Exercise during pregnancy may enable mothers to significantly reduce their children’s chances of developing diabetes and other metabolic diseases later in life, new research suggests.
A study in lab mice has found that maternal exercise during pregnancy prevented the transmission of metabolic diseases from an obese parent – either mother or father – to child.
If the finding holds true in humans, it will have “huge implications” for helping pregnant women ensure their children live the healthiest lives possible, the researchers report in a new scientific paper.
This means that one day soon, a woman’s first trip to the doctor after conceiving might include a prescription for an exercise program.
“Most of the chronic diseases that we talk about today are known to have a fetal origin. This is to say that the parents’ poor health conditions prior to and during pregnancy have negative consequences to the child, potentially through chemical modification of the genes,” said researcher Zhen Yan, a top exercise expert at the University of Virginia School of Medicine.
“We were inspired by our previous mouse research implicating that regular aerobic exercise for an obese mother before and during pregnancy can protect the child from early onset of diabetes.
In this study, we asked the questions, “What if an obese mother exercises only during pregnancy? And what if the father is obese?'”
Obesity and Pregnancy
Scientists have known that exercise during pregnancy helps lead to healthy babies, reducing the risk of pregnancy complications and premature delivery. But Yan, the director of the Center for Skeletal Muscle Research at UVA’s Robert M. Berne Cardiovascular Research Center, wanted to see if the benefits continued throughout the children’s lives.
And his work, both previous and new, suggests it does.
To determine that, Yan and his collaborators studied lab mice and their offspring. Some of the adult mice were fed typical mouse chow before and during pregnancy, while other were fed a high-fat, high-calorie diet to simulate obesity.
Some receiving the high-fat diet before mating had access to a voluntary running wheel only during pregnancy, where they could run all they liked, while others did not, meaning they remained sedentary.
The results were striking: Both mothers and fathers in the high-fat group could predispose their offspring to metabolic disorders. In particular, male offspring of the sedentary mothers on high-fat diets were much more likely to develop high blood sugar and other metabolic problems in adulthood.
To better understand what was happening, the researchers looked at the adult offspring’s metabolism and chemical (epigenetic) modification of DNA.
The good news is that maternal exercise only during pregnancy prevented a host of epigenetic changes that affect the workings of the offspring’s genes, the researchers found. Maternal exercise, they determined, completely blocked the negative effects of either mother’s or father’s obesity on the offspring.
The results, they say, provide the first evidence that maternal exercise only during pregnancy can prevent the transmission of metabolic diseases from parent to child.
“The take-home message is that it is not too late to start to exercise if a mother finds herself pregnant,” Yan said.
“Regular exercise will not only benefit the pregnancy and labor, but also the health of the baby for the long run.
“This is more exciting evidence that regular exercise is probably the most promising intervention that will help us deter the pandemic of chronic diseases in the aging world, as it can disrupt the vicious cycle of parents-to-child transmission of diseases.”
The researchers have published their findings in the Journal of Applied Physiology.
Worldwide guidelines recommend aerobic training during pregnancy from 60 to 150 min/week (Savvaki et al., 2018). Little is known about the number of women practicing this, but numbers as low as 15% have been cited (Kuhrt et al., 2015). Women who exercise as recommended have 30% less risk for developing gestational hypertensive disorders (GHD), including gestational hypertension (GH), characterized by hypertension initiating after the 20th pregnancy week and pre-eclampsia (PE) defined as hypertension and proteinuria after the 20th pregnancy week (Magro-Malosso et al., 2017; Davenport et al., 2018b).
Preliminary data suggest that exercise during pregnancy has a lifelong protective effect resulting in a reduced cardiovascular risk profile in the perimenopause (Clapp, 2008). Maternal physical exercise is also beneficial for the fetus, resulting in less macrosomia and consequently improved cardiovascular health of the child at a later age (Alexander et al., 2015).
Pregnancy can be considered a stress test for the cardiovascular system, imposing profound cardiovascular adaptations including increased blood volume, accompanied by a drop in vascular resistance due to increased angiogenesis and vasodilation, generalized reduction in arterial stiffness and improved endothelial function, increased cardiac output associated with increased right and left chamber size and eccentric hypertrophy, resulting in higher stroke volume and heart rate and a fall in systemic blood pressure (Melchiorre et al., 2012; Chung and Leinwand, 2014; Osol and Bernstein, 2014; Tkachenko et al., 2014; Mannaerts et al., 2019).
Regular physical exercise can boost these adaptations as has been demonstrated for angiogenesis and endothelial function (Skow et al., 2017). In women with GHD, these functional and structural vascular adaptions fail (Mannaerts et al., 2019), and may persist beyond pregnancy (Kirollos et al., 2019), explaining why these women are at a lifelong increased risk for cardiovascular disease (Lane-Cordova et al., 2019).
In this mini review, we will elucidate the vascular adaptation during normal vs. hypertensive pregnancies and we will focus on the potentially beneficial effects of exercise on the vasculature. Based on this concept, physical exercise prior to and during pregnancy may be a promising therapy to prevent GHD and GHD recurrence, however, current data to underscore this hypothesis are still limited.
Vascular Adaptation During Healthy Pregnancy
An optimal adaptation of the cardiovascular system is crucial for a healthy pregnancy. As early as 5 weeks amenorrhea, a significant fall in systemic vascular tone occurs, altering the set-points of the baroreceptors and the stretch receptors (Tkachenko et al., 2014).
As a result, systemic vascular resistance decreases to allow sufficient placental perfusion (Clark et al., 1989). Venous tone decreases as well, resulting in expansion of the venous compartment and increased cardiac preload, ultimately leading to increased cardiac output (Melchiorre et al., 2012; Chung and Leinwand, 2014). To accommodate this blood volume expansion and increased cardiac output, the arterial bed needs to undergo structural and functional changes (Skow et al., 2017).
During pregnancy, structural arterial remodeling is mainly driven by placental growth factor (PlGF)-induced angiogenesis, occurring primarily at the uteroplacental unit (Osol and Bernstein, 2014). Soluble fms-like tyrosine kinase 1 (sFlt-1) is the circulating form of the VEGF receptor-1 and binds VEGF and PlGF thereby reducing their bioavailability.
The ratio of sFlt-1/PlGF is an important indicator of the angiogenic status in pregnancy and is used to predict and diagnose PE. Interestingly, this ratio appears to be indicative of future vascular dysfunction risk (Zeisler et al., 2016). The decrease in total vascular resistance is mediated by VEGF and PlGF as they induce distal angiogenesis (Hasan et al., 2002). Placental growth factor also mediates the cardiac adaptation and insufficient PlGF leads to impaired ventricular remodeling and cardiac dysfunction (Hochholzer et al., 2011).
To accommodate the increased blood volume while maintaining low blood pressure, a generalized reduction in arterial stiffness is of great importance. Central (aortic) pulse wave velocity (PWV), the gold standard for arterial stiffness, is known to be decreased in healthy pregnancy (Mannaerts et al., 2019).
A healthy endothelium controls vasomotor tone, which is essential during pregnancy. The rapidly expanding blood volume and increase in cardiac output pose an increased shear stress on endothelial cells, resulting in increased endothelial nitric oxide (NO) production (Cockell and Poston, 1997; Williams et al., 1997).
Together with higher estrogen levels, this leads to a systemic vasodilation (Meah et al., 2016). In healthy pregnancy, endothelial NO synthase (eNOS) activity is significantly increased (Nelson et al., 2000) which is mirrored in improved flow-mediated dilatation (FMD), the gold standard for endothelial function measurement (Iacobaeus et al., 2017; Mannaerts et al., 2019).
Vascular Maladaptation in Gestational Hypertensive Disorders
Women who develop hypertensive disorders during pregnancy such as GH or PE appear to fail the stress test of pregnancy, in part due to insufficient cardiovascular adaptation. Therefore, the risk of developing cardiovascular disease later in life is 9.5 times higher for women with severe early PE [hazard ratio (HR) = 9.5, 95% confidence interval (CI) = 4.5–20.3] (Mongraw-Chaffin et al., 2010).
Furthermore, PE has been associated with an increased risk for developing end-stage kidney disease (HR = 4.96, 95% CI = 3.9–6.3) (Khashan et al., 2019). Therefore, long-term cardiovascular monitoring and early preventive therapy are advocated (McDonald et al., 2008; Ahmed et al., 2014).
In PE, insufficient arterial remodeling at the spiral arteries results in placental ischemia-reperfusion damage and the production of high amounts of free radicals causing oxidative stress (Figure 1). Circulating free radicals activate peripheral leucocytes and platelets, resulting in an inflammatory state and disturbing proper endothelial function.
The reaction of oxidative products with NO decreases its bioavailability which impairs endothelial function even more (Mannaerts et al., 2018). The abundant placental ischemia and oxidative stress in PE results in an anti-angiogenic state with a three-fold increase in antiangiogenic factors (sFlt-1) and a 90% reduction in angiogenic factors (PlGF and VEGF; Tomimatsu et al., 2017).
Pathophysiology of pre-eclampsia (PE). A pre-existing fragile endothelial situation leads to defective placentation and high circulating levels of oxidative stress. This inadequate response to pregnancy results in arterial stiffness and exacerbates generalized endothelial dysfunction. Physical exercise has beneficial effects on multiple components of the model.
Women suffering from PE have increased arterial stiffness both during and after pregnancy, and arterial stiffness is directly correlated to the severity of the disease (Figure 1; Hausvater et al., 2012; Mannaerts et al., 2019). Carotid-femoral PWV is abnormal from 11 to 13 weeks in patients who develop PE later in pregnancy, which supports the concept that PE is not caused by dysfunctional placentation alone and underlying vascular disease must be present.
Increased arterial stiffness may have an important influence on fetal birth weight and pregnancy outcome (Skow et al., 2017). In addition, central PWV is strongly related to an increased risk for the development of cardiovascular disease later in life, also in PE (Hausvater et al., 2012).
PE is characterized by dysfunction of both resting (L-FMC, low-flow mediated constriction) and recruitable (FMD) endothelial capacity (Mannaerts et al., 2019). Endothelial dysfunction is proven to be present prior to the development of PE, possibly serving as a predictive parameter (Figure 1; Weissgerber, 2014). Further, women with a history of PE appear to have reduced FMD up to 3 years postpartum (Scholten et al., 2014).
Endothelial dysfunction impairs vascular smooth muscle relaxation which enhances arterial stiffness and plays an important role in the development of atherosclerosis. This suggests endothelial dysfunction to be the most plausible common link between the pathophysiology of PE and future cardiovascular disease (Mosca et al., 2011; Weissgerber, 2014).
Effects of Exercise on the Vasculature
Repeated exercise bouts effectively benefit vascular function directly by exerting shear forces on the vascular wall (Hambrecht et al., 2003; Adams et al., 2005; Grimm et al., 2018) and indirectly by the release of anti-inflammatory and anabolic mediators in response to increased muscular energy demands (Goldhammer et al., 2005; Kadoglou et al., 2007; Pedersen et al., 2007; Rehm et al., 2015).
This results in functional adaptation of the local and systemic vasculature to meet increased perfusion demands and to structural arterial remodeling by engagement of neuro-humoral and metabolic mechanisms (Figure 2; Roveda et al., 2003; Adams et al., 2005; Pedersen et al., 2007; Rehm et al., 2015).
Beneficial effects of repeated exercise bouts on the vasculature. AT1 receptor, Angiotensin II receptor type 1; eNOS, endothelial nitric oxide synthase; ET1, endothelin-1; NO, nitric oxide; ROS, reactive oxygen species; TGF-β, transforming growth factor beta.
There is clear evidence that endothelial function is improved by regular physical activity, both in patients with cardiovascular risk factors (Lavrenčič et al., 2000) and in patients with established cardiovascular disease (Linke et al., 2001; Van Craenenbroeck et al., 2010; Van Craenenbroeck E.M. et al., 2015). This exercise-induced benefit on endothelial function is mediated by different factors.
First, increased shear stress during exercise activates eNOS and reduces NAD(P)H oxidase activity, resulting in decreased reactive oxygen species (ROS) and increased NO bioavailability (Hambrecht et al., 2003; Adams et al., 2005). Furthermore, laminar shear stress prevents inflammation-related alterations in eNOS levels and prostacyclin/thromboxane ratio in an atherogenic environment (Grimm et al., 2018).
Second, endurance training has repeatedly been reported to lower levels of pro-inflammatory cytokines (CRP, IL-18, IL-1β, and IL-8) and increase anti-inflammatory cytokines (IL-10; Goldhammer et al., 2005; Kadoglou et al., 2007). The reduction of body fat and the anti-inflammatory and anabolic mediators released from the active skeletal muscle (referred to as “myokines”; Pedersen et al., 2007) induce systemic shifts in the innate and adaptive immunity toward a more pro-resolving and anti-inflammatory status (Rehm et al., 2015).
Third, exercise training modulates the balance between vasodilating and vasoconstricting factors, overall resulting in more vasodilation. Exercise training reduces levels of endothelin-1 and noradrenalin (Mortensen et al., 2009; Dow et al., 2017), reverses the aging-induced increase in the vasoconstrictor thromboxane (Hellsten et al., 2012) and lowers sympathetic tone (Roveda et al., 2003).
Regular physical activity and exercise interventions have been associated with the prevention of age-related increases in arterial stiffness (Fleenor et al., 2010). In a mouse model, the profibrotic cytokine TGF-β1 increased with aging in the carotid adventitia, where it augmented oxidative stress in fibroblasts. This resulted in increased collagen I and III deposition, and arterial stiffness (Fleenor et al., 2010).
The aging-associated elevation in adventitial TGF-β1 is reduced by aerobic exercise both in mice and humans, which in turn reduces large elastic artery stiffening (Fleenor et al., 2010). In addition, increased oxidative stress has been associated with reduced large elastic artery compliance in sedentary vs. habitually exercising postmenopausal women (Moreau et al., 2006).
Exercise has a profound impact on the process of vascular remodeling, which is again driven by increased blood flow and shear stress, by inflammatory cells, as well as by hypoxia-dependent and -independent growth factors (Hoier and Hellsten, 2014; Laughlin, 2016).
The pro-angiogenic effect of exercise is not limited to the exercising skeletal muscle, but also induces angiogenesis in adipose tissue (Van Pelt et al., 2017) and increased coronary collateral flow in patients with coronary artery disease (Möbius-Winkler et al., 2016).
Effects of Exercise in Healthy Pregnancy
Regular exercise is known to decrease cardiovascular disease in the non-pregnant population and is implemented in the treatment of heart failure and coronary artery disease patients (Karlsen et al., 2019; Witvrouwen et al., 2019a). Improved vascular health has been suggested as a major contributing factor (Myers, 2003; Van Craenenbroeck E.M. et al. 2010; 2015, Van Craenenbroeck A.H. et al., 2016).
In an uncomplicated pregnancy, current guidelines recommend moderate exercise at a frequency of two to four times a week and with an exercise duration of 30 min, throughout pregnancy (Savvaki et al., 2018). Overall, both aerobic and resistance exercises do not exert any adverse effects during pregnancy. However, evidence on resistance training is scarce and exercise with heavy loads is discommended (Savvaki et al., 2018). Most recreational exercise is safe, but sports that may cause abdominal trauma, falls or excessive joint stress and scuba diving should be avoided (Kuhrt et al., 2015; Bø et al., 2016; Savvaki et al., 2018).
Whereas the guidelines generally recommend 30 min of moderate exercise two to four times per week, 85% of pregnant women are exercising below these levels (Evenson and Wen, 2010). The most frequent barriers are fatigue, lack of time and pregnancy discomforts, but also safety concerns such as low birth weight, preterm labor and inducing fetal bradycardia could withhold pregnant women and health practitioners to prescribe the recommended amount of physical exercise (Kuhrt et al., 2015; Coll et al., 2017; Harrison et al., 2018; Witvrouwen et al., 2019b). Adequate knowledge on the physiological effects of exercise training in healthy pregnancy should help to overcome these barriers as pregnancy is a unique window of opportunity to improve health outcomes for the mother and also the future generations (Kuhrt et al., 2015).
There is no evidence for the induction of preterm delivery by regular physical activity. On the contrary, even a reduction in preterm birth of 20–50% in women performing exercise during pregnancy compared with sedentary pregnant women has been shown (Juhl et al., 2010).
The same is true for the concerns regarding exercise and low birth weight: maternal exercise was not associated with low birth weight or Apgar score at delivery (Davenport et al., 2018a). The normalization of maternal blood glucose, decrease in insulin resistance and increased placental functional capacity and nutrient delivery are suggested mechanisms to explain the beneficial effect of exercise on birth weight (Clapp, 2003; Kuhrt et al., 2015).
During exercise, peripheral vasodilation in the skin and exercising muscles can lead to reduced placental blood flow. In addition to poor autoregulation of the placental circulation, this may cause reduced oxygen and nutrient delivery to the fetus. Other proposed mechanisms for possible fetal distress during maternal exercise include vagal reflex, cord compression or fetal head compression related to malposition (Artal and O’Toole, 2003). Nevertheless, a significant decrease in mean uterine artery blood flow and fetal bradycardia has only been shown in Olympic level athletes exercising at more than 90% of the maximal maternal heart rate (Salvesen et al., 2011). Moreover, it has been shown that regular exercise improves both maternal cardiovascular adaptations and placental function to maintain sufficient fetal oxygenation and growth and does not adversely affect fetal heart rate (Clapp, 2003; Kuhrt et al., 2015).
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225346/
More information: Rhianna C. Laker et al. Exercise during pregnancy mitigates negative effects of parental obesity on metabolic function in adult mouse offspring, Journal of Applied Physiology (2020). DOI: 10.1152/japplphysiol.00641.2020
