The nurse determines a newborn is small-for-gestational-age based on which characteristics?

Pregnancies Complicated by Small for Gestational Age Infants

Small for gestational age (SGA) is defined as birth weight below the 10th percentile of the referent population. SGA can complicate a normotensive pregnancy or can occur as a complication of a hypertensive pregnancy. The link between birth weight and adult cardiovascular health was first highlighted by David Barker and colleagues in the late 1980s. It was shown that infants born with a low birth weight had a higher mortality rate due to cardiovascular disease compared to infants born with a normal birth weight (Barker et al., 1989). Since then this finding has been confirmed by many other large studies (Eriksson et al., 2001; Lawlor et al., 2005). In addition to the risk for the child, women who deliver SGA infants are at an increased risk of later life CVD (Ngo et al., 2015). Delivery of a SGA infant is associated with an increased risk of developing or dying from overall CVD (RR 1.66, 95% CI 1.26–2.18), ischemic heart disease (RR 1.68, 95% CI 1.31–2.14), and stroke (RR 1.62, 95% CI 1.51–1.74) (Heida et al., 2016). The risk of CVD is also shown to increase in a stepwise manner with delivering one SGA infant is associated with a RR of 1.41 (95% CI 1.36–1.46), two SGA infants with a RR of 1.74 (95% CI 1.58–1.93), and three or more SGA infants with a RR of 1.86 (95% CI 1.35–2.57) (Nilsson et al., 2009). Therefore, women who give birth to SGA infants appear to be at 1.5 times higher risk of CVD compared to women who have uncomplicated pregnancies.

Small for Gestational Age

Infants small for gestational age (SGA) may be born full term or pre-term, yet are smaller than their gestational age-mates. Research results are mixed, with a general association between mental abnormalities and SGA (e.g., Ounsted, Moar, & Scott, 1983; Kahn-D’Angelo, 1987). However, many studies are confounded with other characteristics, such as exposure to neurotoxins before birth, or mothers who were malnourished during pregnancy.

A sample of 44 children, ages 4–42 months, were identified by caregivers as being born small for gestational age. Both term and pre-term children were included in the study, as long as their weight and size at birth were below that of 90 percent of gestational age-mates.

Significant differences in mean scores were found between the SGA group and the matched control group for the Receptive Communication and Gross Motor subtest scaled scores and the Motor Composite score. The mean scores of the SGA group generally were within the normal range, with the scores of the matched control group slightly higher than normal. These scores likely reflect a disproportionate number of children in the SGA sample (and therefore the matched control group) whose parents had high education levels (i.e., more than 12 years of school).

Small-for-Gestational-Age Deliveries

A small-for-gestational-age (SGA) infant is one whose individualized birth weight ratio falls below the 10th percentile and is associated with increased perinatal mortality and morbidity [121]. Some studies of SGA deliveries report reduced placental selenium concentrations (SGA: median [IQR]: 0.14 [0.1, 0.2] compared to 0.15 [0.1–0.24]) in placentae from appropriate-for-gestational-age (AGA) deliveries [122]. However, others report higher selenium in umbilical venous and arterial blood between SGA and AGA [123] and some, unchanged [124]. An investigation into a cohort of poor adolescent pregnant women from two inner cities in the United Kingdom found lower plasma selenium concentrations in mothers who delivered SGA infants compared to those who delivered AGA infants [125]. Geographical variations as well as differing markers of selenium status between these studies may account for some of the inconsistencies.

Catch-Up Growth in Small-for-Gestational-Age Infants

SGA infants have been identified as being at risk for continued growth failure in extrauterine life, learning difficulties, and behavioral problems. Lucas et al86 explored the influence of early nutrition on growth in the first year of life in full-term SGA infants, comparing those receiving breast milk with those receiving formula. This was a subset of a study on early carnitine supplementation. An equal number of breastfed and formula-fed infants received carnitine. Additional demographic, social, clinical, and anthropometric data were collected. Breastfeeding was associated with a greater increase in weight at 2 weeks and 3 months of age, which persisted beyond the actual breastfeeding period. The authors reported greater catch-up growth in head measurement and a greater increase in body length in the breastfed infant. They suggest that breastfeeding promotes faster catch-up growth, and breastfed infants have the potential for improved catch-up growth in developmental parameters as well.86

In a study designed to examine the role of zinc supplementation in catch-up growth in SGA infants, Castillo-Duran et al16 reported that infants who were exclusively breastfed had increased growth compared with those who were formula fed and supplemented with zinc.

Very Premature Infants and Programming

Small-for-gestational-age neonates are often the result of maternal malnutrition that impacts the nutrition of the fetus. This is a problem that has occurred for centuries but came to the forefront by and large from the work of David Barker and colleagues examining adults who were of low birth weight due to caloric deprivation. Currently, a new population of infants may also be at risk, the very premature infant. Similar to the small-for-gestational-age neonate who had intrauterine caloric deprivation, the very premature infant in the neonatal intensive care unit does not receive the same nutrition that would be present if in the womb. In addition, the very premature infant is exposed to a number of drugs and an intrusive environment which may have an impact in later life. The very premature infant is now surviving the neonatal intensive care unit, and many very premature infants are now adults; studies are now emerging showing that the risk factors for chronic disease in later life for the very premature infant are comparable with the small-for-gestational-age infant. However, it should be appreciated that only in the past 30 years are very premature infants surviving into adulthood and thus we do not know the full impact of being born very premature.

Meta-analyses examining the effect of prematurity on blood pressure demonstrate that as with small for gestational age, prematurity is a risk factor for high blood pressure. In one study in which the average birth weight was 1280 g and gestation 30.2 weeks, the systolic blood pressure was 2.5 mm Hg higher at approximately 18 years of age.97 Another study compared adults who were born at less than 37 weeks' gestation with those at term and found a 4.2-mm Hg systolic and 2.6-mm Hg diastolic blood pressure increase in adults born preterm. Blood pressure assessed in young adults born less than 1.5 kg, compared with term infants that were age, sex, and birth hospital matched using 24-hour blood pressure monitoring found that those adults who were very premature had an average 2.4 mm Hg higher blood pressure and a higher prevalence of hypertension than term controls.98 As with small-for-gestational-age offspring, premature infants are at increased risk for developing type 2 diabetes and may be at risk for metabolic syndrome.99

In utero nephrogenesis in the human starts at approximately 10 weeks' gestation and continues until 36 weeks. Although nephron endowment is usually dependent on several factors discussed previously, it is impacted significantly by prematurity. Nephrogenesis occurs predominantly in the third trimester and can continue to occur in neonates born before 36 weeks' gestation.100 However, postnatal accrual of nephrons occurs only for 40 days postnatally.100 Thus, if a premature neonate is born at 24 weeks' gestation and has 40 days to accrue nephrons, the number of nephrons formed will likely be only half of the number if the neonate had remained in the womb.

Renal biopsies performed in patients who were born very low birth weight between 22 and 30 weeks' gestation were evaluated for proteinuria (1.3 to 6 g/day) at an average age of 32 years. Although the patients had normal or mildly impaired renal function, all patients had evidence of focal and segmental glomerulosclerosis, a harbinger of progressive renal disease.101 Although this was a series of a handful of patients, it is unclear what the prognosis for progressive renal disease will be for very low birth weight infants as they age.

Summary

SGA is a unifying diagnosis that encompasses multiple etiologies but is associated with significant short-term and long-term morbidity with risk dependent on early life growth trajectories. Catch up growth is associated with increased adiposity leading to insulin resistance and metabolic syndrome in later life. Growth hormone treatment is licensed for use in those who remain short, but the data on long-term outcomes are limited. It is important we understand the mechanisms driving these growth patterns if we hope to modify them and impact on long-term health at an individual or population level. The challenge going forward is to prevent intrauterine insults and, if present, to develop early lifestyle interventions and/or pharmacotherapy to reverse the pathophysiological changes to prevent the development of metabolic complications in later life.

Intrauterine Growth Retardation and Small for Gestational Age

Small for gestational age (SGA) has been variously defined as birth weight or length below the 10th percentile or 2 SDs below the mean.173,289-291 About 10% to 15% of children born SGA have persistent growth failure beyond 2 to 3 years of age.292 SGA status is associated with increased long-term risk for developing insulin resistance, obesity, and type 2 diabetes mellitus. The term IUGR is sometimes used interchangeably with SGA; however, IUGR actually implies a pathologic process that restricts fetal growth and is diagnosed through serial prenatal ultrasounds.292

The reason for being born SGA is multifactorial and includes intrinsic fetal abnormalities (genetic alterations and syndromes, congenital malformations, congenital infections), placental factors, and maternal factors (e.g., ingestion of drugs, tobacco, and alcohol; malnutrition and intercurrent illness; and uterine abnormalities) (see Tables 22-3 and 22-4). Genetic causes include chromosomal abnormalities, single gene defects, and uniparental disomy (UPD).292-294 Congenital diabetes mellitus and insulin receptor mutations,135 congenital IGF-1 deficiency, and IGF-1 receptor mutations in humans cause IUGR and SGA.46,59,295 In addition, polymorphisms in genes associated with obesity and type 2 diabetes296 and hypertension297 have been observed in patients with SGA. However, the exact origin in any given child remains unknown in up to 60% of cases.298

Russell-Silver Syndrome is a term applied to some children with IUGR and postnatal growth restriction with associated dysmorphic features such as relative macrocephaly, triangular facies, clinodactyly, and subtle body asymmetry. It is a heterogeneous condition with an estimated incidence of 1 in 3,000 to 100,000, depending on the criteria used for diagnosis.299 Clinical scoring systems have been suggested to establish the diagnosis.299 Mean final height is approximately 4 SDs below the mean.300 Approximately 10% have uniparental disomy of maternal chromosome 7, and 60% have hypomethylation of the imprinting control region 1 on chromosome 11p15.301,302 In the latter group, loss of IGF-2 expression in the fetus may contribute to IUGR.302

Nonsyndromic etiologies of IUGR include intrauterine infection, placental disorders (e.g. placenta previa, placental infarcts), maternal disease (vascular disorders and hypercoagulable states), maternal undernutrition, and maternal toxin exposure (e.g., alcohol, illicit drugs, tobacco).303,304 Placental malfunction and altered delivery of nutrients to the fetus are the common pathways that lead to growth restriction. Under adverse conditions, nutrients are redirected toward oxidative metabolism rather than mass accumulation, and organ growth and development can be compromised.305 Placental epigenetic modifications seem to be the major mechanisms by which nutritional and environmental factors affect fetal growth.306 While these adaptations increase the chances of perinatal survival, they lead to permanent changes in tissue structure and function that can predispose to metabolic dysfunction (e.g., insulin resistance) in later life.305,306

The clinical management of children with short stature attributed to SGA involves attempts to ascertain and manage the underlying cause of the condition.289 The FDA has approved GH therapy for SGA children who fail to manifest catch-up growth in height by 2 to 3 years of age. Prior to initiating GH therapy, other causes of short stature must be excluded. GH stimulation testing is not required before starting GH treatment in children born SGA. GH therapy has been found to improve growth rate in these patients, resulting in an adult height gain of 5 to 8 cm, although wide individual variability exists.307 Younger age at initiation has been shown to improve outcome,308 and early initiation of therapy (at 2 to 4 years of age) is recommended for those with severe growth retardation (height <-2.5 SDS).291 Children with a recognized syndrome respond less well to GH than those with nonsyndromic SGA.291 Although some data suggest reduced insulin sensitivity in short SGA children treated with GH,309 to date long-term GH treatment has not been found to increase the risk for type 2 diabetes mellitus.292,310

Undernutrition and Chronic Nonendocrine Disease. Undernutrition sufficient to reduce caloric intake to below 82% to 91% of the recommended level will arrest growth.311,312 This degree of undernutrition is suggested by weight for height, BMI, or body fat below the 10th percentile.313 Undernutrition may result from inadequate nutrient intake (due to psychosocial feeding or eating disorders, or poor appetite due to chronic disease), excessive nutrient output (chronic vomiting or malabsorption as in inflammatory bowel disease, celiac disease, cystic fibrosis, or hepatic disease), or metabolic wastage (as in poorly controlled diabetes mellitus).314,315 A unique cause of malnutrition in infants is diencephalic syndrome. This is characterized by a paucity of body fat resembling lipodystrophy in a hyperalert, otherwise healthy child. Radiosensitive brain tumors in the anterior hypothalamic area are the usual cause. Disturbance of the regulation of appetite, secretion of pituitary lipolytic hormones such as GH, and increased energy expenditure have been postulated as the mechanism.316,317 Deficiency of trace metals such as zinc and copper also causes growth failure.97,98 Rickets due to vitamin D deficiency can be due to inadequate intake, malabsorption, liver disease, or renal disease; impaired growth is a common feature.

Data indicate height attenuation in children treated with stimulants for attention deficit hyperactivity disorder318; although the mechanisms are not known, change in appetite with reduced caloric intake and suboptimal nutrition has been suggested. Strategies to improve nutrition, drug holidays, and altering treatment regimen (stimulant dose reduction or alternate medication) have been suggested as management strategies, but no data exist to support specific guidelines.319

Chronic nonendocrine disorders of virtually any organ system may attenuate growth.320 Generally, weight is suppressed more than height, in contrast to primary endocrine disorders. Mechanisms of growth impairment vary according to the disease and often include undernutrition, medication effects (e.g., supraphysiologic doses of glucocorticoids), chronic acidosis, and/or secondary endocrine dysfunction. Examples include celiac disease, inflammatory bowel disease, chronic renal failure, cardiovascular disease, hematologic disorders, poorly controlled diabetes mellitus, chronic acidosis, cystic fibrosis, and chronic infections. Although the primary disorder is evident in many cases of short stature due to chronic illness, short stature is sometimes the primary presenting feature. This occurs notably in inflammatory bowel disease, celiac disease, and renal dysfunction.

Celiac disease and Crohn’s disease are notorious for presenting as short stature without gastrointestinal complaints. In approximately 2% to 8% of children with short stature and no gastrointestinal symptoms, celiac disease may be the underlying cause, and if other causes of short stature are excluded, the risk for celiac disease is increased in some reports to 19% to 59%.321 Measurement of immunoglobulin (Ig)A tissue transglutaminase and antiendomysial antibodies is a screening test for celiac disease, and sometimes referral to a gastroenterologist is needed.322

Poor growth in Crohn’s disease reflects poor food intake, malabsorption, disease severity, direct effects of the inflammatory process on the growth axis (with evidence implicating tumor necrosis factor [TNFj-α, interleukin [IL]-6, and IL-1-β]), the presence of jejunal disease, and perhaps genetic susceptibility factors (including IL-6 gene polymorphism and polymorphism on the TNF-α promoter gene).149,323-326 GH deficiency has been reported,327 but an actual link between the two conditions is uncertain. Growth in Crohn’s disease can also be adversely affected by glucocorticoid therapy and may improve with nutritional intervention or surgery.149,328 Although many children show an increase in height SDS after beginning treatment for Crohn’s and reach final heights close to target heights, about one fifth have final height significantly lower (>8 cm lower) than target height.325

Preliminary results of GH trials in children with chronic inflammatory disease, including Crohn’s disease, cystic fibrosis, and juvenile rheumatoid arthritis, show promising gains in height as well as non-height benefits.329 Additional, larger, and long-term studies are needed to confirm these findings. GH is not currently FDA-approved for these conditions.

Chronic renal disease—including renal tubular acidosis and chronic renal insufficiency— suppresses growth. Poor growth in chronic renal insufficiency probably reflects chronic acidosis, poor intake, anemia, subnormal formation of 1,25-dihydroxycholecalciferol, renal osteodystrophy, and, at times, use of medications (e.g., glucocorticoids). In addition, serum IGF-1 is generally normal, but IGF bioactivity and free IGF-1 are low,330,331 probably because of excessive circulating IGFBPs.332 The FDA has approved GH for the treatment of short stature due to renal failure before transplantation, and consensus guidelines have been developed.333 An analysis of 16 studies has confirmed that GH treatment improves first year growth velocity in children with chronic renal disease. Second-year growth velocity was reduced but remained significantly greater than in untreated children.334 GH has also been used in some studies after transplantation, with promising results.333,335

Metabolic disorders may affect growth. Chronic acidosis99 or chronic alkalosis336 may cause growth failure. Chronic anemia337 and rickets lead to a delayed growth pattern.338,339 Diabetes mellitus, when poorly controlled, can lead to Mauriac syndrome, involving growth failure and hepatomegaly due to excessive glycogen deposition. In thalassemia, growth impairment may reflect not only chronic anemia, but also endocrine dysfunction due to hemosiderosis.340

Hypoglycaemia Should be Anticipated in the Following Babies

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Small for gestational age (SGA) babies. Many will be normal, healthy, constitutionally small babies. Those that have been growth restricted in utero fail to lay down adipose tissue and glycogen stores and are vulnerable to hypoglycaemia. Generally, they will have asymmetrical growth restriction, with relative sparing of head growth and length. Babies with symmetrical growth retardation are more likely to have an underlying chromosomal problem or congenital infection. These babies often have defective counter-regulatory responses, resulting in a poor ketogenic response, enhanced glycolysis and high insulin levels.

Large for gestational age babies. Some will be healthy, constitutionally large babies while others will be exposed to excessive insulin or insulin-like growth factors in utero (such as infants of diabetic mothers and babies with Beckwith–Wiedemann syndrome).

Preterm babies. Like SGA babies, these babies have a lack of glycogen stores, immature enzymes involved in glucose homeostasis and often inappropriately high insulin levels.

Babies with a history of birth depression (who utilised glycogen stores during delivery).

Polycythaemic babies in whom the erythrocytes utilise glucose.

Maternal or neonatal β-blocker use.

Small-for-Gestational-Age Infants

The term small for gestational age is an arbitrary classification that refers to an infant whose intrauterine growth is less than expected for gestational age at birth. It is, in fact, a heterogeneous category, with a wide range of causes, risk of perinatal complications, and outcomes (Allen, 1992). Small size at birth may be due to parental (especially maternal) small size; insult or injury to the fetus; fetal maldevelopment; or deprivation of supply of oxygen or nutrients due to placental insufficiency, maternal ingestion (e.g., cigarettes, alcohol, narcotics), or maternal illness. Magnitude of risk for death, perinatal complications, and neurodevelopmental disability varies with the cause of the intrauterine growth restriction (IUGR), the timing of the insult (if any), and the perinatal complications that the child encounters.

The small-for-gestational-age (SGA) infant whose mother is small is likely to be only mildly growth restricted and have no increased risk. With trisomy 18, poor fetal growth early in pregnancy is likely, with death within the first several months, or the affected child will develop multiple severe neurodevelopmental disabilities. The SGA infant with fetal alcohol syndrome has prenatal and postnatal growth deficiencies and an increased risk of congenital anomalies (e.g., characteristic facies, joint anomalies, ventricular septal defect) and CNS dysfunction (e.g., mild to moderate mental retardation, tremors, fine motor incoordination, hyperactivity). Uteroplacental insufficiency often manifests later in pregnancy (after 27 or 28 weeks of gestation) and often causes asymmetrical growth restriction with sparing of head growth. IUGR from uteroplacental insufficiency can be viewed as an adaptation to restricted supply of nutrients. Although it may be an effective human adaptation to adverse intrauterine circumstances, there are consequences to this strategy: increased risk of perinatal complications that can affect survival and outcome (e.g., perinatal asphyxia, hypoglycemia), of hypertension later in life, of short stature, and of disability (Allen, 1992; Hollo et al, 2002; Low et al, 1992; Paz et al, 1995; Pena et al, 1988; Pryor et al, 1995; Strauss, 2000, Wocadlo and Rieger, 1994).

Studies that report developmental outcome of SGA infants generally exclude infants with congenital anomalies, genetic syndromes, or congenital infections. They follow primarily infants with placental insufficiency or unknown cause of IUGR, and they distinguish between the fullterm and the preterm SGA infant. Although retrospective studies of children with disability find a higher-than-expected proportion who were SGA infants, prospective studies find only a higher incidence of academic failure (as high as 25% versus 14%) and behavior problems in fullterm SGA children than in fullterm appropriate-for-gestational age (AGA) children (Hollo et al, 2002; Larroque et al, 2001; Low et al, 1992; Paz et al, 1995). Lower mean IQ scores have been found in some samples of fullterm SGA children, but this is not a consistent finding in IUGR infants born to mothers with pregnancy-induced hypertension and in IUGR adults (Goldenberg et al, 1996; McCowan et al, 2002, Paz et al, 1995, 2001; Pryor et al, 1995). Fullterm IUGR adolescents and adults report greater disadvantage when it comes to school failures and dropout, job status, and income (Larroque et al, 2001; Paz et al, 1995; Strauss, 2000).

The preterm SGA infant has the disadvantages of both prematurity and IUGR, but it is difficult to determine how much IUGR further increases the preterm infant's risk of neurodevelopmental disability (Pena et al, 1988; Robertson et al, 1990; Thompson et al, 1993; Wocadlo and Rieger, 1994). Preterm SGA infants have more severe IUGR than that noted in fullterm SGA infants because they already manifest significant growth restriction at the time of their preterm birth. Most preterm SGA children have normal intelligence, but their mean IQ is lower than that of fullterm AGA and SGA children and sometimes even preterm AGA children (depending on whether controls are matched for birth weight or gestational age) (Table 67-5). Major disability occurs in 7% to 23% of preterm SGA children. Learning disabilities occur in 36% to 50% of preterm SGA children at 8 to 11 years, and preterm SGA children are more hyperactive than preterm AGA and fullterm controls (Low et al, 1992; Robertson et al, 1990). The most striking finding of these studies is that all preterm groups, whether SGA or AGA, scored worse than fullterm control groups on measures of growth, intellectual function, visual-motor integration abilities, reading, arithmetic, and behavior. This finding highlights the importance of long-term follow-up evaluation to school age for children with prematurity or IUGR.

Role of Breast-Feeding in Programming

Both small-for-gestational-age and large-for-gestational-age infants are at particular risk for later-onset metabolic disease. As these babies change rapidly over the first 6 months of life to attain the mean weight for their age (both catch-up and catch-down growth), care needs to be taken not to introduce interventions at critical stages of development without evidence of short-term and long-term safety and efficacy. In general, breast-feeding is associated with protection against rapid infant weight gain and later obesity.111-114 Rapid, excess weight gain during the first 6 months of life, however, has consistently been identified as a predictor of later obesity, even among breast-fed infants.115-119 The mechanisms responsible likely involve the delivery of bioactive components that regulate infant appetite, metabolism, and weight/adiposity gain.120

It is quite likely that bioactive components in human milk, including fat composition, adipokine content, and cytokine content, impact the developmental programming paradigm. In one animal study, murine pups born to lean mothers and suckled by an obese mother exhibited increased adiposity and reduced insulin sensitivity after they had been weaned.121 In a separate study, pups born to lean mothers were cross-fostered by diet-induced obese mothers. These offspring displayed increased body weight, an NAFLD phenotype, and increased levels of inflammatory cytokines IL-6 and TNF-α by 3 months of age.122 Control murine pups cross-fostered by mothers with gestational diabetes exhibited abnormal hypothalamic programming in the arcuate nucleus after they had been weaned associated with dysregulated appetite, increased food intake, and increased body weight.123 There are also known associations between maternal high-fat diet in rodent models and up-regulation of offspring obesigenic genes (including PPARA and IGF2).124 In human studies, supplementation with n-3 long-chain polyunsaturated fatty acids (LC-PUFAs) influenced breast milk fatty acid composition, reducing the ratio of n-6 LC-PUFAs to n-3 LC-PUFAs, and led to decreased adiposity of offspring in the first year of life.125

Epidemiologic data from humans are not as conclusive. Exclusive breast-feeding at 2-4 weeks of age among women with gestational diabetes has been associated with increased infant body weight.126 However, in 5- and 16-year-old offspring of mothers with gestational diabetes, breast-feeding was somewhat protective against obesity.127 Maternal BMI factored into that relationship. Obese mothers needed to breast-feed longer to impart protection to their offspring.127 The effects of lactation on infants born to mothers with T2DM (who are most often overweight/obese) have not been systematically studied. Newer findings in large populations suggest that breast-feeding may have little impact on children's BMI.128

Finally, the gut flora—the collection of gut microbes (microbiome)—has recently emerged as a provocative pathway to understanding early changes in both the immune system and energy balance in humans, nonhuman primates, and rodents.129-131 The postnatal assembly of the human microbiota begins at birth and plays an important role in resistance to pathogen invasion, immune stimulation, and other important developmental cues early in life.132 Vaginally delivered infants clearly receive a strong input of vaginal and other urogenital microbes as they pass through the birth canal,133,134 whereas cesarean-delivered infants display reduced colonization of bacteria early in development.135,136 The effects of the delivery mode may have consequences for infant health; infants born by cesarean delivery tend to be at higher risk for obesity, and arguably at greater risk for immune-mediated diseases.137-140 How these microbial shifts influence the maternal-fetal-infant relationship is not well understood.

The infant gut microbiota, which can be influenced by maternal events in early life such as the mode of delivery and feeding, and by later life factors such as diet composition and early antibiotic exposure, may also contribute to the risk for obesity and T2DM later in life.141 The gut microbiome is environmentally acquired from birth;142,143 therefore it may function as an environmental factor that interacts with host genetics (through epigenetic modifications) to shape the phenotype.144-147 Because obesity is associated with altered gut microbial configuration in humans and an obese phenotype can be transmitted via the gut microbiota in animal models of obesity, it is tempting to speculate that transmission of the maternal microbiome to the infant may have an important role in energy retention by the infant. Alterations in intestinal microbial composition in the first year of life may last throughout childhood and contribute to the development of obesity.148,149 Comparisons of the microbiota of the distal of the gut of genetically obese mice and lean controls, as well as those of obese and lean humans, showed that obesity is associated with changes in the relative abundance of two dominant bacterial divisions—Bacteroidetes and Firmicutes; obese mice or humans have a higher ratio of Firmicutes to Bacteroidetes. Biochemical analyses show that these proportional changes affect the metabolic potential of the mouse gut microbiota and that the microbiome from obese animals has an increased capacity to harvest energy from the diet. Members of Firmicutes produce more complete metabolism of a given energy source than do members of Bacteroidetes, promoting more efficient absorption of calories and subsequent weight gain. Furthermore, this trait was transmissible: colonization of germ-free mice with an “obese microbiota” resulted in a significantly greater increase in total body fat than colonization with a “lean microbiota.” Because the gut microbiome is environmentally acquired from birth,142,143 it may function as an environmental factor that interacts with the infant and its genome to shape the phenotype.