Influence of Maternal Aerobic Exercise During Pregnancy on Fetal Cardiac Function and Outflow

Journal Pre-proof Influence of Maternal Aerobic Exercise During Pregnancy on Fetal Cardiac Function and Outflow Linda E. May, PhD, Samantha McDonald, PhD, Lauren Forbes, Rebecca Jones, Edward Newton, MD, Diana Strickland, Christy Isler, MD, Kelly Haven, MD, Dennis Steed, MD, George Kelley, DA, FACSM, Lisa Chasan-Taber, ScD, Devon Kuehn, MD PII:

S2589-9333(20)30015-X

DOI:

https://doi.org/10.1016/j.ajogmf.2020.100095

Reference:

AJOGMF 100095

To appear in:

American Journal of Obstetrics & Gynecology MFM

Received Date: 7 October 2019 Revised Date:

22 January 2020

Accepted Date: 19 February 2020

Please cite this article as: May LE, McDonald S, Forbes L, Jones R, Newton E, Strickland D, Isler C, Haven K, Steed D, Kelley G, Chasan-Taber L, Kuehn D, Influence of Maternal Aerobic Exercise During Pregnancy on Fetal Cardiac Function and Outflow, American Journal of Obstetrics & Gynecology MFM (2020), doi: https://doi.org/10.1016/j.ajogmf.2020.100095. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Inc. All rights reserved.

Title: Influence of Maternal Aerobic Exercise During Pregnancy on Fetal Cardiac Function and Outflow Authors: Linda E May, PhD,1,2,3 Samantha McDonald, PhD1, Lauren Forbes4, Rebecca Jones4, Edward Newton, MD3, Diana Strickland3, Christy Isler, MD3, Kelly Haven, MD3 Dennis Steed, MD4, George Kelley, DA, FACSM5, Lisa Chasan-Taber, ScD6, Devon Kuehn, MD7 Author Institutional Affiliations: 1

Department of Foundational Sciences and Research, ECU, Greenville, NC

2

Department of Kinesiology, East Carolina University (ECU), Greenville, NC

3

Department of Obstetrics and Gynecology, ECU, Greenville, NC

4

Brody School of Medicine, Pediatric Cardiology, ECU, Greenville, NC

5

Department of Biostatistics, West Virginia University, Morgantown, WV

6

Department of Biostatistics & Epidemiology, University of Massachusetts, Amherst, MA

7

Department of Pediatrics, ECU, Greenville, NC

Clinical Trial Registry: ClinicalTrials.gov RCT Trial Number: NCT03517293 Registration/Start Date: July 1st, 2015 Disclosures/Conflict of Interest: The authors have no conflicts of interest to disclose. Financial Support: This study was funded, in part, by the American Heart Association (AHA grant #15GRNT24470029) and by ECU internal funds. Corresponding Author:

Linda E. May, MS, PhD 1851 MacGregor Downs Rd, MS#701 Greenville, NC 27834

252-737-7072 (office) 252-737-7049 (fax) [email protected]

1 1

Condensation: Prenatal aerobic exercise exerts positive effects on fetal right- and left-

2

side cardiac outflow while not appreciably affecting cardiac function in late pregnancy.

3 4

Short Title: Prenatal Exercise and Fetal Cardiac Function

5 6 7

AJOG at a Glance: A. Why was this study conducted?

8

This study was implemented to determine the effects of prenatal aerobic exercise on

9

fetal right and left-side cardiac function and outflow in the 3rd trimester of pregnancy.

10 11

B. What were the key findings?

12

Fetuses of aerobically-trained pregnant women exhibit greater right and left-side cardiac

13

outflow parameters compared to fetuses of non-exercising pregnant women. Prenatal

14

aerobic exercise does not appear to affect right or left-side cardiac function parameters.

15 16

C. What does this study add to what is already known?

17

The findings of this study show that the fetal cardiovascular system is sensitive to

18

beneficial changes related to maternal aerobic exercise beyond the initial

19

developmental period in the 1st trimester of pregnancy, and thus, demonstrates the

20

importance of maternal aerobic exercise throughout pregnancy.

21 22 23 24

Keywords: pregnancy, stroke volume, cardiac index, aerobic exercise, aerobic capacity

2 25

ABSTRACT

26

Objectives: To assess the effects of supervised prenatal aerobic exercise at

27

recommended levels on fetal cardiac function and outflow in the 3rd trimester of

28

pregnancy. We hypothesized that fetuses of aerobically-trained women compared to

29

fetuses of non-exercising women would exhibit increased cardiac function and greater

30

cardiac output.

31

Study Design: Secondary data analyses of a 20-week, randomized controlled exercise

32

intervention trial in pregnant women between 2015 and 2018 in Eastern North Carolina

33

were performed. Eligibility criteria included pregnant women <16 weeks gestation,

34

singleton pregnancy, aged 18 – 40 years, body mass index of 18.5 kg/m2 - 34.99 kg/m2,

35

physician clearance letter for exercise participation, reliable transportation and method

36

of communication. Exclusion criteria included presence of chronic conditions (e.g., type

37

1 or 2 diabetes mellitus), current medications known to adversely affect fetal growth

38

(e.g., antidepressants), alcohol, smoking or illicit drug use. The patient cohort consisted

39

of 133 eligible pregnant women who were randomly assigned to either an aerobic

40

exercise (n=66) group that participated in 150 minutes of supervised, moderate-intensity

41

(40-59% VO2peak; 12-14 on Borg Rating of Perceived Exertion, RPE) aerobic exercise

42

per week or a non-exercising group (n=61) which consisted of 150 minutes per week of

43

light (< 40% VO2peak) stretching and relaxation breathing techniques. Between 34-36

44

weeks gestation, a fetal echocardiogram was performed to assess fetal cardiac function

45

including fetal heart rate, right and left-ventricular stroke volume, stroke volume index,

46

cardiac output, cardiac output index, and cardiac outflow including pulmonary and aortic

47

valve diameters, peak flow velocity, and peak flow velocity-time integral (VTI). Fetal

3 48

activity state (quiet vs active) during the echocardiogram and maternal aerobic capacity

49

(VO2peak) served as covariates. Intention-to-treat and per protocol (participants attending

50

≥ 80% of exercise sessions) Analysis of Covariance regression models were performed.

51

Results: Of the 127 randomized participants, 66 and 50 participants were included in

52

the intention-to-treat and per protocol analyses, respectively. Prenatal aerobic exercise

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significantly increased fetal right-ventricular cardiac measures of RV stroke volume

54

(p=0.001) and stroke index via VTI (p=0.003), RV cardiac output (p=0.002) and cardiac

55

index via VTI (p=0.006), as well as pulmonary artery diameter (p=0.02) and pulmonary

56

valve VTI (p=0.03). Only in the ITT analysis was a significant differences in fetal LV

57

cardiac outflow observed with greater aortic valve peak velocity (p=0.04) found among

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fetuses of aerobically-trained pregnant women. No other statistically significant

59

between-group differences were found.

60

Conclusions: The findings of this study demonstrate that participation in prenatal

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aerobic exercise at recommended levels may improve fetal cardiac function and outflow

62

parameters. Follow-up cardiovascular measures in the postnatal period are needed to

63

determine potential long-term effects on the offspring’s cardiac function and outflow.

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4 65

Introduction

66

In the United States, cardiovascular disease (CVD) is the leading cause of

67

death[1] and risk factors for CVD have been documented in children as young as

68

3 years of age,[2-9] suggesting in utero programming. Thus, the development of

69

the fetal cardiovascular system during pregnancy is likely a preliminary indicator

70

of cardiac health at birth and subsequently, a proxy for the future risk of CVD

71

throughout life.

72

Limited evidence suggests that maternal behaviors during pregnancy,

73

including exercise, may influence the development of the fetal cardiovascular

74

system. Studies show that both fetus and infants of exercising pregnant women

75

have decreased heart rates and increased heart rate variability, which support

76

improved infant cardiovascular autonomic control.[10-12] Increased intensity and

77

duration of prenatal exercise have also been shown to enhance fetal

78

cardiovascular adaptations.[12] Additionally, maternal prenatal exercise has been

79

shown to be associated with increased left ventricular ejection fraction in school-

80

aged children.[13] As fetal heart function increases during normal

81

development,[14, 15] these findings demonstrate the developmental plasticity of

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the fetal cardiovascular system beyond its initial formation in the fourth week of

83

gestation.[16] Limitations of these studies, including the paucity of randomized

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controlled exercise intervention trials, use of self-reported measures, and

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employment of retrospective study designs from non-randomized controlled

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trials, significantly reduce the strength of evidence describing the effects of

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prenatal exercise on fetal cardiovascular development.

5 88

To address these limitations, the purpose of the current study was to conduct a

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secondary analysis of data from a 24-week randomized controlled exercise intervention

90

trial in pregnant women in order to investigate the effects of supervised prenatal aerobic

91

exercise at recommended levels on fetal cardiovascular development in the 3rd trimester

92

of pregnancy. We hypothesized that fetuses of aerobically-trained women would exhibit

93

greater cardiac function characterized by increased stroke volume, stroke index, cardiac

94

output, cardiac index, and ejection fraction, in addition to greater cardiac outflow

95

characterized by increased pulmonary and aortic valve diameters, peak flow velocities,

96

and peak flow velocity-time integral at 36 weeks gestation when compared to the

97

fetuses of non-exercising women. Furthermore, we hypothesized that these changes

98

would be more pronounced on the right side of the fetal heart as the right side of the

99

heart is the dominant contributor to fetal systemic circulation.[17]

100

MATERIALS AND METHODS:

101

Study Participants

102

The purpose of the current study was to determine the effects of prenatal aerobic

103

exercise on fetal cardiac development and function. Data were derived from a

104

prospective, non-blinded, two-arm randomized controlled exercise intervention trial that

105

took place from July 2015 to July 2018. Pregnant women were recruited from local

106

obstetric clinics via brochures, flyers, word-of-mouth and social media. Inclusion criteria

107

for this study were as follows: 1) women with a low-risk, no health issues, singleton

108

pregnancy < 16 weeks gestation, 2) between 18 and 40 years of age, 3) a pre-

109

pregnancy body mass index (BMI) between 18.5 to 34.99 kg/m2, 4) physician clearance

110

to participate in an exercise program, and 5) able to communicate fluently in English

6 111

and be contacted via phone and email. Women were excluded from the study if

112

they 1) had pre-existing medical conditions (e.g., diabetes, hypertension,

113

cardiovascular disease) or comorbidities known to affect fetal development (e.g.,

114

systemic lupus erythematosus), 2) were taking medicine known to affect fetal

115

development or pregnancy outcomes, or 3) were using tobacco, alcohol, or other

116

recreational drugs. Informed consent was obtained from each participant prior to

117

participation. This study was approved by the East Carolina University

118

Institutional Review Board and registered on the Clinicaltrials.gov website

119

(Registry #NCT03517293).

120

Pre-Exercise Testing

121

Prior to randomization, all participants underwent a submaximal exercise

122

treadmill test as validated by Mottola et al. 2006.[13] Briefly, the test consisted of

123

a 5-minute warm-up at 3 mph at 0% grade. Following this, the treadmill grade

124

increased 2% every 2 minutes until volitional fatigue. Oxygen consumption and

125

carbon dioxide production were assessed via breath-by-breath analysis (Parvo

126

Medics, TrueOne 2400, Sandy, UT) to determine VO2peak (ml O2⋅kg-1⋅min-1).

127

Maternal heart rate (HR) was measured continuously with a Polar FS2C HR

128

monitor. This test was performed to determine target HR zones (THR)

129

corresponding to maternal HRs between 40% to 59% VO2peak, reflecting

130

moderate exercise intensity.[14]

131

Randomization

132 133

Participants were randomized to either an aerobic exercise or nonexercising control group based on computerized sequencing generated using

7 134

GraphPad software. The participants and exercise trainers were not blinded to group

135

assignment. However, the sonographer and clinic staff were blinded.

136

Exercise Intervention

137

To enhance compliance, all participants were permitted to tailor their program,

138

choosing 3 days and the time of day to attend supervised sessions with trainers.

139

Participants in both groups wore a Polar FS2C heart rate monitor during all sessions to

140

monitor exercise intensity. Each session began with a 5-minute warm-up (treadmill

141

speed <3.0 mph) and ended with a 5-minute cool-down at low intensity. The aerobic

142

exercise group participated in a supervised, moderate-intensity (40-59% VO2peak; 12-14

143

on Borg Scale)[18], not to exceed THR ranges zones validated for pregnant women,[19]

144

exercise program for 50 minutes, 3 times per week. Aerobic exercise was performed

145

using treadmill, elliptical, or stationary bicycles based on participant preference.

146

Importantly, this exercise intervention met the guidelines of 150 minutes each week of

147

moderate intensity exercise for healthy pregnant women as recommended by the

148

American College of Obstetricians and Gynecologists (ACOG) as well as the U.S.

149

Department of Health and Human Services (USDHHS).[20, 21]

150

The attention-control group performed breathing techniques that consisted of

151

stretches of major muscle groups (shoulders, triceps, legs, chest, and back). Women in

152

the control group remained below 40% of their VO2peak for all sessions. Pregnancy

153

MET·min·wk-1 of exercise was quantified (frequency X duration of session) then

154

multiplied by the MET (metabolic equivalent) level for their specific exercise. The totals

155

for all weeks were summed and averaged for the pre-pregnancy MET·min·wk-1 value.

156

Exercise Adherence

8 157

Exercise session attendance was tracked via an electronic record and calculated

158

by dividing the number of sessions attended by the total number of possible sessions in

159

the participants’ gestational period (16 weeks until delivery). Participants were

160

considered “adherent” if their attendance was ≥ 80%.

161

Fetal Measurements At 34-36 weeks gestation, an obstetrical ultrasound and fetal echocardiogram

162 163

were performed between 12:00 and 1:00 pm at the University-affiliated outpatient clinic

164

by a certified sonographer, blinded to group assignment, using a Logiq P5 ultrasound

165

system (General Electric, Korea),. One sonographer per study patient obtained all

166

images. These procedures are previously validated and found reliable in healthy,

167

normal pregnancies producing accurate measurements of the fetal cardiac chamber

168

dimensions and physiological measures of cardiac function.[22-25] The obstetrical

169

ultrasound and fetal echocardiogram were used to assess fetal morphometric and

170

anatomical cardiac structures that includied estimated fetal weight (EFW; grams), body

171

length (cm), pulmonary valve diameter and aortic valve diameter, respectively. Body

172

length (cm) was calculated based on the standard formula 6.18+0.59Xfemur length

173

(mm).[26] These outflow tract diameters were used to calculate outflow tract area

174

(0.785*diameter2). The fetal echocardiogram was used to assess heart rate (beats·min-

175

1

176

velocities (cm·sec-1) and VTIs (velocity-time integral; cm). Stroke volume (SV) was also

177

calculated using VTI*outflow tract area, since this has been shown to have improved

178

prognostic value over ejection fraction.[27, 28] Cardiac output was calculated by

179

multiplying stroke volume and heart rate. Stroke volume and cardiac output were

), stroke volume (mL·beat-1), cardiac output (L·min-1), pulmonary and aortic peak

9 180

additionally adjusted for body size via body surface area (cm3) to calculate stroke

181

volume index (mL·(m2)-1) and cardiac index (L·(m2)-1), respectively. Body surface area

182

was calculated based on the Mostellar formula:[29] ((  ℎ ∙   ℎ)/

183

60).

184

The fetal activity state, quiet or active, was determined by direct observation of

185

the fetus’ movement and heart rate by the sonographer during the ultrasound and

186

echocardiogram.

187

Statistical Analyses.

188

Sample size was calculated to achieve 80% power (beta=0.20) at an alpha level

189

for statistical significance of <0.05, based on the primary outcomes of the original

190

study.. Based on our preliminary fetal heart rate data (unpublished results), two-sided,

191

two-sample t-tests were performed and justified a sample size of 24 participants per

192

group to detect a statistically significant difference of 7 bpm per activity state at an alpha

193

level of 0.05. Participants with complete fetal echocardiogram data were eligible for

194

analyses. Analysis of Covariance (ANCOVA) models were performed for both

195

intention-to-treat (ITT) (exercise dose as received) and per protocol (participants

196

attending ≥ 80% of exercise sessions) analysis. To determine the effects of prenatal

197

aerobic exercise on fetal cardiac function, ANCOVA regression models were performed

198

while controlling for fetal activity state during the echocardiogram (active vs quiet) and

199

maternal peak aerobic capacity (VO2peak). All statistical analyses were performed

200

using SAS version 9.4 (Cary, NC).

201

RESULTS:

202

Study Participant Recruitment and Retention

10 203

Details on the recruitment and retention of the study participants are

204

shown in Figure 1. Briefly, 138 newly pregnant women were assessed for

205

eligibility, of which 133 were eligible and interested in participating in the study.

206

Only 128 of these pregnant women were randomized to the aerobic exercise

207

intervention group (n=68) or the non-exercising group (n=60). Between 16 and

208

36 weeks gestation, 6 women either refused their group assignment or did not

209

obtain a physician clearance letter for the study. Fifteen (aerobic exercise [n=8]

210

and non-exercising [n=7]) were lost to follow-up or dropped, while 41 of the

211

remaining participants were excluded due to either preterm birth, lack of

212

echocardiogram data, or reports of illicit drug use. Thus, data from 66 healthy

213

pregnant women were eligible for analyses, 41 in the aerobic exercise group and

214

30 in the non-exercising group.

215

Maternal Descriptive Statistics:

216

Maternal demographic characteristics, cardiac function and activity level

217

for the ITT and per protocol samples are summarized in Table 1. No between-

218

group differences were observed for maternal demographics. Significant

219

differences were reported for maternal cardiac function measures, with lower

220

values reported for 36-week heart rate for the per protocol group as well as 36-

221

week systolic and diastolic blood pressure for both the ITT and per protocol

222

samples. Aerobically trained women attending > 80% of total exercise sessions

223

(per protocol) not only exhibited a lower average resting heart rate (HR) and

224

blood pressure compared to controls (Table 1) but also lower values relative to

225

non-adherent (<80% of sessions) aerobic exercisers (data not shown). Lastly, at

11 226

16 weeks gestation, women assigned to the aerobic exercise group possessed higher

227

aerobic capacity as well as MET min/week of exercise when compared to women

228

assigned to the non-exercising control group for both the ITT and per protocol samples.

229

Fetal Descriptive Statistics:

230

Fetal demographic characteristics and morphometrics are summarized in Table

231

2. No between-group differences were observed for infant sex distribution, fetal length,

232

weight or body surface area for both ITT and per protocol samples. A greater proportion

233

of fetuses of aerobic exercisers, for the ITT (90.2% vs 63.3%; p=0.006) and per protocol

234

(88.0% vs 61.5%; p=0.03) samples were observed in the active state during the fetal

235

echocardiogram compared to fetuses of non-exercising moms.

236

Table 3 shows differences in cardiac function and outflow of fetuses between

237

aerobically-trained and non-exercising pregnanct women, by activity status during the

238

electrocardiogram. For fetuses in the active state, significant between-group differences

239

were found for RV stroke volume and index via VTI, cardiac output and cardiac index

240

via VTI, pulmonary valve VTI and pulmonary diameter. Active state fetuses of

241

aerobically-trained pregnant women exhibited greater right-side cardiac function and

242

outflow compared to the fetuses of non-exercising pregnant women. No significant

243

between-group differences were found for fetuses in the quiet state

244

Fetal Cardiac Function and Outflow:

245

For the ITT adjusted ANCOVA analyses (Table S1), we found prenatal aerobic

246

exercise had significant between-group differences were found for fetal right-ventricular

247

(RV) cardiac function with higher fetal cardiac function and outflow observed in fetuses

248

of aerobically- trained pregnant women compared to fetuses of non-exercising pregnant

12 249

women for RV stroke volume (p=0.008) and stroke index (p=0.02) via VTI, RV

250

cardiac output (p=0.01) and cardiac index (p=0.03) via VTI and pulmonary valve

251

VTI (p=0.01). Moreover, fetuses of aerobically-trained pregnant women exhibited

252

larger pulmonary diameters compared to non-exercising pregnant women

253

(p=0.01). However, no significant between group differences were found for RV

254

ejection fraction (p=0.80) or pulmonary valve peak velocity (p=0.58). Similarly, for

255

the ITT analyses, no significant between-group differences were found for left

256

ventricular (LV) cardiac function or outflow, with the exception of aortic valve

257

peak velocity (p=0.04).

258

For the per protocol adjusted ANCOVA analyses (Table 4) controlling for

259

fetal activity state and maternal peak VO2, prenatal aerobic exercise had a

260

significant effect on fetal RV stroke volume (p=0.001) and stroke index (p=0.003)

261

via VTI, RV cardiac output (p=0.002) and cardiac index (p=0.006) via VTI,

262

pulmonary valve VTI (p=0.02) and pulmonar diameter (p=0.02). No significant

263

differences were observed for LV cardiac function or outflow.

264

COMMENT

265

Principal Findings of the Study

266

The focus of this study was to investigate the effects of prenatal aerobic

267

exercise on fetal cardiac function and outflow in late pregnancy. We

268

hypothesized fetuses of aerobically-trained pregnant women would have

269

improved cardiac function measures compared to fetuses of non-exercising

270

pregnant women. We found that prenatal aerobic exercise significantly increased

271

fetal right-ventricular cardiac measures of RV stroke volume and index, RV

13 272

cardiac output and index, as well as pulmonary artery diameter, and pulmonary valve

273

VTI. Additionally, maternal aerobic exercise was associated with increased left-

274

ventricular fetal cardiac measures of aortic valve peak velocity. Lastly, women in the

275

aerobic group demonstrated exercise adaptations at 36 weeks gestation.

276

We observed fetuses of exercising mothers had improved right-ventricular

277

cardiac function measures with an indication of a dose response, observed by larger

278

parameter estimates in the per protocol sample. The finding of significant differences

279

observed for right-ventricular cardiac function is expected since fetal cardiac function is

280

right-side dominant in utero and into the neonatal period.[30] Additionally, right-

281

ventricular measures increase into the neonatal period, whereas only the left VTI

282

increases in the 1st year of life after birth.[30] A previous study found increased LV

283

ejection fraction without significant changes in stroke index in children exposed to

284

maternal exercise in utero, which differ from the current findings.[13] Possible reasons

285

for the differences may be the use of self-reported maternal exercise data in the

286

previous study as opposed to the study design and data collection methods used in the

287

current investigation. Furthermore, one study noted that outflow VTI outperforms LV

288

ejection fraction in predicting adverse cardiovascular outcomes.[28] Increased LV-VTI in

289

adults is significantly associated with less cardiac events (e.g. death), whereas LV

290

ejection fraction and cardiac output does not correlate with cardiac events. [28]

291

Additionally, exercise research in adults and children 7 to 14 years old demonstrated

292

that swim training improves cardiac measures (e.g. LV heart dimensions, heart rate,

293

stroke volume) without changes in ejection fraction, a result similar to our current

14 294

findings.[31-35] Interestingly, our findings are also similar to other studies evaluating the

295

influence of swim training on children.[33-35]

296

We found that fetuses of exercising mothers had improved left-ventricular

297

measures of increased aortic valve peak velocity with trends towards increased

298

aortic valve VTI. Of note, the changes in aortic peak velocity are more distinct in

299

the active state, which may be an indicator of increased compliance and elasticity

300

of the cardiovascular system to changes in cardiac demand. It has been shown

301

that the ventricular elasticity increases with gestational age[30] as the fetus

302

matures. The increased aortic peak velocity and VTI may indicate a more mature

303

cardiovascular system, similar to previous findings of more mature cardiac

304

autonomic control in response to exercise exposure in utero.[10, 36] Similarly,

305

previous research has shown that endurance athletes have increased aortic peak

306

velocity, aortic distensibility, and maximal oxygen uptake relative to adults that do

307

not perform aerobic training.[37] Additionally, aortic compliance affects coronary

308

blood flow,[38] such that increased aortic distensibility with exercise training is

309

associated with left atrial function.[39] Though these adaptations are seen in

310

adults, it is suspected that the cardiac physiology can have a similar adaptation

311

prior to birth.

312

Although we did not repeat the maternal VO2peak measures at 36 weeks

313

gestation to determine if there were greater between-group differences, we found

314

improved maternal cardiovascular measures indicative of a trained response as a

315

result of the exercise intervention. However, during pregnancy, maternal

316

measures at 36 weeks that resulted in lower heart rate and blood pressure are

15 317

indicative of an exercise training response seen previously in the gravid state.[40]

318

Although these measures indicate a maternal training response, there were also

319

significant between-group differences peak in aerobic capacity at 16 weeks. Therefore,

320

it is possible that some of the changes observed in fetal heart measures are due to a

321

healthier maternal physiology prior to conception that could be passed to the fetus via

322

maternal mitochondrial DNA.[41] Although this is a possibility, it is important to note that

323

while controlling for maternal peak aerobic capacity, exercise level had an independent

324

effect in predicting improved measures of fetal heart function. Women in the aerobic

325

exercise group demonstrated evidence of an exercise training adaptation, which is

326

associated with umbilical and uterine artery remodeling to decrease vascular resistance

327

to blood flow.[42] Since each acute exercise stimulates maternal release of

328

catecholamines, which cross the placenta and can stimulate fetal beta receports on

329

cardiac myocytes; a decrease in vascular resistance may allow for increased

330

catecholamines crossing the placenta. Thus, these findings support that the

331

recommended level of exercise during pregnancy is sufficient to produce positive

332

cardiovascular changes for the mother as well as improved fetal cardiac function.

333

Strengths and Limitations

334

The strengths of this study include the initial randomized controlled design from

335

which this secondary analysis derived, including the focus on women achieving

336

recommended levels of exercise during pregnancy. Thus, these findings lend additional

337

support for the ACOG and USDHHS guidelines. To the best of our knowledge, this

338

study was the first RCT that examined the effects of supervised exercise at

339

recommended levels rather than self-reported maternal exercise during pregnancy,

16 340

including specific fetal cardiac function measures. In addition to strengths, we

341

acknowledge limitations. First, our sample size for per protocol analysis was

342

small. Secondly, although we did not control for the presence or absence of fetal

343

breathing movements at the time of the recording, all women were instructed to

344

eat a snack 1 to 1.5 hours prior to the recording and the recording was done at

345

the same time of day. Interestingly, more fetuses of exercisers were in the active

346

state during this time, which made it less likely for fetal breathing to occur and

347

thus compare findings between groups. Lastly, there is a lack of longitudinal

348

measures to determine if the fetal changes persist after birth.

349

Clinical Implications

350

These data further demonstrate that maternal aerobic exercise improves maternal and

351

fetal cardiovascular function. From a clinical perspective, obstetric providers are

352

encouraged to continue promoting prenatal physical activity at the recommended dose

353

in pregnancy.

354

Research Implications

355

Further research should be conducted to determine if these changes persist after birth

356

and for how long during child development. In addition, the effects of various exercise

357

types (resistance and combined training) on fetal cardiovascular health should be

358

investigated, to determine the potential benefits of other forms of training and thus,

359

increasing the choice of exercise modality during pregnancy..

360

Conclusions

361

This secondary analysis of a RCT demonstrates that maternal aerobic exercise at

362

recommended levels during pregnancy improves fetal cardiac function. These findings

17 363

suggest that 150 minutes of moderate intensity maternal aerobic exercise during

364

pregnancy positively influences fetal cardiac development. Further research is needed

365

to determine if the recommended levels of aerobic exercise during pregnancy provides

366

cardiovascular benefits later in life, including decreasing the risk of CVD and healthcare

367

costs and improving quality-of-life.

368 369

18 370

ACKNOWLEDGEMENTS:

371

We are grateful to the women who participated in this study and gave their time and

372

effort.

373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409

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21 Table 1. Maternal descriptive characteristics, cardiac function and activity level partitioned according to analysis type and group. Intention-to-Treat Aerobic

Per Protocol

Control

Aerobic

Control

(n=25)

(n=26)

p-value Characteristics

p-value

(n=41)

(n=30)

Age (years)

30.3 ± 3.4

30.1 ± 4.3

0.78

31.4 ± 2.7

30.4 ± 4.1

0.32

Pre-Preg BMI (kg/m2)

24.7 ± 4.3

26.1 ± 4.3

0.19

24.4 ± 3.7

25.3 ± 4.0

0.38

36.6

50.0

0.26

32.0

42.3

0.45

1 (1,4)

2 (1,4)

0.57

1 (1,4)

2 (1,4)

0.40

0 (0, 2)

1 (0, 2)

0.56

0 (0, 2)

1 (0, 2)

0.82

36 wk HR (bpm)

86.1 ± 12.2

91.6 ± 15.2

0.11

83.1 ± 12.4

91.7 ± 16.0

0.04

36 wk SBP (mmHg)

104.8 ± 11.1

116.5 ± 10.1

<0.0001

101.6 ± 8.4

116.4 ± 8.1

<0.0001

36 wk DBP (mmHg)

60.5 ± 9.0

73.9 ± 10.4

<0.0001

59.3 ± 8.6

74.4 ± 9.4

<0.0001

VO2peak (ml O2·kg-1·min-1)

24.2 ± 4.5

21.8 ± 3.6

0.02

25.3 ± 3.5

21.8 ± 3.8

0.001

Exercise (MET·min/week)

745.7 ± 215.1

372.6 ± 109.2

<0.0001

859.8 ± 146.0

399.1 ± 58.5

<0.0001

Demographics

Overweight/Obese (%) Gravidaa a

Parity

Cardiac Function

Activity Level

Data reported as mean ± SD; a Values reported as median (minimum, maximum) due to nonnormal distributions. Pre-Preg BMI = Pre-Pregnancy body mass index; 36 wk = 36 weeks of gestation; HR = heart rate; SBP = systolic blood pressure; DBP = diastolic blood pressure; MET = metabolic equivalent.

22 Table 2. Fetal descriptive characteristics and morphometrics, by maternal intervention adherence and group. Intention-to-Treat

Sex (% Male) Fetal Length (cm) Fetal Weight (g) Body Surface Area (m2) Fetal Activity State (% Active)

Aerobic

Control

(n=41)

(n=30)

58.5%

46.7%

46.1 ± 1.7

Per Protocol p-value

Aerobic

Control

(n=25)

(n=26)

0.32

59.5%

44.8%

0.23

46.0 ± 1.6

0.74

46.3 ± 1.8

46.0 ± 1.4

0.60

2709.2 ± 397.3

2772.9 ± 317.1

0.48

2748.8 ± 424.4

2782.0 ± 299.1

0.75

0.19 ± 0.02

0.19 ± 0.01

0.63

0.19 ± 0.02

0.19 ± 0.01

0.95

90.2%

63.3%

0.006

88.0%

61.5%

0.03

Data reported as mean ± SD. Fetal activity state was determined during the echocardiogram (active vs quiet). Bold font indicates statistical significance (p<0.05).

p-value

23 Table 3. Fetal cardiac function and outflow parameters, stratified by fetal activity state and intervention group. Per Protocol Analysis Fetal Activity State Active

Quiet

Aerobic

Control

Aerobic

Control

(n=22)

(n=16)

(n=3)

(n=10)

137.9 ± 8.5

141.5 ± 10.0

0.23

117.7 ± 2.5

130.8 ± 11.7

0.09

Stroke Volume (cm3·beat-1)

94.2 ± 17.5

79.5 ± 16.6

0.01

90.7± 6.2

94.1 ± 23.0

0.85

Stroke Index (cm3·beat-1·kg-1)

498.1 ± 83.9

424.5 ± 85.0

0.01

520.6 ± 14.6

489.4 ± 105.6

0.70

Cardiac Output (cm3·min-1)

13008.8 ± 2721.1

11205.2 ± 2223.9

0.04

10577.9 ± 915.9

12202.4 ± 2712.7

0.44

Cardiac Index (cm3·min-1·kg-1)

68455.3 ± 12258.3

59853.5 ± 11420.3

0.04

60638.0 ± 592.6

62925.4 ± 12579.6

0.60

Ejection Fraction (%)

57.9 ± 15.1

56.0 ± 12.2

0.69

57.1 ± 1.1

56.9 ± 12.1

0.95

PV Peak Velocity (cm·sec-1)

80.7 ± 9.0

77.1 ± 11.1

0.26

80.0 ± 11.3

83.1 ± 10.9

0.72

VTI of Pulmonary Valve (cm)

33.6 ± 2.7

31.4 ± 3.2

0.03

33.1 ± 3.2

32.9 ± 3.7

0.6790

Pulmonary Diameter (mm)

10.7 ± 0.9

10.0 ± 1.0

0.03

10.6 ± 0.5

10.5 ± 1.2

0.91

68.4 ± 15.0

61.5 ± 22.0

0.25

63.4 ± 8.6

63.6 ± 25.4

0.99

Cardiac Variables

Heart Rate (bpm)

p-value

p-value

Right Ventricle

Left Ventricle Stroke Volume (cm3·beat-1)

24 Stroke Index (cm3·beat-1·kg-1) Cardiac Output (cm3·min-1) Cardiac Index (cm3·min-1·kg-1)

364.1 ± 74.9

329.1 ± 113.7

0.27

349.9 ± 66.9

347.1 ± 113.07

0.97

9442.7 ± 2194.9

8668.5 ± 3100.5

0.37

7459.2 ± 1008.9

8094.1 ± 2690.8

0.70

50018.1 ± 10737.9 46454.0 ± 16133.6

0.43

410912 ± 7227.4

43994.4 ± 11681.4

0.70

Ejection Fraction (%)

73.8 ± 16.0

75.1 ± 16.3

0.81

76.5 ± 14.2

77.0 ± 25.9

0.90

AV Peak Velocity (cm·sec-1)

107.0 ± 10.9

101.6 ± 15.9

0.22

105.0 ± 5.3

101.0 ± 15.3

0.67

VTI of Aortic Valve (cm)

26.7 ± 2.7

26.0 ± 3.4

0.50

26.6 ± 1.8

25.5 ± 3.2

0.58

Aortic Diameter (mm)

8.5 ± 0.9

8.3 ± 1.1

0.50

8.5 ± 0.6

8.1 ± 1.0

0.58

PV = pulmonary valve; AV = aortic valve; VTI = velocity-time integral; RV = right ventricle; LV = left ventricle.

25 Table 4: Adjusted regression coefficients (ß ± SE; 95% confidence intervals) for the effects of prenatal aerobic exercise (MET·min·week-1) on fetal right- and left-side cardiac function, outflow and anatomical structures. Per Protocol Sample (n=50) Exercise*

95%CI

p-value

-0.01 ± 0.01

-0.02, 0.004

0.22

Stroke Volume (cm3·beat-1)

0.04 ± 0.01

0.02, 0.06

0.001

Stroke Index (cm3·beat-1·kg-1)

0.17 ± 0.06

0.06, 0.29

0.003

Cardiac Output (cm3·min-1)

4.87 ± 1.5

1.9, 7.8

0.002

Cardiac Index (cm3 (m2)-1)

21.4 ± 7.4

6.5, 36.3

0.006

0.003 ± 0.01

-0.01, 0.02

0.70

0.01 ± 0.01

-0.002, 0.02

0.10

0.004 ± 0.002

0.001, 0.008

0.02

Stroke Volume (cm3·beat-1)

0.01 ± 0.01

-0.01, 0.04

0.22

Stroke Index (cm3·beat-1·kg-1)

0.07 ± 0.06

-0.06, 0.19

0.28

Cardiac Output (cm3·min-1)

1.7 ± 1.6

-1.5, 4.9

0.30

Cardiac Index (cm3 (m2)-1)

6.5 ± 8.1

-9.7, 22.8

0.42

-0.01 ± 0.01

-0.03, 0.01

0.35

Cardiac Function and Outflow Fetal Heart Rate (bpm) Right-Ventricular Cardiac Function

Ejection Fraction (%) Right- Ventricular Cardiac Outflow Pulmonary Valve Peak Velocity (cm sec-1) Pulmonary Valve VTI (cm) Left- Ventricular Cardiac Function

Ejection Fraction (%) Left-Ventricular Cardiac Outflow

26 Aortic Valve Peak Velocity (cm sec-1)

0.02 ± 0.01

0.001, 0.03

0.07

0.001 ± 0.002

-0.003, 0.005

0.67

Pulmonary Diameter (mm)

0.001 ± 0.001

0.0002, 0.003

0.02

Aortic Diameter (mm)

0.0003 ± 0.001

-0.001, 0.001

0.67

-0.0001 ± 0.0001

-0.0002 ± 0.0001

0.16

Aortic Valve VTI (cm) Cardiac Anatomical Structures

Aorta: Pulmonary Valve Ratio

*Exercise is expressed as the average metabolic equivalents (METs) minutes per week throughout the intervention period. a Stroke index- Stroke volume adjusted for body surface area. All models were adjusted for fetal activity status (active or quiet) during the echocardiogram and maternal VO2peak (ml O2·kg-1·min-1).

Figure 1. CONSORT Diagram for Participant Recruitment and Retention 144 Assessed for Eligibility

11 Excluded 1 Not meeting inclusion criteria 4 Refused to participate 6 Other reasons

133 Randomized

61 Assigned to stretching/breathing 56 Received “no intervention” as assigned 5 Refused group and/or no physician letter 7 Lost to follow-up or Dropped (n=49) 1 No time 2 Moved 1 Drug use 2 Unknown 1 Non-compliant (exercise regimen) 49 Eligible for analyses 19 Excluded 8 No ultrasound performed 3 No heart measures 7 preterm birth 1 Drug use

13-16 wks GA

~24+ wk intervention

34-36 wk ultrasound

72 Assigned to aerobic exercise 71 Received intervention as assigned 1 Refused group and/or no physician letter 8 Lost to follow-up or Dropped (n=63) 3 No time 3 Moved 1 Drug use 1 Miscarriage

63 Eligible for analyses 22 Excluded 8 No ultrasound performed 7 No heart measures/incomplete data 6 preterm birth 1 Drug use reported

71 Included in Analyses 41 moderate-intensity aerobic exercise 30 low-intensity stretching/breathing