Music specially composed for preterm babies helps strengthen the development of neural networks

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In Switzerland, as in most industrialized countries, nearly 1% of children are born “very prematurely”, i.e. before the 32nd week of pregnancy, which represents about 800 children yearly.

While advances in neonatal medicine now give them a good chance of survival, these children are however at high risk of developing neuropsychological disorders.

To help the brains of these fragile newborns develop as well as possible despite the stressful environment of intensive care, researchers at the University of Geneva (UNIGE) and the University Hospitals of Geneva (HUG), Switzerland, propose an original solution: music written especially for them.

And the first results, published in the Proceedings of the National Academy of Sciences (PNAS) in the United States, are surprising: medical imaging reveals that the neural networks of premature infants who have listened to this music, and in particular a network involved in many sensory and cognitive functions, are developing much better.

And the first results, published in the Proceedings of the National Academy of Sciences (PNAS) in the United States, are surprising: medical imaging reveals that the neural networks of premature infants who have listened to this music, and in particular a network involved in many sensory and cognitive functions, are developing much better.

The Neonatal Intensive Care Unit at the HUG welcomes each year 80 children born far too early – between 24 and 32 weeks of pregnancy, i.e. almost four months ahead of schedule for some of them.

The vast majority will survive, but half will later develop neurodevelopmental disorders, including learning difficulties, attentional or emotional disorders.

“At birth, these babies’ brains are still immature. Brain development must, therefore, continue in the intensive care unit, in an incubator, under very different conditions than if they were still in their mother’s womb,” explains Petra Hüppi, professor at the UNIGE Faculty of Medicine and Head of the HUG Development and Growth Division, who directed this work.

“Brain immaturity, combined with a disturbing sensory environment, explains why neural networks do not develop normally.”

A tailor-made music

The Geneva researchers started from a practical idea: since the neural deficits of premature babies are due, at least in part, to unexpected and stressful stimuli as well as to a lack of stimuli adapted to their condition, their environment should be enriched by introducing pleasant and structuring stimuli.

As the hearing system is functional early on, music appeared to be a good candidate.

But which music? “Luckily, we met the composer Andreas Vollenweider, who had already conducted musical projects with fragile populations and who showed great interest in creating music suitable for premature children,” says Petra Hüppi.

Lara Lordier, PhD in neurosciences and researcher at the HUG and UNIGE, unfolds the musical creation process.

“It was important that these musical stimuli were related to the baby’s condition.

We wanted to structure the day with pleasant stimuli at appropriate times: music to accompany their awakening, music to accompany their falling asleep, and music to interact during the awakening phases.”

To choose instruments suitable for these very young patients, Andreas Vollenweider played many kinds of instruments to the babies, in the presence of a nurse specialized in developmental support care.

“The instrument that generated the most reactions was the Indian snake charmers’ flute (the punji),” recalls Lara Lordier.

Risultati immagini per Indian snake charmers’ flute

“Very agitated children calmed down almost instantly, their attention was drawn to the music!” The composer thus wrote three sound environments of eight minutes each, with punji, harp and bells pieces.

More efficient brain functional connections through music

The study was conducted in a double-blind study, with a group of premature infants who listened to the music, a control group of premature infants, and a control group of full-term newborns to assess whether the brain development of premature infants who had listened to the music would be more similar to that of full-term babies.

Scientists used functional MRI at rest on all three groups of children.

Without music, premature babies generally had poorer functional connectivity between brain areas than full-term babies, confirming the negative effect of prematurity.

“The most affected network is the salience network which detects information and evaluates its relevance at a specific time, and then makes the link with the other brain networks that must act.

This network is essential, both for learning and performing cognitive tasks as well as in social relationships or emotional management,” says Lara Lordier.

This shows a preterm baby listening to music

Premature baby listening to music.. The image is credited to Stéphane Sizonenko – UNIGE HUG.

In intensive care, children are overwhelmed by stimuli unrelated to their condition: doors open and close, alarms are triggered, etc.

Unlike a full-term baby who, in utero, adjusts its rhythm to that of its mother, the premature baby in intensive care can hardly develop the link between the meaning of a stimulus in a specific context.

On the other hand, the neural networks of children who heard Andreas Vollenweider’s music were significantly improved: the functional connectivity between the salience network and auditory, sensorimotor, frontal, thalamus and precuneus networks, was indeed increased, resulting in brain networks organisation more similar to that of full-term infants.

When children grow up

The first children enrolled in the project are now 6 years old, at which age cognitive problems begin to be detectable.

Scientists will now meet again their young patients to conduct a full cognitive and socio-emotional assessment and observe whether the positive outcomes measured in their first weeks of life have been sustained.


Preterm birth has been defined as any birth before 37 weeks completed weeks of gestation. An estimated 15 million infants are born preterm, with resulting complications.

It is the principal cause of an estimated one million neonatal deaths annually and a significant contributor to childhood morbidities. Low and middle income countries (LMIC) carry a higher burden of disease attributed to preterm birth.

The World Health Organisation (WHO) defines preterm birth as any birth before 37 completed weeks of gestation, or fewer than 259 days since the first day of the woman’s last menstrual period (LMP). This is further subdivided on the basis of gestational age (GA):

  • extremely preterm (<28 weeks);
  • very preterm (28–<32 weeks);
  • moderate or late preterm (32–<37 completed weeks of gestation).

This is the most extensively used and accepted definition of preterm birth [1].

The ability to accurately determine the completed weeks of gestation varies widely between pregnancies, with the most precise assessment methods not uniformly available across different settings.

Vaccination in pregnancy has been widely implemented to protect women and their babies from tetanus and pertussis in recent years, with an increasing number of vaccines being developed and trialled for use in pregnancy against a variety of bacterial and viral infections.

As preterm birth is such an important pregnancy outcome that may represent an adverse event, it is important to establish a case definition for use across vaccine studies and post-licensure surveillance that is able to make use of all methodologies used to calculate gestational age, and that incorporates a hierarchy based upon the precision of the various methods used.

The nomenclature of GA is typically discussed in terms of the number of completed weeks (e.g., 33 weeks and 2 days, or 33 2/7 weeks).

Defining GA has been considered useful in terms of neonatal outcome.

In the past, three groups have been classified and utilised according to delivery following the onset of the last menstrual period. Pre-term: less than 259 days (37 weeks), term: 259–293 days (37–41 weeks). Post-term: 294 days (42 weeks) or more.

A term birth has been defined as between 37 and 42 weeks and used to describe the optimal timing for a good outcome for the mother and baby.

The International Classification of Diseases defines term pregnancy as a delivery from 37 completed weeks to less than 42 completed weeks (259–293 days) of gestation.

However, neonatal outcomes vary within this wide gestational age range, with a 2012 international stakeholder working group recommending sub-categorisation of term birth to more accurately describe deliveries and their outcomes.

These sub-categories are: early term (37 0/7 weeks of gestation through 38 6/7 weeks gestation); full term (39 0/7 weeks of gestation through 40 6/7 weeks of gestation); late term (41 0/7 weeks of gestation through 41 6/7 weeks of gestation); and, post term (42 0/7 weeks of gestation and beyond).

The American College of Obstetricians and Gynaecologists (ACOG) and the Society for Maternal–Foetal Medicine (SMFM) has endorsed this recommendation and encourages its use for categorising GA [2][3][4][5].

1.1.1. Pathophysiology of preterm birth

Causes of preterm birth are complex and the pathophysiology that triggers preterm birth is largely unknown, however, contributing maternal, foetal and placental predisposing factors have been identified.

The most common of these include: antepartum haemorrhage or abruption; mechanical factors such as uterine over-distention and cervical incompetence; hormonal changes; and, bacterial infection and inflammation [6][7].

Over the past 20 years the access to assisted reproduction technology (ART) in many high income countries has contributed to the rise in the number of multiple births and an overall increase in the rates of preterm delivery.

Infants born from multiple pregnancies are more likely to be born preterm due to spontaneous labour or premature rupture of membranes (PROM), or as a result of maternal conditions such as pre-eclampsia or foetal disorders [8][9].

Changes to policies which limit the number of embryos implanted as part of ART have led to a decline in the number of preterm births due to assisted fertility [10][11].

Epidemiologic studies have identified preterm birth risk factors as maternal age of less than 17 years or more than 35 years, being underweight, having an overweight pre-pregnancy body mass index, and short stature. Preterm birth rates vary geographically and within ethnic origins, with LMIC consistently having higher rates [7][12].

Physical and psychosocial stress and smoking have also been associated with higher preterm risk as does a previous preterm birth.

The assessment and diagnosis of preterm birth has remained problematic since it is not a defined disease and the WHO definition does not contain universally recognised reference standards. Different methodologies are used for assessing GA and because reporting rates vary widely between and within countries, accurate comparison of reporting rates of preterm birth and trending data is difficult to analyse [13][14][15][16][17].

1.1.2. Preterm birth categorisation

Preterm birth defined as less than 37 completed weeks encompasses a wide gestational age range with rates varying across countries.

The WHO subcategories of ‘extremely preterm’, ‘very preterm’ and ‘moderate or late preterm’ are recommended to improve comparability of preterm birth data in relation to immunisation.

A limitation of the WHO definition is that there is no boundary between spontaneous abortion and a viable birth, complicating the assessment of preterm birth in the extremely preterm group of babies.

A comparison between and within countries becomes complex with varying gestational lower limits of viability over time and across different settings. Determining a lower limit is complex as it is variably defined and arbitrary.

It is often described in terms of risk factors and its causes, and is predominately developed according to postnatal viability and data quality in different settings [17][18][19][20].

Preterm births are reported only for live born infants.

The pregnancy outcomes differ across countries where the upper limit for national or regional criteria for registration of a foetal death range from 16 weeks to 28 weeks, this impacting on the proportion of preterm births [21].

The registrations of births in LMIC often do not routinely record GA and the data on birthweight (BW) is often not recorded or compiled. It has been reported that 58% of babies in these countries are not weighed at birth and home based births are not represented [20][22][23].

1.1.3. Preterm birth following immunisation: what is known in literature?

Pregnant women are at increased risk of morbidity and mortality and adverse pregnancy outcomes, including preterm birth, due to vaccine preventable diseases. Vaccination in pregnancy is a recognised preventive measure for protecting the mother, foetus and infant [24][25][26][27].

Until the 1960s vaccines, including polio, influenza, diphtheria and tetanus toxoid vaccines, were routinely administered to pregnant women in maternal immunisation programmes.

Studies in a variety of developed settings detected no increase in adverse consequences for the mother or foetus in vaccinated women [28][29].

However, the thalidomide teratogenicity disaster in pregnant women resulted in widespread concerns about the safety of all medicine use in pregnancy, including vaccines. Vaccines were then recommended to be only administered in the third trimester of pregnancy to prevent any attribution of teratogenicity risk, as well as to minimise the potential risk to the course of normal gestation such as induction of premature labour [30][31].

Over recent decades, with further development of safe and immunogenic vaccines, as well as improved ability to explore pregnancy outcome datasets, ongoing studies have provided important information on vaccine safety.

Immunisation with inactivated vaccines and toxoids during pregnancy has not been associated with any increased risk to the mother or baby.

The extensive use of Tetanus Toxoid (TT) and Tetanus diphtheria (Td) in pregnant women, to prevent neonatal tetanus, has shown no clinically significant adverse events and no adverse pregnancy outcomes for women who have received the Tetanus, diphtheria, acellular pertussis (Tdap) vaccine during pregnancy [32][33][34].

The US Advisory Committee on Immunisation Practices (ACIP) in 2012 updated their recommendations to providers of prenatal care to implement a Tdap immunisation programme for all pregnant women to reduce the burden of pertussis in infants. Its recommendation is for its use with every pregnancy.

Similarly, in October 2012, the United Kingdom Department of Health recommended a temporary Tdap programme in pregnancy in response to an outbreak [35][36][37][38].

An observational cohort study linking more than 20,000 vaccinated women with pregnancy outcomes showed no increase in stillbirth or other major complications, including preterm birth [39].

Immunisation of pregnant women with inactivated trivalent influenza vaccine has also been recommended and endorsed for more than a decade showing no increase in adverse events. Pregnant women who received H1N1 influenza vaccine during the 2009 H1N1 influenza pandemic were in fact less likely to give birth preterm [40][41][42][43][44][45][46][47].

Live viral vaccines, such as measles, mumps, rubella (MMR); varicella; intranasal live-attenuated influenza; Yellow Fever, and BCG however are contraindicated and not recommended during pregnancies, with a theoretical risk that the vaccine virus could be transmitted to the foetus [48].

Follow up of inadvertent vaccinations of pregnant women with live vaccines have not demonstrated significant adverse effects but these limited data have not been sufficient to change recommendations. The risk benefit to the mother and neonate needs to be taken into account.

1.1.4. Existing case definitions for preterm birth

Historically, preterm birth was determined using neonatal physical examination, reviewing clinical history and socio-demographics [49][50].

Early definitions of prematurity relied on BW, using a birth weight category of less than 2300 or 2500 g.

One of the earliest working definitions was introduced by the World Health Assembly (WHA) in 1948 using a birth weight of 2500 g (5 pounds, 8 ounces) or less as a determinant [49].

Early epidemiological studies of prematurity tended to include all low birth weight babies irrespective of gestation. BW was used as a criterion alone as it was objective, easily measured, and the survival of the very low birth weight (VLBW) neonates was described in birth weight specific categories [51][52][53][54].

BW however, can only be used as a surrogate in the lower gestational age babies where it has been identified to be a specific and sensitive method in assessing the early preterm.

Babies weighing less than 1500 g are predominately assessed as being preterm [55][56]. The lack of standardised birthweight categories makes it difficult to analyse and compare data from different regions [22][57][58][59].

However, BW based standards for preterms are complicated by physiological variables that occur more commonly pregnancies complicated by preterm birth [60][61].

Preterm infants are often growth restricted and conventional BW charts are limited as they do not reflect the degree of growth restriction.

The Foetal Growth Longitudinal Study (FGLS), part of the INTERGROWTH-21 Project developed international growth and size standards for foetuses.

The growth standards are recommended for the clinical interpretation of ultrasound measurements and for comparisons across populations [62].

Foetal growth standards for preterm infants will determine the precise incidence of foetal growth restriction when gestation is known [63][64][65].

The World Health Organisation (WHO) definition of preterm birth remains the most widely utilised and accepted definition.

The International Classification of Diseases (ICD-9, ICD-10) defines preterm birth as less than 37 completed weeks (less than 259 days) of gestation.

The duration of gestation is measured from the first day of the LMP. GA is expressed in completed days or completed weeks (e.g., events occurring 280–286 completed days after the onset of the LMP are considered to have occurred at 40 weeks of gestation).

Where the date of the LMP is not available, GA is based on the best clinical estimate [2].

A search of terminology databases, including the Global Alliance on Prevention of Prematurity (GAPPS), the National Institutes of Health, and the Common Terminology Criteria for Adverse Events (CTCAE) show a consistency with the WHO definition as the onset of labour before 37 completed weeks of pregnancy (full term is 40 completed weeks) [7][66].

Essential in any definition or the sub classification of preterm birth is the need for accurate dating. GA has evolved as the stand alone parameter for determining preterm birth.

In 1949 the U.S. National Centre for Health Statistics of the Centres for Disease Control and Prevention revised the World Health Assembly definition and deleted the reference to BW, to include only the reporting of the length of pregnancy in weeks.

In 1956 this was further revised to specify the reporting of completed weeks of gestation [67].

A 1961 report by the Expert Committee on Maternal and Child Health of the World Health Organisation highlighted the difference between premature and those infants of low birth weight (LBW) and in 1970 a working party of obstetricians and paediatricians at the Second European Congress of Perinatal Medicine set the boundary between preterm and term birth at 37 weeks of gestation [5].

This is the basis of the most recent widely utilised and accepted definition of prematurity [68].

Before the development of more accurate methods of estimating gestation, the LMP remains as the most widely available measure. This method is used where ultrasound (US) is not available or accessible and is recommended by the WHO for determining preterm birth [12][69][70].

When available, in the clinical context, it is a valid and applicable measure, especially when estimating gestation of less than or equal to 33 weeks.

Its limitations are discussed as being a determinant based on self-reporting and therefore felt to be imprecise. Studies have shown, however, that women who were certain of their LMP were accurate in their assessment of pregnancy duration compared with their ultrasound dating [71].

When information about the LMP is absent or uncertain, estimates of gestational age can be determined from a clinical assessment including the description of pregnancy symptoms such as nausea, fatigue, tender swollen breasts, frequent urination, a pelvic examination when performed in the first trimester and fundal height (FH) ascertainment.

One study demonstrated a high correlation between early pregnancy dating up to 9 completed weeks by a clinician based on an examination and history and that determined by ultrasound but this is influenced by the skill and experience of the clinician [72].

Fundal height (FH) is often used in conjunction with LMP and/or the BW of the neonate, especially in low resource settings. Women from many traditional societies however often do not record their LMP date and can present late in the first trimester.

Variability in FH measurements relate to previous caesarean section (C/S), multiple pregnancy, race, maternal height, intrauterine growth retardation, maternal obesity, polyhydramnios, and a difference in examination techniques.

FH measurement is not standardised and use beyond 16 weeks reduces in accuracy, affecting its reliability and the precision of dating [58][73][74].

Its use in combination with more sensitive assessment methods is recommended.

Through the advent of US, the use of early home pregnancy tests, ART such as intrauterine insemination (IUI), and home ovulation test kits, the actual timing of conception can be determined and therefore accurate dating of gestational age performed. Pregnancies achieved through ART represent the most accurate method.

Outside the use of ART, an ultrasound performed in the first trimester (≤13 6/7 weeks), is viewed as the most accurate and reliable measure.

There has been a shift from using LMP to using US for predicting an actual date of delivery.

Estimation of the foetal crown rump length ± biparietal diameter/femur length between the gestational age of 6–18 weeks shows an accuracy within 5–7 days. In women with uncertain dates an early US is recommended for optimal dating [3].

The methodology for US gestational age assessment, however, is not standardised and tends to give a transitory increase in preterm births when compared to the use of LMP alone.

In addition, US accessibility in LMIC is limited for the majority of women and therefore cannot be considered a universal measure for determining preterm birth [20][57][75][76][77][78].

Defining preterm delivery for LMIC would therefore be strengthened by the use of one or both measures when available [4][79][80][81][82][83].

Where measurements such as LMP, US or antenatal clinical assessment are absent or likely to be inaccurate, a recommended criterion for determining preterm birth is a clinical estimation of gestational age based on the physical and neurological examination of the neonate [84][85].

A review of methods used identified tools based on neurological and physical criteria, or physical criteria alone.

Methods that use neurologic criteria are proven, reliable measures with expert operators but the feasibility for use is compromised especially in LMIC, being limited by complexity, and requiring skill and experience to perform [70][86][87][88][89].

Ascertainment of neurologic signs and external characteristics used in the assessment need to be precise and accurate to ensure correct correlation with actual GA [51][90][91].

The physical examination based systems have been refined and modified to improve their applicability and accuracy. Some methods now use external characteristics alone, enabling gestational age to be determined and estimated in all settings.

Using the available methods ranging in the current criteria, there is a correlation with LMP based estimation of over 90%, but an acknowledged range of error for predicting clinical maturity of ±2.4 weeks. Physical examination tools alone, when used for neonates under 28–33 weeks are recognised to be inaccurate and are therefore are not recommended to be used as a measure to accurately estimate the gestation of neonates within the lower limit of viability [92][93][94][95][96][97].

The Ballard Maturational Score, known as the New Ballard Score, uses both physical and neurological assessment and has been refined and expanded to include extremely premature neonates and is described as a valid and accurate gestational assessment tool [98].

Source:
University of Geneva
Media Contacts: 
Petra Hüppi – University of Geneva
Image Source:
The image is credited to Stéphane Sizonenko – UNIGE HUG.

Original Research: The study will appear in PNAS.

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