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Intrauterine Factors that Contribute to Fetal Programming of Obesity and Co-morbidities

Presented by Christine Yip

+Importance of the Study The prevalence of obesity has become an epidemic in the

past three decades 35.1% of adults obese and 69% overweight (CDC, 2015).

> 1/3 of children and adolescents are considered overweight or obese (NIH, 2012)

~ 10% of infants in the U.S. have a high “weight for recumbent length”, a measure similar to BMI but used in children age 2 and under (Harvard T.H. Chan, 2015) Overweight in infancy and childhood puts individuals at a

significantly higher risk of obesity in adulthood

Estimated that the obese youth population at risk for type 2 DM , cholesterol, HTN, stroke, several types of cancers and osteoporosis

Obesity put individuals at risk for mortality, and severe obesity significantly reduces the life expectancy of young adults

+Importance of Study (continued) 45% of women begin pregnancy overweight or obese and 43%

of women gain more weight than recommended during pregnancy.

Recent research suggests that multiple factors such as maternal pre-pregnancy weight, gestational weight gain and the macronutrient composition of maternal dietary intake can contribute to infant obesity by influencing fetal body composition and adiposity, newborn weight and newborn food preferences. This can in turn determine the individual’s likelihood of

obesity and co-morbidities later in life This constellation of factors constitutes a concept known as

fetal programming.

+Problem StatementThe purpose of this literature review is to investigate the role of intrauterine factors on fetal programming leading to obesity and co-morbidities.

+Hypothesis

Beginning pregnancy as an overweight or obese individual, gaining excessive gestational weight and consuming a diet with an unfavorable protein to carbohydrates ratio during pregnancy will likely affect fetal programming. This in turn will increase the risk of fetal and adult obesity and subsequent related co-morbid conditions such as diabetes and metabolic syndrome.

+Delimitations

This review includes studies published between 2006-2016.

This review includes participants of various ethnic backgrounds in studies.

The main studies are of human subjects. However, some references were derived from animal studies.

+Definition of Terms

Intrauterine. Within the uterus. Fetal Programming. Alterations and determinations

of the fetus’ organ structures and associated functions.

Obesity. The state of having a body mass index (BMI) ≥ 30 in adults.

Co-morbidity. The state of having more than one disease or condition (often chronic) at the same time.

+Methods of Literature Review Computerized search conducted at B. Davis Schwartz

Memorial library at Long Island University- Post, Brookville, NY.

Database: Google Scholar The limits for searches:

English language studies Dated from 2006 to 2016.

The following search terms were used to find the research articles: Fetal programming and obesity Fetal programming and diabetes Fetal programming and metabolic syndrome Maternal dietary intake and fetal programming

+Fetal Programming

Research by Barker and Hales linked embryonic and fetal nutritional insufficiency to inherent diseases in adulthood.

Development of the Barker hypothesis of fetal programming: Suggesting that a number of organ structures and associated

functions will undergo programming during prenatal life The metabolism of the fetus is programmed to respond to

environmental cues reflective of what is expected postnatal life. When embryonic/fetal nutrition and endocrine status is altered

during pregnancy developmental adaptations may produce permanent structural, physiological, metabolic & epigenetic changes to the fetusThis process potentially predisposes individuals to obesity/greater adiposity and co-morbidities (at infancy, childhood, adolescence and adulthood).

+Moses, R. G., Luebcke, M., Davis, W. S., Coleman, K. J., Topsell, L. C., Petocz, P., & Brand-Miller, J. C. (2006). Effect of a low-glycemic-index diet during pregnancy on obstetric outcomes. American Journal of Clinical Nutrition, 84(4), 807-812. Purpose: To compare the effects of low GI and conventional dietary

strategies on pregnancy outcomes in healthy women Methods:

Participants (n=62) encouraged to adhere to low GI diet (n=32) or high GI diet (n=30)

3-day food diaries, diet hx, measurements of height and weight collected 5x between <16 weeks of gestation and delivery of their newborn

Maternal blood fasting glucose, insulin resistance and results of glucose tolerance test obtained

Participant’s offspring’s birth weight, length and head circumference noted Results: Mothers who adhered to the high GI diet gave birth to infants with

a higher birth weight, birth centile and ponderal index and had a higher prevalence of LGA compared to mothers who adhered to the low GI diet.

Conclusion: Investigators suggest that women consume to a diet with low GI CHOs during pregnancy, as offspring tends to be of on the smaller end of the normal neonate weight spectrum with less adiposity when dietary guidelines are followed. Additionally, a low GI CHO diet may the risk of gestational DM.

Strengths: Large sample size, high continuation rate, high compliance and precise dietary measurements, women of this study are free-living (helps reduce bias of a large number of individuals following a healthier lifestyle)

Weaknesses: Subjects and investigators were not blinded.

+Cnattingius, S., Villamor, E., Lagerros, Y. T., Wikostrom, A-K, & Granath, F. (2012). High birth weight and obesity- a vicious circle across generations. International Journal of Obesity, 36(10), 1320-1324. Purpose:

To determine the relationship between the mothers’ birth weight and her risks for pre-pregnancy overweight and obesity.

To determine the relationship between the mothers’ birth weight and her adult BMI and the joint effect on risk of having LGA offspring (to understand cross-generational effect)

Methods: Nation-wide Swedish Medical Birth Registry (n= 162,000 mother-offspring

pairs) Data collection: offspring anthropometrics and gestational age, maternal

height and weight, BMI , age, gestational age and mother’s birth weight

Results: Mothers born at lower birth weight had modestly risks of overweight and

obesity during pregnancy compared to mothers born AGA Risk of overweight & obesity during pregnancy were in mothers born

moderately LGA and especially for mothers born LGA. Mothers born LGA were at risk of severe forms of obesity than overweight

compared to mothers born AGA.

+Cnattingius, S., Villamor, E., Lagerros, Y. T., Wikostrom, A-K, & Granath, F. (2012). High birth weight and obesity- a vicious circle across generations. International Journal of Obesity, 36(10), 1320-1324.…….continued

The risk of having an offspring LGA significantly as the mother’s BMI . Risk of a LGA offspring was highest among mothers with a BMI ≥30 kg/m2

who also had a high birth weight. However, mothers born SGA with a BMI ≥ 35 kg/m2 during pregnancy

were observed to be 13x more likely to have an offspring LGA compared to mothers born SGA with a normal BMI during pregnancy.

Conclusion: Prenatal conditions are likely critical in the obesity epidemic and the prevention of LGA offspring may assist in reducing the vicious intergenerational cycles of obesity.

Strengths: Large sample size, the restriction of subjects being relatively young mothers (<34 years of age) and their first-born. Nearly 99% of data on birth weight and gestational age was recorded at delivery for both mothers and offspring.

Weaknesses: The lack of consideration of the macronutrient composition of maternal dietary intake and physical activity during pregnancy

+Meas, T., Deghmoun, S., Alberti, C., Carreiera, E., Armoogum, P., Chevenne, D., & Levy-Marchat, C. (2010). Independent effects of weight gain and fetal programming on metabolic complications in adults born small for gestational age. Diabetologia, 53(5), 907-913.

Purpose: To investigate the impact of fetal growth and weight gain on the progression of insulin resistance and metabolic syndrome over time in adults (22 & 30 years of age).

Methods: Two observations performed on individuals (n=1308) born either SGA

or AGA A standardized questionnaire was used to obtain medical histories. Obtained body wt, BMI, waist circumference, body fat mass %, BP and

blood samples (for measurement of serum lipids, plasma glucose and serum insulin concentrations)

Results: Individuals born SGA were more insulin-resistant and had a

significantly prevalence of metabolic syndrome compared to the AGA group 1st observation: A small number of individuals (1 from AGA group and

15 from SGA) met the criteria for the dx of metabolic syndrome 2nd observation: The risk of developing metabolic syndrome greatly

in the the SGA group Birth weight did not significantly affect the progression of insulin

resistance

+Meas, T., Deghmoun, S., Alberti, C., Carreiera, E., Armoogum, P., Chevenne, D., & Levy-Marchat, C. (2010). Independent effects of weight gain and fetal programming on metabolic complications in adults born small for gestational age. Diabetologia, 53(5), 907-913.…Continued Conclusion: Individuals born SGA are at risk for metabolic

complications as adults when compared to individuals born AGA. The phenomenon of the effects of catch-up growth can extend beyond childhood and can affect individuals during adulthood as well. This is a result of excessive weight gain over time during adulthood and fetal programming on metabolic complications in those born SGA.

Strengths: Large sample size, no particular dx medical condition(s) in each subject, high participation rate

Weaknesses: Self-reported anthropometric data of individuals during the 2nd observation and the lack of laboratory procedures (measurement of serum lipids, plasma glucose and serum insulin concentrations) performed on these individuals

+Pettitt, D. J., Lawrence, J. M., Beyer, J., Hillier, T. A., Liese, A. D., Maver-Davis, B.,…Dabelea, D. (2008). Association between maternal diabetes in utero and age at offspring’s diagnosis of type 2 diabetes. Diabetes Care, 31(11), 2126-2130. Purpose:

To examine the age of DM onset in children who have parents dx with DM. To investigate whether the parent’s DM was dx before or after the child’s birth.

Methods: Participants (n=2,673) completed a survey. Type 1 DM (n= 2,342 ) and type 2 DM

( n=331). Data on DOB, date/type of DM dx, age at dx and race/ethnicity, heights and

weights, family hx of DM.

Results: Children with type 2 DM are more likely to be born of a parent with either type 1 or type 2 DM compared to children with type 1 DM. Type 2 DM was dx 1.68 years earlier in children exposed to DM in-utero compared to children whose mothers’ DM dx after the offspring’s birth. No significant differences were found in participants between the age of dx of type 1 diabetics w/ & w/o in-utero exposure.

Conclusion: The hyperglycemic intrauterine environment potentially predisposes an individual to an earlier onset of type 2 DM. Type 1 DM is not significantly influenced by the intrauterine environment, but rather, as widely known, by genetics. Offspring exposed to a diabetic intrauterine environment may be at a risk for long-term health issues.

Strengths: Large sample (ethnically and socioeconomically diverse), analyzed both type 1 and type 2 DM

Weaknesses: Self-report of parental DM presence and data, parental age of dx was recorded to the nearest year, which may have introduced some degree of bias depending on when the parent was dx

+Ayres, C., Argranonik, M., Portella, A. K., Filion, F., Johnston, C.C., & Silveira, P. P. (2012). Intrauterine growth restriction and the fetal programming of the hedonic response to sweet taste in newborn infants. International Journal of Pediatrics, n/a (n/a), 1-5. Purpose: To investigate whether intrauterine growth restriction led to fetal

programming of a greater desire to sweet foods in newborns as indicated by their hedonic response (pleasure response).

Methods: Data collected from a NICU. Premature infants (born between 25 & 31 weeks of

age) Randomly assigned infants (n=16) to either a syringe of 0.1 mL of 24% sucrose

solution or water. Infants were administered the solution by mouth 1 minute prior to the start of

an invasive or uncomfortable procedure. The infant’s taste reactivity was filmed and analyzed by a trained observer.

Results: The the intrauterine growth restriction, the the level of the hedonic response was observed; as intrauterine growth restriction , the desire for the sweet taste for pleasure .

Conclusion: The altered hedonic response at birth along with food preferences postnatal life may put IUGR individuals at risk for obesity and co-morbidities. A critical concern is that this response may cause an individual to overconsume sweets/ other foods that are considered “more palatable” when attempting to reach a degree of pleasure or especially during times of stress to provide relief.

Strengths: Random assignment of Tx and the premature infants were considered “relatively healthy”

Weaknesses: Small sample size & only tested for one hedonic reaction

+Discussion

This review examined the role of intrauterine factors on fetal programming leading to obesity and co-morbidities

Majority of the studies were either prospective or retrospective cohort studies (1 RCT and 1 parallel-controlled trial)

Most of the studies reviewed had a large sample size. Ayres et al.’s study provided the first evidence of fetal

programming relating intrauterine growth restriction with greater hedonic response of sweet taste.

The majority of the studies relied on self-reported data.

+Discussion (continued) The findings from the reviewed articles supported the

Barker hypothesis of fetal programming. The hypothesis dictated that developmental adaptations in-

utero may cause permanent structural, physiological, metabolic and epigenetic changes to the fetus.

This process predisposes individuals to higher risk of obesity and co-morbidities in life beginning at birth as well as in adulthood.

It is important to know that the associations between maternal weight, gestational weight gain, macronutrient composition of maternal dietary intake, fetal growth, infant body composition, offspring obesity and adulthood obesity are a continuous relationship rather than a threshold response.

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+Conclusion and Recommendations Combat the vicious intergenerational cycle of obesity

Women planning a pregnancy should begin gestation with a healthy body weight and consume a diet with an adequate amount of energy, a healthy balance of macronutrients (exact composition unknown) and with foods low in GI, especially in late pregnancy.

Theme of stressing late pregnancy (without specifying the trimester) as the most critical time of fetal programming. Due to the increased energy needs and weight gain during the second

and third trimester of pregnancy, it is likely that investigators are referring to these trimesters as late pregnancy (CDC, 2016).

Mothers should use the 2009 IOM pregnancy weight gain recommendations (refer to table on next slide) to decrease the risk of offspring born SGA or LGA.

Taking all of these recommendations into consideration may provide an optimal intrauterine environment for the fetus. This may the likelihood of positive or unaltered fetal programming, which may in turn reduce the risk of predisposing the infant to obesity and co-morbid complications.

Due to the diverse and multi-cultural populations reviewed in this paper, it is appropriate to conclude that the recommendations can apply to a considerable number of women around the world.

+IOM Pregnancy Weight Gain Recommendations

+Conclusion and Recommendations (Continued) The concept of fetal programming is complicated and research regarding its

mechanism is limited.

The exact extent of fetal programming as it relates to obesity and co-morbidities cannot be determined at this time.

Further investigation is necessary to clearly extrapolate the mechanism of fetal programming RCTs to determine the most appropriate macronutrient composition intake

and/or level of physical activity as interventions for women planning pregnancy.

Include a larger sample size when determining fetal programming of preferred foods in IUGR infants.

Twin studies to assist in refining the prenatal care guidelines for mothers of twins. (Only singleton pregnancy studies were reviewed)

Findings from such studies may assist in providing guidelines as a preventative measure of maternal obesity as well as offspring obesity/excessive adiposity at infancy, childhood and adulthood to therefore, the risk of obesity’s co-morbidities.

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Thank you!

Questions? Comments?