Progesterone Therapy for Preterm Labor Perinatal Conference April 14, 2006

Prematurity – the problem 1 in 8 babies born in the U.S is premature, 1300 babies/day, 500,000 babies/year Leading cause of neonatal death, approximately 75% Significant cause of birth-related short- and long-term morbidity

Prematurity in Arkansas In an average week, 93 babies are born preterm 16 are born very preterm In % of births were preterm In % of births were preterm, 4,841 births In 2000, hospital costs for infants with diagnosis related to prematurity estimated at $11.9 billion.

Preterm labor and prematurity Preterm labor accounts for 80% of all premature births Preterm birth is the largest single cause of cerebral palsy

Rick scoring system Calvin H et al, Am J Obstet Gynecol, 1994; 170:54

Predicting preterm delivery Papiernik, Creasy – scoring system Cervical ultrasound Screening for vaginal infections Fetal fibronectin Uterine activity monitoring

Preventing preterm birth Cervical cerclage – 5 randomized trial, benefit only to women with 3 or more losses in the second and early third trimester (Harger Obstet Gynecol 2002:100:1313)

Preventing preterm birth Tocolytic therapy – most studies show no reduction in morbidity or mortality but decreased likelihood of preterm delivery within 7 days (Gyetvai et al, Obstet Gynecol 1999;94:869)

Preventing preterm birth Antibiotics – bacterial vaginosis, no reduction in preterm delivery or other adverse outcomes (Carey, et al, NEJM 2000;342:534)

Actions of progesterone Inhibits formation of gap junctions in myometrial cells In animal studies, decrease in plasma progesterone and an increase in estrogen preceding onset of labor Low plasma progesterone levels in women who delivered preterm Progesterone antagonists and an increased rate of labor onset

Progesterone trials Johnson 1975 – 17alpha-hydroxyprogesterone caproate, 0% vs 41% Meta-analysis Goldstein, 1989, no effect Meta-analysis Keirse, 1990, there was an effect Hartikainen-Sorri, 1980, no effect in twins Hauth 1983, active duty military population, no difference

Randomized progesterone trials Randomized 142 high risk singleton pregnancies, at least one previous preterm birth, prophylactic cervical cerclage and uterine malformation Progesterone (100 mg) or placebo vaginal suppository, qHS, weeks Preterm birth 13.8% vs 28.5% in placebo Decreased frequency of contractions with treatment da Fonseca et al, Am J Obstet Gynecol 2003;188:419

Randomized progesterone trials 19 centers Prior preterm delivery weeks to 36 weeks Randomized 2:1 to receive weekly injections of 250 mg 17P or placebo Delivery <37 weeks, 36.3% vs 54.9% Delivery <32 weeks, 11.4% vs 19.6% Significantly lower rates of NEC, IVH, O 2 Meis et al, NEJM 2003;348:2379

Sub-analysis of effect based on prior gestational age at delivery Women with a prior delivery <34 weeks benefited most from progesterone treatment. Spong et al, AJOG 2005;193:1127

Meta-Analysis of progestational agents to prevent preterm birth Sanchez-Ramos et al, Obstet Gynecol 2005;105: RCT’s Treated groups had lower rates of preterm delivery and SGA Concluded progestational agents and 17HP reduced incidence of preterm birth and low birth weight newborns.

Cochrane Database of Systemic Reviews Dodd JM, Flenady V, Cincotta R and Crowther CA January 25, 2006 in Issue 1, 2006 Concluded that there was a reduction in risk of preterm birth <37 and <34 weeks. Decreased low birthweight and IVH No difference in perinatal death No other differences

Safety of 17-alpha hydroxyprogesterone caproate No androgenic activity Animal studies reassuring No increase in malformations

Treatment recommendations Prevention of preterm delivery and preterm labor based on prior history of preterm labor and delivery Prior history of preterm rupture of membranes Start treatment by 24 weeks until 36 weeks Progesterone treatment not recommended as a tocolytic agent

Will 17P treatment make a difference? United States 2002 statistics Estimates on single births to multiparous women Prenatal care within first 4 months Previous preterm birth Recurrent spontaneous preterm birth Reduction in preterm birth Change in U.S. preterm birth rate from 12.1% to 11.8%, 2% reduction Petrini et al, Obstet Gynecol 2005;105:267