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Prenatal Exercise and Cardiovascular Health (PEACH) Study: Impact on Muscle Sympathetic Nerve (Re)Activity

SKOW, RACHEL J.1; FRASER, GRAHAM M.2; STEINBACK, CRAIG D.1; DAVENPORT, MARGIE H.1

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Medicine & Science in Sports & Exercise: June 2021 - Volume 53 - Issue 6 - p 1101-1113
doi: 10.1249/MSS.0000000000002583
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Abstract

Blood pressure regulation during pregnancy is multifaceted and involves coordinated interactions between the sympathetic nervous system and vasculature. Despite rapid and progressive blood volume expansion (1) and increases in cardiac output (2), arterial vasodilation and an increase in muscle sympathetic nervous system activity (MSNA) act to maintain normal blood pressure (3–5). Evidence shows that MSNA is elevated as early as 6 wk of gestation (6–8) with greater sympathetic activation in the third trimester (TM3) approaching 200% of nonpregnant values (5). Combined with minimal or no differences in resting blood pressure in the third trimester (2,9), these indicate a shift in blood pressure regulation throughout healthy pregnancy. Indeed, we have shown that sympathetic baroreflex gain (BRG; changes in MNSA in response to fluctuations in blood pressure) and neurovascular transduction (NVT; changes in blood pressure resulting from fluctuations in MSNA) are both blunted in TM3 compared with nonpregnant controls (10,11). Furthermore, the sympathetic nervous system response to stress (e.g., cold pressor test, or CPT) is either not changed (12) or augmented (13,14) in TM3 in healthy pregnant women.

Conversely, maladaptation of sympathetic cardiovascular control, specifically an augmented response to sympathetic stress during pregnancy, may be an important determinant of hypertensive disorders of pregnancy (15,16). Coupled with heightened basal MSNA before (17) and after the development of gestational hypertension (5), this would suggest that NVT is further blunted in women who later develop hypertension in their pregnancies. This highlights a unique period (i.e., before 20 wk) during which the impairments in blood pressure regulation could be influenced to prevent hypertensive disorders of pregnancy. Understanding how to effectively intervene to prevent the development of hypertensive disorders of pregnancy is still elusive; however, prenatal exercise has been shown to reduce the odds of developing hypertensive disorders of pregnancy by 40% (18). The mechanisms by which exercise confers its benefits in pregnancy are unclear; however, exercise consistently demonstrates a reduction in both resting and reflex reactivity in nonpregnant populations who have sympathetic hyperactivity (e.g., hypertension) (19). Together, these data indicate plasticity of the sympathetic nervous system, which may be modified by aerobic exercise; however, this has not been evaluated in pregnancy. Determining the effects of exercise intervention on sympathetic blood pressure regulation in otherwise healthy pregnant women is an important first step in this line of inquiry.

The primary aim of this study was to determine the influence of a prenatal exercise intervention on basal MSNA, BRG, and NVT in normotensive pregnant women between TM2 and TM3. Secondary aims of this study were to determine the effects of a prenatal exercise intervention on the MSNA and blood pressure responses to CPT. We hypothesized that an exercise intervention would attenuate the rise in resting MSNA and blood pressure, and the blunting in sympathetic BRG and NVT that occurs between the second and third trimesters. We further hypothesized that women who were randomized to the exercise group would have blunted MSNA and blood pressure responses to CPT compared with nonexercising controls.

METHODOLOGY

This study was approved by the University of Alberta Research Ethics Board (Pro00061045) and conforms to the standards set by the latest version of the Declaration of Helsinki. One hundred women contacted the Program for Pregnancy and Postpartum Health for information regarding participation in a randomized controlled trial investigating the effects of aerobic exercise on cardiovascular health (Prenatal Exercise And Cardiovascular Health [PEACH] study, NCT02948439), and 59 consented to participate in the study. Before participation, all participants provided written, informed consent and their maternity health care provider (obstetrician, midwife, etc.) signed the PARmed-X for Pregnancy (20). Women were included if they were older than 18 yr, had a singleton pregnancy, and were without contraindication to exercise as outlined in the PARmed-X for Pregnancy (20). Potential participants were excluded if they engaged in more than 60 min of moderate-to-vigorous physical activity (MVPA) per week (self-report at initial meeting) or had a preexisting cardiovascular, respiratory, or nervous system disorder (e.g., hypertension).

Assessments of neurovascular health were conducted at baseline (16–20 wk of gestation) and repeated postintervention (34–36 wk of gestation). At each time point, women were given a triaxial accelerometer (WGT3X-BT; Actigraph, Pensacola, FL) to measure their level of activity for 7 consecutive days. In addition, at the midpoint of the study (26–28 wk), women in both groups wore the accelerometer for a 7-d period. After the completion of baseline assessments, women received an opaque envelope with their allocation (exercise or control group). Before the start of the study, an individual not associated with the study prefilled sequentially numbered envelopes with group allocation using an online randomizer (www.sealedenvelope.com/simple-randomiser/v1) that randomized in blocks of four to eight.

Neurovascular assessment

Women arrived after a 12-h (overnight) fast, during which they were instructed to avoid all food and drink, except water (including caffeine, alcohol, vitamins, and over-the-counter pain medications). Women were provided a standard breakfast after arrival in the laboratory. Women were also asked to refrain from doing any exercise for at least 12 h before their assessment. After breakfast, the woman’s height (in centimeters; stadiometer) and weight (in kilograms; calibrated scale) were measured. Women then sat in a semireclined chair in a temperature-controlled room and were instrumented to measure heart rate (ECG; lead II; ADInstruments, Colorado Springs, CO), blood pressure using finger photoplethysmography (Finometer Pro; Finapres Medical Systems, Amsterdam, the Netherlands), oxygen saturation (pulse oximeter, Nellcor Oximax N-600X; Medtronic, Minneapolis, MN). Cardiac output (Q˙; derived model flow) was determined using the Finometer and used to calculated systemic vascular resistance (SVR) as mean arterial blood pressure (MAP)/Q˙ × 80 (in dynes per liter per minute).

After instrumentation, MSNA was recorded from the peroneal (fibular) nerve using microneurography (662C-3; University of Iowa Bioengineering, Iowa City, IA). Briefly, a small, tungsten microelectrode (35 mm long, 200 μm in diameter; tapered to a 1- to 5-μm uninsulated tip) was inserted just under the skin below the knee. A second reference electrode was inserted subcutaneously 1–3 cm away to allow for background noise to be filtered out of the signal. Adequate MSNA signals were determined according to standard criteria (21). The raw MSNA signal will be amplified (100,000×), band-pass filtered (700–2000 Hz), rectified, and integrated (0.1-s time constant) to obtain a mean voltage neurogram according to standard practice. Raw MSNA data were sampled at 10,000 Hz and stored for offline analysis (Lab Chart).

Once the MSNA signal was found, we performed three automated blood pressure measurements (BP785; Omron Healthcare, Toronto, Canada) to calibrate the Finometer followed by a 10-min baseline. The baseline was followed by a 3-min CPT (submerging hand up to the wrist in ice water; 4°C). During this protocol, heart rate, arterial blood pressure, and MSNA were continuously recorded. After CPT, women’s hands were rewarmed using a heating pad. All variables were exported into Lab Chart 8 via Powerlab 16/35 data acquisition system (PL3516; ADInstruments) and stored for offline analysis.

Exercise intervention

Women randomized to the exercise intervention were prescribed aerobic exercise three to four times per week with a target heart rate of 50%–70% heart rate reserve as per the 2003 Canadian Clinical Practice Guideline for exercise during pregnancy (22). The first week began with 25 min (5-min warm-up, 15 min at target heart rate, and 5-min cool-down) and increased in duration by 2 min·wk−1 until 40 min per session is achieved (i.e., 30 min at target heart rate) (23). The intervention started at 18–21 wk of gestation and continued until 33–36 wk of gestation. Women were required to attend a minimum of one supervised exercise session per week and were given logbooks to track their unsupervised sessions. Exercise modality included any aerobic exercise (e.g., treadmill, stationary bicycle, and elliptical). Every session began with 5 min of quiet, seated rest where heart rate and RPE were recorded. Heart rate and RPE were recorded twice during the exercise sessions (at approximately one-third and two-thirds of the duration). Immediately after the cool-down, women sat for 5 min and all baseline measures were repeated.

DATA ANALYSIS

All data were deidentified before analysis (i.e., blinded to the person doing the analysis). Hemodynamic data were collected during the last 5 min of quiet rest. Bursts of MSNA were detected using a semiautomated peak detection algorithm (Chart 8.1.3; ADInstruments), and bursts were confirmed by a trained observer (R.S.) based on a pulse-synchronous pattern, which was observed in both the raw and integrated neurograms. MSNA was expressed as integrated burst frequency (BF; in bursts per minute), burst incidence (BI; in bursts per 100 cardiac cycles), and total activity (in arbitrary units). Spontaneous weighted sympathetic BRG was determined as previously described (11) and confirmed by two trained observers (R.S. and C.D.S.). Briefly, the BRG was determined during quiet rest as the slope of the linear relationship between the probability of bursts occurring (BI) at any given diastolic blood pressure (DBP). DBP was determined in 2 mm Hg bins, and burst probability was the percentage of heart beats with bursts occurring/those without bursts. To correct for differences in the number of data points at each diastolic bin, we performed weighted regressions using SPSS (v26; IBM, Armonk, NY). BRG was also determined using total activity (amplitude–incidence) as the dependent variable.

For NVT, MSNA and hemodynamic variables were extracted on a beat-by-beat basis during the resting period (duration was 10.4 ± 3.5 min), saved to Excel spreadsheets and subsequently analyzed using custom software written in MATLAB (The MathWorks, Natick, MA) as previously described (10). Briefly, burst sequences were determined as sequence of heart beats with burst(s) of activity occurring preceded by one heartbeat without a burst and proceeded by one heartbeat without a burst. Nonburst sequences represent the opposite (sequences of heartbeats without MSNA) and give information about the vascular changes in the absence of neural activity. The magnitude of change in MAP was determined after both burst and nonburst sequences according to the sequence type (e.g., singlets, doublets, triplets, and quadruplet+). NVT slopes were determined using a weighted linear regression (SPSS v26; IBM) comparing the increase in MAP with the total MSNA defined according to the mean sum of burst amplitudes within a sequence type that was subsequently separated by quartiles (i.e., 16 data points of increasing total activity). For these, the average amplitude of the lowest quartile within the singlet sequence type was set to 100, and all other quartiles/sequences were scaled according to this (i.e., increasing in total activity). Slopes were deemed adequate if the linear regression was significant (P < 0.05) and r > 0.5 (intermediate and large effect size) (24). CPT reactivity was determined as the increase in MSNA from baseline to the maximal point during the CPT. This was determined as the 1-min segment with the greatest change in MSNA during CPT (14). Accelerometry was analyzed using Actigraph (LLC, Pensacola, FL) by determining the amount of activity occurring in the moderate-to-vigorous intensity category if it occurred for at least 10 min (25). The total time in these 10-min bouts (but not all MVPA) was averaged over a 7-d period (i.e., per week) and compared between groups at each time point.

Statistical analysis

For all outcome variables, we performed intent-to-treat analysis including all women who were randomized. The number of women included in each outcome analysis is reported when it is less than the full group n. All data are reported as mean ± SD, unless otherwise specified. All statistical analyses were performed using GraphPad Prism (v8.4.3). Two-way (group–gestational age) mixed-effects ANOVA was used to assess statistical differences for resting heart rate, blood pressure, basal MSNA, sympathetic BRG, and NVT slopes. This allowed us to determine if there was a main effect of group (i.e., that the control and exercise groups were different from one another), main effect of gestational age (i.e., that there are differences from pre-to-post intervention or between TM2 and TM3), or an interaction effect (i.e., that exercise modified the response across gestation). Post hoc Sidak’s multiple comparison test was used to determine between group differences at each time point where applicable. The change in MAP for each burst and nonburst sequence type (i.e., singlets, doublets, triplets, and quadruplets+) were compared using a three-way mixed-effects ANOVA in GraphPad Prism to compare differences in NVT between sequence type, gestational age, and group; the group–gestational age interaction was also determined from this. Pearson correlations between the change in NVT slopes and the change in resting MSNA BF were completed using GraphPad Prism for all women who had adequate measures at each time point (control, n = 7; exercise, n = 11). CPT reactivity analysis was performed using a three-way mixed-effects ANOVA in GraphPad Prism including time (i.e., minute of CPT), gestational age (i.e., pre–post intervention), and group (control vs exercise) as factors; the group–gestational age interaction was also determined from this. CPT reactivity was further assessed using blood pressure and MSNA data from the peak 1-min bin and compared using two-way mixed-effects ANOVA in GraphPad Prism. P < 0.05 was considered statistically significant for all outcome variables. Where P ≥ 0.05 but less than 0.1, effect size was determined and reported according to https://www.psychometrica.de/effect_size.html; d > 0.8 (large effect size) was interpreted to be a meaningful difference regardless of statistical significance (24,26).

RESULTS

A detailed consort diagram is shown in Figure 1. Briefly, 59 women completed baseline assessments and were randomized into control (n = 28) or exercise conditions (n = 31). Similar numbers of women dropped out of either group; 51 women completed both assessments for the study (n = 23 control, n = 28 exercise). Five women in the control group and three women in the exercise group dropped out before their 34- to 36-wk assessment. Reasons for dropout are shown in Figure 1, and none were specifically related to the intervention. All women delivered healthy babies (i.e., no fetal complications).

FIGURE 1
FIGURE 1:
CONSORT diagram outlining the flow of participants through the study. Randomization occurred after baseline neurovascular assessment was complete. *These values represent the number of women who completed both assessments. Analysis was complete as intent-to-treat and included all women who were randomized (including dropouts). Specific n for analysis varies by outcome and is reported wherever it is less than the group n. PPPH, Program for Pregnancy and Postpartum Health (www.exerciseandpregnancy.ca).

Participant Demographics

Participant demographics (except maternal height), parity, and prepregnancy physical activity were not different between groups at the beginning of the study (Table 1). Women in the exercise group were enrolled in the intervention for an average of 14 ± 1 wk (range, 11–16 wk). Twenty-four (86%) of 28 women who completed the study in the exercise group were compliant (completed at least 75% of the prescribed exercise). Regardless, intention-to-treat analysis including data from all women who were randomized was complete for the outcomes from this study. However, it should be noted that the same results are present when considering only those women who were compliant to and completed the intervention (data not shown). At the midpoint (26–28 wk), data from accelerometry show that women in the control group had decreased their MVPA an average of 41 ± 69 min, whereas women in the exercise group increased their MVPA an average of 21 ± 86 min (P = 0.011) over preintervention levels.

TABLE 1 - Participant demographics, parity, and prepregnancy physical activity levels (all randomized participants)
Control Exercise P
Participant demographics, mean (SD)
 No. women 28 31
 Age, yr 32 (4) 31 (2) 0.251
 Height, cm 168 (6) 165 (8) 0.034
 Prepregnancy weight, kg 70 (14) 73 (25) 0.536
 Prepregnancy BMI, kg·m−2 24.6 (4.8) 26.8 (7.8) 0.215
Parity, n (%)
 No. women 27 31 0.974
 Nulliparous 12 (44) 13 (42)
 Primiparous 8 (30) 10 (32)
 Multiparous 7 (26) 8 (26)
Prepregnancy physical activity levels, n (%)
 No. women 25 31 0.311
 Sedentary 8 (32) 10 (32)
 Moderately active 9 (36) 6 (19)
 Active 8 (32) 15 (48)
Data are presented as mean (SD) for anthropometric data and as n (%) for categorical data (parity and prepregnancy physical activity levels). Prepregnancy data were determined from self-report at 16–20 wk of gestation. Prepregnancy physical activity category was determined using the Godin score (27). Statistical analysis was performed using GraphPad Prism (v8.4.3). Anthropometric data were compared between groups using an unpaired t-test. Parity and prepregnancy physical activity data were compared using the χ2 test.

Resting Hemodynamics

All values (mean ± SD) for resting hemodynamics are presented in Table 2. As expected, resting heart rate increased with gestation (main effect of gestational age, P < 0.0001); however, this increase was attenuated in the exercise group (P = 0.002, interaction effect). Resting blood pressure (systolic blood pressure (SBP), DBP, and MAP) was not different between groups at any time point. MAP and DBP were shown to increase (main effect of gestational age, P < 0.0001), but SBP was not different between TM2 and TM3 (main effect of gestational age, P = 0.248). Contrary to our hypothesis, there was no interaction between gestational age and group (i.e., no effect of intervention) on resting blood pressure (interaction effect: P = 0.241, 0.175, and 0.149 for SBP, DBP, and MAP, respectively). All women, at all assessments, were normotensive. There were no differences between groups for resting Q˙ (main effect of group, P = 0.508), and there was an intermediate effect (d = 0.565) for an increase in Q˙ during the study (main effect of gestational age, P = 0.055); however, there was no interaction between group and gestational age (P = 0.959). SVR was not different across gestation (P = 0.541, main effect of gestational age) or between groups (main effect of group, P = 0.114), and there was no interaction between group and gestational age (P = 0.494).

TABLE 2 - Summary of data for all basal hemodynamic variables and sympathetic BRG.
Control Group Exercise Group P
Preintervention Postintervention Preintervention Postintervention
n Mean (SD) n Mean (SD) n Mean (SD) n Mean (SD) Group Gestational Age Interaction
Gestational age, wk 28 18 (1) 23 35 (2) 31 18 (2) 28 34 (1) n/a
Heart rate, BPM 28 76 (7) 23 88 (11) 31 82 (8) 28 86 (8) 0.238 <0.0001 0.002
SBP, mm Hg 28 108 (11) 23 111 (12) 31 110 (11) 28 110 (9) 0.739 0.248 0.241
DBP, mm Hg 28 61 (7) 23 68 (7) 31 65 (7) 28 62 (8) 0.160 <0.0001 0.175
MAP, mm Hg 28 79 (8) 23 85 (7) 31 83 (7) 28 86 (8) 0.222 <0.0001 0.149
Q˙, L·min−1 28 7.8 (1.8) 22 8.2 (1.8) 31 7.5 (1.6) 28 7.8 (1.6) 0.508 0.055 0.959
SVR, mm Hg·L−1·min−1 28 837 (133) 22 859 (151) 31 909 (172) 28 910 (156) 0.114 0.541 0.494
BRG (probability slope) 14 −5.29 (2.54) 11 −5.17 (1.82) 15 −5.51 (1.99) 16 −4.83 (2.13) 0.429 0.369 0.762
BRG (total MSNA slope) 14 −506 (218) 11 −552 (185) 15 −581 (258) 16 −530 (302) 0.902 0.966 0.461
Bold indicates significance (P < 0.05).
Statistics determined as an intent-to-treat analysis using mixed-effects ANOVA in GraphPad Prism (v8.4.3).

Basal Sympathetic Activity

We successfully obtained 56 adequate MSNA recordings from women in this study (out of a total of 109 assessments). The women in whom we obtained MSNA were not different in maternal age, height, prepregnancy weight or body mass index (BMI), or weight at assessment compared with women who did not have MSNA recordings (data not shown). Data are presented as intent-to-treat analysis including all available assessments (i.e., all women who were randomized).

The changes in basal MSNA during the intervention are shown in Figure 2. Briefly, there was a main effect of gestational age such that MSNA BF and BI were increased in TM3 compared with TM2 (main effect of gestational age; P = 0.002 and P < 0.001, respectively). There was no main effect of group for MSNA BF or BI (P = 0.097 and P = 0.197, respectively). However, Sidak’s multiple comparisons post hoc test revealed that the groups were different at the preintervention time point for both BF and BI (P = 0.009 and P = 0.027, respectively), such that women in the exercise group had higher resting MSNA than did the control group before the intervention but were not different after then intervention (P = 0.999 and P = 0.996, respectively). In line with our hypothesis, we did observe an interaction between group and gestational age such that women randomized to the exercise group had smaller increases in MSNA BF and BI during the intervention period (i.e., from TM2 to TM3) compared with the control group (interaction effect; P = 0.010 and P = 0.002, respectively). Baseline burst amplitude was set to 100% for all women (see Data Analysis); therefore, neither resting burst amplitude nor total MSNA (amplitude–BF; in arbitrary units) were compared.

FIGURE 2
FIGURE 2:
Basal MSNA. Preintervention data (trimester 2) is shown in white bars, and postintervention data (trimester 3) is shown in gray bars. Individual data are presented with lines connecting women in whom we have obtained MSNA signal at both time pints (n = 9 control group, n = 12 exercise group); the n is shown for each group/time point within the bars. A, Basal MSNA BF. The rise in MSNA BF across gestation is attenuated in women in the exercise group. B, Basal MSNA BI. The rise in MSNA BI across gestation is attenuated in women in the exercise group.

Contrary to our hypothesis, sympathetic BRG, assessed as weighted probability slope (11) was not different across gestation (main effect of gestational age, P = 0.300) or between groups (main effect of group, P = 0.258), nor was there a group–gestational age interaction (i.e., effect of the exercise intervention; P = 0.691, interaction effect). The same was true if sympathetic BRG was assessed using total MSNA as the dependent variable (Table 2).

Neurovascular Transduction

Burst sequences

There were no differences between groups in the percentage of bursts occurring in each of the sequence types (singlet, doublet, triplet, quadruplet+; main effect of group, P = 0.974). As expected, there was a main effect of sequence type (P < 0.001) such that there was a greater proportion of smaller sequences (i.e., more singlets). There were no group–gestational age interactions for the distribution of bursts (P = 0.994).

There was a main effect of sequence type for the peak increase in MAP after burst sequences (P < 0.0001) such that larger burst sequences were associated with larger increases in MAP. There was no effect of group or gestation on the magnitude of the MAP response when considering sequences of SNA bursts (P = 0.5988 and P = 0.676, respectively; Fig. 3A, top). There was also no interaction between group and gestational age (i.e., no impact of exercise on the response to advancing gestation, P = 0.575) for the peak MAP response for each sequence type.

FIGURE 3
FIGURE 3:
NVT. A, Changes in MAP after bursts (top) and nonbursts (bottom) of MSNA. MAP response to singlets, doublets, triplets, and sequences with four or more bursts (quadruplets+). Bars represent the mean (SD) response for each group. Preintervention (trimester 2, or TM2) data are shown in solid bars for the control and exercise groups (control group, black; exercise group, white), and postintervention (trimester 3, or TM3) data are shown with hatches (control group, thick black and gray lines; exercise group, white with thin black lines). B, Individual and mean changes in NVT during the intervention. The control group is shown in the left, and the exercise group is shown on the right. Bars represent the group mean (white, preintervention, TM2; gray, postintervention, TM3). Symbols represent individual data points with lines connecting women who had measures at both preintervention and postintervention (circles and squares, respectively). There was an observed blunting across gestation for the MAP NVT slope. C, Correlation between the change in MSNA BF and the change in the MAP NVT slope. The control group is shown in filled black circles, and the exercise group is shown in open white circles. The x-axis represents the absolute change in MSNA BF from preintervention to postintervention, whereby positive values (right side of the axis) represent an increase in MSNA BF across gestation and negative values (left side of the axis) represent a decrease in MSNA BF across gestation. The y-axis represents the absolute change in the MAP NVT slope from preintervention to postintervention, whereby a negative value (below the axis) represents a blunting of the NVT slope (i.e., lesser gain) with advancing gestation and positive values (above the axis) represents an increase in NVT slope (i.e., higher gain) with advancing gestation. Pearson correlation showed a significant correlation between the two measures.

Nonburst sequences

There were no group or gestational age differences in the distribution of nonburst sequences across the four sequence types (P = 0.728 and P = 0.780, respectively). There was a main effect of sequence type (P < 0.0001), which shows a greater proportion of nonbursts occurring in quadruplets+ sequences. Similar to bursts, there was a main effect of sequence type for the nadir MAP response after a nonburst sequence (P < 0.0001) such that larger sequences resulted in greater drops in MAP (Fig. 3A, bottom). There was no effect of gestational age (P = 0.141), but there was a main effect of group (P = 0.037) for the nadir MAP after nonburst sequences such that women in the exercise group (at both time points) had larger drops in MAP after nonburst sequences. However, there was no interaction between group and gestational age (P = 0.609), suggesting no effect of exercise on this observation.

NVT slopes

NVT slopes were determined evaluating the linear relationship between the increase in total MSNA and MAP. Using this approach, we observed a blunting of the NVT gain (slope) in TM3 (P = 0.029, main effect of gestational age; Fig. 3B). However, Sidak’s multiple-comparison post hoc test revealed that this was only true in the control group (P = 0.024) and that there was no difference in the NVT slope between TM2 and TM3 in the exercise group (P = 0.873). Previously, we showed an inverse relationship between basal SNA and transduction slope in TM3 (10). In the current study, we demonstrate that the change in MSNA BF with gestation is correlated with the concurrent change in NVT slope (Fig. 3C). Regardless of group or compliance, women who increased their MSNA BF were more likely to have a decrease in NVT slope (i.e., blunted) as shown in the lower right quadrant of Figure 3C. Similarly, women who had a reduction in MSNA BF during their pregnancy increased their NVT slope as shown in the upper left quadrant of Figure 3C.

CPT Response

CPT data were analyzed using a three-way (group–gestational age–time) mixed-effects ANOVA using raw data (i.e., absolute values). Peak changes during CPT (i.e., the minute with the largest change) were also analyzed using a two-way mixed-effects ANOVA to account for baseline differences in outcome variables. Heart rate was increased during CPT (main effect of time, P < −0.0001) and was higher in the postintervention time point (main effect of gestational age, P < 0.0001), but was not different between the control and exercise groups at either time point (main effect of group, P = 0.160), nor was there an interaction between group–time (P = 0.127). The peak increase in HR during CPT was not different between groups (P = 0.862) or across gestation (P = 0.248), nor was there a group–gestational age interaction (P = 0.131).

The group MAP responses to the CPT are shown in Figure 4A. Briefly, there is a main effect of time such that MAP is increased during the CPT (P < 0.0001). Here we show augmentation in this response between preintervention and postintervention (main effect of gestational age, P < 0.0001), which is echoed in the peak MAP analysis (main effect of gestational age, P = 0.011; Fig. 4B). That is to say, the increase in MAP during CPT is larger in TM3 compared with TM2. However, there was no difference between control and exercising women (main effect of group, P = 0.259) and no interaction between group and gestational age (i.e., no effect of the exercise intervention on the pattern of the response, P = 0.571). The peak responses (defined as the minute with the highest MAP on an individual basis) are shown in Figure 4B. These data also show that there is no effect of group (P = 0.295) or interaction (P = 0.980) for the MAP response to CPT. SBP and DBP showed similar responses to CPT and are therefore not shown.

FIGURE 4
FIGURE 4:
A, Minute-by-minute responses in MAP during the CPT. Data represent the mean (SD) responses in each group at preintervention and postintervention. The control group is shown in black symbols and the exercise group in open circles. The preintervention (trimester 2, or TM2) is shown in the left-hand box, and the postintervention (trimester 3, or TM3) is in the right-hand box. There is a main effect of time such that MAP is increased during CPT, and the increase in MAP during CPT is augmented in TM3, but there is no effect of exercise on the MAP response to CPT. B, Data represent the individual peak responses during the CPT (i.e., the minute with the largest change in MAP during CPT on an individual basis) from preintervention (TM2, mean response shown in white circles) to postintervention (TM3, mean response shown in gray circles). There is an effect of gestational age such that the peak increase in MAP during CPT was larger in the third trimester (i.e., postintervention). C, Minute-by minute responses in MSNA BF during CPT. The symbols are the same as the MAP response. There is a main effect of time such that MSNA is increased during the CPT but no effect of group, gestational age, or interactions. D, MSNA BF peak responses during CPT. There was no significant effect of group, gestational age, or interaction for the peak MSNA response during CPT.

The sympathetic nervous system response to CPT was evaluated in a subset of women and was also analyzed as intent-to-treat including all data from women who were randomized. The minute-by-minute group mean MSNA BF responses during CPT are shown in Figure 4C. Briefly, there was a main effect of time (P < 0.0001) such that MSNA was increased during CPT. However, there was no effect of gestational age (P = 0.605), group (P = 0.451), or a group–time interaction for MSNA BF (P = 0.790). Similarly, the peak MSNA BF response during CPT is shown in Figure 4D and shows no effect of group (P = 0.795), gestational age (P = 0.709), or an interaction between the two (P = 0.766). MSNA BI and total MSNA showed similar responses to CPT and are therefore not shown.

DISCUSSION

Prenatal exercise has been associated with a 40% reduction in the odds of developing hypertension during pregnancy (18). Because hypertensive disorders of pregnancy affect up to 10% of the population (28) and result in long-term cardiovascular consequences for both mother and child (29), understanding how best to prevent them is of utmost importance. We conducted a randomized controlled trial investigating sympathetic neural control of blood pressure; our data suggest that structured prenatal exercise attenuates the normative increase in basal MSNA with gestation, without impacting blood pressure or BRG. Women who were randomized to engage in structured aerobic exercise during their second and third trimesters had smaller increases in MSNA throughout pregnancy and less blunting of NVT (i.e., the functional reactivity of peripheral blood vessels to sympathetic stimulation). Therefore, prenatal exercise may act through the sympathetic nervous system to elicit neurovascular adaptations that decrease hypertension risk and promote cardiovascular health.

Exercise intervention

We prescribed pregnant women in the exercise group to participate in three to four moderate-intensity aerobic exercise sessions for the duration of the intervention (~14 wk) based on the 2003 Canadian Clinical Practice Guideline (22) and heart rate zones outlined in the PARmed-X for Pregnancy (20). Since then, the 2019 Canadian Guideline for Physical Activity throughout Pregnancy was developed (30), which recommends 150 min of moderate-intensity aerobic exercise per week. We recognize that the prescription in the present study falls below these new guidelines and that we may have observed greater changes in resting hemodynamics if we had prescribed according to the new guideline. However, the threshold to alter sympathetic nervous system regulation may be lower. First, we have recently shown that as little as 260 MET·min of exercise per week (i.e., 60-min moderate-intensity walking) can reduce the odds of preeclampsia in pregnancy by at least 25% (18). Second, in nonpregnant populations with sympathetic hyperactivity (e.g., patients with myocardial ischemia), as little at 4 wk of aerobic exercise training (walking at 60% HRpeak, 160 min·wk−1) has been shown to lower MSNA and improve sympathetic BRG (31). In keeping with these previous studies, we believe that our prescribed exercise (achieving 50%–70% heart rate reserve for 120–160 min·wk−1) was sufficient to elicit measurable sympathetic adaptation. Furthermore, in the present randomized controlled trial, 51 of 59 women completed the study (86% retention rate; dropout similar between groups) and 86% of the women in the exercise group achieved 75% of the prescribed exercise.

In the present study, we also observed a decrease in physical activity in women in the control group. Importantly, these participants were not advised to reduce their physical activity levels, but rather did so of their own volition. It is estimated that as many as 85% of pregnant women do not meet the guideline for physical activity throughout pregnancy (32), and as such, this was not unexpected. However, it may have accentuated our findings by increasing the difference in physical activity between the two groups to a greater extent than the exercise prescription alone. Regardless, these data mimic realistic effects of current prenatal care practices, and as such do represent realistic responses of the sympathetic nervous system to normal pregnancy in the absence of physical activity prescription.

It is important to recognize that exercise interventions may exert influences via parallel adaptations. In otherwise healthy women with obesity, 12 wk of aerobic training (40-min cycling, 3 d·wk−1) has been shown to lower resting MSNA and MSNA reactivity during static hand grip or mental stress (19). However, in these aforementioned studies, weight loss without exercise also reduced resting MSNA, highlighting the importance of accounting for differences in weight-gain/loss trajectories. In the present study, none of the participants lost weight during the course of the exercise intervention, and gestational weight gain did not differ between study groups at any time point. Therefore, we expect the results we have observed are the result of the exercise intervention and not any parallel changes in body weight.

Resting hemodynamics

As expected, we observed an overall increase in heart rate and blood pressure between TM2 and TM3. The increase in heart rate was attenuated in the women who participated in the exercise intervention, which is a well-documented effect of exercise training that extends into pregnancy (33). Interestingly, there was no interaction of group and gestational age with respect to resting blood pressure, indicating that women in both groups had similar increases in blood pressure from mid-to-late pregnancy. Two women randomized to the control group developed hypertensive disorders of pregnancy, which aligns with population estimates (28). In contrast, no woman in the exercise group developed hypertensive disorders of pregnancy, which aligns with a recent systematic review and meta-analysis demonstrating that prenatal physical activity reduced the odds of developing hypertensive disorders of pregnancy (18). Therefore, although we did not observe a statistically significant interaction effect with respect to MAP, there was a moderate effect size (24), and post hoc sample size calculations (G-Power3) (34) suggest that there would be differences in MAP between exercise and control women with a larger sample size (78 women per group needed; i.e., likely to occur at the population level). It is worth noting that exercise did not impact resting SVR or cardiac output, which may indicate functional adaptations of the vasculature (i.e., vasodilation). Furthermore, this may indicate changes in cardiac function, which have been previously reported to change both with respect to advancing gestation (2,35) and with exercise training (36). However, in the present study, cardiac output and SVR were determined using the model flow algorithm from the Finometer and are not validated in pregnancy (37); therefore, our interpretation of these data is limited.

Resting MSNA

We know very little about the changes in MSNA during the first half of pregnancy. To date, there have been measures of MSNA in only 22 women in the TM2 (5), and existing evidence would suggest that MSNA may not be different from the nonpregnant state at this point despite observations that MSNA is increased during early (6 wk) gestation (7,8,13). In the present study, there were apparent differences between the control and exercise groups in resting MSNA BF in the second trimester that were unexpected and the result of randomization. Nonetheless, we have shown that the increase in MSNA during the intervention (i.e., from TM2 to TM3) was blunted in women who engage in structured aerobic exercise program.

The present study adds significantly to the limited literature on MSNA in TM2 and highlights the variability in the responses in the first half of pregnancy. Here we show that resting MSNA in TM2 ranged from 16 up to 55 bursts per minute. There is no evidence that this variability is due to differences in maternal age, prepregnancy BMI, or gestational weight gain, as they were not different between study groups. Furthermore, these factors (age, BMI, GWG) were recently shown to have no effect on MSNA BF in TM3 (38). Although Badrov et al. (39) have recently reported that MSNA BF may be increased with increasing parity (i.e., higher in the second pregnancy compared with the first), there were no differences between our two study groups and likely not the cause of the disparity. Based on the findings that aerobic exercise intervention attenuates the increase in MSNA between TM2 and TM3, physical activity levels (including prepregnancy fitness) may have played a role in the changes in basal MSNA before the initiation of this intervention. Future studies that are able to include longitudinal measures starting at prepregnancy will be of utmost importance in continuing to answer these questions.

It is possible that the higher MSNA BF at TM2 may have led to the smaller increase in MSNA across gestation; however, we do not feel that this is the case for two reasons. First, MSNA BF in TM3 ranged from 22 to 54 bursts per minute, which is in line with previous measures in the third trimester (5). Second, BI measures in TM3 ranged from 32 to 64 bursts per 100 heart beats; a maximal value for this measure would be 100, and reports would suggest values >75 have been measured in human pregnancy (40), indicating that the measures in this study are not maximal (i.e., could still have increased further). Furthermore, MSNA BI was not different between the groups at TM2 but was still influenced by our intervention. Regardless, the aim of this study was to determine the effect of exercise on the change in MSNA from TM2 to TM3, which was attenuated in the exercise group in this study. Therefore, evidence from this study suggests that physical activity has an important influence on basal MSNA during pregnancy. Future studies investigating chronic physical activity patterns and fitness on the MSNA responses in pregnancy are needed to elucidate the reasons for the large variability that we are seeing as early as 16 wk.

Although it is unclear how exercise is altering the normative changes in MSNA in human pregnancy, it may also be that changes are occurring at other locations along the neurovascular pathway (i.e., not just MSNA per se). These include potential changes in neurotransmitter release and reuptake, α-adrenergic receptor sensitivity and density. Indeed, normal pregnancy has been shown to increase neurotransmitter concentrations parallel to the increase in MSNA (8,41), and therefore, we may expect neurotransmitter release to be lesser in women who exercise. Normotensive pregnancy may be also associated with an increase in α- and β-adrenergic receptor density and sensitivity (42); however, this evidence is limited to the uterine artery. Furthermore, sex hormone concentration may be correlated with basal MSNA during pregnancy (5) and have been shown to be modified by physical activity (43). Lastly, an increase in soluble-fms–like tyrosine kinase to placental growth factor (sFlt-1:PlGF) is implicated in the pathogenesis of gestational hypertension (44). Pregnant women who are more physically active have been previously shown to have a lower ratio of sFlt-1:PlGF indicating better angiogenic balance (45). Therefore, we suspect the attenuated rise in MSNA to be multifaceted and likely a combination of the aforementioned factors. Future studies are needed to evaluate these mechanisms in more detail.

Baroreflex gain

Contrary to previous reports, we did not observe a blunting of the weighted probability slope for the sympathetic baroreflex with advancing gestation. However, previous reports compared TM3 to nonpregnant women (11), and thus, BRG may have already been blunted by the second trimester. We measured sympathetic BRG (based on burst probability) in the same manner as our previous report (11) and show a similar average slope in TM3. Longitudinal case study reports on three women (7,13) suggest that there are interindividual differences in the pattern of the sympathetic BRG response to pregnancy; however, from these, no discernible pattern could be elucidated. Within the context of this study, we suggest that sympathetic baroreflex is not altered between TM2 and TM3 and also that exercise occurring between mid-to-late pregnancy does not affect the change in BRG during this time. Here we also report BRG based on total MSNA in pregnancy. This measure has been reported once in pregnancy (39); however, a comparison of BRG based on total MSNA between pregnant and nonpregnant women or between trimesters has not been evaluated, and therefore, our results are difficult to interpret in the context of changes during a normal pregnancy. One limitation of this method is that we used spontaneous BRG assessment rather than the gold-standard modified Oxford procedure (i.e., injections of blood pressure lowering and raising medications), as it is not recommended in pregnancy (8). However, the spontaneous BRG method is validated against the modified Oxford protocol (46), and thus, we do not feel that our results would have been altered by a different methodology in this instance. In both healthy and unhealthy (e.g., hypertension) nonpregnant populations, aerobic exercise interventions have shown improvement in BRG compared with controls (19). Future studies need to investigate baroreflex function starting with prepregnancy measures and continue longitudinally throughout pregnancy to determine the full effect of both advancing gestational age and exercise on BRG in pregnancy.

Neurovascular transduction

Similar to our previous work (10), we found that sympathetic NVT was blunted in TM3 compared with TM2; this blunting was most pronounced in the control group. We acknowledge here that our sample size is relatively small, partially because of the high incidence of presyncope during MSNA search in pregnant women (47) and obtaining adequate quality repeated-measures MSNA signals. A post hoc sample-sized calculation based on our data would suggest that 25 women per group would be needed to detect a significant difference in NVT slope change across gestation. In addition, we have previously shown that the relationship between basal SVR and MSNA is blunted in TM3 (14) and possibly in early and midpregnancy (13,48). Combined with the data from the present study, these would suggest that the blunting of NVT is related to the increase in MSNA that occurs in typical normotensive pregnancy, which may be attenuated by aerobic exercise. Indeed, here we show that changes in NVT were correlated with changes MSNA BF, which supports this notion. We have also previously shown that the decrease in MAP after nonburst sequences is unaltered in TM3 compared with nonpregnant controls (10), which was attributed to no difference in vasodilatory mechanisms between pregnant and nonpregnant women. The fact that we see no difference in the decrease in MAP after sequences without bursts in the present study suggests that the underlying vasoconstrictor tone is similar between conditions (i.e., with respect to both gestation and exercise) and complements the previous literature. Together, these data are important because it suggests that an increase in MSNA during pregnancy is not necessary to maintain the same blood pressure. Thus, we posit that augmented MSNA is a consequence of pregnancy per se and not reflex engagement to counter lower vascular resistance.

In the current study, we evaluated NVT based on MAP. Although the communication between MSNA and the vasculature occurs within the resistance vessels, we feel that within a clinical context MAP may be a better and more relevant representation than peripheral (forearm or femoral) vascular conductance, as it represents the systemic/total body effects. In nonpregnant populations where transduction has been evaluated in terms of both local and systemic vasoconstrictions (or a decrease in conductance), the interpretation of the results remains the same if only MAP is considered (49). Furthermore, for some populations, differences between groups may only exist if MAP is considered (e.g., Black vs White males) (50). To date, there have been no observations that forearm or calf vascular resistance is altered in pregnancy. Despite this, Jarvis and colleagues (8) showed that the ratio between resting forearm vascular resistance/MSNA is decreased in the first trimester. Therefore, future studies should investigate the potential differences in local versus systemic vascular transduction in pregnancy. This would be of especial importance in women who are at high risk for hypertension, as they may have altered sympathetic regulation before diagnosis (17).

Reactivity to CPT

In the current study, there was no effect of gestational age or exercise on the sympathetic or blood pressure response to CPT. The CPT is a safe and effective tool to evaluate hemodynamic and sympathetic responsiveness during pregnancy and has been utilized in both healthy and hypertensive pregnancies (51). A larger blood pressure response to CPT in midpregnancy has been previously shown to precede the development of preeclampsia (15); however, this elevated blood pressure responsiveness to CPT has not been observed in cross-sectional studies comparing pregnant women with and without hypertension (12,52). In nonpregnant populations, aerobic exercise has been shown to reduce the responsiveness of the sympathetic nervous system to mental stress and handgrip/knee extension exercise, but not CPT, head-up tilt, or Valsalva (19). The pathways that activate MSNA during CPT (i.e., nociceptors) are different from those in the aforementioned studies (e.g., metaboreceptors), which may explain the differences in response/lack of response to aerobic exercise. Furthermore, we did not control for respiration at rest or during the CPT in the present study. Advanced gestation is associated with increases in minute ventilation, which can influence MSNA (53). Changes in ventilation during the CPT (e.g., deep breathing or hyperventilating) could potentially affect our results such that deep breathing may lower the MSNA response, whereas hyperventilating may increase the response (54). Future work should measure and control for ventilation when performing CPT or other reflex maneuvers in pregnancy. Lastly, CPT reactivity was a secondary (exploratory) outcome and the study sample size was not determined to detect significant changes in the MSNA or BP response to CPT. Using the data obtained from the current study, we estimate that 218 women per group would be needed to detect a difference in the peak MSNA BF response during CPT. Therefore, we are uncertain whether aerobic exercise would affect CPT reactivity in otherwise healthy pregnant women. Future studies investigating this in women who are at high risk for gestational hypertension (e.g., obese) or who have developed gestational hypertension might be able to ascertain if there are populations whose reactivity to stress (e.g., CPT) can be positively altered by aerobic exercise intervention.

Future directions

Within the current study, we examined the role of a structured prenatal aerobic exercise program on basal and reflex MSNA, sympathetic baroreflex, and the NVT (MAP response). Exercise during pregnancy may oppose the abnormal remodeling that occurs in gestational hypertension and preeclampsia through the indirect actions at the level of the vasculature (55). Whether the longitudinal changes across gestation result in differences in forearm or femoral blood flow, reactivity, or transduction is yet to be elucidated. Aerobic exercise may alter blood pressure regulation through improvements in vascular function (i.e., enhanced endothelial function) (56). Data from our nonburst sequences would suggest that basal vasodilatory status is not altered by prenatal physical activity; however, the ability to dilate in response to increases in shear stress may be enhanced with aerobic exercise (57). Prenatal physical activity in the third trimester is associated with increases in normalized flow-mediated dilation (58), and one randomized controlled trial showed that aerobic exercise intervention may increase flow-mediated dilation in pregnancy (27). Furthermore, normal pregnancy is associated with a curvilinear change in arterial stiffness that mirrors SVR and blood pressure (55). Exercise is associated with decreases in arterial stiffness in nonpregnant (59) and recently in pregnant populations (60) and may influence blood pressure control through the direct actions on the vasculature (i.e., remodeling). As reviewed by Green and Smith (57), exercise exerts positive cardiovascular benefit through flow-dependent and endothelium-meditated dilation and remodeling; the sympathetic nervous system plays a role in centrally mediating the functional changes that result in structural adaptations. However, functional or structural changes in specific peripheral vascular beds (e.g., forearm or femoral) may be occurring in response to aerobic exercise during pregnancy and have not yet been considered. Future work in both humans and animal models addressing blood vessel specificity and reactivity will help determine the mechanisms by which prenatal exercise improves cardiovascular health and reduces hypertensive risk. Specifically determining the effects of aerobic exercise on sympathetic neurotransmitter receptor density and sensitivity would help fill in some of the current gaps, in our knowledge.

Despite the overwhelming evidence that prenatal exercise is beneficial for most women, 85% of pregnant women are not meeting exercise guidelines (61). Moreover, up to 10% of pregnant women will develop hypertensive disorders of pregnancy (28). Gestational hypertension is associated with sympathetic hyperactivity, as such the data from our exercise intervention provide some insight into ways by which prenatal exercise might oppose this (i.e., by reducing the increase in MSNA across gestation). Prenatal exercise has been shown to reduce the odds of developing hypertension and preeclampsia by up to 40% (18) and therefore is of importance when considering the long-term cardiovascular health of these women and their children. These data provide a potential mechanism underlying the reduced odds of developing hypertensive disorders of pregnancy in physically active pregnant women. Specifically, the communication between the nervous system and the blood vessels (i.e., NVT) is less changed in women who participated in the structured aerobic exercise program despite the attenuation of the normal increase in MSNA during a normotensive pregnancy. Decreasing the amount of sympathetic hyperactivity while not disrupting blood pressure control (e.g., sympathetic baroreflex and CPT reactivity) may also facilitate long-term vascular adaptations that promote lifelong cardiovascular health. However, more research is needed to fully elucidate the mechanisms behind which the risk of gestational hypertension is reduced by prenatal exercise including the vascular component. Specifically, more research is needed involving women who are at high risk for developing gestational hypertension (e.g., women with history), as the improvements may be greater in this population.

Conclusions

The aim of the present study was to determine whether a structured aerobic exercise program could alter the normative responses of the sympathetic nervous system during pregnancy. Here we show that prenatal aerobic exercise attenuates the increase in MSNA and possibly the decrease in NVT between the second and third trimesters. Thus, the communication between the nervous system and the blood vessels seems to be less changed at rest in women who performed aerobic exercise. Interestingly, resting blood pressure and CPT reactivity were not altered in this study; however, all women were normotensive. We know that gestational hypertension risk is reduced by prenatal exercise (18), and these data show that the sympathetic regulation of blood pressure may be one mechanism behind this observation.

This research has been funded by the Natural Sciences and Engineering Research Council of Canada (RGPIN 05205 (G. M. F.), RGPIN 06637 (C. D. S.), RGPIN 07219 (M. H. D.) and the Heart and Stroke Foundation of Canada (HSFC; G-16-00014033 (M. H. D. and C. D. S.). R. J. S. is funded by a Women and Children’s Health Research Institute Graduate Studentship, Canadian Institute of Health Research Doctoral Award, and Alberta Innovates Health Innovations Graduate studentship. C. D. S. is funded by an HSFC Joint National and Alberta New Investigator Award (C. D. S.). M. H. D. is supported by the Christenson Professorship in Active Healthy Living and an HSFC Joint National and Alberta Improving Hearth Health for Women New Investigator award (M. H. D.).

The authors report no conflict of interest.

The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. Results of the present study do not constitute endorsement by the American College of Sports Medicine.

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Keywords:

NEUROVASCULAR TRANSDUCTION; SYMPATHETIC NERVOUS SYSTEM; SYMPATHETIC BAROREFLEX GAIN; COLD PRESSOR TEST

Copyright © 2020 by the American College of Sports Medicine