Seminars in Fetal & Neonatal Medicine 17 (2012) 126e131

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Seminars in Fetal & Neonatal Medicine

journal homepage: www.elsevier.com/locate/siny

Developmental physiology of late and moderate prematurity

Tonse N.K. Raju a, b, *
a
b

Center for Developmental Biology and Perinatal Medicine, National Institutes of Health, Bethesda, Maryland, USA
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

s u m m a r y
Keywords:
Apnea
Hypoglycemia
Hypothermia
Infection
Preterm
Respiratory distress

This is a brief review of the developmental physiology of selected organ and functional systems in
moderate and late preterm infants. This outline provides a discussion of the physiological underpinnings
for some of the clinical conditions seen in this group of infants, including hypothermia, hypoglycemia,
respiratory distress syndrome, transient tachypnea, severe respiratory failure, apnea, feeding difculties,
jaundice, and increased susceptibility to infections.
Published by Elsevier Ltd.

1. Introduction
In a 2005 workshop organized by the National Institute of
Health and Human Development (NICHD), this author made
a proposal to replace the vague and imprecise phrase near term
with late preterm, to reect the physiological and developmental
immaturity of this group of infants. The expert panel agreed, and
suggested a denition for late preterm as births between 340/7 and
366/7 weeks of gestation. As discussed in the workshop summary,1
there were compelling reasons for the choice of the new phrase and
its lower boundaries. The most important reason was to underscore
that infants born even by a few weeks prior to term were immature,
with higher morbidity and mortality risks compared to those born
at term gestations.2
The NICHD expert panel could not have predicted the degree of
impact of introducing the new phrase late preterm into the lexicon
of perinatal medicine. Several professional societies and organizations in the USA3,4 and in other countries adopted the new term.
The Centers for Disease Control and Prevention began tracking late
preterm births rates.5
The phrase also shifted the paradigm, and stimulated a huge
wave of research interest. More than 300 papers have been published since 2006 on late preterm, including observational and
intervention studies, systematic reviews, editorials, and committee
opinions. The obstetric and pediatric communities began an
important dialogue about this vulnerable group of infants. These
developments seem to have made an impact. As discussed elsewhere in this issue, the US preterm and late preterm birth rates
have begun to decline signicantly.5

* 6100 Executive Blvd, Room 4B03, Bethesda, MD 20952, USA.

E-mail address: rajut@mail.nih.gov.
1744-165X/$ e see front matter Published by Elsevier Ltd.
doi:10.1016/j.siny.2012.01.010

This review will focus on the developmental physiology of the

organ systems in moderate and late preterm infants that are the
underpinning of their morbidity and mortality risk.
2. Generic aspects of developmental maturation
Maturation is a continuous process with no specic endpoints or
goals to be achieved. By contrast, maturational milestones are
developed by us as useful signposts to assess maturation, and to
make clinical decisions. The milestones are also useful for statistical
and denitional purposes, and for developing management
guidelines.
The duration of gestation (or time) is only one of the many
factors that inuence fetal and neonatal developmental maturation
and trajectory. Others include intrauterine environment, maternal
health and disease status, maternal medication use, diet, nutrition,
and lifestyle (e.g. exercise, stress, smoking, drug abuse etc.), the
number of fetuses, fetal sex, and fetal health/diseases.
Maturation is non-linear, in that it is programmed to meet the
needs of the organism for an independent extrauterine existence at
various time points. Thus, different organs tend to mature at
different trajectories relative to each other. For instance, soon after
birth, most late preterm infants can breathe on their own without
assisted respiratory support, reecting their mature breathing
apparatus. However, most of them will have difculty in initiating
and maintaining breastfeeding, reecting their immature brainstem, sucking and swallowing mechanisms.
3. Developmental basis for clinical problems
The following presentation is organized in an approximate
chronological order of clinical disorders in moderate and late
preterm infants.

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127

3.1. Thermal instability/cold stress

Box 1. Physiological basis for hypothermia.
Fetal thermal homeostasis is controlled and regulated by the
maternal thermal homeostasis.6 Because the temperature of the
amniotic uid reects mothers core temperature, the fetus is
constantly nurtured in a warm intrauterine environment. In addition, with an average fetal oxygen consumption of 8 ml/min/kg, it
generates 3e4 W/kg of heat. Since the fetus has to eliminate its heat
through the mother, its temperature remains about 0.5e1.0  C
higher than that of the mother. Through mechanisms not well
understood, fetal thermoregulatory pathways remain dormant
until birth, and fetal temperature is thus passively clamped to that
of the mother, changing along with her temperature. Even at term,
the fetus has little ability to generate heat if challenged by maternal
hypothermia, or lose heat if challenged by maternal hyperthermia,
as in pyrexia.
Under normal circumstances, the placenta eliminates 85% of
fetal heat into maternal circulation. Thus, the fetus and the placenta
are often considered an engine and a radiator, respectively. The
remaining 15% of fetal heat loss occurs through the conductance
from the fetal skin to the amniotic uid, and to the uterine wall.6
As the fetus emerges from a warm intrauterine environment to
the cold external world, hypothermia is inevitable.7,8 In response,
the newborn has to mount a variety of physiological responses
immediately to conserve heat loss, increase heat production and
maintain core temperate with the least amount of oxygen
consumption in the process.6,9,10 Most healthy term infants mount
such responses, but moderate and late preterm infants may not, or
cannot, mount such responses due to the decient, immature or
non-existent thermoregulatory processes (Box 1).6e10
3.2. Respiratory morbidities (Box 2)
Studies using large datasets and systematic reviews11e13
conrm that compared with term infants, all forms of pulmonary
disorders occur at higher frequencies in moderate and late preterm
infants. Developmental immaturity-related pulmonary conditions
are respiratory distress syndrome (RDS), transient tachypnea of the
newborn (TTN), pneumonia, hypoxic respiratory failure and
pulmonary hypertension and apnea of prematurity.
Maturation of the pulmonary apparatus occurs through
progressive stages. By about the 16th week of gestation, the 16
generations of bronchioloar branching are completed. By 24 weeks
gestation, the primitive alveoli can engage in some gas exchange;
but major surge in alveolar generation (alveolization) occurs by
term and continues through early childhood. Between 25 and 36
weeks gestation, the alveolization process goes through a transient
saccular phase. The saccules participate in gas exchange, but they
are compact, thick and primitive. Due to such structural immaturity, they are susceptible for barotraumas. By a process of septation,
the saccules mature into alveoli beginning from 32 weeks gestation, with dramatic, weekly increments. By term, the alveolar count
reaches about 80% of that of the adult alveolar count.14
A study published by the Consortium on Safe Labor11 reported
an incidence of RDS in late preterm infants to be 5.2%, compared to
0.4% in infants born at 37e40 weeks gestation (computed from
their Table 3, Reference11). RDS thus remains the most common
cause of signicant respiratory morbidity in late preterm infants.
RDS is the consequence of qualitative and/or quantitative deciency of pulmonary surfactants superimposed upon an immature
cardiopulmonary system. Pulmonary surfactants are predominantly phospholipids. In the mature fetus, about 80% of phospholipids is phosphatidylcholine, 5e10% is phosphatidylglycerol, with
other minor lipids making up the remainder. However, preterm
fetuses completely lack phosphatidylglycerol, which is an

 Heat loss soon after birth: w135e155 W/m2

B Channels of heat loss
Evaporative: along with evaporative water loss
(w125 g/m2/h ) at room temperature of w26  C
and 40% humidity. Heat loss through this route:
w60e80 W/m2
Radiation: direct loss of heat through electromagnetic radiation in the infrared spectrum
(into the cooler walls of the nursery or the
incubator). This can be up to 50 W/m2
Convection: through the air; a negligible route
of heat loss up to w25 W/m2 especially when the
incubator walls are cold
Conductive heat loss: direct contact through
a cooler object, such as the mattress e this is
a negligible route of heat loss.
 Hypothermia and physiological immaturity
B Deficient subcutaneous fat and non-keratinized, thin
skin: increases the speed and severity of hypothermia with exposure to cool, extrauterine
environment.
 High ratio of surface area:body mass
B Common to all newborn infants, but especially worse
for preterm infants, thus a large surface area is
exposed to environmental cooling and hypothermia.
 Inability to shiver
B Neither term nor preterm infants can mount a shivering response (generating heat through the
muscles) to environmental cooling.
 Deficiency of brown adipose tissue (BAT)
B Oxidation
of BAT is the main source of heat
production in term infants
B BAT development begins around the 20th week of
gestation, reaching a peak at term, accounting for up
to 1% of body weight
B Lack of sufficient BAT mass leads to decreased ability
for generating heat to offset hypothermia from
environmental cooling.
 Immature response of the temperature sensors in the
posterior hypothalamus
B Insufficient release of thermogenic hormones (T4
and norepinephrine)
B Brainstem serotonin deficiency can lead to homeostatic deficits owing to a reduced sympathetic
response to mild cold stress.

important cause of decient surfactant function leading to RDS in

preterm infants.
Around 32 weeks gestation, the surfactant pool size begins to
increase, with a signicant surge around 35 weeks gestation,
reaching a peak at term. Uterine contractions preceding labor and
delivery, and the associated surge of catecholamines and endogenous steroids, enhance pulmonary surfactant secretion from Type II
cells into the alveoli. Initiation of ventilation also contributes to
additional surfactant release. In moderate and late preterm infants,
most of the above processes are either decient or non-existent,
thus setting up a stage for clinical RDS.12e14
TTN is diagnosed in about 4% of late preterm infants making it
the second most common pulmonary disorder.15e17 A lack of timely
clearance of the pulmonary uid from the alveolar airspaces is the
pathophysiological basis for TTN. The risk of TTN is high in infants
born precipitously, without active labor, and in those delivered by
elective cesarean section. These observations gave rise to the

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Box 2. Physiological basis for respiratory disorders.

 Respiratory distress syndrome
B Qualitative and/or quantitative deficiency in surfactant and its function
Deficiency of phospatidylglycerol in preterm
lungs, or its delayed maturation in diabetic
pregnancy
B Elective
caesarean delivery, depriving laborassociated catecholamine and steroid surge,
causing decreased pulmonary surfactant release.
 Transient tachypnea of the newborn (TTN)
B Elective
caesarean delivery, depriving labourassociated catecholamine and steroid surge, preventing lung fluid clearance
B Delayed transition to postnatal life, due to diminished transepithelial absorption of lung fluid from
disrupted functions of the amiloride-sensitive
epithelial sodium channels.
 Hypoxic respiratory failure
B Mild respiratory distress due to TTN is initially
treated with oxygen using oxy-hoods, which can lead
to nitrogen washout, oxygen absorption and alveolar
atelectasis
B Persistent
mild-to-moderate hypoxia leading to
development of pulmonary hypertension, often
requiring treatment with inhaled nitric oxide and/or
extracorporeal membrane oxygenation.
 Pneumonia
B Fetal infection as a cause for preterm delivery, predisposing to sepsis and pulmonary infection
B Mechanical
ventilation leading to injury to the
immature lungs, increasing the risk for pulmonary
infections.
 Central, obstructive and mixed apnea
B Increased chest wall and upper airway compliance
leading to their collapse when the diaphragm
contracts, especially during rapid eye movement
sleep, which is >;60% of total sleep time
B Biphasic ventilatory response to hypoxia
B Blunted ventilatory response to hypercapnea
B Higher incidence of acute life-threatening events and
sudden infant death syndrome in late preterm.

hypothesis that the squeeze on the infant chest during vaginal

birth helps clear fetal lung uid. However, a large body of evidence
contradicts this. The transition from uid-lled fetal lung to airlled postnatal breathing occurs via a multitude of coordinated
hormonal and biochemical events during fetal life, labor and
delivery, and into the hours and days after birth.15e17
Around near-term gestation, the rate of fetal lung uid
production begins slowdown. With the onset of labor, and uterine
contraction-induced hormonal surge, the lung uid gets cleared via
the pulmonary interstitial lymphatics, blood vessels, upper airway,
mediastinum, and the plural spaces. In addition, recent studies
show that amiloride-sensitive epithelial sodium channels (ENaCs)
in the alveolar cells also play a crucial role in lung uid sodium
transport, facilitating water clearance.16,17 Both Type I and Type II
cells in the alveoli are involved in this process, but since Type I cells
constitute >95% of alveolar surface, their contribution to lung uid
clearance appears to be greater than previously considered.16
3.3. Hypoxic respiratory failure
Although TTN is considered a mild condition, sometimes there
are serious complications leading to malignant TTN and severe

hypoxic respiratory failure. Such infants initially would have

received high concentrations of inspired oxygen via an oxygen hood
or a nasal cannula, which can lead to pulmonary nitrogen washout
and alveolar atelectasis. This can be followed by severe hypoxia,
metabolic and respiratory acidosis, and pulmonary hypertension.
Such infants often require inhaled nitric oxide therapy or extracorporeal membrane oxygenation.12 Keszler et al.17 reported that late
preterm infants delivered by elective cesarean and managed as mild
TTN in small hospitals were at great risk for such complications.
3.4. Other respiratory problems
Moderate and late preterm infants are prone for apnea of
prematurity. Similar to other aspects of developmental
phenomena, maturation of brainstem regions and control of
breathing apparatus in the moderate and late preterm infants lie in
between those of extremely preterm and term infants. Brainstem
increases in length and volume throughout gestation, with rapid
increase in rst half of pregnancy, but progressive increments
occurring later.18e20
Obstructive and mixed apnea occur less frequently in moderate
and late preterm infants compared to those born <28 weeks of
gestation. However, they occur at greater frequency and severity
compared to those born at term. Many underlying developmental
features are at play in causing apnea of prematurity.18e20 The chest
wall and the upper airways are highly compliant, which tend to
collapse paradoxically when the diaphragm contracts and generates negative intrathoracic pressure. The contraction of the muscles
of the lower jaw and the tongue tend to dilate the upper airways
and prevent their collapse. However, it is the balance between
these forces that determines whether or not the upper airways
remain open during breathing (Box 2).
3.5. Hypoglycemia
Low plasma glucose, usually dened as 2.0e2.5 mmol/l
(<40e45 mg/dl), has been reported in 5e15% of normal
newborn infants. The frequency and severity of this complication is
probably much higher in moderate and late preterm infants.
The energy demands of the fetus are met by the mother through
the placental transfer of glucose, amino acids, free fatty acids,
ketone, and glycerol. Although normal fetus does not produce
endogenous glucose, throughout gestation its blood glucose
concentration remains >3 mmol/l (54 mg/dl).
Soon after birth, the blood glucose concentration falls precipitously due to the interruption of the placental glucose supply. The
magnitude and duration of such a fall depends upon the fetal
concentrations of glucose and plasma insulin, the infants ability to
mobilize glucose from hepatic glycogen, to initiate gluconeogenesis, and to feed adequately.21,22
In low birth weight and premature infants, gluconeogenesis is
active, accounting for 30e70% of endogenous glucose production.
However, the risk of hypoglycemia remains high due to many
factors (Box 3), including caregiver complacency of not monitoring
them, since many such infants appear normal.
3.6. Hepatic immaturity and jaundice
Jaundice is the most common reason for readmission after initial
hospital discharge in late preterm infants. Although accurate
epidemiological data are lacking, compared to term infants, the risk
of bilirubin-induced neurological injury is more common in
moderate and late preterm infants.23
In all infants, hyperbilirubinemia is a consequence of increased
bilirubin production, diminished metabolism and elimination, or

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129

Box 3. Developmental physiological basis for hypoglycemia.

Box 4. Developmental immaturity of bilirubin metabolism.

 Decreased glycogen stores

B In
moderate and late preterm infants, hepatic
glycogen stores are lower relative to term infants
B In
infants with intrauterine growth restriction,
glycogen stores are depleted in fetal life, perhaps due
to reduced placental supply of energy needs.
 Insulin concentrations and insulin response to
changing glucose levels
B Immaturity of the glucose-regulated insulin response
in the b-islet cells of the pancreas, resulting in
unregulated, continued insulin secretion despite falls
in postnatal glucose concentrations
B High circulating insulin concentrations secondary to
maternal diabetes.
 Increased energy demands
B Cold stress
B Hypoxia
B Sepsis.
 Diminished intake
B Difficulty in sucking and swallowing, and initiation
and maintenance of breastfeeding.

 Bilirubin load
B Higher rates of bilirubin production due to higher
proportion of senescent RBCs
B Lack of feeding leading to increased enterohepatic
load of bilirubin.
 Hepatic bilirubin metabolism
B Limited bilirubin uptake in part due to deficiency of
organic anion transport proteins
B Immaturity of hepatic endoplasmic reticular enzyme,
uridine diphosphoglucuronate glucuronosyltransferase (UGT) that is required for conjugating the fatsoluble indirect bilirubin to water-soluble direct
bilirubin.
 Enterophepatic absorption of bilirubin
B Conversion of the relatively unstable monoglucuronide and diglucuronide bilirubin conjugates from
the duodenum and colon by the enteric mucosal
enzyme, b-glucuronidase causes about 25% of the
excreted bilirubin to be reloaded
B Breastfeeding and delayed ingestion of any milk
leads to persistent activity of b-glucuronidase
activity.

a combination of both. The catabolic breakdown of haemoglobin

from the senescent red blood is the predominant source of bilirubin
during the neonatal period. Heme from hemoglobin is converted
into biliverdin with the catalytic activity of heme oxygenase-1
enzyme (HMOX-1); and biliverdin reductase converts the latter to
bilirubin, which is taken up by the liver for conjugation. The
conjugated bilirubin is then released into the intestines for excretion through the bowel.
During the process of breakdown of 1 mole of heme into 1 mole of
bilirubin, 1 mole of carbon monoxide is released. Thus, by measuring
carbon monoxide (or the carboxy hemoglobin) in the exhaled breath,
one can estimate the rate of bilirubin production. Studies utilizing
such methods have estimated that compared to term infants, the
bilirubin production rates are slightly higher in preterm infants,
perhaps due to higher proportion of senescent red blood cells.
The placenta is the primary route of fetal bilirubin excretion,
because of which the hepatic conjugating system remains dormant
in fetal life and for a few days following birth. (In fact, conjugated
bilirubin is impermeable through the placenta.) Therefore, visible
jaundice is seen in >70% of infants during the rst week of life. In
preterm infants, the hepatic conjugation system remains immature
to a greater degree and for longer durations, which explains the
reasons for early, more severe, and prolonged hyperbilirubinemia.
In addition, feeding difculties lead to a delay in the resolution of
the enterohepatic re-circulation of bilirubin, resulting in further
increase in hepatic bilirubin load. Other factors for prematurityrelated hyperbilirubinemia are listed in Box 4.
3.7. Gastrointestinal immaturity and feeding
Oro-buccal coordination and swallowing mechanisms are
immature in most moderate and late preterm infants. These infants
have considerable difculty in establishing successful breastfeeding.18,24 Because of lack of prior experience, the problem is compounded in primiparous mothers. Mild hypotonia, cold stress, and
general lack of strength add to the difculty of moderate and late
preterm infants to establish and maintain adequate breastfeeding. All
preterm infants have a higher frequency of gastro-oesophageal

reux, further reducing food intake and affecting weight gain. This
chain of events may lead to dehydration and hypernatremia during
the rst few weeks of life. The Academy of Breastfeeding Medicine has
developed a useful protocol to help breastfeed late preterm infants.24
3.8. Immunological maturation
The topic of fetal and neonatal immune maturation is broad and
complex, and only a few aspects are highlighted here.25e38
It is traditionally taught that newborn infants are decient in
acquired or adaptive immune responses; however, immune
maturational processes are more complex. Due to the nonexposure to antigens during intrauterine life, neonates lack
immunological memory, and hence cannot mount an adequate Tcell response soon after exposure to a pathogenic microbe.
However, in a study of lymphocyte subpopulations, Walker et al.25
found that the pattern of T-cell responses was similar in preterm
and term infants. Yet, with increasing prematurity, the absolute
counts of nave helper T-lymphocytes were lower. With postnatal
antigenic stimulation, the T- and B-lymphocyte populations
predictably increased to signicant levels.
The ability to produce immunoglobulin in response to specic
antigenic stimulation is acquired early in fetal life. The predominant circulating immunoglobulin in the healthy fetus is placentally
derived, actively secreted IgG, with a concentration of about 5e10%
higher than that of the mother. Colostrum and human milk are the
major sources of immunological protective agents. Thus, breastfed
infants quickly acquire other immunoglobulins, and a host of nonspecic protective factors (Box 5),29,30 which promote the development of specic immune functions. However, due to the inability
to feed at the breast, or to suck and swallow ineffectively, moderate
and late preterm infants may not receive adequate human milk e
a great source of immunologically valuable diet, increasing their
risks for sepsis, including necrotizing enterocolitis.
Despite a reasonably well-developed adaptive immune system,
the innate immune system is relatively immature in the newborn.
The polymorphonuclear neutrophils (PMNs) from term infants
cannot mount an adequate chemotactic response (directed migration towards the chemo-attracting antigen). This is even worse

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T.N.K. Raju / Seminars in Fetal & Neonatal Medicine 17 (2012) 126e131

Box 5. Immunological advantages from breastfeeding and

feeding of human milk.

Box 6. Developmental immaturity of the innate immunological system.

 Immunoglobulin
B Secretory IgA, IgM and IgG
B IgE, secretory component of IgD.
 Hormones and other biochemical components
B Epidermal growth factor
B Prostaglandin
B Thyroid-releasing hormone
B Thyroid-stimulating hormone
B Thyroxine and triiodothyronine
B Adrenocortical hormone
B Melatonin with diurnal variations matching circadian
rhythm
B Somatostatin
B Neurotensin
B Prolactin
B Erythropoietin.
 Cellular
B Immunologically specific T- and B-lymphocytes
B Neutrophils, macrophages and epithelial cells
B Commensal bacteria colonized on maternal skin
B Other microbiota matching maternal dietary intake.
 Other non-specific factors
B Complement
B Chemotactic factors
B Lactoferrin
B Transferrin
B Several variety of biniding proteins
B Enzymes: lipoproteinlipase, lysozyme, and leukocyte
enzymes.

 Immunoglobulin and complements

B Due to earlier than term birth, preterm infants receive
lesser amounts of IgG via the placenta
B The complement system is decreased in preterm
infants.
 Antimicrobial proteins and peptides
B The maturation of leukocyte-secreted antimicrobial
proteins and peptides increases in a gestational agedependent manner. Some of the critical ones are:
abactericidal/permeability-increasing
protein;
defensins; and several phospholipases.
 Mannose binding lectin
B Required for activating complement pathways, low
in infants <28 weeks, increasing their risk for severe
sepsis.
 Microbial-killing abilities
B Diminished chemotaxis, lower neutrophil pool, deficient opsonization, and other factors due to immaturity limit the ability for phagocytosis.
 Other recently discovered factors
B Functionally impaired dendritic cells
B Functional immaturity of toll-like receptors
B Reduced cytokine-producing capacity of neonatal
monocytes.

among the PMNs from preterm infants. PMNs, however, maintain

adequate phagocytic activity, but because of the deciency of
complement receptors on their surface, phagocytosis is not effective, especially when the invading microbial load is massive relative
to the PMN counts. Other aspects of the immunological basis for
increased susceptibility for neonatal infections in moderate and
late preterm are listed in Box 6.
The human intestinal system is also a major immunological
organ. Soon after birth, the intestinal surface is exposed to a variety
of microbial and dietary antigens. Since the newborn infant is
immunologically nave, during vaginal birth and soon thereafter,
they become colonized by multitudes of microbes, including
Escherichia coli and streptococci. By the end of the rst week of life,
anerobes such as Bacteroides spp., Bidobacterium spp. and Clostridium spp. also colonize the infant gut.
The diversity of microbial ecology in preterm infants is affected by
many factors, including chorioamnionitis, maternal intrapartum
antibiotic exposure, and infant feeding type.38 Infants delivered by
caesarean have less diverse microbial ecology compared to those
delivered vaginally.39 They tend to have fewer E. coli and Bidobacteria spp., but more Klebsiella spp. and Enterobacter spp. The immunological implications of diversity of infant intestinal microbial
ecology needs to be studied to explore their possible effects on sepsis,
necrotizing enterocolitis, infant atopy, allergy, and food intolerance.
4. Summary and conclusions
The foregoing discussion is intended to be a brief overview of
some critical aspects of fetal maturation that operate as underpinnings for common problems seen in moderate and late preterm
infants. One should note that variation in the degree of maturation
among infants of similar gestational ages is very common. Since

development is non-linear, the extent of maturity among various

organs in a given infant might also vary. An understanding of these
principles can help guide treatment strategies.
Conict of interest statement
None declared.
Funding sources
None

Practice points
 Preterm birth, even by a few weeks prior to term, is
associated with a high prevalence of clinical problems
due to:
B immaturity of organ systems (e.g. the lungs, brain;
the gastrointestinal system).
B acquired problems (e.g. infections, hypothermia).
B inadequate monitoring and/or follow-up plans (e.g.
hypoxic respiratory failure; hypoglycemia; kernicterus).
 Developmental processes are non-linear, therefore:
B different organ systems mature at specific rates and
trajectories that are specific to their functions (e.g
infants breathing normally may not feed well, due to
immature sucking/swallowing mechanisms).
 The degree of maturation can vary among infants born
at comparable gestations because time is only one of
the many factors influencing maturation. Others are
B maternal health and disease
B medication use
B lifestyle factors (nutritional status; smoking; illicit
drug use; exercise)
B fetal sex; number of fetuses; fetal disorders
B the dynamics of the intrauterine environment.

T.N.K. Raju / Seminars in Fetal & Neonatal Medicine 17 (2012) 126e131

Research directions
 Understanding the mechanisms that affect the rate and
trajectory of fetal/neonatal organ maturation and
development.
 Assessing the role of intrauterine environment on fetal
organ maturation during the second half of pregnancy.
 Developing biomarkers to:
B identify the status of maturation of specific organ
systems
B predict outcomes of adverse clinical conditions.
 Study impact of preterm birth on the pattern of intestinal microbiota, and their variations to understand how
they affect the current and future health and disease.
 Study how the extrauterine environment affects organ
maturation and development in infants born preterm,
and uncover the underlying process involved in such
effects.
 Use the above knowledge to optimize care and followup of moderate and late preterm infants.

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