In this study, several perinatal risk factors like bronchopulmonary dysplasia (chapters 7 and 8), hypotension (chapters 6 and 8), cystic periventricular leuco- malacia (chapters 6 and 8) and the postnatal use of dexamethasone (chapters 2, 6 and 8) are associated with adverse neurodevelopmental outcome in very preterm infants. Bronchopulmonary dysplasia, cystic periventricular leucomalacia and the use of dexamethasone were also associated with suboptimal later growth (chapter 4), just like intrauterine growth restriction (resulting in being born small-for-ges- tational-age) or extra-uterine growth restriction (PGR) in the neonatal period (chapter 5).
The Leiden Follow-Up Project on Prematurity was started more than 10 years ago. The disadvantage of follow-up studies is that during a follow-up period new techniques and interventions have developed, which could have an influence
on perinatal care. Nowadays in the 21st century for example we use much lower
doses and shorter courses of dexamethasone compared to 1996/1997. Techniques for the cerebral ultrasound scanning have been refined and the use of Magnetic Resonance Imaging (MRI) for detecting cerebral damage has increased. Because of the association of intracerebral abnormalities (especially periventricular leuco- malacia) and the use of dexamethasone with abnormal long-term outcome, these risk factors will be discussed in relation to new insights.
Periventricular leucomalacia
Although cystic periventricular leucomalacia (PVL) results in an increased risk of adverse outcome, many of the extremely preterm infants without cystic PVL
survive with some degree of disability.27 Nowadays, not only the cystic PVL but
also diffuse PVL is considered the principal form of brain injury, and prognosti-
cally important.19 Already in 1992, de Vries et al.28 described the whole spectrum
of leucomalacia using cranial ultrasound. Van Wezel-Meijler et al.29 described in
a follow-up study the degree of echogenicity on cranial ultrasound to carry the highest predictive value for abnormal neurodevelopment at 12 months corrected age, compared to duration of flaring on ultrasound and degree of periventricular
signal intensity change on magnetic resonance imaging (MRI). Olsen et al.27
found, as expected, significant differences between infants with PVL and normal controls, regarding psychological outcomes. Interestingly, preterm infants with-
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out PVL also scored significantly lower than normal controls. So they conclude, like others, that there must be subtle brain changes that cannot be identified by non-functional MRI.
In 1999, Maalouf et al.30 published results of a study in preterm infants with
GA < 30 weeks, where they concluded that abnormalities on MRI are com- monly seen in the brain of preterm infants in the first 48 hours and that further abnormalities develop between birth and term age. A characteristic appearance on MRI of Diffuse and Excessive High Signal Intensity (DEHSI) in the white matter was associated with the development of cerebral atrophy and might be a sign of white matter disease. The major risk factors for this white matter abnor- mality are related to perinatal infection and hypotension associated with use of
inotropics.31 Neonatal cranial ultrasound of the very preterm infant demonstrates
high reliability in the detection of cystic PVL, but has significant limitations in the detection of the noncystic white matter injury. This restriction of neonatal cranial ultrasound is important, because non-cystic PVL is considerably more
common than cystic PVL.32 For detection of DEHSI (and to help to predict the
prognosis), it would be preferable to perform an MRI at term age in preterm infants at risk.
Dexamethasone
After Mammel et al.33 reported in 1983 a significant respiratory benefit from
dexamethasone in preterm infants, a widespread use of high doses of dexameth- asone for periods as long as 6 weeks or more arose. In the late 1990s, more than 25% of all very low birth weight infants were exposed to postnatal ste-
roid therapy.34 The first convincing reports of adverse effects of high-dose dexa-
methasone therapy on subsequent growth and neurodevelopment appeared in
1998/1999.35;36 This resulted in a decrease in prescription of dexamethasone,
demonstrated in a study by Shinwell: use of dexamethasone fell from 22% in
1993/1994 to 6% in 2001, in preterm ventilator-dependent infants.37 However,
in the DART study (Dexamethasone: A Randomized Trial), including infants with GA < 28 weeks or birth weight < 1000 grams, low-dose (0.15 mg/kg/day) dexamethasone treatment after the first week of life, clearly facilitated extubation and shortened the duration of intubation among ventilator-dependent infants,
without any obvious short-term complications.38 Although this trial was stopped
because of recruitment difficulties, rates of disabilities or CP at 2 years of age
outcome was published by Nixon et al.40 who reported improved respiratory
outcome at 8 years of age in preterm born infants treated with dexamethasone, compared to those treated with a placebo, partly as a result from fewer days of mechanical ventilation.
Because dexamethasone facilitates extubation in these infants, the benefits of
a brief course of therapy in such infants could outweigh the risks.41 Grier and
Halliday42 wrote in their guidelines for corticosteroid use in 2005, that there is no
role for use of corticosteroids in the first 4 days of life; the use of this drug should be limited to exceptional clinical circumstances, such as ventilator-dependent infants after the second week of life who cannot be weaned from ventilation and whose condition is worsening. If used, corticosteroids should be prescribed at the lowest effective dose for the shortest possible time.
But, dexamethasone is not the only glucocorticosteroid. In 2003 van der
Heide-Jalving et al.43 reported fewer short- and long-term adverse effects in
infants treated with hydrocortisone compared to dexamethasone in the neonatal
period. Recently, Rademaker et al.44 reported MRI-outcomes at school age (7-8
years old) in a large cohort of preterm infants, comparing infants treated with hydrocortisone for BPD with infants who were not treated with postnatal glu- cocorticosteroids. Infants receiving hydrocortisone had no functional disadvan- tage or structural impairment with MRI. They also published that cerebral gray matter volume was reduced among preterm children compared with children born at term, but volumes were similar in children treated with hydrocortisone
compared to children not treated with hydrocortisone.45 In another publication
of this group, neuromotor development at school age was found to be poorer in preterm infants treated in the neonatal period with dexamethasone for chronic lung disease, compared to infants treated with hydrocortisone or a reference
group.46 These findings are consistent with information from a multicenter ran-
domised trial, in which infants treated with early low-dose hydrocortisone (1 mg/kg/day) showed no evidence of neurodevelopmental compromise at 18 to 22 months corrected age, compared with infants who were treated with a pla-
cebo.47 Kristi Watterberg41 however remarked that we hopefully have learned
from the dexamethasone experience and apply a more scientific approach in case of hydrocortisone. So further randomised trials of low-dose corticosteroids given after the first week of life are warranted and should assess both short- and
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