Prenatal  exposure  to maternal stress is  associated  with  increased  perception  of  dyspnea  in adulthood 28 years later

Andreas Von Leupoldt (7242980)

Bea Van den Bergh (7242989)

Eline Mangelschots (7242983)

Marijke Braeken (5532194)

Nils Niederstrasser (2114038)

Thibo Billiet (7242986)

English

Loughborough University Institutional Repository

1  Letter to the editor: 1  2 Prenatal stress exposure is associated with increased dyspnea perception in adulthood 3  4 Andreas von Leupoldt1, Eline Mangelschots1, Nils Georg Niederstrasser1,2, Marijke 5 Braeken1,3, Thibo Billiet4, Bea R. H. Van den Bergh1,5 6  7 Affiliations 8 1Health Psychology, University of Leuven, Leuven, Belgium 9 2School of Sport, Exercise and Health Sciences, Loughborough University, UK 10 3Rehabilitation Sciences & Physiotherapy, Faculty of Medicine and Life Sciences, Hasselt 11 University, Belgium 12 4Department of Radiology, University Hospitals Leuven, Belgium 13 5Department of Welfare, Public Health and Family, Flemish Government, Brussels, Belgium 14  15 Corresponding author  16 Andreas von Leupoldt 17 Health Psychology 18 University of Leuven 19 Tiensestraat 102 20 B-3000 Leuven (Belgium) 21 Phone: +32-(0)16-32 60 06 22 Fax: +32-(0)16-32 61 44 23 Email: andreas.vonleupoldt@ppw.kuleuven.be 24 25 2  “Take home” message 1  2 Prenatal exposure to maternal stress is associated with increased perception of dyspnea in 3 adulthood 28 years later. 4 5 3  Dyspnea is the aversive cardinal symptom in various prevalent conditions such as respiratory, 1 cardiovascular and neuromuscular diseases and is associated with great individual and 2 socioeconomic burden [1]. Over the past years, not only several physiological, but also 3 psychological factors have been demonstrated to impact the perception of dyspnea [1,2]. For 4 example, high levels of anxiety in adulthood were associated with increased dyspnea 5 perception in patients with asthma or chronic obstructive pulmonary disease (COPD), but also 6 in healthy controls [2]. Moreover, adverse, separation-related experiences in childhood were 7 linked to the subsequent development of increased anxiety and dyspnea [3]. However, the 8 effects of adverse experiences in early, prenatal life on dyspnea perception remain widely 9 unknown, although prenatal exposure to maternal stress and anxiety has convincingly been 10 related to the development of other health- and behavioral problems later in life, including 11 impairments of the respiratory control system and high anxiety levels [4–9]. Therefore, this 12 study investigated the relationship between prenatal exposure to maternal stress and the 13 perception of dyspnea in adulthood 28 years later. 14  15 Subjects were recruited from the ‘Leuven Cohort’, a longitudinal study that started in 1986 16 with 86 pregnant mothers and their firstborn children. The study examines the 17 neurobehavioral effects of prenatal exposure to maternal stress on fetal, infant, and childhood 18 development, continuing into adulthood [10]. At study entry, the sample of mothers consisted 19 of healthy Belgian women without history of psychiatric disorders. Maternal stress levels 20 during pregnancy were operationalized as trait anxiety levels and assessed with the validated 21 State-Trait-Anxiety-Inventory (STAI)[11]. In addition, the following variables with known 22 impact on early life development were obtained: duration of pregnancy (days), birth weight 23 (g), maternal smoking during pregnancy (no. cigarettes/day), maternal caffeine consumption 24 during pregnancy (mg/day) and maternal alcohol consumption during pregnancy (mg/day). 25 4   1 From the original cohort, 40 healthy adults could be included. After obtaining written 2 informed consent and an anamnestic interview, spirometric lung function was measured. 3 Additionally, levels of state and trait anxiety, dyspnea-specific anxiety and somatic symptom 4 burden were assessed with validated questionnaires [11–13]. 5  6 Subsequently, their perception of dyspnea was examined in two magnitude estimation tasks 7 (MET), during which four inspiratory threshold loads (Respironics, Parsippany, US) with 8 different resistances (0, 5, 20 and 40 cmH2O/L/s) were repeatedly being presented. Subjects 9 wore a nose clip and breathed through an antibacterial filter being connected to a two-way, 10 non-rebreathing valve (Hans Rudolph Inc., Shawnee, US). The inspiratory port was connected 11 to a tube (diameter: 2cm; length: 150cm) where threshold loads were introduced. In the first 12 MET, subjects breathed through the loads for one inspiration and rated the intensity of 13 dyspnea on a Borg-scale [14]. Each load was presented four times in random order. In the 14 second MET, subjects breathed for five subsequent inspirations through the loads and rated 15 both the intensity and unpleasantness of dyspnea on a Borg-scale [14]. Each load was 16 presented twice in random order.  17  18 For the analyses, subjects were grouped into a low prenatal stress group (LS) and a high 19 prenatal stress group (HS) as in previous studies [10]. Grouping was based on trait anxiety 20 ratings [11] of their mothers during the 12th to 22nd week of pregnancy (low: <75th vs. 21 high:=/>75th percentile). Perceptual sensitivity for dyspnea was calculated with individual 22 regression slopes (Borg scores against load resistance) [15]. Groups were compared with 23 independent samples t-tests or Mann-Whitney-U-tests, respectively. Additional Spearman 24 correlations were calculated for dyspnea sensitivity slopes. Data are presented as group means 25 5  (+SD) and were analyzed using SPSS 24 software (SPSS Inc., Chicago, US) using a statistical 1 significance threshold of α<0.05.   2  3 Group characteristics including data of the mothers during pregnancy are presented in figure 4 1a. As expected, trait anxiety ratings of the mothers during the 12th to 22nd week of pregnancy 5 were significantly different between groups (p<0.001). No significant group differences were 6 observed in other characteristics of the tested subjects or their mothers (p’s>0.23).  7  8 No significant group differences were observed in the slopes for dyspnea intensity in the first, 9 single-breath MET (HS: 0.17 + 0.06; LS: 0.15 + 0.07; p=0.53; figure 1b) and in the second, 10 five-breath MET (HS: 0.20 + 0.03; LS: 0.16 + 0.08; p=0.30; figure 1c). However, the HS 11 group demonstrated significantly higher slopes for dyspnea unpleasantness than the LS group 12 (HS: 0.20 + 0.03; LS: 0.15 + 0.08; p<0.01; figure 1d). In addition, the slopes for dyspnea 13 unpleasantness showed a significant positive correlation with maternal stress levels (rho=0.34, 14 p<0.05; figure 1e), but not with other variables of the subjects or their mothers (rho’s<0.30, 15 p’s>0.06).  16  17 The present results suggest that prenatal exposure to maternal stress is associated with 18 increased perception of dyspnea, especially its affective unpleasantness, in adulthood 28 years 19 later. This is in line with previous human and animal studies demonstrating that adverse early 20 life experiences such as being exposed as a fetus to maternal stress, is related to the 21 development of health- and behavioral problems later in life [4–9]. However, the specific 22 underlying mechanism for the association between prenatal stress exposure and dyspnea 23 perception in adulthood observed in the present study remains unclear.  24  25 6  Several potentially contributing factors pertaining to current characteristics of the tested 1 subjects [1,2] including lung function, age, weight, height, gender, general and dyspnea-2 specific anxiety levels as well as somatic symptom burden were unrelated to the present 3 findings. Similarly, potential factors related to pregnancy [5,7] such as duration of pregnancy, 4 birth weight and maternal consumption of cigarette smoke, caffeine and alcohol during 5 pregnancy were not related to the present findings. Therefore, future studies are required to 6 test further potential mechanisms that might underlie the observed association between early 7 life adversity and perception of dyspnea later in life. These studies might include measures of 8 the autonomic nervous system, the hypothalamic–pituitary–adrenal (HPA)-axis, the 9 endogenous opioidergic and chemosensitive systems as well as functional and structural 10 measures of the brain, which have not only been suggested to be impacted by prenatal stress 11 exposure [5–8], but are also involved in the processing of dyspnea [2,3,9].  12  13 Future studies should also address the limitations of the present study such as the rather small 14 sample size, which is partly related to the relatively small original cohort. Moreover, the use 15 of inspiratory threshold loads for the experimental induction of transient dyspnea sensations 16 only mirrors some facets of dyspnea (ie, ‘increased work and effort of breathing’) [1,2], and 17 might not be fully comparable to other, more sustained dyspnea experiences outside the lab. 18 Finally, our findings in healthy, younger adults might not be generalizable to patients that 19 frequently experience dyspnea, especially when paralleled by older age such as commonly 20 observed in COPD. Therefore, studies are needed that examine the role of early life adversity 21 on dyspnea perception later in life in dyspneic patients with respiratory, cardiovascular and 22 neuromuscular diseases. If the present findings replicate in these future studies, it would not 23 only improve our knowledge on potential mechanisms involved in dyspnea perception, but 24 also warrant interventions to reduce maternal stress in pregnancy in order to decrease 25 7  symptom burden in future patients with dyspnea. 1  2 In summary, prenatal exposure to maternal stress is associated with increased perception of 3 dyspnea in adulthood in healthy subjects. Future studies are needed to examine the underlying 4 mechanism for this association and the respective effects of early life adversity in patients 5 suffering from dyspnea. 6 7 8  Support statement 1 This study was partly supported by a grant from the European Commission Seventh 2 Framework Programme (FP7–HEALTH.2011.2.2.2-2 BRAINAGE, Grant agreement no: 3 279281) to BvdB and an infrastructure grant from the Herculesstichting, Belgium 4 (AKUL/13/07) to AvL. AvL is supported by the ‘‘Asthenes’’ long-term structural funding 5 Methusalem grant (# METH/15/011) by the Flemish Government, Belgium. 6 9  References 1  2 1. Laviolette L, Laveneziana P, ERS Research Seminar Faculty. Dyspnoea: a 3 multidimensional and multidisciplinary approach. Eur Respir J 2014; 43: 1750–1762. 4 2.  Mahler DA, O’Donnell DE. Dyspnea: Mechanisms, Measurement, and Management, 5 (3rd ed); 2014. CRC Press, Boca Raton. 6 3. Preter M, Klein DF. Lifelong opioidergic vulnerability through early life separation: a 7 recent extension of the false suffocation alarm theory of panic disorder. Neurosci 8 Biobehav Rev 2014; 46: 345–351. 9 4.  Kingston D, Tough S, Whitfield H. Prenatal and postpartum maternal psychological 10 distress and infant development: a systematic review. Child Psychiatry Hum Dev 2012; 11 43: 683–714. 12 5.  Lewis AJ, Galbally M, Gannon T, et al. Early life programming as a target for prevention 13 of child and adolescent mental disorders. BMC Med 2014; 12: 33.  14 6.  Rakers F, Rupprecht S, Dreiling M, et al. Transfer of maternal psychosocial stress to the 15 fetus. Neurosci Biobehav Rev 2017; doi: 10.1016/j.neubiorev.2017.02.019. 16 7.  Van den Bergh BRH, Mulder EJH, Mennes M, et al. Antenatal maternal anxiety and 17 stress and the neurobehavioural development of the fetus and child: links and possible 18 mechanisms. A review. Neurosci Biobehav Rev 2005; 29: 237–258.  19 8.  Braeken MA, Kemp AH, Outhred T, et al. Pregnant mothers with resolved anxiety 20 disorders and their offspring have reduced heart rate variability: implications for the 21 health of children. PloS One 2013; 8:e83186.  22 10  9.  Rousseau JP, Tenorio-Lopes L, Baldy C, et al. On the origins of sex-based differences in 1 respiratory disorders: lessons and hypotheses from stress neuroendocrinology in 2 developing rats. Respir Physiol Neurobiol 2017; doi: 10.1016/j.resp.2017.03.013 3 10. Mennes M, Van den Bergh B, Lagae L, et al. Developmental brain alterations in 17 year 4 old boys are related to antenatal maternal anxiety. Clin Neurophysiol 2009; 120:1116–5 1122.  6 11.  Spielberger CD, Gorsuch RL, Lushene RE. Manual for the State-Trait Anxiety Inventory. 7 1970; Consulting Psychologists Press, Palo Alto, CA 8 12.  Solomon BK, Wilson KG, Henderson PR, et al. A Breathlessness Catastrophizing Scale 9 for chronic obstructive pulmonary disease. J Psychosom Res 2015; 79: 62–68.  10 13.  Kroenke K, Spitzer RL, Williams JBW. The PHQ-15: validity of a new measure for 11 evaluating the severity of somatic symptoms. Psychosom Med 2002; 64: 258–266. 12 14.  Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982; 14: 13 377–381. 14 15.  Kifle Y, Seng V, Davenport PW. Magnitude estimation of inspiratory resistive loads in 15 children with life-threatening asthma. Am J Respir Crit Care Med 1997; 156: 1530–16 1535. 17    18 19 11  Figure legends  1  2 Figure 1.  3 a) Characteristics of subjects with exposure to low prenatal stress and high prenatal stress 4 including data of their mothers during pregnancy. Whereas trait anxiety ratings of the mothers 5 during the 12th to 22nd week of pregnancy are significantly different between groups, there are 6 no significant group differences in other characteristics.  7 Perceptual sensitivity for dyspnea expressed as group means (SE) for individual regression 8 slopes (Borg scores against load resistance) for b) dyspnea intensity during the single breath 9 MET, c) dyspnea intensity during the five-breath MET and d) dyspnea unpleasantness during 10 the five-breath MET. e) Significant correlation between perceptual sensitivity for dyspnea 11 unpleasantness during the five-breath MET (Borg scores against load resistance) and maternal 12 stress levels (STAI) during the 12th to 22nd week of pregnancy. 13 FEV1 = forced expiratory volume in 1s;  14 #analyzed with χ2-test;  15 ameasured with STAI (State-Trait-Anxiety-Inventory); 16 bmeasured with BCS (Breathlessness Catastrophizing Scale);  17 cmeasured with PHQ-15 (Patient Health Questionnaire);  18 **p < 0.01.  19 

Prenatal stress exposure is associated with increased dyspnoea perception in adulthood

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Prenatal stress exposure is associated with increased dyspnoea perception in adulthood

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