Prematurity Special Issue

Short- and Long-Term Outcomes of Moderate

and Late Preterm Infants
Girija Natarajan, MD1 Seetha Shankaran, MD1

1 Department of Pediatrics, Wayne State University, Detroit, Michigan Address for correspondence Girija Natarajan, MD, Department of
Pediatrics, Wayne State University, Detroit, MI
Am J Perinatol (e-mail: gnatara@med.wayne.edu).

Abstract Late (34–36 weeks’ gestational age) and moderate (32–336/7 weeks’ gestational age)
preterm infants constitute approximately 84% of all preterm infants. Over the past few
decades, there is increasing recognition that this population is at risk for short- and long-
Keywords term morbidities and adverse outcomes. This article is an overview of the common
► moderate preterm clinical problems encountered by the clinician during the neonatal period among infants
► late preterm born even a few weeks early. Recent literature highlighting the long-term neuro-

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► outcomes developmental and health risks of those born moderately or late preterm is also
► neurodevelopmental summarized and discussed. Further research on the efficacy and benefits of specific
outcomes therapies in this population is warranted.

The 2005 Eunice Kennedy Shriver National Institute of Child
Health and Human Development (NICHD) workshop on
“Optimizing Care and Outcome of the Near-Term Pregnancy
and the Near-Term Newborn Infant” defined infants born at
34 through 366/7 weeks of gestational age (GA) as late preterm
(LPT) infants.1 It emphasized that the preterm birth rate in the
United States increased by 31% from 1981 to 2005, mainly due
to a rise in LPT births.1,2 According to the World Health
Organization, moderate preterm (MPT) birth is categorized
as birth at 32–336/7 weeks’ GA and very preterm birth as 29–
316/7 weeks’ GA.3 Together, late and moderate preterm
(LMPT) births constitute 84% of all preterm births.4,5 In the
past few decades, there is increasing recognition that LMPT
infants are at increased risk for neonatal mortality, morbid-
ities, and health care resource utilization compared with
infants born at term and have long-term health and neuro-
developmental sequelae.4–6 This review seeks to characterize
the short- and long-term outcomes of LMPT infants.
Short-Term Outcomes
Respiratory Morbidities
A large body of literature in the past two decades has shown
that LMPT infants are at higher risk for respiratory distress
syndrome (RDS), transient tachypnea of the newborn,
pneumonia, and pulmonary hypertension in the neonatal
period, compared with infants born at term.5,7–10 The rates of
severe respiratory disorders requiring treatment with
mechanical ventilation and/or nasal continuous positive
airway pressure (CPAP), all forms of respiratory morbidity,
pneumothorax, and respiratory failure are also higher among
LMPT infants, compared with late term (39–41 weeks’ GA)
infants.5,9–11 The odds of the respiratory morbidities and
need for assisted ventilation appear to decrease with each
advancing week of GA until 38 weeks.7,11 Some experts have
noted that the initial clinical picture of respiratory distress in
the LMPT population may be mild and the course unpredict-
able.5,12 Putative causes of respiratory distress in the LMPT
born infant include immature antioxidant and surfactant
systems and delayed intrapulmonary fluid absorption due
to developmentally regulated epithelial sodium channel
expression.12,13 The reported rates of morbidities have varied
between studies. More recently, among 19 U.S. hospitals,
respiratory morbidity rates were 9% in LPT infants, after
adjusting for mode of delivery, maternal medical conditions,
and birth weight.11 Incidences of persistent pulmonary
hypertension of the newborn (0.38 vs. 0.08%) and respiratory
failure (0.94 vs. 0.11%) are higher in LPT infants, compared
with term controls.11 In an earlier Italian study, approxi-
mately 21% of infants born at 33–34 weeks’ GA and 7% of those

received Copyright © by Thieme Medical DOI http://dx.doi.org/

November 24, 2015 Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0035-1571150.
accepted after revision New York, NY 10001, USA. ISSN 0735-1631.
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Outcomes of Moderate and Late Preterm Infants Natarajan, Shankaran
born at 35–36 weeks’ GA experienced respiratory distress,
compared with 0.6% of infants born at term (37–42 weeks’
GA).14 The reported rates of assisted ventilation and supple-
mental oxygen, although variable, are considerable. Escobar
et al found that 46% of LMPT infants born at 30–34 weeks’ GA
required assisted ventilation and 3.2% continued to receive
supplemental oxygen at 36 weeks’ postmenstrual age.8 The
risk of a requirement for assisted ventilation increased pro-
gressively (odds ratio [OR]: 5.24–31.9) with decreasing GA
from 36 to 33 weeks, compared with term-born infants.7
Among LPT infants born at 35–36 weeks’ GA, 8% needed
oxygen for 1 hour or longer.7 In another population-based
cohort, 30% of infants born at 32 weeks’ GA required nasal
CPAP and mechanical ventilation each.15 Lower rates of
respiratory distress requiring mechanical ventilation have
been reported in other studies in infants born at 34 weeks’
GA (3.3%) and 35 weeks’ GA (1.7%).16 Ventilated LMPT infants
often receive adjunctive therapies such as fluids, vasopres-
sors, surfactant, high-frequency ventilation, and nitric oxide,
despite the lack of strong evidence of their benefit in this
specific cohort.7 A review of the Extracorporeal Life Support
Organization Neonatal Registry noted that mortality on
ECMO was higher (26.2 vs. 11.2%) and duration longer in
LPT infants than in term infants.17 The American College of
Obstetrics and Gynecology recommends a single course of
antenatal steroids for pregnant women between 24 and 34
weeks’ GA at risk for preterm delivery within a week, albeit
with limited data specific to the LMPT infant.18 In the
Cochrane meta-analysis, RDS was significantly reduced in
corticosteroid-treated infants born before 34 weeks (relative
risk [RR]: 0.58; 95% confidence interval [CI]: 0.47–0.72; 5
studies; 1,177 infants) and before 36 weeks (RR: 0.54, 95% CI:
0.41–0.72, 3 studies, 922 infants).19 More recently, the NICHD
Maternal Fetal Medicine Units Network reported no signifi-
cant differences in neonatal respiratory morbidities between
groups of 550 LPT infants who had received prior clinical
antenatal steroids and 5,374 who had not, after controlling for
confounding factors.20 RDS (OR: 0.78 [0.60–1.02]) and venti-
lator support in particular (OR: 0.75 [0.55–1.03]) did not
differ between groups.20 A small randomized controlled trial
did not show any benefit, either.21 The larger (sample size of
2,831) multicenter placebo-controlled randomized con-
trolled trial (Antenatal Late Preterm Steroids ClinicalTrials.
gov NCT01222247) to evaluate the effect of antenatal steroids
12 to 24 hours prior to LPT delivery on need for respiratory
support in the first 72 hours has been recently completed. The
primary outcome for the trial is the need for CPAP or
humidified high-flow nasal cannula for 2 hours or more, or
fraction of inspired oxygen (FiO2) greater than or equal to
0.30 for 4 hours or more, or mechanical ventilation, or ECMO,
stillbirth, or neonatal death in the first 72 hours.
Apnea of Prematurity
LMPT infants are recognized to be at risk of apnea of prema-
turity, due to immaturity of brainstem regions and imperfect
control of breathing.13 In addition, the chest wall and the
upper airways are highly compliant and tend to collapse
paradoxically when the diaphragm contracts during rapid
American Journal of Perinatology
eye movement sleep.22 The ventilatory response to hyper-
carbia is blunted and the response to hypoxia is biphasic.22
The risk of apnea in LPT infants (OR: 15.7; 95% CI: 11.8–20.9),
aggregated over multiple studies, was higher than in full-
term infants.9
Temperature and Glucose Regulation
Temperature instability in the early postnatal period is
significantly more frequent in LPT infants, with 10% requiring
active management for hypothermia.23–25 Laptook and Jack-
son confirmed an increased susceptibility to cold stress in LPT
infants.26 Interventions such as thermal wrap in the delivery
room and incubator in the neonatal intensive care unit (NICU)
may be required in the majority of LMPT infants. The LMPT
cohort of infants have decreased brown fat and subcutaneous
fat, large surface area, nonkeratinized skin, and impaired
release of thyroxine and norepinephrine in response to cold
stress.13 In addition, they are at higher risk of requiring
delivery room interventions for transition and respiratory
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distress. There are currently no guidelines for incubator
weaning or criteria for crib-readiness for LMPT infants.
LMPT infants are at risk of early postnatal hypoglycemia
due to reduced glycogen stores and low activity of gluconeo-
genic and glycogenolytic enzymes, which may be further
exacerbated by cold stress, sepsis, and inadequate intake.13
In a small study, Wang et al reported that 16% of LPT infants
developed hypoglycemia, compared with 5.3% (OR: 3.30; 95%
CI: 1.1–12.2) of term infants and 27% received intravenous
infusions (OR: 6.48; 95% CI: 2.27–22.91).23 A meta-analysis of
22 studies confirmed the higher risk of hypoglycemia in LPT
infants (OR: 7.4; 95% CI: 3–18.1), compared with term in-
fants.9 Altman et al reported a 16% rate of hypoglycemia in a
population-based Swedish cohort of 6,674 MPT (30–34
weeks’ completed GA) infants; rates were similar across these
GAs.27 The American Academy of Pediatrics recommends all
LPT infants to be screened for hypoglycemia prior to each feed
for the initial 24 hours of life.28
Jaundice
Jaundice in LMPT infants results from a higher rate of bilirubin
production and/or decreased bilirubin uptake and conjuga-
tion by the immature liver and an impaired elimination with
increased enterohepatic circulation.13 Feeding difficulties,
especially in the breast-fed infant, may further increase the
risk of hyperbilirubinemia in this population. The risk of
jaundice requiring phototherapy is higher (OR: 5; 95% CI:
1.7–14.6) in LPT infants, compared with infants born at term.9
Bhutani et al demonstrated that LPT infants, especially if large
for GA, were overrepresented in the Pilot Kernicterus Regis-
try.29 Hyperbilirubinemia in LPT infants was more severe, and
its course more prolonged than in term neonates. Bilirubin
neurotoxicity occurred at an earlier postnatal age and the
response to aggressive therapy with minimal or no sequelae
(3.45 vs. 8%) was lower, compared with term infants.29 The
American Academy of Pediatrics practice parameter recog-
nizes the higher risk of bilirubin encephalopathy in LPT
infants and recommends universal screening prior to dis-
charge home, a risk-based nomogram for initiation of
 Outcomes of Moderate and Late Preterm Infants
phototherapy and exchange transfusion therapies, avoidance
of early discharge, and close follow-up for jaundice.30 Rates of
hyperbilirubinemia increase progressively from 48% at 34
weeks’ GA to 76% for infants born at 30 weeks’ GA.27 Despite
this, formal guidelines for threshold for initiation and escala-
tion of therapies are lacking for LMPT infants born between
30 and 34 weeks’ GA.
Feeding Difficulties
LMPT infants have feeding difficulties related to suck–swal-
low incoordination and immature peristalsis and sphincter
control mechanisms.13 In a review of 22 studies, the risk of
feeding problems (OR: 6.5; 95% CI: 2.5–16.9) and necrotizing
enterocolitis (OR: 7.5; 95% CI: 3.3–17.3) were significantly
higher in LPT infants, compared with infants born at term.9
The risk of necrotizing enterocolitis increased with each week
decrease in GA from 36 to 34 weeks.9 The actual rates of
necrotizing enterocolitis are low, ranging from 0.3 to 0.7% in
LMPT infants born at 33–34 weeks’ GA.8,27 Rates increase to
1.9% at 30 weeks’ GA in the Swedish cohort, with a
significantly higher (OR: 5.7; 95% CI: 2.4–14) risk compared
with infants born at 34 weeks’ GA.27 In the NICHD Neonatal
Research Network observational cohort of 5,123 MPT
(29–33 weeks’ GA) infants, 85% were still in hospital at
36 weeks due to apnea, feeding difficulties, or weight gain.31
Infection
LMPT infants are reported to have a fourfold increased risk of
undergoing sepsis evaluations and a fivefold higher risk of
culture-positive infections, compared with their term coun-
terparts.9,16,23,27,32 In a large multicenter registry cohort, the
cumulative incidence of early and late onset sepsis was 4.42
and 6.30 episodes per 1,000 admissions, respectively.33
Gram-positive organisms caused the majority of early and
late onset sepsis episodes. Infants with early onset Gram-
negative sepsis and late onset sepsis were more likely to die
than those without culture-proven infection (OR: 4.39; 95%
CI: 1.71–11.23; p ¼ 0.002; and OR: 3.37; 95% CI: 2.35–4.84;
p<0.001, respectively).33 The risk of meningitis and pneumo-
nia, similarly, are low but higher (OR: 21; 95% CI: 1.1–406; and
OR: 3.5; 95% CI: 1.4–8.9) than in full-term infants.9 The
increased susceptibility of LMPT infants to infection may be
related to invasive procedures, maternal chorioamnionitis as
an etiology of preterm labor and GA-related deficiencies in
immunoglobulin and complement levels and innate
immunity.13
Mortality
LPT infants have higher (RR: 5.9; 95% CI: 5–6.9) risk of
neonatal death within the first 28 days of life and were
almost fourfold (OR: 3.7; 95% CI: 2.9–4.6) more likely to die
within the initial year of life.9 In the Swedish MPT cohort,
overall rates of death before discharge were 1.1%, with a
significantly elevated risk (2.4-fold to 3.3-fold) at 32 and 33
weeks’ GA, compared with birth at 34 weeks’ GA.27 Epide-
miologic studies have made abundantly clear that infant
mortality rates continue to decline until 39 to 41 weeks’
GA; reported rates among MPT infants are 16.2 per 1,000 live
Natarajan, Shankaran
births, compared with 7.1 per 1,000 live births in LPT infants
and 2.1 per 1,000 live births in infants born at 39 to 41 weeks’
GA.4
Intracranial Hemorrhage and Periventricular
Leukomalacia
The evaluation of intracranial hemorrhage (ICH) and peri-
ventricular leukomalacia in LMPT infants is complicated by
the inconsistent rates of screening ultrasonographic imaging,
which vary from 38 to 60%.34,35 In the review of 22 studies by
Teune et al, ICH occurred more frequently (OR: 4.9; 95% CI:
2.1–11.7) in LPT infants.9 Rates of severe ICH (grades 3–4
intraventricular hemorrhage), although low, were also higher
(0.01 vs. 0.004%) in LPT infants.9 Among LMPT infants in the
Swedish Perinatal Quality Registrar, rates of any ICH were 8.3,
6.2, 3.5, and 0.2% for 30, 31, 32, and 33 weeks’ GA, respectively,
and rates for grade 3 or 4 ICH were 1.6, 1.1, 1.1, and <0.1%,
respectively.27 Others have reported rates of 3.3 to 6.3% for
any ICH and less than 0.5 to 2% for grades 3 and 4 ICH in LMPT
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infants 30–34 weeks’ GA who underwent screening head
ultrasounds.3,8,34,36–38 Reported rates of cystic periventricu-
lar leukomalacia are 1.4 to 1.5% in infants born at 30 to 33
weeks’ GA but are again confounded by inconsistent use of
late cranial imaging.34,38 More recently, LMPT (32–366/7
weeks’ GA) infants were found to have lower fractional
anisotropy and higher mean, axial, and radial diffusivities
at term-equivalent age in nearly 70% of the brain’s major
white matter fiber tracts on diffusion-weighted MRI, com-
pared with term controls.39 Structural MRI revealed smaller
brain biparietal diameter, smaller corpus callosum, basal
ganglia and thalami, and cerebellar measurements in the
LMPT group, compared with term controls.40 Myelination of
the posterior limb of the internal capsule was less developed
and gyral maturation was delayed in LMPT infants. A correla-
tion of these findings with later neurodevelopment is lacking.
Long-Term Outcomes
Neurodevelopmental Outcomes
In recent years, there is increasing recognition that children
born LMPT are at risk of developmental sequelae in child-
hood.41 A meta-analysis of 15 studies demonstrated that
mean cognitive scores were directly proportional to GA
(r2 ¼ 0.49), across the entire range of GAs.42 McGowan et
al undertook a systematic review of 10 studies that evaluated
development of children born LPT (34–36 weeks’ GA)
between the ages of 1 and 7 years.43 All studies were con-
ducted between the years 2000 and 2010, most were from
developed countries, and three were prospective observa-
tional cohort studies.44–52 The review excluded studies in
which LPT was defined as other than 34–36 weeks’ GA. Six
studies reported rates of neurodevelopmental disabilities in
LPT infants, broadly defined as cerebral palsy, global devel-
opmental delay, intellectual disability, or language impair-
ments.44,46,49–51 An increased risk of cerebral palsy
(RR range: 2.7–3.39),46,49,51 developmental delay
46,49
(RR: 1.25–1.6), cognitive impairment,51 specific deficits
in visuospatial ability and verbal fluency,44 and disability45
American Journal of Perinatology
Outcomes of Moderate and Late Preterm Infants Natarajan, Shankaran
were reported at 3 to 5 years of age, compared with infants
born at term. In contrast, the Ages and Stages Questionnaire
scores at a mean age of 48 months were comparable in
children born LPT and at term in a single study.50 The three
studies that reported academic performance in school
revealed poorer performance and teacher ratings in writing,
reading, and math in kindergarten and first grade, some of
which persisted through fifth grade.45,47,48
Details of other studies published since 2010 and encompass-
ing broader cohorts of LMPT infants are presented
in ►Table 1.53–66 With a few exceptions, the studies again
showed that children born LMPT are at risk for developmental
delays, cognitive and language delays, and deficits in visuospatial
reasoning and executive functioning between 2 and 15 years of
age.41,53,54 They required special education services more often
at 5 and 7 years, showed less school readiness, and their
academic performance at school was worse than their peers
born at term.55,67,68 In fact, according to one study, GA from 24 to
40 weeks accounted for 10% of the adjusted population attribut-
able fraction of special educational needs.55 The differences in
many studies, however, were subtle and gender-specific.56,57
Complicated LPT birth was shown to be associated with poorer
cognitive performance, compared with term-born children,
whereas uncomplicated LPT birth (n ¼ 28) was not.56 This
suggests that neonatal morbidities may contribute to cognitive
deficits. Importantly, the differences in Mental Developmental
Index (MDI) at younger ages (12 and 18 months) between LPT
and term-born infants disappeared when corrected, rather than
when chronologic age was used.58,69 A review of 28 studies
noted that LMPT (32–366/7 weeks’ GA) infants had more school
problems and lower IQ scores than their term peers, although
mean scores were comparable in both groups.70 The few studies
that have followed up LMPT born infants into adulthood and
adolescence, all from Scandinavian countries, suggest long-term
deficits in cognitive ability, albeit, modified by social and
environmental factors.41,71,72
Neurobehavioral Outcomes
In the meta-analysis by Bhutta et al, an increase in internal-
izing or externalizing behaviors was noted in preterm-born
children in 13 of 16 studies reviewed and a higher prevalence
of problems with attention in 10 of 15 studies reviewed.42
LMPT infants (32–35 weeks’ GA) had higher scores on all
syndrome scales, internalizing and externalizing, and total
problems on the Child Behavior Checklist, compared with
term-born controls73 at 1.5 to 5 years of age. Boys had higher
rates (10.5%) of externalizing problem scores and girls had
higher rates of internalizing scores (9.9%). The risk of somatic
complaints was also higher (OR: 1.92; 95% CI: 1.09–3.38).73 In
contrast, Gurka et al found that social skills and behavioral or
emotional problems were comparable between 53 uncom-
plicated LPT born children and term controls through 15 years
of age.54 An increase in internalizing behavior and attention
problems, after adjusting for maternal IQ and sociodemo-
graphics, has been demonstrated in LPT born children in first
grade and in LMPT (32–35 weeks’ GA) at 7 to 9 years of
age.59,74 In one study, 19% of infants born between 32 and 35
weeks’ GA had an abnormal hyperactivity score, compared
American Journal of Perinatology
with the population norm of 10% by both teachers’ and
parents’ ratings at 7 years of age. About 20% of the children
had borderline or abnormal total behavior difficulty scores.48
A higher risk of schizophrenia, anxiety disorder, and psychi-
atric disorders has been demonstrated in some, although not
all, studies comparing LMPT born and term-born adults and
adolescents.41,49,70,75,76
Hospital Readmissions
LPT infants have been reported to have readmission rates
which are 1.5-fold to 3-fold higher than their term-born
counterparts25,77–82 for durations ranging from 2 weeks to
a year of age. Kuzniewicz et al used the California Kaiser
Permanente database on infants born from 2003 through
2012 at GA  31 weeks and found that, on adjusted analysis,
LPT (OR: 3.88; 95% CI: 3.64–4.14) and MPT (2.53; 2.02–3.16)
births were independently associated with readmissions.83
The commonest reasons for readmissions varied among
studies, and included jaundice,77,82,83 feeding problems,83
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respiratory illness,79 and infections,81 specifically respiratory
syncytial viral infections.78 Escobar et al reviewed Northern
California discharges from the NICU between 1992 and 1995
and found that infants born at 33 to 36 weeks’ GA who stayed
for 96 hours or less in the hospital had the highest readmis-
sion rates within 2 weeks of discharge.84 When births from
1998 to 2004 were included, readmission rates were found to
be predicted by male gender, Asian race, initial hospital stay
<2 days, 36 weeks’ GA, and assisted ventilation.7,83 Rates of
readmissions within 30 days were 2.9% for MPT infants, 3.3%
for term, and 6.3 to 8% for LPT infants.81,83 The timing of
readmission also differed in LPT and MPT groups; MPT infants
were readmitted evenly through the 30 days after discharge,
whereas 80% of readmissions in LPT infants were within
5 days of discharge. Readmission rates within 3 months of
discharge among those born at 30 to 32 weeks’ GA and 33 to
34 weeks’ GA groups were 12.5 and 10.5%, respectively.8 In a
longitudinal study of infants born in a 3-year period in the
United Kingdom, hospital admissions showed an increasing
gradient with decreasing GA, even at 3 and 5 years of age.85
Population attributable fractions of having 3 or more hospital
admissions between 9 months and 5 years of age were 5.7%
(95% CI: 2–10%) at 32–36 weeks’ GA, compared with 3.8% for
very preterm infants (< 32 weeks’ GA). Adjusted risk was
higher at 32 to 33 weeks’ GA (7.8; 2.9–20.7) and at 34 to 36
weeks’ GA (5.1; 3–8.8).85
Some studies have examined readmissions for specific
reasons more closely. In a recent study, 20.9% of LMPT (32–
36 weeks’ GA) infants required admission within a year for
respiratory infection, compared with 6.9% of term infants.86
Assisted ventilation and RDS at birth were risk factors for
readmissions.86 In another population-based cohort of all
children born in Wales, United Kingdom, over a 10-year
period, the risk of emergency respiratory readmissions up
to 5 years of age increased as GA decreased below 40 weeks.87
About 17% of appropriate for GA infants born at 33 to 34
weeks’ GA had an emergency respiratory readmission within
a year and 14% between 1 and 5 years of age. Corresponding
rates for those born at 35 to 36 weeks’ GA were 14% and 13%,
 Table 1 Details of selected studies on neurodevelopmental outcomes of LMPT infants published since 2010

Author (year) Study design LMPT criteria and Controls criteria and Exclusion criteria Age at assessment Instrument Results
sample size sample size
Odd et al (2012) 53 Cohort study LMPT 32–36 wk GA, Term 37–42 wk GA, 8–11 y Wechsler Intelligence Children born LMPT had
n ¼ 741 n ¼ 13,102 Scale for Children, 3rd similar IQ scores to
edition, short version, term-born peers (ad-
memory and attention justed mean difference
testing, reading skills 0.18 [1.88–1.52]). LMPT
children had a higher
risk of having special
educational needs at
school (OR: 1.56 [1.18–
2.07])
Gurka et al (2010) 54 Prospective cohort LPT 34–36 wk GA, Term controls 37–41 wk Major health problems 4–15 y Woodcock–Johnson No difference between
study n ¼ 53 GA, n ¼ 1,245 before or immediately Psychoeducational Bat- LPT and term controls
after birth, discharged tery, child behavior
from hospital >7 d of checklist, Social Skills
age, mother <18 y of Rating system–teacher
age, multiples, drug-de- form, student–teacher
pendent mother, chro- relationship scale
mosomal or genetic
abnormality, congenital
defect, congenital
infection
MacKay et al (2010) 55 Population-based retro- 24–43 wk GA, Birth weight <400 or 4–19 y, median age 12 y School census data LMPT birth at 33–36 wk
spective study n ¼ 407,503 >5,000 g; multiple GA was associated with
births, age <4 or >19 y OR 1.53 (1.43–1.63) risk
of special educational
needs in schoolchildren,
compared with 40 wk
GA at birth.
Baron et al (2010) 56 Single center retrospec- 35–36 wk GA; Term (37 wk GA and Genetic disorders, se- Mean age 3.8 y in all Differential Ability Complicated LPT had
tive cohort study (a) Complicated: admit- 2,500 g), n ¼ 100 vere sensorineural loss, groups Scales-general concep- significantly poorer
ted to the NICU for birth controls brain tumor, or non-En- tual ability (GCA); ver- GCA, nonverbal reason-
weight <2 kg and/or glish speaking bal, nonverbal ing, and spatial scores
clinical instability reasoning, and spatial than term-born con-
(n ¼ 90) scores trols.
(b) uncomplicated LPT males had RR 7.23
(n ¼ 28) (1.24–44.30) for im-
paired GCA compared
with LPT females.
Outcomes of Moderate and Late Preterm Infants

Kerstjens et al (2011) 57 Prospective cohort 32–35 6/7 wk GA, (a) Term (38–416/7 wk Major congenital mal- 43–49 mo Ages and stages Total scores >2 SDs be-
study n ¼ 927 GA), n ¼ 544; formations, congenital questionnaire low the mean found in
(b) early preterm (<32 infections and 8.3% LMPT, 4.2% of
wk GA), n ¼ 512 syndromes term, and 14.9% of early
preterm births. OR for
abnormal scores for
children born LMPT 2.1
(95% CI: 1.3–3.4). So-
cioeconomic status,
small-for-GA status, and
(Continued)

American Journal of Perinatology

Natarajan, Shankaran

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 Table 1 (Continued)

Author (year) Study design LMPT criteria and Controls criteria and Exclusion criteria Age at assessment Instrument Results
sample size sample size
sex were associated with
abnormal scores among
LMPT infants.
Woythaler et al (2011) 58 Prospective national 34–37 wk GA, n ¼ 1200 Term (37 wk GA), Not or unable to be ad- 24 mo of age Bayley Scales of Infant LMPT infants had lower
population-based study equately assessed due Development (BSID) MDI (85 vs. 89) and PDI

American Journal of Perinatology

n ¼ 6,300
Early Childhood Longi- to major congenital short form (88 vs. 92) and higher
tudinal Birth Cohort anomaly or blindness rate of MDI <70 (21 vs.
16%). LMPT had higher
adjusted OR for mental
(1.52; 1.26–1.82) or
psychomotor (1.56;
1.30–189) delay.
Talge et al (2010) 59 Secondary analysis of 34–36 wk GA, n ¼ 168 Term matched within Severe neurologic im- 6y Wechsler Intelligence LPT birth was associated
longitudinal cohort 0.1 SD of birth weight z pairment, multifetal Scale, children’s behav- with a higher risk of full
study. score, n ¼ 168 gestation, missing data ior checklist–teacher scale (aOR: 2.35; 95% CI:
report 1.20–4.61) and perfor-
mance (aOR: 2.04; 95%
Outcomes of Moderate and Late Preterm Infants

CI: 1.09–3.82) IQ<85,

more internalizing and
attention problems.
These effects were in-
dependent of maternal
IQ, sociodemographics,
and residential setting.
Woythaler et al (2015) 60 Longitudinal cohort LPT 34–36 wk GA, Term 37 wk GA, Major congenital anom- 24 mo MDI and school BSID short form at 24 LPT had higher odds of
study n ¼ 950 n ¼ 4,900 alies, blindness, or readiness score at mo; Total School Readi- worse TSRSs (adjusted
deafness kindergarten ness Score (TSRS) de- OR: 1.52 [95% CI: 1.06–
rived from the reading, 2.18]). The positive pre-
Natarajan, Shankaran

math, and expressive dictive value of a child

language tests of the having an MDI of <70 at
cognitive assessment 24 mo and a TSRS <5%
battery at kindergarten was
10.4%. The negative
predictive value of hav-
ing an MDI of >70 at 24
mo and a TSRS >5% was
96.8%.
Blaggan et al (2014) 61 Prospective cohort 32–36 wk GA, n ¼ 219 None Multiples of an included 24 mo corrected Parent Report of Child- Strong association be-
study infant, incomplete as- ren’s Abilities-Revised tween PARCA-R and
sessment or (PARCA-R), Brief Infant BSID-III (r ¼ 0.66).
questionnaire Toddler Social and Emo- Composite BSID-II
tional Assessment, scores <80 were noted
BSID-III cognitive and in 9% infants; language
language scales scores were <80 in 14%
and cognitive in 6%
infants.

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 Table 1 (Continued)

Author (year) Study design LMPT criteria and Controls criteria and Exclusion criteria Age at assessment Instrument Results
sample size sample size
Cserjesi et al (2012)62 Prospective cohort 32–35 wk GA, n ¼ 248 Term 38–416/7 wk GA, Major congenital mal- 7y Wechsler Intelligence LMPT at higher risk (RR:
study n ¼ 130 formations, congenital Scale Dutch version; Rey 1.69; 95% CI: 1.29–2.28)
infections and auditory verbal learning for intelligence and vi-
syndromes test; Developmental suospatial reasoning
Neuropsychological <10th percentile and
Assessment Battery executive functioning
NEPSY-2; Movement problems (RR: 1.94; 95%
Assessment Battery CI: 1.51–2.57). LMPT
boys had significantly
worse visuospatial
reasoning.
Quigley et al (2012) 63 Population-based MPT 32–33 wk GA, Early term (37–38 wk Died within 9–10 mo of 9 mo and 5 y Foundation stage profile 59% of LPT and 63% of
cohort n ¼ 99 and LPT 34–36 GA, n ¼ 1,827); term age at end of the first school MPT children did not
wk GA, n ¼ 537 (39–41 wk GA, year by teachers achieve good overall
n ¼ 6,159); very pre- achievement, compared
term (23–31 wk GA, with 51% of term chil-
n ¼ 106) dren. LPT birth was as-
sociated with a slightly
elevated risk, after ad-
justment for multiple
sociodemographic fac-
tors (OR: 1.12; 95% CI:
1.04–1.22)
Chyi et al (2008) 47 Prospective longitudinal MPT 32–33 wk GA, Term controls, Anoxia or respiratory Kindergarten through Early Childhood Longi- LPT children had adjust-
cohort study n ¼ 203 and LPT 34–36 n ¼ 13,761 distress at birth fifth grade tudinal Study-Kindergar- ed risk for poor reading
wk GA, n ¼ 767 ten cohort test scores, from kindergarten
teacher rating scales, through fifth grade and
and special education lower math scores in
kindergarten and first
grade. MPT children had
lower test and/or
teacher evaluation
scores than term infants
at all grade levels
Mathiasen et al (2010) 64 Longitudinal register- LMPT (31–36 wk) in- All live born infants in a Missing data on GA and/ Completion of basic School examination Birth at 33 (adjusted OR:
based study fants born over a 2-y 2-y period in Denmark, or birth weight school (ninth grade) grades and teacher 1.62; 95% CI: 1.23–2.13)
period, n ¼ 5,449 n ¼ 118,281; term 37– evaluations and 34 wk (aOR: 1.35;
Outcomes of Moderate and Late Preterm Infants

41 wk GA, n ¼ 101,146 95% CI: 1.07–1.71) GA

increased the risk of
failing to complete basic
school. Risk of failure
increased by 0.5% per
week between 31 and
36 wk GA
(Continued)

American Journal of Perinatology

Natarajan, Shankaran

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 Table 1 (Continued)

Author (year) Study design LMPT criteria and Controls criteria and Exclusion criteria Age at assessment Instrument Results
sample size sample size
Nepomnyaschy et al (2012) Cohort study LPT 34–36 wk GA, Term 37–41 wk GA, Multiple births, hospital 2 and 4 y Bayley short form, short LPT children scored
65
n ¼ 400 n ¼ 5,050 stay >3 d, major con- MacArthur Communica- worse than those born
genital anomalies, miss- tive Development In- at term on language use
ing follow-up data ventory and other Early at 2 y, literacy, language
Childhood Longitudinal and math at 4 y, after

American Journal of Perinatology

Survey instruments adjusting for demo-
graphic and obstetric
factors but scored >1
SD below the mean on
only 1 of 18 outcomes.
Johnson et al (2015) 66 Population-based co- LMPT 32–366/7 wk GA, Term 37 wk GA, Major congenital 2y Parental questionnaire Rates of neurosensory
hort study n ¼ 638 n ¼ 765 anomalies to assess vision, hearing, impairment were 1.6%
motor impairments, and in LMPT and 0.3% in
the PARCA-R controls (RR: 4.89; 95%
CI: 1.07–22.25); cogni-
tive impairment: 6.3 vs.
2.4% (RR: 2.09; 95% CI:
1.19–3.64). The adjust-
Outcomes of Moderate and Late Preterm Infants

ed difference between
the PARCA composite
scores between the two
groups was 4.49
(8.36 to 0.62). LMPT
birth was a risk factor for
neurodevelopmental
disability (RR: 2.19; 95%
CI: 1.27–3.75). Inde-
pendent risk factors for
cognitive impairment in
Natarajan, Shankaran

LMPT infants were male

sex, socioeconomic dis-
advantage, nonwhite
ethnicity, preeclampsia,
and not receiving breast
milk at discharge.

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 Table 2 Summary of studies on pulmonary function of LMPT children

Author and year Study design LMPT cohort and Controls and Exclusion criteria Age at evaluation Instrument Results
sample size sample size
Friedrich et al (2007)90 Prospective longitu- Healthy 30–34 wk Term, n ¼ 24 Any mechanical 1 and 2 y Expiratory flows and Decreased forced
dinal study GA, n ¼ 26 ventilation, supple- normal forced vital expiratory flows
mental oxygen for capacities and normal
greater than 48 h, forced vital ca-
or treatment with pacities in LMPT.
surfactant, acute
respiratory symp-
toms in the 3 wk
prior to testing
Kotecha et al (2012)91 All births from the LMPT-33–34 wk GA, Term (37 wk GA), Death before 1 y of 8–9 and 14–16 y of Forced expiratory At 8–9 y of age,
Avon Longitudinal n ¼ 165 and 35–36 n ¼ 13,117 and age age volume in 1 s (FEV1) all spirometry
Study of Parents wk GA, n ¼ 519 early preterm (25– and forced vital ca- measures were
and Children 32 wk GA), n ¼ 160 pacity (FVC) lower in the 33–
34 wk GA group
than in term
controls but sim-
ilar to 25–32 wk
GA. At 14–17 y of
age, FEV1/FVC
and forced expi-
ratory flow at
25–75% were
significantly low-
er in LMPT than in
term controls.
Hoo et al (2002)92 Prospective longitu- LMPT (36 wk GA; None No ventilatory 3 wk of age and Paired measure- Index within nor-
dinal study mean [SD] GA 33.2 support corrected postnatal ments of maximal mal range at 3 wk
[2.2]), n ¼ 24 age (mean  SD) of expiratory flow at but by 1 y, z
57.0  12.2 wk functional residual scores had re-
capacity, expressed duced signifi-
as gender-specific z cantly (mean
scores [95% CI] 1.94
[2.27, 1.60]).
Outcomes of Moderate and Late Preterm Infants

Todisco et al (1993)93 Prospective cohort Mean GA 34.9 wk, Term-born siblings, RDS or artificial 11.6 y in PT and Pulmonary function PT children had a
study n ¼ 34 mean GA 39.5 wk, ventilation 12.5 y in term and bronchial reac- residual volume
n ¼ 34 controls tivity to and residual vol-
methacholine ume/total lung
capacity signifi-
cantly (p<0.01)
increased com-
pared with
(Continued)

American Journal of Perinatology

Natarajan, Shankaran

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 Outcomes of Moderate and Late Preterm Infants Natarajan, Shankaran

respectively. Small-for-GA infants had higher readmissions

wheeze or cough
between groups.

in MPT; reported
(6 vs. 3%) higher
controls. No sig-

Hospitalizations
sponsiveness to
rates consistently.87 The adjusted risk for emergency respira-

medication use
out a cold, and
during or with-
nificant differ-

methacholine
observed for
bronchial re-
tory readmission was higher for 33 to 34 weeks’ (OR: 1.59;

ence was
95% CI: 1.50–1.68) GA and 35 to 36 weeks’ (OR: 1.39; 95% CI:
Results

higher.
1.34–1.45) GA.

Respiratory Function

by respiratory prob-
lems, prevalence of
Number of rehospi-
Limited data suggest that there is an ongoing risk of long-term

talizations caused
respiratory problems in LMPT born children, such as cough,
wheeze, dyspnea, and adverse effects on lung growth.88,89
Instrument

respiratory
symptoms
There have been a few studies which have evaluated pulmo-
nary function of LMPT born children which suggest that they
have limitations in forced expiratory flow, which persist until
mid-childhood (►Table 2).90–93
Age at evaluation

Feeding and Growth Outcomes

Infancy and 5 y

Santos et al reported that LPT infants were at higher risk for

being underweight (adjusted OR: 2.57 and 3.36) and stunted
(adjusted OR: 2.35 and 2.30) at 1 and 2 years of age, compared

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with full-term infants.52 In an evaluation of parental percep-
tions of post-discharge feeding dysfunction at 3, 6, and
12 months of life in 571 LPT and 319 early-preterm (25–
tions or syndromes
Exclusion criteria

336/7 weeks) infants, early preterms had more oromotor

Major congenital

congenital infec-
malformations,

dysfunction at 3 (29 vs. 17%) and 12 months (7 vs. 4%) and

more avoidant feeding behavior at 3 months (33 vs. 29%).94 In
both groups, oromotor dysfunction and avoidant feeding
behavior improved over time. The frequency of hospitaliza-
tion/subspecialty visits, however, were similar in both
groups. Others have found no differences in weight or height
Term, n ¼ 573 and
early PT, n ¼ 551

at 48 months of age between groups of LPT and term

children.50
Controls and
sample size

In conclusion, LMPT infants are at increased risk of adverse

neonatal outcomes and long-term neurodevelopmental and
behavioral sequelae, lower cognitive functioning, and ongo-
ing respiratory and other morbidities. Their care is associated
with substantial costs in the initial hospitalization and
throughout childhood.95 Future research should focus specif-
LMPT cohort and

MPT<36 wk GA,

ically on categories of very preterm and MPT infants and

sample size

explore the comparative effectiveness of therapies in this

population.31 The efficacy and safety of medical treatments,
n ¼ 988

such as antenatal steroids and whole body cooling, need to be

tested specifically in this population through randomized
controlled trials. There is a need for research on the associ-
Prospective cohort

ations between care practices related to nutrition and tem-

perature maintenance and short-term outcomes as well as
Study design

long-term neurodevelopmental and behavioral outcomes.

Finally, the role, if any, of MPT or LPT birth on fetal onset of
adult diseases needs to be examined.
study
Vrijlandt et al (2013)89
Table 2 (Continued)

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