**6. Breastfeeding and infant's brain development**

There is clear and convincing evidence that breastfeeding for 1 year or longer contributes significantly to the higher IQ during adulthood [12]. The relation between length of breastfeeding and adult intelligence may be difficult to substantiate because of the confounding factors including the maternal IQ, which has been substituted with maternal education [13, 14]. Recent studies on the association of breastfeeding and higher IQ demonstrate that higher IQ is associated with larger brain size and higher degree of myelination of the white matter [15, 16]. It is further believed that one or more ingredients of breast milk are implicated in brain growth and optimal brain function. In the past 2 decades comprehensive studies on a number of breast milk ingredients have been carried out to evaluate the causal association of these ingredients with brain growth and IQ of the child. Two major ingredients of breast milk which have generated major interest in scientific circles as well the food industry are docosahexaenoic (DHA) and arachidonic (ARA) acids, which are the components of myelin. A number of published reports have claimed that additional intake of DHA during pregnancy and lactation may improve the IQ of the infants. Furthermore there were claims of supplementation of DHA and ARA of the infant formula result in improved IQ, compared to formulas without supplementation. This resulted in DHA and ARA supplementation of all infant formulas, marketed by the major formula companies, beginning in 2002. More recent studies have demonstrated that these studies are flawed and DHA and ARA supplementation of pregnant and nursing mothers do not increase the IQ of the child [17]. Furthermore supplementation of infant formulas with DHA and ARA did not increase the IQ of the children who were given the supplemented formulas [18].

Breast milk has significantly higher concentration of cholesterol than infant formula and breasted infants at 6 months have higher cholesterol levels than formula-fed infants [19, 20]. Cholesterol is a significant component of myelin and availability of cholesterol is a rate limiting factor in brain maturation in mice [21]. Therefore it could be argued that higher cholesterol in breast milk result in enhanced synaptic connection, higher degree of myelination of the white matter and higher IQ.

Human milk contains significant numbers of maternal hormones and growth factors, oxytocin, thyroxin, estrogens, nerve growth and epidermal growth factors, which could influence myelin production and white matter development. Breast milk estrogens are transcriptional promoters for oxytocin and its receptors in the infant's central nervous system [22]. Oxytocin has a central role in milk ejection and oxytocin knockout (OTKO) mice are unable to nurse their pups [22]. Oxytocin binds to a large number of oxytocin receptors and is implicated in regulating homeostatic functions, social recognition and fear conditioning [22]. Additionally oxytocin reduces neuroendocrine stress signaling and anxiety and depression symptoms [22]. Activation of beta estrogen receptors increases oxytocin gene transcription and reduces anxiety-related behavior [22]. Endogenous oxytocin can suppress corticotrophin releasing factor, CRF, and therefore reduce the activation of HPA axis and reduce the ACTH and cortisol levels [22].

Oxytocin is a neurotransmitter for oxytocinergic system and therefore involved in homeostatic processes [22]. Adults who were breastfed during infancy have lower total and LDL cholesterol, lower blood pressure and lower risk of cardiovascular disorders [13].

### **7. First and second messengers**

The theory of attachment parenting is based on psychological principles and lack of solid scientific foundation. The massive data in the past 2 decades have provided strong and convincing evidence that long term breastfeeding and providing an enriched environment result

There is clear and convincing evidence that breastfeeding for 1 year or longer contributes significantly to the higher IQ during adulthood [12]. The relation between length of breastfeeding and adult intelligence may be difficult to substantiate because of the confounding factors including the maternal IQ, which has been substituted with maternal education [13, 14]. Recent studies on the association of breastfeeding and higher IQ demonstrate that higher IQ is associated with larger brain size and higher degree of myelination of the white matter [15, 16]. It is further believed that one or more ingredients of breast milk are implicated in brain growth and optimal brain function. In the past 2 decades comprehensive studies on a number of breast milk ingredients have been carried out to evaluate the causal association of these ingredients with brain growth and IQ of the child. Two major ingredients of breast milk which have generated major interest in scientific circles as well the food industry are docosahexaenoic (DHA) and arachidonic (ARA) acids, which are the components of myelin. A number of published reports have claimed that additional intake of DHA during pregnancy and lactation may improve the IQ of the infants. Furthermore there were claims of supplementation of DHA and ARA of the infant formula result in improved IQ, compared to formulas without supplementation. This resulted in DHA and ARA supplementation of all infant formulas, marketed by the major formula companies, beginning in 2002. More recent studies have demonstrated that these studies are flawed and DHA and ARA supplementation of pregnant and nursing mothers do not increase the IQ of the child [17]. Furthermore supplementation of infant formulas with DHA and ARA did not increase the IQ of the children who

Breast milk has significantly higher concentration of cholesterol than infant formula and breasted infants at 6 months have higher cholesterol levels than formula-fed infants [19, 20]. Cholesterol is a significant component of myelin and availability of cholesterol is a rate limiting factor in brain maturation in mice [21]. Therefore it could be argued that higher cholesterol in breast milk result in enhanced synaptic connection, higher degree of myelination of

Human milk contains significant numbers of maternal hormones and growth factors, oxytocin, thyroxin, estrogens, nerve growth and epidermal growth factors, which could influence myelin production and white matter development. Breast milk estrogens are transcriptional promoters for oxytocin and its receptors in the infant's central nervous system [22]. Oxytocin has a central role in milk ejection and oxytocin knockout (OTKO) mice are unable to nurse their pups [22]. Oxytocin binds to a large number of oxytocin receptors and is implicated in regulating homeostatic functions, social recognition and fear conditioning [22]. Additionally oxytocin reduces

in every child achieving his fullest potential.

32 Selected Topics in Breastfeeding

were given the supplemented formulas [18].

the white matter and higher IQ.

**6. Breastfeeding and infant's brain development**

The onset of labor begins with a decrease in maternal progesterone blood level, which results in a rise of maternal estrogens to progesterone ratio. Estrogens are transcriptional promoters of oxytocin gene which initiate uterine contractions. Furthermore estrogens are also transcriptional promoters of oxytocin genes in SON and PVN nuclei in the maternal central nervous system. Oxytocin is transported to the posterior pituitary which then enters the maternal circulation and result in the milk ejection from the breast.

Estrogens in the breast milk enter the newborn's circulation and cross the blood brain barrier. Estrogens act as transcriptional promoter for oxytocin gene in the hypothalamic SON and PVN nuclei. Oxytocin is then transported to a number of oxytocin receptors in the newborn's brain. Imaging studies comparing the activation of oxytocin receptor sites in breastfeeding and formula feeding mothers demonstrate significant enhancement of oxytocin receptors in breastfeeding mothers, which correlates with greater neural response [8] (**Figure 1**) Additionally plasma and salivary concentration of oxytocin are reported to be higher in breastfeeding compared to formula feeding mothers, 36% in plasma and 23% in saliva, respectively [23]. Furthermore the 24 hour urine concentration of oxytocin in breastfeeding mothers is significantly higher compared to formula-feeding mothers [8] (**Figure 2**). Postpartum depression appears to be associated with formula feeding and there is an association between Edinburgh postpartum depression scale and urinary oxytocin concentration [8] (**Figure 3**). Similarly other neuropsychiatric disorders which are highly associated with depression and anxiety may share the low oxytocin levels [3].

There is significant evidence that maternal bonding is mediated by oxytocin and the periaqueductal gray matter (PAG), the limbic system and the lateral orbitofrontal cortex are identified with maternal behavior [8]. There is strong evidence that an enriched environment result in increased release of oxytocin from the hypothalamic nuclei and have permanent effects on the physiology and behavior of mammalian species [9, 24–27]. Furthermore the oxytocinergic system appears to regulate the sensory, emotional, motivational and cognitive pathways which are affected in individuals with neurodevelopmental disorders.

Steroid hormones have significant roles in pregnancy. Progesterone is important in maintenance of gestation and estrogens play a significant role in parturition and lactation. The mother provides the first messenger, estrogens during the labor, via the placenta, to the unborn

**Figure 1.** Brain imaging comparing the oxytocin receptors' enhancement in breastfeeding and formula feeding mothers. From Bartel and Zeki [8].

of estradiol results in an increase in plasma oxytocin level in women [28]. Oxytocin binding with oxytocin receptors result in profound changes in the infant's central nervous system. Other ingredients of breast milk, DHA, ARA and cholesterol significantly augment the role of oxytocin in brain development. However it appears that oxytocin has a central role in brain development and lack of oxytocin or the use of oxytocin blockers significantly alter the behav-

**Figure 3.** Comparison of urinary excretion of oxytocin in breastfeeding and formula feeding mothers. From Grewen

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35

The stages of infant and child development have been well-established and correlate with the stages of neuronal migration and myelination [29, 30] (**Figures 4** and **5**). There is clear evidence that any interruption of neuronal migration and myelination result in impaired brain function. Myelination is an ongoing process into early adolescence, in response to neural activity. Neuropsychiatric and neuro-developmental disorders are strongly considered to be

The incidence of neuro-developmental and neuropsychiatric disorders far exceeds all the other genetic, congenital and sporadic causes of mental deficiencies. Most infants with developmental delays, 30–40 years ago, had chromosomal anomalies (the Downs syndrome), birth defects, cerebral palsy, kernicterus and congenital athyroidism. Autism was quite rare and most physicians had never heard of this disorder. Many physicians are still baffled by it and try to avoid taking care of children with autism. Some physicians do not know what causes autism and believe that the child is born with autism trait. There is also no consensus on which specialist should make the diagnosis and which specialist should be taking care of the child with autism. We believe that autism spectrum disorder is the most common cause of developmental delay in developed countries, because of formula feeding, early weaning and

Approximately 50 years ago, Dr. Julius Richmond, who was my first pediatrics professor and later became US Surgeon General, characterized that child development is the basic science of pediatrics [33]. This statement is still true now, because of the ever increasing knowledge

associated with synaptic disconnectivity involving early white matter development.

ior and neurodevelopment of mammalian species.

et al. [23].

lack of mother-baby sensory interactions [31, 32].

accumulated in the past 2 decades on child development.

**Figure 2.** Urinary excretion of oxytocin in post-partum mothers and Edinburgh post-partum depression scale. From Grewen et al. [23].

infant, and after the delivery through her breast milk. Estrogens are transcriptional promoters of oxytocin and its receptors. The second messenger, oxytocin is released by the infant's hypothalamic nuclei, after breastfeeding and mother-baby sensory interactions. A single dose The Influence of Breastfeeding and the Infant's Social Environment on Neuroplasticity and Brain… http://dx.doi.org/10.5772/intechopen.73209 35

**Figure 3.** Comparison of urinary excretion of oxytocin in breastfeeding and formula feeding mothers. From Grewen et al. [23].

of estradiol results in an increase in plasma oxytocin level in women [28]. Oxytocin binding with oxytocin receptors result in profound changes in the infant's central nervous system. Other ingredients of breast milk, DHA, ARA and cholesterol significantly augment the role of oxytocin in brain development. However it appears that oxytocin has a central role in brain development and lack of oxytocin or the use of oxytocin blockers significantly alter the behavior and neurodevelopment of mammalian species.

The stages of infant and child development have been well-established and correlate with the stages of neuronal migration and myelination [29, 30] (**Figures 4** and **5**). There is clear evidence that any interruption of neuronal migration and myelination result in impaired brain function. Myelination is an ongoing process into early adolescence, in response to neural activity. Neuropsychiatric and neuro-developmental disorders are strongly considered to be associated with synaptic disconnectivity involving early white matter development.

The incidence of neuro-developmental and neuropsychiatric disorders far exceeds all the other genetic, congenital and sporadic causes of mental deficiencies. Most infants with developmental delays, 30–40 years ago, had chromosomal anomalies (the Downs syndrome), birth defects, cerebral palsy, kernicterus and congenital athyroidism. Autism was quite rare and most physicians had never heard of this disorder. Many physicians are still baffled by it and try to avoid taking care of children with autism. Some physicians do not know what causes autism and believe that the child is born with autism trait. There is also no consensus on which specialist should make the diagnosis and which specialist should be taking care of the child with autism. We believe that autism spectrum disorder is the most common cause of developmental delay in developed countries, because of formula feeding, early weaning and lack of mother-baby sensory interactions [31, 32].

Approximately 50 years ago, Dr. Julius Richmond, who was my first pediatrics professor and later became US Surgeon General, characterized that child development is the basic science of pediatrics [33]. This statement is still true now, because of the ever increasing knowledge accumulated in the past 2 decades on child development.

infant, and after the delivery through her breast milk. Estrogens are transcriptional promoters of oxytocin and its receptors. The second messenger, oxytocin is released by the infant's hypothalamic nuclei, after breastfeeding and mother-baby sensory interactions. A single dose

**Figure 2.** Urinary excretion of oxytocin in post-partum mothers and Edinburgh post-partum depression scale. From

**Figure 1.** Brain imaging comparing the oxytocin receptors' enhancement in breastfeeding and formula feeding mothers.

From Bartel and Zeki [8].

34 Selected Topics in Breastfeeding

Grewen et al. [23].

a longitudinal and prospective evaluation of infants and toddlers that identifies the areas of risk and referral for further evaluation and treatment. We have utilized this screening tool to evaluate the association of the score at 24 months of age with the length of breastfeeding. Our hypothesis is that increasing the length of breastfeeding will be associated with a higher score. We are utilizing CSBS DP infant and toddler developmental screen that measures seven language predictors, emotion and eye gaze, communication, gestures, sounds, words, understanding and object use [34]. CSBS DP has been successfully tested for validity and reliability with large samples of children [34]. CSBS DP is not predictor for the child's IQ, however it identifies children at risk of communication disorders and more specific, autism spectrum

The Influence of Breastfeeding and the Infant's Social Environment on Neuroplasticity and Brain…

http://dx.doi.org/10.5772/intechopen.73209

37

One hundred and ten children were screened beginning at 6 months of age. The breastfeeding history of the infants were monitored at every well child visit and recorded. All infants including infants with prematurity, chromosomal disorders, birth defects, congenital infections and genetic disorders were also screened for developmental delay; however, they were excluded from this report. The CSBS DP scores were plotted in relation to the duration of

We have previously reported the association of early weaning and formula feeding with autism spectrum disorder [31, 32]. The present study which was based on our direct observation and prospective evaluation of infants and toddlers is further support that breastfeeding results in better developmental outcome. CSBC DP is predictive of the risk of communication disorders and speech problems in toddlers and we have been able to seek services to assist the families with toddlers as young as 18 months of age. Early diagnosis and treatment of at risk

In our previous study we reported on the impact of the infant feeding methods on the development of the autism spectrum disorder [32, 33]. With the current study we are able to predict that breastfeeding longer than 1 year is associated with higher CSBS DP score and lower risk

United States may have the highest rate of autism in the world because of the lack of paid maternity leave. Many mothers who work in low paying jobs return to work 2 weeks after delivery of their infant and a majority do not breastfeed their babies. Modernization has reduced mother-infant sensory interactions. The infants spend more time in the infant seat on the back seat of the family car, in a stroller or a play pan. Mothers do not hold their babies during feeding and the formula bottle is frequently propped up in the infant's crib or the car seat. The combination of formula feeding and absence of mother-baby sensory interaction

Imaging studies of infants and children as young as 10 months to 4 years of age were performed to compare the myelination of the brain on children who were breastfed for at least

disorder.

**8.2. Results**

**8.3. Discussion**

breastfeeding as shown in **Figure 5**.

children result in better outcome.

increases the risk of developmental delay in the child.

of developmental delays.

**Figure 4.** Stages of brain development during infancy and childhood. From Deoni et al. [35].

**Figure 5.** The relationship of CSBSDP scores with the duration of breastfeeding.

#### **8. Infant and toddler developmental screening**

We have previously reported on the association of formula feeding and early weaning with autism spectrum disorder using retrospective parent's report [31, 32]. In the present communication we report on the association of breastfeeding and improved developmental milestones using prospective and longitudinal infant and toddler developmental screening.

#### **8.1. Material and methods**

All infants had developmental evaluation at the following ages during their well-baby visits, 6, 9, 12, 15, 18 and 24 months. All infants were seen by a pediatrics provider and the mother or the father was asked to answer the questions on the evaluation form. The evaluation form was then scored by the provider and the results were discussed with the parent. Therefore this is a longitudinal and prospective evaluation of infants and toddlers that identifies the areas of risk and referral for further evaluation and treatment. We have utilized this screening tool to evaluate the association of the score at 24 months of age with the length of breastfeeding. Our hypothesis is that increasing the length of breastfeeding will be associated with a higher score. We are utilizing CSBS DP infant and toddler developmental screen that measures seven language predictors, emotion and eye gaze, communication, gestures, sounds, words, understanding and object use [34]. CSBS DP has been successfully tested for validity and reliability with large samples of children [34]. CSBS DP is not predictor for the child's IQ, however it identifies children at risk of communication disorders and more specific, autism spectrum disorder.

#### **8.2. Results**

One hundred and ten children were screened beginning at 6 months of age. The breastfeeding history of the infants were monitored at every well child visit and recorded. All infants including infants with prematurity, chromosomal disorders, birth defects, congenital infections and genetic disorders were also screened for developmental delay; however, they were excluded from this report. The CSBS DP scores were plotted in relation to the duration of breastfeeding as shown in **Figure 5**.

#### **8.3. Discussion**

**8. Infant and toddler developmental screening**

**Figure 5.** The relationship of CSBSDP scores with the duration of breastfeeding.

**Figure 4.** Stages of brain development during infancy and childhood. From Deoni et al. [35].

**8.1. Material and methods**

36 Selected Topics in Breastfeeding

We have previously reported on the association of formula feeding and early weaning with autism spectrum disorder using retrospective parent's report [31, 32]. In the present communication we report on the association of breastfeeding and improved developmental milestones using prospective and longitudinal infant and toddler developmental screening.

All infants had developmental evaluation at the following ages during their well-baby visits, 6, 9, 12, 15, 18 and 24 months. All infants were seen by a pediatrics provider and the mother or the father was asked to answer the questions on the evaluation form. The evaluation form was then scored by the provider and the results were discussed with the parent. Therefore this is We have previously reported the association of early weaning and formula feeding with autism spectrum disorder [31, 32]. The present study which was based on our direct observation and prospective evaluation of infants and toddlers is further support that breastfeeding results in better developmental outcome. CSBC DP is predictive of the risk of communication disorders and speech problems in toddlers and we have been able to seek services to assist the families with toddlers as young as 18 months of age. Early diagnosis and treatment of at risk children result in better outcome.

In our previous study we reported on the impact of the infant feeding methods on the development of the autism spectrum disorder [32, 33]. With the current study we are able to predict that breastfeeding longer than 1 year is associated with higher CSBS DP score and lower risk of developmental delays.

United States may have the highest rate of autism in the world because of the lack of paid maternity leave. Many mothers who work in low paying jobs return to work 2 weeks after delivery of their infant and a majority do not breastfeed their babies. Modernization has reduced mother-infant sensory interactions. The infants spend more time in the infant seat on the back seat of the family car, in a stroller or a play pan. Mothers do not hold their babies during feeding and the formula bottle is frequently propped up in the infant's crib or the car seat. The combination of formula feeding and absence of mother-baby sensory interaction increases the risk of developmental delay in the child.

Imaging studies of infants and children as young as 10 months to 4 years of age were performed to compare the myelination of the brain on children who were breastfed for at least

Monika Mustafa MD, Fellow of American Academy of Pediatrics, Assistant Clinical Professor

The Influence of Breastfeeding and the Infant's Social Environment on Neuroplasticity and Brain…

http://dx.doi.org/10.5772/intechopen.73209

39

Lida Niake, Research Assistant, assisted in data collection and creating the graphs for the

The opinions expressed in this manuscript are only the opinions of the authors. The authors

[1] Volkmar FG, Greenough WT. Rearing complexity affects branching of dendrites in the

[2] Weaver ICG, Chevroni N, Champagne FA, et al. Epigenetic programming by maternal

[3] Carter CS. Developmental consequences of oxytocin. Physiology & Behaviour Elsevier

[4] Infant and Young Child Feeding, Fact Sheet, World Health Organization on Global Rates

[5] Shafai T, Mustafa M, Hild T. The promotion of exclusive breastfeeding in low income families by improving the WIC food package for breastfeeding mothers. Breastfeeding

[6] Unvas-Moberg K, Prime DK. Oxytocin effects in mothers and infants during breastfeeding.

[7] Klaus M. Mother and infant: Early emotional ties. Paediatrics. 1998;**102**(Supplement E1):

and Lida Niake2

, Sandra Compsos2

1 University of California, School of Medicine, Riverside, California, USA

of Pediatrics at University of California, Riverside, School of Medicine.

Sandra Campos PAC, assisted in data collection.

manuscript, Undergraduate biology major.

\*, Monika Mustafa1

\*Address all correspondence to: shafaidocs@yahoo.com

2 Children's Medical Group, Riverside, California, USA

visual cortex of the rat. Science. 1972;**176**:1445-1447

behaviour. Nature Neuroscience. 2004;**7**:848-854

of Breastfeeding; February 2015 Bulletin

**Conflict of interest**

**Author details**

Touraj Shafai1

**References**

declare no competing interest.

Inc. 2003;**79**:383-397

Medicine. 2014;**9**:375-376

Infant. 2013;**9**:886-897

1244-1246

**Figure 6.** Association of improved myelination with duration of breastfeeding. From Deoni et al. [35].

3 months, those who were only formula-fed and those who were given mixed breast and formula [35]. The results of this study provide further evidence that breastfed infants have higher degree of myelination compared to the other two groups of children who were formula-fed or given mixed feeding. Furthermore longer duration of breastfeeding results in greater brain myelination as shown in **Figure 6**. The myelination occurs primarily in frontal and temporal white matter, peripheral aspects of the internal capsule and corticospinal tracts, superior longitudinal fasciculus and superior occipital-frontal fasciculus. These regions and pathways are associated with higher order cognition, executive functioning, planning, social-emotional functioning and language [35]. Therefore we can connect structure and function, increased level of myelination with increasing breastfeeding duration. Additionally the percentage of breast milk in an infant's diet has been correlated with cortical thickness in the parietal lobe as well as verbal IQ in adolescents [16].

#### **8.4. Conclusion**

We have documented the superiority of breastfeeding and an enriched environment resulting in higher cognitive ability and IQ. We have also shown that infants should be at least breastfed for the first 3 years of life to realize the maximal benefits of breastfeeding. We have presented strong and convincing evidence from various disciplines that breastfeeding result in higher IQ and cognitive functions that last into adulthood. Early weaning and formula feeding are associated with higher prevalence of childhood communicable diseases, diabetes, childhood leukemia, sudden infant death and autism. Additionally formula feeding strains the health care and public education systems with increased demands and higher expenditures.

The first 1000 days last a life time the rest of our lives, and every child deserves to reach his fullest potentials.

#### **Acknowledgements**

Touraj Shafai MD, PhD (Biochemistry), Fellow of the American Academy of Pediatrics and Fellow of the Academy of Breastfeeding Medicine. He is Assistant Clinical Professor at University of California, Riverside, School of Medicine.

Monika Mustafa MD, Fellow of American Academy of Pediatrics, Assistant Clinical Professor of Pediatrics at University of California, Riverside, School of Medicine.

Sandra Campos PAC, assisted in data collection.

Lida Niake, Research Assistant, assisted in data collection and creating the graphs for the manuscript, Undergraduate biology major.
