Definition of neurodevelopmental outcome from early brain imaging remains a priority for survivors of very preterm (VPT) birth given their persistently high rates of cognitive and motor difficulties. Volumes of the deep grey matter (DGM) structures were measured longitudinally using magnetic resonance imaging from 96 VPT infants studied within 2 weeks of birth and 70 at term-equivalent age. At 4 years of age, 36 children returned for neuropsychological assessments evaluating IQ, language function, and visual motor integration. Multiple hierarchical regressions examined associations of DGM growth with neuropsychological measures. Overall DGM growth, primarily attributed to the caudate and thalamus, predicted Full Scale IQ, core language and VMI scores after controlling for sex and total brain volume. Thalamic growth was additionally associated with measures of neonatal clinical severity, bronchopulmonary dysplasia, and white matter lesions. Longitudinal growth of the DGM, particularly the caudate and thalamus were established as early markers of long-term outcomes.

Background Preterm birth is a leading cause of perinatal morbidity and mortality worldwide, resulting in a pressing need to identify risk factors leading to effective interventions. Limited evidence suggests potential relationships between maternal sleep or vital exhaustion and preterm birth, yet the literature is generally inconclusive. Methods We examined the relationship between maternal sleep duration and vital exhaustion in the first six months of pregnancy and spontaneous (non-medically indicated) preterm birth among 479 Peruvian women who delivered a preterm singleton infant (<37 weeks gestation) and 480 term controls who delivered a singleton infant at term (≥37 weeks gestation). Maternal nightly sleep and reports of vital exhaustion were ascertained through in-person interviews. Spontaneous preterm birth cases were further categorized as those following either spontaneous preterm labor or preterm premature rupture of membranes. In addition, cases were categorized as very (<32 weeks), moderate (32–33 weeks), and late (34- <37 weeks) preterm birth for additional analyses. Logistic regression was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). Results After adjusting for confounders, we found that short sleep duration (≤6 hours) was significantly associated with preterm birth (aOR = 1.56; 95% CI 1.11-2.19) compared to 7–8 hours of sleep. Vital exhaustion was also associated with increased odds of preterm birth (aOR = 2.41; 95% CI 1.79-3.23) compared to no exhaustion (Ptrend <0.001). These associations remained significant for spontaneous preterm labor and preterm premature rupture of membranes. We also found evidence of joint effects of sleep duration and vital exhaustion on the odds of spontaneous preterm birth. Conclusions The results of this case–control study suggest maternal sleep duration, particularly short sleep duration, and vital exhaustion may be risk factors for spontaneous preterm birth. These findings call for increased clinical attention to maternal sleep and the study of potential intervention strategies to improve sleep in early pregnancy with the aim of decreasing risk of preterm birth.

Increasing evidence highlights that term labour is an inflammatory event associated with increased production of pro-­‐inflammatory mediators and leukocyte influx into the intrauterine tissues. Preterm labour (PTL), defined as labour before 37 weeks gestation, is a major clinical problem, and preterm birth is the leading cause of neonatal mortality and morbidity worldwide. The causes of PTL are poorly understood, but intrauterine infection and inflammation have been shown to be important factors. Therefore, there is growing interest in the hypothesis that preterm labour may occur as a result of the premature activation of the inflammatory pathways normally initiated with labour at term, either idiopathically, or in response to a pathological intrauterine infection. The aim of this thesis was to use a mouse model of infection-­induced PTL to: characterise the local inflammatory and immune response to an intrauterine infection; investigate the potential of anti‐inflammatory agents to delay delivery of pups and to improve their survival; and to investigate the role of specific immune cell populations in infection-­induced preterm labour. To characterise the inflammatory and immune response to intrauterine infection, CD1 mice received an intrauterine injection of PBS vehicle or increasing doses of bacterial-­derived lipopolysaccharide (LPS) on day 17 of gestation. Time to delivery, and the number of live born pups were determined. Intrauterine administration of increasing doses of LPS dose-­dependently induced preterm labour and reduced the proportion of live born pups. Analysis of tissues harvested six hours post-­surgery demonstrated that in response to intrauterine LPS administration, there was increased expression of inflammatory cytokines and chemokines within the utero-­placental tissues, amniotic fluid and maternal serum; and an influx of neutrophils into the decidua, compared to mice receiving PBS. Given these results, the potential of anti‐inflammatory agents to delay LPS-­induced preterm delivery and improve pup survival was then investigated using the same mouse model. Prior to intrauterine LPS administration, mice were pre-­‐treated with epi-­lipoxin, BML-­111 (a stable lipoxin analogue), or IL-­10. Time to delivery was unaffected by pre-­treatment with the anti-­inflammatory agents, however epi-­lipoxin significantly increased the proportion of live born pups in mice delivering preterm, compared to mice receiving only LPS. To further investigate the role of immune cells in infection-­induced PTL, antibody-­based depletion strategies were used to selectively deplete specific immune cell populations to determine whether they played a causative role in LPS­‐induced preterm delivery. Despite successful depletion of macrophages or neutrophils, it was not found to significantly affect LPS-­induced preterm delivery, suggesting these immune cells are not required for the induction of preterm labour in response to intrauterine infection. However, it is likely that they contribute to the intrauterine inflammatory response as depletion resulted in altered inflammatory signalling within the intrauterine tissues. Collectively, this work has demonstrated that the presence of intrauterine bacterial LPS, as a surrogate model of infection, induces a robust inflammatory and immune response within the utero‐placental tissues that involves the increased production of inflammatory mediators and the influx of immune cells into the decidua, which ultimately leads to PTL. Whilst the anti-­inflammatory treatments tested here did not delay LPS-­induced PTL, epi-­lipoxin attenuated LPS-­induced mortality in pups born preterm, suggesting this anti‐inflammatory agent may be useful in protecting the fetus from the adverse effects of infection-­induced preterm birth. Using models such as the one described here, are vital to improving our understanding of the events regulating the induction of PTL and will ultimately aid the search for novel therapeutic options for the treatment of PTL.

Background and Aim: Preterm infants frequently receive blood transfusion (BT) during their stay in the neonatal unit. The aim of this study was to measure the effect of BT on cerebral and gut blood flow and oxygenation in preterm infants in relation to postnatal age. Another aim of the study was also to investigate the influence of measured pre-transfusion RCV on gut perfusion in preterm infants receiving first blood transfusion for clinical indication using NIRS and Doppler ultrasound scan. Methods: Preterm infants admitted to neonatal unit were recruited to three postnatal age groups: 1 to 7 days (group 1; n=20), 8 to 28 days (group 2; n=21) & ≥29 days of life (group 3; n=18). Pre and post-BT Anterior Cerebral artery (ACA) Time Averaged Mean Velocity (TAMV) and Superior Vena Cava (SVC) flow were measured to assess cerebral blood flow. Pre and post-BT Superior mesenteric artery (SMA) peak systolic velocity was measured to assess gut or splanchnic blood flow. Cerebral and gut Tissue Haemoglobin Index (THI), Oxygenation Index (TOI) were measured from 15-20 minutes before to 15-20 minutes post-BT using NIRS. Cerebral and gut fractional tissue oxygen extraction (FTOE) was calculated from the TOI and saturation of oxygen (SaO2). Vital parameters and blood pressure (BP) were also measured continuously from overhead monitors. Pretransfusion red cell volume (RCV) was measured by fetal haemoglobin (HbF) dilution method and compared with the cerebral and gut perfusion and oxygenation changes following blood transfusion. The cerebral and gut perfusion and oxygenation were also measured over a three hour period in 12 control infants not receiving blood transfusion. Results: There were 71 infants included in the study; of them 59 were study infants receiving blood transfusion and 12 were control infants. Amongst the vital parameters, mean BP increased significantly, and there was no significant change in heart rate (HR), respiratory rate (RR) or SaO2 following BT. Pre-transfusion ACA TAMV was higher in Group 2 and 3 compared to Group 1 (p < 0.001) which remained significant after multivariate analysis (p < 0.05). Pretransfusion ACA TAMV decreased significantly (p≤0.04) in all 3 postnatal age groups; pre-transfusion SVC flow decreased significantly in Group 1 (p=0.03) and Group 3 (p < 0.001) following transfusion. Pre-transfusion cTOI was significantly lower in Group 3 compared to Group 1 (p=0.02) which remained significant after multivariate analysis (p < 0.011). The cTHI (p < 0.001) and cTOI (p < 0.05) increased significantly post-transfusion in all three postnatal age groups. PDA had no effect on these measurements. Pre-transfusion SMA PSV increased with postnatal age (group 3 vs. group 1: p < 0.01; CI 0.6 to 0.1), proportion of feeds (> 50% feeds: 0.91±0.4 vs. < 50% feeds: 0.71±0.4 m/sec, p < 0.01); and decreased with presence of PDA (closed PDA: 0.94±0.4 vs. open PDA: 0.68±0.3 m/sec, p=0.006, CI 0.07 to 0.45); but remained unaltered following transfusion. The pre-transfusion sTOI varied with postnatal age (Group 2:44.6 vs. Group1: 36.7%; p=0.03, CI -0.6 to -15.2) on univariate analysis but was not significantly different on multivariate analysis; pre-transfusion sTOI was not influenced by feeds or presence of PDA. The sTHI and sTOI increased (p < 0.01) and sFTOE decreased (p < 0.01) significantly following transfusion in all postnatal age groups.

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

Due to a steady increase in the number of babies born prematurely over the past 20 years, prematurity (a birth occurring before 37 weeks gestation) has emerged as an important public health concern. Even with improved survival of these infants, they remain at risk for many unfavorable health outcomes. Most of those risks include cognitive and behavioral deficits that show up later in life, highlighting the importance of studying the development of the brain, in particular. The current study investigates brain development outcomes in the first years of life using: (1) structural magnetic resonance imaging (MRI) to study brain structure, and (2) three novel cognitive assessments of visual working memory, attention, and speed of processing information. Healthy 12-month-old infants were recruited through University of Iowa’s Neonatal Admissions Registry. An MRI imaging acquisition protocol was developed in order to scan infants during their naptime without sedation. Additionally, a new automatic approach to classifying areas of the brain was developed at the University of Iowa Department of Radiology for 12-month-old brain images. These novel cognitive assessments are based on infant eye movements (including how long it takes for an infant to react to certain stimuli and the direction of their looking). Results from this study support the use of these cognitive tasks to detect specific functional changes in performance based on gestational age. Therefore, these tasks may be potential early markers of risk in preterm populations, but continued investigations are necessary to fully elucidate early brain outcomes during this critical period of development.

Preterm birth (PTB) is a global public health problem that has significant adverse effects on neonatal mortality and morbidity. Progress in understanding the pathological mechanisms underlying PTB has been greatly hampered by the complex and polygenic nature of the disease. As a result, a multifaceted approach may hold promise for identifying true causal factors. The main objective of this thesis is to identify genes that play a role in the etiology of PTB using experimental data derived from different molecular levels (genome, transcriptome, and epigenome). To achieve this goal, we performed association studies using a candidate gene approach to identify genetic factors contributing to PTB. Our analysis of genetic variants in three OXT pathway genes (oxytocin (OXT), oxytocin receptor (OXTR), and leucyl/cystinyl aminopeptidase (LNPEP)) revealed several common polymorphisms in LNPEP that show significant association with prematurity. Large-scale sequence analysis of the OXTR gene identified several novel rare coding variants that might be of etiologic importance. Our results suggest that these variants, in aggregate, appear to make some contribution to susceptibility to PTB. We also examined the gene expression profiles in the human placenta to identify, at the transcriptomic level, candidate genes for PTB. Using splicing-sensitive microarray and deep sequencing technologies, we identified transcriptome signatures that differ between term (with and without labor) and preterm placental tissues and between placental and other human tissues. The transcriptome data were analyzed not only at the gene-level, but also at the exon-level, enabling the detection of alternative splicing events. The exon-level analysis revealed more frequent disruption of alternative splicing in preterm than term placental tissues, indicating that alternative splicing may represent one possible mechanism contributing to PTB. Our study at the epigenomic level was pursued through investigation of placental DNA methylation profiles. We, using a genome-wide approach, detected a panel of genes showing labor- and gestational age-associated methylation differences. Selected genes were validated using bisulfite sequencing and methylation-specific PCR. SLC30A3, a validated differentially methylated gene between term labor and preterm labor amnion tissues, for instance, may potentially play a role in the pathogenesis of PTB. Taken together, this thesis work provides a valuable source of novel candidate genes for PTB, and future research using integrative systems biology approaches may shed light on the molecular mechanisms underlying this complex, heterogeneous disease.

The central nervous system (CNS) develops in a temporally and spatially organised manner. Any adverse events happening during the critical periods of early brain formation may lead to arrest in the process or injury to specific developed structures. Infants born at less than 30 weeks of gestation and those with intra-partum asphyxia are at risk of motor delay. The cause of this delay may be related to injuries in the brain such as the motor cortex, basal ganglia and cerebellum, all of which are essential in controlling movements. According to the dynamical systems theory of motor development, other than the CNS, body systems within the infant such as the musculoskeletal system, and external to the infant such as environmental enrichment and supportive child-rearing practice also have a decisive role in motor development in infants. / Paediatric physiotherapists have been involved in the management of these infants since birth. A number of well-established assessment tools are used to assess these infants’ motor functions. Most of these tools typically do not describe the movement patterns of infants but emphasise the achievement of age-specific motor milestones. The Alberta Infant Motor Scale (AIMS) is one of the few tools that acknowledge the importance of movement quality. / The overall aim of the present research was to examine the impact of adverse events in early infancy, including birth prior to 30 weeks of gestation and intra-partum asphyxia, on motor development of infants during the first two years of (corrected) age. One hundred and twenty infants were recruited, including 58 preterm infants, 10 infants with post-asphyxia neonatal encephalopathy (NE) and 52 term born infants as the control group. All the infants were assessed using the AIMS at 4, 8, 12 and 18 months of (corrected) age. / The preterm group scored significantly lower on various sub-scores of the AIMS at all age levels than the control group. Uneven progression in the sit subscale from 4 to 8 months corrected age (CA) was found in the preterm infants, possibly due to a dominant extensor strength, inadequate tonus and postural control in the trunk. At 12 and 18 months CA, limited variations in movements were evident in some preterm infants in the crawling, sitting and standing positions. The ten infants with post-asphyxia NE showed scattered motor development, related mostly to the severity of their NE. The moderate NE group had the most varied motor outcomes ranging from normal to suspected mild cerebral palsy. / The AIMS was shown to be a valid assessment tool in the preterm population although limitations in its use were found at 4 months CA and when the infants walked or were close to independent ambulation. The present results show that motor performance of typically and non-typically developing infants should be investigated longitudinally as variations are the characteristic of early development. The dynamical systems theory provides a more satisfactory explanation of the motoric differences in infants in this study. All these findings have great implications for the clinical management of these at risk infants.

The aim of these studies was to increase knowledge about hospital feeding routines in high-risk neonates. A retrospective medical chart review procedure was used to study routines at the neonatal units of two Swedish hospitals. In Papers I and II, the sample (Uppsala n=21 and Umeå n=21) comprised of small for gestational age (SGA) infants, in Papers III (Uppsala n=64 and Umeå n=59) and IV (n=127), the samples comprised of appropriate for gestational age (AGA) infants. Paper I indicated large enteral/oral milk volumes rendered i.v. administration of glucose unnecessary, reduced weight loss and helped SGA infants regain birth weight earlier. More rapid postnatal growth did not remain up to 18 months with corrected age in any growth variable (Paper II). In Paper III, effects were compared whether the infants’ volume of breast milk intake in hospital was estimated by “clinical indices” or determined by test-weighing. Infants treated in hospitals where test-weighing was practised attained exclusive breastfeeding at an earlier postmenstrual age (PMA), and they were discharged at an earlier PMA. However, the two study units were similar regarding the proportion of infants attaining exclusive breastfeeding. Paper IV revealed preterm AGA infants with higher standard deviation scores (SDS) at birth had more negative changes from birth to discharge for all growth variables. Conclusions: Papers I and II indicated that early initiation of enteral/oral feeding with proactive increases in milk volume was beneficial short term. No evidence was found for a proactive nutrition regimen with initial large volumes of milk resulting in a different pattern of growth up to the corrected age of 18 months. Test-weighing before and after breastfeeding might help infants to attain exclusive breastfeeding at an earlier PMA (study III). Finally, preterm AGA infants with higher SDS at birth are at higher risk of inadequate growth during their hospital stay (study IV).

Children born prematurely exhibit a broad range of neuroanatomical abnormalities. The aim of this study was to investigate the long-term effects of very preterm birth on brain volume (cortical and subcortical), cortical thickness and surface area. The participants were 25 children born very preterm (<32 weeks gestational age) without significant post-natal medical sequelae and 32 term-born children between 7 and 10 years of age. Neuroanatomical measures were derived from an automated pipeline. The results suggest a pattern of decreased brain volume, surface area and cortical thickness for children born preterm and the relation between subcortical gray volume and total brain volume differed between groups. The cortex was significantly thinner for children born preterm than term-born children in focal regions of the parietal and temporal lobes. Therefore, even without significant postnatal medical sequelae, very preterm children still exhibit structural differences that persist into middle childhood.