Management during the first 72h of age of the periviable infant: An evidence-based review
Seminars in perinatology (Impact Factor: 2.68). 02/2014; 38(1):17-24. DOI: 10.1053/j.semperi.2013.07.004
After NICU admission the extremely immature newborn (EIN) requires evaluation and support of each organ system, and the integration of all those supports in a comprehensive plan of care. In this review, I attempt to analyze the evidence for treatment options after the initial transition, during the first 3 days of life, which have been shown to improve survival or short- or long-term morbidity. This review revealed several things: there is little available evidence from studies that have included significant numbers of EINs; interventions affecting different organ systems need to be co-ordinated as any intervention will have multiple effects; and future advances in treatment of this group of patients will require the installation of permanent research networks to have enough power to perform many studies needed to improve outcomes.
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Management during the ﬁrst 72 h of age of the periviable
infant: An evidence-based review
Keith J. Barrington, MB ChB
Sainte Justine University Hospital Center, 3175 Cote Ste Catherine, Montréal, Québec, Canada H3T 1C5
After NICU admission the extremely immature newborn (EIN) requires evaluation and
support of each organ system, and the integration of all those supports in a comprehensive
plan of care. In this review, I attempt to analyze the evidence for treatment options after
the initial transition, during the ﬁrst 3 days of life, which have been shown to improve
survival or short- or long-term morbidity. This review revealed several things: there is little
available evidence from studies that have included signiﬁcant numbers of EINs; inter-
ventions affecting differen t organ systems need to be co-ordinated as any intervention will
have multiple effects; and future advances in treatment of this group of patients will
require the installation of permanent research networks to have enough power to perform
many studies needed to improve outcomes.
& 2014 Elsevier Inc. All rights reserved.
After the immediate transition period of the extremely
immature newborn (EIN) and admission to the NICU, occa-
sional infants succumb quickly as a result of profound
immaturity of several systems. They may be very difﬁcult
to ventilate and oxygenate, or have profound cardiovascular
failure, or severe metabolic disturbance with metabolic
acidosis and uncontrollable hyperglycemia. More commonly,
a period of relative stability follows admission, which is then
followed by the advent of complications in the respiratory,
cardiovascular, and metabolic domains.
I will discuss the potential interventions that may be
effective during this period of relative stability, which have
been shown to improve outcomes in the very preterm infant.
I will discuss these issues by system, but with the clear
understanding that any intervention aimed at one system
will affect other systems. Ventilator practices affect cardio-
vascular function; ﬂuid management affects nutrition, and
has respiratory and cardiovascular effects. This complexity of
responses requires that we consider innovative research
approaches for the future.
2. Fluids, electrolytes, and renal function
Renal vascular resistance is high immediately after birth, and
falls rapidly in the ﬁrst 24 h. This fall is associated with a
major increase in glomerular ﬁltration rate, and urine output,
which is usually clinically evident as an increasing diuresis
by the end of the ﬁrst 24 h of life. After this transition,
preterm renal function is marked by a low ability to excrete
a sodium load, but little restriction of maximal water
There are few studies on which to base a decision regarding
total ﬂuid management in the extremely immature newborn.
The skin of the very immature infant is very permeable, and
huge trans-epidermal water losses occur if they are placed in
a dry environment, the evaporation of water from the skin of
the infant leads to cooling due to the latent heat of vapor-
ization, and it may be impossible to keep the EIN warm in
a dry environment under a radiant heater. Most centers have
now moved to placing EINs in incubators, although there is
no RCT evidence that this is preferable to being under a
radiant heater, it seems likely to be the case. If a radiant
heater is used it must be combined with an arrangement to
0146-0005/14/$ - see front matter & 2014 Elsevier Inc. All rights reserved.
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S EMINARS IN P ERINATOLOGY 38 (2014) 17– 24
keep the humidity around the infant at a high concentration,
such as covering the infant with plastic.
One problem with keeping EINs in a high humidity environ-
ment is that whenever they are accessed to give care (for
example by opening the incubator portholes) the humidity
drops precipitously. This is even more evident when the
“roof” of an incubator with a retractable cover is lifted.
Therefore further methods to reduce trans-epidermal water
loss have been examined, including using ointments
Ointments such as Aquaphor
can reduce trans-epidermal water loss,
but whether they can
improve overall water balance or improve clinical outcomes
is uncertain. The only large study in ELBW infants enrolled
infants (500–1000 g birth weight) starting at an average of
about 24 h of age, and showed an increase in late-onset
coagulase-negative staphylococcal sepsis during prolonged
Maturation of the epithelial barrier after preterm
birth occurs rapidly, a briefer period of barrier treatment
could potentially have beneﬁts without this risk. Semi-
permeable membranes have also been tried; in a small pre–
post study, TEWL appears to have been reduced, ﬂuid
requirements and peak sodium was lower, and there may
have been less BPD
(n ¼ 69; birth weight o1000 g), but there
is no data from RCTs examining clinical outcomes.
2.1. Total ﬂuid intake
What should the total ﬂuid intake be? Clearly this will depend
on overall ﬂuid losses. But the interaction between the
physical environment, and subsequent TEWL, and ﬂuid
administration requirements has not been well studied.
Several studies have randomly compared infants by total
volume of ﬂuid administered. The results are very inconsis-
tent. Those studies have varied in design, in particular by
how sodium intake was controlled.
Although the Cochrane review “Restricted vs liberal water
intake for preventing morbidity and mortality in preterm
suggests that restricted ﬂuid intake improves sev-
eral clinical outcomes, this result is marked by signiﬁcant
heterogeneity, also one of the better studies did not enroll
babies until the 3rd day of life,
and therefore is of little
relevance to this review. After the initial period of adaptation
as mentioned above, the preterm kidney has a relatively good
ability to clear a ﬂuid load. Thus there is little reason to
hypothesize that variation in total free-water administration,
within reasonable limits, will affect total body water. In fact,
one of the studies of water restriction
gave ﬂuids with
identical sodium concentrations in each 100 ml of the intra-
venous ﬂuid, another was designed to examine a relatively
complex protocol allowing either 10% or 15% body weight loss
and therefore varied both water and sodium intakes. These
two studies were therefore studies of combined sodium and
I have performed a systematic review of RCTs of different
ﬂuid administration rates starting on the ﬁrst day of life,
which I have meta-analyzed using the RevMan software,
ﬁxed-effects model I found ﬁve controlled trials (Table 1),
three of which had similar sodium intake in each group, two
varied in both the ﬂuid and the water intake (Fig. 1). As can be
seen, the studies with varying water intake, but no difference
Table 1 – Randomized trials comparing 2 levels of ﬂuid intake or 2 levels of sodium administration in the preterm.
References n Characteristics of
Comparison, ﬂuid intakes Sodium intakes Outcome
100 o1751 g BW, 423
50, 60, 70, 80, 90, 100, 120 Then 150 ml/kg/day vs 80,
100, 120, 150 then 200 ml/kg/day
3 mM/100 ml Na in all the ﬂuids Primary: BPD
88 750–1500-g BW, day
1 of life
Designed for 10% birth weight loss vs 15%, initially,
1000–1500 g 70 ml/kg/day 750–1000 g 80 ml/kg/day.
Thereafter varied according to weight loss
Higher in high ﬂuid group, 1 mM/kg/day on day 1
increasing to 3 in high ﬂuid group or decreasing
to 0.5 in low ﬂuid group, by day 4
No clear primary
56 Premature, day 1 of
60 ml/kg/day vs 150 ml/kg/day for 3 days Unclear No clear primary
Kavvadia et al.
168 o1501 g BW, day 1 of
70 increasing to 150 by day 6, 40 increasing to 150 by
Adjusted to achieve serum concentration of 135–
145 mM/100 ml, no difference between groups
Survival without BPD
Costarino et al.
17 o1000 g, o29 weeks,
day 1 of life
Individualized, not different overall between groups 0 vs 3–4 mM/kg/day Risk of hypernatremia
and large ﬂuid volumes
Hartnoll et al.
46 25–30 weeks with
Individualized, not different between groups 4 mM/kg/day Starting on day 2 vs 0 until weight
decreased by 6%
Risk of continuing oxygen
Ekblad et al.
20 o35 weeks 50 increasing to 110 in each group 0 Increasing to 2, vs 4 mM/kg/day No clear primary
S EMINARS IN P ERINATOLOGY 38 (2014) 17– 2418
in sodium intake showed no effect on mortality, whereas
those which varied both showed a reduction in mortality
with restricted water and sodium intake. It is noteworthy that
this second result is largely the result of a single trial with
a very high mortality in the high water/high sodium group,
and this subgroup shows substantial heterogeneity.
In contrast the preterm kidney has a limited ability to
excrete a sodium load, and excessive sodium administration
may lead to increases in total body water and increases in
water content of vital tissues. This is true even though there
is natriuresis in the ﬁrst few days of life, at least after the ﬁrst
24 h, which accompanies the postnatal diuresis. Administra-
tion of sodium during this period may well upset the post-
natal progressive decrease in extra-cellular ﬂuid, which is
a normal phenomenon in more mature infants.
I performed a systematic review and meta-analysis of RCTs
in preterm infants, which compared two regimes of sodium
administration starting on the ﬁrst day of life (Table 1). The
search found ﬁve studies, two of which are as mentioned,
also studies of varying water intake are mentioned above,
and one with very limited description of clinical outcomes
(other than death).
The total numbers of infants in these
trials is a disappointing 271. Nevertheless there appears to be
a reduction in mortality RR 0.44 (95% CI; 0.22, 0.90) with a
reduced sodium intake, a possible reduction in BPD, RR 0.76
(95% CI; 0.56, 1.04), and a reduction in the combined outcome
of death or BPD, RR 0.39 (95% CI; 0.23, 0.67) (Fig. 2).
The data are therefore probably best interpreted as showing
that delaying all sodium intake until after either 3 days of life
or after a 5% weight loss improves outcomes, whereas restrict-
ing free-water intake by itself has little or no effect. The major
limitation of these data being that very few extremely imma-
ture babies have been included in any of these studies.
2.2. Research needs
Further studies of optimal management of ﬂuids and electro-
lytes in EINs are warranted: they should focus on methods to
further reduce ﬂuid loss, and the potential adverse conse-
quences of any individual technique. The interaction
between physical environment ﬂuid administration and
sodium administration should be controlled and clearly
described. Good evidence regarding the water and sodium
needs of EINs nursed in high humidity environments is
Over the course of the hospitalization of the very preterm
neonate, adequate nutritional intakes are important to
improve outcomes. It is now clear that both enteral and
parenteral nutrition can be commenced early without
adverse effects. Failure to do so leads to a nutritional deﬁcit
which may never be regained.
3.1. Enteral nutrition
There appears to be no good rationale for the traditional
approach of waiting for several days before introducing
enteral nutrition. Feeds should be commenced immediately
as long as there is no speciﬁc concern that the intestines are
under-perfused, such as the infant with shock requiring
inotropes. This is the practice in many European NICUs,
and can be successful. It is abundantly clear that human
milk, preferably the mothers' unpasteurized
milk is the
preferred food. This creates a dilemma, as mothers' milk may
not be immediately available, due to maternal illness and/or
difﬁculties with milk production after extremely preterm
delivery. Should we wait for mother's milk or commence
donor milk feeding? If donor human milk is not available how
long should we wait, if at all, before giving artiﬁcial formula?
Once feeds are started, it has become common practice to
institute several days of “trophic” feedings
; this appears to
be preferable to an equivalent period of not feeding, in terms
of nutritional advantages and no evidence of harm. A period
of trophic feeding compared to immediately starting to
increase feeds, in contrast, has only been studied in one
modestly sized trial,
which was stopped early. This study
however commenced after a prolonged period of being nil by
Fig. 1 – Effects on mortality of studies comparing different levels of ﬂuid intake in the preterm infant starting on the ﬁrst day of
life, separated according to whether sodium intake was also varied between the groups.
S EMINARS IN P ERINATOLOGY 38 (2014) 17– 24 19
mouth (average more than 9 days) prior to starting the feeds,
and therefore has little relevance to the question of immedi-
ate commencement and increase of feed volumes. That study
found that the group with immediately increasing feeds after
a period of non-feeding, had more NEC (seven cases of 70
infants) compared to a period of trophic feeding (one case of
There is no other evidence that feeding patterns have any
inﬂuence on the occurrence of NEC, different patterns of
introducing or advancing feeds appear to have no inﬂuence
on the frequency of NEC, even among infants at high risk as
a result of intrauterine growth restriction with reversed
Doppler ﬂow in the umbilical arteries.
The rate of increasing
feeds should be based on the infant's tolerance and a goal of
increasing by up to 30 ml/kg/day can be instituted without
fear of adverse effects.
3.2. Parenteral nutrition and macro-nutrient intake
Parenteral nutrition can be instituted immediately after birth.
Amino acid solutions are well tolerated, and administration
of at least 1 g /kg/day of protein can prevent catabolism, if
more is given infants can maintain an anabolic state. Imme-
diate institution of up to 3 g/kg/day has been shown to be
Because of lower ﬂuid administration rates in the
ﬁrst few days of life, it has been difﬁcult to achieve good
calorie intake. Hyperglycemia may well follow high glucose
infusion rates, and lipids are traditionally introduced slowly
and then increased over 3–6 days. The safety of much higher
starting lipid doses, and the use of other innovative appro-
aches, such as supplemental enteral lipid administration, is
uncertain. Routine use of omega-3 containing lipid emulsions
has much theoretically to support it, but there is currently no
safety and efﬁcacy data in the EIN.
3.3. Research needs
Trials comparing immediate increase of feeds, compared to
a period of trophic feeding, in infants having early institution
of enteral feeding in the ﬁrst 24 h are required. Comparisons
of different ways to administer an adequate caloric content
would also be useful. Studies of routine use of omega-3
containing lipid emulsions are required.
4. Cardiovascular support
Numerically low blood pressure is very common on the ﬁrst
day of life. If the standards of Watkins are used, about 50% of
extremely low-birth-weight infants will be below 10 percen-
tile at some point in the ﬁrst 24 h.
This occurs because the
norms were constructed from cross-sectional data, but blood
pressure varies from minute to minute. Therefore many
children will drop below statistically derived percentiles
during the early postnatal period.
If a more simplistic
standard, such as BW less than GA is used, even more infants
will be considered hypotensive.
There is little reliable
evidence that hypotension thus deﬁned is a marker for poorer
and no evidence that treating hypotension
according to such thresholds improves outcomes.
infants with low blood pressure have low systemic vascular
resistance and normal systemic perfusion.
Fig. 2 – Effects on (A) mortality, (B) bronchopulmonary dysplasia, and (C) combined outcome of death or bronchopulmonary
dysplasia, in studies comparing two different levels of sodium intake in preterm infants starting on the ﬁrst day of life.
S EMINARS IN P ERINATOLOGY 38 (2014) 17– 2420
hemodynamic pattern probably needs no intervention, other
than surveillance. However, the concern of some neonatolo-
gists that numerically low blood pressure may impair cere-
bral perfusion leads to some centers treating a very high
proportion of their EINs with ﬂuid boluses and inotropes.
Shock may occur in the extremely preterm infant in the ﬁrst
few days of life, either as a result of sepsis or asphyxia. I was
unable to ﬁnd any relevant evidence to choose among treat-
ment options: the role and place of steroids, different ino-
tropic agents, and the role of ﬂuids, and type of ﬂuids are
Closing the PDA in the ﬁrst 3 days of life has no proven clinical
advantages. Prophylactic surgery was shown in one study to
reduce oxygen requirements at 28 days of age,
but not at 36-
weeks PMA. Prophylactic indomethacin is not universally
effective, but does frequently constrict and sometimes close
the PDA. Nevertheless it does not reduce the frequency of
it does seem to reduce the risk of severe pulmonary
hemorrhage and decreases the need for later PDA ligation.
other long-term beneﬁt of closing the PDA has been shown.
4.4. Research needs
Studies investigating the role of the most commonly used
agents in the early life of the EIN, ie ﬂuid boluses and
dopamine are an urgent priority but they will be difﬁcult to
Studies of treatment both of low blood pressure in
clinically stable infants, and infants with signs of systemic
hypoperfusion are both needed. The issues are very different
in these two clinical situations and they should be studied
5. Respiratory management
5.1. Intubation and surfactant, CPAP
Randomized controlled trials comparing prophylactic to res-
cue surfactant have clearly demonstrated a signiﬁcant beneﬁt
of prophylaxis. However in those studies the comparison is
between different timing of surfactant administration to
intubated babies. The comparison between early CPAP, with
early intubation and surfactant for rescue, and prophylactic
intubation for surfactant administration has been studied
more recently. There are now four multi-center high-quality
trials that have compared very early intubation to institution
of CPAP in very immature infants. The trials have all enrolled
babies less than 30-weeks gestation, but the exact ranges of
GA differ between the trials, as well as in some other details
I have performed a meta-analysis of these trials using the
Revman software, using a ﬁxed-effects model (Fig. 2). The
overall frequency of death or BPD was lower with CPAP use
compared to routine intubation, and was marginally
Table 2 – Randomized trials of effects of initial respiratory management on survival and bronchopulmonary dysplasia.
Trial ID n GA of
Age of intubation,
Initial pressure of CPAP
Indications for failure,
1316 24–27 Weeks In DR, surfactant
within 1 h
Death or BPD
610 25–28 Weeks 5 min, Surfactant
optional, according to
40.6, pH o 7.25
Death or BPD
26–29 Weeks 5–15 min, Immediate
either INSURE (group
2) or progressive
wean (group 1)
O (max 7) FiO
40.4 option to
mandatory (or CO
465 or multiple
Death or BPD
208 25–28 Weeks o30 min, INSURE 6–7cmH
pH o 7.2 (multiple
Need for ventilation within
the ﬁrst 5 days of life
INSURE, intubation for surfactant therapy followed by immediate extubation
S EMINARS IN P ERINATOLOGY 38 (2014) 17– 24 21
statistically signiﬁcant (RR 0.93 [95% CI; 0.86, 1.01]; Fig. 3).
Mortality was a little lower with CPAP, but not statistically
signiﬁcant (RR 0.85 [95% CI; 0.69, 1.05]). When creating sub-
groups according to whether intubated infants received
INSURE treatment or standard weaning, there was no differ-
ence between CPAP and INSURE, but a signiﬁcant (barely)
reduction in the combined outcome of death or BPD (RR 0.91
[95% CI; 0.83, 0.99]) in the comparison of CPAP to intubation
with standard weaning. There is no signiﬁcant heterogeneity.
Although there were no infants of 23-weeks GA in these trials
and only 1 included infants of 24-weeks gestation, this result
does suggest that CPAP in the delivery room, if the infant can
be stabilized without intubation, is at least as effective as
routine intubation, and that if the infant can be intubated,
attempts to rapidly wean and extubate within a short period
of time are appropriate.
6. Neurologic interventions
6.1. Preventing IVH
Antenatal steroids decrease the incidence of PDA. The only
known postnatal intervention that reduces IVH is prophylactic
indomethacin. Indomethacin given intravenously before 6 h of
age decreases both the incidence of IVH overall, and the
incidence of the more severe grades of IVH, including intra-
cerebral hemorrhag e.
The large st and highest quality study of
prophylactic indomethacin was unable to show a beneﬁton
neurodevelopmental outcomes, despite a reduction in severe
(grades 3 and 4) IVH from 13% to 9% of the enrolled ELBW
This ﬁnding would not be unexpected if indometha-
cin has no effects on cerebral development other than a
prevention of severe IVH. From other published data, one could
estimate that a 4% reduction in severe IVH would lead to a 2%
reduction in neurodevelopmental impairment. To have sufﬁ-
cient power to demonstrate a signiﬁcant 2% reduction in
adverse outcomes, a trial would require about 9500 patients
per group, which is about 10 times larger than TIPP.
Systematic review and meta-analysis of the studies of
prophylactic indomethacin have conﬁrmed the signiﬁcant
reduction in severe IVH, in 14 trials enrolling over 2500
infants about a 35% reduction in severe IVH has been
RR 0.66 (95% CI; 0.53, 0.82; p ¼ 0.0001).
6.2. Improving long-term outcome
Studies of long-term neurologic and developmental outcome
are a major example of the interconnectedness of all things
in the care of the preterm infant. The major inﬂuences on
long-term outcome are the following: (1) clinical complica-
tions during NICU stay for example, NEC, infections, BPD,
RoP, surgery of any type, inadequate nutrition, and growth
and (2) socioeconomic status of the family.
Improving long-term outcomes will require a concerted
effort to reduce each of these complications, and also early
intervention programs post-discharge, which could be tar-
geted at the families with the greatest needs.
6.3. Research needs
It is important that we ask parents whether the reduction in
severe hemorrhage is a beneﬁt that interests them, even if we
have not shown an improvement in neurodevelopmental
outcomes. They can be assured that there is no evidence of
worsened outcomes, and indeed some subgroup analyses
have shown improved outcomes. It appears to me that it is
likely that parents would prefer to have a reduced likelihood
of being faced with the diagnosis of severe IVH; a 50%
reduction in the need for PDA ligation is another signiﬁcant
beneﬁt that parents may ﬁnd worthwhile.
7. Improving clinical research in the extreme
Parents have for a long time been excluded from setting
research priorities, designing research projects, selecting
Fig. 3 – Effects on the combined outcome of death or BPD in studies comparing delivery room institution of CPAP to very early
S EMINARS IN P ERINATOLOGY 38 (2014) 17– 2422
outcome variables of interest, and monitoring ongoing trials;
this form of paternalism, academic paternalism, should be as
unacceptable as individual clinical paternalism. This must
change; our role as physicians should be to educate parents
and involve them in the neonatal research endeavor.
Research projects should investigate outcomes that parents
think are important.
8. Comprehensive protocols of care
In many areas of medicine, the use of checklists, protocols,
and algorithms have been shown to improve clinical out-
comes: from simple surgical checklists
to algorithms for
assisted ventilation, to complex comprehensive protocols of
care for oncological patients. Such protocols have been tested
very little in the very preterm infant. One study, with a before
and after design, showed a substantial improvement in
survival without serious brain injury in ELBW infants, with
the introduction of a checklist of admission orders.
investigation of the use of such checklists, and comparison
of comprehensive protocols of care, could advance the
clinical science of caring for the extremely preterm infant.
Such protocols will in my opinion be essential as we move
forward. There are so many unknowns, each of which
may impact on several outcomes, and inﬂuence how
other interventions affect those same outcomes, that to
study each variation in care, in isolation, without controlling
other interventions is unlikely to be fruitful. Current
investigational protocols for the treatment of the PDA, for
example, could be much more powerful if initial sodium
management, ventilator management, and nutrition and
ﬂuid management were also controlled in each arm of the
trial. In that way the superiority of one protocol over another
could be evaluated.
9. Research networks
Extreme prematurity is relatively infrequent, although much
more common than many conditions that are being actively
investigated in other ﬁelds of medicine. Permanent infra-
structure to support research networks should be a priority.
Networks developed to perform trials, and evaluate survival
and long-term quality of life of survivors will be essential to
permit the development of the evidence needed for the
appropriate treatment of the extremely low gestational-age
infant. No center has enough power to be able to do trials
with clinically important outcomes in this patient group.
Research networks have been enormously successful in
several domains, in particular in the care of children with
malignant disease. Such networks require a commitment of
the research community (including parents) to perform the
studies that are required, even if the opportunities for
individual academic recognition are reduced. Removing bar-
riers to prospective trials, including academic conﬂicts of
interest and academic paternalism, will be essential for the
future of care.
1. Lorenz JM, Kleinman LI, Ahmed G, Markarian K. Phases of
ﬂuid and electrolyte homeostasis in the extremely low birth
weight infant. Pediatrics. 1995;96(3 Pt 1):484–489.
2. Pabst RC, Starr KP, Qaiyumi S, Schwalbe RS, Gewolb IH. The
effect of application of aquaphor on skin condition, ﬂuid
requirements, and bacterial colonization in very low birth
weight infants. J Perinatol. 1999;19(4):278–283.
3. Knauth A, Gordin M, McNelis W, Baumgart S. Semipermeable
polyurethane membrane as an artiﬁcial skin for the prema-
ture neonate. Pediatrics. 1989;83(6):945–950.
4. Nopper AJ, Horii KA, Sookdeo-Drost S, Wang TH, Mancini AJ,
Lane AT. Topical ointment therapy beneﬁts premature
infants. J Pediatr. 1996;128(5 Pt 1):660–669.
5. Edwards WH, Conner JM, Soll RF, Vermont Oxford Network
Neonatal Skin Care Study Group. The effect of prophylactic
ointment therapy on nosocomial sepsis rates and skin integ-
rity in infants with birth weights of 501 to 1000 g. Pediatrics.
6. Bhandari V, Brodsky N, Porat R. Improved outcome of
extremely low birth weight infants with Tegaderm applica-
tion to skin. J Perinatol. 2005;25(4):276–281.
7. Bell EF, Acarregui MJ. Restricted versus liberal water intake for
preventing morbidity and mortality in preterm infants.
Cochrane Database Syst Rev. 2008(1): [CD000503].
8. Bell EF, Warburton D, Stonestreet BS, Oh W. Effect of ﬂuid
administration on the development of symptomatic patent
ductus arteriosus and congestive heart failure in premature
infants. N Engl J Med. 1980;302(11):598–604.
9. Tammela OKT, Koivisto ME. Fluid restriction for preventing
bronchopulmonary dysplasia? Reduced ﬂuid intake during
the ﬁrst weeks of life improves the outcome of low-birth-
weight infants. Acta Paediatr. 1992;81:207–212.
10. Drukker AMDP, Guignard J-PMD. Renal aspects of the term
and preterm infant: a selective update. Curr Opin Pediatr.
11. Ekblad H, Kero P, Takala J, Korvenranta H, Välimäki I. Water,
sodium and acid–base balance in premature infants: thera-
peutical aspects. Acta Paediatr. 1987;76(1):47–53.
12. Lorenz JM, Kleinman LI, Kotagal UR, Reller MD. Water balance
in very low-birth-weight infants: relationship to water and
sodium intake and effect on outcome. J Pediatr. 1982;101
13. Stockhausen H, Struve M. Die Auswirkungen einer stark
unterschiedlichen parenteralen Flüssigkeitszufuhr bei Früh-
und Neugeborenen in den ersten drei Lebenstagen. Klinische
14. Kavvadia V, Greenough A, Dimitriou G, Hooper R. Randomised
trial of ﬂuid restriction in ventilated very low birthweight
infants. Arch Dis Child Fetal Neonatal Ed. 2000;83:F91–F96.
15. Costarino ATJ, Gruskay JA, Corcoran L, Polin RA, Baumgart S.
Sodium restriction versus daily maintenance replacement in
very low birth weight premature neonates: a randomized,
blind therapeutic trial. J Pediatr. 1992;120(1):99–106.
16. Hartnoll G, Betremieux P, Modi N. Randomised controlled trial
of postnatal sodium supplementation on oxygen dependency
and body weight in 25–30 week gestational age infants. Arch
Dis Child Fetal Neonatal Ed. 2000;82(1):F19.
17. Cossey V, Vanhole C, Eerdekens A, Rayyan M, Fieuws S,
Schuermans A. Pasteurization of mother's own milk for
preterm infants does not reduce the incidence of late-onset
sepsis. Neonatology. 2012;103(3):170–176.
18. Tyson JE, Kennedy KA, Lucke JF, Pedroza C. Dilemmas
initiating enteral feedings in high risk infants: how can they
be resolved?: the evidence base Supp orting nutritional
S EMINARS IN P ERINATOLOGY 38 (2014) 17– 24 23
practices for very low birth weight infants. Semin Perinatol.
19. Berseth CL, Bisquera JA, Paje VU. Prolonging small feeding
volumes early in life decreases the incidence of necrotizing
enterocolitis in very low birth weight infants. Pediatrics.
20. Leaf A, Dorling J, Kempley S, et al. Early or delayed enteral
feeding for preterm growth-restricted infants: a randomi zed
trial. Pediatrics . 2012;129(5):e1260–e1268.
21. Rayyis S, Ambalavanan N, Wright L, Carlo W. Randomized
trial of “slow” versus “fast ” feed advancements on the
incidence of necrotizing enterocolitis in very low birth weight
infants. J Pediatr. 1999;134:293–297.
22. te Braake FW, van den Akker CH, Riedijk MA, van Goudoever
JB. Parenteral amino acid and energy administration to
premature infants in early life. Semin Fetal Neonatal Med.
23. Watkins AMC, West CR, Cooke RWI. Blood pressure and
cerebral haemorrhage and ischaemia in very low birthweight
infants. Early Hum Dev. 1989;19:103.
24. Dempsey EM, Al Hazzani F, Barrington KJ. Permissive hypo-
tension in the extremely low birthweight infant with signs of
good perfusion. Arch Dis Child Fetal Neonatal Ed. 2009;94(4):
25. Dempsey EM, Barrington KJ. Evaluation and treatment of hypo-
tension in the preterm infant. Clin Perinatol. 2009;36(1):75–85.
26. Logan JW, O'Shea TM, Allred EN, et al. Early postnatal
hypotension and developmental delay at 24 months of age
among extremely low gestational age newborns. Arch Dis
Child Fetal Neonatal Ed. 2011;96(5):F321–F328.
27. Osborn DA, Evans N, Kluckow M. Clinical detection of low
upper body blood ﬂow in very premature infants using blood
pressure, capillary reﬁll time, an d central–peripheral temper-
ature difference. Arch Dis Child Fetal Neonatal Ed. 2004;89(2):
28. Laughon M, Bose C, Allred E, et al. Factors associated with
treatment for hypotension in extremely low gestational age
newborns during the ﬁrst postnatal week. Pediatrics. 2007;119
29. Clyman R, Cassady G, Kirk lin JK, Collins M, Philips Iii JB. The
role of patent ductus arteriosus ligation in bronchopulmo-
nary dysplasia: reexamining a randomized controlled trial.
J Pediatr. 2009;154(6):873–876.
30. Cassady G, Crouse DT, Kirklin JW, et al. A randomized,
controlled trial of very early prophylactic ligation of the
ductus arteriosus in babies who weighed 1000 g or less at
birth. N Engl J Med. 1989;320(23):1511–1516.
31. Schmidt B, Roberts RS, Fanaroff A, et al. Indomethacin
prophylaxis, patent ductus arteriosus, and the risk of bron-
chopulmonary dysplasia: further analyses from the Trial of
Indomethacin Prophylaxis in Preterms (TIPP). J Pediatr.
32. Schmidt B, Davis P, Moddemann D, et al. Long-term effects of
indomethacin prophylaxis in extremely-low-birth-weight
infants. N Engl J Med. 2001;344(26):1966–1972.
33. Benitz WE. Treatment of persistent patent ductus arteriosus
in preterm infants: time to accept the null hypothesis?
J Perinatol. 2010;30:241–252.
34. Batton BJ, Li L, Newman NS, et al. Feasibility study of early
blood pressure management in extremely preterm infants.
J Pediatr. 2012;161:65–69.
35. Finer NN, Carlo WA, Walsh MC, et al. Early CPAP versus
surfactant in extremely preterm infants. N Engl J Med.
36. Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB.
Nasal CPAP or intubation at birth for very preterm infants. N
Engl J Med. 2008;358(7):700–708.
37. Dunn MS, Kaempf J, de Klerk A, et al. Randomized trial
comparing 3 approaches to the initial respiratory manage-
ment of preterm neonates. Pediatrics . 2011;128:1069–1076.
38. Sandri F, Plavka R, Ancora G, et al. Prophylactic or early
selective surfactant combined with nCPAP in very preterm
39. Schmidt B, Davis P, Moddemann D, Ohlsson A, Roberts RS,
Saigal Sea. Long-term effects of indomethacin prophylaxis in
extremely-low-birth-weight infants. N Engl J Med. 2001;344
40. Fowlie PW, Davis PG, McGuire W. Prophylactic intravenous
indomethacin for preventing mortality and morbidity in pre-
term infants. Cochrane Database Syst Rev. 2010(7): [CD000174].
41. Haynes AB, Weiser TG, Berry WR, et al. A surgical safety
checklist to reduce morbidity and mortality in a global
population. N Engl J Med. 2009;360(5):491–499.
42. Barrington KJ, Denson-Lino J, Bloch R, Finer NN. Sequential
analysis for quality control in the neonatal intensive care
unit. J Pediatr. 2001;139(6):778–784.
S EMINARS IN P ERINATOLOGY 38 (2014) 17– 2424
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- [Show abstract] [Hide abstract] ABSTRACT: To examine the association between intensity of perinatal care and outcome at 2.5 years' corrected age (CA) in extremely preterm (EPT) infants (<27 weeks) born in Sweden during 2004-2007. A national prospective study in 844 fetuses who were alive at the mother's admission for delivery: 707 were live born, 137 were stillborn. Infants were assigned a perinatal activity score on the basis of the intensity of care (rates of key perinatal interventions) in the infant's region of birth. Scores were calculated separately for each gestational week (gestational age [GA]-specific scores) and for the aggregated cohort (aggregated activity scores). Primary outcomes were 1-year mortality and death or neurodevelopmental disability (NDI) at 2.5 years' CA in fetuses who were alive at the mother's admission. Each 5-point increment in GA-specific activity score reduced the stillbirth risk (adjusted odds ratio [aOR]: 0.90; 95% confidence interval [CI]: 0.83-0.97) and the 1-year mortality risk (aOR: 0.84; 95% CI: 0.78-0.91) in the primary population and the 1-year mortality risk in live-born infants (aOR: 0.86; 95% CI: 0.79-0.93). In health care regions with higher aggregated activity scores, the risk of death or NDI at 2.5 years' CA was reduced in the primary population (aOR: 0.69; 95% CI: 0.50-0.96) and in live-born infants (aOR: 0.68; 95% CI: 0.48-0.95). Risk reductions were confined to the 22- to 24-week group. There was no difference in NDI risk between survivors at 2.5 years' CA. Proactive perinatal care decreased mortality without increasing the risk of NDI at 2.5 years' CA in EPT infants. A proactive approach based on optimistic expectations of a favorable outcome is justified. Copyright © 2015 by the American Academy of Pediatrics.