Association of objectively measured physical fitness during pregnancy with maternal and neonatal outcomes. The GESTAFIT Project

RESEARCH ARTICLE Association of objectively measured physical fitness during pregnancy with maternal and neonatal outcomes. The GESTAFIT Project Laura Baena-Garcı ´a 1☯ , Irene Coll-RiscoID 2,3☯ *, Olga Oco ´n-Herna ´ndez 4 , Lidia RomeroGallardo 3,4,5 , Pedro Acosta-Manzano 3,4,5 , Linda May 6 , Virginia A. Aparicio 2,3 1Department of Nursing, Faculty of Health Sciences, University of Granada, Granada, Spain, 2Department of Physiology, "Jose ´Mataix Verdu ´" Institute of Nutrition and Food Technology (INYTA) and Biomedical Research Centre (CIBM), University of Granada, Granada, Spain, 3Sport and Health University Research Institute (iMUDS), University of Granada, Granada, Spain, 4UGC of Gynaecology and Obstetrics, “San Cecilio” University Hospital, Granada, Spain, 5Department of Physical Education and Sports, Faculty of Sport Sciences, University of Granada, Granada, Spain, 6Department of Foundational Science and Research, School of Dental Medicine, East Carolina University, Greenville, NC, United States of America ☯These authors contributed equally to this work. *[email protected] Abstract Aim To analyse i) the association of physical fitness during early second trimester and late pregnancy with maternal and neonatal outcomes; and ii) to investigate whether physical fitness is associated with the type of birth (vaginal or caesarean section). Methods Pregnant women from the GESTAFIT Project (n = 159) participated in this longitudinal study. Maternal physical fitness including upperand lower-body strength, cardiorespiratory fitness (CRF) and flexibility were measured through objective physical fitness tests at the 16 th and 34 th gestational weeks. Maternal and neonatal outcomes were collected from obstetric medical records. Umbilical arterial and venous blood gas pH and partial pressure of carbon dioxide (PCO 2 ) and oxygen (PO 2 ), were assessed. Results At the 16 th week, greater upper-body muscle strength was associated with greater neonatal birth weight (r = 0.191, p<0.05). Maternal flexibility was associated with a more alkaline arterial pH (r = 0.220, p<0.05), higher arterial PO 2 (r = 0.237, p<0.05) and lower arterial PCO 2 (r = -0.331, p<0.01) in umbilical cord blood. Maternal CRF at the 16 th gestational week was related to higher arterial umbilical cord PO 2 (r = 0.267, p<0.05). The women who had caesarean sections had lower CRF (p<0.001) at the 16 th gestational week and worse clustered overall physical fitness, both at the 16 th (-0.227, p = 0.003, confidence interval (CI): -0.376, -0.078) and 34 th gestational week (-0.223; p = 0.018; CI: -0.432, -0.015) compared with the women who had vaginal births. PLOS ONE | https://doi.org/10.1371/journal.pone.0229079 February 18, 2020 1 / 18 a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 OPEN ACCESS Citation: Baena-Garcı ´a L, Coll-Risco I, Oco ´nHerna ´ndez O, Romero-Gallardo L, Acosta-Manzano P, May L, et al. (2020) Association of objectively measured physical fitness during pregnancy with maternal and neonatal outcomes. The GESTAFIT Project. PLoS ONE 15(2): e0229079. https://doi. org/10.1371/journal.pone.0229079 Editor: Zhong-Cheng Luo, Mount Sinai Health System, University of Toronto, CANADA Received: May 14, 2019 Accepted: January 29, 2020 Published: February 18, 2020 Copyright: ©2020 Baena-Garcı ´a et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the manuscript and its Supporting Information files. Funding: This study was part of VAA fellowship from the Andalucı ´a Talent-Hub Program, launched by the Andalusian Knowledge Agency, co-funded by the European Union’s Seventh Framework Program, Marie Skłodowska-Curie actions (COFUND–Grant Agreement nº291780) and the Junta de Andalucı ´a. ICR (grant number: FPU13/ Conclusion Increasing physical fitness during pregnancy may promote better neonatal outcomes and is associated with a decrease in the risk of caesarean section. This trial was registered at ClinicalTrials.gov (NCT02582567) on October 20, 2015. Introduction Research continues to confirm that exercise during pregnancy contributes to healthier outcomes for both the mother and the fetus [1,2]. Consequently, exercise is currently recommended in all low risk pregnancies [1]. Exercise during pregnancy has been related to an enhanced efficiency of the placenta [3] and the placental uterine perfusion [4], a lower rate of caesarean sections [1], and optimal birth weight [5]. Improved physical fitness is usually observed in women who exercise during pregnancy [6] and is associated with better perinatal health outcomes [7,8]. However, while it is well-established that physical activity improves birth outcomes [9–11], studies looking at the relationships between objective assessments of fitness and delivery type, gestational age, duration of labour stages, birth weight and values of umbilical cord blood gas are limited. The causes of caesarean sections and how to reduce caesarean section rates are now a spotlight of research as this type of delivery has been associated with an increased risk of infection compared with vaginal deliveries, higher wound dehiscence, haemorrhage and reduced fertility [12–14], as well as an increased risk of allergies, type 1 diabetes or respiratory problems [15] in infants, among other complications. Furthermore, it is noteworthy that in 2016 in Spain there were 22% caesarean sections in public hospitals [16], higher than the 15% rate recommended by the World Health Organization [17]. Therefore, it is of great importance for clinical practice to analyse the associations between maternal variables and improvements in the rates of caesarean sections. During pregnancy, uterine blood flow is crucial for appropriate nutrient and gas exchange with the fetus [18]. It is widely known that the umbilical cord blood pH analysis provides vital information about neonatal health status and reflects physiological response to complications that may occur during labour [19]. We previously found that higher levels of light or moderate physical activity during pregnancy were associated with greater umbilical arterial oxygen saturation and higher levels of venous cord blood pH; conversely, we showed that higher levels of sedentary time during pregnancy were related to worse pregnancy outcomes [10]. However, it is unknown whether maternal physical fitness is also a key factor to improve birth outcomes such as gestational age, duration of labour, birth weight and values of umbilical cord blood gas. This study highlights the importance of appropiate levels and quality of fitness that should be emphazised in exercise programs in order to improve birth outcomes. Furthermore, the association of maternal physical fitness with fetal acid-base balance has not been studied. The measurement of gases in the umbilical cord blood is a gold standard in the determination of the foetal acid-base balance [20]. In addition, the determination of PCO 2 is important, since higher levels of PCO 2 and a low pH level indicate a state of fetal acidosis [19,21]. On the other hand, CO 2 production is proportional to oxygen consumption [22], so the interpretation of PO 2 levels and oxygen saturation also provides fundamental information to determine the effectiveness of the fetal compensatory mechanisms and the state of the placenta. Therefore, the aims of this study were: i) to analyse the association of maternal physical-fitness measures during the early second trimester and late pregnancy with maternal (gestational age at birth Association of physical fitness and maternal and neonatal birth outcomes PLOS ONE | https://doi.org/10.1371/journal.pone.0229079 February 18, 2020 2 / 18 01993) was supported by the Spanish Ministry of Education. This study was also partially funded by the Regional Ministry of Health of the Junta de Andalucı ´a (PI-0395-2016) and the University of Granada, Plan Propio de Investigacio ´n 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. and length of the first and second stages of labour) and neonatal (birth weight and umbilical cord blood gas values) outcomes; ii) to investigate whether maternal physical-fitness during the early second trimester and late pregnancy may influence the type of birth (i.e. vaginal or caesarean section). Accordingly, we hypothesized that maternal physical-fitness may be positively associated with improved maternal and neonatal outcomes. The aim of the study was to better understand the influence of maternal fitness during pregnancy on maternal and neonatal outcomes. Materials and methods Study population The detailed procedures, inclusion and exclusion criteria (S1 Table) of the GESTAtion and FITness (GESTAFIT) Project were published elsewhere [23]. Initially, this study was based on a randomized control trial design, that was modified in order to ensure retention of women in the control group. Thus, women were allocated either to an exercise or a control group depending on their personal preference and convenience to attend the intervention sessions and the wave they had been recruited for. In this way, high dropout rates were avoided, which is one of the most frequent methodological barriers in antenatal exercise research, as previously argued [24]. Briefly, the intervention group underwent a supervised aerobic and strength training intervention from the 17 th gestational week until delivery. A total of 384 pregnant women were informed about the Project during their 12 th gestational week visit to the obstetrician at the “San Cecilio” University Hospital and “Virgen de las Nieves” University Hospital (Granada, southern Spain). A final number of 159 women were interested in participating and signed an informed consent. The GESTAFIT study was approved by the Ethics Committee on Clinical Research of Granada, Government of Andalusia, Spain (code: GESTAFIT-0448-N-15, approved on 19/05/2015). Procedures The first evaluation of the study was completed at the 16 th week of gestation (±2 weeks). Women completed a self-reported questionnaire, an anthropometric assessment, and physical fitness tests. On the 34 th week of gestation (±2 weeks), the second assessment of physical fitness tests and height and weight was conducted. Birth and obstetric outcomes of the current pregnancy were collected from the digital medical records (the pregnancy health document and the partogram). Sampling of the umbilical cord occurred 3 minutes after birth. Measurements Maternal sociodemographic data. Sociodemographic data (age, number of children; marital, educational and working status) were assessed with a self-reported questionnaire. A research staff was present at all times for any needed explanation or instruction. Maternal anthropometric assessment. Height and weight were measured using a stadiometer (Seca 22, Hamburg) and a scale (InBody R20; Biospace, Seoul, Korea), respectively. Body mass index was calculated as: weight (Kg)/height (m 2 ). Pregnancy health. The “Pregnancy Health Document” (Cartilla del embarazo in Spanish) is given to all pregnant women by the Andalusian regional government, and it contains obstetric and medical data recorded during all the length of the pregnancy and were collected for the present study. In this way, information about previous pregnancies, births, and gynaecological antecedents were obtained. The gestational age was calculated by the date of the last menstruation corrected for cycles of 28 days and subsequently corrected by ultrasound, if needed [25], Association of physical fitness and maternal and neonatal birth outcomes PLOS ONE | https://doi.org/10.1371/journal.pone.0229079 February 18, 2020 3 / 18 and was used for an accurate timing of the evaluations at the 16 th and the 34 th weeks of pregnancy. Birth outcomes. All data related to the type of birth (spontaneous vaginal, instrumental or caesarean), gestational week at birth, use of epidural analgesia, length of each stage of labour, offspring sex, neonatal weight and Apgar test were obtained from perinatal obstetric records (partogram) from the Hospital after birth. The cause (unplanned or planned, and whether it was elected for physiological reasons) of caesarean sections was annotated. We only had access to the partograms and samples of women who gave birth in the Public Hospitals approved by the Ethics Committee. However, the type of delivery was recorded for all women. The placenta was collected immediately after the delivery and the placental surface clots were removed. The amnion was cut from the basal area and the umbilical cord was completely cut. Subsequently, placenta was weighted with a 3.200 kg Precision Gram Scale (Ohaus Compass TM , USA). Umbilical cord blood gas. For the umbilical cord blood sampling, a trained midwife performed a double clamping of the umbilical cord three minutes after birth, with a minimum distance between both clamps of 10 centimetres. A pre-heparinized 1mL syringe was used for blood extraction. Blood samples were taken from both, umbilical artery and vein. Partial pressure of carbon dioxide (PCO2), partial pressure of oxygen (PO2), oxygen saturation and pH were analysed using a blood analyser (GEM Premier 4000; Instrumentation Laboratory, Bedford, MA, USA). Physical fitness. Physical fitness was assessed in the following order to avoid potentially induced fatigue from other tests: Upper-body muscular strength. Hand grip strength was measured with digital dynamometry (TKK 5101 Grip-D; Takey, Tokyo, Japan) after adjusting for the hand size for an optimal grip [26]. The test was performed twice with both hands, with a rest of 30 seconds and alternating hands. The final value was calculated as a mean of the two values from each hand. Lower-body muscular strength. Muscular strength of the lower-body was measured through the 30-second Chair Stand test. This test counts the maximum number of repetitions completed in 30 seconds, with a full stand to a sitting position and back straight up as one repitition. The participants performed one trial after a familiarization trial [27]. Flexibility.The Back Scratch test was used to assess upper-body flexibility. The test consists in measuring the overall shoulder range of motion by measuring the distance between the middle fingers coming together behind the back. The Back Scratch test outcome is positive for higher flexibility (i.e. hands overlapping behind the back) and negative for lower flexibility (i.e. greater distance between middle fingers behind the back). This test was done twice with both hands and the final score was calculated as the mean between the two attempts of each arm [27]. Cardiorespiratory fitness. Maximal oxygen intake (VO 2max ) was estimated (ml/Kg/min) through the Modified Bruce treadmill protocol [28], a submaximal, incremental, multistage, continuous treadmill test. The test consists of progressive increments in the workload and velocity every 3 minutes to determine limits of maximal exertion. Women were asked to walk on the treadmill during the test until the maternal heart rate reached 75% of the age-predicted maximal heart rate; if the participant requested to end the treadmill test, then the test was also stopped before reaching the heart rate value. Although submaximal treadmill testing is common and safe during pregnancy, women were secured with a harness during the test to prevent any consequences from a fall. This test has been previously used and shown to be safe in pregnant women [28,29]. Statistical analyses. We employed descriptive statistics [mean (standard deviation, SD)] for quantitative variables and number of cases and percentage (%) for categorical variables. All the variables were checked for normality of distribution through kurtosis and skewness Association of physical fitness and maternal and neonatal birth outcomes PLOS ONE | https://doi.org/10.1371/journal.pone.0229079 February 18, 2020 4 / 18 analyses before the analyses. All the outcome variables reasonably met this assumption. The associations of physical fitness levels with maternal (gestational age at birth and length of the first and second stages of labour) and neonatal (birth weight and umbilical cord blood gas values) outcomes were assessed with partial correlations after adjusting for maternal age, parity and BMI (Table 2). The associations of physical fitness levels with duration of the first and second labour stages, as well as neonatal outcomes were also adjusted for epidural analgesia, except for the variable “birth weight” which was only further adjusted for gestational age. Since some variables (gestational age at birth, birth weight, duration of the first and second stages of labor and instrumental delivery) previously showed weak associations with outcome variables (p>0.02), we performed secondary analyses to assess their role as potential confounders. Changes between pre (16 th week) and post (34 th week) evaluations results of fitness tests were analysed via repeated measures T-Tests (S2 Table). Subsequently, the changes (post–pre) were included in the linear regression analyses (Table 3) as predictor variables, whereas the birth outcomes were included as outcome variables in separate models. Relevant confounders suggested by previous literature with significant relationship with the outcomes, that influenced the relationship between the independent and dependent variable (i.e. B of the independent had a meaningful change (p>0.05) when adding the variable), were included in the models. Depending on the aim of the analysis, the models were adjusted for none confounder, for baseline values of cardiorespiratory fitness (CRF), or for baseline values, age, parity, weight change (post–pre), and exercise intervention (only at the 34 th -week analysis). The variables showing the duration of the first and second labour stages, as well as neonatal birth outcomes were additionally adjusted for epidural analgesia (as independent variable), except for the variable “birth weight” which was only further adjusted for gestational age. Logistic regression analysis was also employed to explore the associations between physical fitness levels (predictor variable) and the chances of having a vaginal delivery (spontaneous and instrumental) or caesarean section (outcome variable) (Table 4). We adjusted the analysis for the above-mentioned covariates. We also considered “place of birth” as a potential confounder due to the differences of caesarean section ratios between private and public hospitals in Spain [30]. Hence, we decided to check with the Chi-squared test if the type of hospital might have any influence on outcome variables. Given that we found statistically significant differences in birth outcomes between private and public hospitals within our data, we decided to include this variable as a potential confounder. Finally, in the GESTAFIT project [23], a concurrent physical exercise program was performed. We have also adjusted all the models for the exercise intervention (control or intervention). We created a clustered overall physical fitness (Z-score) as the mean of the standardized scores [(value–mean)/ standard deviation] of body strength (mean of upper and lowerbody strength standardized values), flexibility and CRF at the 16 th week of pregnancy (Fig 2A) and the 34 th week of pregnancy (Fig 2B). Both clustered groups were compared by caesarean or vaginal delivery with an ANCOVA analysis. We adjusted the analysis for maternal age, parity, maternal BMI at the 16 th gestational week, exercise intervention and birth place (public or private hospital). The statistical analyses were conducted with the Statistical Package for Social Sciences (IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp). The statistical significance was set at p<0.05. Results Of all the 159 participants, 158 had complete sociodemographic data (Fig 1). The final sample size was composed of 158 Caucasian pregnant women (age 32.9±4.6 years, BMI 24.9±4.1 kg/ m 2 ) with valid data for the present analyses. At the 16 th and 34 th weeks of pregnancy, 156 and Association of physical fitness and maternal and neonatal birth outcomes PLOS ONE | https://doi.org/10.1371/journal.pone.0229079 February 18, 2020 5 / 18 Fig 1. Flowchart in the selection of study participants for specific study aims. https://doi.org/10.1371/journal.pone.0229079.g001 Association of physical fitness and maternal and neonatal birth outcomes PLOS ONE | https://doi.org/10.1371/journal.pone.0229079 February 18, 2020 6 / 18 124 women participated in the physical fitness tests (Fig 1). A total of 18 partograms were not found in the informatic system (n = 9) or could not be collected as some participants delivered in a private hospital not associated with the study (n = 9) and partograms could not be accessed, neither could the samples of placenta be collected. However, the type of delivery was recorded for the deliveries in private hospitals. Hence, a total of 141 women had complete valid data for birth outcomes. The sociodemographic and clinical characteristics of the study participants are shown in Table 1. Most of the participants lived with their partner and more than half had University education and worked full time. Approximately 61% of the sample were nulliparous and 75.6% had vaginal births. Births took place around 39.5±1.3 weeks of gestation, with a mean neonate body weight of 3305±480.6 grams. At the 16 th and 34 th gestational weeks, mean values were similar in upper-body strength (Hand grip); lower-body strength (Chair stand); and 4.1 ±6.2 cm and 3.9±6 cm in flexibility test (Back Scratch) (all, p>0.05), but decreased in CRF 22.1 ±5.5 ml/Kg/min and 17.9±4.9 ml/Kg/min (p<0.001) (Modified Bruce treadmill test). All umbilical cord blood gas mean values were within normal ranges. Pearson’s partial correlations of physical fitness levels at the 16 th and the 34 th gestational weeks with maternal and neonatal outcomes are shown in Table 2.Regarding the maternal outcomes, physical fitness levels were not associated with these measures. In relation to neonatal outcomes, upper-body muscle strength at the 16 th week of gestation was associated with higher birth weight (r = 0.191, p<0.05). Lower-body muscle strength was not associated with any maternal and neonatal outcome (p>0.05). Greater maternal flexibility at the 16 th week was associated with a more alkaline pH (r = 0.220, p<0.05), higher PO 2 (r = 0.237, p<0.05), higher arterial oxygen saturation (r = 0.242, p<0.05), and lower PCO 2 (r = -0.331, p<0.01) in arterial umbilical cord blood. Maternal CRF at the 16 th week was related to higher PO 2 (r = 0.267, p<0.05) and higher oxygen saturation (r = 0.375, p<0.01) in arterial umbilical cord blood. Physical fitness levels at the 34 th week of pregnancy were not associated with any maternal and neonatal birth outcomes (all, p>0.05). S2 Table, comparing the fitness levels at the 16 th and the 34 th weeks of gestation, there were no differences in flexibility, upperor lower-body strength between the different time points. CRF decreased by 4.14 (5.07) ml/kg/min from the 16 th to the 34 th weeks of gestation (95% CI: 3.01, 5.27; p<0.001). The associations of the changes in CRF with birth outcomes are shown in Table 3. Arterial cord blood PO 2 and O 2 saturation were inversely associated with the CRF change (B = -0.603; 95% CI: -1.101, -0.105; p = 0.019, and B = -1.544; 95% CI: -2.720, -0.368; p = 0.011, respectively), with similar results in the model adjusted for baseline CRF, age, parity, weight change and exercise intervention. The model adjusted only for baseline values of CRF showed an inverse association between CRF change and arterial cord blood PO 2 (B = -0.622; 95% CI: -1.221, -0.023; p = 0.042). Differences in physical fitness levels at the 16 th and 34 th gestational weeks by birth type (vaginal or caesarean section) are shown in Table 4. At the 16 th week of pregnancy, no significant differences were found in upperand lower-body muscle strength between women who had vaginal births compared with women who had caesarean sections (both, p>0.05). The mean of flexibility levels was +2.4 (4.7) cm in the Back Scratch test in women who had caesarean sections compared with +5.0 (6.2) cm in women who had vaginal births (95% CI -0.027, -0.020; p= 0.027). Finally, women who had caesarean sections had a mean of CRF of 18.4 (4.2) ml/kg/min in the Modified Bruce test compared with women with a vaginal birth who had 23.3 (5.7) ml/kg/min in CRF (95% CI: -0.035, -0.009; p = 0.001). For physical fitness at the 34 th week of gestation, flexibility was higher in women who had vaginal births with 4.9 (6.0) cm, than in women with caesarean section, 1.0 (5.8) cm (95% CI: 0.027, 0.001; p = 0.033). Fig 2A and Fig 2B show the clustered overall physical fitness at the 16 th and 34 th weeks of gestation, respectively. Relative to women who had vaginal births, women who had caesarean Association of physical fitness and maternal and neonatal birth outcomes PLOS ONE | https://doi.org/10.1371/journal.pone.0229079 February 18, 2020 7 / 18 Fig 2. https://doi.org/10.1371/journal.pone.0229079.g002 Association of physical fitness and maternal and neonatal birth outcomes PLOS ONE | https://doi.org/10.1371/journal.pone.0229079 February 18, 2020 8 / 18 Table 1. Sociodemographic and clinical characteristics of the study sample (n = 158). Maternal characteristics n Mean (SD) Age, years 158 32.9 (4.6) Body mass index at the 16 th gestational week, Kg/m 2 158 24.9 (4.1) Body mass index at the 34 th gestational week, Kg/m 2 158 27.8 (4.1) Weight at the 16 th gestational week, Kg 157 67.04 (11.8) Weight at the 34 th gestational week, Kg 123 74.57 (10.8) Weight change (from the 16 th to the 34 th gestational weeks) 121 8.7 (3.4) Ethnicity (Caucasian) 158 158 (100) n (%) Living with a partner, 154 (97.5) Educational status 158 Primary or high-school 37 (23.4) Specialized training 27 (17.1) University degree 94 (59.5) Working status 158 Homework/unemployed 48 (30.4) Partial-time employed/student 41 (25.9) Full-time employed 69 (43.7) Type of birth 143 Spontaneous 83 (58) Instrumental vacuum/forceps 24 (16.8) Caesarean section 36 (25.5) Planned (feet or buttocks coming first) 7 (27.5) Birth place 147 Public Hospital 138 (93.9) Private Hospital 8 (5.4) Home 1 (0.7) Parity 158 Nulliparous 96 (60.8) Multiparous 62 (39.2) Physical fitness at the 16 th gestational week Mean (SD) Upper-body strength (Hand grip),mean (Kg) 156 27.2 (4.2) Lower-body strength (Chair stand),number of repetitions 93 15.7 (2.4) Flexibility (Back Scratch),mean (cm) 156 4.1 (6.2) CRF (Modified Bruce test),VO 2max 127 22.2 (5.5) Physical fitness at the 34 th gestational week Upper-body strength (Hand grip),mean (Kg) 124 27.2 (4.4) Lower-body strength (Chair stand),number of repetitions 65 15.9 (2.5) Flexibility (Back Scratch),mean (cm) 123 3.9 (6) CRF (Modified Bruce test),VO 2max 97 17.9 (4.9) Neonatal outcomes Sex (female, n (%)) 141 72 (51.4) Gestational age at birth, wk 141 39.5 (1.3) Birth weight, grams 141 3305 (480.6) Placental weight, grams 106 573.7 (102.6) Apgar score 1 minute 138 8.6 (1) Apgar score 5 minutes 138 9.6 (0.7) Umbilical Cord blood Gas (Continued) Association of physical fitness and maternal and neonatal birth outcomes PLOS ONE | https://doi.org/10.1371/journal.pone.0229079 February 18, 2020 9 / 18 8. Engberg E, Tikkanen HO, Koponen A, Ha ¨gglund H, Kukkonen-Harjula K, Tiitinen A, et al. Cardiorespiratory fitness and health-related quality of life in women at risk for gestational diabetes. Scand J Med Sci Sports. 2018; 28: 203–211. https://doi.org/10.1111/sms.12896 PMID: 28415143 9. Melzer K, Schutz Y, Soehnchen N, Othenin-Girard V, Martinez de Tejada B, Irion O, et al. Effects of recommended levels of physical activity on pregnancy outcomes. Am J Obstet Gynecol. 2010; 202(3):266: e1–6. https://doi.org/10.1016/j.ajog.2009.10.876 PMID: 20022583 10. Baena-Garcı ´a L, Oco ´n-Herna ´ndez O, Acosta-Manzano P, Coll-Risco I, Borges-Cosic M, Romero-Gallardo L, et al. Association of sedentary time and physical activity during pregnancy with maternal and neonatal birth outcomes. The GESTAFIT Project. Scand J Med Sci Sports. 2018; 29: 407–414. https:// doi.org/10.1111/sms.13337 11. Nielsen E, Andersen P, Hegaard H, Juhl M. Mode of Delivery according to Leisure Time Physical Activity before and during Pregnancy: A Multicenter Cohort Study of Low-Risk Women. J Pregnancy. 2017; 13: 6209605. https://doi.org/10.1155/2017/6209605 PMID: 28386483 12. Villar J, Carroli G, Zavaleta N, Donner A, Wojdyla D, Faundes A, et al. Maternal and neonatal individual risks and benefits associated with caesarean delivery: Multicentre prospective study. Br Med J. 2007; 335: 1025. https://doi.org/10.1136/bmj.39363.706956.55 PMID: 17977819 13. Kulas T, Bursac D, Zegarac Z, PlaninicRados G, Hrgovic Z. New Views on Cesarean Section, its Possible Complications and Long-Term Consequences for Children’s Health. Med Arch. 2013; 67: 460–3. https://doi.org/10.5455/medarh.2013.67.460-463 PMID: 25568522 14. Gurol-Urganci I, Bou-Antoun S, Lim CP, Cromwell DA, Mahmood TA, Templeton A, et al. Impact of Caesarean section on subsequent fertility: a systematic review and meta-analysis. Hum Reprod. 2013; 28(7): 1943–52. https://doi.org/10.1093/humrep/det130 PMID: 23644593 15. Boutsikou T, Malamitsi-Puchner A. Caesarean section: Impact on mother and child. Acta Paediatr Int J Paediatr. 2011; 100(12): 1518–22. https://doi.org/10.1111/j.1651-2227.2011.02477.x PMID: 21950660 16. Ministry of Health Social Services and Equality. Annual Report on the National Health System of Spain 2016. 2017; 1–21. Available: http://www.msssi.gob.es/estadEstudios/estadisticas/sisInfSanSNS/ tablasEstadisticas/Comp_Intern_2015_ENG.pdf 17. WHO. World Health Organisation (WHO) Statement on Caesarean Section Rates. Hum Reprod Program. 2015; 23(45): 149–50. https://doi.org/10.1016/j.rhm.2015.07.007 PMID: 26278843 18. Mayhew TM, Charnock-Jones DS, Kaufmann P. Aspects of human fetoplacental vasculogenesis and angiogenesis III. Changes in complicated pregnancies. Placenta. 2004; 25: 127–139. https://doi.org/10. 1016/j.placenta.2003.10.010 PMID: 14972445 19. Armstrong L, Stenson BJ. Use of umbilical cord blood gas analysis in the assessment of the newborn. Arch Dis Child Fetal Neonatal Ed. 2007; 92: 430–4. https://doi.org/10.1136/adc.2006.099846 PMID: 17951550 20. Thorp JA, Rushing RS. Umbilical cord blood gas analysis. Obstet Gynecol Clin North Am. 1999; 26: 695–709. https://doi.org/10.1016/s0889-8545(05)70107-8 PMID: 10587963 21. Neonatal Professional Committee of Chinese Medical Doctor Association. Experts’ consensus on the criteria for the diagnosis and grading of neonatal asphyxia in China. Zhongguo Dang Dai Er Ke Za Zhi. 2013; 2(2): 64–5. https://doi.org/10.7499/j.issn.1008-8830.2013.01.002 22. Blechner JN. Maternal-Fetal AcidBase Physiology. Clin Obstet Gynecol. 1993; 36: 3–12. https://doi. org/10.1097/00003081-199303000-00004 PMID: 8435946 23. Aparicio VA, Oco ´n O, Padilla-Vinuesa C, Soriano-Maldonado A, Romero-Gallardo L, Borges-Co ´sic M, et al. Effects of supervised aerobic and strength training in overweight and grade I obese pregnant women on maternal and foetal health markers: the GESTAFIT randomized controlled trial. BMC Pregnancy Childbirth. 2016; 16: 290. https://doi.org/10.1186/s12884-016-1081-y PMID: 27680325 24. Kehler AK, Heinrich KM. A selective review of prenatal exercise guidelines since the 1950s until present: Written for women, health care professionals, and female athletes. Women and Birth. 2015; 28(4): 93–8. https://doi.org/10.1016/j.wombi.2015.07.004 PMID: 26210535 25. Date ED. Committee opinion no 611: method for estimating due date. Obstet Gynecol. 2014; 124: 863– 6. https://doi.org/10.1097/01.AOG.0000454932.15177.be PMID: 25244460 26. Ruiz-Ruiz J, Mesa JLM, Gutie ´rrez A, Castillo MJ. Hand size influences optimal grip span in women but not in men. J Hand Surg Am. 2002; 27: 897–901. https://doi.org/10.1053/jhsu.2002.34315 PMID: 12239682 27. Rikli R, Jones C. Development and validation of a functional fitness test for community-residing older adults. Gerontologist. 2013; 53: 255–67. https://doi.org/10.1093/geront/gns071 PMID: 22613940 28. Winn HN, Hess O, Goldstein I, Wackers F, Hobbins JC. Fetal responses to maternal exercise: effect on fetal breathing and body movement. Am J Perinatol. 1994; 11: 263–6. https://doi.org/10.1055/s-2007994588 PMID: 7945619 Association of physical fitness and maternal and neonatal birth outcomes PLOS ONE | https://doi.org/10.1371/journal.pone.0229079 February 18, 2020 16 / 18 29. Santos IA, Stein R, Fuchs SC, Duncan BB, Ribeiro JP, Kroeff LR, et al. Aerobic exercise and submaximal functional capacity in overweight pregnant women: A randomized trial. Obstet Gynecol. 2005; 106: 243–9. https://doi.org/10.1097/01.AOG.0000171113.36624.86 PMID: 16055571 30. Spanish Ministry of Health and Consumer´s affaires. Estadı ´stica Nacional de Hospitales. 2017. Available: http://www.msssi.gob.es/estadEstudios/estadisticas/estHospiInternado/inforAnual/home.htm 31. Vodstrcil LA, Tare M, Novak J, Dragomir N, Ramirez RJ, Wlodek ME, et al. Relaxin mediates uterine artery compliance during pregnancy and increases uterine blood flow. FASEB J. 2012; 26: 4035–44. https://doi.org/10.1096/fj.12-210567 PMID: 22744867 32. Jahdi F, Sheikhan F, Haghani H, Sharifi B, Ghaseminejad A, Khodarahmian M, et al. Yoga during pregnancy: The effects on labor pain and delivery outcomes (A randomized controlled trial). Complement Ther Clin Pract. 2017; 27: 1–4. https://doi.org/10.1016/j.ctcp.2016.12.002 PMID: 28438273 33. Tzeng YL, Kuo SY, Tsai SH. Childbirth-Related fatigue during labor: An important but overlooked symptom. J Nurs. 2013; 60: 16–21. https://doi.org/10.6224/JN.60.6.16 PMID: 24310549 34. Hobbs AJ, Mannion CA, McDonald SW, Brockway M, Tough SC. The impact of caesarean section on breastfeeding initiation, duration and difficulties in the first four months postpartum. BMC Pregnancy Childbirth. 2016; 16: 90. https://doi.org/10.1186/s12884-016-0876-1 PMID: 27118118 35. Bisson M, Alme ´ras N, Plaisance J, Rhe ´aume C, Bujold E, Tremblay A, et al. Maternal fitness at the onset of the second trimester of pregnancy: Correlates and relationship with infant birth weight. Pediatr Obes. 2013; 8: 464–474. https://doi.org/10.1111/j.2047-6310.2012.00129.x PMID: 23281128 36. Bohannon RW. Muscle strength: Clinical and prognostic value of hand-grip dynamometry. Curr Opin Clin Nutr Metab Care. 2015; 18: 465–70. https://doi.org/10.1097/MCO.0000000000000202 PMID: 26147527 37. Ekstrand E, Lexell J, Brogårdh C. Grip strength is a representative measure of muscle weakness in the upper extremity after stroke. Top Stroke Rehabil. 2016; 23: 400–405. https://doi.org/10.1080/ 10749357.2016.1168591 PMID: 27145212 38. Araujo Ju ´nior E, Peixoto AB, Zamarian ACP, Elito Ju ´nior J, Tonni G. Macrosomia. Best Pract Res Clin Obstet Gynaecol. 2017; 38: 83–96. https://doi.org/10.1016/j.bpobgyn.2016.08.003 PMID: 27727018 39. Dodds R, MacDonald-Wallis C, Kapasi T, Sayer AA, Robinson S, Godfrey K, et al. Grip strength at 4 years in relation to birth weight. J Dev Orig Health Dis. 2012; 3: 111–115. https://doi.org/10.1017/ S204017441100081X PMID: 25101921 40. Turgut S, Kaptanogˇlu B, Emmungil G, Turgut G. Increased plasma levels of growth hormone, insulinlike growth factor (IGF)-I and IGF-binding protein 3 in pregnant rats with exercise. Tohoku J Exp Med. 2005; 208(1): 75–81. https://doi.org/10.1620/tjem.208.75 PMID: 16340176 41. Lewis RM, Greenwood SL, Cleal JK, Crozier SR, Verrall L, Inskip HM, et al. Maternal muscle mass may influence system A activity in human placenta. Placenta. 2010; 31: 418–22. https://doi.org/10.1016/j. placenta.2010.02.001 PMID: 20206993 42. Petersen LK, Vogel I, Agger AO, Westergård J, Nils M, Uldbjerg N. Variations in serum relaxin (hRLX-2) concentrations during human pregnancy. Acta Obstet Gynecol Scand. 1995; 74: 251–6. https://doi.org/ 10.3109/00016349509024444 PMID: 7732796 43. Dehghan F, Haerian BS, Muniandy S, Yusof A, Dragoo JL, Salleh N. The effect of relaxin on the musculoskeletal system. Scand J Med Sci Sport. 2014; 24(4): 34–48. https://doi.org/10.1111/sms.12149 PMID: 24283470 44. Parry LJ, Vodstrcil LA. Relaxin physiology in the female reproductive tract during pregnancy. Adv Exp Med Biol. 2007; 612: 34–48. https://doi.org/10.1007/978-0-387-74672-2_4 PMID: 18161480 45. Thorell E, Goldsmith L, Weiss G, Kristiansson P. Physical fitness, serum relaxin and duration of gestation. BMC Pregnancy Childbirth. 2015; 15: 168. https://doi.org/10.1186/s12884-015-0607-z PMID: 26272327 46. Hisaw FL. Experimental relaxation of the pubic ligament of the guinea pig. Exp Biol Med. 1926; 185: 76– 80. https://doi.org/10.3181/00379727-23-3107 47. Hemmerich A, Bandrowska T, Dumas GA. The effects of squatting while pregnant on pelvic dimensions: A computational simulation to understand childbirth. J Biomech. 2019; 18;87: 64–74. https://doi. org/10.1016/j.jbiomech.2019.02.017 PMID: 30851977 48. Malin GL, Morris RK, Khan KS. Strength of association between umbilical cord pH and perinatal and long term outcomes: Systematic review and meta-analysis. BMJ. 2010;13; 340: c1471. https://doi.org/ 10.1136/bmj.c1471 PMID: 20466789 49. Mukai M, Uchida T, Itoh H, Suzuki H, Niwayama M, Kanayama N. Tissue oxygen saturation levels from fetus to neonate. J Obstet Gynaecol Res. 2017; 43: 855–859. https://doi.org/10.1111/jog.13295 PMID: 28168777 Association of physical fitness and maternal and neonatal birth outcomes PLOS ONE | https://doi.org/10.1371/journal.pone.0229079 February 18, 2020 17 / 18 50. Dyrstad SM, Anderssen SA, Edvardsen E, Hansen BH. Cardiorespiratory fitness in groups with different physical activity levels. Scand J Med Sci Sport. 2016; 26: 291–298. https://doi.org/10.1111/sms.12425 PMID: 25682984 51. Atay E, Başalan IF. Investigation of the effect of changes in muscle strength in gestational age upon fear of falling and quality of life. Turkish J Med Sci. 2015; 45(4): 977–83. http://dx.doi.org/10.1016/B9780-08-100618-4.00005-4 52. van Doorn M, Wallenburg H, Spinnewijn W, Lotgering F SP. Anaerobic threshold and respiratory compensation in pregnant women. J Appl Physiol. 1995; 78(5): 1772–7. https://doi.org/10.1152/jappl.1995. 78.5.1772 PMID: 7649911 53. Ersal T, McCrory JL, Sienko KH. Theoretical and experimental indicators of falls during pregnancy as assessed by postural perturbations. Gait Posture. 2014; 39: 218–223. https://doi.org/10.1016/j. gaitpost.2013.07.011 PMID: 23953273 54. Kalliokoski P, Rodhe N, Bergqvist Y, Lo ¨fvander M. Long-term adherence and effects on grip strength and upper leg performance of prescribed supplemental vitamin D in pregnant and recently pregnant women of Somali and Swedish birth with 25-hydroxyvitamin D deficiency: A before-and-after treatment study. BMC Pregnancy Childbirth. 2016;15; 16(1): 353. https://doi.org/10.1186/s12884-016-1117-3 PMID: 27846821 55. Lemos A, de Souza AI, de Andrade AD, Figueiroa JN, Cabral-Filho JE. Pregnancy Inter-Recti Abdominis Distance has no impact on respiratory strength. J Phys Ther Sci. 2011; 23: Pregnancy Inter-Recti Abdominis Distance has no im. https://doi.org/10.1589/jpts.23.757 56. Duncombe D, Wertheim EH, Skouteris H, Paxton SJ, Kelly L. Factors related to exercise over the course of pregnancy including women’s beliefs about the safety of exercise during pregnancy. Midwifery. 2009; 25: 430–438. https://doi.org/10.1016/j.midw.2007.03.002 PMID: 18063253 57. Mottola MF, Inglis S, Brun CR, Hammond JA. Physiological and metabolic responses of late pregnant women to 40 min of steady-state exercise followed by an oral glucose tolerance perturbation. J Appl Physiol. 2013;1; 115(5): 597–604. https://doi.org/10.1152/japplphysiol.00487.2013 PMID: 23813524 58. Marshall MR, Pivarnik JM. Perceived exertion of physical activity during pregnancy. J Phys Act Heal. 2015; 12(7): 1039–43. https://doi.org/10.1123/jpah.2013-0458 PMID: 26462301 59. Gatford KL. Placentas on treadmills? Exercise may be more beneficial when started before pregnancy. J Physiol. 2018; 596(23): 5499–5500. https://doi.org/10.1113/JP276679 PMID: 29968375 60. Bruce RA, Kusumi F, Hosmer D. Maximal oxygen intake and nomographic assessment of functional aerobic impairment in cardiovascular disease. Am Heart J. 1973; 85: 546–62. https://doi.org/10.1016/ 0002-8703(73)90502-4 PMID: 4632004 Association of physical fitness and maternal and neonatal birth outcomes PLOS ONE | https://doi.org/10.1371/journal.pone.0229079 February 18, 2020 18 / 18