Infant rhythms versus parental time: Promoting parent–infant synchrony

Infant rhythms versus parental time: Promoting parent–infant synchrony

Journal of Physiology - Paris 105 (2011) 195–200 Contents lists available at SciVerse ScienceDirect Journal of Physiology - Paris journal homepage: ...

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Journal of Physiology - Paris 105 (2011) 195–200

Contents lists available at SciVerse ScienceDirect

Journal of Physiology - Paris journal homepage: www.elsevier.com/locate/jphysparis

Infant rhythms versus parental time: Promoting parent–infant synchrony Antoine Guedeney a,b,⇑, Nicole Guedeney c, Susana Tereno c, Romain Dugravier a, Tim Greacen d, Bertrand Welniarz e, Thomas Saias d, Florence Tubach f, the CAPEDP Study Group 1 a

Hospital Bichat Claude Bernard, APHP, University Paris 7, Paris, France Unité de Recherche, INSERM U669 PSYGIAM, Paris, France c Hospital Institute Mutualiste Monsouris, Paris, France d Hospital Maison Blanche, Paris, France e Hospital EPS Ville-Evrard, France f VRC Hospital Bichat Claude Bernard APHP, France b

a r t i c l e

i n f o

Keywords: Parent–infant synchrony Attachment disorganization Parenting Infant social withdrawal behavior Early prevention and intervention

a b s t r a c t Traditional psychoanalytic theories of early development have been put into question by developmental psychology, and particularly by attachment theory. Psychopathology appears to be more linked to interpersonal relationship problems rather than to intra-psychic conflict, as hypothesized in Freudian drive theory. Establishing synchrony between parent and infant is probably one of the major tasks of the first year of life. Attachment theory appears to be an effective paradigm to understand how caregiver responses to stressful infant situations give way to different regulatory strategies, which impact on the effectiveness of the stress buffer systems and its physiological impact on emotion and stress regulation. This paper underlines the importance of synchronization between infant and caregiver; it highlights the key concept of attachment disorganization and of its relationship with sustained social withdrawal as a defence mechanism and an alarm signal when synchronization fails, and underlines the importance of early interventions promoting parent–infant synchrony. Ó 2011 Elsevier Ltd. All rights reserved.

‘‘Babies can’t wait’’. Selma Fraiberg, Clinical studies in infant mental health, 1980. ‘‘Nothing lasts, and yet nothing passes either. And nothing passes just because nothing lasts’’. Phillip Roth, The Human Stain, 2002.

1. Babies and time Infants are highly sensitive to violations of rhythms and to contingency within the infant–caregiver interaction (Cohn and Tronick, 1987). To quote the Greek philosopher Chrisippe, ‘Only the

present exists’ and this seems to be particularly true for the infant. When infants are faced with repetitive violations of interaction synchronization (Weinberg and Tronick, 1994), they find themselves excluded from the present. Early in life, infants do not have sufficient acquired memory content to retrieve representations of a good caregiver. They have no other solution than to withdraw from the present. Sustained relational withdrawal behavior marks a suspension in time, far from a truly depressive position in the Kleinian sense of the term (Guedeney, 2007a,b). Relational withdrawal behavior is the infant’s way of handling repetitive or durable violations of the expected synchrony within parent–infant relationships (Puura et al., 2010).

2. Synchrony in the first year of life ⇑ Corresponding author. Address: CMP Binet, 64 rue René Binet, 75018 Paris, France. Tel.: +33 1 42 55 03 09; fax: +33 1 42 52 29 72. E-mail address: [email protected] (A. Guedeney). 1 CAPEDP Study Group (Compétences parentales et Attachement dans la Petite Enfance: Diminution des risques liés aux troubles de santé mentale et Promotion de la résilience – Parenting Skills and Attachment in Infants: Reducing Mental Health Risks and Promoting Resilience). CAPEDP Scientific Committee: Elie Azria, Emmanuel Barranger, Jean-Louis Bénifla, Bruno Carbonne, Marc Dommergues, Romain Dugravier, Bruno Falissard, Tim Greacen, Antoine Guédeney, Nicole Guédeney, Alain Haddad, Dominique Luton,  Dominique Mahieu-Caputo (deceased), Laurent Mandelbrot, JeanFrançois Oury, Dominique Pathier, Diane Purper-Ouakil, Thomas Saïas, Susana Tereno, Richard Tremblay, Florence Tubach, Serge Uzan and Bertrand Welniarz. 0928-4257/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.jphysparis.2011.07.005

2.1. Role of parent–infant synchrony on social and emotional development Social and emotional development in early infancy is today recognized as crucial for all aspects of functioning throughout the lifespan (Brazelton et al., 1974; Sroufe, 1995). The infant’s ability to relate to and understand the social world develops through close and continuous interactions with his/her parents. Different factors can have a deleterious effect on early infant social and emotional development: premature birth or illness in utero, genetic risk

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factors or psychosocial risk factors such as living in inadequate or inappropriately stimulating environments, early disruptions in the parent–child relationship and inadequate parental care (Spitz, 1946; Fraiberg, 1982; Lyons-Ruth et al., 1999a,b; Feldmann, 2007). Parental mental illness poses also a risk for infant attachment as well as the child’s social and emotional development (Field, 2001; Murray and Cooper, 1997; Teti et al., 1995). The influence of risk factors on infant development depends on the qualities of both the parent and the child, which together determine the mutual adaptation capacity of the dyad (Mäntymaa, 2006) and its capacity to build parent–infant synchrony within the first 18 months of life (Feldmann, 2007). Successful synchrony is the basis for learning to play, understanding other peoples’ repertoire of actions and reactions, using symbolic exchange, and the ability to empathize (Feldmann, 2007; Stern, 1985; Tronick and Cohn, 1989; Trevarthen and Aitken, 2001). Synchrony is an essential ingredient in the predictability of caregiving, key feature of secure attachment in early relationships with the parent (Bowlby, 1969, 1973). Defined as the temporal coordination of micro-level social behavior, parent–infant synchrony develops through the early childhood years, from biological rhythms during pregnancy through to later symbolic exchange between parent and child. 2.2. Synchrony and physiological mechanisms Synchrony is seemingly linked to physiological mechanisms such as those involving the oxytocin hormone which plays an important role bonding between mammals. Synchrony is a feature of the dyadic system and thus may be compromised by risk conditions in either the mother or the child (Tronick and Cohn, 1989; Feldmann, 2007). Prematurity as a child-related risk and maternal depression as a mother-related risk are the two conditions that have received the most empirical attention to date. Within attachment theory, synchronization plays a major role with the concept of sensitivity of the caregiver response to infant stress. During Ainsworth’s Strange Situation procedure (Ainsworth et al., 1978), measuring heart rate variability and cortisol level clearly shows the buffer role of attachment (Spangler and Grossmann, 1993). Moreover, the more the mother–child dyad is secure, the more their heart rates are synchronized (Zelenko et al., 2005). 3. Attachment disorganization and parent’s disorganizing behavior 3.1. The attachment system and the regulation of fear Selma Fraiberg was probably the first mother–infant psychotherapist to emphasize the importance of fear and loss in disturbed mother–infant interactions (Fraiberg, 1981). Since then, developmental psychology has emphasized the importance of the regulation of fear arousal as one of the major tasks during infant development. This issue is particularly crucial for attachment theory. Attachment theory holds that humans are born with a strong, evolved tendency to seek care, help and comfort from members of the social group whenever they are faced with danger or are suffering from physical or emotional distress (Bowlby, 1969, 1973). The attachment system, although more often active during infancy and childhood, is operative throughout any human being’s life and is powerfully activated during and after any experience of fear, physical or psychological pain or uncertainty (as, for instance, during the transition to parenthood). Within this focus on fear arousal, attachment research has shed light onto the development of the infant’s defensive adaptations to a caregiver’s inability to provide the needed soothing responses to infant fear

or distress. During the many interactions with his/her attachment figure, the infant builds an Internal Working Model (IWM) of attachment with each of attachment figure (Bowlby, 1969). These primary IWMs are revisited and new ones are internalized according to the cognitive development of the child and his or her new relational experiences, although initial IWMs may be elicited if the stress is too severe (Mikulincer and Shaver, 2007). 3.2. The caregiving system The caregiving system is another pre-adapted psychosocial mechanism, functioning in tandem with the attachment system in helping infants regulate fear arousal and develop their competencies (Bowlby, 1973; George and Solomon, 1996). The adult/ caregiver provides proximity and comforting interactions to their offspring. The only way of deactivating the caregiver’s caregiving reaction is to establish or maintain proximity with their suffering infant. Although the caregiving system is influenced by the caregiver’s attachment system, it does not overlap with it exactly. Many influences can directly impact on the caregiving system: biological hormones, life events, psychiatric status, the attachment relationship with the partner, the level of stress and the infant’s cues (George and Solomon, 2008). Both attachment and caregiving systems can be considered as co-evolutionary systems of care-giving and care-seeking (George and Solomon, 2008). 3.3. Intergenerational transmission of disorganized attachment The two models of transmission described on the one hand by Main and Hesse (1990) and, on the other hand, by Solomon and George (1999) and Lyons-Ruth et al. (1999a,b) are known as the first and the second generation effects, respectively. 3.3.1. The traumatic experience of fear or loss: The first generation effect For Hesse and Main (2006), a mother can present an unresolved trauma related to attachment, associated with non integrated affects (fright, sadness and anger). The mother’s psychological state will most likely not allow her to repair the mismatches. Elements of the traumatic experience are not integrated as a whole but rather stored as isolated fragments of sensory perceptions of affective states; these memories can be abruptly and easily activated by stimuli associated with the traumatic event. They may disrupt attention and parental behavior in the form of absorption and unmonitored intrusions of memories, affects and sensory perceptions concerning the trauma (Hesse and Main, 2006). These odd maternal behaviors have been described by Main and Hesse (1990) as frightened or frightening dissociative behaviors which are parallel to the usual reactions to intense fear or stress, i.e. fight, flight or freeze. This dissociative mechanism has been analyzed as underlying the ghosts in the nursery phenomenon, resulting from unresolved traumatic attachment experiences of the caregiver (Fraiberg, 1981). The key point is that, because of these reactions, the mother becomes both the soothing attachment figure and the source of alarm. The infant is exposed to an experience of fright without solution (Main and Hesse, 1990). 3.3.2. The mother as an infant: the second generation effect The infant of a disorganized parent will try to organize strategies to develop control over his/her caregiver (Solomon and George, 1999). By age 3–5 (this phenomenon can be observed even earlier), many children having previously shown disorganized attachment patterns will develop alternative strategies for involving emotionally distant parents, such as punitive attachment behavior with regard to the caregiver or to the contrary, with

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protecting or supportive worrying about the parent (Solomon and George, 1999). Linking developmental stories of disorganized attachment to later adult states of mind through forms of child and adolescent controlling behavior can provide an important explanatory mechanism for continuity in infant adaptation over time and for the transmission of intergenerational disorganization (Melnick et al., 2008). The infant or toddler is too young to be able to integrate such contradictory aspects within the same person; instead of developing a coherent IWM of their attachment figure, they are at risk of developing segregated models of other and self (Bowlby, 1973). In this case, the IWM prefigures not only negative consequences of asking for help and comfort, but also brings on a dissociated multiplicity of dramatic and contradictory expectations from the same attachment figure (Liotti, 2004; Main and Hesse, 1990). Liotti (2004) proposes a description of these multiple representations of an infant’s attachment figure, which he names the ‘‘Drama Triangle’’. The disorganized child has good reasons for construing simultaneously, or in quick sequence, both models of the attachment figure and the self according to the three basic positions of the drama triangle of Persecutor, Rescuer and Victim. The attachment figure is represented negatively as the cause of the ever growing fear experienced by the self (self as victim of a persecutor), but also positively as a rescuer. The parent, although frightened by unresolved traumatic memories, is nonetheless usually willing to offer comfort to the child who may in turn react with fear to such ready comfort. With these two opposed representations of the attachment figure (persecutor and rescuer) meeting a vulnerable and helpless self (victim), the disorganized attachment IWM also conveys a negative representation of a powerful, evil self meeting a fragile or even devitalized attachment figure (the self as a persecutor, held responsible for the fear expressed by the attachment figure). In other cases, the child can come to represent both the self and the attachment figure as the helpless victims of a mysterious, invisible outside source of danger. Finally, in situations in which contact with the child reassures a frightened attachment figure, attachment memories may allow the child to perceive him/herself as a comfort for the frightened adult. When considering this adult as a mother in interaction with her child, the different constellations of parenting behavior can be meaningfully explained as alternate behavioral expressions of this single underlying hostile– helpless dyadic internal model (Lyons-Ruth et al., 1999a,b). Newborns are stressors by definition and some of their characteristics or attitudes or developmental challenges can trigger alternate segregated IWMs in their mother: a model of the other (the mother as evil, an angel, a victim) and the complementary model of the self (as a helpless victim, a good person, a devil). This may place the parent at risk of being flooded by intense affects that they cannot regulate or act on adaptively, leading to a display of hostile responses to their children (Melnick et al., 2008). These experiences of contradictory caregiving responses due to alternating maternal IWMs expose the infant to intense levels of attachment activation, without any repair from his/her attachment figure (Solomon and George, 1999).

3.3.3. The role of the therapeutic/preventive relationship in decreasing the effects of disorganization within the parent–infant relationship Parenthood is a stressful period in itself, babies are in themselves a source of stress and the parent can also be exposed to many other stressors. If the parents are in an insecure state of mind and particularly if they have antecedents of attachment disorganization, they will be particularly sensitive to stress (Mikulincer and Shaver, 2007). Stress is also well known for reducing mentalization abilities (Fonagy et al., 2002).

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When exposed to intense stress (due to the child or to other stressors), there is a risk for any mother, but particularly for insecure mothers, that the different goals of the motivational systems involved in the attachment and caregiving systems enter into collision, for instance when needs of the parent and the child are contradictory (Solomon and George 1999). The attachment system is regarded as being pre-emptive when aroused, and this holds at all ages, because it mobilizes responses aimed at regulating the arousal of fear (Bowlby, 1969, 1973; Lyons-Ruth et al., 2004). The usual strategies used by the caregiver to deactivate their attachment may be in contradiction with caregiving strategies, resulting in what George and Solomon (2008) have described as a competition between the mother’s caregiving and attachment systems. A precondition for mother–infant psychotherapy is for the therapist to resolve the maternal dilemma (Fraiberg, 1981). The best solution for a human being to resolve this motivational paradox if sources of stress cannot be avoided is to receive help from a specific figure perceived as stronger, kind and willing to help (Bowlby, 1973; Marvin et al., 2002). If the therapist provides the conditions for a secure relationship and can take time to get close to the mother, maternal stress will be reduced via an interpersonal soothing response known to alleviate the mother’s fear arousal. The first immediate consequence will be to reduce competition between her attachment and caregiving systems. Her caregiving system may be more functional: the mother will be more able to follow her child’s cues and to repair any miscues if necessary. Second, a secure relationship will deactivate the mother’s own attachment system and reduce recourse to earlier strategies which might influence caregiving behavior. Third, the therapist provides a safe haven for the mother while she is overwhelmed by attachment relevant emotions. This securing relationship favours exploration, maternal mentalization and parental reflective function (Bowlby, 1973; Fonagy et al., 2002).

4. Social withdrawal behavior as infant’s defence mechanism against desynchronization 4.1. Infant social withdrawal as a very early defence mechanism As they unfold, early defence mechanisms give precious indications about what is at stake and at which age. Brazelton et al. (1974) describe the primary defence mode, immediate withdrawal, as a normal part of parent–infant interactions and a way for infants to keep control over the rate of interaction. Over a longer period of time, stronger protesting behavior can lead to increasingly pathological behavior in terms of avoidance, as observed in the Still Face experiment (Cohn and Tronick, 1987) and confirmed in Murray and Trevarthen’s (1986) work on synchronization. Spitz (1946) described social withdrawal as a clinical feature of anaclitic depression. Engel and Schmale (1972) developed the concept of conservation-withdrawal based on the famous Monica case. Engel and Reichsman (1956) had described pathological and sustained relational withdrawal behavior in a marasmic and developmentally retarded infant, Monica, who came to their paediatric service with severe failure to thrive at the age of 14 months. She had esophageal atresia and required feeding through a gastric fistula. When her care was abruptly transferred from her warm and caring grandmother to her isolated mother who was disgusted by her fistula, Monica showed withdraw, cried and lost weight for no apparent physical reason. Today, she would probably be considered as a typical case of disorganized attachment, with a frightened and abdicating caregiver. After prolonged care, she improved and developed normally as an adult and later as a mother, even though she had difficulty feeding her infant (Engel and Reichsman, 1979).

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Fraiberg (1982) described a group of pathological defence mechanisms observed between 3 and 18 months of age in infants who had experienced severe danger and deprivation. These early defence mechanisms, ‘‘avoidance’’, ‘‘freezing’’ and ‘‘fighting’’ are, according to Fraiberg, summoned up from a biological repertoire. Thus, withdrawal plays an important role both in physiology and in pathology in the infant’s repertoire of responses to stress. Although infant withdrawal is a key symptom of infant depression, withdrawal reactions are also associated with attachment disorders, autistic disorders, post traumatic stress syndrome and anxiety. A sustained withdrawal reaction can be seen in many acute and chronic organic conditions. For example, intense and chronic pain in infancy is characterized by a severe behavioral withdrawal reaction that correlates with the intensity of the pain (Gauvain-Piquard et al., 1999). Sustained withdrawal reaction is a good target for early screening in infant mental health, as negative symptoms are more difficult to evaluate than the more obvious positive ones, but also because withdrawal is a major component in the infant’s repertoire of behavioral responses to stress and relationship disorders. Feldman stresses the importance of sustained relational withdrawal behavior in infants as a sign of a dysregulation of parent–infant synchrony (Mäntymaa, 2006; Feldmann, 2007). Based on these previous studies and current results showing the importance of social withdrawal, the present authors have designed a scale to assess social withdrawal behavior in infants aged 2–24 months of age, with good psychometric properties and good trans-cultural validity (Guedeney and Fermanian, 2001; Dollberg et al., 2006; Guedeney, 2007a,b; Guedeney et al., 2008; Puura et al., 2010). 4.2. Maternal depression, infant depression and infant social withdrawal as effects of mother–child dysynchronization Children’s reactions to the interruption or violation of their expectations within mother–child interactions are both obvious and durable (Cohn and Tronick, 1987; Murray and Trevarthen, 1986). Tronick and Weinberg (1997) insist on the effect of maternal postnatal depression in the development of what they call ‘‘dyadic states of consciousness ‘‘. These key studies have shown possible models of transmission of depressive affect between mother and child, following the Still Face paradigm. Depressed mothers are more negative when interacting with their babies. Infants of depressed mothers are less positive and more negative when interacting with their mothers in laboratory situations. Notably, infants of depressed mothers show depressed behavior even with non-depressed adults, demonstrating a generalization of the depressive model of the relationship (Field, 1984, 2001). These behaviors result partially from poorer interaction provided by the mother, as postpartum depressed mothers have been observed to be less contingent and less effectively attuned to their infant (Murray et al., 1996). Children of mothers reporting being more depressed or anxious since childbirth obtain significantly higher Alarm Distress Baby scale B (ADBB) scores (Matthey et al., 2005) and children with higher social withdrawal scores show less optimal behavior when interacting with their mothers (Puura et al., 2007; Dollberg et al., 2006). 5. Conclusion: the CAPDP Project as a parent–infant intervention aimed at modifying maladaptive trajectories Several projects have been developed over the last 10 years with the aim of preventing or decreasing postnatal depression and thus reducing externalized behavior disorders in exposed children (Chabrol and Callahan, 2007; Olds et al., 1998). The CAPEDP Project (Compétences parentales et Attachement dans la Petite Enfance: Diminution des risques liés aux troubles de santé mentale

et Promotion de la résilience - Parenting Skills and Attachment in Infants: Reducing Mental Health Risks and Promoting Resilience) is a randomised controlled program aimed at promoting infant mental health in the Paris region. The aim of the project is to assess the effect of a preventive intervention on psychosocially vulnerable families. Within CAPEDP, we examined in a sub-sample of 120 mother– infant dyads more detailed measures of child attachment style and parental disorganizing behavior and mentalizing abilities. At the child’s first birthday, infant attachment is assessed using the Strange Situation paradigm (Ainsworth et al., 1978). At 18 months, Waters’ Attachment Q-sort is used to assess attachment quality at home (Waters and Deane, 1985). The maternal disrupting behaviors are assessed with Lyons-Ruth’s AMBIANCE scale (Lyons-Ruth et al., 1999a,b). Finally, parental reflexive capacity is evaluated using the Oppenheim and Koren-Karie (2002) Insightfulness Assessment interview. In the intervention programme, home-visiting psychologists are specifically trained and supervised with regard to the use of home video feedback for promoting maternal sensitivity and mentalizing skills and detecting and reducing atypical maternal behavior and disorganized attachment in the child. The use of video is modeled on the most effective existing programs (see Guedeney and Guedeney, 2010 for a review of video-based infant interventions). Using video, the parent becomes their own model of intervention. It provides an opportunity to focus on the baby’s signals and expressions, while stimulating the mother’s observation skills and her empathy with her child. It also enables positive reinforcement of sensitive behavior evidenced by the parent on video. The use of video is even more successful within a supportive relationship that continually recognizes both individual and family strengths within their socio-ecological context. Printed support material on ‘‘Emotional Development in Infants’’ is also referred to home visits when a problem or a question arises in any particular area – but without going so far as to use the document as a guide to parenting. In conclusion, although data collection is still in progress, CAPEDP hopes to provide new perspectives on preventive mental health with vulnerable populations, as well as the opportunity to develop training on specific aspects of early mental health promotion. Although short-term success for treatment interventions exists for improving child mental health, there is little evidence of short-term success for preventive interventions and no preventive or therapeutic studies providing evidence for long-term success. Further research into the prevention and treatment of postnatal depression (PND) including feasibility in terms of cost-effectiveness is needed (Chabrol and Callahan, 2007). Long term effects of maternal PND on academic performances of boys, particularly in the context of additional risks have been described (Murray et al., 1996). Although a large effect size on PND is not to be expected in CAPEDP given the relatively short period of intervention, reducing the effects of PND on parent–child interactions is a feasible expected outcome. This is particularly the case, given that the recruited sample is more vulnerable than expected, with a large proportion of mothers fulfilling the axis I psychopathology criteria and experienced violence and neglect. Recent longitudinal studies have shown differential links to emergent psychopathology stemming from different exposure to potentially traumatic events in early childhood (Brigg-Gowan et al., 2010). On the one hand, exposure to intra-familial violence is associated with an array of symptoms of both internalizing and externalizing disorders, and, on the other hand, non-interpersonal traumatic exposure seems to be linked to specific phobia. Therefore, targeting intergenerational disorganized attachment in these vulnerable populations may well provide important clues for orienting future prevention and care strategies.

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Acknowledgements The authors would like to thank the 440 families who accepted to participate in the study, the researchers, the members of the home visiting team and the research assistants, without whom this project would have been impossible: Joan Augier, Amel Bouchouchi, Anna Dufour, Cécile Glaude, Audrey Hauchecorne, Gaëlle Hoisnard, Virginie Hok, Alexandra Jouve, Anne Legge, Céline Ménard, Marion Milliex, Eléonore Pintaux, Elodie Simon-Vernier, Alice Tabareau, Jessica Aymond, Mila Bortolemi, Capucine De Jerphanion, Aurore Dié, Pauline Drecq, Sophie Gandillot, Claire Lamas, Sylvain Lepagnot, Daniele Luzzo, Liliana Mingita, Anne-Sophie Mintz, Violaine Misticki, Catherine Rabouam, Mathilde Roussel, Andrée Sodjinou, Silan Ulgen, Lauriane Vuliez, Jaqueline Wendland, Francine Messeguem and the team of the Binet Child Community Mental Health Center, Sebastien Favriel and the research team of EPS Maison Blanche for technical support, Estelle Marcault for the logistic support and research implementation, Véronique Laniesse and Alexandra Avonde for administrative support, Cécile Jourdain, Nathalie Fontaine, George Tarabulsy and Michel Boivin, for assistance with developing the research and intervention instruments, and the members of the supervision team: Laure Angladette, Drina Candilis, Judith Fine, Alain Haddad, Joana Matos, Anne-Sophie Mintz, Marie-Odile Pérouse de Montclos, Diane Purper-Ouakil, Françoise Soupre, Susana Tereno, Bertrand Welniarz and Jaqueline Wendland. The project received financial support from the National Ministry of Health Hospital Clinical Research Programme (PHRC AOM 05056), the National Institute of Health and Medical Research (INSERM), the National Health Insurance of Self-Employed Workers, the National Institute for Prevention and Health Education (INPES), and the Public Health Research Institute (IReSP, PREV0702). We would also like to thank the Clinical Research and Development Department of the Assistance-Publique Hôpitaux de Paris for coordinating and facilitating this funding. This paper is dedicated to the memory of Pr. Dominique Mahieu-Caputo, Bichat Claude Bernard Hospital, APHP, member of the CAPEDP Scientific Committee.

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