Study design

EPIPAGE (Etude EPIdémiologique sur les Petits Ages Gestationnels) was a prospective observational population-based cohort that included all births (live births and stillbirths) and late pregnancy terminations that occurred between 22 and 32 completed weeks of gestation in all maternity wards of nine French regions in 1997[20]. A control group of individuals born at term (one in every four births at 39 or 40 weeks of gestation during 1 week in 1997) was also included. Because the study focused on the causes and consequences of prematurity, and because the control group was expected to be more homogenous than the preterm group, less children were included in the control group than in the preterm group.

At recruitment in the maternity or neonatal unit, parents were informed of the study and given written information. Oral consent was given to the medical team in charge of the study in accordance with French rules in force in 1997. The study was approved by the French Commission Nationale de l’Informatique et des Libertés (the French data protection agency).

Data for mothers, pregnancies, births, and neonatal outcomes were recorded on standardized questionnaires at each maternity and neonatal intensive care unit. Maternal data included ethnic origin, tobacco consumption during pregnancy, and causes of preterm birth. Neonatal data included gender, gestational age (determined from the last menstrual period and findings from early prenatal ultrasound scans, calculated in complete weeks), birth weight, postnatal sepsis (defined as a postnatally acquired infection treated with antibiotics for at least 7 days), necrotising enterocolitis, and bronchopulmonary dysplasia (BDP). BPD was defined as the need for supplemental oxygen and/or ventilatory support at 36 weeks of post-menstrual age. Information about the health and the development of the children was subsequently collected by questionnaires sent to the families two months after discharge, and when the child was nine months, and one, two, three, and four years old. At two years of age, a questionnaire was also sent to the child’s physician. At five years of age, the children were invited for a check-up with a physician and a psychologist at local centres in every region. At eight years of age, a questionnaire was sent to the families.

EPIPAGEADO was part of the EPIPAGE study but was restricted to the very preterm born children in four French regions: Paris, Normandie, Pays-de-la-Loire, and Midi-Pyrénées. The EPIPAGEADO (“Etude EPIdémiologique sur les Petits Ages Gestationnels- Adolescents”) study was registered at clinicaltrials.gov (NCT01424553) and approved by the ethical committee CPP Ile de France VI. The inclusion criteria were complete participation in EPIPAGE from birth, available assessment at five and/or eight years of age, coverage by national health insurance, and written parental informed consent. Inclusion took place between November 2011 and June 2013, when adolescents reached the age of 15 years.

Data collection

Data for mothers, pregnancies, births, and neonatal outcomes were recorded on standardised questionnaires at each maternity and neonatal intensive care unit.

The assessment at 15 years of age included a questionnaire completed by the investigator with the participants and their parents (S1 and S2 Figs). Data regarding academic performance, current medical follow-up, and family characteristics were collected. The assessment also included anthropometric measures and lung function tests that were published in a previous study[21].

Statistics

Continuous variables were compared using the Kruskal-Wallis test and categorical variables using the Chi-2 and Fisher’s exact tests. Multivariate logistic regression was used to quantify relationships between academic outcomes and BPD before and after adjustment for potential confounders identified as relevant factors from the literature (S1 Table). Retinopathy of prematurity (ROP) was not included in the main analyses as a parameter for adjustment because 26% of values were missing. However, analyses on a smaller dataset including ROP as a potential confounder were conducted (S2 Table).

Results are reported as crude and adjusted ORs with 95% confidence intervals (CIs). Significance was set at p ≤ 0.05. Analyses were performed with SAS version 9.3 software (SAS Institute, Inc, Cary, NC).

Population

From the 1341 children included in the four French regions participating to EPIPAGEADO, 985 adolescents were eligible and 351 included (Fig 1).

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Fig 1. Flow-chart of the study population.

https://doi.org/10.1371/journal.pone.0222286.g001

The study included 304 adolescents born very preterm, 55 with and 249 without a history of BPD, and 47 controls born full term. Their characteristics are presented in Table 1.

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Table 1. Characteristics of adolescents born very preterm with and without BPD, and controls.

https://doi.org/10.1371/journal.pone.0222286.t001

Compared to adolescents born very preterm, those born full-term lived in families with a higher socio-economic status, from mothers with a higher level of education and a lower level of parity, and more frequently born in France (Table 1).

Among adolescents born very preterm, those with a history of BPD were born at a lower gestational age, with a lower birth weight, had a lower Apgar score at 1 min, were more frequently diagnosed with patent ductus arteriosus, intraventricular haemorrhage of all grades, and sepsis, and were more frequently treated with post-natal steroids (Table 1).

The included adolescents belonged to families characterised by a higher socio-economic status, a higher maternal level of education, and a higher proportion of mothers born in France than those lost to follow-up (S3 and S4 Tables).

Academic achievement

Academic achievement among adolescents born very preterm with or without a history of BPD, and controls born full term, is shown in Table 2.

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Table 2. Academic, health and family outcomes of adolescents born very preterm with BPD, born very preterm without BPD, and controls born full term.

https://doi.org/10.1371/journal.pone.0222286.t002

Significantly more adolescents born very preterm had repeated a grade (i.e., were not considered ready to graduate by their teachers and had to repeat a year at the same grade) than controls born full preterm.

Among adolescents born very preterm, significantly more adolescents with a history of BPD attended a school adapted for children with special needs, had repeated a grade, and needed personalized assistance at school than adolescents without a history of BPD (Table 2). After adjustment for sex, gestational age, small for gestational age, intraventricular hemorrhage, periventricular leukomalacia, necrotising enterocolitis, late-onset sepsis, post-natal steroids, family structure, maternal level of education and socio-economic status, a history of BPD was still associated with attending a school adapted for children with special needs and repeating a grade (Table 3).

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Table 3. Comparison of academic, health and family outcomes of adolescents born very preterm with and without BPD.

https://doi.org/10.1371/journal.pone.0222286.t003

Healthcare use

Significantly more adolescents born very preterm (with and without BPD) had been under the care of a psychologist of a psychiatrist in the previous 12 months than controls born full preterm (Table 2). By contrast, the proportion of adolescents who had been under the care of a medical specialist, a psychomotor therapist, a speech therapist in the previous 12 months, or who required a hospital admission in the past 5 years did not differ significantly between adolescents born very preterm and controls born full term.

Among adolescents born very preterm, those with a history of BPD were more likely to have been under the care of a psychomotor therapist, a speech therapist, and a psychologist or psychiatrist in the previous 12 months (Table 2). However, after adjustment for sex, gestational age, small for gestational age, intraventricular haemorrhage, periventricular leukomalacia, and necrotising enterocolitis, a history of BPD remained only associated with visiting a speech therapist in the previous 12 months (Table 3).

Although the overall use of a specialist or physiotherapist was identical between adolescents with or without a history of BPD, a detailed analysis by specialty showed that BPD infants used more respiratory care resources (S5 Table)

Family characteristics

Neither a history of prematurity nor a history of BPD were associated with the parents’ employment status, family structure, or the presence of younger siblings (Table 2 and S6 Table).