Key words
preeclampsia - HELLP syndrome - arterial stiffness - pulse wave velocity - cardiovascular
risk
Introduction
Up to 8% of pregnant women suffer from a hypertensive disorder of pregnancy such as
preeclampsia, and the incidence is increasing [1], [2]. Preeclampsia is regarded as the leading cause of maternal death in industrialised
nations [3], [4], [5]. Apart from the short-term morbidity, preeclampsia increases the long-term cardiovascular
risk [6]. Women who have had preeclampsia suffer cardiovascular and cerebrovascular events
such as heart attack, heart failure, stroke and terminal kidney failure more often
and earlier [6], [7], [8], [9]. Cardiovascular diseases, in particular, have been accepted for decades as the leading
cause of death globally independent of sex [10]. In Germany alone cardiovascular diseases were the main cause of death in 2015,
with 365 000 deaths (39% of all deaths) and the disease costs were 46.4 billion Euro
(13% of total costs) [11], [12]. Consequently, not only the immediate treatment of hypertensive disorders of pregnancy
[13], but also the (secondary) prevention of cardiovascular disease following hypertensive
disorders of pregnancy is one of the major challenges of innovative medicine in the
21st century.
Regular physical activity can have a positive effect on the lifetime risk for cardiovascular
disease, including after preeclampsia [14], [15]. Both the American Heart Association and the European Society of Cardiology proclaim
in their guidelines at least 75 min of intensive or 150 min of moderately intensive,
aerobic exercise weekly – regardless of pre-existing disease or risk factors – as
cardiovascular prevention for the entire population [16], [17].
Apart from regular physical exercise in the form of active sport, a varied and regular
diet low in carbohydrate and salt and with reduced saturated fatty acids and high
in protein is essential [18], [19], [20], [21].
Pregnancy can also be regarded in otherwise clinically healthy women as a “window
to future health” [22], [23], [24], [25]. In this connection, therefore, the postpartum assessment of cardiovascular health
risks and secondary and tertiary preventive treatment are of great importance.
Arterial stiffness is an important biomarker for predicting cardiovascular events.
Vascular stiffness and thus vascular age increase due to structural changes in the
vessel walls with endothelial dysfunction. Because of the increase in velocity of
the pulse wave generated in systole, this leads to earlier reflection of this in the
periphery and thus to an increase in cardiac afterload. Arterial stiffness is measured
non-invasively by means of pulse wave velocity.
Sanders et al. [26], referring in their comments to Zieman et al. [27], conclude that vascular stiffness can be used as a treatment goal even in a young
population with cardiovascular risks but that studies must show evidence of an improvement
in the results due to treatment-related changes [26], [27].
Arterial stiffness has become an interesting target and the focus of scientific interest
because it is measured non-invasively by aortic pulse wave velocity (aPWV) and it
is readily available and reproducible including in pregnant women and in the puerperium
[28]. Kaihura et al. [29] showed that arterial stiffness is significantly increased at the time of delivery
in women with preeclampsia compared with healthy pregnant women. In both the short
and long term, arterial stiffness and therefore biological vascular age remain markedly
elevated in the group of women who have had preeclampsia [29], [30]. Scholten et al. [14] presented data from an exercise intervention for 12 weeks in women following preeclampsia
6 – 12 months postpartum. They found an improvement in metabolic syndrome factors
in the post-preeclampsia and
control group but no normalisation of the vascular variables in the women who
had had preeclampsia [14]. Thus, both the intervention duration and the timing of the intervention after preeclampsia
appear to influence the success of vascular normalisation.
The aim of this study was the reduction of arterial stiffness after the conclusion
of the puerperium by means of a complex intervention consisting of basic aerobic endurance
exercise and nutritional counselling in women with severe hypertensive disorder of
pregnancy (preeclampsia with or without pre-existing hypertension and/or HELLP syndrome).
In addition, the acceptance, motivation and adherence of the patients with regard
to the planned complex, interdisciplinary, interprofessional and cross-sector interventions
were examined in feasibility analyses.
Methods
Recruitment
The study was conducted at the University Department of Obstetrics and Prenatal Medicine
Halle, (Saale) and at St. Elisabeth and St. Barbara Hospital Halle (Saale) from 2016
to 2019 (ClinicalTrials.gov Identifier: NCT02754778). Recruitment took place over 24 months.
Potential subjects were screened for participation in the study in accordance with
the inclusion and exclusion criteria within 7 days after delivery if they had a severe
hypertensive disorder of pregnancy (preeclampsia with or without pre-existing hypertension
and/or HELLP syndrome) and were invited to take part if the inclusion and exclusion
criteria were met and adequate communication was possible (acquisition). After consenting
to take part in the study, the first study visit took place with randomisation to
the intervention and control group in the ratio 1 : 1 using a web-based random generator
(recruitment).
The inclusion and exclusion criteria and previous findings, especially with regard
to cardiovascular disease were established from the medical history, review of the
maternity log and, if necessary, obtaining previous external reports in the event
of uncertainties.
Inclusion criteria
Women over 18 years with evidence of preeclampsia with or without pre-existing hypertension
and/or HELLP syndrome ([Fig. 1]) on the day of delivery and up to 7 days postpartum after full differential diagnosis
and according to the definition of the 2016 S1 guideline “Diagnosis and treatment
of hypertensive disorders of pregnancy” and who had capacity to give consent were
included [31], [32].
Fig. 1 Definition criteria according to S1 guideline 015/018: Diagnosis and treatment of
hypertensive disorders of pregnancy (as of 12/2013) [45].
Exclusion criteria
Women were excluded who had heart failure > NYHA II, peripheral arterial disease (regardless
of stage) or a serious neurological or orthopaedic disease postpartum, which would
have made exercise training on the bicycle ergometer impossible. Women whose newborn
or premature baby required intensive care at home and who could not have been expected
to make the journey to the weekly exercise session were also excluded.
Discontinuation criteria
If any of the points listed in the exclusion criteria appeared only in the aerobic
basic endurance exercise, these subjects had to drop out of the study.
Internal medicine check-up
The subjects in the intervention group also had a medical check-up 5 weeks postpartum
(± 7 days) to obtain independent medical approval for the exercise intervention.
Reference group of healthy women (inclusion/exclusion criteria)
In the participating hospitals, the same number of women without a history or diagnosis
of pregnancy complications and without known previous cardiovascular disease, who
were legally of age and capable of giving consent and when the babyʼs course was uncomplicated
– regardless of case number estimation – were recruited for the study as a reference
group for aortic pulse wave velocity measurement up to 7 days after delivery (reference
group recruitment target: 38 women).
Measurement of pulse wave velocity
The cuff-based Vicorder® (SMT Medical, Würzburg, Germany) was used to measure the aortic pulse wave velocity
as the gold standard for determining arterial stiffness. This has already been validated
repeatedly in studies against alternative measurement methods such as tonometry and
magnetic resonance imaging [33], [34], [35], [36]. The measurements were done in a standardised setting in the patientʼs air-conditioned
room in the respective hospital (room temperature 22 – 25 °C, in supine position,
after resting for 10 min, upper body elevated 30°). At the patientʼs bedside, the
measurement setting was adjusted to be equivalent to that used for the Vicorder validation
study [37]. Comparable settings were also used in studies elsewhere of non-invasive measurement
of pulse wave velocity (tonometric,
oscillometric), e.g., in children, simultaneously in MRI and in intensive care
units and during angiological interventions in the operating theatre [38], [39], [40], [41], [42]. If the baby had not been transferred to the neonatal ICU but was in the room with
the patient, it was given into the care of the ward nurse while the measurements were
performed. A 10 cm wide BP cuff was then applied around the right thigh to measure
the femoral pulse and a narrow 3 cm cuff was placed around the neck at the level of
the right carotid artery to measure this. The distance between the jugular fossa and
the cranial edge of the cuff applied to the thigh was measured as recommended by the
manufacturer. Unlike the usual use of the Vicorder a tape measure was not used but
rather a pelvimeter so as to avoid an incorrect measurement
of length due to the postpartum distension of the abdominal wall. Both cuffs
were pumped up to 65 mmHg and 2 high-quality measurement curves were recorded for
3 seconds simultaneously by means of a volume displacement, from which the aPWV was
derived [43]. The measurement was repeated 3 times in succession and the mean of all 3 measurements
was used for statistical analysis.
The pulse wave velocity was measured in the intervention and control group both on
the day of inclusion in the study (time 1 [T1]) and after 32 weeks (6 weeks puerperium
+ 6 months intervention period, time 2 [T2]) and at the start of the exercise intervention
in the subjects of the intervention group ([Fig. 2]). In the reference group of healthy subjects, the measurement took place once on
the day of inclusion in the study (T1).
Fig. 2 Flow chart for the different study phases.
In the intervention and control group the first measurement was done at the patientʼs
bedside in the delivery ward and the second measurement and final measurement on an
examination couch. Stressors that influence blood pressure and also the newborn babies
were not present in the examination or patientʼs room during the measurement.
Ergometry
Following the analysis of vascular stiffness, exercise ergometry was performed in
the sport science laboratory in a standardised setting on a bicycle ergometer (motion
cycle 600 med, emotion Fitness, Hochspeyer, Germany). An exercise protocol based on
the WHO protocol was used (initial workload 25 watts, increment 25 watts, stage duration
3 min) at a specified frequency of 60 – 65 revolutions/min. To generate a submaximal
load, reaching a target heart rate of 150 beats/min was defined as stop criterion.
The load stage at which this value was reached was completed and the performance was
reduced to 25 watts in the subsequent active cool-down. Before the start of the test,
at the end of each load stage and after a 2 and 4 minute recovery period, the lactate
level in capillary blood was determined (drawn from the hyperaemised earlobe) and
the heart rate was recorded (RS800 CX, Polar electro Oy, Kempele, Finland). The test
results were analysed using Winlactat software
(version 4.7; mesics GmbH, Münster, Germany) and the individual lactate threshold
(LT) of the lactate performance curve was determined as the limit of the performance
generated mainly aerobically for controlling the load in the subsequent intervention
phase [44].
Exercise programme to increase aerobic basic endurance and general strength endurance
During the 6-month intervention phase an exercise unit was performed once a week under
laboratory conditions. The exercise consisted of a heart rate-controlled exercise
unit on a bicycle ergometer, with the load parameters based on the lactate threshold
test results. Starting with a load duration of 25 min at the heart rate at the LT
(HRLT; mean: 129 beats/min; min.: 121 beats/min; max.: 137 beats/min) the load duration
in the intervention period was gradually increased to 50 min within 14 weeks. The
ergometer training was followed by strength and mobilisation training guided by a
trained midwife. At the start of the intervention phase the focus was on postnatal
and general pelvic floor exercises (c. 15 min). In the course of the intervention
period, depending on individual performance, general trunk-stabilising exercises (isometric
postural exercises, simple coordinated strengthening exercises, mobilisation exercises)
were added. Similarly to the ergometer
training, the exercise duration was gradually increased from 15 to 30 min. The
subjects were responsible for including additional weekly exercise in their daily
routine consisting of a brisk walk at an interval of 2 to 3 days. They were asked
about this at each exercise date and the answer was documented in the training record.
Individual nutritional counselling
Apart from the risk factors according to the guideline [45], the lifestyle factor “Nutrition” was examined in more detail in the hospital discharge
and final interview with all study patients in the intervention and control groups
and the treating doctors explained this factor in their counselling. This counselling,
based on the 10 nutritional rules of the German Nutrition Society (DGE), concentrated
on a Mediterranean diet as well as fat quality, whole-grain products, fruit and vegetable
intake and also salt reduction. All patients were also motivated actively in this
discussion to change their lifestyle (including regular physical exercise).
The patients in the intervention group also had a second and third individual nutritional
counselling session (each of 90 – 120 min, 6 weeks postpartum and 32 weeks postpartum
→ final session). The content of these counselling sessions by a nutritional adviser
and qualified dietician certified according to German Nutrition Society regulations
consisted of:
-
nutritional counselling based on the nutritional rules of the German Nutrition Society
(DGE), including the Mediterranean diet as well as fat quality, whole-grain products,
fruit and vegetable intake and also salt reduction,
-
Medical history (history questionnaire – Society for nutritional therapy and prevention
[FET] e. V.),
-
Determination of body weight and composition (TANITA® BC-545),
-
Recording of the nutritional behaviour using a questionnaire (after Winkler 1998)
[46].
Feasibility analysis
To examine the feasibility of the study, adherence with nutritional counselling and
the aerobic basic endurance exercise were documented by the study personnel at all
contacts. In addition, the subjects were given a direct possibility for feedback through
analysis of nutrition and performance tests at the beginning and end of the aerobic
basic endurance exercise. In the dropout subjects, the reasons were evaluated and
the subjects were asked about this. The subjects were also given the possibility of
giving their feedback on the study personally by email at any time during the nutritional
counselling sessions, measurements of pulse wave velocity or aerobic basic endurance
exercise so as to achieve greater adherence to the study.
In particular, the midwife-supported setting in the context of the exercise, in addition
to ensuring qualified care of the baby, was also designed to give the subjects the
opportunity of obtaining the midwifeʼs advice on specific topics such as postnatal
recovery, breast-feeding or psychosocial questions and problems.
Estimation of case numbers and statistical analysis
In advance of the pilot study, the case numbers were estimated at the Institute for
Medical Epidemiology, Biometrics and Informatics of Martin Luther University Halle-Wittenberg,
based on the changes in pulse wave velocity (primary outcome) within 6 months. At
a significance level of p < 0.05, a power (1-beta) of 80%, a 2-sided t-test and an
assumed difference in the mean of 0.90 m/s between the healthy population of the same
age (pulse wave velocity: 6.35 m/s) and the intervention group after 6 months (7.25 m/s),
at a given standard deviation of 1.00 m/s, at least 17 subjects are needed per group,
with an expected dropout of 20% [47], [48]. Accordingly, 20 subjects would have to be included initially in both groups.
Statistical analysis of the data was performed with SPSS version 25.0 (SPSS Inc.,
IBM, Armonk, NY, USA). Continuous and categorical variables were shown as mean ± standard
deviation (SD) or as a percentage. Differences in the mean were examined by general
linear model. In addition the effect size was calculated according to Hartmann et
al. (1992) (difference in the mean divided by the pooled standard deviation of the
2 measurement times [T]) [49]. The interpretation of the effect sizes is based on Cohenʼs recommendations (1988)
[50]. According to this, small effects (d < 0.5) must be distinguished from moderate
effects (d < 0.8) and large effects (d ≥ 0.8). Positive effect sizes are interpreted
as an increase in performance.
Differences in the mean were interpreted as significant when p < 0.05 and d > 0.5,
ηp
2 > 0.10 and the power (observed power) was greater than 0.8 [51].
Relations between metrically scaled variables were examined by means of product-moment
correlations (Pearson).
Ethics committee approval
The study was approved by the ethics committees of the medical faculty of Martin Luther
University Halle-Wittenberg and of the Medical Council of Saxony-Anhalt (decision
no.: 2015-134) and then registered in ClinicalTrials.gov (identifier: NCT02754778).
Results
Subjects
In the period from May 2016 to April 2018 (24 months) 344 women were screened for
the interventional part of the study and 198 women were approached according to the
inclusion and exclusion criteria and if adequate communication was possible (acquisition).
38 women gave their consent to take part in the study and were randomised (recruitment)
([Table 1]).
Table 1 Demographic and anthropometric subject characteristics.
|
Variables
|
Intervention group
n = 14
|
Control group
n = 15
|
Total
n = 29
|
Total
n = 38
|
|
|
The data are given as ° mean ± standard deviation and * number (percentage).
IUGR: intrauterine growth retardation; BP: blood pressure
|
|
Age (years)°
|
31 ± 3.89
|
31 ± 3.32
|
31 ± 4
|
31 ± 5
|
|
|
Height (cm)°
|
166 ± 5.55
|
167 ± 7.03
|
166 ± 6
|
168 ± 7
|
|
|
Weight (kg)°
|
86.3 ± 14
|
87.5 ± 19.5
|
86.9 ± 17
|
82.3 ± 11
|
|
|
Abdominal girth (cm)°
|
104.2 ± 9.80
|
108.1 ± 16.23
|
106.3 ± 14
|
102.6 ± 10
|
|
|
Thigh circumference (cm)°
|
61.3 ± 8.04
|
62.4 ± 11.32
|
61.9 ± 9.6
|
57.8 ± 7.0
|
|
|
Systolic BP postpartum (mmHg)°
|
148 ± 16
|
148 ± 10
|
148 ± 13
|
120 ± 11
|
p < 0.01
|
|
Diastolic BP postpartum (mmHg)°
|
85 ± 9
|
84 ± 9
|
85 ± 9
|
72 ± 7
|
p < 0.01
|
|
Delivery (weeks of pregnancy)°
|
36 ± 4
|
35 ± 5
|
36 ± 5
|
40 ± 2
|
p < 0.01
|
|
Birth weight (g)°
|
2547 ± 960
|
2114 ± 1054
|
2323 ± 1016
|
3505 ± 513
|
p < 0.01
|
|
Pre-existing hypertension*
|
1 (7)
|
3 (20)
|
4 (14)
|
1 (3)
|
|
|
Primigravida*
|
9 (64)
|
6 (40)
|
15 (52)
|
16 (42)
|
|
|
Primipara*
|
13 (93)
|
10 (67)
|
23 (79)
|
22 (58)
|
|
|
Multiple pregnancy*
|
2 (14)
|
2 (13)
|
4 (14)
|
0 (0)
|
p < 0.05
|
|
Previous infertility treatment*
|
4 (29)
|
4 (27)
|
8 (28)
|
0 (0)
|
p < 0.01
|
|
Pathological uterine resistance*
|
2 (14)
|
4 (27)
|
6 (21)
|
0 (0)
|
p < 0.01
|
|
IUGR*
|
3 (21)
|
6 (40)
|
9 (31)
|
3 (8)
|
p < 0.05
|
For the reference group, 627 women were screened (the entire birth cohort of both
study sites in the period from May 2017 to June 2017). 105 women met the requirements
for inclusion in the reference group; these were addressed by the study team (acquisition).
38 of these women were included in the reference group (recruitment).
The reference group of subjects without previous cardiovascular disease or pregnancy
complications examined postpartum did not differ significantly from the subjects who
had had preeclampsia with or without pre-existing hypertension and/or HELLP syndrome
with regard to age (p = 0.850), height (p = 0.271) and weight (p = 0.496). On the
other hand, significant differences were observed in birth weight (p < 0.01), weeks
of pregnancy at delivery (p < 0.01) and the rate of intrauterine growth retardation
(IUGR) (p < 0.05) and section (p < 0.01). As expected, significant differences were
also found in systolic (p < 0.01) and diastolic (p < 0.01) blood pressure ([Table 1]).
The majority of the patients had a form of late-onset preeclampsia appearing after
34 weeks of pregnancy, and there were no significant differences in the frequency
of diagnosis between the intervention and control groups ([Table 2]).
Table 2 Frequency distribution with regard to diagnosis and time of diagnosis.
|
|
Diagnosis
|
Intervention group
n = 14
|
Control group
n = 15
|
|
The data are given as a number (percentage).
|
|
> 34 weeks
|
Preeclampsia
|
7 (50)
|
6 (40)
|
|
Preeclampsia with pre-existing hypertension
|
1 (7)
|
2 (13)
|
|
HELLP syndrome
|
3 (21)
|
2 (13)
|
|
≤ 34 weeks
|
Preeclampsia
|
1 (7)
|
1 (7)
|
|
Preeclampsia with pre-existing hypertension
|
0 (0)
|
1 (7)
|
|
HELLP syndrome
|
2 (14)
|
3 (20)
|
The average lowest platelet count (p = 0.971) in HELLP syndrome and the average sFlt-1/PlGF
ratio (p = 0.956) did not differ significantly in these groups ([Table 3]).
Table 3 Means of the typical preeclampsia laboratory parameters.
|
Laboratory parameter
|
Intervention group
n = 14
|
Control group
n = 15
|
|
The data are given as mean (standard deviation).
sFlt-1: soluble Fms-like tyrosine kinase-1; PlGF: placental growth factor
|
|
Minimum platelets (Gpt/l)
|
77 ± 45
|
87 ± 33
|
|
sFlt-1/PlGF
|
223 ± 199
|
241 ± 88
|
Effects and test results
The postpartum aPWV at T1 showed a marked difference between subjects who had had
preeclampsia with or without pre-existing hypertension and/or HELLP syndrome and the
healthy reference group ([Fig. 3]). While the average aPWV of the healthy reference group corresponded to the age
class-stratified reference values of the Arterial Stiffness Collaboration Group (< 30
years 6.2 ± 0.75; 30 – 39 years 6.5 ± 1.35) [52], significantly higher pulse wave velocity and thus greater vascular age (6.5 vs.
7.5 m/s, p < 0.01) were found in the subjects with prior preeclampsia and/or HELLP
syndrome.
Fig. 3 Illustration of aortic pulse wave velocity in the study groups at T1 and T3.
Variance analysis (T1 vs. T3; [Table 4]) yielded significant time effects in all parameters when the control and intervention
groups were compared, based on the defined criteria of significance (p < 0.05 and
ηp
2 ≥ 0.10, d ≥ 0.50 and observed power ≥ 0.80), with the exception of the parameters
aPWV, pPWV und AIx. Significant group or interaction effects (time × group) were not
observed in this pilot study, probably due to the lack of power and the case number.
However, the effect for the parameter aPWV between T1 and T3 was markedly greater
in the intervention group than in the control group (d = 0.90 vs. d = 0.56). The greatest
individual effects were found in the intervention group for the parameters mean arterial
pressure (MAP) (d = 2.82) and systolic blood pressure (syst. BP) (d = 2.52) and in
the control group for the parameter syst. BP (d = 1.76).
Table 4 Variance analysis comparison (T1 vs. T3) of the 2 preeclampsia groups.
|
|
Control group (n = 15)
|
Intervention group (n = 14)
|
Variance analysis p (ηp
2)/observed power
|
|
|
T1°
|
T3°
|
d
|
T1°
|
T3°
|
d
|
Group
|
Time
|
Group × time
|
|
The data are given as ° mean ± standard deviation and significant differences are
shown in bold.
d = effect size; significance level: p < 0.05 and ηp
2 ≥ 0.10, d ≥ 0.50 and observed power ≥ 0.80
AIx: augmentation index; AoPP: aortic pulse pressure; CO: cardiac output; MAP: mean
arterial pressure; T: measurement time; BP: blood pressure; SEVR: subendocardial viability
ratio; SV: stroke volume
|
|
Primary outcome
|
|
aPWV (m/s)
|
7.83 ± 1.64
|
7.33 ± 2.25
|
0.54
|
7.20 ± 1.11
|
6.36 ± 0.76
|
0.90
|
0.095 (0.100)/0.386
|
0.072 (0.115)/0.439
|
0.632 (0.009)/0.075
|
|
Secondary outcomes
|
|
pPWV (m/s)
|
16.0 ± 9.78
|
11.4 ± 3.80
|
0.68
|
11.7 ± 2.78
|
10.1 ± 1.82
|
0.70
|
0.069 (0.118)/0.448
|
0.045 (0.140)/0.526
|
0.311 (0.038)/0.169
|
|
AIx (%)
|
22.5 ± 9.27
|
15.7 ± 7.29
|
0.82
|
21.1 ± 13.4
|
15.8 ± 5.99
|
0.55
|
0.815 (0.002)/0.056
|
0.015 (0.200)/0.707
|
0.741 (0.004)/0.062
|
|
AoPP (mmHg)
|
58.0 ± 7.92
|
46.0 ± 8.09
|
1.50
|
55.4 ± 11.1
|
42.7 ± 5.88
|
1.50
|
0.266 (0.046)/0.195
|
< 0.001 (0.643)/1.000
|
0.824 (0.002)/0.055
|
|
CO (l/min)
|
7.23 ± 1.67
|
5.76 ± 1.10
|
1.06
|
7.16 ± 1.66
|
5.30 ± 1.01
|
1.39
|
0.543 (0.014)/0.091
|
< 0.001 (0.555)/1.000
|
0.493(0.018)/0.103
|
|
SEVR (%)
|
127 ± 38.7
|
150 ± 22.2
|
0.76
|
133 ± 24.0
|
156 ± 23.5
|
1.00
|
0.438 (0.022)/0.118
|
0.003 (0.280)/0.878
|
0.951(0.000)/0.050
|
|
SV (ml)
|
88.8 ± 13.1
|
76.4 ± 9.52
|
1.10
|
85.3 ± 12.5
|
71.7 ± 10.0
|
1.21
|
0.283 (0.043)/0.184
|
< 0.001 (0.609)/1.000
|
0.760 (0.004)/0.060
|
|
syst. BP (mmHg)
|
148 ± 10.2
|
127 ± 13.7
|
1.76
|
148 ± 15.5
|
117 ± 9.11
|
2.52
|
0.231 (0.053)/0.219
|
< 0.001 (0.788)/1.000
|
0.095 (0.100)/0.386
|
|
diast. BP (mmHg)
|
83.7 ± 9.30
|
73.7 ± 8.40
|
1.13
|
85.4 ± 8.85
|
68.5 ± 6.29
|
2.23
|
0.483 (0.018)/0.105
|
< 0.001 (0.653)/1.000
|
0.081 (0.108)/0.416
|
|
Pulse pressure (mmHg)
|
64.6 ± 8.93
|
52.9 ± 7.43
|
1.43
|
63.5 ± 10.8
|
48.8 ± 7.06
|
1.65
|
0.338 (0.035)/0.156
|
< 0.001 (0.653)/1.000
|
0.436 (0.024)/0.119
|
|
MAP (mmHg)
|
114 ± 8.72
|
97.4 ± 11.7
|
1.63
|
116 ± 9.50
|
90.4 ± 8.66
|
2.82
|
0.368 (0.031)/0.143
|
< 0.001 (0.798)/1.000
|
0.058 (0.131)/0.480
|
|
Performance at lactate threshold 2 mmol/l (W)
|
–
|
–
|
–
|
51.6 ± 10.6
|
60.1 ± 18.1
|
0.59
|
–
|
0.013 (0.388)/0.756
|
–
|
There was a high correlation between the achieved exercise frequency and performance
at the 2-mmol/l lactate threshold, which acted as an indicator of basic aerobic endurance
(r = 0.739). Accordingly, the increases in performance (9.36 ± 10.8 W; range: − 5
to 32 W) were greater in the intervention group the more frequent the exercise ([Fig. 4]).
Fig. 4 Relationship between exercise frequency and the increase in performance achieved
at a lactate threshold of 2 mmol/l.
Feasibility analysis
266 out of the total of 364 exercise appointments (73%) were kept. Each of the 14
subjects in the intervention group took part in at least 50% of the appointments for
exercise training. With regard to the intervention group a statistically (p = 0.013)
and clinically significant (d = 0.59) increase in ergometer performance at the 2-mmol/l
lactate threshold was observed (T1: 51.6 ± 10.6 vs. T3: 60.1 ± 18.1; [Table 4]). Depending on the exercise frequency and intensity (cut-off: ≥ 80%, n = 7), higher
performance in watts was seen at the 2-mmol/l lactate threshold when the baseline
and final tests were compared (difference in the groups: 18 W vs. 1 W, p = 0.002).
Moreover, greater exercise frequency and intensity implied a tendency to lower PWV
and thus to decreasing arterial stiffness (6.0 vs. 6.6 m/s, p = 0.099).
All patients availed of the postpartum nutritional counselling in the form of lifestyle
changes advised by the study doctors when patients were recruited to the study and
on hospital discharge. Only 11 subjects in the intervention group took part 6 weeks
postpartum in the first individual DGE-based nutritional counselling session with
nutritional analysis, which was conducted by a certified dietitian. 22 of the 28 appointments
(79%) for individual DGE-based nutritional counselling (excluding the nutritional
counselling in the form of advice on lifestyle changes on recruitment to the study)
were kept. Patients who attended both DGE-based nutritional counselling session performed
10 watts more on average on the bicycle ergometer at the conclusion of the intervention
than those who had taken part only in the nutritional counselling in the form of lifestyle
change advised on the occasion of hospital discharge (14 vs. 4 W, p = 0.04). Lower
aPWV and therefore improved arterial
stiffness were also seen in patients who had two individual DGE-based nutritional
counselling sessions compared with only one session (6.1 vs. 6.7 m/s, p = 0.06).
Dropouts
A total of 5 subjects in the intervention group and 4 subjects in the control group
dropped out of the study on their own motivation in all cases. While dealing with
grief because of the postpartum death of the baby was the main reason for dropping
out in one case, there were organisational or structural problems (physical distance,
excessive demands with the child, language and cultural barrier) including in motivation
in the other 8 cases. No dropout was indicated medically. All dropouts occurred between
6 weeks and 32 weeks postpartum.
Discussion
The increasing incidence of preeclampsia in western industrial nations (including
because of the steadily increasing average age of pregnant women), increased life
expectancy and consequently the sequelae of preeclampsia for lifelong cardiovascular
risk are important reasons for focussing scientific research on the secondary and
tertiary prophylaxis of cardiovascular events after preeclampsia [6], [53], [54], [55], [56]. The “window to future health” within pregnancy – acting like a cardiac stress test
– makes possible secondary prevention if indicated of cardiovascular disease in women
who have had hypertensive disorders of pregnancy such as preeclampsia and HELLP syndrome.
An important difficulty in secondary and tertiary prophylaxis is represented by the
apparent recovery of a majority of patients who feel hardly any symptoms at the end
of the postpartum period and who are also liable to be distracted from their own health
because of caring for their infant, with the change in their role from that of a pregnant
woman to that of a mother. In reality, only about a quarter of women who have had
preeclampsia are prepared to take part in an additional exercise/sport unit at least
once a week if it is left up to them (surveyed 6 months postpartum) [57]. In addition, it was apparent that 27 of 78 surveyed patients did sport less frequently
after the index event (preeclampsia) than before the pregnancy (increase in frequency
in only 6 of 78 patients). Available studies show that unaffected women can be motivated
to more physical activity by convincing information about health aspects [58]. In this study, in addition to consistent advice in the pre-discharge discussion
with these patients, involvement of a midwife in the exercise setting subsequently
laid an effective foundation for good adherence of the subjects to the aerobic basic
endurance exercise. Ensuring care of the newborn baby and the possibility of discussing
delivery-related problems with the midwife thus acted as a reassuring factor. In future
studies to confirm the results of this study, inclusion of such an exercise programme
in midwivesʼ clinics in conjunction with postnatal exercise classes is worth considering
for women who have had hypertensive disorders of pregnancy and could further enhance
the already considerable value of the midwives beyond delivery, for instance with
regard to subsequent pregnancies. The psychosocial peer group contacts that take place
in these postnatal classes are also of value. Socioeconomic aspects can be latent
reasons for a) lack of exercise
compliance and b) for rejection of general lifestyle changes and should be investigated
in detail. Future studies should therefore focus, among other things, on the evaluation
of reasons for dropping out of the study and also on the development of alternative
possibilities for patients who cannot follow the exercise training because of exclusion
criteria. Only in this way can secondary and tertiary prevention concepts be devised
that also offer solutions for women in precarious social or familial situations.
A high level of intrinsic patient motivation also remains crucial, and this is inevitably
linked with the care and current health of the baby and sometimes multiple babies
or when she already has older children to care for.
This study in a group of women who had had severe hypertensive disorders of pregnancy
(preeclampsia with or without previous hypertension and/or HELLP syndrome) showed
for the first time that:
-
There is a high level of willingness to take part actively in aerobic basic endurance
exercise in conjunction with nutritional counselling,
-
Aerobic basic endurance exercise (intervention) can reduce arterial stiffness as a
biomarker for the risk of cardiovascular disease.
In the control group, a biological vascular age corresponding to that of the healthy
population at least 10 years older was shown 32 weeks after delivery, while the subjects
in the intervention group showed a pulse wave velocity corresponding to the biological
vascular age of the healthy population of the same age (comparison in [Table 4] and reference values [52]). An increase in PWV of 1 m/s corresponds to a risk increase of 15% for cardiovascular
morbidity and events [59].
The results of this pilot study confirm the hypothesis of the short- and medium-term
effect of a regular exercise intervention to reduce vascular stiffness and hence the
cardiovascular risk at least to the level of the healthy population of the same age
following preeclampsia with or without previous hypertension and/or HELLP syndrome.
Nevertheless, the success of the intervention appears to depend crucially on starting
promptly after the end of the puerperium and continuing for at least 6 months as,
by contrast, Scholten et al. [14] with a similar intervention for only 12 weeks starting 6 months postpartum were
unable to show any improvement in the vascular status of women with previous preeclampsia.
If the preventive effects of the aerobic basic endurance exercise are perpetuated,
women in the intervention group would not develop cardiovascular disease or, if they
did, would at least do so much later. This would result in a gain for the overall
population from the health and economic points of view. For instance, estimates of
the annual costs of disease and absence from work due to lack of exercise and the
resulting cardiovascular disease in Germany alone amount to up to 21 billion Euro
[60], [61].
The results are an impetus to initiate a larger multicentre, randomised, complex interventional
study, which should also look at an evaluation of other risk factors/biomarkers in
addition to standardising the sports and nutritional medicine setting. Only a long-term
follow-up study can confirm the improved outcome, similar to the Framingham study.
Applying the results to the standard care of women with preeclampsia with or without
previous hypertension and/or HELLP syndrome requires calculations of cost-effectiveness,
which take into account, on the one hand, how much the exercise units cost and the
adherence of the participating women and, on the other hand, what reduction in morbidity
can be expected and how much can be saved from the cost of treating cardiovascular
disease.
The results are limited by a high dropout rate (24%). As regards the high dropout
rate, based on the justified reasons given by the subjects, the possibility of taking
part in basic aerobic endurance training, nutritional counselling, medical diagnostics
and health education close to home should be considered in further studies.
Studies also confirm that a healthy diet, as promoted in a lifestyle intervention,
is associated with higher costs and hence with socioeconomic status [62], [63], [64]. Socioeconomic reasons are therefore also decisive for participation in an exercise
programme and for switching diet. Their importance and thus the underlying dropouts
must be recorded more intensively in future so that an equal-opportunity risk reduction
can be achieved, independent of socioeconomic status.
As regards the achieved exercise effects, especially with reference to the non-significant
interaction effects, adaptation of the load parameters of the exercise intervention
should be considered and the exercise should be intensified if appropriate. Because
of a lack of evidence and out of ethical considerations, a comparatively moderate
exercise programme was conceived initially.
The reduction in pulse wave velocity in the control group (d = 0.54) corresponds to
the physiological effect and must be included in the interpretation of the effect
in the intervention group. Morris et al. showed that there was a physiological reduction
in arterial stiffness in normotensive women to pre-conception levels 14 months postpartum
[65]. Yuan et al. [60] also demonstrated this 20 months postpartum in large arteries and described remodelling
of the carotid artery in pregnancy and recovery in the postpartum period. Mersich
et al. [61] found a physiological reduction in arterial stiffness both in normotensive women
and in women with preeclampsia 3 months postpartum compared with the 3rd trimester.
Foo et al. [62] observed this effect as a partial remission of endothelial dysfunction. However,
women with disease did not reach pre-pregnancy
levels [66]. In a 10-year follow-up increased arterial stiffness was found in the previously
hypertensive pregnant women compared with the healthy reference group [30]. Reference levels of the general physiological reduction in arterial stiffness after
pregnancy with and without hypertensive disorders of pregnancy must also be the basis
in further studies for evaluating individual targeted exercise [67].
The validity of this study is limited by the small case number, which is too low to
allow conclusions about influencing factors such as pre-existing hypertension, IUGR,
multiple pregnancies and previous infertility treatments, which were represented heterogeneously
in the intervention and control groups. Subgroup analyses were not possible but would
have to be planned in subsequent studies with larger case numbers. The influence of
pre-existing hypertension, in particular, should be studied separately as a cardiovascular
risk factor involving pre-existing vascular modelling, as the pathogenesis of superimposed
preeclampsia is possibly altered. With this diagnosis, pre-conception lifestyle intervention
might very probably be more effective in influencing arterial stiffness than postpartum
intervention. The absence of a risk reduction for IUGR and superimposed preeclampsia
when aspirin is taken in accordance with guidelines (starting < 16 weeks) in women
with pre-existing
hypertension appears to support the hypothesis [68].
Conclusion
The study confirms the feasibility and the great importance of lifestyle intervention
with aerobic basic endurance exercise starting 6 weeks postpartum. The intervention
shows a significant clinical effect by reducing arterial stiffness to the level of
the general population. An optimal setting in an interdisciplinary team that includes
varied midwife-supported care (incl. pelvic floor exercises, psychosocial support)
beyond childbirth appears decisive for good adherence and the associated success of
cardiovascular risk reduction as well as timely intervention for at least 6 months.
Before this intervention can be included in the standard of care and prevention, follow-up
studies must confirm these results and the medium-term effects on cardiovascular risk.
ClinicalTrials.gov Identifier: NCT02754778
