A randomized controlled trial on the use of pessary plus progesterone to prevent preterm birth in women with short cervical length (P5 trial).

BACKGROUND: Preterm birth is the leading cause of mortality and disability in newborn and infants. Having a short cervix increases the risk of preterm birth, which can be accessed by a transvaginal ultrasound scan during the second trimester. In women with a short cervix, vaginal progesterone and pessary can both reduce this risk, which progesterone more established than cervical pessary. The aim of this study is to compare the use of vaginal progesterone alone versus the association of progesterone plus pessary to prevent preterm birth in women with a short cervix. METHODS: This is a pragmatic open-label randomized controlled trial that will take place in 17 health facilities in Brazil. Pregnant women will be screened for a short cervix with a transvaginal ultrasound between 18 0/7 until 22 6/7 weeks of gestational age. Women with a cervical length below or equal to 30 mm will be randomized to the combination of progesterone (200 mg) and pessary or progesterone (200 mg) alone until 36 + 0 weeks. The primary outcome will be a composite of neonatal adverse events, to be collected at 10 weeks after birth. The analysis will be by intention to treat. The sample size is 936 women, and a prespecified subgroup analysis is planned for cervical length (= < or > 25 mm). Categorical variables will be expressed as a percentage and continuous variables as mean with standard deviation. Time to delivery will be assessed with Kaplan-Meier analysis and Cox proportional hazard analysis. DISCUSSION: In clinical practice, the combination of progesterone and pessary is common however, few studies have studied this association. The combination of treatment might act in both the biochemical and mechanical routes related to the onset of preterm birth. TRIAL REGISTRATION: Brazilian Clinical Trial Registry (ReBec) RBR-3t8prz, UTN: U1111-1164-2636, 2014/11/18.

Methodological issues on planning and running the Brazilian Multicenter Study on Preterm Birth.

OBJECTIVES: Assuming that the occurrence of preterm births and their maternal and neonatal associated conditions in Brazil are not completely known, a multicenter study was proposed. The purpose of this paper is to describe the methods used, its processes, achievements, and challenges. STUDY DESIGN: A multicenter cross-sectional study on preterm births in Brazilian facilities plus a nested case-control study to assess their associated factors. A description of all steps of planning and implementing such a nationwide study, including strategies for dealing with problems arising during the process, is presented. RESULTS: 20 referral hospitals in different regions of Brazil participated in the study. A detailed questionnaire for data collection, an electronic platform for data transcription and monitoring, research materials, and specific monitoring tools were developed; then data management and analyses were performed. Finally, we got information on 4,150 preterm births and 1,146 term births. CONCLUSIONS: This study represented the first step of a planned comprehensive assessment of preterm birth in Brazil, with detailed information that will lead to several analyses and further studies, bringing the knowledge to improve screening, diagnosis, and treatment practices in maternal and perinatal health with the final purpose of reducing the burden of this condition in the country.

Intracluster correlation coefficients for the Brazilian Multicenter Study on Preterm Birth (EMIP): methodological and practical implications.

BACKGROUND: Cluster-based studies in health research are increasing. An important characteristic of such studies is the presence of intracluster correlation, typically quantified by the intracluster correlation coefficient (ICC), that indicate the proportion of data variability that is explained by the way of clustering. The purpose of this manuscript was to evaluate ICC of variables studied in the Brazilian Multicenter Study on Preterm Birth. METHODS: This was a multicenter cross-sectional study on preterm births involving 20 referral hospitals in different regions of Brazil plus a nested case-control study to assess associated factors with spontaneous preterm births. Estimated prevalence rates or means, ICC with 95% confidence intervals, design effects and mean cluster sizes were presented for more than 250 maternal and newborn variables. RESULTS: Overall, 5296 cases were included in the study (4,150 preterm births and 1,146 term births). ICC ranged from <0.001 to 0.965, with a median of 0.028. For descriptive characteristics (socio-demographic, obstetric history and perinatal outcomes) the median ICC was 0.014, for newborn outcomes the median ICC was 0.041 and for process variables (clinical management and delivery), it was 0.102. ICC was <0.1 in 78.4% of the variables and <0.3 for approximately 95% of them. Most of ICC >0.3 was found in some clinical management aspects well defined in literature such as use of corticosteroids, indicating there was homogeneity in clusters for these variables. CONCLUSIONS: Clusters selected for Brazilian Multicenter Study on Preterm Birth had mainly heterogeneous findings and these results can help researchers estimate the required sample size for future studies on maternal and perinatal health.

Non-immune hydrops fetalis: A prospective study of 53 cases.

Non-immune hydrops fetalis (NIHF) is a symptom caused by a heterogeneous group of conditions. Diagnostic investigations may constitute a real challenge. This study aimed to evaluate prospectively and systematically a series of NIHF cases using a research protocol expanded for studying inborn errors of metabolism (IEM) during 2 years-2010 and 2011. We also reviewed the frequency of IEM among the NIHF reported in literature. A clinical or etiopathogenic diagnosis was reached in 46 (86.8%) of the 53 studied cases. The main diagnostic groups were chromosomal anomalies (28.3%), syndromic (18.9%), isolated cardiovascular anomaly (7.5%) and congenital infection (7.5%). Metabolic causes were found in 5.7%, all lysosomal storage disorders (LSD). In seven (13.2%), no diagnosis was found in part because of incomplete evaluation. The hydrops was identified prenatally in 90.5% of cases. In 5.7% a spontaneous and complete resolution of the hydrops occurred during pregnancy. Overall mortality was 75.5%. The IEM frequency in the present study (5.7%) was higher than that usually reported. We suggest performing studies directed to IEMs if the more common causes are excluded.

Brazilian multicenter study on prevalence of preterm birth and associated factors.

BACKGROUND: The occurrence of preterm birth remains a complex public health condition. It is considered the main cause of neonatal morbidity and mortality, resulting in a high likelihood of sequelae in surviving children. With variable incidence in several countries, it has grown markedly in the last decades. In Brazil, however, there are still difficulties to estimate its real occurrence. Therefore, it is essential to establish the prevalence and causes of this condition in order to propose prevention actions. This study intend to collect information from hospitals nationwide on the prevalence of preterm births, their associated socioeconomic and environmental factors, diagnostic and treatment methods resulting from causes such as spontaneous preterm labor, prelabor rupture of membranes, and therapeutic preterm birth, as well as neonatal results. METHODS/DESIGN: This proposal is a multicenter cross-sectional study plus a nested case-control study, to be implemented in 27 reference obstetric centers in several regions of Brazil (North: 1; Northeast: 10; Central-west: 1; Southeast: 13; South: 2). For the cross sectional component, the participating centers should perform, during a period of six months, a prospective surveillance of all patients hospitalized to give birth, in order to identify preterm birth cases and their main causes. In the first three months of the study, an analysis of the factors associated with preterm birth will also be carried out, comparing women who have preterm birth with those who deliver at term. For the prevalence study, 37,000 births will be evaluated (at term and preterm), corresponding to approximately half the deliveries of all participating centers in 12 months. For the case-control study component, the estimated sample size is 1,055 women in each group (cases and controls). The total number of preterm births estimated to be followed in both components of the study is around 3,600. Data will be collected through a questionnaire all patients will answer after delivery. The data will then be encoded in an electronic form and sent online by internet to a central database. The data analysis will be carried out by subgroups according to gestational age at preterm birth, its probable causes, therapeutic management, and neonatal outcomes. Then, the respective rates, ratios and relative risks will be estimated for the possible predictors. DISCUSSION: These findings will provide information on preterm births in Brazil and their main social and biological risk factors, supporting health policies and the implementation of clinical trials on preterm birth prevention and treatment strategies, a condition with many physical and emotional consequences to children and their families.

The role of maternal infection in preterm birth: evidence from the Brazilian Multicentre Study on Preterm Birth (EMIP).

OBJECTIVES: Evidence suggests that infection or inflammation is a major contributor to early spontaneous preterm birth (sPTB). Therefore, this study aimed to investigate the development and causes of maternal infection associated with maternal and neonatal outcomes in women with sPTB. METHODS: This was a secondary analysis of a multicenter cross-sectional study with a nested case-control component, the Brazilian Multicentre Study on Preterm Birth (EMIP), conducted from April 2011 to July 2012 in 20 Brazilian referral obstetric hospitals. Women with preterm birth (PTB) and their neonates were enrolled. In this analysis, 2,682 women undergoing spontaneous preterm labor and premature pre-labor rupture of membranes were included. Two groups were identified based on self-reports or prenatal or hospital records: women with at least one infection factor and women without any maternal infection (vulvovaginitis, urinary tract infection, or dental infection). A bivariate analysis was performed to identify potential individual risk factors for PTB. The odds ratios (ORs) with their respective 95% confidence intervals were calculated. RESULTS: The majority of women with sPTB fulfilled at least one criterion for the identification of maternal infection (65.9%), and more than half reported having urinary tract infection during pregnancy. Approximately 9.6% of women with PTB and maternal infection were classified as having periodontal infection only. Apart from the presence of a partner, which was more common among women with infectious diseases (p=0.026; OR, 1.28 [1.03-1.59]), other variables did not show any significant difference between groups. CONCLUSION: Maternal infection was highly prevalent in all cases of sPTBs, although it was not clearly associated with the type of PTB, gestational age, or any adverse neonatal outcomes.

Maternal and perinatal outcomes and factors associated with twin pregnancies among preterm births: Evidence from the Brazilian Multicenter Study on Preterm Birth (EMIP).

OBJECTIVE: To compare maternal and perinatal outcomes between twin and single preterm births (PTB) and associated factors. METHODS: A cross-sectional multicenter study was conducted in Brazil with 4046 PTBs from April 2011 to July 2012. Causes of PTB, use of tocolytics, corticosteroids, and antibiotics in twin and single pregnancies, and factors possibly associated with twinning were evaluated using χ2 tests. Maternal and perinatal outcomes were assessed with prevalence ratios (PR). RESULTS: The main cause of PTB in twin pregnancy was spontaneous onset of preterm labor. Tocolytics were more frequently used in twins (26.9% vs 20.2%). Factors associated with PTB in twins were: maternal age >25 years (62.3% vs 53.4%); interpregnancy interval >3 years (39.0% vs 33.4%); no history of PTB (87.4% vs 79.6%); no previous maternal conditions (78.0% vs 73.3%); no alcohol abuse (88.5% vs 84.3%); no drug addiction (97.5% vs 94.5%); and >6 prenatal visits (46.5% vs 37.6%). Twin pregnancies run a 46% higher risk of cesarean delivery, while first and second twins face a 20% higher risk of low birth weight. Twin pregnancies run increased risks for admission to the NICU, cerebral hemorrhage, necrotizing enterocolitis, and any adverse perinatal outcome. CONCLUSION: Preterm twin birth is associated with low birth weight and worse neonatal outcomes.

Maternal Work and Spontaneous Preterm Birth: A Multicenter Observational Study in Brazil.

Spontaneous preterm birth (sPTB) is a major pregnancy complication involving biological, social, behavioural and environmental mechanisms. Workload, shift and intensity may play a role in the occurrence of sPTB. This analysis is aimed addressing the effect of occupational activities on the risk for sPTB and the related outcomes. We conducted a secondary analysis of the EMIP study, a Brazilian multicentre cross-sectional study. For this analysis, we included 1,280 singleton sPTB and 1,136 singleton term birth cases. Independent variables included sociodemographic characteristics, clinical complications, work characteristics, and physical effort devoted to household chores. A backward multiple logistic regression analysis was applied for a model using work characteristics, controlled by cluster sampling design. On bivariate analysis, discontinuing work during pregnancy and working until the 7th month of pregnancy were risks for premature birth while working during the 8th - 9th month of pregnancy, prolonged standing during work and doing household chores appeared to be protective against sPTB during pregnancy. Previous preterm birth, polyhydramnios, vaginal bleeding, stopping work during pregnancy, or working until the 7th month of pregnancy were risk factors in the multivariate analysis. The protective effect of variables compatible with exertion during paid work may represent a reverse causality. Nevertheless, a reduced risk associated with household duties, and working until the 8th-9th month of pregnancy support the hypothesis that some sort of physical exertion may provide actual protection against sPTB.

Role of Body Mass Index and gestational weight gain on preterm birth and adverse perinatal outcomes.

The association of body mass index (BMI) and gestational weight gain (GWG) with preterm birth (PTB) remains controversial in the literature. To evaluate different maternal BMI and GWG categories, according to the initial BMI, in relation to different PTB subtypes and perinatal outcomes, we conducted a secondary analysis of a multicentre cross-sectional study, along with a nested case-control study including PTB from 20 centers in Brazil. Pre-pregnancy underweight was associated with a lower risk of provider-initiated PTB, while overweight and obesity were associated with a higher risk of provider-initiated PTB and a lower risk of spontaneous preterm birth. Insufficient gestational weight gain was associated with a higher prevalence of spontaneous PTB and preterm premature rupture of membranes. Excessive GWG correlated with a higher prevalence of provider-initiated PTB or preterm premature rupture of membranes. Irrespective of the initial BMI, the greater the rate of GWG, the higher the predicted probability of all PTB subtypes, except for spontaneous PTB in underweight women and those with normal BMI. On multivariate analysis, the initial BMI was shown to be the only factor associated with pi-PTB. Briefly, further studies evaluating the risk for PTB should consider that GWG may have a different role depending on the initial BMI and PTB subtype.

Evaluation of prenatal corticosteroid use in spontaneous preterm labor in the Brazilian Multicenter Study on Preterm Birth (EMIP).

OBJECTIVE: To evaluate prenatal corticosteroid use in women experiencing spontaneous preterm labor and preterm delivery. METHODS: The present cross-sectional multicenter study analyzed interview data from patients attending 20 hospitals in Brazil owing to preterm delivery between April 1, 2011 and July 30, 2012. Patients were stratified based on preterm delivery occurring before 34 weeks or at 34-36+6  weeks of pregnancy, and the frequency of prenatal corticosteroid use at admission was compared. Prenatal corticosteroid use, sociodemographic data, obstetric characteristics, and neonatal outcomes were examined. RESULTS: There were 1455 preterm deliveries included in the present study; 527 (36.2%) occurred before 34 weeks of pregnancy and prenatal corticosteroids were used in 285 (54.1%) of these pregnancies. Among neonates delivered at 32-33+6  weeks, prenatal corticosteroid use was associated with lower pneumonia (P=0.026) and mortality (P=0.029) rates. Among neonates delivered at 34-36+6  weeks, prenatal corticosteroid use was associated with longer neonatal hospital admission (P<0.001), and an increased incidence of 5-minute Apgar scores below 7 (P=0.010), endotracheal intubation (P=0.042), surfactant use (P=0.006), neonatal morbidities (P=0.048), respiratory distress (P=0.048), and intraventricular hemorrhage (P=0.023). CONCLUSION: Preterm labor and late preterm delivery were associated with worse neonatal outcomes following prenatal corticosteroids. This could reflect a sub-optimal interval between administration and delivery.

The Burden of Provider-Initiated Preterm Birth and Associated Factors: Evidence from the Brazilian Multicenter Study on Preterm Birth (EMIP).

BACKGROUND: About 15 million children are born under 37 weeks of gestation worldwide. Prematurity is the leading cause of neonatal deaths and short/long term morbidities, entailing consequences not only for the individual, but also their family, health agencies, facilities and all community. The provider-initiated preterm birth is currently one of the most important obstetric conditions related to preterm births, particularly in middle and high income countries, thus decreasing the need for therapeutic preterm birth is essential to reduce global prematurity. Therefore detailed knowledge on the factors associated with provider-initiated preterm birth is essential for the efforts to reduce preterm birth rates and its consequences. In this current analysis we aimed to assess the proportion of provider-initiated (pi-PTB) among preterm births in Brazil and identify associated factors. METHODS AND FINDINGS: This is an analysis of a multicenter cross-sectional study with a nested case-control component called Brazilian Multicenter Study on Preterm Birth (EMIP). EMIP was conducted in 20 referral obstetric hospitals located in the three most populated of the five Brazilian regions. We analysed data of women with pi-PTB, defined as childbirth occurring at less than 37 weeks, medically indicated for maternal/fetal compromise or both; and women with term birth, childbirth at or after 37 weeks. Maternal, sociodemographic, obstetric, prenatal care, delivery, and postnatal characteristics were assessed as possible factors associated with pi-PTB, compared to term births. The overall prevalence of preterm births was 12.3%. Of these, approximately one-third of cases were initiated by the provider. Hypertensive disorders, placental abruption, and diabetes were the main maternal conditions leading to pi-PTB. Caesarean section was the most common mode of delivery. Chronic hypertension (OR 7.47; 95%CI 4.02-13.88), preeclampsia/eclampsia/HELLP syndrome (OR 15.35; 6.57-35.88), multiple pregnancy (OR 12.49; 4.86-32.05), and chronic diabetes (OR 5.24; 2.68-10.25) were the most significant factors independently associated with pi-PTB. CONCLUSIONS: pi-PTB is responsible for about one-third of all preterm births, requiring special attention. The decision-making process relative to the choice of provider-initiated birth is complex, and many factors should be elucidated to improve strategies for its prevention, including evidence-based guidelines on proper management of the corresponding clinical conditions.

The role of maternal infection in preterm birth: evidence from the Brazilian Multicentre Study on Preterm Birth (EMIP)

OBJECTIVES: Evidence suggests that infection or inflammation is a major contributor to early spontaneous preterm birth (sPTB). Therefore, this study aimed to investigate the development and causes of maternal infection associated with maternal and neonatal outcomes in women with sPTB. METHODS: This was a secondary analysis of a multicenter cross-sectional study with a nested case-control component, the Brazilian Multicentre Study on Preterm Birth (EMIP), conducted from April 2011 to July 2012 in 20 Brazilian referral obstetric hospitals. Women with preterm birth (PTB) and their neonates were enrolled. In this analysis, 2,682 women undergoing spontaneous preterm labor and premature pre-labor rupture of membranes were included. Two groups were identified based on self-reports or prenatal or hospital records: women with at least one infection factor and women without any maternal infection (vulvovaginitis, urinary tract infection, or dental infection). A bivariate analysis was performed to identify potential individual risk factors for PTB. The odds ratios (ORs) with their respective 95% confidence intervals were calculated. RESULTS: The majority of women with sPTB fulfilled at least one criterion for the identification of maternal infection (65.9%), and more than half reported having urinary tract infection during pregnancy. Approximately 9.6% of women with PTB and maternal infection were classified as having periodontal infection only. Apart from the presence of a partner, which was more common among women with infectious diseases (p=0.026; OR, 1.28 [1.03-1.59]), other variables did not show any significant difference between groups. CONCLUSION: Maternal infection was highly prevalent in all cases of sPTBs, although it was not clearly associated with the type of PTB, gestational age, or any adverse neonatal outcomes.

Brazilian multicentre study on preterm birth (EMIP): prevalence and factors associated with spontaneous preterm birth.

BACKGROUND: Preterm birth rate is increasing and is currently a worldwide concern. The purpose of this study was to estimate the prevalence of preterm birth in a sample of health facilities in Brazil and to identify the main risk factors associated with spontaneous preterm births. METHODS AND FINDINGS: This was a multicentre cross sectional study on preterm births in 20 referral obstetric hospitals with a case-control component to identify factors associated with spontaneous preterm birth. Surveillance was implemented at all centres to identify preterm births. For eligible consenting women, data were collected through a post-delivery questionnaire completed with information from all mother-newborn medical records until death or discharge or at a maximum of 60 days post-delivery, whichever came first. The risk of spontaneous preterm birth was estimated with OR and 95%CI for several predictors. A non-conditional logistic regression analysis was then performed to identify independently associated factors. The overall prevalence of preterm birth was 12.3%. Among them, 64.6% were spontaneous and 35.4% therapeutic. In the case-control component, 2,682 spontaneous preterm births were compared to a sample of 1,146 term births. Multivariate analyses identified the following as risk factors for spontaneous preterm birth among women with at least one previous birth: a previous preterm birth (ORadj = 3.19, 2.30-4.43), multiple pregnancy (ORadj = 29.06, 8.43-100.2), cervical insufficiency (ORadj = 2.93, 1.07-8.05), foetal malformation (ORadj = 2.63, 1.43-4.85), polyhydramnios (ORadj = 2.30, 1.17-4.54), vaginal bleeding (ORadj = 2.16, 1.50-3.11), and previous abortion (ORadj = 1.39, 1.08-1.78). High BMI (ORadj = 0.94, 0.91-0.97) and weight gain during gestation (ORadj = 0.92, 0.89-0.95) were found to be protective factors. CONCLUSIONS: The preterm birth rate in these health facilities in Brazil is high and spontaneous preterm births account for two thirds of them. A better understanding of the factors associated with spontaneous preterm birth is of utmost importance for planning effective measures to reduce the burden of its increasing rates.