Nutrition Publication

NNIW74 - Maternal and Child Nutrition The First 1000 Days: Setting the Future

Editor(s): Z. Bhutta, J. Bhatia, S. Kalhan . 74

Nutrition in the first 1000 days, is a subject discussed widely. Therefore NNI dedicated a workshop to this important topic. Three renown chairs, Prof. Z. Bhutta, Prof J. Bhatia, Prof. S. Kalhan established an outstanding scientific review. Most importantly, it was highlighted that prevention  actually has to start before pregnancy, i.e. with the health of adolescent girls, being in childbearing age, throughout pregnancy and lactation. Overall the importance of appropriate diets during this critical period of high plasticity have been reviewed during the workshop. Finally, it was emphasized that the economic burden of low birth weight and later consequences, such as low education and reduced labour capacity, as well as the elevated risk of metabolic diseases later in life should drive the public health agenda.

Related Articles

The Epidemiology of Low Birthweight

Author(s): M. Kramer

In this paper, I review the epidemiology of low birthweight (LBW). I begin by defining LBW and emphasizing the distinction between infants who are born early (preterm) and those who are born small for their gestational age (SGA). I then review data on the global burden of preterm birth and SGA and the evidence bearing on whether ‘one size fits all’, i.e. whether a single birthweight (or birthweight for gestational age) cutoff is appropriate for different regions and population subgroups. I summarize what is known about the etiologic determinants of preterm and SGA birth, how they differ among countries of varying socioeconomic development and prevalence of risk factors, and how they are changing over time. I conclude with a critical appraisal of LBW prevention as a public health priority and argue that reducing fetal and infant mortality is a more important and achievable target for intervention.

Fetal Malnutrition and Long-Term Outcomes

Author(s): C. Fall

Epidemiological studies have shown that lower birthweight is associated with a wide range of adverse outcomes in later life, including poorer ‘human capital’ (shorter stature, lower cognitive performance), increased risk factors for later disease (higher blood pressure and reduced glucose tolerance, and lung, kidney and immune function), clinical disease (diabetes, coronary heart disease, chronic lung and kidney disease), and increased all-cause and cardiovascular mortality. Higher birthweight is associated with an increased risk of cancer and (if caused by gestational diabetes) obesity and diabetes. The ‘developmental origins of health and disease’ hypothesis proposes that fetal nutrition has permanent effects on growth, structure and metabolism (‘programming’). This is supported by studies in animals showing that maternal under- and overnutrition during pregnancy can produce similar abnormalities in the adult offspring. Common chronic diseases could potentially be prevented by achieving optimal fetal nutrition, and this could have additional benefits for survival and human capital. Recent follow-up of children born after randomized nutritional interventions in pregnancy provides weak evidence of beneficial effects on growth, vascular function, lipid concentrations, glucose tolerance and insulin resistance. Animal studies indicate that epigenetic phenomena may be an important mechanism underlying programming, and that nutritional interventions may need to start preconceptionally.

Intervention Strategies for Preventing Low Birthweight in Developing Countries: Importance of Considering Multiple Interactive Factors

Author(s): R. Uauy, C. Corvalan, P. Casanello, J. Kuzanovic

The need to prevent low birthweight (LBW) defined as a birthweight ≤2,500 g is presently well recognized, not only because of the immediate consequences increasing the risk of neonatal death and burden of disease but also in terms of the impact of being LBW on lifelong health and well-being. Children are born LBW (<2,500 g) either because they were born too early (true preterm LBW infants) or alternatively they failed to grow adequately despite a normal duration of gestation (intrauterine growth retardation IUGR). In this later case, the weight may be over 2,500 g, but the infant is lighter than expected for his/her gestational age. In fact, many preterm infants are to some degree growth retarded. Despite the differences in origin, all LBW categories are considered at increased risk of neonatal death and later morbidity. Preventive actions are more likely to succeed if we consider the nutritional interventions as part of a package that addresses in a holistic manner the full spectrum of needs of women from before conception as well as during pregnancy. We have gained sufficient experience with single nutrient and/or ‘magic bullet’ approaches to learn from this and avoid them in the future. New fetal growth standards (INTERGROWTH 2012) represent major progress in terms of evaluating the effect of early life events on later growth, health and well-being. Thus, for the first time, clinicians and researchers will have sequential longitudinal data that will serve to characterize whole body as well as brain, liver, and long bone growth, relating this indirectly to placental blood flow and transfer function, neonatal health, morbidity and mortality.

Effect of Multiple Micronutrient versus Iron-Folate Supplementation during Pregnancy on Intrauterine Growth

Author(s): U. Ramakrishnan, F. Kobina Grant, A. Imdad, Z. Bhutta, R.Martorell

This review examines the effects of prenatal multiple micronutrient (MM) supplementation ( ≥ 5 micronutrients) on intrauterine growth. We identified publications from 16 randomized controlled trials through PubMed and EMBASE database searches. Meta-analyses were performed by pooling results, and sub-analyses by timing of intervention and amount of iron were also done. The primary outcome measures were birthweight, low birthweight (LBW; <2,500 g) and small for gestational age (SGA). Prenatal MM supplementation significantly reduced the incidence of LBW (risk ratio, RR: 0.86; 95% CI: 0.81– 0.92) and SGA (RR: 0.83; 95% CI: 0.73–0.95) compared to iron-folate supplementation; mean birthweight was significantly higher by 55 g for MM with borderline increases in gestational age. MM supplementation was associated with larger decreases in the risk of LBW and SGA in the subgroup of trials that used supplements containing 60 mg of iron, but were not statistically significantly different from those for trials that used 30 mg iron. Prenatal MM supplementation improved intrauterine growth and can be recommended instead of prenatal IFA supplements in settings where micronutrient deficiencies are common.

Importance of Intervening in the Preconception Period to Impact Pregnancy Outcomes

Author(s): S. Dean, A. Imam, Z. Lassi, Z. Bhutta

Preconception care that begins in adolescence and is provided before and between pregnancies has the potential to impact 136 million women who give birth each year and ensure that newborns receive the healthiest start possible. Providing simple interventions before pregnancy can prevent a significant proportion of maternal and neonatal mortality and morbidity. Interventions to promote adolescent health and prevent teenage pregnancies, encourage contraceptive use and appropriate birth spacing, optimize weight and micronutrient status, and screen for and manage chronic conditions have proven efficacy. These interventions must now be scaled up to maximize delivery. Women who receive preconception care are more likely to adopt healthy behaviors, and therefore have better pregnancy outcomes. Preconception care is particularly effective when men are involved and care is provided in the community setting. All healthcare providers can and should begin to provide preconception care to all adolescent girls, women and couples of reproductive age by asking them if they wish to become pregnant or are actively trying to prevent pregnancy.

Nutritional Regulation of Fetal Growth

Author(s): F. Bloomfield, A. Jaquiery, M. Oliver

Fetal growth is largely regulated by nutritional supply. The placenta is responsible for fetal nutrient supply for much of pregnancy, but in early pregnancy nutrition is histiotrophic. Both placental size and efficiency, and fetal growth, may be affected by maternal nutritional state before and during very early pregnancy. In contrast, manipulating maternal nutrition during later stages of pregnancy has a smaller than expected effect on fetal growth. Maternal nutrition before and during early pregnancy also has a greater effect on gestation length than maternal nutrition later in pregnancy, suggesting that nutritional status may regulate both fetal growth trajectory and gestation length and that these two outcomes may be linked. Thus, determination of the nutritional factors regulating fetal growth, and potentially postnatal growth and body phenotype, may lie with the maternal nutritional status even before conception.

Endocrine Interactions in the Control of Fetal Growth

Author(s): A. Fowden, A. Forhead

Hormones are both growth stimulatory and growth inhibitory in utero. They act as environmental and maturational signals in regulating tissue accretion and differentiation during late gestation. They ensure that fetal development is appropriate for the nutrient supply and is optimal for neonatal survival. Growth- stimulatory hormones, such as insulin, the insulin-like growth factors and the thyroid hormones, have anabolic effects on fetal metabolism and increase cellular nutrient uptake and energy production for tissue accretion. Thyroid hormones also have specific effects on tissue differentiation at key developmental milestones. Similarly, leptin appears to affect development of specific fetal tissues and may counterbalance the maturational actions of other hormones near term. Glucocorticoids inhibit growth in utero but are essential for prepartum tissue differentiation in preparation for delivery. They also affect fetal bioavailability of most of the other growthregulatory hormones. In addition, many of these hormones alter the placental capacity to supply nutrients for fetal growth. In producing a fetoplacental epigenome specific to the prevailing intrauterine environment, hormones interact

Developmental Programming of Obesity and Metabolic Dysfunction: Role of Prenatal Stress and Stress Biology

Author(s): S. Entringer, P. Wadhwa

Epidemiological, clinical, physiological, cellular and molecular evidence suggests the origins of obesity and metabolic dysfunction can be traced back to intrauterine life and supports an important role for maternal nutrition prior to and during gestation in fetal programming. The elucidation of underlying mechanisms is an area of interest and intense investigation. We propose that in addition to maternal nutrition-related processes, it may be important to concurrently consider the potential role of intrauterine stress and stress biology. We frame our arguments in the larger context of an evolutionary-developmental perspective that supports roles for both nutrition and stress as key environmental conditions driving natural selection and developmental plasticity. We suggest that intrauterine stress exposure may interact with the nutritional milieu, and that stress biology may represent an underlying mechanism mediating the effects of diverse intrauterine perturbations, including but not limited to maternal nutritional insults (undernutrition and overnutrition), on brain and peripheral targets of programming of body composition, energy balance homeostasis and metabolic function. We discuss putative maternal-placental-fetal endocrine and immune/inflammatory candidate processes that may underlie the longterm effects of intrauterine stress.

One-Carbon Metabolism, Fetal Growth and Long-Term Consequences

Author(s): S. Kalhan

One-carbon metabolism, or methyl transfer, is critical for metabolism in all cells, is involved in the synthesis of purines, pyrimidines, in the methylation of numerous substrates, proteins, DNA and RNA, and in the expression of a number of genes. Serine is the primary endogenous methyl donor to the one carbon pool. Perturbations in methyl transfer due to nutrient and hormonal changes can have profound effect on cell function, growth and proliferation. It is postulated that at critical stages in development, nutrient and environmental influences by their effect on methyl transfer can impair fetal growth, reprogram metabolism and cause long-term morbidity in the offspring. The potential for their effects is underscored by the unique gestation-related changes in methyl transfer in healthy women, the late expression of transsulfuration cascade in the fetus and the unique metabolism of glycine and serine in the fetus. Dietary protein restriction in animal models and protein malnutrition in humans causes remarkable changes in the methyl transfer in vivo. Although the specific consequences of perturbation in maternal and fetal methyl transfer remain to be determined, a profound influence is suggested by the demonstrated relationship between maternal folate and B 12 insufficiency and metabolic programming.

Influence of Maternal Vitamin B12 and Folate on Growth and Insulin Resistance in the Offspring

Author(s): U. Deshmukh, P. Katre and C. Yajnik

The burden of chronic noncommunicable diseases (NCDs) such as diabetes, obesity and cardiovascular disease is shifting rapidly to low- and middle-income countries. It calls for a review of the classic ‘dogma’ of genetic predisposition, precipitated by adult lifestyle. The paradigm of early life origins of chronic disease has focused attention on maternal health and nutrition as major determinants of the health of the offspring. India has high burden of maternal ill health and also of diabetes and cardiovascular disease, offering unique opportunities to study the links between the two. Pune studies showed that the Indian babies were thin but fat (more adipose) compared to European babies, and that maternal micronutrient status during pregnancy was a determinant of offspring size and body composition. Two thirds of the mothers had low vitamin B 12 concentrations, while folate deficiency was rare. Higher circulating concentrations of homocysteine predicted smaller baby size. Follow-up studies revealed that higher maternal folate in pregnancy predicted higher adiposity and insulin resistance in the child at 6 years of age, and that low maternal vitamin B 12 exaggerated the risk of insulin resistance. Low maternal vitamin B 12 status is also associated with increased risk of neural tube defects and poor offspring cognitive functions. Our results suggest an important role for maternal one-carbon metabolism in offspring growth and programming of NCD risk. These ideas are supported by animal studies. Improvement of adolescent nutrition could effect intergenerational prevention of chronic diseases. 

Immediate Metabolic Consequences of Intrauterine Growth Restriction and Low Birthweight

Author(s): J. Bhatia

Optimal fetal growth resulting in a ‘normally grown’ term infant is of paramount importance for assuring a healthy start for postnatal growth and development. Fetal, infant and childhood growth restriction is an important clinical problem for obstetricians, neonatologists, pediatricians and globally, for public health. Worldwide, an estimated 20 million infants are born with low birthweight and a substantial proportion are small for gestational age. Many advances have been made in defining growth restriction by prenatal techniques, thus allowing the recognition of intrauterine growth restriction. Distinguishing infants who are small but have appropriate growth potential from those with growth restriction is important in order to apply obstetric surveillance, anticipate neonatal problems and plan for postneonatal guidance. It is clear that the fetus in growthrestricted pregnancies has limited supply of nutrients and oxygen. The resultant changes, if involving the placenta as well, can lead to circulatory and metabolic changes affecting both short- and long-term survival and development. In this paper, the causes and immediate consequence of being born with low birthweight, intrauterine growth restriction or small for gestational age will be discussed.

Amino Acid Homeostasis in the Preterm Infant

Author(s): J. van Goudoever

Functional outcome of preterm infants is highly related to the quality and quantity of nutrients provided during the first few weeks of life. New guidelines, as published by the ESPGHAN in 2010, have provided means to prevent undernutrition in the NICU. Especially proteins and amino acids seem to play a pivotal role, and the optimal regimen has not yet been determined. New data on the intrauterine nutrient supply suggest a high amino acid intake during the fetal period. How these results might translate into improvement of especially neurocognitive outcome needs to be investigated.

Interventional Strategies to Promote Appropriate Growth

Author(s): E. Ziegler, S. Carlson, S. Nelson

Appropriate growth of premature infants can be defined as growth that is not associated with adverse consequences in the short and the long term. Growth failure is associated with neurocognitive impairment. The goal of nutritional management therefore is the achievement of appropriate growth by ensuring that nutrient intakes are maintained at all times at adequate levels. Many impediments stand in the way of this goal. Parenteral administration of nutrients must begin immediately at birth and needs to be continued until enteral nutrition is fully established. While nutritional support is provided by parenteral nutrition, gut priming, also beginning at birth, stimulates the immature gastrointestinal tract to undergo maturation. Human milk is the preferred agent for gut priming because it is more effective and safer than alternative agents. As a source of nutrients, however, human milk is incomplete for the premature infant and requires supplementation (fortification) with nutrients. At the authors’ institution, commercial human milk fortifiers and additional sources of protein are being used in efforts to achieve appropriate growth. Data from the authors’ institution indicate that nutrient intakes, especially intakes of protein, have improved in recent years and are approaching adequate levels. Accordingly, growth of infants has improved to the point where on average only a mild degree of postnatal growth failure is observed.

Iron and Other Micronutrient Deficiencies in Low-Birthweight Infants

Author(s): M. Domellöf

Low birthweight (LBW), defined as birthweight <2,500 g, is a major global public health problem and is associated with lifelong cognitive and behavioral problems. Very LBW (VLBW) infants (<1,500 g) are at high risk of multiple macro- and micronutrient deficiencies, but most LBW infants are larger (1,500–2,500 g), and the most common nutritional problem of those infants is iron deficiency (ID). Globally, about 25% of pre-school children have ID anemia (IDA), the most severe form of ID, and there is good evidence that ID is associated with impaired brain development. However, adverse effects of excessive iron supplementation have been observed. Delayed umbilical cord clamping, which increases infant iron stores, should be recommended for all newborns. There is good evidence that intakes of 2 mg of dietary iron per kg daily prevents IDA in LBW infants without causing adverse effects. A recent study shows that this dose of iron supplementation also reduces the risk of behavioral problems at 3 years in infants with birthweights 2,000–2,500 g. VLBW infants need 2–3 mg/kg per day. To achieve these intakes, breastfed LBW infants should receive iron supplements, and formula-fed LBW infants should receive an iron-fortified infant formula.

Improving the Neurodevelopmental Outcomes of Low-Birthweight Infants

Author(s): M. Makrides, A. Anderson, R. Gibson, C. Collins

Infants born with low birthweight (LBW) have poorer neurodevelopmental outcomes compared with their term counterparts with appropriate weight for gestational age. The perinatal period is a time of high energy and high nutrient needs, and any process, such as preterm birth, poor nutrition or placental insufficiency, that interrupts the concentrated flow of nutrients to the fetus may result in babies with LBW. Therefore, it makes logical sense that at least part of the cognitive deficits may be explained by nutritional deprivation. The nutrients commonly deficient in LBW infants include protein and energy and micronutrients such as iron, zinc and long chain polyunsaturated fatty acids. In this review, we aimed to determine the effect of nutrient supplementation on neurodevelopment in LBW infants. While few trials have supported the hypothesis that nutritional supplementation improves neurodevelopment, many studies are limited by sample size and methodological shortcomings. Further large-scale rigorously designed intervention trials, with long-term neurodevelopment follow-up, are required to determine the optimal nutritional supplements and the timing of their administration to LBW infants.