<strong>Background and objectives:</strong> The incidence of preterm birth (PTB), and the extent to which it results in perinatal mortality in sub-Saharan Africa (sSA) is unclear, partly because reliable estimates of gestational age (GA) at birth are lacking. This research: 1) Describes how clinical and ultrasound (US) estimates of gestational age (GA) influence PTB rates and perinatal mortality amongst a population in Kilifi, Kenya; 2) Implements a novel PTB classification system as proof of concept that such systems are feasible in low-income settings, and 3) Presents two novel approaches for estimating GA for women presenting >24 weeks’ gestation. <strong>Methods:</strong> Objectives 1) and 2) used a perinatal surveillance platform developed at the KEMRI/Wellcome Trust Research Programme in Kilifi, Kenya. Ultrasound (US) was offered for GA estimation in women ≤24 weeks’ gestation clinically. To achieve objective 3), two candidate US dating equations were derived by combining a machine learning algorithm with polynomial regression analyses. Lastly, an entirely automated model with the capacity to estimate GA using computational image analysis of the fetal cerebral cortex was developed and tested. <strong>Results:</strong> 1) Between November 2011 and July 2013, 3630 women presented for antenatal care, 1107 women had US and data were available for 950 (86%) of these. The PTB rate by US (US-GA) was 10.0% compared to 17.1% by a best clinical estimate of GA (C-GA), although the number of perinatal deaths that were preterm by US and C-GA were similar; 2) Implementation of a novel PTB classification system is feasible, and 3) New dating equations and an automated model provide estimates in the 3rd trimester with a prediction error at 34 weeks of 12.4 and 14.2 days, respectively. <strong>Conclusion:</strong> Clinical estimates of GA significantly overestimate the rate of PTBs. Despite this, the proportion of perinatal deaths in those identified as preterm by clinical and US methods was similar, suggesting that US may be a better predictor of PTB and its associated mortality. Novel dating methods can estimate GA at 34 weeks’ gestation with an error equivalent to that provided by routine clinical methods at 22 weeks’. This has important implications and may extend capacity to provide GA estimates amongst a large group of women whose birth phenotypes remain poorly described.

O imprinting genômico, processo regulado epigeneticamente segundo o qual os genes se expressam de acordo com sua origem parental, está envolvido no crescimento e desenvolvimento placentário. Na região 11p15.5 encontram-se vários genes regulados por duas regiões controladoras de imprinting (ICR1 e ICR2), onde se encontram as regiões diferencialmente metiladas H19DMR e KvDMR1. Acredita-se que o padrão de imprinting seja dinamicamente regulado durante o desenvolvimento da placenta. Em humanos, há poucas informações sobre imprinting genômico e desenvolvimento placentário, principalmente para estágios precoces do desenvolvimento devido às dificuldades técnicas de obtenção dessas placentas. A descrição de mosaicismo do padrão de metilação restrito a placenta ou entre a placenta e o feto evidencia um perfil epigenético único deste órgão. A 5-hidroximetilação, a qual não tem um papel de silenciamento gênico, pode ser confundida com a metilação do DNA nas análises moleculares. O objetivo principal do presente estudo foi o de verificar a influência da idade gestacional (IG) no perfil de metilação do DNA das ICRs 1 e 2 em vilosidade coriônica, bem como a existência de mosaicismo do perfil de metilação intra-placentário. Neste trabalho também foi investigada a presença de hidroximetilação na KvDMR1. Foram coletadas amostras de tecido placentário, sendo 25 de vilosidades coriônicas (VC) (15 de 3° trimestre gestacional e 10 do 1° trimestre) e nove de cordão umbilical (UC) de 1° trimestre (pareadas com a VC). Quatro placentas de 3° trimestre foram analisadas em separado para o estudo de mosaicismo. O perfil de metilação do DNA das regiões foi verificado por PCR Específica para a Metilação (MS-PCR), Análise Combinada de Bissulfito e Restrição Enzimática (COBRA) e Método de Digestão Enzimática Sensível à Metilação Associada à PCR em Tempo Real (DESM-RT), além do ensaio para hidroximetilação na KvDMR1. Com os ensaios qualitativos (MS-PCR e COBRA) foi observado um perfil de metilação monoalélico, sendo que na H19DMR foi identificada a presença de CpGs diferentemente metilados. Para a H19DMR foram observadas médias de 0,43 de metilação em VC e 0,31 em UC de 1° trimestre, e de 0,41 em VC de 3° trimestre. Para a KvDMR1, foram encontradas médias de 0,47 em VC e 0,57 em UC de 1° trimestre, e de 0,41 em VC de 3° trimestre. A presença de hidroximetilação na KvDMR1 foi excluída. Não foram observadas diferenças significativas entre as médias das diferentes IGs ou entre tecidos pelos testes t e F para ambas as regiões. Não foi observada correlação positiva no perfil de metilação para H19DMR e KvDMR1 entre os tecidos. Em relação ao mosaicismo, não houve diferenças significativas no perfil de metilação entre os diferentes cotilédones amostrados numa mesma placenta. Os resultados demonstram uma discordância entre tecido embrionário (UC) e extraembrionário (VC). Apesar de não serem observadas alterações significantes nos perfis de metilação da H19DMR e KvDMR1 em diferentes IGs, as informações apresentadas são importantes para as pesquisas sobre a dinâmica do fenômeno de imprinting genômico ao longo da gestação, para os estudos de mosaicismo intraplacentário bem como o perfil epigenético da placenta em relação a outros tecidos. / Genomic imprinting, an epigenetically regulated process by which genes are expressed accordingly to their parental origin, is involved in placental growth and development. In 11p15.5 region, there are many genes regulated by two Imprinting Control Regions (ICR1 and ICR2), in which are found two Differentially Methylated Regions, H19DMR and KvDMR1, respectively. Imprinting patterns seem to be adjusted during placenta development. In humans, there is little information on genomic imprinting and placental development, especially for early stages of development due to technical difficulties in obtaining these placentas. The description of mosaicism in methylation pattern restricted to placenta or between placenta and fetus shows a unique epigenetic profile of this organ. The 5-hidroxymethylation, which has no role in gene silencing, can be confused with DNA methylation in molecular analysis. The main aim of our study was to verify the influence of gestational age (GA) in DNA methylation profile of ICRs 1 and 2 in chorionic villi, as well as the existence of intra-placental methylation profile mosaicism. The presence of hydroximethylation in the KvDMR1 was also investigated. Samples were collected from placentas, 25 from chorionic villi (CV) (15 of the 3rd gestational trimester and 10 of the 1st trimester) and nine from umbilical cord (UC) in 1st trimester (paired with the CV samples). Four 3rd trimester placentas were separately analyzed for mosaicism. DNA methylation profile was verified by Methylation Specific PCR (MS-PCR), and Combined Bisulfite Restriction Analysis (COBRA) and Methylation-Sensitive Enzyme Digestion Method associated with Real-Time PCR (DESM-RT), in addition to hydroximethylation test in the KvDMR1 region. With qualitative assays (MS-PCR and COBRA), it was observed a monoallelic methylation pattern, and, only for the H19DMR, differently methylated CpGs were observed. For the H19DMR, we observed methylation means of 0.43 in CV and 0.31 in UC of 1st trimester, and 0.41 in CV of 3rd trimester. For KvDMR1, we observed means of 0.47 in CV and 0.57 in UC of 1st trimester, and 0.41 in CV of 3rd trimester. No hydroximethylation in the KvDMR1 was observed. There were no significant differences between the means of different GAs or between tissues by F and t tests for both regions. No positive correlation was found on methylation profile for H19DMR and KvDMR1 between tissues. In relation to mosaicism, there were no significant differences in methylation profile between different cotyledons sampled in the same placenta. The results showed a discrepancy between embryonic (UC) and extra-embryonic (CV) tissues. Although it was not observed significant changes in methylation profiles of H19DMR and KvDMR1 in different GAs, the presented results are important to research on dynamics of genomic imprinting phenomenon during pregnancy, studies of intra-placental mosaicism and placenta epigenetic profile in relation to other tissues.

Introdução: Os recém-nascidos pré-termo (RNPTs), apesar de apresentarem medidas antropométricas menores ao nascimento quando comparadas a recém-nascidos a termo (RNTs), sofrem um rápido ganho de peso, o qual resulta em maior ganho de massa gorda e menor ganho de massa magra, o que pode elevar o risco a longo prazo de doenças crônicas não transmissíveis e obesidade. Objetivo: Comparar o crescimento e a composição corporal de RNPTs após o nascimento e na idade corrigida com RNTs. Métodos: Estudo longitudinal envolvendo 70 recém-nascidos adequados para a idade gestacional, média de 35,95 (0,66) semanas gestacionais e 58 RNTs com idade gestacional média de 39,91 (0,26) semanas. As avaliações antropométricas e de composição corporal foram feitas de 12 a 72 após o parto e com 40 semanas de idade gestacional corrigida no caso dos RNPTs e de 12 a 72 horas no grupo de RNTs. Foram avaliados peso, comprimento, índice ponderal, circunferência cefálica (CC), circunferência torácica (CT), percentual de gordura, massa gorda, massa livre de gordura, índice de massa gorda e índice de massa livre de gordura. A composição corporal foi estimada por pletismografia pelo equipamento PEA POD® (COSMED USA, Concord, CA, EUA, precisão de 0,1g). As diferenças nas medidas antropométricas e de composição corporal e outras variáveis investigadas entre os grupos de crianças pré-termo e a termo foram calculadas pelos testes ² para variáveis qualitativas e t de Student para variáveis quantitativas. Resultados: Ao nascimento, os valores de peso, comprimento, CC, CT, porcentagem de gordura, massa gorda e massa livre de gordura foram menores no grupo pré-termo (p < 0,05). Na idade corrigida, os lactentes pré-termo apresentaram médias significativamente maiores de peso, comprimento, índice ponderal, porcentagem de gordura, massa gorda em gramas, e índice de massa gorda (p < 0,05). As variáveis massa livre de gordura e índice de massa livre de gordura foram maiores em RNTs (p < 0,0001). Conclusão: Apesar de apresentarem todas as medidas inferiores ao nascimento, RNPTs na idade corrigida tiveram maior acúmulo de gordura e menor ganho de massa magra do que RNTs ao nascimento. / Introduction: Preterm Newborns, despite having lower anthropometric measurements at birth compared to infants at term, experience a rapid weight gain, which results in greater fat mass gain and less lean mass gains. This increase in adiposity may increase the risk of long-term chronic diseases and obesity. Aim: To compare the growth and body composition of preterm infants after birth and corrected age with term newborns. Methods: A longitudinal study involving 70 newborns appropriate for gestational age, with an average of 35,95 (0,66) weeks and 58 term newborns with mean gestational age of 39,91 (0,26) weeks. Anthropometric and body composition evaluations were done 12-72 after delivery and 40 weeks corrected gestational age in preterm group and 12-72 hours in term newborns group. We evaluated weight, length, weight index, head circumference (HC), chest circumference (CC), fat percentage, fat mass, fat free mass, fat mass index and free mass index fat. Body composition was estimated by plethysmography in the PEA POD® equipment (COSMED USA, Concord, CA, USA, Precision 0.1g). The differences in anthropometric and body composition and other variables investigated between preterm and full-term groups were calculated by the ² test for qualitative variables and t test for quantitative variables. Results: At birth, weight, length, HC, CC, fat percentage, fat mass and fat-free mass were lower in the preterm group (p <0.05). In the corrected age, preterm infants had significantly higher mean weight, length, weight index, body fat percentage, fat mass in grams, and fat mass index (p <0.05). Fat free mass and fat free mass index were higher in the term group (p <0.0001). Conclusion: Although they showed all measurements less at birth, preterm infants at corrected age had greater accumulation of fat mass and less fat free mass gain than term newborns.

Introdução: O comprimento telomérico é estudado em vários processos da relação saúdedoença, tais quais estresse oxidativo, processo inflamatório e estresse crônico e parece ser modulado por fatores genéticos e ambientais, além de estar associado a doenças como aterosclerose, doença de Alzheimer, insuficiência cardíaca e disqueratose congênita. Nosso estudo buscou entender a relação entre os telômeros de recém-nascidos e a gestação sob condições adversas. Objetivo: avaliar o impacto da exposição a diferentes ambientes intrauterinos sobre o comprimento de telômeros dos recém-nascidos. Métodos: o comprimento telomérico foi avaliado através do método de qPCR (Razão T/S) de células da mucosa oral de uma amostra conveniência de 239 pares de mãe e recémnascido, divididos nos seguintes grupos de mães: diabéticas (DM) (n=39), hipertensas (HAS) (n=16), tabagistas (n=52), controle (n=99) e mães que tiveram filhos pequenos para a idade gestacional (PIG) (n=33). Resultados: Em todos os grupos observamos uma correlação fraca entre o comprimento telomérico da mãe e da criança (r= 0,229) (p<0,001). Não houve diferença significativa no comprimento telomérico entre os grupos DM, HAS, PIG, Tabaco e Controle. Entretanto, dentro do grupo Tabaco houve diferença significativa numa relação dose-resposta inversa, de maior consumo de cigarro e comprimento telomérico menor, tanto para a mãe (p=0,020) quanto para o recém-nascido (p=0,033). Conclusão: os achados deste estudo sugerem que o uso do tabaco na gestação pode exercer influência negativa sobre o comprimento dos telômeros tanto da mãe quanto do seu filho. / Background: Telomere lenght has been studied in several health-disease processes, such as oxidative stress, inflammatory process and chronic stress. It seems to be influenced by genetic and environmental issues, and it is associated with diseases such as atherosclerosis, Alzheimer's disease, heart failure and congenital dyskeratosis. Our study searched to understand the relationship between newborns telomeres and adverse intrauterine conditions. Objective: to evaluate the impact of exposure to different intrauterine environments on the telomere length of newborns. Methods: the telomere length was evaluated by qPCR (T/S ratio) on oral mucosa cells of a convenience sample of 239 pairs of mother and newborn, divided according to the following groups of mothers: diabetic (DM) (n = 39), hypertensive (HAS) (n = 16), tobacco (n = 52), controls (n = 99) and mothers who had small children for gestational age (SGA) (n = 33). Results: In all groups we observed a weak correlation between the telomere of the mother and the son (r= 0.229) (p <0.001). There was no significant difference in telomere size between DM, HAS, SGAG, Tobacco and Control groups. However, in the Tobacco group there was a significant difference in an inverse dose-response relationship: higher cigarette consumption and lower telomere length, both for the mother (p = 0.020) and for the newborn (p = 0.033). Conclusion: the findings of this study suggest that tobacco use during gestation may induce a negative influence on the telomere length of both the mother and her child.

Thesis (MPH.) -- University of Limpopo, 2018 / Children born preterm and low birth weight may have long-term negative consequences for visual function, compared with children born at full term. Visual memory (sensory), perceptual skills and learning are of fundamental importance for a range of functions and everyday activities, such as normal classroom learning, school performance and social interactions and may contribute to academic difficulties.The purpose of this study was to investigate the effect of gestational age and birth weight on visual perceptual skills.The study was approved by the University of Limpopo, Turfloop Research Ethics Committee. The Department of Education, Limpopo Province granted permission to conduct the study. Written informed consent was obtained from parents of the children and the study adhered to the tenets of the Helsinki Declaration.

Vitamin D status is assessed with circulating 25-hydroxyvitamin D [25(OH)D]. As some evidence suggests that low vitamin D status adversely affects neonatal health, this project aimed to determine the association between cord blood 25(OH)D levels and preterm birth (PTB; <37 weeks gestation), low birthweight (LBW; <2500 grams) and small for gestational age (SGA; <10th percentile) and to examine the relationship between maternal 25(OH)D levels during the first trimester of pregnancy and fetal 25(OH)D levels at birth in a Canadian population. This nested case-control study used serums, questionnaires and chart reviews collected in Quebec City. Compared to 25(OH)D concentrations ≥75 nmol/L, concentrations 37.5-<75, 50-<75, and <75 nmol/L were associated with lower odds of LBW, PTB and an adverse neonatal composite outcome, and PTB as well as LBW, respectively. Maternal and neonatal 25(OH)D were correlated (r=0.23, p<0.01; adjusted r=0.46, p<0.01). This study contributes to evidence for identifying further policy and research directions.

Introduction: The past decade has seen a significant shift in the demographics of childbearing in the United States. The average age of women at first birth has steadily increased over the last four decades, with the birth rate for women aged 40-44 more than doubling from 1990 to 2012. The aim of this study was to evaluate the risk of adverse pregnancy outcomes with increasing maternal age and paternal age using national health statistics data. Methods: The study population included 3 495 710 live births among women 15-54+ years of age from the 2012 Natality dataset. Outcomes were modeled for both maternal and paternal 5-year age groups using logistic regression analysis to calculate adjusted and unadjusted odds ratios (AORs, ORs) with 95% confidence intervals. Analysis was performed to examine the association between maternal and paternal age across seven different adverse outcomes, including low birthweight, low Apgar score, early term pregnancies, abnormal newborn conditions and presence of congenital anomalies. Results: The risks for most outcomes paralleled with advanced maternal age and paternal age. Logistic regression models demonstrated that maternal age groups 40-44, 45-49 and 50-54+ were at highest risk for an adverse pregnancy outcome compared to the 30-34 year old reference group. Abnormal newborn conditions including assisted ventilation, NICU admission and use of antibiotics were significant for all age groups 40 and older. Low Apgar score, low birthweight and early term pregnancies were significantly higher among mothers as well as fathers with advanced age. Conclusions: These findings suggest that advanced maternal age is a risk factor for a variety of adverse pregnancy outcomes. Women aged 35-39 have a similar risk of an adverse outcome as their younger counterparts. This suggests that perhaps we should begin assessing high-risk pregnancies as starting at an older age versus the de facto standard of 35.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

The adverse effects of maternal smoking on infant mortality and morbidity has been well documented in the literature. Maternal tobacco use is causally associated with fetal growth restriction and correlates negatively with folate intake and metabolism. Studies have examined the association between smoking and folate levels during pregnancy, but very few have assessed this relationship using objective and accurate measures of both variables. Furthermore, despite evidence of a causal association between smoking in pregnancy and intrauterine growth restriction, and a plausible relationship between tobacco use and low maternal folate which is required for optimal fetal growth, no experimental study has investigated the potential benefit of folic acid in mitigating the adverse effects of maternal smoking on fetal outcomes. The objectives of this study were to investigate the relationship between maternal smoking and folate levels and examine the efficacy of higher-strength folic acid supplementation, in combination with enrollment in a smoking cessation program, in promoting fetal body and brain growth. Our hypothesis was that women who smoke during pregnancy have lower peri-conceptional folic acid reserves than non-smoker pregnant women and that folic acid reserves will decrease with increasing cotinine level. Additionally, smoker pregnant women on higher-strength folic acid (4mg daily) in combination with smoking cessation programs will experience faster fetal brain growth and have infants with larger body size at birth compared to smokers on the standard dose of folic acid (0.8mg daily). Participants were pregnant women (smokers and non-smokers) who received antenatal care between 2010-2014 at the Genesis Clinic of Tampa, a community health center affiliated with the Department of Obstetrics and Gynecology of the University of South Florida (USF). They were aged 18-44 years and had a gestational age of less than 21 weeks at study enrollment. To determine the peri-conceptional folic acid reserves in smoking versus nonsmoking women during pregnancy and associated sociodemographic factors, baseline (crosssectional) data from a double-blinded randomized controlled trial were analyzed using Tobit regression models (n=496). Smoking information was assessed using salivary cotinine, a sensitive and specific tobacco use biomarker. Folate reserve was measured using red blood cell folate. To investigate the efficacy of higher-strength folic acid on fetal body and brain size, baseline and follow-up data from pregnant smokers enrolled in the randomized controlled trial were utilized (n=345). All primary analyses of the clinical trial data were conducted on a modified intention-to-treat basis and included participants who completed the trial with an observed endpoint, irrespective of compliance to protocol. Multilevel modeling, linear regression, and log-binomial regression analyses were conducted. A significant inverse association between salivary cotinine level and periconceptional red blood cell folate concentration was found among pregnant women in the early to midpregnancy period. Smokers on high-dose folate during pregnancy had infants with a 140.38g higher birth weight than infants of their counterparts on standard dose folate (P =0.047). Mothers who received higher strength folate had a 31.0% lower risk of having babies with SGA compared to their mothers on the standard-dose (adjusted relative risk-ARR=0.69, 95% CI: 0.46–1.03; (P =0.073)). High-dose folate had no significant effect on the intrauterine rate of growth in head circumference, and head circumference and brain weight at birth in our trial sample. However, the brain-body ratio of infants of mothers who received high-dose treatment was 0.33 percentage-point lower than that for infants of mothers who received the standard dose of folate (P =0.044). Higher strength folic acid supplementation in pregnant women who smoke might be a cost-effective and safe option to improve birth outcomes and reduce low birth weight and SGA associated infant morbidity and mortality. Future studies with larger sample sizes and diverse populations are indicated to confirm or refute the results of this study. Randomized controlled trials starting during the preconception period and with follow-up until delivery are warranted, to identify the most folate-sensitive period of fetal growth and determine the optimal dose of folic acid supplement. Further research investigating several pathways through which the effects of prenatal smoking on adverse birth outcomes can be mitigated is needed.