1. Prospective randomized clinical trial (RCT) of vaginal progesterone vs. placebo in women with a short cervix: This was a multicenter, randomized, double-blind, placebo-controlled trial to determine the efficacy and safety of micronized vaginal progesterone gel (90mg) to reduce the risk of preterm birth (PTB) and associated neonatal complications in asymptomatic women with a singleton pregnancy and a sonographic short cervix (10-20 mm) at 19-23.9 weeks of gestation. Women were allocated to receive vaginal progesterone gel or placebo daily from 20-23.9 weeks until 36.9 weeks, rupture of membranes or delivery. Randomization sequence was stratified by center and history of a previous PTB. Approximately 32,000 women were screened worldwide. Of 465 women randomized, 458 were included in the analysis (vaginal progesterone gel, n=235;placebo, n=223). Women allocated to receive vaginal progesterone had a lower rate of PTB <33 weeks (primary endpoint) than those allocated to placebo (8.9% vs. 16.1%;RR 0.55;95% CI, 0.33-0.92;P=0.02). The effect remained significant after adjustment for co-variates. Vaginal progesterone was also associated with a significant reduction in the rate of PTB at <28 weeks (by 50%) and <35 weeks (by 35%), respiratory distress syndrome (by 61%), any neonatal morbidity or mortality event and birthweight <1500 g. There were no differences in the frequency of treatment-related adverse events between the groups. This is the first RCT that demonstrates that the administration of vaginal progesterone in women with a short cervix can reduce the rate of early PTB and neonatal morbidity. 2. Universal screening of pregnant women with sonographic cervical length and treatment with vaginal progesterone to prevent preterm birth is cost-effective: a decision and economic analysis: Prior to the availability of the results of our RCT described above, our group conducted a decision-analytic and cost-effectiveness analysis to determine which strategy for the prevention of PTB and associated morbidity is the most cost-effective. Four strategies were tested (using quality-adjusted life-years, cost in US dollars, and number of PTB prevented). Universal sonographic screening for cervical length and treatment with vaginal progesterone was the most cost-effective strategy and was the dominant choice over the other three alternatives, which were: 1) sonographical cervical screening limited to women with a previous history of PTB and treatment with vaginal progesterone;2) treatment of women with a history of previous PTB with 17 alpha-hydroxyprogesterone caproate (17-OHP-C);and 3) no screening or treatment. Universal screening represented savings of $1339 ($8325 vs. $9664), when compared with treatment with 17-OHP-C, and led to a reduction of 95,920 PTB annually in the US. We concluded that universal sonographic screening for short cervical length and treatment with vaginal progesterone appears to be cost-effective and yields the greatest reduction in PTB at <34 weeks'gestation. The results of this study provide compelling evidence for the change in healthcare policy in the US to prevent preterm delivery, reduce neonatal morbidity and decrease the economic burden of the leading cause of infant mortality. 3. Identification of feto-placental rejection as a mechanism of disease in preterm birth: We had previously proposed that an abnormal allogeneic reaction was responsible for several obstetrical syndromes, including spontaneous preterm labor and delivery. The fetus in mammals is a semi-allograft, as 50% of its genome is of paternal origin. The mechanisms responsible for tolerance of this allograft have been subject to investigation;yet, our Program focused on determining whether rejection of the semi-allograft may be identified by studying the human placenta and the characterization of such lesions. We published a number of studies which support the view that chronic chorioamnionitis and villitis of unknown etiology (VUE) are closely related immunologic inflammatory lesions, harboring features of allograft rejection of the mother and graft-versus-host disease of the fetus. We demonstrated that a subset of women with chronic chorioamnionitis have circulating maternal anti-fetal antibodies, and that such antibodies can cross the placenta and induce complement activation and a novel form of systemic fetal inflammation never described before. We reported a cross-sectional study to examine the frequency and significance of anti-HLA antibodies in maternal and fetal sera according to the presence of chronic chorioamnionitis in the context of spontaneous PTB. Maternal anti-HLA class I seropositivity in PTB was higher than in normal term births (p=0.005). Chronic chorioamnionitis was associated with a higher maternal anti-HLA class I seropositivity in both preterm and term births (each p<0.01). VUE was associated with increased maternal and fetal anti-HLA class I and II seropositivity (each p<0.05). C4d immune complex deposition on umbilical vein endothelium was more frequent in PTB than at term (77% vs. 11%;p<0.001). Logistic regression analysis revealed that chronic chorioamnionitis (OR=6.1), maternal anti-HLA class I seropositivity (OR=5.9), and C4d deposition on umbilical vein endothelium (OR=36.2) were associated with preterm labor/delivery. Collectively, this evidence suggests that a subset of spontaneous PTB is the result of maternal anti-fetal cellular and antibody-mediated rejections with links to fetal graft-versus-host disease and alloimmune reactions. Future studies will focus on the identification of biomarkers for this mechanism of disease, as well as elucidation of the mechanisms responsible for spontaneous preterm labor in these patients. 4. Molecular imaging for the detection of fetal microglial activation: Our Program has established a role for intrauterine inflammation/inflammation in the development of periventricular leukomalacia (PVL) and cerebral palsy (CP). Neuroinflammation is characterized by activation of the microglial cells, which play a key role in the pathogenesis of white matter injury and PVL. A major challenge is the identification of neuroinflammation at the time of birth. Diagnosis of clinically silent neuroinflammation would allow early treatment and prevention of motor disorders. We conducted a series of studies to determine if microglial activation can be detected using molecular imaging. PK11195 is a ligand that is selective for the translocator protein expressed on activated microglia and macrophages, and 11 C PK11195 can effectively be used as a ligand in positron emission tomography (PET) for the detection of activated microglial cells in various neuroinflammatory conditions. A model of fetal inflammation was generated by administering bacterial endotoxin to pregnant rabbits at 28 days of gestation. Kits were born spontaneously at 31 days and underwent PET imaging on the day of birth, and neurobehavioral testing. Using ROC curves, we identified an optimal cutoff for detecting abnormal neurobehavioral scores consistent with the phenotype of CP in neonatal rabbits. We observed that an increased uptake of 11 C PK11195 in the brain over time had a sensitivity of 100% (AUC >0.82) for all parameters tested. The magnitude of 11 C PK11195 binding measured in vivo by PET imaging correlated strongly with the severity of motor deficits in the neonatal rabbit. This suggested that molecular imaging in the neonatal period can identify neuroinflammation (microglial activation) which is clinically significant. This observation would allow identification of the newborn at risk for neurologic injury and early treatment.

Project Start
Project End
Budget Start
Budget End
Support Year
20
Fiscal Year
2011
Total Cost
$4,612,483
Indirect Cost
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Griffith, Oliver W; Chavan, Arun R; Protopapas, Stella et al. (2018) Reply to Liu: Inflammation before implantation both in evolution and development. Proc Natl Acad Sci U S A 115:E3-E4
Fitzgerald, Wendy; Freeman, Michael L; Lederman, Michael M et al. (2018) A System of Cytokines Encapsulated in ExtraCellular Vesicles. Sci Rep 8:8973
Miller, Derek; Romero, Roberto; Unkel, Ronald et al. (2018) CD71+ erythroid cells from neonates born to women with preterm labor regulate cytokine and cellular responses. J Leukoc Biol 103:761-775
Erez, Offer; Romero, Roberto; Vaisbuch, Edi et al. (2018) Tissue factor activity in women with preeclampsia or SGA: a potential explanation for the excessive thrombin generation in these syndromes. J Matern Fetal Neonatal Med 31:1568-1577
Romero, Roberto; Chaemsaithong, Piya; Tarca, Adi L et al. (2018) Maternal plasma-soluble ST2 concentrations are elevated prior to the development of early and late onset preeclampsia - a longitudinal study. J Matern Fetal Neonatal Med 31:418-432
Gomez-Lopez, Nardhy; Romero, Roberto; Arenas-Hernandez, Marcia et al. (2018) Intra-amniotic administration of lipopolysaccharide induces spontaneous preterm labor and birth in the absence of a body temperature change. J Matern Fetal Neonatal Med 31:439-446
Thomason, Moriah E; Hect, Jasmine; Waller, Rebecca et al. (2018) Prenatal neural origins of infant motor development: Associations between fetal brain and infant motor development. Dev Psychopathol 30:763-772
Kwon, Ja-Young; Aldo, Paulomi; You, Yuan et al. (2018) Relevance of placental type I interferon beta regulation for pregnancy success. Cell Mol Immunol 15:1010-1026
Gomez-Lopez, Nardhy; Romero, Roberto; Xu, Yi et al. (2018) The immunophenotype of amniotic fluid leukocytes in normal and complicated pregnancies. Am J Reprod Immunol 79:e12827
Romero, Roberto; Kim, Yeon Mee; Pacora, Percy et al. (2018) The frequency and type of placental histologic lesions in term pregnancies with normal outcome. J Perinat Med 46:613-630

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