Background: Improved neonatal care has resulted in an increasing population of surviving infants. Neonatal morbidity in preterm infants is, however, high, and retinopathy of prematurity (ROP) is one of the major neonatal morbidities. Observations have suggested that ROP might have a different course in extremely preterm compared to more mature infants. Aims: To study the incidence, natural history and treatment of the disease, and the implications regarding screening recommendations for the population of extremely preterm infants. Methods: A national, population-based study of neonatal morbidity in infants born before 27 gestational weeks was performed in Sweden during 2004 to 2007. ROP screening started in the 5th postnatal week and continued until the retina was completely vascularized. Results: Of the 506 infants surviving until the first ROP examination, 73% developed ROP; 38% mild ROP and 35% severe ROP. Ninety-nine infants (20%) were treated. A log-linear relationship was found between severe ROP and gestational age (GA) at birth, and the risk of ROP was reduced by 50% for each week of increase in GA at birth (Paper I). Postmenstrual age (PMA) at onset of ROP was significantly related to GA at birth, as was the site of onset of ROP. ROP had a predilection to start in the nasal retina in the most immature infants. There were significant relations between PMA at onset of ROP and severity of ROP as well as between the site of onset of ROP and severe ROP (Paper III). The most immature infants had a higher risk of reaching treatment criteria for ROP, a higher risk of progression from ROP 3 to treatment criteria, and they reached these criteria at an earlier PMA than the less immature infants (Paper II). According to our results, the first examination can be postponed until a PMA of 31 weeks in infants born before 27 weeks of gestation, since onset of ROP 3 did not occur before this age, and criteria for treatment were not reached before 32 weeks. The majority of infants (75%) were treated during a limited period, i.e. before a PMA of 39 weeks (Paper IV).

<b>Background:</b> The survival rate of preterm children has risen steadily due to advances in obstetric and neonatal intensive care. Children born extremely preterm (&le;28 weeks of gestation) are at high risk of long term developmental problems, including cerebral palsy, motor and cognitive impairment, visual and auditory deficits and behavioural problems. This can have serious implications for their quality of life and that of their family and carers. These children take up a disproportionate amount of neonatal intensive care unit resources and overall costs, and as they grow up are more likely to require additional health and social care services beyond routine care to compensate for their functional limitations. The early identification and management of factors that mediate long term outcome is necessary to assist healthcare professionals in selecting appropriate treatment pathways, and to develop, target and evaluate interventions. Many risk factor analyses for neurodevelopmental impairment have been published in preterm populations, but this vast literature has not been formally summarised. Furthermore, there is a dearth of studies reporting longitudinal analysis of neurodevelopmental trajectories from early childhood to adulthood. <b>Objectives:</b> The first aim of this thesis was to perform a comprehensive systematic review of the world literature over the last two decades, to consolidate the evidence about the prognosis of neurodevelopmental outcome in children born very preterm or with very low birth weight. The second aim was to conduct a longitudinal analysis of a cohort of extremely preterm participants followed up into early adulthood to investigate the trajectories of long term sequelae over time, and to examine the association of neurodevelopmental course in relation to the predictive factors identified in the systematic review. <b>Methods:</b> A systematic review was conducted using MEDLINE, EMBASE and PyscINFO databases to identify studies published between January 1 1990 and June 1 2014 reporting multivariable prediction models for the neurodevelopment of children born &le;32 weeks of gestation or with a birth weight &le;1250 grams (protocol registration number CRD42014006943). Seventy-eight studies reporting 222 risk factor models for neurodevelopmental outcome were identified. Two independent reviewers extracted key information about study design, outcome definition, risk factor selection, model development, reporting, and conducted a risk of bias assessment. To address the second objective of the study, a longitudinal analysis of cognitive and behavioural trajectories was conducted using a prospective, population-based cohort study in the United Kingdom and the Republic of Ireland. Three hundred and fifteen surviving infants born less than 26 completed weeks of gestation recruited at birth in 1995 and 160 term-born classroom peers recruited at age six were followed-up to 19 years. Participants were invited for up to four standardized, blinded cognitive assessments and the parent-completed Strengths and Difficulties Questionnaire was used to assess behavioural problems. <b>Results:</b> The systematic review of risk factors for motor impairment in children born very preterm or with very low birth weight provided strong evidence that neonatal brain injury is a robust prognostic factor for cerebral palsy, and some evidence that the use of postnatal steroids increases the risk and the use of antenatal steroids reduces the risk of cerebral palsy. There was moderate evidence that male sex was prognostic for motor impairment at school age in children free of major disability. The systematic review of risk factors for cognitive impairment identified male sex, non-white ethnicity, lower levels of parental education and lower birth weight as significant predictors of global cognitive dysfunction in early infancy, with parental education having a sustained impact after five years of age. There was also evidence that male sex was predictive of delayed language development in early infancy. Gestational age was found to be of limited use as prognostic factor for cerebral palsy, motor and cognitive impairment in cohorts restricted to &le;32 weeks of gestation. There was a dearth of good quality studies investigating risk factors for behavioural problems and psychiatric disorders and the findings of this review were inconclusive. The only factors that appeared to be consistent predictors of general behavioural problems were markers of socio-economic deprivation, neurodevelopmental or cognitive delay, and an abnormal behavioural screen in early infancy. In the longitudinal analysis of the prospective, population-based cohort of extremely preterm children, cognitive trajectories were stable in both the extremely preterm and term-born groups over time with persistent deficit in the extremely preterm group of 25.2 IQ points (95&percnt; CI: -27.8 to -22.6, p&LT;0.001) and only minimal catch-up over time. Participants with neonatal brain injury and of male sex had the largest deficits, but a lower level of maternal education and earlier gestational age at birth were also associated with reduced IQ scores. Behavioural problems were also more prevalent among the extremely preterm participants who had a mean Total Difficulties Score of 4.81 points above their term-born peers (95&percnt; CI: 3.76 to 5.87, p&LT;0.001) and which persisted over the time period. Behavioural difficulties were mainly due to hyperactivity, inattention and peer problems and were strongly associated with a positive behavioural screen in early infancy. <b>Conclusions:</b> The most robust predictors of poor neurodevelopmental outcome identified by the systematic review were neonatal brain injury, male sex, and markers of social disadvantage. The unclear findings for many risk factors may reflect differences in study design, study population, methodological quality and lack of standardization of measures. Or it may simply reflect the fact that prognostic modelling in such a heterogeneous population is challenging and complex, with multiple risk factors acting sequentially over time, and often with the existence of multiple impairments within the same individual. The main conclusions from the longitudinal analysis of children born extremely preterm is that being born too soon appears to place limits on brain plasticity and function which is not recovered over time; with the most vulnerable being males and those with evidence of brain injury early in life. These structural abnormalities may disturb neurodevelopmental processes and impede the brain from maintaining a normal developmental trajectory. If extremely preterm children fail to achieve optimum levels of cognitive function and are still experiencing behavioural problems once they have reached maturity, then this has implications for health and well-being in later adulthood and old age. Cognitive test scores in infancy and early childhood reflect early adult outcomes and a positive behavioural screen in infancy is strongly associated with early adult behavioural outcomes. <b>Recommendations:</b> The systematic review revealed some shortcomings in methodology and reporting that could be improved in future studies, and confirmed that that there is a dearth of properly designed and well-conducted prognostic modelling studies in this field. The findings and recommendations of this critical review should be used as a basis for the design, analysis and reporting of future studies seeking to develop multivariate risk factor or prognostic models in this population. There is an urgent need for larger population cohorts followed up routinely beyond two years as subtle outcomes such as impairment of executive function and fine motor skills cannot be reliably assessed at this age, and the natural course of some disorders may have their onset later in childhood. / Studies with larger sample sizes and greater power are needed for studying less common conditions in preterm populations and there should be more standardisation of outcome and risk factor measurements, particularly with the use of standard diagnostic evaluations to assess psychiatric disorders. Future studies should include a term-born comparison group and adopt appropriate statistical analysis techniques to analyse longitudinal outcome data and the impact of risk factors on these trajectories. Additional research is required to improve the prediction of individual differences, and to identify the neuropathological differences underlying different developmental trajectories and their interaction with environmental influences over time.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13580号 / 論医博第2302号 / 新制||医||1069(附属図書館) / (主査)教授 平井 豊博, 教授 江木 盛時, 教授 齋藤 潤 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Sammanfattning Mål: Tidigare studier visar att delar av den fysiska och psykiska tillväxten och utvecklingen hos för tidigt födda barn kan påverkas av den förkortade graviditetsperioden. De odontologiska aspekterna av prematuritet har ännu inte till fullo studerats. Syftet med denna studie är att undersöka om tandmognaden påverkas av för tidig födsel och om enskilda tänder i högre utsträckning är mer påverkade.Material och Metod: I studien deltog 116 barn: 36 extremt för tidigt födda barn (extremely preterm - EPT), 38 mycket för tidigt födda barn (very preterm – VPT) och 42 fullgångna kontroller (controls – C). Panoramaröntgenbilder analyserades av fem kalibrerade observatörer, enligt en metod som utvecklats av Demirjian och Goldstein. Röntgenbilderna avidentifierades och mognadsgraden av de 7 permanenta tänderna i underkäkens vänstra sida (tand 31-37) bedömdes enligt ett 8-stegs system. De 7 bedömningarna adderades sedan till en tandmognadspoäng (maturity score) som motsvarade barnets tandmognadsgrad. Detta möjliggjorde jämförelser på såväl gruppnivå som tandnivå. Observatörernas tillförlitlighet och metodens reproducerbarhet utvärderades genom att 27 slumpvis utvalda röntgenbilder bedömdes ytterligare en gång. Statistiska analyser utfördes av studiens resultat samt av reproducerbarheten.Resultat: Resultatet, med hänsyn till variationer i observatörernas bedömningar, visade att EPT-gruppen hade en genomsnittlig tandmognadspoäng mellan 81.9 och 86.7, VPT 85.2-89.1 och kontrollgruppen 88.1-91.0. Samtliga fem observatörer uppvisade statistiskt signifikanta skillnader mellan EPT-gruppen och kontrollgruppen (p≤0.006). På tandnivå uppvisade alla observatörer en signifikant fördröjning (p≤0.002) av tandmognaden för tand 37 när EPT-gruppen jämfördes mot kontrollgruppen. Signifikanta skillnader mellan ett flertal andra tänder erhölls men konsensus mellan observatörerna saknades. Överensstämmelsen inom varje enskild observatör (intra-observer agreement) beräknades med ett Kappa-test, där resultaten varierade mellan 0.16-1.00. Kappa-beräkningen av reproducerbarheten mellan samtliga observatörer (inter-observer agreement) varierade mellan 0.31-0.71.Slutsats: Resultaten i denna studie tyder på en allmän försening av tandmognaden vid 9 års ålder hos de extremt för tidigt födda barnen (EPT), jämfört med fullgångna barn (C). En förkortad gestationsperiod tycks indikera en fördröjning av tandmognaden jämfört med tandmognaden hos fullgångna barn.

Background: Optical coherence tomography (OCT), multifocal electroretinography (mfERG) and full-field electroretinography (ffERG) give important information about retinal structure and function. Purpose: To collect normative data of macular Cirrus Spectral domain (SD)-OCT assessments and of mfERG measurements of healthy children (papers I and II). To assess the macular thickness with Cirrus SD-OCT and the retinal function with ffERG in 6.5-year-old children born extremely preterm and in children born at term (papers III and IV). Methods: Study participants aged 5-15 years and living in Uppsala County were randomly chosen from the Swedish Birth Register (papers I and II). In papers III and IV, the study participants consisted of children born extremely preterm and children born at term – all were aged 6.5 years. In paper III, the children were living in Stockholm and Uppsala health care regions and, in paper IV, in Uppsala health care region only. Macular thickness was assessed with Cirrus SD-OCT and macular function with mfERG, using the Espion Multifocal system and DTL-electrodes. The retinal function was assessed with ffERG and DTL-electrodes, using the Espion Ganzfield system. Results: Altogether, 58 children participated in paper I and 49 children in paper II. In paper I, the repeatability and reproducibility of the OCT assessments were good. In paper II, the results of the mfERG measurements were in accordance with retinal cone density and there were no significant differences between the right and left eyes. In paper III, 134 preterm children and 145 children born at term constituted the study population. The central macular thickness was significantly thicker in the preterm group than in the control group. Within the preterm group, gestational age (GA), former retinopathy of prematurity (ROP) and male gender were all important risk factors for an increased macular thickness. In paper IV, 52 preterm children and 45 control children constituted the study population. Significantly lower amplitudes and prolonged implicit times of the combined rod and cone responses, as well as of the isolated cone responses, were found in the preterm group when compared with the control group. In paper IV, there was no association between GA, ROP or male gender and the ffERG assessments. Conclusion: Normative data of Cirrus SD-OCT and mfERG assessments were reported. The results of the assessments were reliable. Children aged 6.5 years, born extremely preterm, had a significantly thicker central macula and both rod and cone function were significantly reduced in comparison to children born at term. ROP had an influence on retinal structure but not retinal function in the present cohorts. Our results suggest that retinal development is abnormal in children born extremely preterm. Long-term follow-up studies are necessary in order to evaluate the functional ophthalmological outcome in this vulnerable population of children growing up today.

Caesarean section is a common major surgical procedure and long-term complications have not been fully investigated. By longitudinal population based register studies, based on National health registers and medical data records, maternal complications after caesarean delivery at subsequent labour (N=7 683), among extremely preterm births (N=406), and at remote gynaecologic surgery (N=25 354) were explored. In Paper I, uterine closure was investigated in respect to uterine rupture in a subsequent delivery after caesarean section. Uterine rupture occurred in 1.3 % of women with a previous caesarean section. There was no increased risk of uterine rupture with single compared with double layers for closure of the uterus (adjusted Odds Ratio 1.17, 95 % CI 0.78-1.70). Modifiable risk factors of uterine rupture in a trial of labour after caesarean section included induction of labour and use of epidural analgesia. In Paper II, maternal outcomes and surgical aspects of caesarean section in the extremely preterm period were assessed. Maternal complications were more frequently reported in extremely preterm- compared with term caesarean delivery. No increase in short-term morbidity was observed at 22-24 compared with 25-27 gestational weeks, but uterine corporal incisions were performed more frequently (18.1 % vs. 9.6 %, p=0.02). Furthermore, risk factors for abdominal adhesions after caesarean section and organ injury in remote gynaecologic surgery were analysed (Paper III and IV). Numbers of prior caesarean sections were the most important factor for formation of adhesions. Advanced maternal age, obesity, infection and delivery year 1997-2013 were factors associated with adhesions in conjunction with caesarean section. Organ injury occurred in 2.2 % of women undergoing benign hysterectomy. A history of caesarean section increased the risk (adjusted Odds Ratio 1.74, 95 % CI 1.41-2.15), but was only partly explained by the presence of adhesions. The organ affected depended on medical history; prior caesarean predisposed for bladder injury, prior bowel/pelvic surgery for bowel injury and endometriosis was associated with ureter injury at time of hysterectomy. In conclusion; data from National health registers indicates that caesarean delivery is associated with long-term complications, although the absolute risk of severe complications for the woman is low.

Background Modern neonatal care has improved the survival rate of extremely preterm infants. These infants are at high risk of malnutrition and growth failure during 3-4 months of hospital care. The objectives of this study was to investigate nutritional intakes during hospitalization and explore associations between nutritional intakes, postnatal growth and retinopathy of prematurity (ROP). Perioperative nutrition in infants undergoing surgery for patent ductus arteriosus (PDA) was also investigated. Methods This is a population-based study of Swedish extremely preterm infants (&lt;27 weeks) born during 2004-2007 (n=602). Detailed data on nutritional supply and anthropometric measurements during hospitalization were retrospectively retrieved from hospital records. Comprehensive data on cohort characteristics, neonatal morbidity and infant mortality were obtained from the Extremely Preterm Infants in Sweden Study (EXPRESS). Results During the first 70 days of life, intakes of energy, protein and several micronutrients, with the exception of iron and some vitamins, were less than estimated requirements, and infants showed severe postnatal growth failure. Energy and protein intake predicted growth in all anthropometric outcomes even when adjusting for severity of illness, and fat intake was positively associated with head growth. Low folate intake was positively correlated with poor weight and length gain while high iron intake, mainly explained by blood transfusions, was negatively associated with poor length gain. Furthermore, a low energy intake was associated with severe ROP (stage 3-5). An increased energy intake of 10 kcal/kg/d was associated with 24% decrease in severe ROP (p=0.01). During the first month, 99% of the infants were exclusively fed human milk. Infants who underwent surgery for PDA (n=140) were malnourished, with energy and macronutrient intakes below minimum estimated requirements before, during and after surgery. Conclusions The severe postnatal growth failure observed in Swedish extremely preterm infants may be prevented by improved intakes of energy, protein, fat and folate and a reduction of the number of blood transfusions. Human milk is the main enteral food source and analyses of human milk macronutrient contents facilitates individualized fortification. Provision of adequate energy intakes during the first four weeks of life may be an effective way to reduce the risk of severe ROP. Perioperative nutrition in infants undergoing PDA surgery needs to be improved. The study results have important implications for nutritional regimens, postnatal growth and health outcome in this new generation of survivors.

Abstrakt Bakgrund: Sverige är idag världsledande gällande överlevnaden hos extremt underburna barn. Den högspecialiserade vården i Sverige är centraliserad till regionsjukhus vilket leder till att flertalet av dessa barn behöver transporteras från hemsjukhus till regionsjukhus för fortsatt vård. Motiv: Föräldrars känslor i samband med att deras barn behöver neonatal intensivvård är väl studerat i tidigare forskning både internationellt och nationellt. Då det finns begränsat med kunskap angående dessa föräldrars behov av stöd i samband med flytt av deras extremt underburna barn till annat sjukhus finns det möjligheter till förbättring inom området. Syfte: Syftet med studien var att belysa vilket stöd föräldrar till extremt underburna barn önskade när deras barn behövde flyttas till en annan neonatalavdelning på ett annat sjukhus.Metod: Studien genomfördes som en kvalitativ enkätstudie med öppna frågor med empirisk design. Enkäterna analyserades via en kvalitativ innehållsanalys med induktiv ansats av Elo &amp; Kyngnäs. Föräldrarna (n=63) rekryterades via ett strategiskt urval från hela Sverige. Resultat: Resultatet delas in i två huvudkategorier; ”Föräldrars behov av förberedelser inför flytt till annat sjukhus” samt ”Föräldrars behov av emotionellt och personligt stöd”. Resultatet visar att det finns ett stort behov av stöd hos föräldrarna för att minimera de negativa upplevelser som kan uppstå då deras extremt underburna barn behöver flyttas till en annan neonatalavdelning. Föräldrarna beskriver att de önskar få information om avdelningen de flyttar till avseende rutiner och faciliteter samt när flytt förväntas ske och att denna information idag är bristfällig. Föräldrarna beskriver även att deras känslor och upplevelser behöver bli bekräftade av personalen och att behovet av en kontaktperson är stort. Konklusion: Resultatet belyser vilket stöd föräldrar efterfrågar i samband med flytt av sitt extremt underburna barn vilket skapar möjligheter för en framtida utveckling av neonatalvården. Implementering av stödjande vårdrutiner samt förbättrat samarbete mellan sjukhusen skulle öka möjligheterna för en förbättrad föräldraupplevelse och därmed minskad psykisk ohälsa. / AbstractBackground: Sweden is world-leading when it comes to survival rates among extremely preterm infants. Highly specialized care units are centralized to regional hospitals, resulting in that many extremely preterm infants need to be moved from their home hospital to a regional hospital for additional care. Motive: Parents' emotions when their extremely preterm infant requires neonatal intensive care is a well-studied area in both national and international studies. The authors therefore believe that there is a reason for further research regarding parents’ need for support in connection to the relocation of their extremely preterm infant to another hospital. Since there is limited research regarding the needs of these parents, there are opportunities for improvement in the area.Aim: The purpose of this study was to illustrate what support parents of extremely preterm infants need when their infant needs to be moved to another neonatal unit at another hospital. Methods: The study was conducted as a qualitative questionnaire study with open questions with empirical design. The questionnaires were analysed using a qualitative content analysis with an inductive approach by Elo &amp; Kyngnäs. The parents (n=63) were recruited via a strategic selection from all over Sweden.Result: The result is divided into two main categories; “Parents’ need for preparation when moving to another hospital” and “Parents’ need for emotional and personal support”. The result shows that there is a great need for support among parents to minimize the negative experiences that can occur when their extremely preterm infant needs to be moved to another neonatal unit. The parents describe that they wish to receive more information about routines and facilities at the unit they are moving to, and then the move is expected to take place. The parents also describe that their feelings and experiences could be further confirmed by the staff and that they have a need for establishing a relation with a contact person. Conclusion: The result highlights what support parents request in relation to transportation of their extremely preterm infant, creating opportunities for further improvements in neonatal care. Implementation of supportive care routines and improved collaboration between hospitals could increase the opportunities for an improved parental experience and by that reduced mental illness.