Classification of Preterm Birth With Placental Correlates.

Premature birth lacks a widely accepted classification that unites features of the clinical presentation with placental pathology. To further explore associations between the clinical categories of preterm birth and placental histology, 109 infants with gestational age <34 weeks and birth weight <2000 g were selected and, based on electronic records, were classified into preterm birth categories of preterm labor, prelabor premature rupture of membranes, preeclampsia, indicated preterm birth for maternal factors (other than preeclampsia), indicated preterm birth for fetal factors, and the clinical diagnosis of abruption. Corresponding placentas were analyzed for gross and microscopic variables, with findings grouped into categories of amniotic fluid infection, lymphocytic inflammation, maternal vascular malperfusion, and fetal vascular malperfusion. Placental features of maternal vascular malperfusion were pervasive in all preterm birth categories and were commonly associated with amniotic fluid infection and lymphocytic inflammation. Features of maternal vascular malperfusion were significantly associated with preterm birth due to preeclampsia, and amniotic fluid infection was highly associated with prelabor preterm rupture of membranes. Findings of lymphocytic inflammation were significantly increased in cases of abruption. Laminar decidual necrosis was present in all cases of abruption. Placentas from multiple gestations had significantly less histologic findings compared to singletons. Given that 75% of placentas demonstrated at least 1 feature of maternal vascular malperfusion despite different clinical presentations, seemingly different pathologies such as ascending amniotic fluid infection or lymphocytic inflammation may be mechanistically related to processes established early in pregnancy. The concept of "uterine ischemia" may be too simplistic to account for all of the changes attributed to maternal vascular malperfusion in the preterm placenta.

Factores etiopatogénicos de la prematuridad en el hospital universitario Sant Joan de Déu de Barcelona / Etiopathogenic factors of prematurity in the Sant Joan de Déu Hospital in Barcelona (Spain)

Objetivo. Determinar la tasa de partos prematuros durante el 2010 en el Hospital Universitario Sant Joan de Déu de Barcelona, y clasificarlos según la causa principal utilizando un algoritmo de asignación etiológica para establecer las principales causas de parto prematuro. Sujetos y métodos. Se revisan todos los partos prematuros de menos de 37 semanas de gestación que se producen en el Hospital Universitario Sant Joan de Déu de Barcelona durante 2010 (396 casos), y se les asigna un grupo de etiología principal. Resultados. La tasa de parto prematuro es de 9,8%. Las causas inflamatorias representan el 36% de todos los partos prematuros seguidas de las causas idiopáticas (29%). En los partos prematuros de gestaciones múltiples las causas inflamatorias alcanzan el 44%. Conclusiones. Las causas inflamatorias son la principal etiología de parto prematuro, siendo más frecuente en las gestaciones múltiples (AU)

Objective. To determine the rate of preterm births in 2010 at the Sant Joan de Déu University Hospital in Barcelona, and classify them according to the main cause by using a mapping algorithm to establish the main etiological causes of preterm birth. Subjects and methods. All preterm births at less than 37 weeks’ gestation occurring in the Sant Joan de Déu University Hospital in 2010 (n=396) were reviewed and assigned to a group according to their primary etiology. Results. The preterm birth rate was 9.8%. Inflammatory causes accounted for 36% of all preterm births followed by idiopathic causes (29%). In preterm deliveries of multiple gestations, inflammatory causes accounted for 44%. Conclusions. Inflammatory causes are the main etiology of preterm births and are more common in multiple gestations (AU)

Complicaciones a corto plazo de los recién nacidos pretérmino tardíos / Short-term complications of late preterm infants

Introducción: Los recién nacidos pretérmino tardíos, entre las 34-36+6 semanas de edad gestacional son fisiológicamente más inmaduros que los recién nacidos a término y, por tanto, tienen mayor riesgo de morbi-mortalidad. Dado que los resultados de salud en la prematuridad pueden variar en función de factores locales nos hemos propuesto conocer en nuestro medio las complicaciones que presentan a corto plazo estos recién nacidos. Pacientes y métodos: Estudio observacional retrospectivo de los recién nacidos ≥ 34 semanas de edad gestacional ingresados en el Hospital Virgen del Rocío desde Mayo de 2005 hasta diciembre de 2008. Dividimos la población en dos grupos: pretérmino tardío (34-36+6 semanas de edad gestacional, n = 769) y a término (37-41+6 semanas de edad gestacional, n = 1.460) comparando la mortalidad y la morbilidad a corto plazo entre los dos grupos. Resultados: La prematuridad tardía se asoció con la reproducción asistida, la gestación gemelar, la preclampsia materna y el parto por cesárea. El riesgo de ingreso hospitalario fueseis veces mayor en estos recién nacidos, siendo cerca de dos veces mayor la necesidad de ingreso en la unidad de cuidados intensivos neonatal. El tiempo de estancia hospitalaria fue el doble en este grupo. En cuanto a los motivos de ingresos, se evidenció una mayor incidencia de distrés respiratorio e ictericia. La necesidad de surfactante, oxigenoterapia y soporte respiratorio (presión positiva continua en la vía aérea y ventilación mecánica convencional) fue igualmente mayor. No hubo diferencias significativas entre ambos grupos en relación con la presencia de hipoglucemia que precisara ingreso ni en cuanto a la mortalidad neonatal. Conclusiones: Los recién nacidos pretérmino tardíos de nuestro medio representan un colectivo bien definido de riesgo de presentar complicaciones por lo que deben disponerse los recursos necesarios para su atención diferenciada (AU)

Introduction: Late preterm infants, born at 34-36+6 weeks gestation, are physiologically more immature than term infants. As a consequence, they have an increased risk of morbidity and mortality. Since health outcomes in prematurity may change depending on local factors we have proposed determine the short-term medical problems of these infants in our hospital. Patients and methods: A retrospective observational study was carried out on all newborn ≥ 34 weeks gestation admitted to Virgen del Rocio hospital from May 2005 to December 2008. We divided this cohort into late preterm (34-36+6 weeks, n = 769) and term (37-41+6 weeks, n = 1460) groups. We compared mortality and morbidity data between the 2 groups. Results: Late preterm group was associated with assisted reproduction, twin pregnancy, caesarean delivery and preeclampsia during pregnancy. The risk of hospitalization was six times greater in these infants and neonatal intensive care admissions were twice as common. The hospital stay was double in this group. Neonatal respiratory morbidity and jaundice were greater in the preterm group. The use of surfactant, oxygen and respiratory support (CPAP and CMV ) was also higher. There were no significant differences in hypoglycaemia and neonatal mortality between both groups. Conclusions: Late preterm infants represent a well-defined risk group for developing complications and should be available the necessary resources should be made available for their special care (AU)

Metabolomics in premature labor: a novel approach to identify patients at risk for preterm delivery.

OBJECTIVE: Biomarkers for preterm labor (PTL) and delivery can be discovered through the analysis of the transcriptome (transcriptomics) and protein composition (proteomics). Characterization of the global changes in low-molecular weight compounds which constitute the 'metabolic network' of cells (metabolome) is now possible by using a 'metabolomics' approach. Metabolomic profiling has special advantages over transcriptomics and proteomics since the metabolic network is downstream from gene expression and protein synthesis, and thus more closely reflects cell activity at a functional level. This study was conducted to determine if metabolomic profiling of the amniotic fluid can identify women with spontaneous PTL at risk for preterm delivery, regardless of the presence or absence of intraamniotic infection/inflammation (IAI). STUDY DESIGN: Two retrospective cross-sectional studies were conducted, including three groups of pregnant women with spontaneous PTL and intact membranes: (1) PTL who delivered at term; (2) PTL without IAI who delivered preterm; and (3) PTL with IAI who delivered preterm. The first was an exploratory study that included 16, 19, and 20 patients in groups 1, 2, and 3, respectively. The second study included 40, 33, and 40 patients in groups 1, 2, and 3, respectively. Amniotic fluid metabolic profiling was performed by combining chemical separation (with gas and liquid chromatography) and mass spectrometry. Compounds were identified using authentic standards. The data were analyzed using discriminant analysis for the first study and Random Forest for the second. RESULTS: (1) In the first study, metabolomic profiling of the amniotic fluid was able to identify patients as belonging to the correct clinical group with an overall 96.3% (53/55) accuracy; 15 of 16 patients with PTL who delivered at term were correctly classified; all patients with PTL without IAI who delivered preterm neonates were correctly identified as such (19/19), while 19/20 patients with PTL and IAI were correctly classified. (2) In the second study, metabolomic profiling was able to identify patients as belonging to the correct clinical group with an accuracy of 88.5% (100/113); 39 of 40 patients with PTL who delivered at term were correctly classified; 29 of 33 patients with PTL without IAI who delivered preterm neonates were correctly classified. Among patients with PTL and IAI, 32/40 were correctly classified. The metabolites responsible for the classification of patients in different clinical groups were identified. A preliminary draft of the human amniotic fluid metabolome was generated and found to contain products of the intermediate metabolism of mammalian cells and xenobiotic compounds (e.g. bacterial products and Salicylamide). CONCLUSION: Among patients with spontaneous PTL with intact membranes, metabolic profiling of the amniotic fluid can be used to assess the risk of preterm delivery in the presence or absence of infection/inflammation.

A subset of patients destined to develop spontaneous preterm labor has an abnormal angiogenic/anti-angiogenic profile in maternal plasma: evidence in support of pathophysiologic heterogeneity of preterm labor derived from a longitudinal study.

OBJECTIVE: An imbalance between angiogenic and anti-angiogenic factors in maternal blood has been observed in several obstetrical syndromes including preeclampsia, pregnancies with fetal growth restriction and fetal death. Vascular lesions have been identified in a subset of patients with spontaneous preterm labor (PTL). It is possible that PTL may be one of the manifestations of an anti-angiogenic state. The aim of this study was to determine if patients prior to the clinical diagnosis of PTL leading to preterm delivery had plasma concentrations of angiogenic and anti-angiogenic factors different from normal pregnant women. STUDY DESIGN: This longitudinal nested case-control study included normal pregnant women (n = 208) and patients with PTL leading to preterm delivery (n = 52). Maternal blood samples were collected at 6 gestational age intervals from 6 to 36.9 weeks of gestation. The end point (time of diagnosis) of the study, 'True PTL', was defined as patients presenting with PTL and delivered within 1 day. Plasma concentrations of sVEGFR-1, sVEGFR-2, sEng and PlGF were determined by ELISA. Analysis was performed with both cross-sectional and longitudinal (mixed effects model) approaches. RESULTS: (1) Plasma sEng concentration in patients destined to develop PTL was higher than that in normal pregnant women from 15-20 weeks of gestation. The difference became statistical significant at 28 weeks of gestation, or approximately 5-10 weeks prior to the diagnosis of 'true PTL'. (2) Backward analysis suggests that plasma concentrations of PlGF and sVEGFR-2 were lower, and those of sVEGFR-1 were higher in patients with PTL than in normal pregnant women less than 5 weeks prior to the diagnosis of 'true PTL'; and (3) Plasma concentrations of sEng and sVEGFR-1 were higher and those of PlGF and sVEGFR-2 were lower in patients diagnosed with PTL and delivery within 1 day than in normal pregnant women who delivered at term. CONCLUSION: The changes in sEng are demonstrable several weeks prior to the onset of preterm parturition. In contrast, the changes in the other angiogenic proteins are present close to the onset of PTL and delivery. This observation supports the view that an imbalance of angiogenic factors participates in the pathophysiology of spontaneous preterm parturition.

Epidemiology of preterm birth and its clinical subtypes.

Preterm birth (<37 weeks) complicates 12.5% of all deliveries in the USA, and remains the leading cause of perinatal mortality and morbidity, accounting for as many as 75% of perinatal deaths. Despite the recent temporal increase in preterm birth, efforts to understand the problem of prematurity have met with little success. This may be attributable to the under-appreciation of the etiologic heterogeneity of preterm birth as well as the heterogeneity in its underlying clinical presentations--spontaneous onset of labor, preterm premature rupture of membranes, and medically indicated preterm birth. In this paper, we review data regarding preterm births with particular focus on its incidence, temporal trends, and recurrence. Studies of births from the USA indicate that the recent temporal increase in the overall preterm birth rate is driven by an impressive concomitant increase in medically indicated preterm birth. However, the largest temporal decline in perinatal mortality has also occurred among medically indicated preterm births (relative to other clinical subtypes), suggesting that these obstetric interventions at preterm gestational ages are associated with a reduction in perinatal mortality. Recent data indicate that spontaneous preterm birth is not only associated with increased recurrence of spontaneous, but also medically indicated, preterm birth, and vice versa. This suggests that the clinical subtypes may share common underlying etiologies. Since medically indicated preterm birth accounts for as many as 40% of all preterm births, efforts to understand the reasons for such interventions and their impact on short- and long-term morbidity in newborns is compelling. Further research is necessary in order to understand the mechanisms and etiology of preterm birth, thus leading to the possibility of effective preventive or therapeutic strategies.

Defining the problem: the epidemiology of preterm birth.

Preterm birth is the major clinical problem associated with perinatal mortality, serious neonatal morbidity and moderate to severe childhood disability in prosperous countries. Its prevalence is affected by the way in which gestational age is assessed, by national differences in the registration of births, associated practices, such as burial costs, or maternity benefits, which encourage or discourage registration, and by the perceived viability of extremely preterm infants. Despite these uncertainties, there is reliable evidence that preterm births are increasing, especially births before 28 weeks gestation. Contributing factors include births following assisted reproductive therapy and ovulation induction, especially multiple births, and the increasing proportion of births among women >34 years. On the other hand, improvements in neonatal care have substantially increased the survival of preterm infants during the last 15 years. There is wider acceptance of the importance of infection as a factor in preterm birth, and increasing recognition that processes leading to preterm birth may be initiated in very early pregnancy (the initiation of pre-eclampsia, major birth defects, premature placental separation), or even prior to pregnancy (prior pregnancy losses). It is unclear whether the familiar clinical presentations of preterm labour and birth reflect different pathophysiological processes. The pathways which link those processes to the consistent pattern of social differences in the probability of preterm birth have prompted new research approaches but in 2002 'the stubborn challenge of preterm birth' remains just that.

Classification and heterogeneity of preterm birth.

Three main conditions explain preterm birth: medically indicated (iatrogenic) preterm birth (25%; 18.7-35.2%), preterm premature rupture of membranes (PPROM) (25%; 7.1-51.2%) and spontaneous (idiopathic) preterm birth (50%; 23.2-64.1%). The majority of multiple pregnancies (10% of all preterm births) are delivered preterm (50% for medical reasons). Although medical indications relate more to feto-maternal conditions, PPROM to infections and idiopathic preterm birth to lifestyle, these risk factors are identified in any category, emphasising that preterm birth has a multifactorial origin. Still, several incidences of preterm birth are not completely explained with a plausible cause for PPROM or spontaneous preterm labour suggesting that other causes have yet to be identified. In addition, preterm birth is associated with unrecognised severe congenital anomalies. Variability within the main categories may be explained by the studied population, ethnic group, social class and preventive interventions towards reducing spontaneous preterm birth where the proportion of medically-indicated preterm birth is increased. Despite being retrospective a classification according to gestational age at birth is important for neonatal prognosis. Preterm birth is stratified into mild preterm (32-36 weeks), very preterm (28-31 weeks) and extremely preterm (<28 weeks) with increasing neonatal mortality and morbidity. Recent studies suggested that infection was mostly responsible for extreme preterm birth, while stress and lifestyle accounted for mild preterm birth, and a mixture of both conditions contributed to very preterm birth.

Contribución de la prematurez extrema, moderada y leve a la mortalidad neonatal / Contribution of the extreme prematurity, moderate and mild at neonatal mortality

Objetivos: Estimar la contribución del parto prematuro extremo (EG 28-31), moderado (32-33) y leve (34-36 semanas) a la mortalidad neonatal. Métodos: Diseño caso-control de una cohorte hospitalaria. Población: 16.159 registros del Sistema Informático Perinatal del Hospital Materno Infantil Ramón Sardá de Buenos Aires (1992-1994). Resultados Principales: Riesgo crudo, Riesgo Relativo y Riesgo Atribuible Poblacional de la Mortalidad Neonatal Precoz (0-6 días), Tardía (7-27 días) y Postneonatal (= o >28 días) hasta el egreso hospitalario para los Prematuros Extremos, Moderados y Leves nomalformados (n=2192) en comparación con los RN al término (= o >37 semanas; n= 13.967). Resultados: Tasa de prematurez: 13.5 por ciento. Riesgo crudo de muerte neonatal global entre Prematuros Extremos, Moderados y Leves: 368, 12.4 y 6.1 por mil respectivamente. El RR de Mortalidad Neonatal Precoz fue de 445 (IC 95 por ciento 266-758), 12,1 (4-36) y 6.7 (3.1-14.4) para prematuros Extremos, Moderados y Leves respectivamente. El RAP para la Mortalidad Neonatal Precoz fue de 88 por ciento, 19 por ciento y 37 por ciento, respectivamente, para la prematurez Extrema, Moderada y Leve. Los correspondientes RAP para la Mortalidad Neonatal Tardía fueron 55 por ciento, 20 por ciento y 21 por ciento respectivamente. Conclusiones: En los países en desarrollo el parto prematuro continúa siendo uno de los mayores problemas de salud pública. El prematuro leve, y especialmente el moderado, presentan un elevado RR de muerte durante los primeros 28 días y son responsables de una importante fracción de la mortalidad neonatal precoz y tardía. (AU)

Comparative accuracy of clinical estimate versus menstrual gestational age in computerized birth certificates.

OBJECTIVE: This study compares gestational age data obtained by clinical estimate with data calculated from the date of the last menstrual period (LMP) as recorded on birth certificates. METHODS: The authors analyzed 476,034 computerized birth records from three overlap years, that is, those that contained both menstrual and clinical estimates of gestational age, concentrating on cases within the biologically plausible range of 20-44 weeks. RESULTS: The overall exact concordance between the two measurements was 46%. For +1 week it was 78%, and for +2 weeks it was 87%. Incidence of prematurity was 16% with menstrual gestational age, while it was 12% with clinical estimate. About 47% of the LMP-based preterm births were classified as term by clinical estimate. Eighty-three percent of clinical estimate-based preterms were also preterms by LMP-based gestation. Birthweight frequency distribution curves for LMP-based gestational age are bimodal, indicating probable miscoding of term births. An apparent over-representation of births coded as exactly 40 weeks by clinical estimate suggests rounding off near term for this method. CONCLUSION: Agreement between menstrual and clinical estimates of gestational age occurs most often close to term, with significant disagreement in preterm and postterm births. Use of different methods of determining gestation in different years or geographic populations will result in artifactual differences in important indicators such as prematurity rate.

Defining preterm delivery--the epidemiology of clinical presentation.

It is possible that preterm delivery is not a single entity but a cluster of conditions with different aetiologies that ultimately result in the delivery of an infant before 37 completed weeks of gestation. Whereas some researchers have reported aetiological heterogeneity, others have found no differences between subtypes or have disputed the desirability and utility of classifying preterm birth into subtypes. This study explores the relationship of maternal risk factors to type of preterm delivery in a cohort of over 7000 black and white women delivering singleton infants at the University of California, San Francisco's Moffitt Hospital between 1980 and 1990. Although the magnitude of the effect of individual risk factors differed between preterm delivery subtypes, the set of risk factors significantly associated with both categories of spontaneous preterm delivery was identical, while that associated with medically indicated preterm births was different. This study indicates that whereas the distinction between spontaneous preterm deliveries and those that are medically indicated seems valid, distinguishing between types of spontaneous preterm births may not lead to useful aetiological inferences.

The role of life events in different categories of preterm birth in a group of women with previous poor pregnancy outcome.

The aim of the present study was to determine whether mothers reporting more life events experience more preterm births following both complicated and uncomplicated pregnancies. A Life Events Inventory was administered prospectively to women at high risk for poor obstetric and neonatal outcomes who took part in the Pregnancy Home Visiting Program (PHVP), a randomized controlled trial of the effect of a programme of antenatal home visits by midwives on the incidence of preterm birth. This study took place in Western Australia in the years 1984-1987. All women in the study had had a previous poor pregnancy outcome. The women were classified into two groups--those with complicated and those with uncomplicated pregnancies. Pregnancies classified as 'complicated' were defined as a pregnancy in which there was antenatal hospital admission(s) for hypertension, antepartum haemorrhage or other medical reason except for preterm birth. Pregnancies classified as 'uncomplicated' refer to all pregnancies without these complications. No significant association was found between life events and preterm birth although the total stress score for women with uncomplicated pregnancies almost reached significance, as did the number of life events for both women with complicated and women with uncomplicated pregnancies considered together. Life events were not shown to have a predictive relationship to preterm birth even when stratified by etiologically different groups. However, although stress was not an important predictor of preterm birth in this group of women at biological risk it may yet be so in a group at social risk.

[Etiologic classification of premature labor and its importance for prevention]. / Atiologische Klassifikation der Frühgeburt und ihre Bedeutung für die Prävention.

A retrospective analysis of 202 premature deliveries before 37 weeks was performed to identify major pathologies related to preterm delivery. The most frequent pathologies were premature rupture of membranes (32.4%), premature labour without recognisable aetiology (19.1%), hypertensive diseases in pregnancy (15.6%), multiple pregnancies (14.4%), malformations (9.8%) and bleeding in the 3rd trimester (6.4%). The majority of premature deliveries are related to 4 major pathogenetic disturbances: infection, problems of placentation, pathology of the foetus, pathology of the uterus. Each of these pathologies can lead to premature delivery via premature labour, premature rupture of membranes or termination of pregnancy for foetal or maternal pathology. In one third of premature labour, in another preterm premature rupture of membranes with labour after a variable latent period led to delivery, and in the remaining third, delivery was performed by a primary caesarean section or induction of labour for foetal or maternal pathology. Less than 25% cases were considered as failures of tocolytic treatment. Tocolytics, steroids or antibiotics, may help to improve the survival-rate in particular with very low birth-weight infants at less than 30 weeks gestation. A decrease in the overall rate of prematurity can be achieved only by a general improvement of the socio-economic working and living conditions of the female population, in particular of pregnant women.

Classification of threatened premature labor related to treatment with a prostaglandin inhibitor: indomethacin.

68 patients complaining of premature uterine contractions were treated with a prostaglandin synthetase inhibitor--indomethacin. This agent had a marked effect on uterine contractions suppressing them completely after 1--8 h from the administration of the drug. Classificaiton of the premature contractions according to a scoring system method is analyzed in this study. The score classified the patients into three groups and enabled us to treat them with a correct dosage and period according to the clinical findings at admission of the patients. Indomethacin treatment was effective in all the 68 patients. The drug was well tolerated by all the patients with minimal side effects. The outcome of the newborns was satisfactory, and laboratory tests on various systems of the pregnant women and newborns were normal during and after treatment with indomethacin.