Sage Journals: Discover world-class research

Abstract

17-α hydroxyprogesterone caproate is a synthetic form of the natural progestin 17-α hydroxyprogesterone that is US FDA approved for the prevention of recurrent spontaneous preterm birth in women with a history of a prior singleton preterm birth. For women with a history of a prior spontaneous preterm birth between 20 weeks and 36 weeks and 6 days of gestation, the use of 17-α hydroxyprogesterone caproate has been shown to reduce the risk of recurrent preterm birth by more than 30%. This medication is the only Drug currently FDA approved for the prevention of preterm birth, and it is the first Drug the FDA has approved for use exclusively during pregnancy in approximately 15 years.

Keywords

17-α hydroxyprogesterone caproate preterm birth prevention progesterone

Preterm birth (defined as delivery prior to 37 weeks of gestation) complicates one out of eight pregnancies in the USA. While the rate of preterm birth in the USA rose from 10.6% in 1990 to a peak of 12.8% in 2006, more recent data from 2008, the latest year for which US data are available, demonstrated a slight improvement. The preterm birth rate in 2008 was 12.3%, which represents a 3% decline from the previous year [1]. Approximately 80% of preterm births are considered to be spontaneous due to either preterm labor or preterm premature rupture of membranes (PPROM) [2]. The remaining 20% are considered to be medically indicated preterm births, usually due to pre-eclampsia, intrauterine growth restriction or other indications.

Preterm birth is associated with significant neonatal morbidity and mortality. Prematurity is the leading cause of infant death in infants born without birth defects, accounting for 16.9% of infant deaths in 2008 [1], and is associated with significant short- and long-term morbidities. Short-term morbidities related to prematurity include respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, sepsis, bronchopulmonary dysplasia, retinopathy of prematurity, periventricular leu-komalacia and patent ductus arteriosus. More concerning, however, are the long-term morbidities associated with preterm birth such as cerebral palsy and cognitive and behavioral deficits.

Prematurity is associated with a high economic burden. According to the Institute of Medicine, short-term hospital costs during the first year of life are estimated to be US$5.6 billion. Prematurity is also associated with at least US$26 billion in overall societal costs per year in the USA, which equates to more than US$51,000 per premature infant [3].

While the absolute cause of preterm birth is difficult to identify in most individual cases, risk factors for preterm birth have been identified and include African–American ethnicity, vaginal bleeding during pregnancy, low BMI, anemia, certain vaginal or urinary tract infections during pregnancy, multifetal gestation, a history of a cervical excisional procedure, such as a cone biopsy, a short cervix during pregnancy, and a history of a prior spontaneous preterm birth [4]. Despite these known risk factors, attempts at significantly reducing the rate of preterm birth have largely failed with few exceptions.

Progestin supplementation during pregnancy has been studied since the 1950s as a means to reduce the risk of preterm birth, particularly in women identified to be at high risk of preterm birth based on historical risk factors or physical examination. 17-α hydroxyprogesterone caproate (17OHPC) is one form of progestin treatment that has been studied in pregnancy to reduce the risk of spontaneous preterm birth. In the past, 17OHPC was marketed under such brand names Delalutin™ and Hydrogest™. However, it fell out of use during the 1990s due to controversy over its effectiveness in preventing pregnancy-related complications and improving neonatal outcomes. Interest in the Drug was revitalized by a multicenter randomized controlled trial in the USA that was published in 2003 [5].

In February 2011, the US FDA approved 17OHPC for use during pregnancy for the prevention of recurrent spontaneous preterm birth in women with a history of a prior singleton preterm birth. Currently marketed in the USA under the trade name Makena™, 17OHPC has been shown to reduce the rate of recurrent preterm birth in women carrying a singleton gestation who have had a prior spontaneous preterm birth of a singleton pregnancy. It is FDA-approved for this indication only, and the recommended dosing and administration is 250 mg to be administered intramuscularly on a weekly basis starting at 16–20 weeks of gestation and to be continued through 36 weeks gestation or delivery, whichever is achieved first. In the USA, 17OHPC is also available via compounding pharmacies; due to concern regarding patient access to the Drug, the FDA indicated in a March 2011 press release that it would not take enforcement action against compounding pharmacies that fill a valid prescription for 17OHPC.

Overview of the market

Currently, there are few available therapies that have been shown to reduce the rate of preterm birth in women identified to be at high risk of preterm birth. For years, most interventions instituted during pregnancy have focused on reducing risks of neonatal morbidity related to prematurity, and not the rate of prematurity itself. Two examples are corticosteroids and magnesium sulfate. Corticosteroids (e.g., betamethasone or dexamethasone) administered to pregnant women at risk of preterm birth have been shown to reduce the risk of neonatal morbidities such as respiratory distress syndrome and intraventricular hemorrhage and perinatal mortality [6]. Magnesium sulfate administered to pregnant women at risk of imminent preterm birth is associated with a lower risk of cerebral palsy in offspring [7,8]. But few therapies have been shown to reduce the chance of preterm birth itself.

Attempts to arrest preterm labor with tocolytics have been shown to be largely unsuccessful. A number of trials have evaluated the efficacy of tocolytic agents, such as calcium channel blockers, β-agonists, magnesium sulfate and nonsteroidal anti-inflammatory Drugs, with variable results. A meta-analysis, however, concluded that while they may increase the duration of pregnancy up to 1 week, tocolytics in general do not reduce the risk of preterm birth and are associated with significant fetal and maternal side effects [9]. This delay in delivery does have the benefit of allowing for administration of antenatal corticosteroids.

Antibiotics have also been studied as a means to delay preterm birth in patients with preterm labor or PPROM. For patients with PPROM, antibiotic therapy has been shown to prolong the interval of time from membrane rupture to delivery, but it has not been shown to reduce the risk of preterm birth in these women [10,11]. On the other hand, for women with preterm labor and intact membranes, antibiotic treatment has neither been shown to delay delivery nor reduce the risk of preterm birth [12].

Given these limitations, much of the focus in recent years has been on identifying women at high risk of preterm birth and instituting measures to prevent preterm birth before the onset of preterm labor or ruptured membranes. Progestins have been shown to reduce the risk of spontaneous preterm birth in a number of different high-risk populations. 17OHPC, the topic of this review, has been shown to reduce the risk of recurrent preterm birth in the unique population of women with a prior singleton spontaneous preterm birth [5]. Recent studies have also demonstrated that other forms of progestins reduce the risk of preterm birth in various populations. Vaginal progesterone administered either in capsule, gel or suppository form has also been shown to reduce the risk of preterm birth in high-risk women. One randomized controlled trial demonstrated that vaginal progesterone 100-mg suppositories administered on a nightly basis reduced the risk of preterm birth <37 weeks in women with a history of preterm birth, uterine malformation or incompetent cervix [13]. However, a later study on the use of vaginal progesterone gel in patients with a history of a prior preterm birth did not show a significant difference in the risk of recurrent preterm birth [14]. Other randomized controlled trials have demonstrated that vaginal progesterone is associated with a reduced risk of preterm birth in women found to have a short cervix in the second trimester. Vaginal progesterone 200 mg capsules administered nightly were associated with a reduced risk of preterm birth in women with a short cervix detected via transvaginal ultrasound in the midtrimester [15]. Another trial also demonstrated a reduction in the risk of preterm birth with daily vaginal micronized progesterone gel in women with a short cervix [16].

To summarize, given the difficulty in arresting preterm labor once it starts, there has been recent interest in initiating preventative measures in women identified to be at high risk of preterm birth before preterm labor starts. To date, progestin supplementation has held the most promise in preventing spontaneous preterm birth for women identified to be at high risk of preterm birth. 17OHPC has been shown to reduce the risk of preterm birth in the unique population of women with a history of prior singleton spontaneous preterm birth.

The compound & its chemistry

Progestins are steroid hormones and represent a class of Drugs comprised of exogenous or synthetic forms of progesterone. 17OHPC is a synthetic progestin hormone that is an esterified derivative of 17-α-hydroxyprogesterone ( Figure 1 ).

Figure 1.

17-α hydroxyprogesterone caproate.

17-α-hydroxyprogesterone is a naturally occurring metabolite of progesterone that was originally isolated from the adrenal glands. It is metabolized from progesterone via 17-hydroxylase or from 17-hydroxypregnenolone via 3-β-hydroxysteroid dehydrogenase/Δ5–4 isomerase. During pregnancy, 17-α-hydroxyprogesterone is primarily produced in the adrenal glands, both maternal and fetal; it is also generated by the corpus luteum to a lesser degree. It has minimal progestational activity, which is in contrast to 17OHPC, which has substantial progestational activity and a longer duration of action. 17-α-hydroxyprogesterone and 17OHPC have minimal androgenic activity.

Pharmacodynamics

Preterm labor is thought to be a consequence of independent changes in the cervix and the uterus. During both term and preterm labor, the cervix changes from its firm, long and closed state to a soft and pliable tissue, a biochemical process characterized by remodeling of the extracellular matrix and an increase in tissue concentrations of inflammatory mediators. During labor, the uterus demonstrates an increase in contractility and sensitivity to endogenous hormones such as oxytocin. Preterm labor appears to be associated with premature activation of cytokine release in the decidua and cervix. IL-1β, TNF-α and IL-6 increase production and activation of matrix metalloproteinases (MMP-1, −8 and-9), which digest collagen in the extracellular matrix of the cervix leading to effacement and softening of the cervix [17]. These cytokines are also released by leukocytes in the myometrium, resulting in the production of prostaglandins and oxytocin, which stimulate uterine contractions [18].

In early human pregnancy, progesterone is produced by the corpus luteum and acts to maintain the pregnancy until the placenta takes over at 7–9 weeks of gestation. This conclusion is supported by the observation that removal of the corpus luteum in the early first trimester is associated with miscarriage, as is the use of progesterone receptor blockers [19,20]. In later pregnancy, progesterone appears to maintain pregnancy via modulation of the immune response by reducing the production of proinflammatory cytokines. Progesterone appears to act on the myometrium by relaxing myometrial smooth muscle, blocking the action of oxytocin and inhibiting the formation of gap junctions. These actions maintain uterine quiescence. Furthermore, progesterone also appears to modulate the expression of cytokines, prostaglandins and inflammatory mediators in the cervix, inhibiting the cervical ripening process [21,22]. Animal studies in rabbits and rats have shown that high levels of progesterone maintain uterine quiescence until a fall in progesterone at the end of pregnancy leads to labor and delivery [23]. In humans and primates, however, labor is not preceded by a reduction in progesterone levels. There appears to be modulation of progesterone receptors in the decidua, amnion and cervix, which leads to a functional progesterone withdrawal prior to the onset of labor, which allows for the release of proinflammatory cytokines [24]. Thus, progesterone appears to prevent preterm birth by having a direct effect on inflammatory mediators in both the uterus and cervix.

The mechanism by which 17OHPC prevents preterm birth is not as well understood. Unlike progesterone, 17OHPC does not appear to exert an effect on the myometrium or decidua. One study evaluated the effects of 17OHPC on human myometrial tissue and the production of TNF-α (an inflammatory cytokine) and the expression of COX-2 (an enzyme that mediates the production of prostaglandins). The authors found no difference in the tissues that had been treated with 17OHPC versus those that had not [25]. Similarly, 17OHPC does not appear to have an effect on uterine contractility. A study using human myometrial tissue compared the contractility of tissue treated with progesterone to that of tissue treated with 17OHPC [26]. The authors found that the tissue treated with progesterone at similar concentrations to that found in the placenta and uterus inhibited spontaneous myometrial contractility. However, this effect was not seen in the tissue treated with 17OHPC.

The primary effect of 17OHPC in prolonging gestation appears to be within the cervix. A study in rats found that both 17OHPC and progesterone delayed cervical collagen degradation, with progesterone having a greater effect than 17OHPC [27]. Another study evaluated certain inflammatory mediators in the cervix in patients given 17OHPC versus control and found that in the treatment group, there was a significant decrease in the proinflammatory mediator IL-1β but not in IL-6, IL-8, TNF-α or nitric oxide [28]. Clinically, 17OHPC has been associated with less cervical shortening as measured by ultrasound when compared with placebo [29]. This effect on cervical length, however, was not substantiated by a larger study performed later that evaluated patients with a history of a prior preterm birth who were treated with 17OHPC according to the standard recommendations [30].

Thus, 17OHPC appears to exert its primary effect on the cervix in preventing or delaying premature cervical ripening. Further study on the pharmacodynamics of the Drug are warranted to clarify its mechanism of action.

Pharmacokinetics & metabolism

Pharmacokinetics

Several studies have assessed the pharmacokinetics of 17OHPC: the first in nonpregnant women; the second in women carrying singleton gestations; and the third in women with twin and triplet pregnancies. The first study evaluated nonpregnant women who were receiving hydroxyprogesterone caproate for endometrial carcinoma [31]. Five patients received a single intramuscular injection of 1000 mg. The peak serum concentration for the Drug was 44–81 nmol/l, which was reached after 3–7 days. The data were insufficient to evaluate serum half-life. This study also evaluated patients who received a loading dose of 1000 mg every day for 5 days and then either weekly or every 2 weeks. For these patients, the mean peak serum concentrations for the Drug were reached at 2 weeks after the start of the treatment. Both groups had similar serum levels at 5 weeks, but there was a significant difference in the concentration at 13 weeks (140 ± 33 nmol/l in the group receiving weekly doses versus 72 ± 12 nmol/l in the group receiving doses every 2 weeks, p = 0.02). This study found no correlation between patient weight and serum Drug concentration.

A second study presented as a scientific abstract but not published in manuscript form, evaluated the pharmacokinetics of 17OHPC in 17 women carrying a singleton gestation who had a history of spontaneous preterm birth [32]. The peak serum values were achieved at day 2 and ranged from 13 to 41 ng/ml. Gestational age did not appear to impact plasma concentrations and timing of peak concentrations. The terminal half-life of 17OHPC was 17 days after administration of the last dose.

A third study evaluated patients with twin or triplet pregnancies who were receiving 17OHPC for the prevention of preterm birth [33]. These patients received an intramuscular dose of 250 mg every week from 16 weeks gestation until 35 weeks gestation or delivery. This dosing is similar to what is recommended for patients carrying singleton pregnancies who have a history of spontaneous preterm birth. The average peak concentration was 17.3 ± 6.7 ng/ml, which was reached at the first postinjection sample at 1 day (1.2 ± 0.41 days). The apparent half-life was 10.0 ± 4.0 days. The results were consistent with a high intersubject variation in absorption and metabolism. They also found a significant linear relationship between 17OHPC plasma concentrations and BMI (r = −0.28 at 24–28 weeks gestation and r = −0.33 at 32–35 weeks gestation; p < 0.01) and found lower 17OHPC plasma concentrations in African–American women compared with Caucasian women (p = 0.051).

Thus, the 250 mg weekly intramuscular dose of 17OHPC reaches an average peak concentration at postinjection day 1 with an average half-life of 10–17 days.

Metabolism

17OHPC does not appear to be metabolized to 17-α-hydroxyprogesterone and caproate. One study demonstrated that 17OHPC is not hydrolyzed into these compounds by esterase enzymes found in human plasma, liver or placenta [34]. 17OHPC appears to be metabolized by human adult hepatocytes and, to a lesser extent, the placenta, forming three major metabolites, which are mono-, di- and trihydroxylated derivates of progesterone and caproate. Metabolism is mediated by the CYP3A4 and CYP3A5 enzymes. The intrinsic clearance of 17OHPC is similar between adult and fetal hepatocytes [35]. Rat studies have shown that the Drug metabolites are 72% excreted in the feces and 12.5% in urine [36]. 17OHPC does appear to penetrate the placental barrier and is detectable in the fetal circulation [37].

Clinical efficacy

Phase II

A number of Phase II trials have evaluated the use of progestins to prevent adverse pregnancy outcomes. The difficulty in drawing conclusions from many of these trials lies in the fact that some studies used different forms and doses of progestins, had varied inclusion criteria, and evaluated different pregnancy outcomes. A meta-analysis published in 1990 was the first to limit evaluation to trials of 17OHPC only [38]. The goal of the meta-analysis was to evaluate the effect of 17OHPC on pregnancy loss and spontaneous preterm birth. This meta-analysis included five trials that assessed the risk of preterm birth in patients at high risk for preterm delivery treated with 17OHPC and found an odds ratio of 0.50 (95% CI: 0.30–0.85) for the risk of preterm birth in women who received 17OHPC. 17OHPC was not associated with a reduction in the risk of pregnancy loss. While the risk of preterm birth was reduced, there was no difference in the risk of neonatal morbidity or mortality between the groups. As a result, the authors concluded that although they were concerned with the small power and wide confidence intervals of the individual trials, the 50% reduction in the odds of preterm birth was important enough to warrant further research.

If one analyzes the five studies that they included in their meta-analysis, only two of the studies evaluated patients with inclusion criteria and treatment protocols similar to what is currently recommended today. One of these two studies was published in 1975 and included 43 patients with a history of at least two miscarriages or preterm births. Women were treated with 17OHPC 250 mg weekly from the time of initiation of care until 37 weeks [39]. 17OHPC was associated with a reduction in the risk of preterm birth from 41% in the patients receiving placebo to none in the patients treated with 17OHPC (p < 0.01). The other trial published in 1985 included 80 patients with the same inclusion criteria and treatment protocol as the last study [40]. However, in this trial, all of the patients received a prophylactic cervical cerclage. Nonetheless, the authors found a significant reduction in the risk of preterm birth from 37.8% in the patients receiving placebo to 16.1% in the patients treated with 17OHPC (p < 0.05).

Phase III

Phase III trials have evaluated the effect of 17OHPC for preventing preterm birth in several different populations.

History of a prior spontaneous preterm birth

The first major randomized, double-blind, placebo-controlled trial was conducted in the USA by the National Institute of Child Health and Human Development (NICHD). This trial enrolled women carrying a singleton gestation who had a documented history of spontaneous preterm delivery of a live-born singleton infant between 20 weeks and 36 weeks and 6 days of gestation due to spontaneous labor or PPROM [5]. Four hundred and sixty three women were randomized in a 2:1 ratio to receive 250 mg of intramuscular 17OHPC or placebo weekly starting at 16 weeks to 20 weeks and 6 days until delivery or through 36 weeks gestation. The baseline characteristics of the two groups were similar except that in the placebo group women had a higher median number of previous preterm deliveries per participant. The primary outcome of delivery before 37 weeks occurred in 36.3% of the 17OHPC group and 54.9% in the placebo group, which was statistically significant (p < 0.001). There were no significant differences in the rates of spontaneous miscarriage or fetal death. As far as neonatal outcomes, there was a significant reduction in the rate of low-birth-weight (birth weight less than 2500 g) but not very-low-birth-weight (birth weight less than 1500 g) infants. Furthermore, a reduction in the risk of several neonatal morbidities including the rates of necrotizing enterocolitis, need for supplemental oxygen, and intraventricular hemorrhage was observed with 17OHPC treatment. There was no difference in infant death between the groups.

While this study was largely met with enthusiasm from the obstetric community, several criticisms of the study were raised. One major criticism of the study was the high baseline rate of recurrent preterm birth in the placebo group. However, this criticism has been refuted on the basis of demography [41]. Approximately 60% of women enrolled were African–American, a known risk factor for preterm birth, the mean gestational age of the prior preterm birth was 31 weeks, and 32% of enrollees had more than one prior preterm birth. Therefore, the population studied was at high risk of recurrent preterm birth based on these factors. Women in the placebo group were found to have a higher median number of preterm births. But, since the study was able to demonstrate not just a reduction in the risk of preterm birth but also in the risk of several neonatal morbidities, these findings had a significant impact on obstetrical care of women with a history of preterm birth in the USA, prompting the American College of Obstetricians and Gynecologists to release a statement within 1 year of the study's publication indicating that some form of progestin supplementation may be considered for women with a history of a prior singleton preterm birth.

Other indications

Since the publication of the NICHD singleton trial, there have been several large studies evaluating the use of 17OHPC to prevent preterm birth in other patient populations at risk of preterm birth.

*Multifetal gestations

Two large studies looked at the use of 17OHPC in women with twin and triplet pregnancies. In the first, 661 women with twin pregnancies were randomized to 17OHPC starting at 16–20 weeks and continuing until delivery or 35 weeks [42]. The primary outcome of delivery or fetal death prior to 35 weeks was not significantly reduced in the progesterone group. In the second study, 134 women with triplet pregnancies were randomized to 17OHPC in a similar fashion [43]. In this study, there was also no significant difference in the primary outcome of delivery or fetal death prior to 35 weeks. Therefore, 17OHPC does not appear to reduce the risk of preterm birth in patients carrying a multifetal pregnancy.

*Short cervix/cerclage

Additional studies have also looked at patients at risk for preterm birth based on a short cervix by ultrasound during the pregnancy. One randomized controlled trial of 79 patients with a cervical length less than 25 mm compared 17OHPC to cerclage and found no difference in spontaneous preterm birth at less than 35 weeks between the two groups [44]. In a different secondary analysis of a randomized controlled trial, the effect of 17OHPC on the risk of preterm birth was evaluated in women with a short cervix in the midtrimester (<25 mm) who also had a history of a prior singleton preterm birth [45]. In this study, some of the women received cerclage. The authors observed no additional benefit of 17OHPC to patients who had received a cerclage, but 17OHPC reduced the risk of previable birth and perinatal mortality for patients with a short cervix who had not received cerclage. A third study, a secondary analysis of patients with twin pregnancies who also had a cervical length less than 25 mm, found no benefit from 17OHPC for these patients [46]. Therefore, at the present time, there is a lack of data demonstrating a benefit of 17OHPC in women with a short cervix, and it is not recommended for this indication.

*Preterm premature rupture of membranes

While the NICHD singleton trial included patients with a history of PPROM in the study and found a benefit to 17OHPC in the overall analysis, one study evaluated the benefit of 17OHPC in reducing the risk of preterm birth for women presenting with PPROM in their current pregnancy. In this randomized controlled trial, 69 women carrying a singleton gestation were randomized to 17OHPC or placebo if they presented with PPROM between 20 and 30 weeks of gestation. 17OHPC was not associated with pregnancy prolongation [47].

In summary, a Phase III trial supports the benefit of 17OHPC in reducing the risk of recurrent spontaneous preterm birth for women carrying a singleton gestation who have a history of spontaneous preterm birth of a singleton gestation. Data do not support the use of 17OHPC for other populations at risk of preterm birth such as multifetal pregnancies, women with a short cervix or pregnancies affect by PPROM.

Postmarketing surveillance

Due to the recent FDA approval of Makena in February 2011, no postmarketing information is currently available. Postmarketing studies are currently ongoing to confirm the safety and the efficacy of the Drug in reducing the rate of preterm birth. A search of www.clinicaltrials.gov using keywords ‘hydroxyprogesterone caproate’ reveals that KV Pharmaceutical is currently sponsoring two postmarketing trials. One is a confirmatory study of 17OHPC versus vehicle for the prevention of preterm birth in women carrying a singleton gestastion who have a history of a prior singleton preterm birth. The primary outcomes are rate of preterm birth <35 weeks and the rate of neonatal morbidity/mortality. Within this study, the investigators plan to evaluate pharmacokinetics of 17OHPC. The second study is a noninterventional follow-up trial to evaluate developmental status of children exposed to 17OHPC in utero.

Safety & tolerability

Maternal safety & tolerability

There have been few safety and tolerability concerns related to 17OHPC. In the NICHD singleton trial, 50% of patients reported at least one adverse side effect but most of these side effects were related to local injection-site reactions [5]. The most common side effects reports were soreness (34.2%), swelling (14.1%), itching (11.3%) and bruising (6.7%). Only swelling at the injection site or a lump at the injection site were more common in the 17OHPC group than in the placebo group. Similar results were found in the two studies of 17OHPC in twin and triplet pregnancies [42,43]. These adverse side effects did not appear to affect compliance. In the NICHD singleton trial, compliance was 91.5% but they did not address the reasons for noncompliance [5]. In the study of 17OHPC in twin and triplet pregnancies, compliance was also greater than 90% [42,43]. In these studies, only two patients discontinued the medication for severe local injection-site reactions and one patient for an adverse side effect not related to the injection site.

Several studies have raised concerns about a possible association of 17OHPC with an increased risk of developing gestational diabetes [48,49], but another large study has found no association [50].

Fetal safety

A number of longitudinal observational studies have evaluated the effect that 17OHPC exposure in utero has on the fetus. Several early studies demonstrated no evidence of teratogenic side effects [51,52]. In the NICHD singleton trial, the risk of congenital malformations was 2% in both the 17OHPC and placebo groups, which is similar to the overall background risk of congenital malformations, and there was no suspicious pattern to the congenital malformations in the 17OHPC group [5]. A follow-up study by the NICHD approximately 4 years after the original trial showed no difference in health status or physical exam on children of mothers who participated in the study and received 17OHPC compared with those who received placebo [53].

One area of controversy has been the risk of spontaneous abortion. In the NICHD singleton trial, the risk of miscarriage prior to 20 weeks in the group of patients who received 17OHPC was 1.6% compared with none in the placebo group, but this difference was not statistically significant [5]. Other trials have found either no difference in the miscarriage rate [42 –44] or a lower risk of miscarriage in patients who received 17OHPC [16]. Based on these data, 17OHPC does not appear to be associated with an increased risk of spontaneous abortion.

Regulatory affairs

17OHPC has been approved by the FDA under the trade name Makena. It is approved for use in patients with singleton pregnancies who have a history of spontaneous preterm birth in a singleton pregnancy.

Conclusion

17OHPC is a synthetic form of the natural progestin 17-α-hydroxyprogesterone that is FDA-approved for the prevention of recurrent spontaneous preterm birth in women with a history of a prior singleton spontaneous preterm birth. For women with a history of a prior spontaneous preterm birth between 20 weeks and 36 weeks and 6 days of gestation, the use of 17OHPC has been shown to reduce the risk of recurrent preterm birth by more than 30%. It has not been shown to benefit women with other risk factors for preterm birth such as multifetal pregnancy, short cervix or PPROM in the current pregnancy.

Future perspective

The last 10 years have brought a greater understanding of some of the mechanisms behind preterm birth and means to prevent preterm birth. While progestins appear to be effective in preventing preterm birth in high-risk patients, the mechanism of action needs to be further elucidated and indications for which they are beneficial. Promising work is being accomplished in the area of the genetics of preterm birth. Certain gene polymorphisms related to cytokine and progesterone receptors have been identified and linked to an increased risk of preterm birth [54 –56]. The hope is that we will one day more effectively identify women at highest risk of preterm birth and target our preventative measures according to the risk factors.

Executive summary

Background

The rate of preterm birth in the USA is approximately 12%.

Preterm birth is a significant public health problem and is associated with short- and long-term health problems for the infant.

One of the strongest known risk factors for preterm birth is prior spontaneous preterm birth in a singleton pregnancy.

Overview of the market

Until recent years, the only effective intervention for preterm birth focused on the reduction of neonatal morbidity in patients with signs or symptoms of preterm labor.

Progestins are a class of Drugs found to decrease the risk of preterm delivery in patients who are at high risk based on their history or because of a short cervix.

17-α hydroxyprogesterone caproate (17OHPC) is a type of progestin that has been shown to decrease the risk of spontaneous preterm birth in patients with prior spontaneous preterm birth in a singleton pregnancy.

Mechanisms of action

17OHPC is administered via weekly intramuscular injection of 250 mg starting at 16–20 weeks of gestation to be continued until 36 weeks of gestation or delivery, whichever comes first.

The mechanism of action is poorly understood, but 17OHPC appears to exert its primary effect on the cervix in preventing premature cervical ripening.

Pharmacokinetic properties

The 250-mg weekly intramuscular dose reaches an average peak concentration at postinjection day 1 with an average half-life of 10 days.

There is a linear association between 17OHPC plasma concentration and BMI and there is a lower 17OHPC plasma concentration in African-American women.

17OHPC is metabolized by both adult and fetal hepatocytes and, to a lesser extent, the placenta, and is excreted in the feces and urine.

Clinical efficacy

In patients with a prior spontaneous singleton preterm birth after 20 weeks gestation, 17OHPC has been shown to reduce the rate of recurrent spontaneous preterm birth before 37 weeks by more than 30%.

It has also been shown to reduce the rate of low-birth-weight infants and several neonatal morbidities in this population.

17OHPC does not appear to reduce the risk of preterm birth in patients with multifetal pregnancies, preterm premature rupture of membranes or short cervical length.

Safety & tolerability

The majority of maternal adverse effects reported are local injection-site reactions.

The Drug appears to be well-tolerated as compliance rates in large trials are over 90%.

It does not appear to be associated with teratogenic effects in the fetus.

Regulatory status

17OHPC has been approved by the US FDA under the tradename Makena™.

Conclusion

17OHPC is FDA-approved for the indication of reducing the risk of recurrent preterm birth in patients carrying a singleton gestation with a prior spontaneous preterm birth of a singleton fetus.

Footnotes

AS Roman has served as a consultant for KV Pharmaceutical. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

References

Papers of special note have been highlighted as:.

of interest.

of considerable interest.

Mathews

Arialdi

Osterman

MJK

Strobino

Guyer

. Annual summary of vital statistics: 2008. Pediatrics 127, 146–157 (2011).

Lockwood

Kuczynski

. Risk stratification and pathological mechanisms in preterm delivery. Pediatr. Perinat. Epidemiol. 15(Suppl. 2), 78–79 (2001).

Committee on Understanding Premature Birth and Assuring Healthy Outcomes, Board on Health Sciences Policy. Preterm Birth: Causes, Consequences and Prevention. Behrman

Butler

(Eds). Institute of Medicine of the National Academies, The National Academies Press, Washington, DC, USA (2007).

Mercer

Goldenberg

Das

The preterm prediction study: a clinical risk assessment system. Am. J. Obstet. Gynecol. 174, 1885–1893 (1996).

Meis

Klebanoff

Thorn

Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N. Engl. J. Med. 346(24), 2379–2385 (2003).

Clinical Phase III trial that was the basis for US FDA approval of 17-α hydroxyprogesterone caproate (17OHPC) for the prevention of recurrent singleton spontaneous preterm birth .

10.

American College of Obstetricians and Gynecologists Committee Opinion No. 475. Antenatal corticosteroid therapy for fetal maturation. Obstet. Gynecol. 117, 422–424 (2011).

11.

American College of Obstetricians and Gynecologists Committee Opinion No. 455. Magnesium sulfate before anticipated preterm birth for neuroprotection. Obstet. Gynecol. 115, 669–671 (2010).

12.

Doyle

Crowther

Middleton

Magnesium sulfate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst. Rev. 1, CD004661 (2009).

13.

Gyetvai

Hannah

Hodnett

Ohlsson

. Tocolytic for preterm labor: a systematic review. Obstet. Gynecol 94, 869–877 (1999).

14.

Mercer

Miodovnik

Thurnau

Antibiotic therapy for reduction of infant morbidity after preterm premature rupture of the membranes: a randomized controlled trial. JAMA 278, 989–995 (1997).

15.

Kenyon

Taylor

Tarnow-Mordi

, ORACLE Collaborative Group. Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomized trial. Lancet 357, 979–988 (2001).

16.

Kenyon

Taylor

Tarnow-Mordi

, ORACLE Collaborative Group. Broad-spectrum antibiotics for spontaneous preterm labor: the ORACLE II randomized trial. Lancet 357, 989–994 (2001).

17.

da Fonseca

Bittar

Carvalho

Zugaib

. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study. Am. J. Obstet. Gynecol. 188(2), 419–424 (2003).

18.

O'Brien

Adair

Lewis

Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial. Ultrasound Obstet. Gynecol. 30, 687–696 (2007).

19.

Fonseca

Celik

Parra

Singh

Nicolaides

. Progesterone and the risk of preterm birth among women with a short cervix. N. Engl. J. Med. 357(5), 462–469 (2007).

20.

Hassan

Romero

Vidyadhari

Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet. Gynecol. 38(1), 18–31 (2011).

21.

Peltier

. Immunology of term and preterm labor. Reprod. Biol. Endocrinol. 1, 122–132 (2003).

22.

Young

Thomson

Ledingham

Jordan

Greer

I A

Norman

. Immunolocalization of proinflammatory cytokines in myometrium, cervix, and fetal membranes during human parturition at term. Biol. Reprod. 66, 445–449 (2002).

23.

Csapo

Pulkkinen

. Indispensibility of the human corpus luteum in the maintenance of early pregnancy. Luteectomy evidence. Obstet. Gynecol. Surv. 33, 69–81 (1978).

24.

Peyron

Aubeny

Targosz

Early termination of pregnancy with mifepristone (RU 486) and the orally active prostaglandin misoprostol. N. Engl. J. Med. 328, 1509–1513 (1993).

25.

Gonzalez

Ofori

Elovitz

. Preventing cervical ripening: the primary mechanism by which progestational agents prevent preterm birth? Am. J. Obstet. Gynecol. 198, 314, e1–e8 (2008).

26.

Elucidates mechanism of action of 17OHPC and other progestins .

27.

Kelly

. Pregnancy maintenance and parturition: the role of prostaglandin in manipulating the immune and inflammatory response. Endocr. Rev. 15, 684–706 (1994).

28.

Csapo

. Progesterone block. Am. J. Anat. 98, 273–291 (1956).

29.

Zakar

Hertelendy

. Progesterone withdrawal: key to parturition. Am. J. Obstet. Gynecol. 196, 289–296 (2007).

30.

Patel

Goodwin

Effect of 17-alpha hydroxyprogesterone caproate on the production of tumor necrosis factor-alpha and the expression of cyclooxygenase-2 in lipopolysaccharide-treated gravid human myometrial explants. J. Perinatol 30, 584–589 (2010).

31.

Ruddock

Shi

Jain

Moore

Hankins

Romero

Garfield

. Progesterone but not 17-alpha hydroxyprogesterone caproate, inhibits human myometrial contractions. Am. J. Obstet. Gynecol. 199(4), 391.e1–391.e7 (2008).

32.

Elucidates mechanism of action of 17OHPC and other progestins .

33.

Kuon

Shi

Maul

Sohn

Balducci

Maner

Garfield

. Pharmacological actions of progestins to inhibit cervical ripening and prevent delivery depend upon their properties, the route of administration and the vehicle. Am. J. Obstet. Gynecol. 202, 455.e1–455.e9 (2010).

34.

Elucidates mechanism of action of 17OHPC and other progestins .

35.

Facchinetti

Dante

Venturini

Paganelli

Volpe

. 17 alpha hydroxyprogesterone effects on cervical proinflammatory agents in women at risk for preterm delivery. Am. J Perinatol. 25, 503–506 (2008).

36.

Facchinetti

Paganelli

Comitini

Dante

Volpe

. Cervical length changes during preterm cervical ripening: effect of 17 alpha hydroxyprogesterone caproate. Am. J. Obstet. Gynecol. 453, e1–e4 (2007).

37.

Durnwald

Lynch

Walker

Iams

. The effect of treatment with 17alpha-hydroxyprogesterone caproate on changes in cervical length over time. Am. J. Obstet. Gynecol. 201, 410, e1–e5 (2009).

38.

Onsrud

Paus

Haug

Intramuscular administration of hydroxyprogesterone caproate in patients with endometrial carcinoma. Acta Obstet. Gynecol. Scand. 64, 519–523 (1985).

39.

Caritis

Sharma

Zhang

Pharmacokinetics of 17-hydroxyprogesterone caproate (170HCP) in singleton gestation. Reprod. Sci. l6(Suppl. 3), 85A (2009).

40.

Caritis

Sharma

Venkataramana

Pharmacokinetics of 17-hydroxyprogesterone caproate in multifetal gestation. Am. J. Obstet. Gynecol. 205, 40, e1–e8 (2011).

41.

Yan

Fokina

Hankins

Ahmed

Nanovskaya

. The effect of esterases on 17 alpha-hydroxyprogesterone caproate. Am. J. Obstet. Gynecol. 198(2), 229.e1–229.e5 (2008).

42.

Yan

Nanovskaya

Zharokova

Metabolism of 17 alpha-hydroxyprogesterone caproate by hepatic and placental microsomes of human and baboons. Biochem. Pharmacol. 75(9), 1848–1857 (2008).

43.

Kimbel

Willenbrink

Junkmann

. Distribution and excretion of 17 alpha-hydroxyprogesterone caproate in rats. Acta Endocrinol. 28(4), 502–506 (1958).

44.

Hernauer

Yan

Patrikeeva

Transplacental transfer and metabolism of 17-alpha-hydroxyprogesterone caproate. Am. J. Obstet. Gynecol 199(2), 169.e1–l69.e5 (2008).

45.

Keirse

. Progestogen administration in pregnancy may prevent preterm delivery. Br. J. Obstet. Gynecol 97, 149–154 (1990).

46.

Early meta-analysis demonstrating a benefit of 17OHPC in preventing recurrent spontaneous preterm birth .

47.

Johnson

JWC

Austin

Jones

Efficacy of 17α-hydroxyprogesterone caproate in the prevention of preterm labor. N. Engl. J. Med. 293(14), 675–680 (1975).

48.

Yemini

Borenstein

Dreazen

Prevention of premature labor by 17 alpha-hydroxyprogesterone caproate. Am. J. Obstet. Gynecol. 151(5), 574–577 (1985).

49.

Iams

. Was the preterm birth rate in the placebo group too high in the Meis MFMU Network trial of 17-OHPC? Am. J. Obstet. Gynecol. 202, 409–410 (2010).

50.

An interesting commentary on strengths and weaknesses of the National Institute of Child Health and Human Development (NICHD) trial on 17OHPC in singleton gestations .

51.

Rouse

Caritis

Peaceman

A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins. N. Engl. J. Med. 357(5), 454–461 (2007).

52.

Caritis

Rouse

Peaceman

Prevention of preterm birth in triplets using 17 alpha-hydroxyprogesterone caproate: a randomized controlled trial. Obstet. Gynecol. 113(2 Pt 1), 285–292 (2009).

53.

Keeler

Kiefer

Rochon

A randomized trial of cerclage vs 17 alpha-hydroxyprogesterone caproate for treatment of short cervix. J. Perinat. Med. 37(5), 473–479 (2009).

54.

Berghella

Figueroa

Szychowski

17-alpha-hydroxyprogesterone caproate for the prevention of preterm birth in women with prior preterm birth and a short cervical length. Am. J. Obstet. Gynecol. 202(4), 351.1–351.e6 (2010).

55.

Durnwald

Momirova

Rouse

Second trimester cervical length and risk of preterm birth in women with twin gestations treated with 17-alpha-hydroxyprogesterone caproate. J. Matern. Fetal Neonatal Med. 23(12), 1360–1364 (2010).

56.

Briery

Veillon

Klauser

Women with preterm premature rupture of the membranes do not benefit from weekly progesterone. Am. J. Obstet. Gynecol. 204, 54.e1–54.e5 (2011).

57.

Rebarber

Istwan

Russo-Stieglitz

Increased incidence of gestational diabetes in women receiving prophylactic 17 alpha-hydroxyprogesterone caproate for prevention of recurrent preterm delivery. Diabetes Care 30(9), 2277–2280 (2007).

58.

Waters

Schultz

Mercer

Catalano

. Effect of 17 alpha hydroxyprogesterone caproate on glucose intolerance in pregnancy. Obstet. Gynecol. 114(1), 45–49 (2009).

59.

Gyamfi

Horton

Momirova

The effect of 17-alpha hydroxyprogesterone caproate on the risk of gestational diabetes in singleton or twin pregnancies. Am. J. Obstet. Gynecol. 201(4), 392, e1–e5 (2009).

60.

Schardein

. Congenital abnormalities and hormones during pregnancy: a clinical review. Teratology 22, 251–270 (1980).

61.

Raman-Wilms

Tseng

Wighardt

Einarson

Koren

. Fetal genital effects of first-trimester sex hormone exposure: a meta-analysis. Obstet. Gynecol. 85, 141–149 (1995).

62.

Northen

Norman

Anderson

Follow up of children exposed to 17 alpha-hydroxy-progesterone caprote compared with placebo. Obstet. Gynecol. 110, 865–872 (2007).

63.

Harper

Zheng

Thorn

Cytokine gene polymorphisms and length of gestation. Obstet. Gynecol. 117(1), 125–130 (2011).

64.

Manuck

Major

Varner

Progesterone receptor genotype, family history, and spontaneous preterm birth. Obstet. Gynecol. 115(4), 765–770 (2010).

65.

Ehn

Cooper

Orr

Evaluation of fetal and maternal genetic variation in the progesterone receptor gene for contributions to preterm birth. Pediatr. Res. 62(5), 630–635 (2007).

17-α Hydroxyprogesterone Caproate for the Prevention of Preterm Birth

Abstract

Keywords

Overview of the market

The compound & its chemistry

Pharmacodynamics

Pharmacokinetics & metabolism

Pharmacokinetics

Metabolism

Clinical efficacy

Phase II

Phase III

History of a prior spontaneous preterm birth

Other indications

*Multifetal gestations

*Short cervix/cerclage

*Preterm premature rupture of membranes

Postmarketing surveillance

Safety & tolerability

Maternal safety & tolerability

Fetal safety

Regulatory affairs

Conclusion

Future perspective

Footnotes

References