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Association of preterm birth and intrauterine growth restriction with childhood motor development: Brisa cohort, brazil
Infant Behavior and Development 58 (2020) 101429
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Association of preterm birth and intrauterine growth restriction with childhood motor development: Brisa cohort, brazil
T
Paulo Ricardo H. Rochaa,*, Maria da C.P. Saraivab, Marco A. Barbieria, Alexandre A. Ferraroc, Heloisa Bettiola a
Department of Puericulture and Pediatrics, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil Department of Pediatric Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil c Department of Pediatrics, Faculty of Medicine, University of Sao Paulo, SP, Brazil b
A R T IC LE I N F O
ABS TRA CT
Keywords: Motor skills Cohort studies Risk factors Prematurity Intrauterine growth restriction
The present study investigated the association between preterm birth PT conditions, intrauterine growth restriction IUGR and the combination of both PT-IUGR with infant motor development. A cohort with 1006 children was monitored during prenatal, at birth, and two years of age. BayleyIII screening was used to evaluate of fine and gross motor skills. The data did not indicate an increased risk for motor delays in the PT or IUGR, composed mainly by mild cases. However, the combination of the conditions PT-IUGR increased the risk of delays in motor, which emphasizes the importance of monitoring the motor development of the group.
1. Introduction During childhood, motor development emerges in a sequential, cumulative and continuous manner within an expected time “window”. Therefore, marked delays in the acquisition of motor skills often indicate losses of the mechanisms and structures underlying development, in addition to being associated with morbidities and behavioral difficulties throughout life (Ghassabian et al., 2016; Haga, 2008; Linke et al., 2018). Although different factors are associated with childhood motor delays (Golding, Emmett, IlesCaven, Steer, & Lingam, 2014), several studies have reported that adverse conditions present as early as the prenatal period and at birth, such as preterm birth (PT) and intrauterine growth restriction (IUGR), may act significatively on the course of motor development (Kieviet, Piek, Aarnoudse-Moens, & Oosterlaan, 2009; Levine et al., 2015). PT birth (< 37 weeks of gestation) and IUGR (fetal growth below the genetic potential) are associated with increased risks of complications and perinatal mortality (Blencowe et al., 2012; Cosmi, Fanelli, Visentin, Trevisanuto, & Zanardo, 2011), and important neurological and cognitive changes (Kieviet, Zoetebier, van Elburg, Vermeulen, & Oosterlaan, 2012; Murray et al., 2015; Spinillo et al., 2009). Although often related, PT birth and IUGR are independent conditions caused by different factors that may affect childhood development differently. Some studies have pointed out that prematurity, more than IUGR, may be associated with the risks of delayed neurodevelopmental parameters (Gortner et al., 2003; Procianoy, Koch, & Silveira, 2007). However, there is evidence that the interaction between PT birth and IUGR (PT-IUGR) maximizes the risks of losses in different neurophysiological and
Abbreviations: T-NIUGR, term non-restricted; T-IUGR, term + intrauterine growth restriction; PT-NIUGR, preterm + non-restricted; PT-IUGR, preterm + intrauterine growth restriction ⁎ Corresponding author at: Departamento de Pediatria, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes, 3900, Monte Alegre, Ribeirão Preto, SP, 14049-900, Brazil. E-mail address: [email protected] (P.R.H. Rocha). https://doi.org/10.1016/j.infbeh.2020.101429 Received 1 May 2019; Received in revised form 14 February 2020; Accepted 15 February 2020 0163-6383/ © 2020 Published by Elsevier Inc.
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behavioral aspects (El Ayoubi et al., 2016; Esteban et al., 2010; Lodygensky et al., 2008). Regarding motor development, the few studies that investigated fine and gross motor skills in PT-IUGR infants observed difficulties only in the performance of fine motor tasks (El Ayoubi et al., 2016; Esteban et al., 2010; Padilla et al., 2011). This effect could indicate that these children may present characteristics of restrictions that could lead to atypical development in tasks that demand control of small muscle groups and sensorimotor integration, but not in organizational tasks or in coordination of large muscle groups that characterize gross motor skills (Krampe, 2002; Piek, Dawson, Smith, & Gasson, 2008). However, although some studies have indicated a connection between PT birth and/or IUGR with delayed motor development, the results are still inconclusive and often controversial (Bassan et al., 2011; de Jong, Verhoeven, Lasham, Meijssen, & van Baar, 2015; Gortner et al., 2003). In general, factors such as reduced sample size, the use of motor constructs that do not differentiate between the types of motor skills and the heterogeneity in the ways different researchers controlled for confounding variables contribute to the discordant results (Esteban et al., 2010; Kieviet et al., 2009; Levine et al., 2015). Furthermore, studies investigating the association of PT-IUGR with behavioral measures often do not include in their analysis infants born with only one of the two adverse conditions (PT or IUGR) or born without these adversities.This fact impairs the identification of the condition (PT or IUGR) that would significantly affect the occurrence of behavioral losses (Levine et al., 2015). Since motor developmental delay among PT, IUGR and PT-IUGR infants is still controversial, the objective of this study was to investigate the association of these birth conditions with the development of fine and gross motor skills. 2. Method 2.1. Participants The data of the present study are part of a cohort investigation entitled: “Etiological factors of preterm birth and consequences of perinatal factors for infant health: birth cohorts in two Brazilian cities, Ribeirão Preto and São Luís – BRISA” (Da Silva et al., 2014). For this study, we analyzed the data for the Ribeirão Preto prenatal cohort. The city is in the state of São Paulo, Southeastern Brazil. The first evaluation phase of the prenatal cohort took place between February 2010 and February 2011. A comvenience sample was used due to the impossibility of obtaining a representative random sample of pregnant women from the population, since there was a lack of records for pregnant women or women receiving prenatal care. Therefore, pregnant women were identified in hospitals and in health units on the occasion of a prenatal visit attended up to the 5th month of gestation. Women with singleton pregnancies who had undergone an obstetrical ultrasound during the first three months of gestation were invited to participate. The prenatal Ribeirão Preto cohort included 1400 pregnant women evaluated between 22 and 25 weeks of gestation. A previously trained team colleted data on reproductive health, demographic and socioeconomic status, characteristics of the pregnancy, and life habits of the participants. Data were collected at the Clinical Research Unit of the University Hospital, Faculty of Medicine of Ribeirão Preto, University of São Paulo (HCFMRP-USP). A total of 1369 mothers were reevaluated at childbirth. Excluding one case of abortion, 97.8 % of the eligible women from the initial cohort participated in this stage. From April 2010 to July 2011, teams of trained collaborators visited daily the maternities in the city in order to locate and interview the mothers, collecting information about mothers and their newborn babies with the use of a standardized questionnaire. Anthropometric newborn baby data, such as weight and length, were also obtained from the medical records. The field team was trained to perform data collection at the maternities, and all the employees of the maternities responsible for newborn baby anthropometry were trained before the beginning of the study. All equipment was calibrated periodically. In the beginning of the second year of the infant’s life, mothers and children underwent a new evaluation. The development of each baby was evaluated individually at the HCFMRP-USP using a standardized questionnaire administered to the mothers by a trained team. Six stillbirths and seven deaths during the first year of life were identified. Thus, 1356 participants were eligible for evaluation during the second follow-up period, with 1080 mother-child pairs participating in these evaluations. Specifically in this study, 74 participants were excluded for not performing the evaluation of motor development, resulting in 1006 infants, 74.2 % of the eligible babies. The age and economic class of the mothers were the only difference between completers and dropouts. The dropouts were younger and from lower economic classes than the completers (Supplementary material A.1). None of the babies from the follow-up showed congenital or acquired health problems that would justify exclusion from the study. The study was approved by the Research Ethics Committee of HCFMRP-USP (protocol 2.790.415) and all participants gave written informed consent to participate. 2.2. Birth status IUGR was determined on the basis of birth weight ratio, which is the ratio between the child’s birth weight and the mean weight for sex and gestational age (Kramer, Platt, Yang, McNamara, & Usher, 1999) according to the curve of the International Fetal and Newborn Growth Consortium for the 21 st Century (Villar et al., 2014). For the current study, a birth weight ratio < 0.85 was defined as IUGR and a birth weight ratio > 0.85 non-restricted intrauterine growth (NIUGR) (Kramer et al., 1999; Silveira et al., 2018). A gestational age < 37 weeks at birth was defined as PT, while > 37 week was considered to be term (T). Gestational age was calculated using the last date of menstruation provided by the mother during the prenatal interview and the earliest ultrasound date, available in her medical records or in her prenatal care card. When this information was compatible, assuming a + 7% error for ultrasound, gestational age was calculated by considering the duration of amenorrhea; if incompatible, only the ultrasound information was considered. The assumed gestational age was adjusted for the date of delivery, providing the definitive age (Verburg 2
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et al., 2008). Four groups were formed: T-NIUGR (term non-restricted), T-IUGR (term + intrauterine growth restriction), PT-NIUGR (preterm + non-restricted), and PT-IUGR (preterm + intrauterine growth restriction) in order to study the association between PT and/or IUGR on infant motor development. 2.3. Measures The development of motor skills was assessed using the fine and gross motor subscales of the Bayley Scales of Infant and Toddler Development Third Edition - screening - Bayley-III screening (Bayley, 2006). The infants were evaluated within the 13 to 30-month age range during cohort follow-up. The scale enabled us to determine whether development was progressing according to normal expectations or if a more in-depth evaluation is necessary. For evaluation, children born < 37 weeks had their age corrected, subtracting from the chronological age of follow-up the number of weeks until the gestational age of 40 weeks. According to the test guidelines, the age correction was not performed for the preterm children assessed after two full years. Bayley-III screening provides the classification of performance on the motor subscales according to the cut-off point for age, defined as Competent, Emergent and Risk. In this screening, Emergent and Risk classifications are equivalent to two standard deviations under average (standard score of 70). Thus, in the present study, the classifications were analyzed dichotomously as Competent and Emergent/Risk. 2.4. Confounding variables The minimum adjustment necessary for the confounding variables was determined by constructing a directed acyclic graph using the DAGitty software version 2.3 (Supplementary material A.2). Based on the directed acyclic graph, the following maternal variables from the prenatal phase were considered as potential confounders: hypertension (Yes or No), diabetes (Yes or No), use of alcohol and/ or tobacco during pregnancy regardless of quantity (Does not use, Uses alcohol or tobacco and Uses alcohol and tabacco), level of physical activity (Craig et al., 2003) (high, moderate and low/no activity), maternal schooling as years of study (> 12, 9–11 and ≤ 8 years), maternal age (< 20 years, 20–34 years and > 34 years) and economic class according to the Brazil Criterion of Economic Classification of the Brazilian Association of Research Companies (Associação Brasileira de Empresas de Pesquisa [ABEP], 2008) (AB, C and DE, with AB being the most priviledged an DE the least privileged). From the information obtained at birth, only sex was considered for adjustment of the analytical model. 2.5. Statistical analysis Data were analyzed statistically using the Stata package version 14 (College Station, Texas, USA). The differences in characteristics (T-NIUGR; T-IUGR; PT-NIUGR and PT-IUGR) were determined by the Chi-Square test. Group comparison regarding the fine and gross motor subscales classification was based on the Chi-Square test. In order to determine the association between groups and classification on the motor subscales (competent and emergent/risk), we calculated the relative risk using Poisson regression with robust estimation of variance with adjustment for the covariables identified by the directed acyclic graph. The level of significance was set at alpha = .05 in all analyses. 3. Results Of the total number of infants followed-up, 83.3 % were assigned to the T-NIUGR group, 7.6 % to the T-IUGR group, 7.6 % to the PT-NIUGR group, and 1.4 % to the PT-IUGR group. Group differences were observed regarding birth weight and gestational age, which were significantly lower in PT and/or IUGR infants according to the definition of the groups themselves, and also regarding type of delivery, presence of hypertension during pregnancy and use of alcohol and tobacco by the mothers. The PT-IUGR group showed a higher relative frequency of infants born by cesarean section (85.7 %), of mothers with hypertension (50 %) and of mothers who used alcohol and tobacco during pregnancy (28.6 %) compared to the remaining groups (Table 1). The PT-IUGR group presented lower averages compared to the other groups in both motor subscales (Supplementary material A.3). Table 2 shows the classification of the groups on the motor subscale, with differences between groups being obseved for both subscales. The PT-IUGR group showed a higher relative frequency of infants classified as emergent/risk on the fine motor subscale (28.6 %) and on the gross motor subscale (35.7 %) compared to the remaining groups. The adjusted Poisson regression model with robust estimation of variance revealed that PT-IUGR infants had a higher risk to be classified as emergent/risk on the fine motor subscale (RR = 3.12, 95 %CI 1.39;7.00,p = 0.006) and gross motor subscale (RR = 2.91,95 %CI 1.34;6.32,p = 0.007) than T-NIUGR infants (Table 3). No differences were observed between the remaining groups and the T-NIUGR group. 4. Discussion The present results revealed risks of motor delays on the fine and gross motor subscales of Bayley-III screening among PT-IUGR infants compared to infants born at term without IUGR. The results of the PT-NIUGR and T-IUGR groups did not show differences in classification on the fine and gross motor subscales compared to the reference group (T-NIUGR), suggesting that adverse birth conditions (PT or IUGR), when dissociated, were not 3
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Table 1 Comparison of the characteristics of the T-NIUGR, T-IUGR, PT-NIUGR and PT-IUGR groups. Characteristics
Birth weight > 2500 g 1500-2500 g < 1500 g Gestational age > 39 weeks 37-38 weeks 34-36 weeks < 33 weeks Newborn’s sex Male Female Type of delivery Vaginal Cesarean section Hypertension No Yes Diabetes No Yes Alcohol/tobacco Does not use Alcohol or Tobacco Alcohol and Tobacco Level of maternal physical activity High Moderate None/Low Maternal schooling > 12 9–11 years < 8 years Maternal age 20–34 < 20 > 34 Economic class A-B C D-E Age at follow-up (months)** Median (interquartile interval)
T-NIUGR N (%)
Groups T-IUGR N (%)
PT-NIUGR N (%)
PT-IUGR N (%)
838 (83.3)
77 (7.6)
77 (7.6)
14 (1.4)
838 (100) 0 (0) 0 (0)
54 (70.1) 23 (29.9) 0 (0)
53 (68.8) 18 (23.4) 6 (7.8)
0 (0) 9 (64.3) 5 (35.7)
534 (63.7) 304 (36.3) 0 (0) 0 (0)
52 (67.5) 25 (32.5) 0 (0) 0 (0)
0 (0) 0 (0) 62 (80.5) 15 (19.5)
0 (0) 0 (0) 10 (71.4) 4 (28.6)
397 (47.4) 441 (52.6)
44 (57.1) 33 (42.9)
44 (57.1) 33 (42.9)
9 (64.3) 5 (35.7)
510 (60.9) 328 (39.1)
52 (67.5) 25 (32.5)
40 (51.9) 37 (48.1)
2 (14.3) 12 (85.7)
723 (86.3) 115 (13.7)
68 (88.3) 9 (11.7)
62 (80.5) 15 (19.5)
7 (50.0) 7 (50.0)
828 (98.8) 10 (1.2)
77 (100) 0 (0)
77 (100) 0 (0)
14 (100) 0 (0)
591 (70.6) 194 (23.2) 52 (6.2)
48 (62.3) 21 (27.3) 8 (10.4)
45 (58.4) 26 (33.8) 6 (7.8)
9 (64.3) 1 (7.1) 4 (28.6)
387 (46.7) 265 (32.0) 177 (21.3)
28 (37.3) 26 (34.7) 21 (28.0)
37 (48.7) 24 (31.6) 15 (19.7)
7 (50.0) 5 (35.7) 2 (14.3)
70 (8.3) 542 (64.8) 225 (26.9)
3 (3.9) 47 (61.0) 27 (35.1)
6 (7.8) 58 (75.3) 13 (16.9)
1 (7.1) 6 (42.9) 7 (50.0)
635 (75.8) 120 (14.3) 83 (9.9)
59 (76.6) 13 (16.9) 5 (6.5)
58 (75.3) 8 (10.4) 11 (14.3)
10 (71.4) 2 (14.3) 2 (14.3)
227 (27.5) 515 (62.3) 84 (10.2) 22 (21–24)
25 (33.3) 47 (62.7) 3 (4.0) 22 (21–24)
25 (32.5) 47 (61.0) 5 (6.5) 22(19–24)
2 (15.4) 10 (76.9) 1 (7.7) 21.5(19–24)
p-value*
< 0.001
< 0.001
0.099
0.001
0.001
0.567
0.004
0.731
0.067
0.698
0.406
0.134
The differences observed in the totals in relation to the reference (n) were due to missing information, T-NIUGR (term and non-restricted); T-IUGR (term + intrauterine growth restriction); PT-NIUGR (preterm + non-restricted); PT-IUGR (peterm + intrauterine growth restriction). *chi-square test. **Kruskal-Wallis test.
related to motor delays. The similarity of infants who were only PT to the reference group may be an indication of signs of recovery from the motor delays usually exhibited by PT infants at the end of the first year and beginning of the second year of life (Formiga & Linhares, 2011; Kieviet et al., 2009). In addition, evidence has suggested that losses of developmental parameters are smaller among PT infants born close to the 37th week of gestation (de Jong et al., 2015). In the present series, 80.5 % of the PT-NIUGR infants were born between 34 and 36 weeks of gestation, which may have been an attenuating factor for the motor delays of the group. Moreover, among T-IUGR infants, the similarity to the reference group may have been a result of the absence of infants with birth weight of less than < 1500 g, considered to be a possible factor inducing more severe losses (Pena, Teberg, & Finello, 1988). Another possible explanation is the presence of a sparing effect of the neurophysiological structures as a way to adapt to the process of IUGR, thus, minimizing potential harmful effects of intrauterine conditions (Figueras et al., 2011). On the other hand, the PT-IUGR group showed risks of delays in fine and gross motor skills. Certain characheristics of IUGR infants born PT such as structural changes in the brain (Egaña-Ugrinovic, Sanz-Cortés, Couve-Pérez, Figueras, & Gratacós, 2014; Padilla et al., 2014; Simões et al., 2017), losses of cognitive functions (Esteban et al., 2010; Figueras et al., 2011), difficulties with social skills (El Ayoubi et al., 2016) and lower anthropometric measures (Padilla et al., 2010), could be acting as restrictions that
4
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Table 2 Absolute and relative frequency for the participants as a whole and for the groups according to the classification on the motor subscales. Classification
TOTAL N (%)
T-NIUGR N (%)
T-IUGR N (%)
PT-NIUGR N(%)
PT-IUGR N(%)
Fine motor subscale Competent Emergent/Risk
917 (91.2) 89 (8.8)
770 (91.9) 68 (8.1)
69 (89.6) 8 (10.4)
68 (88.3) 9 (11.7)
10 (71.4) 4 (28.6)
Gross motor subscale Competent Emergent/Risk
906 (90.1) 100 (9.9)
759 (90.6) 79 (9.4)
73 (94.8) 4 (5.2)
65 (84.4) 12 (15.6)
9 (64.3) 5 (35.7)
P-value*
0.040
0.002
*Chi-square test. T-NIUGR (term and non-restricted); T-IUGR (term + intrauterine growth restriction); PT-NIUGR (preterm + non-restricted); PT-IUGR (preterm + intrauterine growth restriction). Table 3 Adjusted Poisson regression analysis of the association between classification on the motor subscales and groups. Fine motor subscale
Group T-NIUGR T-IUGR PT-NIUGR PT-IUGR
Gross motor subscale
RR
95 % CI
p-Valor
RR
95 % CI
p-value
1.00 1.06 1.42 3.12
0.54; 2.07 0.72; 2.82 1.39; 7.00
0.861 0.309 0.006
1.00 0.51 1.49 2.91
0.19; 1.33 0.81; 2.72 1.34; 6.32
0.167 0.195 0.007
Model adjusted for maternal hypertension, diabetes, use of alcohol and/or tobacco during pregnancy, level of maternal physical activity, maternal schooling, maternal age, economic class and newborn’s sex. T-NIUGR (term and non-restricted); T-IUGR (term + intrauterine growth restriction); PT-NIUGR (preterm + non-restricted); PT-IUGR (preterm + intrauterine growth restriction).
result in behaviors considered atypical when compared to their peers with typical development (Clark & Metcalfe, 2002). The data does not allow any conclusion about the underlying mechanisms that act as restriction factors for the motor development of PT-IUGR infants. However, during the monitoring of this cohort, which started in the prenatal period, there was a higher frequency of mothers with hypertension and/or who consumed alcohol and tobacco during pregnancy in children of the PT-IUGR group. Therefore, the data suggest that the factors present during prenatal deserve special attention in order to prevent PT-IUGR and reduce risks of motor delays in childhood. In contrast to the present study, previous reports by Esteban et al. (2010), Padilla et al. (2011), and El Ayoubi et al. (2016) did not observe delays in gross motor skills in PT-IUGR infants. In a study by El Ayoubi et al. (2016), a possible explanation given by the authors regarding typical development of PT-IUGR infants in certain behaviors, including gross motor skills, is the fact that the studied population was selected from a specialized center for neonatal assistance. Therefore, specific types of care given at neonatal centers, but not given to the population in general, could have mitigated potential difficulties in PT-IUGR children. In case-control studies, Padilla et al. (2011) and Esteban et al. (2010) pointed out that the limited sample size might have impaired the observation of statistically significant differences in certain behaviors between groups. Although the number of PT-IUGR infants studied in the current investigation was similar to that of the cited studies, this was a cohort study with a considerably larger reference group recruited from the general population, a fact that enabled the detection of differences between groups. As a limitation, the number of PT-IUGR infants was small in this study, since the sample was recruited from the general population. Furthermore, due to the adopted selection criteria, only women with singleton pregnancy and at least one prenatal exam until the 5th month of gestation were invited. The care taken during this stage could have been important to prevent PT-IUGR. Nonetheless, the PT-IUGR group showed increased risks for motor delays compared to the other groups. It is also worth highlighting the wide age range within which the children were evaluated, since older children could have more time to recover from potential limitations associated with motor delays. However, the median age at follow-up and the interquartile interval was similar for all groups. To minimize the age effect, the classification of Bayley scale was used since it considers the score related to the age when the child performed the test. In conclusion, the present study reveals that in the IUGR or PT populations, mostly consisting of mild cases, there was no difference in the development of motor skills in relation to the T-NIUGR group. In contrast, the combination of the two conditions (PT-IUGR) increased the risk of delays in fine and gross motor skills. Authors’ contribution Conception and design of the study: Paulo Ricardo H. Rocha, Marco A. Barbieri, Heloisa Bettiol, Maria da C. P. Saraiva. Data 5
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analysis and interpretation, writing of the study, and critical revision: Paulo Ricardo H. Rocha, Maria da C. P. Saraiva, Alexandre A. Ferraro, Marco A. Barbieri, Heloisa Bettiol. All authors approved the submitted final version of the manuscript. Funding São Paulo State Research Foundation (FAPESP) (Grant 2008/53593-0). Declaration of Competing Interest The authors declare no conflict of interest. Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi: https://doi.org/10.1016/j.infbeh.2020. 101429. References Associação Brasileira de Empresas de Pesquisa [ABEP] (2008). Dados com base no Levantamento Sócio Econômico – 2005. Retrieved fromIBOPEhttp://www.abep.org. Bassan, H., Stolar, O., Geva, R., Eshel, R., Fattal-Valevski, A., Leitner, Y., et al. (2011). Intrauterine growth-restricted neonates born at term or preterm: How different? 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Outcome in preterm small for gestational age infants compared to appropriate for gestational age preterms at the age of 2 years: A prospective study. European Journal of Obstetrics Gynecology and Reproductive Biology, 110(SUPPL), 93–97. https://doi.org/10.1016/S0301-2115(03)00178-7. Haga, M. (2008). The relationship between physical fitness and motor competence in children. Child: Care, Health and Development, 34(3), 329–334. https://doi.org/ 10.1111/j.1365-2214.2008.00814.x. Kieviet, J. F., Piek, J. P., Aarnoudse-Moens, C. S., & Oosterlaan, J. (2009). Motor development in very preterm and very low birth weight children. JAMA, 302(20), 2235–2242. https://doi.org/10.1001/jama.2009.1708. Kieviet, J. F., Zoetebier, L., van Elburg, R. M., Vermeulen, R. J., & Oosterlaan, J. (2012). Brain development of very preterm and very low-birthweight children in childhood and adolescence: A meta-analysis. Developmental Medicine and Child Neurology, 54(4), 313–323. https://doi.org/10.1111/j.1469-8749.2011.04216.x. Kramer, M. S., Platt, R., Yang, H., McNamara, H., & Usher, R. H. (1999). Are all growth-restricted newborns created equal(ly)? Pediatrics, 103(3), 599–602. https://doi. org/10.1542/peds.103.3.599. Krampe, R. T. (2002). Aging, expertise and fine motor movement. Neuroscience and Biobehavioral Reviews, 26, 1–8. Levine, T. A., Grunau, R. E., McAuliffe, F. M., Pinnamaneni, R., Foran, A., & Alderdice, F. A. (2015). Early childhood neurodevelopment after intrauterine growth restriction: A systematic review. Pediatrics, 135(1), 126–141. https://doi.org/10.1542/peds.2014-1143. Linke, A. C., Wild, C., Zubiaurre-Elorza, L., Herzmann, C., Duffy, H., Han, V. K., et al. (2018). Disruption to functional networks in neonates with perinatal brain injury predicts motor skills at 8 months. NeuroImage Clinical, 18(November (2017)), 399–406. https://doi.org/10.1016/j.nicl.2018.02.002. Lodygensky, G. A., Seghier, M. L., Warfield, S. K., Tolsa, C. B., Sizonenko, S., Lazeyras, F., et al. (2008). Intrauterine growth restriction affects the preterm infant’s hippocampus. Pediatric Research, 63(4), 438–443. https://doi.org/10.1203/PDR.0b013e318165c005. Murray, E., Fernandes, M., Fazel, M., Kennedy, S. H., Villar, J., & Stein, A. (2015). Differential effect of intrauterine growth restriction on childhood neurodevelopment: A systematic review. BJOG: An International Journal of Obstetrics and Gynaecology, 122(8), 1062–1072. https://doi.org/10.1111/1471-0528.13435. Padilla, N., Falcón, C., Sanz-Cortés, M., Figueras, F., Bargallo, N., Crispi, F., et al. (2011). Differential effects of intrauterine growth restriction on brain structure and development in preterm infants: A magnetic resonance imaging study. Brain Research, 1382, 98–108. https://doi.org/10.1016/j.brainres.2011.01.032. Padilla, N., Junqué, C., Figueras, F., Sanz-Cortes, M., Bargalló, N., Arranz, A., et al. (2014). Differential vulnerability of gray matter and white matter to intrauterine growth restriction in preterm infants at 12 months corrected age. Brain Research, 1545, 1–11. https://doi.org/10.1016/j.brainres.2013.12.007.
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Padilla, N., Perapoch, J., Carrascosa, A., Acosta-Rojas, R., Botet, F., & Gratacós, E. (2010). Twelve-month neurodevelopmental outcome in preterm infants with and without intrauterine growth restriction. Acta Paediatrica, 99(10), 1498–1503. https://doi.org/10.1111/j.1651-2227.2010.01848.x. Pena, I. C., Teberg, A. J., & Finello, K. M. (1988). The premature small-for-gestational-age infant during the first year of life: Comparison by birth weight and gestational age. The Journal of Pediatrics, 113(6), 1066–1073. Piek, J. P., Dawson, L., Smith, L. M., & Gasson, N. (2008). The role of early fine and gross motor development on later motor and cognitive ability. Human Movement Science, 27(5), 668–681. https://doi.org/10.1016/j.humov.2007.11.002. Procianoy, R. S., Koch, M. S., & Silveira, R. C. (2007). Neurodevelopment outcome of small for gestational age very low birth weight infants. Acta Paediatrica, 96(456), 112. Silveira, P. P., Pokhvisneva, I., Gaudreau, H., Rifkin-Graboi, A., Broekman, B. F. P., Steiner, M., et al. (2018). Birth weight and catch up growth are associated with childhood impulsivity in two independent cohorts. Scientific Reports, 8(1), 1–10. https://doi.org/10.1038/s41598-018-31816-5. Simões, R. V., Muñoz-Moreno, E., Cruz-Lemini, M., Eixarch, E., Bargalló, N., Sanz-Cortés, M., et al. (2017). Brain metabolite alterations in infants born preterm with intrauterine growth restriction: Association with structural changes and neurodevelopmental outcome. American Journal of Obstetrics and Gynecology, 216(1), 62. https://doi.org/10.1016/j.ajog.2016.09.089 e1-62.e14. Spinillo, A., Montanari, L., Gardella, B., Roccio, M., Stronati, M., & Fazzi, E. (2009). Infant sex, obstetric risk factors, and 2-year neurodevelopmental outcome among preterm infants. Developmental Medicine and Child Neurology, 51(7), 518–525. https://doi.org/10.1111/j.1469-8749.2009.03273.x. Verburg, B. O., Steegers, E. A. P., De Ridder, M., Snijders, R. J. M., Smith, E., Hofman, A., et al. (2008). New charts for ultrasound dating of pregnancy and assessment of fetal growth: Longitudinal data from a population-based cohort study. Ultrasound in Obstetrics and Gynecology, 31(4), 388–396. https://doi.org/10.1002/uog. 5225. Villar, J., Ismail, L. C., Victora, C. G., Ohuma, E. O., Bertino, E., Altman, D. G., Lambert, A., et al. (2014). International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project. Lancet, 384(9946), 857–868.
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Infant Behavior and Development journal homepage: www.elsevier.com/locate/inbede
Association of preterm birth and intrauterine growth restriction with childhood motor development: Brisa cohort, brazil
T
Paulo Ricardo H. Rochaa,*, Maria da C.P. Saraivab, Marco A. Barbieria, Alexandre A. Ferraroc, Heloisa Bettiola a
Department of Puericulture and Pediatrics, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil Department of Pediatric Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil c Department of Pediatrics, Faculty of Medicine, University of Sao Paulo, SP, Brazil b
A R T IC LE I N F O
ABS TRA CT
Keywords: Motor skills Cohort studies Risk factors Prematurity Intrauterine growth restriction
The present study investigated the association between preterm birth PT conditions, intrauterine growth restriction IUGR and the combination of both PT-IUGR with infant motor development. A cohort with 1006 children was monitored during prenatal, at birth, and two years of age. BayleyIII screening was used to evaluate of fine and gross motor skills. The data did not indicate an increased risk for motor delays in the PT or IUGR, composed mainly by mild cases. However, the combination of the conditions PT-IUGR increased the risk of delays in motor, which emphasizes the importance of monitoring the motor development of the group.
1. Introduction During childhood, motor development emerges in a sequential, cumulative and continuous manner within an expected time “window”. Therefore, marked delays in the acquisition of motor skills often indicate losses of the mechanisms and structures underlying development, in addition to being associated with morbidities and behavioral difficulties throughout life (Ghassabian et al., 2016; Haga, 2008; Linke et al., 2018). Although different factors are associated with childhood motor delays (Golding, Emmett, IlesCaven, Steer, & Lingam, 2014), several studies have reported that adverse conditions present as early as the prenatal period and at birth, such as preterm birth (PT) and intrauterine growth restriction (IUGR), may act significatively on the course of motor development (Kieviet, Piek, Aarnoudse-Moens, & Oosterlaan, 2009; Levine et al., 2015). PT birth (< 37 weeks of gestation) and IUGR (fetal growth below the genetic potential) are associated with increased risks of complications and perinatal mortality (Blencowe et al., 2012; Cosmi, Fanelli, Visentin, Trevisanuto, & Zanardo, 2011), and important neurological and cognitive changes (Kieviet, Zoetebier, van Elburg, Vermeulen, & Oosterlaan, 2012; Murray et al., 2015; Spinillo et al., 2009). Although often related, PT birth and IUGR are independent conditions caused by different factors that may affect childhood development differently. Some studies have pointed out that prematurity, more than IUGR, may be associated with the risks of delayed neurodevelopmental parameters (Gortner et al., 2003; Procianoy, Koch, & Silveira, 2007). However, there is evidence that the interaction between PT birth and IUGR (PT-IUGR) maximizes the risks of losses in different neurophysiological and
Abbreviations: T-NIUGR, term non-restricted; T-IUGR, term + intrauterine growth restriction; PT-NIUGR, preterm + non-restricted; PT-IUGR, preterm + intrauterine growth restriction ⁎ Corresponding author at: Departamento de Pediatria, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes, 3900, Monte Alegre, Ribeirão Preto, SP, 14049-900, Brazil. E-mail address: [email protected] (P.R.H. Rocha). https://doi.org/10.1016/j.infbeh.2020.101429 Received 1 May 2019; Received in revised form 14 February 2020; Accepted 15 February 2020 0163-6383/ © 2020 Published by Elsevier Inc.
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behavioral aspects (El Ayoubi et al., 2016; Esteban et al., 2010; Lodygensky et al., 2008). Regarding motor development, the few studies that investigated fine and gross motor skills in PT-IUGR infants observed difficulties only in the performance of fine motor tasks (El Ayoubi et al., 2016; Esteban et al., 2010; Padilla et al., 2011). This effect could indicate that these children may present characteristics of restrictions that could lead to atypical development in tasks that demand control of small muscle groups and sensorimotor integration, but not in organizational tasks or in coordination of large muscle groups that characterize gross motor skills (Krampe, 2002; Piek, Dawson, Smith, & Gasson, 2008). However, although some studies have indicated a connection between PT birth and/or IUGR with delayed motor development, the results are still inconclusive and often controversial (Bassan et al., 2011; de Jong, Verhoeven, Lasham, Meijssen, & van Baar, 2015; Gortner et al., 2003). In general, factors such as reduced sample size, the use of motor constructs that do not differentiate between the types of motor skills and the heterogeneity in the ways different researchers controlled for confounding variables contribute to the discordant results (Esteban et al., 2010; Kieviet et al., 2009; Levine et al., 2015). Furthermore, studies investigating the association of PT-IUGR with behavioral measures often do not include in their analysis infants born with only one of the two adverse conditions (PT or IUGR) or born without these adversities.This fact impairs the identification of the condition (PT or IUGR) that would significantly affect the occurrence of behavioral losses (Levine et al., 2015). Since motor developmental delay among PT, IUGR and PT-IUGR infants is still controversial, the objective of this study was to investigate the association of these birth conditions with the development of fine and gross motor skills. 2. Method 2.1. Participants The data of the present study are part of a cohort investigation entitled: “Etiological factors of preterm birth and consequences of perinatal factors for infant health: birth cohorts in two Brazilian cities, Ribeirão Preto and São Luís – BRISA” (Da Silva et al., 2014). For this study, we analyzed the data for the Ribeirão Preto prenatal cohort. The city is in the state of São Paulo, Southeastern Brazil. The first evaluation phase of the prenatal cohort took place between February 2010 and February 2011. A comvenience sample was used due to the impossibility of obtaining a representative random sample of pregnant women from the population, since there was a lack of records for pregnant women or women receiving prenatal care. Therefore, pregnant women were identified in hospitals and in health units on the occasion of a prenatal visit attended up to the 5th month of gestation. Women with singleton pregnancies who had undergone an obstetrical ultrasound during the first three months of gestation were invited to participate. The prenatal Ribeirão Preto cohort included 1400 pregnant women evaluated between 22 and 25 weeks of gestation. A previously trained team colleted data on reproductive health, demographic and socioeconomic status, characteristics of the pregnancy, and life habits of the participants. Data were collected at the Clinical Research Unit of the University Hospital, Faculty of Medicine of Ribeirão Preto, University of São Paulo (HCFMRP-USP). A total of 1369 mothers were reevaluated at childbirth. Excluding one case of abortion, 97.8 % of the eligible women from the initial cohort participated in this stage. From April 2010 to July 2011, teams of trained collaborators visited daily the maternities in the city in order to locate and interview the mothers, collecting information about mothers and their newborn babies with the use of a standardized questionnaire. Anthropometric newborn baby data, such as weight and length, were also obtained from the medical records. The field team was trained to perform data collection at the maternities, and all the employees of the maternities responsible for newborn baby anthropometry were trained before the beginning of the study. All equipment was calibrated periodically. In the beginning of the second year of the infant’s life, mothers and children underwent a new evaluation. The development of each baby was evaluated individually at the HCFMRP-USP using a standardized questionnaire administered to the mothers by a trained team. Six stillbirths and seven deaths during the first year of life were identified. Thus, 1356 participants were eligible for evaluation during the second follow-up period, with 1080 mother-child pairs participating in these evaluations. Specifically in this study, 74 participants were excluded for not performing the evaluation of motor development, resulting in 1006 infants, 74.2 % of the eligible babies. The age and economic class of the mothers were the only difference between completers and dropouts. The dropouts were younger and from lower economic classes than the completers (Supplementary material A.1). None of the babies from the follow-up showed congenital or acquired health problems that would justify exclusion from the study. The study was approved by the Research Ethics Committee of HCFMRP-USP (protocol 2.790.415) and all participants gave written informed consent to participate. 2.2. Birth status IUGR was determined on the basis of birth weight ratio, which is the ratio between the child’s birth weight and the mean weight for sex and gestational age (Kramer, Platt, Yang, McNamara, & Usher, 1999) according to the curve of the International Fetal and Newborn Growth Consortium for the 21 st Century (Villar et al., 2014). For the current study, a birth weight ratio < 0.85 was defined as IUGR and a birth weight ratio > 0.85 non-restricted intrauterine growth (NIUGR) (Kramer et al., 1999; Silveira et al., 2018). A gestational age < 37 weeks at birth was defined as PT, while > 37 week was considered to be term (T). Gestational age was calculated using the last date of menstruation provided by the mother during the prenatal interview and the earliest ultrasound date, available in her medical records or in her prenatal care card. When this information was compatible, assuming a + 7% error for ultrasound, gestational age was calculated by considering the duration of amenorrhea; if incompatible, only the ultrasound information was considered. The assumed gestational age was adjusted for the date of delivery, providing the definitive age (Verburg 2
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et al., 2008). Four groups were formed: T-NIUGR (term non-restricted), T-IUGR (term + intrauterine growth restriction), PT-NIUGR (preterm + non-restricted), and PT-IUGR (preterm + intrauterine growth restriction) in order to study the association between PT and/or IUGR on infant motor development. 2.3. Measures The development of motor skills was assessed using the fine and gross motor subscales of the Bayley Scales of Infant and Toddler Development Third Edition - screening - Bayley-III screening (Bayley, 2006). The infants were evaluated within the 13 to 30-month age range during cohort follow-up. The scale enabled us to determine whether development was progressing according to normal expectations or if a more in-depth evaluation is necessary. For evaluation, children born < 37 weeks had their age corrected, subtracting from the chronological age of follow-up the number of weeks until the gestational age of 40 weeks. According to the test guidelines, the age correction was not performed for the preterm children assessed after two full years. Bayley-III screening provides the classification of performance on the motor subscales according to the cut-off point for age, defined as Competent, Emergent and Risk. In this screening, Emergent and Risk classifications are equivalent to two standard deviations under average (standard score of 70). Thus, in the present study, the classifications were analyzed dichotomously as Competent and Emergent/Risk. 2.4. Confounding variables The minimum adjustment necessary for the confounding variables was determined by constructing a directed acyclic graph using the DAGitty software version 2.3 (Supplementary material A.2). Based on the directed acyclic graph, the following maternal variables from the prenatal phase were considered as potential confounders: hypertension (Yes or No), diabetes (Yes or No), use of alcohol and/ or tobacco during pregnancy regardless of quantity (Does not use, Uses alcohol or tobacco and Uses alcohol and tabacco), level of physical activity (Craig et al., 2003) (high, moderate and low/no activity), maternal schooling as years of study (> 12, 9–11 and ≤ 8 years), maternal age (< 20 years, 20–34 years and > 34 years) and economic class according to the Brazil Criterion of Economic Classification of the Brazilian Association of Research Companies (Associação Brasileira de Empresas de Pesquisa [ABEP], 2008) (AB, C and DE, with AB being the most priviledged an DE the least privileged). From the information obtained at birth, only sex was considered for adjustment of the analytical model. 2.5. Statistical analysis Data were analyzed statistically using the Stata package version 14 (College Station, Texas, USA). The differences in characteristics (T-NIUGR; T-IUGR; PT-NIUGR and PT-IUGR) were determined by the Chi-Square test. Group comparison regarding the fine and gross motor subscales classification was based on the Chi-Square test. In order to determine the association between groups and classification on the motor subscales (competent and emergent/risk), we calculated the relative risk using Poisson regression with robust estimation of variance with adjustment for the covariables identified by the directed acyclic graph. The level of significance was set at alpha = .05 in all analyses. 3. Results Of the total number of infants followed-up, 83.3 % were assigned to the T-NIUGR group, 7.6 % to the T-IUGR group, 7.6 % to the PT-NIUGR group, and 1.4 % to the PT-IUGR group. Group differences were observed regarding birth weight and gestational age, which were significantly lower in PT and/or IUGR infants according to the definition of the groups themselves, and also regarding type of delivery, presence of hypertension during pregnancy and use of alcohol and tobacco by the mothers. The PT-IUGR group showed a higher relative frequency of infants born by cesarean section (85.7 %), of mothers with hypertension (50 %) and of mothers who used alcohol and tobacco during pregnancy (28.6 %) compared to the remaining groups (Table 1). The PT-IUGR group presented lower averages compared to the other groups in both motor subscales (Supplementary material A.3). Table 2 shows the classification of the groups on the motor subscale, with differences between groups being obseved for both subscales. The PT-IUGR group showed a higher relative frequency of infants classified as emergent/risk on the fine motor subscale (28.6 %) and on the gross motor subscale (35.7 %) compared to the remaining groups. The adjusted Poisson regression model with robust estimation of variance revealed that PT-IUGR infants had a higher risk to be classified as emergent/risk on the fine motor subscale (RR = 3.12, 95 %CI 1.39;7.00,p = 0.006) and gross motor subscale (RR = 2.91,95 %CI 1.34;6.32,p = 0.007) than T-NIUGR infants (Table 3). No differences were observed between the remaining groups and the T-NIUGR group. 4. Discussion The present results revealed risks of motor delays on the fine and gross motor subscales of Bayley-III screening among PT-IUGR infants compared to infants born at term without IUGR. The results of the PT-NIUGR and T-IUGR groups did not show differences in classification on the fine and gross motor subscales compared to the reference group (T-NIUGR), suggesting that adverse birth conditions (PT or IUGR), when dissociated, were not 3
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Table 1 Comparison of the characteristics of the T-NIUGR, T-IUGR, PT-NIUGR and PT-IUGR groups. Characteristics
Birth weight > 2500 g 1500-2500 g < 1500 g Gestational age > 39 weeks 37-38 weeks 34-36 weeks < 33 weeks Newborn’s sex Male Female Type of delivery Vaginal Cesarean section Hypertension No Yes Diabetes No Yes Alcohol/tobacco Does not use Alcohol or Tobacco Alcohol and Tobacco Level of maternal physical activity High Moderate None/Low Maternal schooling > 12 9–11 years < 8 years Maternal age 20–34 < 20 > 34 Economic class A-B C D-E Age at follow-up (months)** Median (interquartile interval)
T-NIUGR N (%)
Groups T-IUGR N (%)
PT-NIUGR N (%)
PT-IUGR N (%)
838 (83.3)
77 (7.6)
77 (7.6)
14 (1.4)
838 (100) 0 (0) 0 (0)
54 (70.1) 23 (29.9) 0 (0)
53 (68.8) 18 (23.4) 6 (7.8)
0 (0) 9 (64.3) 5 (35.7)
534 (63.7) 304 (36.3) 0 (0) 0 (0)
52 (67.5) 25 (32.5) 0 (0) 0 (0)
0 (0) 0 (0) 62 (80.5) 15 (19.5)
0 (0) 0 (0) 10 (71.4) 4 (28.6)
397 (47.4) 441 (52.6)
44 (57.1) 33 (42.9)
44 (57.1) 33 (42.9)
9 (64.3) 5 (35.7)
510 (60.9) 328 (39.1)
52 (67.5) 25 (32.5)
40 (51.9) 37 (48.1)
2 (14.3) 12 (85.7)
723 (86.3) 115 (13.7)
68 (88.3) 9 (11.7)
62 (80.5) 15 (19.5)
7 (50.0) 7 (50.0)
828 (98.8) 10 (1.2)
77 (100) 0 (0)
77 (100) 0 (0)
14 (100) 0 (0)
591 (70.6) 194 (23.2) 52 (6.2)
48 (62.3) 21 (27.3) 8 (10.4)
45 (58.4) 26 (33.8) 6 (7.8)
9 (64.3) 1 (7.1) 4 (28.6)
387 (46.7) 265 (32.0) 177 (21.3)
28 (37.3) 26 (34.7) 21 (28.0)
37 (48.7) 24 (31.6) 15 (19.7)
7 (50.0) 5 (35.7) 2 (14.3)
70 (8.3) 542 (64.8) 225 (26.9)
3 (3.9) 47 (61.0) 27 (35.1)
6 (7.8) 58 (75.3) 13 (16.9)
1 (7.1) 6 (42.9) 7 (50.0)
635 (75.8) 120 (14.3) 83 (9.9)
59 (76.6) 13 (16.9) 5 (6.5)
58 (75.3) 8 (10.4) 11 (14.3)
10 (71.4) 2 (14.3) 2 (14.3)
227 (27.5) 515 (62.3) 84 (10.2) 22 (21–24)
25 (33.3) 47 (62.7) 3 (4.0) 22 (21–24)
25 (32.5) 47 (61.0) 5 (6.5) 22(19–24)
2 (15.4) 10 (76.9) 1 (7.7) 21.5(19–24)
p-value*
< 0.001
< 0.001
0.099
0.001
0.001
0.567
0.004
0.731
0.067
0.698
0.406
0.134
The differences observed in the totals in relation to the reference (n) were due to missing information, T-NIUGR (term and non-restricted); T-IUGR (term + intrauterine growth restriction); PT-NIUGR (preterm + non-restricted); PT-IUGR (peterm + intrauterine growth restriction). *chi-square test. **Kruskal-Wallis test.
related to motor delays. The similarity of infants who were only PT to the reference group may be an indication of signs of recovery from the motor delays usually exhibited by PT infants at the end of the first year and beginning of the second year of life (Formiga & Linhares, 2011; Kieviet et al., 2009). In addition, evidence has suggested that losses of developmental parameters are smaller among PT infants born close to the 37th week of gestation (de Jong et al., 2015). In the present series, 80.5 % of the PT-NIUGR infants were born between 34 and 36 weeks of gestation, which may have been an attenuating factor for the motor delays of the group. Moreover, among T-IUGR infants, the similarity to the reference group may have been a result of the absence of infants with birth weight of less than < 1500 g, considered to be a possible factor inducing more severe losses (Pena, Teberg, & Finello, 1988). Another possible explanation is the presence of a sparing effect of the neurophysiological structures as a way to adapt to the process of IUGR, thus, minimizing potential harmful effects of intrauterine conditions (Figueras et al., 2011). On the other hand, the PT-IUGR group showed risks of delays in fine and gross motor skills. Certain characheristics of IUGR infants born PT such as structural changes in the brain (Egaña-Ugrinovic, Sanz-Cortés, Couve-Pérez, Figueras, & Gratacós, 2014; Padilla et al., 2014; Simões et al., 2017), losses of cognitive functions (Esteban et al., 2010; Figueras et al., 2011), difficulties with social skills (El Ayoubi et al., 2016) and lower anthropometric measures (Padilla et al., 2010), could be acting as restrictions that
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Table 2 Absolute and relative frequency for the participants as a whole and for the groups according to the classification on the motor subscales. Classification
TOTAL N (%)
T-NIUGR N (%)
T-IUGR N (%)
PT-NIUGR N(%)
PT-IUGR N(%)
Fine motor subscale Competent Emergent/Risk
917 (91.2) 89 (8.8)
770 (91.9) 68 (8.1)
69 (89.6) 8 (10.4)
68 (88.3) 9 (11.7)
10 (71.4) 4 (28.6)
Gross motor subscale Competent Emergent/Risk
906 (90.1) 100 (9.9)
759 (90.6) 79 (9.4)
73 (94.8) 4 (5.2)
65 (84.4) 12 (15.6)
9 (64.3) 5 (35.7)
P-value*
0.040
0.002
*Chi-square test. T-NIUGR (term and non-restricted); T-IUGR (term + intrauterine growth restriction); PT-NIUGR (preterm + non-restricted); PT-IUGR (preterm + intrauterine growth restriction). Table 3 Adjusted Poisson regression analysis of the association between classification on the motor subscales and groups. Fine motor subscale
Group T-NIUGR T-IUGR PT-NIUGR PT-IUGR
Gross motor subscale
RR
95 % CI
p-Valor
RR
95 % CI
p-value
1.00 1.06 1.42 3.12
0.54; 2.07 0.72; 2.82 1.39; 7.00
0.861 0.309 0.006
1.00 0.51 1.49 2.91
0.19; 1.33 0.81; 2.72 1.34; 6.32
0.167 0.195 0.007
Model adjusted for maternal hypertension, diabetes, use of alcohol and/or tobacco during pregnancy, level of maternal physical activity, maternal schooling, maternal age, economic class and newborn’s sex. T-NIUGR (term and non-restricted); T-IUGR (term + intrauterine growth restriction); PT-NIUGR (preterm + non-restricted); PT-IUGR (preterm + intrauterine growth restriction).
result in behaviors considered atypical when compared to their peers with typical development (Clark & Metcalfe, 2002). The data does not allow any conclusion about the underlying mechanisms that act as restriction factors for the motor development of PT-IUGR infants. However, during the monitoring of this cohort, which started in the prenatal period, there was a higher frequency of mothers with hypertension and/or who consumed alcohol and tobacco during pregnancy in children of the PT-IUGR group. Therefore, the data suggest that the factors present during prenatal deserve special attention in order to prevent PT-IUGR and reduce risks of motor delays in childhood. In contrast to the present study, previous reports by Esteban et al. (2010), Padilla et al. (2011), and El Ayoubi et al. (2016) did not observe delays in gross motor skills in PT-IUGR infants. In a study by El Ayoubi et al. (2016), a possible explanation given by the authors regarding typical development of PT-IUGR infants in certain behaviors, including gross motor skills, is the fact that the studied population was selected from a specialized center for neonatal assistance. Therefore, specific types of care given at neonatal centers, but not given to the population in general, could have mitigated potential difficulties in PT-IUGR children. In case-control studies, Padilla et al. (2011) and Esteban et al. (2010) pointed out that the limited sample size might have impaired the observation of statistically significant differences in certain behaviors between groups. Although the number of PT-IUGR infants studied in the current investigation was similar to that of the cited studies, this was a cohort study with a considerably larger reference group recruited from the general population, a fact that enabled the detection of differences between groups. As a limitation, the number of PT-IUGR infants was small in this study, since the sample was recruited from the general population. Furthermore, due to the adopted selection criteria, only women with singleton pregnancy and at least one prenatal exam until the 5th month of gestation were invited. The care taken during this stage could have been important to prevent PT-IUGR. Nonetheless, the PT-IUGR group showed increased risks for motor delays compared to the other groups. It is also worth highlighting the wide age range within which the children were evaluated, since older children could have more time to recover from potential limitations associated with motor delays. However, the median age at follow-up and the interquartile interval was similar for all groups. To minimize the age effect, the classification of Bayley scale was used since it considers the score related to the age when the child performed the test. In conclusion, the present study reveals that in the IUGR or PT populations, mostly consisting of mild cases, there was no difference in the development of motor skills in relation to the T-NIUGR group. In contrast, the combination of the two conditions (PT-IUGR) increased the risk of delays in fine and gross motor skills. Authors’ contribution Conception and design of the study: Paulo Ricardo H. Rocha, Marco A. Barbieri, Heloisa Bettiol, Maria da C. P. Saraiva. Data 5
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analysis and interpretation, writing of the study, and critical revision: Paulo Ricardo H. Rocha, Maria da C. P. Saraiva, Alexandre A. Ferraro, Marco A. Barbieri, Heloisa Bettiol. All authors approved the submitted final version of the manuscript. Funding São Paulo State Research Foundation (FAPESP) (Grant 2008/53593-0). Declaration of Competing Interest The authors declare no conflict of interest. Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi: https://doi.org/10.1016/j.infbeh.2020. 101429. References Associação Brasileira de Empresas de Pesquisa [ABEP] (2008). Dados com base no Levantamento Sócio Econômico – 2005. Retrieved fromIBOPEhttp://www.abep.org. Bassan, H., Stolar, O., Geva, R., Eshel, R., Fattal-Valevski, A., Leitner, Y., et al. (2011). Intrauterine growth-restricted neonates born at term or preterm: How different? 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