The Role of Physical Activity During Pregnancy on Metabolic Function, Inflammation, and Maternal and Neonatal Outcomes
Condition: Obesity; Pregnancy Related
MeSH terms: Inflammation
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      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).
    

Intervention name(s): Exposure to high-fat smoothie
Intervention type(s): Other
Intervention description(s): Both groups will drink the high-fat smoothie and the study team will observe how they respond metabolically in the subsequent four hours using metabolic analyzer and blood draws.
Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Participants will be recruited from several local obstetrics offices, as well as through
        word of mouth, university-wide emails, and local flyers (with IRB approval).
      
Biospecimen description: 
      maternal- whole blood, red blood cells (after spinning and removing plasma), plasma cord
      blood- cord blood plasma, cord blood red blood cells
    
Keywords: exercise; inflammation; metabolic inflexibility; insulin resistance; neonatal adiposity