Cardiovascular Immaturity in Extremely Low Gestational Age Newborns: a Fundamental Prospective Study

Summary

Birth is a major turning point in the life of the newborn, as it moves from intrauterine life to extrauterine life. This sudden transition forces the newborn to adapt quickly. Oxygenation, which was only provided by the placenta during uterine life, will have to be provided by the lungs, which will open when the newborn cries for the first time. This phenomenon will change the way blood reaches the lungs and will require the newborn's heart to work harder. In addition, the cardiac workload will also increase due to the clamping of the umbilical cord, which will force the heart to pump through more resistant blood vessels.

This transition, generally well tolerated in newborns at term, can be much more complicated in premature newborns, particularly in extremely low gestational age newborns (e.g. ELGAN, born before 28 weeks of amenorrhoea). There are several causes of this difficult adaptation on the cardiovascular system: poor heart function, difficulty in revascularizing lungs due to the physiological characteristics of premature newborns (high pulmonary vascular resistance, persistence of the ductus arteriosus), and a tone of the blood vessel muscles that is probably immature. In addition, respiratory failure is often associated with pulmonary immaturity.

The consequences of a difficult adaptation to extrauterine life, combined with cardiovascular failure, will be poor organ perfusion, whose brain. Moreover, ELGANs have immature regulation of their brain vascularisation. Variations in the vascularisation of the brain (in the event of cardiovascular failure) may be responsible for irreversible lesions with intraventricular hemorrhage. Ultimately, these bleedings carry a high risk of mortality or severe disability in premature infants.

Several hypotheses have been put forward as to the causes of this poor adaptation to extrauterine life, but there are few recommendations on adapted medical management. Cardiac ultrasound and the use of drugs to support the heart and blood vessels have been suggested. However, a large number of ELGANs will develop complications that investigators cannot predict or intervene in time. In addition, studies on the drugs used have not been carried out on ELGANs, which limits the conclusions investigators can draw.

These factors encourage us to improve our fundamental knowledge of the cardiovascular system in the ELGANs. The aim is to identify the most effective clinical tools and treatments for assessing and treating neonatal cardiovascular failure at an early stage, before complications appear. Investigators aim to compare the architecture and composition of the heart, blood vessels, and blood of fetuses under 28 weeks of amenorrhea gestation with those of fetuses over or equal to 34 weeks of amenorrhea gestation.

For this research, investigators need tissues (heart muscle, blood, and vessels) from fetuses of different ages. These tissues are usually already taken during the foetopathology examination to try to provide a medical explanation of the medical abortion. There will be no change to the foetopathology examination carried out on the foetus, with the exception that some of the tissue taken will have additional analyses carried out in our INSERM laboratory attached to the Montpellier University Hospital.

Population resulting from medical abortion is motivated by the ethical impossibility of taking such invasive samples from live newborns. The non-use of animals is justified by the difficulty of extrapolating results to humans. The indication for abortion and its performance will be carried out by current practice. Participants will be offered and explained the study during the pre abortion visit.

This research does not alter the patient's care. No additional examination or consultation is required. No personal benefit is expected from the study, but it will enable us to gain a better understanding of ELGAN's hemodynamics and to consider future clinical studies.

Conditions

• ELGAN (22-28SA)
• Extremely Low Gestational Age Newborns
• Cardiovascular Immaturity

Interventions

OTHER

Medical abortion

Medical abortion performed according to standard practice with cord blood sample (1 to 10ml) collected on EDTA tube before injection of foeto toxic agent. EDTA tube transfered to laboratory on ambient temperature. Blood sample will be centrifuged to isolate the extracellular vesicles once in the laboratory.

OTHER

Foetopathology exam

Foetopathology exam is performed according to standard practice on the day after abortion (H12 to H48 from foetus death). Investigator will recover 2 horizontal slices (in line with the heart) between 3 and 5 mm thick, including the right and left ventricles put them in a cold physiological saline solution, and transfer them rapidly to the laboratory. Investigator will also recover segments of the descending aorta (approximately 2cm, between the ductus arteriosus and the celiac trunk) and the left renal artery. The isolated segments will be separated from the fat and connective tissue by the foetopathology team and put in a cold physiological saline solution.

OTHER

Outcomes mesurement

* From the myocardial samples, 10 µm thick sections will be prepared and slides will be incubated with antibodies directed against proteins of interest (adrenergic receptors, protein kinase A, ryanodine receptor, PDE3, troponin). After washing, fluorescent secondary antibodies will be used and slides will be observed under a fluorescence microscope. Rest of the cardiac tissue will be frozen in liquid nitrogen in order to perform Western blots. * Vessel samples will be put in a myograph to study contractile function. Concentration-response curves will be constructed by cumulative application of noradrenaline or U46619. For the study of endothelial function, arteries with and without functional endothelium will be pre-contracted to 80% of maximal contraction with U46619. When contraction reaches a plate, cumulative addition of different vasodilating agents will be performed. The vessels will also be cannulated on an arteriograph to assess dilation in response to flow and myogenic tone.

Sponsors & Collaborators

• INSERM U1046 Physiologie et médecine expérimentale du coeur et des muscles

  collaborator UNKNOWN

• University Hospital, Montpellier

  lead OTHER

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2025-01-01

Primary Completion

2025-12-31

Completion

2025-12-31

Countries

• France

Study Locations