Gas6 drives Zika virus-induced neurological complications in humans and congenital syndrome in immunocompetent mice.

Zika virus (ZIKV) has the ability to cross placental and brain barriers, causing congenital malformations in neonates and neurological disorders in adults. However, the pathogenic mechanisms of ZIKV-induced neurological complications in adults and congenital malformations are still not fully understood. Gas6 is a soluble TAM receptor ligand able to promote flavivirus internalization and downregulation of immune responses. Here we demonstrate that there is a correlation between ZIKV neurological complications with higher Gas6 levels and the downregulation of genes associated with anti-viral response, as type I IFN due to Socs1 upregulation. Also, Gas6 gamma-carboxylation is essential for ZIKV invasion and replication in monocytes, the main source of this protein, which was inhibited by warfarin. Conversely, Gas6 facilitates ZIKV replication in adult immunocompetent mice and enabled susceptibility to transplacental infection. Our data indicate that ZIKV promotes the upregulation of its ligand Gas6, which contributes to viral infectivity and drives the development of severe adverse outcomes during ZIKV infection.

Adverse effects of antiretroviral therapy in pregnant women infected with HIV in Brazil from 2000 to 2015: a cohort study.

BACKGROUND: Antiretroviral therapy (ART) use in pregnancy presents unquestionable benefits in preventing mother-to-child transmission (MTCT) of HIV although it is associated with maternal adverse effects. The aim of this study was to evaluate the adverse effects of antiretroviral therapy in pregnant women infected with HIV. METHODS: Cohort study of pregnant women infected with HIV followed at the CAISM/UNICAMP Obstetric Clinic from 2000 to 2015. The following maternal adverse effects were observed: anemia, thrombocytopenia, allergy, liver function test abnormalities, dyslipidemia and diabetes. Data collected from patients' files was added to a specific database. Descriptive analysis was shown in terms of absolute (n) and relative (%) frequencies and mean, median and standard deviation calculations. Chi-square or Fisher exact test (n < 5) and relative risk (RR) with its respective p values were used for categorical variables and Student t-test (parametric data) or Mann-Whitney (non-parametric data) for the quantitative ones. A 95% confidence interval (CI) and a significant level of 0.05 were used. A multivariate Cox Logistic Regression was also done. Data analysis was conducted using SAS version 9.4. RESULTS: Data from 793 pregnancies were included. MTCT rate was 2.3%, with 0.8% in the last 5 years. Maternal adverse effects were: dyslipidemia (82%), anemia (56%), liver function test abnormalities (54.5%), including hyperbilirubinemia (11.6%), fasting glycemia alteration (19.2%), thrombocytopenia (14.1%), and allergic reaction (2.7%). The majority of adverse effects deemed related to ART in this study were mild according to DAIDS scale. In the multivariate analysis, co-infections and starting ART during pregnancy were risk factors for maternal anemia, while CD4 count higher than 200 cells/mm3 was protective. Nevirapine, nelfinavir and atazanavir regimens increased the risk for liver function tests abnormalities. Lopinavir use during pregnancy increased the risk for fasting glycemia alteration. CONCLUSION: The evolution of the national guidelines of antiretroviral therapy for pregnant women improved adherence to the treatment and resulted in a significant reduction of MTCT. Despite the high frequency of maternal adverse effects, they are mostly of low severity. Newer ART medications with improved efficacy and significantly more favorable tolerability profiles should reduce the incidence of ART-related adverse effects.

Adverse effects in children exposed to maternal HIV and antiretroviral therapy during pregnancy in Brazil: a cohort study.

BACKGROUND: Antiretroviral therapy (ART) in pregnancy was associated with a drastic reduction in HIV mother-to-child transmission (MTCT), although it was associated with neonatal adverse effects. The aim of this study was to evaluate the neonatal effects to maternal ART. METHODS: This study was a cohort of newborns from HIV pregnant women followed at the CAISM/UNICAMP Obstetric Clinic from 2000 to 2015. The following adverse effects were evaluated: anemia, thrombocytopenia, liver function tests abnormalities, preterm birth, low birth weight and congenital malformation. Data collected from patients' files was added to a specific database. Descriptive analysis was shown in terms of absolute (n) and relative (%) frequencies and mean, median and standard deviation calculations. The association between variables was tested through Chi-square or Fisher exact test (n < 5) and relative risk (RR) with its respective p values for the categorical ones and t-Student (parametric data) or Mann-Whitney (non-parametric data) for the quantitative ones. The significant level used was 0.05. A multivariate Cox Logistic Regression was done. Statistical analysis was performed using SAS version 9.4. RESULTS: Data from 787 newborns was analyzed. MTCT rate was 2.3%, with 0.8% in the last 5 years. Observed neonatal adverse effects were: liver function tests abnormalities (36%), anemia (25.7%), low birth weight (22.5%), preterm birth (21.7%), children small for gestational age (SGA) (18%), birth defects (10%) and thrombocytopenia (3.6%). In the multivariate analysis, peripartum CD4 higher than 200 cells/mm3 was protective for low birth weight and preterm birth, and C-section was associated with low birth weight, but not with preterm birth. Neonatal anemia was associated with preterm birth and exposure to maternal AZT. Liver function tests abnormalities were associated with detectable peripartum maternal viral load and exposure to nevirapine. No association was found between different ART regimens or timing of exposure with preterm birth, low birth weight or congenital malformation. CONCLUSION: Highly active antiretroviral treatment in pregnant women and viral load control were the main factors associated with MTCT reduction. Antiretroviral use is associated with a high frequency but mainly low severity adverse effects in newborns.

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.

The effect of body mass index on maternal and perinatal outcomes in COVID-19 infection during pregnancy and postpartum: Secondary analysis from the REBRACO cohort study.

OBJECTIVES: To compare maternal and perinatal outcomes among women with obesity, overweight, and normal body mass index, associated with COVID-19 infection during pregnancy and postpartum. METHOD: Prospective Cohort Study, within the REBRACO (Brazilian Network of COVID-19 in Pregnancy) multicenter initiative. Confirmed positive cases of SARS-CoV-2 were included, and women categorized into three groups according to their pre-pregnancy BMI: obesity (BMI ≥ 30), overweight (BMI <30 but >25), and normal BMI. Sociodemographic, clinical, and obstetric characteristics and different maternal and perinatal outcomes were compared, and a multiple regression analysis was performed to investigate factors independently associated with adverse maternal and perinatal outcomes. RESULTS: Two hundred eighty-nine women positive for SARS-CoV-2 infection were considered, and 202 had available data on maternal BMI for the current analysis. Overall, 72 (35.6%)obese, 68 (33.6%) overweight, and 60 (29.7%) normal BMI. Obesity was associated with increased adverse clinical outcomes including sepsis (P = 0.02), acute respiratory distress syndrome (P = 0.002), and the need for mechanical ventilation (P = 0.044). Considering perinatal outcomes, a multiple regression model confirmed obesity as an independent factor associated with adverse results (adjusted odds ratio 3.73, 95% CI 1.54-9.08). CONCLUSION: Obesity and overweight were associated with worse clinical outcomes, severe/critical COVID-19, and adverse perinatal outcomes.

The experience of pregnant women and their families who were infected with covid-19 before vaccination: A qualitative approach within a multicenter study in Brazil.

BACKGROUND: Pregnant and postpartum women infected by COVID-19 are at increased risk of adverse outcomes, including negative effects on their mental health. Brazilian maternal mortality rate due to COVID-19 is 2.5 times higher than overall mortality rates. This study aimed to understand how pregnant/postpartum women experienced the COVID-19 suspicion/investigation or confirmed infection in different Brazilian cities, the pandemic's consequences to women and their families, and their needs to improve maternal health services during public health emergencies. METHODS: We conducted a qualitative study with 27 women with COVID-19 and 6 of their family members, as part of a multicenter study among 15 maternity hospitals in Brazil. We applied in-depth interviews through telephone calls when women received the diagnostic or had a suspect infection and after 60 days. Another semi-structured interview was applied to their close family members. The interviews were considered through thematic analysis. RESULTS: From the thematic content analysis three major themes emerged from the first and second interviews: (Cucinotta and Vanelli, 2020) assistance received by the woman and newborn in the medical services; (World Health Organization (WHO) 2021) stigma/fear of contamination from health workers and from family and friends reported by the women; (Allotey et al., 2020) the COVID-19 pandemic impact. CONCLUSION: Before the availability of the COVID-19 vaccine, pregnant women experienced fear of death, hospitalization, quarantine, loss of family members, and financial repercussions, resulting in physical, psychological, and socioeconomic impacts on these women's lives.

Morphological placental findings in women infected with SARS-CoV-2 according to trimester of pregnancy and severity of disease.

INTRODUCTION: Placental morphology findings in SARS-CoV-2 infection are considered nonspecific, although the role of trimester and severity of infection are underreported. Therefore, we aimed to investigate abnormal placental morphology, according to these two criteria. METHODS: This is an ancillary analysis of a prospective cohort study of pregnant women with suspected SARS-CoV-2 infection, managed in one maternity, from March 2020 to October 2021. Charting of clinical/obstetric history, trimester and severity of COVID-19 infection, and maternal/perinatal outcomes were done. Placental morphological findings were classified into maternal and fetal circulatory injury and acute/chronic inflammation. We further compared findings with women with suspected disease which tested negative for COVID-19. Diseases' trimester of infection and clinical severity guided the analysis of confirmed COVID-19 cases. RESULTS: Ninety-one placental discs from 85 women were eligible as a COVID-19 group, and 42 discs from 41 women in negative COVID-19 group. SARS-CoV-2 infection occurred in 68.2% during third trimester, and 6.6% during first; 16.5% were asymptomatic, 61.5% non-severe and 22.0% severe symptomatic (two maternal deaths). Preterm birth occurred in 33.0% (one fetal death). Global maternal vascular malperfusion (MVM) were significant in COVID-19 group whether compared with negative COVID-19 tests group; however, fetal vascular malperfusion lesions and low-grade chronic villitis were not. Three placentas had COVID-19 placentitis. Decidual arteriopathy was associated with infection in first/mid trimester, and chorangiosis in asymptomatic infections. DISCUSSION: Placental abnormalities after an infection by COVID-19 were more frequent after first/mid-trimester infections. Extensive placental lesions are rare, although they may be more common upon underlying medical conditions.

Role of biomarkers (sFlt-1/PlGF) in cases of COVID-19 for distinguishing preeclampsia and guiding clinical management.

OBJECTIVES: To analyze soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factors (PlGF) concentrations and their ratio in pregnant and postpartum women with suspected COVID-19, and further investigate conditions associated with an increased ratio (sFlt-1/PlGF > 38), including preeclampsia (PE) and severe acute respiratory syndrome (SARS). STUDY DESIGN: The present study is a secondary analysis of a prospective cohort. Blood samples were collected at time of COVID-19 investigation and the serum measurements of sFlt-1 and PlGF were performed. Clinical background, SARS-CoV-2 infection characteristics, maternal and perinatal outcomes were further analyzed. MAIN OUTCOME MEASURES: Serum measurements of sFlt-1 and PlGF; obstetrics and clinical outcomes. RESULTS: A total of 97 SARS-CoV-2 unvaccinated women with suspected infection were considered, 76 were COVID-19 positive cases and 21 COVID-19 negative. Among COVID-19 positive cases, 09 presented with SARS and 11 were diagnosed with PE, of which 6 had SARS-CoV-2 infection in first and second trimester (04 with sFlt-1/PlGF ≥ 38) and 05 with PE and COVID-19 diagnosed at the same time, during third trimester (03 with sFlt-1/PlGF ≥ 38). Five presented with PE with severe features. sFlt-1/PlGF ratio was significantly higher in the COVID-19 positive/PE positive group compared to COVID-19 positive/PE negative group (p-value = 0.005), with no increase in cases complicated by SARS. CONCLUSIONS: sFlt-1/PlGF ratio could be a useful tool for differential diagnosis and adequate counseling among cases of COVID-19 and PE, especially if severe disease. COVID-19 early in pregnancy could potentially be a risk factor for PE later during gestation.

Preeclampsia among women with COVID-19 during pregnancy and its impact on maternal and perinatal outcomes: Results from a national multicenter study on COVID in Brazil, the REBRACO initiative.

OBJECTIVE: To evaluate the prevalence of preeclampsia among cases of COVID-19 infection during pregnancy and the association between both conditions, in a multicenter cohort of Brazilian women with respiratory symptoms. STUDY DESIGN: Ancillary analysis of the Brazilian Network of COVID-19 in Obstetrics (REBRACO) study. We performed a nested case-control analysis selecting all women with COVID-19 and compared outcomes between women with and without PE. MAIN OUTCOMES: Maternal, gestational, and clinical characteristics and perinatal outcomes. MEASURES: Prevalence ratio (PR) and its 95%CI for each of the predictors and outcomes. RESULTS: A total of 203 women were included: 21 (10.3%) in PE group and 182 (89.7%) in non-PE group. Preeclampsia was not different among women with and without COVID-19 (10.3% vs 13.1%, p-value = 0.41), neither complication such as eclampsia and HELLP syndrome. Chronic hypertension (33.4%) (p < 0.01) and obesity (60.0%) (p = 0.03) were the most frequent comorbidities in PE group, and they were significantly more frequent in this group. Women with PE had more cesarean section (RR 5.54 [1.33 - 23.14]) and their neonates were more frequently admitted to neonatal intensive care unit (PR 2.46[1.06 - 5.69]), most likely due to preterm-birth-related complications. CONCLUSION: The prevalence of PE among women with COVID-19 infection during pregnancy was around 10%; women with COVID-19 and a history of chronic hypertension or obesity are more likely to have preeclampsia. Cesarean section is increased among women with PE and COVID-19, with increased rates of neonatal admission to intensive care units, mostly due to prematurity.

The COVID-19 pandemic in Brazilian pregnant and postpartum women: results from the REBRACO prospective cohort study.

Brazil presented a very high number of maternal deaths and evident delays in healthcare. We aimed at evaluating the characteristics of SARS-CoV-2 infection and associated outcomes in the obstetric population. We conducted a prospective cohort study in 15 Brazilian centers including symptomatic pregnant or postpartum women with suspected COVID-19 from Feb/2020 to Feb/2021. Women were followed from suspected infection until the end of pregnancy. We analyzed maternal characteristics and pregnancy outcomes associated with confirmed COVID-19 infection and SARS, determining unadjusted risk ratios. In total, 729 symptomatic women with suspected COVID-19 were initially included. Among those investigated for COVID-19, 51.3% (n = 289) were confirmed COVID-19 and 48% (n = 270) were negative. Initially (before May 15th), only 52.9% of the suspected cases were tested and it was the period with the highest proportion of ICU admission and maternal deaths. Non-white ethnicity (RR 1.78 [1.04-3.04]), primary schooling or less (RR 2.16 [1.21-3.87]), being overweight (RR 4.34 [1.04-19.01]) or obese (RR 6.55 [1.57-27.37]), having public prenatal care (RR 2.16 [1.01-4.68]), planned pregnancies (RR 2.09 [1.15-3.78]), onset of infection in postpartum period (RR 6.00 [1.37-26.26]), chronic hypertension (RR 2.15 [1.37-4.10]), pre-existing diabetes (RR 3.20 [1.37-7.46]), asthma (RR 2.22 [1.14-4.34]), and anaemia (RR 3.15 [1.14-8.71]) were associated with higher risk for SARS. The availability of tests and maternal outcomes varied throughout the pandemic period of the study; the beginning was the most challenging period, with worse outcomes. Socially vulnerable, postpartum and previously ill women were more likely to present SARS related to COVID-19.

Mother-to-child transmission of human immunodeficiency virus in aten years period.

OBJECTIVES: to evaluate mother-to-child transmission (MTCT) rates and related factors in HIV-infected pregnant women from a tertiary hospital between 2000 and 2009. SUBJECTS AND METHOD: cohort of 452 HIV-infected pregnant women and their newborns. Data was collected from recorded files and undiagnosed children were enrolled for investigation. STATISTICAL ANALYSIS: qui-square test, Fisher exact test, Student t test, Mann-Whitney test, ANOVA, risk ratio and confidence intervals. RESULTS: MTCT occurred in 3.74%. The study population displayed a mean age of 27 years; 86.5% were found to have acquired HIV through sexual contact; 55% were aware of the diagnosis prior to the pregnancy; 62% were not using HAART. Mean CD4 cell-count was 474 cells/ml and 70.3% had undetectable viral loads in the third trimester. HAART included nevirapine in 35% of cases and protease inhibitors in 55%; Zidovudine monotherapy was used in 7.3%. Mean gestational age at delivery was 37.2 weeks and in 92% by caesarian section; 97.2% received intravenous zidovudine. Use of AZT to newborn occurred in 100% of them. Factors identified as associated to MTCT were: low CD4 cell counts, elevated viral loads, maternal AIDS, shorter periods receiving HAART, other conditions (anemia, IUGR (intra uterine growth restriction), oligohydramnium), coinfecctions (CMV and toxoplasmosis) and the occurrence of labor. Use of HAART for longer periods, caesarian and oral zidovudine for the newborns were associated with a decreased risk. Poor adhesion to treatment was present in 13 of the 15 cases of transmission; in 7, coinfecctions were diagnosed (CMV and toxoplasmosis). CONCLUSION: Use of HAART and caesarian delivery are protective factors for mother-to-child transmission of HIV. Maternal coinfecctions and other conditions were risk factors for MTCT.

Mortality in pregnancy and the postpartum period in women with severe acute respiratory distress syndrome related to COVID-19 in Brazil, 2020.

OBJECTIVE: To estimate fatality rates due to severe acute respiratory distress syndrome (ARDS) related to COVID-19 in Brazilian women, comparing pregnant and postpartum women with nonpregnant women. METHODS: A cross-sectional study of 12 566 pregnant and postpartum women (obstetric group) and 90 025 nonpregnant women (nonobstetric group) aged 15-49 years reported with severe ARDS in 2020. The Brazilian ARDS Surveillance System was used to compare the outcome (death or cure) between the groups, considering age, race, or comorbidities. RESULTS: The mortality rate related to ARDS/COVID-19 in the obstetric group was 7.8% (377/4853) compared with 13.9% (5946/42 915) in the nonobstetric group. Comorbidity was associated with increased fatality cases for both groups, but higher in the nonobstetric group (22.8% vs 13.3%). In the obstetric group, deaths related to COVID-19 were concentrated in the third trimester or postpartum period. If comorbidity was present, deaths by COVID-19 were 4.4 times higher than ARDS due to other etiologies, and twice higher in women who self-reported as black (13.7%) than white women (6.7%). Considering ADRS etiology, deaths by COVID-19 were 3.4-6.7 times higher than any other etiology. CONCLUSION: ARDS related to COVID-19 in obstetric patients was an important factor for worse clinical outcomes, with 3-6 times higher death rates than other ARDS etiologies. Pregnant and postpartum women with severe ARDS related to COVID-19 had a lower fatality rate than nonpregnant women, even with associated comorbidity.

Facing the COVID-19 pandemic inside maternities in Brazil: A mixed-method study within the REBRACO initiative.

INTRODUCTION: COVID-19 pandemic posed major challenges in obstetric health care services. Preparedness, development, and implementation of new protocols were part of the needed response. This study aims to describe the strategies implemented and the perspectives of health managers on the challenges to face the pandemic in 16 different maternity hospitals that comprise a multicenter study in Brazil, called REBRACO (Brazilian network of COVID-19 during pregnancy). METHODS: Mixed-method study, with quantitative and qualitative approaches. Quantitative data on the infrastructure of the units, maternal and perinatal health indicators, modifications on staff and human resources, from January to July/2020. Also, information on total number of cases, and availability for COVID-19 testing. A qualitative study by purposeful and saturation sampling was undertaken with healthcare managers, to understand perspectives on local challenges in facing the pandemic. RESULTS: Most maternities early implemented their contingency plan. REBRACO centers reported 338 confirmed COVID-19 cases among pregnant and post-partum women up to July 2020. There were 29 maternal deaths and 15 (51.8%) attributed to COVID-19. All maternities performed relocation of beds designated to labor ward, most (75%) acquired mechanical ventilators, only the minority (25%) installed new negative air pressure rooms. Considering human resources, around 40% hired extra health professionals and increased weekly workload and the majority (68.7%) also suspended annual leaves. Only one center implemented universal screening for childbirth and 6 (37.5%) implemented COVID-19 testing for all suspected cases, while around 60% of the centers only tested moderate/severe cases with hospital admission. Qualitative results showed that main challenges experienced were related to the fear of the virus, concerns about reliability of evidence and lack of resources, with a clear need for mental health support among health professionals. CONCLUSION: Study findings suggest that maternities of the REBRACO initiative underwent major changes in facing the pandemic, with limitations on testing, difficulties in infrastructure and human resources. Leadership, continuous training, implementation of evidence-based protocols and collaborative initiatives are key to transpose the fear of the virus and ascertain adequate healthcare inside maternities, especially in low and middle-income settings. Policy makers need to address the specificities in considering reproductive health and childbirth during the COVID-19 pandemic and prioritize research and timely testing availability.

Brazilian network of COVID-19 during pregnancy (REBRACO: a multicentre study protocol).

INTRODUCTION: The aim of this study was to evaluate the clinical, epidemiological and laboratory aspects of SARS-CoV-2 infection during pregnancy and postpartum in 16 maternity hospitals. METHODS AND ANALYSIS: A prospective multicentre study, with five axes. First, the prevalence of SARS-CoV-2 infection among women admitted for childbirth will be described in a cross-sectional study. Second, maternal and perinatal outcomes will be assessed in a prospective cohort study including pregnant or postpartum women with suspected COVID-19. Third, a cohort of positive COVID-19 cases with sampling of a variety of biological material. Histopathological and viral analysis of biological maternal and neonatal samples will be performed, and the assessment of nutritional variables to evaluate the association between vitamin D and severity of infection. Fourth, a monitoring and evaluation committee to collect relevant healthcare information and plan actions in centres facing the pandemic. Furthermore, qualitative studies will be performed to study pregnant women, their families and health professionals. Fifth, an ecological study will monitor the number of live births, stillbirths and other outcomes to explore any trend among the periods before, during and after the pandemic. Data will systematically be collected in an electronic platform following standardised operational procedures. For quantitative study components, an appropriate statistical approach will be used for each analysis. For qualitative data, in-depth interviews recorded in audio will be transcribed, checking the text obtained with the recording. Subsequently, thematic analysis with the aid of the NVivo programme will be performed. ETHICS AND DISSEMINATION: Ethical approval was obtained (letters of approval numbers 4.047.168, 4.179.679 and 4.083.988). All women will be fully informed to sign the consent form before enrolment in the study. Findings will be disseminated through peer-reviewed journals and scientific conferences.

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.