Maternal anxiety forecasts shorter prolongation of pregnancies complicated by early-onset preeclampsia

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Bolte, Marc E.A. Spaanderman, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1823427/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Purpose: In early-onset preeclampsia, each additional day of pregnancy prolongation reduces offspring infant mortality about 9%. We evaluated if maternal stress at admission to hospital for early-onset preeclampsia predicted admission-to-delivery intervals in days. Methods : This prospective, longitudinal cohort-study involved 15 singleton pregnancies with a diagnosis of preeclampsia before 34 weeks gestation with intended expectant management. Upon hospital admission, maternal psychological stress was assessed with questionnaires and physiological stress with hair cortisol. Hair samples were analysed in three hair segments representing the preconception period, and the first and second trimester of pregnancy. Results: Mean pregnancy prolongation was 15 days. Higher maternal anxiety at hospital admission significantly correlated with shorter admission-to-delivery intervals ( r =-.64, p =.01). Chronically increased hair cortisol concentrations (i.e., from preconception through the second trimester) of pregnancy tended to be related to shorter admission-to-delivery intervals ( p =.06). Conclusion: Higher reported anxiety is, and chronically high hair cortisol tended to be, related with fewer days of prolongation from admission to delivery in women with early-onset preeclampsia. These findings suggest that maternal stress might be a potential determinant of disease progression. Future research into early innovative stress-reducing interventions for early-onset preeclampsia may shed more light on the etiology and treatment of this disease. Early-onset preeclampsia stress anxiety hair cortisol pregnancy prolongation Figures Figure 1 Figure 2 What Does This Study Adds To The Clinical Work? The results of this first study with prospectively collected psychological and physiologic data relating maternal stress to pregnancy prolongation in women admitted to hospital for early-onset preeclampsia are innovative and of potential clinical value. Higher maternal anxiety at hospital admission predicted significantly shorter admission-to-delivery intervals. Introduction Preeclampsia affects 3% of all pregnancies [ 1 , 2 ]. Preeclampsia occurring before 34 weeks of gestation (10% of preeclampsia cases) is considered early-onset and is associated with substantially increased maternal and neonatal morbidity and mortality [ 1 , 3 , 4 ]. The only known treatment for preeclampsia is delivery. Aggressive ‘interventionist management’ with delivery within 24 to 48 hours, may benefit maternal outcome at the expense of increased neonatal morbidity and mortality. Conservative ‘expectant management’ to prolong pregnancy, may increase the risk for maternal complications, such as eclampsia, liver rupture, intracranial haemorrhage, pulmonary oedema, and kidney failure but may, however, improve offspring outcome [ 5 , 6 ]. When interventionist management is compared to expectant management, the expectant approach results in decreased offspring morbidity; each additional day of prolongation reduces offspring infant mortality about 9% [ 7 ]. As such, expectant management is generally pursued in the Netherlands with continuous, vigilant surveillance of mother and foetus, with scheduled delivery for features of severe maternal disease or signs of foetal compromise [ 7 , 8 ]. Little is known about maternal factors predicting shorter or longer prolongation. Knowing more about these factors may facilitate the development of future early interventions aimed at improving outcomes in women with early-onset preeclampsia. This study aims to investigate whether maternal psychological and physiological stress is associated with the number of days until delivery (i.e., admission-to-delivery intervals) in women hospitalized with early-onset preeclampsia. In non-clinical populations, evidence is accumulating that maternal psychological stress and anxiety during pregnancy forecast adverse perinatal outcomes, including shorter gestations [ 9 , 10 ]. A few studies investigated women hospitalized during pregnancy, and those most distressed were at highest obstetric risk [ 11 , 12 ]. Next to measuring stress through self-report, stress can also be measured at a physiological level. When exposed to psychological or physical stress, the Hypothalamic-Pituitary-Adrenal (HPA)-axis is activated, resulting in the release of cortisol. Higher cortisol concentrations affect inflammatory responses, oxidative stress and endothelial function, and even uteroplacental blood flow, all correlates of gestational hypertensive disease [ 13 – 15 ]. These findings raise the question whether maternal psychological and physiological stress may be predictors of shorter or longer prolongation in early-onset preeclampsia. The present study investigate maternal psychological and physiological stress upon hospital admittance with expectant management in women diagnosed with early-onset preeclampsia. Stress questionnaires included pregnancy-specific stress and anxiety, such as fear of bearing a child with disabilities, as these have also been related to adverse perinatal outcomes [ 9 ]. Physiological stress, i.e., HPA-axis activity, is assessed by cortisol concentrations in maternal hair. Hair cortisol permits evaluating cortisol output over longer periods of time [ 16 , 17 ]. In this study, hair cortisol not only provides information about the concentrations during the disease (i.e. second trimester), but also allows preconception and first trimester concentrations to be determined. We hypothesized that higher psychological and physiological stress would be related to shorter admission-to-delivery intervals during expectant management in women hospitalized with early-onset preeclampsia. Methods This study included women with early-onset preeclampsia (< 34wks gestation) hospitalized at a single tertiary referral care centre (Radboudumc, the Netherlands) during 2016–2017. The definition of the International Society for the Study of Hypertension in Pregnancy (ISSHP) [ 18 ] was used to define preeclampsia. At Radboudumc, women with early-onset preeclampsia are admitted to the Obstetric High Care unit [ 4 ]. Corticosteroids for foetal lung maturation, antihypertensives and, magnesium sulphate, are administered according to the local protocol. At hospital admission, women with early-onset preeclampsia were asked to participate and after informed consent, filled in questionnaires and donated a sample of hair prior to corticosteroid treatment. Results of both assessments were blinded for participants and professionals. The study was approved by the local ethical committee, registered under CMO number 2015–2255 (NL-nr: 55946.091.15). The primary outcome was prolongation of pregnancy in days from admission to delivery, representing the admission-to-delivery interval. Indication for delivery and prolongation of pregnancy were retrieved from the medical records. Independent variables were psychological stress and anxiety and hair cortisol concentrations. Validated questionnaires were used to measure general and pregnancy-specific stress and anxiety. General state anxiety was assessed by means of the State-Trait Anxiety Inventory (STAI) [ 19 ]. General daily hassles were assessed by means of a Dutch questionnaire: the Everyday Problem Checklist [ 20 ]. Pregnancy-specific anxiety was assessed by means of the Pregnancy-specific Anxieties Questionnaire – Revised (PRAQ-R) [ 21 ]. Two subscales were used, namely fear of giving birth, and fear of bearing a child with disabilities. Depressive symptoms were assessed by the Edinburgh Postnatal Depression Scale (EPDS) [ 22 ]. The hair sample was analysed in 3-centimeter segments representing the cortisol concentrations in the preconception period (-13 to 0 weeks), the first trimester (1 to 13 weeks) and the second trimester (14 to 26 weeks), as hair growths 1 cm per month [ 16 , 17 ]. Corticosteroid therapy for foetal lung maturation did not affect hair cortisol, as the hair was cut before or immediately after corticosteroid administration. Cortisol concentrations were assayed at Dresden LAB Service GmbH, Germany, using a column-switching LC-APCI-MS/MS method [ 23 ]. Because of non-normality, log transformations were applied. To investigate the associations between the admission-to-delivery intervals and the psychological stress and anxiety measures, (partial) correlations or regression analyses were performed, depending on the number of confounders that were (marginally) significantly related to prolongation. We considered the following confounders: pre-pregnancy body mass index, pregnancy smoking, maternal age, maternal educational level, and gestational age upon admission. To test whether prolongation of pregnancy was correlated to cortisol over the course of preconception to the second trimester, longitudinal regression analyses using mixed-model (multilevel) designs were performed. In these analyses, the hair cortisol measures representing the preconception period, first trimester, and second trimester were used at Level 1 and nested within the women at Level 2. Thereafter, a build-up strategy was followed in which variables (i.e. confounders, time, prolongation in days, and the interaction between time and prolongation) were added one-by-one to the model with random intercept and random slope. After adding each variable, the change in deviance on the − 2log likelihood ratio scale after generalized least square estimations was assessed. Variables that did not improve the model by significantly reducing the deviance were excluded. The model with the best model fit is presented in the results. Results Descriptives Baseline characteristics are reported in Table 1. We analysed 15 cases of early-onset preeclampsia with a mean gestational age at admission of 30.0 weeks. The mean prolongation of pregnancy in days was 15.0 days, and in all cases, pregnancy was terminated at medical indication because of deterioration in maternal condition. Five women developed HELLP-syndrome, none eclampsia. All women received anti-hypertensive treatment, almost all with additionally magnesium sulphate. The mean score for general anxiety (STAI) was 42.93. Clinically significant anxiety scores, above 40 points [ 24 ], were reported in 12 out of 15 cases. The mean for depressive symptoms (EPDS) was 10.41. In 9 out of 15 patients, the score was ≥ 10, which indicates possible depression [ 22 ]. The remaining questionnaires do not have clinical cut-off values. Table 2 provides the correlations between the questionnaires, the hair cortisol measures, and pregnancy prolongation in days. Higher maternal anxiety at hospital admission predicted significantly less prolongation in days ( r =-.64, p = .01), and higher hair cortisol concentrations during the second trimester tended to predict less prolongation in days ( r =-45, p = .09). Psychological stress and anxiety As the confounders, including gestational age at hospital admittance, were not significantly related to admission-to-delivery interval (all p -values > .378), we could rely on the correlations provided in Table 1. These correlations indicate that higher maternal anxiety, measured with the STAI at diagnosis, significantly forecasts fewer days of prolongation of pregnancy (Fig. 1). The other questionnaire measures were not significantly related to admission-to-delivery intervals. Cortisol in hair To investigate the associations between prolongation days and the hair cortisol measurements, multilevel analyses were performed. The final multilevel model is reported in Table 3. A significant effect of time was found, indicating that cortisol concentrations rise over the course of pregnancy, as was expected. A marginally significant negative effect of prolongation days on hair cortisol concentrations was found ( p = .06). This effect of prolongation in days was not moderated by time, indicating that overall higher cortisol concentrations (from preconception till the second trimester), tended to be related to fewer prolongation days. To visualize these results, two groups were created (≤ 14 days prolongation, N = 9, versus ≥ 15 days prolongation, N = 6), and their mean hair cortisol concentrations were plotted (Fig. 2). This figure shows that the cortisol concentrations of the mothers with the fewest prolongation days was higher, from preconception till the second trimester. Discussion This study investigated whether maternal stress upon hospital admission was associated with fewer days of prolongation (i.e. admission-to-delivery intervals) in women hospitalized with early-onset preeclampsia. Stress was evaluated by stress and anxiety questionnaires, and by assessment of cortisol concentrations in hair. Higher anxiety, as reported by the participants at admission, correlated with shorter admission-to-delivery intervals. Moreover, higher overall hair cortisol, from preconception till the second trimester, was marginally related to shorter admission-to-delivery intervals. The other questionnaire measures were not significantly associated to prolongation days. Psychological stress and anxiety The results are in accordance with previous studies in non-clinical populations showing that anxiety and stress during pregnancy are associated with shorter gestational duration [ 9 , 15 , 25 ]. Psychological stress could influence and increase systemic blood pressure by hyperstimulation of the sympathetic nervous system [ 15 , 26 ]. Sympathetic overactivity has been observed in formerly preeclamptic women, with consequential sympathetically driven hyperdynamic circulation and increased shear stress on the vascular endothelium. These abnormal hemodynamic changes are thought to contribute to the hypertensive deterioration of pregnancy. Anti-hypertensive treatment may not be effective (enough) in these stressed, anxious patients, and preterm delivery might be unavoidable. Future research is needed to determine whether adding psychological stress-reducing interventions to the treatment of women with early-onset preeclampsia can extend admission-to-delivery intervals, as suggested in previous literature [ 27 ]. Whether the heightened anxiety at hospital admission was pre-existent or due to the situation is unknown. As prenatal stress and anxiety are stable in late pregnancy [ 19 , 24 ], it is plausible that the women already suffered from anxiety. However, pregnant women facing acute medical crises or when admitted to hospital for pregnancy complications have been found to have higher levels of anxiety [ 12 ]. It is also possible that the feelings of anxiety are a result of the disease manifestation itself. The augmented sympathetic nervous system activity, seen in women with a history of preeclampsia [ 26 ], could be a pathophysiological explanation for the feelings of these women. The STAI-questionnaire statements ‘I am tense’ or ‘I feel strained’ for example, could describe these feelings and result in a high anxiety score. Therefore, stress-reducing interventions, such as cognitive behavioural therapy or mindfulness-based stress reduction therapy, may be effective in reducing symptoms and potentially positively affect the woman’s health. A randomized controlled trial in uncomplicated pregnancies with high reported Pregnancy-Related Anxiety indeed showed that mindfulness reduced maternal anxiety and improved pregnancy outcome [ 28 ]. These findings suggest that women prone to experience anxiety may profit from mindfulness-based stress reduction interventions, maybe even before pregnancy, to prevent pregnancy complications and negative outcomes. Cortisol in hair In this study, hair cortisol concentrations were marginally associated to prolongation of pregnancy in early-onset preeclampsia. This effect was not moderated by time, indicating that overall higher cortisol concentrations, from preconception till the second trimester, tended to be related to shorter admission-to-delivery intervals. This is in line with a review showing that mothers delivering preterm had higher cortisol concentrations in blood or saliva at 27–37 weeks GA as compared to mothers delivering at term [ 10 ]. An increase in the release of cortisol and catecholamines triggers physiological responses, such as contractions of the peripheral blood vessels and an increase in blood pressure and heart rate, which in turn adversely affects the condition of mother and foetus. Cortisol concentrations in hair could possibly be indicating poor adaptation of the sympathetic nervous system to pregnancy in these women, resulting in a shorter admission-to-delivery interval in early-onset preeclampsia. Future research is needed to determine whether hair cortisol might be used as a biomarker of preconceptional risk estimation for pregnancy complications. Especially in women with a history of preeclampsia or a cardiovascular risk profile, as well as mental health complaints, it could be useful to know the risk of progression to severe disease in future pregnancies. Furthermore, preventive interventions are sorely needed for these women. Next to de-stressing psychological interventions mentioned earlier, aerobic training may be an effective intervention. Indeed, in a previous study on formerly pre-eclamptic women [ 26 ], aerobic training improved plasma volume expansion and reduced sympathetic overactivity, and as a result perhaps reduced a cause for stress. Associations between anxiety and cortisol during pregnancy Both reported anxiety as well as hair cortisol concentrations (tended to be) related to shorter admission-to-delivery intervals. From the correlation table (Table 2), it can be seen that the reported anxiety measures were moderately related to hair cortisol concentrations ( r’s = .20-.42). This result is in line with previous studies who also found no or moderate correlations between maternal reports of stress/anxiety and cortisol measures during pregnancy [ 9 , 29 ]. Note, however, that most previous studies measured cortisol in saliva, blood, and urine, reflecting more current and acute levels of cortisol, while the current study used hair cortisol. This enables retrospective examination of the cortisol production of the past months, representing more chronic levels of cortisol [ 17 ]. A study combining reported stress with hair cortisol measures in the first, second and third trimester in normotensive pregnancies [ 25 ], found a positive relation between self-reported stress (Perceived Stress Scale) at 16 weeks and second-trimester cortisol concentrations. Also, perceived stress at 16 weeks and second-trimester hair cortisol concentrations were positively associated with preterm delivery [ 25 ], suggesting that heightened cortisol might, to some extent, underlie links between psychological stress and pregnancy outcomes [ 9 ]. Strengths and limitations The strengths of this study are the prospectively collected psychological and physiologic data, and an innovative non-invasive biomarker of cortisol production covering the period from preconception to the second trimester. Also, we used multilevel analyses with repeated measures of hair cortisol to increase our statistical power. However, and in line with the rarity of early-onset preeclampsia, the size of the study is rather small and our results should be interpreted with caution. Future multi-center studies are needed to increase sample size and replicate our findings. Conclusions The results of this first study relating maternal stress to pregnancy prolongation in women admitted to hospital for early-onset preeclampsia are innovative and of potential clinical value. The mean general anxiety scores of these women were above the cut-off for clinically significant anxiety. Moreover, higher maternal anxiety at hospital admission predicted significantly shorter admission-to-delivery intervals. Also, chronically increased hair cortisol concentrations (i.e., from preconception through the second trimester) were marginally significantly related to shorter admission-to-delivery intervals. Our findings regarding hair cortisol are contributing to a growing literature which suggests that chronic cortisol exposure may have important implications for health [ 17 , 23 , 25 ] and highlights the use of hair cortisol as a promising method for understanding the role of stress on pregnancy outcome. Future research into early innovative stress-reducing interventions for early-onset preeclampsia may shed more light on the etiology and treatment of this disease. Declarations Author Contributions J.J.A. van Esch: protocol and project development, data collection, data analysis, manuscript writing A.C. Bolte: project development, manuscript editing M.E.A. Spaanderman: manuscript editing F.P.H.A. Vandenbussche: manuscript editing C. de Weerth: project development, manuscript editing R. Beijers: project development, data analysis, manuscript editing Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Competing Interests The authors have no relevant financial or non-financial interests to disclose. Author Contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Joris van Esch and Roseriet Beijers. The first draft of the manuscript was written by Joris van Esch and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Ethics approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the local Ethics Committee of Radboud University, registered under CMO number 2015-2255 (NL-nr: 55946.091.15). Consent to participate Informed consent was obtained from all individual participants included in the study. 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Biol Res Nurs 20(3):292–299 Hoftiezer L et al (2016) Defining small-for-gestational-age: prescriptive versus descriptive birthweight standards. Eur J Pediatr 175(8):1047–1057 Tables Table 1. Sociodemographic and medical characteristics Mean unless otherwise specified SD (range) N 15 Maternal age 30.0 ± 5.5 (19 – 40) Parity Nulliparous (%) 87 Parous (%) 13 Ethnicity Caucasian (%) 93 Body mass index Before pregnancy (kg/m 2 ) 25 ± 4.8 (20-35) Maternal educational level Secondary education (%) 54 College or university (%) 46 Smoking in pregnancy Yes (%) 20 Maternal disease descriptives Gestational age at admission (weeks) 30.1 ± 2.5 (24-33) Antihypertensive medications (n) 2 (1-3) Intravenous magnesium sulfate (%) 87 24-hours urine protein at admission (g/24h) 4.3 ± 4.3 (0.3-15.0) Highest urine protein/creatinine ratio after admission (g/10mmol) 3.8 ± 3.8 (0.3-11.9) HELLP-syndrome during hospital stay (%) 33.3 Eclampsia during hospital stay (%) 0 Delivery outcomes Termination on maternal indication (%) 100 Induction of labour, vaginal delivery (%) 40 Induction of labour, assisted delivery (%) 7 Caesarean section (%) 53 Infant characteristics Gestational age at birth (weeks) 32.2 ± 3.2 (25-37) Birth weight (grams) 1612 ± 518 (550-2848) Small for gestational age (<p10) § (%) 47 NICU days 8 ± 8.3 (0-29) 5’APGAR score 9 ± 2.5 (0-10) Primary outcome Prolongation of pregnancy (days) 14.7 ± 10.2 (1-33) Psychological stress questionnaires Anxiety (STAI) 42.9 ± 5.7 (31-51) Daily hassles (APL) 2.2 ± 0.7 (0-3) Fear of giving birth (PRAQ-R) 6.1 ± 3.5 (3-15) Fear of child with disabilities (PRAQ-R) 9.6 ± 5.3 (4-20) Depression (EPDS) 10.4 ± 4.3 (4-16) Cortisol in hair (nmol/l) Preconception 2.2 ± 2.3 (0.4-9.0) First trimester 3.3 ± 3.0 (0.6-2.0) Second trimester 7.2 ± 5.9 (2.0-25.0) STAI = state-trait anxiety inventory (state was used), APL = Dutch daily hassles questionnaire, PRAQ-R = pregnancy-specific anxiety questionnaire–revised, EPDS = Edinburgh Postnatal Depression Scale Footnote : § Small for gestational age was defined as a birth weight below the 10th percentile of the new Dutch reference ‘Perined-Hoftiezer’ curves [30] Table 2. Pearson correlations of predictor and outcome variables during pregnancy STAI = state-trait anxiety inventory, APL = Dutch daily hassles questionnaire, PRAQ-R = pregnancy-specific anxiety questionnaire–revised, EPDS = Edinburgh Postnatal Depression Scale † Correlation is significant at the 0.10 level (2-tailed) * Correlation is significant at the 0.05 level (2-tailed) Table 3. Estimates for the best fitting multilevel model for hair cortisol measurements Estimate SE p-value Intercept .10 .14 0.46 Time .28 .03 0.00** Prolongation of pregnancy (days) ̶ .01 .01 0.06 ** Correlation is significant at the 0.01 level (2-tailed) Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 11 Sep, 2022 Reviewers invited by journal 11 Sep, 2022 Editor invited by journal 06 Jul, 2022 Editor assigned by journal 06 Jul, 2022 First submitted to journal 04 Jul, 2022 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1823427","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":135727481,"identity":"c3465f6b-6f02-4042-8214-97f919999b0e","order_by":0,"name":"Joris J.A. van Esch","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEUlEQVRIiWNgGAWjYBAC9gYGhgNglvwBBmaGCiDjBhDzgIWYG7BpYYRrkQAqYTiDooURpxYGuBbGNmK0tPc+PPiD4bC8uQT7w8+F8+7J891uPibxtm2bPIN0I3YtPccNDvMwHDbcOb/HWHrmtmLDmXeOpUnObbtt2CBzELuWGWkMhxkY0hg33OBhY+bdlgBk5JhJ87bdTmCQSMSpBeiwNPsNN9ifMfPOSbAnqEUQqOUAD4NN4oYbDGbMvA0JiQS1SPMcYzjMY2CTDHSYMZCTkAz0S7LlnHO3DdtwaOFjb2P++KNCwnbD/eMPP/PUJNj23W4+eONN2W15fonkA9i0QIABNkE23OpHwSgYBaNgFBAAAIz9ZEn0D5x+AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-5666-1049","institution":"Radboudumc","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Joris","middleName":"J.A. van","lastName":"Esch","suffix":""},{"id":135727482,"identity":"87b2655f-3384-42e3-90c1-a3a008ca4ea6","order_by":1,"name":"Antoinette C. Bolte","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Antoinette","middleName":"C.","lastName":"Bolte","suffix":""},{"id":135727483,"identity":"98781484-150c-4e69-9bb0-8e55d65f6767","order_by":2,"name":"Marc E.A. Spaanderman","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Marc","middleName":"E.A.","lastName":"Spaanderman","suffix":""},{"id":135727484,"identity":"91f4f64a-0b29-4379-a47a-5ae218b74f66","order_by":3,"name":"Frank P.H.A. Vandenbussche","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Frank","middleName":"P.H.A.","lastName":"Vandenbussche","suffix":""},{"id":135727485,"identity":"3de9ba45-afb6-4018-8b59-736400548a7b","order_by":4,"name":"Carolina de Weerth","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Carolina","middleName":"","lastName":"de Weerth","suffix":""},{"id":135727486,"identity":"e93a8151-86ff-473c-b6ef-0956f0af5e2e","order_by":5,"name":"Roseriet Beijers","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Roseriet","middleName":"","lastName":"Beijers","suffix":""}],"badges":[],"createdAt":"2022-07-04 10:52:54","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1823427/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1823427/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":26422888,"identity":"5a518dd8-8128-41bc-a773-fea6170539db","added_by":"auto","created_at":"2022-09-13 21:22:33","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":25322,"visible":true,"origin":"","legend":"\u003cp\u003eScatterplot of correlation of anxiety and prolongation days (\u003cem\u003er\u003c/em\u003e = -.64, \u003cem\u003ep\u003c/em\u003e = .01*)\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-1823427/v1/2331caeec996979c0111925b.png"},{"id":26422889,"identity":"6118f6f8-b0cc-479e-b1cb-e550e3412e14","added_by":"auto","created_at":"2022-09-13 21:22:33","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":15199,"visible":true,"origin":"","legend":"\u003cp\u003eVisualization of the association between hair cortisol measurements over the course of pregnancy and prolongation days, divided in two groups\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-1823427/v1/79c301b58350375e24525cae.png"},{"id":26422890,"identity":"93102f2c-4b36-4e4d-b3a3-c757ac225f64","added_by":"auto","created_at":"2022-09-13 21:22:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":400072,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1823427/v1/bc2e4274-2d50-44b9-b834-770cd4687d0b.pdf"}],"financialInterests":"","formattedTitle":"Maternal anxiety forecasts shorter prolongation of pregnancies complicated by early-onset preeclampsia","fulltext":[{"header":"What Does This Study Adds To The Clinical Work?","content":"\u003cp\u003eThe results of this first study with prospectively collected psychological and physiologic data relating maternal stress to pregnancy prolongation in women admitted to hospital for early-onset preeclampsia are innovative and of potential clinical value. Higher maternal anxiety at hospital admission predicted significantly shorter admission-to-delivery intervals.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003ePreeclampsia affects 3% of all pregnancies [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Preeclampsia occurring before 34 weeks of gestation (10% of preeclampsia cases) is considered early-onset and is associated with substantially increased maternal and neonatal morbidity and mortality [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The only known treatment for preeclampsia is delivery. Aggressive \u0026lsquo;interventionist management\u0026rsquo; with delivery within 24 to 48 hours, may benefit maternal outcome at the expense of increased neonatal morbidity and mortality. Conservative \u0026lsquo;expectant management\u0026rsquo; to prolong pregnancy, may increase the risk for maternal complications, such as eclampsia, liver rupture, intracranial haemorrhage, pulmonary oedema, and kidney failure but may, however, improve offspring outcome [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. When interventionist management is compared to expectant management, the expectant approach results in decreased offspring morbidity; each additional day of prolongation reduces offspring infant mortality about 9% [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. As such, expectant management is generally pursued in the Netherlands with continuous, vigilant surveillance of mother and foetus, with scheduled delivery for features of severe maternal disease or signs of foetal compromise [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Little is known about maternal factors predicting shorter or longer prolongation. Knowing more about these factors may facilitate the development of future early interventions aimed at improving outcomes in women with early-onset preeclampsia. This study aims to investigate whether maternal psychological and physiological stress is associated with the number of days until delivery (i.e., admission-to-delivery intervals) in women hospitalized with early-onset preeclampsia.\u003c/p\u003e \u003cp\u003eIn non-clinical populations, evidence is accumulating that maternal psychological stress and anxiety during pregnancy forecast adverse perinatal outcomes, including shorter gestations [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. A few studies investigated women hospitalized during pregnancy, and those most distressed were at highest obstetric risk [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Next to measuring stress through self-report, stress can also be measured at a physiological level. When exposed to psychological or physical stress, the Hypothalamic-Pituitary-Adrenal (HPA)-axis is activated, resulting in the release of cortisol. Higher cortisol concentrations affect inflammatory responses, oxidative stress and endothelial function, and even uteroplacental blood flow, all correlates of gestational hypertensive disease [\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. These findings raise the question whether maternal psychological and physiological stress may be predictors of shorter or longer prolongation in early-onset preeclampsia.\u003c/p\u003e \u003cp\u003eThe present study investigate maternal psychological and physiological stress upon hospital admittance with expectant management in women diagnosed with early-onset preeclampsia. Stress questionnaires included pregnancy-specific stress and anxiety, such as fear of bearing a child with disabilities, as these have also been related to adverse perinatal outcomes [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Physiological stress, i.e., HPA-axis activity, is assessed by cortisol concentrations in maternal hair. Hair cortisol permits evaluating cortisol output over longer periods of time [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In this study, hair cortisol not only provides information about the concentrations during the disease (i.e. second trimester), but also allows preconception and first trimester concentrations to be determined. We hypothesized that higher psychological and physiological stress would be related to shorter admission-to-delivery intervals during expectant management in women hospitalized with early-onset preeclampsia.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis study included women with early-onset preeclampsia (\u0026lt;\u0026thinsp;34wks gestation) hospitalized at a single tertiary referral care centre (Radboudumc, the Netherlands) during 2016\u0026ndash;2017. The definition of the International Society for the Study of Hypertension in Pregnancy (ISSHP) [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] was used to define preeclampsia. At Radboudumc, women with early-onset preeclampsia are admitted to the Obstetric High Care unit [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Corticosteroids for foetal lung maturation, antihypertensives and, magnesium sulphate, are administered according to the local protocol. At hospital admission, women with early-onset preeclampsia were asked to participate and after informed consent, filled in questionnaires and donated a sample of hair prior to corticosteroid treatment. Results of both assessments were blinded for participants and professionals. The study was approved by the local ethical committee, registered under CMO number 2015\u0026ndash;2255 (NL-nr: 55946.091.15).\u003c/p\u003e \u003cp\u003eThe primary outcome was prolongation of pregnancy in days from admission to delivery, representing the admission-to-delivery interval. Indication for delivery and prolongation of pregnancy were retrieved from the medical records. Independent variables were psychological stress and anxiety and hair cortisol concentrations. Validated questionnaires were used to measure general and pregnancy-specific stress and anxiety. General state anxiety was assessed by means of the State-Trait Anxiety Inventory (STAI) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. General daily hassles were assessed by means of a Dutch questionnaire: the Everyday Problem Checklist [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Pregnancy-specific anxiety was assessed by means of the Pregnancy-specific Anxieties Questionnaire \u0026ndash; Revised (PRAQ-R) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Two subscales were used, namely fear of giving birth, and fear of bearing a child with disabilities. Depressive symptoms were assessed by the Edinburgh Postnatal Depression Scale (EPDS) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe hair sample was analysed in 3-centimeter segments representing the cortisol concentrations in the preconception period (-13 to 0 weeks), the first trimester (1 to 13 weeks) and the second trimester (14 to 26 weeks), as hair growths 1 cm per month [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Corticosteroid therapy for foetal lung maturation did not affect hair cortisol, as the hair was cut before or immediately after corticosteroid administration. Cortisol concentrations were assayed at Dresden LAB Service GmbH, Germany, using a column-switching LC-APCI-MS/MS method [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Because of non-normality, log transformations were applied.\u003c/p\u003e \u003cp\u003eTo investigate the associations between the admission-to-delivery intervals and the psychological stress and anxiety measures, (partial) correlations or regression analyses were performed, depending on the number of confounders that were (marginally) significantly related to prolongation. We considered the following confounders: pre-pregnancy body mass index, pregnancy smoking, maternal age, maternal educational level, and gestational age upon admission.\u003c/p\u003e \u003cp\u003eTo test whether prolongation of pregnancy was correlated to cortisol over the course of preconception to the second trimester, longitudinal regression analyses using mixed-model (multilevel) designs were performed. In these analyses, the hair cortisol measures representing the preconception period, first trimester, and second trimester were used at Level 1 and nested within the women at Level 2. Thereafter, a build-up strategy was followed in which variables (i.e. confounders, time, prolongation in days, and the interaction between time and prolongation) were added one-by-one to the model with random intercept and random slope. After adding each variable, the change in deviance on the \u0026minus;\u0026thinsp;2log likelihood ratio scale after generalized least square estimations was assessed. Variables that did not improve the model by significantly reducing the deviance were excluded. The model with the best model fit is presented in the results.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eDescriptives\u003c/h2\u003e \u003cp\u003eBaseline characteristics are reported in Table\u0026nbsp;1. We analysed 15 cases of early-onset preeclampsia with a mean gestational age at admission of 30.0 weeks. The mean prolongation of pregnancy in days was 15.0 days, and in all cases, pregnancy was terminated at medical indication because of deterioration in maternal condition. Five women developed HELLP-syndrome, none eclampsia. All women received anti-hypertensive treatment, almost all with additionally magnesium sulphate.\u003c/p\u003e \u003cp\u003eThe mean score for general anxiety (STAI) was 42.93. Clinically significant anxiety scores, above 40 points [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], were reported in 12 out of 15 cases. The mean for depressive symptoms (EPDS) was 10.41. In 9 out of 15 patients, the score was \u0026ge;\u0026thinsp;10, which indicates possible depression [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The remaining questionnaires do not have clinical cut-off values. Table\u0026nbsp;2 provides the correlations between the questionnaires, the hair cortisol measures, and pregnancy prolongation in days. Higher maternal anxiety at hospital admission predicted significantly less prolongation in days (\u003cem\u003er\u003c/em\u003e=-.64, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.01), and higher hair cortisol concentrations during the second trimester tended to predict less prolongation in days (\u003cem\u003er\u003c/em\u003e=-45, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.09).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003ePsychological stress and anxiety\u003c/h2\u003e \u003cp\u003eAs the confounders, including gestational age at hospital admittance, were not significantly related to admission-to-delivery interval (all \u003cem\u003ep\u003c/em\u003e-values\u0026thinsp;\u0026gt;\u0026thinsp;.378), we could rely on the correlations provided in Table\u0026nbsp;1. These correlations indicate that higher maternal anxiety, measured with the STAI at diagnosis, significantly forecasts fewer days of prolongation of pregnancy (Fig.\u0026nbsp;1). The other questionnaire measures were not significantly related to admission-to-delivery intervals.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eCortisol in hair\u003c/h2\u003e \u003cp\u003eTo investigate the associations between prolongation days and the hair cortisol measurements, multilevel analyses were performed. The final multilevel model is reported in Table\u0026nbsp;3. A significant effect of time was found, indicating that cortisol concentrations rise over the course of pregnancy, as was expected. A marginally significant negative effect of prolongation days on hair cortisol concentrations was found (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.06). This effect of prolongation in days was not moderated by time, indicating that overall higher cortisol concentrations (from preconception till the second trimester), tended to be related to fewer prolongation days. To visualize these results, two groups were created (\u0026le;\u0026thinsp;14 days prolongation, \u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9, versus \u0026ge;\u0026thinsp;15 days prolongation, \u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6), and their mean hair cortisol concentrations were plotted (Fig.\u0026nbsp;2). This figure shows that the cortisol concentrations of the mothers with the fewest prolongation days was higher, from preconception till the second trimester.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study investigated whether maternal stress upon hospital admission was associated with fewer days of prolongation (i.e. admission-to-delivery intervals) in women hospitalized with early-onset preeclampsia. Stress was evaluated by stress and anxiety questionnaires, and by assessment of cortisol concentrations in hair. Higher anxiety, as reported by the participants at admission, correlated with shorter admission-to-delivery intervals. Moreover, higher overall hair cortisol, from preconception till the second trimester, was marginally related to shorter admission-to-delivery intervals. The other questionnaire measures were not significantly associated to prolongation days.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePsychological stress and anxiety\u003c/h2\u003e \u003cp\u003eThe results are in accordance with previous studies in non-clinical populations showing that anxiety and stress during pregnancy are associated with shorter gestational duration [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Psychological stress could influence and increase systemic blood pressure by hyperstimulation of the sympathetic nervous system [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Sympathetic overactivity has been observed in formerly preeclamptic women, with consequential sympathetically driven hyperdynamic circulation and increased shear stress on the vascular endothelium. These abnormal hemodynamic changes are thought to contribute to the hypertensive deterioration of pregnancy. Anti-hypertensive treatment may not be effective (enough) in these stressed, anxious patients, and preterm delivery might be unavoidable. Future research is needed to determine whether adding psychological stress-reducing interventions to the treatment of women with early-onset preeclampsia can extend admission-to-delivery intervals, as suggested in previous literature [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhether the heightened anxiety at hospital admission was pre-existent or due to the situation is unknown. As prenatal stress and anxiety are stable in late pregnancy [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], it is plausible that the women already suffered from anxiety. However, pregnant women facing acute medical crises or when admitted to hospital for pregnancy complications have been found to have higher levels of anxiety [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. It is also possible that the feelings of anxiety are a result of the disease manifestation itself. The augmented sympathetic nervous system activity, seen in women with a history of preeclampsia [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], could be a pathophysiological explanation for the feelings of these women. The STAI-questionnaire statements \u0026lsquo;I am tense\u0026rsquo; or \u0026lsquo;I feel strained\u0026rsquo; for example, could describe these feelings and result in a high anxiety score. Therefore, stress-reducing interventions, such as cognitive behavioural therapy or mindfulness-based stress reduction therapy, may be effective in reducing symptoms and potentially positively affect the woman\u0026rsquo;s health. A randomized controlled trial in uncomplicated pregnancies with high reported Pregnancy-Related Anxiety indeed showed that mindfulness reduced maternal anxiety and improved pregnancy outcome [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. These findings suggest that women prone to experience anxiety may profit from mindfulness-based stress reduction interventions, maybe even before pregnancy, to prevent pregnancy complications and negative outcomes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eCortisol in hair\u003c/h2\u003e \u003cp\u003eIn this study, hair cortisol concentrations were marginally associated to prolongation of pregnancy in early-onset preeclampsia. This effect was not moderated by time, indicating that overall higher cortisol concentrations, from preconception till the second trimester, tended to be related to shorter admission-to-delivery intervals. This is in line with a review showing that mothers delivering preterm had higher cortisol concentrations in blood or saliva at 27\u0026ndash;37 weeks GA as compared to mothers delivering at term [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. An increase in the release of cortisol and catecholamines triggers physiological responses, such as contractions of the peripheral blood vessels and an increase in blood pressure and heart rate, which in turn adversely affects the condition of mother and foetus. Cortisol concentrations in hair could possibly be indicating poor adaptation of the sympathetic nervous system to pregnancy in these women, resulting in a shorter admission-to-delivery interval in early-onset preeclampsia. Future research is needed to determine whether hair cortisol might be used as a biomarker of preconceptional risk estimation for pregnancy complications. Especially in women with a history of preeclampsia or a cardiovascular risk profile, as well as mental health complaints, it could be useful to know the risk of progression to severe disease in future pregnancies. Furthermore, preventive interventions are sorely needed for these women. Next to de-stressing psychological interventions mentioned earlier, aerobic training may be an effective intervention. Indeed, in a previous study on formerly pre-eclamptic women [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], aerobic training improved plasma volume expansion and reduced sympathetic overactivity, and as a result perhaps reduced a cause for stress.\u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003eAssociations between anxiety and cortisol during pregnancy\u003c/h2\u003e \u003cp\u003eBoth reported anxiety as well as hair cortisol concentrations (tended to be) related to shorter admission-to-delivery intervals. From the correlation table (Table\u0026nbsp;2), it can be seen that the reported anxiety measures were moderately related to hair cortisol concentrations (\u003cem\u003er\u0026rsquo;s\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.20-.42). This result is in line with previous studies who also found no or moderate correlations between maternal reports of stress/anxiety and cortisol measures during pregnancy [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Note, however, that most previous studies measured cortisol in saliva, blood, and urine, reflecting more current and acute levels of cortisol, while the current study used hair cortisol. This enables retrospective examination of the cortisol production of the past months, representing more chronic levels of cortisol [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. A study combining reported stress with hair cortisol measures in the first, second and third trimester in normotensive pregnancies [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], found a positive relation between self-reported stress (Perceived Stress Scale) at 16 weeks and second-trimester cortisol concentrations. Also, perceived stress at 16 weeks and second-trimester hair cortisol concentrations were positively associated with preterm delivery [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], suggesting that heightened cortisol might, to some extent, underlie links between psychological stress and pregnancy outcomes [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section3\"\u003e \u003ch2\u003eStrengths and limitations\u003c/h2\u003e \u003cp\u003eThe strengths of this study are the prospectively collected psychological and physiologic data, and an innovative non-invasive biomarker of cortisol production covering the period from preconception to the second trimester. Also, we used multilevel analyses with repeated measures of hair cortisol to increase our statistical power. However, and in line with the rarity of early-onset preeclampsia, the size of the study is rather small and our results should be interpreted with caution. Future multi-center studies are needed to increase sample size and replicate our findings.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe results of this first study relating maternal stress to pregnancy prolongation in women admitted to hospital for early-onset preeclampsia are innovative and of potential clinical value. The mean general anxiety scores of these women were above the cut-off for clinically significant anxiety. Moreover, higher maternal anxiety at hospital admission predicted significantly shorter admission-to-delivery intervals. Also, chronically increased hair cortisol concentrations (i.e., from preconception through the second trimester) were marginally significantly related to shorter admission-to-delivery intervals. Our findings regarding hair cortisol are contributing to a growing literature which suggests that chronic cortisol exposure may have important implications for health [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] and highlights the use of hair cortisol as a promising method for understanding the role of stress on pregnancy outcome. Future research into early innovative stress-reducing interventions for early-onset preeclampsia may shed more light on the etiology and treatment of this disease.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJ.J.A. van Esch: protocol and project development, data collection, data analysis, manuscript writing\u003c/p\u003e\n\u003cp\u003eA.C. Bolte: project development, manuscript editing\u003c/p\u003e\n\u003cp\u003eM.E.A. Spaanderman: manuscript editing\u003c/p\u003e\n\u003cp\u003eF.P.H.A. Vandenbussche: manuscript editing\u003c/p\u003e\n\u003cp\u003eC. de Weerth: project development, manuscript editing\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eR. Beijers: project development, data analysis, manuscript editing\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting Interests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthor Contributions\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Joris van Esch and Roseriet Beijers. The first draft of the manuscript was written by Joris van Esch and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEthics approval\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the local Ethics Committee of Radboud University, registered under CMO number 2015-2255 (NL-nr: 55946.091.15).\u0026nbsp;\u003c/p\u003e\n\n\u003cp\u003e\u003cem\u003eConsent to participate\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLisonkova S, Joseph KS (2013) \u003cem\u003eIncidence of preeclampsia: risk factors and outcomes associated with early- versus late-onset disease\u003c/em\u003e.Am J Obstet Gynecol, \u003cb\u003e209\u003c/b\u003e(6): p. 544 e1-544 e12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMol BWJ et al (2016) Pre-eclampsia Lancet 387(10022):999\u0026ndash;1011\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWithagen MI, Visser W, Wallenburg HC (2001) Neonatal outcome of temporizing treatment in early-onset preeclampsia. Eur J Obstet Gynecol Reprod Biol 94(2):211\u0026ndash;215\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan Esch JJA et al (2017) Early-onset preeclampsia is associated with perinatal mortality and severe neonatal morbidity. J Matern Fetal Neonatal Med 30(23):2789\u0026ndash;2794\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evon Dadelszen P et al (2011) Prediction of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERS model. Lancet 377(9761):219\u0026ndash;227\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan Oostwaard MF et al (2017) Maternal and neonatal outcomes in women with severe early onset pre-eclampsia before 26 weeks of gestation, a case series. BJOG 124(9):1440\u0026ndash;1447\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMulder EG et al (2020) \u003cem\u003eEffect of pregnancy prolongation in early-onset pre-eclampsia on postpartum maternal cardiovascular, renal and metabolic function in primiparous women: an observational study\u003c/em\u003e.BJOG,\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChurchill D et al (2018) Interventionist versus expectant care for severe pre-eclampsia between 24 and 34 weeks' gestation. Cochrane Database Syst Rev 10:CD003106\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeijers R, Buitelaar JK, de Weerth C (2014) Mechanisms underlying the effects of prenatal psychosocial stress on child outcomes: beyond the HPA axis. Eur Child Adolesc Psychiatry 23(10):943\u0026ndash;956\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZijlmans MA, Riksen-Walraven JM, de Weerth C (2015) Associations between maternal prenatal cortisol concentrations and child outcomes: A systematic review. Neurosci Biobehav Rev 53:1\u0026ndash;24\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaloni JA et al (2002) Dysphoria among high-risk pregnant hospitalized women on bed rest: a longitudinal study. Nurs Res 51(2):92\u0026ndash;99\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarber CC, Starkey NJ (2015) Predictors of anxiety among pregnant New Zealand women hospitalised for complications and a community comparison group. Midwifery 31(9):888\u0026ndash;896\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSikkema JM et al (2001) Salivary cortisol levels and anxiety are not increased in women destined to develop preeclampsia. J Psychosom Res 50(1):45\u0026ndash;49\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang S et al (2013) Association between mental stress and gestational hypertension/preeclampsia: a meta-analysis. Obstet Gynecol Surv 68(12):825\u0026ndash;834\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMulder EJ et al (2002) Prenatal maternal stress: effects on pregnancy and the (unborn) child. Early Hum Dev 70(1\u0026ndash;2):3\u0026ndash;14\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStaufenbiel SM et al (2013) Hair cortisol, stress exposure, and mental health in humans: a systematic review. Psychoneuroendocrinology 38(8):1220\u0026ndash;1235\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRussell E et al (2012) Hair cortisol as a biological marker of chronic stress: current status, future directions and unanswered questions. Psychoneuroendocrinology 37(5):589\u0026ndash;601\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrown MA et al (2018) Hypertensive Disorders of Pregnancy: ISSHP Classification, Diagnosis, and Management Recommendations for International Practice. Hypertension 72(1):24\u0026ndash;43\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpielberger CD, Vagg PR (1984) Psychometric properties of the STAI: a reply to Ramanaiah, Franzen, and Schill. J Pers Assess 48(1):95\u0026ndash;97\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVingerhoets AJJM, Jeninga AJ, Menges LJ (1989) The Measurement of Daily Hassles and Chronic Stressors - the Development of the Everyday Problem Checklist (Epcl, Dutch - Apl), vol 17. Gedrag \u0026amp; Gezondheid, pp 10\u0026ndash;17. 1\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVan den Bergh BR et al (1989) The effect of (induced) maternal emotions on fetal behaviour: a controlled study. Early Hum Dev 19(1):9\u0026ndash;19\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCox JL, Holden JM, Sagovsky R (1987) Detection of postnatal depression. Development of the 10-item Edinburgh Postnatal Depression Scale. Br J Psychiatry 150:782\u0026ndash;786\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStalder T, Kirschbaum C (2012) Analysis of cortisol in hair\u0026ndash;state of the art and future directions. Brain Behav Immun 26(7):1019\u0026ndash;1029\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrant KA, McMahon C, Austin MP (2008) Maternal anxiety during the transition to parenthood: a prospective study. J Affect Disord 108(1\u0026ndash;2):101\u0026ndash;111\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHoffman MC et al (2016) Measures of Maternal Stress and Mood in Relation to Preterm Birth. Obstet Gynecol 127(3):545\u0026ndash;552\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eScholten RR et al (2015) Aerobic Exercise Training in Formerly Preeclamptic Women: Effects on Venous Reserve. Hypertension 66(5):1058\u0026ndash;1065\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan Esch JJA et al (2020) Differences in hair cortisol concentrations and reported anxiety in women with preeclampsia versus uncomplicated pregnancies. Pregnancy Hypertens 21:200\u0026ndash;202\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZarenejad M et al (2020) The effect of mindfulness-based stress reduction on maternal anxiety and self-efficacy: A randomized controlled trial. Brain Behav 10(4):e01561\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDuffy AR et al (2018) Comparison of Hair Cortisol Levels and Perceived Stress in Mothers Who Deliver at Preterm and Term. Biol Res Nurs 20(3):292\u0026ndash;299\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHoftiezer L et al (2016) Defining small-for-gestational-age: prescriptive versus descriptive birthweight standards. Eur J Pediatr 175(8):1047\u0026ndash;1057\u003c/span\u003e\u003c/li\u003e \u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Sociodemographic and medical characteristics\u003c/p\u003e\n\u003ctable border=\"0\" width=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" valign=\"top\" width=\"70.1912260967379%\"\u003e\n\u003cp\u003eMean\u003c/p\u003e\n\u003cp\u003eunless otherwise specified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" valign=\"top\" width=\"29.808773903262093%\"\u003e\n\u003cp\u003eSD \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; (range)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u003cstrong\u003eMaternal age\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e30.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026plusmn; 5.5\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e(19 \u0026ndash; 40)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u003cstrong\u003eParity\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Nulliparous (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e87\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Parous (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u003cstrong\u003eEthnicity\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Caucasian (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e93\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;Body mass index\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Before pregnancy (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026plusmn; 4.8\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e(20-35)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u003cstrong\u003eMaternal educational level\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Secondary education (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e54\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; College or university (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e46\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u003cstrong\u003eSmoking in pregnancy\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Yes (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u003cstrong\u003eMaternal disease descriptives\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Gestational age at admission (weeks)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e30.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026plusmn; 2.5\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e(24-33)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003eAntihypertensive medications (n)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e(1-3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Intravenous magnesium sulfate (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e87\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; 24-hours urine protein at admission (g/24h)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e4.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026plusmn; 4.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e(0.3-15.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Highest urine protein/creatinine ratio\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; after admission \u0026nbsp;(g/10mmol)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026plusmn; 3.8\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(0.3-11.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;HELLP-syndrome during hospital stay (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e33.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Eclampsia during hospital stay (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u003cstrong\u003eDelivery outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003eTermination on maternal indication (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003eInduction of labour, vaginal delivery (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003eInduction of labour, assisted delivery (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003eCaesarean section (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e53\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u003cstrong\u003eInfant characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Gestational age at birth (weeks)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e32.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026plusmn; 3.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e(25-37)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Birth weight (grams)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e1612\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026plusmn; 518\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e(550-2848)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Small for gestational age (\u0026lt;p10)\u003csup\u003e\u0026sect;\u0026nbsp;\u003c/sup\u003e(%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e47\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; NICU days\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026plusmn; 8.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e(0-29)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; 5\u0026rsquo;APGAR score\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026plusmn; 2.5\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e(0-10)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary outcome\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003eProlongation of pregnancy (days)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e14.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026plusmn; 10.2\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e(1-33)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u003cstrong\u003ePsychological stress questionnaires\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Anxiety (STAI)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e42.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026plusmn; 5.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e(31-51)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Daily hassles (APL)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e2.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026plusmn; 0.7\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e(0-3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Fear of giving birth (PRAQ-R)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e6.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026plusmn; 3.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e(3-15)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Fear of child with disabilities (PRAQ-R)\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e9.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026plusmn; 5.3\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e(4-20)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Depression (EPDS)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e10.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026plusmn; 4.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e(4-16)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u003cstrong\u003eCortisol in hair (nmol/l)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Preconception\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e2.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026plusmn; 2.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e(0.4-9.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003eFirst trimester\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e3.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026plusmn; 3.0\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e(0.6-2.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Second trimester\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e7.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026plusmn; 5.9\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e(2.0-25.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"61.64229471316086%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"8.548931383577052%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"10.686164229471316%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"19.122609673790777%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\" valign=\"top\" width=\"100%\"\u003e\n\u003cp\u003eSTAI = state-trait anxiety inventory (state was used), APL = Dutch daily hassles questionnaire, PRAQ-R = pregnancy-specific anxiety questionnaire\u0026ndash;revised, EPDS = Edinburgh Postnatal Depression Scale\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eFootnote\u003c/strong\u003e: \u003csup\u003e\u0026sect;\u003c/sup\u003eSmall for gestational age was defined as a birth weight below the 10th percentile of the new Dutch reference \u0026lsquo;Perined-Hoftiezer\u0026rsquo; curves [30]\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Pearson correlations of predictor and outcome variables during pregnancy\u003c/p\u003e\n\u003cp\u003e\u003cimg 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\" alt=\"\" /\u003e\u003c/p\u003e\n\u003cp\u003eSTAI = state-trait anxiety inventory, APL = Dutch daily hassles questionnaire, PRAQ-R = pregnancy-specific anxiety questionnaire\u0026ndash;revised, EPDS = Edinburgh Postnatal Depression Scale\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026dagger; Correlation is significant at the 0.10 level (2-tailed)\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e* Correlation is significant at the 0.05 level (2-tailed)\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e Estimates for the best fitting multilevel model for hair cortisol measurements\u003c/p\u003e\n\u003ctable border=\"1\" width=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 11.8676%;\" valign=\"top\" width=\"16.024653312788907%\"\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.5449%;\" valign=\"top\" width=\"10.169491525423728%\"\u003e\n\u003cp\u003e\u003cstrong\u003eEstimate\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.5449%;\" valign=\"top\" width=\"10.169491525423728%\"\u003e\n\u003cp\u003e\u003cstrong\u003eSE\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.5449%;\" valign=\"top\" width=\"10.169491525423728%\"\u003e\n\u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 11.8676%;\" valign=\"top\" width=\"16.024653312788907%\"\u003e\n\u003cp\u003eIntercept\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.5449%;\" valign=\"top\" width=\"10.169491525423728%\"\u003e\n\u003cp\u003e.10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.5449%;\" valign=\"top\" width=\"10.169491525423728%\"\u003e\n\u003cp\u003e.14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.5449%;\" valign=\"top\" width=\"10.169491525423728%\"\u003e\n\u003cp\u003e0.46\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 11.8676%;\" valign=\"top\" width=\"16.024653312788907%\"\u003e\n\u003cp\u003eTime\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.5449%;\" valign=\"top\" width=\"10.169491525423728%\"\u003e\n\u003cp\u003e.28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.5449%;\" valign=\"top\" width=\"10.169491525423728%\"\u003e\n\u003cp\u003e.03\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.5449%;\" valign=\"top\" width=\"10.169491525423728%\"\u003e\n\u003cp\u003e0.00**\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 11.8676%;\" valign=\"top\" width=\"16.024653312788907%\"\u003e\n\u003cp\u003eProlongation of pregnancy (days)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.5449%;\" valign=\"top\" width=\"10.169491525423728%\"\u003e\n\u003cp\u003e̶ .01\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.5449%;\" valign=\"top\" width=\"10.169491525423728%\"\u003e\n\u003cp\u003e.01\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.5449%;\" valign=\"top\" width=\"10.169491525423728%\"\u003e\n\u003cp\u003e0.06\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 48.0204%;\" colspan=\"4\" valign=\"top\" width=\"64.66973886328725%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 74.2706%;\" colspan=\"4\" valign=\"top\" width=\"100%\"\u003e\n\u003cp\u003e\u003cem\u003e** Correlation is significant at the 0.01 level (2-tailed)\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"archives-of-gynecology-and-obstetrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"arch","sideBox":"Learn more about [Archives of Gynecology and Obstetrics](https://www.springer.com/journal/404)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/arch/default.aspx","title":"Archives of Gynecology and Obstetrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Early-onset preeclampsia, stress, anxiety, hair cortisol, pregnancy prolongation","lastPublishedDoi":"10.21203/rs.3.rs-1823427/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1823427/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003ePurpose:\u003c/strong\u003e\u003c/em\u003e In early-onset preeclampsia, each additional day of pregnancy prolongation reduces offspring infant mortality about 9%. We evaluated if maternal stress at admission to hospital for early-onset preeclampsia predicted admission-to-delivery intervals in days.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/em\u003e: This prospective, longitudinal cohort-study involved 15 singleton pregnancies with a diagnosis of preeclampsia before 34 weeks gestation with intended expectant management. Upon hospital admission, maternal psychological stress was assessed with questionnaires and physiological stress with hair cortisol. Hair samples were analysed in three hair segments representing the preconception period, and the first and second trimester of pregnancy.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/em\u003e Mean pregnancy prolongation was 15 days. Higher maternal anxiety at hospital admission significantly correlated with shorter admission-to-delivery intervals (\u003cem\u003er\u003c/em\u003e=-.64, \u003cem\u003ep\u003c/em\u003e=.01). Chronically increased hair cortisol concentrations (i.e., from preconception through the second trimester) of pregnancy tended to be related to shorter admission-to-delivery intervals (\u003cem\u003ep\u003c/em\u003e=.06).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/em\u003e Higher reported anxiety is, and chronically high hair cortisol tended to be, related with fewer days of prolongation from admission to delivery in women with early-onset preeclampsia. These findings suggest that maternal stress might be a potential determinant of disease progression. Future research into early innovative stress-reducing interventions for early-onset preeclampsia may shed more light on the etiology and treatment of this disease.\u003c/p\u003e","manuscriptTitle":"Maternal anxiety forecasts shorter prolongation of pregnancies complicated by early-onset preeclampsia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-09-13 21:22:31","doi":"10.21203/rs.3.rs-1823427/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2022-09-11T10:04:57+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2022-09-11T09:18:29+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"Archives of Gynecology and Obstetrics","date":"2022-07-06T20:11:31+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-07-06T11:59:34+00:00","index":"","fulltext":""},{"type":"submitted","content":"Archives of Gynecology and Obstetrics","date":"2022-07-04T06:51:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"archives-of-gynecology-and-obstetrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"arch","sideBox":"Learn more about [Archives of Gynecology and Obstetrics](https://www.springer.com/journal/404)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/arch/default.aspx","title":"Archives of Gynecology and Obstetrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"43db56e1-0fd7-48f2-97c5-148726fbb75a","owner":[],"postedDate":"September 13th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2022-10-25T03:06:06+00:00","versionOfRecord":[],"versionCreatedAt":"2022-09-13 21:22:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1823427","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1823427","identity":"rs-1823427","version":["v1"]},"buildId":"i_I_jhV-QviBjPLXJga9V","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}