Randomized Trial of Maternal Progesterone Therapy

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.

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