Randomized Trial of Maternal Progesterone Therapy

Study Overview
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Brief Summary
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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
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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: improves fetal brain growth and maturation, increases myelination during fetal brain development, reduces pre-operative brain white matter injury, and reduces post-operative white matter injury.

Official Title
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Randomized Trial of Maternal Progesterone Therapy to Improve Neurodevelopmental Outcomes in Infants With Congenital Heart Disease

Conditions
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Congenital Heart Disease, Periventricular Leucomalacia, Brain Development, Cardiac Surgery, Neurodevelopmental Disability, Fetal Neuroprotection

Intervention / Treatment
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* Drug: Progesterone
* Drug: Vaginal lubricant


Participation Criteria
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Eligibility Criteria
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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: Major genetic or extra-cardiac anomaly other than 22q11 deletion Language other than English spoken in the home 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) Prescription or ingestion of medications known to interact with progesterone (e.g. Bromocriptine, Rifamycin, Ketoconazole or Cyclosporin) Maternal use of progesterone within 30 days of enrollment History of preterm birth or short cervix (defined as cervical length ≤ 25 mm at 18-24 weeks GA necessitating progesterone therapy Multiple gestation Maternal contraindication for magnetic resonance imaging (MRI) Subjects with a known history of non-compliance with medical therapy
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Progesterone<br>Vaginal gel, 90mg twice a day (BID) | Drug: Progesterone<br>* Crinone is supplied in a single use, disposable, white polypropylene vaginal applicator with a teal twist-off cap. Each applicator delivers 1.125 grams of Crinone gel containing 90 mg (8% gel) of progesterone in a base containing glycerin, mineral oil, polycarbophil, carbomer 934P, hydrogenated palm oil glyceride, sorbic acid, purified water and may contain sodium hydroxide. Crinone 8% is administered vaginally at a dose of 90 mg twice daily. The rounded tip of the applicator is inserted into the vagina. After insertion, the plunger is pushed to release the gel into the vagina. The applicator is removed.<br>* Other names: Crinone 8%;|
| Placebo Comparator: Vaginal Lubricant<br>Vaginal twice a day (BID) | Drug: Vaginal lubricant<br>* Replens Long-Lasting Moisturizer is supplied in pre-filled, sealed and individually wrapped applicators.Replens Long-Lasting Moisturizer will also be dosed at one applicator intravaginally twice daily.<br>* Other names: Replens;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Motor Scale of the Bayley Scales of Infant and Toddler Development-III | The composite motor score is normed and has a mean of 100 (SD 15) and a range of 40-160. Scores between 71 and 85 indicate mild impairment and scores lower than 70 indicate moderate or severe impairment. | When baby is 18 months of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive and Language Scales of the Bayley Scale of Infant and Toddler Development-III | The composite cognitive and language scores are normed and have a mean of 100 (SD 15) and a range of 40-160. Scores between 71 and 85 indicate mild impairment and scores lower than 70 indicate moderate or severe impairment. | When baby is 18 months of age | 
| Fetal Brain Growth and Maturation by MRI | Total maturation scale (TMS) is an observational rating scale to assess the appropriateness of the gross brain appearance on MRI. The TMS scale has been used to demonstrate the negative effect of heart anatomy on post-natal, pre-surgical brain MRIs in infants with congenital heart. Similarly, a fetal TMS scale (fTMS) was developed to define the progress of brain development in-utero. Here we use the fTMS to define developmental/maturational changes occurring during gestation. The fTMS was graded on an ordinal scale, minimum = 4, maximum = 17 where a lower number indicates a less mature fetal brain and a higher number indicates a more mature fetal brain on MRI. | fTMS score change from 24-28 weeks gestational age to 34-36 weeks gestational age | 
| Myelination During Fetal Brain Development by MRI | Myelination is part of the fetal TMS rating system and is scored as follows. - If there is myelin in the brainstem, cerebellar peduncle and inferior tectum only - If there is myelin in the ventrolateral thalamus as well as in #1 - If there is myelin present in the posterior limb of the internal capsule as well as in #2 | Change from 24-28 weeks gestational age to 34-36 weeks gestational age | 
| Prevalence of PVL/WMI in the Pre Operative Study Participants | Periventricular leukomalacia (PVL), also known in the literature as white matter injury (WMI), is an acquired brain injury to the white matter of the brain seen in 20% of infants with congenital heart and up to 80% post-operatively. PVL/WMI is seen on T1 MPR sequences as abnormal hyperintensities in the white matter which are quantified by manual segmentation to achieve total volumes and regional volumes of the injury. Yes indicates the presence of PVL and no indicates the absence of PVL on the pre operative MRI. | Preoperative on day of surgery | 
| Prevalence of PVL/WMI in the Post Operative Study Participants | PVL/WMI will be measured on the post operative brain MRI with manual segmentations from the T1MPR sequence. Yes indicates the presence of new or worse PVL and no indicates the absence of new or worse PVL on the post operative MRI. | Postoperative within 10 days of surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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progesterone, congenital heart disease, periventricular leucomalacia, brain development, cardiac surgery, neurodevelopmental disability, fetus, fetal neuroprotection