Impact of the Administration of Fludrocortisone in Very Premature Infants

Extreme prematurity affects about 2% of births per year in France and is subject to a significant morbidity and mortality. It is likely that the fluid and electrolyte imbalances associated with mineralocorticoid adrenal insufficiency transient observed in this population of vulnerable newborns contribute to the occurrence of complications that will influence the prognosis medium and long term these children. The expected impact of our pilot study is a direct benefit to the patient, with reduced kidney soda losses from the 3rd day of life and throughout the first week of life (assessed by a non-invasive method: urine collection to compress and measurement of urinary Na / creatinine). This physiological approach (substitution of the deficient hormone) allow better control of sodium and water balance. This could limit a number of common complications of extreme prematurity, occurring in the first weeks of life, such as patent ductus arteriosus, intra-ventricular hemorrhage and bronchopulmonary dysplasia.

The administration of glucocorticoids during the postnatal period (with action both glucocorticoid and mineralocorticoid) enables a reduction in the incidence of bronchopulmonary dysplasia severe. However, such treatment is associated with an increased incidence of neurodevelopmental effects related to activation of the glucocorticoid pathway. Using a specific mineralocorticoid agonist should preserve the beneficial effects without the adverse effects observed. The results of this pilot study will in a second time to consider a clinical trial Phase III national or international evaluating the significant reduction of these complications after substitution by Fludrocortisone the first week of life in the great premature. These results should have a major medical and economic impact. Indeed, neonatal morbidity indicators (intraventricular hemorrhage, patent ductus arteriosus, bronchopulmonary dysplasia and enterocolitis necrotizing) are associated with the subsequent development of neurodevelopmental sequelae (cerebral palsy and / or cognitive impairment) at the age of two and five years.

• Oral Fludrocortisone (enteral) (Drug): Oral Fludrocortisone (enteral) at a dose of 10 mcg 2 times daily (every 12 hours) for 8 days from day 1 (first administration between H24 and H30, and then every 12 hours) until day 8.
• Placebo Oral Tablet (Drug): oral placebo (enteral) at a dose of 10 mcg 2 times daily (every 12 hours) for 8 days from day 1 (first administration between H24 and H30, and then every 12 hours) until day 8.

Primary outcomes

• Urinary sodium loss evaluated by the urinary ratio Na / creatinine [day 3 (when urinary sodium losses are at their highest in very premature infants)]: Measurement of Na / urinary creatinine ratio at day 3 (evaluating the efficacity of Fludrocortisone action on the kidney by lowering sodium losses, that are very high in very premature infants) by collection of a urinary spot collected on a gauze compress, placed in the diaper of the newborn.

Secondary outcomes

• Urinary sodium loss evaluated by the urinary ratio Na / creatinine [day1, day5, day8, day10 and day15]: Measurement of Na / urinary creatinine ratio at day 1, 5, 8, 10 and 15 (evaluating the efficacity of Fludrocortisone action on the kidney by lowering sodium losses, that are very high in very premature infants) by collection of a urinary spot collected on a gauze compress, placed in the diaper of the newborn.
• urinary sodium and potassium concentrations [day1,day3, day5, day8, day10 and day15]
• plasma sodium and potassium concentrations [day1, day3, day8 et day15]
• plasma renin concentrations [day1, day3, day8 et day15]
• Number of blood tests [day1,day3, day5, day8, day10 and day15]
• Neonatal complications [up to 36 post-conceptional weeks (PCW)]
• Patent ductus arteriosus (diagnosed by ultrasound) [Between day2 and day5 and between day7 and day15]
• Presence of intraventricular hemorrhage (diagnosed by ultrasound) [between day2 and day5, and between day7 and day15, and at the age of 36 PCW]
• Oxygen inspired fraction (FiO2) [At Day 28 and 36 PCW]
• Blood pressure [From day1 to day8, at day10, at day15, at one month, three month, six month, twelve month and at 36 PCW]
• urinary dosage of aldosterone and cortisol [At one month, three month, six month and twelve month.]
• urinary index (Aldosterone/Nau) [day3, day8 and day15]
• number of days of invasive and non invasive ventilation [At Day 28 and 36 PCW]
• weight newborns [from day1 to day 8, at day 10 and day 15and at 36 PCW]

Sex: All, ages: 26 Weeks to 32 Weeks

Inclusion Criteria:

* Very premature newborns defined by a gestational age <32 and ≥ 26 gestational weeks
* Eutrophic: birth weight between the 10th and 90th percentile of the French reference curves
* Absence of malformations or chromosomal abnormality identified
* Lack of adrenal, pituitary or gonadal diseases diagnosed prior birth
* Lack of participation in another research protocol
* "Inborn": born and hospitalized in the four neonatology departments participating in the study
* Informed consent of the holders of parental authority

Exclusion criteria:

* Maternal treatment prior to pregnancy: systemic or inhaled corticosteroids, hormone therapy for adrenal or pituitary insufficiency, antihypertensive treatment (calcium channel blockers, beta blockers, angiotensin)
* Lack or incomplete treatment of antenatal glucocorticoids (betamethasone)

• Martinerie Laetitia, PHD, Principal investigator, APHP