Exploring the occurrence, prediction and impact of fetal growth restriction

Orientador: Jose Guilherme CecattiTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: Introdução: A restrição de crescimento fetal (RCF) é uma condição heterogênea; avaliação de risco e predição ainda são estratégias desafiadoras para a Obstetrícia moderna. Os fatores clínicos podem orientar na seleção de mulheres que se beneficiam de métodos complementares para vigilância fetal. Biomarcadores laboratoriais podem ser úteis na abordagem da RCF. Objetivos: Analisar a RCF de uma forma ampla, incluindo avaliação de risco, predição e diagnóstico. Objetivos específicos: analisar os recém-nascidos pequenos para a idade gestacional (PIG) como desfecho secundário do estudo Preterm-SAMBA quanto aos fatores clínicos de risco; realizar revisão narrativa da literatura sobre o rastreio de RCF e aplicação da metabolômica no seu estudo; e desenvolver uma revisão sistemática da literatura sobre a acurácia da metabolômica na predição dos recém-nascidos PIG, e a identificação de biomarcadores. Métodos: Para o Preterm-SAMBA, nulíparas de risco obstétrico habitual foram incluídas entre 19+0-20+6 semanas de uma gestação única, e acompanhadas até o parto. Dados sociodemográficos, clínicos e reprodutivos foram obtidos na 1ª visita; dados perinatais foram acessados nos prontuários médicos. O peso ao nascer abaixo do percentil 10 da curva customizada de peso foi considerado como proxy para RCF. Recém-nascidos com peso entre os percentis 10 e 90 foram considerados adequados para a idade gestacional (AIG). Para a revisão sistemática, dois pesquisadores independentes pesquisaram onze bases de dados eletrônicas, selecionaram os estudos e extraíram os dados. Um terceiro revisor dirimiu dúvidas. A pesquisa foi realizada em fevereiro 2018 e novembro 2018, sem restrições de idiomas ou limites. Resultados: A prevalência de PIG na amostra do SAMBA foi 12,8%. Os grupos PIG e AIG foram semelhantes em relação às características maternas, exceto pela assistência pré-natal pública (p 0,012) e a presença de qualquer infecção na primeira metade da gestação (p 0,016). Essas características se associaram a maior risco para PIG na análise multivariada (RR 2,02; 95%CI 1,23-3,33; e RR 1,36; 95%CI 1,10-1,68, respectivamente). Na revisão sistemática da literatura, foram incluídos 15 estudos. Meta-análise não foi realizada devido à heterogeneidade na seleção dos participantes e métodos empregados. Análise do sangue ou cabelo materno no 2º trimestre da gestação apresentou alta capacidade preditiva em estudos individuais do tipo untargeted. Os metabólitos preditivos compreendem onze classes químicas, e a subclasse mais prevalente foi a dos ácidos graxos. Conclusão: A prevalência de PIG numa população é um marcador do seu desenvolvimento socioeconômico. Avaliação de risco clínico deve ser amplamente oferecida durante a gravidez. Os achados de biomarcadores envolvidos com o metabolismo dos lipídios no 2º trimestre da gestação são promissores; a validação destes achados é encorajadaAbstract: Background: Fetal growth restriction (FGR) is a heterogeneous condition; risk assessment and prediction are still challenging for modern obstetrics. Clinical factors may guide selection of women who benefit from additional methods for fetal surveillance. Laboratory biomarkers may be useful in addressing FGR. Objectives: To comprehensively analyze the FGR condition, including risk assessment, prediction and diagnosis. Secondary objectives: to analyze clinical risk factors for small for gestational age (SGA) infants as a secondary outcome of the Preterm-SAMBA study; to carry out narrative reviews of literature on the screening for FGR and the use of metabolomics for its evaluation; and to develop a systematic review of the literature on the accuracy of metabolomics in the prediction of SGA infants, and the identification of biomarkers. Methods: For the Preterm-SAMBA study, nulliparous low-risk women were enrolled between 19+0 - 20+6 weeks of a single pregnancy and were followed up until delivery. Sociodemographic, clinical and reproductive data were obtained at the first visit; perinatal data were accessed on medical records. SGA, defined as having customized birth weight below the 10th centile, was considered proxy for FGR. Newborns with birthweight 10th - 90th centiles were adequate for gestational age (AGA). For the systematic review, two independent researchers assessed eleven electronic databases, selected studies, and extracted data. A third reviewer has helped to resolve discrepancies. The literature search was performed in February 2018 and November 2018, with no limits or language restrictions. Results: SGA prevalence in the Preterm-SAMBA was 12.8%. SGA and AGA groups were similar regarding maternal characteristics, except for public prenatal care (p 0.012) and the presence of any infection in the first half of gestation (p 0.016). These characteristics were associated with an increased risk for SGA in the multivariate analysis (RR 2.02, 95% CI 1.23-3.33 and RR 1.36, 95% CI 1.10-1.68, respectively). In the systematic review, 15 studies were included. Meta-analysis was not performed due to heterogeneity in the selection of participants and methods employed by the original studies. Analysis of maternal blood or hair in the second trimester of pregnancy presented high predictive accuracy in untargeted studies. Predictive metabolites comprise eleven chemical classes, and the most prevalent subclass was fatty acids. Conclusions: SGA prevalence is a marker of socioeconomic development. Clinical risk assessment should be widely offered during pregnancy. The findings of biomarkers involved with lipid metabolism in the second trimester of gestation are promising; the validation of these results is encouragedDoutoradoTocoginecologiaDoutora em Ciências da Saúd

Endometriose profunda: achados clínicos e epidemiológicos de mulheres diagnosticadas segundo critérios do international deep endometriosis analysis group (IDEA)

Introduction: endometriosis occurs when tissue similar to the endometrium affects the peritoneum, which can infiltrate structures and organs such as the bowel, ureter, bladder or vagina and is usually accompanied by an inflammatory process. It is estimated that the disease affects 6 to 10% of women of reproductive age and more than 50% of infertile women. The clinical and epidemiological data of patients with DE come from studies whose women were selected by surgery, therefore subject to selection bias. Transvaginal pelvic ultrasound with bowel preparation (TVUBP) has high specificity and sensitivity values. Objective: analyze the clinical and epidemiological profile of patients with DE diagnosed through the TVUBP. Methods: a cross-sectional study that analyzed 227 patients with an ultrasound diagnosis of deep endometriosis. Results: infertility affected 43.8% of women. Painful symptoms considered as moderate or severe (visual analogue scale, VAS, >3) had the following prevalence and mean values on the VAS scale, respectively: dysmenorrhea in 84.7% (6.9), dyspareunia in 69.1%, (4.2) menstrual dyschezia in 60.7% (4.3) and menstrual dysuria in 35.7% of patients. A history of multiple surgeries occurred in 10.4% and only 6.8% of patients had undergone physiotherapy for the pelvic floor. Conclusion: the DE population had a high prevalence of infertility and pain symptoms, findings that reflect the social impact on the quality of life and family planning of these women. The high frequency of history of multiple surgical approaches and the low incidence of history of pelvic physiotherapy in the population with DE, contrary to the currently established ideal treatment recommendations, indicate the difficulty of access for patients to specialized centers.Introdução: Endometriose ocorre quando o tecido semelhante ao endométrio acomete o peritônio, podendo infiltrar estruturas e órgãos como o intestino, o ureter, a bexiga ou a vagina e geralmente está acompanhado de processo inflamatório. Estima-se que a doença acometa 6 a 10% das mulheres em idade reprodutiva e mais de 50% das mulheres inférteis. Os dados clínicos e epidemiológicos das pacientes com EP disponíveis na literatura são provenientes de estudos cujas amostras foram selecionadas por cirurgia, portanto passíveis de vieses de seleção. A ultrassonografia pélvica endovaginal com preparo intestinal (USGTVP) tem valores de especificidade e sensibilidade elevados. Objetivo: analisar o perfil clínico e epidemiológico das pacientes portadoras de EP diagnosticadas através da USGTVP. Método: estudo transversal, que analisou 227 pacientes com diagnóstico ultrassonográfico de endometriose profunda. Resultados: infertilidade acometeu 43,8% das mulheres. Sintomas álgicos considerados como moderado ou grave (escala visual analógica, EVA, >3) apresentaram respectivamente a seguinte prevalência e valores médios na escala de EVA: dismenorreia em 84,7% (6,9), dispareunia em 69,1%, (4,2) disquezia menstrual em 60,7% (4,3) e disúria menstrual em 35,7% das pacientes. Antecedente de múltiplas cirurgias ocorreu em 10,4 % e apenas 6,8 % das portadoras haviam realizado fisioterapia para assoalho pélvico. Conclusão: a população portadora de EP apresentou alta prevalência de infertilidade e sintomas álgicos, achados que refletem o impacto social na qualidade de vida e no planejamento familiar dessas mulheres. A alta frequência de antecedentes de múltiplas abordagens cirúrgicas e a baixa incidência de antecedente de realização de fisioterapia pélvica na população com EP, contrariando as recomendações de tratamento ideal atualmente já estabelecidas, sinalizam a dificuldade de acesso das portadoras a centros especializados

Metabolomics applied to maternal and perinatal health : a review of new frontiers with a translation potential

The prediction or early diagnosis of maternal complications is challenging mostly because the main conditions, such as preeclampsia, preterm birth, fetal growth restriction, and gestational diabetes mellitus, are complex syndromes with multiple underlying mechanisms related to their occurrence. Limited advances in maternal and perinatal health in recent decades with respect to preventing these disorders have led to new approaches, and “omics” sciences have emerged as a potential field to be explored. Metabolomics is the study of a set of metabolites in a given sample and can represent the metabolic functioning of a cell, tissue or organism. Metabolomics has some advantages over genomics, transcriptomics, and proteomics, as metabolites are the final result of the interactions of genes, RNAs and proteins. Considering the recent “boom” in metabolomic studies and their importance in the research agenda, we here review the topic, explaining the rationale and theory of the metabolomic approach in different areas of maternal and perinatal health research for clinical practitioners. We also demonstrate the main exploratory studies of these maternal complications, commenting on their promising findings. The potential translational application of metabolomic studies, especially for the identification of predictive biomarkers, is supported by the current findings, although they require external validation in larger datasets and with alternative methodologies

Mean arterial blood pressure : potential predictive tool for preeclampsia in a cohort of healthy nulliparous pregnant women

Background: Prediction of preeclampsia is a challenge to overcome. The vast majority of prospective studies in large general obstetric populations have failed in the purpose of obtain a useful and effective model of prediction, sometimes based on complex tools unavaible in areas where the incidence of preeclampsia is the highest. The goal of this study was to assess mean arterial blood pressure (MAP) levels at 19–21, 27–29 and 37–39 weeks of gestation and performance of screening by MAP for the prediction of preeclampsia in a Brazilian cohort of healthy nulliparous pregnant women. Methods: This was a cohort approach to a secondary analysis of the Preterm SAMBA study. Mean arterial blood pressure was evaluated at three different time periods during pregnancy. Groups with early-onset preeclampsia, late-onset preeclampsia and normotension were compared. Increments in mean arterial blood pressure between 20 and 27 weeks and 20 and 37 weeks of gestation were also calculated for the three groups studied. The accuracy of mean arterial blood pressure in the prediction of preeclampsia was determined by ROC curves. Results: Of the 1373 participants enrolled, complete data were available for 1165. The incidence of preeclampsia was 7.5%. Women with early-onset preeclampsia had higher mean arterial blood pressure levels at 20 weeks of gestation, compared to the normotensive group. Women with late-onset preeclampsia had higher mean arterial blood pressure levels at 37 weeks of gestation, than the normotensive groups and higher increases in this marker between 20 and 37 weeks of gestation. Based on ROC curves, the predictive performance of mean arterial blood pressure was higher at 37 weeks of gestation, with an area under the curve of 0.771. Conclusion: As an isolated marker for the prediction of preeclampsia, the performance of mean arterial blood pressure was low in a healthy nulliparous pregnant women group. Considering that early-onset preeclampsia cases had higher mean arterial blood pressure levels at 20 weeks of gestation, future studies with larger cohorts that combine multiple markers are needed for the development of a preeclampsia prediction model

Identification of earlier predictors of pregnancy complications through wearable technologies in a Brazilian multicentre cohort : Maternal Actigraphy Exploratory Study I (MAES-I) study protocol

Introduction Non-invasive tools capable of identifying predictors of maternal complications would be a step forward for improving maternal and perinatal health. There is an association between modification in physical activity (PA) and sleep–wake patterns and the occurrence of inflammatory, metabolic, pathological conditions related to chronic diseases. The actigraphy device is validated to estimate PA and sleep–wake patterns among pregnant women. In order to extend the window of opportunity to prevent, diagnose and treat specific maternal conditions, would it be possible to use actigraphy data to identify risk factors for the development of adverse maternal outcomes during pregnancy? Methods and analysis A cohort will be held in five centres from the Brazilian Network for Studies on Reproductive and Perinatal Health. Maternal Actigraphy Exploratory Study I (MAES-I) will enrol 400 low-risk nulliparous women who will wear the actigraphy device on their wrists day and night (24 hours/day) uninterruptedly from 19 to 21 weeks until childbirth. Changes in PA and sleep–wake patterns will be analysed throughout pregnancy, considering ranges in gestational age in women with and without maternal complications such as pre-eclampsia, preterm birth (spontaneous or provider-initiated), gestational diabetes, maternal haemorrhage during pregnancy, in addition to perinatal outcomes. The plan is to design a predictive model using actigraphy data for screening pregnant women at risk of developing specific adverse maternal and perinatal outcomes

Incidence and risk factors for preeclampsia in a cohort of healthy nulliparous pregnant women : a nested case-control study

The objective of this study is to determine the incidence, socio-demographic and clinical risk factors for preeclampsia and associated maternal and perinatal adverse outcomes. This is a nested case-control derived from the multicentre cohort study Preterm SAMBA, in fve diferent centres in Brazil, with nulliparous healthy pregnant women. Clinical data were prospectively collected, and risk factors were assessed comparatively between PE cases and controls using risk ratio (RR) (95% CI) plus multivariate analysis. Complete data were available for 1,165 participants. The incidence of preeclampsia was 7.5%. Body mass index determined at the frst medical visit and diastolic blood pressure over 75mmHg at 20 weeks of gestation were independently associated with the occurrence of preeclampsia. Women with preeclampsia sustained a higher incidence of adverse maternal outcomes, including C-section (3.5 fold), preterm birth below 34 weeks of gestation (3.9 fold) and hospital stay longer than 5 days (5.8 fold) than controls. They also had worse perinatal outcomes, including lower birthweight (a mean 379g lower), small for gestational age babies (RR 2.45 [1.52–3.95]), 5-minute Apgar score less than 7 (RR 2.11 [1.03–4.29]), NICU admission (RR 3.34 [1.61–6.9]) and Neonatal Near Miss (3.65 [1.78–7.49]). Weight gain rate per week, obesity and diastolic blood pressure equal to or higher than 75mmHg at 20 weeks of gestation were shown to be associated with preeclampsia. Preeclampsia also led to a higher number of C-sections and prolonged hospital admission, in addition to worse neonatal outcomes

Clinical and epidemiological factors associated with spontaneous preterm birth : a multicentre cohort of low risk nulliparous women

The objective of this study was to determine incidence and risk factors associated with spontaneous preterm birth (sPTB). It was a prospective multicentre cohort study performed in fve Brazilian referral maternity hospitals and enrolling nulliparous women at 19–21 weeks. Comprehensive maternal data collected during three study visits were addressed as potentially associated factors for sPTB. Bivariate and multivariate analysis estimated risk ratios. The main outcomes measures were birth before 37 weeks due to spontaneous preterm labour or premature rupture of membranes (sPTB). The comparison group was comprised of women with term births (≥37weeks). Outcome data was available for 1,165 women, 6.7% of whom had sPTB, 16% had consumed alcohol and 5% had used other illicit drugs during the frst half of pregnancy. Current drinking at 19–21 weeks (RR 3.96 95% CI [1.04–15.05]) and a short cervix from 18–24 weeks (RR 4.52 95% CI [1.08–19.01]) correlated with sPTB on bivariate analysis. Increased incidence of sPTB occurred in underweight women gaining weight below quartile 1 (14.8%), obese women gaining weight above quartile 3 (14.3%), women with a short cervix (<25mm) at 18–24 weeks (31.2%) and those with a short cervix and vaginal bleeding in the frst half of pregnancy (40%). Cervical length (RRadj 4.52 95% CI [1.08–19.01]) was independently associated with sPTB. In conclusion, the incidence of sPTB increased in some maternal phenotypes, representing potential groups of interest, the focus of preventive strategies. Similarly, nulliparous women with a short cervix in the second trimester require further exploration

The food patterns of a multicenter cohort of Brazilian nulliparous pregnant women

Assessment of human nutrition is a complex process, in pregnant women identify dietary patterns through mean nutrient consumption can be an opportunity to better educate women on how to improve their overall health through better eating. This exploratory study aimed to identify a posteriori dietary patterns in a cohort of nulliparous pregnant women. The principal component analysis (PCA) technique was performed, with Varimax orthogonal rotation of data extracted from the 24-h dietary recall, applied at 20 weeks of gestation. We analysed 1.145 dietary recalls, identifying five main components that explained 81% of the dietary pattern of the sample. Dietary patterns found were: Obesogenic, represented by ultra-processed foods, processed foods, and food groups rich in carbohydrates, fats and sugars; Traditional, most influenced by natural, minimally processed foods, groups of animal proteins and beans; Intermediate was similar to the obesogenic, although there were lower loads; Vegetarian, which was the only good representation of fruits, vegetables and dairy products; and Protein, which best represented the groups of proteins (animal and vegetable). The obesogenic and intermediate patterns represented over 37% of the variation in food consumption highlighting the opportunity to improve maternal health especially for women at first mothering

Profile of calories and nutrients intake in a Brazilian multicenter study of nulliparous women

Objective: To assess the calorie intake and nutritional content of the maternal diet in regions with different culinary traditions and typical foods, and to understand the nutritional profile so as to provide information about the consumption of this population and promote maternal and perinatal health. Methods: From a cohort of 1145 pregnant women with diverse socio-backgrounds we analyzed the dietary characteristics profile according to three guidelines and compared the differences between regions of Brazil. Results: Women from the northeast had the lowest level of income, occupation, education, and age (P < 0.001). Intakes of unprocessed/minimally processed foods and processed foods were more prevalent in women from the northeast than in southern/southeastern women (P < 0.001). The consumption of dairy products and vegetables was less than the recommended intake, with lower intake in southern/southeastern women (P < 0.001). This study showed a lower consumption of dairy and vegetables, with a shortfall of vitamins K and D, iron, calcium, folate, magnesium, and chromium from natural and fortified foods. We observed a greater consumption of unprocessed or minimally processed food in women from the northeast of Brazil. Conclusion: Our findings indicate the importance of differentiating the source of calorie intake between regional nutritional guidance and the diversity of local cuisine