Enrique Oyarzún

Prevalence and diversity of microbes in the amniotic fluid, the fetal inflammatory response, and pregnancy outcome in women with preterm pre-labor rupture of membranes.

Citation DiGiulio DB, Romero R, Kusanovic JP, Gómez R, Kim CJ, Seok K, Gotsch F, Mazaki‐Tovi S, Vaisbuch E, Sanders K, Bik EM, Chaiworapongsa T, Oyarzún E, Relman DA. Prevalence and diversity of microbes in the amniotic fluid, the fetal inflammatory response, and pregnancy outcome in women with preterm pre‐labor rupture of membranes. Am J Reprod Immunol 2010; 64: 38–57

Viral Infection of the Placenta Leads to Fetal Inflammation and Sensitization to Bacterial Products Predisposing to Preterm Labor

Pandemics pose a more significant threat to pregnant women than to the nonpregnant population and may have a detrimental effect on the well being of the fetus. We have developed an animal model to evaluate the consequences of a viral infection characterized by lack of fetal transmission. The experiments described in this work show that viral infection of the placenta can elicit a fetal inflammatory response that, in turn, can cause organ damage and potentially downstream developmental deficiencies. Furthermore, we demonstrate that viral infection of the placenta may sensitize the pregnant mother to bacterial products and promote preterm labor. It is critical to take into consideration the fact that during pregnancy it is not only the maternal immune system responding, but also the fetal/placental unit. Our results further support the immunological role of the placenta and the fetus affecting the global response of the mother to microbial infections. This is relevant for making decisions associated with treatment and prevention during pandemics.

Identification of fetal and maternal single nucleotide polymorphisms in candidate genes that predispose to spontaneous preterm labor with intact membranes

OBJECTIVE The purpose of this study was to determine whether maternal/fetal single nucleotide polymorphisms (SNPs) in candidate genes are associated with spontaneous preterm labor/delivery. STUDY DESIGN A genetic association study was conducted in 223 mothers and 179 fetuses (preterm labor with intact membranes who delivered <37 weeks of gestation [preterm birth (PTB)]), and 599 mothers and 628 fetuses (normal pregnancy); 190 candidate genes and 775 SNPs were studied. Single locus/haplotype association analyses were performed; the false discovery rate was used to correct for multiple testing. RESULTS The strongest single locus associations with PTB were interleukin-6 receptor 1 (fetus; P=.000148) and tissue inhibitor of metalloproteinase 2 (mother; P=.000197), which remained significant after correction for multiple comparisons. Global haplotype analysis indicated an association between a fetal DNA variant in insulin-like growth factor F2 and maternal alpha 3 type IV collagen isoform 1 (global, P=.004 and .007, respectively). CONCLUSION An SNP involved in controlling fetal inflammation (interleukin-6 receptor 1) and DNA variants in maternal genes encoding for proteins involved in extracellular matrix metabolism approximately doubled the risk of PTB.

A genetic association study of maternal and fetal candidate genes that predispose to preterm prelabor rupture of membranes (PROM).

OBJECTIVE We sought to determine whether maternal/fetal single-nucleotide polymorphisms (SNPs) in candidate genes are associated with preterm prelabor rupture of membranes (pPROM). STUDY DESIGN A case-control study was conducted in patients with pPROM (225 mothers and 155 fetuses) and 599 mothers and 628 fetuses with a normal pregnancy; 190 candidate genes and 775 SNPs were studied. Single locus/haplotype association analyses were performed; false discovery rate was used to correct for multiple testing (q* = 0.15). RESULTS First, a SNP in tissue inhibitor of metalloproteinase 2 in mothers was significantly associated with pPROM (odds ratio, 2.12; 95% confidence interval, 1.47-3.07; P = .000068), and this association remained significant after correction for multiple comparisons. Second, haplotypes for Alpha 3 type IV collagen isoform precursor in the mother were associated with pPROM (global P = .003). Third, multilocus analysis identified a 3-locus model, which included maternal SNPs in collagen type I alpha 2, defensin alpha 5 gene, and endothelin 1. CONCLUSION DNA variants in a maternal gene involved in extracellular matrix metabolism doubled the risk of pPROM.

Antibiotic treatment in preterm labor and intact membranes: A randomized, double-blinded, placebo-controlled trial

Although an association between microbial invasion of amniotic cavity and preterm birth has been extensively demonstrated, there is conflicting evidence regarding the benefits of antibiotic therapy in patients with preterm labor and intact membranes. We attempted to assess the efficacy of amoxicillin and erythromycin on pregnancy outcome in those patients. A randomized, double-blinded, placebo-controlled trial was designed and implemented. A total of 196 patients with singleton pregnancies and preterm labor with intact membranes (22-36 weeks) were randomly allocated to receive either antibiotics or placebo, plus adjunctive parenteral tocolysis, and 173 patients (antibiotics group n = 83 vs. placebo group n = 90) completed the treatment. The overall prevalence of microbial invasion of the amniotic cavity was 5.2% (9/173). No significant difference between both groups was found in maternal outcomes, including duration of randomization-to-delivery interval, frequency of preterm delivery, and frequency of clinical chorioamnionitis and endometritis. Rate of cesarean section was significantly higher in the placebo group (28% vs. 12%). Regarding neonatal outcome, no significant difference was detected between both groups in neonatal death, respiratory distress syndrome, proven sepsis, and birthweight. Suspected sepsis was significantly more frequent in the placebo group (6/90 vs. 0/78). The results of this trial indicate that amoxicillin and erythromycin do not prolong pregnancy in patients with preterm labor and intact membranes. A significant reduction in the rate of cesarean section was observed in patients receiving antibiotics. A significant reduction in the rate of neonatal suspected sepsis was also demonstrated.

Polymorphisms in maternal and fetal genes encoding for proteins involved in extracellular matrix metabolism alter the risk for small-for-gestational-age

Objective. To examine the association between maternal and fetal genetic variants and small-for-gestational-age (SGA). Methods. A case–control study was conducted in patients with SGA neonates (530 maternal and 436 fetal) and controls (599 maternal and 628 fetal); 190 candidate genes and 775 SNPs were studied. Single-locus, multi-locus and haplotype association analyses were performed on maternal and fetal data with logistic regression, multifactor dimensionality reduction (MDR) analysis, and haplotype-based association with 2 and 3 marker sliding windows, respectively. Ingenuity pathway analysis (IPA) software was used to assess pathways that associate with SGA. Results. The most significant single-locus association in maternal data was with a SNP in tissue inhibitor of metalloproteinase 2 (TIMP2) (rs2277698 OR = 1.71, 95% CI [1.26–2.32], p = 0.0006) while in the fetus it was with a SNP in fibronectin 1 isoform 3 preproprotein (FN1) (rs3796123, OR = 1.46, 95% CI [1.20–1.78], p = 0.0001). Both SNPs were adjusted for potential confounders (maternal body mass index and fetal sex). Haplotype analyses resulted in associations in α 1 type I collagen preproprotein (COL1A1, rs1007086-rs2141279-rs17639446, global p = 0.006) in mothers and FN1 (rs2304573-rs1250204-rs1250215, global p = 0.045) in fetuses. Multi-locus analyses with MDR identified a two SNP model with maternal variants collagen type V α 2 (COL5A2) and plasminogen activator urokinase (PLAU) predicting SGA outcome correctly 59% of the time (p = 0.035). Conclusions. Genetic variants in extracellular matrix-related genes showed significant single-locus association with SGA. These data are consistent with other studies that have observed elevated circulating fibronectin concentrations in association with increased risk of SGA. The present study supports the hypothesis that DNA variants can partially explain the risk of SGA in a cohort of Hispanic women.

Determinación de la portación de streptococcus agalactiae: grupo B en embarazadas durante el tercer trimestre mediante inmunoensayo

RESUMENDado que la sepsis neonatal por Streptococcus Grupo B es una enfermedad de alta letalidad, yconsiderando ademas que la portacion de este germen en nuestra poblacion de embarazadas se acercaa 20%, es que, resulta muy importante disponer de algun test rapido y confiable para realizar screening.Este estudio evalua el rendimiento de un inmunoensayo para pesquisa de Streptococcus agalactiae enembarazadas sin factores de riesgo y a fines del tercer trimestre. Los resultados muestran una bajasensibilidad y un bajo valor predictivo positivo para este metodo, lo que no lo hace recomendable para suimplementacion clinica.PALABRAS CLAVES: Sepsis por Streptococcus Grupo B, inmunoensayoSUMMARYNeonatal sepsis of early onset by group B Streptococcus has a high mortality rate. Twenty percent ofour pregnant population have vaginal colonization by this bacterial agent, so clinical practice require a fastand efficient screening test.This report checks a Group B Streptococcus immunoassay screening test in the last trimester forpregnant women without risk factors. The low sensitivity and low positive predictive value of the test makeit not recomendable for clinical practice.KEY WORDS: Group B Streptococcus, immunoassay, perinatal sepsis

Urgencias en obstetricia

Resumen Tradicionalmente, el embarazo es considerado un evento fisiologico. Sin embargo, cerca de un 20% de las embarazadas desarrolla patologias obstetricas que se asocian a mortalidad materna y perinatal. A nivel mundial, cada ano medio millon de mujeres fallece durante el embarazo y parto debido a estas complicaciones. Desafortunadamente, un numero significativo de las urgencias obstetricas ocurre en pacientes sin factores de riesgo, por lo que la prevencion, identificacion precoz e intervencion a tiempo de estos eventos juegan un rol fundamental para contrarrestar un resultado perinatal adverso. En el presente capitulo hemos seleccionado las emergencias que concentran la mayor morbimortalidad de nuestra especialidad. Si bien algunas han quedado fuera, creemos que los temas aqui presentados representan las urgencias obstetricas mas importantes que enfrentamos a diario, para las cuales debemos estar preparados con el fin de realizar un manejo optimo del embarazo y parto para la obtencion de un resultado perinatal favorable.

PREVALENCIA DE COLONIZACION POR STREPTOCOCCUS AGALACTIAE (GRUPO B) EN EL TERCER TRIMESTRE DEL EMBARAZO. EVALUACION DEL CULTIVO SELECTIVO. EXPERIENCIA EN 2192 PACIENTES

SUMMARY Group B Streptococcus (GBS) is the most important bacterial agent in early-onset neonatal sepsis. Infection is usually acquired during labor in colonized women. Among pregnant women streptococcal colonization ranges from 2% to 34%, with highgest rates when using combined vaginal and anal culture in a selective broth medium. The aim of this study was to know the GBS prevalence in pregnant women controlled in our hospital and the real improvement in GBS recovery because the use of selective media. Among 2192 pregnant women enrolled, using selective medium, we identifed GBS in 19.8% of them. With non selective medium the prevalence would have reached only 12.7%. This finding support the systematic screening for GBS in our hospital, using selective medium only.

Trombosis venosa en el embarazo

Resumen La incidencia de Tromboembolismo Venoso (TEV) en el embarazo se incrementa aproximadamente de 4 a 50 veces mas en comparacion con mujeres no embarazadas, debido a las modificaciones que el propio embarazo produce sobre los factores de la coagulacion y los sistemas fibrinoliticos. Se estima que la TEV complica entre 1 y 1,5 por cada 1.000 embarazos. Durante el embarazo la hemostasia materna se caracteriza por ser un estado protrombotico en el cual se producen cambios en el sistema hemostatico, con el objetivo de prevenir una posible hemorragia durante las primeras etapas del embarazo, parto y puerperio. Sin embargo, la adaptacion del sistema hemostatico materno al embarazo predispone a la madre a un riesgo incrementado de TEV. El diagnostico de los eventos tromboembolicos en el embarazo constituye un reto para los equipos tratantes, ya que los hallazgos clinicos y de laboratorio caracteristicos de esta enfermedad pueden estar enmascarados en los cambios fisiologicos propios de la gestacion, por lo que el inicio de su evaluacion suele ser complejo. Para el correcto y oportuno diagnostico de TVP y TEP se requiere de una combinacion de varios elementos que incluye: sintomas y signos, estudios de laboratorio e imagenologia. El uso de anticoagulantes en pacientes obstetricas requiere de un plan de interrupcion del embarazo lo mas controlado posible. En la practica clinica cotidiana esto no siempre es posible, debido a la incapacidad de predecir el momento de inicio del trabajo de parto. Por este motivo las recomendaciones relativas al manejo analgesico y anestesico del parto estan basadas en el conocimiento de los cambios fisiologicos, farmacocinetico y farmacodinamico de los anticoagulantes utilizados, lo que se analiza en extenso en esta revision.