Pregnancy and infancy comprise the most critical stages for conditioning an individual’s health, with a number of implications for subsequent risks of morbidity, mortality, and reproductive health. Nutrition may influence both the overall pregnancy outcome and the growth trajectory and immune system of the fetus and infant, with short- and long-term effects on the health of the offspring. Within this context, leading experts at Expo Milano 2015 in Milan, Italy, discussed up-to-date knowledge while providing suggestions and challenges before, during, and after pregnancy. This narrative review summarizes the key issues raised by the experts concerning the interplay between the nutritional environment from conception to early infancy and the offspring’s immediate and lifelong health, with a particular focus on epigenetic mechanisms, probiotics, vitamin D, and breastfeeding. Taken together, the findings strengthen the awareness that nutritional exposures occurring from preconception to the postnatal period may be strong determinants of the offspring’s health and may provide supportive evidence for current nutritional recommendations and guidelines for pregnant women and infants. Critical topics to be addressed in future research and translated into recommendations of public health relevance are also highlighted.

INTRODUCTION

Pregnancy and infancy comprise the most critical stages for conditioning a human being’s health. The interconnected stages, events, and factors that, from preconception to early infancy, influence the offspring’s health in both the short and the long term are schematized in Figure 1.

Figure 1

The continuum of interplay between a woman of reproductive age, the nutritional environment, and the offspring’s lifelong health from conception, through pregnancy, until the cessation of breastfeeding. Pregnancy consists of uninterrupted stages from preconception to the postpartum period, and of continuous adjustments in nutrient metabolism and immune function. Fetal growth is regulated by balances between the fetus’s demand for nutrients and the maternal–placental unit’s supply. The timing of nutritional insults may induce specific alterations in both maternal reproductive health and embryonic/fetal development. Infancy is sensitive to both the quantity and the quality of the nutrient supply, which may affect a range of health outcomes in the short, medium, and long term. Milk, including breast milk, may be the only food an infant consumes for the first 6 months. Afterward, it must be adequately complemented with foods. The timely progression from a milk-based diet to complementary and family foods helps shape the offspring’s health and eating environment. Abbreviations: CF, complementary feeding; IUGR, intrauterine growth restriction; LMP, last menstrual period; T, trimester.

Figure 1

The continuum of interplay between a woman of reproductive age, the nutritional environment, and the offspring’s lifelong health from conception, through pregnancy, until the cessation of breastfeeding. Pregnancy consists of uninterrupted stages from preconception to the postpartum period, and of continuous adjustments in nutrient metabolism and immune function. Fetal growth is regulated by balances between the fetus’s demand for nutrients and the maternal–placental unit’s supply. The timing of nutritional insults may induce specific alterations in both maternal reproductive health and embryonic/fetal development. Infancy is sensitive to both the quantity and the quality of the nutrient supply, which may affect a range of health outcomes in the short, medium, and long term. Milk, including breast milk, may be the only food an infant consumes for the first 6 months. Afterward, it must be adequately complemented with foods. The timely progression from a milk-based diet to complementary and family foods helps shape the offspring’s health and eating environment. Abbreviations: CF, complementary feeding; IUGR, intrauterine growth restriction; LMP, last menstrual period; T, trimester.

Pregnancy is a dynamic state and consists of a continuum of phases from conception to birth, with the periconceptional period playing a critical role in shaping fetal development.1,2 Fetal growth depends on maternal nutrition and metabolism, uteroplacental blood flow, and the size and transfer capabilities of the placenta.3 Adjustments in the metabolism of nutrients evolve continuously, switching from an anabolic condition during early pregnancy to a catabolic one in late pregnancy.3 Gestation-dependent immune adaptations also occur throughout pregnancy to ensure the capacity to adequately recognize and adapt defenses to specific pathogens. The immune cells and organs of the progeny proliferate in the first trimester and become mature in the late fetal and early neonatal periods. This delay in maturation of fetal defenses is countered by the uterine decidua, through which antimicrobial protection of mother and fetus is balanced with the need for immune tolerance to prevent fetal rejection.4 Adequate maternal nutrition is crucial for fulfilling the increased energy and nutrient requirements to support fetal growth and to modulate both gut microbiota composition and functions such as gene expression, nervous system development, hormonal secretion, immune system maturation.5–8

Infancy is a complex period of rapid growth and development. Although the immune system is qualitatively complete at birth, exposures during infancy and early childhood are essential for priming the adaptive cell populations.9 Furthermore, postnatally, the developing human brain, being functionally flexible, is very sensitive to external cues, which can shape structural/functional aspects of the brain as well as behavior.10 Mounting evidence exists about associations between variations in infant feeding and health outcomes in both the short and the long term, with early growth acceleration linked to the early appearance of overweight and obesity.11,12 For the first 6 months after birth, milk is the only food an infant should consume, with breast milk being the optimal form of nutrition for healthy infants.13 Afterward, milk, even breast milk, alone is no longer sufficient to meet an infant’s energy and nutrition requirements.12 Besides meeting nutritional needs, the timely progression from a milk-based diet to one that includes complementary and family foods requires infants and toddlers to learn how to eat by achieving oral-motor abilities14 and sensory experiences.10

The “developmental origins of health and disease” paradigm envisions health as being determined by early-life events in utero and infancy, when key regulatory systems are sensitive to immediate environmental exposures that permanently modify the body’s structure, function, immune and metabolic phenotype, and, consequently, the risk of disease.15 This implies a developmental plasticity through which alternative phenotypes are generated from a specific genotype by adjusting or adapting the developmental program in response to prevailing environmental cues. During different periods, human growth and the immune system demonstrate plasticity, which is modulated by energy resources, and the degree of plasticity may have markedly different implications for subsequent risks of morbidity, mortality, and reproductive fitness.16

Nutrition is one of the major environmental factors influencing pregnancy outcome and the growth trajectory of the fetus, with immediate and long-lasting effects on offspring health. The early life stages may represent an opportune time to influence an offspring’s health and potential, not only by avoiding nutritional insults that have immediate adverse implications but also by establishing healthy eating habits that may be crucially important in preventing pediatric overweight/obesity, noncommunicable diseases, and micronutrient deficiencies, all of which have increased in prevalence worldwide.17

Overweight and obesity have pervasively increased in all age groups, resulting in immediate and long-term health risks.18–20 It is alarming that at least 41 million children under the age of 5 years are overweight or obese, and overweight/obesity in females 10–24 years of age increased between 1990 and 2013, reaching a prevalence of nearly 1 in 5 young people in countries where noncommunicable diseases are predominant.19 This poses a serious threat to health from childhood to adulthood.19,21 In particular, maternal overweight and obesity lead to increased maternal morbidity and infant mortality, and pediatric obesity has become a major contributor to adult obesity, diabetes, and noncommunicable diseases.20

Noncommunicable diseases, comprising mainly cardiovascular disease, cancer, diabetes, and chronic lung disease, are the leading causes of mortality and morbidity globally.22 The number of deaths due to noncommunicable diseases has increased from 27 million in 1990 to nearly 38 million in 2013,23 with over 14 million deaths occurring in people between the ages of 30 and 70 years.22 Rapid shifts in contemporary food patterns toward diets characterized by higher intakes of energy-dense, nutrient-poor foods and beverages, along with sedentary lifestyles, have likely contributed to an obesogenic environment.24

Micronutrient deficiencies are also widespread, mostly during infancy and pregnancy, because of the overall increased demand for nutrients.25 Worldwide, the prevalence of iron-deficiency anemia among pregnant women is nearly 19%.20 Undernutrition and deficiencies of vitamin A and zinc, along with suboptimal breastfeeding, are estimated to be responsible for nearly 3.1 million deaths of children under 5 years of age.25 Worrisome is the coexistence of under- and overnutrition, ie, the so-called dual burden of malnutrition, as individuals may suffer overweight and obesity coupled with micronutrient deficiencies.26

At Expo Milano 2015, in Milan, Italy, leading experts discussed up-to-date knowledge about the conditioning of offspring health through the link between nutritional exposures occurring from conception to the postnatal period and the sensitive critical points involved in lifelong health (ie, epigenetics and the immune system), with a specific focus on dietary patterns, probiotics, vitamin D, and breastfeeding. Their goal was to highlight potential issues to be addressed in future research or translated into recommendations and to provide obstetricians, neonatologists, and pediatricians with specific aids to improve their skills in supporting patient care.

The main objective of this review, which reflects the authors’ view, is to summarize the key topics critically debated in the conference concerning the cascade of effects and factors that determine the interplay between the nutritional environment from conception to early infancy and the offspring’s lifelong health. First, environmentally sensitive critical points involved in lifelong health, that is, the potential health effects of changes in imprinted gene expression and microbiota determinants to environmental signals (ie, epigenetic mechanisms and immune system development/function, respectively) are discussed. Then, updated and relevant findings about associations between pre- and postnatal nutrition in terms of dietary patterns and components, probiotics, vitamin D, and infant feeding practices (ie, breastfeeding vs formula feeding) and the overall risks for reproductive outcomes and offspring morbidity are examined. Finally, the biological plausibility of the potential effect of early nutritional exposures on lifelong metabolic and allergic disease is discussed. In order to construct an objective and comprehensive picture about this issue, a broad array of studies are presented.

CRITICAL ENVIRONMENTALLY SENSITIVE POINTS IN LIFELONG HEALTH

Epigenetics during development: permanent effect of changes in imprinted gene expression on offspring health

Epigenetic mechanisms are responsible for the stable regulation of gene expression without changes to the DNA sequence. They trigger initiation and/or maintenance of cell-type-specific transcriptional profiles by modulating the chromatin structure and by organizing the global 3-dimensional structure of the genome and nuclear architecture, thereby participating in the control of transcription.27 Because of their dynamic nature, epigenetic mechanisms are sensitive to the environment, and the epigenome serves as an interface between the environment and the genome. Pollutants, nutrition, hormonal factors, and drugs may ultimately alter epigenetic landscapes during a particular spatiotemporal window in a tissue- and sex-specific manner.2,28

The methylation of DNA in the imprinted gene is one of the most studied epigenetic mechanisms implicated in the programming of cellular growth and the development of gametes, the embryo, and the fetus.1,29 In comparison with their unexposed same-sex siblings, individuals who were periconceptionally exposed to famine had, 6 decades later, lower methylation of 5 CpG dinucleotides within the insulin-like growth factor-II differentially methylated region (DMR).30 They also had higher methylation of loci within candidate genes involved in metabolic and cardiovascular disease, which differed depending on each individual’s gender and gestational timing of exposure.31 Likewise, the methylation status of specific CpGs from candidate genes in umbilical cord tissue DNA from healthy neonates was positively associated with a child’s adiposity at age 9 years and was inversely associated with maternal carbohydrate intake in early pregnancy.32 Children who were overweight/obese at 1 year of age had significantly higher methylation percentages at the H19 DMR in cord blood leukocyte DNA at birth compared with nonobese children.33

Immunological development in infancy and offspring health: host–microbe crosstalk from mother to newborn through pregnancy and caregiving

The gut microbiota is one of the early environmental factors that determine adult health. The antenatal composition of the microbiome at various time points and body sites is likely involved in immune and metabolic programming and probably influences the risk of gastrointestinal disease, allergy, autoimmune disease, and metabolic disorders in later life.34

The growing number of clinical conditions apparently linked to imbalance of the gut microbiota composition has fuelled clinical research interest in host–microbe crosstalk at early ages.35,36 The main microbial exposure for the fetus, the neonate, and the infant is provided by the maternal microbiota in utero, during delivery, and via breastfeeding, whereby disturbances in the mother’s microbiota composition and activity may not only immediately impact reproductive health but may also be transferred to the newborn (Figure 2). Recent scientific advances challenge traditional thinking that the human fetus is sterile, since microbe traces were detected in placenta, amniotic fluid, fetal membranes, and meconium.37–39 Subsequent sources of bacteria include mammary glands through breastfeeding, the mother’s skin and oral microbes, and the neonate’s initial environment.35 Several factors, combined with host influences, may modulate the dynamic composition of the mother–offspring microbiota interplay.40 These include maternal weight41–43 and diet,7 mode of delivery,43,44 environment,45,46 medical interventions,47 and feeding practices.48,49

Figure 2

Microbial colonization of the offspring’s gut: the stepwise routes from mother to infant. The fetus comes into contact with microbes that originate in the maternal gut via the placenta and amniotic fluid. Afterward, transmission of bacteria from mother to newborn may occur through contact or transfer during birth (ie, vaginal delivery) and lactation. Breastfeeding, along with skin-to-skin contact and nursing, is also a source of maternal bacteria and modulates neonatal bacterial colonization and immune maturation. Disturbances in maternal microbiota composition and activity may be transferred to the infant by the same routes: during pregnancy, at birth, and after delivery. Maternal nutrition, pregnancy, obstetric and perinatal complications, formula feeding, and the environment may influence early microbial contact, intestinal colonization, and the subsequent risk of immune-mediated and metabolic disease in a detrimental manner (dotted lines). Abbreviations: CF, complementary feeding; IUGR, intrauterine growth restriction.

Figure 2

Microbial colonization of the offspring’s gut: the stepwise routes from mother to infant. The fetus comes into contact with microbes that originate in the maternal gut via the placenta and amniotic fluid. Afterward, transmission of bacteria from mother to newborn may occur through contact or transfer during birth (ie, vaginal delivery) and lactation. Breastfeeding, along with skin-to-skin contact and nursing, is also a source of maternal bacteria and modulates neonatal bacterial colonization and immune maturation. Disturbances in maternal microbiota composition and activity may be transferred to the infant by the same routes: during pregnancy, at birth, and after delivery. Maternal nutrition, pregnancy, obstetric and perinatal complications, formula feeding, and the environment may influence early microbial contact, intestinal colonization, and the subsequent risk of immune-mediated and metabolic disease in a detrimental manner (dotted lines). Abbreviations: CF, complementary feeding; IUGR, intrauterine growth restriction.

The interaction of the gut microbiota composition with energy extracted from foods and storage in the human body suggests that the microbiome may be considered a proxy of nutritional status and/or a target for modulation. Overall, term infants delivered vaginally at home and breastfed exclusively seem to have the most beneficial gut microbiota,50 whereas antibiotic treatment and cesarean delivery seem to promote suboptimal development of the microbiota in early infancy.45

MATERNAL NUTRITION AND OFFSPRING HEALTH FROM CONCEPTION TO THE POSTNATAL PERIOD

When elucidating the potential effects of nutrition on reproductive outcomes, the composition of the diet, along with the intake of single foods and food compounds, must be examined, since health outcomes are endpoints for different conditions. Maternal weight status, lifestyle, and sociodemographic characteristics as well as and macroenvironmental factors may be important predictors of health concerns for both mother and child.

Nurture at conception: the role of parental nutrition

Most reproductive failures originate during the periconceptional period and may be influenced by the age and lifestyle of the parents-to-be.1 In particular, inadequate prepregnancy diets may impact the overall reproductive and/or pregnancy cycle.5 For instance, increased adherence to dietary recommendations enhanced the chance of ongoing pregnancy in women undergoing in vitro fertilization treatment.51 Moreover, a significantly increased risk of gestational diabetes mellitus was associated with high consumption of animal fats52 or intake of a diet high in glycemic load or low in cereal fiber.53

Derangements in one-carbon metabolism driving both the synthesis of proteins, biogenic amines, and lipids necessary for growth and the methylation of DNA and histones essential for regulation of gene expression are linked to reproductive disorders in women and men and to poor pregnancy outcomes.1 Malnutrition is recognized to disturb one-carbon metabolism, and, most importantly, poor nutrition around conception may enhance susceptibility to noncommunicable diseases. This increased susceptibility may be transmitted to succeeding generations, the underlying mechanisms of which may be explained by epigenetics.15 New insights reveal that not only periconceptional maternal nutrition but also paternal nutrition may impact fertility and embryonic growth trajectories.1,54

Nurture in utero: the role of maternal diet

Large prospective studies have demonstrated associations between the maternal diet during pregnancy and negative outcomes such as poor fetal growth trajectories, small for gestational age, inadequate length of gestation or preterm delivery, preeclampsia, and impaired glucose tolerance or gestational diabetes mellitus.

Healthy (traditional) dietary patterns such as the New Nordic Diet55 and Mediterranean-type diets56 were accompanied by fewer small-for-gestational-age infants, while a potential causal link between maternal intake of junk foods (ie, soft drinks, fast food, and/or processed meat and chips) and large-sized offspring has been identified.57 The degree of adherence to a Mediterranean diet was positively associated not only with parameters of intrauterine size but also with plasma folate and serum vitamin B12 concentrations and was inversely associated with uteroplacental vascular resistance, plasma homocysteine levels, and high-sensitivity C-reactive protein levels.56 Inverse relationships were reported between adherence to a Mediterranean diet,58 prudent and traditional diets,59 and risk of preterm delivery.

Interesting results emerged when potential links to consumption of specific food item(s)/substances were explored. A lower risk of preterm delivery was found among women who met the recommendations for fish intake,59 in agreement with a meta-analysis indicating that never consuming fish in pregnancy could be an extremely strong risk factor for preterm delivery.60 Caffeine intake was consistently associated with lower birth weight and higher odds of small-for-gestational-age offspring, not only when consumption exceeded the World Health Organization’s recommendation (300 mg/d) but also when it exceeded the recommendation in Nordic countries and the United States (maximum 200 mg/d), which suggests a risk of small-for-gestational-age infants even at very low intakes of caffeine.61 In contrast to sugar-sweetened beverages, foods that naturally contain sugar, such as fresh and dried fruits, were inversely associated with the onset of preeclampsia, suggesting that, compared with foods containing industrially added sugars, foods with natural sugars contain other compounds such as dietary fiber that may be able to favorably modulate the influence of sugar on the onset of preeclampsia.62 The consumption of probiotic milk products also seemed to play a beneficial role, mostly by preventing severe preeclampsia, with a lower risk observed even at moderate intakes (nearly 30 mL/d).63 Additionally, daily consumption of 200 g of probiotic yogurt for 9 weeks was efficient in maintaining stable serum insulin levels among pregnant women in the third trimester, which indicates a preventive effect against insulin resistance.64

Diet quality appears to influence the risk of impaired glucose tolerance during pregnancy, too.65 Impaired glucose tolerance late in pregnancy is not only associated with high intakes of saturated fat, trans fat, and added sugar and lower intakes of fiber66 but is also significantly reduced by increasing carbohydrate vs fat intake67 during the second trimester. This supports the idea that high-fat/low-carbohydrate diets early in pregnancy may result in a higher risk of gestational diabetes mellitus. Likewise, a Mediterranean diet is likely protective against the onset of gestational diabetes mellitus, as greater adherence is associated with better glucose tolerance and a lower incidence of gestational diabetes mellitus.68

A Mediterranean diet in pregnancy also seems to have a long-lasting protective influence against offspring allergies, while maternal consumption of olive oil, dairy products, and vitamin D may affect the risk of infantile wheeze and asthma, as shown in examples in Table 1.69–75

Table 1

Relationship between offspring allergies early in life and maternal diet, food, and nutrient intake during pregnancy

Reference Name, type, and country of study Maternal dietary pattern Outcome Results 
Chatzi et al. (2013)69 
  • Multicenter INfancia y Medio Ambiente study (Spain) and RHEA study (Greece)

  • Meta-analysis

 
Mediterranean diet Risk of wheeze and eczema in the first year of life 
  • No association with adherence to Mediterranean diet

  • Increased risk of wheeze associated with high meat intake (RR = 1.22, 1.00–0.49) and processed-meat intake (RR = 1.18, 1.02–1.37)

  • Decreased risk of wheeze significantly associated with high intake of dairy products (RR = 0.83, 0.72–0.96)

 
Castro-Rodriguez et al. (2010)70 
  • Part of the Estudio Internacional de Sibilancias en Lactantes

  • Birth cohort study

  • Spain

 
Mediterranean diet and olive oil for cooking/dressing salads Wheezing during the first year of life Olive oil intake associated with less wheezing (OR = 0.57, 0.4–0.9, P = 0.002) 
Garcia-Marcos et al. (2013)71 Meta-analysis of studies, stratified into Mediterranean and non-Mediterranean centers Mediterranean diet Asthma prevalence in children 
  • Current wheeze: negative association with the highest tertile of Mediterranean diet score : OR=0.85, 0.75–0.98, P = 0.02 (all centers); OR = 0.79, 0.66–0.94, P = 0.009 (Mediterranean centers)

  • Current severe wheeze: R = 0.82, 0.55–1.22, P = 0.330 (all); OR = 0.66, 0.48–0.90, P = 0.008 (Mediterranean centers)

  • Asthma: OR = 0.86, 0.78–0.95, P = 0.004 (all); OR = 0.86, 0.74–1.01, P = 0.06 (Mediterranean centers); OR = 0.86, 0.75–0.98, P = 0.027 (non-Mediterranean centers)

 
Sausenthaler et al. (2007)72 
  • Influences of Lifestyle-related Factors on the Immune System and the Development of Allergies in Childhood Study

  • Prospective birth cohort study

  • Germany

 
Diet in the last 4 wk of pregnancy Allergic sensitization and eczema at 2 y of age 
  • Eczema: positive association with high intake of margarine (OR = 1. 49, 1.08–2.04), vegetable oils (OR = 1.48, 1.14–1.91); negative association with high fish intake (OR = 0.75, 0.57–0.98)

  • Sensitization against food allergens: increased risk with high celery intake (OR = 1.85, 1.18–2.89) or citrus fruit intake (OR = 1.73, 1.18–2.53)

  • Sensitization against inhalant allergens: positively related to a high intake of deep-fried vegetable fat (OR = 1.61, 1.02–2.54), raw sweet pepper (OR = 2.16, 1.20– 3.90), citrus fruit (OR = 1.72, 1.02–2.92)

 
Miyake et al. (2010)73 
  • Osaka Maternal and Child Health Study

  • Prospective cohort study

  • Japan

 
Dairy products, calcium, and vitamin D Risk of wheeze and eczema at 16–24 mo of age 
  • Decreased risk of infantile wheeze related to higher intake of total dairy products (OR = 0.45, 0.25–0.79; P = 0.007), milk (OR = 0.50, 0.28–0.87; P = 0.02), cheese (OR = 0.51, 0.31–0.85; P = 0.02), calcium (OR = 0.57, 0.32–0.99; P = 0.04)

  • Categorization of vitamin D by cutoff at 25th percentile: significantly reduced risk of wheeze (OR = 0.64, 0.43–0.97), eczema (OR = 0.63, 0.41–0.98)

 
Errkola et al. (2009)74 
  • Type 1 Diabetes Prediction and Prevention Study

  • Multidisciplinary, prospective, population-based cohort study

  • Finland

 
Vitamin D intake Asthma, allergic rhinitis, atopic eczema by the age of 5 y 
  • Mean intake = (5.1 ± 2.6) mg from food; (1.4 ± 2.6) mg from supplements

  • Vitamin D from food negatively related to asthma (HR = 0.80, 0.64–0.99; P < 0.05), AR (HR = 0.85, 0.75–0.97; P < 0.05) risk

  • Vitamin D supplements not associated

 
Camargo et al. (2007)75 
  • Project Viva

  • Prospective prebirth cohort study

  • USA

 
Vitamin D intake Risk of asthma in children at 3 y of age 
  • Mean total intake = (548 ± 167) IU/d

  • Lowest quartile (median, 356 IU) vs highest quartile (724 IU): lower risk of recurrent wheeze (OR = 0.38, 0.22–0.65; P < 0.001).

  • 100-IU increase associated with lower risk (OR = 0.81, 0.71–0.93), regardless of vitamin D source

 
Reference Name, type, and country of study Maternal dietary pattern Outcome Results 
Chatzi et al. (2013)69 
  • Multicenter INfancia y Medio Ambiente study (Spain) and RHEA study (Greece)

  • Meta-analysis

 
Mediterranean diet Risk of wheeze and eczema in the first year of life 
  • No association with adherence to Mediterranean diet

  • Increased risk of wheeze associated with high meat intake (RR = 1.22, 1.00–0.49) and processed-meat intake (RR = 1.18, 1.02–1.37)

  • Decreased risk of wheeze significantly associated with high intake of dairy products (RR = 0.83, 0.72–0.96)

 
Castro-Rodriguez et al. (2010)70 
  • Part of the Estudio Internacional de Sibilancias en Lactantes

  • Birth cohort study

  • Spain

 
Mediterranean diet and olive oil for cooking/dressing salads Wheezing during the first year of life Olive oil intake associated with less wheezing (OR = 0.57, 0.4–0.9, P = 0.002) 
Garcia-Marcos et al. (2013)71 Meta-analysis of studies, stratified into Mediterranean and non-Mediterranean centers Mediterranean diet Asthma prevalence in children 
  • Current wheeze: negative association with the highest tertile of Mediterranean diet score : OR=0.85, 0.75–0.98, P = 0.02 (all centers); OR = 0.79, 0.66–0.94, P = 0.009 (Mediterranean centers)

  • Current severe wheeze: R = 0.82, 0.55–1.22, P = 0.330 (all); OR = 0.66, 0.48–0.90, P = 0.008 (Mediterranean centers)

  • Asthma: OR = 0.86, 0.78–0.95, P = 0.004 (all); OR = 0.86, 0.74–1.01, P = 0.06 (Mediterranean centers); OR = 0.86, 0.75–0.98, P = 0.027 (non-Mediterranean centers)

 
Sausenthaler et al. (2007)72 
  • Influences of Lifestyle-related Factors on the Immune System and the Development of Allergies in Childhood Study

  • Prospective birth cohort study

  • Germany

 
Diet in the last 4 wk of pregnancy Allergic sensitization and eczema at 2 y of age 
  • Eczema: positive association with high intake of margarine (OR = 1. 49, 1.08–2.04), vegetable oils (OR = 1.48, 1.14–1.91); negative association with high fish intake (OR = 0.75, 0.57–0.98)

  • Sensitization against food allergens: increased risk with high celery intake (OR = 1.85, 1.18–2.89) or citrus fruit intake (OR = 1.73, 1.18–2.53)

  • Sensitization against inhalant allergens: positively related to a high intake of deep-fried vegetable fat (OR = 1.61, 1.02–2.54), raw sweet pepper (OR = 2.16, 1.20– 3.90), citrus fruit (OR = 1.72, 1.02–2.92)

 
Miyake et al. (2010)73 
  • Osaka Maternal and Child Health Study

  • Prospective cohort study

  • Japan

 
Dairy products, calcium, and vitamin D Risk of wheeze and eczema at 16–24 mo of age 
  • Decreased risk of infantile wheeze related to higher intake of total dairy products (OR = 0.45, 0.25–0.79; P = 0.007), milk (OR = 0.50, 0.28–0.87; P = 0.02), cheese (OR = 0.51, 0.31–0.85; P = 0.02), calcium (OR = 0.57, 0.32–0.99; P = 0.04)

  • Categorization of vitamin D by cutoff at 25th percentile: significantly reduced risk of wheeze (OR = 0.64, 0.43–0.97), eczema (OR = 0.63, 0.41–0.98)

 
Errkola et al. (2009)74 
  • Type 1 Diabetes Prediction and Prevention Study

  • Multidisciplinary, prospective, population-based cohort study

  • Finland

 
Vitamin D intake Asthma, allergic rhinitis, atopic eczema by the age of 5 y 
  • Mean intake = (5.1 ± 2.6) mg from food; (1.4 ± 2.6) mg from supplements

  • Vitamin D from food negatively related to asthma (HR = 0.80, 0.64–0.99; P < 0.05), AR (HR = 0.85, 0.75–0.97; P < 0.05) risk

  • Vitamin D supplements not associated

 
Camargo et al. (2007)75 
  • Project Viva

  • Prospective prebirth cohort study

  • USA

 
Vitamin D intake Risk of asthma in children at 3 y of age 
  • Mean total intake = (548 ± 167) IU/d

  • Lowest quartile (median, 356 IU) vs highest quartile (724 IU): lower risk of recurrent wheeze (OR = 0.38, 0.22–0.65; P < 0.001).

  • 100-IU increase associated with lower risk (OR = 0.81, 0.71–0.93), regardless of vitamin D source

 

Abbreviation: HR, hazard ratio; IU, international units; MD, Mediterranean diet; OR odds ratio; RR, relative risk.

Nurture in the postnatal period: the importance of breastfeeding

There is international consensus that infants should be breastfed exclusively for the first 6 months of life to achieve optimal growth, development, and health, with appropriate complementary foods introduced thereafter and breastfeeding continued for up to 2 years or beyond.76 When the optimal 6 months of exclusive breastfeeding is not achievable, the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition recommends that “complementary foods should be introduced not earlier than 17 weeks of age and not later than 26 weeks.”77 Depending on the duration and amount of breastfeeding (exclusive vs partial), relationships between breastfeeding and a range of health outcomes in the short, medium, and long term have been observed.

Eating behavior.

The type, timing, and duration of the milk-feeding regimen (breast vs formula) in early postnatal life may exert different effects on flavor learning and the establishment of food preferences, which appear to be long lived.78 Prolonged breastfeeding may influence the initial acquisition of acceptance/preference of tastes and foods, facilitating the transition to adult foods.79 In fact, breastfed children are likely more willing to try novel foods than formula-fed children.80 Interestingly, greater exposure to breast milk is linked to healthier dietary patterns in both childhood81,82 and adulthood.83

Obesity.

Compared with formula feeding, breastfeeding seems to impart a protective effect against later obesity, despite complex and confounding relationships between early-life feeding practices and later risk of child obesity.84,85 The issue has been recently questioned.86 Overall, exclusive breastfeeding for longer than 4 months seems to be associated with lower weight gain and body mass index during age 6 to 12 months.87 Infants breastfed from birth to 6 months of age gain weight, length, and adiposity more slowly and are of smaller size during infancy than those fed formula milk, independent of the timing of introducing solid foods.88,89

Immune system.

Breastfeeding is likely associated with lower rates of overall infection up to 1 year of age. Breastfeeding exclusively for at least 4 months and continued partially thereafter seems to be protective against lower respiratory and gastrointestinal infections until the age of 6 months and against respiratory tract infections between the ages of 7 and 12 months.90 During the first 6 months of life, exclusive breastfeeding is more protective against gastrointestinal infection than partial breastfeeding.91 Protection against diarrhea and ear infections seems to be provided in a dose–response manner.92 A positive association was also found between breastfeeding and reduced risk of asthma/wheezing in children with the probability of respiratory illness during childhood, with risk being significantly reduced in those breastfed exclusively for 15 weeks.93

POTENTIAL LINKS BETWEEN EARLY-LIFE NUTRITIONAL EXPOSURES AND LIFELONG METABOLIC AND ALLERGIC DISEASES

Anti-inflammatory, antiatherogenic, immunomodulatory, and epigenetic factors of food compounds

The beneficial effects of healthy diets during pregnancy may be attributed to distinct dietary characteristics (ie, high intakes of fruits/vegetables, fish, whole-grain cereals, oils), which translate into the intake of beneficial compounds. Omega-3 polyunsaturated fatty acids from fish may have beneficial anti-inflammatory, antiatherogenic, and immunomodulatory effects.94 Sources of dietary fiber, vitamins, minerals, and bioactive compounds – such as vegetables, fruits, oils, nuts, and whole grains – may exert protective effects by reducing inflammation, oxidative stress, and endothelial dysfunction and lowering low-density lipoprotein cholesterol and glycemic response.95–97 Owing to their highly fermentable carbohydrate content, fruits, vegetables, and whole grains may also serve as prebiotic foods, which enhance the composition of the gut microbiota, implicated in the regulation of host energy homoeostasis and systemic/local immunity.98,99

Several of the aforementioned dietary components are also linked to epigenetic processes.6 Indeed, nutrients and their metabolites may be direct activators or inhibitors of the epigenetic enzymes or substrates for membrane and nuclear receptors, leading to local chromatin changes at targeted gene sequences. In particular, folate, as a methyl-group donor in one-carbon metabolism, is involved in DNA methylation, together with vitamin B12 and methionine.100 Subtle variations in one-carbon metabolism genes and deficiencies in one-carbon substrates/cofactors, together with poor lifestyle, may provoke derangements in one-carbon metabolism, thereby compromising offspring health.1 Periconceptional folic acid supplementation is internationally recommended for the prevention of neural tube defects.101 However, high maternal levels of folate during pregnancy predicted higher adiposity and insulin resistance in offspring at age 6 years, whereas low levels of vitamin B12 predicted higher insulin resistance,102 and infants exposed to higher folic acid supplements later in pregnancy were more likely to develop eczema at 1 year of age than those born to mothers with lower intakes.103 Epigenetic modifications of chromatin, ie, aberrant reprogramming of DNA methylation, may occur as a consequence of alterations in one-carbon metabolism.1 Hoyo et al.105 found that 17-month-old children of mothers who used periconceptional folic acid at 400 µg/d had a significantly higher methylation of insulin growth factor II-DMR than nonexposed children,104 while methylation at the H19 DMR in cord blood leukocytes was significantly lower in neonates of mothers who took periconceptional folic acid than in infants born to nonusers of folic acid.

Vitamin D: specific importance in pregnancy and early life

Circulating concentrations of the hormonally active form of vitamin D [calcitriol, 1,25(OH)2D] are typically very tightly regulated. Despite this, serum concentrations in the expectant mother begin to rise early in the first trimester and double by the end of third trimester. Pregnancy-specific tissues, including the placenta and the decidua, also express hormonal vitamin D receptors. Both the placenta and the decidua have the capacity to synthesize CYP27B1, the key enzyme of vitamin D metabolism, providing further support for a specific role for vitamin D in pregnancy.4

Calcitriol elicits protective effects on vascular function by decreasing endothelial adhesion molecules and exerting anti-inflammatory activity. It also protects against inflammatory diseases and immune-mediated disorders by inhibiting adaptive immunity and enhancing innate immunity. Specifically, calcitriol inhibits the production of proinflammatory cytokines while promoting the emergence of regulatory T cells expressing proteins that mediate transplantation tolerance, strengthening the modulation of T-cell responses.106

The pro-tolerogenic effects of calcitriol at the maternofetal interface may contribute to the immunological adaptation by the mother, which is required for the maintenance of normal pregnancy. Furthermore, these immunomodulatory effects could also explain the reported association between vitamin D and a reduced risk of preeclampsia, for which evidence has been obtained from observational studies and clinical trials.107

The priming of the immune system occurs prenatally and during the first years of life, and therefore it is possible that the immunological effects of vitamin D could have longer-term influences for the offspring as well. In support of this hypothesis are studies reporting a protective association between vitamin D supplementation in infants and a reduced risk of type 1 diabetes.108 A large number of studies have investigated the association between vitamin D and the subsequent risk of allergies and asthma, with prevention of deficiency and modest increases in vitamin D intakes typically suggesting a protective association.73–75 However, there is also evidence to suggest that mothers with very high calcitriol concentrations or infants with high supplementation intakes may have an increased risk,109,110 which is compatible with the suggested shift towards a Th2-dominant immune-response pattern. The classical effect of calcitriol is the regulation of calcium metabolism and bone health, and observational data suggest that higher maternal vitamin D status is associated with a greater fetal femur volume and higher birth weight.111 Randomized controlled trials of maternal vitamin D supplementation have provided evidence for beneficial effects on birth weight.112

Most vitamin D is obtained through endogenous synthesis by ultraviolet radiation after sun exposure of the skin, while typical diets are very low in vitamin D. The Institute of Medicine (United States) recommends 600 IU of vitamin D per day for expectant mothers and 400 IU per day for infants. Given that case reports suggest life-threatening implications for infants and children exposed to extreme vitamin D deficiency,113 it is important to ensure adequate maternal and infant vitamin D intakes through supplementation, particularly in the absence of adequate exposure to sunlight and also because breast milk is very low in vitamin D.

Impact of probiotic consumption on the immune system

Evidence accumulated so far suggests that modulating the microbiota composition by means of probiotics in the prenatal and early postnatal periods may counteract pregnancy complications and allergic/inflammatory conditions in offspring. Table 2 summarizes some of the clinical trials investigating the effects of perinatal oral administration of probiotic bacteria to pregnant women alone or to child–mother pairs.114–120

Table 2

Effects of perinatal probiotic supplementation on pregnancy, breast milk, and offspring

Reference Population, study design Probiotic Outcome Results 
Dolatkhah et al. (2015)114 
  • Pregnant women with GDM

  • RCT: probiotic vs placebo; 8-wk study period

 
Lactobacillus (L.) acidophilus LA-5 + Bifidobacterium (B.) BB-12 + Streptococcus thermophilus STY-31 + L. delbrueckii bulgaricus LBY-27 Maternal glucose metabolism and weight changes Significantly lower weight gain; significantly higher decrease in fasting blood sugar 
Luoto et al. (2010)115 
  • NAMI program: prospective, randomized mother–infant nutrition and probiotic study

  • Pregnant women; RCT: probiotic vs placebo; study period: from the first trimester

 
L. rhamnosus GG (LGG) (ATCC 53103) + B. lactis GDM Significantly reduced: 13% vs 36% 
Enomoto et al. (2014)116 Pregnant women and their healthy infants Open trial: probiotic vs control; study period from 1 mo prior to delivery to 6 mo afterwards B. breve M-16V + B. longum BB536 Allergic diseases in offspring in the first 18 mo of age Eczema/AD reduced at 10 mo (OR = 0.231, 0.084–0.628; P = 0.007) and 18 mo (OR = 0.304, 0.105–0.892; P = 0.033) 
Rautava et al. (2012)117 
  • Mothers with allergic disease and atopic sensitization

  • RCT: probiotic-1 vs probiotic-2 vs placebo; study period from 2 mo before delivery and during the first 2 mo of BF

 
  • Probiotic-1 = L. rhamnosus LPR + B. longum BL999 (LPR1BL999)

  • Probiotic-2 = L. paracasei ST11 + B. longum BL999 (ST111BL999)

 
Eczema in offspring during the first 24 mo of life 
  • Eczema reduced: probiotic-1 = 0.17 (0.08–0.35), P < 0.001; probiotic-2 = 0.16 (0.08–0.35), P < 0.001

  • Chronically persistent eczema: probiotic-1 = 0.30 (0.12–0.80; P = 0.016); probiotic-2 = 0.17 (0.05–0.56; P = 0.003)

 
Rautava et al. (2002)118 
  • Pregnant and lactating mothers, with and without atopic disease

  • RCT: probiotic vs placebo; study period from 4 wk before delivery and throughout BF

 
LGG (ATCC 53103) Immunoprotective potential of breast milk; atopic eczema in offspring in the first 2 y of life 
  • Eczema reduced: 15% vs 47%; RR = 0.32 (0.12–0.85), P = 0.0098

  • Breast milk TGF-β2: significantly higher

 
Grüber et al. (2007)119 
  • Infants aged 3–12 mo with mild-to-moderate AD

  • RCT: probiotic vs placebo; 12-wk study period

 
LGG Therapeutic effect on AD No therapeutic effect with LGG in infants aged 3–12 mo with mild-to-moderate AD 
Wickens et al. (2008)120 
  • Child–mother pairs

  • RCT: probiotic-1 vs probiotic-2 vs placebo; study period from the wk 35 of gestation until 6 mo postpartum

 
  • Probiotic-1 = L. rhamnosus

  • Probiotic-2 = B. animalis subsp lactis

 
Eczema and atopy in offspring by 2 y of age 
  • Probiotic-1: eczema reduced; HR = 0.51 (0.30–0.85), P = 0.01

  • Probiotic-2: no effect

 
Reference Population, study design Probiotic Outcome Results 
Dolatkhah et al. (2015)114 
  • Pregnant women with GDM

  • RCT: probiotic vs placebo; 8-wk study period

 
Lactobacillus (L.) acidophilus LA-5 + Bifidobacterium (B.) BB-12 + Streptococcus thermophilus STY-31 + L. delbrueckii bulgaricus LBY-27 Maternal glucose metabolism and weight changes Significantly lower weight gain; significantly higher decrease in fasting blood sugar 
Luoto et al. (2010)115 
  • NAMI program: prospective, randomized mother–infant nutrition and probiotic study

  • Pregnant women; RCT: probiotic vs placebo; study period: from the first trimester

 
L. rhamnosus GG (LGG) (ATCC 53103) + B. lactis GDM Significantly reduced: 13% vs 36% 
Enomoto et al. (2014)116 Pregnant women and their healthy infants Open trial: probiotic vs control; study period from 1 mo prior to delivery to 6 mo afterwards B. breve M-16V + B. longum BB536 Allergic diseases in offspring in the first 18 mo of age Eczema/AD reduced at 10 mo (OR = 0.231, 0.084–0.628; P = 0.007) and 18 mo (OR = 0.304, 0.105–0.892; P = 0.033) 
Rautava et al. (2012)117 
  • Mothers with allergic disease and atopic sensitization

  • RCT: probiotic-1 vs probiotic-2 vs placebo; study period from 2 mo before delivery and during the first 2 mo of BF

 
  • Probiotic-1 = L. rhamnosus LPR + B. longum BL999 (LPR1BL999)

  • Probiotic-2 = L. paracasei ST11 + B. longum BL999 (ST111BL999)

 
Eczema in offspring during the first 24 mo of life 
  • Eczema reduced: probiotic-1 = 0.17 (0.08–0.35), P < 0.001; probiotic-2 = 0.16 (0.08–0.35), P < 0.001

  • Chronically persistent eczema: probiotic-1 = 0.30 (0.12–0.80; P = 0.016); probiotic-2 = 0.17 (0.05–0.56; P = 0.003)

 
Rautava et al. (2002)118 
  • Pregnant and lactating mothers, with and without atopic disease

  • RCT: probiotic vs placebo; study period from 4 wk before delivery and throughout BF

 
LGG (ATCC 53103) Immunoprotective potential of breast milk; atopic eczema in offspring in the first 2 y of life 
  • Eczema reduced: 15% vs 47%; RR = 0.32 (0.12–0.85), P = 0.0098

  • Breast milk TGF-β2: significantly higher

 
Grüber et al. (2007)119 
  • Infants aged 3–12 mo with mild-to-moderate AD

  • RCT: probiotic vs placebo; 12-wk study period

 
LGG Therapeutic effect on AD No therapeutic effect with LGG in infants aged 3–12 mo with mild-to-moderate AD 
Wickens et al. (2008)120 
  • Child–mother pairs

  • RCT: probiotic-1 vs probiotic-2 vs placebo; study period from the wk 35 of gestation until 6 mo postpartum

 
  • Probiotic-1 = L. rhamnosus

  • Probiotic-2 = B. animalis subsp lactis

 
Eczema and atopy in offspring by 2 y of age 
  • Probiotic-1: eczema reduced; HR = 0.51 (0.30–0.85), P = 0.01

  • Probiotic-2: no effect

 

Abbreviations: AD, atopic dermatitis; BF, breastfeeding; GDM, gestational diabetes mellitus; NAMI, Nutrition, Allergy, Mucosal immunology and Intestinal; RCT, randomized control trial; TGF, transforming growth factor.

Administration of specific probiotics perinatally, namely in utero and/or in the first months of life (to lactating mothers and/or their infants), may promote healthy immune maturation and reduce allergies in the offspring. In fact, probiotic supplements administered in utero exerted a protective effect against sensitization in high-risk infants.121 Moreover, the occurrence of eczema or chronically persistent eczema by the second year of age was significantly reduced both in at-risk infants of mothers given different mixtures of specific strains of lactobacilli/bifidobacteria during pregnancy and breastfeeding117 and in infants supplemented pre- and postnatally with a combination of bifidobacteria.116 Interestingly, maternal probiotic supplementation with Lactobacillus rhamnosus GG during pregnancy and lactation not only lowered the risk of atopic eczema in the first 2 years of life in the offspring but also increased the amount of transforming growth factor (TGF)-β2 in breast milk, thus augmenting breast milk’s immune-protective potential.118 On the other hand, no effect on atopic dermatitis and eczema was detected in infants 3- to 12-month-old with mild-to-moderate atopic dermatitis who were supplemented with L. rhamnosus GG119 or in infants given, together with their mothers, pre- and postnatal supplementation with Bifidobacterium animalis subsp lactis.120 Indeed, when the Committee on Nutrition of the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition evaluated data about the health effects of formula supplemented with probiotics and/or prebiotics vs unsupplemented formula, evidence to recommend the routine use of probiotic-supplemented formula was deemed insufficient, despite some clinical benefits associated with a few probiotics added to infant or follow-on formulas and given beyond early infancy.122 These conflicting results likely signify that the effects of probiotics are strain specific and that interventions are most effective if commenced during pregnancy.

Besides beneficially enhancing the composition of the gut microbiota, probiotics may restore increased intestinal permeability to normal, improve the intestine’s immunological barrier function, and reduce the generation of proinflammatory cytokines.46 Accordingly, maternal probiotic supplementation with B. lactis or B. lactis + L. rhamnosus GG significantly modulated the expression of Toll-like receptor (TLR)-related genes in both placenta and the fetal gut.38 Probiotics also appear to beneficially influence glucose metabolism and weight gain in pregnant women.114 Maternal supplementation with mixed lactobacilli/bifidobacteria from the first trimester of pregnancy to the end of exclusive breastfeeding resulted in a significant reduction in the risk of gestational diabetes mellitus as well as the risk of maternal central adiposity over the 12-month postpartum period.115 Probiotics are postulated to be involved in the control of body weight and energy metabolism through modulation of both energy homeostasis and the low-grade inflammatory state that characterizes overweight/obesity and the onset of metabolic disorders such as insulin resistance and type 2 diabetes mellitus.123

On the basis of the currently available literature, pre-, peri-, and postnatal interventions with specific probiotic preparations may have potentially beneficial effects on child health and well-being. The safety of this approach in pregnancy has been proven by the normal duration of pregnancies, with neither adverse events in mothers or children nor significant variations in pre- or postnatal growth rates observed. Furthermore, no interference with the long-term composition or the quantity of gut microbiota has been reported. In particular, a targeted manipulation of gut microbiota seems to be an effective approach. However, it is worth noting that, owing to a lack of consistency across studies, to methodological limitations, and to data from single studies only, there is an urgent need for confirmatory, well-designed, adequately powered clinical research studies to establish the efficacy of supplemental probiotics and/or prebiotics in infant products.122,124–126

Human milk: benefits beyond food and growth

Breastfeeding is acknowledged to be beneficial for infants, providing a balanced supply of nutrients, bioactive proteins, indigestible oligosaccharides, and bifidogenic bacteria.85 Reflecting the pattern of development and maturation of the intestinal permeability and mucosal immune system of the infant, the biologically active components of human milk exhibit qualitative and quantitative changes during lactation that provide exogenous signals and components for gut ontogeny.127,128

Besides meeting the infant’s increasing nutrient requirements, human milk primes the immune system and confers protection against pathogens. It transfers passive immune protection through products of the maternal adaptive immune system and its own innate immune system as well. The innate immune system of human milk comprises lactoferrin and lysozyme (involved in pathogen degradation), free fatty acids and monoglycerides (capable of destabilizing the cell membranes of pathogens), and glycans (able to inhibit binding of specific pathogens to intestinal epithelial receptors).129 Breast milk contains compounds that modulate the gut microbiota composition by acting as prebiotics (ie, human milk oligosaccharides) and the developmental trajectory of the immune system (ie, anti-inflammatory cytokines such as the TGF-β2), thereby quenching proinflammatory processes and promoting immune tolerance.35,129 It supplies probiotic bacteria, which colonize the infant’s gut, beneficially modify the gut microbiota composition, and contribute to the reduced incidence/severity of infection and the maturation of infant immune system.130 Human milk accelerates maturation of the gut barrier function through human milk oligosaccharides that were shown ex vivo to attenuate pathogen-associated molecular pattern (PAMP)-stimulated acute-phase inflammatory cytokine proteins while stimulating expression of cytokines involved in tissue repair and homeostasis128, and enhancing in vitro epithelial cell kinetics and function.131 When formula-fed and breastfed infants were compared, breastfed infants exhibited significantly higher levels of TGF-β2 and lower levels of the proinflammatory cytokines tumor necrosis factor-α and interleukin 2 throughout the first year of life and beyond the duration of breastfeeding.132 Moreover, striking differences in gut microbiota composition were found, with bifidobacteria dominating in breastfed infants and Bacteroides species, Clostridium coccoides, and Lactobacillus species predominating in formula-fed infants.45

The preventive effects of breast milk against obesity and metabolic disorders in childhood and beyond likely depend on several growth factors and peptide/protein hormones that play roles in the regulation of appetite and food intake, energy balance, growth patterns, body composition, and glucose homeostasis early in infancy.

There are remarkable differences between formula-fed and breastfed infants. As a consequence of both the breast milk composition and the way an infant feeds at the breast, breastfed infants are believed to better regulate their food intake.133 Changes in ghrelin, leptin, and fat levels in foremilk and hindmilk, which do not occur in formula milk, may explain the association of human milk with the infant’s self-control of feeding.134 A significantly higher percentage of weight gain has been found in formula-fed infants compared with both exclusively breastfed and partially breastfed infants, probably stimulated by a different pattern of the insulin growth factor axis.135 The lower protein content of breast milk compared with formula milk is associated with a decreased weight-gain velocity.136 Interestingly, breastfeeding is related to greater appetite regulation than bottle-feeding, regardless of the type of milk. When investigating whether feeding mode (bottle vs breast) and type of milk in the bottle (formula vs expressed breast milk) in the first 6 months of age influenced a child’s later eating behavior, infants fed breast milk in a bottle exhibited both a higher consumption of milk in the second 6 months 137 and a lower satiety responsiveness at 3to 6 years of age138 than those directly breastfed.

These findings suggest that breastfeeding itself, rather than breast milk, is related to greater appetite regulation, which highlights the importance of maternal–infant bonding in infants’ eating behavior.139 Through breastfeeding, mothers learn to become responsive, namely to recognize the infant’s signals of hunger and satiety, thus feeding or stopping accordingly, and to develop a feeding style that is less controlling, thus allowing infants to maintain their natural ability to regulate energy intake, with long-lasting effects on complementary feeding.140 In contrast, bottle feeding may provide misleading visual cues, leading mothers or caregivers to feed in response to amounts in the bottle rather than responsively to the infant’s cues.

CONCLUSION

In recent years, there has been increased awareness that interactions between pre- and postnatal environmental nutrition may ultimately determine offspring health.17 The current obesogenic environment, which compromises the nutrient supply by providing foods with a low nutrient density as the major contributors to total energy, carbohydrate, and fat intakes, is potentially of concern because some pregnancy-related diseases are linked to the offspring’s growth trajectory and to gene–epigenome variations implicated in the developmental origins of health and disease. Reducing the prevalence of malnutrition and its consequences is of great importance for public health. Therefore, a consistent translation of research results into nutrition recommendations and policy endorsements needs to be achieved. Education and translational research to support the adoption of a healthy lifestyle from the periconceptional period onward, if integrated into patient care, may have important implications for the prevention of short-term adverse reproductive outcomes and long-term health. This may offer substantial benefits for the health of current and succeeding generations, ultimately leading to healthcare and societal cost savings. Emergent findings show that not only maternal but also paternal nutrition is crucial for optimal conception, pregnancy, and lifelong health of the offspring

Personalized interventions to improve parental nutrition should be implemented right at the start of a new life. Indeed, individuals are much more likely to be motivated to improve their nutrition and lifestyle behaviors during the vulnerable reproductive period, because of the immediate benefit of having a healthy child.141 Most of the findings about in utero nutrition, despite being observational, highlight the importance of diet composition for both pregnancy and the long-term health of mother and child, including ramifications for the gut flora and the body’s immune response. As practical recommendations, pregnant women should be encouraged to eat a balanced diet and to lower their consumption of sugar-sweetened beverages and processed meats, as suggested by current national and international dietary guidelines, and should consume 200 g of fatty fish per week to reach the recommended intake of n-3 long-chain polyunsaturated fatty acids while remaining below the tolerable upper intake for contaminants.142 There is evidence to suggest that maternal vitamin D status may have important short- and long-term influences on both a pregnant woman’s health and the health of her offspring. The diet is typically a very poor source of vitamin D; hence, in the absence of adequate sunlight-induced vitamin D synthesis, supplementation may be required.

The gut plays a central role in the ontogenic development of immune tolerance, and a well-balanced microbial composition in utero through infancy is pivotal for the establishment of immune homeostasis later in life. Overall, term infants born vaginally and breastfed exclusively have the most beneficial gut microbiota, while antibiotic treatment and cesarean delivery promote suboptimal development of the microbiota in early infancy. Specific probiotics have been reported to modulate immune responses. Experimental trials seem to indicate the potential for supplementation with probiotics (or probiotic-containing foods such as yogurt) and/or prebiotics (or prebiotic-containing-foods) during pregnancy and breastfeeding as a safe and effective strategy to prevent certain complications of pregnancy and to enhance the immune-protective potential of breast milk, perhaps reducing allergic/inflammatory conditions in offspring. In its guidelines for prevention of allergic disease, the World Allergy Organization recommends the use of probiotics in pregnant women at high risk of having an allergic child; in women who breastfeed infants at high risk of developing allergy; and in infants at high risk of developing allergy, albeit conditionally.126 Indeed, each probiotic strain is inherently unique, and similar health effects cannot be expected even from closely related strains. Overall, recommendations and guidelines for treatment interventions should be meticulously defined.143 For probiotics, it is important to characterize each probiotic to the species and strain level and to select strains with documented properties, as the probiotic potential is strain specific.126,144 It is also important to document preclinical effects by means of markers relevant to the clinical condition in question. This means that further well-powered and carefully conducted clinical trials with long-term follow-up are needed.145

Breastfeeding is strongly recognized as a healthy behavior with many short- and long-term benefits for mother and infant, including the facilitation of mother–infant bonding.146 To promote and support breastfeeding, neonatologists and pediatricians need specific knowledge and skills. In maternity hospitals and neonatal units, appropriate organizational interventions to facilitate the initiation of breastfeeding and the use of mother’s/human milk should be implemented.147 Hence, all maternity units should be encouraged to implement significant strategies and practical changes to achieve accreditation as a United Nations Children's Fund/World Health Organization Baby-Friendly Hospital by complying with the Ten Steps to Successful Breastfeeding, which may represent an effective strategy to increase both the rates of breastfeeding initiation and the duration of breastfeeding.148

Acknowledgments

The authors are grateful to Sabino Maria Frassà, General Director of the Giorgio Pardi Foundation, and Ama Nutri Cresci for having conceived and directed the international scientific congresses at Expo Milano 2015. They also thank the Giorgio Pardi Foundation and Ama Nutri Cresci for overall support.

Funding/support. This research was partially funded by the Giorgio Pardi Foundation. The funder had no role in the development, preparation, or review of the manuscript.

Declaration of interest. The authors have no relevant interests to declare.

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