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Neuroendocrinology of childbirth and mother–child attachment: The basis of an etiopathogenic model of perinatal neurobiological disorders

April 2014
Frontiers in Neuroendocrinology 35(4)

April 2014
35(4)

DOI:10.1016/j.yfrne.2014.03.007

Source
PubMed

Authors:

Ibone Olza

European Institute of Perinatal Mental Health

Miguel Marín Gabriel

Hospital Universitario Puerta de Hierro-Majadahonda

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This review focuses on the neuroendocrine mechanisms in the mother and the newborn that are involved in the generation and consolidation of mother-child attachment. The role that different hormones and neurotransmitters play on the regulation of these mechanisms during parturition, the immediate postpartum period and lactation is discussed. Interferences in the initiation of mother-child attachment may have potential long-term effects for the behavior and affection of the newborn. Therefore, the possible consequences of alterations in the physiological neuroendocrine mechanisms of attachment, caused by elective Cesarean section, intrapartum hormonal manipulations, preterm delivery, mother-infant postpartum separation and bottle-feeding instead of breastfeeding are also discussed.

Hormonal actions during parturition and early postpartum involved in the regulation of maternal care and the bonding between the mother and her newborn. (A) Vaginal delivery results in increased brain oxytocin release which will facilitate mother-infant bonding. In addition, oxytocin during labor changes the effect of GABA in the fetal brain from being excitatory to be inhibitory, allowing a protective effect of GABA from delivery hypoxia. In the baby, the passage of the head through the birth canal is accompanied by a massive release of catecholamines and vasopressin that probably facilitate newborn physiological adaptation after delivery. Furthermore, maternal uterine contractions during labor facilitate neonatal olfactory learning in the newborn. (B) In the early postpartum period, noradrenaline, oxytocin, vasopressin and prolactin promote olfactory learning in the mother and maternal care. In rodents corticosterone affects neural plasticity in different brain regions, decreases hippocampal neurogenesis and impairs spatial learning. In humans, higher cortisol levels in the mother are associated with higher preference for her newborn body odor. Skin-to-skin contact of the mother with her newborn and the initiation of breastfeeding promote increased levels of oxytocin in the mother and the baby. Oxytocin contributes to mother-infant affect synchrony, promoting the attachment of the mother and the newborn. This attachment is essential for the regulation of emotions, stress reactivity, metabolic adaptation and social and cognitive development of the baby.

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Review

Neuroendocrinology of childbirth and mother–child attachment: The

basis of an etiopathogenic model of perinatal neurobiological disorders

Ibone Olza-Fernández

, Miguel Angel Marín Gabriel

, Alfonso Gil-Sanchez

, Luis M. Garcia-Segura

⇑

Maria Angeles Arevalo

Department of Psychiatry, Autonomous University of Madrid, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain

Department of Pediatrics, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain

Unidad Docente de Salud Mental de la Región de Murcia, Hospital General Universitario Santa María del Rosell de Cartagena, Murcia, Spain

Instituto Cajal, CSIC, Madrid, Spain

article info

Article history:

Available online 3 April 2014

Keywords:

Autism

Cesarean section

Childbirth

Maternal behavior

Mother–child attachment

Noradrenaline

Oxytocin

Progesterone

Prolactin

Vasopressin

abstract

This review focuses on the neuroendocrine mechanisms in the mother and the newborn that are involved

in the generation and consolidation of mother–child attachment. The role that different hormones and

neurotransmitters play on the regulation of these mechanisms during parturition, the immediate post-

partum period and lactation is discussed. Interferences in the initiation of mother–child attachment

may have potential long-term effects for the behavior and affection of the newborn. Therefore, the pos-

sible consequences of alterations in the physiological neuroendocrine mechanisms of attachment, caused

by elective Cesarean section, intrapartum hormonal manipulations, preterm delivery, mother–infant

postpartum separation and bottle-feeding instead of breastfeeding are also discussed.

1. Introduction: Childbirth as a neurobiological and

neuroendocrine event

Physiological changes in the dynamics and mechanics of labor

in women have been thoroughly studied (Liao et al., 2005). How-

ever, the peripartal neurohormonal scenery in the brain of the

mother, the fetus and the newborn has received little attention.

Here we will approach human childbirth as a neurohormonal event

rather than a mechanical one and we will speciﬁcally focus on the

peripartal neuroendocrine mechanisms that participate in the gen-

eration of mother–child attachment. We will also consider possible

disrupting effects that some obstetrical interventions during the

peripartal period may have on the neuroendocrine mechanisms

of mother–child attachment, as well as its possible long-term con-

sequences for the newborn. Birth outcomes have traditionally been

measured in terms of maternal and neonatal morbidity in the short

term, indicators that may not be valid to study the impact of hypo-

thetical changes in the brain during childbirth or the early postna-

tal period. This impact may only be manifested later in life, during

adolescence or even in adulthood. Understanding the neuroendo-

crine events involved in mother–child attachment that happen in

both maternal and fetal brains during the peripartum period may

allow the building of an etiopathogenic model of some mental

disorders that would be better understood as the consequence of

peripartal neuroendocrine alterations.

Motherhood entails neurochemical, morphological and func-

tional brain changes designed to ensure the survival of newborns.

Hormonal changes during different life stages are associated with

the regulation of speciﬁc neuroplastic events that generate appro-

priate physiological and behavioral responses in adaptation to and

in prediction of changing life conditions (Garcia-Segura, 2009).

Pregnancy is one of the life stages characterized by prominent

hormonal changes and is also a period of enhanced-neuroplastic

changes that result even in the reduction of brain size in humans

(Oatridge et al., 2002) and of hippocampal volume in rats (Galea

et al., 2000). The neuroendocrine and neuroplastic events during

pregnancy that facilitate the onset of adequate maternal behaviors

have been extensively studied and characterized in different mam-

malian species. These events, which involve different actions of

steroid hormones, neurosteroids, prolactin, oxytocin, vasopressin,

catecholamines and endorphins (Keverne, 1988; Torner and

Neumann, 2002; Russell et al., 2003; Douglas, 2005; Brunton

http://dx.doi.org/10.1016/j.yfrne.2014.03.007

⇑

Corresponding author. Address: Instituto Cajal, CSIC, Avenida Doctor Arce 37,

E-28002 Madrid, Spain. Fax: +34 915854754.

E-mail address: lmgs@cajal.csic.es (L.M. Garcia-Segura).

Frontiers in Neuroendocrinology 35 (2014) 459–472

Contents lists available at ScienceDirect

Frontiers in Neuroendocrinology

journal homepage: www.elsevier.com/locate/yfrne

et al., 2008; Brunton and Russell, 2008, 2010), will not be reviewed

in the present paper.

In this review we will speciﬁcally focus on the hormonal cas-

cade in the maternal and the newborn brain, at parturition, the

early postpartum period and lactation, which primes the mother

and the newborn for attachment initiation and consolidation

(Fig. 1). Attachment theory, proposed by Bowlby, has become the

dominant model of human emotional and social development.

According to Bowlby, attachment between the infant and his or

her mother is an innate biological response that increases the

probability of survival (Bowlby, 1978). Our hypothesis is that in

humans, like in other mammalian species (Mogi et al., 2011),

peripartal neuroendocrine events play an essential role in the ini-

tiation of the bonding of the mother and the newborn immediately

after birth. A disruption in these neuroendocrine events, even

when intervention is necessary due to serious medical reasons, is

likely to have not only a short-term impact on mother–child

attachment but also long-term effects in the newborn, increasing

the risk of behavioral alterations or mental health problems that

may have not yet been causally related to a peripartal origin. Thus,

we will also review in the present paper several potential etiopath-

ogenic neurohormonal scenarios during labor and the early

postpartum period that are associated with neuroendocrine modi-

ﬁcations, such as elective Cesarean section, intrapartum hormonal

manipulations, preterm delivery, mother–infant postpartum sepa-

ration and bottle-feeding instead of breastfeeding (Fig. 2).

2. Neuroendocrine events at parturition that affect

mother–child attachment

2.1. Neuroendocrine events in the mother at parturition

2.1.1. Oxytocin

Studies in rodents and sheep indicate that the stimulation of the

vagina and cervix at birth plays an important role in the induction

of maternal behavior (Keverne et al., 1983; Yeo and Keverne, 1986;

Kendrick and Keverne, 1991). Vaginal and cervix stimulation also

triggers in sheep the formation of olfactory recognition memory

that is essential for the selective recognition of lambs and for the

formation of maternal bonding (Keverne et al., 1983; Kendrick

et al., 1991b). These effects on maternal behavior and olfactory rec-

ognition may be mediated by the increased levels of oxytocin in

the brain caused by the stimulation of the vagina and cervix. In-

deed, one of the most important neuroendocrine events in the

mother at parturition in relation with mother–child attachment

is the activation of the oxytocinergic system. In rodents, gonadal

steroids prime the oxytocin system to become activated in prepa-

ration of birth and maternal behavior (Crowley et al., 1995; Amico

et al., 1997; Windle et al., 2006; Donner et al., 2007). However,

oxytocinergic neurons remain at rest during pregnancy, avoiding

premature birth (Brunton and Russell, 2010). Several mechanisms

and hormonal systems contribute to maintain oxytocinergic neu-

rons at rest until parturition (Brunton et al., 2014). These include

actions of central opioids, which contribute to restrain premature

oxytocin release by acting on

-receptors on magnocellular oxyto-

cinergic neurons or on presynaptic inputs to these neurons (Dondi

et al., 1991; Douglas et al., 1993, 1995; Wigger et al., 1999). In

addition, the progesterone metabolite allopregnanolone, prevents

the release of oxytocin in late gestation through potentiation of

the inhibitory effect of GABA

receptors on magnocellular oxyto-

cinergic neurons (Brunton and Russell, 2010; Brunton et al.,

2014) and by inducing opioid inhibition over these neurons

(Brunton et al., 2012, 2014).

While the activation of the oxytocinergic system is inhibited

during pregnancy by the above mentioned mechanisms, its activa-

tion is necessary for parturition and for the onset of lactation and

maternal behavior. Consistently with the essential role of oxytocin

release by magnocellular neurons for parturition and lactation,

functional and anatomical plastic changes in oxytocin neurons

and associated glial cells are manifested around parturition and

the onset of lactation in rodents (Leng et al., 1999; Theodosis and

Poulain, 2001; Tasker et al., 2002; Koksma et al., 2005; Theodosis

et al., 2006). These neuroplastic events include changes in oxytocin

immunoreactivity (Jirikowski et al., 1989), in neuronal ﬁring

(Lincoln and Wakerley, 1974; Leng et al., 1999), in the number of

glutamatergic and GABAergic synaptic inputs (Theodosis and

Poulain, 2001), in the release of glutamate and GABA (Stern et al.,

Parturition

Catecholamines

Vasopressin

Olfactory

learning

Oxytocin

Prolactin

Endorphins

Facilitation of

mother-infant attachment

Vasopressin

Prolactin

Oxytocin

Noradrenaline

Odor information

Maternal care

Cortisol

Neurogenesis

Spatial learning

-Emotions

-Stress reactivity

-Metabolic adaptation

-Social and cognitive

development

Oxytocin

Early Postpartum

Attachment

Fig. 1. Hormonal actions during parturition and early postpartum involved in the

regulation of maternal care and the bonding between the mother and her newborn.

(A) Vaginal delivery results in increased brain oxytocin release which will facilitate

mother–infant bonding. In addition, oxytocin during labor changes the effect of

GABA in the fetal brain from being excitatory to be inhibitory, allowing a protective

effect of GABA from delivery hypoxia. In the baby, the passage of the head through

the birth canal is accompanied by a massive release of catecholamines and

vasopressin that probably facilitate newborn physiological adaptation after deliv-

ery. Furthermore, maternal uterine contractions during labor facilitate neonatal

olfactory learning in the newborn. (B) In the early postpartum period, noradren-

aline, oxytocin, vasopressin and prolactin promote olfactory learning in the mother

and maternal care. In rodents corticosterone affects neural plasticity in different

brain regions, decreases hippocampal neurogenesis and impairs spatial learning. In

humans, higher cortisol levels in the mother are associated with higher preference

for her newborn body odor. Skin-to-skin contact of the mother with her newborn

and the initiation of breastfeeding promote increased levels of oxytocin in the

mother and the baby. Oxytocin contributes to mother–infant affect synchrony,

promoting the attachment of the mother and the newborn. This attachment is

essential for the regulation of emotions, stress reactivity, metabolic adaptation and

social and cognitive development of the baby.

460 I. Olza-Fernández et al. / Frontiers in Neuroendocrinology 35 (2014) 459–472

2000; Tasker et al., 2002) and in the expression, function and

clustering of postsynaptic receptors (Brussaard et al., 1997, 1999;

Koksma et al., 2005). Synaptic changes in oxytocin neurons are

associated with the remodeling of astroglia processes. Glial pro-

cesses, which normally separate the oxytocin-containing magno-

cellular neurons, are retracted during pregnancy, birth, and

lactation, allowing electrical coupling and then the pulsatile re-

lease of oxytocin (Theodosis and Poulain, 2001; Carter, 2014).

In women, the best known effect of peripheral oxytocin during

childbirth is to increase uterine contractions with a positive feed-

back, which will culminate with the ejection reﬂex, a physiological

process that makes childbirth successful mechanically and explain

the rapid deliveries (Odent, 2009). The importance of spontaneous

birth reﬂex explains the detrimental effects of sustained Valsalva

bearing down efforts and supine positioning (Roberts and Hanson,

2007). It also explains why directed pushing during childbirth is

not associated with optimal results (Brancato et al., 2008; Hanson,

2009).

In addition, vaginal delivery results in increased levels of oxyto-

cin not only in the periphery but also in the brain, as indicated by

animal studies showing increased levels of the hormone at partu-

rition in the cerebrospinal ﬂuid and the paraventricular nucleus

of sheep (Kendrick et al., 1991a; Da Costa et al., 1996) and in the

brain of rats (Neumann et al., 1991, 1993a,b; Landgraf et al.,

1992). In addition, oxytocin receptor expression in rats is also in-

creased at parturition in different brain regions, such as the bed

nucleus of the stria terminalis and medial preoptic area (Caughey

et al., 2011). In humans there is also a signiﬁcant increase in oxy-

tocin levels in the cerebrospinal ﬂuid during normal labor (Takeda

et al., 1985). Interestingly, changes in the central and peripheral

levels of oxytocin during parturition in women do not show the

same pattern. Thus, while plasma levels of oxytocin increase before

labor, oxytocin levels in the cerebrospinal ﬂuid are higher after la-

bor than before labor. This suggests that plasma and brain levels of

oxytocin are regulated by different mechanisms and probably have

different functions (Takeda et al., 1985).

The central increase in oxytocin levels during delivery in

women may affect maternal behavior, since it is well known that

central actions of oxytocin are necessary for the expression of

an adequate maternal behavior, at least in sheep and rodents

(Kendrick et al., 1997;Da Costa et al., 1996; Bosch and Neumann,

2012). In particular, the central increase in oxytocin levels may

contribute to the generation of mother–infant bonding, which

may be associated with an increase activation of oxytocin and

dopamine pathways in the brain (Nissen et al., 1998; Strathearn,

2011). High levels of endogenous oxytocin in humans are corre-

lated with feelings of well-being, conﬁdence, love, social memory

and even mystical experiences (Baumgartner et al., 2008;

Heinrichs et al., 2009; Keri and Kiss, 2010; Ishak et al., 2011).

Feelings of love, transpersonal and transcendental experiences

during labor are often narrated by mothers from different cultures

(Callister et al., 1999; Callister, 2004). These psychological changes

may facilitate the mother–infant bonding process.

2.1.2. Cortisol

Another hormone that changes during parturition in women

and that may affect the interaction of the mother with her baby

is cortisol. In women, the levels of cortisol are increased during la-

bor (Willcox et al., 1985; Campbell et al., 1987; Ohana et al., 1996).

This increase in cortisol levels may also contribute to the develop-

ment of mother–child attachment, since circulating or salivary cor-

tisol levels in human mothers have been positively correlated with

several aspects of maternal behavior (Fleming et al., 1987, 1997;

Stallings et al., 2001; Krpan et al., 2005), including the recognition

and attraction for baby odors (Fleming et al., 1997). Corticosterone

also increases maternal behavior in postpartum rats (Graham et al.,

2006) (see Section 3.1).

Parturition Early Postpartum

Cesarean section

Neurohormonal manipulations

Anesthetic drugs (opioid agonists)

Mother-infant

separation

Synthetic oxytocin

Oxytocin receptor antagonists

Preterm delivery

Bottle-feeding

Peripartal neurohormonal disruptions

Maternal Psychopathology:

PPD, PTSD.

Maternal Care Hippocampal development

Developmental Psychopathology:

Attachment , autism, ADHD, anxiety,

feeding, learning disabilities.

Attachment disruption

Fig. 2. Altered neurohormonal scenarios that may affect mother–infant attachment, according to the chronological time when hormonal alterations happen during

childbirth. Modiﬁcations in the neuroendocrine regulation at perinatal period are likely to increase susceptibility to problems in the newborn latter in life. Several

etiopatothogenic scenarios during labor and the postpartum period can be envisaged. These include interventions during parturition, such as Cesarean section, administration

of synthetic oxytocin, oxytocin receptor antagonists or opioids, preterm delivery, mother–infant separation after delivery or the substitution of breastfeeding by bottle-

feeding. All these conditions and circumstances result in modiﬁcations in the physiological levels of some key hormones, such as oxytocin, which are involved in the process

of mother–infant attachment. These peripartal neurohormonal disruptions may contribute to alterations in maternal care and be a risk factor for the development of affective

disorders in the mother, such as postpartum depression (PPD) or posttraumatic stress disorder (PTSD). Hormonal alterations and the disruption of attachment may also affect

the development of some regions in the brain in the newborn, such as the hippocampus and may represent a risk factor for the development of autism, attention deﬁcit

hyperactive disorder (ADHD), anxiety, feeding disorders, learning disabilities or other mental disorders.

I. Olza-Fernández et al. / Frontiers in Neuroendocrinology 35 (2014) 459–472 461

2.2. Neuroendocrine events in the fetus at parturition

An investigation of the mechanism of labor using real time MRI

conﬁrmed that human fetuses must negotiate a curve to be born. An

MRI video from that study shows clearly the strong physical com-

pression that the fetal brain undergoes during labor (Bamberg

et al., 2012). This intrapartum mechanical compression of the fetal

brain probably leads to a massive neurohormonal release and to

electrophysiological changes that have not yet been thoroughly

studied. In rats, a dramatic surge of neurotransmitters, neuroster-

oids, neuropeptides, and neuromodulators occurs during the birth

process and shortly thereafter, facilitating physiological processes

such as respiration (Ronca and Alberts, 1995) and suckling (Abel

et al., 1998). In humans, the passage of the baby head through the

birth canal is accompanied by a substantial activation of the sympa-

thoadrenal axis and the enhanced release of noradrenaline, cortisol

and vasopressin (Gennser et al., 1977; Puolakka et al., 1983; Costa

et al., 1988; Wellmann et al., 2010). This situation has been called

by some authors ‘‘the stress of labor’’, which is both beneﬁcial

and necessary for newborns (Lagercrantz and Slotkin, 1986). It

has been hypothesized that this eustressor acts to prime the fetal

genome to trigger optimal responses to extra uterine life (Dahlen

et al., 2013). The massive sympathoadrenal activation stimulates

lung ﬂuid reabsorption and facilitates newborn physiological

adaptation after delivery. It promotes lung maturity, increases

blood ﬂow, regulates circulating cytokine levels, mobilizes fuel

and activates the central nervous system (Chen et al., 1998;

Malamitsi-Puchner et al., 2005; Miller et al., 2005; Yektaei-Karin

et al., 2007). The alterations produced by vaginal birth are resolved

after birth by vagal stimulation produced by skin to skin contact and

early suckling (Bystrova et al., 2003; Ferber and Makhoul, 2004).

The increase in noradrenaline levels in the newborn at parturi-

tion (Puolakka et al., 1983; Costa et al., 1988) may facilitate

mother–child attachment, since noradrenaline levels in the new-

born are positively correlated with olfactory learning shortly after

birth (Varendi et al., 2002). During a natural childbirth the odor of

the mother is supposed to be the ﬁrst biologically relevant odor

that the newborn confronts. Therefore, the increase in noradrena-

line levels caused by vaginal delivery may contribute to the identi-

ﬁcation of maternal odor and to the consequent establishment of

the attachment of the newborns with their mothers. This is sug-

gested by the ﬁndings of Varendi et al. (2002), who exposed babies

born by Cesarean section to an odor for 30 min shortly after birth.

Babies from births with uterine labor contractions before Cesarean

delivery showed increased preference for the exposed odor when

exposed to a new odor, compared to babies from births without

uterine contractions. These ﬁndings suggest that labor-induced

noradrenaline release facilitates olfactory learning in the newborns

shortly after birth and therefore may facilitate mother–child

attachment.

Vaginal birth is also associated with an extremely steep rise of

circulating vasopressin in the newborn (Schubert et al., 1981),

higher than that observed in critically ill adult patients with shock

or brain injury (Wellmann et al., 2010). The consequences of this

massive increase in vasopressin in human newborns have not been

studied, although it has been proposed that the vasopressin rise

may be involved in the analgesic effects caused by vaginal delivery

in human newborns (Wellmann and Buhrer, 2012).

3. Immediate postpartum: Sensitive period

3.1. Mother–child synchrony: Importance of skin-to-skin contact

Humans are born biologically prepared to establish coordinated

interactions from the ﬁrst hours of life. Right after delivery occurs

the so-called sensitive period, a quiet alertness state that lasts for

about two hours (Bystrova et al., 2009). The neonatal sensitive per-

iod includes the spontaneous onset of breastfeeding in the ﬁrst two

hours of life. The ﬁrst hours after birth are also a critical period for

the development of attachment behavior (Mehler et al., 2011).

In humans, randomized controlled studies suggest that the

body of the mother is the natural habitat for the naked infant

(Winberg, 2005). Skin-to-skin contact immediately after delivery

helps the baby to conserve energy, adjust acid–base balance and

breathing and has a calming effect (Uvnäs-Moberg, 1996; Winberg,

2005). It also increases maternal attention to her baby (Winberg,

2005) and reduces cortisol levels in the mother (Handlin et al.,

2009). Skin-to-skin contact with both mothers and fathers reduce

infants’ crying (Christensson et al., 1995; Erlandsson et al., 2007)

and promotes vocal communication between parents and

newborns (Velandia et al., 2010). It is likely that oxytocin released

during the skin-to-skin contact also increases the parental respon-

siveness to infant cues (Velandia et al., 2010). As a consequence of

early skin-to-skin contact, infant regulation of emotions, stress

reactivity, metabolic adaptation, social and cognitive development

and future interaction between mother and infant are promoted

(Bystrova et al., 2009; Velandia et al., 2010). It is the beginning of

the continuous development of mother–child synchrony (Winberg,

2005), facilitated mostly by lactation and oxytocin. Indeed, salivary

oxytocin levels between mothers and infants are signiﬁcantly cor-

related, being high oxytocin levels associated with greater degree

of mother–infant affect synchrony (Feldman et al., 2010a).

Increased oxytocin levels in the newborn caused by skin-to-skin

contact probably play an important role in the initiation of breast-

feeding. The smell of the breast helps the baby to initiate breast-

feeding. Natural maternal breast odors reduce crying (Doucet

et al., 2007) and elicit approach behavior in newborns whereas

unpleasant odors induce avoidant behavior (Varendi and Porter,

2001). Newborns guided by smell spontaneously seek the nipple

and usually initiate breastfeeding in the ﬁrst hour of life (Porter

and Winberg, 1999; Varendi et al., 2002) if they are placed in

skin-to-skin contact with their mothers (Widstrom et al., 1987).

In rats, maternal skin-to-skin contact increases central oxytocin

in the pups, facilitating the induction of preference for maternal

odor and the establishment of social afﬁliation (Kojima and

Alberts, 2011; Kojima et al., 2012). Furthermore, higher levels of

noradrenaline immediately after birth may support better odor

learning in rat pups (Miller and Spear, 2008). Thus, odor exposure

after birth likely occurs under a different internal neurochemical

milieu for the pup odor exposure later in life (Ronca et al., 2006).

Indeed, the neonatal surge of noradrenaline may induce an olfac-

tory imprinting-like occurrence in mammals without the need

for an explicit reinforcer to form a lasting odor preference (Sullivan

et al., 1991). This is also probably the case in humans, in which nor-

adrenaline released in the newborn during labor facilitates learn-

ing and recognition of the mother odor (Varendi et al., 2002).

In most mammals, pup odors elicit maternal behavior in the

mother (Kinsley and Amory-Meyer, 2011; Levy et al., 2004).

Human mothers also show changes in olfaction and recognize

the odors of their babies as pleasant. Interestingly, human mothers

have increased oxytocin levels during the ﬁrst hour after delivery

(Nissen et al., 1995), corresponding to the sensitive period. Oxyto-

cin plays a key role in the processing of olfactory information by

mothers and the infusion of oxytocin in the olfactory bulb

produces a rapid onset of maternal behavior in rats. This, in turn,

modulates the release of noradrenaline, which is involved in olfac-

tory learning not only in the newborn but also in the mother (Levy

et al., 2004; Kinsley and Amory-Meyer, 2011). In rats corticoste-

rone enhances maternal behavior and maternal memory (Graham

et al., 2006). In women, cortisol plays an important role in the

attraction to the body odor of their infants in human mothers.

462 I. Olza-Fernández et al. / Frontiers in Neuroendocrinology 35 (2014) 459–472

Indeed, postpartum cortisol levels in women are positively corre-

lated with attraction for the odor of their own babies and with

the ability to recognize their own baby’s odor (Fleming et al.,

1997).

Vasopressin is also involved in maternal behavior, regulating

maternal care and maternal aggression (Bosch and Neumann,

2008). In rats, the vasopressin system in the mother is activated

around parturition and in lactation, with increased expression of

vasopressin in the paraventricular nucleus of the hypothalamus

and increased release in different structures, such as the bed nu-

cleus of the stria terminalis and the medial preoptic area (Landgraf

et al., 1991; Bosch and Neumann, 2008; Bosch, 2011). This in-

creased release of vasopressin is necessary for the maintenance

of maternal care (Bosch, 2011). In addition, vasopressin release in

the central amygdala correlates with the amount of maternal

aggression, which may be in part mediated by the regulation of

maternal anxiety (Bosch, 2011). In humans, mothers who are car-

riers of RS3 long alleles in the promoter region of the arginine vaso-

pressin receptor 1A gene show decreased maternal sensitivity to

child’s needs and signals and less supportive and guiding behavior

(Avinun et al., 2012; Bisceglia et al., 2012).

Animal studies suggest that the hormonal regulation of mater-

nal behavior may be in part mediated by hormonal regulation of

brain plasticity at parturition and the early postpartum period. In

addition to the plastic changes in the mother hypothalamus asso-

ciated with oxytocinergic and vasopressinergic neurons, there are

other neuroplastic changes during the postpartum period in rats

that may be driven by the decrease in gonadal hormones and the

increase in corticosterone levels (Darnaudery et al., 2007; Leuner

et al., 2007; Green and Galea, 2008; Pawluski et al., 2009, 2011,

2012; Workman et al., 2012). Decreased neurogenesis in the den-

tate gyrus of the dam hippocampus has been observed during

the early postpartum period (Darnaudery et al., 2007; Leuner

et al., 2007; Pawluski and Galea, 2007) in association with an

impairment of spatial learning (Darnaudery et al., 2007). Adrenal-

ectomy and low dose corticosterone administration prevents this

decrease in dentate gyrus neurogenesis in postpartum dams

(Leuner et al., 2007). In contrast, estradiol withdrawal decreases

dentate gyrus neurogenesis after a hormone-simulated pregnancy

(Green and Galea, 2008). Neuroplastic changes during the postpar-

tum period have been also reported in other brain regions (Kinsley

and Lambert, 2008; Kinsley and Amory-Meyer, 2011). For instance,

the cell volume of medial preoptic area neurons is increased after

pregnancy in rats (Keyser-Marcus et al., 2001). In addition, not only

neurons but also glial cells are affected by motherhood. Thus, the

number of oligodendrocytes in the corpus callosum is higher in lac-

tating female rats than in virgin rats (Maheu et al., 2009). Mother-

hood also affects glutamate metabolism in astrocytes in the

cingulate cortex of rats (Salmaso et al., 2011).

Neuroplastic changes during the postpartum period in the

mother brain are inﬂuenced by the interaction with their pups

(Rasia-Filho et al., 2004; Kinsley et al., 2006; Pawluski and Galea,

2006; Akbari et al., 2007; Leuner et al., 2007; Kinsley and Lambert,

2008; Furuta and Bridges, 2009; Brus et al., 2010). Thus, maternal

behavior increases neurogenesis in the subventricular zone (Furuta

and Bridges, 2009) and removal of nursing pups prevents the de-

crease in neurogenesis in the dam dentate gyrus (Leuner et al.,

2007). Maternal experience in rats also affects the complexity of

the dendritic arbor and/or density of dendritic spines in CA3 and

CA1 pyramidal neurons in the hippocampus (Kinsley et al., 2006;

Pawluski and Galea, 2006) and in the neurons of the caudate nu-

cleus, the nucleus accumbens shell, the medial preoptic area and

the medial amygdala (Rasia-Filho et al., 2004). Therefore, the inter-

action of the mother with her pups seems to be necessary for the

generation of speciﬁc neuroplastic changes in the mother brain

during the postpartum period. It is unknown if similar neuroplastic

changes occur in the brain of human mothers, although the limited

fMRI studies available suggest the existence of functional modiﬁca-

tions in the hypothalamus, amygdala and cerebral cortex in the

brain of women during the postpartum period (Kim et al., 2010;

Lord et al., 2012; Rupp et al., 2014). In addition, these functional

modiﬁcations in the brain of postpartum women are inﬂuenced

by the interaction with their infants (Kim et al., 2010; Musser

et al., 2012).

3.2. Lactation

In most mammals, the stimulation of the teats by her pups

elicits a modiﬁcation in the activity of oxytocin magnocellular neu-

rons, resulting in a pulsatile release of oxytocin in the neurohy-

pophysis that leads to periodic milk ejections (Poulain and

Wakerley, 1982). In humans, nipple stimulation also increases oxy-

tocin levels in breastfeeding mothers (Dawood et al., 1981; Amico

and Finley, 1986; Uvnäs-Moberg et al., 1990; Uvnäs-Moberg, 1996;

Matthiesen et al., 2001; White-Traut et al., 2009). In parallel to the

release of oxytocin in the neurohypophysis, there is also an in-

creased intracerebral release of oxytocin during lactation, together

with an increased expression of oxytocin receptors, in speciﬁc

brain regions (Kendrick et al., 1988; Moos et al., 1989; Neumann

et al., 1993a,b; Bealer and Crowley, 2001; Veenema and Neumann,

2008). This increase in intracerebral oxytocinergic signaling may

mediate the association between breastfeeding and mother–child

attachment, since central oxytocin promotes maternal care in ro-

dents (Bosch and Neumann, 2012). Although the relation of periph-

eral and central oxytocin is not well understood (Neumann et al.,

2013), in women there is a positive correlation between salivary

oxytocin levels and affectionate maternal behavior during

mother–child interactions (Feldman et al., 2010b). Furthermore,

the interaction with their infants causes higher circulating oxyto-

cin levels and increased activation of mesocorticolimbic reward re-

gions in women with secure attachment than in women with

insecure/dismissing attachment (Strathearn et al., 2009a; Strath-

earn, 2011). Higher circulating oxytocin in fathers is also correlated

with more affectionate and stimulatory behaviors when interact-

ing with their children (Feldman et al., 2010a,b; Gordon et al.,

2010).

Breastfeeding has additional affective consequences for moth-

ers that may also facilitate their interactions with their infants.

Lactation in humans and other mammals reduces physiological

reactivity to various stressors (Stern et al., 1973; Neumann et al.,

1998; Johnstone et al., 2000; Walker et al., 2001; Heinrichs et al.,

2001, 2002; Slattery and Neumann, 2008; Bosch and Neumann,

2012). In rats, lactation reduces corticotropin-releasing factor

mRNA expression in the parvocellular paraventricular hypotha-

lamic neurons (Johnstone et al., 2000; Walker et al., 2001; Klampﬂ

et al., 2013) and reduced expression of corticotropin-releasing fac-

tor receptors in the pituitary corticotrophs (Neumann et al., 1998).

In women, breastfeeding decreases adrenocorticotropic hormone,

total plasma cortisol and salivary free cortisol and the HPA axis re-

sponse to physical and psychosocial stress (Altemus et al., 1995;

Heinrichs et al., 2001, 2002). Nursing mothers often describe a

state of decreased anxiety (Carter and Altemus, 1997) and interact

more positively with their babies, touching and directing more

smiles towards them, than those using artiﬁcial feeding (Duna

and Richards, 1977). Similarly, there is a reduction of the auto-

nomic responses, such as modiﬁcations in heart rate and skin con-

ductance, to the cries of babies in lactating versus non-lactating

mothers (Wiesenfeld et al., 1985). This reduction in stress response

associated with breastfeeding, could be seen as an adaptive re-

sponse that protects mothers from an exaggerated response to

stressful stimuli ensuring successful breastfeeding (Carter and

Altemus, 1997).

I. Olza-Fernández et al. / Frontiers in Neuroendocrinology 35 (2014) 459–472 463

It is also important to consider that breastfeeding may have

long-term consequences for the infants. Some studies suggest that

early exclusive breastfeeding may be associated with better cogni-

tive skills latter in life (Isaacs et al., 2010; Hallowell and Spatz,

2012; Deoni et al., 2013; Kafouri et al., 2013). In a study using

MRI, infant breastfeeding was associated with improved develop-

mental growth in late maturing white matter association regions

involved in higher-order cognition, such as executive functioning,

planning, social-emotional functioning and language, domains in

which breastfed infants were also found to have improved perfor-

mance (Deoni et al., 2013; Julvez et al., 2014). In the same study

breastfeeding duration beyond 15 months was associated with im-

proved white matter structure and cognitive performance (Deoni

et al., 2013). In this regard it is important to consider that the dura-

tion of breastfeeding in humans is estimated to range physiologi-

cally from two and a half to seven years of life (Detwyler, 1995)

and that the World Health Organization (WHO) recommends

breastfeeding continuation for up to two years of age or beyond

(WHO, 2003). Breastfeeding statistics indicate that most women

breast their baby soon after birth (95% in Norway, 92% in Australia,

89% in Canada and 76.5% in the United States). In the United States,

of infants born in 2010, 49% were breastfeeding at 6 months and

27% at 12 months (Gionet, 2013; National Center for Chronic

Disease Prevention and Health Promotion, 2013).

4. Potential etiopathogenic neurohormonal scenarios during

labor and the early postpartum period

4.1. The intrapartum period

4.1.1. Omission of all the stages of labor: elective Cesarean section

4.1.1.1. Consequences for the newborn. Several circumstances may

potentially disrupt the neuroendocrine mechanisms of mother–

child attachment during the peripartal period in humans (Fig. 2).

One of these is the elimination of labor in planed Cesarean sections.

The use of Cesarean section for delivery is continuously rising

worldwide, often for non medical reasons. Cesarean rates were of

32.8% in the US in 2011 (Hamilton et al., 2013), 48% in China in

2010 (Lumbiganon et al., 2010; Souza et al., 2010) and 45.9% in

Brazil and 41.9% in Iran in 2008 (Gibbons et al., 2012). In some cul-

tural groups Cesarean can be perceived as a preferred way to deli-

ver (Nuttall, 2000) or even as a safer option, without a medical

reason for it. Although there is a growing concern about the effects

of Cesarean section on brain maturation of infants (Kapellou,

2011), the potential long term consequences of elective Cesarean

sections in both the maternal and the newborn brain have received

little attention. The studies that assess the effects of Cesareans typ-

ically consider only short term health outcomes and physical mor-

bidity (Chiossi et al., 2013).

In planned Cesarean sections the neurohormonal transition is

quite sharp, very different to the neuroendocrine cascade that hap-

pens in a physiological vaginal delivery. As mentioned before, with

vaginal delivery there is a dramatic surge of circulating vasopressin

(approximately 100-fold) in the newborn that does not occur after

programmed Cesarean section (Wellmann et al., 2010; Wellmann

and Buhrer, 2012). The consequences that for the neonate born

by Cesarean section may have the abolition of this increase in vaso-

pressin levels are unknown (see Section 2.2). In addition, catechol-

amines and cortisol levels are relatively low in babies born by

Cesarean section compared to babies born by vaginal delivery

(Gitau et al., 2001; Mears et al., 2004; Miller et al., 2005). These dif-

ferences in catecholamines and cortisol levels may be related with

the reported differences in respiratory distress, a complication that

is more frequent after elective Cesarean sections than after normal

vaginal deliveries (Wankaew et al., 2013). Cesarean section

delivery may also alter gut colonization and immunological devel-

opment (Malamitsi-Puchner et al., 2005; Vogl et al., 2006) and may

cause epigenetic changes in the neonate (Dahlen et al., 2013). In-

deed, an increased DNA-methylation in leucocytes has been de-

tected in infants delivered by Cesarean section compared to

infants vaginally born (Schlinzig et al., 2009), although another

study did not detect an effect of the type of delivery on global

methylation of DNA from blood isolated from umbilical venous

cord at birth (Virani et al., 2012).

A crucial event that occurs in the newborn brain at parturition

is the shift of GABA neurotransmission from being excitatory be-

fore birth to be inhibitory after birth (Cherubini et al., 1991). This

is because during embryonic development the intracellular chlo-

ride concentration [Cl



]

in neurons is higher than in postnatal

neurons. Thus, when GABA opens the GABA

channel, there is a

chloride efﬂux and depolarization in prenatal neurons and a chlo-

ride inﬂux and hyperpolarization in postnatal neurons (Cherubini

et al., 1991). Oxytocin plays an essential role in the reduction of

[Cl



]

in neurons during parturition (Tyzio et al., 2006; Khazipov

et al., 2008). This action of oxytocin protects the newborn brain

from delivery hypoxia and also exerts analgesic actions in the new-

born (Tyzio et al., 2006; Mazzuca et al., 2011). In addition, the ac-

tion of oxytocin on GABAergic neurons during delivery may also

decrease the risk of long-term deleterious consequences on an en-

hanced neuronal activity and may contribute to prevent the devel-

opment of autism (Tyzio et al., 2014). The origin of oxytocin in the

offspring brain during parturition is under debate. In rodents, the

synthesis of brain oxytocin increase progressively during fetal

development (Altstein and Gainer, 1988). However, the amidate

mature oxytocin is not produced after term (Altstein and Gainer,

1988; Lipari et al., 2001). Thus, it has been proposed that maternal

oxytocin, which is known to cross the placenta (Malek et al., 1996),

is the main source of oxytocin for the fetal brain in rodents (Tyzio

et al., 2006). However, there is evidence of production of oxytocin

by the human fetal brain (Tyzio et al., 2007). With independence of

the origin of oxytocin, an important question that remains to be

determined is whether the reduction of [Cl



]

in neurons during

parturition, and the consequent shift of GABA neurotransmission

from excitatory to inhibitory, is altered in absence of labor.

Experiments in mice suggest that the omission of the stages of

labor in elective Cesarean sections may affect brain development of

the offspring. Vaginal delivery, but not Cesarean section, induces

the expression of mitochondrial uncoupling protein 2 (UCP2) in

the newborn hippocampus (Simon-Areces et al., 2012). UCP2 is in-

volved in synaptogenesis, fuel utilization, and mitochondrial bio-

energetics and proliferation. Therefore, the induction of UCP2 by

vaginal delivery may have important consequences for the devel-

oping brain. Indeed, the relevance of the induction of UCP2 in the

newborn hippocampus is suggested by the fact that the pharmaco-

logical inhibition or the genetic ablation of UCP2 lead to dimin-

ished neuronal number, neuronal size, dendritic growth and

synaptogenesis in vitro and impaired spatial memory in adulthood

(Simon-Areces et al., 2012).

Human studies also suggest that the omission of labor may af-

fect brain development in the newborn. The limited available data

indicate that children born from Cesarean delivery at maternal

request, i.e. from Cesarean sections performed when labor is not

initiated, may face more emotional disturbances and sleep prob-

lems at preschool age. In one study, preschool children born by

Cesarean deliveries at maternal request presented signiﬁcantly

more anxiety/depression, withdrawal and sleep problems. In addi-

tion, they had statistically signiﬁcantly higher values on internaliz-

ing problems (Kelmanson, 2013). A study of breech-presenting

children did not detect an inﬂuence of the mode of delivery on

the incidence of organic brain disorders in later childhood (Preis

et al., 2012). However, some studies suggest that Cesarean surgery

464 I. Olza-Fernández et al. / Frontiers in Neuroendocrinology 35 (2014) 459–472

may increase the risk of autism (Glasson et al., 2004). Autism cases

were more likely to have experienced fetal distress, been delivered

by an elective or emergency Cesarean section, and had an Apgar

score of less than 6 at 1 min (Glasson et al., 2004). Preterm birth

and planned Cesarean section have been also identiﬁed as risk fac-

tors for autism and other Pervasive Developmental Disorders in an-

other study (Guinchat et al., 2012). In a meta-analysis, Cesarean

delivery was associated with a 26% increased risk of autism that

did not reach statistical signiﬁcance (Gardener et al., 2011). Birth

by Cesarean section is also a risk factor for attention deﬁcit hyper-

active disorder (ADHD) in children (Amiri et al., 2012). Unfortu-

nately most studies that review risk for autism or ADHD in

children do not differentiate between elective and urgent

Cesareans.

Concerning the potential consequences that elective Cesarean

section may have for brain development in the newborn it is also

relevant to mention that Cesarean sections may be programmed

earlier than in the due date. This is because the length of human

gestation shows a considerable variation (Jukic et al., 2013), which

can reach even one month. This is a relevant issue, since there is

increasing evidence that birth at 39–41 weeks provides develop-

mental advantages compared to birth at 37–38 weeks. Indeed,

greater gestational age is associated with greater maturity of

movement, better regulation, less excitability and less educational

needs (MacKay et al., 2010; Fink et al., 2012).

A central issue for the main subject of the present paper is the

impact that the omission of labor may have on the process of

mother–child attachment. The lack of the labor-associated nor-

adrenaline peak in the babies born by elective Cesarean section

could hinder the olfactory orientation for the initiation of breast-

feeding. Indeed, as mentioned in Section 2.2, babies born by Cesar-

ean section performed during labor showed a better olfactory

learning during the ﬁrst hour after birth compared to babies born

by elective Cesarean section without labor (Varendi et al., 2002).

Thus, the omission of labor may potentially affect one of the ﬁrst

steps in the generation of mother–child attachment. More recent

studies have shown that, depending on the type of delivery, there

are differences in the behavioral responses of the newborns to

maternal separation. A pilot study by our group revealed that neo-

natal crying following brief maternal separation was reduced in

the neonates born by a planned Cesarean section compared to vag-

inally delivered neonates (Olza Fernandez et al., 2013). In addition,

when proximity to the mother was restored, most neonates born

by planned Cesarean section did not cry at all or cried less than

vaginally delivered neonates, which in addition continued crying

for longer time. These different responses could reﬂect modiﬁca-

tions in early infant attachment behavior (Olza Fernandez et al.,

2013). This different newborn behavior in response to maternal

separation should be understood within the attachment theory

paradigm: lack of response to maternal separation is an early

symptom of un-attachment, which could mean that the generation

of attachment is more difﬁcult for babies born after a planned

Cesarean. Also, the altered response to maternal separation could

indicate an alteration of the stress response, which could be related

to later difﬁculties with attention or spatial memory processes

similar to the ﬁndings in rats described by Simon-Areces et al.

(2012).

The potential negative effects of Cesarean section in children

may be in part due to the impact of Cesarean section on maternal

attitudes and behaviors in relation to their children. Therefore, in

the next section we will review the potential consequences of

Cesarean section for the mother.

4.1.1.2. Consequences for the mother. Cesarean section is associated

with signiﬁcantly lower maternal levels of catecholamines, adreno-

corticotropic hormone, cortisol, prolactin, corticotropin-releasing

factor, beta-endorphin and oxytocin in plasma (Takagi et al.,

1985; Takeda et al., 1985; Nissen et al., 1996; Vogl et al., 2006). It

might be hypothesized that, in mothers who give birth by planned

Cesarean section, the absence of the neuroendocrine changes asso-

ciated with physiological labor may produce difﬁculties in the

bonding process and in the recognition by the mother of her child

as her own. This may explain the feeling of estrangement and bond-

ing difﬁculties that some mothers have described after Cesarean

section (Beck, 2004).

The reduced levels of oxytocin in the cerebrospinal ﬂuid of

mothers in absence of labor (Takagi et al., 1985; Takeda et al.,

1985) may impair maternal adaptations normally induced during

labor and may inﬂuence her interactive ability to calm the infant

(Nissen et al., 1998). Although one study found that the mode of

delivery does not affect maternal interaction with the newborn

(Carlander et al., 2010), functional neuroimaging studies have

shown that mothers who give birth by Cesarean have a signiﬁ-

cantly less response in the brain to the cries of their babies than

those who had a vaginal birth (Swain et al., 2008). Lower levels

of brain oxytocin in the mother in absence of labor may also reduce

breastfeeding, which in turn may further affect the process of

mother–child attachment, since breastfeeding increases the intra-

cerebral release of oxytocin in the brain (see Section 3.2). Indeed,

it has been reported that risk of breastfeeding failure is higher after

Cesarean delivery, particularly if primary and scheduled before

39 weeks of gestation (Zanardo et al., 2012, 2013). Several studies

have also investigated the association between type of delivery and

risk of developing postpartum depression. It has been suggested

that Cesarean section may increase the risk of depression (Ryding

et al., 1998). A recent prospective longitudinal study, that recruited

1100 women, reported that those who underwent Cesarean sec-

tion, urgent or elective, had higher scores in the Edinburgh Postna-

tal Depression Scale (EPDS), although six months after birth these

differences were no longer detectable (Rauh et al., 2012). This pos-

sible effect of Cesarean section on maternal depression is also rel-

evant for mother–child attachment, since postpartum depression

causes alterations in the relation of the mother with her baby

(Kingston et al., 2012).

4.1.2. Intrapartum neurohormonal manipulations

4.1.2.1. Synthetic oxytocin. Intrapartum neurohormonal manipula-

tions happen when birth is induced or stimulated with synthetic

oxytocin (Pitocin) or when anesthetic drugs with a central effect

are administered to mothers during childbirth. Other subtle

manipulations happen when birth is disturbed by obstetric inter-

ventions such as amniotomy, lithotomy or unsupportive care but

this have rarely taken into account. Mothers may receive Pitocin

before delivery to induce labor or after delivery to prevent postpar-

tum hemorrhage. In several cases the use of Pitocin is needed for

the health and wellbeing of the mother and child. However, the

use of intrapartum exogenous oxytocin has increased considerably

in recent years (Clark et al., 2009). Possible long-term conse-

quences of the manipulation with synthetic oxytocin in humans

at the time of birth have not been extensively studied, although

some studies suggest that the administration of Pitocin is associ-

ated with an increased number of women abandoning breastfeed-

ing (Ounsted et al., 1978a,b; Wiklund et al., 2009).

The intrapartum administration of oxytocin results in altered

postpartum oxytocin levels in the mother. Thus, higher amount

of exogenous intrapartum oxytocin predicts higher plasma oxyto-

cin levels at 2 months postpartum (Prevost et al., 2014). However,

mothers who receive intrapartum Pitocin, present lower levels of

endogenous oxytocin and increased levels of prolactin two days

after delivery. These changes may be the consequence of a dose-

dependent alteration of the feedback mechanism of both hormones

by Pitocin (Jonas et al., 2009). Thus, it has been proposed that the

I. Olza-Fernández et al. / Frontiers in Neuroendocrinology 35 (2014) 459–472 465

systemic administration of Pitocin, to induce or enhance uterine

contractions, may alter the recycling of oxytocin receptors in the

brain, reducing their availability in the postsynaptic membrane

and therefore decreasing the response to new oxytocin stimuli

(Wahl, 2004). Such a mechanism in the uterus may explain the in-

creased risk of severe maternal bleeding observed when synthetic

oxytocin is administered at birth (Belghiti et al., 2011). Pitocin use

also increases the risk of operative delivery and emergency Cesar-

ean (Buchanan et al., 2012) which in turn may increase the risk of

maternal posttraumatic stress disorder (PTSD) following childbirth

(Beck et al., 2011). The high prevalence of complete or partial PTSD

after childbirth observed in different studies (Ryding et al., 1997;

Wijma et al., 1997; Creedy et al., 2000; Soderquist et al., 2002;

Ayers et al., 2008) raises the question of whether peripartal hor-

monal manipulation alters the maternal neurohormonal milieu at

a time primed for lasting memories.

In addition to the possible effects in the mother, it is also impor-

tant to determine whether intrapartum Pitocin may affect the

newborn. The increase in autism spectrum disorders in the recent

decades and the observation that perinatal factors play a role in

their etiology has led to the hypothesis that oxytocin administra-

tion at birth for labor induction could contribute to the develop-

ment of these diseases (Gardener et al., 2011). Indeed, induction/

augmentation of labor may result in an increased risk of autism,

being this probability increased in male children (Gregory et al.,

2013). Recent studies suggest that Pitocin may interfere with the

initiation of breastfeeding by the newborn (Olza Fernandez et al.,

2012). In a pilot study, we observed a negative association between

oxytocin dose and newborn suckling (Olza Fernandez et al., 2012).

Similar ﬁndings have been recently reported in the hour following

birth: fewer prefeeding cues were observed in infants exposed ver-

sus unexposed to Pitocin (Bell et al., 2013). The mechanisms in-

volved in these effects of Pitocin are unknown.

4.1.2.2. Oxytocin receptor antagonists. Oxytocin receptor antago-

nists are frequently used to prevent preterm labor. Atosiban is a

mixed oxytocin/vasopressin V1a receptor antagonist that provides

an effective and more safety therapy than other tocolytic drugs to

delay delivery, being more effective as gestation progresses and the

expression of oxytocin receptor increases (Haas et al., 2012). The

possible long-term consequences of the treatment with Atosiban

for the brain of the mother and the fetus have not been studied.

However, treatment of pregnant rats from days 15 to 20 of gesta-

tion with Atosiban caused impaired lactation, resulting in poor

neonatal survival in offspring (McAnulty and Burns, 2004). In addi-

tion, oxytocin receptor antagonist treatment in pregnant and lac-

tating rats was also shown to increase maternal anxiety levels

and the HPA axis responsiveness, measured as corticosterone lev-

els (Neumann et al., 2000). Furthermore, the intracerebroventricu-

lar administration of an oxytocin receptor antagonist to lactating

dams reduced suckling-evoked activity in different brain regions

related with olfaction, such as the insular cortex, the piriform cor-

tex, the anterior olfactory nucleus and the olfactory tubercle. Other

brain regions in which the oxytocin receptor antagonist reduced

suckling-evoked activity include the prefrontal cortex, the dentate

gyrus and the hippocampal CA1 and CA3 (Febo et al., 2005). There-

fore, this suggests that the antagonism of brain oxytocin receptors

may impair olfactory and cognitive responses elicited by suckling

in the mother brain, which in turn may alter the process of bonding

with the newborn.

Concerning the fetus, since oxytocin is protective for fetal neu-

rons, the antagonism of its receptors may increase the susceptibil-

ity for hypoxic-ischemic insults (Ceanga et al., 2010). Furthermore,

in agreement with the analgesic effect of oxytocin, Atosiban

administration increases pain in rat newborns (Mazzuca et al.,

2011). However, it is unclear whether Atosiban administrated to

the mother may directly affect the newborn. A minimal placental

transfer of Atosiban was detected in a study with eight women

undergoing Cesarean section at term (Valenzuela et al., 1995).

However, the antagonism of oxytocin receptors in the mother

may inﬂuence the fetus by indirect mechanisms. Therefore, future

studies are necessary to determine the possible long-term conse-

quences in the infant (Papatsonis et al., 2013).

4.1.2.3. Morphine. In view of the importance of the endogenous

opioid system in modulating oxytocin release, it is of interest to

consider the consequences of the use of exogenous opioids as anal-

gesics in human parturition. Morphine provides women in latent

labor with analgesia and rest and contractions may cease soon

after injection. Morphine is not only used for analgesia, but also

to differentiate true labor from false (Mackeen et al., 2014). The

clinical observation that morphine gives patients rest from con-

tractions and delays childbirth is likely to be due to inhibition of

oxytocin release. As the drug wears off, or as opioid receptors are

down regulated, oxytocin levels rebound signiﬁcantly and the pa-

tient enters in active labor or return to baseline uterine activity

without labor (Wilson et al., 2010).

A Cochrane systematic review (Anim-Somuah et al., 2011) re-

ported that the use of epidural analgesia in women was associated

with an increase risk of assisted vaginal birth (RR 1.42, 95% CI

1.28–1.57, 23 trials, 7935 women), longer second stage of labor

(MD 13.66 min, 95% CI 6.67–20.66, 13 trials, 4233 women), oxyto-

cin administration (RR 1.19, 95% CI 1.03–1.39, 13 trials, 5815

women) and an increased risk of Cesarean section for fetal distress

(RR 1.43, 95% CI 1.03–1.97, 11 trials, 4816 women). However,

epidural analgesia did not affect the neonatal status, assessed with

the Apgar score. However, further research is needed to evaluate

rare but potential severe adverse effects of epidural analgesia on

women in labor, long-term neonatal outcomes and the impact of

this analgesia on infant–mother attachment and infant

neurodevelopment.

Concerning breastfeeding, although many studies have raised

the question of whether labor epidural analgesia inclusive of opi-

oids has a negative impact on breastfeeding success, the answer re-

mains uncertain. Studies are both conﬂicting and fraught with

potentially confounding variables such as the mode of delivery,

prior breastfeeding success and parity (Wieczorek et al., 2010;

Szabo, 2013). In the largest study to date, Wilson et al. randomized

1054 patients to various epidural and non-epidural regimens and

did not detect signiﬁcant differences in breastfeeding success

(Wilson et al., 2010). Further research is needed to elucidate the

speciﬁc relationship between neuraxial opioids and breastfeeding

and whether these drugs may act directly on the neonatal brain

to attenuate exhibition of breastfeeding behaviors (Dondi et al.,

1991).

4.2. Preterm delivery

The main factor that interferes with the attachment process in

premature babies is their incomplete brain maturation. Thus, the

full response to olfactory stimuli, which allows the newborn to lo-

cate the nipple, does not take place until about the 29th gestational

week. Also, the response to auditory stimuli, such as the voice of

the mother, cannot be appreciated until near the 32nd gestational

week (Lagercrantz and Changeux, 2010). The bonding process of

the mother and the newborns is also impaired by the separation

of the preterm newborns from their mothers, as a result of their

need of intensive care (see Section 4.3). In consequence, the neuro-

endocrine changes that are associated with mother–child syn-

chrony are not elicited in premature babies. This may have

consequences not only for the preterm newborn but also for the

parents. Preterm birth and hospitalization of the preterm infant

466 I. Olza-Fernández et al. / Frontiers in Neuroendocrinology 35 (2014) 459–472

have been associated with a high incidence of parental PTSD that

may persist even eighteen months after birth and impair parent–

infant interaction (Pierrehumbert et al., 2003; Forcada-Guex

et al., 2006; Shaw et al., 2009). Thus it seems crucial to include

perinatal specialized psychological care in the entire context of

prematurity for these families (Hatters Friedman et al., 2013) and

to promote actions to restore contact of the newborn with the

mother or father, such as Kangaroo Mother care (KMC) method

and the Newborn Individualized Developmental Care and Assess-

ment Program (NIDCAP). The KMC implies continuous skin-to-skin

contact between the mother and the infant, exclusive breastfeed-

ing and early home discharge in the kangaroo position (Charpak

et al., 2005). It has been reported that KMC enhances bonding

and attachment, reduces maternal postpartum depression symp-

toms, enhances infant physiologic stability, reduces pain, increases

parental sensitivity to infant cues, contributes to the establishment

and longer duration of breastfeeding and has positive effects on in-

fant development and infant/parent interaction (Nyqvist et al.,

2010). The NIDCAP also mimics the intrauterine environment, min-

imizing environmental stress and promoting physiological individ-

ualized care (Als et al., 1996).

4.3. Mother–infant postpartum separation

Sometimes, as consequence of maternal or neonatal pathology,

or due to practices without scientiﬁc evidence, such as limiting

access to parents to neonatal units or avoiding the postpartum

mother–infant skin-to-skin contact, separation occurs between

the mother and the newborn immediately after childbirth.

Mother–infant postpartum interaction modiﬁes oxytocin levels in

both the mother and the newborn brain (Kendrick, 2000). There-

fore, the deprivation of the physical and tactile stimuli provided

by the mother may have potential long-term consequences for

the newborn. Although this question has not been adequately

studied in humans, it is known that the deprivation of contact with

the mother results in long-term affective and cognitive alterations

in rodents (Meaney et al., 2002; Nagasawa et al., 2012; Marco et al.,

2013).

Maternal separation in rodents not only affects the newborns

but also the behavior of the mother. In rats, maternal separation re-

duces maternal care (Aguggia et al., 2013). In addition, long periods

of mother–infant separation during the postnatal period inhibit

subsequent maternal behavior, probably though oxytocin receptor

modulation in the brain (Boccia and Pedersen, 2001). In humans,

separation and swaddling of the baby at birth impairs the interac-

tion with the mother during breastfeeding and also affects the

behavior of the mother with her child (Dumas et al., 2013). The ef-

fects of the early maternal separation are durable. A study reported

that, regardless of other variables, when newborns spend the ﬁrst

two hours separated from their mothers there was a worse

mother–baby interaction one year after birth (Bystrova et al.,

2009). The stress of prolonged mother–infant separation is also

associated with reduced maternal sensitivity and more negative

patterns of mothering throughout the ﬁrst 3 years of life (NICHD

Early Child Care Research Network, 1999).

4.4. Bottle-feeding versus breastfeeding

Neuroendocrine setting of bottle-feeding may be very different

from lactation. In bottle-feeding, the absence of the increased re-

lease of oxytocin and prolactin in the mother induced by breast-

feeding may affect the bonding process with her newborn. This

has led some authors to hypothesize that, for the maternal brain,

not breastfeeding may mean the ‘death’ of the newborn. Therefore,

the brain might be involved in a postpartum mourning state that

may explain the higher incidence of postpartum depression in

the case of bottle-feeding (Gallup et al., 2010). Indeed, a lack of

brain activation in response to the crying of the newborn, similar

to what it has been described after elective Cesarean sections,

has been reported in mothers that use bottle-feeding (Swain

et al., 2008; Kim et al., 2011). Long term consequences of these

differences are still unknown. Duration of breastfeeding has been

inversely associated with risk of subsequent maternal neglect in

a large 15-year longitudinal study of over 7000 mother–infant

dyads (Strathearn et al., 2009b). In addition, a signiﬁcant correla-

tion between stress, dysphoric moods and decreased levels of

interferon-

have been detected in formula feeder mothers, an ef-

fect consistent with depression of cellular immunity (Groer and

Davis, 2006). Furthermore, recent studies suggest that breastfeed-

ing reduces women’s risk of Alzheimer’s disease and that women

with shorter breastfeeding duration have increased risk of Alzhei-

mer’s disease (Fox et al., 2013).

4.5. Summation of effects

Unfortunately many mother infant dyads suffer not one but

many of these peripartum disruptions. For instance, prematurity

can be associated to betamethasone and Atosiban exposure in

uterus, followed by an emergency Cesarean birth, maternal infant

separation, prolonged hospitalization and formula feeding. In some

countries maternal infant abandonment may be followed by for-

mula feeding and institutionalization until 10 months of age with-

out a primary caregiver (Gribble, 2006). The consequences of the

accumulative effects of these events, which impact on the neuro-

endocrine homeostasis of the baby, are unknown. However, it

has been reported that birth complications and early child rejec-

tion increases the risk of violent behavior in adulthood (Raine

et al., 1994, 1997). It is unknown if the summation of potential

etiopathogenic neurohormonal scenarios during labor and the

early postpartum period may represent an increased risk for other

neurobiological disorders that affect systems and functions regu-

lated by neurohormones such as attachment disorders, childhood

anxiety disorders, early feeding disorders, changes in sexual behav-

ior in adulthood or primary enuresis.

5. Conclusions

Childbirth can be considered as a neurohormonal event where

both maternal and fetal brains participate and where a speciﬁc

neurohormonal scenario is settled. The studies reviewed in this

paper suggest that hormonal changes in the maternal and the fe-

tal/newborn brains during parturition, the immediate postpartum

period and lactation are involved in the generation of mother–

child attachment in humans. Several hormones seem to play a

key role in the mechanisms of initiation and consolidation of this

attachment. However, our knowledge on these mechanisms is

still incomplete. Little is known on the neurohormonal changes

during intrapartum and we ignore the neurobiological and neuro-

endocrine changes that may occur in the maternal and the fetal

brain as the fetus goes down the birth channel. Also, we need

to increase our knowledge on the mechanisms that initiate

attachment behavior between the mother and the newborn

immediately postpartum. This knowledge will allow the imple-

mentation of adequate actions to minimize the negative effects

of peripartum disruptions. For this it is essential to obtain a sys-

tematic recollection of data regarding any peripartum attachment

disruption in the medical records, such as the time, dose and

duration of synthetic oxytocin exposure or of maternal infant

separation. More investigation is needed to develop scores to as-

sess peripartum disruptions and identify high risk neonates and

dyads.

I. Olza-Fernández et al. / Frontiers in Neuroendocrinology 35 (2014) 459–472 467

The limited available evidence suggests that the disruption of

the neurohormonal process of childbirth in humans may increase

the risk of developing mental, learning, attachment and personality

disorders later in life. Therefore, several actions to counteract the

effects of birth interventions disrupting peripartal neuroendocrine

events have been proposed, including strategies that maximizie

skin-to-skin contact, carrying the child frequently, providing mas-

sage, co-sleeping and co-bathing (see also Section 4.2). In general,

it would be convenient to educate both professionals and parents

on the critical issues that take place in the central nervous system

at delivery or during perinatal period as well as to promote phys-

iological care during childbirth, accommodating hospital routines

to newborns basic biological needs (Bergman and Bergman,

2013), minimizing pharmacological interventions that may disrupt

the neuroendocrine cascade involved in mother–child attachment,

performing Cesarean sections as physiological as possible (Smith

et al., 2008) and promoting strategies to decrease the alarmingly

high birth rate by Cesarean sections, many of them unnecessary

(Young, 2011). Routine mother infant separation should be

avoided. Instead, skin-to-skin contact with the mother for the ﬁrst

24 h should be provided when possible to keep uninterrupted ac-

cess to the breast. When breastfeeding is not possible, or is not

the preferred option, it is recommended to bottle feed mimicking

breastfeeding, holding the child in a breastfeeding position with

the child skin-to-skin with the mother bare breasts, using a

slow-ﬂow bottle teat and changing sides while bottle feeding

(Gribble, 2006). If maternal illness causes infant separation, skin

to skin contact with the father or other relatives should be pro-

vided and intensive breastfeeding should be promoted after re-

union with the mother to restore brain oxytocin levels. Finally,

screening for perinatal mental health disorders seems to be critical

to optimize maternal well-being and attachment. Perinatal and in-

fant mental health services should be provided to all families who

experience traumatic childbirth and or prematurity.

Acknowledgments

Grant support from the Fondo de Investigaciones Sanitarias

(PI10/00791) and Ministerio de Economía y Competitividad, Spain

(BFU2011-30217-C03-01).

References

Abel, R.A., Ronca, A.E., Alberts, J.R., 1998. Perinatal stimulation facilitates suckling

onset in newborn rats. Dev. Psychobiol. 32, 91–99.

Aguggia, J.P., Suarez, M.M., Rivarola, M.A., 2013. Early maternal separation:

neurobehavioral consequences in mother rats. Behav. Brain Res. 248, 25–31.

Akbari, E.M., Chatterjee, D., Lévy, F., Fleming, A.S., 2007. Experience-dependent cell

survival in the maternal rat brain. Behav. Neurosci. 121, 1001–1011.

Als, H., Duffy, F.H., McAnulty, G.B., 1996. Effectiveness of individualized

neurodevelopmental care in the newborn intensive care unit (NICU). Acta

Paediatr. Suppl. 416, 21–30.

Altemus, M., Deuster, P.A., Galliven, E., Carter, C.S., Gold, P.W., 1995. Suppression of

hypothalmic-pituitary-adrenal axis responses to stress in lactating women. J.

Clin. Endocrinol. Metab. 80, 2954–2959.

Altstein, M., Gainer, H., 1988. Differential biosynthesis and posttranslational

processing of vasopressin and oxytocin in rat brain during embryonic and

postnatal development. J. Neurosci. 8, 3967–3977.

Amico, J.A., Finley, B.E., 1986. Breast stimulation in cycling women, pregnant

women and a woman with induced lactation: pattern of release of oxytocin,

prolactin and luteinizing hormone. Clin. Endocrinol. (Oxf) 25, 97–106.

Amico, J.A., Thomas, A., Hollingshead, D.J., 1997. The duration of estradiol and

progesterone exposure prior to progesterone withdrawal regulates oxytocin

mRNA levels in the paraventricular nucleus of the rat. Endocr. Res. 23, 141–156.

Amiri, S., Malek, A., Sadegfard, M., Abdi, S., 2012. Pregnancy-related maternal risk

factors of attention-deﬁcit hyperactivity disorder: a case-control study. ISRN

Pediatr. 2012, 458064.

Anim-Somuah, M., Smyth, R.M., Jones, L., 2011. Epidural versus non-epidural or no

analgesia in labour. Cochrane Database Syst. Rev. 12, CD000331.

Avinun, R., Ebstein, R.P., Knafo, A., 2012. Human maternal behaviour is associated

with arginine vasopressin receptor 1A gene. Biol. Lett. 8, 894–896.

Ayers, S., Joseph, S., McKenzie-McHarg, K., Slade, P., Wijma, K., 2008. Post-traumatic

stress disorder following childbirth: Current issues and recommendations for

future research. J. Psychosom. Obste. Gynaecol. 29, 240–250.

Bamberg, C., Rademacher, G., Guttler, F., Teichgraber, U., Cremer, M., Buhrer, C.,

Dudenhausen, J.W., 2012. Human birth observed in real-time open magnetic

resonance imaging. Am. J. Obstet. Gynecol. 206, 505.e1-6.

Baumgartner, T., Heinrichs, M., Vonlanthen, A., Fischbacher, U., Fehr, E., 2008.

Oxytocin shapes the neural circuitry of trust and trust adaptation in humans.

Neuron 58, 639–650.

Bealer, S.L., Crowley, W.R., 2001. Histaminergic control of oxytocin release in the

paraventricular nucleus during lactation in rats. Exp. Neurol. 171, 317–322.

Beck, C.T., 2004. Post-traumatic stress disorder due to childbirth: the aftermath.

Nurs. Res. 53, 216–224.

Beck, C.T., Gable, R.K., Sakala, C., Declercq, E.R., 2011. Posttraumatic stress disorder

in new mothers: results from a two-stage U.S. National survey. Birth 38, 216–

227.

Belghiti, J., Kayem, G., Dupont, C., Rudigoz, R.C., Bouvier-Colle, M.H., Deneux-

Tharaux, C., 2011. Oxytocin during labour and risk of severe postpartum

haemorrhage: a population-based, cohort-nested case-control study. BMJ Open

1, e000514.

Bell, A.F., White-Traut, R., Rankin, K., 2013. Fetal exposure to synthetic oxytocin and

the relationship with prefeeding cues within one hour postbirth. Early Hum.

Dev. 89, 137–143.

Bergman, J., Bergman, N., 2013. Whose choice? advocating birthing practices

according to baby’s biological needs. J. Perinatal Edu. 22, 8–13.

Bisceglia, R., Jenkins, J.M., Wigg, K.G., O’Connor, T.G., Moran, G., Barr, C.L., 2012.

Arginine vasopressin 1a receptor gene and maternal behavior: evidence of

association and moderation. Genes Brain. Behav. 11, 262–268.

Boccia, M.L., Pedersen, C.A., 2001. Brief vs. long maternal separations in infancy:

contrasting relationships with adult maternal behavior and lactation levels of

aggression and anxiety. Psychoneuroendocrinology 26, 657–672.

Bosch, O.J., 2011. Maternal nurturing is dependent on her innate anxiety: the

behavioral roles of brain oxytocin and vasopressin. Horm. Behav. 59, 202–212.

Bosch, O.J., Neumann, I.D., 2008. Brain vasopressin is an important regulator of

maternal behavior independent of dams’ trait anxiety. Proc. Natl. Acad. Sci. USA

105, 17139–17144.

Bosch, O.J., Neumann, I.D., 2012. Both oxytocin and vasopressin are mediators of

maternal care and aggression in rodents: from central release to sites of action.

Horm. Behav. 61, 293–303.

Bowlby, J., 1978. Attachment theory and its therapeutic implications. Adolesc.

Psychiatry 6, 5–33.

Brancato, R.M., Church, S., Stone, P.W., 2008. A meta-analysis of passive descent

versus immediate pushing in nulliparous women with epidural analgesia in the

second stage of labor. J. Obstet. Gynecol. Neonatal. Nurs. 37, 4–12.

Brunton, P.J., Russell, J.A., 2008. The expectant brain: adapting for motherhood. Nat.

Rev. Neurosci. 9, 11–25.

Brunton, P.J., Russell, J.A., 2010. Endocrine induced changes in brain function during

pregnancy. Brain Res. 1364, 198–215.

Brunton, P.J., Russell, J.A., Douglas, A.J., 2008. Adaptive responses of the maternal

hypothalamic-pituitary-adrenal axis during pregnancy and lactation. J.

Neuroendocrinol. 20, 764–776.

Brunton, P.J., Bales, J., Russell, J.A., 2012. Allopregnanolone and induction of

endogenous opioid inhibition of oxytocin responses to immune stress in

pregnant rats. J. Neuroendocrinol. 24, 690–700.

Brunton, P.J., Russell, J.A., Hirst, J.J., 2014. Allopregnanolone in the brain: protecting

pregnancy and birth outcomes. Prog. Neurobiol. 113, 106–136.

Brus, M., Meurisse, M., Franceschini, I., Keller, M., Lévy, F., 2010. Evidence for cell

proliferation in the sheep brain and its down-regulation by parturition and

interactions with the young. Horm. Behav. 58, 737–746.

Brussaard, A.B., Kits, K.S., Baker, R.E., Willems, W.P., Leyting-Vermeulen, J.W., Voorn,

P., Herbison, A.E., 1997. Plasticity in fast synaptic inhibition of adult oxytocin

neurons caused by switch in GABA(A) receptor subunit expression. Neuron 19,

1103–1114.

Brussaard, A.B., Devay, P., Leyting-Vermeulen, J.L., Kits, K.S., 1999. Changes in

properties and neurosteroid regulation of GABAergic synapses in the supraoptic

nucleus during the mammalian female reproductive cycle. J. Physiol. 516, 513–

524.

Buchanan, S.L., Patterson, J.A., Roberts, C.L., Morris, J.M., Ford, J.B., 2012. Trends and

morbidity associated with oxytocin use in labour in nulliparas at term. Aust. N.

Z. J. Obstet. Gynaecol. 52, 173–178.

Bystrova, K., Widström, A.M., Matthiesen, A.S., Ransjö-Arvidson, A.B., Welles-

Nyström, B., Wassberg, C., Vorontsov, I., Uvnäs-Moberg, K., 2003. Skin-to-skin

contact may reduce negative consequences of ‘‘the stress of being born’’: a

study on temperature in newborn infants, subjected to different ward routines

in St. Petersburg. Acta Paediatr. 92, 320–326.

Bystrova, K., Ivanova, V., Edhborg, M., Matthiesen, A.S., Ransjo-Arvidson, A.B.,

Mukhamedrakhimov, R., Widstrom, A.M., 2009. Early contact versus separation:

effects on mother–infant interaction one year later. Birth 36, 97–109.

Callister, L.C., 2004. Making meaning: women’s birth narratives. J. Obstet. Gynecol.

Neonatal. Nurs. 33, 508–518.

Callister, L.C., Semenic, S., Foster, J.C., 1999. Cultural and spiritual meanings of

childbirth. Orthodox jewish and mormon women. J. Holist. Nurs. 17, 280–

295.

Campbell, E.A., Linton, E.A., Wolfe, C.D., Scraggs, P.R., Jones, M.T., Lowry, P.J., 1987.

Plasma corticotropin-releasing hormone concentrations during pregnancy

and parturition. J. Clin. Endocrinol. Metab. 64, 1054–1059.

468 I. Olza-Fernández et al. / Frontiers in Neuroendocrinology 35 (2014) 459–472

Carlander, A.K., Edman, G., Christensson, K., Andolf, E., Wiklund, I., 2010. Contact

between mother, child and partner and attitudes towards breastfeeding in

relation to mode of delivery. Sex. Reprod. Healthc. 1, 27–34.

Carter, C.S., 2014. Oxytocin pathways and the evolution of human behavior. Annu.

Rev. Psychol. 65, 17–39.

Carter, C.S., Altemus, M., 1997. Integrative functions of lactational hormones in

social behavior and stress management. Ann. N. Y. Acad. Sci. 807, 164–174.

Caughey, S.D., Klampﬂ, S.M., Bishop, V.R., Pfoertsch, J., Neumann, I.D., Bosch, O.J.,

Meddle, S.L., 2011. Changes in the intensity of maternal aggression and central

oxytocin and vasopressin V1a receptors across the peripartum period in the rat.

J. Neuroendocrinol. 23, 1113–1124.

Ceanga, M., Spataru, A., Zagrean, A.M., 2010. Oxytocin is neuroprotective against

oxygen–glucose deprivation and reoxygenation in immature hippocampal

cultures. Neurosci. Lett. 477, 15–18.

Charpak, N., Ruiz, J.G., Zupan, J., Cattaneo, A., Figueroa, Z., Tessier, R., Cristo, M.,

Anderson, G., Ludington, S., Mendoza, S., Mokhachane, M., Worku, B., 2005.

Kangaroo mother care: 25 years after. Acta Paediatr. 94, 514–522.

Chen, D.C., Nommsen-Rivers, L., Dewey, K.G., Lonnerdal, B., 1998. Stress during labor

and delivery and early lactation performance. Am. J. Clin. Nutr. 68, 335–344.

Cherubini, E., Gaiarsa, J.L., Ben-Ari, Y., 1991. GABA: an excitatory transmitter in early

postnatal life. Trends Neurosci. 14, 515–519.

Chiossi, G., Lai, Y., Landon, M.B., Spong, C.Y., Rouse, D.J., Varner, M.W., Eunice

Kennedy Shriver National Institute of Child Health and Human Development

(NICHD) Maternal-Fetal Medicine Units (MFMU) Network, 2013. Timing of

delivery and adverse outcomes in term singleton repeat cesarean deliveries.

Obstet. Gynecol. 121, 561–569.

Christensson, K., Cabrera, T., Christensson, E., Uvnas-Moberg, K., Winberg, J., 1995.

Separation distress call in the human neonate in the absence of maternal body

contact. Acta Paediatr. 84, 468–473.

Clark, S.L., Simpson, K.R., Knox, G.E., Garite, T.J., 2009. Oxytocin: new perspectives

on an old drug. Am. J. Obstet. Gynecol. 35, e1–e6.

Costa, A., De Filippis, V., Voglino, M., Giraudi, G., Massobrio, M., Benedetto, C.,

Marozio, L., Gallo, M., Molina, G., Fabris, C., 1988. Adrenocorticotropic hormone

and catecholamines in maternal, umbilical and neonatal plasma in relation to

vaginal delivery. J. Endocrinol. Invest. 11, 703–709.

Creedy, D.K., Shochet, I.M., Horsfall, J., 2000. Childbirth and the development of

acute trauma symptoms: incidence and contributing factors. Birth 27, 104–111.

Crowley, R.S., Insel, T.R., O’Keefe, J.A., Kim, N.B., Amico, J.A., 1995. Increased

accumulation of oxytocin messenger ribonucleic acid in the hypothalamus of

the female rat: induction by long term estradiol and progesterone

administration and subsequent progesterone withdrawal. Endocrinology 136,

224–231.

Da Costa, A.P., Guevara-Guzman, R.G., Ohkura, S., Goode, J.A., Kendrick, K.M., 1996.

The role of oxytocin release in the paraventricular nucleus in the control

of maternal behaviour in the sheep. J. Neuroendocrinol. 8, 163–177.

Dahlen, H.G., Kennedy, H.P., Anderson, C.M., Bell, A.F., Clark, A., Foureur, M., Downe,

S., 2013. The EPIIC hypothesis: intrapartum effects on the neonatal epigenome

and consequent health outcomes. Med. Hypotheses 80, 656–662.

Darnaudery, M., Perez-Martin, M., Del Favero, F., Gomez-Roldan, C., Garcia-Segura,

L.M., Maccari, S., 2007. Early motherhood in rats is associated with a

modiﬁcation of hippocampal function. Psychoneuroendocrinology 32, 803–812.

Dawood, M.Y., Khan-Dawood, F.S., Wahi, R.S., Fuchs, F., 1981. Oxytocin release and

plasma anterior pituitary and gonadal hormones in women during lactation. J.

Clin. Endocrinol. Metab. 52, 678–683.

Deoni, S.C., Dean 3rd., D.C., Piryatinksy, I., O’Muircheartaigh, J., Waskiewicz, N.,

Lehman, K., Dirks, H., 2013. Breastfeeding and early white matter development:

a cross-sectional study. Neuroimage 15, 77–86.

Detwyler, K., 1995. A time to wean. In: Stuar-Macadam, P., Detwyler, K. (Eds.),

Breastfeeding Biocultural Perspectives. Aldine De Gruyter, New York, pp. 39–73.

Dondi, D., Maggi, R., Panerai, A.E., Piva, F., Limonta, P., 1991. Hypothalamic

opiatergic tone during pregnancy, parturition and lactation in the rat.

Neuroendocrinology 53, 460–466.

Donner, N., Bredewold, R., Maloumby, R., Neumann, I.D., 2007. Chronic intracerebral

prolactin attenuates neuronal stress circuitries in virgin rats. Eur. J. Neurosci.

25, 1804–1814.

Doucet, S., Soussignan, R., Sagot, P., Schaal, B., 2007. The ‘‘smellscape’’ of mother’s

breast: effects of odor masking and selective unmasking on neonatal arousal,

oral, and visual responses. Dev. Psychobiol. 49, 129–138.

Douglas, A.J., 2005. Central noradrenergic mechanisms underlying acute stress

responses of the Hypothalamo-pituitary-adrenal axis: adaptations through

pregnancy and lactation. Stress 8, 5–18.

Douglas, A.J., Dye, S., Leng, G., Russell, J.A., Bicknell, R.J., 1993. Endogenous opioid

regulation of oxytocin secretion through pregnancy in the rat. J.

Neuroendocrinol. 5, 307–314.

Douglas, A.J., Neumann, I., Meeren, H.K., Leng, G., Johnstone, L.E., Munro, G., Russell,

J.A., 1995. Central endogenous opioid inhibition of supraoptic oxytocin neurons

in pregnant rats. J. Neurosci. 15, 5049–5057.

Dumas, L., Lepage, M., Bystrova, K., Matthiesen, A.S., Welles-Nystrom, B., Widstrom,

A.M., 2013. Inﬂuence of skin-to-skin contact and rooming-in on early mother-

infant interaction: a randomized controlled trial. Clin. Nurs. Res. 22, 310–336.

Duna, J., Richards, M., 1977. Observation on the developing relationship between

mother and baby in the neonatal period. In: Scaefeer, H.R. (Ed.), Studies in

Mother–Infant Interaction. Academic Press, New York, pp. 427–455.

Erlandsson, K., Dsilna, A., Fagerberg, I., Christensson, K., 2007. Skin-to-skin care with

the father after cesarean birth and its effect on newborn crying and prefeeding

behavior. Birth 34, 105–114.

Febo, M., Numan, M., Ferris, C.F., 2005. Functional magnetic resonance imaging

shows oxytocin activates brain regions associated with mother-pup bonding

during suckling. J. Neurosci. 25, 11637–11644.

Feldman, R., Gordon, I., Zagoory-Sharon, O., 2010a. The cross-generation

transmission of oxytocin in humans. Horm. Behav. 58, 669–676.

Feldman, R., Gordon, I., Schneiderman, I., Weissman, O., Zagoory-Sharon, O., 2010b.

Natural variations in maternal and paternal care are associated with systematic

changes in oxytocin following parent-infant contact.

Psychoneuroendocrinology 35, 1133–1141.

Ferber, S.G., Makhoul, I.R., 2004. The effect of skin-to-skin contact (kangaroo care)

shortly after birth on the neurobehavioral responses of the term newborn: a

randomized, controlled trial. Pediatrics 113, 858–865.

Fink, N.S., Tronick, E., Olson, K., Lester, B., 2012. Healthy newborns’ neurobehavior:

norms and relations to medical and demographic factors. J. Pediatr. 161, 1073–

1079.

Fleming, A.S., Steiner, M., Anderson, V., 1987. Hormonal and attitudinal correlates of

maternal behaviour during the early postpartum period in ﬁrst-time mothers. J.

Reprod. Infant Psychol. 5, 193–205.

Fleming, A.S., Steiner, M., Corter, C., 1997. Cortisol, hedonics, and maternal

responsiveness in human mothers. Horm. Behav. 32, 85–98.

Forcada-Guex, M., Pierrehumbert, B., Borghini, A., Moessinger, A., Muller-Nix, C.,

2006. Early dyadic patterns of mother-infant interactions and outcomes of

prematurity at 18 months. Pediatrics 118, e107–e114.

Fox, M., Berzuini, C., Knapp, L.A., 2013. Maternal breastfeeding history and

Alzheimer’s disease risk. J. Alzheimers Dis. 37, 809–821.

Furuta, M., Bridges, R.S., 2009. Effects of maternal behavior induction and pup

exposure on neurogenesis in adult, virgin female rats. Brain Res. Bull. 80, 408–

413.

Galea, L.A., Ormerod, B.K., Sampath, S., Kostaras, X., Wilkie, D.M., Phelps, M.T., 2000.

Spatial working memory and hippocampal size across pregnancy in rats. Horm.

Behav. 37, 86–95.

Gallup Jr, G.G., Nathan Pipitone, R., Carrone, K.J., Leadholm, K.L., 2010. Bottle feeding

simulates child loss: postpartum depression and evolutionary medicine. Med.

Hypotheses 74, 174–176.

Garcia-Segura, L.M., 2009. Hormones and Brain Plasticity. Oxford University Press,

New York.

Gardener, H., Spiegelman, D., Buka, S.L., 2011. Perinatal and neonatal risk factors for

autism: a comprehensive meta-analysis. Pediatrics 128, 344–355.

Gennser, G., Ohrlander, S., Eneroth, P., 1977. Fetal cortisol and the initiation of

labour in the human. Ciba Found. Symp. 47, 401–426.

Gibbons, L., Belizan, J.M., Lauer, J.A., Betran, A.P., Merialdi, M., Althabe, F., 2012.

Inequities in the use of cesarean section deliveries in the world. Am. J. Obstet.

Gynecol. 206, 331.

Gionet, L., 2013. Breastfeeding trends in Canada. Health at a Glance. November.

Statistics Canada, Catalogue No. 82-624-X.

Gitau, R., Menson, E., Pickles, V., Fisk, N.M., Glover, V., MacLachlan, N., 2001.

Umbilical cortisol levels as an indicator of the fetal stress response to assisted

vaginal delivery. Eur. J. Obstet. Gynecol. Reprod. Biol. 98, 14–17.

Glasson, E.J., Bower, C., Petterson, B., de Klerk, N., Chaney, G., Hallmayer, J.F., 2004.

Perinatal factors and the development of autism: a population study. Arch. Gen.

Psychiatry 61, 618–627.

Gordon, I., Zagoory-Sharon, O., Leckman, J.F., Feldman, R., 2010. Prolactin, oxytocin,

and the development of paternal behavior across the ﬁrst six months of

fatherhood. Horm. Behav. 58, 513–518.

Graham, M.D., Rees, S.L., Steiner, M., Fleming, A.S., 2006. The effects of

adrenalectomy and corticosterone replacement on maternal memory in

postpartum rats. Horm. Behav. 49, 353–361.

Green, A.D., Galea, L.A., 2008. Adult hippocampal cell proliferation is suppressed

with estrogen withdrawal after a hormone-simulated pregnancy. Horm. Behav.

54, 203–211.

Gregory, S.G., Anthopolos, R., Osgood, C.E., Grotegut, C.A., Miranda, M.L., 2013.

Association of autism with induced or augmented childbirth in North Carolina

birth record (1990–1998) and education research (1997–2007) databases. JAMA

Pediatr. 167, 959–966.

Gribble, K.D., 2006. Mental health, attachment and breastfeeding: implications for

adopted children and their mothers. Int. Breastfeed J. 1, 5.

Groer, M.W., Davis, M.W., 2006. Cytokines, infections, stress, and dysphoric moods

in breastfeeders and formula feeders. J. Obstet. Gynecol. Neonatal. Nurs. 35,

599–607.

Guinchat, V., Thorsen, P., Laurent, C., Cans, C., Bodeau, N., Cohen, D., 2012. Pre-,

peri- and neonatal risk factors for autism. Acta Obstet. Gynecol. Scand. 91,

287–300.

Haas, D.M., Caldwell, D.M., Kirkpatrick, P., McIntosh, J.J., Welton, N.J., 2012. Tocolytic

therapy for preterm delivery: systematic review and network meta-analysis.

BMJ 345, e6226.

Hallowell, S.G., Spatz, D.L., 2012. The relationship of brain development and

breastfeeding in the late-preterm infant. J. Pediatr. Nurs. 27, 154–162.

Hamilton, B.E., Hoyert, D.L., Martin, J.A., Strobino, D.M., Guyer, B., 2013. Annual

summary of vital statistics: 2010–2011. Pediatrics 131, 548–558.

Handlin, L., Jonas, W., Petersson, M., Ejdebäck, M., Ransjö-Arvidson, A.B., Nissen, E.,

Uvnäs-Moberg, K., 2009. Effects of sucking and skin-to-skin contact on maternal

ACTH and cortisol levels during the second day postpartum-inﬂuence of

epidural analgesia and oxytocin in the perinatal period. Breastfeed Med. 4, 207–

220.

Hanson, L., 2009. Second-stage labor care: challenges in spontaneous bearing down.

J. Perinat. Neonatal Nurs. 23, 31–39.

I. Olza-Fernández et al. / Frontiers in Neuroendocrinology 35 (2014) 459–472 469

Hatters Friedman, S., Kessler, A., Nagle Yang, S., Parsons, S., Friedman, H., Martin, R.J.,

2013. Delivering perinatal psychiatric services in the neonatal intensive care

unit. Acta Paediatr. 102, e392–e397.

Heinrichs, M., Meinlschmidt, G., Neumann, I., Wagner, S., Kirschbaum, C., Ehlert, U.,

Hellhammer, D.H., 2001. Effects of suckling on hypothalamic-pituitary-adrenal

axis responses to psychosocial stress in postpartum lactating women. J. Clin.

Endocrinol. Metab. 86, 4798–4804.

Heinrichs, M., Neumann, I., Ehlert, U., 2002. Lactation and stress: protective effects

of breast-feeding in humans. Stress 5, 195–203.

Heinrichs, M., von Dawans, B., Domes, G., 2009. Oxytocin, vasopressin, and human

social behavior. Front. Neuroendocrinol. 30, 548–557.

Isaacs, E.B., Fischl, B.R., Quinn, B.T., Chong, W.K., Gadian, D.G., Lucas, A., 2010. Impact

of breast milk on intelligence quotient, brain size, and white matter

development. Pediatr. Res. 67, 357–362.

Ishak, W.W., Kahloon, M., Fakhry, H., 2011. Oxytocin role in enhancing well-being: a

literature review. J. Affect. Disord. 130, 1–9.

Jirikowski, G.F., Caldwell, J.D., Pilgrim, C., Stumpf, W.E., Pedersen, C.A., 1989.

Changes in immunostaining for oxytocin in the forebrain of the female rat

during late pregnancy, parturition and early lactation. Cell Tissue Res. 256, 411–

417.

Johnstone, H.A., Wigger, A., Douglas, A.J., Neumann, I.D., Landgraf, R., Seckl, J.R.,

Russell, J.A., 2000. Attenuation of hypothalamic-pituitary-adrenal axis stress

responses in late pregnancy: changes in feedforward and feedback mechanisms.

J. Neuroendocrinol. 12, 811–822.

Jonas, K., Johansson, L.M., Nissen, E., Ejdeback, M., Ransjo-Arvidson, A.B., Uvnas-

Moberg, K., 2009. Effects of intrapartum oxytocin administration and epidural

analgesia on the concentration of plasma oxytocin and prolactin, in response to

suckling during the second day postpartum. Breastfeed Med. 4, 71–82.

Jukic, A.M., Baird, D.D., Weinberg, C.R., McConnaughey, D.R., Wilcox, A.J., 2013.

Length of human pregnancy and contributors to its natural variation. Hum.

Reprod. 28, 2848–2855.

Julvez, J., Guxens, M., Carsin, A.E., Forns, J., Mendez, M., Turner, M.C., Sunyer, J., 2014.

A cohort study on full breastfeeding and child neuropsychological

development: the role of maternal social, psychological, and nutritional

factors. Dev. Med. Child Neurol. 56, 148–156.

Kafouri, S., Kramer, M., Leonard, G., Perron, M., Pike, B., Richer, L., Paus, T., 2013.

Breastfeeding and brain structure in adolescence. Int. J. Epidemiol. 42, 150–

159.

Kapellou, O., 2011. Effect of caesarean section on brain maturation. Acta Paediatr.

100, 1416–1422.

Kelmanson, I., 2013. Emotional and behavioural features of preschool children born

by caesarean deliveries at maternal request. Eur. J. Dev. Psychol. 10, 676–690.

Kendrick, K.M., 2000. Oxytocin, motherhood and bonding. Exp. Physiol. 85, 111S–

124S.

Kendrick, K.M., Keverne, E.B., 1991. Importance of progesterone and estrogen

priming for the induction of maternal behavior by vaginocervical stimulation in

sheep. Effects of maternal experience. Physiol. Behav. 49, 745–750.

Kendrick, K.M., Keverne, E.B., Chapman, C., Baldwin, B.A., 1988. Microdialysis

measurement of oxytocin, aspartate, gamma aminobutyric acid and glutamate

release from the olfactory bulb of sheep during vaginocervical stimulation.

Brain Res. 442, 171–177.

Kendrick, K.M., Keverne, E.B., Hinton, M.R., Goode, J.A., 1991a. Cerebrospinal ﬂuid

and plasma concentrations of oxytocin and vasopressin during parturition and

vaginocervical stimulation in the sheep. Brain Res. Bull. 26, 803–807.

Kendrick, K.M., Lévy, F., Keverne, E.B., 1991b. Importance of vaginocervical

stimulation for the formation of maternal bonding in primiparous and

multiparous parturient ewes. Physiol. Behav. 50, 595–600.

Kendrick, K.M., Da Costa, A.P., Broad, K.D., Ohkura, S., Guevara, R., Lévy, F., Keverne,

E.B., 1997. Neural control of maternal behaviour and olfactory recognition of

offspring. Brain Res. Bull. 44, 383–395.

Keri, S., Kiss, I., 2010. Oxytocin response in a trust game and habituation of arousal.

Physiol. Behav. 102, 221–224.

Keverne, E.B., 1988. Central mechanisms underlying the neural and neuroendocrine

determinants of maternal behaviour. Psychoneuroendocrinology 13, 127–141.

Keverne, E.B., Lévy, F., Poindron, P., Lindsay, D., 1983. Vaginal stimulation. An

important determinant of maternal bonding in sheep. Science 219, 81–83.

Keyser-Marcus, L., Staﬁsso-Sandoz, G., Gerecke, K., Jasnow, A., Nightingale, L.,

Lambert, K.G., Kinsley, C.H., 2001. Alterations of medial preoptic area neurons

following pregnancy and pregnancy-like steroidal treatment in the rat. Brain

Res. Bull. 55, 737–745.

Khazipov, R., Tyzio, R., Ben-Ari, Y., 2008. Effects of oxytocin on GABA signalling in

the foetal brain during delivery. Prog. Brain Res. 170, 243–257.

Kim, P., Leckman, J.F., Mayes, L.C., Feldman, R., Wang, X., Swain, J.E., 2010. The

plasticity of human maternal brain: longitudinal changes in brainanatomy

during the early postpartum period. Behav. Neurosci. 124, 695–700.

Kim, P., Feldman, R., Mayes, L.C., Eicher, V., Thompson, N., Leckman, J.F., Swain, J.E.,

2011. Breastfeeding, brain activation to own infant cry, and maternal

sensitivity. J. Child Psychol. Psychiatry 52, 907–915.

Kingston, D., Tough, S., Whitﬁeld, H., 2012. Prenatal and postpartum maternal

psychological distress and infant development: a systematic review.

Child Psychiat. Hum. Dev. 43, 683–714.

Kinsley, C.H., Amory-Meyer, E., 2011. Why the maternal brain? J. Neuroendocrinol.

23, 974–983.

Kinsley, C.H., Lambert, K.G., 2008. Reproduction-induced neuroplasticity: natural

behavioural and neuronal alterations associated with the production and care

of offspring. J. Neuroendocrinol. 20, 515–525.

Kinsley, C.H., Trainer, R., Staﬁsso-Sandoz, G., Quadros, P., Marcus, L.K., Hearon, C.,

Lambert, K.G., 2006. Motherhood and the hormones of pregnancy modify

concentrations of hippocampal neuronal dendritic spines. Horm. Behav. 49,

131–142.

Klampﬂ, S.M., Neumann, I.D., Bosch, O.J., 2013. Reduced brain corticotropin-

releasing factor receptor activation is required for adequate maternal care

and maternal aggression in lactating rats. Eur. J. Neurosci. 38, 2742–2750.

Kojima, S., Alberts, J.R., 2011. Oxytocin mediates the acquisition of ﬁlial, odor-

guided huddling for maternally-associated odor in preweanling rats. Horm.

Behav. 60, 549–558.

Kojima, S., Stewart, R.A., Demas, G.E., Alberts, J.R., 2012. Maternal contact

differentially modulates central and peripheral oxytocin in rat pups during a

brief regime of mother–pup interaction that induces a ﬁlial huddling

preference. J. Neuroendocrinol. 24, 831–840.

Koksma, J.J., Fritschy, J.M., Mack, V., Van Kesteren, R.E., Brussaard, A.B., 2005.

Differential GABAA receptor clustering determines GABA synapse plasticity in

rat oxytocin neurons around parturition and the onset of lactation. Mol. Cell.

Neurosci. 28, 128–140.

Krpan, K.M., Coombs, R., Zinga, D., Steiner, M., Fleming, A.S., 2005. Experiential and

hormonal correlates of maternal behavior in teen and adult mothers. Horm.

Behav. 47, 112–122.

Lagercrantz, H., Changeux, J.P., 2010. Basic consciousness of the newborn. Semin.

Perinatol. 34, 201–206.

Lagercrantz, H., Slotkin, T.A., 1986. The ‘‘stress’’ of being born. Sci. Am. 254, 100–

107.

Landgraf, R., Neumann, I., Pittman, Q.J., 1991. Septal and hippocampal release of

vasopressin and oxytocin during late pregnancy and parturition in the rat.

Neuroendocrinology 54, 378–383.

Landgraf, R., Neumann, I., Russell, J.A., Pittman, Q.J., 1992. Push-pull perfusion and

microdialysis studies of central oxytocin and vasopressin release in freely

moving rats during pregnancy, parturition, and lactation. Ann. N. Y. Acad. Sci.

652, 326–339.

Leng, G., Brown, C.H., Russell, J.A., 1999. Physiological pathways regulating the

activity of magnocellular neurosecretory cells. Prog. Neurobiol. 57, 625–655.

Leuner, B., Mirescu, C., Noiman, L., Gould, E., 2007. Maternal experience inhibits the

production of immature neurons in the hippocampus during the postpartum

period through elevations in adrenal steroids. Hippocampus 17, 434–442.

Levy, F., Keller, M., Poindron, P., 2004. Olfactory regulation of maternal behavior in

mammals. Horm. Behav. 46, 284–302.

Liao, J.B., Buhimschi, C.S., Norwitz, E.R., 2005. Normal labor: mechanism and

duration. Obstet. Gynecol. Clin. North Am. 32, 145–164.

Lincoln, D.W., Wakerley, J.B., 1974. Electrophysiological evidence for the activation

of supraoptic neurones during the release of oxytocin. J. Physiol. 242, 533–554.

Lipari, E.F., Lipari, D., Gerbino, A., Di Liberto, D., Bellaﬁore, M., Catalano, M.,

Valentino, B., 2001. The hypothalamic magnocellular neurosecretory system in

developing rats. Eur. J. Histochem. 45, 163–168.

Lord, C., Steiner, M., Soares, C.N., Carew, C.L., Hall, G.B., 2012. Stress response

in postpartum women with and without obsessive-compulsive symptoms: an

fMRI study. J. Psychiatry Neurosci. 37, 78–86.

Lumbiganon, P., Laopaiboon, M., Gulmezoglu, A.M., Souza, J.P., Taneepanichskul, S.,

Ruyan, P., World Health Organization Global Survey on Maternal and Perinatal

Health Research Group, 2010. Method of delivery and pregnancy outcomes in

asia: the WHO global survey on maternal and perinatal health 2007–08. Lancet

375, 490–499.

MacKay, D.F., Smith, G.C., Dobbie, R., Pell, J.P., 2010. Gestational age at delivery and

special educational need: Retrospective cohort study of 407,503 schoolchildren.

PLoS Med. 7, e1000289.

Mackeen, A.D., Fehnel, E., Berghella, V., Klein, T., 2014. Morphine sleep in pregnancy.

Am. J. Perinatol. 31, 085–090.

Maheu, M.E., Akbari, E.M., Fleming, A.S., 2009. Callosal oligodendrocyte number in

postpartum Sprague-Dawley rats. Brain Res. 1267, 18–24.

Malamitsi-Puchner, A., Protonotariou, E., Boutsikou, T., Makrakis, E., Sarandakou, A.,

Creatsas, G., 2005. The inﬂuence of the mode of delivery on circulating cytokine

concentrations in the perinatal period. Early Hum. Dev. 81, 387–392.

Malek, A., Blann, E., Mattison, D.R., 1996. Human placental transport of oxytocin. J.

Matern. Fetal Med. 5, 245–255.

Marco, E.M., Valero, M., de la Serna, O., Aisa, B., Borcel, E., Ramirez, M.J., Viveros,

M.P., 2013. Maternal deprivation effects on brain plasticity and recognition

memory in adolescent male and female rats. Neuropharmacology 68, 223–231.

Matthiesen, A.S., Ransjo-Arvidson, A.B., Nissen, E., Uvnas-Moberg, K., 2001.

Postpartum maternal oxytocin release by newborns: effects of infant hand

massage and sucking. Birth 28, 13–19.

Mazzuca, M., Minlebaev, M., Shakirzyanova, A., Tyzio, R., Taccola, G., Janackova, S.,

Gataullina, S., Ben-Ari, Y., Giniatullin, R., Khazipov, R., 2011. Newborn analgesia

mediated by oxytocin during delivery. Front. Cell. Neurosci. 5, 3.

McAnulty, P.A., Burns, L.M., 2004. Evaluation of the maternal and neonatal effects of

the oxytocin antagonist, atosiban, in a cross-fostering study in rats. Reprod.

Toxicol. 19, 65–70.

Meaney, M.J., Brake, W., Gratton, A., 2002. Environmental regulation of the

development of mesolimbic dopamine systems: a neurobiological mechanism

for vulnerability to drug abuse? Psychoneuroendocrinology 27, 127–138.

Mears, K., McAuliffe, F., Grimes, H., Morrison, J.J., 2004. Foetal cortisol in relation to

labour, intrapartum events and mode of delivery. J. Obstet. Gynaecol. 24, 129–

132.

Mehler, K., Wendrich, D., Kissgen, R., Roth, B., Oberthuer, A., Pillekamp, F., Kribs, A.,

2011. Mothers seeing their VLBW infants within 3 h after birth are more likely

470 I. Olza-Fernández et al. / Frontiers in Neuroendocrinology 35 (2014) 459–472

to establish a secure attachment behavior: evidence of a sensitive period with

preterm infants? J. Perinatol. 31, 404–410.

Miller, S.S., Spear, N.E., 2008. Olfactory learning in the rat neonate soon after birth.

Dev. Psychobiol. 50, 554–565.

Miller, N.M., Fisk, N.M., Modi, N., Glover, V., 2005. Stress responses at birth:

determinants of cord arterial cortisol and links with cortisol response in

infancy. BJOG 112, 921–926.

Mogi, K., Nagasawa, M., Kikusui, T., 2011. Developmental consequences and

biological signiﬁcance of mother–infant bonding. Prog.

Neuropsychopharmacol. Biol. Psychiatry 35, 1232–1241.

Moos, F., Poulain, D.A., Rodriguez, F., Guerne, Y., Vincent, J.D., Richard, P., 1989.

Release of oxytocin within the supraoptic nucleus during the milk ejection

reﬂex in rats. Exp. Brain Res. 76, 593–602.

Musser, E.D., Kaiser-Laurent, H., Ablow, J.C., 2012. The neural correlates of maternal

sensitivity: an fMRI study. Dev. Cogn. Neurosci. 2, 428–436.

Nagasawa, M., Okabe, S., Mogi, K., Kikusui, T., 2012. Oxytocin and mutual

communication in mother–infant bonding. Front. Hum. Neurosci. 6, 1–10.

National Center for Chronic Disease Prevention and Health Promotion, 2013.

Breastfeding Report Card United States/2013. Centers for Disease Control and

Prevention, Atlanta, GA.

Neumann, I., Russell, J.A., Wolff, B., Landgraf, R., 1991. Naloxone increases the

release of oxytocin, but not vasopressin, within limbic brain areas of conscious

parturient rats: a push-pull perfusion study. Neuroendocrinology 54, 545–551.

Neumann, I., Ludwig, M., Engelmann, M., Pittman, Q.J., Landgraf, R., 1993a.

Simultaneous microdialysis in blood and brain: oxytocin and vasopressin

release in response to central and peripheral osmotic stimulation and suckling

in the rat. Neuroendocrinol. 58, 637–645.

Neumann, I., Russell, J.A., Landgraf, R., 1993b. Oxytocin and vasopressin release

within the supraoptic and paraventricular nuclei of pregnant, parturient and

lactating rats: a microdialysis study. Neuroscience 53, 65–75.

Neumann, I.D., Johnstone, H.A., Hatzinger, M., Liebsch, G., Shipston, M., Russell, J.A.,

Landgraf, R., Douglas, A.J., 1998. Attenuated neuroendocrine responses to

emotional and physical stressors in pregnant rats involve adenohypophysial

changes. J. Physiol. 508 (Pt 1), 289–300.

Neumann, I.D., Torner, L., Wigger, A., 2000. Brain oxytocin: differential inhibition of

neuroendocrine stress responses and anxiety-related behaviour in virgin,

pregnant and lactating rats. Neuroscience 95, 567–575.

Neumann, I.D., Maloumby, R., Beiderbeck, D.I., Lukas, M., Landgraf, R., 2013.

Increased brain and plasma oxytocin after nasal and peripheral administration

in rats and mice. Psychoneuroendocrinology 38, 1985–1993.

NICHD Early Child Care Research Network, 1999. Child care and mother-child

interaction in the ﬁrst 3 years of life. Dev. Psychol. 35, 1399–1413.

Nissen, E., Lilja, G., Widström, A.M., Uvnäs-Moberg, K., 1995. Elevation of oxytocin

levels early post partum in women. Acta Obstet. Gynecol. Scand. 74, 530–533.

Nissen, E., Uvnas-Moberg, K., Svensson, K., Stock, S., Widstrom, A.M., Winberg, J.,

1996. Different patterns of oxytocin, prolactin but not cortisol release during

breastfeeding in women delivered by caesarean section or by the vaginal route.

Early Hum. Dev. 45, 103–118.

Nissen, E., Gustavsson, P., Widstrom, A.M., Uvnas-Moberg, K., 1998. Oxytocin,

prolactin, milk production and their relationship with personality traits in

women after vaginal delivery or cesarean section. J. Psychosom. Obstet.

Gynaecol. 19, 49–58.

Nuttall, C., 2000. Caesarean section controversy. The caesarean culture of brazil. BMJ

320, 1074.

Nyqvist, K.H., Anderson, G.C., Bergman, N., Cattaneo, A., Charpak, N., Davanzo, R.,

Ewald, U., Ibe, O., Ludington-Hoe, S., Mendoza, S., Pallás-Allonso, C., Ruiz Peláez,

J.G., Sizun, J., Widström, A.M., 2010. Towards universal Kangaroo Mother Care:

recommendations and report from the First European conference and Seventh

International Workshop on Kangaroo Mother Care. Acta Paediatr. 99, 820–826.

Oatridge, A., Holdcroft, A., Saeed, N., Hajnal, J.V., Puri, B.K., Fusi, L., Bydder, G.M.,

2002. Change in brain size during and after pregnancy: study in healthy women

and women with preeclampsia. Am. J. Neuroradiol. 23, 19–26.

Odent, M., 2009. The instincts of motherhood: bringing joy back into newborn care.

Early Hum. Dev. 85, 697–700.

Ohana, E., Mazor, M., Chaim, W., Levy, J., Sharoni, Y., Leiberman, J.R., Glezerman, M.,

1996. Maternal plasma and amniotic ﬂuid cortisol and progesterone

concentrations between women with and without term labor. A comparison.

J. Reprod. Med. 41, 80–86.

Olza Fernandez, I., Marin Gabriel, M., Malalana Martinez, A., Fernandez-Canadas

Morillo, A., Lopez Sanchez, F., Costarelli, V., 2012. Newborn feeding behaviour

depressed by intrapartum oxytocin: a pilot study. Acta Paediatr. 101, 749–754.

Olza Fernandez, I., Marin Gabriel, M.A., Garcia Murillo, L., Malalana Martinez, A.M.,

Costarelli, V., Millan Santos, I., 2013. Mode of delivery may inﬂuence neonatal

responsiveness to maternal separation. Early Hum. Dev. 89, 339–342.

Ounsted, M.K., Boyd, P.A., Hendrick, A.M., Mutch, L.M., Simons, C.D., Good, F.J.,

1978a. Induction of labour by different methods in primiparous women. II.

neuro-behavioural status of the infants. Early Hum. Dev. 2, 241–253.

Ounsted, M.K., Hendrick, A.M., Mutch, L.M., Calder, A.A., Good, F.J., 1978b. Induction

of labour by different methods in primiparous women. I some perinatal and

postnatal problems. Early Hum. Dev. 2, 227–239.

Papatsonis, D.N., Flenady, V., Liley, H., 2013. Maintenance therapy with oxytocin

antagonists for inhibiting preterm birth after threatened preterm labour.

Cochrane Database Syst. Rev. 10, CD005938.

Pawluski, J.L., Galea, L.A., 2006. Hippocampal morphology is differentially affected

by reproductive experience in the mother. J. Neurobiol. 66, 71–81.

Pawluski, J.L., Galea, L.A., 2007. Reproductive experience alters hippocampal

neurogenesis during the postpartum period in the dam. Neuroscience 149,

53–67.

Pawluski, J.L., Brummelte, S., Barha, C.K., Crozier, T.M., Galea, L.A., 2009. Effects of

steroid hormones on neurogenesis in the hippocampus of the adult female

rodent during the estrous cycle, pregnancy, lactation and aging. Front.

Neuroendocrinol. 30, 343–357.

Pawluski, J.L., van den Hove, D.L., Rayen, I., Prickaerts, J., Steinbusch, H.W., 2011.

Stress and the pregnant female: impact on hippocampal cell proliferation, but

not affective-like behaviors. Horm. Behav. 59, 572–580.

Pawluski, J.L., Charlier, T.D., Fillet, M., Houbart, V., Crispin, H.T., Steinbusch, H.W.,

van den Hove, D.L., 2012. Chronic ﬂuoxetine treatment and maternal adversity

differentially alter neurobehavioral outcomes in the rat dam. Behav. Brain Res.

228, 159–168.

Pierrehumbert, B., Nicole, A., Muller-Nix, C., Forcada-Guex, M., Ansermet, F., 2003.

Parental post-traumatic reactions after premature birth: implications for

sleeping and eating problems in the infant. Arch. Dis. Child. Fetal Neonatal

Ed. 88, F400–F404.

Porter, R.H., Winberg, J., 1999. Unique salience of maternal breast odors for

newborn infants. Neurosci. Biobehav. Rev. 23, 439–449.

Poulain, D.A., Wakerley, J.B., 1982. Electrophysiology of hypothalamic

magnocellular neurones secreting oxytocin and vasopressin. Neuroscience 7,

773–808.

Preis, K., Bidzan, M., Swiatkowska-Freund, M., Peplinska, A., 2012. Long-term

follow-up for organic dysfunction in breech – presenting children. Med. Sci.

Monit. 18, CR741–CR746.

Prevost, M., Zelkowitz, P., Tulandi, T., Hayton, B., Feeley, N., Carter, C.S., Joseph, L.,

Pournajaﬁ-Nazarloo, H., Yong Ping, E., Abenhaim, H., Gold, I., 2014. Oxytocin in

pregnancy and the postpartum: relations to labor and its management. Front.

Public Health 2, 1.

Puolakka, J., Kauppila, A., Tuimala, R., Jouppila, R., Vuori, J., 1983. The effect

of parturition on umbilical blood plasma levels of norepinephrine. Obstet.

Gynecol. 61, 19–21.

Raine, A., Brennan, P., Mednick, S.A., 1994. Birth complications combined with early

maternal rejection at age 1 year predispose to violent crime at age 18 years.

Arch. Gen. Psychiatry 51, 984–988.

Raine, A., Brennan, P., Mednick, S.A., 1997. Interaction between birth complications

and early maternal rejection in predisposing individuals to adult violence:

speciﬁcity to serious, early-onset violence. Am. J. Psychiatry 154, 1265–1271.

Rasia-Filho, A.A., Fabian, C., Rigoti, K.M., Achaval, M., 2004. Inﬂuence of sex, estrous

cycle and motherhood on dendritic spine density in the rat medial amygdala

revealed by the Golgi method. Neuroscience 126, 839–847.

Rauh, C., Beetz, A., Burger, P., Engel, A., Haberle, L., Fasching, P.A., Faschingbauer, F.,

2012. Delivery mode and the course of pre- and postpartum depression. Arch.

Gynecol. Obstet. 286, 1407–1412.

Roberts, J., Hanson, L., 2007. Best practices in second stage labor care: maternal

bearing down and positioning. J. Midwifery Womens Health 52, 238–245.

Ronca, A.E., Alberts, J.R., 1995. Simulated uterine contractions facilitate fetal and

newborn respiratory behavior in rats. Physiol. Behav. 58, 1035–1041.

Ronca, A.E., Abel, R.A., Ronan, P.J., Renner, K.J., Alberts, J.R., 2006. Effects of labor

contractions on catecholamine release and breathing frequency in newborn

rats. Behav. Neurosci. 120, 1308–1314.

Rupp, H.A., James, T.W., Ketterson, E.D., Sengelaub, D.R., Ditzen, B., Heiman, J.R.,

2014. Amygdala response to negative images in postpartum vs

nulliparouswomen and intranasal oxytocin. Soc. Cogn. Affect. Neurosci. 9, 48–

54.

Russell, J.A., Leng, G., Douglas, A.J., 2003. The magnocellular oxytocin system, the

fount of maternity: adaptations in pregnancy. Front. Neuroendocrinol. 24, 27–

61.

Ryding, E.L., Wijma, B., Wijma, K., 1997. Posttraumatic stress reactions after

emergency cesarean section. Acta Obstet. Gynecol. Scand. 76, 856–861.

Ryding, E.L., Wijma, K., Wijma, B., 1998. Psychological impact of emergency

cesarean section in comparison with elective cesarean section, instrumental

and normal vaginal delivery. J. Psychosom. Obstet. Gynaecol. 19, 135–144.

Salmaso, N., Cossette, M.P., Woodside, B., 2011. Pregnancy and maternal behavior

induce changes in glia, glutamate and its metabolism within the cingulate

cortex. PLoS ONE, e23529.

Schlinzig, T., Johansson, S., Gunnar, A., Ekstrom, T.J., Norman, M., 2009. Epigenetic

modulation at birth altered DNA-methylation in white blood cells after

cesarean section. Acta Paediatr. 98, 1096–1099.

Schubert, F., George, J.M., Rao, M.B., 1981. Vasopressin and oxytocin content of

human fetal brain at different stages of gestation. Brain Res. 213, 111–117.

Shaw, R.J., Bernard, R.S., Deblois, T., Ikuta, L.M., Ginzburg, K., Koopman, C., 2009. The

relationship between acute stress disorder and posttraumatic stress disorder in

the neonatal intensive care unit. Psychosomatics 50, 131–137.

Simon-Areces, J., Dietrich, M.O., Hermes, G., Garcia-Segura, L.M., Arevalo, M.,

Horvath, T.L., 2012. Ucp2 induced by natural birth regulates neuronal

differentiation of the hippocampus and related adult behavior. PLoS ONE 7,

e42911.

Slattery, D.A., Neumann, I.D., 2008. No stress please! mechanisms of stress

hyporesponsiveness of the maternal brain. J. Physiol. 586, 377–385.

Smith, J., Plaat, F., Fisk, N.M., 2008. The natural caesarean: a woman-centred

technique. BJOG 115, 1037–1042.

Soderquist, J., Wijma, K., Wijma, B., 2002. Traumatic stress after childbirth: the role

of obstetric variables. J. Psychosom. Obstet. Gynaecol. 23, 31–39.

I. Olza-Fernández et al. / Frontiers in Neuroendocrinology 35 (2014) 459–472 471

Souza, J. P., Gulmezoglu, A., Lumbiganon, P., Laopaiboon, M., Carroli, G., Fawole, B.,

WHO Global Survey on Maternal and Perinatal Health Research Group., 2010.

Caesarean section without medical indications is associated with an increased

risk of adverse short-term maternal outcomes: The 2004–2008 WHO global

survey on maternal and perinatal health. BMC Med. 8, 71.

Stallings, J., Fleming, A.S., Corter, C., Worthman, C., Steiner, M., 2001. The effects of

infant cries and odors on sympathy, cortisol and autonomic responses in new

mothers and nonpostpartum women. Parent. Sci. Pract. 1, 71–100.

Stern, J.M., Goldman, L., Levine, S., 1973. Pituitary-adrenal responsiveness

during lactation in rats. Neuroendocrinol. 12, 179–191.

Stern, J.E., Hestrin, S., Armstrong, W.E., 2000. Enhanced neurotransmitter release at

glutamatergic synapses on oxytocin neurones during lactation in the rat. J.

Physiol. 526, 109–114.

Strathearn, L., 2011. Maternal neglect: oxytocin, dopamine and the neurobiology of

attachment. J. Neuroendocrinol. 23, 1054–1065.

Strathearn, L., Fonagy, P., Amico, J., Montague, P.R., 2009a. Adult attachment

predicts maternal brain and oxytocin response to infant cues.

Neuropsychopharmacology 34, 2655–2666.

Strathearn, L., Mamun, A.A., Najman, J.M., O’Callaghan, M.J., 2009b. Does

breastfeeding protect against substantiated child abuse and neglect? A 15-

year cohort study. Pediatrics 123, 483–493.

Sullivan, R.M., McGaugh, J.L., Leon, M., 1991. Norepinephrine-induced plasticity and

one-trial olfactory learning in neonatal rats. Brain Res. Dev. Brain Res. 60, 219–

228.

Swain, J.E., Tasgin, E., Mayes, L.C., Feldman, R., Constable, R.T., Leckman, J.F., 2008.

Maternal brain response to own baby-cry is affected by cesarean section

delivery. J. Child Psychol. Psychiatry 49, 1042–1052.

Szabo, A.L., 2013. Review article: intrapartum neuraxial analgesia and breastfeeding

outcomes: limitations of current knowledge. Anesth. Analg. 116, 399–405.

Takagi, T., Tanizawa, O., Otsuki, Y., Haruta, M., Yamaji, K., 1985. Oxytocin in the

cerebrospinal ﬂuid and plasma of pregnant and non-pregnant subjects. Horm.

Metab. Res. 17, 308–310.

Takeda, S., Kiwabara, Y., Mizuno, M., 1985. Effects of pregnancy and labor on

oxytocin levels in human plasma and cerebrospinal ﬂuid. Endocrinol. Jpn. 32,

875–880.

Tasker, J.G., Di, S., Boudaba, C., 2002. Functional synaptic plasticity in hypothalamic

magnocellular neurons. Prog. Brain Res. 139, 113–119.

Theodosis, D.T., Poulain, D.A., 2001. Maternity leads to morphological synaptic

plasticity in the oxytocin system. Prog. Brain Res. 133, 49–58.

Theodosis, D.T., Trailin, A., Poulain, D.A., 2006. Remodeling of astrocytes, a

prerequisite for synapse turnover in the adult brain? insights from the

oxytocin system of the hypothalamus. Am. J. Physiol. Regul. Integr. Comp.

Physiol. 290, R1175–R1182.

Torner, L., Neumann, I.D., 2002. The brain prolactin system: involvement in stress

response adaptations in lactation. Stress 5, 249–257.

Tyzio, R., Cossart, R., Khalilov, I., Minlebaev, M., Hübner, C.A., Represa, A., Ben-Ari, Y.,

Khazipov, R., 2006. Maternal oxytocin triggers a transient inhibitory switch in

GABA signaling in the fetal brain during delivery. Science 314, 1788–1792.

Tyzio, R., Cossart, R., Khalilov, I., Represa, A., Ben-Ari, Y., Khazipov, R., 2007.

Response to comment on ‘‘Maternal oxytocin triggers a transient inhibitory

switch in GABA signaling in the fetal brain during delivery’’. Science 317, 197.

Tyzio, R., Nardou, R., Ferrari, D.C., Tsintsadze, T., Shahrokhi, A., Eftekhari, S., Khalilov,

I., Tsintsadze, V., Brouchoud, C., Chazal, G., Lemonnier, E., Lozovaya, N.,

Burnashev, N., Ben-Ari, Y., 2014. Oxytocin-mediated GABA inhibition during

delivery attenuates autism pathogenesis in rodent offspring. Science 343, 675–

679.

Uvnäs-Moberg, K., 1996. Neuroendocrinology of the mother–child interaction.

Trends Endocrinol. Metab. 7, 126–131.

Uvnäs-Moberg, K., Widström, A.M., Werner, S., Matthiesen, A.S., Winberg, J., 1990.

Oxytocin and prolactin levels in breast-feeding women. Correlation with milk

yield and duration of breast-feeding. Acta Obstet. Gynecol. Scand. 69, 301–306.

Valenzuela, G.J., Craig, J., Bernhardt, M.D., Holland, M.L., 1995. Placental passage of

the oxytocin antagonist atosiban. Am. J. Obstet. Gynecol. 172, 1304–1306.

Varendi, H., Porter, R.H., 2001. Breast odour as the only maternal stimulus elicits

crawling towards the odour source. Acta Paediatr. 90, 372–375.

Varendi, H., Porter, R.H., Winberg, J., 2002. The effect of labor on olfactory exposure

learning within the ﬁrst postnatal hour. Behav. Neurosci. 116, 206–211.

Veenema, A.H., Neumann, I.D., 2008. Central vasopressin and oxytocin release:

regulation of complex social behaviours. Prog. Brain Res. 170, 261–276.

Velandia, M., Matthisen, A.S., Uvnas-Moberg, K., Nissen, E., 2010. Onset of vocal

interaction between parents and newborns in skin-to-skin contact immediately

after elective cesarean section. Birth 37, 192–201.

Virani, S., Dolinoy, D.C., Halubai, S., Jones, T.R., Domino, S.E., Rozek, L.S., Nahar, M.S.,

Padmanabhan, V., 2012. Delivery type not associated with global methylation at

birth. Clin. Epigenetics 4, 8.

Vogl, S.E., Worda, C., Egarter, C., Bieglmayer, C., Szekeres, T., Huber, J., Husslein, P.,

2006. Mode of delivery is associated with maternal and fetal endocrine stress

response. BJOG 113, 441–445.

Wahl, R.U., 2004. Could oxytocin administration during labor contribute to autism

and related behavioral disorders? – a look at the literature. Med. Hypotheses 63,

456–460.

Walker, C.D., Toufexis, D.J., Burlet, A., 2001. Hypothalamic and limbic expression of

CRF and vasopressin during lactation: implications for the control of ACTH

secretion and stress hyporesponsiveness. Prog. Brain Res. 133, 99–110.

Wankaew, N., Jirapradittha, J., Kiatchoosakun, P., 2013. Neonatal morbidity and

mortality for repeated cesarean section vs. normal vaginal delivery to

uncomplicated term pregnancies at Srinagarind Hospital. J. Med. Assoc. Thai.

96, 654–660.

Wellmann, S., Buhrer, C., 2012. Who plays the strings in newborn analgesia at birth,

vasopressin or oxytocin? Front. Neurosci. 6, 78.

Wellmann, S., Benzing, J., Cippa, G., Admaty, D., Creutzfeldt, R., Mieth, R.A., Bucher,

H.U., 2010. High copeptin concentrations in umbilical cord blood after vaginal

delivery and birth acidosis. J. Clin. Endocrinol. Metab. 95, 5091–5096.

White-Traut, R., Watanabe, K., Pournajaﬁ-Nazarloo, H., Schwertz, D., Bell, A., Carter,

C.S., 2009. Detection of salivary oxytocin levels in lactating women. Dev.

Psychobiol. 51, 367–373.

World Health Organization, 2003. Global Strategy for Infant and Young Child

Feeding. World Health Organization, Geneva.

Widstrom, A.M., Ransjo-Arvidson, A.B., Christensson, K., Matthiesen, A.S., Winberg,

J., Uvnas-Moberg, K., 1987. Gastric suction in healthy newborn infants. Effects

on circulation and developing feeding behaviour. Acta Paediatr. Scand. 76, 566–

572.

Wieczorek, P.M., Guest, S., Balki, M., Shah, V., Carvalho, J.C., 2010. Breastfeeding

success rate after vaginal delivery can be high despite the use of epidural

fentanyl: an observational cohort study. Int. J. Obstet. Anesth. 19, 273–277.

Wiesenfeld, A.R., Malatesta, C.Z., Whitman, P.B., Granrose, C., Uili, R., 1985.

Psychophysiological response of breast- and bottle-feeding mothers to their

infants’ signals. Psychophysiology 22, 79–86.

Wigger, A., Lörscher, P., Oehler, I., Keck, M.E., Naruo, T., Neumann, I.D., 1999.

Nonresponsiveness of the rat hypothalamo-pituitary-adrenocortical axis to

parturition-related events: inhibitory action of endogenous opioids.

Endocrinology 140, 2843–2849.

Wijma, K., Soderquist, J., Wijma, B., 1997. Posttraumatic stress disorder after

childbirth: a cross sectional study. J. Anxiety Disor. 11, 587–597.

Wiklund, I., Norman, M., Uvnas-Moberg, K., Ransjo-Arvidson, A.B., Andolf, E., 2009.

Epidural analgesia: breast-feeding success and related factors. Midwifery 25,

e31–e38.

Willcox, D.L., Yovich, J.L., McColm, S.C., Phillips, J.M., 1985. Progesterone, cortisol

and oestradiol-17 beta in the initiation of humanparturition: partitioning

between free and bound hormone in plasma. Br. J. Obstet. Gynaecol. 92, 65–71.

Wilson, M.J., MacArthur, C., Cooper, G.M., Bick, D., Moore, P.A., Shennan, A., COMET

Study Group UK, 2010. Epidural analgesia and breastfeeding: a randomised

controlled trial of epidural techniques with and without fentanyl and a non-

epidural comparison group. Anaesthesia 65, 145–153.

Winberg, J., 2005. Mother and newborn baby: mutual regulation of physiology and

behavior–a selective review. Dev. Psychobiol. 47, 217–229.

Windle, R.J., Gamble, L.E., Kershaw, Y.M., Wood, S.A., Lightman, S.L., Ingram, C.D.,

2006. Gonadal steroid modulation of stress-induced hypothalamo-pituitary-

adrenal activity and anxiety behavior: role of central oxytocin. Endocrinology

147, 2423–2431.

Workman, J.L., Barha, C.K., Galea, L.A., 2012. Endocrine substrates of cognitive and

affective changes during pregnancy and postpartum. Behav. Neurosci. 126, 54–

72.

Yektaei-Karin, E., Moshfegh, A., Lundahl, J., Berggren, V., Hansson, L.O., Marchini, G.,

2007. The stress of birth enhances in vitro spontaneous and IL-8-induced

neutrophil chemotaxis in the human newborn. Pediatr. Allergy Immunol. 18,

643–651.

Yeo, J.A.G., Keverne, E.B., 1986. The importance of vaginal–cervical stimulation for

maternal behaviour in the rat. Physiol. Behav. 37, 23–26.

Young, D., 2011. ‘‘Gentle cesareans’’: better in some respects, but fewer cesareans

are better still. Birth 38, 183–184.

Zanardo, V., Savona, V., Cavallin, F., D’Antona, D., Giustardi, A., Trevisanuto, D., 2012.

Impaired lactation performance following elective delivery at term: role of

maternal levels of cortisol and prolactin. J. Matern. Fetal Neonat. Med. 25,

1595–1598.

Zanardo, V., Pigozzo, A., Wainer, G., Marchesoni, D., Gasparoni, A., Di Fabio, S.,

Trevisanuto, D., 2013. Early lactation failure and formula adoption after elective

caesarean delivery: cohort study. Arch. Dis. Child. Fetal Neonatal Ed. 98, F37–

F41.

472 I. Olza-Fernández et al. / Frontiers in Neuroendocrinology 35 (2014) 459–472

Tipos de partos y niveles de oxitocina, cortisol y hormonas tiroideas en plasma del cordón umbilical

Article

Full-text available

Mar 2023
Rev Chil Obstet Ginecolog

Introducción: La placenta sintetiza y secreta varias hormonas que permiten la regulación del embarazo, el trabajo de parto y la adaptación metabólica materno-fetal. Su comportamiento asociado al tipo de parto puede dar información relevante sobre efectos epigenéticos. Objetivo: Describir el tipo de parto con los niveles de oxitocina, cortisol y hormonas tiroideas en plasma de cordón umbilical al nacer. Método: A 50 mujeres con embarazos principalmente normales se les cuantificaron los niveles neurohormonales en plasma de cordón umbilical, obtenido inmediatamente tras el periodo expulsivo. Los resultados se incorporaron a la base de datos clínicos de cada participante y se analizaron con Stata v.14.0. El protocolo fue aprobado por el comité de ética. Resultados: Hubo 33 partos vaginales (12 espontáneos, 13 acelerados y 8 inducidos) y 17 cesáreas (7 electivas y 10 de urgencia). Se observaron mayores niveles de cortisol en los partos vaginales acelerados; las cesáreas tuvieron menores niveles de cortisol y hormona estimulante de la tiroides. Las intervenciones clínicas, con altos o bajos niveles hormonales, están en directa relación con el tipo de parto. Conclusiones: El cortisol y la hormona estimulante de la tiroides medidos en plasma de cordón umbilical variaron según el tipo de parto. Esto es una primera cuantificación de hormonas en plasma de cordón umbilical y su posible regulación placentaria a propósito del tipo de parto.

Skin-to-Skin Contact in the Third Stage of Labor and Postpartum Hemorrhage Prevention: A Scoping Review

Article

Full-text available

Mar 2023
MATERN CHILD HLTH J

Introduction Literature supports numerous benefits of skin-to-skin contact for neonatal adaptation to extrauterine life and bonding/attachment, but few studies explore the effects of skin-to-skin contact on maternal outcomes. This review aims to map the evidence on skin-to-skin contact in the third stage of labor for postpartum hemorrhage prevention. Methods Scoping review, which covered stages recommended by the Institute Joanna Briggs, including studies from the PubMed, EMBASE, CINAHL, LILACS, Web of Science, and Scopus databases, using the descriptors “Postpartum hemorrhage”, “Labor stages, third”, “Prevention” and “Kangaroo care/Skin-to-skin”. Results 100 publications on the subject found, 13 articles met the inclusion criteria, with 10,169 dyads were assessed in all studies. Publications from 2008 to 2021 were mostly written in English and designed as a randomized controlled trial. Skin-to-skin contact was effective and significant in: reducing the duration of the third stage of labor; placenta delivery; uterine contractility and physiological involution; absence of atony, decreasing blood loss with lower rates of erythrocyte and hemoglobin drop; reducing the need for synthetic oxytocin and/or ergometrine to control bleeding; and reducing changing pads per period and length of stay. Discussion Skin-to-skin contact was considered an effective, low-cost, and safe strategy, with positive effects already established in the literature for infants and extremely favorable results in postpartum hemorrhage prevention cases, being highly recommended in assistance for the dyad. Open Science Framework Registry (https://osf.io/n3685).

Microbiome and Long-Term Health Considerations

Chapter

Full-text available

Apr 2024

José Octavio Zavala-Soto

All the tissues of our body are formed by cells, but there are at least 1–10 times more microbes than cells in it, which coexist in balance and help us maintain our health. Most of them are found in the intestine; through their interaction with the food, they produce a great variety of functions related to nutrition and the functioning of the nervous, immune, and cardiovascular systems through their influence on gene programming, among others. It is now known that there are periods in life that are more sensitive and have greater long-term impacts that depend on the proper functioning of this large number of microbes in the human body. Pregnancy, birth, and the first 2 years of the life of a human are crucial stages that can predispose a person to health or disease, and in this chapter, we will be able to delve into the role played by cesarean section as a way of birth in this regard.

Impact of intrapartum oxytocin administration on neonatal sucking behavior and breastfeeding

Article

Full-text available

Mar 2024

This study aimed to examine the effect of intrapartum oxytocin administration on neonatal sucking behavior and breastfeeding. A total of 64 pairs (29 in the group treated with intrapartum oxytocin and 35 in the control group) of normal infants within 24–48 h of birth and their mothers were recruited. Sucking ability was evaluated by measuring Non-Nutritive Sucking (NNS) for 5 min. Data on the rate of exclusive breastfeeding at 1 month postpartum were collected. In the adjusted multiple regression models, intrapartum oxytocin exposure was significantly associated with fewer total NNS bursts (95% confidence interval (CI), −7.02 to −0.22), longer pause times (95% CI, 1.33 to 10.21), and greater pause-time variability (95% CI, 3.63 to 63.92). Effects estimated using structural equation modeling revealed that intrapartum oxytocin exposure had a significant negative and direct effect on the practice of exclusive breastfeeding 1 month postpartum (β = −0.238, p = 0.047). However, no NNS-mediated indirect effects were observed. This report demonstrates that infants born to mothers who receive intrapartum oxytocin may have impaired sucking ability for at least the first 48 h after birth, and breastfeeding support should be provided.

Case report: Psychotherapy for enhancing psychological adjustment to dysphoric milk ejection reflex

Article

Full-text available

Jan 2024

Reem Deif

Given its endless benefits, breastfeeding is widely acknowledged as the optimal choice for both maternal and infant health. Nevertheless, breastfeeding mothers often encounter various challenges that may hinder their ability to fully embrace this experience. This report delves into a compelling case of Dysphoric Milk Ejection Reflex (D-MER), a largely underexamined mental health issue among lactating mothers. D-MER is characterized by intense aversion right before milk let down, which can significantly impede a mother’s willingness to breastfeed. The primary aim of this case report is to provide a comprehensive psychological understanding of D-MER, emphasizing aspects of attachment, the transition into motherhood, and the sociocultural sexualization of the female body. We also offer an overview of the psychotherapeutic journey, highlighting key insights and progress achieved over a span of six months. Therapy adopted an integrative approach combining narrative techniques and skills training such as mindfulness to facilitate a comprehensive therapeutic experience. This case underscores the psychological dimensions of the breastfeeding experience, complementing the well-established biochemical and physiological aspects of D-MER. It also emphasizes the need for further research into the psychological facets of both successful and less successful breastfeeding experiences.

Impact of Early Bonding During the Maternal Sensitive Period on Long-Term Effects: A Systematic Review

Article

Full-text available

Jan 2024

This research project examines the long-term effects of maternal-neonatal bonding during a mother's "sensitive period." The review explores how early contact between a mother and her newborn can affect their psychosocial and emotional well-being in the future. Within an hour after birth, oxytocin levels increase for mothers, while catecholamine surges enhance neonates' memory retention to encourage immediate skin-to-skin contact (SSC), which promotes breastfeeding with benefits, such as quicker placenta expulsion, less bleeding, and lower stress. As per sources to date, there is no systematic review on this subject; however, numerous studies exist regarding short-term outcomes, exclusive breastfeeding, and childhood problems. The exploration involves rigorous searches of academic databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for transparency and reproducibility by using the Population, Intervention, Comparison, and Outcome (PICO) framework. Of the 516 initially identified articles, only five were relevant based on refined selection criteria, making it clear from the analysis that sensitive-period bonding produces long-term impacts in infants. Few studies are available, particularly in recent years; thus, more research is required in this area.

Is Birth Method Associated with Sensory Hyperreactivity in Children 3-4 Years in an Upper-Middle-Income Country?

Article

Full-text available

Nov 2023
Occup Ther Int

Background Research has shown that pressure in the vaginal birth process aids the infant's neurophysiological adaption to extrauterine life, including their ability to regulate their responses to diverse sensory stimuli. As pressure is absent in elective caesarean section births, we hypothesised that these children may be at higher risk for developing sensory hyperreactivity (SHR), a sensory modulation difficulty which negatively impacts on the child's engagement in their occupations. This paper reports on a study which investigated associations between birth method and SHR. Method In this cross-sectional study, 91 children aged three and four years from various language, cultural, and socioeconomic groups were recruited and categorised based on birth method (caesarean section or vaginal birth). Caregivers of each child completed the Short Sensory Profile-2 and a demographic questionnaire. The prevalence of SHR between the birth method groups was compared. Results The prevalence of SHR was greater in the vaginal birth group (29%) than the caesarean section group (9%). Mothers in the vaginal birth group were younger (p ≤ 0.001), of lower-income level (p = 0.003), and more likely to be single (p = 0.037). During data collection with the vaginal birth group, comprehensibility of certain items in the Short Sensory Profile-2 proved challenging for many caregivers. Conclusion The statistically significant higher prevalence of SHR in the vaginal birth group supported a null hypothesis. However, the results are questioned due to the challenges related to data collection. Given this, the study supports the need for further investigation of how sociocultural and socioeconomic factors influence the assessment of SHR in the South African context.

Infant feeding practices and autism spectrum disorder in US children aged 2–5 years: the national survey of children’s health (NSCH) 2016–2020

Article

Full-text available

Aug 2023

Objective To investigate the relationship between infant feeding practices and autism spectrum disorder (ASD) among children aged 2–5 years in the United States (US). Methods Data from the 2016–2020 National Survey of Children’s Health, a nationally representative cross-sectional survey, were utilized for this study. Questionnaires were administered to parents of children aged 2–5 years to gather information on ASD diagnosis, infant feeding practices, and demographic factors (e.g., child sex, ethnic group, and maternal age at birth). Logistic regression with sample weights was employed to assess the association between infant feeding practices and ASD, while controlling for demographic variables. Polynomial regression models were used to examine trends in exclusive breastfeeding and ever breastfeeding rates among children with and without ASD. Results A total of 35,050 children aged 2–5 years were analyzed, including 616 diagnosed with ASD, after excluding participants with missing information on breastfeeding and ASD diagnosis. Of these children with ASD, 76.6% (n = 472) had a breastfeeding history, with 67.5% (n = 416) engaged in partial breastfeeding and 9.1% (n = 56) exclusively breastfed. Adjusted odds ratios for each additional month of breastfeeding compared to never being breastfed were 0.98 (95% CI, 0.96–1.01). The adjusted odds ratios for breastfeeding durations of > 0–6 months, > 6–12 months, > 12–24 months, and > 24 months were 0.81 (95% CI, 0.50–1.31), 0.65 (95% CI, 0.36–1.18), 0.81 (95% CI, 0.44–1.49), and 0.48 (95% CI, 0.23–1.01), respectively. Compared to children who were never breastfed, the adjusted odds ratio for children who were ever breastfed was 0.74 (95% CI, 0.47–1.18). Among children with ASD, the proportion of ever breastfeeding declined from 82.0% in 2017 to 64.3% in 2020, while exclusive breastfeeding decreased from 12.0% in 2016 to 4.2% in 2020. Conclusions and relevance Although no significant association was found between infant feeding practices and ASD among US children aged 2–5 years, the rates of breastfeeding, particularly exclusive breastfeeding, were suboptimal among children with ASD. This highlights the need for specific policies and practices to promote and support breastfeeding among parents of children with ASD or those at high risk of having a child with ASD.

Impact of intrapartum oxytocin administration on neonatal sucking behavior and breastfeeding

Preprint

Full-text available

Sep 2023

This study aimed to examine the effect of intrapartum oxytocin administration on neonatal sucking behavior and breastfeeding. A total of 64 pairs (29 in the group treated with intrapartum oxytocin and 35 in the control group) of normal infants within 24–48 h of birth and their mothers were recruited. Sucking ability was evaluated by measuring Non-Nutritive Sucking (NNS) for 5 min. Data on the rate of exclusive breastfeeding at 1 month postpartum were collected. In the adjusted multiple regression models, intrapartum oxytocin exposure was significantly associated with fewer total NNS bursts (95% confidence interval (CI), -6.811 to -0.311), longer pause times (95% CI, 0.320 to 9.223), and greater pause-time variability (95% CI, 4.453 to 62.738). Effects estimated using structural equation modeling revealed that intrapartum oxytocin exposure had a significant negative and direct effect on the practice of exclusive breastfeeding 1 month postpartum (β=-.238, p = 0.047). However, no NNS-mediated indirect effects were observed. This report demonstrates that infants born to mothers who receive intrapartum oxytocin may have impaired sucking ability for at least the first 48 h after birth, and breastfeeding support should be provided.

Bases scientifiques et niveau de preuve des soins de développement

Chapter

Jan 2017

Making Meaning:Women’s Birth Narratives

Article

Full-text available

Jan 2004

Lynn Callister

Stress during labor and delivery and early lactation performance

Article

Aug 1998

The amount of stress experienced by both the mother and fetus during labor and delivery varies considerably and is likely to be different in primiparous and multiparous women. In this study we explored relations between the birth experience and lactation performance of 40 women. Stress hormones were measured in serum or plasma during pregnancy, parturition (cord and maternal blood), and lactation. Milk samples were obtained and breast-feeding frequency was recorded each day during the first 2 wk postpartum. Four outcomes were used as markers of lactogenesis: the time when the subject first felt fullness in the breasts, 24-h milk volume on day 5 postpartum, milk lactose concentration on day 5, and the day of appearance of casein in the milk as determined by gel electrophoresis. There were significant intercorrelations among the outcome variables, except for milk lactose. Compared with multiparous women, primiparous mothers experienced a delay in breast fullness and lower milk volume on day 5. In multiple regression analyses excluding subjects who had cesarean deliveries (n = 5), markers of both fetal and maternal stress during labor and delivery (cord glucose concentration and maternal exhaustion score) were associated with delayed breast fullness and casein appearance; delayed casein appearance was also associated independently with a longer duration of labor. Milk volume on day 5 was lower in women with higher exhaustion scores, and, in multiparous women, those who breast-fed less frequently on day 2. The milk lactose concentration was inversely related to pregnancy weight gain. These results indicate that primiparity, long labor, stress to the mother and fetus during labor and delivery, and elevated cord glucose concentrations are risk factors for delayed lactogenesis.

Separation Distress Call in the Human Neonate in the Absence of Maternal Body Contact

Article

Feb 1996

Review Article: Intrapartum Neuraxial Analgesia and Breastfeeding Outcomes

Article

Jun 2014
Obstet Anesth Digest

A.L. Szabo

(Anesth Analg. 2013;116(2):399–405)

Increased accumulation of oxytocin messenger ribonucleic acid in the hypothalamus of the female rat: induction by long term estradiol and progesterone administration and subsequent progesterone withdrawal.

Article

Jan 1995

To examine a possible role for gonadal steroid hormones in the enhanced accumulation of hypothalamic oxytocin (OT) messenger RNA (mRNA) and peptide in late pregnancy, we used an established model (22) in which sequential administration of estradiol (E2) and progesterone (P) SILASTIC capsules to ovariectomized rats is followed by removal of P. Long term and sustained E2 combined with abrupt P withdrawal mimics the gonadal steroid hormone pattern of late gestation in the rat (22). Using this paradigm, we demonstrate that OT mRNA is increased in the rat hypothalamus after long term P treatment, but only in the presence of E2 and only when P capsules are removed 48 h before killing. Furthermore, we show that P replacement in primiparous rats during late pregnancy blunts the increase in OT mRNA normally observed at the end of gestation. Our results support a role for E2 priming and P withdrawal in the enhanced accumulation of OT mRNA in the hypothalamus of the female rat.

Observations on the developing relationship between mother and baby in the neonatal period

Article

Jan 1977

Hormones and Brain Plasticity

Article

Jun 2009

L.M. Garća-Segura

One of the most fascinating developments in the field of neuroscience in the second half of the 20th century was the discovery of the endogenous capacity of the brain for reorganization during adult life. Morphological and functional mechanisms underlying brain plasticity have been extensively explored and characterized. However, our understanding of the functional significance of these plastic changes is still fragmentary. This book shows that brain plasticity plays an essential role in the regulation of hormonal levels. The second aim is to propose that hormones orchestrate the multiple endogenous plastic events of the brain for the generation of adequate physiological and behavioral responses in adaptation to and in prediction of changing life conditions. The book starts by introducing the conceptual backgrounds on the interactions of hormones and brain plasticity. It then devotes itself to the analysis of the role of brain plasticity in the regulation of the activity of endocrine glands. It examines different hormonal influences on brain plasticity. Then, it goes on to cover the interactions of hormones and brain plasticity along the life cycle under physiological and pathological conditions.

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