Obesity Clinical Trial
Official title:
The Role of Physical Activity During Pregnancy on Metabolic Function, Inflammation, and Maternal and Neonatal Outcomes
Maternal obesity during pregnancy is a serious public health concern as it contributes to inflammation, insulin resistance, and excessive gestational weight gain- all of which negatively impact maternal and neonatal health. Fortunately, physical activity during pregnancy improves obstetric and infant outcomes associated with obesity. Specifically, data from our group demonstrated that irrespective of body weight, women who were physically-active during pregnancy had lower levels of systemic inflammation; however, the mechanism/s driving these changes are poorly understood. Previous studies in non-gravid populations suggest obesity-associated overnutrition may contribute to inflammation and this subsequent inflammation may lead to further metabolic dysfunction- perpetuating a vicious cycle. However, the connections between physical activity, inflammation, and metabolic dysfunction (i.e. metabolic inflexibility), particularly in response to a high-fat meal (similar to that which is typically consumed in a Western diet), among lean and obese pregnant women have not been studied. Thus, this study will examine the impact of a physically-active lifestyle on inflammatory and metabolic responses to a high-fat meal in lean and obese pregnant women. Understanding mechanisms connecting maternal physical activity to improved outcomes will better inform future targeted intervention strategies. The goal of this study is to determine the role of a physically-active lifestyle during pregnancy on metabolic function and inflammation following a high-fat meal in lean and obese pregnant women.
Maternal obesity is a significant public health concern in the United States as one in three
women enter pregnancy obese, and maternal obesity is associated with a large number of
unfavorable maternal and neonatal outcomes. Fortunately, a physically active lifestyle during
pregnancy has been shown to improve unfavorable outcomes often associated with obesity.
Physical activity during pregnancy has been shown to improve maternal insulin resistance and
reduce maternal gestational weight gain. In addition, neonates of physically active women
have lower adiposity compared to neonates born to inactive women. Although the relationships
between physical activity and maternal and neonatal outcomes are well-established, little is
known about the potential for metabolic dysfunction and/or inflammation to serve as
mechanisms mediating the positive impact of physical inactivity on maternal and neonatal
health. Understanding mechanisms connecting maternal physical activity to improved outcomes
will better inform future targeted intervention strategies.
Metabolic adaptations, specifically changes in lipid and carbohydrate metabolism, occur
during normal physiologic pregnancy to provide an adequate nutrient supply to the developing
fetus despite intermittent maternal dietary intake. However, in obese pregnant women these
metabolic adaptations may be augmented by additional maternal metabolic dysfunction. Further,
it is well-established that metabolic dysfunction in obese pregnant women has serious
implications for maternal and neonatal health. Maternal substrate metabolism not only
contributes to maternal health conditions such as gestational diabetes, but it also plays a
major role in fetal growth and development. The "fetal origins hypothesis" suggests that an
altered intrauterine metabolic environment may contribute to the programming of short and
long-term neonatal outcomes.
Metabolic inflexibility may play a major role in maternal and neonatal health; however, it
has not been studied during pregnancy. In non-gravid populations, physical activity is
positively correlated with metabolic flexibility, and physical activity improves metabolic
flexibility in lean and obese individuals.
The role of physical activity in modulating metabolic inflexibility in lean and obese
pregnant women has not been studied. However, an impaired ability to switch to fat metabolism
after a high-fat load is likely a better indicator of metabolic dysregulation than metabolism
during resting conditions. Therefore, the current study proposes to look at the role of a
physically active lifestyle on metabolic function in lean and obese pregnant women.
This project will also determine the relationships between inflammation, metabolic
flexibility, and other important maternal (gestational weight gain) and neonatal (adiposity
and insulin resistance) outcomes.The goal of this project is to investigate the impact of a
physically-active lifestyle on inflammatory and metabolic responses to a high-fat meal in
lean and obese pregnant women.
The investigators hypothesize that a physically-active lifestyle among lean and obese
pregnant women will improve metabolic function and inflammation thus mediating the positive
effects of physical activity on maternal and neonatal health outcomes
Sixty women (30 lean, 30 obese) will be recruited between 28-32 weeks of pregnancy.
Consent and Physical Activity Assessment The study team will meet and consent the patient at
a private office. Participants will be given an Actigraph Link Accelerometer (ActiGraph LLC,
Pensacola, FL) to objectively confirm their self-reported physical activity levels. The Link
will be placed on the non-dominant wrist with non-removable hospital-grade wristbands.
Wrist-worn tri-axel accelerometers are a valid measure of physical activity energy
expenditure in pregnant women. In addition, previous data on acceptability suggest
participants do not object to wearing wrist-worn devices 24 hours/day, and we believe
wrist-worn devices with hospital-type wristbands would give us the best compliance and 24
hours/day wear data. Data will be collected for seven consecutive days at 30 Hz. The
accelerometer output will be sampled by a 12-bit analog-to-digital converter. The percentage
of time spent sedentary as well as the amount of time spent participating in different
categories of physical activity ranging from light and lifestyle to moderate will be
calculated using algorithms corresponding to the following activity counts: sedentary: 0 - 99
counts/min, light: 100 - 759 counts/min, lifestyle: 760 - 1951 counts/min, moderate:
1952-5724 counts/min.
Maternal Metabolic Inflexibility and Inflammation in Response to a High-Fat Meal Participants
will report to the Exercise Laboratory located on the Medical Health Complex in Bowling
Green, KY at approximately 8:00am after a 10-hour fast. Participants will be provided with
written instructions for consuming a standardized diet the day before with approximately 50%
carbohydrate, 30% fat, and 20% protein. The participant's weight, height, and vitals will be
taken upon arrival. Body composition will be measured using skinfold anthropometry in order
to determine maternal percent body fat. Body fat percentage will be determined by pressing
folds of the skin at seven sites with a caliper (Harpenden Skinfolds Caliper, Baty
International, United Kingdom), recording skin fold thickness, and entering the data into a
standardized equation that accounts for age, a technique that has been used during pregnancy
in prior studies.
Resting metabolic rate and respiratory quotient will be measured for ~30minutes using the
TrueOne Canopy Option and TrueOne Metabolic Cart (TrueOne 2400, Parvomedics, Sandy, UT).
Lipid and carbohydrate oxidation rates will be calculated by measurement of oxygen
consumption and carbon dioxide production as previously described. After the baseline resting
metabolism measurement, a baseline blood draw will be obtained (time point- 0). After the
baseline blood draw, participants will consume a standard 1000-kcal meal that is high in fat,
similar in composition to previous studies. The high-fat meal will consist of a Smoothie from
Smoothie King (55.9% fat, 29.4% carbs, 14.7% protein). Additional blood samples will be taken
60, 120, and 240 minutes after the meal is consumed. Resting metabolic rate and respiratory
quotient will be obtained a second time for ~30minutes from minute 210 to 240 minutes post
meal consumption. A total of 32mL maternal blood will be drawn. Time points for assessment of
metabolic responses to a high-fat load were chosen based on data from previous studies
exploring metabolic inflexibility and inflammation in response to a high-fat meal in other
populations.
Blood draws will be used to analyze maternal plasma glucose, insulin, c-peptide, free fatty
acids, lipids (triglycerides, HDL, LDL), and inflammatory markers (IL-6, TNF-α, IL-1α). All
blood samples will be analyzed using standardized protocols at the Biochemistry Lab at WKU or
the Washington University Core Laboratory for Clinical Studies. These data will provide
additional information regarding metabolic responses to the high-fat load. Baseline insulin
and glucose levels will be used to calculate the homeostatic model assessment-insulin
resistance (HOMA-IR), an index of insulin resistance that reflects fasting glucose
concentration measured at the fasting insulin concentration. Data on each participants' oral
glucose tolerance test (performed ~24-28 weeks gestation) will also be obtained from prenatal
charts to examine insulin resistance.
During the four hour study period, participants will be asked to remain reclined and resting.
Participants will complete several surveys during this time as well including the National
Institutes of Health's validated Dietary History Questionnaire II to determine potential
differences in day-to-day diet and the Pregnancy Physical Activity Questionnaire to determine
domain and mode of physical activities.
Neonatal Outcomes At parturition, neonatal weight, length, and head circumference will be
obtained via labor and delivery nurses. Approximately 20mL umbilical cord blood will be
obtained, centrifuged within one hour of delivery, and placed in a -80º C freezer. Neonatal
insulin, glucose, inflammatory markers (IL-6, TNF-α, IL-1α), and free fatty acids will be
determined from the umbilical cord plasma.
Within 48 hours of delivery, neonatal body composition (fat and lean mass) will be measured
by skin fold thickness measurement at the patients' bedside. Maternal prenatal charts will be
obtained in order to determine gestational weight gain and any other medical conditions that
may influence the interpretation of study outcomes.
Statistical Procedures Sample Size Calculation Due to the lack of data regarding metabolic
inflexibility during pregnancy and the exploratory nature of the study, data from a previous
study comparing metabolic inflexibility between several non-gravid populations using the same
methodology as the current study was used, where 29 subjects per group would provide 80%
power to detect differences in metabolic flexibility (via indirect calorimetry) between
active and inactive pregnant women.
Statistical Analyses Normality of the distribution for each variable will be tested using
Kolmogorov-Smirnov tests. Pearson product-moment correlation coefficients for normally
distributed variables or Spearman's rank-order correlation coefficient for non-normally
distributed variables will be used to assess the degree of the relationship between
variables. Partial correlations will be used to adjust for potential confounders. Student's
independent t-tests for normally distributed variables and Mann-Whitney U tests for
non-normally distributed variables will be used to compare outcomes between lean and obese
pregnant women. All tests will be two-sided with a p-value <0.05 denoting statistical
significance. All data analyses will be conducted using IBM SPSS Statistics, Version 22
(Armonk, New York).
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