While previous studies have found that a preterm (PT) birth leads to a higher risk for numerous adverse outcomes, including neurodevelopmental and behavioural problems, few, if any, have investigated the consistency of conceivable behavioural problems over time. The aim of this study was to investigate the existence and the stability of behavioural problems from four to eight years of age in a group of 18 children born PT without diagnosed neurological or developmental morbidity, in comparison to a group of 19 children born full term (FT). Additionally, the effects of gestational age (GA) as well as possible associations between behavioural problems and cognitive ability were investigated. Also, differences related to parents’ level of education were observed. Behavioural problems were evaluated with Child Behavior Checklist (CBCL) and cognitive ability was assessed at eight years of age by using Wechsler Intelligence Scale for Children (WISC-IV). Results showed significant differences between the groups regarding cognitive ability where children born PT had lower scores. Contrary to most previous findings, no evident differences between the two groups regarding amount of behavioural problems were found. Children born PT increased in amount of anxiety problems from four to eight years of age, while children born FT decreased, and a lower GA was related to increasing oppositional defiant problems. Generally, the mothers of children born PT had a lower level of education than those of the FT group. Thus, interpretations with caution due to the relatively small number of participants, these initial findings reveal the need for further prospective follow-up studies on the relationship between birth status and the change of behaviour problems in relation to both inter- and intra-effectors over time. / Tidigare forskning har visat att en för tidig födsel leder till en ökad risk för ett antal ofördelaktiga utfall, inklusive neuroutvecklingsrelaterade svårigheter och beteendeproblem. Få studier, om några, har undersökt stabiliteten av potentiella beteendeproblem över tid. Syftet med denna studie var att undersöka förekomst och stabilitet av beteendeproblematik mellan fyra till åtta års ålder i en grupp bestående av 18 barn födda för tidigt, utan neurologiska eller utvecklingsrelaterade störningar, jämfört med 19 barn födda fullgångna. Vidare undersöktes effekten av gestationsålder samt möjliga associationer mellan beteendeproblem och kognitiv förmåga. Skillnader i föräldrarnas utbildningsnivå mellan grupperna undersöktes också. Beteendeproblem skattades med Child Behavior Checklist (CBCL) och kognitiv förmåga bedömdes vid åtta års ålder med hjälp av Wechsler Intelligence Scale for Children (WISC-IV). Resultaten visade signifikanta skillnader mellan grupperna gällande kognitiv förmåga, där barn födda för tidigt hade lägre poäng. I motsats till vad flera tidigare studier funnit så visade vår studie inga signifikanta skillnader mellan grupperna gällande omfattning av beteendeproblem. Barn födda för tidigt uppvisade en ökning av ångestproblem från fyra till åtta års ålder medan barn fullgånget födda uppvisade en minskning, och lägre gestationsålder korrelerade med ökade trotsproblem. Generellt sett så hade mödrar till barn födda förtidigt en lägre utbildningsnivå än de i den fullgångna gruppen. Med försiktiga tolkningar på grund av det relativt låga antalet deltagare visar resultaten ett behov av vidare uppföljningsstudier av sambanden mellan födelsestatus och förändringen av beteendeproblem i relation till både inter- och intra-påverkande faktorer. / The relation between sensory-motor, behaviour functioning and brain development in preterm born children

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / Antepartum suicidal behaviors are a leading cause of maternal injury and death. Previous research has not investigated associations between antepartum suicidal ideation and perinatal complications. Our study objective was to evaluate the relationship of antepartum suicidal ideation with low infant birthweight, small for gestational age, and preterm birth. A cohort study was conducted among 1,108 women receiving prenatal care in Peru. Suicidal ideation was measured using the Patient Health Questionnaire-9 during pregnancy. Birth outcomes were extracted from medical records. Linear regressions and multivariable logistic regressions were used to estimate were used to investigate associations between suicidal ideation and pregnancy outcomes. The prevalence of suicidal ideation was 8.7%, preterm delivery was 5.7%, low birthweight was 4.4%, and small for gestational age was 3.4%. In an adjusted model, infant birthweight was 94.2 grams lower for mothers with antepartum suicidal ideation (95% CI: −183.0, −5.5, p = 0.037) compared with those without suicidal ideation. After adjusting for confounders including depression, participants with suicidal ideation had a nearly four-fold increased odds of delivering a small for gestational age infant (OR: 3.73; 95% CI: 1.59–8.74). These findings suggest suicidal ideation during pregnancy is associated with adverse perinatal outcomes, especially low infant birthweight. / Revisión por pares

This thesis uses a multi-disciplinary approach to study cognitive-neurophysiological processes underlying attention-deficit/hyperactivity disorder (ADHD), and the underlying risk pathways from preterm birth to ADHD. In the first part of the thesis we use a measure of peripheral arousal (skin conductance) to better understand arousal dysregulation in ADHD and how it relates to cognitive performance. We show, using a large ADHD and control sibling sample, that ADHD is associated with peripheral hypo-arousal, and that a familial aetiology underlies the relationship between hypo-arousal and fluctuating reaction times, and between hypoarousal and ADHD. Our findings further suggest that peripheral hypo-arousal is an enduring deficit in ADHD, as it is observed in both ADHD remitters and ADHD persisters in our followup investigation. The second part of the thesis focuses on preterm birth as a risk factor for ADHD: we compare data we obtain from a new sample of preterm-born adolescents and their siblings to data from ADHD and control sibling pairs. First, we find that preterm-born individuals show several of the same cognitive-neurophysiological impairments as individuals with ADHD, but they also show further, additional impairments. Second, our results indicate that cognitive-neurophysiological impairments in the preterm group differentiate into those that are in line with a causal effect of preterm birth, and those that are not. Third, our findings further suggest that the association between ADHD symptoms and specific cognitive impairments is largely due to familial influences among term-born individuals, but largely due to non-shared effects (including preterm birth as an environmental insult) among pretermborn individuals. Overall, by using a combination of cognitive, neurophysiological, developmental and sibling-comparison designs, our findings provide new insight into arousal dysregulation in individuals with ADHD, and inform on cognitive-neurophysiological and aetiological processes that may underlie the association between preterm birth and ADHD.

Background: Environmental chemicals may interrupt physiological adaptations necessary in pregnancy, contributing to pregnancy complications with health implications for the mother and child. Nutrients may modify the impact of chemical exposures by blocking their absorption or facilitating their excretion. However, the nature, directionality, and implications of these relationships remain unclear. Objectives: We sought to understand: 1) the potential bidirectional nature of the relationship between vitamin D (25-hydroxyvitamin D, 25OHD) and the toxic metals cadmium (Cd) and lead (Pb) in pregnancy; 2) the association between metals (Cd, Pb, arsenic (As), mercury) and preterm birth and the potential modification of that association by 25OHD; and 3) the long-term association of pregnancy complications with maternal cardiometabolic health. Methods: We used data from the Maternal-Infant Research on Environmental Chemicals Study (n=1983) pregnancy cohort, including long-term follow-up approximately 9 years post-pregnancy. We used cross-lagged panel models to determine the direction of the relationship of 25OHD with Cd and Pb in pregnancy, discrete-time survival analysis to examine the association between metals in pregnancy and preterm birth, and multivariable linear regression to investigate the association of pregnancy complications with long-term maternal outcomes. Results: Each doubling in first trimester 25OHD concentrations was associated with 9% (95% CI: -15%, -3%) lower 3rd trimester Cd and 3% (-7, 0.1%) lower Pb. One-unit increases in Pb (μg/dL) and arsenic (μg/L) concentrations in pregnancy were associated with an increased relative risk (RR) of preterm birth (RR_Pb: 1.48, 95% CI: 1.00, 2.20; RR_As: 1.10, 95% CI 1.02, 1.19); the association with Pb was stronger among those with lower 25OHD. Finally, relative to uncomplicated pregnancy, experiencing a pregnancy complication was positively associated with body fat percentage (β=2.6, 95% CI: 0.3, 4.8) and systolic (average increase of 9.0 mm Hg, 95% CI 5.1, 12.8) and diastolic (average increase of 5.5 mm Hg, 95% CI: 2.6, 8.4) blood pressure 9 years later. Conclusions: Nutrient status during pregnancy may affect and interact with environmental chemicals to impact pregnancy outcomes. Future studies should continue to use methods that elucidate the causal direction of associations and evaluate interactions. Chemicals associated with pregnancy complications could have lasting impacts on maternal health.

Preterm birth is the leading cause of neonatal mortality and long-term morbidity. Neonatologists can adjust nutrition to preterm neonates to control their weight gain so that the possibility of long-term morbidity can be minimized. This optimization of growth trajectories of preterm infants can be achieved by studying a cohort of selected healthy preterm infants with weights observed during day 1 to day 21. However, missing values in such a data poses a big challenge in this case. In fact, missing data is a common problem faced by most applied researchers. Most statistical softwares deal with missing data by simply deleting subjects with missing items. Analyses carried out on such incomplete data result in biased estimates of the parameters of interest and consequently lead to misleading or invalid inference. Even though many statistical methods may provide robust analysis, it will be better to handle missing data by imputing them with plausible values and then carry out a suitable analysis on the full data. In this thesis, several imputation methods are first introduced and discussed. Once the data get completed by the use of any of these methods, the growth trajectories for this cohort of preterm infants can be presented in the form of percentile growth curves. These growth trajectories can now serve as references for the population of preterm babies. To find out the explicit growth rate, we are interested in establishing predictive models for weights at days 7, 14 and 21. I have used both univariate and multivariate linear models on the completed data. The resulting predictive models can then be used to calculate the target weight at days 7, 14 and 21 for any other infant given the information at birth. Then, neonatologists can adjust the amount of nutrition given in order to preterm infants to control their growth so that they will not grow too fast or too slow, thus avoiding later-life complications. / Thesis / Master of Science (MSc)

The major objective of the research is to assess the risk of preterm birth associated with maternal proximity to hazardous waste and pollution from the Sydney Tar Pond sites in Nova Scotia, Canada. The design is spatial modelling of risks of preterm birth in population living in the Cape Breton regional municipality in 1996. The subjects are: 1604 observed cases of preterm birth out of total population of 17559 at risk in 1996. The analysis was done using both the frequentist and the Bayesian approaches. In the frequentist approach, the Poisson model for aggregated data was fitted using the quasi-likelihood approach to accommodate over-dispersion. Weighted regression was also used. In order to accommodate both the random effect and the anticipated spatial effects, Bayesian hierarchical modelling was also used to fit the Poisson model. The result of the Bayesian modelling shows that there is no significant spatial association of risk in the area studied. All the models also show that there is no decrease in risk of preterm birth as we move from the Tar Pond site to other region. None of the other covariates in the model show any significant association with increase risk of preterm birth either. There was no obvious clustering of risk in any region or part. / Thesis / Master of Science (MS)

Globally, in both developed and developing countries, the twinning rates have increased since the early 70’s. A large proportion of twins are born preterm and/or small-for-gestational-age (SGA) and/or with a low birth weight. Several studies have been performed on the long-term effect of these non-optimal birth characteristics on future reproductive performance and morbidity. Yet, most studies exclude twins or higher order pregnancies and thus the findings are based on singleton pregnancies only. The aim of the present thesis was therefore to investigate the impact of non-optimal birth characteristics in terms of preterm birth, small-for-gestational age, and low birth weight, on the reproductive pattern and morbidity among twins and singletons Furthermore, the present thesis attempted to establish whether twins and singletons were affected in the same manner. The studies included in this thesis are prospective population-based register studies, including all men and women, alive and living in Sweden at age 13, who were born between 1973 and 1983 (1,000,037 singletons and 16,561 twins) for the first three studies with follow-up till the end of 2006 and 2009. The last study included all men and women, alive and living in Sweden at age 13, who were born between 1973 and 1993 (2,051,479 singletons and 39,726 twins) with follow-up till the end of 2012. In general, twins were found less likely to reproduce between 13 and 33 years of age compared with singletons. Stratifying data by different birth characteristics, it was found that twins had a lower likelihood of reproducing on several different birth characteristics (appropriate-for-gestational-age, normal birth weight, low birth weight, term birth, preterm birth). However, twins born very preterm had an increased likelihood of reproducing compared with singletons born very preterm. Not taking birth characteristics into account, twinning was associated with a higher degree of hospitalization. However, accounting for the diverging birth characteristics this difference diminished and for some diagnoses the relationship was reversed such that twins were actually less likely to be hospitalized compared with singletons. In terms of the heritability of non-optimal birth characteristics singleton mothers born preterm were more predisposed to give birth to a child that was preterm while singleton mothers born SGA more often gave birth to a child either born preterm or SGA. Among twins this heritability was not as evident. The only difference observed was among twin mothers born SGA who were more likely to give birth to a child born SGA. In the extended cohort comprising those born between 1973 and 1993, male and female twins were found to be less likely to become parents compared with singletons. No difference was found among women in terms of having a second child, while male twins were more likely to have a second child compared with male singletons. It was also found that the likelihood of becoming a first-time parent and second-time parent was positively associated with the number of siblings.

Worldwide, more than 1 million infants die as a result of premature birth. In the United States, where 1 in 10 births occurs preterm, premature birth is the leading cause of infant mortality. Premature infants have high rates of mortality and morbidity, with the highest rates seen in those infants born extremely preterm -- prior to 30 weeks gestation. Severe morbidity in these infants often contributes to life-long health problems. Maternal hypertension (HTN) is one contributor to preterm birth and also contributes to fetal growth restriction, resulting in birth weights which are small for gestational age (SGA, and generally within the lowest 10th percentile). Within this high risk population, SGA infants have increased risk of mortality compared to appropriate for gestational age infants. Therefore the impact of maternal HTN on neonatal outcome might be presumed to be negative. Previous studies however, have been contradictory, with both higher and lower rates of infant mortality reported in infants born to mothers with HTN, as well as differing reports analyzing the relationship between serious morbidity and maternal HTN. Utilizing the Vermont Oxford Network Very Low Birth Weight database, a collaborative database of Level III Neonatal Intensive Care Units across the world, 88,275 North American infants born between 22+0 and 29+6 weeks gestational age between 2008 and 2011 were identified. This dissertation explores the relationship between maternal HTN and gestational age at time of birth within this population, and the reported rates of morbidity and mortality in infants born prior to 30 weeks gestation. The independent contributions of maternal HTN with neonatal morbidity and mortality in our population were estimated using logistic regression and adjusting for factors previously known to be associated with risk, including birth weight, antenatal steroid exposure, infant sex, maternal race/ethnicity, prenatal care, inborn/outborn status, and birth year. We hypothesized that mortality rates would be lower for infants born to mothers with HTN compared to those born due to other factors, when corrected for the noted confounding variables and surviving infants would have better prognoses, as evidenced by lower rates of severe morbidity, including bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, and infection. Within the higher-risk SGA population, we hypothesized that mortality rates would be higher than observed in appropriately grown infants, but decreased in those born to mothers with HTN, despite the association between maternal HTN and SGA. This dissertation begins with an explanation of current knowledge about preterm birth, maternal HTN, and their associations. Chapter 2 focuses on the relationship between maternal HTN and infant mortality in extremely preterm infants. Chapter 3 examines the risk associated with severe morbidities in surviving infants. In addition, we also use a combined morbidity risk assessment score which has previously been used to determine future risk of long term disability. In Chapter 4, SGA infants are separately evaluated for their risk of mortality and the association with maternal HTN. These analyses support the high mortality and morbidity rates seen in extremely preterm infants. Maternal HTN, after adjustment, results in reduced risk of both mortality and severe morbidities in infants compared to infants born to mothers with other underlying contributors to preterm birth. This suggests that clinical practices and parental counseling should reflect differing risk profiles in sub-populations of extremely preterm infants.

Preterm birth is defined as delivery prior to 37 weeks’ completed gestation. It affects an average of 11% of pregnancies worldwide and is the leading cause of death in children under age 5. Many studies have identified associations between pregnancy lipid levels and increased risk for preterm birth. This thesis investigates the role of genetic variability associated with lipids and its relationship with preterm birth, and the relationship between pre-pregnancy dyslipidemia and risk for preterm birth. Genetic variability in the form of single-nucleotide polymorphisms, previously identified by genome-wide association studies for association with lipid levels, was analyzed for association with risk for preterm birth. The study population included 992 women in California with banked 2nd trimester serum samples. Serum lipid levels and DNA were used. Genetic risk scores were constructed for each subject using published SNPs associated with lipid levels as an indicator of genetic burden. These genetic risk scores were then analyzed for association with risk for preterm birth. The GRS were not associated with the overall risk for preterm birth. However, a higher HDL-C GRS was associated with increased risk for spontaneous preterm birth. Higher triglyceride and total cholesterol GRS were associated with decreased risk for spontaneous preterm birth. The relationship between pre-pregnancy dyslipidemia and risk for preterm birth was assessed in a cohort of 2,962,434 women giving birth in the state of California from 2007-2012. Dyslipidemia, as defined by medical diagnostic codes, was associated with a 1.5-fold increase in risk for preterm birth. This association was consistent across race/ethnicity, body mass index, type of dyslipidemia, and type of preterm birth. This thesis identified counter-intuitive associations between lipid GRS and spontaneous preterm birth, while also identifying a strong relationship between pre-pregnancy dyslipidemia and all types of preterm birth including spontaneous. Together, these findings suggest that the previously reported associations between lipids and preterm birth may be reflecting unidentified dyslipidemias. One possible interpretation of the counter-intuitive genetic findings is that while extreme dyslipidemia predisposes to preterm birth a genetic predisposition to low total cholesterol also confers increased risk for spontaneous preterm birth. An alternative explanation is that these results are simply an artefact of the data and additional genetic loci and lifestyle factors confer stronger effects on risk for spontaneous PTB than the effects of the genetic loci included in this thesis.

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