Long Term Medical and Social Consequences of Preterm Birth

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original article

T h e n e w e n g l a n d j o u r n a l o f medicine

n engl j med 359;3 www.nejm.org july 17, 2008262

Long-Term Medical and Social

Consequences of Preterm BirthDag Moster, M.D., Ph.D., Rolv Terje Lie, Ph.D.,

and Trond Markestad, M.D., Ph.D.

From the Department of Public Healthand Primary Health Care (D.M., R.T.L.) andthe Section for Pediatrics, Department ofClinical Medicine (T.M.), University ofBergen; the Department of Pediatrics,Haukeland University Hospital (D.M.,T.M.); and the Medical Birth Registry ofNorway, Norwegian Institute of PublicHealth (R.T.L.) all in Bergen, Norway.Address reprint requests to Dr. Moster atthe Department of Public Health and Pri-mary Health Care, University of Bergen,P.O. Box 7804, N-5020 Bergen, Norway,or at [email protected].

N Engl J Med 2008;359:262-73.Copyright 2008 Massachusetts Medical Society.

A b s t r a c t

Background

Advances in perinatal care have increased the number of premature babies who sur-vive. There are concerns, however, about the ability of these children to cope withthe demands of adulthood.

Methods

We linked compulsory national registries in Norway to identify children of differentgestational-age categories who were born between 1967 and 1983 and to follow themthrough 2003 in order to document medical disabilities and outcomes reflecting so-cial performance.

Results

The study included 903,402 infants who were born alive and without congenitalanomalies (1822 born at 23 to 27 weeks of gestation, 2805 at 28 to 30 weeks, 7424 at31 to 33 weeks, 32,945 at 34 to 36 weeks, and 858,406 at 37 weeks or later). The pro-portions of infants who survived and were followed to adult life were 17.8%, 57.3%,85.7%, 94.6%, and 96.5%, respectively. Among the survivors, the prevalence of hav-ing cerebral palsy was 0.1% for those born at term versus 9.1% for those born at 23to 27 weeks of gestation (relative risk for birth at 23 to 27 weeks of gestation, 78.9;95% confidence interval [CI], 56.5 to 110.0); the prevalence of having mental retar-dation, 0.4% versus 4.4% (relative risk, 10.3; 95% CI, 6.2 to 17.2); and the prevalenceof receiving a disability pension, 1.7% versus 10.6% (relative risk, 7.5; 95% CI, 5.5 to10.0). Among those who did not have medical disabilities, the gestational age at birthwas associated with the education level attained, income, receipt of Social Securitybenefits, and the establishment of a family, but not with rates of unemployment orcriminal activity.

Conclusions

In this cohort of people in Norway who were born between 1967 and 1983, the risksof medical and social disabilities in adulthood increased with decreasing gestationalage at birth.

The New England Journal of Medicine

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Medical and Social Consequences of Preterm Birth

n engl j med 359;3 www.nejm.org july 17, 2008 263

Recent advances in the care of pre-

mature infants have resulted in increasingrates of survival. However, the increased

prevalence of medical disabilities, learning diffi-culties, and behavioral and psychological problemsamong surviving preterm infants has raised con-cerns that these infants may have difficulties in

coping with adult life.1-6 Some primarily hospital-based cohorts of infants with very low birth weightwho have been followed to young adulthood haveshown reduced scores on cognitive and psychologi-cal tests as compared with controls with normalbirth weights.7-16 Other follow-up studies haveshown more encouraging results.17,18 However, thelong-term social and behavioral outcomes of pre-term birth are not well described. Most follow-upstudies have focused on extremely premature in-fants (gestational age


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Point estimates and confidence intervals for thelarger categories were based on log-binomial re-gression.

Additional analyses of medical disabilities werestratified according to the year of birth, with theuse of the time intervals of 1967 to 1972, 1973 to1978, and 1979 to 1983, and analyses of medical

disabilities and outcomes reflecting social func-tion were stratified according to sex. Autism andschizophrenia were not included in these strati-fied analyses because the numbers in the sub-groups were too small.

Results

Study Cohort

A total of 903,402 children who were born alivebetween 1967 and 1983, with a gestational age atbirth of at least 23 weeks and without known

congenital anomalies, were identified through theMBRN. Among these, 13,582 died before their20th birthday and 22,128 were not registered asresidents in Norway as adults, leaving 867,692 inthe cohort as adults (Fig. 1). Five-year survival in-creased from 20% for children born at 23 to 27weeks of gestation to 99% for those born at term.The baseline characteristics of the cohort areshown in Table 1, and survival of the children bygestational age is shown in Figure 2. From 1967to 1983, the neonatal mortality rates decreasedsteadily for all gestational ages (Fig. 3).

Outcomes

The risk of serious medical disabilities such ascerebral palsy, mental retardation, and disordersof psychological development, behavior, and emo-tion, as well as of other major disabilities such asblindness or low vision, hearing loss, and epilepsyincreased markedly with decreasing gestationalage (Table 2). We also observed a significant as-sociation of autism-spectrum disorders with verylow gestational age, but these findings were based

on a very small number of cases in the lowestgestational-age groups (Table 2). At 19 to 35 yearsof age, nearly 1 of 9 persons who had been bornat 23 to 27 weeks of gestation received a disabil-ity pension, as compared with 1 of 12 who hadbeen born at 28 to 30 weeks, 1 of 24 born at 31to 33 weeks, 1 of 42 born at 34 to 36 weeks, and1 of 59 born at term (P


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(P = 0.006), and of having a high income (P


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hort study.18 A lower level of academic achievementand a reduced tendency to have biologic childrenamong persons born very prematurely, as com-pared with those born at term, were previously

reported in a study that involved members of thecohort of the current study, but that study did notexclude those with medical disabilities from theseanalyses.30

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CumulativeSurvival

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Figure 2. Survival Curves According to Gestational Age.

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19671969 19701972 19731975 19761978 19791981 19821983

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Figure 3. Secular Trend of Neonatal Mortality (per Thousand), Excluding Children with Congenital Anomalies.

The New England Journal of Medicine

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We defined prematurity according to gesta-tional age instead of birth weight, which is thedefinition that was used in many previous stu-dies.7-12,15-17 Although this approach resulted inthe exclusion of about 4% of the births, owing to

missing data on gestational age, it avoided thepotential for misclassification of more mature ba-bies who were small for gestational age as morepreterm than they actually were.

Among the strengths of our study are the co-

Table 2. Medical Disabilities According to Gestational Age at Birth.*

Disability Subjects P Value for Trend

no./total no.(%) relative risk (95% CI)

Cerebral palsy


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hort design that included all births in the coun-try, the linkage of comprehensive and compulsorydatabases that had reliable information, and theminimal loss to follow-up. Furthermore, we stud-ied a wide range of gestational ages to assessgradients or thresholds in the relationship betweenthe degree of prematurity and several outcomes.The weaknesses of our study include the lack ofdetailed information on the severity of disabilitiesor on any functional capacity related to cognitiveand social skills that was not reflected in educa-tional level, income, criminal records, or the abil-ity to establish a family. The misclassification ofsome diagnoses is possible when NIS data areused, but it is likely that diseases or disabilitiesthat add a substantial burden to the individual orthe family are recorded in this database. Duringthe years when this cohort was born, there wereno organized follow-up programs for prematurechildren in Norway. Furthermore, the NIS would

not have released financial support to a personwho had received a given diagnosis unless thefunctional capacity of the person was substantiallyreduced. Therefore, overdiagnosis of disabilitiesamong the most premature cohort owing to anincreased use of services is unlikely.

The associations we observed between pretermbirth and adverse adult outcomes may representlong-term effects of subtle brain dysfunctioncaused by preterm birth. Underlying biologic andsocial factors may, however, influence both the

likelihood of preterm birth and adverse adultoutcomes.31-33 Therefore, to reduce potential con-founding, we adjusted all analyses for sex, year ofbirth, multiple births, single motherhood, mater-nal age at the time of the birth, mothers and fa-thers level of education, and immigrant status ofthe parents. Confounding still remains possibleowing to factors for which we could not adjust,such as parental IQ, other socioeconomic factors,and the use of tobacco, alcohol, or illicit drugs.Also, we cannot rule out the possibility that anunderlying and unknown medical condition insome infants led to both preterm delivery and sub-sequent social or health problems.

The survival rates among the children with thelowest gestational ages increased over time andcoincided with an increased prevalence of cerebralpalsy. There was no change in diagnostic criteriaor screening procedures for cerebral palsy duringthe study period, leaving increased survival as the

most likely explanation for the increased preva-lence. Neonatal intensive care has continued toimprove considerably in the years since this cohortwas born.34 Among preterm survivors, the prev-alence of cerebral palsy may be decreasing,35,36although it is uncertain whether the same trendis occurring with respect to the prevalence of lesssevere functional impairments such as behavioral,social, and learning difficulties among preschooland school-age children.37 Studies have shown in-creased prevalences of attention deficits, with-

Table 2. (Continued.)

Disability Subjects P Value for Trend

no./total no.(%) relative risk (95% CI)

Any medical disability severely affecting workingcapacity


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drawal, anxiety, and reduced academic and socialskills among schoolchildren with low birth weightas compared with children with normal birthweight.38,39 More recent survivors of preterm birthmay therefore have diff iculties similar to those

of the present cohort when they become adults,although further follow-up of more recent co-horts is needed to address this question.

Despite the higher prevalence of disabilitiesamong persons who were born prematurely, it

Table 3. (Continued.)

Variable and Gestational Age at Birth Subjects P Value for Trend

no./total no. (%) relative risk (95% CI)

Married or cohabitating


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should be recognized that a large proportion of theadults who were born prematurely and who did nothave severe medical disabilities completed high-er education and seemed to be functioning well.

The current study shows that there is a continu-ous relationship between decreasing gestationalage at birth and a wide range of adverse outcomes,

without any obvious threshold. Since most pretermbirths occur at moderate rather than extreme pre-maturity, most of those with special needs may be

those who were born at a moderately prematuregestational age. On the other hand, the survivalrate of very preterm infants who are at higher riskhas continued to increase. Studies are needed toidentify modifiable factors that predict adult out-comes among children born prematurely in orderto improve preventive and therapeutic strategies.

Supported by the Western Norway Regional Health Authorityand the University of Bergen, Norway.

No potential conflict of interest relevant to this article wasreported.

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