There are no such things as applied sciences, only applications of science. - Louis Pasteur
Preterm birth remains a cause of significant morbidity and mortality in the newborn. In 2008, the March of Dimes reported that 11.9 percent of all live-born infants were born premature in the state of South Dakota. After congenital anomalies, preterm birth is a leading cause of morbidity and mortality in neonates. Preterm neonates are at higher risk of complications, which are increased in frequency and severity the earlier in gestation at the time of delivery. These complications comprise, but are not limited to, intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia and the need for prolonged neonatal intensive care unit stays. These difficulties are not only life-threatening but also can have a significant impact on neurodevelopment and the need for lifelong specialized medical care.
17-hydroxyprogesterone is a naturally occurring, intermediate in the steroidal pathways of the adrenal gland and ovary. 17-hydroxyprogesterone is produced by 17-hydroxylation of progesterone or conversion of 17-hydroxypregnenolone by 3-ßhydroxysteroid dehydrogenase. 17-hydroxyprogesterone is converted to 11-deoxycortisol by 21-hydroxylase in the synthetic pathway to cortisol. The most common cause of congenital adrenal hyperplasia, 21-hydroxylase (CYP21) deficiency, causes marked elevations in 17- hydroxyprogesterone and is consequently an important component of the newborn screen.
17-hydroxyprogesterone caproate is the caproic acid of 17-hydroxyprogesterone and was initially marketed as Delalutin. 17-hydroxyprogesterone with the trade name, Delalutin, was originally approved by the FDA in 1956 and used for a number of indications: luteal phase support, recurrent miscarriages, to treat anovulation either amenorrhea or irregular bleeding, premenstrual tension, mastalgia, postpartum pain and as a test of endogenous estrogen and progesterone production. During this time it was also used off-label for the prevention of preterm labor. In 2000, Delalutin's approval was voluntarily removed by Bristol- Myers Squibb, but this withdrawal was not related to safety or efficacy of the agent.
In 2003, the National Institute of Child Health and Development Maternal-Fetal Medicine Network performed a study evaluating 17-hydroxyprogesterone caproate in the prevention of labor in singleton pregnancies below 37 weeks gestational age. Four hundred and fifty nine women with a history of preterm delivery (average of 30.7 weeks gestation) at 16 to 20 weeks were randomized to 250 mg of 17-hydroxyprogesterone or placebo intramuscularly. This study was discontinued early when it demonstrated a significant reduction in preterm birth.1 In a four-year follow-up study, 17-hydroxyprogesterone was shown to reduce low birth weight and complications of prematurity, and there were no significant health issues related to prematurity in the children.2 Another trial verified reduction in preterm births using prophylactic, vaginal micronized progesterone,3 while other trials have shown conflicting results with no improvement.4
For a number of years, 17-hydroxyprogesterone was only available through compounding pharmacies. Recently 17-hydroxyprogesterone was approved as an orphan drug by the FDA for prevention of preterm birth in singleton pregnancies. KV Pharmaceutical renamed 17-hydroxyprogesterone as "Makena". After receiving FDA approval, KV Pharmaceutical sent out letters to warn compounding pharmacies to cease compounding of 17-hydroxyprogesterone and that the FDA would enforce its ban on compounding. Following this, the manufacturer increased the cost of Makena from $10 to $20 per dose (compounded prescription) up to $1,500 per injection.
The American College of Obstetricians and Gynecologists, American Academy of Pediatrics, American College of Nurse-Midwives and other involved groups were concerned that this enormous increase in price would leave many in the highest risk groups of patients unable to afford this treatment. Subsequent to this outcry the manufacturer reduced the cost from $1,500 to $690 per dose, which while it is a significant reduction is still an extremely high cost for this critical preventive medicine. In response to this controversy, the FDA issued a statement that it would not interfere with compounding pharmacies continuing to compound prescriptions for 17-hydroxyprogesterone. 17-hydroxyprogesterone remains an important medication in the management of patients at high risk for preterm birth, and ought to be available and affordable for all who require it.
REFERENCES
1. Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B, Moawad AH, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. National Institute of Child Health and Human Development Maternal- Fetal Medicine Units N Engl J Med 2003;348:2379–85. Network (published erratum appears in N Engl J Med 2003;349:1299).
2. Northen AT, Norman GS, Anderson K, Moseley L, Divito M, Cotroneo M, et al. Follow-up of children exposed in utero to 17 alpha-hydroxyprogesterone caproate compared with placebo. National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network. Obstet Gynecol 2007;110: 865–72.
3. da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled doubleblind study. Am J Obstet Gynecol 2003;188:419–24.
4. Rouse DJ, Caritis SN, Peaceman AM, Sciscione A, Thom EA, Spong CY, et al. A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. N Engl J Med 2007;357:454–61.
©Copyright Keith A. Hansen, M.D.
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