www.thelancet.com Vol 371 March 8, 2008 787
Long-term outcome for very preterm infants
See Articles page 813
In England and Wales, in 2005, there were 11 657 infants
born at less than 33 weeks of gestation, more than
90% of whom survived the immediate postpartum
period.1 In the USA, in 2004, there were about
80 000 such births.2 The 2% of births before 33 weeks
lead to many vulnerable infants, and questions from
both health-care profes sionals and concerned parents
about the short-term and long-term health-care needs
of such infants. In today’s Lancet, Béatrice Larroque and
colleagues report a 5-year follow-up of 1800 French
infants born before 33 weeks (the EPIPAGE study) that
might help to provide some answers.3
Two cohorts with long-term outcomes of very
premature infants have focused on the much smaller
group of infants born before 26 weeks (8% of those born
before 33 weeks)4,5 or 28 weeks (15% of those born before
33 weeks).6 Both cohorts show similar proportions of
severe disabilities in survivors (10–15%) and substantial
rates of cognitive disability (about 40%). Follow-
up studies of more mature infants (up to 32 weeks’
gestation) from Germany7 and the UK8,9 in the 1980s
and early 1990s pre-date improvements in survival in
very premature infants due to the widespread uptake of
surfactants and other therapies in the 1990s.
The fi ndings of EPIPAGE are stratifi ed by gestational
age, and confi rm previous studies. About half of infants
born at 24–28 weeks of gestation have a disability
at age 5 years, similar to the proportion observed in
the UK-based EPICure study.5 In the infants born later
(29–32 weeks’ gestation), about a third have a disability
at age 5 years. The prevalence of cerebral palsy in the
EPIPAGE population (9%) is a little higher than that
reported in the Surveillance of Cerebral Palsy in Europe
study in children born at similar gestational age (6%),10
which possibly refl ects better case ascertainment by the
EPIPAGE group rather than a real diff erence. Diff erences
between studies in the classifi cation of cognitive function
make direct comparison with earlier work more diffi cult.
Further evidence of the prevalence of these outcomes after
premature birth will be useful for clinicians and parents.
The results from EPIPAGE about the use of special
health-care services by these children at age 5 years will
be particularly useful to those who plan health services.
The study showed that 42% of those born at
24–28 weeks were receiving some special support at the
5-year follow-up, with over half of these children receiving
care from psychologists or psychiatrists. Even in survivors
born later (29–32 weeks), 31% were accessing special
health-care services, with two-thirds receiving support
from a psychologist or psychiatrist at 5 years. 20% of chil-
dren receiving special health-care at age 5 years did not
have a disability (ie, they had no motor or sensory dis abil-
ity) and had a cognitive-function score above 85 (ie, in the
normal range). If we translate these proportions into abso-
lute fi gures for England and Wales by use of 2005 popu-
lation estimates,1 more than 3500 children born each year
require special health-services support well into childhood.
We might compare this fi gure with estimates of the
incidence of cystic fi brosis of one in 2415 livebirths11 (to
give an expected number of new cases in England and
Wales of 267 each year), and with an estimate of the
prevalence of any form of autistic spectrum disorder
in children aged 9–10 years of 116 per 10 000 (about
7500 aff ected children in that age group).12 The EPIPAGE
study reminds us that children born before 33 weeks
need care and support that lasts far beyond discharge
from the neonatal care unit.
Mary Jane Platt
Division of Public Health, University of Liverpool,
Liverpool L69 3GB, UK
I declare that I have no confl ict of interest.
Science Photo Library
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www.thelancet.com Vol 371 March 8, 2008
In today’s Lancet, Alain Tissot and colleagues1 report
a new strategy to treat hypertension. In patients with
mild-to-moderate hypertension, these investigators
used active immunisation against angiotensin II with
a vaccine in which the endogenous peptide is linked to
a virus-like particle. This study is the fi rst to show that
vaccination against a vasoactive endogenous substance
can reduce blood pressure in human beings. Previous
attempts have been unsuccessful2 or in animal models.3
This phase IIa study was double-blind, placebo-
controlled, and randomised: 24 patients were given a
placebo, and a further two groups of 24 each received
the vaccine (100 μg or 300 μg), with a booster at weeks 4
and 12.1 The primary objective of the study was to assess
safety and tolerability. No serious adverse events occurred
during the study dura tion of 16 weeks, and the vaccine
was well tolerated. A secondary study objective was
to assess the eff ect on blood pressure. Although this
was not a primary endpoint, the fi nding of a modest
but statistically signifi cant reduc tion in day-time blood
pressure is intriguing and promising.
Should we now have any concerns about circulating
antibodies against angiotensin II? The half-life of the
antibody against angiotensin II after the second booster
dose given by Tissot and colleagues was 17 weeks—
much longer than that of any drug which inhibits the
renin–angiotensin–aldosterone system (RAAS). This fi nd-
ing raises the question of whether it will be safe to inhibit
the actions of circulating angiotensin II for several months
without the ability to quickly reverse inhibition, which is
easily done for drugs by withdrawal of treatment. Tissot
underlines that the blood-pressure-lowering eff ect was
greatest during the early morning when the RAAS is most
stimulated. But, importantly, other situations can occur
when a patient will also need a fully activated RAAS.
The RAAS is phylogenetically a very old system that
developed when primitive vertebrates left life in salt
water to live in air in more hostile environments.4 The
system regulates tonicity and volume of body fl uids.
Thus, the RAAS plays a fundamental part in electrolyte
and volume homoeostasis. In situations of salt or
volume depletion, such as severe dehydration, trauma,
and clinical shock, rapid activation of the RAAS is crucial.
Inhibition of the RAAS in conjunction with salt
and volume depletion can cause life-threatening
hyperkalaemia and renal shut-down.5 Whether this
safety concern can be solved by doses of the vaccine
that result in only partial inhibition of the activity of
angiotensin II is unknown.
Another important safety issue is whether repeated
stimulation of the immune system by booster doses of
an endogenous peptide linked to a virus-like particle
can cause autoimmune disease. A trial in 300 patients
with Alzheimer’s disease of vaccination against an
endogenous peptide was stopped for this reason
in 2001.6–8 Although Tissot and colleagues did not
fi nd any clinically important changes in immune-cell
populations, including activated T cells, in the 48 treated
patients, the study was probably too small to detect such
The benefi cial eff ects of blocking the RAAS to prevent
cardiac, renal, and vascular damage are largely attributed
1 Moser K, Macfarlane A, Chow YH, Hilder L, Dattani N. Introducing new data
on gestation-specifi c infant mortality among babies born in 2005 in
England and Wales. Health Stat Q 2007; 35: 13–27.
Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Kirmeyer S.
Births: fi nal data for 2004. Natl Vital Stat Rep 2006; 55: 1–101.
Larroque B, Ancel P-Y, Marret S, for the EPIPAGE Study group.
Neurodevelopmental disabilities and special care of 5-year-old children
born before 33 weeks of gestation (the EPIPAGE study): a longitudinal
cohort study. Lancet 2008; 371: 813–20.
Marlow N, Hennessy EM, Bracewell MA, for the EPICure Study Group.
Motor and executive function at 6 years of age after extremely preterm
birth. Pediatrics 2007; 120: 793–804.
Marlow N, Wolke D, Bracewell MA, Samara M, for the EPICure Study Group.
Neurologic and developmental disability at six years of age after extremely
preterm birth. N Engl J Med 2005; 352: 9–19.
Bowen JR, Gibson FL, Hand PJ. Educational outcome at 8 years for children
who were born extremely prematurely: a controlled study.
J Paediatr Child Health 2002; 38: 438–44.
7 Wolke D, Meyer R. Cognitive status, language attainment, and prereading
skills of 6-year-old very preterm children and their peers: the Bavarian
Longitudinal Study. Dev Med Child Neurol 1999; 41: 94–109.
Cooke RW, Foulder-Hughes L. Growth impairment in the very preterm and
cognitive and motor performance at 7 years. Arch Dis Child 2003;
Pharoah PO, Stevenson CJ, Cooke RW, Stevenson RC. Clinical and subclinical
defi cits at 8 years in a geographically defi ned cohort of low birthweight
infants. Arch Dis Child 1994; 70: 264–70.
10 Platt MJ, Cans C, Johnson A, et al. Trends in cerebral palsy among infants of
very low birthweight (<1500 g) or born prematurely (<32 weeks) in
16 European centres: a database study. Lancet 2007; 369: 43–50.
11 Dodge JA, Morison S, Lewis PA, for the UK Cystic Fibrosis Survey
Management Committee. Incidence, population, and survival of cystic
fi brosis in the UK, 1968–95. Arch Dis Child 1997; 77: 493–96.
12 Baird G, Simonoff E, Pickles A, et al. Prevalence of disorders of the autism
spectrum in a population cohort of children in South Thames: the Special
Needs and Autism Project (SNAP). Lancet 2006; 368: 210–15.
Vaccination against high blood pressure: a new strategy
See Articles page 821