Fetal programming and adult obesity

May 1, 2013

In utero exposures to altered maternal nutrition, stress, or environmental toxins may alter organ structure or function, leading to adult obesity.

 

Dr. Ross is a professor in the Department of Obstetrics and Gynecology, Geffen School of Medicine, University of California, Los Angeles (UCLA), and Harbor-UCLA Medical Center, Torrance, California.

Dr. Desai is an associate professor in the Department of Obstetrics and Gynecology, Geffen School of Medicine, University of California, Los Angeles (UCLA), and Director of Perinatal Research, Department of Obstetrics and Gynecology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.

Dr. Ross is Medical Director of Cervilenz Inc., Chagrin Falls, Ohio, and a consultant to Sense4Baby Inc., San Diego, California. Dr. Desai has no conflict of interest to disclose with respect to the content of this article.

Mary Jane is a 28-year-old G2P1 whom you are seeing for prenatal care at 8 weeks' gestation. She is 5 ft 6 in tall and weighs 105 lb. She works in a highly visible technology position and strongly desires to maintain her body image during pregnancy. In her first pregnancy, she gained only 10 lb and delivered a healthy infant at 39 weeks weighing 4.85 lb. How should you counsel the patient regarding nutrition and weight gain in this pregnancy?

Prenatal care

Formalized prenatal care in the United States originated in the early 1900s with a program of just 3 pregnancy visits. Maternal mortality rates at the beginning of the 20th century approached 1% of pregnancies, with the principle etiologies being that of preeclampsia, infection, and hemorrhage. Accordingly, prenatal care focused on 3 complications: Patients’ blood pressure and urine protein were measured at each visit for the diagnosis of preeclampsia, urinalysis was performed for urinary tract infection, and hematocrit was determined to prevent anemia and consequences of hemorrhage. These interventions as well as other healthcare improvements (blood banking, attention to asepsis, antibiotics) resulted in a dramatic reduction in maternal mortality, to rates now approaching 1 per 10,000 pregnancies in the United States. With this dramatic reduction in maternal mortality, the goals of prenatal care shifted to the reduction of fetal and neonatal morbidity and mortality, prematurity,1 and more recently to the diagnosis (diagnostic ultrasound, biomarkers, amniocentesis), prevention (folate supplementation), and treatment (in utero and neonatal surgery) of congenital anomalies.

Developmental programming     

 Prenatal care is just now beginning to focus on the longer-term consequences of optimizing fetal health so as to prevent childhood and adult disease. Developmental programming may be defined as the permanent alteration in tissue structure or function as a result of the in utero environment. The concept of fetal programming has gained increased credence supported by strong findings from human epidemiologic studies and animal models.2,3 Specifically, in utero exposures to altered maternal nutrition (excess and deficient), stress (eg, glucocorticoids), or environmental toxins, among others, may alter organ structure or function. As approximately 50% of all cell divisions for growth occur from conception to birth, it is not surprising that environmental stresses may impact cell number. Although the genotype of programmed offspring does not change, modified gene expression may be a consequence of exposure-mediated epigenetic changes, thus altering the expression of regulatory peptides and organ function (Figure 1). In fact, 2 common historical obstetrical “teratogens” act via epigenetic programming. Thalidomide, which was prescribed in the 1950s as a sedative and morning sickness prescription, and included in more than 50 over-the-counter products, acts to truncate limb development by an epigenetic process that inhibits angiogenesis.4 Of equal concern, diethylstilbestrol (DES) was used off label in women with a history of miscarriage prior to US Food and Drug Administration (FDA) approval in 1947. Only in 1971 did the FDA respond to evidence that DES-programmed female offspring have an increased risk of vaginal clear cell carcinoma, a response that occurs via an epigenetic process of gene hypermethylation in utero.5

 

 

 

Low birth weight

Obstetricians are well aware that genetic mutations, which occur typically over long epochs, are beneficial for species survival, and are generally irreversible. In contrast, developmental programming may have evolutionarily developed to permit an individual fetus to prepare for a postnatal environment, particularly an environment of drought and famine. Under conditions of famine, maternal nutrient reduction results in low-birth-weight (LBW) infants who, historically, would experience a continued environment of limited food access throughout their lives. Notably, LBW infants often exhibit a "thrifty phenotype," marked by increased appetite and food intake, efficient metabolism, and reduced energy expenditure-a programmed "couch potato" (Figure 2).6 Thus, Hales and Barker have postulated that LBW thrifty phenotype infants would have a survival advantage in an environment of reduced nutrient availability.

      However, pregnancies in the United States result in a phenomenon of "inadvertent thrifty phenotype" newborns. Women with significant medical illnesses often deliver LBW infants, whereas less than a century ago these women would often not live to the age of conceiving or childbearing. A plethora of abused substances (eg, cocaine, methamphetamine, tobacco) contribute importantly to growth restriction, while in vitro fertilization has resulted in an explosion of LBW offspring from multiple gestations. Whereas in the past many, if not most, extremely LBW infants would not survive, the tremendous improvement in neonatal care has enhanced survival such that infant viability is now commonly defined at .97 lb. These surviving LBW infants, programmed as thrifty phenotype, are then exposed to the high-fat/high-calorie diet with the low energy-requiring environment of modern Western society.

 

 

Programmed obesity

In part a consequence of perinatal programming, obesity is a preeminent public health problem, with more than 66% of US adults overweight, and 36% of US adults obese.7 Race/ethnicity is independently related to childhood and adolescent obesity with higher prevalence occurring among African Americans, Mexican Americans, and Native Americans as compared with other ethnic groups.8,9 Epidemiologic studies confirm the effects of maternal undernutrition on the programming of metabolic syndrome. Barker and colleagues demonstrated a marked increase in the rates of metabolic syndrome with decreasing birth weight.2 As an index of the contribution to morbidity, LBW is associated with a significant increase in adult heart disease, impaired glucose tolerance, and diabetes. Notably, the prevalence of LBW infants is highest among black women (11.8%) as compared with white (7.1%), Hispanic (5.3%), and Asian/Pacific Islander (8.4%) women.10

      As discussed above, the thrifty phenotype fetus has been "prepared" for an extrauterine environment of low nutrition. Gluckman and Hanson elaborated a “match-mismatch” thesis whereby programmed obesity becomes evident when the thrifty phenotype fetus is exposed to an abundance or excess of nutrients postnatally followed by a Western high-fat diet.11 Indeed, rapid "catch-up” growth of LBW newborns may be a predictor of childhood and adult obesity (Figure 2).6

Mechanisms of programmed obesity

Laboratory animal studies have revealed several potential mechanisms of metabolic programming by nutrient and hormonal signals and epigenetic pathways.12-14 Hormones may respond to intrauterine conditions to maximize the survival in utero and after birth, while predisposing the adult to altered physiological functions and ultimately disease. Numerous studies have demonstrated that dietary deficiencies or supplementation can dramatically alter a heritable phenotype in mice via epigenetic processes that change DNA methylation and/or chromatin packaging (eg, histone acetylation, methylation). Critical growth and development genes that may be epigenetically regulated include the glucocorticoid receptor, appetite/satiety regulatory peptides, leptin, and glucose transporters.

      Studies by our laboratory and others have confirmed that LBW offspring eat more, as a result of increased appetite and reduced satiety responses. Brain appetite centers (ie, arcuate nucleus) demonstrate impaired satiety signaling to leptin and reduced neuronal populations of satiety neurons. Compounding the effects of increased food intake, LBW adipose tissue is programmed for enhanced fat proliferation and lipid storage.15 Additional organ systems including the kidney (impaired nephrogenesis), lung (reduced alveolar development), placenta (increased apoptosis) and vascular bed (reduced vasculogenesis) likely contribute to the phenotype of adult metabolic syndrome.

      Studies throughout the world are exploring the mechanistic pathways, biomarkers of programmed obesity, and novel preventive and therapeutic approaches. Obesity is not simply a lack of self-control; rather individuals are clearly programmed to have enhanced appetite and fat storage.

 

 

Maternal obesity

In addition to the effects of LBW, human studies indicate that exposure to maternal obesity leads to an increased risk for childhood and adult obesity.16 The 25% to 36% increase in maternal BMI over the last decade has translated to an approximately 25% increase in the incidence of high-birth-weight babies, who show increased adipose tissue mass and an increased risk of adult obesity and diabetes in later life. Importantly, as the prevalence of obesity among pregnant women continues to rise, increasing numbers of children are exposed to an “obese intrauterine environment” during development. This portends a self-perpetuating cycle of increasing obesity rates. Animal studies confirm the developmental programming effects of in utero overnutrition.

       Thus, epidemiologic studies confirm that the relationship between human birth weight and adult obesity, hypertension, and/or insulin resistance is a U-shaped curve. Perhaps most importantly, the relation of fetal growth to offspring obesity and metabolic syndrome is a continuum rather than a threshold response. There may well be an optimal newborn weight (potentially specific to an individual mother) at which the programming of obesity potential is minimized.

            The sequela of gestational programming was originally focused on metabolic syndrome. It is now recognized that a myriad of childhood and adult medical disorders may be influenced by the in utero environment, including psychological/behavioral disturbances, autism, cognitive limitations, Alzheimer disease, childhood asthma, autoimmune disorders, and osteoporosis, among others. In particular, the substantial increase in prevalence of autism17 has been associated with potential perinatal risk factors, including LBW.18 Furthermore, children with autism are at risk for overweight and obesity.19 Epigenetic dysregulation of DNA methylation and histone modifications could play a prominent role in the pathophysiology of autism.20-22

Environmental endocrine disruptors

Recent studies indicate that environmental pollutants and environmental agents that act as endocrine disruptors may have similar adverse effects on offspring programming.23 In July 2012, the FDA issued an announcement that infant baby bottles and drinking cups can no longer contain bisphenol A (BPA), a common plastic agent that is known to have potent estrogenic and potential programming effects. Of note, BPA is found in hundreds of plastic items, from water bottles to CDs.

         Although exposure to BPA may have potential adverse effects on babies and young children, exposure during pregnancy may have silent effects on fetal development that are only exhibited in the adult offspring. Animal studies have shown that in utero or neonatal exposure to BPA is associated with higher body weight, increased breast and prostate cancer, and altered reproductive function.24-26 The proadipogenic effects of BPA are well acknowledged with specific effects on adipocyte proliferation, differentiation, and lipogenic function.23

         In addition to adipogenic effects, maternal BPA exposure has been shown to accelerate neurogenesis and neuronal migration in mice, and result in aberrant neuronal network formation.27,28 There is compelling evidence of BPA-mediated epigenetic effects that have potential for transgenerational effects. BPA causes hypomethylation of DNA in mice and maternal dietary supplementation (methyl donors such as folic acid or the phytoestrogen genistein) negates the DNA hypomethylating effect of BPA.24

 

 

Clinical implications, therapies, and conclusions

We are at the precipice of a transition in prenatal care to incorporate a goal of optimizing fetal and neonatal health so as to prevent or reduce adult-onset diseases. Yet, simple decisions remain a dilemma: What is the optimal nutrition and weight gain for underweight or overweight gravidas? Is it of benefit to deliver small-for-gestational-age fetuses preterm, so as to avoid a prolongation of an “adverse” intrauterine environment? Should we avoid plastic cups containing BPA during pregnancy? What is the long-term risk/benefit of maternal glucocorticoids on developmental programming of adult disease? What is the most effective feeding strategy for LBW newborns?

The existing evidence supports that limiting the rapid weight gain in the neonatal period may be beneficial. Similarly, breastfeeding may decrease the incidence of obesity in childhood as well as the weight of the nursing mother.29,30 Undoubtedly, there is no single mechanism or fixed developmental window that impacts on each organ or system development. As a result, the ultimate management of fetuses and newborns is likely to be individualized rather than universal.

      Finally, how do we advise our new prenatal patient Mary Jane? Certainly, we should educate our patient that although evidence is limited, extremes of maternal nutrition may have long-term adverse effects on her children. Thus, she should be counseled to achieve normal weight gain and, optimally, deliver a normal-weight infant. Supplementation with folate (which reduces birth defects via epigenetic mechanisms) is advised. Exposures to potential developmental modulators (cigarette smoke, alcohol, pollutants) should be minimized, if possible. Ultimately, prenatal management decisions will await additional studies exploring mechanisms of developmental programming and the consequences or benefits of altered perinatal management. In the interim, we should strive for preconception normalization of maternal weight and balanced maternal nutrition during pregnancy. Pregnancy care providers will increasingly have a role in the optimization of long-term adult health.

References

1.Hamilton BE, Hoyert DL, Martin JA, Strobino DM, Guyer B. Annual summary of vital statistics: 2010-2011. Pediatrics. 2013;131(3):548-558.

2.Barker DJ, Hales CN, Fall CH, Osmond C, Phipps K, Clark PM. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia. 1993;36(1):62-67.

3.Ross MG, Desai M. Gestational programming: population survival effects of drought and famine during pregnancy. Am J Physiol Regul Integr Comp Physiol. 2005;288(1):R25-R33.

4.Figg WD, Dahut W, Duray P, et al. A randomized phase II trial of thalidomide, an angiogenesis inhibitor, in patients with androgen-independent prostate cancer. Clin Cancer Res. 2001;7(7):1888-1893.

5.Hoover RN, Hyer M, Pfeiffer RM, et al. Adverse health outcomes in women exposed in utero to diethylstilbestrol. N Engl J Med. 2011;365(14):1304-1314.

6.Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia. 1992;35(7):595-601.

7.Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity in the United States, 2009-2010. NCHS Data Brief. 2012;(82):1-8.

8.Caprio S, Daniels SR, Drewnowski A, et al. Influence of race, ethnicity, and culture on childhood obesity: implications for prevention and treatment: a consensus statement of Shaping America's Health and the Obesity Society. Diabetes Care. 2008;31(11):2211-2221.

9.Singh GK, Kogan MD, Van Dyck PC, Siahpush M. Racial/ethnic, socioeconomic, and behavioral determinants of childhood and adolescent obesity in the United States: analyzing independent and joint associations. Ann Epidemiol. 2008;18(9):682-695.

10.  Wu YW, Xing G, Fuentes-Afflick E, Danielson B, Smith LH, Gilbert WM. Racial, ethnic, and socioeconomic disparities in the prevalence of cerebral palsy. Pediatrics. 2011;127(3):e674-e681.

11.  Gluckman P, Hanson M. Mismatch: Why Our World No Longer Fits Our Bodies. Oxford, New York: Oxford University Press; 2006.

12.  Desai M, Gayle D, Babu J, Ross MG. Programmed obesity in intrauterine growth-restricted newborns: modulation by newborn nutrition. Am J Physiol Regul Integr Comp Physiol. 2005;288(1):R91-R96.

13.  Desai M, Li T, Ross MG. Hypothalamic neurosphere progenitor cells in low birth-weight rat newborns: neurotrophic effects of leptin and insulin. Brain Res. 2011;1378:29-42.

14.  Dolinoy DC, Jirtle RL. Environmental epigenomics in human health and disease. Environ Mol Mutagen. 2008;49(1):4-8.

15.  Yee JK, Lee WN, Ross MG, et al. Peroxisome proliferator-activated receptor gamma modulation and lipogenic response in adipocytes of small-for-gestational age offspring. Nutr Metab (Lond). 2012;9(1):62.

16.  Armitage JA, Poston L, Taylor PD. Developmental origins of obesity and the metabolic syndrome: the role of maternal obesity. Front Horm Res. 2008;36:73-84.

17.  Autism and Developmental Disabilities Monitoring Network Surveillance Year 2008 Principal Investigators; Centers for Disease Control and Prevention. Prevalence of autism spectrum disorders-Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008. MMWR Surveill Summ. 2012;61(3):1-19.

18.  Gardener H, Spiegelman D, Buka SL. Perinatal and neonatal risk factors for autism: a comprehensive meta-analysis. Pediatrics. 2011;128(2):344-355.

19.  Egan AM, Dreyer ML, Odar CC, Beckwith M, Garrison CB. Obesity in young children with autism spectrum disorders: prevalence and associated factors. Child Obes. 2013;9(2):125-131.

20.  Miyake K, Hirasawa T, Koide T, Kubota T. Epigenetics in autism and other neurodevelopmental diseases. Adv Exp Med Biol. 2012;724:91-98.

21.  Samaco RC, Hogart A, LaSalle JM. Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Hum Mol Genet. 2005;14(4):483-492.

22.  Schanen NC. Epigenetics of autism spectrum disorders. Hum Mol Genet. 2006;15(Spec No 2):R138-R150.

23.  Janesick A, Blumberg B. Obesogens, stem cells and the developmental programming of obesity. Int J Androl. 2012;35(3):437-448.

24.  Dolinoy DC, Huang D, Jirtle RL. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci U S A. 2007;104(32):13056-13061.

25.  Yaoi T, Itoh K, Nakamura K, Ogi H, Fujiwara Y, Fushiki S. Genome-wide analysis of epigenomic alterations in fetal mouse forebrain after exposure to low doses of bisphenol A. Biochem Biophys Res Commun. 2008;376(3):563-567.

26.  Zhang XF, Zhang LJ, Feng YN, et al. Bisphenol A exposure modifies DNA methylation of imprint genes in mouse fetal germ cells. Mol Biol Rep. 2012;39(9):8621-8628.

27.  Nakamura K, Itoh K, Yaoi T, Fujiwara Y, Sugimoto T, Fushiki S. Murine neocortical histogenesis is perturbed by prenatal exposure to low doses of Bisphenol A. J Neurosci Res. 2006;84(6):1197-1205.

28.  Nakamura K, Itoh K, Sugimoto T, Fushiki S. Prenatal exposure to bisphenol A affects adult murine neocortical structure. Neurosci Lett. 2007;420(2):100-105.

29.  Harder T, Bergmann R, Kallischnigg G, Plagemann A. Duration of breastfeeding and risk of overweight: a meta-analysis. Am J Epidemiol. 2005;162(5):397-403.

30.  Metzger MW, McDade TW. Breastfeeding as obesity prevention in the United States: a sibling difference model. Am J Hum Biol. 2010;22(3):291-296.

 

Racial health disparities and fetal programming

In the United States, the rate of maternal and infant mortality and adverse perinatal outcomes for African Americans is 2 to 4 times greater than for whites. The disparity in African-American maternal mortality has been linked to comorbidities that include hypertension and obesity.1 In fact, hypertension and heart disease are major contributors to overall maternal mortality.  Furthermore, pregnancy complications such as prematurity and preeclampsia significantly affect risk for early-onset cardiovascular events such as stroke and myocardial infarction. Racial and ethnic health disparities in perinatal outcomes and adult diseases, such as obesity, hypertension, and diabetes, are not just a matter of quality of care and socioeconomic status.

Hypertension, diabetes, and obesity are generational, but not necessarily “genetic,”  in African Americans. Studies dating back several decades indicate higher rates of low-birth-weight and preterm infants born to African-American women. Is the racial disparity seen in hypertension and obesity in adulthood and thereby in pregnancy a matter of inheritance, or is it a matter of generational fetal programming that cannot be overcome without achieving ideal birth weights?

Epidemiologic studies confirm that there is a relationship between low birth weight and adult obesity, hypertension, and/or insulin resistance. The concept of fetal programming and the “thrifty phenotype,” with its impact on appetite, food intake, and lifestyle, can now be clearly linked to adolescent and adult medical conditions and pregnancy comorbidities.

The solution to racial perinatal and adult health disparities for coming generations is not simple, especially if they are to overcome intrauterine programming and environmental influences they face through infancy, adolescence, and adulthood.

The health benefits to immediate and long-term breastfeeding for both mother and infant are well established. The duration of breastfeeding is inversely and linearly associated with risk of the infant being overweight. The risk for being overweight or obese decreases by 4% for each month of breastfeeding.2 Additional long-term adult health benefits for breastfed infants include lower blood pressure and lower risk for cardiovascular disease, metabolic syndrome, and diabetes, which are also inversely related to breastfeeding duration.

In the United States, non-Hispanic black  women have lower rates for in-hospital initiation of breastfeeding, breastfeeding at 6 months, and exclusive breast feeding at 6 months compared to whites, Hispanics, and Asians. Breastfeeding should be considered an infant’s first health and life insurance and may cancel out some of the adverse effects of low birth weight from either prematurity or fetal undergrowth. The additional benefits of breastfeeding for the infants of African-American women, particularly low-birth-weight infants, could ultimately impact generational health disparities in both the short and long term.

 

--Haywood I. Brown, M.D.

Dr. Brown is the Roy T. Parker Professor and Chair of the Division of Maternal Fetal Medicine, Duke University School of Medicine, Durham, NC. He is also a member of the Contemporary OB/GYN Editorial Advisory Board.

References

1. Callaghan WM. Overview of maternal mortality in the United States. Semin Perinatol. 2012;36(1):2-6.

2. Harder T, Bergmann R, Kallischnigg G, Plagemann A. Duration of breastfeeding and risk of overweight: a meta-analysis. Am J Epidemiol. 2005;162(5):397-403.