¿Son útiles los antimicrobianos en pacientes con trabajo de parto prematuro, espontáneo, membranas intactas e infección bacteriana ascendente? Una revisión narrativa / Are antibiotics useful in patients with preterm and spontaneous labor, intact membranes and ascendant bacterial infection? A narrative review

El parto prematuro (PP) es la principal causa de morbilidad/mortalidad perinatal y frecuentemente es espontáneo, con membranas intactas (MI). La infección intrauterina es su causa más común en un hospital público de Chile. Existe evidencia que la infección bacteriana ascendente desde la vagina es responsable de la infección/inflamación intraamniótica, del PP y de los resultados adversos maternos y perinatales. Esta revisión narrativa incluye ensayos controlados aleatorizados (ECAs), publicados en PubMed, Cochrane, Embase, Scielo, Science Direct, Wiley Online Library, sobre los mecanismos que intervienen en el ascenso de la infección vaginal, los factores infecciosos que participan en el resultado adverso materno-perinatal y la eficacia de los antimicrobianos en estos casos. Estos trabajos no recomiendan usar antimicrobianos profilácticos porque producen daño a corto y largo plazo en los hijos. Pero este resultado tiene sesgo porque no se evaluó la presencia de infección/inflamación subclínica, lo que disminuye el grado de recomendación. También existen ECAs, que erradican la infección/inflamación intraamniótica, reducen la morbilidad/mortalidad neonatal, pero son trabajos aislados, obtenidos de subanálisis, con bajo nivel de evidencia. Se requieren revisiones sistemáticas y metaanális de ECAs con estudio de infección/inflamación subclínica para evaluar si son útiles los antimicrobianos en el PP espontáneo con MI.

Preterm labor (PL) is the leading cause of perinatal morbidity/ mortality and is frequently spontaneous with intact membranes (IM). Intrauterine infection is its most common cause in a public hospital in Chile. There is evidence that ascending bacterial infection from the vagina is responsible for intraamniotic infection/inflammation, PL, and adverse maternal and perinatal outcomes. This narrative review includes randomized controlled trials (RCTs), published in PubMed, Cochrane, Embase, Scielo, Science Direct, Wiley Online Library on the mechanisms involved in the rise of vaginal infection, the infectious factors involved in adverse maternal-perinatal outcomes, and the efficacy of antibiotics in these cases. They do not recommend the use of prophylactic antibiotics because they cause short and long-term damage to children. But this result is biased because the presence of subclinical infection/inflammation was not evaluated, which lowers the degree of recommendation. There are also RCTs that eradicate intra-amniotic infection/inflammation, reduce neonatal morbidity/ mortality, but they are isolated studies, obtained from subanalyses, with a low level of evidence. Systematic reviews and meta-analyses of RCTs with subclinical infection/inflammation study are required to assess whether antibiotics are useful in spontaneous PL with IM.

Beneficios de los antibióticos en la rotura prematura de membranas de pretérmino y factores que intervienen en la eficacia del tratamiento: revisión narrativa / Benefits of antibiotics in preterm premature rupture of membranes and factors involved in the efficacy of the treatment: narrative review

Resumen El parto prematuro es la principal causa de morbilidad y de mortalidad perinatal, y hasta un tercio de los casos presentan rotura prematura de membranas. La infección intrauterina que asciende desde la vagina es su principal causa en un hospital público de Chile. Esta revisión narrativa mediante búsqueda en PubMed, Cochrane, Embase, Scielo, Science Direct y Wiley Online Library incluye estudios publicados sobre los diferentes factores infecciosos que intervienen en el resultado adverso perinatal y la eficacia de los antibióticos en la rotura prematura de membranas de pretérmino. Además, contiene recomendaciones de sociedades científicas sobre el uso de antibióticos en estos casos. Los ensayos concluyen que los antimicrobianos prolongan el embarazo, disminuyen la corioamnionitis clínica y reducen variadas morbilidades neonatales, pero no reducen la mortalidad perinatal ni las secuelas tardías en la infancia. Los resultados adversos obstétricos, especialmente los neonatales, y las secuelas dependen de la existencia de invasión microbiana de la cavidad amniótica o de infección cérvico-vaginal, de la virulencia de los microorganismos aislados, del compromiso inflamatorio/infeccioso de la placenta (corioamnionitis histológica, funisitis) y de la respuesta inflamatoria fetal. Para mejorar los resultados adversos obstétricos neonatales en la rotura prematura de membranas de pretérmino, los esquemas de antibióticos deben ser eficaces, cubriendo el amplio espectro microbiológico existente y actuando sobre los factores infecciosos implicados en la gravedad de la infección. Además, deben administrarse de manera intensiva y prolongada hasta el parto.

Abstract Preterm birth is the leading cause of perinatal morbidity and mortality, and up to a third of them have premature rupture of membranes. Intrauterine infection that rises from the vagina is its main cause in a public hospital in Chile. This narrative review by searching PubMed, Cochrane, Embase, Scielo, Science Direct and Wiley Online Library includes published studies of the different infectious factors involved in perinatal adverse outcome and of the efficacy of antibiotics in preterm premature rupture of membranes. It also contains recommendations from scientific societies on the use of antibiotics in these cases. These trials conclude that antimicrobials prolong pregnancy, decrease clinical chorioamnionitis, and reduce various neonatal morbidities, but do not reduce perinatal mortality or infant sequelae. Obstetric and especially neonatal adverse outcomes in these patients depend on the existence of microbial invasion of the amniotic cavity and/or cervicovaginal infection, of the virulence of the isolated microorganisms, of inflammatory/infectious involvement of the placenta (histological chorioamnionitis, funisitis) and fetal inflammatory response. To improve adverse neonatal obstetric outcomes in preterm premature rupture of membranes, antibiotic regimens must be effective, covering the wide existing microbiological spectrum and acting on infectious factors responsible for the severity of the infection. In addition, they must be administered aggressively and for a long time until delivery.

The Identification of Immune-Related Plasma Proteins Associated with Spontaneous Preterm Delivery and Intra-Amniotic Infection in Women with Premature Cervical Dilation or an Asymptomatic Short Cervix

BACKGROUND: We aimed to investigate whether various immune-related plasma proteins, alone or in combination with conventional clinical risk factors, can predict spontaneous preterm delivery (SPTD) and intra-amniotic infection in women with premature cervical dilation or a short cervix (≤ 25 mm).METHODS: This retrospective study included 80 asymptomatic women with premature cervical dilation (n = 50) or a short cervix (n = 30), who underwent amniocentesis at 17–29 weeks. Amniotic fluid (AF) was cultured, and maternal plasma was assayed for interleukin (IL)-6, matrix metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinases (TIMP)-1, and complements C3a and C5a, using enzyme-linked immunosorbent assay (ELISA) kits. The primary outcome measures were SPTD at < 32 weeks and positive AF cultures.RESULTS: The plasma levels of IL-6, C3a, and C5a, but not of MMP-9 and TIMP-1, were significantly higher in women with SPTD at < 32 weeks than in those who delivered at ≥ 32 weeks. The women who delivered at < 32 weeks had more advanced cervical dilatation, and higher rates of antibiotic and tocolytic administration and were less likely to be given vaginal progesterone than those who delivered at ≥ 32 weeks. Using a stepwise regression analysis, a combined prediction model was developed, which included the plasma IL-6 and C3a levels, and cervical dilatation (area under the curve [AUC], 0.901). The AUC for this model was significantly greater than that for any single variable included in the predictive model. In the univariate analysis, plasma IL-6 level was the only significant predictor of intra-amniotic infection.CONCLUSION: In women with premature cervical dilation or a short cervix, maternal plasma IL-6, C3a, and C5a levels could be useful non-invasive predictors of SPTD at < 32 weeks. A combination of these biomarkers and conventional clinical factors may clearly improve the predictability for SPTD, as compared with the biomarkers alone. An increased plasma level of IL-6 predicted intra-amniotic infection.

Complement C3a, But Not C5a, Levels in Amniotic Fluid Are Associated with Intra-amniotic Infection and/or Inflammation and Preterm Delivery in Women with Cervical Insufficiency or an Asymptomatic Short Cervix (≤ 25 mm)

BACKGROUND: We aimed to estimate whether elevated levels of complement C3a and C5a in amniotic fluid (AF) are independently associated with increased risks of intra-amniotic infection and/or inflammation (IAI) and spontaneous preterm delivery (SPTD) in women with cervical insufficiency or a short cervix (≤ 25 mm). METHODS: We conducted a retrospective cohort study of 96 consecutive women with cervical insufficiency (n = 62) or a short cervix (n = 34) at 17 to 27 weeks, and who underwent an amniocentesis. AF was cultured and analyzed for C3a and C5a by enzyme-linked immunosorbent assay kits. The primary outcome measures were IAI (defined as a positive AF culture and/or an elevated AF interleukin-6 level [≥ 7.6 ng/mL]) and SPTD at < 32 weeks. RESULTS: In multivariable analysis, AF level of C3a was the only variable significantly associated with IAI, whereas C5a level in AF and serum C-reactive protein level were not associated with IAI. Using SPTD at < 32 weeks as the outcome variable in logistic regression, elevated AF levels of C3a were associated with increased risk of SPTD at < 32 weeks after adjusting for other baseline confounders, whereas elevated AF levels of C5a were not. CONCLUSION: In women with cervical insufficiency or a short cervix, elevated AF level of C3a, but not C5a, is independently associated with increased risks of IAI and SPTD at < 32 weeks. These findings suggest that subclinical IAI or SPTD in the context of cervical insufficiency is related to activation of complement system in AF.

Intra-amniotic thyroxine to treat fetal goiter

A 35-year-old pregnant woman visited our department and had been treated with 100 microg of daily oral levothyroxine for hypothyroidism. An ultrasonography screening was performed at 25 weeks gestation and revealed a fetal goiter and an increased amniotic fluid volume. Fetal hypothyroidism was confirmed by cordocentesis and amniotic hormone levels at 26 weeks gestation. We treated the mother with 200 microg of daily oral levothyroxine to optimize the transplacental transfer. A total of four intra-amniotic injections of levothyroxine were administered, resulting in progressive reduction in the fetal thyroid volume of goiter as measured by 3D ultrasonography and increased amniotic fluid volume. Following birth, neonatal serum thyroid stimulating hormone level was within the normal range, but free T4 was reduced. Based on this case, we suggest that monitoring amniotic fluid thyroid hormone concentration and intra-amniotic levothyroxine injection can be used to reduce the thyroid volume of goiters and to prevent polyhydramnios.

Corioamnionitis subclínica: correlación histológicamicrobiológica y morbilidad neonatal / Subclinical chorioamnionitis: histologically correlation microbiological and neonatal morbidity

Objetivo: Determinar la existencia de corioamnionitis histológica en pacientes con ruptura prematura de membranas, independientemente del tiempo de evolución y su asociación con la morbilidad neonatal en el Servicio de Obstetricia del Hospital “Miguel Pérez Carreño. Métodos: Se tomaron mujeres con embarazos simples, entre 30 y 41 semanas más 6 días, con ruptura prematura de membranas, independientemente del tiempo de evolución, sin signos clínicos de infección intraamniótica. Se procedió a tomar la muestra del canal endocervical con un aplicador estéril. También se procedió a la revisión de las historias clínicas de los recién nacidos, para verificar si estos presentaron alguna complicación asociada a la infección intraamniótica. Resultados: El 37,1 % de las pacientes con corioamnionitis presentaron un tiempo de evolución de ruptura prematura de membranas menor a 8 horas, el 2,9 % cursó con ruptura prematura de membranas más allá de las 24 horas de evolución. A pesar de que la duración de la ruptura prematura de membranas fue mayor en pacientes con corioamnionitis, esta no difirió estadísticamente de las pacientes que tuvieron menor tiempo de ruptura prematura de membranas cuando no tenían corioamnionitis (P = 0,596). El 97,1.% de los cultivos de secreción endocervical en pacientes con corioamnionitis histológica fue positivo. El microorganismo más frecuente aislado fue la Echerichia coli, en 29,4 % de los casos. Conclusiones: Independientemente del tiempo de evolución de ruptura prematura de membranas podemos encontrar corioamnionitis subclínica y que a su vez esto influye en la morbilidad neonatal.

Objective: To determine the presence of histologic chorioamnionitis in patients with premature rupture of membranes, regardless of time of evolution and its association with neonatal morbidity. Method: We took women of childbearing age, singleton pregnancies between 30 and 41 weeks plus 6 days, premature rupture of membranes, regardless of time of evolution, without clinical signs of intraamniotic infection. We proceeded to sample the endocervical canal with a sterile applicator. Also proceeded to review the medical records of newborns, to verify whether these had any complications associated with intra-amniotic infection. Results: 37.1 % of patients with chorioamnionitis had a duration of less than 8 hours premature rupture of membranes, 2.9 % progressed with premature rupture of membranes more than 24 hours after onset. Although the length of the premature rupture of membranes was greater in patients with chorioamnionitis, this did not differ statistically from the patients that had less time when they had chorioamnionitis premature rupture of membranes (P = 0.596). 97.1 % of endocervical secretion cultures in patients with histologic chorioamnionitis was positive The most common organism isolated was E. coli, in 29.4 % of cases. Conclusions: That regardless of the duration of subclinical chorioamnionitis can find premature rupture of membranes and this in turn influences the neonatal morbidity.

Intra-Amniotic Infection/Inflammation as a Risk Factor for Subsequent Ruptured Membranes after Clinically Indicated Amniocentesis in Preterm Labor

The aim of this study was to determine whether intra-amniotic infection/inflammation (IAI) was associated with subsequent ruptured membranes in women with preterm labor and intact membranes who had a clinically indicated amniocentesis. This retrospective cohort study included 237 consecutive women with preterm labor (20-34.6 weeks) who underwent amniocentesis. The clinical and laboratory parameters evaluated included demographic variables, gestational age, C-reactive protein (CRP) and amniotic fluid (AF) white blood cell, interleukin-6 (IL-6) and culture results. IAI was defined as a positive AF culture and/or an elevated AF IL-6 level (>2.6 ng/mL). The primary outcome was ruptured membranes in the absence of active labor occurring within 48 hours of amniocentesis. Preterm premature rupture of membranes subsequently developed in 10 (4.2%) women within 48 hr of amniocentesis. Multivariate analysis demonstrated that only IAI was independently associated with the ruptured membranes occurring within 48 hr of amniocentesis. In the predictive model based on variables assessed before amniocentesis, only CRP level was retained. IAI is an independent risk factor for subsequent ruptured membranes after clinically indicated amniocentesis in preterm labor. Prior to amniocentesis, measurement of serum CRP level can provide a risk assessment for the subsequent development of ruptured membranes after the procedure.

Denaturing Gradient Gel Electrophoresis for Detection of Bacterial Population and Diversity in Amniotic Fluids and Neonatal Gastric Fluids

PURPOSE: Intra-amniotic infection (IAI) is often polymicrobial, and the 16S rDNA PCR assay has a major limitation that its interpretation is difficult in the presence of multiple 16S rDNAs. Denaturing gradient gel electrophoresis (DGGE) can overcome this limitation by separating PCR products based on sequence. We performed the DGGE analysis to investigate bacterial prevalence and diversity in amniotic fluids from pregnant women with preterm births and gastric fluids from their newborns. METHODS: DNA was extracted from bacterial cells in amniotic fluid (AF) and gastric fluid (GF) and was amplified with universal 16S rDNA primers. For DGGE analysis, the PCR products were loaded onto polyacrylamide gels that were made with denaturing gradients. RESULTS: Bacterial 16S rDNA was detected by PCR from all AF and GF samples. The bacterial species in AF samples were the following: Lactobacillus reuteri (87.0%), uncultured Enterococcus species (65.2%), Ureaplasma urealyticum (13.0%), and Enterococcus faecalis (4.3%). The bacterial species in GF samples were the following: Lactobacillus reuteri (95.2%), uncultured Enterococcus species (42.9%), and Ureaplasma urealyticum (4.8%). Two or more species were identified from 69.6% of AF and 47.6% of GF samples. CONCLUSION: We suggest that DGGE analysis allows improved understanding of microbial diversity and community in AF and GF.

Outcome of intra-amniotic hypertonic saline instillation for second-trimester abortion.

Objective: To evaluate the efficacy and safety of intra-amniotic hypertonic saline instillation for second trimester abortion. Methods: The pregnant women whose pregnancies were complicated by serious fetal abnormalities, trisomy 21 and thalassemia HbE disease, were admitted at Siriraj Hospital from January 1, 2009 to April 30, 2010. The patients were legally induced abortion by intra-amniotic hypertonic saline instillation. Results: A total of 42 pregnant women were retrospectively studied. The average gestational age was 22.4 ± 2.2 weeks. The average instillation-abortion time was 34.8 ± 18.2 hours. All abortuses were dead at the time of abortion. The number of complete abortions were 39 cases (92.9%). There were no serious complications in this study. Conclusion: Intra-amniotic hypertonic saline instillation for second trimester abortion should be considered as a good method in terms of efficacy and safety.

Gérmenes presentes en cultivos de aspirado gástrico de recién nacidos de pacientes con sospecha de infección intramniótica / Germs present in newborns gastric aspírate cultures from intramnioticinfecction suspected patients

El presente trabajo desarrollado en el Maternológico infantil Geman Urquidi de Cochabamba, persigue, identificar mediante cultivo, el o los gérmenes presentes en el liquido amniotico, aspirado de la cavidad gástrica de recién nacidos, dentro los primeros 5 minutos de nacido (patógenos potenciales de infecciones materno infantiles), de madres con sospecha de infección intraamniotica, cuyas gestaciones fueron complicadas con rotura prematura de membranas. Se realizo un estudio prospectivo, longitudinal, laboratorial, correlacional, tomándose como muestra a 40 pacientes que reunían los criterios de inclusión para el estudio, cuyas muestras de líquido amniotico fueron cultivadas en el laboratorio Gastroenterológico Boliviano Japonés, al mismo tiempo fueron estudiadas histopatológicamente las placentas de las pacientes. Se obtuvo como resultado, cultivos positivos en un 75 % de las muestras, donde el germen presente mas frecuente cultivado en medios comunes, fue la Escherichia coli, seguido del Stafilococo aureus, cuyas sensibilidades antibióticas se mostraban adecuadas para las quinolonas y cefalosporinas , dejando de lado a los medicamentos convencionales, por la resistencia que presentaban, así mismo se pudo demostrar que la la corioamnionitis histológica, es con mucho mas frecuente que la corioamnionitis clínica, siendo positivo inclusive en aquellos casos que no se cultivo germen alguno.

The purpose ofthe current work, carried out atthe Maternal-lnfant Hospital "Germán Urquidi" in Cochabamba, isto identify, by means of a culture, the germ(s) present in the amniotic fluid, aspirated from the gastric cavity of newborns, within the first 5 minutes of being born (potential pathogens of maternal-infant infections), of mothers suspected of intra-amniotic infection, whose pregnancies were complicated and presented premature sack breakage. A prospective, longitudinal, laboratory, correlational study was performed, taking samples from 40 patients who met the criteria for inclusion in the study and whose amniotic fluid samples were cultivated at the Bolivian Japanese Gastroenterological laboratory. At the same time, patients'afterbirths were studied histopathologically. As a result, positive cultures were identified in 75% ofthe samples, where the most common germ present was Escherichia coli, followed by Stafilococo aureus, whose antibiotic sensitivities were found to be adequate for quinolones and cephalos porins, disregarding conventional drugs, due to the resistance they showed. Likewise, it was possible to demonstrate that histological chorioamnionitis is much more frequent than clinical chorioamnionitis, resulting positive even in cases in which no germ at all was cultivated.

Conservative Treatment of Viable Cervical Pregnancy with Intra-amniotic Methotrexate / 대한산부인과학회잡지

OBJECTIVE: The purpose of this study was to determine the effectiveness of intra-amniotic methotrexate instillation for the treatment of viable cervical pregnancy. MATERIALS AND METHODS: Four patients were enrolled in this study after confirmation of cervical pregnancy by ultrasonography. Viable cervical pregnancy was determined by ultrasonographic findings with the entire chorionic sac containing a live fetus below the internal os, empty uterine cavity, and significantly dilated or barrel shaped cervical canal. Under the transvaginal ultrasonographic guidence, 50 mg of methotrexate was injected directly into the amniotic sac after complete aspiration of amniotic fluid. Serial serum beta-human chorionic gonadotropin (beta-hCG) was evaluated weekly until normalized. RESULTS: All the patients were successfully treated with conservative method and one patient received hysterectomy due to arterio-venous malformation diagnosed during follow up. Initial serum beta-hCG concentration was 22,484-93,803 mIU/ml and decreased by log scale after treatment. CONCLUSION: Intra-amniotic methotrexate instillation without concomitant feticide injection or feticidal procedure can be used for the initial treatment in viable cervical pregnancy. Initial titer or falling rate pattern of serum beta-hCG did not seem to be related with the prognosis.

Leukocyte esterase activity, gram stain, cell count and glucose concentration in intra-amniotic infection

Intraamniotic infection, a common cause of maternal and prenatal morbidity and mortality, is a challenging problem for the obstetrician. This study aims to determine the value of leukocyte esterase activity, grams stain, cell count, and glucose concentration of the amniotic fluid in the diagnosis of intraamniotic infection. Of the 53 subjects,. 35 had intact bag of water and 18 with premature rupture of membranes. In the group with intact bag of water, leukocyte esterase test, Grams stain and quantitative glucose of 84%, 80% and 88% respectively, whereas cell count and quantitative glucose were sensitive at 64% and 90% respectively. In the group with premature rupture membranes, leukocyte esterase test and qualitative glucose had specificities of 81% and 67% respectively, whereas Grams stain, cell count and quantitative glucose had sensitivities of 56% 83% and 100% respectively.