Progesterone for preterm birth prevention

Preterm birth—delivery before 37 weeks of gestation—is the second leading cause of infant mortality in the United States after congenital malformations. Spontaneous preterm birth, due to either preterm labor or preterm premature membrane rupture, encompasses approximately 75% of all preterm births, almost 400,000 births per year. Since the 1960s, different formulations of progesterone have been investigated for preterm birth prevention. This article addresses the use of progesterone for the prevention of preterm birth, including selection of candidates for progesterone, pharmacokinetics, dosing, and formulations. This article aims to provide a practical guide for using progesterone in clinical practice.     

Progestin treatment for the prevention of preterm birth

Progestin supplementation appears to be a promising approach to both preventing initiation of preterm labor and treating it once it is already established, given the role of progesterone in maintaining pregnancy, as well as support from basic and clinical research. Progesterone and 17α-hydroxyprogesterone acetate slow the process of cervical ripening, and this is the rationale for prophylactic long-term progestin supplementation mostly studied so far. However, progesterone (but not 17α-hydroxyprogesterone acetate) also inhibits myometrial activity even after the cervix has already ripened. Moreover, these effects depend greatly on the vehicle used and the route of administration. Understanding different mechanisms of action, as well as the importance of progestin formulation, vehicle and route of administration, is the key to finding the optimal progestin treatment for prevention of preterm birth.     

Cervical cerclage for the prevention of preterm birth

Contemporary evidence supports the concept that cervical insufficiency is anything but a well-defined and distinct clinical entity. Instead, it is only 1 component of the larger and more complex preterm birth syndrome. Premature cervical ripening, as evidenced by shortening and effacement beginning at the internal os, provides strong evidence that parturition has begun and is the result of multiple interrelated pathways and inciting factors. Ultrasonographic screening of the cervix and treatment with cerclage for cervical shortening in the mid-trimester is reserved for women with prior spontaneous preterm birth (Fig. 1). Although cerclage benefit increases as the cervix shortens to less than 25 mm, it is appropriate to offer cerclage to women with shortened cervical length of less than 25 mm, and particularly those with a coexistent U-shaped funnel.     

Progestational agents for the prevention of preterm birth

Abstract In a risk/benefit analysis, currently the use of PAs used in women with a previous history of PTB appears to be worthwhile though the impact on the PTB rate may be minor since 80-90% of women who deliver preterm have no past history. PTB is a heterogeneous condition. With the exception of extremes of gestational age, PTB is due in equal parts to SPTL, preterm prelabour rupture of the membranes (PPROM) and elective PTB for fetomaternal indications. The assessment of the use of PAs to prevent PTB should only relate to previous and subsequent SPTL and not to PTB due to fetomaternal indications.     

孕激素在预防早产中的作用

早产的发生率仍持续不降,甚至逐年攀升,早产及由此出生的早产儿是导致围产儿死亡及致残的重要原因,究其原因是早产的预防及治疗效果不佳。早产的预防和治疗中强调以综合方案为主,近年来孕激素在早产的预防和治疗中的应用取得了一定的效果,但也存在较大的争议,文章就国内外相关的临床研究、专家共识等文献资料进行回顾,希望对临床有所裨益。     

Current options for mechanical prevention of preterm birth

Cervical insufficiency can be defined by a combination of obstetric history, cervical dilation on exam, and/or short cervical length in women with prior preterm birth. Options for mechanical intervention include cerclage and pessary. There is evidence to support the benefit of a cervical cerclage in women with singleton gestations who have a diagnosis of cervical insufficiency either based on second trimester painless cervical dilatation leading to recurrent early preterm births, or a history of early spontaneous preterm birth and a second trimester transvaginal ultrasound short cervical length or cervical dilation on exam. For women with multiple gestations, the benefit of a cerclage is uncertain, and further study is warranted. The pessary has also been studied for mechanical prevention of preterm birth in various populations, however the results so far have been mixed and warrants further study prior to routine use.     

Oral micronized progesterone for prevention of preterm birth

Objective

To evaluate oral micronized progesterone (OMP) to prevent preterm birth (PTB).

Methods

A randomized, double-blind, placebo-controlled trial of 150 women with at least one PTB who received 100 mg of OMP or placebo twice a day from recruitment (18-24 weeks) until 36 weeks or delivery.

Results

PTB occurred in 29 (39.2%) women in the OMP group (n = 74) compared with 44 (59.5%) in the control group (n = 74, P = 0.002). Mean gestational age at delivery was higher in the OMP group (36.1 vs 34.0 weeks, P < 0.001). Fewer preterm births occurred between 28 and 31 weeks plus 6 days in the OMP group (RR 0.20; 95% CI, 0.05-0.73, P < 0.001). Neonatal age at delivery (34 vs 32 weeks, P < 0.001), birth weight (2400 vs 1890 g, P < 0.001), NICU stay (> 24 h, P < 0.001), and Apgar scores (P < 0.001) were more favorable in the OMP group, and fewer neonatal deaths occurred (3 vs 7, P = 0.190).

Conclusion

OMP reduced the risk of PTB between 28 and 31 weeks plus 6 days, NICU admissions, and neonatal morbidity and mortality in high risk patients.     

Progesterone supplementation and the prevention of preterm birth

Preterm birth is currently the most important problem in maternal-child health in the United States and possibly throughout the world. It complicates one in eight US deliveries, and accounts for over 85% of all perinatal morbidity and mortality. Although survival of preterm infants has increased steadily over the past four decades-due in large part to the use of antenatal corticosteroids, improvements in neonatal resuscitation, and the introduction of neonatal intensive care units-efforts to prevent preterm birth have been largely unsuccessful. On February 3, 2011, the US Food and Drug Administration (FDA) approved the use of progesterone supplementation (hydroxyprogesterone caproate) during pregnancy to reduce the risk of recurrent preterm birth in women with a history of at least one prior spontaneous preterm delivery. This is the first time that the FDA has approved a medication for the prevention of preterm birth, and represents the first approval of a drug specifically for use in pregnancy in almost 15 years. This article reviews the evidence behind the use of progesterone for the prevention of preterm birth, and provides guidelines for the use of progesterone supplementation in clinical practice. A number of areas of ongoing controversy are addressed, including the optimal formulation and route of administration, the safety of progesterone supplementation in pregnancy, and its proposed mode of action.     

The Alabama preterm birth prevention project

A preterm birth prevention program consisting of risk scoring, intensive weekly observation including cervical examinations, and detailed education about preterm labor signs and symptoms was tested in a predominantly black, indigent population. One thousand high-risk women were randomized to treatment or control groups. Although more preterm labor was diagnosed and treated in the treatment group, there were no significant differences between the groups with respect to mean birth weight or gestational age, spontaneous preterm delivery rates, or low or very low birth weight rates. The rates of respiratory distress syndrome and fetal and neonatal mortality, although greater in the treatment group, were not statistically different. However, the treatment-group infants had significantly more intracranial hemorrhages and spent more days on ventilators. At this institution, the preterm birth prevention program was not effective.     

Cervical cerclage in the prevention of preterm birth

Cervical cerclage has been used in the management of cervical insufficiency for several decades, yet the indications are uncertain and benefits marginal. It remains a controversial intervention. The diagnosis of cervical insufficiency is traditionally based on a history of recurrent second trimester miscarriages, or very preterm delivery whereby the cervix is unable to retain the pregnancy until term. Cervical cerclage has been the subject of many observational and randomised controlled trials. This article reviews the literature regarding the effectiveness of elective or emergency transvaginal cerclage and transabdominal cerclage.     

Efficacy of progesterone for prevention of preterm birth

Preterm birth (PTB) occurs in 5–18% of pregnancies and is the leading cause of neonatal morbidity, mortality and infant death. Up to 30% of PTBs are due to iatrogenic reasons, but the remainder are due to the spontaneous onset of labour or pre-labour premature rupture of membranes (P-PROM). During pregnancy, the uterus remains quiescent and the cervix remains long and closed. Although the exact mechanisms that lead to spontaneous PTB (sPTB) are not fully understood, it is likely that the terminal pathways that are common to term labour are activated prematurely. Despite continued research efforts to develop preventative strategies, there have been no major advances resulting in the reduction of sPTB rates. Progesterone is the most researched prophylactic agent, yet, there is lack of consistency in the reported beneficial effects for the prevention of PTB and improvement in neonatal outcome. This is likely to stem from the multifactorial aetiology of sPTB, the varied patient cohorts recruited and the use of different preparations and routes of administration for progesterone. This review summarises the scientific rationale supporting the efficacy of progesterone and the results of major randomised controlled trials and finally emphasizes how targeted studies with more detailed patient stratification are essential to understand which population would benefit.     

Progesterone for the prevention of preterm birth: a systematic review

OBJECTIVE: We performed a systematic review to assess the benefits and harms of progesterone administration for the prevention of preterm birth in women and their infants. DATA SOURCES: The Cochrane Controlled Trials Register was searched, and reference lists of retrieved studies were searched by hand. No date or language restrictions were placed. METHODS OF STUDY SELECTION: Randomized trials comparing antenatal progesterone for women at risk of preterm birth were considered. Studies were evaluated for inclusion and methodological quality. Primary outcomes were perinatal death, preterm birth before 34 weeks, and neurodevelopmental handicap. TABULATION, INTEGRATION AND RESULTS: Eleven randomized controlled trials (2,425 women and 3,187 infants) were included. For women with a history of spontaneous preterm birth, progesterone was associated with a significant reduction in preterm birth before 34 weeks (one study, 142 women, RR 0.15, 95% CI 0.04-0.64, number needed to treat 7, 95% CI 4-17), but no statistically significant differences were identified for the outcome of perinatal death. For women with a short cervix identified on ultrasound, progesterone was not associated with a significant difference in perinatal death (one study, 274 participants, RR 0.38, 95% CI 0.10-1.40), but there was a significant reduction in preterm birth before 34 weeks (one study, 250 women, RR 0.58, 95% CI 0.38-0.87, number needed to treat 7, 95% CI 4-25). For women with a multiple pregnancy, progesterone was associated with no significant difference in perinatal death (one study, 154 participants, RR 1.95, 95% CI 0.37-10.33). For women presenting after threatened preterm labor, no primary outcomes were reported. For women with "other" risk factors for preterm birth, progesterone was not associated with a significant difference in perinatal death (two studies, 264 participants, RR 1.10, 95% CI 0.23-5.29). CONCLUSION: Progesterone is associated with some beneficial effects in pregnancy outcome for some women at increased risk of preterm birth.     

Randomized investigation of magnesium sulfate for prevention of preterm birth

One hundred fifty-six women with preterm labor between 24 and 34 weeks' gestation were randomized to receive either intravenous magnesium sulfate or no tocolytic therapy. Magnesuim sulfate infusions of up to 3 gm/hr were used in 76 pregnancies and resulted in a mean serum magnesium concentration of 5.5 +/- 1.4 mEq/L (mean +/- SEM). Compared with 80 control pregnancies, magnesium sulfate tocolysis had no significant effect on duration of gestation, birth weight, neonatal morbidity, and perinatal mortality. We conclude that clinically safe infusions of magnesium sulfate are ineffective when used to prevent preterm birth.