Neurodevelopment in Relation to Breastfeeding Experiences Among Hungarian Preterm Infants at 12 Months of Corrected Age: A Cross-Sectional Study


 BackgroundPreterm and low birth weight infants are at higher risk of neurodevelopmental outcomes. Breastfeeding offers several beneficial aspects for them both physically and psychologically. This study aimed to describe the average neurodevelopmental outcomes of preterm infants and examine the associations between neurodevelopment and breastfeeding among Hungarian preterm infants at 12 months of corrected age.MethodsOne hundred fifty-four preterm infants with low birth weight (< 2500 g) and gestational age < 37 weeks and their mothers living in Hungary were participated in this cross-sectional examination. Bayley-III Screening Test (Bayley Scales of Infant and Toddler Development Screening Test, Third Edition) was administered to measure cognitive, language, and motor skills of infants. Breastfeeding data was obtained through parental anamnesis. To analyze data Mann-Whitney tests and Spearmen's rank correlation test were used to.ResultsConcerning risk of developmental delay, receptive and expressive language and fine motor subscales were the lowest. Examination of the duration of breastfeeding and neurodevelopmental performance identified higher neurodevelopmental outcomes in infants who were breastfed, significantly higher cognitive (U = 2047.5, p = 0.023) and fine motor (U = 2096.0, p = 0.037) skills were found. We identified significant positive correlations between the duration of breastfeeding and cognitive, expressive language and fine motor skills.ConclusionsBreastfed infants had better cognitive and fine motor skills at 12 months of corrected age, but we cannot unambiguously conclude that the duration of breastfeeding had a sole positive effect on the neurodevelopment at 12 months of corrected age. With the Bayley-III Screening Test we could identify the most affected skills in terms of risk for developmental delay, which are needed to improve.


Results
Concerning risk of developmental delay, receptive and expressive language and ne motor subscales were the lowest. Examination of the duration of breastfeeding and neurodevelopmental performance identi ed higher neurodevelopmental outcomes in infants who were breastfed, signi cantly higher cognitive (U = 2047.5, p = 0.023) and ne motor (U = 2096.0, p = 0.037) skills were found. We identi ed signi cant positive correlations between the duration of breastfeeding and cognitive, expressive language and ne motor skills.

Conclusions
Breastfed infants had better cognitive and ne motor skills at 12 months of corrected age, but we cannot unambiguously conclude that the duration of breastfeeding had a sole positive effect on the neurodevelopment at 12 months of corrected age. With the Bayley-III Screening Test we could identify the most affected skills in terms of risk for developmental delay, which are needed to improve.

Background
According to the WHO (World Health Organization) de nition, preterm birth means to be born before 37 completed weeks of gestation. Preterm birth is commonly associated with an overlapping perinatal risk, low birth weight. Each year approximately 15 million children are born preterm worldwide [1]. In Hungary, this proportion is 8% of the population (approximately 8.000 new-borns) [2]. Nutritional needs of premature babies signi cantly differ from their full-term counterparts, as they need more of any nutrient per unit body weight. This phenomenon is mainly due to the physical development of premature infants, i.e. the development of newly formed tissues is faster than in full-term counterparts. As well as, intercurrent diseases that often associated with preterm birth can also affect nutritional needs [3].
Breast-milk is the primary and most valuable source of nutrition and the main natural immune booster of both healthy new-borns and preterm infants, making them resistant to acute diseases and reducing the risk of developing pathological conditions [4]. Breastfeeding has bene cial effects on immunological, gastrointestinal, nutritional, and psychological aspects [5]. Regarding its components, the milk of mothers of preterm infants is different from mothers of full-term babies. It contains more protein, energy, fat and immunising agents, less lactose and more mineral salts [6]. Breastmilk protects the premature baby from gastrointestinal and respiratory infections, reduces the risk of developing NEC (necrotizing enterocolitis) and acute in ammatory bowel disease. In breast-milk fatty acids found to be easily digested for newborns, protective enzymes and hormones are essential for the growth and maturation of the digestive system, while lipids and fatty acids are indispensable for the balanced development of nervous system [5]. As a result, preterm infants experience fewer infections, spend fewer days in NICUs (neonatal intensive care units), and show better outcomes in tests of intellectual ability compared to formula-fed counterparts in later life [6].
However, the incidence and duration of breastfeeding are usually lower among premature infants compared to full-term babies. The lower incidence may be associated with breastfeeding challenges (e.g. maintaining milk supply), preterm delivery and immaturity of the new-born [7]. According to literature recommendations, exclusive breastfeeding is recommended for 6 months [8].
Despite of the bene ts and protective factors of breastfeeding, preterm infants can be regarded as a vulnerable population, not only in terms of neurodevelopmental outcomes (apnoea, ROP, BPD, PH) but also in terms of intellectual development [9][10][11]. Therefore, in order to prevent future di culties and developmental de cits, cognitive, motor end language screening of children at risk is especially signi cant as early as possible.
The objectives of this study are the description of neurodevelopmental outcomes on Bayley-III Screening Test subscales (cognitive, receptive and expressive, ne and gross motor skills) and the examination of the association between neurodevelopmental outcomes on Bayley-III Screening Test, breastfeeding and the duration of breastfeeding adjusted for premature and low birth weight children at 12 months of corrected age in a Hungarian sample.

Methods
Sample 154 low birth weight (< 2500 g) and preterm infants (< 37 weeks) at 12 months of corrected age were examined at the Pediatric Psychology and Psychosomatic Unit of the Department of Pediatrics of the University of Debrecen between December 2017 and January 2019. All of them were delivered in the same maternity ward, at the Department of Obstetrics and Gynecology of the University of Debrecen. Only those infants were included in our study who underwent developmental assessment using the ve distinct subscales of the Bayley-III Screening Test. Based on the Screening Test Manual, correction for prematurity was made [12]. In compliance with the Ethical Principles of the World Medical Association Declaration of Helsinki, the study was approved by the Medical Research Council of Hungary. Written informed consent was obtained from the parents of subjects'.

Bayley-III Screening Test (Bayley Scales of Infant and Toddler Development Screening Test, Third Edition)
In the identi cation of developmental di culties and delays BSID-III (Bayley Scales of Infant and Toddler Development -Third Edition) is currently, the most advanced developmental tool for early prevention [13].
Both the full BSID-III and its screening test version were adapted and standardized in 2017 in Hungary. To assess the early developmental performance, we used the Bayley-III Screening Test, which allows the quick investigation of cognitive, language and motor skills of infants and toddlers between 1 to 42 months. Within the language scale, the test distinguishes receptive and expressive communication subscales, while within the motor scale differentiate ne and gross motor subscales. Its primary purpose is to determine that the development of child is appropriate or further diagnostically testing is needed. With the Screening Test, degree of risk for developmental delay can be distinguished: high, moderate and low risk for can be determined [12,14].
Developmental characteristics and the duration of breastfeeding Developmental characteristics of the child (gestational week, birth weight) were obtained from the clinical database of the Department of Pediatrics of the University of Debrecen. Information about early feeding, the duration of breastfeeding, and the socio-demographic characteristics was obtained based on a maternal anamnesis.
Statistical analysis IBM SPSS Statistics v25 was used for statistical analysis. The normality of the sample was calculated by one-sample Kolmogorov-Smirnov test. Most of our data did not follow a normal distribution, so nonparametric tests were used. Mann-Whitney tests were used for group comparisons, and Spearmen's rank correlation test was used to measure the correlation between neurodevelopmental outcomes and duration of breastfeeding. P-values below 0.05 were considered statistically signi cant.

Results
General data (means and standard deviations) All infants involved in the study (n = 154) were Hungarian with valid health insurance. The gender ratio was nearly balanced, 73 females and 81 males were examined. The mean birth weight of the children was between 540 and 2490 g (M = 1802.27, SD = 543), and the mean gestational age of the children was between 24 and 36 weeks (M = 32.81, SD = 3.09). The main perinatal and socio-demographic characteristics of the sample are summarised in Table 1.  Table 2.). Breastfeeding and neurodevelopmental performance In our sample, 99 (64.28%) mothers were able to breastfeed their newborns, while 53 (34.41%) mothers failed to start breastfeeding (they feed their babies with donor milk or preterm formula). In 2 cases we had no information about breastfeeding. Examining the relationship between breastfeeding and neurodevelopment, we found a higher average performance on the cognitive, expressive language and motor subcales. For the cognitive (U = 2047.5; p = 0.023) and ne motor subscales (U = 2096.0; p = 0.037), the differences were found to be signi cant between breastfed and non-breastfed children (see Table 3.). We also examined the effect of duration of breastfeeding period on the developmental performance. In our sample, breastfeeding period ranged from 2 weeks to 14 months. Using the Spearman's rank correlation test, we identi ed signi cant positive correlations between the duration of breastfeeding and cognitive (r = 0.218; p = 0.07), expressive language (r = 0.209; p = 0.01), and ne motor (r = 0.181, p = 0.026) skills. However, the value of the coe cient of determination (r 2 ) is low for all three subscale variables (r cog 2 : 0.04; r exp 2 : 0.04; r n 2 :0.03). Perinatal and socio-demographic characteristics of breastfed and non-breastfed groups are summarised in Table 4.

Neurodevelopmental outcomes on Bayley-III Screening Test
The Bayley-III Screening Test, in addition to providing a comprehensive picture of cognitive, language and motor developmental characteristics in early childhood, is able to screen for children at risk for delayed development, thus differentiating children at high, moderate, or low risk for developmental delays. However, based on its results, no child can be considered to be delayed in neurodevelopment [12].
Regarding the neurodevelopmental results of our sample, the lowest performance was identi ed on the receptive, expressive language and ne motor subscales. This result is consistent with the most literature ndings. It is well-known, preterm infants have signi cantly lower neurodevelopmental skills in early ages compared to their full-term counterparts. Di culties in the motor skills may negatively affect the communication skills, such as joint attention and face-to-face interaction (complicating the process of language acquisition) [15][16].
The connection between neurodevelopment, breastfeeding and the duration of breastfeeding According to the results of Mann-Whitney tests, breastfed children had better cognitive and ne motor skills at 12 months of corrected age. The more the duration of breastfeeding was the better performance measured on cognitive, expressive and ne motor subscales. However, the low coe cients of determination (r 2 ) indicate that other factors and variables may contribute to the neurodevelopmental performance. A potential confounding factor can be, for example, the birth weight, duration of pregnancy, sex, duration of hospitalization, family socioeconomic condition just to mention a few. Thus, we cannot conclude that the increase in neurodevelopment is due to breastfeeding unequivocally. With breastfeeding, mothers provide a cognitively more stimulating environment for their babies, so not only the components of breastmilk but the family environment and the mother-child interaction also contribute to the development of the child.

Conclusions
Due to the consequences of prematurity, premature babies regarded as a vulnerable population [22], who begins the early life with a neurodevelopmental disadvantage. Breastfeeding can help them redressing this disadvantage. For public health, it is essential to draw the attention to the importance of breastfeeding, to inform mothers about its extensive positive effects on the child and mother, and to involve premature babies in psychological screening as soon as possible. Bayley-III Screening Test is an excellent tool to identify those neurodevelopmental areas where the interventions are needed. In summary breastfed infants have shown signi cantly better cognitive and ne motor skills in the Bayley-III Screening Test at 12 months of corrected age. However, these ndings should be treated with caution, because of the potential confounding factors. The importance of the reported study is increased by that it is one of the rst pieces of research with Bayley-III Screening Test in Hungary.

Abbreviations
Our results are consistent with literature ndings that emphasise both the short-and long-term positive effects of breastfeeding on the child's psychological and intellectual development. Jardí et al. [17] found that exclusive breastfeeding for at least 4 months results in a higher neurodevelopmental index at 6 and 12 months of age. The meta-analytical study of Horta et al. [18] focused on the investigation of long-term effects, their results emphasized that children who were breastfed in infancy, signi cantly performed better on intelligence tests (mean difference 3.44 points) in childhood and adolescence compared to nonbreastfed counterparts. Breastfed preterm infants with ELBW are characterised by higher mental, motor and behavioural performance at 18 and 30 months of age [19].
Among preterm infants, examining the effects of exclusive breastfeeding and formula feeding, differences can be identi ed also. According to the study of Wei Li et al. [20], among children with a gestational age of 28 and 30 weeks, breastfeeding played an important role in weight gain, reduced feeding intolerance, the incidence of NEC, and length of hospital stay. No correlations were found among formula milk feeding group. Lucas et al. [21] found that breastfed preterm infants perform better on intelligence tests later in life compared their formula-fed counterparts. Overall, we can conclude that breastfeeding for preterm infants is bene cial not only from a nutritional, gastrointestinal, immunological point of view, but developmental and psychological also.

Limitations
One of the potential limitations of our study is the absence of adjusted control group. Description of the neurodevelopmental outcomes we used the Hungarian standard values as a reference, but the comparison with it should be treated with caution, as children were included in standardization process from 2 to 42 months of age. Another limitation of our research is that potential confounding factors that may affect neurodevelopmental performance were not statistically controlled. To overcome this limitation, we re-assess the children in our sample at the 24 months of corrected age and take into consideration other variables when evaluate the development.