Showing papers by "Roberto Romero published in 2011"

Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial

Abstract: Objectives Women with a sonographic short cervix in the mid-trimester are at increased risk for preterm delivery. This study was undertaken to determine the efficacy and safety of using micronized vaginal progesterone gel to reduce the risk of preterm birth and associated neonatal complications in women with a sonographic short cervix. Methods This was a multicenter, randomized, doubleblind, placebo-controlled trial that enrolled asymptomatic

Listeriosis in human pregnancy: a systematic review.

Abstract: Listeria is commonly found in processed and prepared foods and listeriosis is associated with high morbidity and mortality. Preventative measures are well prescribed and monitoring and voluntary recall of contaminated products has resulted in a 44% reduction in the prevalence of perinatal listeriosis in the USA. Pregnant women are at high risk for listeriosis, but symptoms are non-specific and diagnosis is difficult. The intracellular life-cycle of Listeria protects the bacterium from host innate and adaptive immune responses. Antibiotic treatment requires agents able to penetrate, distribute, and remain stable within host cells. Prolonged use of high-dose ampicillin can significantly improve neonatal outcome.

Placental lesions associated with maternal underperfusion are more frequent in early-onset than in late-onset preeclampsia.

Abstract: Objective Preeclampsia (PE) has been classified into early- and late-onset disease. These two phenotypic variants of PE have been proposed to have a different pathophysiology. However, the gestational age cut-off to define ‘early’ versus ‘late’ PE has varied among studies. The objective of this investigation was to determine the prevalence of lesions consistent with maternal underperfusion of the placenta in patients with PE as a function of gestational age.

Damage-associated molecular patterns (DAMPs) in preterm labor with intact membranes and preterm PROM: a study of the alarmin HMGB1.

Abstract: Objective. Preterm parturition is a syndrome caused by multiple etiologies. Although intra-amniotic infection is causally linked with intrauterine inflammation and the onset of preterm labor, other patients have preterm labor in the absence of demonstrable infection. It is now clear that inflammation may be elicited by activation of the Damage-Associated Molecular Patterns (DAMPs), which include pathogen-associated molecular patterns (PAMPs) as well as “alarmins” (endogenous molecules that signal tissue and cellular damage). A prototypic alarmin is high-mobility group box 1 (HMGB1) protein, capable of inducing inflammation and tissue repair when it reaches the extracellular environment. HMGB1 is a late mediator of sepsis, and blockade of HMGB1 activity reduces mortality in an animal model of endotoxemia, even if administered late during the course of the disorder. The objectives of this study were to: (1) determine whether intra-amniotic infection/inflammation (IAI) is associated with changes in amniotic ...

Placental bed disorders in preterm labor, preterm PROM, spontaneous abortion and abruptio placentae ☆

Abstract: Failure of physiologic transformation of the spiral arteries has been studied using placental bed biopsies in several obstetrical syndromes. Contrary to what was originally believed, this lesion is not restricted to preeclampsia and/or intrauterine growth restriction. A review of published evidence indicates that failure of physiologic transformation can be observed in women with spontaneous second trimester abortions, preterm labor with intact membranes, preterm prelabor rupture of membranes and abruptio placentae. Therefore, disorders of deep placentation are present in a wide range of complications of pregnancy, emphasizing the importance of understanding the physiology and pathology of transformation of the spiral arteries. We propose that changes in the population and function of immunocytes at the maternal-fetal interface can be part of the mechanism of disease of obstetrical disorders, and this requires further investigation.

Complement Activation Triggers Metalloproteinases Release Inducing Cervical Remodeling and Preterm Birth in Mice

Abstract: Inflammation is frequently linked to preterm delivery (PTD). Here, we tested the hypothesis that complement activation plays a role in cervical remodeling and PTD. We studied two mouse models of inflammation-induced PTD. The first model was induced by vaginal administration of lipopolysaccharide (LPS) and the second one by administration of progesterone antagonist RU486. Increased cervical C3 deposition and macrophages infiltration and increased serum C3adesArg and C5adesArg levels were observed in both models when compared to gestational age matched controls. A significant increase in collagen degradation, matrix metalloproteinase 9 (MMP-9) activity and tissue distensibility was observed in the cervix in both models. Mice deficient in complement receptor C5a did not show increased MMP-9 activity and cervical remodeling and did not deliver preterm in response to LPS or RU486, suggesting a role for C5aR in the cervical changes that precede PTD. In vitro studies show that macrophages release MMP-9 in response to C5a. Progesterone diminished the amount of C5aR on the macrophages surface, inhibited the release of MMP-9 and prevented PTD. In addition, macrophages depletion also prevented cervical remodeling and PTD in LPS-treated mice. Our studies show that C5a-C5aR interaction is required for MMP-9 release from macrophages, and the cervical remodeling that leads to PTD. Complement inhibition and supplementation with progesterone may be good therapeutic options to prevent this serious pregnancy complication.

Maternal plasma concentrations of angiogenic/anti-angiogenic factors are of prognostic value in patients presenting to the obstetrical triage area with the suspicion of preeclampsia

Abstract: Objective: To determine whether maternal plasma concentrations of placental growth factor (PlGF), soluble endoglin (sEng), soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and -2 could identify patients at risk for developing preeclampsia (PE) requiring preterm delivery. Study design: Patients presenting with the diagnosis “rule out PE” to the obstetrical triage area of our hospital at <37 weeks of gestation (n=87) were included in this study. Delivery outcomes were used to classify patients into four groups: I) patients without PE or those with gestational hypertension (GHTN) or chronic hypertension (CHTN) who subsequently developed PE at term (n = 19); II): mild PE who delivered at term (n = 15); III): mild disease (mild PE, GHTN, CHTN) who subsequently developed severe PE requiring preterm delivery (n = 26); and IV): diagnosis of severe PE (n = 27). Plasma concentrations of PlGF, sEng, sVEGFR-1 and -2 were determined at the time of presentation by ELISA. Reference ranges for analytes we...

miR-210 targets iron-sulfur cluster scaffold homologue in human trophoblast cell lines: siderosis of interstitial trophoblasts as a novel pathology of preterm preeclampsia and small-for-gestational-age pregnancies.

Abstract: This study was performed to assess the biological significance of miR-210 in preeclampsia and small-for-gestational-age (SGA) pregnancies. Placental miR-210 expression was evaluated by quantitative RT-PCR (RT-qPCR) in the following groups: i) appropriate-for-gestational-age pregnancies (n = 72), ii) preeclampsia (n = 52), iii) SGA (n = 66), and iv)preeclampsia with SGA (n = 31). The effects of hypoxia (1% O2) on miR-210 and iron-sulfur cluster scaffold homologue (ISCU) expressions and miR-210 binding to ISCU 3′ UTR were examined in Swan 71 and BeWo cell lines. Perls' reaction (n = 229) and electron microscopy (n = 3) were conducted to verify siderosis of trophoblasts. miR-210 expression was increased in preeclampsia and SGA cases and was decreased with birth weight and gestational age. In both cell lines, miR-210 was induced by hypoxia, whereas ISCU expression was decreased. The luciferase assay confirmed miR-210 binding to ISCU mRNA 3′ UTR. RNA interference knockdown of ISCU expression in Swan 71, but not in BeWo, cells resulted in autophagosomal and siderosomal iron accumulation and a fourfold decrease of Matrigel invasion (P = 0.004). Placental ISCU expression was decreased in preeclampsia (P = 0.002) and SGA (P = 0.002) cases. Furthermore, hemosiderin-laden trophoblasts were more frequent in the placental bed of preterm preeclampsia and/or SGA births than in control cases (48.7% versus 17.9%; P = 0.004). Siderosis of interstitial trophoblasts is a novel pathological feature of preeclampsia and SGA. The findings herein suggest that ISCU down-regulation by miR-210 perturbing trophoblast iron metabolism is associated with defective placentation.

Placental Viral Infection Sensitizes to Endotoxin-Induced Pre-Term Labor: A Double Hit Hypothesis

Abstract: Problem Among pregnant women, acquired viral infections with a concurrent bacterial infection is a detrimental factor associated to poor prognosis. We evaluate the effect of a viral infection that does not lead to pre-term labor on the response to low doses of lipopolysaccharide (LPS). Our objectives were (i) to characterize the effect of a viral infection concurrent with exposure to microbial products on pregnancy outcome and (ii) to characterize the placental and fetal immune responses to the viral sensitization to LPS.

A Signature of Maternal Anti-Fetal Rejection in Spontaneous Preterm Birth: Chronic Chorioamnionitis, Anti-Human Leukocyte Antigen Antibodies, and C4d

Abstract: Background Chronic chorioamnionitis is found in more than one-third of spontaneous preterm births. Chronic chorioamnionitis and villitis of unknown etiology represent maternal anti-fetal cellular rejection. Antibody-mediated rejection is another type of transplantation rejection. We investigated whether there was evidence for antibody-mediated rejection against the fetus in spontaneous preterm birth.

Posttraumatic stress symptoms following pregnancy complicated by hyperemesis gravidarum

Abstract: Objective. Hyperemesis gravidarum (HG) can be accompanied by severe physical and emotional distress. Most studies have focused on the physical and psychological stress associated with this condition during the affected pregnancy. This study explores posttraumatic stress symptoms (PTSS) and negative life outcomes following HG pregnancies. Methods. A total of 610 women (HG ¼377 and control ¼233) were recruited and completed an online survey. w-square analyses were used to compare the HG and control groups on various life outcome variables. Results. Eighteen percent of women with HG reported full criteria PTSS (n ¼68). Negative life outcomes regarding financial and marital status, career, as well as psychological and physical well-being differed significantly for the HG groups compared to the control group (0.0015p50.05). Conclusions. PTSS is common following HG pregnancies and is associated with negative life outcomes including inability to breastfeed, marital problems, financial problems, and inability of self care.

Injectable PAMAM dendrimer-PEG hydrogels for the treatment of genital infections: formulation and in vitro and in vivo evaluation.

Abstract: Local intravaginal drug therapy is preferred for treatment of ascending genital infections during pregnancy. In the present study, an in situ forming biodegradable hydrogel for sustained release of amoxicillin in the cervicovaginal region is described. A generation 4 poly(amidoamine) [G4-(NH2)64] dendrimer with peripheral thiopyridyl terminations is cross-linked with 8-arm polyethylene glycol (PEG) bearing thiol terminations. The hydrogels were formulated and tested in vivo in a pregnant guinea pig model for volume, retention times, biodegradation, tolerability and transport across fetal membrane. The physicochemical characterization of the hydrogels was carried out using differential calorimetry, SEM, and confocal imaging. The hydrogels offer antibacterial activity arising from sustained release of amoxicillin from gels. The in vivo studies in guinea pig showed that 100–200 μL of gel sufficiently covered the cervicovaginal region with a residence time of at least 72 h and gel was primarily retained in th...

Health-related quality of life in women with nausea and vomiting of pregnancy: the importance of psychosocial context.

Abstract: To test whether women with hyperemesis gravidarum (HG) demonstrated lower health-related quality of life (HRQoL) scores compared with those with nausea and vomiting of pregnancy (NVP). Women with HG or NVP were examined during the first trimester. Multivariate models identified characteristics of women at risk for low HRQoL, as measured by an NVP-specific HRQoL test and a generic HRQoL test, the Short Form (SF)-36. Although the SF-36 assessment did not discriminate between the two groups, the NVP-specific test showed that women with HG (N=29) were 3–6 times more likely than women with NVP (N=48) to have low HRQoL. Both tests demonstrated that perceived physical symptoms and multiple psychosocial factors, such as depression and marital status, seemed to be equally or more important than having HG. Although a low HRQoL was associated with an HG diagnosis, multiple physical symptoms and psychosocial factors placed both groups of women at risk.

Cervical Remodeling/ripening At Term And Preterm Delivery: The Same Mechanism Initiated By Different Mediators And Different Effector Cells

Abstract: Background: Premature cervical remodeling/ripening is believed to contribute to preterm delivery (PTD), the leading cause of perinatal morbidity and mortality. Despite considerable research, the causes of term and PTD remain unclear, and there is no effective treatment for PTD. We previously demonstrated that complement activation plays a causative role in cervical remodeling that leads to PTD in mice. Methodology/Principal Findings: Here we found that complement activation is not required for the physiological process that leads to term delivery in mice. Neither increased C3 cervical deposition nor increased C3a and C5a serum levels were observed at term. In addition, macrophages infiltration was found in PTD in contrast to term delivery were no leukocytes were found. Despite the different role of complement and different cellular effector cells, PTD and term delivery share a common dowsntream pathway characterized by increased metalloproteinases (MMPs) release and increased collagen degradation. However, different sources of MMPs were identified. Macrophages are the source of MMPs in PTD while cervical fibroblasts and columnar epithelial cells synthesize MMPs at term delivery. A dramatic diminution in serum progesterone levels precedes parturition at term but not in PTD, suggesting that progesterone withdrawal initiates cervical remodeling at term. On the other hand, MMPs release in PTD is triggered by C5a. Conclusion and Significance: In conclusion, preterm and term cervical remodeling occur through the same mechanism but they are initiated by different mediators and effector cells. That complement activation is required for PTD but not for the physiological process that leads to term delivery, suggests that complement is a potential specific biomarker and selective target to prevent PTD and thus avert neonatal mortality and morbidity.

The frequency and risk factors of funisitis and histologic chorioamnionitis in pregnant women at term who delivered after the spontaneous onset of labor

Abstract: Objective. To examine the frequency and risk factors of funisitis and histologic chorioamnionitis in the placentas of term pregnant women who delivered after the spontaneous onset of labor.Methods. The frequency of funisitis and histologic chorioamnionitis was examined in consecutive pregnant women at term with singleton pregnancies who delivered after the spontaneous onset of labor. Nonparametric statistics were used for data analysis.Results. (1) The frequency of funisitis and histologic chorioamnionitis was 6.7% (88/1316) and 23.6% (310/1316), respectively; (2) Patients with funisitis had significantly higher rates of nulliparity, regional analgesia, operative vaginal delivery, longer duration of labor and rupture of membranes (ROM), and higher gestational age and birthweight than those without funisitis (p < 0.05 for each); (3) Patients with histologic chorioamnionitis had significantly higher rates of nulliparity, oxytocin augmentation, regional analgesia, cesarean section or operative vaginal delive...

Fetal ERAP2 variation is associated with preeclampsia in African Americans in a case-control study.

Abstract: Preeclampsia affects 3-8% of pregnancies and is a major cause of maternal and perinatal morbidity and mortality worldwide. This complex disorder is characterized by alterations in the immune and vascular systems and involves multiple organs. There is strong evidence for a genetic contribution to preeclampsia. Two different single nucleotide polymorphisms (SNPs) in the endoplasmic reticulum aminopeptidase 2 (ERAP2) gene were recently reported to be associated with increased risk for preeclampsia in two different populations. ERAP2 is expressed in placental tissue and it is involved in immune responses, inflammation, and blood pressure regulation; making it is an attractive preeclampsia candidate gene. Furthermore, ERAP2 expression is altered in first trimester placentas of women destined to develop preeclampsia. A case-control design was used to test for associations between two SNPs in ERAP2, rs2549782 and rs17408150, and preeclampsia status in 1103 Chilean maternal-fetal dyads and 1637 unpaired African American samples (836 maternal, 837 fetal). We found that the fetal minor allele (G) of rs2549782 was associated with an increased risk for preeclampsia in the African American population (P = 0.009), but not in the Chilean population. We found no association between rs17408150 and risk for preeclampsia in the Chilean population. Association between rs17408150 and risk for preeclampsia was not tested in the African American population due to the absence of the minor allele in this population. We report an association between fetal ERAP2 and preeclampsia in an African American population. In conjunction with previous studies, which have found maternal associations with this gene in an Australian/New Zealand population and a Norwegian population, ERAP2 has now been associated with preeclampsia in three populations. This provides strong evidence that ERAP2 plays a role in the development of preeclampsia.

Varying coefficient model for gene–environment interaction

Abstract: Motivation: The genetic basis of complex traits often involves the function of multiple genetic factors, their interactions and the interaction between the genetic and environmental factors. Gene–environment (G×E) interaction is considered pivotal in determining trait variations and susceptibility of many genetic disorders such as neurodegenerative diseases or mental disorders. Regression-based methods assuming a linear relationship between a disease response and the genetic and environmental factors as well as their interaction is the commonly used approach in detecting G×E interaction. The linearity assumption, however, could be easily violated due to non-linear genetic penetrance which induces non-linear G×E interaction. Results: In this work, we propose to relax the linear G×E assumption and allow for non-linear G×E interaction under a varying coefficient model framework. We propose to estimate the varying coefficients with regression spline technique. The model allows one to assess the non-linear penetrance of a genetic variant under different environmental stimuli, therefore help us to gain novel insights into the etiology of a complex disease. Several statistical tests are proposed for a complete dissection of G×E interaction. A wild bootstrap method is adopted to assess the statistical significance. Both simulation and real data analysis demonstrate the power and utility of the proposed method. Our method provides a powerful and testable framework for assessing non-linear G×E interaction. Contact: [email protected] Supplementary information: Supplementary data are available at Bioinformatics online.

Unexplained fetal death has a biological signature of maternal anti-fetal rejection: chronic chorioamnionitis and alloimmune anti-human leucocyte antigen antibodies.

Abstract: Aims Chronic chorioamnionitis is a histological manifestation of maternal anti-fetal cellular rejection. Failure of graft survival being the most catastrophic event in organ transplantation, we hypothesized that fetal death could be a consequence of rejection of the mother against the fetus. This study was conducted to assess evidence of cellular and antibody-mediated rejection in fetal death cases.