Very Low Birth Weight Infants as Young Adults : Focus on aspects of cognition, behavior and sleep

Major advances in the treatment of preterm infants have occurred during the last three decades. Survival rates have increased, and the first generations of preterm infants born at very low birth weight (VLBW; less than 1500 g) who profited from modern neonatal intensive care are now in young adulthood. The literature shows that VLBW children achieve on average lower scores on cognitive tests, even after exclusion of individuals with obvious neurosensory deficits. Evidence also exists for an increased risk in VLBW children for various neuropsychiatric disorders such as attention-deficit hyperactivity disorder (ADHD) and related behavioral symptoms. Up till now, studies extending into adulthood are sparse, and it remains to be seen whether these problems persist into adulthood. The aim of this thesis was to study ADHD-related symptoms and cognitive and executive functioning in young adults born at VLBW. In addition, we aimed to study sleep disturbances, known to adversely affect both cognition and attention. We hypothesized that preterm birth at VLBW interferes with early brain development in a way that alters the neuropsychological phenotype; this may manifest itself as ADHD symptoms and impaired cognitive abilities in young adulthood. In this cohort study from a geographically defined region, we studied 166 VLBW adults and 172 term-born controls born from 1978 through 1985. At ages 18 to 27 years, the study participants took part in a clinic study during which their physical and psychological health was assessed in detail. Three years later, 213 of these individuals participated in a follow-up. The current study is part of a larger research project (The Helsinki Study of Very Low Birth Weight Adults), and the measurements of interest for this particular study include the following: 1) The Adult Problem Questionnaire (APQ), a self-rating scale of ADHD-related symptoms in adults; 2) A computerized cognitive test battery designed for population studies (CogState®) which measures core cognitive abilities such as reaction time, working memory, and visual learning; 3) Sleep assessment by actigraphy, the Basic Nordic Sleep Questionnaire, and the Morningness-Eveningness Questionnaire. Actigraphs are wrist-worn accelerometers that separate sleep from wakefulness by registering body movements. Contrary to expectations, VLBW adults as a group reported no more ADHD-related behavioral symptoms than did controls. Further subdivision of the VLBW group into SGA (small for gestational age) and AGA (appropriate for gestational age) subgroups, however, revealed more symptoms on ADHD subscales pertaining to executive dysfunction and emotional instability among those born SGA. Thus, it seems that intrauterine growth retardation (for which SGA served as a proxy) is a more essential predictor for self-perceived ADHD symptoms in adulthood than is VLBW birth as such. In line with observations from other cohorts, the VLBW adults reported less risk-taking behavior in terms of substance use (alcohol, smoking, and recreational drugs), a finding reassuring for the VLBW individuals and their families. On the cognitive test, VLBW adults free from neurosensory deficits had longer reaction times than did term-born peers on all tasks included in the test battery, and lower accuracy on the learning task, with no discernible effect of SGA status over and above the effect of VLBW. Altogether, on a group level, even high-functioning VLBW adults show subtle deficits in psychomotor processing speed, visual working memory, and learning abilities. The sleep studies provided no evidence for differences in sleep quality or duration between the two groups. The VLBW adults were, however, at more than two-fold higher risk for sleep-disordered breathing (in terms of chronic snoring). Given the link between sleep-disordered breathing and health sequelae, these results suggest that VLBW individuals may benefit from an increased awareness among clinicians of this potential problem area. An unexpected finding from the sleep studies was the suggestion of an advanced sleep phase: The VLBW adults went to bed earlier according to the actigraphy registrations and also reported earlier wake-up times on the questionnaire. In further study of this issue in conjunction with the follow-up three years later, the VLBW group reported higher levels of morningness propensity, further corroborating the preliminary findings of an advanced sleep phase. Although the clinical implications are not entirely clear, the issue may be worth further study, since circadian rhythms are closely related to health and well-being. In sum, we believe that increased understanding of long-term outcomes after VLBW, and identification of areas and subgroups that are particularly vulnerable, will allow earlier recognition of potential problems and ultimately lead to improved prevention strategies.

En knapp procent av finländska barn föds som små prematurer (födelsevikt under 1500 g). Utvecklingen inom intensivvården av nyfödda har avancerat snabbt de senaste årtiondena. De små prematurer, som fötts efter introduktionen av modern neonatal intensivvård i slutet av 70- och början av 80-talet, är nu unga vuxna. Studier visar att små prematurer i barndomen presterar svagare resultat i kognitiva tester jämfört med barn som fötts vid beräknad tid. De har också en ökad risk för neuropsykiatriska störningar såsom ADHD. Man vet inte om problemen kvartstår i vuxen ålder. Målet med doktorsavhandlingen är att öka kunskapen om små prematurers hälsa i vuxen ålder, med fokus på kognitiva funktioner, ADHD-symptom, och sömn. Doktorsavhandlingen är en del av projektet Små prematurers hälsa i vuxen ålder (Pikku-k, The Helsinki study of very low birth weight adults). Studien omfattar 166 små prematurer som vårdats på Helsingforsregionens universitetscentralsjukhus under åren 1978-1985, samt en kontrollgrupp bestående av 172 personer födda efter fullgången graviditet. Vid 18-27 års ålder deltog de i en klinisk studie, följd av en uppföljningsstudie tre år senare. I avhandlingens första delarbete undersöks ADHD-relaterade symptom med ett frågeformulär riktat till studiedeltagarna (The Adult Problem Questionnaire). I det andra delarbetet studeras kognitiva funktioner såsom närminne, reaktionssnabbhet och inlärning med ett datoriserat test (Cogstate). De tre sista delarbetena behandlar olika aspekter av sömn, som undersökts med aktigrafi, en aktivitetsmätare som skiljer vakenhet från sömn, samt frågeformulär (Basic Nordic Sleep Questionnaire, Morningness-Eveningness Questionnaire). Som vuxna lever de flesta små prematurer ett normalt, friskt liv. Studien visade att vuxna födda som små prematurer inte uppgav mer ADHD-symptom än jämnåriga kontrollindivider. Däremot uppgav den grupp av små prematurer, vars födelsevikt var speciellt låg i förhållande till graviditetens längd (SGA; small for gestational age), mer symptom än både övriga små prematurer och kontroller. Tillväxthämning under fosterstadiet verkar därför vara en större riskfaktor för självupplevda ADHD-symptom i vuxen ålder än prematuritet i sig. Fyndet står i motsats till tidigare studier som visar att små prematurer i barndomen löper högre risk för ADHD. Det är möjligt att ADHD-symptomen hos små prematurer skiljer sig från vanliga ADHD-symptom och de kan också ha en tendens att bli mildare under livets gång. I linje med tidigare studier rapporterade små prematurer mindre riskbeteende i form av rökning, alkohol- och droganvändning − vilket är uppmuntrande för små prematurer själva samt deras familjer. I det kognitiva testet presterade prematurerna i genomsnitt svagare resultat, trots att analyserna begränsades till friska individer. Sömnstudierna påvisade ingen skillnad i sömnkvalitet- eller längd mellan grupperna, men små prematurer löpte dubbelt större risk för snarkning, och de kan därför anses vara en riskgrupp för sömnstörd andning och dess följder. Prematurerna hade även en tidigarelagd dygnsrytm, ett oväntat fynd som kom fram i både objektiva och subjektiva mätningar vid olika tidpunkter. Vi håller på att vidareundersöka det här fyndet som eventuellt kan hjälpa oss förstå hur människans dygnsrytm utvecklas.