Student: Carolain Alejandra Lopez Lopez Supervisor: prof. Jolanta Kudzytė

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LITHUANIAN UNIVERSITY OF HEALTH SCIENCES

FACULTY OF MEDICINE

DEPARTMENT OF PAEDIATRICS

COMPLEMENTARY FEEDING:

WHEN AND WHAT?

Student: Carolain Alejandra Lopez Lopez

Supervisor: prof. Jolanta Kudzytė

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ABSTRACT

Aim: Complementary Feeding (CF) marks the introduction of the first solid and liquid foods, other

than breast milk, given to infants to meet healthy nutritional requirements. Allergenic foods are included into the CF category and refer to those foods known to potentially induce an immune reaction. The goal of the study is to determine the types of CF, the best suited time for their introduction, and the effect of early or late CF and allergenic food introduction on infant’s health.

Materials and Methods: Articles from PubMed, NCBI Research Gate were collected and analyzed to

meet the most suitable criteria, excluding non-English, non-human and including filters: last 10 years, free full text and infants. The search through PubMed NCBI was conducted using Key words:

complementary feeding, allergenic food, childhood overweight, infant sleep, anemia, feeding

difficulties, asthma, and atopic disease. The initial search resulted in the collection of 1861 articles and after filter addition 50 articles were left for literature review and 10 for discussion. 1 additional article was added through BMC Public Health.

Results: 1 pilot and 1 supplemental study concluded that various countries start with the introduction

of different types of CF and the best ages for introduction are between the 4-6 months of age. 2 cross- sectional, 4 cohorts, 2 randomized trials, 1 systematic review concluded that the timing of CF affect the development of health outcomes such as obesity, anemia, feeding and sleeping difficulties.

Additionally, it was determined that allergenic foods introduction time also impact the infant’s health in the future development of allergies.

Conclusion: First CF given varies among several countries and is introduced between the ages of 4-6

months. The early or late CF introduction increases the risk of obesity and anemia while sleeping and eating difficulties results remain inconclusive. The early allergenic food introduction of eggs and peanuts decrease their allergy development risk, whereas the late increases the risk. Early fish and gluten introduction decrease the risk of asthma and atopic dermatitis respectively, with no effect in the case of late introduction.

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ACKNOWLEDGEMENT

I would like to give my most sincere gratitude to my supervisor prof. Jolanta Kudzytė for guiding me throughout the undertaking of my master thesis.

CONFLICT OF INTEREST

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LIST OF ABBREVIATIONS

 AAP – American Academy of Pediatrics

 APAPARI – Asia Pacific Association of Pediatric Allergy, Respirology and Immunology

 BEAT – Beating Egg Allergy

 BSACI – British Society for Allergy and Clinical Immunology

 BF – Breastfeeding

 CF – Complementary Feeding

 CPS – Canadian Pediatric Society

 DGKJ – Deutsche Gesellschaft für Kinder- und Jugendmedizin (German Society of Pediatrics and Adolescent Medicine)

 EAACI – European Academy of Allergy and Clinical Immunology

 EAT – Enquiring About Tolerance

 EIG – Early Introduction Group

 EBF – Exclusive Breastfeeding

 EFSA – European Food and Safety Authority

 ESPGHAN – European Society for Pediatric Gastroenterology Hepatology and Nutrition

 EU – European Union

 HEAP – Hen’s Egg Allergy Prevention

 IU – International Units

 LEAP – Learning Early About Peanut Allergy

 NHMRC – National Health and Medical Research Council

 PETIT – Prevention of Egg Allergy in Infants with Atopic Dermatitis

 SIG – Standard Introduction Group

 STAR – Solids Timing for Allergy Research

 UAE – United Arab Emirates

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INTRODUCTION

Complementary feeding (CF) is defined as the start of using solid foods and liquids at a time when breast milk or formula feeding is not sufficient in itself to comply with the infant’s nourishment requirements. During the CF time frame, several variations in the infant’s diet are introduced including changes in food consistency and flavors that were previously never tried by the infant. Regardless of these variations, in order to promote the optimal growth and development of an infant especially during the first 2 critical years of life and to relish the short-term and long-term health benefits associated to well-organized CF, it is imperative for CF to provide the essential macro and micronutrients at the right time (8,10).

The time of introducing CF differs notably between countries of higher and lower income. Interestingly, these differences can be noted especially among countries with diverse cultures

including some in Europe. Generally, the introduction of complementary feeding is performed earlier in lower income countries than in higher income countries where CF is usually introduced closer to the stipulated time as suggested by the guidelines. The World Health Organization (WHO) guidelines conclude that infants should be exclusively breastfed for the first 6 months of life and only thereafter can CF be introduced. On the other hand, the ESPGHAN guidelines state that the introduction of solid foods can begin already after the first 4 months of life, however, similarly to the guidelines by the WHO the optimal recommended feeding time was also at 6 months of life. Despite these official recommendations, several countries introduce CF at different times possibly due to their cultural, geographical and socioeconomic differences. (9,11,49)

A clear distinction should be made between the difference of CF and allergenic food introduction. While the former refers to all the essential nutrients needed for the child’s adequate development, the latter implies the exposure of infants to specific allergenic foods during the crucial period of immune development in the aim of inducing some sort of tolerance to the allergen. (34) The relationship between the timing of CF and allergenic food introduction impact on infant’s health is still not entirely clear, however it is presumed to play a significant role.

This literature review aims to determine the first types of CF given in various countries, clarify the best suited time for their introduction and to find out whether there is any impact on the infant’s health with the early or late CF and allergenic food introduction.

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AIMS AND OBJECTIVES

Aim: To investigate the types of infant’s complementary feeding and allergenic foods and its impact

on child’s health according to the time of introduction.

Objectives:

1. To find out what types of complementary food are given to infants in various countries. 2. To determine the best suited time to introduce complementary feeding to the infants.

3. To find out the importance of early or late introduction of complementary food to the infant’s health.

4. To determine the importance of early or late introduction of allergenic food to the infant’s health.

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1. LITERATURE REVIEW

Complementary Feeding

Definition

The start of using solid foods and liquids when breast milk or formula feeding is not sufficient to comply with the infant’s nourishment requirements. (8)

Types of Complementary Feeding

There is a clear intercontinental difference on what CF are given to infants, one of the reasons why is mainly due to the wide variety of cultures around the world. Nonetheless, all infants should meet certain nourishment daily requirements for their appropriate development and growth. (1) Nutritional recommendations on CF for infants between 6-12 months are as follows:

1. The daily energy requirements are 70-75 Kcal/Kg/d.

2. The carbohydrate intake should be between 45-60% of the total amount of calories. It is preferable to include starchy foods such as bread, cereals, pasta, potatoes and rice and avoid sugars like fruit juices and sweetened products.

3. Lipid requisites comprehend 40% of the total calories but no less than 25%, limiting saturated fats and giving preference to unsaturated ones such as the ones from fish origin.

4. Protein intake requirements are around 10% (1,1 g/Kg/d).

5. Legumes, fruit and vegetables rich in fibers are recommended as well.

6. It is important to remember the consumption of micronutrients such as vitamin D (400 IU) in foods like cod liver oil, fish, butter, cheese and egg and iron (7 mg/day) in meats and fish.

7. As a last remark, it is recommended not to add additional salt and sugar to the infant’s food. (2)

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As adapted from D’Auria et al. (3)

As it was mentioned before, various countries start with different types of CF which differ among them due to geographical, socioeconomic and cultural reasons, among others. For instance, in Lithuania, CF is usually started from the average age of 6 months, starting with pureed vegetables or cereal and in later ages including various foods such as fruits, meat, fish and others. (50)

Table 1. Timing of Complementary Feeding (50)

Food Time Notes

Infant formula From the moment when the amount of mother’s

milk is insufficient

-

Pureed vegetables From 6 or 8 months Best to start with potato puree.

Pureed cereal From 6 or 8 months Best to start with pureed rice, as it is the least

allergenic.

Oil, butter From 6 months Added to purees only.

Fresh fruits, berries, vegetables and their juices

From 6.5 months Manufactured purees should only be given if fresh ones

are not available. Meat, beef liver From 7 months Cooked veal and rabbit

meats are the best because their iron is absorbed most

efficiently. Fish From 10–12 months Cooked low-fat fish is the

best choice. White bread, rusks When the baby wants to No more than 5 – 20 g a

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Adult’s food (mashed, without spices)

From 10–12 months Introduced gradually, little by little, teaching to chew.

Cottage cheese, egg, cow’s milk, goat’s milk

Not recommended in the first year. Cow’s milk can be added to pureed cereals.

Meat and fish broth Not recommended to infants and children because it is a very allergenic low nutrient

meal containing toxic ingredients.

On the other hand, in Spain, the first types of CF given are cereals and fruits at the average age of 5 months. Vegetables are given later, at the age of 6 months on average, followed by yogurt and meat at 7 months. Usually, foods like fish, cheese, eggs and legumes are introduced later, at the ages of 9, 9 and a half, 10 and 11 months of age, respectively. (49)

Figure 2. The age of introduction of each food category into the Spanish infants’ diets.

As adapted from Klerks et al. (49)

In another Mediterranean country, Italy, the first solid foods given are fresh fruits at a median average of 5.6 months and then vegetables at around 6 months of age. Cereals, bread, pasta and rice are introduced at the ages of 6.3 months; milk products at 6.2 months and meat at around 6 and a half months. The last foods to be introduced are cow’s milk and honey (around 1 year of age) and nuts and seeds at almost 16 months of age. (52)

As for other European countries, there are several examples that could be mentioned: In Norway, CF introduction starts usually with industrially made porridge from 5.5 months of age. (53) Irish infants’ first foods are commonly baby rice and less often, infant cereals, and fruits or vegetables. The timing of their introduction is between the 17 and 26 weeks of age. (54) Recommendations on the

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first solid foods in Germany include the introduction of mashed vegetables, potatoes and meat followed by cereal milk or fruit porridge, with an average introduction at the age of 6 months. (55) In Abu Dhabi, a city belonging to the United Arab Emirates (UAE), the most popular first foods are fruits and vegetables (especially potatoes, carrots, apples, bananas and squash), cereals and rice. (56)

The most frequent types of first foods given to infants in some of the Asian Pacific regions (Australia, China, Japan and Vietnam) are rice or their derivatives. In contrast, in the Maldives, wheat flour and fish are being introduced first as part of their national food tradition. (4) Interestingly, among infants coming from Hawaii, the Philippines and other areas of the Pacific Islands, the most common CF given at first is their traditional poi, made from steamed mashed taro. (5)

On the other hand, within African countries, fish and leafy vegetables consumption is surprisingly high and play an important role in the infant’s nutrition process, whereas in South Asia, grains are the most common solid foods provided for infants from the age of 6 months (other CF such as fruits, vegetables and meat are less prominent). (6,7)

Unexpectedly, in Canada, some researches stated that CF was started as early as 3 months with the introduction of rice cereals predominantly, fruits and vegetables in less amounts and the later introduction of meat and dairy products. (51) There is some worrisome data from the United States that suggest that 18-33% of infants starting from 7 months of age did not consume a wide range of vegetables and almost 33% of them did not consume any types of fruits. Shockingly, French fries were one of the most commonly consumed foods among the ages of 9 to 11 months and almost 50% of infants between 7 and 8 months of age already have some sweets incorporated into their diet. (60) This is a serious topic of concern because the poor diet of these infants can bring about negative health outcomes in the future such as an increased risk of overweight and obesity.

Timing of introduction of Complementary Feeding

CF introduction time differs among various countries around the world. This difference can be noted even among countries inside the European Union (EU). In general, in lower income countries (such as Latin American countries), the introduction of complementary feeding is presented earlier (at 2-3 months of age) compared to higher income countries (commonly between 4-6 months). This is a very severe issue, since the incorrect introduction of CF in such early ages might result in

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12 The early introduction of CF in South America, East Asia and the Caribbean region is

especially troublesome, with introductions of solid foods to infants within the ages of 4 months and even earlier. On the other hand, 1/3 of infants at 6-8 months in other intercontinental regions have still not been introduced to CF. (9) The timing of CF introduction is key because for instance, the early introduction of solids could involve a shorter period of EBF, which subsequently has been

demonstrated to increase the risk for morbidity. (4) Despite the fact that several countries around the world introduce CF at different times, there are standard recommendations from the World Health Organization (WHO), which state that infants should be EFB until the age of 6 months following only at around this age the subsequent introduction of CF. (9,10) Additionally, the ESPGHAN guidelines recommend to EBF until the age of 6 months, with a minimum duration of EBF until the age of 4 months, recognizing that some infants might need an earlier introduction of CF before 6 months, but never earlier than 4 months. (11)

Table 2. Appropriate age of introduction of specific foods recommended by the current guidelines as

per ESPGHAN (12)

Appropriate age

Wheat Over 24 weeks

Rice Over 17 weeks

Cow’s Milk Over 52 weeks

Meat Over 17 weeks

Poultry Over 17 weeks

Fish Over 24 weeks

Eggs Over 24 weeks

Yoghurt Over 24 weeks

Honey Over 52 weeks

Fruit Over 17 weeks

Vegetables Over 17 weeks

Furthermore, the timing of introduction of CF is not only affected by the increasing

nutritional demands with age, but additionally by the infant’s neurological maturity and other factors such as food interest. (2)

Table 3. The appropriate timing of CF introduction according to the physiological and neurological

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Age Physiological/Neurological maturation

At birth Self-feeding based on nutritive suckling reflex

4 months Child is able to metabolize nutrients due to

maturation of renal and gastrointestinal function

4–6 months -Cortical and cognitive development improve tongue

mobility, associated with increasing oral cavity volume

-Progressive control of oral food transport

-Motor skills required to accept and swallow pureed complementary feeding

6 months Appearance of temporary inferior and superior

incisors to handle biting

9–12 months -Motor skills required to handle semisolid foods or

self-feeding

-Infant can drink from a cup using both hands -Infant can eat adapted family foods

12–18 months -Appearance of molars improving intraoral food-

mixing ability

6 years Complex, specialized, and structured oral

movements

Further recommendations provided by The European Food and Safety Authority (EFSA) and the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) suggest that CF and allergenic foods that are introduced between 4 and 6 months diminish the risk for food allergies. Furthermore, the European Academy of Allergy and Clinical Immunology (EAACI) recommend the introduction of allergenic foods no later than the 4 months of age. (13,14)

Naturally, there are many other guidelines within various countries all around the world. Examples of such include: The Dutch Nutrition Centre guidelines which approve the start of CF between the ages of 4-6 months (11); The German Society of Pediatrics and Adolescent Medicine (DGKJ) which issued recommendations on CF to include the initiation of such no later than the start of 7 months of age, but not earlier than the beginning of 5 months in infants. (15); The American

Academy of Pediatrics (AAP) which announced that CF should not be started before the age of 6 months. (4); In Asia, guidelines among countries differ as well. For instance, the Ministry of Health of China recommended that the introduction of CF should commence after the age of 4 months, while the National Health and Medical Research Council (NHMRC) infant feeding guidelines of Australia approve the commencement of solid foods at the age of 6 months. (4)

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14 These aforementioned guidelines apply only for full-term infants, since preterm infants have higher demands for nutritional requirements. Consequently, official guidelines for this group are absent. Nevertheless, some evidence suggests that CF could be introduced earlier in this case to compensate for the higher dietary needs, so that the start is to be set at the age of 3 months. (16)

Health Outcomes according to CF timing of introduction

Obesity

Obesity during childhood is one of the most serious concerns in the world. The incidence has increased over the years and it is currently considered a global epidemic with 20% of school children in the EU and 31.8% of US children and teenagers affected by it. Therefore, obesity is currently a public health priority task mainly within developed countries. (42) The consequences of obesity are numerous including heart disease, metabolic syndrome, rheumatologic and endocrinology problems, among others. From the very early years of life of a child, there is a crucial window of time where reaction to stimuli, hormonal changes and dietary habits are the most important factors to potentially prevent obesity during adulthood. For this reason, it is undeniably important to promote healthy eating lifestyles for infants, paying special attention during their CF introduction times. (17,18)

Several studies have been conducted to investigate whether there is a relationship between the early or late introduction of CF and the development of childhood obesity. While some studies

concluded that there is indeed an association, some others deny this correlation and determine that there is no link between timing of introduction of CF and obesity in childhood. On the other hand, many remain inconclusive due to inconsistent evidence (3,19,20)

A study was conducted by Bell et al. with 953 children from Australia who participated in a cohort study (SMILE). Online questionnaires filled in by the mothers were collected at 3, 4, 6, 12 months and 1 year of age and contained information about the duration of BF and the age of

introduction of CF of these children. The weight and height of the infants were monitored and their BMI was calculated. Based on the results, it was concluded that the early or late CF introduction exhibited no link with obesity outcomes in children at the ages of 24 to 36 months. (21,22,23)

A systematic review lead by Pearce et al. studied the link between early CF introduction and childhood overweight. Data was collected regarding the age of CF introduction in children up to 1 years of age and their BMI or body fat percentage measures. The data was collected from several

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countries including Australia, UK, Denmark, Brazil, China and India, among others. From all the data collected, it was determined that the early introduction of CF (before 4 months of age) may lead to a higher risk for childhood obesity. These findings could be due to the thought that CF introduction increases ghrelin hormone secretion, which activates the hunger mechanism and in turn increases the food consumption by the infant, who consequently will be at a higher risk for childhood obesity. (42)

A study conducted by Tahir et al. collected information from the Nurses’ Health Study (NHS) II prospective cohort study. The data was analyzed and it was discovered that the late introduction of CF at 9 months of age or later was associated with a higher risk of obesity at the age of 5 years. The reason remains uncertain, nevertheless, there seems to be a sensitive period of time when the late CF introduction affects the child’s health in a negative manner, causing feeding difficulties and

diminished consumption of fruits and vegetables. (17)

Anemia

Anemia is described as a hemoglobin (Hb) concentration of less than 110 g/L, as stipulated by the WHO diagnostic indicator. Iron deficiency anemia is quite frequently seen in children. It is a sign of poor health and nutrition conditions and leads to a negative impact in the neurological development of the child, leading to worse outcomes in terms of cognitive and physical performance status. (24) Iron amount in breast milk is plenty sufficient only for the first 6 months of life, therefore CF should be adequately introduced in time to suffice the needs of the growing infant to avoid anemia. In 2013, a report approximated the prevalence of global anemia to be the highest in children less than 5 years old (43%), especially those living in Asia and Africa. According to the WHO, half of these cases of anemia arise from iron deficiency. Therefore, special attention should be paid during the ages of 6 to 11 months when the iron requirements are the highest. (25,26)

A cross-sectional study was conducted among 485 children between the ages of 6-23 months in South Ethiopia. Blood samples were collected to determine Hb concentration and age of

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16 diagnosed with iron deficiency anemia and according to the results, it was concluded that the early or late (before 4 months or after 6 months of age) CF introduction lead to a twofold increased risk of childhood anemia. (26)

Infant sleep

Sleep is one of the most essential steps for the appropriate cognitive and physical

development of a child. Nowadays, sleeping difficulties are quite prevalent, with 20-30% of children younger than 3 years of age suffering from these, which commonly manifest as short duration of sleep and frequently waking up at night. Many studies have reported correlations between infant feeding and sleeping difficulties.

For instance, the French national birth cohort ELFE noted the relationship between early introduction of CF at less than 4 months of age with higher sleep onset difficulties and shorter total sleep duration (<12 hours of sleep/day), specifying that the early introduction (before 5 months) of infant cereals was associated with poor sleep quality outcomes. Furthermore, the later introduction of CF (at >6 months of age) was linked to a decreased risk of sleep onset difficulty. This study disagrees with the common popular belief among parents that the early introduction of CF promotes a better sleep quality for infants, which can have favorable long-term health effects such as the decrease risk of obesity and diabetes. (27)

On the other hand, a few studies suggest that the early introduction of CF induces a better sleep quality for infants. This is the case of the secondary analysis by Perkin et al. with 2 randomized groups of infants. The first group was assigned to an early CF introduction, whereas the second group was assigned to a standard CF introduction (at 6 months of age). Infants from the first group slept on average 7 minutes longer during the night than those in the second group, with 17 minutes more of sleep being the maximum difference at 6 months. Although this study confirms the common belief among parents, further research is still needed to confirm that this method indeed improves infant sleep. (29)

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Feeding difficulties

As it is well known, the recommended timing for introduction of CF has changed over the years. For example, in the 1950s, guidelines suggested that CF introduction should start from the age of 2 months, whereas in the 1900s it was recommended to start CF only from the age of 9 months. Currently in the UK, guidelines propose EBF until the age of 6 months followed only then by the introduction of CF.

Some studies suggest that there are critical periods of time when infants are more receptive to newly introduced flavors and consistencies. As an example, a study carried out by Northstone et al. compiled data from the Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC): Infants were divided into 3 groups according to the age when they were introduced to their first lumpy foods. The first group encompasses around 10% of the infants introduced to lumpy solids at less than 6 months of age; the second group (~ 70%) between 6 and 9 months of age; and the third group (~20%) after 10 months. Based on the observations, it was concluded that those infants who were introduced to lumpy foods at the ages of 10 months or later developed higher risks for feeding difficulties. Despite these results, there is still little known about children’s eating difficulties and their relationship with the timing of CF introduction, therefore more research is needed to clarify the correlation between the two. (30,31)

Allergenic Foods timing of introduction and Infant’s Health

Throughout the infant’s life, there is a hypothesized critical period of time at around 4-6 months of age, when the process of acquiring immune tolerance is at its most sensitive stage. It is well- known that the infant’s diet contains all the important elements for the production of metabolites which up regulate the infant’s immune response and tolerance. For this reason, it was thought that there is a possibility that allergenic foods which are introduced early during the infant’s life could take part into the infant’s immune tolerance process and therefore impact the occurrence of allergy

sensitization and atopy. Moreover, since anaphylactic reactions are life-threatening situations, any developments on avoiding food allergies would be undoubtedly extremely beneficial. Several studies have been conducted to investigate this area of research, however there is still controversy on whether the timing of introduction of allergenic foods actually plays any significant role in the phenomenon of allergic sensitization. (14)

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18 There are many popular studies who based their research on the aforementioned statement. Examples of these studies include: The Learning Early About Peanut Allergy (LEAP); Enquiring About Tolerance (EAT); Solids Timing for Allergy Research (STAR); Prevention of Egg Allergy in Infants with Atopic Dermatitis (PETIT); Hen’s Egg Allergy Prevention (HEAP); Beating Egg Allergy (BEAT), among others. (45,57,61)

The EAT study is a randomized controlled trial with 1303 infants of 3 months of age who were divided into 2 groups. The first group referred to infants in the early introduction group (EIG), who were introduced early (from 3 months of age) to several types of allergenic foods (cow’s milk, peanuts, egg, sesame, cod and wheat). On the other hand, the infants who belonged to the standard introduction group (SIG) were not introduced to allergenic foods before the age of 6 months and followed the British recommendations of EBF until 6 months of age. According to the findings, one of the conclusions was that the early introduction of allergenic foods had no negative impact on the duration of BF. This is significantly important due to the fact that according to certain studies, BF provides a positive effect of tolerance induction in those individuals with allergic disease.

Furthermore, the study concluded that the early introduction of eggs and peanuts decreased the future risk of such food allergies. When comparing both groups, the EIG had a diminished risk of egg and peanut allergy (1,4% and 0% respectively) compared to the SIG (5,55 and 2,5% respectively). Interestingly, there was no difference in allergic disease development within the remaining food allergens among both groups. (57)

In addition to the study mentioned above, many other studies concord with the conclusion that the early introduction of allergenic foods is beneficial in avoiding food allergies. More examples include a systematic review article conducted by Larson et al. suggesting, that those infants that are at low risk for food allergies should be introduced early to allergenic and complementary foods,

especially between the 4-6 months of age, since supposedly the late introduction of both predisposes children to a higher risk for allergic disease development in the future. Similarly, a retrospective case- control study by Onizawa et al. determined that introducing cow’s milk in an early fashion lead to its lower incidence of IgE sensitization risk. (43,46)

In contrast, the HEAP study results demonstrate another perspective on this matter. This study is a randomized placebo-controlled trial which included 800 infants of 4 to 6 months of ages who were randomly given either egg white powder or rice powder 3 times per week from 4-6 months of age until the age of 1 year. The results showed that more infants receiving egg white powder were confirmed to have egg allergy at the age of 1 year than those only receiving placebo (2.1% vs 0.6%).

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Therefore, it was determined that the early introduction of eggs at the ages between the 4 and 6 months do not decrease the risk of egg allergy and this early egg introduction could in turn result in more allergic reactions. (58)

In addition to the aforementioned study, a study conducted by Hicke-Roberts et al. investigated about whether the late introduction of solids might be a risk factor for the future

development of food allergy within children from southwestern and northern Sweden. Questionnaires were distributed within the population to be studied enquiring about allergies or intolerances that these children currently have to attempt to relate it to their eating habits as they were infants. Questions were specific and asked about allergies towards cow’s milk, fish, peanuts, cereals and nuts and age of

introduction of these. As a result, after a thorough analysis of all the data, it was concluded that the late introduction of solids after the age of 7 months was related to a higher incidence of self reported allergies. (48).

Despite these aforementioned studies, current recommendations from the WHO, the EAACI, the AAP, the EFSA, the ESPGHAN and the British Society for Allergy and Clinical Immunology (BSACI) show the absence of sufficient information about the appropriate timing of allergenic food introduction for the prevention of allergic disease. Therefore, it is of critical importance to conduct more research with the aim to obtain unanimous guidelines that are currently of utmost importance. However, some Asian countries have decided to introduce recommendations on the aforementioned topic in an attempt to clarify the current uncertainty, such as those guidelines issued by the Asia Pacific Association of Pediatric Allergy, Respirology and Immunology (APAPARI) 2018 that recommend the introduction of allergenic foods from the 6 months of age in all infants. (32,33) There are also increasing affirmations such as the Canadian Pediatric Society (CPS) article, where it is denoted that the early allergenic food introduction between the ages of 4 and 6 months could

potentially prevent food allergy, especially egg and peanut allergies in infants who are at high risk of allergic disease development. Hence, for those infants at high risk, the new recommendations for allergenic products encompass the introduction of these at approximately the age of 6 months and not earlier than 4 months. Following this advice, food allergens could potentially be introduced

simultaneously at the time of CF introduction by the age of 4 months. (36,37,45)

One clarification that it is needed to be mentioned at once is the distinction in terminology between allergenic food and CF introduction, since there seems to be some confusion between these terms in the current literature. Allergenic foods refer to those foods to be known to commonly cause a

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20 potential immune reaction. (34) As of today, the most common allergenic foods are: eggs, fish, cow’s milk, peanuts, nuts, fish, shellfish, soy and wheat, among others. (35)

Asthma

Asthma and food allergy are two of the most prevalent conditions globally and they frequently end up coexisting together. It has been proved that food allergy is a risk factor that could lead to the predisposition of asthma and that both conditions together increase the chances of an anaphylaxis reaction in the case of exposure to a food allergen. As determined by Roberts et al., children who suffered from food allergy were 6 times more likely to develop asthma in comparison to children who were not diagnosed with food allergies. Since both conditions produce a negative impact on the child’s health, several measures such as the early introduction of allergenic foods and the appropriate care of the skin barrier have been introduced and linked to prevent the occurrence of asthma and food allergy. (39)

The prospective longitudinal study cohort in western Sweden aimed to determine the impact of early fish introduction and the risk of asthma development in 4051 children born in 2003. At the age of 8 years, 5.7% of the children were diagnosed with asthma and from these, 65% suffered from atopic asthma whereas the rest had non-atopic asthma. At the end of the study, it was determined that early fish introduction to infants before 9 months of age decreases the risk of asthma in children during their school ages. Moreover, the study found out that this positive effect was only true for the children diagnosed with atopic asthma, finding no significant difference among those children with non-atopic asthma. (47) Despite this study, the timing of introduction of different types of CF or allergenic foods (besides fish) in relation to asthma or atopy have not been quite researched. Therefore, more

investigations are needed to shed light on the relationship between asthma and allergenic food introduction time. (40)

Atopic dermatitis

Atopic dermatitis is one of the most frequent skin conditions in children and it is one of the most troublesome to both children and parents. Globally, the incidence is increasing in developed

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countries, therefore efforts to diminish its incidence have been contemplated. For example, many studies have been carried out to investigate the possible interaction between the timing of introducing CF and the atopic dermatitis risk. A systematic review and meta-analysis led by Waidyatillake aimed to determine whether there was a relationship between the timing of allergenic food introduction and atopic dermatitis. After several sources had been reviewed, the authors concluded that there was not sufficient data to find out if both factors were related, however, a mild correlation was found out: according to one randomized controlled trial, there was a weak link between early allergenic food introduction (at 4 months of age) and the decreased risk of atopic dermatitis. Additionally, only one birth cohort study determined that the late introduction of allergenic foods increased the risk of eczema. (41)

The KOALA birth cohort study conducted in Southern Netherlands collected data from 2558 infants about the timing of cow’s milk introduction and other allergenic products and the main

outcomes in these infants, such as the occurrence of atopic dermatitis. Questionnaires were collected at several periods of time enquiring about any allergies or sensitizations towards cow’s milk, egg or peanuts at 3 and 7 months of age and 1 and 2 years of age. The results concluded that the delay of introduction of cow’s milk in the infant’s diet resulted in an increased risk of atopic dermatitis and in addition, the delay of introduction of other foods was linked to an increased risk of atopy occurrence at 2 years of age. (59)

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2. METHODOLOGY

This systematic review was written according to the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P). The following key words were used combined to collect the literature used in this review:

(Global complementary feeding practices) OR (timing allergenic food introduction AND allergic disease) OR (infants AND introduction of allergenic foods) OR (complementary feeding AND infant’s health) OR (introduction of solids AND infant body mass) OR (timing of solid food AND childhood overweight) OR (early introduction of solids AND infant sleep) OR (age of complementary foods AND anemia) OR (age solid foods AND feeding difficulties) OR (introduction of fish AND risk of asthma) OR (allergenic food introduction AND childhood atopic disease)

The initial search was conducted on PubMed with the above mentioned key words and 1861 results were obtained. Afterwards, the following filters were added: free full text, articles’ publication date within the past 10 years, human studies, English text and infants (birth-23 months). After the application of such filters, 576 articles were left for further screening. Out of those 576 articles, titles and abstracts were read and 516 were discarded due to their irrelevancy to the topic of interest, thus leaving 60 articles remaining, out of which 10 were used for the discussion section and 50 for the literature review. Finally, one additional article was added through BMC Public Health for the discussion part.

Table 4. Inclusion and exclusion criteria

Inclusion criteria Exclusion criteria

Free full text Studies conducted on animals Articles within the past 10 years Non-English texts

Studies conducted on human beings Not CF specific

English text Literature reviews

CF and allergenic foods specific Adults

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Figure 3. Prisma flow chart on article selection for the literature review

1 additional article was added through BMC Public Health Identification PubMed 2011-2021 N=1861 Screening

Remaining articles after filters and screening

N=576

Eligibility

Exclusion and Inclusion criteria applied

N=60

Articles used in the literature review

N=50

Articles used in the discussion section

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24

3. RESULTS

Table 5. Summary of the 11 articles included in the final master thesis discussion

Year of the study Author Study type Summary

2010 Allcutt and

Sweeney (12)

A pilot study Appropriate age of introduction of specific CF products

2017 White et al. (9) Supplemental study Recommended age of introduction of CF

2016 Sun et al. (18) Cross-sectional study

Early (<4 months) and delayed (>7 months) CF introduction  increases risk for obesity. Aor for 4 months = 1.75. It is within the 95% CI (1.10-2.80). aOR for >7 months = 2.64. It is within the 95% CI (1.26-5.54) (18) 2018 Papoutsou et al. (22) Cross-sectional study Late (>7 months) CF introduction  increases risk of obesity. OR 1.38, within 95% CI, 1.01-1.88. Early (<4 months) CF introduction  decreases risk of obesity. OR 0.63,

(25)

within 95% CI, 0.47-0.84 (22) 2017 Wang et al. (25) Cohort study Earlier CF

introduction (3-6 months)  higher risk of anemia and lower Hb. OR 1.14; 95% CI: 1.01–1.28 (25)

2018 Perkin et al. (28) Randomized clinical trial

Early introduction of solids (<6 months)  longer infant sleeping times. Infants in the early introduced group slept 16.6 minutes longer compared to the standard introduction group. (within 95% Confidence Interval, 7.8-25.4) (28)

2016 Hollis et al. (30) Cohort study CF introduction at >=6 months  decreased risk of feeding difficulties (95% CI 0.59 – 0.91) (30)

2016 Perkin et al. (44) Randomized trial Early introduction of CF group  lower prevalence of

(26)

26 other foods allergy

development compared to standard introduction group (peanut: 0% vs. 2.5%; egg: 1.4% vs. 5.5%) (44) 2016 Ierodiakonou et al. (37) Systematic review and meta-analysis Early peanut introduction (4-11 months); early egg introduction (4-6 months);  decreased risk for these allergies. Risk ratio 0.29; 95% CI, 0.11-0.74 and risk ratio 0.56 and 95% CI, 0.36- 0.87, respectively. (37)

2019 Klingberg et al. (40)

Cohort study Introduction of fish to infants earlier than 43 weeks of age  diminished risk for incidence of asthma.

Participant number: 9727 children 2017 Elbert et al. (14) Cohort study Introduction of

gluten to infants less than 6 months  diminished risk for atopic

(27)

dermatitis. 95% CI: 0.84 (0.72- 0.99) (14)

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28

4. DISCUSSION

Types of CF

Based on current literature, there is no unanimous type of CF to be introduced first due to the fact that many countries around the world introduce different types of ´first´ foods. A reason for this could be due to the geographical and climate conditions differences among various countries which, in turn, could influence what types of foods are more available in a given country and given time. Furthermore, many countries often have predominant religious beliefs which may restrict consumption of certain foods. Additionally, the level of education and average annual income of the general population varies globally. This socioeconomic variability seen in any population

inarguably plays a key role in the choice of foods. (49,50)

Timing of CF introduction

Despite the fact that not all countries follow the already existing unanimous guidelines on when to introduce CF to infants, it is mostly agreed upon to start from the age of 6 months as stipulated by the WHO. Nevertheless, in certain instances, CF can be started as early as 4 months, as suggested by the ESPGHAN. (9) With that being said, CF introduction between the ages of 4-6 months is optimal. (12)

Impact of CF introducing time on infant’s health

A cross-sectional study carried out with 3153 infants from Melbourne aimed to evaluate the impact of CF timing of introduction on body mass index (BMI). In this study, data about the

participants’ weight, length and feeding profile (CF introduction time and BF data) was collected from 9 to 15 months of age and BMI was calculated. It was determined that those infants who were fully breastfed for at least 5-6 months had less risks of developing a high BMI compared to infants who were only fully breastfed for 1 month or not breastfed at all. In addition, infants from the latter groups who were breastfed for shorter times (0-2 months of age) were more prone to be introduced to CF before the age of 4 months. Moreover, the early (at 4 months of age or earlier) or late (at 7 months or later) introduction of CF was linked to higher risk of developing a BMI above normal, therefore, higher risk of obesity or overweight outcomes at 1 year of age. Infants introduced to CF at 4 months or earlier had a threefold increased risk of a higher BMI, regardless whether they were fully breastfed for more than 4 months or not. In parallel, infants to whom CF introduction was delayed at 7 months or

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later was linked to a higher risk of abnormal BMI only in those infants not breastfed longer than 4 months. The findings also confirmed that CF introduction at the standard recommended times (around 6 months of age) decreased the risk for an abnormally high BMI in 1-year-old infants. (18)

The IDEFICS study also investigated the relationship between timing of CF introduction and obesity. It consists of a cross-sectional study collecting data from 8 European countries from 16,228 children of ages 2-9 years. Questionnaires were issued collecting data from the infant’s timing of CF introduction, BF timings and BMI. Findings concluded that the late introduction of CF (at more than 7 months of age) was linked to a higher prevalence of childhood obesity for EBF children. However, the early CF introduction (at less than 4 months of age) was related to a lower obesity incidence,

interestingly among children whom BF was discontinued prior the age of 4 months. This last result did not take into consideration what type of diet were given to these infants. These results were expected because there is a possibility that the participants followed an appropriate diet high in fibers and low in sugars which could definitely play a positive impact in their weight status. (22)

An obvious disparity is observed from the above mentioned studies due to the fact that their conclusions differ. However, what it is noticed to be in agreement within these studies is the impact of BF in the decrease risk of obesity in childhood. Therefore, according to the results, it can be concluded that BF has a protective effect against obesity development. BF appears to boost the self-regulation of the child’s energy intake, which aids the mother to notice her child’s hunger and satiety patterns, resulting in the possibility of avoiding overfeeding, which could subsequently lead to obesity. In this case, the earlier introduction of CF may result in the reduction of breast milk

ingestion by the infant and consequently affecting the self-regulation of energy intake increasing the risk of obesity. (22) For this reason, it is very important to promote BF to subsequently and

potentially lower the risk of obesity and it would be as well of utmost importance to introduce CF in the recommended timings at around 6 months of age not to disturb the BF process.

In a prospective cohort study in China by Wang et al, the relationship between CF

introduction and anemia was investigated in 18,446 children with feeding records from the ages of 3 to 6 months and to whom Hb concentrations were measured at the ages of 4 to 6 years. The anemia incidence was determined to be 14.3% within the participants and it was determined that the

introduction of CF before the age of 6 months (at 3-6 months of age) was linked to an increased risk of anemia and diminished concentrations of Hb in infants of age 4-6 years compared to those to whom CF was introduced at the ages of 6 months. These results could be confusing since one might think that

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30 iron is most required since breast milk does not contain enough iron levels to support the growing infant after some period of time. Nevertheless, these results are possible due to the fact that plant- based CF (such as porridge, tofu, bread, rice cereal and pureed noodles) generally consist of low quantities of iron and additionally contain phytate, a component thought to impair iron absorption. In addition to this study, several investigations came to the same conclusion that early CF introduction could lead to infants being exposed to pathogenic microbes which could cause GI disturbances and subsequently the decrease in iron absorption, which could be another explanation for these findings. On the other hand, the late CF introduction could also suppose that infants have no other sources of iron other than breast milk, which consequently increases the risk of anemia development. (25) All these findings remark once more the importance of an adequate timing of CF introduction and

highlight the importance of what types of CF should be introduced since it is important to confirm that infants are receiving the appropriate amount of nutrients for their suitable development.

A randomized clinical trial carried out by Perkin et al. studied the relationships between early CF introduction and the impact on infant sleep within 1303 infants from the EAT study.

Questionnaires were collected and it was observed that the early introduction of CF before 6 months (and as early as 3 months) had a positive impact in infant sleep. This study presented 2 groups: early introduction group (EIG), in whom CF was introduced as early as 3 months and standard introduction group (SIG), in whom CF was introduced following the British guidelines for CF introduction (from the age of 6 months). It was concluded that the EIG sleeping times were longer compared to the SIG (on average of 17 minutes more). This group also woke up notably less often at night and less serious sleeping problems were reported compared to the SIG group. (28) This expected finding could reflect the aforementioned common belief popular among parents. Providing earlier introduction of CF to infants could mean that infants are receiving a higher amount of nutrients which could be translated in longer sleeping times because of satiety reasons: when an organism overeats, it tends to feel sleepier due to the fact that after meals the digestive system receives more blood flow, which subsequently translates to less blood flow to the brain, ergo increasing the sleeping times. On the other hand, several investigations assessed as well the correlation between infant eating habits and sleep, reporting different results according to the age of the child and the type of study. Because of the many controversies, the decision on what is the best timing of CF introduction for the infant’s healthy sleep still remains inconclusive.

The Southampton Women’s survey (SWS) conducted a study on whether the age of

introducing solid foods causes feeding issues during childhood. It was concluded that infants who were introduced to solid foods at the age of 6 months or after, have a lower risk of developing eating

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difficulties (such as being picky with food or not eating sufficient food) than the infants being

introduced to CF before the age of 6 months (concretely between 4-6 months), who seemed to have a higher risk of developing eating difficulties. (30) The conclusions of this article could definitely be arguable, since children are more likely to accept those food flavors and textures which they have been previously exposed to as stipulated by the ALSPAC study. Therefore, the best timing to introduce CF to avoid feeding difficulties during childhood is yet to be known and more investigations should be conducted.

A randomized trial by Perkin et al. compiled 1303 EBF 3 months old infants who were randomly assigned to either early allergenic food introduction of peanuts, eggs, cow’s milk, sesame, cod and wheat or to a standard introduction as stipulated by the UK with EBF until around the age of 6 months. The results indicated that the early introduction group developed less food allergies compared to the standard introduction group (2.4% vs 7.3%). It was specified that there were significant

differences among both groups only when it comes to egg and peanut allergy development, with the early introduction group developing less allergies towards the two compared to the standard

introduction group (peanut allergy prevalence: 0% vs 2.5%; egg allergy prevalence: 1.4% vs 5.5%) with no significant differences in the case of cow’s milk, sesame, cod and wheat allergy development prevalence. Finally, it was determined that the weekly consumption of 2 grams of peanuts or egg whites were related to a diminished occurrence of allergy against these 2 products. (44)

In concordance with the previous study, a systematic review and meta-analysis study extracted data from 146 studies to determine the relationships between introduction timing of allergenic foods and the risk of allergic disease development. After a meticulous screening and analysis, it was determined that the early peanut introduction at the ages of 4-11 months or the early egg introduction at the ages 4-6 months decreased significantly the risk of peanut or egg allergy respectively. However, there were no significant findings about the early introduction of other allergenic foods different from eggs or peanuts on allergic disease development. (37)

On the other hand, it is also crucial to mention that international guidelines propose that there is a higher risk of allergy if allergenic foods such as egg, fish, peanut, gluten, seeds and cow’s milk are introduced earlier than 3 or 4 months of age and, with no prove either that the delay of introduction of these after the age of 4 months provides a protective effect against allergy risk. This is one of the most delicate topics since it was noted that the incidence of anaphylactic reactions increased when allergenic foods were introduced too early. (38)

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32 whether the early introduction of fish had an impact on later asthma development. It was determined that the introduction of fish to infants earlier than 43 weeks of age was linked to a diminished risk for the incidence of asthma as compared to the later introduction of fish which did not seem to have any effects. Explanations for these findings have been proposed, such as the fact that fish contains polyunsaturated fatty acids and vitamin D, which indeed play a significant role in terms of our immune system since they are known to regulate the allergic sensitization process. For this reason, it can be concluded that the early fish introduction may be beneficial for infants as it potentially

decreases the risk of asthmatic disease. (40)

In a population-based cohort study conducted by Elbert et al., 5,202 children participated with the aim to investigate if the timing of CF introduction and the types of allergenic foods being given had any impact on the allergic sensitization process, with questionnaires used within the research with the purpose of collecting all the data. At the 10 years of age, these children would be assessed by a skin prick test to determine if they developed any food allergies. From the results, it was concluded that those children who were introduced to gluten at 6 months of age or earlier had a decreased risk of atopic dermatitis than those introduced to gluten later than 6 months of age. Additionally, children who were given 3 or more allergenic foods at 6 months of age or earlier had also a diminished risk of inhalant allergies. Moreover, the early introduction of egg (at 4-6 months) and peanut (at 4-11 months) resulted in a decreased risk of allergy development towards the two, with a 44% diminished risk of egg allergy and a 71% decreased risk of peanut allergy at the ages of 3-5 years old. The cause of all of the above findings could be that at such early ages (less than 6 months) infants receive much smaller number of allergenic foods (such as eggs, fish, peanuts and gluten-containing products) compared to older children who potentially receive higher amounts. As a consequence, the immune system of these older children can cause T cell activation instead of immune tolerance. (14) These outcomes concord with many other studies and suggest that there is indeed a sensitive period of time for immune tolerance development when certain allergenic foods should be introduced in an attempt to induce immune tolerance. In conclusion, the early introduction of allergenic foods seems beneficial in decreasing the risk of certain diseases and allergic disease development.

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5. STUDY LIMITATION

The limitations of this study are only two databases (PubMed, NCBI and BMC Public Health) to write this short overview. Additionally, only one individual participated in the writing procedure, therefore some articles that might have been relevant for the study could have been overlooked or not reviewed. Finally, the biggest limitation was the short supply of articles referring to the specific types of CF being provided around the world.

6. CONCLUSIONS

1. CF should include solid and liquid foods in order to meet the healthy nutritional standard requirements of infants in their everyday life, although, it was determined that various countries start the introduction with different types of CF due to cultural, geographical or socioeconomic reasons.

2. CF introduction practices are very different in various countries. However, the WHO and ESPGHAN guidelines among others, recommend that CF is to be introduced within 4-6 months of age.

3. The early or late introduction of CF increases the risk of obesity and anemia outcomes, whereas infant’s sleep and feeding difficulties correlations remain inconclusive

4. The early introduction of egg and peanuts allergenic foods decrease the risk of their respective allergy development, while the late increases the risk. Early introduction of fish and gluten decreases the risk of asthma and atopic dermatitis development risk respectively, with no impact in relations to the late introduction.

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34

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40 Identifying infants at high risk of peanut allergy: The Learning Early About

Peanut Allergy (LEAP) screening study. Journal of Allergy and Clinical Immunology. 2013 Jan 1;131(1):135-143.e12.