An infant is considered to be preterm when born prior to 8 and a half months (37 weeks) of pregnancy. Their organs are not all ready to face the challenges of extrauterine life. Recent medical advances are now able to compensate for and reduce the consequences of this immaturity, at least to a certain degree. Research is still continuing with the aim of further improving the management of the growing number of infants who come into this world a little too soon.

  • More than 50,000 births per year including 10% very preterm and 5% extremely preterm infants
  • 4 organs are mainly affected: Brain, Lungs, Gastrointestinal tract, Arterial duct
  • 2 kg This is the weight at which a baby can be taken out of the incubator
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Report drawn up in collaboration with Pierre-Yves Ancel, Inserm Research Director, Director of the Obstetric, Perinatal and Pediatric Epidemiology Team (EPOPé), Centre de recherche épidémiologie et statistique (Inserm Unit 1153) and Jean-Christophe Rozé, Professor of Pediatrics, Head of the Neonatal and Pediatric Intensive Care Department (CHU de Nantes)

 

Loupe comprendre Understanding prematurity

A preterm birth occurs before the term of pregnancy, which corresponds to 41 weeks, i.e., 9 and a half months from the date of the last period. An infant is considered to be preterm when born prior to 37 weeks of pregnancy (GA for Gestational Age), i.e., 8 and a half months of pregnancy.

Three levels of prematurity are defined:

  • moderate preterm which corresponds to births between 32 and 36 weeks of pregnancy inclusive (7 to 8 months of pregnancy),
  • very preterm corresponding to births between 28 and 32 weeks GA (6 to 7 months of pregnancy),
  • and extremely preterm for births prior to 28 weeks, i.e., prior to 6 months of pregnancy.

No births have survived prior to 23 weeks, i.e., prior to five months of pregnancy.

The preterm birth rate in France and numerous developed countries has risen in recent years. Preterm infants increased from 5.9% of births in 1995 to 7.4% in 2010. Between 50,000 and 60,000 preterm infants are born each year in France. 85% of these are moderate preterm (32-37 GA), 10% very preterm (28-32 GA), and 5% extremely preterm, born prior to 28 GA.

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Prematurity, neonates in an incubator © Inserm/Depardieu, Michel

Pictogramme foetus Multiple causes

Approximately 50% of preterm births are spontaneous, due to early contractions, the cause of which is rarely identified, or premature rupture of membranes (rupture can sometimes be due to infection).

The remaining half of preterm births are induced births. This is then due to a medical decision, and birth usually takes place via C-section. The decision for preterm birth may be made owing to a risk of fetal or maternal death during the pregnancy. This risk may be related to serious fetal growth retardation, severe maternal hypertension, or maternal hemorrhage the cause of which is not always explained.

Severe maternal hypertension accounts for approximately 20% of the reasons for delivery prior to 32 weeks of pregnancy. This may lead to serious complications such as pre-eclampsia, characterized by renal abnormalities, or eclampsia evidenced by seizures in the mother owing to brain damage. It may also cause hepatic disorders, destruction of red blood cells and blood platelets.

Other possible causes of premature birth include: genitourinary or generalized infections, uterine or placental abnormalities (such as placenta previa which may be complicated by hemorrhage), maternal diabetes, or, indeed, placental abruption (premature detachment of the placenta accompanied by hematoma).

A third of preterm infants are from multiple pregnancies.

Other factors, such as difficult socioeconomic conditions, older mothers, stress, or even tobacco use, can also be involved. Hence, the preterm birth rate is two times lower among women in senior positions compared to female workers and employees.

Preparing for preterm birth

Medical follow-up during pregnancy serves to identify at-risk situations and screen for complications liable to result in preterm birth (growth retardation, maternal hypertension, etc.). When faced with the threat of preterm birth, administration of corticosteroids during the 10 days prior to birth is able to accelerate fetal lung maturation, and to prevent certain cases of neonatal cerebral and respiratory problems, together with death. Under these circumstances, the mother should be referred to a "type III" maternity unit with neonatal intensive care facilities.

Rouages Immaturity in preterm neonates and corresponding care

Imagerie fonctionnelle par ultrasons : visualisation des vaisseaux de petit et moyen calibre dans le cortex central d’un prématuré (en collaboration avec Olivier Baud, chef du service Néonatalogie de l'hôpital Robert-Debré) ©  Inserm/Demené, Charlie/Baud, Olivier/Biran, Valérie/Alison, Marianne/Pernot, Mathieu/Tanter, Mickaël
Functional ultrasound imaging: visualization of small and medium caliber vessels in the central cortex of a preterm infant © Inserm, C. Demené, O. Baud, V. Biran, A. Marianne, M. Pernot, M. Tanter

Preterm birth interrupts the infant's in utero development: their organs are present, but are still immature. This mainly concerns four organs: the brain, lungs, gastrointestinal tract and ductus arteriosus.

Immaturity of the central nervous system

Although the brain structures are in place, brain immaturity is observed in very preterm infants. Essential stages of brain development occur between 24 and 32 weeks of gestation. Preterm birth therefore interrupts the normal maturation process and optimum brain development.

Regular monitoring by EEG and imaging techniques is essential in the first few weeks to screen for any abnormalities, particularly in very preterm infants.

When faced with the threat of preterm birth, administration of corticosteroids to the mother reduces the risk of brain hemorrhage in the infant. Magnesium sulfate, sometimes administered in combination, also appears to reduce the risk of cerebral palsy.

Immature lungs

Mature lungs secrete a substance which coats the surface of the pulmonary alveoli and allows them to function properly: surfactant. Preterm infant lungs are not yet able to secrete this substance, which leads to respiratory difficulties. Infants are able to produce surfactant after 32 weeks on average; however, this may vary considerably from one infant to another.

It is thus essential to administer exogenous surfactant to preterm infants through a tube. Respiratory assistance in the form of mechanical ventilation via the nasal route or intubation is also used to compensate for immature lungs.

Unfortunately, in certain infants, mechanical ventilation associated with immature lungs can become complicated by inflammation and bronchial hyperresponsiveness which causes pulmonary disease: bronchopulmonary dysplasia. This complication is one of the main causes of morbidity among preterm infants.

Furthermore, preterm infants born prior to 34-36 weeks of pregnancy frequently present pauses in breathing (apnea) due to immature neurorespiratory control. These pauses may lead to decreased blood oxygen levels, thus necessitating respiratory assistance. Treatment with a caffeine derivative stimulates the neurorespiratory centers. This is routinely given to very preterm infants.

Écrans de surveillance des grands prématurés par système de monitoring néonatal mise au point par l'équipe SEPIA Surveillance ©  Inserm/Latron, Patrice
Laboratoire Traitement du Signal de l'Image (LTSI), SEPIA team

Cardiorespiratory immaturity

Slowing of heart rate is common in preterm infants, owing to the immaturity of the heart rate control system which makes it highly sensitive to any changes (lack of oxygen, pause in breathing, gastric reflux, etc.). Moreover, in the fetus, a vessel exists which connects the aorta and pulmonary artery throughout fetal development. This vessel is blocked spontaneously and permanently at birth. However, in preterm infants, closure is delayed and may result in reflux of blood to the lungs. In this case, medicinal treatment is necessary to induce closure.

Immaturity of the digestive system

Preterm infants have not yet acquired the sucking reflex, and swallowing and breathing mechanisms are not coordinated. Hence, prior to a gestational age of 34 weeks, infants require enteral nutrition, using a tube which passes through the mouth, into the gastrointestinal tract. The choice of milk depends on gestational age. Breast milk is recommended, either from the mother or milk bank (with human milk from other women). Enriched milk may be used. Specific milk for preterm infants is also available.

Immaturity of the digestive system may become complicated by a rare, but fatal and not widely known disease: necrotizing enterocolitis. This corresponds to destruction of the gastrointestinal tract. Although this disease only affects 2% of very preterm infants, it sometimes only occurs three to four weeks after birth, when carers believe the most difficult stage is behind them.

Other immature functions

Owing to hepatic immaturity, preterm infants often show signs of jaundice, from the second or third day after birth, lasting a few days. This stems from the natural degradation of red blood cells. Jaundice is treated by phototherapy.

The kidneys are also immature, hence the volume and composition of the urine needs to be regularly monitored, so as to adapt the neonate's nutrient requirements or erythropoietin produced by the kidneys.

Lastly, immune system immaturity may exist, which can lead to serious infections.

Pictogramme bloc notes diagnostic et stéthoscope Preterm infant care

Management of the infant depends on the degree of prematurity. Extremely preterm and very preterm infants are cared for in neonatal intensive care departments where they receive the necessary care adapted to their risks, and undergo intensified monitoring. They are then referred to intensive care, then to a neonatal department once their health status is stable.

Preterm infants are placed in incubators to keep them at 34°/35° C, equivalent to the temperature in the mother's womb. The incubator atmosphere should, moreover, have a humidity level of 80%. The infants can leave the incubator once they have reached 2 kg.

Furthermore, their management should insofar as possible follow their wake/sleep rhythm, so as to reduce stress caused by external stimulation. Developmental care (the most comprehensive program being NIDCAP) allows tailored management of the preterm infant following careful examination by carers. The objective of this care is to reflect the intrauterine environment as closely as possible: low level of light, no alternating day/night patterns, low level of noise, postures in keeping with the physiological flexion position, etc. In this context, "skin-to-skin" contact with the parents is strongly encouraged. This close contact reassures the infant, reduces their stress and stimulates maternal milk flow. Infants having regular "skin-to-skin" contact with their parents have a more favorable outcome, with an improvement in heart rate, respiratory rate and even sleep.

Infants can generally leave hospital once they have achieved independent respiratory and gastrointestinal function. Home hospitalization is able to shorten the in-patient hospitalization period.

The changes in health status depends on each infant, and there are no accurate markers to determine whether an infant will develop complications and long-term sequelae. There are nonetheless some more favorable factors: a more advanced gestational age, higher than normal weight for gestational age, or even female gender. There is a continuous relationship between the increase in gestational age and the reduction in neonatal mortality and morbidity. The risks of severe respiratory distress or neurological damage, together with the average length of stays in neonatal hospitalization units, decrease with gestational age.

In France, no intervention is attempted on preterm infants born at 23 weeks of pregnancy. The management of extremely preterm infants is determined based on a collective decision, if carers believe it is appropriate, and with parental agreement.

Neurological sequelae are common, particularly in very preterm infants. These may manifest as motor disorders with delayed walking or difficulty walking, cognitive disorders with oral or written language difficulties, or even attention disorders and sensory, visual or hearing disorders.

The Epipage 1 study, conducted in 1997 among very preterm infants, showed that nearly 40% of these infants presented a motor, sensory or cognitive deficiency at the age of five years, compared with 11% among full-term infants of the same age. In total, the risk of deficiency was approximately four times higher among very preterm infants, again relative to full-term infants. However, severe forms of deficiency only affected 5% of infants. After 32 weeks of pregnancy, the risk of immediate and long-term complications is markedly reduced, but is not non-existent: 4% of infants born at 32 GA present cerebral palsy at the age of 5 years. The hospitalization rate for infants born at 38 GA is also higher than that observed for full-term infants (8.8% versus 6.4%). Moderately preterm infants should not therefore be taken lightly.

A significant improvement between 1997 and 201

Due to the changing "context" of premature births since 1997, with an increase in cases and advances in medical practices in the field of obstetrics and neonatology, a new study was set in place in 2011 with a view to obtaining more up-to-date data: Epipage 2. The initial study results showed that the survival rate is 59% at 25 GA, 75% at 26 GA, 94% between 27-31 GA, and 99% between 32 and 34 GA. Discharge rates from neonatal units without a serious neonatal disorder correspond to 30% at 25 GA, 48% at 26 GA, 81% between 27-31 GA, and 97% between 32-34 GA. Prior to 25 weeks gestational age, the prognosis for these infants is still very uncertain. At present, the initial data from Epipage 2 show a significant improvement in survival without severe neonatal morbidity among infants born between 25 and 31 weeks since 1997.

After discharge from hospital, weight gain in preterm infants is faster than for full-term infants. Furthermore, when pediatricians compare psychomotor milestones acquired by preterm infants with those of full-term infants, they take the "corrected age" in account, rather than real age. When a preterm infant is born after 7 months of pregnancy, they are said to be 2 months early. When the infant is legally 10 months old, their corrected age will be 8 months.

In French : Grands prématurés entre progrès et questions – reportage – 5 min 33 – 2011

Pictogramme microscope Challenges facing research

The Epipage 2 study, conducted by Inserm since 2011, is a vast observational research project on preterm births in France, incorporating numerous sub-studies. It involves Inserm and university research teams, together with hospital teams from 25 regions in France.

This study is based on data relating to more than 7,000 births prior to 35 weeks of pregnancy (live births or stillbirths), in 25 French regions. 4,200 infants having survived the neonatal period will be followed up until the age of 12 years. The objective is to gain further insight into the neurodevelopmental and health outcomes in these infants, in the light of changes in medical practices and health care organization. This also involves evaluating hospital practices associated with the best results, so that these can be implemented more extensively.

One of the novel features of the Epipage 2 study is the creation of complementary, multidisciplinary projects in the field of brain imaging, biomarkers, nutrition, mother-infant interactions, pain and ethics.  Several research teams have rallied around these projects, particularly those focusing on:

  • biological markers for complications in the infant relating to prematurity (BIOPAG project),
  • the infectious context of pregnancy and the relationship with infant outcome (CHORHIST project),
  • the prognostic value of brain lesions on infant development, using transfontanelle ultrasonography and new magnetic resonance imaging techniques (EPIRMEX project),
  • the existing link between the quality of early mother-infant interactions and infant neurodevelopmental outcome (OLIMPE project),
  • the relationship between establishment of the intestinal microbiota and the risk of later complications in very preterm infants (EPIFLORE project).
  • early nutritional factors related to infant development (EPINUTRI project);
  • stressful or painful procedures performed during the neonatal period and subsequent infant neurological development (EPPIPAIN 2 project).

Picto Foetus Protecting the fetal brain

Protecting the fetal brain will be the major challenge in the next few years: this organ suffers the most at birth, and no specific treatment is currently available to physicians to protect it. Inserm scientists are conducting a study along these lines to evaluate the protective role of melatonin naturally produced by the body and which plays a role in the wake-sleep rhythm. A recent MELIP (MELatonin In Preterm) study showed that preterm neonates secrete less melatonin than full-term infants. A new study, PREMELIP, is currently in progress at Hôpital Robert Debré in Paris to evaluate the benefit of administering melatonin to mothers prior to premature delivery to protect the fetal brain.

Very preterm infants are usually placed on respiratory assistance in the form of positive pressure nasal ventilation. This procedure requires intubation and may cause nasal and pulmonary lesions. Scientists are therefore developing gentler strategies taking into account the preterm infant's fragile organs and tissues.

In French : Olivier Baud – interview – 2 min 29 – (2009-2010)

Pictogramme femme enceinte Shedding light on the causes of preterm births

A Premimage platform, coordinated by Fondation PremUp, uses the most innovative imaging, ultrasensitive ultrasound, and quantitative elastography techniques, to study disorders which can affect mother and infant with the aim of improving management. The placenta is at the center of this research since placental malformation or dysfunction is directly related to intrauterine growth retardation and preterm births. This involves more effectively screening for vascularization problems and, if possible, to match these with blood markers for earlier diagnosis of the risks of dysfunction.