in

birtngal dy opected. This is reassuring, but there are still concerns about future psycho-ndcabich

Neonatal intensive care started in thindustrialised countries. The next decade wwhen neonatal intensive care units (NICUs)It was not until the 1980s that survival ofstarted to improve and approached 50%. Rep

t (VLBto em

e the lig targe overewer p

face. Further, with increasing age, there are fears that they may

This issue is devoted to the long-term outcome of the tiniest ormost immature babies. Several eminent international investigatorsare presenting a broad array of outcomes. Althoughmany outcomes

focus on the residual limitations and challenges, adult role func-

all for gestationalnd by the growth. The longitudinall, or from regionalwith disabilities.limited studies of

extremely preterm infants are gestational-age-based, and the old-est will soon be reaching adulthood. Outcomes from the earlierstudies will therefore be reported by birth weight, unless speciedotherwise.

In the last decade, there have been several studies of prematureinfants to adulthood using two different designs. Until recently, themajority of studies to adulthood were descriptive cohort studieswith matched controls that were followed longitudinally. These

* Address: 1280 Main St West, Room HSC 4F, Hamilton, Ontario, Canada L8S 4K1.Tel.: 1 905 521 2100x76959; fax: 1 905 521 5007.

Contents lists availab

Seminars in Fetal &

.e

Seminars in Fetal & Neonatal Medicine 19 (2014) 125e130E-mail address: saigal@mcmaster.ca.infants may face in the future, some of which might still beunknown. exclusively ELBW infants to adulthood. The current studies ofencounter a higher prevalence of cardiovascular and metabolicproblems than the normal term population [4e9]. Thus, theemergence of problems is age-dependent and not necessarily cu-mulative. Physicians who will assume their subsequent care needto be aware of the special challenges that the aging premature

were

onastudies provide meticulously collected information using validatedstandardised tests, self-completed questionnaires, and interviews,and allow us to observe changes in outcomes over time. On thenegative side, they are time-consuming and very expensive toconduct, attrition rates can be quite high, and they are limited bysmall sample sizes that do not permit further exploratory analyses[2,10]. However, the information collected is rich, and provides amore accurate account of the diagnoses and severity of disabilities,behavioral and emotional problems, and self-perception of thehealth-related quality of life (HRQL).

Recently, the Scandinavians have taken a more innovativeapproach by using data from large epidemiological National Reg-istries that have resulted in an explosion of publications to adult-hood [11e14]. These databases have unique identiers that linkbirth data with subsequent vital statistics, allowing a wealth ofinformation to be collected on various aspects of the individual. Notonly are they cheaper than longitudinal cohort studies, but alsothere are minimal losses to follow-up. These large sample sizesprovide the power for subgroup analyses, exploration of con-founders, and the impact of gestational age gradients on outcomes(the gestational ages in these large databases before the use ofroutine ultrasound may also be imprecise, particularly for infants

eonadetachment increases with age, it is imperative that these youngadults be followed through life.

3.3. Audiological problems

The reported incidence of deafness is quite variable and rangesfrom 0% [24] to 7% [21] in ELBW young adults. The incidence ofdeafness in VLBW young adults was 1.2% in the Cleveland study[22], 7.4% in the Dutch study [26], and 5.8% in Swedish VLBWmales[23].

4. Adult functioning

4.1. Educational achievements

In terms of school completion, a gestational age gradient wasagain observed in the Norwegian study [11]: at 23e27 completedweeks of gestation 68% had completed high school, and 25% hadcompleted a bachelors degree: the corresponding gures for 28e30 weeks of gestation were 70% and 28%, compared with 75% and35% for those born at term. Although Lefebvre et al. [21] reportedthat fewer ELBW subjects had obtained a secondary schooldiploma compared to normal birth weight group (56% vs 85%),this was related to the fathers socio-economic score. Somestudies have reported no statistically signicant differences be-tween ELBW and controls in the proportion that graduated fromhigh school (82% vs 87%) [20]. Sex differences were observedwithin this ELBW group, with a higher proportion of male par-ticipants with less than high school education (25% vs 10%,P 0.01), and fewer males enrolled in, or graduated from, post-secondary education (49% vs 71%, P 0.01). Also, a signicantlylower proportion of ELBW young adults was enrolled in post-secondary education (23% vs 37%, P 0.01). A similar ndingwas reported in the Swedish National cohort study [12], with 26%of those born with a gestational age of 28 weeks who hadcompleted university education, compared to 38% of those born atNBW; there were no differences in high school attainment bygestational age. In a much smaller, geographically dened Swed-ish cohort born in the late 1980s, informationwas elicited throughmailed questionnaires at age 20 years. No differences were notedin education, occupation, or social situation compared to controls[27]. Similar to the ndings by Saigal et al. [20], Hack et al. [22]reported a female advantage, with 66% of VLBW males and 81%of VLBW females who completed high school, compared with 75%of term males and 90% of term females. Ironically, the rates ofcompletion of high school education among ELBW young adults inthe Ontario study [20] and in a Minnesota single hospital report ofbirths between 23 and 26 weeks of gestation [28] were similar tothat of the NBW controls in the Cleveland study [22], demon-strating the powerful effect of social class on educationalattainment.

4.2. Employment

As a group, adults born very preterm or very low birth weighthave higher rates of unemployment and lower net income, partly asa consequence of being disabled. Moster et al. [11] showed thatalthough unemployment rates were not different, Norwegianyoung adults born between 23 and 27 completed weeks of gesta-tion had lower job-related income (23%) than those born at term(20%) and a higher proportion received social security benets(19.9% versus 17.6%), but the differences were not statistically sig-nicant (RR: 1.2; 95% CI: 0.9e1.5). When people with disabilitieswere excluded, there was still a signicant, though weaker, asso-

S. Saigal / Seminars in Fetal & Nciation between lower gestational age overall and the proportionswho attained a higher education, obtained a better-paying job, orwho received social benets. Similar ndings were reported fromthe Swedish National Cohort study [12]. A higher proportion ofadults born between 24 and 28 weeks of gestation compared withthose born at term were receiving social welfare (5% vs 1.8%) anddisability assistance (0.6% vs 0.1%). However, overall a signicantproportion of all those born between 24 and 28 weeks of gestationwere employed and more were paying taxes than receivingbenets.

At a mean age of 23 years, 48% of Ontario ELBW subjects vs 57%of controls had permanent employment, and there were no dif-ferences in occupational prestige between the groups [20].

However, in a sub-analysis, a higher proportion of ELBW thanNBW participants were neither employed, nor at school (26% vs15%, P 0.02), largely due to chronic illnesses or permanentdisability (46% vs 15%, P 0.03). Female ELBW subjects were moredisadvantaged in terms of employment. In the Dutch study [26],three times as many VLBW 19-year-olds than controls were neitheremployed nor at school (7.6% and 2.6%, respectively).

4.3. Living arrangements, dating and marriage

A higher proportion of 24e28-week gestation young adults thancontrols were living at home with their parents between 23 and 29years of age in the Swedish National Study (18.3% vs 15.0%,P 0.001).12 In the Helsinki study, VLBW young adults who werefree of major disabilities (age range: 18e27 years) were 1.7-foldmore likely to be living in the parental home than controls (95%CI: 1.01e3.05; P 0.05); this association was signicant only formen [29]. Interestingly, although Finnish and Canadian cohorts hadsimilar socio-demographic background and access to health care,no statistically signicant differences were observed in the pro-portion of ELBW young adults compared with controls still living athome (55% vs 47%) in the latter study [20].

Moster [11] reported that a lower proportion of Norwegianyoung adults born between 23 and 27 weeks of gestation thancontrols were either married or cohabiting (10.0% vs 18.3%,respectively; RR: 0.7; CI: 0.5e1.0). This was also true for theSwedish [12] and the Finnish cohorts [29]. Further, several studieshave reported that VLBW young adults were less likely to expe-rience sexual intercourse, and they had fewer sexual partnerscompared with controls [22,29,30]. In another Swedish regionalcohort study of infants born between 1987 to 1988, no differenceswere observed at age 20 years between VLBW and NBW youngadults in employment, living independently or cohabiting, aselicited through postal questionnaires [27]. Cooke [31] also re-ported no differences in sexual experiences or intimate re-lationships between the VLBW and control subjects for eithergender.

4.4. Reproduction

Who would have thought that one day we would be discussingreproduction as an outcome in our extremely premature survivors?Biological parenthood was reported in 28.7% of subjects born 23e27weeks, but was lower than the rate of 43.1% in term controls (RR:0.8; 0.6e1.0) in the Norwegian study [11]. Hack et al. [22] reportedfewer pregnancies in women, but not in the partners of men, at age20 years. Saigal et al. [20] reported no differences in reproductiverates or parenthood in a longitudinal cohort study of ELBW infantscompared to term-born controls. However, the power to detectsuch differences was limited by the small sample sizes and theyoung age of the participants.

The Norwegian Medical Birth Registry study [13] of births be-

tal Medicine 19 (2014) 125e130 127tween 1967 and 1976 reported strong evidence of lower

onareproductive rates for both men and women who had been bornvery preterm. Only 25% of women and 13.9% of men who had beenborn between 22 and 27 weeks of gestation had subsequentlyreproduced, in contrast to 68% of women and 50% of men born atterm. Interestingly, only female premature participants were atincreased risk of recurrent preterm birth, with a dose responsebased on the degree of maternal prematurity. The risk of having apreterm offspring was 14% for women born between 22 and 27weeks of gestation compared to 6.4% for NBW women. A subse-quent Swedish population-based registry [32] has conrmed theabove nding of reduced probability of reproduction by very pre-mature males and females (HR: 0.78; 95% CI: 0.70e0.86 for males;HR: 0.81; 95% CI: 0.75e0.88 for females). Without these large da-tabases, the evidence for reduced reproductive rates would havebeen very weak.

Apart from the biological and physiological factors for thereduced reproductive rates, psychosocial, nutritional, and eco-nomic factors may affect the ability to reproduce. As Swamy et al.[13] point out, survivors born pretermmay have more difculties innding a partner because of medical factors, disabilities andcognitive decits. Moreover, several studies have shown that fewerpremature infants, and particularly those with disabilities, experi-ence sexual intercourse [22,29,30,33]. Also, in western societies themean age of parenting is increasing, and this may additionallycontribute to decreased fertility and possible childlessness in thefuture.

4.5. Social relationships and risk-taking behaviours

A Swiss study [34] reported poorer social relations in VLBWyoung adults: there were fewer visits from friends and family(P 0.04); VLBW young adults spent less time with friends(P 0.001), and had lower mean number of friends than controls.Cooke [31] reported that VLBW young adults in Liverpool partici-pated similarly to controls in social activities. Saigal et al. [33] re-ported similar peer, partner and family relationships, includingmean number of friends, and involvement in clubs and social ac-tivities, among ELBW young adults and term controls. The rates ofoverall criminality in the Norwegian National Study were similar inthose born 23e27 weeks (9.6%) than in those born at term (8.7%;RR: 1.1; 0.8e1.6) [11].

Most studies, however, are consistent in the nding of lowerrisk-taking behaviours among premature young adults comparedto their term-born peers [12,22,30,31,33]. These include a lowerproportion that used drugs or consumed alcohol, smoked cigarettesor marijuana, exhibited delinquent behaviours, rates of crimeconviction or incarceration, or contact with police. It is not entirelyclear, but the reasons for these behaviours may be due to increasedparental monitoring [22], shy personality [35,36], and possiblyfewer social opportunities.

5. Functional status and quality of life

How do we dene functional outcomes, and what variables andmeasurement tools should we consider in assessing the same? Inthe past, the ability of a person to perform the routine activities ofdaily living, as well as leisure and socially allocated roles, wasconsidered as an acceptable functional outcome. Functional statusis therefore a way of reporting the limitations resulting from adisease or illness in an objective manner.

Although most studies show that the general health of formerpremature infants improves by adulthood, they are still left withsome residual functional limitations. These include visual andhearing decits (described above), dexterity and clumsiness; and,

S. Saigal / Seminars in Fetal & Ne128in a minority, reduced self-care abilities [24]. These limitationsremained signicant, even when young adults with disabilitieswere excluded. Consistent with this study, several investigatorshave reported that VLBW young adults lead a more sedentarylifestyle, and have limited participation in strenuous physical ac-tivities [22e24,37].

The above traditional biomedical model of reporting functionallimitations per se is no longer considered sufcient. With the cur-rent broader approach in dening patient outcomes, this denitionhas been expanded to combine biomedical factors with social sci-ence approaches to obtain a more holistic picture of an individualsfunctioning. It is therefore recommended that the subjectiveviews e how a person feels e should be elicited directly from theperson most affected by the process. Yet, there are few studies thataddress the personal perspectives of the individual in question atadulthood.

Several reviews of the denition and conceptual framework ofQoL have been published [38,39]. However, in the context of healthcare, most studies report the health-related quality of life (HRQL),that allows an individual to implicitly weigh aspects of their healthand provide a personal valuation of the same. It is this personalvaluation that distinguishes HRQL from other measures of healthand function [38,39].

Many different techniques and measures have been used toassess the HRQL of premature infants at adulthood. Using astructured questionnaire that included both objective and sub-jective measures, Danish investigators [40,41] reported that onboth these variables, non-impaired VLBW 18e20-year-olds weresimilar to their NBW peers. However, the QoL was lower in thosewith impairments. Three studies used the SF36, a mailed healthquestionnaire. In the British study [31], VLBW 19e22-year-oldmales rated themselves lower only in physical functioning andhealth perception compared to their NBW peers. The Swiss study[37] reported no differences in both physical and psychologicalfunctioning in their 23-year-old young adults

[1] Hack M. Adult outcomes of preterm children. J Dev Behav Pediatr 2009;30:

and death from ischaemic heart disease. Lancet 1989;2(8663):577e80.[5] Hovi P, Andersson S, Eriksson JG, Jrvenp AL, Strang-Karlsen S. Glucose

regulation in young adults with very low birth weight. N Engl J Med2007;356:2053e63.

[6] Finken MJ, Keijzer-Veen MG, Dekker FW, Frolich M, Hille ETM, Romijn JA,et al. Preterm birth and later insulin resistance: effects of birth weight andpostnatal growth in a population based longitudinal study from birth intoadult life. Diabetologia 2006;49:478e85.

*[7] Rotteveel J, van Weissenbruch MM, Twisk JW, Delemarre-Van de Waal HA.Infant and childhood growth patterns, insulin sensitivity, and blood pressurein prematurely born young adults. Pediatrics 2008;122:313e21.

[8] Eriksson JG, Forsen T, Tuomilehto J, Winter PD, Osmond C, Barker DJ. Catch-up growth in childhood and death from coronary heart disease: longitudinalstudy. BMJ 1999;318:427e31.

[9] Dalziel SR, Parag V, Rodgers A, Harding JE. Cardiovascular risk factors at age30 following pre-term birth. Int J Epidemiol 2007;36:907e15.

[10] Saigal S, Streiner D. Commentary on Socio-economic achievements of in-dividuals born very preterm at the age of 27e29 years. Dev Med ChildNeurol 2009;51:848e50.

*[11] Moster D, Lie RT, Markestad T. Long-term medical and social consequences ofpreterm birth. N Engl J Med 2008;359:262e73.

*[12] Lindstrom K, Windbladh B, Haglund B, Hjern A. Preterm infants as youngadults: a Swedish national cohort study. Pediatrics 2007;120:70e7.

*[13] Swamy GK, Ostbye T, Skjaerven R. Association of preterm birth with long-term survival, reproduction, and next-generation preterm birth. JAMA2008;299:1429e36.

[14] Mathiasen R, Hansen BM, Nybo Anderson AM, Greisen G. Socio-economicachievements of individuals born very preterm at the age of 27 to 29 years: anationwide cohort study. Dev Med Child Neurol 2009;51:901e8.

eonaprovides complementary information to traditional biomedicaloutcomes, and should be elicited from individuals to obtain theirpersonal perceptions, and to tailor their care to their perceivedneeds.

6. Prematurity, aging, and mortality in young adulthood

In a Norwegian meta-analysis, an inverse relationship wasfound between birth weight and mortality in adulthood [48].There was a 6% lower risk of deaths per kilogram among higherbirth weights (adjusted HR: 0.94; 95% CI: 0.92e0.97). However,the rst large study to gauge the effects of gestational age onmortality at young adulthood was derived from the National Birthand Death Registry from Sweden [15]. Included in this study weresingletons born between 1973 and 1979 and who survived therst year of life. Mortality rates (per 1000 person-years) bygestational age at birth were 0.94 for 22e27 weeks and 0.86 for28e33 weeks of gestation. There was an independent, stepwiseinverse relationship between gestational age and mortality, and itaffected both sexes similarly. Preterm birth was associated withincreased mortality even among those born late preterm. Theunderlying mechanisms are unknown, but may be related to fetaland postnatal nutritional abnormalities, hormonal alterations orgenetic factors. Prematurity rates in Sweden are only 5%, andmortality risk will no doubt have a larger impact in countrieswhere the prematurity rates are higher. This may be furthercompounded by the current survival of more and more immatureinfants.

7. Conclusion

Although most VLBW infants go through signicant dif-culties in childhood and adolescence, by and large, by the timethey reach adulthood, they do better than expected in terms ofadult functioning. Many young adults may still have chronichealth conditions and some functional limitations, but despitethat, they seem to be fairly resilient and lead relatively normallives [1e3,11,29]. A most rewarding nding is that a signicantmajority of VLBW and ELBW participants rated their QoL equiv-alent to that of their peers. Certainly, although there is a gesta-tional age gradient in the incidence and severity of disabilities,there is no such difference in terms of subjective valuation oftheir QoL. Whether these ndings are generalisable to the morerecent survivors remains to be seen. One might anticipate thattheir outcomes might be substantially better, as these infants arethe beneciaries of technological and social advances in care.However, there are also some reservations as increasing numbersof extremely immature infants are surviving, and disability rateshave not declined correspondingly.

The mean age of follow-up of the studies reported to adulthoodso far is still fairly young. It is likely that the disparity in occupa-tional prestige and income may widen signicantly when they arein their 30s or 40s. There is also some suggestion of higher rates ofpsychopathology as they become older [49,50]. In addition, thereare concerns that other problems, such as diabetes, hypertension,atherosclerosis and cardiovascular diseases may manifest as theyreach middle-age [4,8]. There is already some evidence of insulinresistance [5e7], and higher blood pressure among VLBW youngadults [7,9,51,52].

Thus, we need to be vigilant regarding the long-term outlookfor the former preemies in their middle age, and ensure thatfurther follow-up of the above populations is continued. Inaddition, the current cohorts who are now adolescents from therecent era of neonatal intensive care need to be monitored to

S. Saigal / Seminars in Fetal & Nadulthood.460e70.*[2] Doyle LW, Anderson PJ. Adult outcome of extremely preterm infants. Pedi-

atrics 2010;126:342e51.[3] Saigal S, Rosenbaum P. What matters in the long term: reections on the

context of adult outcomes versus detailed measures in childhood. SeminFetal Neonatal Med 2007;12:415e22.

[4] Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ. Weight in infancyNone.

ReferencesConict of interest statement

None declared.

Funding sources

Practice points

Residual neurodevelopmental disabilities and functionallimitations persist to adulthood.

Most studies report lower educational attainment andlower income.

The proportions married or cohabiting and reproductiverates are lower.

The quality of life is similar to term-born peers. There is early evidence of more psychopathology, higherblood pressure and insulin resistance.

Research directions

Longer-term follow-up to monitor the cardiovascular andmetabolic sequelae until middle age.

Monitor and treat psychopathology, particularly infemales.

Collect data tomiddle adulthood on the current survivors.

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