Clinical trial NCT03596125: Correction of Neonatal Glutathione by N-acetylcysteine in Pregnant Women at Risk of Premature Birth (GSH MAP)
Official title: Correction of Neonatal Glutathione by N-acetylcysteine in Pregnant Women at Risk of Premature Birth
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Preterm Delivery
Keywords: Glutathione
Antioxidant
Oxidative stress
Preterm
Lead sponsor: Nantes University Hospital
Sponsor class: OTHER
First posted: 2018-07-23
Enrollment: 39
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Birth exposes the newborn to oxidative stress, as due to the switch from a protected, relatively hypoxic intrauterine milieu into an environment with a high oxygen pressure. The full-term newborn is well prepared to this massive redox challenge at the time of birth due to his well-integrated antioxidant defenses. On the contrary, numerous bibliographical data and our own work demonstrate the fragility of preterm newborns in this context of oxidative stress, linked to the immaturity of his antioxidant defenses.

Premature birth abruptly propels the fetus from the protected, relatively hypoxic intrauterine milieu to an environment at risk of free radical injury caused by mechanical ventilation strategies, including the use of high inspired oxygen fractions or inhaled nitric oxide, generating excessive reactive oxidative species (ROS). Several studies highlight the key role of ROS in adverse outcomes of preterm infant suffering from low birth weight, bronchopulmonary dysplasia, necrotizing enterocolitis or retinopathy.

This project aims to evaluate a therapeutic anti-oxidative strategy in order to correct the oxidative status of preterm infants. The investigators propose an early intervention that consists in an antenatal maternal supplementation with N-acetylcysteine (NAC), the acetylated precursor of both cysteine and glutathione, a key physiological antioxidant. This strategy could be promising for the development of simplified and personalized care of preterm infants.

GSH MAP is a randomized, single-blind, placebo-controlled study that aims to determine if NAC supplementation in women admitted to hospital care due to preterm labor (prior to 34 weeks of gestational age) may correct glutathione deficiency in neonatal cord blood.

Detailed description: GSH MAP is a randomized single-blind, placebo-controlled study. The design will include the recruitment of 120 pregnant women admitted to hospital care due to preterm labor (above 18 yrs of age, gestational age between 24 and 34 weeks). According to the risk of preterm delivery, women will be treated following two different schedules :

* High risk of prematurity: NAC supplementation -9 g intravenously-6g/day per os until day 7-1,8g/day per os until 37 weeks of gestational age.
* Moderate risk of prematurity: NAC supplementation -6g/day per os until day 7-1,8g/day per os until 37 weeks of gestational age.

Biological samples collected: maternal blood at inclusion, maternal/cord blood and placenta at delivery, breast milk samples during the first week of lactation in case of exclusive breastfeeding.

Levels of glutathione and related metabolites will be measured in plasma, red blood cells, placenta and breast milk.

In ancillary studies, metabolome and lipidome profilings will be performed on maternal and cord blood and on breast milk samples.

Eligibility criteria: Inclusion Criteria:

* Age \>= 18 years old
* Moderate or severe risk of prematurity
* Mono-fetal pregnancy
* And a term of pregnancy \> = 24 weeks and \<34 weeks of gestation at diagnosis
* subjects affiliated with an appropriate social security system
* written signed informed consent form

Exclusion Criteria:

* Age \< 18 years old
* Major under trusteeship or curatorship
* Maternal refusal and / or Incapacity to understand the benefits and potential risks of the protocol and to sign an informed consent form.
* A sonographic cervix ≥ 20 mm
* Mothers WITH:

  * A Body mass index less than 18 kg/m2 and greater than 40 kg/m2 before pregnancy
  * Type I, II diabetes
  * Epileptic disorders
  * A history of asthma
  * A hemorrhagic pathology
  * Maternal infection (HIV, hepatitis B and C) other than chorioamnionitis
* Patients in labour treated with magnesium sulphate
* Multiple pregnancy
* A known allergy/ hypersensitivity to N-acetylcysteine
* Fetal pathology other than intrauterine growth retardation (such as: karyotype abnormality, malformation, intrauterine growth retardation \<10th percentile)
* Current high doses of antioxidants treatments (vitamin supplements, ...)
* Patient with proven pre-eclampsia
* Patient with heart failure
* Patient with nephropathy
* Patient with medically known lactose intolerance
* Patient not affiliated with an appropriate social security system

Primary outcomes:
measure: Venous umbilical cord blood concentration of glutathione (micromoles/L) following antenatal NAC supplementation.
timeFrame: 13 weeks
Secondary outcomes:
measure: Number of days between the NAC-therapeutic initialization and childbirth.
timeFrame: until childbirth
measure: Glutathione concentration in arterial blood at birth
timeFrame: 13 weeks
measure: Maternal blood concentrations of glutathione (micromoles/L) and their total antioxidant capacity at inclusion.
timeFrame: 18 weeks
measure: Maternal blood concentrations of glutathione (micromoles/L) and their total antioxidant capacity at delivery, following antenatal NAC supplementation.
timeFrame: 18 weeks
measure: Placental total antioxidant capacity at delivery
timeFrame: at delivery
measure: Breast milk sulphur amino acid pattern on day 7 of the postpartum period following NAC supplementation.
timeFrame: 19 weeks
measure: Total antioxidant capacity on day 7 of the postpartum period following NAC supplementation.
timeFrame: 19 weeks
measure: Maternal metabolome and lipidome at delivery following the antenatal NAC supplementation.
timeFrame: 18 weeks
measure: Weight variations
timeFrame: Hospital discharge (4 months)
measure: Lenght variations
timeFrame: Hospital discharge (4 months)
measure: Head circumference variations
timeFrame: Hospital discharge (4 months)
measure: Postnatal follow up of newborn blood concentration of glutathione during his first days of life.
timeFrame: from birth until hospital discharge (4 months)
measure: Postnatal follow up of newborn blood concentration of total antioxidant capacity during his first days of life.
timeFrame: from birth until hospital discharge (4 months)
measure: Postnatal follow up of newborn blood concentration of and metabolome/lipidome during his first days of life.
timeFrame: from birth until hospital discharge (4 months)
measure: Improvement of the clinical outcome of the newborn until discharge from hospital.
timeFrame: 4 months
Other outcomes:
Locations:
city: Nantes
country: France
facility: Chu de Nantes
Study officials:
affiliation: Nantes University Hospital Nantes
name: Alice Küster, Dr
role: PRINCIPAL_INVESTIGATOR
References: