Clinical trial NCT02133573: Randomized Trial of Maternal Progesterone Therapy
Official title: Randomized Trial of Maternal Progesterone Therapy to Improve Neurodevelopmental Outcomes in Infants With Congenital Heart Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Congenital Heart Disease
Periventricular Leucomalacia
Brain Development
Cardiac Surgery
Neurodevelopmental Disability
Fetal Neuroprotection
Keywords: progesterone
congenital heart disease
periventricular leucomalacia
brain development
cardiac surgery
neurodevelopmental disability
fetus
fetal neuroprotection
Lead sponsor: Children's Hospital of Philadelphia
Sponsor class: OTHER
First posted: 2014-05-08
Enrollment: 102
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Neurodevelopmental disability is now recognized as the most common long-term complication after cardiac surgery in neonates. Research studies have shown that progesterone is critical to the development of the brain and in a variety of clinical situations including brain injury can protect the brain.

The purpose of this research study is to determine whether progesterone administered during the 3rd trimester of pregnancy (24-39 weeks) to pregnant women protects the brain of unborn babies with CHD and improves their neurodevelopmental outcomes after heart surgery.

Detailed description: In the United States, approximately 1 in every 100 newborns is diagnosed with congenital heart disease (CHD). Many of these newborns (25%-35%) will require either corrective or palliative open heart surgery. As recently as the 1960's, only 20% of newborns with critical CHD survived to adulthood. Today, thanks to better diagnostic technologies and methods (including prenatal diagnosis), advances in surgery, and improved postoperative care, early survival is over 90%. However, with improved early outcomes has come the sobering recognition that there is an ongoing risk of late mortality, as well as significant morbidity for these children. In particular, neurodevelopmental disability is now recognized as the most common complication of critical CHD (i.e. those patients requiring cardiac surgery in infancy) and has the most negative impact on quality of life, academic performance and opportunity for independence as an adult.

The altered fetal hemodynamics secondary to CHD lead to decreased blood flow and/or oxygen delivery to the fetal brain. In turn, this impairment in blood flow and oxygenation results in impaired brain growth and altered structural and cellular maturation, particularly of the white matter. Fetal MRI studies have shown that during the third trimester, normally a time of rapid brain growth and development, brains of infants with CHD fail to grow at the same rate as the brains of fetuses without CHD. This growth delay results in microcephaly, immature cellular elements of the white matter and decreased cortical folding at birth. It has been demonstrated that brain immaturity at birth is a primary major risk factor underlying the hypoxic-ischemic white matter brain injury and subsequent neurodevelopmental disability seen in over 50% of infants following surgery for CHD. In addition, there is increasing evidence in the CHD population that even late pre-term birth (prior to 39 weeks GA) is associated with increased mortality, increased peri-operative morbidity, and worse neurodevelopmental outcomes.

Progesterone is an essential hormone in the occurrence and maintenance of pregnancy. Progesterone administration has also been shown to be neuroprotective in a variety of clinical situations, including traumatic brain injury (TBI). Sex steroid hormones, including progesterone, are critically involved in axonal myelination, forming the basis of white matter connectivity in the central nervous system (CNS). Progesterone and its metabolites not only promote the viability and regeneration of neurons, but also act on myelinating glial cell oligodendrocytes in the CNS and play an important role in the formation of myelin sheaths. Progesterone has also been shown to increase myelination and enhance maturation of immature oligodendrocytes progenitor cells to mature oligodendrocytes, which are more resistant to hypoxic/ischemic injury. Therapeutic administration of progesterone has also been demonstrated to prevent preterm birth. Thus, there are two potential mechanisms by which pre-natal progesterone therapy may improve neurodevelopmental outcomes in neonates with CHD: 1) a direct neuroprotective effect, and 2) decreasing the occurrence of pre-term birth.

Study Objectives

Primary: Develop preliminary evidence to support a multi-institutional study to determine whether, in women carrying fetuses (maternal-fetal dyad) with CHD, prophylactic vaginal natural progesterone therapy is neuroprotective, and compared to placebo improves neurodevelopmental outcomes at 18 months of age.

Secondary: Develop preliminary evidence to support a multi-institutional study to determine whether, in women carrying fetuses (maternal-fetal dyad) with CHD, prophylactic vaginal natural progesterone therapy is neuroprotective, and compared to placebo:

1. improves fetal brain growth and maturation,
2. increases myelination during fetal brain development,
3. reduces pre-operative brain white matter injury, and
4. reduces post-operative white matter injury.

Eligibility criteria: Inclusion Criteria: Mother carrying a fetus with CHD (maternal-fetal dyad) requiring surgery with cardiopulmonary bypass (CPB) prior to 44 weeks corrected gestational age (GA) identified prior to 28 weeks GA.

Exclusion Criteria:

1. Major genetic or extra-cardiac anomaly other than 22q11 deletion
2. Language other than English spoken in the home
3. Known sensitivity or listed contraindication to progesterone (known allergy or hypersensitivity to progesterone, severe hepatic dysfunction, undiagnosed vaginal bleeding, mammary or genital tract carcinoma, thrombophlebitis, thromboembolic disorders, cerebral hemorrhage, porphyria)
4. Prescription or ingestion of medications known to interact with progesterone (e.g. Bromocriptine, Rifamycin, Ketoconazole or Cyclosporin)
5. Maternal use of progesterone within 30 days of enrollment
6. History of preterm birth or short cervix (defined as cervical length ≤ 25 mm at 18-24 weeks GA necessitating progesterone therapy
7. Multiple gestation
8. Maternal contraindication for magnetic resonance imaging (MRI)
9. Subjects with a known history of non-compliance with medical therapy

Primary outcomes:
measure: Motor Scale of the Bayley Scales of Infant and Toddler Development-III
timeFrame: When baby is 18 months of age
Secondary outcomes:
measure: Cognitive and Language Scales of the Bayley Scale of Infant and Toddler Development-III
timeFrame: When baby is 18 months of age
measure: Fetal Brain Growth and Maturation by MRI
timeFrame: fTMS score change from 24-28 weeks gestational age to 34-36 weeks gestational age
measure: Myelination During Fetal Brain Development by MRI
timeFrame: Change from 24-28 weeks gestational age to 34-36 weeks gestational age
measure: Prevalence of PVL/WMI in the Pre Operative Study Participants
timeFrame: Preoperative on day of surgery
measure: Prevalence of PVL/WMI in the Post Operative Study Participants
timeFrame: Postoperative within 10 days of surgery
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
Study officials:
affiliation: Children's Hospital of Philadelphia
name: J. William Gaynor, MD
role: PRINCIPAL_INVESTIGATOR
References: