An individual patient meta-analysis conducted by our program showed that vaginal progesterone is effective in preventing preterm birth (PTB) in women with and without a history of a previous PTB. Cervical cerclage has been proposed to prevent preterm birth in women with a short cervix and a history of previous PTB. Which is preferable medical treatment with vaginal progesterone or a cervical cerclage, which requires anesthesia and surgery? No studies have compared the benefits and risks of these two interventions. To address this, we also conducted an indirect patient meta-analysis of randomized clinical trials to compare the treatment effects of vaginal progesterone vs cerclage to prevent PTB in asymptomatic women with a short cervix (<25 mm) in the midtrimester, singleton gestation, and previous spontaneous PTB. This method has emerged as an accepted and valid approach for comparing competing interventions with each other using a common comparator. 9 trials were included: 4 evaluated vaginal progesterone vs placebo (n=158) and 5 evaluated cerclage vs no cerclage (n=504). The use of either vaginal progesterone or cerclage was associated with a significant reduction in the risk of PTB <32 weeks of gestation and composite perinatal morbidity/mortality when compared with placebo and no cerclage, respectively. Treatment with vaginal progesterone was associated with a non-significant 29% reduction in the risk of PTB <32 weeks of gestation and a non-significant 33% decrease in the risk of composite perinatal morbidity and mortality when compared with cerclage. There were no significant differences between the efficacy of either in the prevention of PTB at <37, <35, and <28 weeks of gestation or adverse perinatal outcomes. The selection of the optimal treatment will depend upon adverse events and cost-effectiveness of the interventions, as well as patient/ physicians preferences.(1) However, medical treatment with vaginal progesterone is as efficacious as surgical treatment. Fetal death is a major obstetrical challenge with the prevalence of 3 million cases worldwide. An imbalance of angiogenic/anti-angiogenic factors has been implicated in the pathophysiologic description of preeclampsia, pregnancies with small-for-gestational-age (SGA) neonates, stillbirth, and other obstetrical complications. A prospective cohort study was conducted to determine whether maternal plasma concentrations of PlGF, sVEGFR-1 and sEng at 30-34 weeks of gestation can identify patients at risk for stillbirth, late preeclampsia, and delivery of small-for gestational-age neonates. The results showed that a plasma concentration of PlGF/sVEGFR-1 <0.12 MoM at 30-34 weeks of gestation had a sensitivity of 80%, a specificity of 94%, and a likelihood ratio of a positive test of 14 for the identification of subsequent stillbirth. This is the first test that can assess the risk of fetal death in mothers without risk factors at the beginning of the third trimester of pregnancy.(5) Massive perivillous fibrin deposition (MPFD) and maternal floor infarction (MFI) are related placental lesions often associated with recurrent fetal death and fetal growth restriction. The Branch conducted a study to determine whether this complication of pregnancy could reflect maternal anti-fetal rejection. We found that the prevalence of plasma cell deciduitis in the placenta was significantly higher in cases with MPFD than in those with uncomplicated term deliveries (40% vs 8.6%, P=0.01). Patients with MPFD had a significantly higher frequency of maternal anti-HLA class I positivity during the second trimester than those with uncomplicated term deliveries (80% vs 36%, P=0.01). Strongly positive C4d deposition was observed on umbilical vein endothelium in cases of MPFD. A specific maternal antibody against fetal HLA antigen class I or II was identified in all cases of MPFD. The mean maternal plasma concentration of CXCL-10, which has been reported to be increased in the maternal blood of patients with solid organ transplant rejection, was higher in patients with evidence of MPFD than in those without (P<0.001). These studies provide evidence that this serious placental lesion is associated with evidence of maternal anti-fetal rejection.(2) Since MPFD is associated with fetal death and fetal growth restriction, conditions reported to be associated with an imbalance of angiogenic/anti-angiogenic factors, we conducted a longitudinal study to examine whether maternal plasma concentrations of angiogenic/anti-angiogenic factors in MPFD differ from those of uncomplicated pregnancies prior to the time of diagnosis. Patients who eventually delivered placentas with MPFD had a lower mean plasma concentration of placental growth factor (PlGF), and higher mean plasma concentrations of sVEGFR-1 and sEng than controls. Differences in mean sVEGFR-1, sEng, and the ratios of PlGF to sVEGFR-1 and PlGF to sEng were observed before 20 weeks of gestation. This provides, for the first time, evidence that an imbalance of angiogenic/anti-angiogenic factors is present in patients with MPFD prior to the diagnosis and these changes may participate in the mechanisms responsible for adverse pregnancy outcomes.(3) These findings also open avenues for therapeutic intervention. Preeclampsia is a pregnancy-specific syndrome which affects 3-5% of all pregnancies. A frequent clinical challenge is to identify those patients who present to the obstetrical triage area with the suspicion of preeclampsia (based upon an elevation of blood pressure or other symptoms), and will require preterm delivery or develop maternal and/or neonatal complications. Having first reported that this may be feasible based upon a retrospective study, we have now completed a prospective study. The results confirm (in another population) that a classification system proposed by our Program, based upon the determination of biomarkers in maternal blood, has prognostic value in identifying patients at risk for preterm delivery or adverse maternal/neonatal outcome. Among patients presenting prior to 34 weeks of gestation, those classified as high risk had a 94% probability of preterm delivery, and 70% developed maternal and/or neonatal complications within 2 weeks. On the other hand, patients classified as low risk were unlikely to deliver within 2 weeks or develop maternal and/or neonatal complications.(4) This has practical implications for the management of this common complication of pregnancy. We first described the fetal inflammatory response syndrome (FIRS) as a condition associated with preterm labor or preterm PROM, intra-amniotic infection and acute inflammatory lesions of the placenta (funisitis). We discovered a different form of fetal systemic inflammation characterized by an elevation of CXCL10 in association with chronic placental inflammatory lesions, and termed this FIRS type II - associated lesions are chronic chorioamnionitis, villitis of unknown etiology, and plasma cell deciduitis. These lesions occur in the context of maternal anti-fetal rejection. We found that chronic placental inflammation correlates with maternal seropositivity for class I and class II HLA panel-reactive antibodies (PRA), and that maternal HLA PRA seropositivity during the second trimester of pregnancy is a risk factor for spontaneous preterm delivery, especially for late PTB, which represents 70% of all preterm births. Molecular profiling of fetal blood demonstrated distinct changes in the fetal blood transcriptome and proteome according to the presence or absence of FIRS type II. Differential expression of 128 genes and 20 proteins whose abundance differed between fetuses with and without FIRS type II were reported. Altogether, the findings suggest that maternal anti-fetal rejection can be a novel mechanism of disease in spontaneous preterm labor (6,7).

Project Start
Project End
Budget Start
Budget End
Support Year
22
Fiscal Year
2013
Total Cost
$22,294,736
Indirect Cost
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State
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Conde-Agudelo, Agustin; Romero, Roberto (2014) Prediction of preterm birth in twin gestations using biophysical and biochemical tests. Am J Obstet Gynecol :
Maddipati, Krishna Rao; Romero, Roberto; Chaiworapongsa, Tinnakorn et al. (2014) Eicosanomic profiling reveals dominance of the epoxygenase pathway in human amniotic fluid at term in spontaneous labor. FASEB J 28:4835-46
Romero, Roberto; Dey, Sudhansu K; Fisher, Susan J (2014) Preterm labor: one syndrome, many causes. Science 345:760-5
Stampalija, Tamara; Chaiworapongsa, Tinnakorn; Romero, Roberto et al. (2014) Soluble ST2, a modulator of the inflammatory response, in preterm and term labor. J Matern Fetal Neonatal Med 27:111-21
Deter, Russell L; Lee, Wesley; Sangi-Haghpeykar, Haleh et al. (2014) Individualized fetal growth assessment: critical evaluation of key concepts in the specification of third trimester size trajectories. J Matern Fetal Neonatal Med 27:543-51
Miranda, Jezid; Romero, Roberto; Korzeniewski, Steven J et al. (2014) The anti-aging factor *-klotho during human pregnancy and its expression in pregnancies complicated by small-for-gestational-age neonates and/or preeclampsia. J Matern Fetal Neonatal Med 27:449-57
Chaiworapongsa, Tinnakorn; Romero, Roberto; Korzeniewski, Steven J et al. (2014) Plasma concentrations of angiogenic/anti-angiogenic factors have prognostic value in women presenting with suspected preeclampsia to the obstetrical triage area: a prospective study. J Matern Fetal Neonatal Med 27:132-44
Aldo, Paulomi B; Racicot, Karen; Craviero, Vinicius et al. (2014) Trophoblast induces monocyte differentiation into CD14+/CD16+ macrophages. Am J Reprod Immunol 72:270-84
Romero, Roberto; Yeo, Lami; Chaemsaithong, Piya et al. (2014) Progesterone to prevent spontaneous preterm birth. Semin Fetal Neonatal Med 19:15-26
Hamill, Neil; Romero, Roberto; Hassan, Sonia et al. (2013) The fetal cardiovascular response to increased placental vascular impedance to flow determined with 4-dimensional ultrasound using spatiotemporal image correlation and virtual organ computer-aided analysis. Am J Obstet Gynecol 208:153.e1-13

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