Role of the prenatal environment in the development of obesity

MEDICAL PROGRESS

R

Role of the prenatal environment in the development

of obesity Robert C. Whitaker, MD, MPH, and William H. Dietz, MD, PhD

Establishing that prenatal life is a critical or sensitive period for the development of obesity may focus basic research and clinical prevention efforts on this period. This review summarizes evidence that the intrauterine environment influences the risk of later obesity and considers the mechanisms by which this may occur. The association between birth weight and adult weight suggests that there are enduring effects of the intrauterine environment on later obesity risk. We examine whether the maternal factors of diabetes, obesity, and pregnancy weight gain alter the intrauterine environment and thereby increase the risk of later obesity in the offspring. Of these maternal factors, evidence is strongest for the role of maternal diabetes. No single mechanism explains how these maternal factors could change the intrauterine environment to increase obesity risk. However, all potential mechanisms involve an altered transfer of metabolic substrates between mother and fetus, which may influence the developing structure or function of the organs involved in energy metabolism. (J Pediatr 1998;132:768-76)

Primary prevention of obesity is important because obesity is common,1,2 associated with significant morbidity,3 and difficult to treat.4 Although obesity results from an imbalance of energy intake and expenditure, prevention efforts are difficult to implement because the biologic mechanisms that lead to this energy

imbalance are not completely known. Intrauterine life may be a critical period for the development of obesity.5 Closer examination of this period may provide insights into the mechanisms involved in the onset and persistence of obesity.5 Our purpose is to review the evidence that fatness at birth and in later life are mediated

From the Department of Pediatrics, Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, and the Department of Pediatrics, New England Medical Center, Boston, Massachusetts. Supported in part by the Generalist Physician Faculty Scholars Award from the Robert Wood Johnson Foundation, Princeton, N.J. (Dr. Whitaker), and by grants DK/HD 50537 and P30-DK46200 from the National Institutes of Health (Dr. Dietz). Presented in part at a workshop entitled “Prevention and Treatment of Childhood Obesity: Research Directions,” sponsored by the National Institutes of Health, the National Task Force on Prevention and Treatment of Obesity, and the International Life Sciences Institute, Bethesda, Md., Sept. 11, 1995. Submitted for publication Jan. 11, 1996; revisions received Jan. 3, 1997, Mar. 27, 1997, and June 4, 1997; accepted June 6, 1997. Reprint requests: Robert C. Whitaker, MD, MPH, Children’s Hospital Medical Center, Division of General and Community Pediatrics, CH-1S, 3333 Burnet Avenue, Cincinnati, OH 45229-3039. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/19/83970

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by alterations in the prenatal environment caused by maternal diabetes, obesity, and pregnancy weight gain. BMI GDM IDDM NIDDM

Body mass index: weight/height2 Gestational diabetes mellitus Insulin-dependent diabetes mellitus Non-insulin-dependent diabetes mellitus

Few longitudinal studies have assessed the relationship between the intrauterine environment and later obesity, and it was not possible to directly compare these studies. Varying definitions of fatness and obesity were used. Obesity can be considered an excess of body fat,6 but in children the definition of “excess” is usually statistical rather than health-related.7 We have attempted to provide the cutoff points for defining obesity that were used in the cited studies. In doing so, we recognize that relative weight measures, such as body mass index, only indirectly assess fatness and that important biologic relationships between variables may not be detected when categorical variables are used.8

EVIDENCE Fetal Growth Birth weight is the most easily measured outcome of the impact of the intrauterine environment on fetal growth. Despite variations in eight studies (Table I) that related birth weight to relative weight in adulthood (after age 20 years),9-16 seven showed a positive association. None of these studies, however, adjusted birth weight for either birth length or gestational age. Such adjust-

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Table I. Studies relating birth weight and adult (age ≥20 years) relative weight

Age (yr) at assessment

Birth Sample year(s) size

Study population*

Adult outcome measure/definition of overweight or obese

20-30

1945– 1955

366

Rochester, N.Y.

36

1947

3249

United Kingdom

22

1947

442

Newcastle upon Tyne, England

60-71

1923– 1930 1949– 1963

297

Hertfordshire, BMI/continuous England: all female measure San Antonio, Tex.: 46% BMI/continuous female; 25% nonmeasure Hispanic white; 75% Mexican-American Minnesota BMI/continuous measure

30-32

541

28-52

1936– 1955

7,118

46-71

1921– 1946

71,100

United States: all female; 95% white

46-81

1911– 1946

22,846

United States: all male

% Median weightfor-height and age/ >110% vs ≤110% BMI/males, ≥25 vs <25; females, ≥24.3 vs <24.3 % Median weight-forheight/continuous measure

BMI/highest (>29.2) vs lowest (<21.9) quintile BMI/highest (>28.2) vs lowest (<23.2) quintile

Use of birth weight in analysis

Statistical test and strength of association

>75th %ile vs ≤75th %ile

Risk ratio = (p = 0.04)

1.6†

Continuous measure

Males, p <0.001‡; females, NS

10

Continuous measure

Correlation coefficient: males, r = 0.08 (NS); females, r = 0.18 (p < 0.01) Chi-square test for trend§ (p = 0.05) Analysis of variance| : male, NS; female, NS

11

Correlation coefficient: r = 0.078 (p < 0.0005) Highest (>10 lb) Logistic regression vs referent odds ratio¶ = (7.1-8.5 lb) 1.62 (1.38-1.90) Highest (>10 lb) Logistic regression vs referent odds ratio¶ = (7.0-8.4 lb) 2.08 (1.73-2.50)

14

6 categories 3 categories

Continuous measure

Reference 9

12 13

15

16

NS, Not significant. *Race/ethnicity and gender indicated if reported by authors. †Risk of adult overweight given high birth weight category. ‡Comparison of mean birth weight in two adult weight categories, by gender; statistical test not specified. §Test of trend of increasing adult BMI across birth weight categories. | Mean adult BMI compared across birth weight categories with separate analysis by gender and ethnicity. ¶Age-adjusted odds ratio of being in the highest adult BMI quintile if birth weight was in highest versus referent category.

ments might improve classification of fatness at birth and increase the strength of the observed associations. No studies have examined the relationship between birth weight and adult relative weight while controlling for both maternal and paternal weight. However, in one study of a large female cohort, the authors reported an association between high birth weight and adult obesity after controlling for maternal weight.15 A study of both male and female subjects followed to 17 years of age showed an increased risk of obesity (odds ratio for >90th percentile BMI = 1.65 for male

and 2.11 for female subjects) in those born large for gestational age (birth weight >97th percentile) after controlling for social status, birth order, and maternal BMI.17 These studies suggest that the prenatal environment exerts a lasting effect on adult relative weight that is independent of maternal fatness. Intrauterine growth, however, involves a complex interaction between parental genes and the intrauterine environment. We will next review the evidence that the maternal factors of diabetes, obesity, and pregnancy weight gain alter the intrauterine envi-

ronment and thereby increase the risk of later obesity.

Maternal Obesity Maternal obesity is associated with increased birth weight.18,19 Direct measures of fatness such as skinfolds are also greater in newborn infants of obese mothers.20,21 Few studies of the relationship between maternal obesity and birth weight have controlled for maternal glucose tolerance,22 but the risk to obese mothers of delivering macrosomic babies is greater than the risk explained by diabetes alone.18 We are aware of only one 769

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study that has related maternal prepregnant weight to offspring fatness during childhood.23 Maternal prepregnant weight was higher in mothers of the most obese 7-year-old children (highest 5% of weight/height ratio) than in mothers of the leanest 7-year-old children (lowest 5% of weight/height ratio). Maternal obesity affects offspring obesity risk through transmitted genes and effects on both the prenatal and postnatal environment. Therefore it is difficult to isolate the possible effect of an altered intrauterine environment. For example, maternal obesity may affect both the transfer of metabolic substrate to the fetus in utero and the diet and activity patterns of the child after birth. One epidemiologic approach to this dilemma would be to relate childhood fatness in nontwin siblings to maternal fatness at the time of pregnancy.

Weight Gain During Pregnancy Pregnancy weight gain is positively associated with birth weight24-27 and with newborn skinfold thickness.21 The effect of pregnancy weight gain on birth weight may differ according to prepregnant weight. Most studies suggest that weight gain during pregnancy influences birth weight more in women who are underweight than in women who are overweight,25,28-30 but other studies show similar effects of pregnancy weight gain on birth weight in mothers with different prepregnant weights.31 We identified only two studies that examined the effect of pregnancy weight gain on later obesity in the offspring. In one, maternal pregnancy weight gain was not significantly different between mothers of the most obese (highest 5% of weight/height ratio) and the most lean (lowest 5% of weight/ height ratio) 4-year-old children.23 However, a preliminary report showed an increased risk of offspring obesity (BMI >90th percentile) at age 17 years in those born to mothers with the highest pregnancy weight gain (>16 kg).32 This relationship persisted after control for maternal prepregnant weight and parity, as well as for infant birth weight, birth order, and gestational age. The “Dutch Famine” study provided suggestive evidence that low, rather than 770

THE JOURNAL OF PEDIATRICS MAY 1998 high, maternal energy intake in pregnancy increased obesity risk in the offspring.33 Ravelli et al.33 compared obesity rates in cohorts of young adult men that had been exposed in utero to maternal nutrient deprivation during different periods of gestation. These authors defined obesity as weight-for-height of 120% or greater of a reference standard. Maternal caloric deprivation in the first two trimesters of pregnancy was associated with an obesity prevalence of 2.8% in 19-year-old offspring, in comparison with a prevalence of 1.5% among control subjects. Whereas the risk ratio for the effect of this early maternal caloric deprivation on offspring obesity was 1.9, the absolute risk of obesity in both groups was very low. In contrast to these findings, an analysis of adult women born during the same famine showed that the women exposed in utero to famine weighed less in adulthood than those not exposed.34 Furthermore, these effects on the female offspring were explained by the lower birth weight in the famine-exposed group. Several factors hinder the interpretation of this natural experiment in maternal nutrient deprivation. No data were available on total pregnancy weight gain, and the causal relationship between pregnancy weight gain and energy intake is difficult to prove.28,35 The energy intakes of the mothers in the famine-affected regions were estimated from historical documents detailing the available food rations at that time and not from dietary record or recall of individual subjects.36 Excess deaths may have occurred in early life among the famine-exposed offspring who were least prone to obesity, and it is not clear that maternal undernutrition, in the range now experienced in developed countries, has an effect on offspring fatness.14 Investigators have not consistently reproduced the findings of the Dutch Famine in animal experiments.37-42 Another line of evidence suggests an association of low maternal energy intake in pregnancy and offspring obesity in adult life. Barker and colleagues have shown that small birth size is a risk factor for hypertension, glucose intolerance, and dyslipidemia in adulthood,43,44 the

metabolic “syndrome X.”45 In subjects from the United Kingdom, glucose intolerance was greatest in those who moved from a low birth weight category to a high BMI category as adults.12,46 Furthermore, there was an inverse association between birth weight and adult waist-to-hip ratio among those of similar BMI. However, Barker and colleagues43,44 have not shown a direct association between small birth size and adult BMI, a finding that would be contrary to the evidence presented in Table I. They have also not shown that those subjects with low birth weight in whom syndrome X develops have higher rates of obesity. Valdez et al.13 were able to replicate, in a biethnic population of young U.S. adults, many of the British findings related to syndrome X, but they failed to show a relationship between birth weight and either BMI or waist-to-hip ratio in young adulthood. They did, however, show an inverse relationship between birth weight and the ratio of adult subscapular to triceps skinfold thickness, another proxy measure for central adiposity. No study has assessed the relationship between birth weight and direct measures of visceral fat later in life. In summary, several studies have shown a direct relationship between pregnancy weight gain and birth weight, but only a single study has shown an independent effect of pregnancy weight gain on offspring obesity later in life. Low pregnancy weight gain, maternal undernutrition, or both have also been implicated in later obesity risk, but the evidence supporting this relationship is weak. Although some studies support the association of small birth size with glucose intolerance in adulthood, data were not available in these studies to show that small birth size was associated with either low pregnancy weight gain or maternal undernutrition. There is no evidence that obesity, per se, is entrained during gestation by maternal undernutrition or that glucose intolerance itself causes obesity.

Maternal Diabetes During Pregnancy The newborn infants of diabetic mothers show increased fat mass when it is

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Table II. Studies relating maternal diabetes and offspring weight in childhood or adulthood

Age (yr) at assessment

Sample size (cases/ controls)

1-20

105/0

5 (mean)

239/68

1-31

200/0

1-19

231/0

5-13

51/0

Birth year(s)

Type(s) of maternal diabetes

Study population*

1936– 1953

IDDM

Massachusetts

Not reported

IDDM

Sweden

1935– 1963 1948– 1966 1964– 1972

IDDM

Melbourne, Australia

IDDM

Edinburgh, Scotland

IDDM

London, England

17

87/10,804

1974– 1976

IDDM

Jerusalem, Israel

7

33/30

1960– 1963

IDDM, GDM

Providence, R.I.

15-19

24/518

≥1965 GDM

NIDDM,

Arizona: Pima Indians

6-8

124/0

1977– 1983

IDDM, GDM

10-16

88/80

1977– 1983

IDDM, GDM

5-10

58/257

1985– 1986

GDM

Chicago, Ill.: 43% white, 25% Hispanic, 23% black, 9% other Chicago, Ill.: 55% white, 13% Hispanic, 27% black, 5% other; 54% male Seattle, Wash.: 94% non-Hispanic white; 51% male

Outcome measure(s) and strength of association†

Reference

50% of boys and 20% of girls >30 lb above “standard weight-for-height and age” Mean weight-for-age z score greater in case patients than in control subjects (maternal diabetes onset after delivery) (p < 0.001) 21% at >90th %ile weight-for-age Weight/height index‡: 22% >1.25; 2.5% <0.75 Weight-for-age, ~31% >90th %ile§; triceps skinfold, ~20% >90th %ile§; subscapular skinfold, ~17% >90th %ile§ Percentage at >90th %ile BMI for gender; diabetic offspring = 10.3%, control offspring = 9.7% (p > 0.05) Percentage with weight/height index‡ ≥1.2; diabetic offspring = 27%, control offspring = 3% (p = 0.014)| Percentage ≥140% of midpoint of range of “desirable weight-for-height”; diabetic offspring = 58%, control offspring = 17% (p < 0.001) Mean weight/height index‡greater than expected (1.0) at all ages after 1 yr¶ (p < 0.05) Mean BMI (unadjusted for age or gender); diabetic offspring = 22.8, control offspring = 20.3 (p = 0.001) Percentage with BMI at ≥85th %ile for age and gender; diabetic offspring = 19%, control offspring = 24% (p = 0.40)

54

55

56 57 58

59

60

61

62

63**

64

*Race/ethnicity

and gender indicated if reported by authors. population used for standardizing weight differs across studies and is reported in each reference; p value is indicated if reported by authors. ‡Weight/height index = (Actual weight/50th percentile weight-for-age and gender)/(Actual height/50th percentile height-for-age and gender). §Proportion estimated from figures in reference. | By Fisher exact test with data provided. ¶The actual mean values (and variance) of weight/height index for cases were not reported by authors. **Later report on the cohort studied in reference 79, with different outcome measure and including control subjects. †Reference

measured directly. Sacks53 reviewed the studies showing an association between maternal diabetes during pregnancy and increased birth weight, an indirect measure of newborn fatness. We identified

11 studies (Table II) that related maternal diabetes during pregnancy to offspring weight in childhood or young adulthood.54-64 We considered only studies in which weight values were com-

pared with those of a control group (six studies) or with those of an identified reference population. Despite variation in study design, five of the six studies that dealt exclusively with offspring of moth771

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ers with insulin-dependent diabetes showed increased relative weight in the offspring. Four of the studies that examined the offspring of pregnancies affected by gestational diabetes (first onset or recognition of glucose intolerance during pregnancy) showed increased childhood relative weight.60-63 However, the analysis in all four of these studies included offspring of mothers with either known IDDM60,62,63 or non-insulin-dependent diabetes.61 An unresolved question is whether the risk of childhood obesity differs between offspring born to mothers with GDM, IDDM, and NIDDM. This is an important question because the increasing prevalence of obesity in U.S. women of childbearing age2 may increase the number of pregnancies affected by GDM or NIDDM.65 No study has separately analyzed offspring obesity rates in pregnancies affected by NIDDM. Until recently, the effects of GDM on offspring fatness had also not been examined separately. We compared BMI in two groups of 8- to 10-year-old children.64 One group were offspring of mothers with GDM (treated with diet alone), and the control group were offspring of mothers with negative results on screening tests for GDM. The GDM offspring had higher birth weight (adjusted for gestational age and gender), but there was no significant difference in BMI between the two groups at any point after 6 months of age. Although offspring of mothers with GDM and IDDM are both exposed to intrauterine hyperglycemia, the intrauterine environments created in IDDM and GDM pregnancies may differ and so may the effects on fetal development and later obesity. IDDM mothers are no fatter than control subjects,66 but GDM mothers are.67 Differences between GDM and IDDM mothers in triglyceride levels may also affect fetal fatness. Triglyceride levels in IDDM mothers are lower than those in control subjects during early pregnancy66 but are comparable to those in control subjects during late pregnancy.68 In contrast, mothers are GDM have significantly higher triglyceride levels than do control subjects in mid pregnancy.69 772

THE JOURNAL OF PEDIATRICS MAY 1998 Several studies suggest that an altered intrauterine environment, rather than inherited genes for obesity, mediates the effect of maternal diabetes on offspring fatness. The association between diabetes during pregnancy and offspring relative weight during childhood is independent of maternal weight.61 In addition, the amniotic fluid insulin level, a marker for fetal insulin production, is associated with relative weight in childhood after adjustment for maternal prepregnant weight.62,70 The risk of obesity is greater in offspring born to mothers who had diabetes during pregnancy than in offspring of mothers in whom diabetes developed after pregnancy.71 Finally, chemically induced diabetes in pregnant rats produced heavier newborn rats.72 Although the intrauterine environment created by maternal diabetes may alter susceptibility to obesity, the expression of that susceptibility may be incomplete at birth, and it may be delayed or altered by other developmental stages or environmental influences. For example, offspring from diabetic pregnancies were heavier at birth, but it was not until approximately 4 to 5 years of age that they again had significantly higher relative weight.60,62 Furthermore, offspring of mothers with diabetes were found to have higher relative weight in childhood and adolescence, even after researchers controlled for birth weight.73 In summary, maternal diabetes during pregnancy has been associated with later obesity in the offspring, and there is evidence that this association is independent of genetic factors. The type of maternal diabetes (IDDM, NIDDM, or GDM) and its severity may affect the degree of offspring obesity risk.

MECHANISMS Maternal diabetes, obesity, or weight gain during pregnancy alters the transfer of metabolic substrates between mother and fetus. The intrauterine environment that results from this altered substrate transfer may affect the developing structure and function of the fetal organs involved in energy metabolism.

Increased Glucose Transfer from Mother to Fetus and Altered Insulin Production and Activity in the Offspring Human and animal studies support Pedersen’s original model74,75 to explain how the metabolic alterations of the diabetic pregnancy increase infant fatness at birth. Starting in mid gestation, fetal pancreatic beta-cell hyperplasia76 and fetal hyperinsulinemia77 are induced and sustained by increased amounts of maternal glucose and amino acids transferred to the fetus.78-80 Markers of fetal hyperinsulinemia, such as increased levels of amniotic fluid and cord blood Cpeptide,81,82 correlate with levels of the circulating maternal metabolic substrates such as glucose70 and amino acids.83,84 Fetal hyperinsulinemia may promote the development of excess adipose tissue mass in the third trimester of pregnancy through its effects on adipose cell size85,86 and, possibly, adipose cell number.87,88 Fetal insulin production also correlates with birth weight81 and fat mass at birth.52,86 How intrauterine exposure to hyperglycemia, hyperinsulinemia, or both might lead to later obesity remains uncertain. One hypothesis is that diminished insulin secretion, increased resistance to insulin action, or both play a role in causing obesity in offspring of diabetic mothers. Freinkel and Metzger89,90 proposed that the persistent effects of the intrauterine environment might be greatest on those tissues, like pancreas, muscle, and adipose, that are most completely developed and differentiated at birth. For example, the number of insulin receptors or postinsulin receptor signaling in the fetus may be altered in diabetic pregnancies because muscle and adipose tissue develop in the presence of hyperinsulinemia and hyperglycemia. Alternatively, chronic stimulation of fetal beta cells by hyperglycemia may impair or down-regulate glucose-stimulated insulin secretion. It is also possible that leptin production by adipocytes may be affected by intrauterine hyperglycemia.91 Greater glucose intolerance occurs in offspring of diabetic mothers, but the mechanism is unknown. Rates of diabetes and glucose intolerance were high-

THE JOURNAL OF PEDIATRICS VOLUME 132, NUMBER 5 er among offspring of Pima Indian mothers who had diabetes during pregnancy than among offspring of mothers in whom diabetes developed after pregnancy.71,92 Increased rates of diabetes and glucose intolerance persisted after controlling for the father’s diabetes status, the age at onset of maternal diabetes, and offspring age and weight. Abnormalities in glucose tolerance have also been shown in adolescent offspring of nonNative-American diabetic mothers.63 Even if insulin production or activity is altered in the offspring of mothers with diabetes, it is difficult, without longitudinal studies, to determine whether these factors cause or reflect obesity. Controlled studies must carefully examine carbohydrate metabolism, fatness, and fat distribution prospectively to delineate the mechanism of glucose intolerance in the offspring of mothers with diabetes and its possible relationship to fatness and subsequent diabetes. Barker and colleagues46,93,94 suggested that altered insulin production may also represent the link between maternal undernutrition and later NIDDM in the offspring, but the causal link to later obesity in the offspring remains unclear. These investigators speculated that small fetal size is related to maternal undernutrition, which reduces beta-cell number, size, and function. They further proposed that the underdeveloped pancreas may have abnormal vascularity or innervation that impairs its ability to secrete insulin. These mechanisms are supported by experiments in rats that show reduced beta-cell mass and impaired insulin secretion in offspring of mothers undernourished in pregnancy.95,96 If there are intrauterine effects of undernutrition on pancreatic development that impair insulin production, then excess nutrient intake after birth, leading to obesity, may be required for the future expression of diabetes. Thus maternal undernutrition in pregnancy may increase diabetes susceptibility only in those who later become obese. In summary, attention has focused on insulin as a mediator of long-term obesity risk in the offspring of both diabetic and undernourished mothers. Human and animal data suggest that these two maternal

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conditions alter offspring insulin production, function, or both. Whether these alterations in insulin cause later offspring obesity remains to be shown.

Increased Fat Fuel Transfer from Mother to Fetus Diabetes,97,98 obesity, or excess weight gain in pregnancy may each cause excess fatness in the newborn infant through an increased transfer of maternal fat fuels to the fetus, but this possibility has not been well studied. GDM is associated with abnormalities of lipid metabolism.69,90 The elevation of plasma triglyceride seen in GDM may also occur in women with mild glucose intolerance who are obese99-101 or who gain excess weight during pregnancy. These women may not meet criteria for GDM based on glucose tolerance testing.102 Increased serum levels of maternal fatty acids and triglycerides may increase fatty acid transfer to the fetus. Maternal free fatty acids can cross the placenta, and placental lipoprotein lipase hydrolyzes triglycerides to fatty acids that can cross the placenta.103,104 Because lipids may play a role in adipocyte differentiation,105 increased maternal fat fuel transfer could affect fetal and subsequent adiposity. For example, fetal fat cell number, size, or lipoprotein lipase activity may be influenced by the presence of excess fatty acid levels in the fetus, especially in the third trimester, when adipose tissue grows rapidly. In turn, the number and size of fat cells at birth may have long-term implications for obesity risk.106 Triglyceride levels in mothers with GDM correlate with infant birth weight,90 but fatty acid levels in mothers with either IDDM or GDM are not correlated to fat mass in the newborn infants. Triglyceride levels are elevated in newborn infants of obese, nondiabetic mothers, in comparison with control subjects.107 Nonetheless, only a weak relationship exists between maternal triglyceride levels and birth weight for infants of mothers without diabetes,67,108 and no relationship has been shown between maternal fatty acid levels and newborn fat mass in mothers without diabetes.109 No studies have linked infant birth weight to triglyceride levels in obese and

nonobese mothers with and without excessive weight gain. In summary, there is currently no strong evidence that maternal dyslipidemia from either GDM, maternal obesity, or excess pregnancy weight gain results in excess transfer of fat fuel to the fetus. Furthermore there is only speculation about the mechanism by which any excess fat fuel is transferred to the fetus would affect long-term obesity risk.

Fetal Central Nervous System Development Ravelli et al.33 suggested that maternal energy deprivation early in pregnancy might affect fetal hypothalamic development, impair appetite regulation, and promote later obesity.33 Unfortunately, no dietary intake data were available on the offspring in the Dutch Famine to allow examination of this proposed mechanism. The offspring of rats deprived of calories early in pregnancy do not always demonstrate hyperphagia38,39,41 or increased body fat41 even when body weight is increased in comparison with that of control subjects. Other animal data involving intrauterine deprivation suggest that any effects on hypothalamic development might result in a long-term decrease, rather than an increase, in food intake.110 Few animal studies of the effects of maternal undernutrition have included careful studies of energy balance. Because obesity can result from reduced energy expenditure or excess energy intake, it is essential to make careful comparisons of metabolic rate and the energy spent on activity in exposed offspring and control subjects. Finally, specific micronutrients may inhibit or promote obesity, perhaps through nutrient-gene interactions. There may exist an obesity-promoting or -inhibiting micronutrient. For example, the set point, or responsiveness for a hypothalamic “adipostat,”111 perhaps involving gene expression of the leptin receptor,112 might be modified by the availability of certain nutrients in utero.

SUMMARY Increased birth weight and intrauterine exposure to maternal diabetes, par773

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ticularly IDDM, are both associated with higher relative weight later in life. Neither association appears to be due entirely to the inheritance of obesity-related genes. No single mechanism explains how maternal diabetes, obesity, or either high or low weight gain during pregnancy can affect the development or persistence of offspring obesity. Altered exposure of the fetus to metabolic substrates could influence insulin secretion and sensitivity; fat cell number, size, and function; or the regulation of appetite by the central nervous system. Close regulation of glucose in diabetic pregnancies may help decrease the risk of offspring obesity, but there is currently no evidence that recommendations for body weight and weight gain during pregnancy28 should be revised to decrease offspring obesity risk. Because many of the studies we reviewed were not designed to examine the effects of fetal exposures on subsequent adiposity, measures of the mother, fetus, and growing child were rarely precise. Prospective studies are needed to determine whether maternal glucose intolerance during pregnancy causes subsequent obesity, visceral fat deposition in the offspring, or both. The metabolic effects of GDM and IDDM on offspring fatness should be studied separately. These studies require adequate controls and the careful measurement of fatness, fat distribution, and glucose tolerance in both parents and offspring. Finally, study designs must attempt to distinguish whether offspring fatness or glucose intolerance is caused by an altered intrauterine environment or by inherited parental genes. We gratefully acknowledge Robert H. Knopp, MD, and Irvin R. Emanuel, MD, for their careful review of earlier drafts of this manuscript.

REFERENCES 1. Troiano RP, Flegal KM, Kuczmarski RJ, Campbell SM, Johnson CL. Overweight prevalence and trends for children and adolescents: National Health and Nutrition Examination Surveys, 1963 to 1991. Arch Pediatr Adolesc Med 1995; 149:1085-91.

774

THE JOURNAL OF PEDIATRICS MAY 1998 2. Kuczmarski RJ, Flegal KM, Campbell SM, Johnson CL. Increasing prevalence of overweight among U.S. adults: National Health and Nutrition Examination Surveys, 1960 to 1991. JAMA 1994; 272:205-11. 3. Pi-Sunyer FX. Medical hazards of obesity. Ann Intern Med 1993;119:655-60. 4. NIH Technology Assessment Conference Panel. Methods for voluntary weight loss and control. Ann Intern Med 1993;119:764-70. 5. Dietz WH. Critical periods in childhood for the development of obesity. Am J Clin Nutr 1994;59:955-9. 6. Kraemer HC, Berkowitz RI, Hammer LD. Methodological difficulties in studies of obesity. I. Measurement issues. Ann Behav Med 1990;12:112-8. 7. Robinson TN. Defining obesity in children and adolescents: clinical approaches. Crit Rev Food Sci Nutri 1993;33:313-20. 8. Ragland DR. Dichotomizing continuous outcome variables: dependence of the magnitude of association and statistical power on the cutpoint. Epidemiology 1992;3:434-40. 9. Charney E, Goodman H, McBride M, Lyon B, Pratt R. Childhood antecedents of adult obesity: do chubby infants become obese adults? N Engl J Med 1976;295:6-9. 10. Braddon FEM, Rodgers B, Wadsworth MEJ, Davies JMC. Onset of obesity in a 36-year birth cohort study. BMJ 1986;293:299-303. 11. Miller FJW, Billewicz W, Thomson AM. Growth from birth to adult life of 442 Newcastle Upon Tyne children. Br J Prev Soc Med 1972;26:224-30. 12. Fall CH, Osmond C, Barker DJ, Clark PM, Hales CN, Stirling Y, et al. Fetal and infant growth and cardiovascular risk factors in women. BMJ 1995;310:428-32. 13. Valdez R, Athens MA, Thompson GH, Bradshaw BS, Stern MP. Birthweight and adult health outcomes in a biethnic population in the USA. Diabetologia 1994;37:624-31. 14. Allison DB, Paultre F, Heymsfield SB, Pi-Sunyer FX. Is the intra-uterine period really a critical period for the development of adiposity? Int J Obes Relat Metab Disord 1995;19:397-402. 15. Curhan GC, Chertow GM, Willett WC, Spiegelman D, Colditz GA, Manson JE, et al. Birth weight and adult hypertension and obesity in women. Circulation 1996; 94:1310-5. 16. Curhan GC, Willett WC, Rimm EB, Spiegelman D, Ascherio AL, Stampfer MJ. Birth weight and adult hypertension, diabetes mellitus, and obesity in U.S. men. Circulation 1996;94:3246-50. 17. Seidman DS, Laor A, Gale R, Stevenson DK. Excessive intrauterine growth and

being overweight at 17 years of age [abstract]. Pediatr Res 1995;37(4, pt.2):115A. 18. Gross T, Sokol RJ, King KC. Obesity in pregnancy: risks and outcome. Obstet Gynecol 1980;56:446-50. 19. Edwards LE, Dickes WF, Alton IR, Hakanson EY. Pregnancy in the massively obese: course, outcome, and obesity prognosis of the infant. Am J Obstet Gynecol 1978;131:479-83. 20. Whitelaw AGL. Influence of maternal obesity on subcutaneous fat in the newborn. BMJ 1976;24:985-6. 21. Udall JN, Harrison GG, Vaucher Y, Walson PD, Morrow G. Interaction of maternal and neonatal obesity. Pediatrics 1978;62:17-21. 22. Harrison GG, Udall JN, Morrow G. Maternal obesity, weight gain in pregnancy, and infant birth weight. Am J Obstet Gynecol 1980;136:411-2. 23. Fisch RO, Bilek MK, Ulstrom R. Obesity and leanness at birth and their relationship to body habitus in later childhood. Pediatrics 1975;56:521-8. 24. Simpson JW, Lawless RW, Mitchell AC. Responsibility of the obstetrician to the fetus. II. Influence of prepregnancy weight and pregnancy weight gain in birthweight. Am J Obstet Gynecol 1975; 45:481-7. 25. Kramer MS. Determinants of low birth weight: methodological assessment and meta-analysis. Bull World Health Organ 1987;65:663-737. 26. Eastman NJ, Jackson E. Weight relationships in pregnancy. I. The bearing of maternal weight gain and prepregnancy weight and birthweight in full term pregnancies. Obstet Gynecol Surv 1968; 23:1003-25. 27. Niswander K, Jackson EC. Physical characteristics of the gravida and their association with birth weight and perinatal death. Am J Obstet Gynecol 1974; 119:306-13. 28. Subcommittee on Nutritional Status and Weight Gain During Pregnancy Subcommittee on Dietary Intake and Nutrient Supplements During Pregnancy, Committee on Nutritional Status During Pregnancy and Lactation, Food and Nutrition Board, Institute of Medicine, National Academy of Sciences. Nutrition during pregnancy. Part I: Weight gain. Part II: Nutrient supplements. Washington (DC): National Academy Press; 1990. 29. Abrams BF, Laros RK. Prepregnancy weight, weight gain, and birth weight. Am J Obstet Gynecol 1986;154:503-9. 30. Abrams B, Parker JD. Maternal weight gain in women with good pregnancy outcome. Obstet Gynecol 1990;76:1-7. 31. Rush D, Davis H, Susser M. Antecedents of low birthweight in Harlem, New York City. Int J Epidemiol 1972;1:375-87.

THE JOURNAL OF PEDIATRICS VOLUME 132, NUMBER 5 32. Seidman DS, Laor A, Shemer J, Gale R, Stevenson DK. Excessive maternal weight gain during pregnancy and being overweight at 17 years of age [abstract]. Pediatr Res 1996;39:112A. 33. Ravelli GP, Stein ZA, Susser MW. Obesity in young men after famine exposure in utero and early infancy. N Engl J Med 1976;295:349-53. 34. Lumey LH, Stam GA, Ravelli GP, Stein ZA. Birth weight, birth cohort, and adult weight among women born during the Dutch Famine of 1944–1945 [abstract]. Am J Epidemiol 1992;136:951-2. 35. Susser M. Maternal weight gain, infant birthweight, and diet: causal sequences. Am J Clin Nutr 1991;53:1384-96. 36. Stein Z, Susser M, Saenger G, Marolla F. Famine and human development: the Dutch Hunger Winter of 1944–1945. New York: Oxford University Press; 1975. 37. Fiorotto ML, Davis TA, Schoknecht P, Mersmann HJ, Pond WG. Both maternal over- and undernutrition during gestation increase the adiposity of young adult progeny in rats. Obes Res 1995; 3:131-41. 38. Jones AAP, Friedman MI. Obesity and adipocyte abnormalities in offspring of rats undernourished during pregnancy. Science 1982;215:1518-9. 39. Jones AP, Simson EL, Friedman MI. Gestational undernutrition and the development of obesity in rats. J Nutr 1984;114:1484-92. 40. Jones AP, Assimon SA, Friedman MI. The effect of diet on food intake and adiposity in rats made obese by gestational undernutrition. Physiol Behav 1986; 37:381-6. 41. Pond WG, Mersmann HJ, Yen JT. Severe feed restriction of pregnant swine and rats: effects on postweaning growth and body composition of progeny. J Nutr 1985;115:179-89. 42. Enns MP, Wilson MW, Grinker JA, Faust IM. Prenatal food restriction and subsequent weight gain in male rats. Science 1983;219:1093-4. 43. Barker DJ. The intrauterine origins of cardiovascular disease. Acta Paediatr 1993;82(Suppl 391):93-9. 44. Goldberg GR, Prentice AM. Maternal and fetal determinants of adult diseases. Nutr Rev 1994;52:191-200. 45. Reaven GM. Role of insulin resistance in human disease [Banting Lecture 1988]. Diabetes 1988;37:1595-607. 46. Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C, et al. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 1991;303:1019-22. 47. Law CM, Barker DJ, Osmond C, Fall CH, Simmonds SJ. Early growth and abdominal fatness in adult life. J Epidemiol Community Health 1992;46:184-6.

WHITAKER AND DIETZ

48. Fee BA, Weil WB. Body composition of infants of diabetic mothers by direct analysis. Ann N Y Acad Sci 1963; 110:869-97. 49. Naeye RL. Infants of diabetic mothers: a quantitative, morphologic study. Pediatrics 1965;35:980-8. 50. Osler M. Body water of newborn infants of diabetic mothers. Acta Endocrinol 1960;34:261-76. 51. Osler M. Body fat of newborn infants of diabetic mothers. Acta Endocrinol 1960; 34:277-86. 52. Krew MA, Kehl RJ, Thomas A, Catalano PM. Relation of amniotic fluid C-peptide levels to neonatal body composition. Am J Obstet Gynecol 1994;84:96-100. 53. Sacks DA. Fetal macrosomia and gestational diabetes: what’s the problem? Obstet Gynecol 1993;81:775-81. 54. White P, Koshy P, Duckers J. The management of pregnancy complicating diabetes and of children of diabetic mothers. Med Clin North Am 1953;37:1481-96. 55. Hagbard L, Olow I, Reinand T. A follow-up study of 514 children of diabetic mothers. Acta Paediatr 1959;48:184-97. 56. Breidahl HD. The growth and development of children born to mothers with diabetes. Med J Aust 1966;1:268-70. 57. Farquhar JW. Prognosis for babies born to diabetic mothers in Edinburgh. Arch Dis Child 1969;44:36-47. 58. Cummins M, Norrish M. Follow-up of diabetic mothers. Arch Dis Child 1980; 55:259-64. 59. Seidman DS, Laor A, Stevenson DK, Sivan E, Gale R, Shemer J. Macrosomia does not predict overweight in late adolescence in infants of diabetic mothers. Acta Obstet Gynecol Scand 1998;77:5862. 60. Vohr BR, Lipsitt LP, Oh W. Somatic growth of children of diabetic mothers with reference to birth size. J Pediatr 1980;97:196-9. 61. Pettitt DJ, Baird HR, Aleck KA, Bennett PH, Knowler WC. Excessive obesity in offspring of Pima Indian women with diabetes during pregnancy. N Engl J Med 1983;308:242-5. 62. Silverman BL, Rizzo T, Green OC, Cho NH, Winter RJ, Ogata ES, et al. Longterm prospective evaluation of offspring of diabetic mothers. Diabetes 1991; 40(Suppl 2):121-5. 63. Silverman BL, Metzger BE, Cho NH, Loeb CA. Impaired glucose tolerance in adolescent offspring of diabetic mothers: relationship to fetal hyperinsulinism. Diabetes Care 1995;18:611-7. 64. Whitaker RC, Pepe MS, Wright JA, Seidel KD, Dietz WH. Early adiposity rebound and the risk of adult obesity. Pediatrics 1998;101:e5. 65. Schaubert DR, Mayer DA, Shireley LA.

Pregnancies complicated by diabetes— North Dakota, 1980–1992. MMWR Mortal Morbid Wkly Rep 1994;43:837-9. 66. Peterson CM, Jovanovic-Peterson L, Mills JL, Conley MR, Knopp RH, Reed GF, et al. The Diabetes in Early Pregnancy Study: changes in cholesterol, triglycerides, body weight, and blood pressure. Am J Obstet Gynecol 1992; 166:513-8. 67. Knopp RH, Magee MS, Walden CE, Bonet B, Benedetti TJ. Prediction of infant birth weight by GDM screening tests: importance of plasma triglyceride. Diabetes Care 1992;15:1605-13. 68. Knopp RH, Van Allen MI, McNeely M, Walden CE, Plovie B, Shiota K, et al. Effect of insulin-dependent diabetes on plasma lipoproteins in diabetic pregnancy. J Reprod Med 1993;38:703-10. 69. Hollingsworth DR, Grundy SM. Pregnancy-associated hypertriglyceridemia in normal and diabetic women: differences in insulin-dependent, non-insulin-dependent, and gestational diabetes. Diabetes 1982;31:1092-7. 70. Metzger BE, Silverman BL, Freinkel N, Dooley SL, Ogata ES, Green OC. Amniotic fluid insulin concentration as a predictor of obesity. Arch Dis Child 1990;65:1050-2. 71. Pettitt DJ, Aleck KA, Baird HR, Carraher MJ, Bennett PH, Knowler WC. Congenital susceptibility to NIDDM: role of intrauterine environment. Diabetes 1988;37:622-8. 72. Aerts L, van Assche FA. Endocrine pancreas in the offspring of rats with experimentally induced diabetes. J Endocrinol 1981;88:81-8. 73. Pettitt DJ, Knowler WC, Bennett PH, Aleck KA, Baird HR. Obesity in offspring of diabetic Pima Indian women despite normal birth weight. Diabetes Care 1987;10:76-80. 74. Pedersen J. Hyperglycemia-hyperinsulinism theory and birth weight. In: Pedersen J, editor. The pregnant diabetic and her newborn: problems and management. 2nd ed. Baltimore: Williams & Wilkins, 1977. p. 211-20. 75. Pedersen J. Weight and length at birth of infants of diabetic mothers. Acta Endocrinol 1954;16:330-42. 76. Hellerstrom C, Swenne I. Functional maturation and proliferation of fetal pancreatic β-cells. Diabetes 1991;40(Suppl 2):89-93. 77. Reiher H, Fuhrmann K, Noack S, Woltanski KP, Jutzi E, Dorsche HH, et al. Age-dependent insulin secretion of the endocrine pancreas in vitro from fetuses of diabetic and nondiabetic patients. Diabetes Care 1983;6:446-51. 78. Milner RD, Ashworth MA, Barson AJ. Insulin release from human fetal pan-

775

WHITAKER AND DIETZ

creas in response to glucose, leucine and arginine. J Endocrinol 1972;52:497-505. 79. Persson B, Pschera H, Lunell NO, Barley J, Gumaa KA. Amino acid concentrations in maternal plasma and amniotic fluid in relation to fetal insulin secretion during the last trimester of pregnancy in gestational and type I diabetic women and women with small-for-gestationalage infants. Am J Perinatol 1986;3:98103. 80. Metzger BE, Phelps RL, Freinkel N, Navickas IA. Effects of gestational diabetes on diurnal profiles of plasma glucose, lipids, and individual amino acids. Diabetes Care 1980;3:402-9. 81. Sosenko IR, Kitzmiller JL, Loo SW, Blix P, Rubenstein AH, Gabbay KH. The infant of the diabetic mother: correlation of increased cord C-peptide levels with macrosomia and hypoglycemia. N Engl J Med 1979;301:859-62. 82. Ogata ES, Freinkel N, Metzger BE, Phelps RL, Depp R, Boehm JJ, et al. Perinatal islet function in gestational diabetes: assessment by cord plasma C-peptide and amniotic fluid insulin. Diabetes Care 1980;3:425-9. 83. Metzger BE. Biphasic effects of maternal metabolism onfetal growth: quintessential expression of fuel-mediated teratogenesis. Diabetes 1991;40(Suppl 2):99-105. 84. Lin CC, River P, Moawad AH, Lowensohn RI, Blix PM, Abraham M, et al. Prenatal assessment of fetal outcome by amniotic fluid C-peptide levels in pregnant diabetic women. Am J Obstet Gynecol 1981;141:671-6. 85. Whitelaw A. Subcutaneous fat in newborn infants of diabetic mothers: an indication of quality of diabetic control. Lancet 1977;1:15-8. 86. Enzi G, Inelmen EM, Caretta F, Villani F, Zanardo V, DeBiasi F. Development of adipose tissue in newborns of gestational-diabetic and insulin-dependent diabetic mothers. Diabetes 1980;29:100-4. 87. Ginsberg-Fellner F. Growth of adipose tissue in infants, children and adolescents: variations in growth disorders. Int J Obes Relat Metab Disord 1981;5:605-11. 88. Bjorntorp P, Enzi G, Karlsson K, Krotkiewski M, Sjostrom L, Smith U. The effect of maternal diabetes on adipose tissue cellularity in man and rat. Diabetologia 1974;10:205-9.

776

THE JOURNAL OF PEDIATRICS MAY 1998 89. Freinkel N, Metzger BE. Pregnancy as a tissue culture experience: the critical implications of maternal metabolism for fetal development. In: Pregnancy metabolism, diabetes and the fetus. Amsterdam: Excerpta Medica; 1979. p. 3-28. (CIBA Found Symposium No. 63). 90. Freinkel N. Of pregnancy and progeny. [Banting Lecture 1980.] Diabetes 1980; 29:1023-35. 91. Kolaczynski JW, Nyce MR, Considine RV, Boden G, Nolan JJ, Henry R, et al. Acute and chronic effect of insulin on leptin production in humans: studies in vivo and in vitro. Diabetes 1996;45:699-701. 92. Pettitt DJ. The long-range impact of diabetes during pregnancy: the Pima Indian experience. IDF Bulletin 1986;31:70-1. 93. Barker DJ, Hales CN, Fall CH, Osmond C, Phipps K, Clark PM. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidemia (syndrome X): relation to reduced fetal growth. Diabetologia 1993;36:62-7. 94. Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabetes mellitus: the thrify phenotype hypothesis. Diabetologia 1992;35:595-601. 95. Weinkove C, Weinkove EA, Pimstone BL. Insulin release and pancreatic islet volume in malnourished rats [abstract]. South Afr Med J 1974;48:1888. 96. Snoeck A, Remacle C, Reusens B, Hoet JJ. Effect of a low protein diet during pregnancy on the fetal rat endocrine pancreas. Biol Neonate 1990;57:107-18. 97. Szabo AJ, Szabo O. Placental free-fattyacid transfer and fetal adipose-tissue development: an explanation of fetal adiposity in infants of diabetic mothers. Lancet 1974;2:498-9. 98. Szabo AJ, Oppermann W, Hanover B, Gugliucci C, Szabo O. Fetal adipose tissue development: relationship to maternal free fatty acid levels. In: CameriniDavalos RA, Cole HS, editors: Early diabetes in early life. New York: Academia Press; 1975. p. 167-76. 99. Tallarigo L, Giampietro O, Penno G, Miccoli R, Gregori G, Navalesi R. Relation of glucose tolerance to complications ofpregnancy in nondiabetic women. N Engl J Med 1986;315:989-92. 100. Knopp RH, Bergelin RO, Wahl PW, Walden CE, Chapman M, Irvin S. Population-based lipoprotein lipid reference

values for pregnant women compared to nonpregnant women classified by sex hormone usage. Am J Obstet Gynecol 1982;143:626-37. 101. Knopp R, Magee S, Bonet B, GomezCoronado D. Lipid metabolism in pregnancy. In: Cowet RM, editor: Principles of perinatal and neonatal metabolism. New York: Springer Verlag; 1991. p. 169-91. 102. Coustan DR. Diagnosis of gestational diabetes: what are our objectives? Diabetes 1991;40(Suppl 2):14-7. 103. Knopp RH, Warth MR, Charles D, Childs M, Li JR, Mabuchi H, et al. Lipoprotein metabolism in pregnancy, fat transport to the fetus, and the effects of diabetes. Biol Neonate 1986;50:297-317. 104. Bonet B, Brunzell JD, Gown AM, Knopp RH. Metabolism of very-lowdensity lipoprotein triglyceride by human placental cells: the role of lipoprotein lipase. Metabolism 1992;41:596-603. 105. Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell 1994;79:1147-56. 106. Roche AF. The adipocyte-number hypothesis. Child Dev 1981;52:31-43. 107. Kliegman R, Gross T, Morton S, Dunnington R. Intrauterine growth and postnatal fasting metabolism in infants of obese mothers. J Pediatr 1984;104:601-7. 108. Knopp RH, Bergelin RO, Wahl PW, Walden CE. Relationships of infant birth size to maternal lipoproteins, apoproteins, fuels, hormones, clinical chemistries, and body weight at 36 weeks’ gestation. Diabetes 1985;34(Suppl 2):71-7. 109. Enzi G, Inelmen EM, Caretta F, Rubaltelli F, Grella P, Baritussio A. Adipose tissue development “in utero”: relationships between some nutritional and hormonal factors and body fat mass enlargement in newborns. Diabetologia 1980;18:135-40. 110. Widdowson EM. Undernutrition and retarded growth before and after birth. Nutr Metab 1977;21:76-87. 111. Weigle DS. Human obesity: exploding the myths. West J Med 1990;153:421-8. 112. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995; 83:1263-71.