, in combination with 4,6-diamidino-2-phenylindole (DAPI) staining, by confocal microscopy. We found that NETs were present in the amniotic fluid of women with intra-amniotic infection. All of the amniotic fluid samples had detectable live and dead bacteria associated with the presence of NETs. In contrast to neutrophils from the maternal circulation, amniotic fluid neutrophils did not require phorbol-12-myristate-13-acetate (PMA) stimulation to form NETs, and neither maternal nor neonatal neutrophils form NETs in the amniotic fluid of women without intra-amniotic infection. 1. Romero R, Nicolaides K, Conde-Agudelo A, O-Brien JM, Cetingoz E, Da Fonseca E, Creasy GW, Hassan SS. Vaginal progesterone decreases preterm birth 34 weeks of gestation in women with a singleton pregnancy and a short cervix: an updated meta-analysis including data from the OPPTIMUM study. Ultrasound Obstet Gynecol 2016;48(3):308-317. PMID: 27444208 2. Thomason ME, Scheinost D, Manning JH, Grove LE, Hect J, Marshall N, Hernandez-Andrade E, Berman S, Pappas A, Yeo L, Hassan SS, Constable RT, Ment LR, Romero R. Weak functional connectivity in the human fetal brain prior to preterm birth. Sci Rep 2017;7:1-10. PMID: 28067865 3. Racicot K, Aldo P, El-Guindy A, Kwon JY, Romero R, Mor G. Cutting edge: Fetal/placental Type I IFN can affect maternal survival and fetal viral load during viral infection. J Immunol 2017;198:3029-3032. PMID: 28264970 4. Gomez-Lopez N, Romero R, Xu Y, Miller D, Unkel R, Shaman M, Jacques SM, Panaitescu B, Garcia-Flores V, Hassan SS. Neutrophil extracellular traps in the amniotic cavity of women with intra-amniotic infection: a new mechanism of host defense. Reprod Sci 2017. In Press PMID: 27884950

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Panaitescu, Bogdan; Romero, Roberto; Gomez-Lopez, Nardhy et al. (2018) In vivo evidence of inflammasome activation during spontaneous labor at term. J Matern Fetal Neonatal Med :1-14
Fitzgerald, Wendy; Gomez-Lopez, Nardhy; Erez, Offer et al. (2018) Extracellular vesicles generated by placental tissues ex vivo: A transport system for immune mediators and growth factors. Am J Reprod Immunol 80:e12860
Romero, Roberto; Conde-Agudelo, Agustin; Da Fonseca, Eduardo et al. (2018) Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data. Am J Obstet Gynecol 218:161-180
Xu, Yi; Romero, Roberto; Miller, Derek et al. (2018) Innate lymphoid cells at the human maternal-fetal interface in spontaneous preterm labor. Am J Reprod Immunol 79:e12820
Erez, Offer; Romero, Roberto; Vaisbuch, Edi et al. (2018) The pattern and magnitude of ""in vivo thrombin generation"" differ in women with preeclampsia and in those with SGA fetuses without preeclampsia. J Matern Fetal Neonatal Med 31:1671-1680
Kusanovic, Juan P; Romero, Roberto; Martinovic, Carolina et al. (2018) Transabdominal collection of amniotic fluid ""sludge"" and identification of Candida albicans intra-amniotic infection. J Matern Fetal Neonatal Med 31:1279-1284
Frascoli, Michela; Coniglio, Lacy; Witt, Russell et al. (2018) Alloreactive fetal T cells promote uterine contractility in preterm labor via IFN-? and TNF-?. Sci Transl Med 10:
Conde-Agudelo, Agustin; Romero, Roberto; Da Fonseca, Eduardo et al. (2018) Vaginal progesterone is as effective as cervical cerclage to prevent preterm birth in women with a singleton gestation, previous spontaneous preterm birth, and a short cervix: updated indirect comparison meta-analysis. Am J Obstet Gynecol 219:10-25
Docheva, Nikolina; Romero, Roberto; Chaemsaithong, Piya et al. (2018) The profiles of soluble adhesion molecules in the ""great obstetrical syndromes"". J Matern Fetal Neonatal Med :1-24
Madar-Shapiro, Liora; Karady, Ido; Trahtenherts, Alla et al. (2018) Predicting the Risk to Develop Preeclampsia in the First Trimester Combining Promoter Variant -98A/C of LGALS13 (Placental Protein 13), Black Ethnicity, Previous Preeclampsia, Obesity, and Maternal Age. Fetal Diagn Ther 43:250-265

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