Australian and New Zealand Journal of Obstetrics and Gynaecology 2015; 55: 27–33
DOI: 10.1111/ajo.12300
Original Article
Exercise in pregnancy does not alter gestational weight gain, MCP-1 or leptin in obese women Marloes DEKKER NITERT,1,2 Helen L. BARRETT,1,2 Kerina J. DENNY,3 H. David MCINTYRE,1,4 and Leonie K. CALLAWAY1 for the BAMBINO group 1
School of Medicine, The University of Queensland, 2UQ Centre for Clinical Research, The University of Queensland, Herston, 3School of Biomedical Science, The University of Queensland, St Lucia, and 4Mater Health Services, South Brisbane, Queensland, Australia
Background: Increasing physical activity in pregnancy may improve pregnancy outcomes for obese women. Exercise could reduce gestational weight gain, improve the maternal circulating lipid profile as well as alter leptin, Interleukin-8 (IL-8) and Monocyte Chemoattractant Protein-1 (MCP-1) levels. Aim: The aim of this study was to investigate the effects of exercise on gestational weight gain, maternal circulating lipids, IL-8, MCP-1 and leptin levels in obese pregnant women. Materials and Methods: The analysis was performed in the 35 obese women enrolled in the pilot BAMBINO randomised controlled trial who provided blood samples at 12- and 28-weeks gestation. Women in the exercise intervention arm received an individualised exercise plan. Blood samples, exercise diary and pedometer data were obtained at 12-, 20-, 28- and 36-weeks’ gestation. Cord blood was obtained at delivery. Results: Women in the exercise arm exercised more than those in the control arm (P = 0.038). There was no difference in gestational weight gain, excess gestational weight gain, MCP-1 and leptin levels between women in the exercise intervention (n = 19) or the control arm (n = 16). IL-8 was not detectable. Exercise did not alter the maternal lipid profile. Conclusions: The low level of physical activity achieved in obese women in the exercise intervention arm was insufficient to alter gestational weight gain, MCP-1, leptin or circulating lipid levels. Key words: exercise, gestational weight gain, lipids, obesity, pregnancy.
Introduction Maternal obesity is associated with an increased risk of pregnancy complications for both mother and baby. These complications include gestational diabetes, pre-eclampsia, macrosomia, admittance to special nursery and future metabolic and cardiovascular disease for mother and baby.1 Gestational weight gain (GWG) within the limits set by the Institute of Medicine reduces the likelihood of pregnancy complications.2 For women with a body mass index (BMI) >30 kg/m2, a healthy gestational weight gain is between 5 and 9 kg over the course of the pregnancy.2 Strategies to limit GWG usually focus on reducing dietary intake, increasing moderate physical activity or a combination of those. There have been a number of lifestyle intervention studies in overweight and obese
Correspondence: Dr Marloes Dekker Nitert, UQCCR level 7, School of Medicine, RBWH Campus, The University of Queensland, Butterfield Street, Herston, Qld 4029, Australia. Email: [email protected] Received 31 August 2014; accepted 11 November 2014.
pregnant women that have evaluated GWG: some studies reported an overall reduction in GWG,3–5 one reported reduced rates of excess GWG, but no overall reduced GWG6 and four reporting no effect on GWG.7–10 Recently, the results of the large LIMIT randomised controlled trial (RCT) of intensive dietary and lifestyle interventions in pregnancy in overweight and obese women showed no effect on GWG or on excess GWG.11 Increasing or maintaining physical activity can be a strategy for limiting GWG. A Cochrane meta-analysis of aerobic exercise during pregnancy concluded that regular exercise appears to improve or maintain physical fitness, but the heterogeneity of the data precluded statistical analysis of physical fitness or any maternal and infant outcomes.12 A meta-analysis of the effects of exercise interventions during pregnancy to prevent gestational diabetes concluded that physical exercise was not a successful strategy to prevent gestational diabetes mellitus.13 Many of the studies included in these meta-analyses are relatively small in size and difficult to compare due to the large heterogeneity in the intervention strategies. Physical activity in pregnancy may have beneficial effects even in the absence of an effect on GWG or gestational
© 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists The Australian and New Zealand Journal of Obstetrics and Gynaecology
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diabetes mellitus. Exercise may result in a lower circulating triglycerides, as it does outside pregnancy.14 Outside pregnancy, exercise increases the release of a number of cytokines from skeletal muscle cells,15 which can account for exercise-associated immune and metabolic changes. One of these cytokines is Interleukin-8 (IL-8), which can stimulate angiogenesis and is increased in response to vigorous exercise that involves eccentric muscle contractions such as running. Monocyte Chemoattractant Protein-1 (MCP-1) is another cytokine that is increased in skeletal muscle samples from lean, obese and type 2 diabetes subjects after a bout of moderate-intensity aerobic exercise.16 Furthermore, exercise may affect the levels of the satiety hormone leptin. In the nonpregnant population, most studies have shown no change in leptin levels acutely following exercise, but there is some evidence for a delayed reduction in leptin following an exercise episode and the duration of the training session and length of the exercise intervention is likely important.17 In pregnancy, there is a steady increase in maternal serum-free leptin levels, which reaches a plateau in the late second or early third trimester. The increase in leptin is due to placental production, which outside pregnancy is mainly synthesised in adipose tissue.18 High leptin levels may contribute to altered satiety signalling in the brain and increased leptin resistance, which may serve to increase maternal energy intake in order to cover the energy needs of the growing fetus.19 In the placenta, leptin regulates many processes, including increased lipolysis20 and amino acid transport.21 Serum-free leptin levels are increased in obesity.22 The hypothesis of this study was that in obese pregnant women, exercise reduces GWG, improves the circulating lipid profile and decreases maternal leptin levels in the circulation. The aim of this study was to firstly analyse whether an exercise intervention reduces GWG in obese pregnant women participating in a pilot RCT of exercise to prevent gestational diabetes mellitus. The second aim was to investigate whether physical activity alters maternal and cord blood lipid profiles as well as IL-8, MCP-1 or leptin levels in obese pregnant women.
Written informed consent was obtained from all study participants. This study was approved by the Royal Brisbane and Women’s Hospital Human Research Ethics committee. This trial was registered with the Australian Clinical Trials Registry (accession number ACT RN012606000271505).
Intervention At 12-weeks’ gestation, all participants attended a group education session where written information on exercise,24 nutrition25 and adequate GWG was provided. The exercise intervention consisted of an individualised exercise plan meeting the specified energy expenditure requirements based on personal preferences and ability, monthly face-to-face exercise advice by physiotherapists and paper-based diaries for self-monitoring of activity. Women not meeting the specified energy expenditure requirements were offered additional face-to-face support to identify barriers and alterations to the exercise plan.
Outcome measures At baseline (12 weeks), 20-, 28- and 36-weeks’ gestation, the study participants had review visits with research midwives and physiotherapists. At each visit, participants completed the Pregnancy Physical Activity Questionnaire (PPAQ),26 which is a validated questionnaire for occupational, household, sedentary and exercise energy expenditure in pregnancy. Energy expenditure is expressed in kCal/week. Additionally, overnight fasting blood samples and anthropometric measurements were obtained at each time-point. At baseline and 28-week gestation, a 75 g fasting oral glucose tolerance was performed; an additional fasting serum sample was obtained at these time-points and stored at 20°C until analysis. At delivery, cord blood was obtained for the analysis of metabolic parameters in EDTA and SST tube, spun and stored at 20°C until analysis. Within three days of delivery, neonatal anthropometric and skinfold measurements were performed. The analysis is restricted to those women who completed the 36-weeks follow-up: 16 women in the control arm, 19 women in the exercise intervention arm.
Materials and Methods Participants
Metabolic measurements
In the pilot BABMINO study, 50 obese pregnant women (BMI ≥ 30 kg/m2) were recruited at 12-weeks’ gestation and equally randomised to an individualised exercise intervention (described below) or standard obstetric care until delivery. The inclusion and exclusion criteria for enrolment have been described previously.23 Women were randomised to the intervention or standard care arm by random number allocation through an external service. Stratification of the randomisation was based on BMI (≤40 or >40 kg/m2) and parity (0 or ≥1). GWG, blood lipid and leptin levels were not outcomes of the original BAMBINO pilot RCT.
Fasting glucose (oxygen rate method), insulin (chemiluminescent immunoassay, DxI 800 Immunoassay system; Beckman Coulter, Brea, CA, USA), triglycerides (Beckman DXC800), total, HDL and LDL cholesterol (Beckman DXC800) were analysed with standard assays by the pathology department of the Royal Brisbane and Women’s Hospital. At baseline and 28-weeks’ gestation, IL-8, MCP-1 and leptin were measured in the additional serum samples of 12 women in the control arm and 15 women in the exercise intervention arm with the Human Serum Adipokine panel B MilliplexTM ELISA (HADK261K-B; Millipore, St Charles, MO, USA). This method is
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© 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists
Exercise effects in obese pregnancy
based on simultaneous analysis of multiple analytes through the coupling of specific immunoassays to the surface of fluorescent-coded beads. Undiluted samples were measured in duplicate and quantitated against a standard curve of known concentrations.
Statistics The analysis was done on per-protocol basis only, including those women who completed all study visits and supplied both fasting blood samples. Continuous variables are summarised as mean standard deviation for parametric data and as median interquartile range for nonparametric data. Comparisons between the women in the exercise and control arms were performed by repeated measures ANOVA. Proportions were compared by Fisher’s exact test. P < 0.05 was considered statistically significant.
Results Maternal effects In this study, 19 obese women completed an exercise intervention during pregnancy from 12-weeks’ gestation until delivery with 16 obese pregnant women randomised to routine care as a comparison. Table 1 lists maternal characteristics throughout the pregnancy. Exercise did not significantly alter GWG (controls 8.28 6.10 vs exercise 7.87 4.00 kg, P = 0.81). The proportion of women who exceeded the IOM guidelines for gestational weight gain (gained >9.07 kg) was 43.8% in the control group
and 47.4% in the intervention group (P = 1.00). Exercise did not alter maternal blood glucose, insulin, triglyceride, total, HDL or LDL cholesterol levels at any stage of pregnancy. Maternal leptin levels increased significantly from baseline to 28-week gestation (12 weeks 30.2 (interquartile range 24.9–47.7) vs 28 weeks 49.7 (40.5–68.1) lg/mL, P = 0.003; Fig. 1A). However, there was no difference in maternal leptin (Fig. 1A) or MCP-1 (Fig. 1B) concentrations between women in the exercise or control arm of the study. Circulating maternal IL-8 levels were below the limit of detection at both baseline and 28-weeks gestation.
Physical activity during pregnancy All obese pregnant women who completed the study had low levels of physical activity throughout pregnancy (Table S1). Figure 2 shows the physical activity attributed to exercise in obese pregnant women over the course of pregnancy. The pattern is similar for women randomised to the exercise and the control arm of the study with a doubling in energy expenditure attributable to exercise at 20-weeks gestation that returned to baseline levels at 36-weeks gestation (P < 0.001 for changes over gestation). Women in the exercise intervention arm had higher energy expenditure from exercise activity (P = 0.038).
Infant outcomes Maternal exercise during pregnancy did not change any of the neonatal outcomes nor did it affect cord blood
Table 1 Maternal characteristics
n Age (years) Weight (kg) Gestational weight gain (kg) Body mass index (kg/m2) SBP (mmHg) DBP (mmHg) Fasting glucose (mmol/L) Fasting insulin (lU/mL) Fasting Cholesterol (mmol/L) Fasting Triglycerides (mmol/L) Fasting HDL cholesterol (mmol/L) Fasting LDL cholesterol (mmol/L)
Baseline control
Baseline exercise
20-Weeks control
20-Weeks exercise
28-Weeks control
28-Weeks exercise
36-Weeks control
36-Weeks exercise
16 30.3 (5.6) 97.1 (23.4) –
19 30.8 (4.9) 96.9 (24.0) –
16 – 98.3 (23.5) 1.45 (2.45)
19 – 97.7 (24.1) 1.45 (2.05)
16 – 101.7 (21.4) 4.62 (4.36)
19 – 102.3 (23.5) 5.35 (2.84)
16 – 105.4 (20.8) 8.28 (6.10)
19 – 104.8 (24.6) 7.87 (4.00)
35.6 (9.0)
35.8 (7.3)
36.2 (9.0)
35.9 (7.5)
37.2 (8.2)
37.5 (7.1)
38.56 (7.9)
38.45 (7.2)
112 (12) 65 (6) 4.5 (0.3)
110 (10) 67 (9) 4.5 (0.4)
107 (12) 66 (7) 4.4 (0.5)
110 (10) 67 (8) 4.3 (0.4)
108 (11) 65 (7) 4.6 (0.4)
112 (7) 66 (4) 4.4 (0.5)
114 (13) 70 (10) 4.3 (0.7)
115 (11) 71 (9) 4.2 (0.5)
11.7 (4.4)
14.5 (9.8)
11.0 (4.28)
11.0 (4.3)
15.3 (6.4)
15.3 (5.8)
18.9 (10.8)
16.0 (9.0)
5.2 (0.8)
5.0 (0.8)
6.2 (1.0)
6.0 (0.9)
6.8 (1.2)
6.5 (1.1)
7.5 (1.4)
6.6 (1.1)
1.2 (0.3)
1.4 (0.6)
1.6 (0.5)
1.9 (0.5)
2.0 (0.6)
2.2 (0.6)
2.7 (1.1)
2.7 (0.7)
1.9 (0.5)
1.8 (0.4)
2.2 (0.6)
2.0 (0.4)
2.1 (0.7)
2.0 (0.5)
1.9 (0.6)
1.7 (0.4)
2.7 (0.7)
2.5 (0.7)
3.3 (0.9)
3.1 (0.9)
3.7 (1.0)
3.5 (1.0)
4.3 (1.3)
3.6 (1.0)
SBP, systolic blood pressure; DBP, diastolic blood pressure. Data are represented as mean (SD). © 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists
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(A)
(B)
Figure 1 Maternal serum levels of leptin (A) and MCP-1 (B) measured at baseline (BL) and 28-week gestation (28) in obese pregnant women. Boxes represent median and IQR with whiskers at 2.5 and 97.5 centile. White boxes, women randomised to the control arm (n = 12); dark grey boxes, women randomised to the exercise intervention arm (n = 15); light grey boxes, all pregnant obese women (n = 27). **P < 0.01.
Table 2 Infant characteristics Control
Figure 2 Exercise activity of obese pregnant women in the BAMBINO trial throughout gestation. White circles, women in the control arm (n = 16); grey squares, women in the exercise intervention arm (n = 19).
concentrations of glucose, insulin, triglycerides or cholesterol (Table 2). More women in the exercise intervention group were delivered by caesarean section, but this was not significantly different from the control group (Fisher’s exact test, RR = 0.56 (CI 0.21–1.48), P = 0.3).
Discussion This pilot exercise intervention study in obese pregnant women showed that exercise at the levels achieved does not reduce overall or excessive GWG in this cohort. Physical activity did not alter circulating lipids, MCP-1 or leptin. We have previously reported that in this cohort, exercise did not alter the HOMA-IR index even though it increased energy expenditure.23
Gestational weight gain Exercise interventions have been reported to have mixed effects on GWG. One recent RCT study of 224 pregnant women showed that a combined dietary and physical activity interventions reduced the proportion of women with excessive GWG in pregnancy from 54% to 35% in the intervention group.6 However, there was no significant effect on overall mean GWG, similar to our findings.6 30
n Gestational age delivery (days) Five minute Apgar score C-section (n) (% of group) Birth weight (g) Length (cm) Head circumference (cm) Abdominal circumference (cm) Mid upper arm circumference (cm) Triceps skinfold thickness (mm) Subscapular skinfold thickness (mm) Cord glucose (mmol/L) Cord insulin (lU/mL) Cord Cholesterol (mmol/L) Cord Triglycerides (mmol/L) Cord HDL cholesterol (mmol/L) Cord LDL cholesterol (mmol/L)
16 277.9 9.1 4 3597 50.5 34.5 33.5 11.8 5.3 4.8 5.0 6.4 1.5 0.4 0.6 0.7
(8.4) (0.4) (25%) (304) (1.8) (1.3) (2.0) (0.6) (1.1) (0.5) (1.4) (5.6) (0.4) (0.1) (0.2) (0.2)
Exercise 19 278.4 9.0 9 3548 50.6 34.6 33.2 11.3 4.9 4.7 4.3 7.6 1.7 0.4 0.6 0.9
(9.8) (0.3) (47%) (459) (2.2) (2.0) (1.8) (1.0) (1.1) (0.9) (1.3) (6.0) (0.5) (0.1) (0.2) (0.3)
Data are represented as mean (SD).
Another RCT of combined dietary and physical activity intervention in 100 pregnant women also reported no difference in overall GWG: of the obese women only 20% and 33% adhered to IOM guidelines in the control and intervention group, respectively.8 A significant reduction in excessive GWG and postpartum weight retention in 65 overweight and obese women was reported in a Canadian study combining an individualised walking intervention and a nutritional intervention when compared to a matched historical cohort.4 This program started at 16- to 20-weeks gestation when many of the participants with excessive GWG already had gained in excess of the IOM guidelines at study entry. A Swedish intervention of diet and physical activity in 155 obese women also showed a significant decrease in GWG in the intervention group which was associated with less postnatal weight retention than those 193 women who were cluster-randomised to standard care.3 Many of these studies unfortunately do not report the actual amount of physical activity, which precludes exact comparisons of the effects between
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studies. However, most exercise intervention studies, including our study, do not start until the second trimester for practical reasons. Since many women already start gaining excessive weight in their first trimester,4 exercise interventions likely need to begin very early in pregnancy or perhaps prepregnancy to achieve maximal effects. First trimester symptoms, including nausea, vomiting and extreme fatigue should be taken into account when designing these interventions.27,28 Our results indicated that, as pregnancy progresses, exercise becomes harder to accomplish, again emphasising the need for starting exercise early in pregnancy.
Circulating metabolic markers Triglyceride levels increase over the course of pregnancy independent of physical activity.29 In this study, we saw a similar rise in maternal triglycerides, total cholesterol and LDL cholesterol over the course of pregnancy independent of intervention allocation. Exercise did not alter maternal lipid profiles. A recent RCT study showed that a combined dietary and physical activity intervention reduced the intake of total calories, total fat, saturated fat and cholesterol in pregnancy in the intervention group.6 However, this RCT did not measure cord blood metabolic markers, and it is unclear if the changes in diet would change the levels of lipids in cord blood. In our study, there were no differences in cord blood glucose and insulin levels between the study arms. Cord blood insulin concentrations in our study were higher than those reported for infants of normal-weight mothers, whereas cord blood glucose levels were similar.7,30,31 However, they are similar to the levels previously reported in obese women32 and likely are a reflection of fetal insulin resistance.
Leptin levels In the nonpregnant population, the concentrations of the satiety hormone leptin decrease with long-term exercise.33 In this study, we did not find an effect of exercise on maternal leptin levels. It is not clear if the lack of effect of exercise on free leptin levels was the result of the relatively low levels of physical activity achieved by the pregnant women in this cohort or if the free leptin levels mainly reflect placental leptin secretion, which may not be regulated by physical activity. A lack of effect of exercise on leptin levels during pregnancy has been shown previously: in a study of aerobic stationary cycling training during pregnancy from 20- to 35-week gestation, there was a significant decrease in birth weight but not body composition in the exercise intervention group with no differences in leptin levels between the exercise and the control arms.30 Another exercise intervention study in women in the US military also reported an increase in leptin levels over the course of pregnancy but no effect of exercise.34 The leptin levels reported in these studies were lower than in our study, but this likely due to the difference in mean BMI: around 25
versus 35.7 kg/m2 in our cohort. Higher leptin levels in obese pregnant women, similar to the levels measured in this study, have been reported previously.32 The increase in serum-free leptin levels is similar in obese and normalweight pregnancy, but the starting point is higher in obese women. Prepregnancy leptin resistance may further affect leptin’s actions in the placenta during pregnancy.35 Furthermore, circulating leptin levels are correlated with the level of insulin resistance in pregnancy,36 which is likely to be high in this cohort.
MCP-1 and IL-8 levels MCP-1 is a pro-inflammatory adipokine which is increased in obesity,37,38 MCP-1 is also synthesised in skeletal muscle cells and circulating MCP-1 is increased after exercise.38 MCP-1 enhances the recruitment of monocytes and T lymphocytes into tissues and promotes insulin resistance. Furthermore, high glucose concentrations increase MCP-1 secretion from endothelial cells.39 The placenta synthesises IL-8 and MCP-1. Maternal MCP-1 levels at baseline in this study are very similar to the levels previously reported for women with a BMI > 30 kg/m2.37 Previously, it has been reported that the differences in MCP-1 levels between obese and normal-weight women present in early pregnancy – with the obese women having higher MCP-1 concentrations – disappeared in late pregnancy.37 This was due to an increase in MCP-1 levels in normal weight women with the progression of pregnancy which was not evident in obese women who at baseline already were in a more inflammatory state. The change in MCP-1 levels was independent of GWG.37 In our study, no change in MCP-1 levels was observed over the course of pregnancy in our cohort of obese women and no effect of exercise was noted. However, the increases in circulating MCP-1 levels after exercise may be transient and disappear after acute exercise,38 which could explain the lack of effect of exercise in our cohort as could the amount and intensity of the exercise. The adipo-myokine IL-8 has increased expression in visceral adipose tissue in people with insulin resistance as well as in type 2 diabetes. Furthermore, circulating IL-8 levels correlate with measures of insulin resistance. Moderately vigorous exercise reduces plasma IL-8 concentrations in obese individuals.40 However, IL-8 could not be reliably detected in the serum of obese pregnant women at any stage of pregnancy in this study.
Study limitations The BAMBINO cohort is a pilot cohort of relatively small size. The level of actual exercise – as measured by diary, questionnaires and pedometer – was low and may have affected the lack of changes measured. Furthermore, as shown in Figure 2, the women randomised to the control group also increased their level of physical activity, which further reduces the power of the study to detect differences. GWG changes to blood lipids and leptin levels
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M. Dekker Nitert et al.
were not primary or secondary outcomes for the BAMBINO trial, and therefore, the sample size may be insufficient to detect small differences. While the sample size of this study is small, the results are in line with those of other studies,6–8 indicating the difficulties in affecting changes through exercise in obese pregnant women.
10
11
Conclusion In summary, in our cohort of obese pregnant women, an exercise intervention did not affect maternal overall GWG and excess GWG, maternal blood lipids or circulating levels of MCP-1 and leptin. The overall level of physical activity of obese pregnant women is low. These results indicate that the levels of physical activity achieved need to be significant in order to be effective.
12 13
14
15
Acknowledgements The collaborators on the BAMBINO project are gratefully acknowledged for their contributions to the trial: Katie Foxcroft, Barbara Lingwood, Paul Colditz, Nuala Byrne, Ingrid Rowlands, Ainsley Groves, Xanthe Sansome, Briony O’Connor and Susan Croaker. This study was funded by a Royal Brisbane and Women’s Hospital Foundation strategic initiative grant.
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28 Downs DS, Hausenblas HA. Women’s exercise beliefs and behaviors during their pregnancy and postpartum. J Midwifery Womens Health 2004; 49: 138–144. 29 Bessinger RC, McMurray RG, Hackney AC. Substrate utilization and hormonal responses to moderate intensity exercise during pregnancy and after delivery. Am J Obstet Gynecol 2002; 186: 757–764. 30 Hopkins SA, Baldi JC, Cutfield WS et al. Effects of exercise training on maternal hormonal changes in pregnancy. Clin Endocrinol (Oxf) 2011; 74: 495–500. 31 Ong K, Kratzsch J, Kiess W et al. Size at birth and cord blood levels of insulin, insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-3, and the soluble IGF-II/mannose-6-phosphate receptor in term human infants. J Clin Endocrinol Metab 2000; 85: 4266–4269. 32 Catalano PM, Presley L, Minium J, Hauguel-de Mouzon S. Fetuses of obese mothers develop insulin resistance in utero. Diabetes Care 2009; 32: 1076–1080. 33 Balducci S, Zanuso S, Nicolucci A et al. Anti-inflammatory effect of exercise training in subjects with type 2 diabetes and the metabolic syndrome is dependent on exercise modalities and independent of weight loss. Nutr Metab Cardiovasc Dis 2010; 20: 608–617. 34 Ko CW, Napolitano PG, Lee SP et al. Physical activity, maternal metabolic measures, and the incidence of gallbladder sludge or stones during pregnancy: a randomized trial. Am J Perinatol 2014; 31: 39–48.
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Supporting Information Additional Supporting Information may be found in the online version of this article: Table S1. Exercise in obese pregnant women.
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DOI: 10.1111/ajo.12300
Original Article
Exercise in pregnancy does not alter gestational weight gain, MCP-1 or leptin in obese women Marloes DEKKER NITERT,1,2 Helen L. BARRETT,1,2 Kerina J. DENNY,3 H. David MCINTYRE,1,4 and Leonie K. CALLAWAY1 for the BAMBINO group 1
School of Medicine, The University of Queensland, 2UQ Centre for Clinical Research, The University of Queensland, Herston, 3School of Biomedical Science, The University of Queensland, St Lucia, and 4Mater Health Services, South Brisbane, Queensland, Australia
Background: Increasing physical activity in pregnancy may improve pregnancy outcomes for obese women. Exercise could reduce gestational weight gain, improve the maternal circulating lipid profile as well as alter leptin, Interleukin-8 (IL-8) and Monocyte Chemoattractant Protein-1 (MCP-1) levels. Aim: The aim of this study was to investigate the effects of exercise on gestational weight gain, maternal circulating lipids, IL-8, MCP-1 and leptin levels in obese pregnant women. Materials and Methods: The analysis was performed in the 35 obese women enrolled in the pilot BAMBINO randomised controlled trial who provided blood samples at 12- and 28-weeks gestation. Women in the exercise intervention arm received an individualised exercise plan. Blood samples, exercise diary and pedometer data were obtained at 12-, 20-, 28- and 36-weeks’ gestation. Cord blood was obtained at delivery. Results: Women in the exercise arm exercised more than those in the control arm (P = 0.038). There was no difference in gestational weight gain, excess gestational weight gain, MCP-1 and leptin levels between women in the exercise intervention (n = 19) or the control arm (n = 16). IL-8 was not detectable. Exercise did not alter the maternal lipid profile. Conclusions: The low level of physical activity achieved in obese women in the exercise intervention arm was insufficient to alter gestational weight gain, MCP-1, leptin or circulating lipid levels. Key words: exercise, gestational weight gain, lipids, obesity, pregnancy.
Introduction Maternal obesity is associated with an increased risk of pregnancy complications for both mother and baby. These complications include gestational diabetes, pre-eclampsia, macrosomia, admittance to special nursery and future metabolic and cardiovascular disease for mother and baby.1 Gestational weight gain (GWG) within the limits set by the Institute of Medicine reduces the likelihood of pregnancy complications.2 For women with a body mass index (BMI) >30 kg/m2, a healthy gestational weight gain is between 5 and 9 kg over the course of the pregnancy.2 Strategies to limit GWG usually focus on reducing dietary intake, increasing moderate physical activity or a combination of those. There have been a number of lifestyle intervention studies in overweight and obese
Correspondence: Dr Marloes Dekker Nitert, UQCCR level 7, School of Medicine, RBWH Campus, The University of Queensland, Butterfield Street, Herston, Qld 4029, Australia. Email: [email protected] Received 31 August 2014; accepted 11 November 2014.
pregnant women that have evaluated GWG: some studies reported an overall reduction in GWG,3–5 one reported reduced rates of excess GWG, but no overall reduced GWG6 and four reporting no effect on GWG.7–10 Recently, the results of the large LIMIT randomised controlled trial (RCT) of intensive dietary and lifestyle interventions in pregnancy in overweight and obese women showed no effect on GWG or on excess GWG.11 Increasing or maintaining physical activity can be a strategy for limiting GWG. A Cochrane meta-analysis of aerobic exercise during pregnancy concluded that regular exercise appears to improve or maintain physical fitness, but the heterogeneity of the data precluded statistical analysis of physical fitness or any maternal and infant outcomes.12 A meta-analysis of the effects of exercise interventions during pregnancy to prevent gestational diabetes concluded that physical exercise was not a successful strategy to prevent gestational diabetes mellitus.13 Many of the studies included in these meta-analyses are relatively small in size and difficult to compare due to the large heterogeneity in the intervention strategies. Physical activity in pregnancy may have beneficial effects even in the absence of an effect on GWG or gestational
© 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists The Australian and New Zealand Journal of Obstetrics and Gynaecology
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diabetes mellitus. Exercise may result in a lower circulating triglycerides, as it does outside pregnancy.14 Outside pregnancy, exercise increases the release of a number of cytokines from skeletal muscle cells,15 which can account for exercise-associated immune and metabolic changes. One of these cytokines is Interleukin-8 (IL-8), which can stimulate angiogenesis and is increased in response to vigorous exercise that involves eccentric muscle contractions such as running. Monocyte Chemoattractant Protein-1 (MCP-1) is another cytokine that is increased in skeletal muscle samples from lean, obese and type 2 diabetes subjects after a bout of moderate-intensity aerobic exercise.16 Furthermore, exercise may affect the levels of the satiety hormone leptin. In the nonpregnant population, most studies have shown no change in leptin levels acutely following exercise, but there is some evidence for a delayed reduction in leptin following an exercise episode and the duration of the training session and length of the exercise intervention is likely important.17 In pregnancy, there is a steady increase in maternal serum-free leptin levels, which reaches a plateau in the late second or early third trimester. The increase in leptin is due to placental production, which outside pregnancy is mainly synthesised in adipose tissue.18 High leptin levels may contribute to altered satiety signalling in the brain and increased leptin resistance, which may serve to increase maternal energy intake in order to cover the energy needs of the growing fetus.19 In the placenta, leptin regulates many processes, including increased lipolysis20 and amino acid transport.21 Serum-free leptin levels are increased in obesity.22 The hypothesis of this study was that in obese pregnant women, exercise reduces GWG, improves the circulating lipid profile and decreases maternal leptin levels in the circulation. The aim of this study was to firstly analyse whether an exercise intervention reduces GWG in obese pregnant women participating in a pilot RCT of exercise to prevent gestational diabetes mellitus. The second aim was to investigate whether physical activity alters maternal and cord blood lipid profiles as well as IL-8, MCP-1 or leptin levels in obese pregnant women.
Written informed consent was obtained from all study participants. This study was approved by the Royal Brisbane and Women’s Hospital Human Research Ethics committee. This trial was registered with the Australian Clinical Trials Registry (accession number ACT RN012606000271505).
Intervention At 12-weeks’ gestation, all participants attended a group education session where written information on exercise,24 nutrition25 and adequate GWG was provided. The exercise intervention consisted of an individualised exercise plan meeting the specified energy expenditure requirements based on personal preferences and ability, monthly face-to-face exercise advice by physiotherapists and paper-based diaries for self-monitoring of activity. Women not meeting the specified energy expenditure requirements were offered additional face-to-face support to identify barriers and alterations to the exercise plan.
Outcome measures At baseline (12 weeks), 20-, 28- and 36-weeks’ gestation, the study participants had review visits with research midwives and physiotherapists. At each visit, participants completed the Pregnancy Physical Activity Questionnaire (PPAQ),26 which is a validated questionnaire for occupational, household, sedentary and exercise energy expenditure in pregnancy. Energy expenditure is expressed in kCal/week. Additionally, overnight fasting blood samples and anthropometric measurements were obtained at each time-point. At baseline and 28-week gestation, a 75 g fasting oral glucose tolerance was performed; an additional fasting serum sample was obtained at these time-points and stored at 20°C until analysis. At delivery, cord blood was obtained for the analysis of metabolic parameters in EDTA and SST tube, spun and stored at 20°C until analysis. Within three days of delivery, neonatal anthropometric and skinfold measurements were performed. The analysis is restricted to those women who completed the 36-weeks follow-up: 16 women in the control arm, 19 women in the exercise intervention arm.
Materials and Methods Participants
Metabolic measurements
In the pilot BABMINO study, 50 obese pregnant women (BMI ≥ 30 kg/m2) were recruited at 12-weeks’ gestation and equally randomised to an individualised exercise intervention (described below) or standard obstetric care until delivery. The inclusion and exclusion criteria for enrolment have been described previously.23 Women were randomised to the intervention or standard care arm by random number allocation through an external service. Stratification of the randomisation was based on BMI (≤40 or >40 kg/m2) and parity (0 or ≥1). GWG, blood lipid and leptin levels were not outcomes of the original BAMBINO pilot RCT.
Fasting glucose (oxygen rate method), insulin (chemiluminescent immunoassay, DxI 800 Immunoassay system; Beckman Coulter, Brea, CA, USA), triglycerides (Beckman DXC800), total, HDL and LDL cholesterol (Beckman DXC800) were analysed with standard assays by the pathology department of the Royal Brisbane and Women’s Hospital. At baseline and 28-weeks’ gestation, IL-8, MCP-1 and leptin were measured in the additional serum samples of 12 women in the control arm and 15 women in the exercise intervention arm with the Human Serum Adipokine panel B MilliplexTM ELISA (HADK261K-B; Millipore, St Charles, MO, USA). This method is
28
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Exercise effects in obese pregnancy
based on simultaneous analysis of multiple analytes through the coupling of specific immunoassays to the surface of fluorescent-coded beads. Undiluted samples were measured in duplicate and quantitated against a standard curve of known concentrations.
Statistics The analysis was done on per-protocol basis only, including those women who completed all study visits and supplied both fasting blood samples. Continuous variables are summarised as mean standard deviation for parametric data and as median interquartile range for nonparametric data. Comparisons between the women in the exercise and control arms were performed by repeated measures ANOVA. Proportions were compared by Fisher’s exact test. P < 0.05 was considered statistically significant.
Results Maternal effects In this study, 19 obese women completed an exercise intervention during pregnancy from 12-weeks’ gestation until delivery with 16 obese pregnant women randomised to routine care as a comparison. Table 1 lists maternal characteristics throughout the pregnancy. Exercise did not significantly alter GWG (controls 8.28 6.10 vs exercise 7.87 4.00 kg, P = 0.81). The proportion of women who exceeded the IOM guidelines for gestational weight gain (gained >9.07 kg) was 43.8% in the control group
and 47.4% in the intervention group (P = 1.00). Exercise did not alter maternal blood glucose, insulin, triglyceride, total, HDL or LDL cholesterol levels at any stage of pregnancy. Maternal leptin levels increased significantly from baseline to 28-week gestation (12 weeks 30.2 (interquartile range 24.9–47.7) vs 28 weeks 49.7 (40.5–68.1) lg/mL, P = 0.003; Fig. 1A). However, there was no difference in maternal leptin (Fig. 1A) or MCP-1 (Fig. 1B) concentrations between women in the exercise or control arm of the study. Circulating maternal IL-8 levels were below the limit of detection at both baseline and 28-weeks gestation.
Physical activity during pregnancy All obese pregnant women who completed the study had low levels of physical activity throughout pregnancy (Table S1). Figure 2 shows the physical activity attributed to exercise in obese pregnant women over the course of pregnancy. The pattern is similar for women randomised to the exercise and the control arm of the study with a doubling in energy expenditure attributable to exercise at 20-weeks gestation that returned to baseline levels at 36-weeks gestation (P < 0.001 for changes over gestation). Women in the exercise intervention arm had higher energy expenditure from exercise activity (P = 0.038).
Infant outcomes Maternal exercise during pregnancy did not change any of the neonatal outcomes nor did it affect cord blood
Table 1 Maternal characteristics
n Age (years) Weight (kg) Gestational weight gain (kg) Body mass index (kg/m2) SBP (mmHg) DBP (mmHg) Fasting glucose (mmol/L) Fasting insulin (lU/mL) Fasting Cholesterol (mmol/L) Fasting Triglycerides (mmol/L) Fasting HDL cholesterol (mmol/L) Fasting LDL cholesterol (mmol/L)
Baseline control
Baseline exercise
20-Weeks control
20-Weeks exercise
28-Weeks control
28-Weeks exercise
36-Weeks control
36-Weeks exercise
16 30.3 (5.6) 97.1 (23.4) –
19 30.8 (4.9) 96.9 (24.0) –
16 – 98.3 (23.5) 1.45 (2.45)
19 – 97.7 (24.1) 1.45 (2.05)
16 – 101.7 (21.4) 4.62 (4.36)
19 – 102.3 (23.5) 5.35 (2.84)
16 – 105.4 (20.8) 8.28 (6.10)
19 – 104.8 (24.6) 7.87 (4.00)
35.6 (9.0)
35.8 (7.3)
36.2 (9.0)
35.9 (7.5)
37.2 (8.2)
37.5 (7.1)
38.56 (7.9)
38.45 (7.2)
112 (12) 65 (6) 4.5 (0.3)
110 (10) 67 (9) 4.5 (0.4)
107 (12) 66 (7) 4.4 (0.5)
110 (10) 67 (8) 4.3 (0.4)
108 (11) 65 (7) 4.6 (0.4)
112 (7) 66 (4) 4.4 (0.5)
114 (13) 70 (10) 4.3 (0.7)
115 (11) 71 (9) 4.2 (0.5)
11.7 (4.4)
14.5 (9.8)
11.0 (4.28)
11.0 (4.3)
15.3 (6.4)
15.3 (5.8)
18.9 (10.8)
16.0 (9.0)
5.2 (0.8)
5.0 (0.8)
6.2 (1.0)
6.0 (0.9)
6.8 (1.2)
6.5 (1.1)
7.5 (1.4)
6.6 (1.1)
1.2 (0.3)
1.4 (0.6)
1.6 (0.5)
1.9 (0.5)
2.0 (0.6)
2.2 (0.6)
2.7 (1.1)
2.7 (0.7)
1.9 (0.5)
1.8 (0.4)
2.2 (0.6)
2.0 (0.4)
2.1 (0.7)
2.0 (0.5)
1.9 (0.6)
1.7 (0.4)
2.7 (0.7)
2.5 (0.7)
3.3 (0.9)
3.1 (0.9)
3.7 (1.0)
3.5 (1.0)
4.3 (1.3)
3.6 (1.0)
SBP, systolic blood pressure; DBP, diastolic blood pressure. Data are represented as mean (SD). © 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists
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(A)
(B)
Figure 1 Maternal serum levels of leptin (A) and MCP-1 (B) measured at baseline (BL) and 28-week gestation (28) in obese pregnant women. Boxes represent median and IQR with whiskers at 2.5 and 97.5 centile. White boxes, women randomised to the control arm (n = 12); dark grey boxes, women randomised to the exercise intervention arm (n = 15); light grey boxes, all pregnant obese women (n = 27). **P < 0.01.
Table 2 Infant characteristics Control
Figure 2 Exercise activity of obese pregnant women in the BAMBINO trial throughout gestation. White circles, women in the control arm (n = 16); grey squares, women in the exercise intervention arm (n = 19).
concentrations of glucose, insulin, triglycerides or cholesterol (Table 2). More women in the exercise intervention group were delivered by caesarean section, but this was not significantly different from the control group (Fisher’s exact test, RR = 0.56 (CI 0.21–1.48), P = 0.3).
Discussion This pilot exercise intervention study in obese pregnant women showed that exercise at the levels achieved does not reduce overall or excessive GWG in this cohort. Physical activity did not alter circulating lipids, MCP-1 or leptin. We have previously reported that in this cohort, exercise did not alter the HOMA-IR index even though it increased energy expenditure.23
Gestational weight gain Exercise interventions have been reported to have mixed effects on GWG. One recent RCT study of 224 pregnant women showed that a combined dietary and physical activity interventions reduced the proportion of women with excessive GWG in pregnancy from 54% to 35% in the intervention group.6 However, there was no significant effect on overall mean GWG, similar to our findings.6 30
n Gestational age delivery (days) Five minute Apgar score C-section (n) (% of group) Birth weight (g) Length (cm) Head circumference (cm) Abdominal circumference (cm) Mid upper arm circumference (cm) Triceps skinfold thickness (mm) Subscapular skinfold thickness (mm) Cord glucose (mmol/L) Cord insulin (lU/mL) Cord Cholesterol (mmol/L) Cord Triglycerides (mmol/L) Cord HDL cholesterol (mmol/L) Cord LDL cholesterol (mmol/L)
16 277.9 9.1 4 3597 50.5 34.5 33.5 11.8 5.3 4.8 5.0 6.4 1.5 0.4 0.6 0.7
(8.4) (0.4) (25%) (304) (1.8) (1.3) (2.0) (0.6) (1.1) (0.5) (1.4) (5.6) (0.4) (0.1) (0.2) (0.2)
Exercise 19 278.4 9.0 9 3548 50.6 34.6 33.2 11.3 4.9 4.7 4.3 7.6 1.7 0.4 0.6 0.9
(9.8) (0.3) (47%) (459) (2.2) (2.0) (1.8) (1.0) (1.1) (0.9) (1.3) (6.0) (0.5) (0.1) (0.2) (0.3)
Data are represented as mean (SD).
Another RCT of combined dietary and physical activity intervention in 100 pregnant women also reported no difference in overall GWG: of the obese women only 20% and 33% adhered to IOM guidelines in the control and intervention group, respectively.8 A significant reduction in excessive GWG and postpartum weight retention in 65 overweight and obese women was reported in a Canadian study combining an individualised walking intervention and a nutritional intervention when compared to a matched historical cohort.4 This program started at 16- to 20-weeks gestation when many of the participants with excessive GWG already had gained in excess of the IOM guidelines at study entry. A Swedish intervention of diet and physical activity in 155 obese women also showed a significant decrease in GWG in the intervention group which was associated with less postnatal weight retention than those 193 women who were cluster-randomised to standard care.3 Many of these studies unfortunately do not report the actual amount of physical activity, which precludes exact comparisons of the effects between
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studies. However, most exercise intervention studies, including our study, do not start until the second trimester for practical reasons. Since many women already start gaining excessive weight in their first trimester,4 exercise interventions likely need to begin very early in pregnancy or perhaps prepregnancy to achieve maximal effects. First trimester symptoms, including nausea, vomiting and extreme fatigue should be taken into account when designing these interventions.27,28 Our results indicated that, as pregnancy progresses, exercise becomes harder to accomplish, again emphasising the need for starting exercise early in pregnancy.
Circulating metabolic markers Triglyceride levels increase over the course of pregnancy independent of physical activity.29 In this study, we saw a similar rise in maternal triglycerides, total cholesterol and LDL cholesterol over the course of pregnancy independent of intervention allocation. Exercise did not alter maternal lipid profiles. A recent RCT study showed that a combined dietary and physical activity intervention reduced the intake of total calories, total fat, saturated fat and cholesterol in pregnancy in the intervention group.6 However, this RCT did not measure cord blood metabolic markers, and it is unclear if the changes in diet would change the levels of lipids in cord blood. In our study, there were no differences in cord blood glucose and insulin levels between the study arms. Cord blood insulin concentrations in our study were higher than those reported for infants of normal-weight mothers, whereas cord blood glucose levels were similar.7,30,31 However, they are similar to the levels previously reported in obese women32 and likely are a reflection of fetal insulin resistance.
Leptin levels In the nonpregnant population, the concentrations of the satiety hormone leptin decrease with long-term exercise.33 In this study, we did not find an effect of exercise on maternal leptin levels. It is not clear if the lack of effect of exercise on free leptin levels was the result of the relatively low levels of physical activity achieved by the pregnant women in this cohort or if the free leptin levels mainly reflect placental leptin secretion, which may not be regulated by physical activity. A lack of effect of exercise on leptin levels during pregnancy has been shown previously: in a study of aerobic stationary cycling training during pregnancy from 20- to 35-week gestation, there was a significant decrease in birth weight but not body composition in the exercise intervention group with no differences in leptin levels between the exercise and the control arms.30 Another exercise intervention study in women in the US military also reported an increase in leptin levels over the course of pregnancy but no effect of exercise.34 The leptin levels reported in these studies were lower than in our study, but this likely due to the difference in mean BMI: around 25
versus 35.7 kg/m2 in our cohort. Higher leptin levels in obese pregnant women, similar to the levels measured in this study, have been reported previously.32 The increase in serum-free leptin levels is similar in obese and normalweight pregnancy, but the starting point is higher in obese women. Prepregnancy leptin resistance may further affect leptin’s actions in the placenta during pregnancy.35 Furthermore, circulating leptin levels are correlated with the level of insulin resistance in pregnancy,36 which is likely to be high in this cohort.
MCP-1 and IL-8 levels MCP-1 is a pro-inflammatory adipokine which is increased in obesity,37,38 MCP-1 is also synthesised in skeletal muscle cells and circulating MCP-1 is increased after exercise.38 MCP-1 enhances the recruitment of monocytes and T lymphocytes into tissues and promotes insulin resistance. Furthermore, high glucose concentrations increase MCP-1 secretion from endothelial cells.39 The placenta synthesises IL-8 and MCP-1. Maternal MCP-1 levels at baseline in this study are very similar to the levels previously reported for women with a BMI > 30 kg/m2.37 Previously, it has been reported that the differences in MCP-1 levels between obese and normal-weight women present in early pregnancy – with the obese women having higher MCP-1 concentrations – disappeared in late pregnancy.37 This was due to an increase in MCP-1 levels in normal weight women with the progression of pregnancy which was not evident in obese women who at baseline already were in a more inflammatory state. The change in MCP-1 levels was independent of GWG.37 In our study, no change in MCP-1 levels was observed over the course of pregnancy in our cohort of obese women and no effect of exercise was noted. However, the increases in circulating MCP-1 levels after exercise may be transient and disappear after acute exercise,38 which could explain the lack of effect of exercise in our cohort as could the amount and intensity of the exercise. The adipo-myokine IL-8 has increased expression in visceral adipose tissue in people with insulin resistance as well as in type 2 diabetes. Furthermore, circulating IL-8 levels correlate with measures of insulin resistance. Moderately vigorous exercise reduces plasma IL-8 concentrations in obese individuals.40 However, IL-8 could not be reliably detected in the serum of obese pregnant women at any stage of pregnancy in this study.
Study limitations The BAMBINO cohort is a pilot cohort of relatively small size. The level of actual exercise – as measured by diary, questionnaires and pedometer – was low and may have affected the lack of changes measured. Furthermore, as shown in Figure 2, the women randomised to the control group also increased their level of physical activity, which further reduces the power of the study to detect differences. GWG changes to blood lipids and leptin levels
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were not primary or secondary outcomes for the BAMBINO trial, and therefore, the sample size may be insufficient to detect small differences. While the sample size of this study is small, the results are in line with those of other studies,6–8 indicating the difficulties in affecting changes through exercise in obese pregnant women.
10
11
Conclusion In summary, in our cohort of obese pregnant women, an exercise intervention did not affect maternal overall GWG and excess GWG, maternal blood lipids or circulating levels of MCP-1 and leptin. The overall level of physical activity of obese pregnant women is low. These results indicate that the levels of physical activity achieved need to be significant in order to be effective.
12 13
14
15
Acknowledgements The collaborators on the BAMBINO project are gratefully acknowledged for their contributions to the trial: Katie Foxcroft, Barbara Lingwood, Paul Colditz, Nuala Byrne, Ingrid Rowlands, Ainsley Groves, Xanthe Sansome, Briony O’Connor and Susan Croaker. This study was funded by a Royal Brisbane and Women’s Hospital Foundation strategic initiative grant.
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Supporting Information Additional Supporting Information may be found in the online version of this article: Table S1. Exercise in obese pregnant women.
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