Metabolomics in Prenatal Medicine: A Review.

Pregnancy is a complicated and insidious state with various aspects to consider, including the well-being of the mother and child. Developing better non-invasive tests that cover a broader range of disorders with lower false-positive rates is a fundamental necessity in the prenatal medicine field, and, in this sense, the application of metabolomics could be extremely useful. Metabolomics measures and analyses the products of cellular biochemistry. As a biomarker discovery tool, the integrated holistic approach of metabolomics can yield new diagnostic or therapeutic approaches. In this review, we identify and summarize prenatal metabolomics studies and identify themes and controversies. We conducted a comprehensive search of PubMed and Google Scholar for all publications through January 2020 using combinations of the following keywords: nuclear magnetic resonance, mass spectrometry, metabolic profiling, prenatal diagnosis, pregnancy, chromosomal or aneuploidy, pre-eclampsia, fetal growth restriction, pre-term labor, and congenital defect. Metabolite detection with high throughput systems aided by advanced bioinformatics and network analysis allowed for the identification of new potential prenatal biomarkers and therapeutic targets. We took into consideration the scientific papers issued between the years 2000-2020, thus observing that the larger number of them were mainly published in the last 10 years. Initial small metabolomics studies in perinatology suggest that previously unidentified biochemical pathways and predictive biomarkers may be clinically useful. Although the scientific community is considering metabolomics with increasing attention for the study of prenatal medicine as well, more in-depth studies would be useful in order to advance toward the clinic world as the obtained results appear to be still preliminary. Employing metabolomics approaches to understand fetal and perinatal pathophysiology requires further research with larger sample sizes and rigorous testing of pilot studies using various omics and traditional hypothesis-driven experimental approaches.

Changes in mediators of pro-cell growth, senescence, and inflammation during murine gestation.

PROBLEM: Senescence of the fetal membranes and senescence-associated inflammation have been associated with parturition at term and pre-term in both mice and humans. Using a pregnant mouse model, we determined changes in multiple molecular signalers contributing to senescence and inflammation associated with parturition. METHOD OF STUDY: Fetal membranes were collected from timed-pregnant CD-1 mice on gestation days (E) 13, 15, 17, 18, and 19. Immunohistochemistry (IHC) localized pro-cell growth factors glycogen synthase kinase 3ß (GSK3ß) and ß-catenin. Gestational age-associated changes in pro-cell growth vs senescence mediators (p38 mitogen-activated protein kinase [p38MAPK]), prooxidants (heme oxygenase-1 [HO-1], peroxisome proliferator-activated receptor γ [PPARγ]), and pro- and anti-inflammatory cytokines (IL-6, IL-8, IL-10, and IL-1ß) were determined by Western blots and Luminex assays. RESULTS: Fetal membrane expressions of phosphorylated forms of GSK3ß (inactivation) and p38MAPK (activation) increased, while ß-catenin expression decreased, as gestation progressed. Antioxidant HO-1 expression decreased while PPARγ increased toward term gestation. IL-6 and IL-8 concentrations were highest on E19 (day of delivery), while IL-10 and IL-1ß concentrations were highest on E15. CONCLUSION: Mouse fetal membranes showed a progressive senescence marker increase coincided with downregulation of cell growth factors. Development of senescence is associated with inflammation. Senescence-associated changes are natural and physiologic and indicative of fetal membranes' readiness for parturition.

Repeated lipopolysaccharide exposure leads to placental endotoxin tolerance.

PROBLEM: Placental infection induces increased levels of pro-inflammatory cytokines, which have been implicated in the pathogenesis of pre-term labor. Endotoxin tolerance is a phenomenon in which exposure to a dose of endotoxin makes tissue less responsive to subsequent exposures. The objective of our study was to determine whether repeated exposure to endotoxin will induce a tolerant phenotype in normal human second-trimester placental tissue. METHODS OF STUDY: Human second-trimester placental explants from elective termination of pregnancy were cultured and exposed to endotoxin (LPS). After 24 hours, the media was collected for analysis, and the explants were re-exposed to LPS after adding fresh media for another 24 hours. This process was repeated for a total of 4 LPS doses. The media was collected from each day and analyzed for cytokine levels. RESULTS: The first LPS treatment stimulated the secretion of the pro-inflammatory cytokines IL-1ß and TNF-α. However, their production was significantly diminished with repeated LPS doses. Production of the anti-inflammatory cytokines, IL-1ra and IL-10, was also stimulated by the first LPS treatment, but secretion was more gradually and moderately decreased with repeated LPS doses compared to the pro-inflammatory cytokines. The ratios of the anti-inflammatory/pro-inflammatory mediators (IL-1ra/IL-1ß and IL-10/TNF-α) indicate a progressively more anti-inflammatory milieu with repeated LPS doses. CONCLUSION: Repeated LPS exposure of human second-trimester placental tissues induced endotoxin tolerance. We speculate that endotoxin tolerance at the maternal-fetal interface will protect the fetus from exaggerated inflammatory responses after repeated infectious exposure.

The immunological basis of villitis of unknown etiology - review.

Villitis of unknown etiology (VUE) represents a common placental inflammatory lesion, primarily, but not exclusively, identifiable T lymphocytes at term. Despite considerable evidence to contest that this simply represents a benign pathological finding, VUE remains a significantly undervalued diagnosis. Given its association with adverse pregnancy outcomes; including fetal growth restriction, preterm birth, and recurrent pregnancy loss, an increased awareness amongst clinician obstetricians is certainly warranted. The underlying immunopathogenesis of VUE remains uncertain. Despite initial theories that this represents an infectious placental lesion of undiagnosed pathogenic source, a more complex sequence of events involving the "breakdown" of maternal-fetal tolerance is emerging. Characterization of a unique inflammatory phenomenon in which both maternal and fetal T lymphocytes and Höfbauer cells interact has captivated particular research interest and has generated analogies to both the problems of allograft rejection and graft-versus-host disease (GvHD). Within the context of VUE, this review evaluates how disruption of the multidimensional immunological mechanisms underlying feto-maternal tolerance may permit abnormal lymphocyte infiltration into placental villi. We shall review the existing evidence for these events in VUE and outline areas of certain future interest.

Detección de infección por Mycoplasma en las gestantes con riesgo de parto pretérmino / Detection of Mycoplasma infection in pregnants with a risk of preterm delivery

Introducción: el parto pretérmino es el que se produce antes de las 37 sem de gestación; la sepsis vaginal constituye uno de los factores de riesgo predisponentes para este, de ahí que continúe siendo motivo de preocupación para obstetras y neonatólogos. Objetivo: evaluar el uso del Test Mycoplasma System Plus en gestaciones con riesgo de parto pretérmino, así como algunos de sus aspectos clínicos. Métodos: se realizó un estudio retrospectivo descriptivo de enero a septiembre de 2010 en el Hospital Profesor Eusebio Hernández, la muestra estuvo constituida por 88 pacientes ingresadas en el servicio de cuidados especiales perinatales con gestaciones menores de 34 sem a las que se les realizó el test y tuvieron el parto en este centro, los datos fueron recogidos de las historias clínicas e informes de microbiología agrupados en un formulario y procesados mediante estadísticas descriptivas y de distribución de frecuencia. Resultados: el 67 porciento, de las pacientes presentaban infección moderada o severa a ureaplasma mientras que los exudados vaginales simples fueron negativos en un 71,5 porciento, el antimicrobiano más utilizado fue la eritromicina. Conclusiones: la mayoría de las pacientes después del tratamiento adecuado llegaron al término de la gestación, así como presentaban exudados vaginales simple negativos, pero con un alto índice de infección a ureaplasma urealyticum(AU)

Introduction: the pre-term labor is produced before the 37 weeks of pregnancy; the vaginal sepsis is one of the predisposing risk factors to it, being a motive of worry for obstetricians and neonatologists. Objective: to assess the use of Test Mycoplasma System Plus in pregnancies with risk of pre-term labor, as well as of its clinical features. Methods: a descriptive and retrospective study was conducted from January to September, 2010 in the Profesor Eusebio Hernández Hospital; sample included 88 patients admitted in the perinatal special care unit with pregnancies under 34 weeks and performing of test who gave birth in this institution; data were collected from the medical records and microbiology reports grouped in a form and processed by descriptive statistics and of frequency distribution. Results: the 6l7 percent of patients had a moderate or severe infection due to ureaplasma where as the vaginal exudates were negatives in the 71.5 percent, the more used antimicrobial agents was the erythromycin. Conclusions: most of patients after an appropriate treatment arrive to a term pregnancy and also had negative simple vaginal exudate but with a high rate of infection due to ureaplasma urelyticum(AU)

Detección de infección por Mycoplasma en las gestantes con riesgo de parto pretérmino / Detection of Mycoplasma infection in pregnants with a risk of preterm delivery

Introducción: el parto pretérmino es el que se produce antes de las 37 sem de gestación; la sepsis vaginal constituye uno de los factores de riesgo predisponentes para este, de ahí que continúe siendo motivo de preocupación para obstetras y neonatólogos. Objetivo: evaluar el uso del Test Mycoplasma System Plus en gestaciones con riesgo de parto pretérmino, así como algunos de sus aspectos clínicos. Métodos: se realizó un estudio retrospectivo descriptivo de enero a septiembre de 2010 en el Hospital Profesor Eusebio Hernández, la muestra estuvo constituida por 88 pacientes ingresadas en el servicio de cuidados especiales perinatales con gestaciones menores de 34 sem a las que se les realizó el test y tuvieron el parto en este centro, los datos fueron recogidos de las historias clínicas e informes de microbiología agrupados en un formulario y procesados mediante estadísticas descriptivas y de distribución de frecuencia. Resultados: el 67 porciento, de las pacientes presentaban infección moderada o severa a ureaplasma mientras que los exudados vaginales simples fueron negativos en un 71,5 porciento, el antimicrobiano más utilizado fue la eritromicina. Conclusiones: la mayoría de las pacientes después del tratamiento adecuado llegaron al término de la gestación, así como presentaban exudados vaginales simple negativos, pero con un alto índice de infección a ureaplasma urealyticum

Introduction: the pre-term labor is produced before the 37 weeks of pregnancy; the vaginal sepsis is one of the predisposing risk factors to it, being a motive of worry for obstetricians and neonatologists. Objective: to assess the use of Test Mycoplasma System Plus in pregnancies with risk of pre-term labor, as well as of its clinical features. Methods: a descriptive and retrospective study was conducted from January to September, 2010 in the Profesor Eusebio Hernández Hospital; sample included 88 patients admitted in the perinatal special care unit with pregnancies under 34 weeks and performing of test who gave birth in this institution; data were collected from the medical records and microbiology reports grouped in a form and processed by descriptive statistics and of frequency distribution. Results: the 6l7 percent of patients had a moderate or severe infection due to ureaplasma where as the vaginal exudates were negatives in the 71.5 percent, the more used antimicrobial agents was the erythromycin. Conclusions: most of patients after an appropriate treatment arrive to a term pregnancy and also had negative simple vaginal exudate but with a high rate of infection due to ureaplasma urelyticum

Servicio de Medicina Fetal y el Hogar Materno en el seguimiento del embarazo múltiple / Fetal Medicine Service and the maternal home in follow-up of a multiple pregnancy

INTRODUCCIÓN: El embarazo múltiple se asocia a un incremento de la morbimortalidad perinatal. Su incidencia se ha incrementado debido al desarrollo de la reproducción asistida. OBJETIVOS: Identificar el embarazo múltiple y relacionarlo con la edad gestacional al ingreso y al parto; determinar la edad gestacional al parto en relación con el peso de los neonatos; evaluar el momento en que se utilizaron los inductores de la madurez pulmonar fetal y relacionarlo con el síndrome de dificultad respiratoria, así como describir las entidades más frecuentes. MÉTODOS: Se realizó un estudio observacional descriptivo de 566 gestantes, de ellas 40 gemelares ingresadas en el Hogar Materno Ismaelillo entre los años 2006-2009. Se revisaron las historias clínicas y se emplearon los softwares StatGraphic Plus V5 y Excel 2007. RESULTADOS: La gemelaridad constituyó el 7,0 por ciento del total. Entre las que ingresaron antes de las 20 sem la prematuridad fue del 15 por ciento; la incidencia del bajo peso a término fue del 27,5 por ciento; se identificó el síndrome de dificultad respiratoria en el 5,0 por ciento a las 28 sem; la anemia en el 55,0 por ciento y la amenaza de parto pretérmino en el 37,5 por ciento. CONCLUSIONES: El ingreso precoz no guardó relación significativa con el parto pretérmino; predominó el bajo peso a térrmino; el síndrome de dificultad respiratoria fue más frecuente en los grupos en los que se administraron tempranamente los inductores de la madurez pulmonar fetal y la anemia fue la más frecuente (AU)

The multiple pregnancy is associated with an increase of perinatal mortality and morbidity. Its incidence has increased due to the development of the assisted reproduction OBJECTIVES: To identify the multiple pregnancy related to gestational age ad admission and to labor, to determine the gestational age at labor in relation to the neonate weight, to assess the moment to use the fetal pulmonary maturity inductors and relate it to breathlessness and to describe the more frequent entities. METHODS: A descriptive and observational study was performed in 566 pregnants (40 twins) admitted in the Ismaelillo Maternal home between 2006 and 2009. Medical records were reviewed and StatGrahic Puls V5 and Excel 2007 were used. RESULtS: The twinning was the 7.0 percent of total. Among those admitted before twinning was of 15.6 percent; incidence of term low weight was of 27.5 percent; breathlessness syndrome was identified in the 6.0 percent at 28 weeks; anemia in the 55.0 percent and preterm labor threat in the 37.5 percent. CONCLUSIONS: The early admission hasn't a significant relation to the preterm labor, there was predominance of term low weight, where the breathlessness syndrome was the more frequent in groups with early applications of inductors of fetal pulmonary maturity and the anemia was also the more frequent (AU)

Servicio de Medicina Fetal y el Hogar Materno en el seguimiento del embarazo múltiple / Fetal Medicine Service and the maternal home in follow-up of a multiple pregnancy

El embarazo múltiple se asocia a un incremento de la morbimortalidad perinatal. Su incidencia se ha incrementado debido al desarrollo de la reproducción asistida. OBJETIVOS: Identificar el embarazo múltiple y relacionarlo con la edad gestacional al ingreso y al parto; determinar la edad gestacional al parto en relación con el peso de los neonatos; evaluar el momento en que se utilizaron los inductores de la madurez pulmonar fetal y relacionarlo con el síndrome de dificultad respiratoria, así como describir las entidades más frecuentes. MÉTODOS: Se realizó un estudio observacional descriptivo de 566 gestantes, de ellas 40 gemelares ingresadas en el Hogar Materno Ismaelillo entre los años 2006-2009. Se revisaron las historias clínicas y se emplearon los softwares StatGraphic Plus V5 y Excel 2007. RESULTADOS: La gemelaridad constituyó el 7,0 por ciento del total. Entre las que ingresaron antes de las 20 sem la prematuridad fue del 15 por ciento; la incidencia del bajo peso a término fue del 27,5 por ciento; se identificó el síndrome de dificultad respiratoria en el 5,0 por ciento a las 28 sem; la anemia en el 55,0 por ciento y la amenaza de parto pretérmino en el 37,5 por ciento. CONCLUSIONES: El ingreso precoz no guardó relación significativa con el parto pretérmino; predominó el bajo peso a térrmino; el síndrome de dificultad respiratoria fue más frecuente en los grupos en los que se administraron tempranamente los inductores de la madurez pulmonar fetal y la anemia fue la más frecuente (AU)

The multiple pregnancy is associated with an increase of perinatal mortality and morbidity. Its incidence has increased due to the development of the assisted reproduction OBJECTIVES: To identify the multiple pregnancy related to gestational age ad admission and to labor, to determine the gestational age at labor in relation to the neonate weight, to assess the moment to use the fetal pulmonary maturity inductors and relate it to breathlessness and to describe the more frequent entities. METHODS: A descriptive and observational study was performed in 566 pregnants (40 twins) admitted in the Ismaelillo Maternal home between 2006 and 2009. Medical records were reviewed and StatGrahic Puls V5 and Excel 2007 were used. RESULtS: The twinning was the 7,0 percent of total. Among those admitted before twinning was of 15,6 percent; incidence of term low weight was of 27,5 percent; breathlessness syndrome was identified in the 6,0 percent at 28 weeks; anemia in the 55,0 percent and preterm labor threat in the 37,5 percent. CONCLUSIONS: The early admission hasn't a significant relation to the preterm labor, there was predominance of term low weight, where the breathlessness syndrome was the more frequent in groups with early applications of inductors of fetal pulmonary maturity and the anemia was also the more frequent (AU)

Servicio de Medicina Fetal y el Hogar Materno en el seguimiento del embarazo múltiple / Fetal Medicine Service and the maternal home in follow-up of a multiple pregnancy

El embarazo múltiple se asocia a un incremento de la morbimortalidad perinatal. Su incidencia se ha incrementado debido al desarrollo de la reproducción asistida. OBJETIVOS: Identificar el embarazo múltiple y relacionarlo con la edad gestacional al ingreso y al parto; determinar la edad gestacional al parto en relación con el peso de los neonatos; evaluar el momento en que se utilizaron los inductores de la madurez pulmonar fetal y relacionarlo con el síndrome de dificultad respiratoria, así como describir las entidades más frecuentes. MÉTODOS: Se realizó un estudio observacional descriptivo de 566 gestantes, de ellas 40 gemelares ingresadas en el Hogar Materno Ismaelillo entre los años 2006-2009. Se revisaron las historias clínicas y se emplearon los softwares StatGraphic Plus V5 y Excel 2007. RESULTADOS: La gemelaridad constituyó el 7,0 por ciento del total. Entre las que ingresaron antes de las 20 sem la prematuridad fue del 15 por ciento; la incidencia del bajo peso a término fue del 27,5 por ciento; se identificó el síndrome de dificultad respiratoria en el 5,0 por ciento a las 28 sem; la anemia en el 55,0 por ciento y la amenaza de parto pretérmino en el 37,5 por ciento. CONCLUSIONES: El ingreso precoz no guardó relación significativa con el parto pretérmino; predominó el bajo peso a térrmino; el síndrome de dificultad respiratoria fue más frecuente en los grupos en los que se administraron tempranamente los inductores de la madurez pulmonar fetal y la anemia fue la más frecuente

The multiple pregnancy is associated with an increase of perinatal mortality and morbidity. Its incidence has increased due to the development of the assisted reproduction OBJECTIVES: To identify the multiple pregnancy related to gestational age ad admission and to labor, to determine the gestational age at labor in relation to the neonate weight, to assess the moment to use the fetal pulmonary maturity inductors and relate it to breathlessness and to describe the more frequent entities. METHODS: A descriptive and observational study was performed in 566 pregnants (40 twins) admitted in the Ismaelillo Maternal home between 2006 and 2009. Medical records were reviewed and StatGrahic Puls V5 and Excel 2007 were used. RESULtS: The twinning was the 7,0 percent of total. Among those admitted before twinning was of 15,6 percent; incidence of term low weight was of 27,5 percent; breathlessness syndrome was identified in the 6,0 percent at 28 weeks; anemia in the 55,0 percent and preterm labor threat in the 37,5 percent. CONCLUSIONS: The early admission hasn't a significant relation to the preterm labor, there was predominance of term low weight, where the breathlessness syndrome was the more frequent in groups with early applications of inductors of fetal pulmonary maturity and the anemia was also the more frequent