Effects of Obesity and Physical Inactivity on Pregnancy Outcomes
Condition: Obesity; Sedentary
MeSH terms: Obesity
Study type: Observational

Summary: 
      Regular maternal physical activity leads to the delivery of lighter, leaner infants. Higher
      birth weights and childhood obesity are both strong predictors for adult obesity, suggesting
      that the impact of maternal physical activity on the future health of a child is substantial.
      However, the mechanisms underlying the relationships between maternal physical activity and
      improved infant outcomes are unclear. Thus, the purpose of this project is to measure two
      potential contributing factors: maternal fat metabolism and maternal oxidative stress
      profiles. The investigators believe that maternal physical activity leads to beneficial
      alterations in maternal fat metabolism and oxidative stress profiles. Further, the
      investigators believe that both maternal fat metabolism and oxidative stress levels are
      related to infant outcomes such as obesity and insulin resistance. Therefore, exercise will
      improve maternal metabolic factors that can lead to improvements in infant outcomes. The
      investigators will compare these factors between obese inactive pregnant women and obese
      active pregnant women. This study design will allow us not only to determine the effect of
      physical activity on maternal and neonatal pregnancy outcomes, but also to establish whether
      obesity or physical inactivity should be a primary area of focus when prescribing pregnancy
      interventions in clinical practice.
    

Detailed description: 
      Exercise during pregnancy is associated with the delivery of leaner, lighter, and healthier
      infants (Clapp 1990, Clapp 2000). Subsequently, high infant adiposity and birth weight are
      strong predictors of childhood obesity and adult adiposity (Catalano 2006, Danielzk 2002).
      Therefore, maternal physical inactivity during pregnancy may have significant ramifications
      for the child, the effects of which may extend well into adulthood. Exercise during pregnancy
      also plays an important role in the health of the mother. Active pregnant women tend to gain
      less weight during pregnancy (Clapp 1995) and retain less weight following pregnancy
      (O'Toole, 2003). With excessive gestational weight gain being the strongest risk factor for
      maternal overweight and obesity postpartum, as well as being associated with many adverse
      maternal and neonatal metabolic outcomes such as adiposity and insulin resistance (Heerwagen
      2010), the impact of exercise on maternal and neonatal outcomes could be substantial. The
      mechanisms underlying these changes are poorly understood and studies which strive to expose
      them are critical.

      Habitual physical activity in non-gravid individuals has been shown to positively alter lipid
      metabolism by increasing fatty acid oxidation (Martin 1996), but the effect of physical
      activity on maternal lipid metabolism during pregnancy has not been studied. Due to previous
      research suggesting that an altered intrauterine metabolic environment may play a significant
      role in fetal programming (Heerwagen 2010), it is reasonable to believe improvements in
      maternal lipid metabolism may contribute to improved neonatal metabolic outcomes in
      exercising pregnant women. Preliminary data from our group found that in obese and lean
      pregnant women, lipid oxidation rate was significantly correlated to offspring birth weight;
      suggesting maternal lipid metabolism may contribute to neonatal metabolic outcomes. In
      inactive pregnant women, impaired lipid oxidative capacity in conjunction with known
      increased physiologic adipose tissue lipolysis that occurs during pregnancy and obesity would
      result in excess un-oxidized plasma fatty acids that are likely to be re-esterified in
      adipose tissue and/or delivered to the fetus. This series of events may contribute to
      increased maternal and neonatal adiposity.

      In addition, generation of excess reactive oxygen species, known byproducts of lipid
      metabolism, may contribute to altered/abnormal oxidative stress profiles in obese pregnant
      women. Reactive oxygen species are up-regulated during physiologic pregnancy as well as
      non-gravid obesity, and research suggests oxidative stress may be related to poorer neonatal
      outcomes (Heerwagen 2010) . In non-gravid individuals, long-term physical activity has been
      shown to improve oxidative stress profiles (Fisher-Wellman 2009). Therefore, women who
      exercise during pregnancy may also have higher antioxidant capacity and lower markers of
      oxidative stress; both of which may contribute to favorable neonatal outcomes. However, this
      has not yet been studied.

      Obesity is also believed to adversely influence lipid metabolism, oxidative stress, and
      neonatal outcomes in pregnancy. Therefore, we plan to compare these parameters in obese
      active and obese inactive pregnant women. This study design will allow us to compare groups
      in order to determine if unfavorable maternal lipid metabolism and oxidative stress profiles,
      and neonatal metabolic outcomes (adiposity and insulin resistance) are more attributable to
      physical inactivity or obesity. Previous research with non-gravid adults suggests that the
      presence of comorbidity is more correlated with physical activity levels than with body
      weight (Blair 1989, 1999, Sui 2007). This finding is contrary to much of the previous
      literature on pregnancy which suggests "obesity may be the most common health risk for the
      developing fetus" (Heerwagen 2010). Knowledge about maternal lipid metabolism and oxidative
      stress profiles and their relationships in neonatal outcomes in active and inactive pregnant
      women can guide lifestyle and medical interventions designed to target factors that may be
      contributing to poor outcomes in obese pregnancy. Currently, we have collected data on lean,
      inactive pregnant women that can be used for comparison at the end of all data collection.

      This is the first study to examine the relationship between physical activity, lipid
      metabolism and oxidative stress in obese pregnancy. We anticipate that results from the
      proposed study will demonstrate the importance of a physically active lifestyle during
      pregnancy (irrespective of body weight) in order to maximize the short and long-term health
      of the neonate. In addition, we hope that these results will encourage obese and overweight
      women of childbearing age to remain or become physically active by demonstrating that
      physical inactivity has a greater effect on poor neonatal outcomes than obesity. These
      findings are unique as much of the current literature focuses on the negative impact of
      maternal obesity on neonatal outcomes. Blair et al. has consistently demonstrated in
      non-gravid populations that physical inactivity is a stronger predictor of all-cause
      mortality than obesity (Blair 1989, 1999). Similarly, we believe physical activity in
      pregnancy is more important than simply maintaining a healthy body weight in improving
      neonatal outcomes. This idea is novel and innovative as it is previously unexplored in
      pregnancy and pregnancy outcomes.

      In addition to determining the effect of regular physical activity on neonatal outcomes,
      measuring maternal lipid metabolism and oxidative stress profiles will provide valuable
      knowledge about mechanisms responsible for improved outcomes in physically active pregnant
      women. Also, measuring maternal lipid metabolism and oxidative stress profiles during
      exercise is novel and clinically insightful. This paradigm holds the potential to reveal
      alterations in maternal metabolism and/or oxidative stress profiles that may not be detected
      when measuring these factors at rest. Additionally, measuring metabolism and oxidative stress
      during exercise is clinically useful by providing information about maternal metabolism
      during activities that will mimic daily lifestyle tasks such as childcare, household chores,
      etc. (~3-5 METS). Thus, this study design will provide us with valuable insight and enhanced
      understanding of maternal lipid metabolism and oxidative stress profiles during everyday
      lifestyle activities.

      METHODS

      Subjects:

      All women who seek pre-natal care at the Women's Health Clinic at Barnes Jewish
      Hospital/Washington University will be screened for inclusion BMI by history at the clinic.
      Subjects will be recruited late in their 2nd trimester at the women's health clinic after
      asking about their exercise habits. All patients who meet criterion with on-going pregnancies
      will be approached for enrollment in the study. This study will compare 2 groups of pregnant
      women between 30 and 35 weeks gestation. The first group will inactive obese women and the
      other will be active obese women. We will recruit ~15 subjects per group (N=30). Groups will
      be race-matched.

      Sample Size Calculation Data from Pomeroy et al.in 2012 stated that when using an
      accelerometer to measure physical activity and air displacement plethysmography to measure
      neonatal body composition (the same measurements we are proposing to use), the Spearman
      correlation coefficient showing the association between maternal physical activity level and
      neonatal fat free mass is r=0.5226. Using this R-value and an alpha of 0.05, 30 total
      participants (15 per group) are needed to adequately power our study at .85 (beta=.15).

      Study Procedures:

      All study procedures will be performed at the Washington University School of Medicine (WUSM)
      Institute for Clinical and Translational Sciences Clinical Research Unit (CRU).

      CRU Visit #1 of 2: Body composition and Fitness Assessment (32-37 weeks gestation):

      Maternal Body Composition:

      A skin fold measurement will be performed to determine maternal body composition (% body
      fat). This will be done by pressing folds of the skin at 7 sites with a caliper and recording
      its thickness as previously described (Jackson and Pollock 1980).

      Maternal Physical Fitness Levels:

      Maternal fitness levels will be assessed using a submaximal cycle test on a recumbent
      bicycle. Subjects will sit comfortably on the bicycle while the pedals are properly adjusted
      so there is a slight bend in the knee when legs are extended. They will then complete the
      YMCA submaximal multistage cycle ergometer test according ACSM's guidelines for exercise
      testing and prescription (Thompson 2010). Sady and colleagues concluded that the VO2-Heart
      Rate extrapolation method is the most precise way to predict VO2max in pregnancy (1985)., and
      the YMCA test utilizes this method. A 3-lead ECG will be applied to monitor heart rate during
      the exercise test.

      Maternal Physical Activity Levels:

      Daily maternal physical activity will be assessed in the week following these tests using the
      ActiGraph GT3X+ accelerometer (ActiGraph LLC, Pensacola, FL) in order to objectively measure
      daily physical activity levels. ActiGraph data will be collected for seven consecutive days
      on the non-dominant wrist at 30 Hertz. Time spent in sedentary and active (light, lifestyle,
      moderate, vigorous, and very vigorous) activities will be calculated using algorithms from
      Freedson and colleagues using ActiGraph software (Freedson 1998). We will also measurement
      maternal physical activity levels subjectively using the Pregnancy Physical Activity
      Questionnaire (PPAQ). The PPAQ is a valid and reliable instrument to measure physical
      activity levels during pregnancy (Chasan-Taber 2011). Not only will the PPAQ provide us with
      additional details about their activity levels, but it will allow us to account for
      activities that the actigraph may be unable to detect (i.e. riding a stationary bicycle).

      Dietary Intake and Composition:

      In order to account for differences in diet, subjects will complete the National Institutes
      of Health's Dietary History Questionnaire II. This dietary assessment has been rigorously
      validated (Subar 2001) and is widely used among many different populations. Previous
      literature also demonstrates that dietary history questionnaires are valid and reproducible
      among pregnant populations (Vioque 2013).

      CRU Visit #2 of 2: Lipid metabolism during exercise study (32-37 weeks gestation):

      After obtaining height, weight, and vitals, a catheter (IV) will be placed in a hand vein and
      heated in a warming box prior to each blood draw. Participants will rest for approximately 30
      minutes prior to measuring lipid oxidation rate using indirect calorimetry (True One 2400,
      Parvo Medics, Sandy, UT). Participants will lay supine while a hood device is placed over
      their head for 15 minutes to measure oxygen consumption and carbon dioxide production in
      order to determine lipid oxidation rate34. After the initial indirect calorimetry measurement
      is taken, basal blood collection will be obtained. Basal insulin and glucose levels will be
      used to calculate maternal insulin resistance via a homeostatic model assessment-insulin
      resistance (HOMA-IR). After this blood draw, participants will exercise at approximately 50%
      of their predicted VO2max (based on the YMCA submaximal cycle test) for 30 minutes on the
      recumbent cycle ergometer (Lode Corvial, InMed, New South Wales, Australia). Blood will be
      collected at various time points during exercise. Indirect calorimetry (using a mouthpiece,
      nose clip, and exercise version of the software) will also be performed for 2 minutes at a
      time to measure lipid oxidation and total body oxygen consumption during low-level exercise.
      After exercise termination, participants will return to a supine position. Recovery blood
      draws will be taken and indirect calorimetry will be performed.

      Blood drawn at different time points will be used to measure glucose, insulin, free fatty
      acids, reactive oxygen species (F2- isoprostanes by mass spectrometry (also referred to as
      8-iso-PGF2α) (Milne 2007)), and total antioxidant capacity (Total Antioxidant Capacity Assay
      (TAC), Cell Biolabs, Inc., San Diego, CA). All of these measurements will help us to better
      understand insulin resistance, oxidative stress, and mechanisms that could be contributing to
      either condition.

      Parturition:

      At parturition, maternal weight will be measured and gestational weight gain will be
      determined. Neonatal weight, length, and head circumference will also be obtained. Infant
      HOMA-IR and fatty acid delivery to the fetus will be determined by measuring umbilical cord
      plasma glucose, insulin, and fatty acid concentrations at parturition. Within 48 hours of
      delivery, neonatal body composition (fat and lean mass) will be measured by skin fold
      thickness measurement and by air displacement plethysmography (Pea Pod, Life Measurement,
      Inc., Concord, CA) in the CRU at WUSM.

      Statistical Analysis: Repeated measures ANOVA (group x time) will be used to compare lipid
      oxidation rates and oxidative stress profiles between the 2 groups during pregnancy before,
      during, and after exercise. Pearson product moment correlation coefficients for normally
      distributed variables and Spearmen's rank order coefficients for non-normally distributed
      variables will be used to examine the relationships between maternal lipid oxidation rate,
      plasma oxidative stress markers, and neonatal metabolic outcomes. We may also use a
      regression analysis to examine the relationship between maternal physical activity levels in
      obese women and neonatal body composition and/or insulin resistance (similar to what has been
      done in normal weight pregnant women by Pomeroy et al. 2012).
    

Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        All women who seek pre-natal care at the Women's Health Clinic at Barnes Jewish
        Hospital/Washington University will be screened for inclusion BMI by history at the clinic.
        Subjects will be recruited late in their 2nd trimester at the women's health clinic after
        asking about their exercise habits. All patients who meet criterion with on-going
        pregnancies will be approached for enrollment in the study. This study will compare 2
        groups of pregnant women between 32 and 37 weeks gestation. The first group will inactive
        obese women and the other will be active obese women. We will recruit 15 subjects per group
        (N=30). Groups will be race-matched.
      
Biospecimen description: 
      The investigators are collecting maternal blood at 7 different time points (all in one
      day/visit) during the 3rd trimester of thier pregnancy. The investigators are also collecting
      cord blood when the babies are born. All of these samples are stored at -80 with patient
      identification numbers.
    
Keywords: Obesity; Physical Inactivity; Lipid Oxidation; Oxidative stress; pregnancy; neonatal adiposity; neonatal insulin sensitivity