- Email: [email protected]
Threatened preterm labor is a risk factor for impaired cognitive development in early childhood
Accepted Manuscript Threatened preterm labor is a risk factor for impaired cognitive development in early childhood Cristina Paules, MD, Victoria Pueyo, MD, PhD, Elena Martí, Susana Vilchez, Irina Burd, MD, PhD, Pilar Calvo, MD, Daniel Oros, MD, PhD PII:
S0002-9378(16)30917-6
DOI:
10.1016/j.ajog.2016.10.022
Reference:
YMOB 11352
To appear in:
American Journal of Obstetrics and Gynecology
Received Date: 11 June 2016 Revised Date:
21 September 2016
Accepted Date: 17 October 2016
Please cite this article as: Paules C, Pueyo V, Martí E, Vilchez S, Burd I, Calvo P, Oros D, Threatened preterm labor is a risk factor for impaired cognitive development in early childhood, American Journal of Obstetrics and Gynecology (2016), doi: 10.1016/j.ajog.2016.10.022. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Threatened preterm labor is a risk factor for impaired cognitive development in early childhood Paules, Cristina MD1; Pueyo, Victoria MD, PhD2; Martí, Elena3; Vilchez, Susana3; Burd, Irina MD, PhD4; Calvo, Pilar MD1 and Oros, Daniel MD, PhD1
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Affiliations: 1ISS Aragón, Obstetrics Department, Hospital Clínico Universitario Lozano Blesa, Zaragoza, University of Zaragoza, Spain; 2ISS Aragón, Ophthalmology Department, Hospital Universitario Miguel Servet Zaragoza, University of Zaragoza, Spain; 3ISS Aragón. Psychology Department, University of Zaragoza, Spain; and
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4Integrated Research Center for Fetal Medicine, Department of Gynecology and
Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
are relevant to this article.
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Potential conflicts of interest: The authors have no conflicts of interest to disclose that
Funding: This work was funded by the Government of Aragon (2012-2014-B-87). The authors have no financial relationships to disclose that are relevant to this article. Presented in part at the 12th World Congress of Perinatal Medicine, Madrid, Spain,
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November 3-6, 2015
Address correspondence to: Victoria Pueyo, Hospital Universitario Miguel Servet, Isabel la Católica 1-3, 50006, Zaragoza, Spain, [email protected]. Phone:
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+34659050804
Words: Abstract 276 words. Main text: 2056 words.
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Figure 1 should be to appear in the print issue.
ACCEPTED MANUSCRIPT Condensation: An episode of threatened preterm labor should be considered a risk factor for neurodevelopmental deficits in early childhood
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Short title: Threatened preterm labor and impaired neurodevelopment
ACCEPTED MANUSCRIPT Abstract Background Threatened preterm labor is a leading cause of hospital admission during pregnancy. Patients presenting with an episode of threatened preterm labor who deliver at term are considered to have false preterm labor. However, threatened preterm labor has been
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proposed as a pathological insult that is not always sufficient to induce irreversible spontaneous 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
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risk factor of neurodevelopmental deficits of children at 2 years of age. Study Design
Two-year-old children born late preterm (n=22) or at term after threatened preterm
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labor (n=23) were compared with at-term control children (n=42). Neurodevelopment was evaluated at a corrected age of 24-29 months using the Merrill-Palmer-Revised Scales of Development. Results
Children born at term after threatened preterm labor had lower scores than control
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children on global cognitive index (95.4 vs. 104.2; p=0.011), cognition (95.1 vs. 103.1; p=0.021), fine motor (95.2 vs. 103.4; p=0.003), gross motor (84.7 vs. 99.8; p=0.001), memory (92.9 vs. 100.4; p=0.015), receptive language (93.9 vs. 102.9; p=0.03), speed of processing (105.7 vs. 113.3; p=0.011), and visual motor coordination (98.8 vs. 106.7;
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p=0.003) subtests. Children born at term after threatened preterm labor had an increased risk of mild neurodevelopmental delay compared with control children (odds ratio for global cognitive index=2.06; 95% confidence interval: 1.09, 3.88; p=0.033). There were
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no significant differences in any cognitive domain between children born late preterm and children 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: Threatened preterm labor, preterm birth, neurodevelopment Abbreviations: Confidence interval, CI; M-P-R, Merrill-Palmer-Revised Scales of Development; OR, odds ratio; standard deviation, SD.
ACCEPTED MANUSCRIPT Introduction Threatened preterm labor, which occurs in approximately 9% of all pregnancies, is the leading cause of hospital admission during pregnancy, excluding labor at term.1 Within this population of women, the incidence of preterm birth is 30-40%.2 Preterm
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birth is the final common result of a variety of etiologies with very different biological mechanisms,3 including intrauterine infection, uterine ischemia, uterine overdistension, abnormal allogenic recognition, allergic-like reaction, cervical disease, and endocrine
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disorders, some of which are related to poor neonatal outcomes.4,5 Although
neurobehavioral competencies in newborns are mainly related to neurological
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maturation,6,7 preliminary evidence suggests that poor outcomes among infants born late preterm or early term may not only be due to physiological immaturity but also to other biological determinants.8 Many studies show that late-preterm children are at increased risk of cognitive and behavioral problems at preschool age.9-14
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Previous reports suggest that at-term infants whose mothers experienced an episode of threatened preterm labor could be at increased risk for fetal growth restriction.15,16 However, randomized clinical trials assessing the effect of tocolysis have
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not shown differences in early childhood cognitive outcomes among at-term and late-
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preterm infants after threatened preterm labor.17 On this basis, it has been suggested that symptoms of threatened preterm labor may result from a pathological insult whose nature and/or severity is not sufficient to induce irreversible 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.
ACCEPTED MANUSCRIPT Materials and Methods
Subjects We conducted a prospective cohort study of children born late preterm (32-36 weeks) or at term (≥37 weeks) after threatened preterm labor between September 2011
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and May 2013 at a tertiary University Center. Congenital malformations, chromosomopathies, infections, multiple gestations, postnatal diagnosis of children with a severe disease, and delivery not in our medical center were excluded. This cohort was
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compared with a group of children born from singleton pregnancies at term (≥37 weeks) without threatened preterm labor, randomly sampled from our general obstetric
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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 registered by cardiotocography and ultrasound cervical length less
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than 25 mm19 in the presence of intact membranes at gestational age of 24+0 to 36+6 weeks. Pregnancies were dated according to first-trimester crown-rump length.20 Tocolysis with atosiban (Tractocile, Ferring Pharmaceuticals, Madrid, Spain) and
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intramuscular betamethasone (2×12 mg/24 h) was performed for some cases according to manufacturer recommendations and international clinical standards.21
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Maternal sociodemographic characteristics were recorded in the hospital
database at study inclusion. Information regarding pregnancy follow-up and standard perinatal outcomes was prospectively collected. Infants with a birth weight below the 10th percentile according to local standards were considered as small-for-gestational age. 22 Umbilical, uterine and middle cerebral artery Doppler was carried out in smallfor-gestational age fetuses in order to diagnosed intrauterine growth restriction.
ACCEPTED MANUSCRIPT Metabolic acidosis was defined as the presence of an umbilical artery pH below 7.10 and base excess greater than -12 mEq/l.23 Neurodevelopmental assessment Neurodevelopment was assessed at a corrected age of 24-29 months using the
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Merrill-Palmer-Revised Scales of Development (M-P-R; Roid & Sampers, 2004) 24, which assesses cognitive (verbal and nonverbal reasoning memory),
language/communication (receptive and expressive language, evaluated by examiner
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and parent), and motor (fine motor and gross motor) abilities. Especially useful in
assessing children born preterm, the M-P-R is a standardized measure of development
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used with children aged 1 month to 78 months which permits an early identification 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 individuals previously identified as developmentally delayed. It provides
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a global assessment with criterion-specific scores.24, 25 Two trained psychologists who were blind to group and perinatal outcomes conducted the assessment. Children were assessed in the afternoon in a quiet room in the presence of at least one parent. M-P-R
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subtest scores below one standard deviation were considered as mild neurodevelopmental delay. The main reason of missing during this period was the
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impossibility of contacting the patients because of the address and telephone changes. Statistical analysis
Normal distributions were assessed using the Kolmogorov-Smirnov test. Chi-
square tests and analysis of variance (ANOVA) were used to analyze categorical and continuous variables, respectively. Significant effects were followed by Bonferroni correction. Effect sizes were calculated using odds ratios (ORs) and 95% confidence intervals (CIs). Data are presented as mean±standard deviation (SD), median (range), or
ACCEPTED MANUSCRIPT number of subjects (%). Two-sided p-values <0.05 were considered statistically significant. Statistical analyses were performed using SPSS software (v. 20, SPSS Inc.,
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Chicago, IL, USA).
ACCEPTED MANUSCRIPT Results Of the 108 children who met the inclusion 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 gave birth to infants late preterm, and 23
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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
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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
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(p=0.02). As expected, late preterm infants had significantly lower birth weights and younger gestational ages at delivery and were more likely to be admitted to the neonatal unit (p<0.001). We found no differences in maternal educational level among the groups. The administration of corticosteroids for fetal lung maturation was performed
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for all infants born at term after threatened preterm labor, but it was performed for only 54.5% of infants born late preterm because labor could not be arrested or hospital admission for threatened preterm labor took place after 34 weeks of gestational age.
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Average scores on M-P-R subtests are shown in Table 2. There were significant effects of groups on all subtest scores, expect for expressive language score. The results
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of Bonferroni post-hoc tests are shown in Figure 1. Children who were born at term after threatened preterm labor scored significantly lower than children 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 preterm labor and children who were born late preterm.
ACCEPTED MANUSCRIPT Following standard methodology, the presence of mild neurodevelopmental delay was adjusted for gestational age at birth, birthweight, gender, cesarean section and maternal education (secondary education or higher) by logistic regression analysis. (Table 3) Children born at term after threatened preterm labor had a significantly
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increased risk of mild neurodevelopmental delay compared with children born at term for all cognitive domains except for cognition (p=0.071) and expressive language (p=0.91).
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As increased risk of cognitive deficits was observed for both children born late preterm and children born at term after threatened preterm labor, we analyzed M-P-R
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subtest scores according to treatment with antenatal corticosteroids to identify any potential bias. There were no statistically significant differences between groups in any cognitive domains (data not shown; p-values ranged from 0.46 to 0.90). Finally, the estimated power of this study, taking previously reported differences
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among groups in global cognitive index into account, was 0.96 as calculated by a one-
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way ANOVA pairwise two-sided equality test.
ACCEPTED MANUSCRIPT 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 born at term without threatened preterm labor, children born at term after threatened preterm labor
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scored significantly lower in all cognitive domains except for expressive language. They had an increased risk of mild neurodevelopmental delay. Moreover, the pattern of
developmental deficits in children born at term after threatened preterm labor was
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similar to that of children born late preterm.
The impact of late preterm birth on cognition is not fully characterized.
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Methodological issues, such as the correction of age by prematurity, may explain inconsistent results among different studies.10,26,27 However, healthy late-preterm infants seem to have greater risks of developmental delay, disability, and school-related problems throughout childhood.10,28,29 Even as early as 2 years of age, children born late
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preterm have more internalizing behavior problems and exhibit subtle deficits in cognition, fine and gross motor skills, and receptive and expressive communication.30,31 Consistent with these reports, we found poorer cognition, visual motor skills, fine and
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gross motor abilities, memory, receptive language, and speed of processing in both children born late preterm and those born at term after threatened preterm labor.
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Expressive language was the only cognitive domain that did not show group differences. This may be because verbal abilities are more heavily influenced by parental education and socioeconomic status compared with other cognitive domains.32 Symptoms of threatened preterm labor may result from a pathological insult whose nature and/or severity is not sufficient to induce irreversible spontaneous preterm birth but is enough to disturb pregnancy.15 In relation to this, some authors suggest that gestational age is a causal link between biological determinants of preterm birth and
ACCEPTED MANUSCRIPT neonatal outcomes.8 Biological determinants 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. 33,34 In addition, impaired placental function
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reduces delivery of oxygen and nutrients to the fetus.35 In line with this hypothesis,
women with an episode of increased uterine contractility requiring hospitalization who subsequently give birth at term are at an increased risk of having a small-for-gestational
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age infant.15,16 Although not statistically significant, we also found that 22% of infants born at term after threatened preterm labor were small-for-gestational age. This may be
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due to an adverse intrauterine environment associated with preterm labor, which could affect fetal growth and neurodevelopment. Moreover, several studies demonstrate that small-for-gestational age infants exhibit neurodevelopmental deficits.36-39 After threatened preterm labor, fetuses could be exposed to different noxious
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stimuli, but also to similar treatments that could also interfere with development. Antenatal corticosteroids reduce neonatal mortality and morbidity40, 41 and therefore are the basis of treatment for threatened preterm labor. On the other hand, antenatal use of
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corticosteroids may retard fetal growth and induce cognitive impairments, especially when administrated in multiple doses.42-44 However, a recent meta-analysis found no
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effect of antenatal corticosteroids on full, verbal, or performance IQ in the Wechsler Intelligence Scale for Children.45 So far, the concern regarding threatened preterm labor has focused on preventing
preterm birth, but threatened preterm labor might also be a risk factor for prenatal and postnatal adverse outcomes, suggesting the need for more surveillance. The neurodevelopment of children born at term after threatened preterm labor during the first 2 years of life has never been studied. Developmental screening in early childhood
ACCEPTED MANUSCRIPT may aid in identifying the first signs of developmental delay and initiating rehabilitative programs. Further studies are also needed to discover clinical or biological markers for identifying high-risk infants. The main strength of our study is that no previous studies have examined the
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effect of threatened preterm labor on neurodevelopment; therefore, this is the first study to show an association between threatened preterm labor and suboptimal
neurodevelopment. Other strength of our study is the use of a global standardized
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assessment to evaluate cognition, which aids in the targeting of specific educational interventions. However, our study also has some limitations. First, our study was
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performed in a clinic setting on a single occasion; therefore, the full capabilities of a child may not have been well represented compared with a home setting, particularly in domains related to language. A more exhaustive follow-up of these children is important for better characterization. Second, the design of our study did not allow us to
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examine whether biological determinants, the higher percentage of small-for-gestational age infants, or treatment with antenatal corticosteroids was the main cause of cognitive deficits. Future research is required to confirm these findings in larger cohorts of
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children and to analyze the impact of each factor related to preterm labor on neurodevelopment.
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Conclusion
In conclusion, we propose that an episode of threatened preterm labor should be
considered a risk factor for neurodevelopmental deficits in early childhood. We consider that “false preterm labor” is not always a benign condition.
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Table 1. Demographic and clinical characteristics and perinatal outcomes. Born late
Born at term after
preterm
threatened preterm
Born at term
p value
labor
Caucasian ethnicity (%)
31 (5.3)
30.6 (5.0)
32.1 (5.5)
0.49
24.2 (3.5)
21.9 (3.2)
23.6 (3.4)
0.10
18 (82)
22 (96)
37 (88)
0.35
Maternal educational level (%) 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 (%)
11 (50)
14 (65)
0.52
Previous preterm birth (%)
5 (24)
3 (13)
0
0.02
0.56
0
0
2 (5)
0.30
Cesarean delivery (%)
1 (5)
6 (26)
6 (14)
0.13
2 (9)
3 (13)
9 (21)
0.40
17 (77)
21 (91)
38 (91)
0.26
246.6 (8.5)
276.8 (7.7)
278.2 (8.4)
<0.001
2463 (457)
3131 (402)
3336 (400)
<0.001
10 (46)
13 (57)
18 (43)
0.56
2 (9)
5 (22)
3 (7)
0.21
12 (55)
23 (100)
0
<0.001
0
1 (4)
1 (2)
0.62
Neonatal unit admission (%)
11 (50)
1 (5)
2 (5)
<0.001
Breastfeeding (%)
21 (95)
22 (96)
36 (86)
0.28
26.4 (1.2)
26.0 (2.2)
26.1 (1.3)
0.61
Operative vaginal delivery (%) Spinal anesthesia (%)
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22 (53)
Pre-eclampsia (%)
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None
n=42
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Maternal body mass index (kg/m2)
n=23
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Maternal age (years)
n=22
Birth weight (g) Male (%)
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Gestational age at delivery (days)
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Small for gestational age (%)
Antenatal corticosteroid treatment (%) Metabolic acidosis (%)
Age at assessment (months)
Data are shown as number of subjects (%) or mean (SD).
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p value
n=23
Age at evaluation (months)
26.4 (1.25)
25.9 (2.21)
26.1 (1.34)
0.610
Global cognitive index
93.9 (12.3)
95.4 (12.2)
104 (13.4)
0.001
Cognition
94.0 (11.2)
95.1 (11.5)
103 (10.7)
0.003
Fine motor
93.9 (8.97)
95.2 (10.1)
103 (8.92)
<0.001
Gross motor
91.0 (15.4)
84.7 (18.0)
99.8 (12.8)
0.001
Memory
91.4 (9.73)
92.9 (11.6)
100 (9.29)
0.001
Receptive language
91.5 (14.8)
93.9 (13.7)
103 (11.7)
0.002
90.6 (14.6)
95.6 (14.7)
94.4 (13.8)
0.470
104 (11.9)
106 (11.5)
113 (6.85)
<0.001
98.4 (8.53)
98.8 (8.77)
107 (9.21)
<0.001
Visual motor
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Speed of processing
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Expressive language
n=42
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n=22
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Table 2. Cognitive neurodevelopment as assessed by the M-P-R: ANOVA results. Born late Born at term after Born at term preterm threatened preterm labor
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Data are shown as mean (SD). ANOVA, analysis of variance; M-P-R, Merrill-PalmerRevised Scales of Development.
ACCEPTED MANUSCRIPT Table 3. Risk of mild development delay due to threatened preterm labor, adjusted for confounding variables.
Born at term
Global cognitive index (%)
47.8
14.6
Cognition (%)
43.5
22.0
Fine motor (%)
60.9
26.8
Gross motor (%)
56.6
22.5
Memory (%)
56.5
Receptive language (%)
43.5
Expressive language (%)
22.7
Speed of processing (%)
p value
1.09 - 3.88
0.004
1.60
0.86 - 2.97
0.071
2.10
1.16 - 3.81
0.007
1.98
1.09 - 3.60
0.006
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2.06
1.84
1.02 - 3.29
0.019
14.6
1.92
1.02 -3.66
0.011
21.4
1.19
0.60 - 2.23
0.910
43.5
17.1
1.93
1.03 –3.60
0.022
52.2
12.2
2.65
1.36 - 5.27
0.001
Data are shown as number of subjects (%) OR, odds ratio; CI, confidence interval.
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95% CI
26.8
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Visual motor (%)
n=42
OR
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Born at term after threatened preterm labor n=23
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Figure 1. Cognitive neurodevelopment as assessed by the M-P-R: results of Bonferroni correction. Data are shown as mean.
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ACCEPTED MANUSCRIPT Contributors’ Statements: Dr. Paules designed the data collection instruments, coordinated and supervised data collection, carried out the statistical analyses, drafted the initial manuscript, and approved the final manuscript as submitted.
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Ms. Martí and Ms. Vilchez performed the cognitive evaluations, reviewed the manuscript, and approved the final manuscript as submitted. Dr. Oros and Dr. Pueyo designed the study, supervised data collection, carried out the statistical analyses, reviewed and revised the manuscript, and approved the final manuscript as submitted.
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Dr. Calvo designed the data collection instruments, supervised data collection, carried out the statistical analyses, reviewed manuscript, and approved the final manuscript as submitted.
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Dr. Burd designed the study, carried out the statistical analyses, reviewed and revised the manuscript, and approved the final manuscript as submitted.
S0002-9378(16)30917-6
DOI:
10.1016/j.ajog.2016.10.022
Reference:
YMOB 11352
To appear in:
American Journal of Obstetrics and Gynecology
Received Date: 11 June 2016 Revised Date:
21 September 2016
Accepted Date: 17 October 2016
Please cite this article as: Paules C, Pueyo V, Martí E, Vilchez S, Burd I, Calvo P, Oros D, Threatened preterm labor is a risk factor for impaired cognitive development in early childhood, American Journal of Obstetrics and Gynecology (2016), doi: 10.1016/j.ajog.2016.10.022. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Threatened preterm labor is a risk factor for impaired cognitive development in early childhood Paules, Cristina MD1; Pueyo, Victoria MD, PhD2; Martí, Elena3; Vilchez, Susana3; Burd, Irina MD, PhD4; Calvo, Pilar MD1 and Oros, Daniel MD, PhD1
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Affiliations: 1ISS Aragón, Obstetrics Department, Hospital Clínico Universitario Lozano Blesa, Zaragoza, University of Zaragoza, Spain; 2ISS Aragón, Ophthalmology Department, Hospital Universitario Miguel Servet Zaragoza, University of Zaragoza, Spain; 3ISS Aragón. Psychology Department, University of Zaragoza, Spain; and
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4Integrated Research Center for Fetal Medicine, Department of Gynecology and
Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
are relevant to this article.
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Potential conflicts of interest: The authors have no conflicts of interest to disclose that
Funding: This work was funded by the Government of Aragon (2012-2014-B-87). The authors have no financial relationships to disclose that are relevant to this article. Presented in part at the 12th World Congress of Perinatal Medicine, Madrid, Spain,
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November 3-6, 2015
Address correspondence to: Victoria Pueyo, Hospital Universitario Miguel Servet, Isabel la Católica 1-3, 50006, Zaragoza, Spain, [email protected]. Phone:
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+34659050804
Words: Abstract 276 words. Main text: 2056 words.
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Figure 1 should be to appear in the print issue.
ACCEPTED MANUSCRIPT Condensation: An episode of threatened preterm labor should be considered a risk factor for neurodevelopmental deficits in early childhood
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Short title: Threatened preterm labor and impaired neurodevelopment
ACCEPTED MANUSCRIPT Abstract Background Threatened preterm labor is a leading cause of hospital admission during pregnancy. Patients presenting with an episode of threatened preterm labor who deliver at term are considered to have false preterm labor. However, threatened preterm labor has been
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proposed as a pathological insult that is not always sufficient to induce irreversible spontaneous 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
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risk factor of neurodevelopmental deficits of children at 2 years of age. Study Design
Two-year-old children born late preterm (n=22) or at term after threatened preterm
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labor (n=23) were compared with at-term control children (n=42). Neurodevelopment was evaluated at a corrected age of 24-29 months using the Merrill-Palmer-Revised Scales of Development. Results
Children born at term after threatened preterm labor had lower scores than control
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children on global cognitive index (95.4 vs. 104.2; p=0.011), cognition (95.1 vs. 103.1; p=0.021), fine motor (95.2 vs. 103.4; p=0.003), gross motor (84.7 vs. 99.8; p=0.001), memory (92.9 vs. 100.4; p=0.015), receptive language (93.9 vs. 102.9; p=0.03), speed of processing (105.7 vs. 113.3; p=0.011), and visual motor coordination (98.8 vs. 106.7;
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p=0.003) subtests. Children born at term after threatened preterm labor had an increased risk of mild neurodevelopmental delay compared with control children (odds ratio for global cognitive index=2.06; 95% confidence interval: 1.09, 3.88; p=0.033). There were
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no significant differences in any cognitive domain between children born late preterm and children 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: Threatened preterm labor, preterm birth, neurodevelopment Abbreviations: Confidence interval, CI; M-P-R, Merrill-Palmer-Revised Scales of Development; OR, odds ratio; standard deviation, SD.
ACCEPTED MANUSCRIPT Introduction Threatened preterm labor, which occurs in approximately 9% of all pregnancies, is the leading cause of hospital admission during pregnancy, excluding labor at term.1 Within this population of women, the incidence of preterm birth is 30-40%.2 Preterm
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birth is the final common result of a variety of etiologies with very different biological mechanisms,3 including intrauterine infection, uterine ischemia, uterine overdistension, abnormal allogenic recognition, allergic-like reaction, cervical disease, and endocrine
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disorders, some of which are related to poor neonatal outcomes.4,5 Although
neurobehavioral competencies in newborns are mainly related to neurological
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maturation,6,7 preliminary evidence suggests that poor outcomes among infants born late preterm or early term may not only be due to physiological immaturity but also to other biological determinants.8 Many studies show that late-preterm children are at increased risk of cognitive and behavioral problems at preschool age.9-14
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Previous reports suggest that at-term infants whose mothers experienced an episode of threatened preterm labor could be at increased risk for fetal growth restriction.15,16 However, randomized clinical trials assessing the effect of tocolysis have
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not shown differences in early childhood cognitive outcomes among at-term and late-
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preterm infants after threatened preterm labor.17 On this basis, it has been suggested that symptoms of threatened preterm labor may result from a pathological insult whose nature and/or severity is not sufficient to induce irreversible 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.
ACCEPTED MANUSCRIPT Materials and Methods
Subjects We conducted a prospective cohort study of children born late preterm (32-36 weeks) or at term (≥37 weeks) after threatened preterm labor between September 2011
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and May 2013 at a tertiary University Center. Congenital malformations, chromosomopathies, infections, multiple gestations, postnatal diagnosis of children with a severe disease, and delivery not in our medical center were excluded. This cohort was
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compared with a group of children born from singleton pregnancies at term (≥37 weeks) without threatened preterm labor, randomly sampled from our general obstetric
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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 registered by cardiotocography and ultrasound cervical length less
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than 25 mm19 in the presence of intact membranes at gestational age of 24+0 to 36+6 weeks. Pregnancies were dated according to first-trimester crown-rump length.20 Tocolysis with atosiban (Tractocile, Ferring Pharmaceuticals, Madrid, Spain) and
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intramuscular betamethasone (2×12 mg/24 h) was performed for some cases according to manufacturer recommendations and international clinical standards.21
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Maternal sociodemographic characteristics were recorded in the hospital
database at study inclusion. Information regarding pregnancy follow-up and standard perinatal outcomes was prospectively collected. Infants with a birth weight below the 10th percentile according to local standards were considered as small-for-gestational age. 22 Umbilical, uterine and middle cerebral artery Doppler was carried out in smallfor-gestational age fetuses in order to diagnosed intrauterine growth restriction.
ACCEPTED MANUSCRIPT Metabolic acidosis was defined as the presence of an umbilical artery pH below 7.10 and base excess greater than -12 mEq/l.23 Neurodevelopmental assessment Neurodevelopment was assessed at a corrected age of 24-29 months using the
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Merrill-Palmer-Revised Scales of Development (M-P-R; Roid & Sampers, 2004) 24, which assesses cognitive (verbal and nonverbal reasoning memory),
language/communication (receptive and expressive language, evaluated by examiner
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and parent), and motor (fine motor and gross motor) abilities. Especially useful in
assessing children born preterm, the M-P-R is a standardized measure of development
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used with children aged 1 month to 78 months which permits an early identification 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 individuals previously identified as developmentally delayed. It provides
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a global assessment with criterion-specific scores.24, 25 Two trained psychologists who were blind to group and perinatal outcomes conducted the assessment. Children were assessed in the afternoon in a quiet room in the presence of at least one parent. M-P-R
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subtest scores below one standard deviation were considered as mild neurodevelopmental delay. The main reason of missing during this period was the
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impossibility of contacting the patients because of the address and telephone changes. Statistical analysis
Normal distributions were assessed using the Kolmogorov-Smirnov test. Chi-
square tests and analysis of variance (ANOVA) were used to analyze categorical and continuous variables, respectively. Significant effects were followed by Bonferroni correction. Effect sizes were calculated using odds ratios (ORs) and 95% confidence intervals (CIs). Data are presented as mean±standard deviation (SD), median (range), or
ACCEPTED MANUSCRIPT number of subjects (%). Two-sided p-values <0.05 were considered statistically significant. Statistical analyses were performed using SPSS software (v. 20, SPSS Inc.,
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Chicago, IL, USA).
ACCEPTED MANUSCRIPT Results Of the 108 children who met the inclusion 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 gave birth to infants late preterm, and 23
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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
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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
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(p=0.02). As expected, late preterm infants had significantly lower birth weights and younger gestational ages at delivery and were more likely to be admitted to the neonatal unit (p<0.001). We found no differences in maternal educational level among the groups. The administration of corticosteroids for fetal lung maturation was performed
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for all infants born at term after threatened preterm labor, but it was performed for only 54.5% of infants born late preterm because labor could not be arrested or hospital admission for threatened preterm labor took place after 34 weeks of gestational age.
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Average scores on M-P-R subtests are shown in Table 2. There were significant effects of groups on all subtest scores, expect for expressive language score. The results
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of Bonferroni post-hoc tests are shown in Figure 1. Children who were born at term after threatened preterm labor scored significantly lower than children 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 preterm labor and children who were born late preterm.
ACCEPTED MANUSCRIPT Following standard methodology, the presence of mild neurodevelopmental delay was adjusted for gestational age at birth, birthweight, gender, cesarean section and maternal education (secondary education or higher) by logistic regression analysis. (Table 3) Children born at term after threatened preterm labor had a significantly
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increased risk of mild neurodevelopmental delay compared with children born at term for all cognitive domains except for cognition (p=0.071) and expressive language (p=0.91).
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As increased risk of cognitive deficits was observed for both children born late preterm and children born at term after threatened preterm labor, we analyzed M-P-R
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subtest scores according to treatment with antenatal corticosteroids to identify any potential bias. There were no statistically significant differences between groups in any cognitive domains (data not shown; p-values ranged from 0.46 to 0.90). Finally, the estimated power of this study, taking previously reported differences
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among groups in global cognitive index into account, was 0.96 as calculated by a one-
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way ANOVA pairwise two-sided equality test.
ACCEPTED MANUSCRIPT 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 born at term without threatened preterm labor, children born at term after threatened preterm labor
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scored significantly lower in all cognitive domains except for expressive language. They had an increased risk of mild neurodevelopmental delay. Moreover, the pattern of
developmental deficits in children born at term after threatened preterm labor was
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similar to that of children born late preterm.
The impact of late preterm birth on cognition is not fully characterized.
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Methodological issues, such as the correction of age by prematurity, may explain inconsistent results among different studies.10,26,27 However, healthy late-preterm infants seem to have greater risks of developmental delay, disability, and school-related problems throughout childhood.10,28,29 Even as early as 2 years of age, children born late
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preterm have more internalizing behavior problems and exhibit subtle deficits in cognition, fine and gross motor skills, and receptive and expressive communication.30,31 Consistent with these reports, we found poorer cognition, visual motor skills, fine and
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gross motor abilities, memory, receptive language, and speed of processing in both children born late preterm and those born at term after threatened preterm labor.
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Expressive language was the only cognitive domain that did not show group differences. This may be because verbal abilities are more heavily influenced by parental education and socioeconomic status compared with other cognitive domains.32 Symptoms of threatened preterm labor may result from a pathological insult whose nature and/or severity is not sufficient to induce irreversible spontaneous preterm birth but is enough to disturb pregnancy.15 In relation to this, some authors suggest that gestational age is a causal link between biological determinants of preterm birth and
ACCEPTED MANUSCRIPT neonatal outcomes.8 Biological determinants 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. 33,34 In addition, impaired placental function
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reduces delivery of oxygen and nutrients to the fetus.35 In line with this hypothesis,
women with an episode of increased uterine contractility requiring hospitalization who subsequently give birth at term are at an increased risk of having a small-for-gestational
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age infant.15,16 Although not statistically significant, we also found that 22% of infants born at term after threatened preterm labor were small-for-gestational age. This may be
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due to an adverse intrauterine environment associated with preterm labor, which could affect fetal growth and neurodevelopment. Moreover, several studies demonstrate that small-for-gestational age infants exhibit neurodevelopmental deficits.36-39 After threatened preterm labor, fetuses could be exposed to different noxious
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stimuli, but also to similar treatments that could also interfere with development. Antenatal corticosteroids reduce neonatal mortality and morbidity40, 41 and therefore are the basis of treatment for threatened preterm labor. On the other hand, antenatal use of
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corticosteroids may retard fetal growth and induce cognitive impairments, especially when administrated in multiple doses.42-44 However, a recent meta-analysis found no
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effect of antenatal corticosteroids on full, verbal, or performance IQ in the Wechsler Intelligence Scale for Children.45 So far, the concern regarding threatened preterm labor has focused on preventing
preterm birth, but threatened preterm labor might also be a risk factor for prenatal and postnatal adverse outcomes, suggesting the need for more surveillance. The neurodevelopment of children born at term after threatened preterm labor during the first 2 years of life has never been studied. Developmental screening in early childhood
ACCEPTED MANUSCRIPT may aid in identifying the first signs of developmental delay and initiating rehabilitative programs. Further studies are also needed to discover clinical or biological markers for identifying high-risk infants. The main strength of our study is that no previous studies have examined the
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effect of threatened preterm labor on neurodevelopment; therefore, this is the first study to show an association between threatened preterm labor and suboptimal
neurodevelopment. Other strength of our study is the use of a global standardized
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assessment to evaluate cognition, which aids in the targeting of specific educational interventions. However, our study also has some limitations. First, our study was
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performed in a clinic setting on a single occasion; therefore, the full capabilities of a child may not have been well represented compared with a home setting, particularly in domains related to language. A more exhaustive follow-up of these children is important for better characterization. Second, the design of our study did not allow us to
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examine whether biological determinants, the higher percentage of small-for-gestational age infants, or treatment with antenatal corticosteroids was the main cause of cognitive deficits. Future research is required to confirm these findings in larger cohorts of
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children and to analyze the impact of each factor related to preterm labor on neurodevelopment.
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Conclusion
In conclusion, we propose that an episode of threatened preterm labor should be
considered a risk factor for neurodevelopmental deficits in early childhood. We consider that “false preterm labor” is not always a benign condition.
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G. Neurodevelopmental outcome after a single course of antenatal steroids in children born preterm. A systematic review and meta-analysis. Obs Gynecol. 2015;125:1385-1396.
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Table 1. Demographic and clinical characteristics and perinatal outcomes. Born late
Born at term after
preterm
threatened preterm
Born at term
p value
labor
Caucasian ethnicity (%)
31 (5.3)
30.6 (5.0)
32.1 (5.5)
0.49
24.2 (3.5)
21.9 (3.2)
23.6 (3.4)
0.10
18 (82)
22 (96)
37 (88)
0.35
Maternal educational level (%) 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 (%)
11 (50)
14 (65)
0.52
Previous preterm birth (%)
5 (24)
3 (13)
0
0.02
0.56
0
0
2 (5)
0.30
Cesarean delivery (%)
1 (5)
6 (26)
6 (14)
0.13
2 (9)
3 (13)
9 (21)
0.40
17 (77)
21 (91)
38 (91)
0.26
246.6 (8.5)
276.8 (7.7)
278.2 (8.4)
<0.001
2463 (457)
3131 (402)
3336 (400)
<0.001
10 (46)
13 (57)
18 (43)
0.56
2 (9)
5 (22)
3 (7)
0.21
12 (55)
23 (100)
0
<0.001
0
1 (4)
1 (2)
0.62
Neonatal unit admission (%)
11 (50)
1 (5)
2 (5)
<0.001
Breastfeeding (%)
21 (95)
22 (96)
36 (86)
0.28
26.4 (1.2)
26.0 (2.2)
26.1 (1.3)
0.61
Operative vaginal delivery (%) Spinal anesthesia (%)
TE D
22 (53)
Pre-eclampsia (%)
M AN U
None
n=42
RI PT
Maternal body mass index (kg/m2)
n=23
SC
Maternal age (years)
n=22
Birth weight (g) Male (%)
EP
Gestational age at delivery (days)
AC C
Small for gestational age (%)
Antenatal corticosteroid treatment (%) Metabolic acidosis (%)
Age at assessment (months)
Data are shown as number of subjects (%) or mean (SD).
ACCEPTED MANUSCRIPT
p value
n=23
Age at evaluation (months)
26.4 (1.25)
25.9 (2.21)
26.1 (1.34)
0.610
Global cognitive index
93.9 (12.3)
95.4 (12.2)
104 (13.4)
0.001
Cognition
94.0 (11.2)
95.1 (11.5)
103 (10.7)
0.003
Fine motor
93.9 (8.97)
95.2 (10.1)
103 (8.92)
<0.001
Gross motor
91.0 (15.4)
84.7 (18.0)
99.8 (12.8)
0.001
Memory
91.4 (9.73)
92.9 (11.6)
100 (9.29)
0.001
Receptive language
91.5 (14.8)
93.9 (13.7)
103 (11.7)
0.002
90.6 (14.6)
95.6 (14.7)
94.4 (13.8)
0.470
104 (11.9)
106 (11.5)
113 (6.85)
<0.001
98.4 (8.53)
98.8 (8.77)
107 (9.21)
<0.001
Visual motor
M AN U
EP
Speed of processing
TE D
Expressive language
n=42
RI PT
n=22
SC
Table 2. Cognitive neurodevelopment as assessed by the M-P-R: ANOVA results. Born late Born at term after Born at term preterm threatened preterm labor
AC C
Data are shown as mean (SD). ANOVA, analysis of variance; M-P-R, Merrill-PalmerRevised Scales of Development.
ACCEPTED MANUSCRIPT Table 3. Risk of mild development delay due to threatened preterm labor, adjusted for confounding variables.
Born at term
Global cognitive index (%)
47.8
14.6
Cognition (%)
43.5
22.0
Fine motor (%)
60.9
26.8
Gross motor (%)
56.6
22.5
Memory (%)
56.5
Receptive language (%)
43.5
Expressive language (%)
22.7
Speed of processing (%)
p value
1.09 - 3.88
0.004
1.60
0.86 - 2.97
0.071
2.10
1.16 - 3.81
0.007
1.98
1.09 - 3.60
0.006
M AN U
SC
2.06
1.84
1.02 - 3.29
0.019
14.6
1.92
1.02 -3.66
0.011
21.4
1.19
0.60 - 2.23
0.910
43.5
17.1
1.93
1.03 –3.60
0.022
52.2
12.2
2.65
1.36 - 5.27
0.001
Data are shown as number of subjects (%) OR, odds ratio; CI, confidence interval.
AC C
95% CI
26.8
TE D
EP
Visual motor (%)
n=42
OR
RI PT
Born at term after threatened preterm labor n=23
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Figure 1. Cognitive neurodevelopment as assessed by the M-P-R: results of Bonferroni correction. Data are shown as mean.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT Contributors’ Statements: Dr. Paules designed the data collection instruments, coordinated and supervised data collection, carried out the statistical analyses, drafted the initial manuscript, and approved the final manuscript as submitted.
RI PT
Ms. Martí and Ms. Vilchez performed the cognitive evaluations, reviewed the manuscript, and approved the final manuscript as submitted. Dr. Oros and Dr. Pueyo designed the study, supervised data collection, carried out the statistical analyses, reviewed and revised the manuscript, and approved the final manuscript as submitted.
SC
Dr. Calvo designed the data collection instruments, supervised data collection, carried out the statistical analyses, reviewed manuscript, and approved the final manuscript as submitted.
AC C
EP
TE D
M AN U
Dr. Burd designed the study, carried out the statistical analyses, reviewed and revised the manuscript, and approved the final manuscript as submitted.