Maternal voice induces an increase of oxytocin in premature babies reducing pain

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A baby born prematurely often has to be separated from its parents and placed in an incubator in intensive care. For several weeks, he or she will undergo routine medical procedures that can be painful, without being relieved by too many pharmaceutical painkillers, which are risky for his or her development. So how can we act for the good of the baby?

A team from the University of Geneva (UNIGE), in collaboration with the Parini Hospital in Italy and the University of Valle d’Aosta, observed that when the mother spoke to her baby at the time of the medical intervention, the signs of the baby’s expression of pain decreased and his oxytocin level – the hormone involved in attachment and also linked to stress – increased significantly, which could attest to better pain management.

These results, to be read in the journal Scientific Reports, demonstrate the importance of parental presence with premature babies, who are subjected to intense stress from birth, a presence that has a real impact on their well-being and development.

As soon as they are born before 37 weeks of gestation, premature babies are separated from their parents and placed in an incubator, often in intensive care. They have to undergo daily medical interventions, necessary to keep them alive (intubation, blood sampling, feeding tube, etc.), which have potential impacts on their development and pain management.

The difficulty? It is not always possible to relieve them with pharmaceutical painkillers, as the short and long term side effects on their neurological development can be significant.

There are other ways to relieve the baby, such as wrapping, restraint, sugar solutions or non-nutritive sucking with a teat.

However, for several years now, studies have shown that the presence of a mother or father has a real calming effect on the child, particularly through the emotional modulations of the voice.

This is why the team of Didier Grandjean, full professor at the Psychology Section of the Faculty of Psychology and Educational Sciences (FPSE) and at the Swiss Center for Affective Sciences (CISA) of the UNIGE, has been interested in the early vocal contact between the mother and the premature baby, in the impact of the mother’s voice on the management of pain resulting from the routine practices necessary for the follow-up of the babies, and in the psychological and cerebral mechanisms that would be involved.

Including the mother in the heel prick

To test this hypothesis, the scientists followed 20 premature babies at the Parini Hospital in Italy and asked the mother to be present during the daily blood test, which is done by extracting a few drops of blood from the heel. “We focused this study on the maternal voice, because in the first days of life it is more difficult for the father to be present, due to working conditions that do not always allow days off,” says Dr. Manuela Filippa, a researcher in Didier Grandjean’s group and first author of the study.

The study was conducted in three phases over three days, allowing for comparison: a first injection was taken without the mother being present, a second with the mother talking to the baby and a third with the mother singing to the baby. The order of these conditions changed randomly.

“For the study, the mother started talking or singing five minutes before the injection, during the injection and after the procedure,” says the Geneva researcher. We also measured the intensity of the voice, so that it would cover surrounding noise, as intensive care is often noisy due to ventilations and other medical devices.

Signs of pain expression significantly reduced

First, the research team observed whether the baby’s pain decreased in the presence of the mother. To do this, they used the Preterm Infant Pain Profile (PIPP), which establishes a coding grid between zero and 21 for facial expressions and physiological parameters (heartbeat, oxygenation) attesting to the baby’s painful feelings.

“In order to code the behavior of premature babies, we filmed each blood test and judged the videos ‘blind,” by trained personnel, without sound, so as not to know whether the mother was present or not,” notes Didier Grandjean.

The results are significant: the PIPP is 4.5 when the mother is absent and drops to 3 when the mother talks to her baby. “When the mother sings, the PIPP is 3.8. This difference with the spoken voice can be explained by the fact that the mother adapts her vocal intonations less to what she perceives in her baby when she sings, because she is in a way constrained by the the melodic structure, which is not the case when she speaks,” emphasizes the Geneva professor.

Maternal voice induces an increase in oxytocin

The scientists then looked at what changes in the baby when it hears its mother speak. “We quickly turned to oxytocin, the so-called attachment hormone, which previous studies have already linked to stress, separation from attachment figures and pain,” explains Dr. Manuela Filippa.

Using a painless saliva sample before the mother spoke or sang and after the heel prick, the research team found that oxytocin levels rose from 0.8 picograms per milliliter to 1.4 when the mother spoke. “In terms of oxytocin, this is a significant increase,” she says.

These results show the positive impact of the mother’s presence when premature babies undergo painful medical procedures. “We demonstrate here the importance of bringing parents and child together, especially in the delicate context of intensive care,” Manuela Filippa emphasizes.

“Furthermore, parents play a protective role here and can act and feel involved in helping their child to be as well as possible, which strengthens the essential attachment bonds that are taken for granted in a full-term birth,” concludes Didier Grandjean.


xytocin is a neuropeptide hormone that functions in the physiological responses to pain and stress (Neumann et al., 2000) and promotes prosocial behaviors (Carter, 1998). In particular, during the early period after birth, OXT regulates maternal behaviors (Pedersen, 1997) by promotion of social interactions and positive emotions (Uvnas-Moberg, 1998). Inhibition of OXT receptors or a decrease in OXT production, such as following separation of the mother and infant or stress during the critical neonatal period, correlate with poor maternal behaviors, and this has long-term negative consequences on the prosocial behaviors of mothers and infants. Animal studies have documented the protective effect of OXT administration, in that a single dose can reverse the effects of maternal separation and the many adverse sequelae in rodent pups (Lee et al., 2007). PTI often experience early maternal separation and painful events or procedures in the NICU, and these two risk factors are often simultaneous and appear to interact synergistically.

Positive social interactions can suppress internal physiologic systems that are activated by stress, and stimulate other internal systems that attenuate stress. OXT plays a crucial role in the attenuation of stress by enhancing the buffering effect of social support on stress responsiveness (Heinrichs et al., 2003). The cumulative effects of early maternal contact and an increased level of OXT can protect PTIs against many sequelae of early maternal separation and their painful experiences during their first weeks of life in the NICU. In this context, the maternal voice can have positive effect on infant recovery from stressful events (Seltzer et al., 2010).

Creating an environment that decreases the negative effects associated with preterm birth is one of the main aims of individualized developmental care in the NICU. Implementation of a series of protective actions during the different stages of painful procedures, mediated by the OXT system, can reduce the impact of these procedures on PTIs during their time in the NICU (Figure 1).

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FIGURE 1
Possible effect of early contact on the different phases of a preterm infant’s experience of pain in the NICU and role of the OXT system.

In light of the many studies reviewed here, we suggest the following protective actions for pain management in the NICU:

simple – Active involvement of parents with the infant during all phases of painful procedures in the NICU, including the

simple – preparation phase, the phase of acute pain, and the consolatory/reunion phase;

simple – Active involvement of nursing staff in supporting parental involvement with their infants during the preparation and consolatory phases of painful NICU procedures;

simple – Use of EVC as a non-pharmacological intervention to encourage contact between parents and PTIs, by use of live and directed speech and songs directed to the PTIs.

A limitation of this review is the lack of human studies, especially on the impact of pain and early maternal separation on the OXT system. Moreover, additional human studies are necessary to improve our understanding of the impact of exogenous administration – or endogenous production – of OXT on an infant’s brain and social behaviors.

Finally, further research is needed to investigate the impact of early contact between parents and infants in the NICU on regulation of the OXT system. Identification of the role of the OXT system during stressful conditions, such as painful procedures in the NICU, seems to be a particularly promising topic for future research.

. . .

Parental Contact During Routine Painful Procedures Provides Protection by Stimulating the OXT System
Early social experiences can affect social behaviors during adulthood by modifying the OXT system (Meaney, 2001). In particular experiences of early contact or separation have long-term effects – even transgenerational effects – by modulating the OXT system.

In parallel, early and repeated painful experiences (especially in PTIs) induce long-term over-sensitization to pain and stress, and have significant consequences on infant social and emotional competencies. As with maternal separation, the OXT system also plays a crucial role in repairing and reconstructing the infant’s resilience in response to painful stimuli. Thus, clinical and maternal care can act by increasing the endogenous activation of the OXT system.

These results suggest that the care of PTIs should consider establishment of an appropriate ecological niche to promote infant development (Browne, 2017) and administration of individualized care (Als et al., 2004). A positive social environment, with experiences of the social interactions of daily life, continuously activates the OXT system.

Interventions that sustain social engagement, especially when there is diminished mother-infant contact due to infant prematurity or postpartum depression (Feldman et al., 2010), can have a positive impact on the OXT systems of the infant and mother and on subsequent social and emotional competencies.

Effect of Early Vocal Contact on Stress and Pain of Neonates

Recent research has shown that non-pharmacological analgesic interventions, such as SSC, can diminish the adverse outcomes associated with neonatal pain and reduced maternal care. In addition, Seltzer et al. (2010) demonstrated that infant-directed speech (“motherese”) led to increased peripheral OXT release in 6 year-old children who were exposed to a social stressor. Thus, vocalizations may be as important as skin-to-skin contact for the neuroendocrine regulation of social bonding in humans.

Recent animal studies have also identified the effect of social vocalizations on OXT regulation and social behaviors (Tops et al., 2011; Theofanopoulou et al., 2017). Interestingly, electrophysiological studies in mice reported activation of the mother’s auditory cortex in response to pup ultrasonic vocalizations (USVs), but no such activation in females not exposed to these USVs (Liu and Schreiner, 2007; Cohen et al., 2011).

Two species of “singing mice” (Scotinomys teguina and Scotinomys xerampelinus), which have a complex vocal repertoire, exhibit high OXT receptor binding in brain regions related to social memory, including the hippocampus and medial amygdala (Campbell et al., 2009). Moreover, OXT null mutant mice were less vocal than wild-type controls during separations from the mother and peers (Winslow et al., 2000).

Remarkably, OXT also mediates the response to acoustic social stimuli (Marlin et al., 2015). Furthermore, the injection of OXT into the hypothalamus increases the rate and duration of USVs by female hamsters, suggesting that OXT controls these USVs as a crucial component in the initiation or maintenance of social contact (Floody et al., 1998).

Given that a rat’s OXT receptors are very active in the auditory cortex of the mother, and are activated by USVs, it is plausible that reciprocal vocalizations or calls play a fundamental role in the mother-infant bonding, possibly by activating a dopaminergic response and activation of OXT receptors. Studies of 2 week-old Octodon degus rodents reported an increased density of the NMDA receptors in limbic brain areas at 3 days after 6 episodes of brief parental deprivation and exposure to an unfamiliar environment, and that parental vocalizations during the separation period suppressed this response (Ziabreva et al., 2003).

Moreover, behavioral observations indicated that parental vocalizations suppress the exploratory activity of rat pups, most likely through its “anxiolytic” effect (Braun et al., 2003). There is also evidence that parental vocal communications regulate the pup’s physical development (Poeggel and Braun, 1996; Braun and Scheich, 1997) and behavior, and presumably protect the pup from exposure to frightening situations and reduce the level of anxiety during stressful experiences, such separation or pain.

During and after exposure to pain, maternal protective and consolatory vocal behaviors are essential for emotional recovery of offspring, even though these behaviors do not directly impact the origin of pain. OXT plays a crucial role in these consolatory behaviors (Burkett et al., 2016).

Potential Effects of Early Vocal Contact on OXT Regulation

In light of these previous studies, early vocal contact (EVC) in the form of live maternal speech and songs, can be an effective method for reducing pain in infants who are undergoing medical procedures. EVC is an early family-based intervention with a high degree of contact, in which mothers and fathers speak and sing intimately with their preterm infant (Filippa et al., 2017b). This increases the PTI’s emotional and autonomic stability (Filippa et al., 2013) and reduces maternal anxiety (Arnon et al., 2014). The support from a music therapist can allow the PTI to engage in communicative musicality (Haslbeck, 2014) when they hear specific songs of kin (“lullabies”) (Loewy, 2015).

Moreover, EVC, as a form of live and dynamic musical contact, decreases an infant’s sensitivity to painful stimuli. Maternal singing is one of the most widespread forms of intuitive and nurturing music experiences among humans. This ubiquitous form of communication provides early social and communicative cues to the infant. It is finely tuned to the infant’s needs and expectancies. The infant is not merely a passive receiver, but experiences an active “call” for participation in a reciprocal musical play. Music can affect social interactions among humans, and Chanda and Levitin (2013) proposed that the OXT system plays a crucial role in this response. EVC is also an effective method because it is a social vocalization involving emotions.

OXT and Recognition of Vocal Emotions

It is well known that emotional prosody can affect socialization and the capacity of humans to infer the mental states of others, either implicitly, or explicitly (Grandjean et al., 2006). Many studies found that OXT plays a crucial role in improving recognition of emotions from vocalizations.

For example, intranasal administration of OXT improves the recognition of emotions associated with different facial expressions (Domes et al., 2010; Shahrestani et al., 2013) and body postures (Bernaerts et al., 2016). Tops et al. (2011) suggested that individuals who have a specific OXT receptor polymorphism (GG genotype, rs53576), which presumably has stronger binding to OXT, have increased sensitivity to social processing and fewer difficulties in hearing and understanding people in the presence of background noise.

Similarly, Hovey et al. (2018) showed that activation of the OXT pathway, specifically the aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) gene, is significantly associated with the ability to recognize audio-visual emotions. Other research showed that nasal administration of OXT specifically enhanced the ability to discern the emotional states of others, but not with inferring their beliefs.

In particular, Aoki et al. (2014) performed a clinical double-blind, placebo-controlled, within-subject crossover trial of subjects with autism spectrum disorders, and found that intranasal OXT administration increased the rate of correctly inferring the social emotions of others, but not inferring their beliefs.

Their imaging analysis also indicated that the right anterior insula, which was initially negatively correlated with difficulties in emotion inferences in these subjects, is significantly increased and correlated with the enhanced ability to infer the emotions of others following OXT administration. Furthermore, Hollander et al. (2007) reported improved recognition of emotion in vocalizations following OXT administration to patients with autism spectrum disorders. These findings thus establish relationships of vocal communication, social processing, and OXT level.

OXT as a Neuroprotective Factor in the Development of Preterm Infants

In addition to the potential effect of EVC and OXT on reducing pain and stress in infants, there is also evidence that OXT acts as a direct neuroprotective factor during development of the infant brain, and that OXT has different mechanisms and potential molecular targets in this process.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454868/


More information: Maternal speech decreases pain scores and increases oxytocin levels in preterm infants during painful procedures, Scientific Reports (2021). DOI: 10.1038/s41598-021-96840-4

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