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OBSTETRICS

Threatened preterm labor is a risk factor for

impaired cognitive development in early childhood
Cristina Paules, MD; Victoria Pueyo, MD, PhD; Elena Martí; Susana de Vilchez; Irina Burd, MD, PhD;
Pilar Calvo, MD; Daniel Oros, MD, PhD

BACKGROUND: Threatened preterm labor is a leading cause of
hospital admission during pregnancy. Patients with an episode of
threatened preterm labor who deliver at term are considered to have
false preterm labor. However, threatened preterm labor has been
proposed as a pathologic insult that is not always sufficient to induce
irreversible spon-taneous preterm birth but that could alter the
normal course of pregnancy. OBJECTIVE: The aim of this study was
to evaluate threatened preterm labor during pregnancy as a risk
factor of neurodevelopmental deficits of children at 2 years of age.
STUDY DESIGN: Two-year-old children who were born late preterm
(n¼22) or at term after threatened preterm labor (n¼23) were
compared with at-term control children (n¼42). Neurodevelopment
was evaluated at a corrected age of 24e29 months with the use of
the Merrill-Palmer-Revised Scales of Development.
RESULTS: Children who were born at term after threatened preterm
labor had lower scores than control children on global cognitive index
(95.4 vs 104.2; P¼.011), cognition (95.1 vs 103.1; P¼.021), fine motor
(95.2 vs 103.4; P¼.003), gross motor (84.7 vs 99.8; P¼.001), memory
(92.9 vs 100.4; P¼.015), receptive language (93.9 vs 102.9; P¼.03),
speed of processing (105.7 vs 113.3; P¼.011), and visual motor
coor-dination (98.8 vs 106.7; P¼.003) subtests. Children born at
term after threatened preterm labor had an increased risk of mild
neuro-developmental delay compared with control children (odds
ratio for global cognitive index, 2.06; 95% confidence interval,
1.09e3.88; P¼.033). There were no significant differences in any
cognitive domain between children who were born late preterm and
children who were born at term after threatened preterm labor.
CONCLUSIONS: Threatened preterm labor is a risk factor for
impaired cognitive development at 2 years of age, even if
birth occurred at term.
Key words: neurodevelopment, preterm birth, threatened preterm labor

Materials and Methods

T hreatened preterm labor, which
occurs in approximately 9% of all
pregnancies, is the leading cause of hos-
pital admission during pregnancy,
1 Many studies show that children who are
excluding labor at term. Within this
population of women, the incidence of
2 cognitive and behavioral problems at
preterm birth is 30-40%. Preterm birth is
the final common result of a variety of
causes with very different biologic mech-
3
anisms, which include intrauterine
infection, uterine ischemia, uterine over-
distension, abnormal allogenic recogni-tion,
allergic-like reaction, cervical disease, and
endocrine disorders; some of which are
4,5
related to poor neonatal out-comes.
Although neurobehavioral competencies
in newborn infants are related mainly to
6,7
neurologic matura-tion, preliminary
evidence suggests that
Cite this article as: Paules C, Pueyo V, Martı´ E, et
al. Threatened preterm labor is a risk factor for
impaired cognitive development in early childhood.
Am J Obstet Gynecol 2017;216:157.e1-7.
0002-9378/$36.00
ª 2016 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2016.10.022
Related editorial, page 89.
poor outcomes among infants who are
born late preterm or early term may not
only be due to physiologic immaturity but
also to other biologic determinants.8
born late-preterm are at increased risk of
preschool age.9-14
Previous reports suggest that infants
who are born at-term and whose mothers
experienced an episode of threatened
preterm labor could be at increased risk
for fetal growth restriction.15,16
However, randomized clinical trials that
have assessed the effect of tocolysis have
not shown differences in early childhood
cognitive outcomes among infants who
were born at-term and late-preterm after
threatened preterm labor.17 On this basis,
it has been suggested that symptoms of
threatened preterm labor may result from
a pathologic insult whose nature and/or
severity is not sufficient to induce irre-
versible spontaneous preterm parturition
but that could alter the normal course of
pregnancy. Therefore, the aim of this
study was to evaluate threatened preterm
labor as a marker of neurodevelopment at
2 years of age.
Subjects
We conducted a prospective cohort
study of children who were born late
preterm (32-36 weeks of gestation) or
at term ( 37 weeks of gestation) after
threatened preterm labor between
September 2011 and May 2013 at a ter-
tiary University Center. Congenital
malformations, chromosomopathy,
infections, multiple gestations, postnatal
diagnosis of children with a severe dis-
ease, and delivery not in our medical
center were excluded. This cohort was
compared with a group of children who
were born from singleton pregnancies at
term ( 37 weeks of gestation) without
threatened preterm labor, randomly
sampled from our general obstetric
population during the same time period.
The local ethics committee approved the
study protocol, and parents provided
written informed consent.
Threatened preterm labor was
defined18 as the presence of regular and
painful uterine contractions that regis-
tered by cardiotocography and ultra-
sound cervical length <25 mm19 in the
presence of intact membranes at

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TABLE 1
Demographic and clinical characteristics and perinatal outcomes
Born at term after threatened
Variable Born late preterm (n¼22) preterm labor (n¼23) Born at term (n¼42) P value
Maternal age, ya 31 5.3 30.6 5.0 32.1 5.5 .49
Maternal body mass index, kg/m2a 24.2 3.5 21.9 3.2 23.6 3.4 .10
White ethnicity, n (%) 18 (82) 22 (96) 37 (88) .35
Maternal educational level, n (%) .56
None 1 (5) 1 (4) 0
Primary 4 (20) 7 (30) 6 (14)
Secondary 10 (45) 8 (35) 20 (48)
University 7 (30) 7 (30) 16 (38)
Nulliparous, n (%) 11 (50) 14 (65) 22 (53) .52
Previous preterm birth, n (%) 5 (24) 3 (13) 0 .02
Preeclampsia, n (%) 0 0 2 (5) .30
Cesarean delivery, n (%) 1 (5) 6 (26) 6 (14) .13
Operative vaginal delivery, n (%) 2 (9) 3 (13) 9 (21) .40
Spinal anesthesia, n (%) 17 (77) 21 (91) 38 (91) .26
Gestational age at delivery, da 246.6 8.5 276.8 7.7 278.2 8.4 <.001
Birthweight, ga 2463 457 3131 402 3336 400 <.001
Male, n (%) 10 (46) 13 (57) 18 (43) .56
Small for gestational age, n (%) 2 (9) 5 (22) 3 (7) .21
Antenatal corticosteroid treatment, n (%) 12 (55) 23 (100) 0 <.001
Metabolic acidosis, n (%) 0 1 (4) 1 (2) .62
Neonatal unit admission, n (%) 11 (50) 1 (5) 2 (5) <.001
Breastfeeding, n (%) 21 (95) 22 (96) 36 (86) .28
Age at assessment, moa 26.4 1.2 26.0 2.2 26.1 1.3 .61
a
Data are shown as mean standard deviation.
Paules et al. Threatened preterm labor and impaired neurodevelopment. Am J Obstet Gynecol 2017.

gestational age of 24 þ0 to 36 þ 6 weeks. considered to be small-for-gestational

Pregnancies were dated according to
first-trimester crown-rump length.20
Tocolysis with atosiban (Tractocile; Fer-
ring Pharmaceuticals, Madrid, Spain)
and intramuscular betamethasone
(2 12 mg/24 hr) was performed for
some cases according to manufacturer
recommendations and international
clinical standards.21
Maternal sociodemographic charac-
teristics were recorded in the hospital
database at study inclusion. Information
regarding pregnancy follow up and
standard perinatal outcomes was
collected prospectively. Infants with a
birthweight of <10th percentile,
according to local standards, were
22
age. Umbilical, uterine, and middle
cerebral artery Doppler scans were
carried out in small-for-gestational age
fetuses to diagnose intrauterine growth
restriction. Metabolic acidosis was defined
as the presence of an umbilical artery 23
<7.10 and base excess > e12 mEq/L.
Neurodevelopmental assessment
Neurodevelopment was assessed at a
corrected age of 24-29 months with the
use of the Merrill-Palmer-Revised Scales
of Development (M-P-R),24 which
assesses cognitive (verbal and nonverbal
reasoning memory), language/commu-
nication (receptive and expressive
language, evaluated by examiner and
parent), and motor ( fi ne motor and
gross motor) abilities. Especially useful
in assessing children who were born
preterm, the M-P-R is a standardized
measure of development that is used
pH
with children aged 1 month to fi
78
months that permits an early identi ca-
tion of developmental delays and
learning difficulties. This test is ideal for
the screening of infants and children
with possible developmental delays or
disabilities and for revaluations of in-
dividuals who previously were identified
as developmentally delayed. It provides a
global assessment with criterion-specific
scores.24,25 Two trained psychologists
who were blind to group and perinatal
outcomes conducted the assessment.

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TABLE 2
Cognitive neurodevelopment as assessed by the Merrill-Palmer-Revised Scales of
Development: Analysis of variance results
Born at term after threatened
Born late preterm (n¼22), preterm labor (n¼23), Born at term (n¼42),
Variable mean standard deviation mean standard deviation mean standard deviation P value
Age at evaluation, mo 26.4 1.25 25.9 2.21 26.1 1.34 .610
Global cognitive index 93.9 12.3 95.4 12.2 104 13.4 .001
Cognition 94.0 11.2 95.1 11.5 103 10.7 .003
Fine motor 93.9 8.97 95.2 10.1 103 8.92 <.001
Gross motor 91.0 15.4 84.7 18.0 99.8 12.8 .001
Memory 91.4 9.73 92.9 11.6 100 9.29 .001
Receptive language 91.5 14.8 93.9 13.7 103 11.7 .002
Expressive language 90.6 14.6 95.6 14.7 94.4 13.8 .470
Speed of processing 104 11.9 106 11.5 113 6.85 <.001
Visual motor 98.4 8.53 98.8 8.77 107 9.21 <.001
Paules et al. Threatened preterm labor and impaired neurodevelopment. Am J Obstet Gynecol 2017.

Children were assessed in the afternoon
in a quiet room in the presence of at least
1 parent. M-P-R subtest scores <1
standard deviation were considered as
mild neurodevelopmental delay. The
main reason of missing during this period
was the impossibility of contact-ing the
patients because of address and telephone
changes.
Statistical analysis
Normal distributions were assessed with
the use of the Kolmogorov-Smirnov test.
Chi-square tests and analysis of variance
were used to analyze categoric and
continuous variables, respectively. Sig-
nificant effects were followed by Bon-
ferroni correction. Effect sizes were
calculated with the use of odds ratios
(ORs) and 95% confidence intervals
(CIs). Data are presented as mean-
standard deviation (SD), median (range),
or number of subjects (%). Two-sided
probability values of <.05 were
considered statistically significant.
Statistical analyses were performed with
SPSS software (version 20; SPSS Inc,
Chicago, IL).
Results
Of the 108 children who met the inclu-
sion criteria, we contacted 98 parents
and received consent from 87 parents.
Forty-five women were admitted to the
hospital for threatened preterm labor
during pregnancy; 22 women gave birth
to infants late preterm, and 23 women
gave birth to infants at term. The other 42
women gave birth to infants at term
without threatened preterm labor.
Clinical characteristics and perinatal
outcomes are shown in Table 1. Women
who gave birth late preterm or at term
after threatened preterm labor were
significantly more likely to have had a
previous preterm birth compared with
control women (P¼.02). As expected,
late preterm infants had significantly
lower birthweights and younger gesta-
tional ages at delivery and were more
likely to be admitted to the neonatal unit
(P<.001). We found no differences in
maternal educational level among the
groups. The administration of cortico-
steroids for fetal lung maturation was
performed for all infants who were born
at term after threatened preterm labor, but
it was performed for only 54.5% of
infants who were born late preterm
because labor could not be arrested or
hospital admission for threatened pre-
term labor took place after 34 weeks of
gestation.
Average scores on M-P-R subtests are
shown in Table 2. There were significant
effects of groups on all subtest scores,
except for expressive language score.
The results of Bonferroni post-hoc tests
are shown in the Figure. Children who
were born at term after threatened
preterm labor scored significantly lower
than children who were born at term in
global cognitive index, cognition, fine
and gross motor, memory, receptive
language, speed of processing, and visual
motor coordination. No significant
differences were observed between
children who were born at term after
threatened pre-term labor and children
who were born late preterm.
Following standard methodology, the
presence of mild neurodevelopmental
delay was adjusted for gestational age at
birth, birthweight, gender, cesarean
delivery, and maternal education (sec-
ondary education or higher) by logistic
regression analysis. (Table 3) Children
who were born at term after threatened
preterm labor had a signifi-cantly
increased risk of mild neuro-
developmental delay compared with
children who were born at term for all
cognitive domains, except for cognition
(P¼.071) and expressive language
(P¼.91).
As increased risk of cognitive deficits
was observed for both children who were
born late preterm and children who were
born at term after threatened preterm

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FIGURE
Cognitive neurodevelopment

Cognitive neurodevelopment as assessed by the Merrill-Palmer-Revised Scales of Development: results of Bonferroni

correction. Data are shown as the mean.
Paules et al. Threatened preterm labor and impaired neurodevelopment. Am J Obstet Gynecol 2017.

labor, we analyzed M-P-R subtest scores
according to treatment with antenatal
corticosteroids to identify any potential
bias. There were no statistically signifi-
cant differences between groups in any
cognitive domains (data not shown;
probability values ranged from .46e.90).
Finally, the estimated power of this
study (with previously reported
differences among groups in global
cognitive index taken into account) was
0.96 as calculated by a 1-way analysis
of variance pairwise 2-sided equality
test.
Comment
Our results suggest that an episode of
threatened preterm labor is a risk factor for
neurodevelopmental deficits at 2 years of
age. Compared with children who were
born at term without threatened preterm
labor, children who were born at term

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TABLE 3
Risk of mild development delay because of threatened preterm labor, adjusted for confounding variables
Born at term after threatened 95% Confidence
Variable preterm labor (n¼23), % Born at term (n¼42), % Odds ratio interval P value
Global cognitive index 47.8 14.6 2.06 1.09e3.88 .004
Cognition 43.5 22.0 1.60 0.86e2.97 .071
Fine motor 60.9 26.8 2.10 1.16e3.81 .007
Gross motor 56.6 22.5 1.98 1.09e3.60 .006
Memory 56.5 26.8 1.84 1.02e3.29 .019
Receptive language 43.5 14.6 1.92 1.02e3.66 .011
Expressive language 22.7 21.4 1.19 0.60e2.23 .910
Speed of processing 43.5 17.1 1.93 1.03e3.60 .022
Visual motor 52.2 12.2 2.65 1.36e5.27 .001
Paules et al. Threatened preterm labor and impaired neurodevelopment. Am J Obstet Gynecol 2017.

after threatened preterm labor scored
significantly lower in all cognitive do-
mains, except for expressive language.
They had an increased risk of mild neu-
rodevelopmental delay. Moreover, the
pattern of developmental deficits in chil-
dren who were born at term after threat-
ened preterm labor was similar to that of
children who were born late preterm.
The impact of late preterm birth on
cognition is not characterized fully.
Methodologic issues, such as the
correction of age by prematurity, may
explain inconsistent results among
different studies.10,26,27 However,
healthy infants who were born late-
preterm seem to have greater risks of
developmental delay, disability, and
school-related problems throughout
10,28,29
childhood. Even as early as 2 years
old, children who were born late preterm
have more internalizing behavior prob-
lems and exhibit subtle deficits in
cognition, fine and gross motor skills,
and receptive and expressive communi-
cation.11,30 Consistent with these re-
ports, we found poorer cognition, visual
motor skills, fine and gross motor abili-
ties, memory, receptive language, and
speed of processing in both those chil-
dren who were born late preterm and
who were born at term after threatened
preterm labor. Expressive language was
the only cognitive domain that did not
show group differences. This may be
because verbal abilities are influenced
more heavily by parental education and
socioeconomic status compared with
other cognitive domains.31
Symptoms of threatened preterm la-bor
may result from a pathologic insult the
nature and/or severity of which is not
sufficient to induce irreversible sponta-
neous preterm birth but is enough to
disturb pregnancy.15 In relation to this,
some authors suggest that gestational age
is a causal link between biologic
determinants of preterm birth and
neonatal outcomes.8 Biologic
determinants that are related to preterm
labor are associated with poor neonatal
outcomes.4 Previous authors have
reported that intrauterine inflammation
that is insufficient to cause parturition
may be sufficient to induce fetal brain
injury, even without a maternal immune
response.32,33 In addition, impaired
placental function reduces the delivery of
oxygen and nutrients to the fetus.34 In
line with this hypothesis, women with an
episode of increased uterine contractility
that requires hospitalization who subse-
quently give birth at term are at an
increased risk of having a small-for-
gestational age infant.15,16 Although not
statistically significant, we also found that
22% of infants who were born at term
after threatened preterm labor were
small-for-gestational age. This may be
due to an adverse intrauterine environ-
ment that is associated with preterm
labor, which could affect fetal growth and
neurodevelopment. More-over, several
studies demonstrate that
small-for-gestational age infants exhibit
neurodevelopmental deficits.35-38
After threatened preterm labor, fetuses
could be exposed not only to different
noxious stimuli but also to similar treat-
ments that could also interfere with
development. Antenatal corticosteroids
reduce neonatal mortality and morbidity
rates39,40 and therefore are the basis of
treatment for threatened preterm labor. On
the other hand, antenatal use of
corticosteroids may retard fetal growth and
induce cognitive impairments, espe-cially
41-43
when administrated in multiple doses.
However, a recent metaanalysis found no
effect of antenatal corticoste-roids on full,
verbal, or performance intelligence quotient
in the Wechsler Intelligence Scale for
44
Children.
So far, the concern regarding threat-
ened preterm labor has focused on the
prevention of preterm birth, but threat-
ened preterm labor might also be a risk
factor for prenatal and postnatal
adverse outcomes, which suggests the
need for more surveillance. The neuro-
development of children who are born
at term after threatened preterm labor
during the first 2 years of life has never
been studied. Developmental screening
in early childhood may aid in the iden-
tification of the first signs of develop-
mental delay and the initiation of
rehabilitative programs. Further studies
are also needed to discover clinical or
biologic markers for the identification
of high-risk infants.

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Original Research OBSTETRICS
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FEBRUARY 2017 American Journal of Obstetrics & Gynecology
Original Research
Author and article information
From ISS Arago´n, the Obstetrics Department, Hospital Clı´nico
Universitario Lozano Blesa, Zaragoza (Drs Paules, Calvo, and
Oros), the Ophthalmology Department, Hos-pital Universitario
Miguel Servet Zaragoza (Dr Pueyo), and the Psychology
Department (Ms Martı´ and Ms Vilchez), University of Zaragoza,
Zaragoza, Spain; and the Inte-grated Research Center for Fetal
Medicine, Department of Gynecology and Obstetrics, Johns
Hopkins University School of Medicine, Baltimore, MD (Dr Burd).
Received June 11, 2016; revised Sept.
21, 2016; accepted Oct. 17, 2016.
Supported by the Government of Aragon
(2012-2014-B-87).
The authors report no conflict of interest.
Presented, in part, at the 12th World Congress of Perinatal
Medicine, Madrid, Spain, November 3-6, 2015.
Corresponding author: Victoria Pueyo,
MD, PhD. vpueyo@unizar.es
157.e7