Scholarly article on topic 'Exercise improves glycaemic control in women diagnosed with gestational diabetes mellitus: a systematic review'

Exercise improves glycaemic control in women diagnosed with gestational diabetes mellitus: a systematic review Academic research paper on "Health sciences"

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Journal of Physiotherapy
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{Exercise / "Gestational diabetes" / "Blood glucose" / Pregnancy / "Systematic review"}

Abstract of research paper on Health sciences, author of scientific article — Anne L Harrison, Nora Shields, Nicholas F Taylor, Helena C Frawley

Abstract Question: Does exercise improve postprandial glycaemic control in women diagnosed with gestational diabetes mellitus? Design: A systematic review of randomised trials. Participants: Pregnant women diagnosed with gestational diabetes mellitus. Intervention: Exercise, performed more than once a week, sufficient to achieve an aerobic effect or changes in muscle metabolism. Outcome measures: Postprandial blood glucose, fasting blood glucose, glycated haemoglobin, requirement for insulin, adverse events and adherence. Results: This systematic review identified eight randomised, controlled trials involving 588 participants; seven trials (544 participants) had data that were suitable for meta-analysis. Five trials scored ≥ 6 on the PEDro scale, indicating a relatively low risk of bias. Meta-analysis showed that exercise, as an adjunct to standard care, significantly improved postprandial glycaemic control (MD –0.33mmol/L, 95% CI –0.49 to –0.17) and lowered fasting blood glucose (MD –0.31 mmol/L, 95% CI –0.56 to –0.05) when compared with standard care alone, with no increase in adverse events. Effects of similar magnitude were found for aerobic and resistance exercise programs, if performed at a moderate intensity or greater, for 20 to 30minutes, three to four times per week. Meta-analysis did not show that exercise significantly reduced the requirement for insulin. All studies reported that complications or other adverse events were either similar or reduced with exercise. Conclusion: Aerobic or resistance exercise, performed at a moderate intensity at least three times per week, safely helps to control postprandial blood glucose levels and other measures of glycaemic control in women diagnosed with gestational diabetes mellitus. Registration: PROSPERO CRD42015019106. [Harrison AL, Shields N, Taylor NF, Frawley HC (2016) Exercise improves glycaemic control in women diagnosed with gestational diabetes mellitus: a systematic review. Journal of Physiotherapy 62: 188–196]

Academic research paper on topic "Exercise improves glycaemic control in women diagnosed with gestational diabetes mellitus: a systematic review"

Journal of

PHYSIOTHERAPY

journal homepage www.elsevier.com/locate/jphys

Research

Exercise improves glycaemic control in women diagnosed with gestational

diabetes mellitus: a systematic review

Anne L Harrison a,b, Nora Shields a,c, Nicholas F Taylora,d, Helena C Frawleya,e

a School of Allied Health, La Trobe University; b Physiotherapy Department, Werribee Mercy Hospital;c Northern Health; d Allied Health Clinical Research Office, Eastern Health;

e Centre for Allied Health Research and Education, Cabrini Health, Melbourne, Australia

KEY WORDS

ABSTRACT

Exercise

Gestational diabetes Blood glucose Pregnancy Systematic review

Question: Does exercise improve postprandial glycaemic control in women diagnosed with gestational diabetes mellitus? Design: A systematic review of randomised trials. Participants: Pregnant women diagnosed with gestational diabetes mellitus. Intervention: Exercise, performed more than once a week, sufficient to achieve an aerobic effect or changes in muscle metabolism. Outcome measures: Postprandial blood glucose, fasting blood glucose, glycated haemoglobin, requirement for insulin, adverse events and adherence. Results: This systematic review identified eight randomised, controlled trials involving 588 participants; seven trials (544 participants) had data that were suitable for metaanalysis. Five trials scored > 6 on the PEDro scale, indicating a relatively low risk of bias. Meta-analysis showed that exercise, as an adjunct to standard care, significantly improved postprandial glycaemic control (MD -0.33 mmol/L, 95% CI -0.49 to -0.17) and lowered fasting blood glucose (MD -0.31 mmol/L, 95% CI -0.56 to -0.05) when compared with standard care alone, with no increase in adverse events. Effects of similar magnitude were found for aerobic and resistance exercise programs, if performed at a moderate intensity or greater, for 20 to 30 minutes, three to four times per week. Meta-analysis did not show that exercise significantly reduced the requirement for insulin. All studies reported that complications or other adverse events were either similar or reduced with exercise. Conclusion: Aerobic or resistance exercise, performed at a moderate intensity at least three times per week, safely helps to control postprandial blood glucose levels and other measures of glycaemic control in women diagnosed with gestational diabetes mellitus. Registration: PROSPERO CRD42015019106. [Harrison AL, Shields N, Taylor NF, Frawley HC (2016) Exercise improves glycaemic control in women diagnosed with gestational diabetes mellitus: a systematic review. Journal of Physiotherapy XX: XX-XX] © 2016 Australian Physiotherapy Association. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Gestational diabetes mellitus (GDM) is carbohydrate or glucose intolerance of variable severity that has its onset during pregnancy.1,2 It is diagnosed through laboratory screening, using a pregnancy oral glucose tolerance test that is performed between

24 and 28 weeks gestation.1,3 GDM is a common complication of pregnancy, with an incidence ranging from 3.5 to 12%; it also has an increasing prevalence.1,4-7 If poorly controlled, GDM results in hyperglycaemia,1,2 which affects both the mother and the developing baby. The short-term adverse consequences of hyperglycaemia may include hypertension and pre-eclampsia for the mother, and birth trauma from macrosomia (ie, excessive birth weight) for the baby.1,7 GDM also has longer-term health implications. For the mother, these include a 35 to 50% increase in risk of recurrence of GDM in subsequent pregnancies,8 with a seven-fold increased risk of developing type 2 diabetes mellitus.9 For the child of a GDM pregnancy, there is an increased risk of obesity and type 2 diabetes mellitus later in life,10,11 and those born with macrosomia have an increased lifetime risk of cardiovascular disease12 and an increased risk of leukaemia.13

For these reasons, the increasing rate of GDM has public health ramifications.14,15

Glycaemic control is a critical factor in combatting the adverse effects associated with poorly controlled GDM.6 Management of GDM typically consists of dietary modifications, regular self-monitoring of postprandial (ie, post-meal) acute capillary blood glucose levels3 and - where diet modification does not achieve euglycaemia - insulin therapy.16-18 There is strong evidence that exercise, particularly structured aerobic and/or resistance training, is a beneficial adjunctive therapy in the management of type 2 diabetes mellitus through its ability to increase glucose uptake and improve insulin sensitivity.19-24 Exercise, particularly activation of large muscles such as the quadriceps, stimulates glucose uptake in muscle, increases energy expenditure and improves glucose transportation, which results in improved glucose tolerance.22,25 Exercise is associated with a reduction of glycated haemoglobin (HbA1c), a measure of the average plasma glucose in the longer term (2 to 3 months), in people with type 2 diabetes mellitus;26,27 it is optimised by training of 150 minutes or more per week at moderate intensity.21,28 Exercise is also recommended as beneficial for women with uncomplicated pregnancies.29-31

http://dx.doi.org/10.1016/jjphys.2016.08.003

1836-9553/© 2016 Australian Physiotherapy Association. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

However, to date, the evidence regarding the benefits of exercise for the management of GDM has been equivocal - largely due to small sample sizes and heterogeneity of exercise type and outcome measures. In addition, the synthesis of the evidence on the benefits of exercise for the management of GDM has been limited to a review completed almost a decade ago.32

Several international guidelines and reviews recommend exercise in the management of GDM.4,16,33-35 While these guidelines recommend exercise as an adjunct to standard GDM care, there has not been supporting evidence from a systematic review with meta-analysis of the effects of exercise on postprandial blood glucose levels. There is good justification for postprandial glucose levels to be the main outcome of interest among this population due to the continuous relationship with macrosomia and birth defects.1,2,7,16 Fasting blood glucose levels and HbAlc are, however, important as secondary outcomes because, other than their established physiological relevance to complications of diabetes,15 some trials may only include these measures rather than an oral glucose tolerance test (OGTT).

Therefore, the research questions for this systematic review were:

1. Can adjunctive exercise improve the acute postprandial control of blood glucose in women diagnosed with GDM when compared with standard GDM care?

2. Does adjunctive exercise improve fasting blood glucose levels and the longer-term measure, HbA1c, in women diagnosed with GDM when compared with standard GDM care?

3. What are the characteristics of exercise programs that are effective in lowering postprandial blood glucose levels for women with GDM and the variables affecting adherence to exercise?

Method

The review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.36

Identification and selection of studies

One reviewer (AH) performed a search of the following electronic databases from the earliest possible date (ie, from database inception) until November 2015: AMED, CINAHL, Medline, Embase, Psyclnfo, Cochrane Library, PEDro, SPORTDiscus, Joanna Briggs Institute and Trip. To ensure full representation of the evidence, no search limitations were used. The search strategy consisted of four key concepts: GDM, physical activity, blood glucose and randomised, controlled trials. For each concept, key words and MeSH search terms were combined with the 'OR' operator. The results of the searches of the four key concepts were combined with the 'AND' operator. An example of the search strategy is presented in Appendix

1 on the eAddenda. Reference lists from the included studies were

manually searched and relevant articles were screened and

reviewed for possible inclusion. Using Google Scholar and Web of

Science, citation tracking was also performed on the included

articles to identify any additional, relevant articles.

Two reviewers (AH and HF or NT) independently reviewed the

title and abstracts of the articles yielded by the search, according to

the inclusion criteria presented in Box 1 and the exclusion criteria

outlined below. lf eligibility was unclear from the review of title

and abstract, full text was obtained and reviewed by two

researchers working independently. Disagreements were resolved

by discussion between reviewers.

Assessment of characteristics of studies

Participants

Trials were excluded if the participants had existing type 1 or

type 2 diabetes. This was because the aetiologies are somewhat

Box 1. Inclusion criteria. Design

• Randomised, controlled trial

• Full-text articles published in English in a peer-reviewed journal

Participants

• Pregnant women diagnosed with GDM a during the current pregnancy

Intervention

• Cardiovascular exercise or strengthening exercises sufficient to achieve aerobic effect or changes in muscle metabolism b

• Exercise performed more than once a week c

• Exercise in any setting Primary outcome measure

• Self-monitored postprandial blood glucose levels Secondary outcome measures

• Fasting blood glucose levels

• HbA1c

• Requirement for insulin Comparisons

• Standard care of GDM, including diet and/or insulin

a GDM, as diagnosed by a pregnancy oral glucose tolerance test performed at 24 to 28 weeks1,3

b Based on the American College of Sports Medicine & American Diabetes Association joint position statement19

c Chosen to exclude single bouts of exercise but to keep search broad, as aiming to identify sufficient exercise to improve self-monitored postprandial blood glucose levels.

different or, at least, the aetiology may be only transient in GDM and because the chronic physiological effects of longer-term diabetes could confound findings.1,35

Intervention

As the minimum level of exercise to improve self-monitored postprandial blood glucose levels is not well established, the inclusion criteria for this review were set broadly to include trials of interventions with exercise frequency greater than weekly. If individual studies provided an exercise intervention dosage that met the recommended guidelines,19 then it was considered that the exercise intervention would provide sufficient stimulus to achieve aerobic effect or changes in muscle metabolism. lt was acceptable for the exercise intervention to be combined with dietary modification and insulin, as required, along with self-monitoring of blood glucose; this is considered standard care for women diagnosed with GDM.7,16,33,35

Outcome measures

As outlined in Box 1, postprandial glucose levels, fasting blood glucose levels and HbA1c were the outcome measures chosen to reflect treatment of existing GDM. Because the primary aim of this review was to evaluate the treatment effect of exercise on postprandial control of glycaemia in women with GDM, not to prevent it, trials were excluded if prevention of GDM was an outcome measure.

Risk of bias

Risk of bias was assessed using the Physiotherapy Evidence Database (PEDro) scale.37 This scale scores the risk of bias of studies out of 10, providing a comprehensive description for each item to improve inter-rater reliability37 and is considered a valid and reliable tool for measuring methodological quality.38,39 For the purposes of this review, trials achieving a PEDro score of > 6 were considered as being at low, or slightly greater than low, risk of bias.40 Two reviewers (AH and NS) assessed the risk of bias independently. Disagreements between allocated scores were resolved by discussion.

Figure 1. Flow of studies through the review.

Data extraction and analysis

Data were extracted from each included article using a standardised data extraction form. Data were extracted by one reviewer (AH), and checked by a second reviewer (HF). The extracted data included: authors, year of publication, sample size, demographic information about the participants (age, gestation at inclusion, parity, history of previous GDM, body mass index, socioeconomic status, cultural background/ethnicity), the intervention (exercise type, frequency, intensity, session duration, mode, duration of intervention program), results (postprandial blood glucose levels, fasting blood glucose levels, glycated haemoglobin levels, adverse events, adherence rates) and study conclusions. Authors were contacted for missing data when it was related to the primary outcome of the review. To provide homogeneous unit measures, postprandial blood glucose levels and fasting blood glucose levels were converted using an online blood sugar conversion calculator41 from mg/dL units into mmol/L.

Meta-analyses were conducted using RevMan42 to pool the data. As the units of the measure within each outcome were common, a mean difference (MD) measure of effect was calculated. A random-effects model was used to ensure a conservative

estimate of the meta-analysed effect estimate of the MD with 95% confidence intervals (95% CI).43 A meta-analysis using odds ratios (OR) with a random-effects model was conducted to compare the effect of adjunctive exercise versus standard GDM care on the proportion of participants requiring insulin therapy. The characteristics of exercise programs and adherence to the exercise programs were synthesised descriptively.

Results

Flow of studies through the review

The initial search yielded 351 articles (Figure 1). The yield included three papers that were published in languages other than English; however, as titles and abstracts for all three papers were

available in English, they were included in the screening process. None of these three papers was a randomised, controlled trial and

therefore all were ineligible. Through reference checking and

citation tracking, four additional articles were identified by title. On review of these abstracts, all were excluded: two because they were not randomised, controlled trials, one because the outcomes related to the foetus, and the other because the intervention was a single bout of exercise. Following the screening process, eight trials were included in the review (Figure 1).

Characteristics of included studies

Risk of bias

Table 1 provides the details of the PEDro scoring for risk of bias. These trials involved an exercise intervention, so it was not anticipated that it would be possible to blind either participants or therapists; therefore, the maximum score expected was 8/10. Five of the eight trials scored > 6 on the PEDro scale, representing a low, or slightly greater than low, risk of bias.

Participant characteristics

The mean age of participants in the included trials ranged from 31 to 33 years (Table 2, and for more detailed data about the characteristics of the participants, see Table 3 on the eAddenda).44-

51 Consistent with standard diagnostic testing for GDM occurring between 24 to 28 weeks, participants were recruited from 24 weeks gestation through to 31 weeks gestation. Parity and past history of GDM (with previous pregnancies) were reported in two of the trials.46,51 Five trials provided mean pre-pregnancy body mass index with a range of 25.4 to 27.6 kg/m2.44-47,50

Intervention characteristics

The exercise interventions were all low impact, but the type of exercise varied (Table 2, and for more detailed data about the characteristics of the interventions, see Table 4 on the eAddenda). Two trials used circuit-type resistance training,44,45 two trials used cycling on upright cycle ergometers46,47 (one of which combined cycling with walking47), one trial used a recumbent cycle ergometer48 and another trial used an arm ergometer.49 Of the two remaining trials, one used brisk walking50 and the other used yoga as the exercise intervention.51

Table 1

Risk of bias assessment - PEDro scores of included studies.

Trial Random Concealed Groups Participant Therapist Assessor <15% lntention- Intergroup Point estimate Total

allocation allocation similar at blinding blinding blinding dropouts to-treat comparison and variability Score

baseline analysis reported measures (0 to 10)

Avery47 Yes No Yes No No No No No Yes Yes 4

Bo50 Yes No Yes No No No Yes Yes Yes Yes 6

Brankston45 Yes Yes Yes No No No No Yes Yes Yes 6

Bung48 Yes No Yes No No No No No No Yes 3

de Barros44 Yes Yes Yes No No Yes Yes Yes Yes Yes 8

Halse46 Yes Yes Yes No No No Yes No Yes Yes 6

Jovanovic-Peterson49 Yes No No No No No Yes No Yes Yes 4

Youngwanichsetha51 Yes Yes Yes No No No Yes Yes Yes Yes 7

Table 2

Summary of included studies (n » 8).

Study Participantsa Intervention b Outcome measures

Avery47 n = 29 Exp = cycle ergometer, indiv, superv, 30 min x 2/wk x 6 wk (70% predHRmax) and • Postprandial BGL

USA Age (yr) = 31 (SD 5) walking, indiv, unsuperv, 30 min x 2/wk x 6 wk (70% predHRmax via Borg Scale) • Fasting BGL

Gestation (wk) = 28 (SD 4) Con = usual activity • Need for insulin

BMI (kg/m2) = 26.5 (SD 6.3) Both = usual diet

BGL (mmol/L) =10.3 (SD 1.1)

Bo50 n = 200 Exp = brisk walking, indiv, unsupervc, 20 minx 7/wkx ~25 wk(Borg 12 to 14) ± • Postprandial BGL

Italy Age (yr) = elig 18 to 50 behavioural advice d • Fasting BGL

Gestation (wk) = elig 24 to 26 Con = ± behavioural advice d • HbAlc

BMI (kg/m2) = 27.6 (SD 4.2) Both = individually prescribed diet • Need for insulin

BGL (mmol/L) = n/s

Brankston45 n = 32 Exp = circuit resistance ex, indiv, superv for 3 sessions then unsuperv c, 2 to • Postprandial BGL

Canada Age (yr) = 31 (SD 5) 3 sets x 15 to 20 reps x 3/wk x ~8 wk ('somewhat hard') • Fasting BGL

Gestation (wk) = 29 (SD 2) Con = usual activity • Need for insulin

BMI (kg/m2) = 26.5 (SD 4.1) Both »prescribed diet

BGL (mmol/L) = 9.8 (sD 1.2)

Bung48 n = 34 Exp = recumbent cycle ergometry, indiv, superv, 45 min x 3/wk x ~10 wk (50% • Fasting BGL

USA Age (yr) = 31 (SD 5) VO2max)

Gestation (wk) = 30 (SD 2) Con = insulin

BMI (kg/m2) = n/s Both »prescribed diet

BGL (mmol/L) = n/s

de Barros44 n = 64 Exp = circuit resistance ex, indiv, superv 2/wk and unsuperv 1/wk, 30 to 40 min x • Postprandial BGL

Brazil Age (yr) = 32 (SD 5) 3/wk x ~8 wk ('somewhat heavy') • Need for insulin

Gestation (wk) = 31 (SD 2) Con = usual activity

BMI (kg/m2) = 25.4 (SD 4.0) Both »prescribed diet

BGL (mmol/L) = 9.1 (sD 1.4)

Halse46 n = 40 Exp = home cycle ergometer, indiv, superv 3/wk and unsuperv 2/wk, 25 to • Postprandial BGL

Australia Age (yr) = 33 (SD 4) 45 min x 5/wk x ~6 wk (55 to 85% predHRmax) • Fasting BGL

Gestation (wk) = 29 (SD 1) Con = usual activity • HbA1c

BMI (kg/m2) = 25.8 (SD 6.9) Both = dietary advice • Need for insulin

BGL (mmol/L) = 8.8 (sD 1.1)

Jovanovic-Peterson49 n= 19 Exp = arm ergometer e, 20min x 3/wk x 6 wk (70% predHRmax) • Postprandial BGL

USA Age (yr) = 32 (SD 5) Con = usual activity • Fasting BGL

Gestation (wk) = n/s Both = diet • HbA1c

BMI (kg/m2) = n/s • Need for insulin

BGL (mmol/L) =10.2 (SD 0.9)

Youngwanichsetha51 n = 170 Exp=yoga breathing, postures and movements, indiv, some superv, 15 to • Postprandial BGL

Thailand Age (yr) = 32 (5) 20min x 5/wk x 8 wk (intensity n/s) + mindfulness eating • Fasting BGL

Gestation (wk) = elig 24 to 30 Con = usual care, including dietary advice • HbA1c

BMI (kg/m2) = n/s

BGL (mmol/L) = 9.9 (SD 1.1)

BGL=blood glucose level, BMI = body mass index, con = control group, elig=eligibility range, ex=exercise, exp = experimental group, indiv=individual, superv = supervised, unsuperv=unsupervised.

a Age and gestation are at enrolment, BMI is pre-pregnancy, and BGL is postprandial at enrolment. Where participant characteristics are not stated but similar measures were reported (eg, BMI at enrolment instead of pre-pregnancy), these are reported in Table 3 on the eAddenda. b For more detailed characteristics of the interventions, see Table 4 on the eAddenda. c Occasional phone call and/or visit.

d This trial was factorially randomised, meaning that half the participants in the exp and con groups were randomly allocated behavioural recommendations. e It was unclear whether the arm ergometry was individual or group exercise and whether it was supervised or unsupervised.

The frequency of exercise ranged from three to seven sessions per week. Exercise intensity was variable: four trials used an age-predicted heart rate maximum varying from 50 to 70%,46-49 two trials used Borg exertional scale ratings of 12 to 14,47,50,52 one trial used the OMNI exertional scale44,53 and one trial did not state the exercise intensity.51 Where descriptors of exertion were used, they were generally between 'moderate' and 'somewhat hard'. Exercise session durations ranged from 20 to 45 minutes, which included short warm-up and cool-down periods. Where specified, all of the exercise interventions were delivered in individual sessions. Two interventions were centre-based with direct supervision,47,48 four interventions were predominantly home-based with a combination of direct supervision, indirect supervision (phone monitoring) and unsupervised,45,46,50,51 and two interventions were a combination of both home and centre-based.44,47 The duration of the exercise programs, where specifically stated, was 6 weeks, although others were until 38 weeks gestation50 or to the end of pregnancy.44

In seven trials, the exercise intervention was an adjunct to standard care and was compared with standard care alone. The exception to this was the trial by Bung et al, which evaluated an intervention group receiving exercise without insulin, compared with insulin therapy.48

Baseline comparability of the randomised groups

Baseline data, where reported, showed that the control and intervention groups were similar at baseline (see Table 3 on the eAddenda). Baseline data were reported for mean postprandial blood glucose measures by six trials,44-47,49,51 fasting blood glucose by seven trials,44-49,51 and HbA1c by three trials.46,47,49

Effect of adding exercise to standard care

Postprandial blood glucose

Data from seven trials,44-47,49-51 with a total of 554 participants, compared the effect of exercise plus standard care with the effect of standard care alone on postprandial blood glucose levels (Figure 2, see Figure 3 on the eAddenda for a detailed forest plot). There was a significant between-group difference in postprandial blood glucose levels favouring exercise (MD -0.45 mmol/L, 95% CI -0.68 to -0.22, I2 = 76%). One trial49 with a relatively high risk of bias (PEDro score = 4/10) and a small sample of 19 participants had a larger favourable mean difference and wider confidence interval compared to the other six trials (Figure 2). The I2 value reduced to 48% when this study49 was removed in a sensitivity analysis, but the new pooled effect (MD -0.33 mmol/L, 95% CI -0.49 to -0.17)

MD (95% CI) Random

Avery47 --

Bo50 --

Brankston45 --

de Barros44 -

Halse46 - -

Jovanovic-Peterson49 - -

Youngwanichsetha51 --

Pooled i ♦ i i i

-2 -1 Favours Exp

(mmol/L)

12 Favours Con

Figure 2. Mean difference (95% CI) in effect of exercise plus usual care versus usual care only on postprandial blood glucose (mmol/L) in women with gestational diabetes mellitus.

MD (95% CI) Random

Avery47 Bo50

Brankston45 Halse46

Jovanovic-Peterson49 Youngwanichsetha51 Pooled

-2 -1 Favours Exp

(mmol/L)

Favours Con

Figure 6. Mean difference (95% CI) in effect of exercise plus usual care versus usual care only on fasting blood glucose (mmol/L) in women with gestational diabetes mellitus.

still significantly favoured exercise (Figure 4, see Figure 5 on the eAddenda for a detailed forest plot).

Fasting blood glucose

Data from six trials,45-47,49-51 with a total of 500 participants, compared the effect of exercise plus standard care with the effect of standard care alone on fasting blood glucose (Figure 6, see Figure 7 on the eAddenda for a detailed forest plot). There was a significant between-group difference in fasting blood glucose favouring exercise (MD -0.31 mmol/L, 95% CI -0.56 to -0.05,12 = 82%). A seventh trial measured fasting blood glucose, but did not report data with standard deviations and so was unable to be included in the meta-analysis.44

Glycated haemoglobin

Data from four trials,46,49-51 with a total of 439 participants, compared the effect of exercise plus standard care with the effect of standard care alone on glycated haemoglobin (Figure 8, see Figure 9 on the eAddenda for a detailed forest plot). There was a significant between-group difference in glycated haemoglobin favouring exercise (MD -0.33%, 95% CI -0.48 to -0.18, I2 = 60%).

MD (95% CI) Study Random

Halse46

Jovanovic-Peterson49 Youngwanichsetha51 Pooled

-1 -0.5 0 0.5 1 Favours Exp (%) Favours Con

Figure 8. Mean difference (95% CI) in effect of exercise plus usual care versus usual care only on glycated haemoglobin (%) in women with gestational diabetes mellitus.

Need for insulin therapy

Data from six trials,44-47,49,50 with a total of 384 participants, compared the effect of exercise plus standard care with the effect of standard care alone on the proportion of participants requiring insulin therapy (Figure 10, see Figure 11 on the eAddenda for a

MD (95% CI) Random

Avery47

Brankston45 de Barros44 Halse46

Youngwanichsetha51 — — Pooled

-1 -0.5 Favours Exp

(mmol/L)

0.5 1 Favours Con

Figure 4. Mean difference (95% CI) in effect of exercise plus usual care versus usual care only on postprandial blood glucose (mmol/L) in women with gestational diabetes mellitus, in a sensitivity analysis excluding the study by Jovanovic-Peterson et al49 due to heterogeneity.

Odds Ratio (95% CI) Random

Avery47 Bo50

Brankston45 de Barros44 Halse46

Jovanovic-Peterson49a

Pooled

—I—

0.1 0.2 0.5 0 2 5 Favours Exp Favours Con

—i— 0.5

Figure 10. Odds ratio (95% CI) for insulin requirement with exercise plus usual care versus usual care only in women with gestational diabetes mellitus. a An odds ratio and 95% Cl for the study by Jovanovic-Peterson49 could not be calculated because there was no insulin use in either group.

Table 5

Reported information about measures of safety considered in the included studies (n = 8).

Measures of safety mentioned

Reported results

Avery4 Bo50

Brankston45

Bung48 de Barros44

Halse4

Jovanovic-Peterson4 Youngwanichsetha5

Apgar scores, gestational age at birth, infant birth weight, caesarean births 'Complications'a

Maternal: pregnancy-induced hypertension, infectious diseases, cholestasis during pregnancy, and peri- and post-partum complications

Neonate: birth weight > 90th percentile, pre-term birth, and any neonatal conditions requiring a specific treatment or a prolonged in-hospital stay Other 'adverse events'a

An investigator 'made weekly contact to ensure the safety of participants'a Premature rupture of membranes, premature labour, birth weights Post-exercise hypoglycaemia, capillary glycaemia > 250 mg/dL BMI, pregnancy weight gain, gestational age at delivery, caesarean sections n/s

Maternal: uterine activity, hypoglycaemia (< 60 mg/dL), maternal morbidity Neonate: foetal bradycardia, gestational age at birth, infant morbidity n/s

Similar scores in both groups No complications in either group Reduced maternal/infant complications: OR 0.50 (95% CI 0.28 to 0.89)

No adverse events in either group n/s

'Similar rate of complications in each group'a No events in either group No significant difference between groups 'No adverse effects were reported in response to exercise'

No complications in either group No adverse events occurred during practice

n/s = not stated. a Not specified further.

Table 6

Reported information about exercise adherence among participants in the experimental group in the included studies (n = 8).

Exercise (sessions/week) mean (SD)

Mean adherence (% of prescribed)

Avery47 Bo50

Brankston45

Bung48 de Barros44 Halse46

Jovanovic-Peterson49 Youngwanichsetha51

3.0 (0.6) n/s

2.0 (0.9)

n/s 2.4 (0.4) Superv 2.8 (n/s) a Unsuperv 2.0 (1.0) 3 (n/s) Classes 2 (0) Home ex n/s

75% a 66% a 67% a > 90% 80% a Superv 96% Unsuperv 100% a 100%

Classes 100% Home ex > 80%

Ex = exercise, n/s = not stated, superv = supervised, unsuperv=unsupervised. a Calculated from data in the paper.

detailed forest plot). Meta-analysis of these six trials favoured exercise, but did not reach statistical significance (OR 0.59, 95% CI 0.28 to 1.22).

Adverse events

Adverse events were defined and analysed in varying detail in the included trials, as presented in Table 5. One trial50 reported significantly reduced maternal/neonatal complications due to exercise (OR 0.50, 95% CI 0.28 to 0.89). Some trials reported no adverse events in either group. Other trials reported that maternal and neonatal outcomes were similar or not significantly different between the randomised groups. None of the trials reported that exercise caused a significant increase in adverse events or a significant worsening of maternal/neonatal outcomes.

Effect of exercise versus insulin therapy

One trial48 evaluated the effect of exercise and diet compared with insulin therapy and diet. There was no statistical difference in the weekly fasting blood glucose levels between the exercise group and the insulin group. This trial reported a similar rate of complications (premature rupture of membranes, premature labour, birth weights) in each group.

Adherence

All of the included trials reported some information about the level of adherence to exercise in the experimental group (Table 6), although the method of collecting these data was not well described. Two trials reported 'satisfactory' adherence, with participants exercising 2 to 2.4 times a week.44,45 Another trial50 stated 'good' adherence, as reported by participants in surveys; however, actual exercise attendance was 66%. Three trials reported a specific percentage of adherence with exercise: one trial reported

> 90% attendance for centre-based exercise;48 one trial reported 96% adherence to home-based stationary cycling;46 and one trial reported 100% attendance at centre-based training then 80% adherence to the home-based yoga exercise program.51

Discussion

Evidence from seven randomised, controlled trials found that exercise as an adjunct to standard care significantly improved postprandial control of glycaemia and lowered fasting blood glucose for women with GDM compared with standard care alone. There was no increase in adverse events in the exercise groups. A previous systematic review conducted a decade ago concluded that there was insufficient evidence to determine whether exercise should be prescribed to reduce maternal and perinatal morbidity in women with GDM.32 The current systematic review provides evidence that exercise is beneficial for postprandial control of glycaemia in women diagnosed with GDM. This evidence is likely to be robust because it relies on multiple meta-analyses; the included studies examined various exercise types, and the studied populations were representative of the wider target population of women with GDM. The current systematic review therefore provides strong new comprehensive evidence to support the many recommendations in the literature to use exercise in this population;4,6,15,16,33-35 the recommendations were based on other forms of evidence such as narrative reviews, physiological rationales, consensus opinion or systematic reviews of fewer studies.

Lower postprandial blood glucose levels are associated with fewer perinatal complications.16 These results are clinically important because they indicate the potential of exercise to assist in reducing acute blood glucose levels to within the normal range: postprandial blood glucose (MD -0.45 mmol/L, 95% CI -0.68 to -0.22) and fasting blood glucose levels

(MD -0.31 mmol/L, 95% CI -0.56 to -0.05). Glycated haemoglobin levels, which measure longer-term (2 to 3 months) glycaemic control,26 also improved significantly for the exercise group when compared with standard care.46,49-51

It remains uncertain whether adjunctive exercise, in controlling glycaemic levels in women with GDM, has the potential to reduce or delay the need for insulin therapy, which can be costly, invasive and poorly accepted by women.45,54 This is relevant because high insulin levels, as occur in hyperglycaemia, may be associated with vascular damage; so the lower the dose of insulin required, the better.55 In the exercise intervention groups, it was observed that there were fewer women requiring insulin (26 out of 194, 13%) compared with those receiving standard care (39 out of 190, 21%), although the meta-analysis of the studies contributing to these pooled data did not identify a statistically significant difference. A larger cohort would provide greater power to determine whether exercise decreases the number of women requiring insulin. One trial44 found that participants who exercised were prescribed less insulin (p < 0.01) and another48 concluded that adjunctive exercise was as effective as insulin in maintaining normoglycaemia and could therefore be useful in obviating the need for insulin therapy.

There is a plausible physiological explanation to support exercise as a therapeutic adjunct for improving postprandial control of glycaemia in women with GDM. Although dietary modification is the basis of standard GDM management for maintaining normal postprandial glycaemic levels and optimising maternal and foetal outcomes, postprandial control of glycaemia is not maintained with diet therapy alone in as many as 39% of women with GDM.56 Poor control leads to fasting and/or postprandial hyperglycaemia triggering the prescription of insu-lin.57 However, insulin administration does not address insulin resistance per se. In contrast, an acute bout of exercise increases insulin action by stimulating glucose uptake in muscle, via activation of intracellular glucose transporters, and increasing use of intracellular fatty acids.24,58 Exercise training also alters expression of muscle proteins involved in insulin responsivenes-s.59Activation of large muscles, such as the quadriceps, improves glucose uptake.22,25 In type 2 diabetes, the acute effects of a bout of aerobic exercise are to regulate fat and glucose metabolism.24 This improves insulin sensitivity, promotes glucose uptake and results in a decrease in blood glucose levels for up to 72 hours afterwards.27 Glucose uptake is also influenced by the duration and intensity of exercise performed: the more intense the exercise, the stronger the glycaemic lowering effect.60

The variation of exercise prescription across the trials hinders the identification of an optimal exercise regimen. However, the results from these trials suggest that a program of either aerobic exercise or resistance training appears equally effective, as long as it is performed at least at a moderate intensity or greater, for 20 to 30 minutes, three to four times a week, to provide a repeated stimulus that facilitates improved blood glucose uptake and induces increases in insulin sensitivity. Consistent with the findings of a previous systematic review on type 2 diabetes,28 this suggests that as long as the dosage is similar, there is flexibility in type of exercise. This is relevant to translation into a person-centred model of care. This would enable exercise programs to be tailored to suit an individual's preference, which may help adherence.

Although the ideal situation is prevention, a recent review investigating the effect of exercise combined with diet for the prevention of GDM reported that there was little difference between the exercise plus diet group and the control group who received no intervention; however, limitations with the available evidence were acknowledged.61 Therefore, with increasing prevalence of GDM,4-7 improved management of GDM is important. As maintaining acute postprandial blood glucose levels within the recommended targeted range is associated with improved perinatal outcomes in women diagnosed with GDM,16 and as exercise appears to improve HbA1c in the longer-term,46,49-51 this suggests that commencement of adjunctive exercise as early as

possible in pregnancies complicated by GDM may be beneficial. Larger and more rigorous studies are needed to further investigate the effect of exercise earlier in pregnancy in relation to GDM onset and blood glucose control.

Not all studies in this review reported on each outcome. Generally, however, exercise with greater levels of frequency and/ or intensity, combined with some form of supervision to improve adherence, appeared to confer better overall outcomes.50,51 Further research is needed to provide better understanding of the exercise dose-response relationship and more systematic reporting of levels of adherence to exercise.

Although adherence is considered necessary to realising the potential of the intervention and achieving optimal clinical benefit,62 none of the trials systematically investigated or evaluated adherence determinants, mediators or adherence strategies. Level of exercise adherence appeared to be collected through attendance and participation, but this was not consistently or well described. Participants in the trial of Bo et al50 self-reported good adherence, but attendance was 69%. This highlights that self-reporting is liable to overestimation due to the possibility of social desirability bias; this reduces the level of confidence in the actual adherence to the intervention and, thereby, the certainty of the optimal exercise dosage required to achieve the physiological effect. Greater supervision, either face-to-face or via phone follow-up, appeared to be associated with higher levels of adherence.46,48,49,51 The convenience of a supervised, home-based exercise program was suggested as a reason for good adherence.46,51 Home-based exercises involving little or no equipment, such as brisk walking,50 resistance exercises with exercise bands44,45 or yoga,51 are more accessible for most women and less expensive in terms of access costs compared with clinic attendance; and they have equivalent beneficial effects on blood glucose control. All interventions were individually delivered, which has the advantage of tailoring to the individual, thereby facilitating adherence. Future research is needed to explore determinants of exercise adherence in women with GDM and to subsequently evaluate the effect of exercise adherence strategies on glycaemic control outcomes.

No trials reported using group exercise interventions, which may provide social support and be a cost-effective healthcare option. In the reviewed trials, neither socio-economic status nor cultural characteristics were well reported. These factors may influence a woman's attitude, health literacy level and acceptability of the intervention, which may affect clinical outcomes and are therefore important considerations in future research. One trial51 provided culturally appropriate exercise, and when combined with supervision achieved good compliance and positive results across the reported outcomes. Although reporting of cultural background and socio-economic details was scant, the geographical breadth of the trial locations (Canada, United States of America, Brazil, Thailand and Australia) and reported cultural backgrounds (Caucasian, South-East Asian and Spanish) improve the generali-sability of the findings.

The differing types of exercise among the included studies could be seen as a potential limitation. A previous systematic review28 concluded that aerobic or resistance exercise, or a combination, were similarly effective in improving glycaemic control in people with type 2 diabetes mellitus; therefore, the present study deemed it acceptable to combine different types of exercise, provided they were similar in dosage. As no trial included a follow-up phase, the lasting effects of exercise and lifestyle modification on long-term prevention of type 2 diabetes mellitus in this population is unknown.

In conclusion, the results of this review provide evidence to support the recommendation that exercise, as an adjunct to standard GDM care, is beneficial in controlling postprandial blood glucose levels and in glycaemic control in women diagnosed with GDM. Programs of either aerobic or resistance exercise appear effective. Characteristics of effective exercise programs for management of GDM appear to be exercise performed at a moderate intensity and for a minimum of three times a week.

JPHYS-271; No. of Pages 9 ARTICLE IN PRESS

Harrison et al: Exercise in gestational diabetes mellitus

What is already known on this topic: Poorly controlled gestational diabetes mellitus may have adverse consequences for the mother and the developing baby. Gestational diabetes mellitus management includes dietary modification, self-monitoring of blood glucose levels, exercise and, if necessary, use of insulin. Although exercise improves various measures of blood glucose, its effect on postprandial blood glucose requires explication.

What this study adds: Adding exercise to usual care of gestational diabetes mellitus reduces postprandial blood glucose, fasting blood glucose and glycated haemoglobin. Exercise is safe and may reduce maternal and neonatal complications in gestational diabetes mellitus.

eAddenda: Figures 3, 5, 7, 9 and 11, Tables 3 and 4, and Appendix 1 can be found online at: doi:10.1016/j.jphys.2016.08. 003.

Ethics approval: Not applicable. Competing interests: Nil. Source of support: Nil. Acknowledgements: Nil.

Provenance: Not commissioned. Peer reviewed. Correspondence: Anne Harrison, Physiotherapy Department, Werribee Mercy Hospital, Australia. Email: AHarrison@mercy.com. au

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