Long-term follow-up studies indicate that very-low-birth-weight (VLBW) newborns are at increased risk of long-term morbidity due to prenatal or neonatal problems. Thus, 15–30 % of VLBW infants have a birth weight below the 10th percentile for their gestational age (i.e. they are small for gestational age - SGA), while infants who experience intra-uterine growth restriction (IUGR) are considerably more liable to mortality and morbidity(Reference Torrance, Bloemen and Mulder1–Reference Sharma, McKay and Rosenkrantz4). IUGR is a clinical concept, describing newborns with malnutrition and IUGR, regardless of their birth weight percentile, and resulting from maternal, placental, fetal or genetic factors. Various maternal factors, such as age, health, behavioural habits and infection, may affect the growth of the fetus and provoke IUGR. A mismatch between the placental supply and the nutritional demands of the fetus can also result in IUGR. In some cases, too, fetal malformations, congenital metabolic errors or chromosomal abnormalities may produce IUGR(Reference Torrance, Bloemen and Mulder1).
The Nutrition Committee of the American Academy of Pediatrics recognises the importance of providing premature newborns with adequate nutrition during the first days of life, with contributions of energy and macronutrients similar to those received by the intra-uterine fetus(Reference Ehrenkranz, Das and Wrage5,Reference Bonsante, Iacobelli and Latorre6) . However, nutritional energy deficits inevitably occur in some cases, especially during the first week of life(Reference Embleton, Pang and Cooke7), often due to severe prematurity-related conditions such as intraventricular haemorrhage, necrotising enterocolitis, persistent ductus arteriosus, periventricular leucomalacia or bronchopulmonary dysplasia(Reference Laptook, O’Shea and Shankaran8,Reference Stoll, Hansen and Bell9) or to other factors such as poor tolerance of enteral nutrition, concern about the parenteral tolerance of high contributions of macronutrients (proteins, carbohydrates and lipids) or the need to restrict parenteral fluid intake, as part of persistent ductus arteriosus therapy.
Some studies have reported that IUGR infants are more likely to present inadequate visual and psychomotor development(Reference Pinello, Manea and Visona Dalla Pozza10,Reference Bardin, Piuze and Papageorgiou11) , while others have associated prematurity in fetuses affected by IUGR with hyperactivity disorders, but with little impact on cognitive development(Reference Bickle Graz, Tolsa and Fischer Fumeaux12). Furthermore, imaging tests in SGA infants with IUGR have revealed structural alterations and lower brain volume than in appropriate-birth weight premature infants(Reference Tolsa, Zimine and Warfield13).
After preterm delivery, the nutritional and energy contributions to the fetus from the placenta are abruptly interrupted, provoking a nutritional and energy deficit in the VLBW newborn at a crucial moment, which may influence the development of the brain and its glial cells. Variations in the establishment of early nutrition – possibly due to enteral intolerance, restricted fluid intake or the non-availability of central venous access – might affect development of the brain(Reference Iacobelli, Viaud and Lapillonne14).
Increased energy and protein intake in the first week of life has been associated with improved neurodevelopmental outcomes in VLBW infants(Reference Stephens, Walden and Gargus15). In this respect, too, Schneider et al. (Reference Schneider, Fischer Fumeaux and Duerden16) observed that increased energy intake during the first 2 weeks of life of VLBW infants is related to better brain development, of both white and grey matter. Other authors have observed that postnatal growth restriction, caused by a nutritional deficit, is associated with alterations in the cortical microstructure(Reference Vinall, Grunau and Brant17).
Our study aim is to evaluate the impact on neurodevelopment in VLBW infants of IUGR and of inadequate nutrition during the early neonatal period.
Subjects and methods
This retrospective, longitudinal cohort study was conducted of neonates born at the San Cecilio Clinical Hospital (Granada) between January 2008 and December 2017. The study protocol was approved by the Ethics Committee of the hospital, and all current regulations regarding data confidentiality were respected.
Inclusion and exclusion criteria
All newborns weighing <1500 g admitted to the neonatal intensive care unit during the study period were included in our initial analysis. Subsequently, each child was followed up in Neonatology and Neurology consultations. Infants who died in the first 28 d of life and those transferred to other hospitals were excluded from the analysis. Also excluded were neonates with congenital infections, proven genetic alterations, major malformations and an incomplete record of nutritional intake during the first week of life, together with those who did not attend the scheduled follow-ups. Fig. 1 shows the flow diagram representing the process applied for patient recruitment and inclusion.
Fig. 1. Flow diagram for the very-low-birth-weight (VLBW) newborns included in the study.
Anthropometry
Table 1 shows the weights and z-scores obtained at birth and during the first week of life. Fenton tables were used to calculate the z-scores(Reference Fenton and Sauve18). IUGR is defined as a reduced rate of weight increase, resulting in a weight below the 10th percentile for gestational age(Reference Levine, Grunau and McAuliffe19). In our sample, all cases of IUGR were diagnosed by intra-uterine ultrasound study. In accordance with Alexander et al. (Reference Alexander, Himes and Kaufman20), SGA is defined as birth weight below the 10th percentile for gestational age.
Table 1. Pregnancy, neonatal and nutritional characteristics
(Number and percentages; median and interquartile range)
BPD, bronchopulmonary dysplasia; PDA, patent ductus arteriosus; IVH, intraventricular haemorrhage; ROP, retinopathy of prematurity; NEC, necrotising enterocolitis; CRIB, clinical risk index for babies; SGA, small for gestational age; PVL, periventricular leukomalacia.
* Supplemented by <25% of the weekly volume with premature formula milk, IUGR, intra-uterine growth retardation; IVF, in vitro fertilisation; PIH, pregnancy induced hypertension; PPROM, preterm pre-labour rupture of membranes; IUGR, intra-uterine growth restriction (decrease in the rate of weight increase that manifests as weight below the 10th percentile for gestational age).
Nutritional management
The nutritional strategy was applied and the neonates’ fluid intake controlled in accordance with the standard protocol of our neonatal unit and with the recommendations of the Nutrition and Metabolism Group of the Spanish Neonatology Society(Reference Uberos, Narbona and Gormaz21,Reference Narbona, Uberos and Armada22) . In all cases, 1·2 µm filters were used for parenteral nutrition (PN) (Pall, Medical). Two changes were made to this nutritional practice during the study period. In April 2011, first-day PN (early PN) began to be applied with an amino acid solution (2 g/kg) and with glucose at 5 mg/kg/min. Previously, amino acid had not been supplied during the first hours of life. This change, which aligned our action protocols with international recommendations, increased the newborns’ energetic intake in the first week of life and, secondarily, enabled us to assess the energy repercussions more effectively. The second modification concerned the lipid emulsion used. In July 2016, SMOFlipid (Fresenius Kabi) was introduced, replacing intralipid (Fresenius Kabi) as an emulsion commonly used in PN. The repercussions of this change with respect to energy intake are taken into account in our analysis of the results.
The normal procedure during the first days of life is to complement enteral nutrition with PN when complete enteral nutrition cannot be established. The daily requirements of liquids, proteins and lipids are calculated daily. At our hospital, breast milk composition is determined according to the Standardized Reporting of Neonatal Nutrition and Growth checklist, and formula composition is assessed according to commercial notifications(Reference Cormack, Embleton and van Goudoever23). In all cases, the aim is that during the first week of life the minimum nutritional requirements to ensure growth should be met, according to standard recommendations(Reference Thureen24). For the purposes of the present study, the inputs of liquids, energy, proteins, carbohydrates and lipids during the first week of life were recorded.
Since January 2008, the neonatal intensive care unit has prospectively recorded in an Excel database the daily enteral and parenteral nutritional intake of all VLBW admitted, specifying the intake per kg body weight of energy, proteins, carbohydrates and fats. The time of initiation and type and volume of enteral nutrition are also recorded.
Low energy intake
In our sample, energy intake below the 25th percentile was assumed to represent energy restriction, and so this was chosen as the cut-off point for increased risk of neurological disorder. This value is equivalent to about 60 % of the recommended energy intake during the first week of life.
Morbidity
In accordance with the thresholds proposed by National Institute of ChildHealth and Human Development (NIHCD)(Reference Doyle, Halliday and Ehrenkranz25) and by Jobe and Bancalari(Reference Jobe and Bancalari26), bronchopulmonary dysplasia is defined as a need for supplemental oxygen > 21 % at 28 d of life and/or a need for supplemental oxygen > 21 % or for positive airway pressure at 36 weeks’ corrected gestational age.
A diagnosis of clinical sepsis is made when a Prediction of nosocomial sepsis (NOSEP)-1 score > 8 is recorded. On this scale, the presence of c-reactive protein (CRP) > 0·014 g/l is assigned five points; that of neutrophils > 50 %, three points; that of thrombocytopaenia < 150 × 109/l, five points and that of fever > 38·2ºC, five points(Reference Mahieu, De Muynck and De Dooy27). The clinical risk index for babies II score for each newborn was performed using the following variables: sex, gestational age (in weeks), birth weight (in grams) and excess base. The total clinical risk index for babies II score (range 0 to 27) was calculated(Reference Brito, Matsuo and Gonzalez28).
The diagnosis and staging of retinopathy of prematurity were performed following a retinal examination before discharge from the neonatal unit(Reference Lad, Hernandez-Boussard and Morton29,30) .
Persistent ductus arteriosus is diagnosed by Doppler ultrasound and treated when clinical repercussions are observed or when the diameter is greater than 2 mm.
The diagnosis of intraventricular haemorrhage is based on Papile’s classification(Reference Papile, Burstein and Burstein31). All neonates in this study received a transfontanellar ultrasound examination on the third day of life and every week thereafter.
For the diagnosis of necrotising enterocolitis, patients are classified according to Bell’s criteria(Reference Caplan and Jilling32). Cases classified as spontaneous intestinal perforations were excluded from this diagnosis.
Psychomotor and sensory development
At our hospital, this parameter is monitored during neuropaediatric consultation. For each infant included in the study, four such reviews were conducted, at the following times (median value and interquartile range): Review 1 at 13 months(Reference Bickle Graz, Tolsa and Fischer Fumeaux12), Review 2 at 24 months(Reference Levine, Grunau and McAuliffe19), Review 3 at 36 months (29·5–39) and Review 4 at 48 months (36·5–50). For the present study, motor alterations are classified as (a) mild motor disorder, which includes motor coordination disorders that are not the consequence of cognitive or neurological alterations evidenced by imaging tests; this category includes fine and gross motor abilities that are significantly below the level expected; (b) monoparesis, i.e. motor alteration affecting a single limb, muscle or muscle group; (c) hemiparesis, i.e. motor alteration affecting an arm or leg on the same side of the body and (d) tetraparesis, i.e. motor alteration affecting all four limbs. Visual and auditory sensory capacities were determined by measuring the evoked potentials. Motor, coordination, language, social and cognitive development was evaluated and the mental development index (MDI) scored by means of the Brunet-Lezine and Bayley III scale. The level of cognitive delay was determined according to the mental age derived from the MDI and the resulting intelligence quotient, as follows: mild delay (IQ: 50–70), moderate delay (IQ: 35–50) or severe delay (IQ: 20–35), in accordance with the International Statistical Classification of Diseases and Related Health Problems (ICD, Ed. 10). When two or more motor or sensory impairments were detected, this was considered a multiple deficiency. Behavioural disorders were assessed by the CUMANIN questionnaire and the Wechsler Intelligence Scale. Cerebral palsy is a set of developmental disorders affecting movement and posture, thereby limiting activity. The condition is attributed to a non-progressive aggression on the developing brain, during the fetal period or early years of life, and is frequently associated with sensory disturbances(Reference Krigger33). When detected, the presence of epilepsy, defined as repeated seizures with alterations in electrical activity in the electroencephalogram, was also recorded.
Statistical analysis
The descriptive data were summarised using medians (p50) and the interquartile range (p25–p75) for the continuous values and frequency distribution for the categorical ones. Univariate comparisons of the continuous variables were performed using the Mann–Whitney test and of the categorical ones by the χ 2 test. The risk of motor, visual and hearing disorders, delayed cognitive development, behavioural disorder, multiple deficiency, cerebral palsy and epilepsy was first assessed by univariate regression analysis and then by multivariate logistic regression analysis. Birth weight is strongly associated with gestational age and so this variable was not taken into account, in order to avoid over-fitting phenomena that might bias the associations obtained in the regression analysis. No adjustment was made for the CRIB index because this was calculated from gestational age, weight and male sex, among other variables, and these were previously taken into account in the regression analysis. The main adjustment factors considered are the co-morbidities of VLBW that are associated with poorer neurological outcomes, especially lower gestational age, late-onset sepsis, bronchopulmonary dysplasia, patent ductus arteriosus, SGA, intraventricular haemorrhage and leukomalacia.
All statistical analyses were performed using IBM SPSS 20.0 for Windows (IBM).
Reporting
The STROBE checklist for reporting observational studies was used(Reference von, Altman and Egger34).
Results
During the period from 1 January 2008 until 31 December 2017, 396 newborns weighing < 1500 g were treated in our neonatal unit. Of these, fifty four died in the neonatal period and five had congenital malformations and were excluded from the study. The remaining 337 newborns were included in our analysis. Among this population, sixty-four infants had experienced IUGR. At birth, sixty two had a birth weight below the 10th percentile and were classified SGA (Table 1). During follow-up, the infants presenting normal development were discharged. Fig. 1 describes the follow-up cohort remaining after each neurological and sensory evaluation. Comparison of the z-score variables for weight and gestational age, between the infants discharged and those who remained in the study, at each of the reviews performed, only revealed significant differences for the gestational age variable. In general, the patients with a lower gestational age remained in follow-up for longer.
Table 1 shows the maternal and neonatal characteristics of the study cohort, revealing significant differences between the infants with and without IUGR according to the maternal variables: preterm premature rupture of membranes, chorioamnionitis and maternal antibiotics. In every case, these conditions were more prevalent in the group without IUGR, which we ascribe to the fact that infection and chorioamnionitis are present in about one-third of all cases of prematurity. Mean gestational age in the IUGR group was 32 weeks and delivery by caesarean section often indicated placental insufficiency, resulting in decreased fetal well-being and chronic malnutrition(Reference Dennison, Fall and Cooper35). Among other neonatal co-morbidities observed, the VLBW newborns with appropriate weight had a greater prevalence of grade 1 or 2 intraventricular haemorrhage and a significantly lower mean gestational age. For the remaining neonatal co-morbidities, no significant differences were observed between the study groups.
Following the incorporation of early PN in the standard protocol for the neonatal unit, an increase in average energy intake during the first week of life was observed. Table 1 shows the weight and z-score data in this respect. The weight loss during the first week of life was greater among the infants with IUGR, although they received similar energy and macronutrient inputs to those without IUGR.
Table 2 shows the prevalence of neurological abnormalities detected in our study cohort after a mean follow-up of 50 months. Although no significant differences were observed overall, mild motor disorder was present in 10 % of the newborns with IUGR and SGA v. 3·2 % of those with appropriate birth weight. Moreover, mild cognitive delay was detected in 35·6 % of the infants with IUGR v. 24 % of those with appropriate birth weight. Table 3 shows the OR for neurological disorders in the IUGR neonates who were followed up for 50 months. After adjusting for differentiating maternal variables (Table 1) and for neonatal variables relevant to neurodevelopment, we observed a significant association between IUGR and behavioural disorders (OR 2·60; 95 % CI 1·25, 5·40) and between IUGR and delayed cognitive development (OR 2·64; 95 % CI 1·34, 5·20).
Table 2. Neurological disorders observed. Average follow-up of 50 months
(Number and percentages)
Table 3. Regression analysis for neurological disorders and the existence of IUGR in VLBW newborns. Follow-up until 50 months of age
(Odd ratio and 95 % confidence intervals)
* Adjusted for chorioamnionitis, antibiotics, PPROM, preterm pre-labour rupture of membranes; gestational age (w); IVH, intraventricular haemorrhage; PVL: periventricular leukomalacia.
** P ≤ 0·01,
*** P < 0·05.
In our study cohort, mean energy intake during the first week of life was 459 kcal/kg/w, with the 25th percentile being 390 kcal/kg/w. In accordance with the method applied in previous studies(Reference Uberos, Jimenez-Montilla and Molina-Oya36), for the following risk analyses the value of the 25th percentile of energy intake during the first week of life (390 kcal/kg/w) was considered a limit value for low energy intake. As shown in Table 1, there were no differences in energy and macronutrient intake between newborns with or without IUGR. Table 4 describes the risk of neurological alteration associated with low energy intake during the first week of life, in newborns with or without IUGR. Of the 273 newborns with no IUGR, 63 had an energy intake in the first week of life below that of the 25th percentile of the study cohort. Logistic regression analysis was performed to evaluate the risk of specific neurological alterations associated with low energy intake (i.e., < 390 kcal/kg/w) during the first week of life. The OR values obtained, whether unadjusted or following statistical adjustment for variables that may have neurological repercussions (gestational age, sepsis, bronchopulmonary dysplasia, necrotising enterocholitis, persistent ductus arteriosus, SGA, intraventricular haemorrhage or leukomalacia), reveal significant associations between energy restriction in the first week of life and visual disorders (OR 2·96; 95 % CI 1·26, 6·84) and cerebral palsy (OR 3·05; 95 % CI 1·00, 9·54).
Table 4. Neurological disorders associated with low energy intake during the first week of life of very-low-birth-weight (VLBW) newborns with appropriate birth weight. Follow-up to 50 months of age
(Odds ratio and 95 % confidence intervals)
* Adjusted for gestational age (w), sepsis, bronchopulmonary dysplasia, necrotising enterocholitis ≥ 2 (NEC ≥ 2), persistent ductus arteriosus (PDA), small for gestational age (SGA), intraventricular haemorrhage (IVH), periventricular leukomalacia (PVL).
**P ≤ 0·001, ***P ≤ 0·01, ****P < 0·05.
Among the full-term VLBW neonates, we observed a significant association between the mental development index at age 13 months and energy intake during the first week of life. However, there was no significant association between this index and protein intake. Lipid intake during the first week of life was significantly associated with the mental development index at age 24, 36 and 48 months (see Fig. 2).
Fig. 2. Regression analysis for the mental development index at 14, 25, 33 and 50 months and the contribution of energy (A), proteins (B) and lipids (C) in the first week of life of very-low-birth-weight (VLBW) newborns with no Intra-uterine growth retardation (IUGR).
Discussion
Our findings show that the prenatal energy restriction manifested by IUGR is associated with behavioural disorders in the VLBW newborn. Moreover, postnatal energy restriction is significantly associated with motor disorders, infantile cerebral palsy and sensory disorders.
IUGR is defined as the growth rate of a fetus below the 10th percentile of expected growth for that gestational age. An infant is considered SGA when the birth weight is below the 10th percentile. Suboptimal fetal growth is an important cause of perinatal mortality and morbidity. In our study population, all of the VLBW infants with IUGR were SGA.
Postnatal nutritional and energy intake did not vary significantly between VLBW infants with or without IUGR. Nor was it associated with the neurological morbidity observed in our cohort after IUGR. Among the common co-morbidities observed in VLBW infants (Table 1), the only differences observed were in the prevalence of intraventricular haemorrhage grades 1 and 2, which was higher in newborns without IUGR, undoubtedly due to their lower gestational age.
Prematurity in itself does not appear to be associated with higher scores on the attention deficit hyperactivity disorder rating scales. However, prematurity associated with SGA, which is observed after IUGR, is significantly associated with higher attention deficit hyperactivity disorder scores(Reference Heinonen, Raikkonen and Pesonen37). According to the latter authors, the degree of SGA at birth and IUGR, regardless of gestational age at birth, is related to hyperactivity. On the other hand, attention deficit, which forms part of the attention deficit hyperactivity disorder syndrome, is more strongly related to extreme prematurity(Reference Hack, Taylor and Schluchter38,Reference Johnson, Hollis and Kochhar39) . Our results corroborate Bickle Graz et al. (Reference Bickle Graz, Tolsa and Fischer Fumeaux12), who observed behavioural disorders, especially hyperactivity, in 76 % of SGA VLBW infants. In this respect, too, Silva et al. (Reference Silva, Cunha and Linhares40) studied newborns with late prematurity and observed no differences in neurodevelopment between SGA infants and those with appropriate birth weight. Finally, Hartkopf et al. (Reference Hartkopf, Schleger and Keune41) observed in newborns with late prematurity that the presence of IUGR is associated with cognitive delays and a significantly lower MDI, in comparison with appropriate-birth-weight infants.
After adjusting for differentiating variables, our data also reflect a significant association between IUGR in VLBW infants and their delayed cognitive development. Specifically, the risk of cognitive delay after IUGR is 2·64 (95 % CI 1·34, 5·20) (Table 3).
Stephens et al. (Reference Stephens, Walden and Gargus15) observed that increased energy and protein intake in VLBW infants during the first week of life are associated with better rates of mental development. On the other hand, Buddhavarapu et al. (Reference Buddhavarapu, Manickaraj and Lodha42) reported that increased protein intake in the first week of life was not associated with better rates of mental development in preterm infants; however, in this study, the group with a ‘high’ protein intake did not achieve 3·5 g/kg/d until the sixth day of life.
Lacobelli et al. (Reference Iacobelli, Viaud and Lapillonne14) recorded a significant association between energy and macronutrient intake during the first weeks of life and brain development. In this study, preterm infants who experienced postnatal growth restriction, possibly due to nutritional deficits, showed poor cortical microstructure development. Lipids and energy contributed more to the beneficial effect of nutrition, with lipids providing a third of total energy intake. It remains to be determined whether the impact of lipids is due to their high energy content (which reduces the energy deficit and the need for protein catabolism) and/or to the provision of fatty acids, especially essential fatty acids. In line with the above-cited studies, our findings show that increased energy intake in the first week of life of VLBW infants is associated with higher scores on the MDI at the age of 18 months, and that lipid intake is significantly associated with the MDI for the first 50 months of life (Fig. 2). In other words, energy restriction in the first week of life can increase the risk of infantile cerebral palsy threefold.
During the period addressed in this study, changes took place in the hospital’s nutritional policy, from reliance on PN with soybean oil as the sole lipid contribution (n-3: n-6, ratio of 1:7) to a diet incorporating SMOFlipid (fish, soya, olive and coconut oil) (n-3: n-6, ratio of 2:5). In our neonatal unit, the intake of parenteral lipids is normally limited to 3 g/kg/d, in order to avoid possible pro-inflammatory effects from an excessive intake of parenteral lipids. However, the early intake of at least 0·5 g/kg/day of lipids, from the first day of life, is associated with a significant increase in the growth pattern, which is maintained until the 36th week of gestational age(Reference Fischer, Maucort-Boulch and Essomo Megnier-Mbo43). The accretion of lipids in the fetus begins at the 25th week of gestational age, which is why extremely low birth weight newborns have fewer deposits of long-chain PUFA. n-3 and n-6 fatty acids are essential for brain and retina development, and many studies have associated decreased long-chain PUFA levels in the VLBW newborn with late psychomotor development(Reference Vlaardingerbroek and van Goudoever44,Reference Hsiao, Tsai and Chen45) . Our findings show that the MDI may be associated with the contribution of lipids in the first week of life until the age of 50 months (95 % CI 40·7, 59·0) (Fig. 2). In this respect, Moon et al. (Reference Moon, Rao and Schulzke46) conducted a meta-analysis, following the Cochrane methodology, finding no significant effects of n-3 long-chain PUFA supplementation on the MDI or visual acuity of newborns. However, Shultkin et al. (Reference Shulkin, Pimpin and Bellinger47), in a meta-analysis of 33 clinical trials, observed that supplementation of n-3 long-chain PUFA in mothers and preterm infants was associated with higher MDI scores and enhanced visual acuity.
The progressive decrease in the number of patients remaining for follow-up, as infants are discharged from hospital following successive reviews, must be considered. This aspect of the study is viewed as a limitation, since it represents a decrease in the statistical power obtained. However, when a subsidiary neurological disorder is ruled out, it is normal for patients to be discharged from clinical follow-up. On the other hand, although intra-uterine malnutrition frequently provokes IUGR, in a small number of cases its cause cannot be established, and this source of bias should be taken into account. Although the present study, based on a retrospective cohort, has evident limitations we believe the data presented provide valuable support for future meta-analysis studies in this field. We are aware that some of the alterations described are not fixed and will evolve or diminish in periods after those considered in our study. Nevertheless, our findings highlight the strength of evidence that energy and protein intake in the first weeks of life is an important factor in the neurological development of the newborn(Reference Ohnishi, Ichiba and Tanaka48).
Conclusions
In VLBW infants, IUGR is associated with behavioural disorders and with poorer cognitive development. Moreover, nutritional energy restriction during the early postnatal period is associated with visual disorders and can increase the risk of infantile cerebral palsy threefold. Early lipid intake is associated with better MDI scores at 50 months of age.
Acknowledgements
The authors thank the neonatologists, nurses and psychologists involved for their invaluable collaboration.
No external funding was received for this study. The authors declare that they have no financial relationships relevant to this article to disclose.
J. U. designed the analysis and data interpretation procedures, co-wrote the article and critically reviewed it for important intellectual content. He approves the present version for publication. He accepts responsibility for all aspects of the work, including the proper investigation and resolution of questions related to its accuracy and completeness. S. J-M., A. C-M., E. F-M. and I. M-C. made substantial contributions to the conception and design of the study, co-wrote the article and critically reviewed it for important intellectual content. They approve the present version for publication. They accept responsibility for all aspects of the work, including the proper investigation and resolution of questions related to its accuracy and completeness. C. L-R. conducted the psychological tests involved in this study, made substantial contributions to data acquisition, co-wrote the article and critically reviewed it for important intellectual content. She approves the present version for publication. She accepts responsibility for all aspects of the work, including the proper investigation and resolution of questions related to its accuracy and completeness.
The authors declare that the work presented in this manuscript is original and is not currently being evaluated by any other journal. The authors have no relevant conflicts of interest to declare.
