Marie Carbonnel
email: carbonnelmarie@gmail.com

Domitille Brot

Charlotte Benedetti

Titouan Kennel

Rouba Murtada

Aurelie Revaux

Jean-Marc Ayoubi

RISKS FACTORS FOR WOUND COMPLICATIONS AFTER CESAREAN SECTION

Keywords: Wound, Cesarean, infection, hematoma, complications, risk factors

Objective: The primary outcome was to determine risks factors for wound complications after cesarean section. Secondary outcome was the management of these complications.

Study Design: We performed a retrospective cohort study of consecutive cesarean deliveries performed at a secondary care facility between June 2017 and June 2019. Composite wound complications included infection, disruption and fluid collection occurring 30 days postoperatively. Medical records were reviewed and data including patient demographics, comorbidities, intra-partum characteristics were evaluated as potential risk factors for wound complications using multivariate logistic regression. Secondarily, post-operative management of wound complications was described.

Results: Among 1520 patients undergoing cesarean section during the period of study, 67 developed wound complications (4.4%). Mean Duration of local wound care was 41.35 days (2-95). Mean number of wound care related visits in our hospital was 4.85(1-11). Multivariate logistic regression analysis showed 2 significant independant risk factors: preeclampsia with OR 5.60, 95% CI 2.83, 11.11 (p:<0.001), and premature rupture of the membranes with OR 9.76, 95% CI 2.13, 44.77 (p: 0.003).

Conclusion: Preeclampsia and premature rupture of the membrane were independent risk factors for wound complications after cesarean section. Information regarding higher rates of wound complications and preventive measures should be provided to high-risk women prior to surgery.

INTRODUCTION

Cesarean section (CS) is one of the most common surgeries performed worldwide. Its rate varies among countries, representing approximately 20% of deliveries in France and as high as 60% in some areas of Latin America [START_REF] Villar | Caesarean delivery rates and pregnancy outcomes: the 2005 WHO global survey on maternal and perinatal health in Latin America[END_REF][START_REF] Zbiri | Cesarean delivery rate and staffing levels of the maternity unit[END_REF]. Wound complications including superficial infection, separation and fluid collection such as seroma or hematoma are common, affecting 3-15% of cases [START_REF] Conner | Maternal obesity and risk of postcesarean wound complications[END_REF][START_REF] Temming | Impact of evidence-based interventions on wound complications after cesarean delivery[END_REF]. They often require prolonged scar nursing care and in some cases, prolonged maternal hospitalization and reoperation. This leads to anxiety and a potential negative impact on mother and newborn interaction in the critical post-partum period [START_REF] Salim | Risk factors for infection following cesarean delivery: an interventional study[END_REF]. Superficial infection is part of the Surgical-Site Infections (SSI) spectrum. The Centers for Disease Control and Prevention (CDC) defined SSI as an infection occurring within 30 days in the part of the body where the surgery took place. SSI complicates 1 to 5% of cesarean deliveries [START_REF] Conroy | Infectious morbidity after cesarean delivery: 10 strategies to reduce risk[END_REF][START_REF] Wloch | Risk factors for surgical site infection following caesarean section in England: results from a multicentre cohort study[END_REF]. This risk has significantly decreased in the course of the last decade, due mainly to improvements in hygiene conditions, and antibiotic prophylaxis [START_REF] Gibbs | Clinical risk factors for puerperal infection[END_REF][START_REF] Krieger | Surgical site infection following cesarean deliveries: trends and risk factors[END_REF]. Other wound complications are represented by disruption and fluid collection (hematomas and seromas). These complications are related.

Hematomas are usually the consequence of a failure in primary hemostasis and/or an increase in bleeding induced by anticoagulation therapy. Vigorous coughing or severe hypertension immediately after surgery may contribute to the formation of hematomas. Wound hematomas or seromas are described in 2-5% of women after Cesarean section [START_REF] Kawakita | Surgical site infections after cesarean delivery: epidemiology, prevention and treatment[END_REF]. They cause wound dehiscence in 2-7% of cases and act as a promoter for the development of wound infection [START_REF] Kawakita | Surgical site infections after cesarean delivery: epidemiology, prevention and treatment[END_REF].

Several studies focused on risks factors for SSI. Independent risk factors reported in studies in which multivariate analysis was performed were young age, obesity, hypertension or preeclampsia, diabetes mellitus, chorioamnionitis, nulliparity, increased operative blood loss, less than seven pre-natal visits, prolonged rupture of membranes to delivery time, emergency cesarean delivery, lack of appropriate antibiotic prophylaxis, increased surgical time, and twin deliveries [START_REF] Salim | Risk factors for infection following cesarean delivery: an interventional study[END_REF][START_REF] Krieger | Surgical site infection following cesarean deliveries: trends and risk factors[END_REF][START_REF] Olsen | Risk factors for surgical site infection after low transverse cesarean section[END_REF][START_REF] Schneid-Kofman | Risk factors for wound infection following cesarean deliveries[END_REF][START_REF] Tran | Risk factors for postcesarean surgical site infection[END_REF][START_REF] Farret | Risk factors for surgical site infection following cesarean section in a Brazilian Women's Hospital: a case-control study[END_REF]. Some studies focused on surgical techniques as risks factors for wound disruption, such as the absence of subcutaneous suture [START_REF] Naumann | Subcutaneous tissue approximation in relation to wound disruption after cesarean delivery in obese women[END_REF], use of staples instead of suture for skin closure [START_REF] Anderson | Techniques and materials for closure of the abdominal wall in caesarean section[END_REF] or early staple removal [START_REF] Nuthalapaty | A randomized controlled trial of early versus delayed skin staple removal following caesarean section in the obese patient[END_REF]. The purpose of the current study was to determine the risks factors of all wound complications including infection, disruption and fluid collection after cesarean section and describe their evolution after treatment.

MATERIALS AND METHODS

We conducted a retrospective cohort study of all consecutive CS performed between June 2017 and June 2019 in Foch Hospital. It is a level II maternity ward in the Paris area with an average of 3500 deliveries per year with a CS rate of 20%. The study was approved by our institutional review board (CEROG 2018-OBS-1202). Composite wound complications were defined as infection (abscess), disruption and fluid collection occurring within the first 30 days. We compared patients in whom wound complications occurred with patients without wound complications after CS, during the same period (control group). Medical records were reviewed in our computerized database. Demographic information, putative factors, and surgical indications were collected. Patient characteristics included age, gravidity, parity, body mass index (BMI) at the end of pregnancy (last weight available before delivery), gestational age at delivery, child birthweight (in grams) and previous CS. Comorbidities investigated were diabetes mellitus, preeclampsia, cigarette smoking, threatened preterm labor (THL), premature rupture of membranes (PROM) [START_REF] Promberger | Anti-Mullerian hormone as a parameter for endometrial trauma in Asherman syndrome: A retrospective data analysis[END_REF], intrauterine growth restriction (IUGR), group B strep test results, and twin pregnancy.

Surgery and intra-partum related variables included emergency or planned CS, rupture of membranes duration, fever (38°C or more), type of abdominal incision, post-partum hemorrhage (PPH), subcutaneous suture and type of cutaneous sutures. Post-partum information including the use of anticoagulants, enhanced recovery and duration of hospital stay were evaluated as well.

For patients with wound complications, we looked at antibiotic therapy use, rehospitalizations, reoperations, duration of local wound care and number of wound care related visits in our hospital.

CS procedures were standardized. Prophylactic antibiotics with 2g single dose of cefazolin were given to all women undergoing CS before skin incision. We used iodine for pre-operative skin preparation, the surgical team including all surgeons and surgical assists had two pairs of gloves and replaced their outer surgical gloves with a new pair of sterile gloves after sterile draping and just prior to abdominal fascia closure. Unique injection of 100µg of carbetocine was performed after cord clamping. Another iodine application, draping and change of surgical instruments was performed before each abdominal fascia closure. Mobilization after CS was performed on day 1 and patients were discharged between 4 and 5 days post-operatively in cases without complications. Enhanced recovery was performed for planned CS, in ASA 1 patients according to the American Society of Anesthesiologists classification, and above 18 years of age [START_REF] Owens | ASA physical status classifications: a study of consistency of ratings[END_REF]. It was not applied in cases of emergency CS and patients with a high-risk pregnancy (preeclampsia, gestational diabetes requiring insulinotherapy). In enhanced recovery, mobilization was performed 6 hours after CS and the patient was discharged on day 3. Modalities of enhanced recovery have been described in a previous study [START_REF] Rousseau | Comparative study about enhanced recovery after cesarean section: What benefits, what risks?[END_REF]. Anticoagulant therapy was performed according to international guidelines [START_REF] Bates | VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines[END_REF]. Half of the Staples were usually removed by a nurse on day 6 post CS and the remaining half on day 8 in the absence of disruption or hematomas.

Patients with complications requiring wound care had once or twice weekly follow-up in dedicated wound care consultations in our hospital and daily nurse care at home until complete healing. All CS patients had a post-operative appointment with their surgeon.

Statistical analysis was performed using descriptive evaluation with the mean standard deviation for continuous variables and frequency and percentage for categorical variables. Student's t-test for independent samples was used for comparing means between groups and chi-square test to compare categorical variables. Variables associated with the outcome in univariate analysis with a significance level below 0.2 were included in a multivariate logistic regression model. The odds ratios for various factors and outcomes and the respective 95% confidence intervals were calculated. Stepwise backward multiple regression was performed to reveal the best set of predictors for wound complications. Microsoft Excel software was used for data recording and analyses were performed using SAS v9.4.

RESULTS

A total of 1522 patients underwent cesarean section at Foch Hospital over the 2-year study period, of which 67(4.4%) were diagnosed with wound complications while 1455 remained without complication (control group). Within the wound complication group, 26 patients developed wound infection (abscess), 20 developed hematoma and 35 disruption. No seroma was reported. Wound complications were often associated: in 2 cases all three complications occured, there were otherwise 8 disruptions associated with infection, 7 with hematoma, and 5 hematomas associated with infection. Thirty-two patients required antibiotic therapy, 8 required local wound care with compress dressing, 10 were rehospitalized, 11 were reoperated. All had nursing care: among them 43 had iodine irrigation, 31 dressings for wound healing by secondary intention and one had vacuum assisted closure. Mean Duration of local nursing care was 41.35 days .

Mean number of wound care related consultations in our hospital was 4.85 [START_REF] Villar | Caesarean delivery rates and pregnancy outcomes: the 2005 WHO global survey on maternal and perinatal health in Latin America[END_REF][START_REF] Zbiri | Cesarean delivery rate and staffing levels of the maternity unit[END_REF][START_REF] Conner | Maternal obesity and risk of postcesarean wound complications[END_REF][START_REF] Temming | Impact of evidence-based interventions on wound complications after cesarean delivery[END_REF][START_REF] Salim | Risk factors for infection following cesarean delivery: an interventional study[END_REF][START_REF] Conroy | Infectious morbidity after cesarean delivery: 10 strategies to reduce risk[END_REF][START_REF] Wloch | Risk factors for surgical site infection following caesarean section in England: results from a multicentre cohort study[END_REF][START_REF] Gibbs | Clinical risk factors for puerperal infection[END_REF][START_REF] Krieger | Surgical site infection following cesarean deliveries: trends and risk factors[END_REF][START_REF] Kawakita | Surgical site infections after cesarean delivery: epidemiology, prevention and treatment[END_REF][START_REF] Olsen | Risk factors for surgical site infection after low transverse cesarean section[END_REF]

DISCUSSION

Many studies have addressed the risk factors for post-cesarean SSI including superficial, deepspace and organ infections [START_REF] Salim | Risk factors for infection following cesarean delivery: an interventional study[END_REF][START_REF] Krieger | Surgical site infection following cesarean deliveries: trends and risk factors[END_REF][START_REF] Olsen | Risk factors for surgical site infection after low transverse cesarean section[END_REF][START_REF] Tran | Risk factors for postcesarean surgical site infection[END_REF][START_REF] Horan | CDC definitions of nosocomial surgical site infections, 1992: a modification of CDC definitions of surgical wound infections[END_REF]. There have been studies about risk factors for wound disruption [START_REF] Anderson | Techniques and materials for closure of the abdominal wall in caesarean section[END_REF]. However, few studies have focused on all wound complications (infection, hematoma and disruption) following CS [START_REF] Temming | Impact of evidence-based interventions on wound complications after cesarean delivery[END_REF]. Addressing wound complications as a whole is the strength of our work. Our rate of wound complications was relatively low. Our CS procedure was standardized and in accordance with well-established guidelines. Our study had inherent limitations due to its retrospective design. Although a large database is a powerful tool for identifying risk factors, the study failed to further evaluate intra-partum variables (duration of labor and surgery, chorioamnionitis, exact BMI the day of the CS...) and pre-partum details concerning cigarette consumption in smoking patients or insulin therapy in diabetic patients. The number of lost to follow up patients was another weakness in our study. Similarly, an information bias can be assumed for patients who might have consulted for a wound complication in another facility or if the surgeon failed to make written mention of complications during the post-operative visit. Due to these factors, the wound complication group have been underestimated.

While the diagnosis of chorioamnionitis -being a strong factor of SSI-was not available in our computerized medical records, the mean number of fever cases in our wound complication group was not higher. Consistent with previous studies, PROM was a significant independent risk factor [START_REF] Krieger | Surgical site infection following cesarean deliveries: trends and risk factors[END_REF]. It could be responsible for a subclinical abnormal bacterial colonization that causes contamination of the surgical site. We did not evaluate the duration of surgery nor the duration of labor. Some authors found that surgery longer than 1 hour was associated with an increase in SSI [START_REF] Tran | Risk factors for postcesarean surgical site infection[END_REF]. Similarly, prolonged labor, prolonged interval between rupture of membranes and delivery, and excess vaginal manipulation have also been associated with infection [START_REF] Farret | Risk factors for surgical site infection following cesarean section in a Brazilian Women's Hospital: a case-control study[END_REF][START_REF] Wilkinson | Manual removal of placenta at caesarean section[END_REF]. Our data didn't show a negative impact of a duration of ruptured membranes exceeding 12 hours.

Emergency cesarean is another factor associated in literature with increased SSI [START_REF] Farret | Risk factors for surgical site infection following cesarean section in a Brazilian Women's Hospital: a case-control study[END_REF], which may be the result of suboptimal operative site preparation and insufficient prophylactic antibiotic treatment in an emergency setting. We didn't find an association between wound complications and emergency CS. and THL were independent risks factors in our study.

Preeclampsia increased the risk of post-partum infection [START_REF] Tran | Risk factors for postcesarean surgical site infection[END_REF]. It is also involved in hematomas because of associated bleeding disorders and severe hypertension. The risk of postoperative infection has been shown to be proportional to the volume of blood loss during delivery [START_REF] Tran | Risk factors for postcesarean surgical site infection[END_REF]. The correlation between wound complications and PPH was only noticed in univariate analysis in our results probably due to a lack of power. We didn't find a correlation between obesity and wound complications. This is in opposition with previous trials [START_REF] Conner | Maternal obesity and risk of postcesarean wound complications[END_REF][START_REF] Wloch | Risk factors for surgical site infection following caesarean section in England: results from a multicentre cohort study[END_REF][START_REF] Emmons | Development of wound infections among women undergoing cesarean section[END_REF]. This could be due to a lack of statistical power too, because we did find a difference in univariate analysis for patients with BMI>25. It is however usually difficult to have a precise measure of the patient's weight at the time of delivery. We used by default the last weight available in our medical records prior to delivery, but the interval time was variable among women. A previous large multicenter study found a correlation between extreme obesity (BMI>45) and wound complications [START_REF] Smid | Extreme Obesity and Postcesarean Wound Complications in the Maternal-Fetal Medicine Unit Cesarean Registry[END_REF], however our rate of extreme obesity was too low to be exploited. A subcutaneous layer depth of more than 2cm could be a more interesting risk factor than BMI. It could explain why subcutaneous suture has been found to reduce the risks of wound complications [START_REF] Anderson | Techniques and materials for closure of the abdominal wall in caesarean section[END_REF]. In our unit, subcutaneous suture was left to the surgeon's appreciation and not standardized, and performed in around 15% of cases. We removed staples for all patients in two steps at day 6 and day 8 in order to avoid disruption. Delayed staple removal could be indicated in obese patients to reduce the risk of disruption [START_REF] Nuthalapaty | A randomized controlled trial of early versus delayed skin staple removal following caesarean section in the obese patient[END_REF]. Diabetes mellitus is a well-known comorbidity associated with wound complications [START_REF] Temming | Impact of evidence-based interventions on wound complications after cesarean delivery[END_REF]. Poorly controlled diabetes decreases immune response and delays epithelialization of wounds [START_REF] Takoudes | Risk of cesarean wound complications in diabetic gestations[END_REF]. Our study included all cases of diabetes, which could have biased our results. Twin pregnancy, smoking, previous CS, mode of abdominal incision and skin suture and use of anticoagulants weren't found to be risk factors for CS wound complications.

A number of evidence-based interventions have been suggested to decrease post CS wound complications [START_REF] Dahlke | Evidence-based surgery for cesarean delivery: an updated systematic review[END_REF]. We used iodine for preoperative skin preparation. Chlorhexidine-alcohol should be preferred because it reduces the risk of SSI [START_REF] Tuuli | A Randomized Trial Comparing Skin Antiseptic Agents at Cesarean Delivery[END_REF]. We performed a change in gloves prior to abdominal closure, which significantly reduces the incidence of post-operative wound complications [START_REF] Scrafford | Effect of intra-operative glove changing during cesarean section on post-operative complications: a randomized controlled trial[END_REF]. Prophylactic antibiotic therapy significantly reduces the incidence of wound infection, endometritis and serious infectious complications by 60% to 70% [START_REF] Smaill | Antibiotic prophylaxis versus no prophylaxis for preventing infection after cesarean section[END_REF]. Its administration 30-60 minutes prior to skin incision was performed in all elective cesarean as recommended [START_REF] Weber | The timing of surgical antimicrobial prophylaxis[END_REF]. Closure of the subcutaneous layer in cases of subcutaneous depth ≥ 2 cm, and subcuticular skin closure with suture should be preferred to staples, because it significantly reduces the risk of wound separation [START_REF] Anderson | Techniques and materials for closure of the abdominal wall in caesarean section[END_REF][START_REF] Dahlke | Evidence-based surgery for cesarean delivery: an updated systematic review[END_REF][START_REF] Tuuli | Staples compared with subcuticular suture for skin closure after cesarean delivery: a systematic review and metaanalysis[END_REF]. Even if the implementation of evidence-based measures can significantly reduce wound complications by 25%, the residual risk remains high especially in patients with risk factors [START_REF] Temming | Impact of evidence-based interventions on wound complications after cesarean delivery[END_REF]. Mean duration of local nursing care was very high causing numerous additional consultations in the wound complication group. As a consequence, it can be a source of anxiety and quality of life as well as mother-child relationship can be negatively impacted. Accurate Information regarding higher rates of wound complications should be provided for patients with PROM, THL and preeclampsia and post-operative follow up reinforced. More studies about wound complications are required especially prospective work with a larger cohort in order to provide clearer and more precise answer.

Table 1

 1 . Characteristics in the wound complications group and the control group are described in table 1. No difference was observed between groups except for BMI which was higher in the wound complication group. However, the overall number of patients with or without obesity wasn't different. Potential risk factors for wound complications are described in table 2 including comorbid conditions, intra and post-operative variables. Multivariate analysis results are summarized in table 3. Multivariable logistic regression analysis summarized in table 3 showed 2 significant independent risk factors: preeclampsia with OR 5.60, 95% CI 2.83, 11.11 (p:<0.001), and premature rupture of the membranes with OR 9.76, 95% CI 2.13, 44.77 (p: 0.003). Post-partum hemorrhage and BMI>25 were significant risk factor only in univariate analysis. Characteristic of wound complications and control group

	Characteristics	Wound Complications	Control Group	OR [95% IC]	p
		(n=67)	(n=1453)		value
	Gestational age (weeks)	38.61 ± 2.52	38.83 ± 2.15	0.95 [0.86 -1.06]	0.39
	Birth Weight(grams)	3114.9 ± 707.9	3186.4 ± 644.4	0.99 [0.97-1.01]	0.38
	Age (years)	34.76 ± 4.43	34.44 ± 4.49	1.02 [0.96 -1.08]	0.59
	Parity	1.51 ± 0.84	1.69 ± 0.78	0.70 [0.49 -1.01]	0.06
	Gestity	1.89 ± 1.60	1.86 ± 0.99	1.04 [0.82 -1.31]	0.80
	BMI	24.76±5.36	23.33 ±4.07	1.07 [1.02 -1.12]	0.007
	Previous CS	11(16.7%)	285(19.6%)	0.79 [0.41 -1.53]	0.49

Table 2

 2 Potential Risks factors for Wound Complications after CS

	Characteristics			Wound Complications	Control Group	OR [95% IC]	p value
					(n=67)	(n=1453)
	BMI			>25	24 (36.9%)	297 (23.0%)	1.96 [1.17 -3.23]	0.01
					(n=65)	(n=1292)
	BMI			>30	5 (7.5%)	61 (4.7%)	1.68 [0.65 -4.34]	0.28
					(n=65)	(n=1292)
	BMI			>35	3 (4.6%)	24 (1.9%)	2.56 [0.75 -8,72]	0.13
					(n=65)	(n=1292)
	Delivery Mode		Planned CS	14 (20.9%)	443 (30.5%)	1	0.10
				Emergency CS	53 (79.1%)	1010 (69.5%)	1.66 [0.91 -3.02]
	RM >12hours		Yes	24 (35.8%)	391 (26.9%)	1.52 [0.91 -2.53]	0.11
	Group B strep test	Yes	29 (43.3%)	495 (34.1%)	1.48 [0.90 -2.42]	0.12
	PPH			Yes	9 (13.4%)	77 (5.4%)	2.74 [1.31 -5.73]	0.008
						(n=1435)
	Fever			Yes	3 (4.5%)	35 (2.4%)	1.87 [0.56 -6.26]	0.31
						(n=1435)
	Enhanced Recovery	Yes	9 (13.4%)	297 (20.7%)	0.59 [0.29 -1.21]
						(n=1435)		0.15
	Pregnancy		Single	65 (97.0%)	1272 (89.1%)	1	0.06
				Twin	2 (3.0%)	156 (10.9%)	0.25 [0.06 -1.03]
	Mode	of	abdominal	Starck	56 (87.5%)	1209 (84.6%)	1	0.74
	Incision			Pfannenstiel	5 (7.8%)	117 (8.2%)	0.92 [0.34 -2.35]
				Mouchel	3 (4.7%)	103 (7.2%)	0.63 [0.19 -2.04]
					(n=64)	(n=1429)
	Mode of cutaneous suture	Staples	55 (83.3%)	1235 (86.5%)	1	0.75
				SI. Sutures	10 (15.2%)	179 (12.5%)	1.25 [0.63 -2.50]
				CS. Sutures	1 (1.5%)	14 (1.0%)	1.60 [0.21 -12.42]
	Subcutaneous suture	Yes	4 (6%)	138 (9.5%)	0.605 [0.22 -1.69]	0.34
						(n=1452)
	Cigarette Smoking	Yes	9 (13.4%)	203 (14.3%)	0.93 [0.45 -1.90]	0.84
						(n=1419)
	Diabetes			Yes	13 (19.4%)	220 (16.1%)	1.25 [0.67 -2.33]	0.48
						(n=1362)
	THL			Yes	1 (3.3%)	64 (4.7%)	0.70 [0.09 -5.21]	0.73
						(n=1362)
	Preeclampsia		Yes	16 (23.9%)	58 (4.2%)	7.07 [3.80 -13.15]	<0.001
						(n=1366)
	PROM			Yes	3 (4.5%)	12 (0.8%)	5.61 [1.54 -20.36]	0.01
						(n=1447)
	IUGR			Yes	6 (9.0%)	104 (7.6%)	1.12 [0.50 -2.83]	0.69
						(n=1366)
	LOS( days)			6.43 ± 2.59	6.21 ± 2.79	1.02 [0.96 -1.09]	0.52
	Anticoagulant		Yes	38 (56.7%)	686 (48.5%)	1.39 [0.85 -2.28]	0.19
	Therapy					(n=1414)

BMI, body mass index; CS, Continuous Subcuticular; UGR, intrauterine growth restriction; LOS, Length of stay; PPH: Post-partum Hemorrhage, PROM, premature rupture of membranes; RM, Rupture of Membranes; SI, Simple interupted; THL threatened preterm labor (THL).

Table 3 .

 3 Multiple Logistic Regression Analysis and Independent Risk Factors for Wound

	complications after CS
			OR [95% IC]	P value
	Characteristics
	Delivery Mode	Planned	1	0.86
		Emergency	0.93 [0.43 ; 2.02]
	RM>12h		0.75 [0.53 ; 1.61]	0.46
	Group B Strept test		0.99 [0.56 ; 1.84]	0.97
	Enhanced recovery		0.95 [0.41 ; 2.19]	0.90
	PPH		2.20 [0.97; 4.96]	0.06
	Pregnancy	Single	1	0.10
		Twin	0.28 [0.06 ; 1.25]
	BMI >25		1.07 [0.97 ; 4.96]	0.06
	Preeclampsia		5.60 [2.83 ; 11.11]	<0.001
	PROM		9.76 [2.13 ; 44.77]	0.003
	Anticoagulant therapy		1.11 [0.66 ; 1.88]	0.69
	Parity		0.80 [0.55 ; 1.19]	0.27
	BMI, body mass index; h: hours; PPH: Post-partum Hemorrhage, PROM,
	premature rupture of membranes; RM, Rupture of Membranes.


M.D Valérie Julian
email: vjulian@chu-clermontferrand.fr

David Thivel

Maud Miguet

Chloé Brengues

Bruno Pereira

Daniel Courteix

Ruddy Richard

Martine M Duclos

Bone response to eccentric versus concentric cycling in adolescents with obesity

Keywords: Childhood obesity, Bone mineral density, Bone strength, Eccentric training, Concentric training

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Pediatric obesity is a serious public health challenge [START_REF] Daniels | Overweight in children and adolescents: pathophysiology, consequences, prevention, and treatment[END_REF]. Although excess body weight has traditionally been considered to have a positive effect on bones, this idea has become subject to debate [START_REF] Sabhaney | Bone fractures in children: is there an association with obesity?[END_REF][START_REF] Dimitri | Obesity is a risk factor for fracture in children but is protective against fracture in adults: a paradox[END_REF][START_REF] Fintini | The Bones of Children With Obesity[END_REF]. Recent findings indicate that fat accumulation compromises bone mass and quality [START_REF] Shapses | Bone metabolism in obesity and weight loss[END_REF][START_REF] Dimitri | The Impact of Childhood Obesity on Skeletal Health and Development[END_REF], particularly in adolescents with obesity, who show a high propension to fracture [START_REF] Dimitri | Obesity is a risk factor for fracture in children but is protective against fracture in adults: a paradox[END_REF][START_REF] Goulding | Bone and body composition of children and adolescents with repeated forearm fractures[END_REF][START_REF] Goulding | Overweight and obese children have low bone mass and area for their weight[END_REF]. Multidisciplinary weight loss (WL) interventions combining nutrition and physical activity are now considered as effective treatment strategies in adolescents with obesity, favoring a decreased body mass index (BMI) and fat mass (FM) [START_REF] Boff R De | Weight loss interventions for overweight and obese adolescents: a systematic review[END_REF]. However, WL would also generate a bone breakdown [START_REF] Fintini | The Bones of Children With Obesity[END_REF][START_REF] Shapses | Bone metabolism in obesity and weight loss[END_REF] related to decreased mechanical loading on the skeleton [START_REF] Shapses | Bone metabolism in obesity and weight loss[END_REF], decreased caloric intake [START_REF] Shapses | Bone metabolism in obesity and weight loss[END_REF] and alter the secretion of some key hormones and peptides involved in bone regulation [START_REF] Dimitri | The Impact of Childhood Obesity on Skeletal Health and Development[END_REF][START_REF] Gómez-Ambrosi | The Bone-Adipose Axis in Obesity and Weight Loss[END_REF]. Indeed, WL would decrease circulating estrogen and other sex hormones and increase sex hormone-binding globulin, which negatively influences bone osteoblastic and osteoclastic activity, directly or indirectly due to increased levels of cytokines (i.e. IL-1, IL-6 and tumor necrosis factor-α). Several other factors would also major bone resorption during WL, such as changes in bone modulating adipokines (leptin, adiponectine, insulin-like growth factor-1), the rise in the Ca-PTH axis and modifications in gut peptides that regulate both satiety and bone metabolism [START_REF] Shapses | Bone metabolism in obesity and weight loss[END_REF].

Such negative bone adaptations to WL reinforce the need to include physical activity in multidisciplinary programs, since it strengthens the bones [START_REF] Turner | Designing exercise regimens to increase bone strength[END_REF], particularly during adolescence, when the bone's ability to adapt to mechanical loading is the greatest [START_REF] Parfitt | The two faces of growth: benefits and risks to bone integrity[END_REF]. Based on the need to include physical interventions in WL programs, much research on physical activity has been conducted for the last 10-15 years to identify the best modality. While studies have shown the beneficial effects of interventions including moderate-intensity continuous training, high-intensity interval training, or concurrent-training on both FM and lean mass (LM) [START_REF] Miguet | Cognitive restriction accentuates the increased energy intake response to a 10-month multidisciplinary weight loss program in adolescents with obesity[END_REF], their effectiveness on bone adaptations remains uncertain in adolescents with obesity [START_REF] Chaplais | Effects of interventions with a physical activity component on bone health in obese children and adolescents: a systematic review and meta-analysis[END_REF]. Longer interventions using higher exercise intensities and inducing a greater loss of FM and increase in LM would be associated with a trend of improved bone mass [START_REF] Chaplais | Effects of interventions with a physical activity component on bone health in obese children and adolescents: a systematic review and meta-analysis[END_REF][START_REF] Ivuskans | Bone mineral density in 11-13-year-old boys: relative importance of the weight status and body composition factors[END_REF].

Recent studies supporting the mechanostat theory demonstrated that bone fragility might be prevented if LM is maintained [START_REF] Kelley | Effects of a Randomized Weight Loss Intervention Trial in Obese Adolescents on Tibia and Radius Bone Geometry and Volumetric Density[END_REF][START_REF] Sioen | Associations Between Body Composition and Bone Health in Children and Adolescents: A Systematic Review[END_REF]. LM, rather than FM, is the most important contributor to bone parameters [START_REF] Sioen | Associations Between Body Composition and Bone Health in Children and Adolescents: A Systematic Review[END_REF]. Compared with aerobic training alone, combined aerobic and resistance training induces a greater gain in bone mineral content (BMC) during WL [START_REF] Campos | Aerobic plus resistance training improves bone metabolism and inflammation in adolescents who are obese[END_REF].

Recently, studies have focused on the use of eccentric (ECC) contraction modality, over the common concentric (CON) one, as an efficient and promising anti-obesity strategy for both adults and youths with obesity [START_REF] Julian | Eccentric Training Improves Body Composition by Inducing Mechanical and Metabolic Adaptations: A Promising Approach for Overweight and Obese Individuals[END_REF][START_REF] Julian | Eccentric cycling is more efficient in reducing fat mass than concentric cycling in adolescents with obesity[END_REF][START_REF] Paschalis | Beneficial changes in energy expenditure and lipid profile after eccentric exercise in overweight and lean women[END_REF]. Muscles generate force by lengthening during ECC contractions or by shortening during CON contractions. For the same oxygen consumption (V ̇O2), ECC cycling is characterized by a 3 to 4 times higher mechanical load (i.e. higher force applied on the skeleton) in comparison with CON cycling [START_REF] Julian | Eccentric cycling is more efficient in reducing fat mass than concentric cycling in adolescents with obesity[END_REF][START_REF] Hoppeler | Moderate Load Eccentric Exercise; A Distinct Novel Training Modality[END_REF]. Our team recently demonstrated that ECC cycling training is two times more efficient than CON cycling training for decreasing whole-body FM and increasing LM in adolescents with obesity and induces greater strength gains and metabolic improvements than CON training performed at the same V ̇O2 [START_REF] Julian | Eccentric cycling is more efficient in reducing fat mass than concentric cycling in adolescents with obesity[END_REF]. Based on the same population and considering the specific mechanical properties of ECC training (higher load developed in ECC for the same V ̇O2), it seems relevant to better evaluate the impact of ECC cycling on bone adaptations. Therefore, the present study aimed to determine the impact of ECC cycling versus classical CON cycling performed at the same metabolic rate on bone density, geometry, and strength among adolescents with obesity.

Material and methods

Study participants

Thirty five adolescents (Tanner stages 3-4; 50% females girls) were included in this study.

Patients met the following criteria: (1) 12-16 years old (Tanner age 3-4), (2) BMI > 90 th percentile according to the international cut-off points, (3) regular menstruations for females (4) no medication affecting energy metabolism and no regular tobacco or alcohol use; and [START_REF] Shapses | Bone metabolism in obesity and weight loss[END_REF] no contraindication to exercise. All the adolescents underwent a full medical examination.

Informed consent was obtained from all individual participants included in the study and their parents. The trial has been conducted according to the Declaration of Helsinki principles, was approved by the relevant ethical committee (Comité de Protection des Personnes Est IV) and is registered with ClinicalTrials.gov (NCT02925572).

Study design and training program

The adolescents of the training groups were enrolled in a pediatric obesity center (Children Medical Centre for Adolescents with Obesity, La Bourboule, France). They were randomized using random size blocks to the 12-week CON or ECC cycling group. The training intervention was described in detail previously [START_REF] Julian | Eccentric cycling is more efficient in reducing fat mass than concentric cycling in adolescents with obesity[END_REF]. In brief, it consisted of a 12-week physical activity program with 36 total sessions (3 per week). The training consisted of three phases: i) Phase 1, a 2-week habituation period (i.e. progressive increase in exercise intensity and session time) to protect individuals from delayed-onset muscle soreness; ii) Phase 2 consisted of 40-minute ECC or CON cycling sessions at 50% V ̇O2peak for 5 weeks; and iii) Phase 3 consisted of 40minute sessions with ECC or CON cycling at 70% V ̇O2peak for 5 weeks. ECC training was performed on ECC motor-driven ergometers (Cyclus2 Eccentric Recumbent; MSE Medical, France) and CON training on classical CON ergometers (Optibike Med 600; MSE Medical, France). A physical therapist and an exercise physiologist supervised all of the training sessions. The CTR group, which did not perform any physical training during 12 weeks, served as a control to distinguish the influence of growth on bone parameters. It was constituted, for ethical reasons of adolescents who were expecting their admission in the pediatric obesity center. All participants received the same dietary counseling (normo-caloric diet) throughout the 12-week period, without any guidelines for nutritional energy restriction [START_REF] Julian | Eccentric cycling is more efficient in reducing fat mass than concentric cycling in adolescents with obesity[END_REF].

Anthropometric, body composition, and bone assessments were measured before (T1) and after (T2) the 12-week intervention period.

Two types of bone analyses were conducted: i) dual-energy X-ray absorptiometry (DXA), which is considered as the reference method for assessing bone mineral density (BMD); and ii) quantitative bone ultrasound evaluation at the calcaneum, which was selected as a convenient estimate of bone in children because of the short examination time, easy implementation in routine activities, and absence of harmful effects. This focus on the calcaneum was conducted because of the potential differences between the 2 exercise modalities considering the mechanical constraint applied on the foot pedals and the pulls linked to muscular activity via the Achilles tendon.

Body composition and bone measurements by DXA

All subjects underwent DXA (Discovery A; Hologic Inc., Bedford, MA, USA) by a trained blinded technician for the assessment of body composition, bone densitometry assessment, trabecular bone score (TBS) and hip structural analysis (HSA) (QDR-4500A DXA; Hologic, Bedford, MA, USA). Body composition data were analyzed using the Hologic QDR Software for Windows version 12.6 to assess total LM and FM for whole-body and standard body regions [START_REF] Julian | Eccentric cycling is more efficient in reducing fat mass than concentric cycling in adolescents with obesity[END_REF]. BMD (in g/cm 2 ) and BMC (in g) were determined at the total body less head (TBLH), lumbar spine (LS, L2-L4) and non-dominant hip. BMD measurements were converted to Zscores. The TBS, which is related to bone microarchitecture and fracture risk, was calculated using TBS iNsight software (Medimaps SA, France). The HSA was performed at the narrow neck (NN; narrowest part of the femoral neck), femoral shaft (FS; across the shaft 1.5 cm from the NN to the intersection of the neck and shaft axes), and the intertrochanteric region (IT; along the bisector of the angle of the axes of the NN and FS). The following parameters were obtained: cross-sectional area (in cm 2 ; index of resistance to axial forces), BMD (g/cm 2 ), endocortical diameter (in cm), average cortical thickness (in cm), width (in cm), cross-sectional moment of inertia (in cm 4 ; estimate of resistance to bending forces in a cross-section), section modulus (Z, cm 3 ; index of bending strength), and buckling ratio (BR; index of susceptibility to cortical buckling under compressive loads) [START_REF] Chaplais | Geometric and Mechanical Bone Response to a Multidisciplinary Weight Loss Intervention in Adolescents With Obesity: The ADIBOX Study[END_REF]. Higher values are associated with greater predicted femoral strength for all HSA-derived parameters except BR, for which values over 10 are predictive of fracture risk [START_REF] Beck | Extending DXA beyond bone mineral density: understanding hip structure analysis[END_REF].

Bone measurements by quantitative ultrasound

Broadband ultrasound attenuation (BUA) and speed of sound (SOS) values were measured at the calcaneum of the dominant limb in a circular region of interest using an Achilles Insight+ (Achilles Insight, GE, Lunar Corporation, Madison, WI, USA), a quantitative ultrasound (QUS) imaging device that quickly produces real-time images of the heel bone without transducer movement [START_REF] Ferry | The bone tissue of children and adolescents with Down syndrome is sensitive to mechanical stress in certain skeletal locations: a 1-year physical training program study[END_REF].

Statistical analysis

Statistical analyses were performed using Stata software (version 13; StataCorp, College Station, TX, USA). The tests were two-sided with a type I error set at 5%. Continuous data are expressed as mean ± standard deviation according to statistical distribution. Normality was assessed using the Shapiro-Wilk test. Random-effects models for correlated data (bone parameters) were performed to measure time (T1 versus T2) and group (ECC, CON and CTR groups) effects and their interaction of time × group considering intra-and inter-patient variability (subject as random effect). The normality of residuals from these models was studied using the Shapiro-Wilk test. When appropriate, a logarithmic transformation was proposed to achieve normality of the dependent outcome. The relationships between continuous parameters (i.e. variations in weight, LM, FM and bone parameters) were studied by estimating Pearson or Spearman correlation coefficients and applying Sidak's type I error correction due to multiple comparisons.

Results

Thirty-four adolescents completed the study, as one adolescent in the ECC group dropped out due to family reasons, resulting in n = 11 (6 females girls, 5 males boys) in the ECC group, n = 12 in the CON group (6 females girls, 6 males boys) and n = 11 in the CTR group (6 females girls, 5 males boys). The mean patient age was 13.3 ± 1.2 years in the CON group, 13.6 ± 1.3 years in the ECC group and 13.7 ± 1.3 years in the CTR group (p = 0.49). The mechanical load were 3.7 times higher in the ECC group compared to the CON group (216.3 ± 70.2 W versus 59.2 ± 22.3 W for phase 1 ; 313.3 ± 94.9 W versus 82.5 ± 36.0 W for phase 2 p <0.001).

Anthropometric, body composition and strength parameters

LM percentage and quadriceps strength increased only in the ECC group (p <0.05).The anthropometric, body composition and functional parameters before versus after the training program were published elsewhere [START_REF] Julian | Eccentric cycling is more efficient in reducing fat mass than concentric cycling in adolescents with obesity[END_REF] and are summarized in Table 1. BMI decreased significantly at T1 versus T0 in both training groups (p <0.001). Whole-body FM percentage decreased significantly at T1 versus T0 in both CON (p <0.05) and ECC groups (p <0.01), though to a larger extent in the ECC group (time × group interaction between ECC and CON, p = 0<0.05). Whole-body LM percentage increased significantly at T1 versus T0 in both CON (p <0.05) and ECC (p <0.01) groups, with a greater increase in the ECC group (time × group interaction, p <0.05). BMI, whole-body FM and LM percentages were nor modified at T1 versus T0 in the CTR group (p = 0.782; p = 0.837 and p = 0.925 respectively). Leg LM percentage and quadriceps strength increased only in the ECC group (p <0.05).The anthropometric, body composition and functional parameters before versus after the training program were published elsewhere [START_REF] Julian | Eccentric cycling is more efficient in reducing fat mass than concentric cycling in adolescents with obesity[END_REF] and are summarized in Table 1.

Bone parameters

TBLH BMD and BMC increased significantly at T1 versus T0 in both CON and ECC groups (p <0.001) but were not modified significantly in the CTR group (p = 0.262 and p = 0.629, respectively). The time x group interactions were significant between ECC and CTR (p <0.001 for BMD and p <0.01 for BMC). LS BMD also increased significantly at T1 versus T0 in both training groups (p <0.05) whereas it was not modified in the CTR group (p = 0.723).

At the NN, BMD decreased at T1 versus T0 only in the CTR group (p <0.05), with significant time x group interactions between CTR and CON (p <0.05) and CTR and ECC (p <0.05). ACT decreased only in the CTR group (p <0.05), with a significant time x group interaction between CTR and ECC (p <0.05). At the FS and IT, BR increased significantly in the CTR and in the CON groups (p <0.01 and p <0.05, respectively) whereas it was not modified in the ECC group (p = 0.380 and p = 0.391, respectively). The time x group interaction was significant between CTR and ECC at the IT (p <0.05).

Bone parameters measured by DXA, including bone density and content, geometric and mechanical properties, are summarized in Table 2.

Concerning QUS at the calcaneum, SOS increased from 1581 ± 52.s -1 at T0 to 1601 ± 50 m.s -1 at T1 in the ECC group (p <0.01), whereas it did not change significantly in the CON group (1585 ± 52 m.s -1 at T0 versus 1590 ± 52 m.s -1 at T1, p = 0.064) and in the CTR group (1568 ± 44 m.s -1 at T0 versus 1569 ± 47 m.s -1 at T1, p = 0.948). BUA was not modified significantly in the CON (117 ± 18.6 dB.MHz -1 at T0 versus 113 ± 12.4 dB.MHz -1 at T1, p = 0.639), ECC (122 ± 20.7 dB.MHz -1 at T0 versus 122 ± 18.7 dB.MHz -1 at T1, p = 0.830) and CTR (123 ± 12.6 dB.MHz -1 at T0 versus 125 ± 12.5 dB.MHz -1 at T1, p = 0.805) groups.

Spearman correlation tests revealed no significant correlations between variations in weight, LM, FM, or bone parameters.

Discussion

Although ECC cycling has been recently shown to improve FM and LM to a greater extent than CON cycling performed at the same V ̇O2 in adolescents with obesity, its effects on bone parameters remain unknown. Thus, the present study aimed to compare the bone density, geometry, and strength responses to ECC versus CON cycling training matched for V ̇O2 in adolescents with obesity. Based on the TEXTOO trial, to our knowledge, the present analysis is the first to date to assess the effects of ECC cycling on bone parameters in adolescents with obesity. Our results show that a 12-week ECC cycling program is at least as efficient as classical CON cycling at improving BMC, BMD and several geometric and mechanical hip parameters measured by DXA in adolescents with obesity during a WL program and would prevent the increased BR (risk of fracture) that is usually observed after classical CON training.

Bone parameters measured at T0 in all groups are in line with those recently described by Chaplais et al., who reported using DXA lower quantitative bone health in adolescents with obesity versus maturation-matched lean adolescents [START_REF] Chaplais | Geometric and Mechanical Bone Response to a Multidisciplinary Weight Loss Intervention in Adolescents With Obesity: The ADIBOX Study[END_REF]. This reinforces then the actual literature demonstrating that fat accumulation compromises bone quality [START_REF] Fintini | The Bones of Children With Obesity[END_REF][START_REF] Shapses | Bone metabolism in obesity and weight loss[END_REF]. The significant increases observed in the training groups for total body BMD and BMC demonstrate the adaptations of bone to physiological loads (being peak forces caused by muscles) and are concordant with those of previous interventional studies showing that physical activity can increase bone synthesis in children [START_REF] Kondiboyina | Skeletal Effects of Nine Months of Physical Activity in Obese and Healthy Weight Children[END_REF] and adolescents with obesity during WL programs, particularly if LM is maintained [START_REF] Kelley | Effects of a Randomized Weight Loss Intervention Trial in Obese Adolescents on Tibia and Radius Bone Geometry and Volumetric Density[END_REF][START_REF] Sioen | Associations Between Body Composition and Bone Health in Children and Adolescents: A Systematic Review[END_REF][START_REF] Campos | Aerobic plus resistance training improves bone metabolism and inflammation in adolescents who are obese[END_REF][START_REF] Hoppeler | Moderate Load Eccentric Exercise; A Distinct Novel Training Modality[END_REF]. Thus, both training methods (ECC and CON) improved FM and LM and maintained sufficient loads to stimulate osteogenesis, which is of high importance since it has been demonstrated that skeletal adaptations may be compromised during growth relative to body mass and FM location [START_REF] Farr | Relationship of total body fat mass to weight-bearing bone volumetric density, geometry, and strength in young girls[END_REF][START_REF] Laddu | Longitudinal relationships between whole body and central adiposity on weight-bearing bone geometry, density, and bone strength: a pQCT study in young girls[END_REF]. The increased intensity of training during the different phases of the present protocol (Phase 1 to 3) may have prevent the accommodation of bone cells, which can be a limitation in some training programs including only routine loading signals. Indeed, the prevention of the accommodation of bone cells is recognize as a fundamental rule that govern bone adaptations [START_REF] Turner | Designing exercise regimens to increase bone strength[END_REF].

The osteogenic index of an exercise session, depending on its intensity, can be defined by the loads applied to the bone and calculated as magnitude of load (or stress) multiplied by the loading frequency [START_REF] Turner | Three rules for bone adaptation to mechanical stimuli[END_REF]. Thus, as the mechanical load in the ECC group was 3-4 times higher than in the CON group [START_REF] Julian | Eccentric cycling is more efficient in reducing fat mass than concentric cycling in adolescents with obesity[END_REF], better improvements of BMD and BMC would have been expected in the ECC group. Nevertheless, time x group interactions were significant between ECC and CTR groups whereas they remain non significant between CON and CTR groups. Interestingly, SOS at the calcaneum, which has significantly been correlated with BMD in adults and adolescents [START_REF] Chin | Calcaneal quantitative ultrasound as a determinant of bone health status: what properties of bone does it reflect?[END_REF][START_REF] Torres-Costoso | Agreement Between Dual-Energy X-Ray Absorptiometry and Quantitative Ultrasound to Evaluate Bone Health in Adolescents: The PRO-BONE Study[END_REF], increased only in the ECC group. The high mechanical constraint applied on the foot pedals and the high pulls linked to muscular activity via the Achilles tendon during ECC modality would have induced a specific impact on bone mechanical properties measured at the calcaneum. QUS parameters have recently been recognized as added and complementary values to DXA assessments [START_REF] Høiberg | Diagnostic devices for osteoporosis in the general population: A systematic review[END_REF]. Thus, the results of the present study remain concordant with those of a previous trial suggesting that resistance training combined with aerobic training would induce greater bone improvements than aerobic training alone [START_REF] Campos | Aerobic plus resistance training improves bone metabolism and inflammation in adolescents who are obese[END_REF]. Nevertheless, despite the high load developed during ECC cycling, weight-bearing ECC exercise modalities (such as downhill running), which generate high impacts, may have a greater osteogenic potential. Indeed, a recent randomized trial performed in young rats compared a CON uphill running group with two ECC downhill running groups, one training at the same mechanic rate (same slope in both CON and ECC groups but lower V ̇O2 in the ECC group) and one training at the same metabolic rate (same V ̇O2 in both CON and ECC groups but higher slope in the ECC group), and a control group (without training), on femoral BMD [START_REF] Chin | Calcaneal quantitative ultrasound as a determinant of bone health status: what properties of bone does it reflect?[END_REF]. Although they also failed to show any significant difference between the ECC and CON modalities, the CON group showed a significant increase in BMD only on proximal femur, whereas the two ECC groups showed significant improvements in total femoral BMD, with larger improvements (on both epiphysis and diaphysis) in the ECC group trained with the greater downhill slope [START_REF] Touron | Impact of Eccentric or Concentric Training on Body Composition and Energy Expenditure[END_REF]. However, while the fracture risk in adolescents who lose weight is of major concern [START_REF] Sabhaney | Bone fractures in children: is there an association with obesity?[END_REF][START_REF] Dimitri | Obesity is a risk factor for fracture in children but is protective against fracture in adults: a paradox[END_REF][START_REF] Goulding | Bone and body composition of children and adolescents with repeated forearm fractures[END_REF],

ECC training seems to prevent the increase in BR observed in the CTR and the CON training.

Moreover, it would prevent the decreased ACT observed in the CTR group at the NN. The increases in BR have previously been observed in adolescents with obesity at the end of classical multidisciplinary interventions, with BR scores approaching the threshold of fracture prediction, particularly at the NN [START_REF] Chaplais | Geometric and Mechanical Bone Response to a Multidisciplinary Weight Loss Intervention in Adolescents With Obesity: The ADIBOX Study[END_REF]. Our results are also in line with those of a previous trial performed in older adults with obesity, showing increased BR at the NN, IT, and FS in a dietbased WL group, while the increased BR was prevented in the diet plus exercise WL intervention, which included resistance exercises [START_REF] Armamento-Villareal | Weight loss in obese older adults increases serum sclerostin and impairs hip geometry but both are prevented by exercise training[END_REF]. BR stabilization in the ECC group is of clinical importance since, with ACT, it is the parameter that is the most associated with the incidence of hip fractures independently of BMD [START_REF] Kaptoge | Prediction of incident hip fracture risk by femur geometry variables measured by hip structural analysis in the[END_REF]. The present results support that bone quality can be preserved with ECC training during WL programs in adolescents with obesity.

Although this study is the first to question the impact of ECC training on bone adaptation in adolescents, its results must be considered in light of some limitations. The first limitation is its relatively small sample size, as it was initially estimated based on body composition parameters that required 10-15 individuals per group [START_REF] Julian | Eccentric cycling is more efficient in reducing fat mass than concentric cycling in adolescents with obesity[END_REF]. Other methods such as peripheral quantitative computed tomography may have provided important information on bone size, geometry, and quality [START_REF] Specker | Quantitative Bone Analysis in Children: Current Methods and Recommendations[END_REF]. Nevertheless, despite its inability to distinguish trabecular and cortical bone and determine volumetric BMD [START_REF] Ivuskans | Bone mineral density in 11-13-year-old boys: relative importance of the weight status and body composition factors[END_REF], DXA remains the most common noninvasive technique for assessing pediatric bone health. The clinical assessment of bone geometry and microstructure using HSA can be helpful for monitoring weight management in adolescents with obesity [START_REF] Chaplais | Geometric and Mechanical Bone Response to a Multidisciplinary Weight Loss Intervention in Adolescents With Obesity: The ADIBOX Study[END_REF], who are susceptible to postural, balance, motor disturbances and fractures [START_REF] Goulding | Bone and body composition of children and adolescents with repeated forearm fractures[END_REF]. It would have also been interesting to include a follow-up assessment to analyze whether the observed changes are maintained over time after the training programs, which has not been possible for practical reasons. Furthermore, it would have been relevant to assess daily energy intake, in particular concerning dairy products, which consumption has recently been associated with beneficial changes in circulating levels of bone-related biochemical markers in adolescents with obesity following an exercise training [START_REF] Josse | Dairy product intake decreases bone resorption following a 12-week diet and exercise intervention in overweight and obese adolescent girls[END_REF]. It would have also been relevant to determine whether the trajectory of change in bone parameters was influenced by the different 3 phases of exercise intensity, which has not been possible in the present study for practical reasons.

ECC cycling training induces at least similar improvements in bone density and content and several geometric and mechanical hip parameters compared to CON cycling training performed at the same metabolic rate in adolescents with obesity but may prevent some alterations of bone resistance observed during WL interventions based on classical CON cycling training. Thus, the present results support the idea that bone fragility during WL, from a compromised relationship between density, geometry, and strength, might be prevented with an increased gradual intensity cycling training based on ECC modality. Thus, considering that ECC cycling training features greater adiposity reductions and additional beneficial effects on muscle mass, muscle strength, and metabolic risk parameters compared with CON cycling training [START_REF] Julian | Eccentric cycling is more efficient in reducing fat mass than concentric cycling in adolescents with obesity[END_REF], it would represent an optimal and appropriate training modality for patients with obesity to prolong WL while maintaining bone resistance. To improve future exercise prescriptions, larger interventional studies should investigate the impact of ECC and CON cycling programs on bone parameters using standardized experimental conditions of power output (same V ̇O2 and mechanical power). The potential beneficial effect of ECC training performed with the same mechanical load but lower V ̇O2 than CON training would be suitable for various chronic pathologies resulting in cardiac, respiratory, or muscular limitations to their exercise capacities. Moreover, whether other ECC training modalities such as weight bearing, which can be obtained by descending stairs or walking downhill, would have greater effects on bone density, geometry, and strength, remains unknown.

Table 1 :

 1 Anthropometric, body composition and strength parameters before (T0) versus after (T1) the 12-week intervention for the control (CTR), the concentric (CON) and the eccentric (ECC) groups of adolescents with obesity (n = 34; mean ± SD)

	CTR (n = 11)			CON (n = 12)	ECC (n = 11)
	T1	T2	T1	T2	T1	T2

Table 2 :

 2 Bone parameters measured by DXA before versus after the 12-week intervention for the control (CTR), the concentric (CON) and the eccentric (ECC) groups of adolescents with obesity (n = 34; mean ± SD) , average cortical thickness; BMC, bone mineral content; BMD, bone mineral density; BR, buckling ratio; CSA, cross-sectional area; CSMI, cross-sectional moment of inertia; ED, endocortical diameter; FS, femoral shaft; IT, intertrochanteric region; NN, narrow neck; TBLH, total body less head; TBS, trabecular bone score; Z, section modulus. Intra-group interaction (time effect): *p <0.05. Time x group interacAon : † p <0.05, significant difference with CTRL

			CTR		CON		ECC
		T1	T2	T1	T2	T1	T2
	TBLH
	BMD (g.cm -2 )	1.066 ± 0.75	1.079 ± 0.79	1.002 ± 0.102	1.067 ± 0.95 *	1.040 ± 0.1218	1.11 ± 0.12 * †
	BMC (g)	2132 ± 290	2146 ± 285	1920 ± 399	1982 ± 353 *	2052 ± 447	2159 ± 423 * †
	Lumbar spine
	BMD (g.cm -2 )	0.951 ± 0.139	0.955 ± 0.155	0.880 ± 0.130	0.902 ± 0.123 *	0.930 ± 0.130	0.960 ± 0.122 *
	TBS	1 .28 ± 0.17	1.26 ± 0.16	1.27 ± 0.08	1.29 ± 0.09	1.30 ± 0.12	1.33 ± 0.12
	BMC (g)	51.23 ± 13.05	51.73 ± 11.39	44.80 ± 11.35	46.84 ± 11.01 *	52.61 ± 7.38	53.53 ± 10.20
	Hip
	BMD (g.cm -2 )	1.037 ± 0.123	1.009 ± 0.074	0.967 ± 0.124	0.962 ± 0.121	1.025 ± 0.174	1.025 ± 0.163
	BMC (g)	33.7 ± 5.6	33.4 ± 4.0	32.7 ± 6.9	32.2 ± 6.9	35.1 ± 8.4	34.8 ± 7.1
	NN
	BMD (g.cm -2 )	1.218 ± 0.141	1.166 ± 0.123 *	1.070 ± 0.191	1.066 ± 0.164 †	1.145 ± 0.212	1.151 ± 0.196 †
	ED (cm)	2.66 ± 0.32	2.72 ± 0.33	2.69 ± 0.34	2.78 ± 0.42	2.70 ± 0.25	2.74 ± 0.27
	ACT (cm)	0.24 ± 0.03	0.22 ± 0.03 *	0.21 ± 0.04	0.21 ± 0.03	0.22 ± 0.05	0.23 ± 0.04 †
	WIDTH (cm)	3.15 ± 0.32	3.14 ± 0.27	3.11 ± 0.36	3.19 ± 0.44	3.16 ± 0.24	3.18 ± 0.24
	CSA (cm 2 )	3.66 ± 0.71	3.51 ± 0.28	3.18 ± 0.80	3.26 ± 0.80	3.44 ± 0.69	3.48 ± 0.59
	CSMI (cm 4 )	2.93 ± 1.32	2.65 ± 0.64	2.47 ± 1.22	2.81 ± 1.81	2.70 ± 0.78	2.83 ± 0.72
	Z (cm 3 )	1.76 ± 0.58	1.59 ± 0.30	1.47 ± 0.54	1.59 ± 0.69 †	1.63 ± 0.38	1.69 ± 0.35 †
	BR	6.85 ± 1.27	7.54 ± 1.85	8.03 ± 1.47	8.38 ± 1.51	7.60 ± 1.56	7.61 ± 1.68
	IT
	BMD (g.cm -2 )	1.100 ± 0.162	1.081 ± 0.090	1.031 ± 0.163	1.028 ± 0.154	1.130 ± 0.185	1.119 ± 0.204
	ED (cm)	4.59 ± 0.35	4.68 ± 0.33	4.25 ± 0.50	4.58 ± 0.78 *	4.48 ± 0.38	4.62 ± 0.40 *
	ACT (cm)	0.48 ± 0.04	0.46 ± 0.05 *	0.45 ± 0.08	0.45 ± 0.09	0.48 ± 0.09	0.47 ± 0.08
	WIDTH (cm)	5.56 ± 0.37	5.60 ± 0.32	5.14 ± 0.57	5.28 ± 0.86 *	5.44 ± 0.37	5.56 ± 0.31 *
	CSA (cm 2 )	5.83 ± 0.53	5.80 ± 0.61	5.08 ± 1.12	5.38 ± 1.23	5.85 ± 1.02	5.91 ± 1.01
	CSMI (cm 4 )	14.9 ± 2.96	15.3 ± 4.0	14.60 ± 4.74	14.02 ± 7.33	15.16 ± 4.02	15.78 ± 3.10
	Z (cm 3 )	4.93 ± 0.75	4.93 ± 0.91	4.08 ± 1.34	4.44 ± 1.74	5.06 ± 1.09	5.18 ± 0.94
	BR	6.28 ± 0.67	6.88 ± 0.90*	6.33 ± 0.73	6.58 ± 0.92 *	6.56 ± 1.62	6.57 ± 1.45 †
	FS
	BMD (g.cm -2 )	1.507 ± 0.102	1.497 ± 0.107	1.542 ± 0.158	1.494 ± 0.200	1.573 ± 0.304	1.551 ± 0.269

ACT


Abir Abid
email: abir.abid@etu.univ-orleans.fr.

Economic Policy Uncertainty and Exchange rates in Emerging Markets: Short and Long Runs Evidence

Keywords: Economic policy uncertainty, exchange rates, emerging economies, cointegration. JEL classification: G15, E44, C22

We revisit the association between fundamentals and exchange rates in emerging markets relying on the role of the Economic Policy Uncertainty (EPU) in explaining /forecasting currency movements. Using ARDL model, we show that EPU plays a key role in explaining exchange rates in short and long runs. We also find that the EPU improves the forecasting power of macroeconomic models of exchange rate in both horizons. Our findings provide an empirical justification of the scapegoat theory.

Introduction

Since the global financial crisis, concerns about Economic Uncertainty (EU) have intensified [START_REF] Baker | Measuring Economic Policy Uncertainty[END_REF]. The EU reflects "the situation where economic agents lack the knowledge necessary to assess the current situation with sufficient confidence"1 . Thus, uncertainty is an intrinsically unobservable concept which plays an important role in shaping the economic conjuncture. One of its most discussed features, the Economic Policy Uncertainty (EPU) refers to the particular uncertainty surrounding future evolutions of economic policies [START_REF] Pástor | Political Uncertainty and Risk Premium[END_REF][START_REF] Baker | Measuring Economic Policy Uncertainty[END_REF]. In this regard, the literature concludes adverse effects of EPU on economic activity. This is clear with respect to its depressive effect on investment demand and/or consumption including precautionary spending cutbacks by households and an upward pressure on the cost of finance [START_REF] Baker | Measuring Economic Policy Uncertainty[END_REF][START_REF] Pástor | Political Uncertainty and Risk Premium[END_REF][START_REF] Gilchrist | Uncertainty, Financial Frictions, and Investment Dynamics[END_REF].

Furthermore, the EPU is seen as a driving force of financial assets dynamics [START_REF] Brogaard | The Asset-Pricing Implications of Government Economic Policy Uncertainty[END_REF]Pástor andVeronesi, 2012, Arouri et al. 2016).

The aim of this paper is to complement this literature by investigating the extent to which the exchange rates can be determined by EPU. Even though the literature argues significant effects of monetary and real variables on exchange rates [START_REF] Obstfeld | Exchange Rate Dynamics Redux[END_REF][START_REF] Engel | Exchange Rates and Fundamentals[END_REF][START_REF] Steinsson | The Dynamic Behavior of the Real Exchange Rate in Sticky Price Models[END_REF][START_REF] Ravn | Consumption, Government Spending, and the Real Exchange Rate[END_REF], notable studies point out that the models of exchange rate determination/prediction fail to provide a close link between macroeconomic variables and exchange rates especially in the short run (Cheung et al. 2005, Engel and[START_REF] Engel | Exchange Rates and Fundamentals[END_REF][START_REF] Meese | Empirical Exchange Rate Models of the Seventies: Do they Fit out of Sample[END_REF] 2 . Relatedly, we assume that the "scapegoat theory" of Bacchetta andVan Winscoop, (2004, 2013) provides a potential reason behind such a puzzle. This approach assumes that exchange rate might fluctuate in response to unobservable factors rather than observed macroeconomic ones (Bacchetta and Van Winscoop, 2013). Particularly, when uncertainty occurs, economic agents seek for a scapegoat to account for exchange rates movements which are inconsistent with their prior structural relationship (Fratzscher et al. 2015). Hence, in a rational market, excessive weight is attributed to observable variables (scapegoats) in explaining the exchange rate dynamics. Consequently, possible unobservable determinants are ignored (Bacchetta and Van Winscoop, 2013;[START_REF] Pozzi | Detecting Scapegoat Effects in the Relationship between Exchange Rates and Macroeconomic Fundamentals: A News Approach[END_REF]2018).

Given that market expectations are influenced by fundamentals and other unobservable factors (Fratzscher et al. 2015), much is to be gained through testing whether or not EPU, as an unobservable factor, should be explicitly incorporated into macroeconomic models of exchange rates determination. This is particularly important when dealing with short run dynamics for it may thus give an answer to the weak empirical relationship between exchange markets and fundamentals.

The contribution of this paper is threefold: First, we consider the EPU as an alternative of unobservable variables discussed in the scapegoat theory. Second, we relate different strands of the literature that involved separately: (i) the one the weak empirical performance of macroeconomic factors on exchange rate movements, (ii) the literature on possible omission of unobservable factors that can explain such a weakness and (iii) the literature on the relationship between the economic policies and the macroeconomics (Alesina et al. 1997, among others). Then, using the AutoRegressive Distributed Lag (ARDL) approach, we provide a coherent picture not only of the long and short dynamics between the variables, but we also appreciate the explanatory (forecasting) power of EPU on exchange rates with an in-sample (out of sample) analysis. To the best of our knowledge, our study is the first to investigate simultaneously the short and long runs EPU's effects on exchange rate in emerging markets. Moreover, the direct effects of EPU on exchange markets, especially in emerging economies, does not yet garner a great deal of attention. This context is relevant since emerging countries have (i) high levels of uncertainty comparing to advanced economies [START_REF] Bloom | Fluctuations in Uncertainty[END_REF], (ii) experienced strong currencies fluctuations after the shift from fixed to floating exchange regime which is known to be weakly explained by fundamentals [START_REF] Engel | Exchange Rates and Fundamentals[END_REF] and (iii) trade structures primarily based on volatile commodities prices resulting in strong currencies movements [START_REF] Guesmi | How strong is the global integration of emerging market regions? An empirical assessment[END_REF].

In what follows, section 2 provides further details on the methodology and the data used. Results survey is presented in section 3. Finally, section 4 concludes the work.

Empirical model and data

The baseline model

In order to test the extent to which EPU affects exchange rates movements, the ARDL bound testing developed by [START_REF] Pesaran | Bounds Testing Approaches to the Analysis of Level Relationships[END_REF] is applied for several reasons. First, it covers not only the long-run (cointegration equation) but also the short-run dynamics using an Error Correction Representation of the model (ARDL-ECM). Second, unlike traditional models of cointegration such as Engle and Granger (1987), this approach has the advantages of (i) considering a mixture of stationary and non-stationary time series, (ii) being among the most effective cointegration approaches in small samples [START_REF] Ozturk | Electricity consumption and real GDP causality nexus: evidence from ARDL bounds testing approach for 11 MENA countries[END_REF] and (iii) managing a possible endogeneity problems [START_REF] Pesaran | Bounds Testing Approaches to the Analysis of Level Relationships[END_REF].

In line with the scapegoat approach, we attempt to introduce the EPU as an unobservable explanatory variable of exchange rate movements in the following ARDL specification:

∆ = α + β + ∑ γ + ∑ δ ∆ + ∑ ∑ θ ∆ + (1)
Where, (St) is the exchange rate at time t, is the k th variable from n macroeconomic fundamentals detailed below, qk is the optimal lag for the k th variable, chosen according to the information criteria and is the error term. Based on theoretical considerations, we use as macroeconomic variables the short-term interest rate "IR", foreign reserves excluding gold "FR", the money supply "M1" that captures central banks' concerns regarding money market dynamics, the consumer price index "CPI" to control for inflation, the terms of trade "TOT" and the industrial production index "IPI" respectively used as proxies of foreign trade stance and output.

The most straightforward way to analyse the impact of the EPU is to extract it from the unobservable factors that in Eq.1 may contain. Accordingly, our estimated model is reformulated as follows:

∆ = α + β + ∑ γ + ∑ δ ∆ + ∑ ∑ θ ∆ + ϑ"#$ + ∑ ρ ∆"#$ + & (2)
Where, the new error term

( & ) = -[ϑ"#$ + ∑ ρ ∆"#$ ]
and represents potential unobservable factors other than the EPU that may affect the variable of interest.

Once the ARDL coefficients estimated, the next step is to check for the presence of cointegration using the [START_REF] Pesaran | Bounds Testing Approaches to the Analysis of Level Relationships[END_REF]'s bound testing. If such a property is retained, firstly, the following Eq.3 of the long-run elasticity is estimated:

= A, + - (3)
Where, , a vector including a constant, the macroeconomic factors detailed above and the EPU index, A is the loading matrix that captures the response dynamics of the exchange rate to the explanatory variables.

Secondly, the short-run elasticity as reflected in the ARDL-ECM model in Eq.4 is estimated:

∆ = α + ∑ δ ∆ + ∑ ∑ θ ∆ + ∑ ρ ∆"#$ + "./ 0 + 1 0 (4)
Where "./ is the Error Correction Term extracted from the Eq. 3.

Data

This empirical investigation is centred on five emerging economies, namely, South Korea, India, Brazil, Mexico and Chile. Our analysis is performed on a country-by-country basis using data set that comprises monthly observations covering the period from 01:2000 to 12:20163 . The data on macroeconomic fundamentals are collected from several databases, namely, the Federal Reserve Bank of Saint Louis (FRED), the OECD and DataStream. Our measure of EPU is the Baker et al. (2016)'s index, which is a monthly coverage of newspapers articles containing terms related to "uncertainty", "economy" and "policy"4 . As there is no objective or perfect measure of policy uncertainty, many proxies have been developed in the recent literature. The selected index is advantageous since it does not refer to a specific agent category (such as disagreement among forecasters) or a specific market (such as the VIX as a proxy of financial uncertainty).

Empirical findings and discussion

Preliminary tests

The estimation of the ARDL model evolves some preliminary tests. First, we conduct the KPSS unit root test primarily to avoid the inclusion of I(2) variables not appropriate in such an approach. Our findings show that all exchange rate series are I(1) and the explanatory variables display a mixture of I(0) and I(1) series. Accordingly, our variables reflect the properties required by ARDL model.

Next, we check for the presence of cointegration relationship using the bound testing procedure of [START_REF] Pesaran | Bounds Testing Approaches to the Analysis of Level Relationships[END_REF]. As revealed in Table 1, F-statistics lie above the upper bounds in all cases.

Such a result reflects the rejection of the null hypothesis of no cointegration for all the countries and supports the adequacy of long and short runs estimations outlined in Eqs 3 and 4. Finally, we check for the stability of the models using the tests of cumulative sum (CUSUM) and cumulative sum of squares (CUSUMQ). The obtained results broadly support the stability of all the estimated models5 .

Long-run dynamics

We start the assessment of our results with the long-run elasticities reported in the part (A) of Table 2. A first look at the results shows interesting long-run explanatory power of EPU and macroeconomic variables on exchange rates as the coefficients of determination (R²) vary between 0.69 and 0.94. The EPU coefficients are statistically significant and of the expected sign,

suggesting that EPU has a negative impact on exchange rate movements. Moreover, our findings highlight suitable individual explaining power of the macroeconomic variables i.e. a higher number of significant coefficients in each country. Thus, we support the literature suggesting that macroeconomic factors significantly explain exchange rate movements at least in the long run.

Turning to the core question of the paper, our results support the long-run negative effect of the EPU on exchange rate for all countries excepting India 6 . Hence, a rise in the domestic EPU leads to local currency depreciation and vice versa. When the EPU is high, economic agents adjust their expectations about the future of economic policies [START_REF] Krol | Economic Policy Uncertainty and Exchange Rate Volatility[END_REF][START_REF] Denis | The Impact of Uncertainty Shocks on the UK Economy[END_REF][START_REF] Creal | Monetary Policy Uncertainty and Economic Fluctuations[END_REF]Fernández-Villaverde et al. 2015;[START_REF] Chuliá | Impact of US Uncertainties on Emerging and mature markets: Evidence from a quantile-vector autoregressive approach[END_REF]. ). They adopt a 'waitand-see' attitude by reporting /cancelling their investment or consumption decisions which lead to a depreciation of the local currency [START_REF] Cheng | Effects of Foreign and Domestic Economic Policy Uncertainty Shocks on South Korea[END_REF] 7 . Moreover, with increased EPU in a context of general uncertainty, ambiguity adverse agents require higher ambiguity premium to hold financial assets [START_REF] Gábor-Tóth | Economic Policy Uncertainty and Stock Market Participation[END_REF][START_REF] Brenner | Asset Pricing and Ambiguity: Empirical Evidence[END_REF]. This reduces the attractiveness of financial markets to both national and international investors.

Naturally, exchange rates depreciate. 6 The EPU effect on exchange rate in India is negative but statistically not significant. 7 See Bloom (2009) for the 'wait and see' attitude of economic agent regarding uncertainty. Optimal lag for each variable is selected on consideration to AIC information criterion. Then, the following ARDL lags are retained : South Korea (2, 7, 0, 5, 1,7. 0, 8) ; India (2,1,4,7,0,7,6,2);Brazil (4,1,6,3,5,5,2,0);Mexico (3,5,1,7,3,0,4,4)and Chile (3,8,8,8,1,8,6,8). Note that our variables are introduced in the model in the following order (S) ; (EPU) ; (IR) ; (FR) ; (M1) ; (CPI) ; (TOT) and (IPI). Regarding the short-run dynamics, only significant coefficients are reported in order to save space and provide clear information. Then, we conducted Fisher test of joint nullity of coefficients to compare between two models: unconstrained ECM (our baseline model) and constrained ECM (after moving non-significant coefficients). In doing so, unconstrained specification is chosen for all countries. The results of our Fisher test can be provided upon request. As for residual diagnostic, we have a sustained interest in the quality of the model using diagnostic tests such as serial correlation (Breusch-Godfrey LM test), heteroscedasticity tests (Breusch-Pagan-Godfrey) or stationarity of the residuals (ADF). The results of these tests will be provided upon request.

Short-run dynamics

The second question of interest is whether the significant effect of EPU on exchange rate also holds in the short run. The results of the ARDL-ECM models are summarized in part B of Table 2. Our findings reveal that the Error Correction Terms (ECTs) are negative and statistically significant, which ensures a long-run equilibrium convergence in the model. Specifically, a closer look at the magnitude of the estimated ECTs indicates that nearly 16%, 6%, 15 %, 6.5% and 7% of any disequilibrium between the exchange rates and the explanatory variables respectively in Korea, Brazil, India, Mexico and Chile is corrected within one month. Given that the higher the ECT is, the higher the speed of adjustment would be, the exchange rate adjustment is faster in Asian than in Latin American economies. Therefore, the latter are more vulnerable to fundamental shocks than the former. Interestingly, our estimation is an empirical illustration of the scapegoat theory since the coefficients of determination R² (Table 2) are relatively high (ranging from 0.5 to 0.69) compared to other studies not taking the EPU into account (e.g. [START_REF] Baku | Exchange Rate Predictability in Emerging Markets[END_REF]. Such evidence sheds lights on the higher explanatory power of our specification in the short run. Similarly to the long-run evidence, we find that in all countries the exchange rate changes significantly decrease in response to higher EPU changes. For example, Brazil and Chile have migrated to the floating regime in 1999, nearly after the emerging financial crisis namely one year before the beginning of our sample period. Thus, economic change resulted in increased uncertainty surrounding economic policies causing the depreciation of the local currency.

Regarding the macroeconomic impacts, it appears from Table . 2 that monetary variables perform better in explaining exchange rate changes than real ones in the short run. Precisely, the terms of trade affect exchange rates changes in Mexico, Brazil and India. The latter, with Korean currency changes, are also impacted by industrial production changes. However, Chilean currency is not significantly sensitive to any of the two factors. Conversely, strong effects of the monetary variables are broadly observable. In fact, currency changes in Latin American countries significantly react to all monetary variables. In Asian economies, by contrast, interest rates alone do not significantly explain currency movements in any country 8 . Such a slight difference can be driven by country-specific actions implemented to reduce currency fluctuations. Asian economies' central banks massively hold foreign reserves in order to prevent exchange rates 8 Money supply changes only impact exchange rate movements in Korea.

appreciation [START_REF] Hernandez | Post-Crisis Exchange Rate Policy In Five Asian Countries: Filling in the 'Hollow Middle'?[END_REF][START_REF] Aizenman | International Reserves and Swap Lines: Substitutes or Complements?[END_REF]. However, policy intervention in Latin American countries can be through foreign reserves and/or interest rates manipulation 9 .

For example, the Brazilian economy adopts the Real plan to support the exchange rate appreciation by offering higher interest rates to encourage foreign capital inflows.

Forecasting exchange rates movements

As a last step, we test the forecasting power of our model relying on out-of-sample forecasts.

Attempting to appreciate the predictability of exchange rate fluctuation by the EPU, we implement a two-stage procedure that compares forecasts from two models: with or without the EPU. First, we apply our baseline model for each country 3 times, reserving each time 12, 36 and 60 months respectively in order to conduct short (1-year), medium (3-year) and long (5-year) runs forecasts. Then, the analysis is centred on the Root Mean Square Error (RMSE) and MAE (Mean Absolut Error) criteria widely used in time series studies to evaluate the forecasting accuracy. The corresponding results are reported in Table 3. Our evidence shows that models with EPU generally provide the lowest RMSE and MAE for all countries 10 . Accordingly, these models produce better forecasts of exchange rate movements than those without EPU in short, medium and long horizons. Therefore, we argue for the significant role of EPU in predicting exchange rate in different horizons. This appears to be particularly 9 Several central banks in Latin American countries are losing foreign reserves. For example, Brazil and Argentina have experienced high levels of inflation resulting in lower competitiveness and decrease in foreign reserves. As a result, the national currencies decreased. Moreover, since the adoption of the inflation-targeting regime, the interest rate has played a key role in policy intervention in these countries. 10 Only the medium-and long-run forecasts of India and the long-run forecast for South Korea present equality in MAE criteria between the two models.

interesting since the long-run fluctuations of exchange rates are determined by macroeconomic variables, but short-run fluctuations are difficult to predict [START_REF] Beckmann | Exchange Rate Expectations and Economic Policy Uncertainty European[END_REF].

Conclusion

In this study, we revisit the association between macroeconomic fundamentals and exchange rate in emerging markets relying on the potential explaining and/or predicting role of EPU. Our main findings suggest that the local currency is negatively driven by EPU in almost of the countries.

Particularly, we show that introducing the EPU into macroeconomic models of exchange rates translates in higher explanatory power of such models and improve their forecasting ability in the short as well as in the long run. Thus, our findings (i) take a step further from some studies showing modest empirical performance of fundamentals in explaining currency movements in emerging economies (e.g. [START_REF] Fratzscher | On Currency Crises and Contagion[END_REF] and (ii) provide an empirical justification of the scapegoat theory. Then, we suggest that macroeconomic models of exchange rates "are not as bad as you think" [START_REF] Engel | Exchange Rate Models Are Not As Bad As You Think[END_REF] when unobservable variables are considered. Overall, we contend that EPU is valuable information to which emerging economies decision makers should account in their exchange rate policy management.

A natural extension of our study is to ask whether foreign EPU accounts for currency fluctuations. This question is with prominent importance since the recent literature is extensively providing evidence of emerging markets integration and spillover effects of foreign EPU to financial markets [START_REF] Gauvin | Policy Uncertainty Spillovers to Emerging Markets -Evidence from Capital Flows[END_REF][START_REF] Su | Understanding Stock Market Volatility: What is the Role of U.S. Uncertainty?[END_REF]Arouri et al. 2016 among others).

Table . 1 Results of the cointegration test

 . This Tablereportsthe[START_REF] Pesaran | Bounds Testing Approaches to the Analysis of Level Relationships[END_REF] bound test of cointegration. H0 assumes no cointegration relationship. * and ***reflect the rejection of the null hypothesis at 1 and 10% levels respectively. UB and LB are respectively upper and lower bounds for the model with constant and without trend. See, the Table of[START_REF] Pesaran | Bounds Testing Approaches to the Analysis of Level Relationships[END_REF] for more details on bounds values. H0 is rejected when the calculated F-statistic is greater than the upper bound value.

	South Korea	Brazil		India	Mexico	Chile
	F-statistic	4.10***	2.94*		4.22*	4.10***	5.46***
	Critical Values	1%	2.5%		5%		10%
	UB	LB	UB	LB	UB	LB	UB	LB
	2.73	3.9	2.43	3.51	2.17	3.21	1.92	2.89

Table 2 . ARDLs-ECMs estimation results A. Long-run relationship (dependent variable (S))

 2 Significance of the coefficients estimated at 1, 5 and 10% levels is indicated respectively by *,**and***. Standard deviations are mentioned between parentheses. ECTs are error correction terms.

		South Korea		Brazil		India		Mexico		Chile
	c	-15.0820***(0.986)	0.537(1.243)	-5.294***(0.132)	3.572**(1.584)	-2.555**(1.04)
	EPU	-0.054***(0.007)	-0.060***(0.018)	-0.004(0.007)	-0.024***(0.007)	-0.079***(0.015)
	IR	0.1361***(0.018)	-0.194***(0.055)	0.356***(0.063)	0.003(0.016)	0.025***(0.009)
	FR	0.105***(0.034)	0.316***(0.021)	0.095**(0.046)	0.338***(0.052)	0.449***(0.048)
	M1	0.092**(0.043)	-0.458***(0.113	-0.080(0.076)	-0.573***(0.105)	-0.355***(0.093)
	CPI	-1.702***(0.208)	-0.686***(0.158)	-0.084***(0.078)	0.121(0.295)	-0.232(0.285)
	TOT	0.084(0.079)	0.520***(0.109)	0.390***(0.057)	0.366***(0.054)	0.680***(0.07)
	IPI	0.415***(0.085)	1.371***(0.180)	0.688***(0.132)	0.121(0.192)	0.262(0.107)
	R²	0.83		0.81		0.93		0.94		0.69
	B. Error Correction Representation of ARDL models (dependent variable ∆2 ))
		South Korea		Brazil		India		Mexico		Chile
	C	0.001(0.002)	c	-0.011**(0.005)	c	0.009***(0.002)	c	0.003(0.003)	c	0.004(0.004)
	345	-0.157***(0.044)	345	-0.058**(0.023)	345	-0.147***(0.037)	345	-0.065*(0.028)	345	-0.070**(0.033)
	∆2 )	0.388***(0.100)	∆2 )	0.557***(0.086)	∆2 )	0.283***(0.080)	∆2367)	-0.005*(0.002)	∆2 )	0.343***(0.086)
	∆2367)	-0.007*(0.003)	∆2 ) 8	-0.149**(0.065)	∆2367)	-0.007***(0.002)	∆29:)	-0.075***(0.026)	∆2367)	-0.022***(0.006)
	∆2;:)	0.718***(0.154)	∆2 ) <	0.142*(0.083)	∆2;:)	0.277***(0.057)	∆2;:)	0.100**(0.048)	∆2367)	-0.013*(0.007)
	∆2;:) =	0.199**(0.086)	∆2367)	-0.032***(0.006)	∆2;:) >	0.117*(0.065)	∆2;:) =	0.122***(0.046)	∆236?) <	-0.014*(0.008)
	∆2@ )	-0.092**(0.045)	∆29:)	-0.190*(0.106)	∆469 <	0.537***(0.182)	∆2;:) A	-0.087*(0.046)	∆2367) B	-0.016***(0.006)
	∆2469)	-0.856**(0.431)	∆29:) 8	-0.212**(0.099)	∆2469) A	0.389**(0.184)	∆2@ )	-0.381***(0.107)	∆29:)	0.026**(0.011)
	∆2469)	0.888**'(0.413)	∆29:) >	0.190**(0.073)	∆25C5) <	0.160*(0.082)	∆2@ )	-0.199*(0.114)	∆29:) A	-0.023**(0.011)
	∆2469) <	-1.166**(0.470)	∆2;:) 8	0.092*(0.050)	∆5C5 >	-0.262**(0.101)	∆25C5)	0.841***(0.069)	∆2;:)	0.140***(0.053)
	∆2469) A	-0.868**(0.417)	∆2@ ) =	0.196***(0.052)	∆2969)	0.105*(0.055)	∆25C5) 8	0.193***(0.098)	∆2@ )	-0.296**(0.131)
	∆2969)	-0.151***(0.064)	∆2469) <	-2.512**(1.230)			∆2969)	-0.304**(0.134)	∆2469)	-1.504**(0.581)
			∆2469) =	2.368**(0.929)			∆2969) <	0.313**(0.129)	∆2469) >	-1.642***(0.605)
									∆2469) A	1.256**(0.609)
									∆25C5) >	0.410**(0.189)
									∆2969) D	-0.123**(0.059)
	R²	0.68	R²	0.50	R²	0.55	R²	0.69	R²	0.55
	F-statistic	8.10	F-statistic	4.91	F-statistic	4.21	F-statistic	10.50	F-statistic	2.94

Table 3 . Out-of-sample forecasts results

 3

			RMSE			MAE
		SR	MR	LR	SR	MR	LR
	South Korea
	Model (a)	0.014	0.013	0.015	0.011	0.011	0.013
	Model (b)	0.015	0.015	0.016	0.013	0.012	0.013
	Brazil
	Model (a)	0.032	0.032	0.031	0.026	0.026	0.025
	Model (b)	0.034	0.035	0.033	0.030	0.027	0.026
	India
	Model (a)	0.011	0.017	0.020	0.008	0.013	0.015
	Model (b)	0.013	0.017	0.021	0.009	0.013	0.015
	Mexico
	Model (a)	0.015	0.012	0.013	0.013	0.010	0.011
	Model (b)	0.018	0.013	0.014	0.016	0.011	0.012
	Chile
	Model (a)	0.017	0.021	0.021	0.013	0.016	0.016
	Model (b)	0.020	0.024	0.023	0.015	0.018	0.018
	Model (a) is the model including EPU and model (b) is the one incorporating either EPU or
	macroeconomic variables. SR, MR and LR refer respectively to short run, medium run and long run
	forecast horizons.

Reference:"The impact of uncertainty in activity in the euro area". European Central Bank publication (2017).

According Meese and Rogoff (1983), a simple random walk model outperforms the macroeconomic models in forecasting exchange rates in the short run.

Exceptionally, the sample starts in January 2003 for India due to the availability the EPU index.

More information about the EPU index of[START_REF] Baker | Measuring Economic Policy Uncertainty[END_REF] is available in the official website of the paper www.policyuncertainty.com.

Results not provided here but available upon request.