Gynecological Endocrinology, 2012; 28(11): 925932 2012 Informa UK, Ltd.

. ISSN 0951-3590 print/ISSN 1473-0766 online DOI: 10.3109/09513590.2012.730576

PROGESTERONE AND PREGNANCY

The role of progesterone in maternal and fetal medicine 

Gian Carlo Di Renzo, Irene Giardina, Graziano Clerici, Alberto Mattei, Alia H. Alajmi & Sandro Gerli
Department of Gynecology and Obstetrics, Centre for Reproductive and Perinatal Medicine, University of Perugia, Perugia, Italy Progesterone is an essential hormone in the process of reproduction. It has been extensively studied in the treatment of dierent gynecological pathologies, as a contraceptive and in assisted reproductive technologies. However, the use of progesterone in the pathophysiology of pregnancy remains controversial. Progesterone, and its synthetic form 17 -hydroxyprogesterone caproate (17 OHP-C), oer an eective intervention when the continuation of pregnancy is at risk from immunological factors, luteinic and neuroendocrine deciencies, and myometrial hypercontractility. Progesterone has been successfully used as prophylaxis in the prevention of spontaneous miscarriage, with treatment beginning from the rst trimester of pregnancy. There is substantial evidence, too, to indicate that women with idiopathic recurrent miscarriage may benet from the immunomodulatory properties of progesterone in early pregnancy. The use of progesterone and 17 OHP-C has been extensively studied in the prevention of preterm birth in a variety of settings. Transvaginal ultrasound measurement of cervical length in singleton pregnancies between 19 and 24 weeks gestation has been deemed the best way to identify women (approximately 2% of the pregnant population) who would benet from prophylactic progesterone treatment for the prevention of spontaneous preterm birth. This paper reviews the evidence for the safety and ecacy of the use of progesterone in each of these indications. Keywords: Progesterone, maternal fetal medicine, preterm labour, recurrent abortion, micronised progesterone the target tissues. Oral administration guarantees optimal compliance by patients but is limited by extreme variability in plasma concentrations due to individual variability in gastric filling and enteropathic circulation. In addition, food intake can influence the rate and extent of progesterone absorption by reducing the rate of gastric emptying, decreasing gastrointestinal motility, increasing gastrointestinal secretions, and increasing splanchnic blood flow. Another major issue with oral administration of progesterone is that its effect is mediated by metabolites produced during liver passage; this is also shown by the discrepancy between progesterone levels and endometrial histology [2]. A number of synthetic oral progestogens have been developed to overcome the problem of low oral bioavailability. Their pharmacologic effects, however, differ from human progesterone and may result in increased androgenic effects, fluid retention, alterations in high-density lipoproteins, headaches, mood disturbances, and possible teratogenicity. Oral administration can also result in further side effects such as nausea and sleepiness. Micronized progesterone was formulated in the late 1980s in an attempt to improve the characteristics of oral administration of human progesterone. Despite being manufactured from chemicals derived from plants (Mexican wild yams, Dioscorea barbasco), it has a molecular structure identical to human progesterone [3]. Micronization of progesterone in particle sizes of less than 10 m increases the available surface area of the drug and enhances the aqueous dissolution rate and intestinal absorption of progesterone. Suspension in oil and packaging in a gelatin capsule has been shown to further enhance the intestinal absorption of micronized progesterone [4]. Vaginal administration of progesterone results in higher concentrations of the drug in the uterine tissue [1,5]. Bulletti et al. demonstrated that a first uterine pass effect (direct preferential vagina-to-uterus transport) occurs when progesterone is administered vaginally, confirming that the vaginal route permits targeted drug delivery to the uterus [5]. This maximizes the desired effects of progesterone treatment while minimizing the potential for adverse systemic effects [6]. Time to peak concentration tends to be slightly longer after vaginal administration of progesterone than after oral delivery of the micronized preparation. It is not uncommon for plasma concentrations to display a plateau-like profile after vaginal administration, representing a more constant drug concentration over time than is achieved through oral delivery. However, peak plasma levels appear to be variable and not consistently greater or less than corresponding peak plasma values after oral administration of micronized progesterone [4].

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Introduction
Progesterone is an essential hormone in the process of reproduction. It is involved in the menstrual cycle, implantation and is essential for pregnancy maintenance. Although the pharmacokinetics and pharmacodynamics of progesterone have been extensively studied since it was first synthesized in 1935, its use in the pathophysiology of pregnancy remains controversial.

Formulations and routes of administration

Once the therapeutic need for progesterone is established, deciding on the optimal route of administration should take into account considerations such as peak plasma concentrations, possible side effects, and compliance [1]. Progesterone is typically administered by one of three routes orally, vaginally or intramuscularly and a wide range of preparations is available (Table I). The modality of progesterone absorption depends upon the formulation used, blood flow at the site of administration, and solubility of progesterone in

Correspondence: Gian Carlo Di Renzo, MD, PhD, Professor and Chairman, Department of Gynecology and Obstetrics, Centre for Perinatal and Reproductive Medicine, Santa Maria della Misericordia University Hospital, University of Perugia, Perugia, Italy. Tel: +39 075 5783829; +39 075 5783231. Fax: +39 075 5783829. E-mail: direnzo@unipg.it

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926 G. C. Di Renzo et al. Historically, the most common delivery method of progesterone has been through intramuscular injection [4]. The primary advantages of intramuscular administration are that it leads to optimal plasma concentrations of progesterone compared with either oral or vaginal delivery, that it can be administered in patient with vaginal bleeding, and that it can be given in a single daily dose [1,5]. Side effects of intramuscular administration include local discomfort and, occasionally, non-septic abscess at the injection site. Cicinelli et al. compared progesterone concentrations in serum and endometrial tissue from hysterectomy specimens after intramuscular or vaginal administration of progesterone gel. Confirming the direct vagina-to-uterus transport of progesterone, the ratio of endometrial to serum progesterone concentrations were markedly higher in women treated by the vaginal route than in women given intramuscular injections of progesterone [7]. Other routes of progesterone administration have been described. Delivery of progesterone by transdermal patch is a viable alternative method; however, upon being absorbed through the skin progesterone is rapidly metabolized by the 5--reductase enzyme, which converts it to 5--dihydro-progesterone, thereby lowering plasma progesterone levels. Absorption of progesterone
Table I. Progesterone: pharmacologic types and protocols. Type Route Dose (mg) Timing Synthetic 17P IM 250 Weekly from 1620 wk IM 341 Twice weekly IM 250 Thrice weekly IM 500 Weekly IM 250 Every 3 days from 28 wk IM 1000 Weekly from 16 wk IM 25 Every 5 days Natural progesterone Vaginal 200 Nightly, 2433 wk Vaginal 400 Daily, 18wk to delivery Vaginal 100 Daily capsules to 34 wk Vaginal 90 Daily, 18wk to delivery Oral 9001600 Daily, from onset of PTL
Modified from Tita and Rouse 2009 [8]. 17P, 17--hydroxyprogesterone; IM, intramuscular; PTL, preterm labor; wk, week.

administered rectally is subject to wide variability, and there is a lack of empiric evidence concerning rectal administration of progesterone and its effects on the endometrium. Interpretation and comparison of randomized controlled trials with respect to the route of administration of progesterone is complicated by the wide range of doses used. In an important review by Tita and Rouse, who report all formulations and treatment protocols from nine individual clinical trials of progesterone for preventing preterm birth published between 2000 and 2009, dosages of progesterone administered vaginally ranged from 90 to 400 mg daily, initiated from 18 to 25 weeks. Intramuscular delivery of 17 -hydroxyprogesterone caproate (17 OHP-C) was also subject to variable doses and schedules [8] (Tables I and II).

Role of progesterone
Progesterone has been proposed and used in the treatment of different gynecological pathologies, such as endometrial hyperplasia, dysfunctional uterine bleeding, amenorrhea, luteal phase deficiency, and premenstrual syndrome, as well as being used as a contraceptive tool alone or in combination with estrogens and in assisted reproductive technologies and the maintenance of pregnancy [9]. The therapeutic application of progesterone in pregnant women is restricted to the prevention and treatment of threatened miscarriage, recurrent miscarriage (typically defined as three or more consecutive pregnancy losses) and preterm birth. Progesterone is efficacious when continuation of pregnancy is hampered by immunological factors, luteinic and neuroendocrine deficiencies, and myometrial hypercontractility. Immunological factors and implantation Maternal immune response has a key role in pregnancy, in particular during implantation. An established pregnancy maternal immune tolerance is established in the decidua, in a specific area defined as the feto-maternal interface, and the fetus is allowed to develop. However, if there is an alteration of the complex local immune network and the maternal immune cells recognize the embryo as semi-allograft, implantation will fail and abortion will occur [10]. The association between pro-inflammatory cytokines and recurrent miscarriages is due to an increase in cell-mediated maternal

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Table II. Individual clinical trials of progesterone for preventing preterm birth since 2000 included in the review by Tita and Rouse [8]. Study Design Sample size Progesterone intervention Population (indication) Primary outcome(s) Meis et al., 2003 [29] RCT (placebo 463 250mg 17P IM weekly Prior SPTB, 16 wk PTB < 37 wk controlled) da Fonseca et al, 2003 [35] RCT (placebo 142 100mg daily vaginal Prior SPTB, 24wk onward PTB < 37 wk controlled) suppository until 34 wk OBrien et al., 2007 [49] RCT (placebo 65 990mg vaginal gel Prior SPTB, 1822 wk PTB 32 wk controlled) Fonseca et al., 2007 [45] RCT (placebo 250 200mg vaginal capsule daily Short cervix 15mm at Spontaneous controlled) until 34 wk 2025 wk PTB < 34 wk Rouse et al., 2007 [61] RCT (placebo 661 250mg 17P IM until 35 wk Twins at 1620 wk (1) PTB < 35wk or controlled) IUFD < 35 wk Facchinetti et al., 2007 [37] RCT (no placebo) 60 341mg 17P IM twice weekly Arrested PTL Change in cervical length Borna and Sahabi, 2008 [34] RCT (no placebo) 70 400mg vaginal suppository Daily arrested (threatened) (1) Latency (days) PTL (2) Recurrence of PTL Combs et al., 2010 [62] RCT (placebo 240 250mg 17P IM weekly Diamniotic-dichorionic Reduction of composite controlled) twins at 1634 wk neonatal morbidity Berghella et al., 2010 [43] RCT 148 250mg 17P IM weekly Singleton gestations, prior PTB < 35 wk SPTB and CL<25mm, 1636 wk
17P, 17--hydroxyprogesterone; IM intramuscular; IUFD, intrauterine fetal demise; PTB, preterm birth; PTL, preterm labor; RCT, randomized clinical trial; SPTB, spontaneous preterm birth; wk, week.

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Role of progesterone927 immune response with low antibody production. Th1-type cytokines (IFN-, IL-2, TFN-) promote allograft rejection and compromise pregnancy, whereas Th2-type cytokines (IL-3, IL-4, IL-5, IL-10, TGF-2), which inhibit pro-inflammatory Th1 responses, promote allograft tolerance and may improve fetal survival. On the basis of this mechanism, the prevention of recurrent miscarriage relies on finding ways to downregulate pro-inflammatory cytokines and/or to upregulate anti-inflammatory cytokines [11]. Progestogens such as progesterone and dydrogesterone are among the most promising agents for this, with progesterone-induced blocking factor (a molecule produced by a progesterone-induced gene in lymphocytes) implicated in modulating the inhibitory effects of progesterone on cell-mediated immune responses [1113]. The presence of progesterone, and its interaction with progesterone receptors at the decidua level, appears to play a major role in the maternal defense strategy [14]. Progesterone induces an important suppression of T-cell reactions, inhibits natural killer cells, and exerts a synergistic action with prostaglandin E2 [15,16] (Figure 1). Luteal deciency In early pregnancy, before the placenta starts to produce progesterone, corpus luteum production is vital for the survival of the fetus. Luteal phase defect is associated with both implantation failure and miscarriage [17], although it has been speculated that low levels of progesterone may be merely a reflection of an already failed pregnancy rather than a cause of the failure [18]. Nevertheless, it has been demonstrated that supplementation with exogenous progesterone may promote the invasion of extravillous trophoblasts to the decidua by inhibiting apoptosis of extravillous trophoblasts [19], confirming the rationale for its use for luteal-phase support. In assisted reproductive cycles, progesterone supplementation is recommended after ovum pick up during the period when production of human chorionic gonadotropin is not sufficient for early implantation [20]. Myometrial hypercontractility Progesterone has been shown to exert a tocolytic effect on the myometrium, both in vitro and in vivo, during pregnancy. It has also been shown in vivo to be concentration dependent; only high doses of progesterone exert a tocolytic effect in early pregnancy, with optimal dosage ranging from 100 to 200mg/day depending upon maternal weight. This dosage has also proven to be effective in the maintenance of uterine quiescence during cervical cerclage (during the first trimester of pregnancy) and/ or following abdominal surgery (e.g. appendectomy) [5]. By contrast, 17 OHP-C has been shown in vitro to lack a direct inhibitory effect on human myometrial contractions. Surprisingly, in fact, a dose-dependent stimulatory effect on contractility has been demonstrated [21].

Threatened miscarriage
The various causes of spontaneous abortion make it difficult to prevent and manage the condition. A high percentage of so-called threatened miscarriages settle spontaneously as a result of bed rest or no treatment, and vaginal bleeding in early pregnancy is not synonymous with threatened miscarriage [1]. A causative factor in many cases of miscarriage may be the insufficient secretion of progesterone from the placenta. Although there is no evidence to support their routine use in early to midpregnancy to prevent miscarriage, progestogens have successfully been used to prevent spontaneous miscarriage, beginning from the first trimester of pregnancy, in women with a history of recurrent miscarriage [22]. A 2004 review by Sotiriadis et al. found that, although bed rest and progesterone supplements are often advised for women with threatened abortion, there is little good evidence that they reduce the risk of miscarriage [23]. Similarly, although Kalinka and Szekeres-Bartho found a positive association between progestogen treatment and progestogen-induced blocking factor in women with threatened abortion, there was no significant effect on pregnancy outcomes [24]. The lack of scientifically rigorous evidence regarding the use of progesterone in women with threatened abortion, however, does not necessarily correspond with a lack of efficacy. In a randomized, parallel-group, double-blind, doubledummy, controlled study, Czajkowski et al. investigated the effect of micronized vaginal progesterone versus oral dydrogesterone

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Figure 1. The pivotal role of progesterone receptor-mediated immunomodulation in successful pregnancy. LAK cells, lymphokine activated killer cell; NK, natural killer cells; PBMC, peripheral blood mononuclear cells.

2012 Informa UK, Ltd.

928 G. C. Di Renzo et al. on uteroplacental circulation in women with threatened abortion, as indicated by the pulsatility index and resistance index of spiral arteries in the uterus. Results showed that vaginal progesterone, significantly lowered both indices, indicating improved uteroplacental circulation [25] (Figure 2). at term) to the group with unproven autoimmunity treated with aspirin alone (Unpublished data).

Preterm labor
Labor is triggered by increased production of prostaglandin by amnio-chorion-decidua and promoted by estrogen [29]. Progesterone counteracts this effect in several ways: adequate progesterone concentrations in myometrium inhibits prostaglandin stimulatory activity, decreases the concentration of myometrial oxytocin receptors and gap junctions [5,30]. Endogenous progesterone (usually administered vaginally) and related synthetic compounds such as 17 OHP-C (usually administered by intramuscular injection), as well as other progestogens, have been tested in clinical trials to prevent preterm labor and birth [30]. Ferre et al. laid the groundwork for these trials in 1984 with an exploratory study looking at the pharmacodynamics of micronized progesterone administered to 15 pregnant women immediately prior to elective cesarean section. The study revealed a significant increase in plasma and myometrial concentrations of progesterone 150 min after administration, indicating a very rapid gastrointestinal absorption and release in the target tissue (myometrium) without alteration in the concentration of progesterone in the placenta [31]. The tocolytic effect of oral micronized progesterone in women at risk for premature labor was demonstrated as early as 1983, when Noblot et al. showed that regular doses of progesterone (400mg dose at admission followed by 400mg every 6h on the first day, 400 mg every 8 h on the second day and 300 mg every 8h on the third day) significantly reduced not only the need for -mimetics to achieve tocolysis, but also the length of stay in hospital [32]. Two years later, Erny et al. presented a study in which 88% of women treated with high-dose oral micronized progesterone (400 mg) had decreased uterine activity compared with 42% of the women treated with placebo [4]. Later research suggested that, given the slowness with which the tocolytic action of progesterone takes effect, progesterone should be used in conjunction with -agonists when acute tocolysis is required [5]; the two agents work synergistically, avoiding the potentially dangerous side effects associated with high-dosage -agonists [1,5]. Baumbach et al. recently showed that adding nifedipine and indomethacin to high-dose progesterone therapy increased the already significant inhibition of uterine contractions [33].

Recurrent miscarriage
The pathophysiology of recurrent miscarriage is complex and includes a range of anatomical, genetic, and molecular abnormalities, as well as endocrine disorders, thrombophilias, and anti-phospholipid syndrome. Extensive investigation of women with recurrent miscarriage fails to identify a recognizable cause (e.g. luteal phase defects and immunotolerance derangements) in up to one-third of all cases [1,5]. Given the importance of progesterone as an immunomodulatory agent in early pregnancy, there is a rationale basis for the benefits of progesterone supplementation in women with idiopathic recurrent miscarriage, probably conferred through the expression, modulation, and inhibition of various growth factors, cytokines, cell adhesion molecules, and decidual proteins [18]. However, the existing evidence base is largely composed of old studies of poor quality, such as the two meta-analyses from Goldstein et al. and Daya demonstrating a slight increase in the rate of pregnancies that continues beyond 20 weeks with progestogen treatment compared with placebo or no treatment [26,27]. Whether progesterone supplementation in the first trimester of pregnancy can consistently lower spontaneous abortion rates among women with recurrent miscarriage needs to be confirmed in well conducted clinical trials. The 2005 Prevention of Miscarriage Study (PROMIS) has already demonstrated in a scientifically rigorous setting that oral dydrogesterone in early pregnancy can improve pregnancy outcome in women with recurrent miscarriage [28]. Our group conducted a casecontrol study to test the role of micronized progesterone in recurrent miscarriages (defined as women with three or more consecutive pregnancy losses) in 125 women with positive or negative anamnesis for autoimmunity (especially for, but not limited to, thyroid autoantibodies) treated with acetylsalicylic acid (aspirin) 100mg/day alone or in combination with progesterone 200 mg/day, or no treatment. Results showed that the women with proven autoimmunity treated with aspirin and progesterone had similar outcomes (live birth rate

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Figure 2. Effect of micronized vaginal progesterone versus dydrogesterone on uteroplacental circulation in threatened abortion.

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Role of progesterone929 In 2008, Borna et al. conducted a trial in which 70 women at 2434 weeks gestation were randomized to vaginal progesterone or placebo upon presenting with symptoms of threatened preterm labor (defined as >6 contractions in 30min, along with cervical shortening or dilation) and arrested uterine activity. The use of vaginal progesterone suppositories following successful tocolysis was associated with a longer pre-delivery interval in this study compared with placebo (36.1 vs. 24.5 days), but did not significantly reduce the frequency of readmission for preterm labor. Women in the progesterone group were less likely than women in the placebo group to deliver neonates of low birth weight (27 vs. 51.5%; mean birth weight 3101 g vs. 2609 g), and neonates were less likely to develop respiratory distress syndrome (10.8 vs. 36.4%). No significant group differences were found with respect to other neonatal/maternal safety outcomes [34]. Even at doses as low as 100 mg/day, progesterone has been shown to have a protective effect against preterm birth (Table II). In a randomized, double-blind study of 142 high-risk singleton pregnancies in Brazilian women, preterm birth occurred in 13.8 and 28.5% of the progesterone- and placebo-treated women, respectively (p < 0.05). Vaginal progesterone 100 mg/day effectively reduced the incidence of uterine contractions and the number of deliveries before 34 weeks compared with placebo (23.6 vs. 54.3% and 2.7 vs. 18.5%, respectively; p < 0.05 for both). Overall preterm birth rate was 21.1% (30/142) [35]. Cetingoz et al. reported similarly positive results from a study in 150 Turkish women with high-risk pregnancies (prior spontaneous preterm birth, twin pregnancy, uterine malformation) randomized to vaginal micronized progesterone prophylaxis (100 mg/day) or placebo. Preterm labor occurred in 25.0% of women in the progesterone group compared with 45.7% in the placebo group (p < 0.05). Preterm birth before 34 weeks gestation was reported in 8.8% of the progesterone group and 24.3% of the placebo group (p < 0.05); however, neonatal death did not differ significantly between the two groups [36]. There is contrasting evidence for 17 OHP-C as a potential tocolytic agent. Some studies have shown no tocolytic effect of the synthetic formulation, while others have demonstrated a benefit of prophylactic 17 OHP-C in preventing preterm labor [29,30]. As discussed above, the findings of Ruddock et al. even suggested that 17 OHP-C was associated with a dose-dependent increase in uterine contractility [21]. In a study by Facchinetti et al., 60 women in labor between 25 and 34 weeks of gestation submitted to tocolysis with atosiban without premature rupture of membrane were randomized to receive either 17 OHP-C 341mg twice weekly until 36 weeks gestation or observation alone. Fewer preterm births occurred in the treated group compared with the observational group (16.0% [5/30] vs. 57.0% [17/30]; p = 0.004). 17 OHP-C treatment was also associated with significant reductions in cervical shortening at 7 days and 21 days after tocolysis (p = 0.002 at both timepoints) [37]. 2011 Guidelines from the European Association of Perinatal Medicine recommend both micronized progesterone and 17 OHP-C as early prophylaxis for preterm birth in asymptomatic women with prior history of preterm birth, starting from early second trimester [30]. A study by Istwan et al. demonstrated that a previous term delivery confers a reduction in risk for preterm delivery in women receiving prophylactic 17 OHP-C who have a history of one (but not more) prior spontaneous preterm delivery [38]. Preventing preterm birth in multiple pregnancies Based on the available evidence, the 2011 Guidelines from the European Association of Perinatal Medicine concluded that
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neither micronized progesterone nor 17 OHP-C had a protective effect against preterm berth in multiple pregnancies (women having twins or triplets) [30]. Research in this area dates back to 1980, when Hartikainen-Sorri et al. found no difference in gestational length, birth weight and neonatal outcome in 77 twin pregnancies treated with weekly injections of either 17 OHP-C or placebo during the third trimester up until 37 weeks gestation [39]. More recently, the results of the multicenter PREDICT (Prevention of Preterm Delivery in Twin Gestations) randomized controlled trial in 677 Danish and Austrian women confirmed that progesterone treatment fails to prevent preterm delivery at <34 weeks in twin gestations [40]. Preventing preterm birth in women with a short cervix Short cervical length was determined in a population-based, prospective study of 40,995 unselected pregnancies to be the best single predictive factor for preterm birth, predicting 61.2% of cases. An additional 4.4% of cases were predicted by the two-factor model of short cervical length and history of spontaneous preterm birth (65.6% total) [41]. A planned secondary analysis of vaginal progesterone gel (90 mg) versus placebo in 46 women with a cervical length <28 mm (12 had >1 prior preterm birth) reported a rate of preterm birth at 32 weeks of 29.6% in the placebo group versus 0 in the progesterone group; 7 of the women in the progesterone group and 5 in the placebo group had a history of >1 prior preterm birth [42]. More recently, Berghella et al. evaluated the effect of 17 OHP-C in 300 women with singleton gestations, cervical length <25 mm and prior spontaneous preterm birth randomized to cerclage or no cerclage. Neither group reported an effect of 17 OHP-C on the rate of preterm birth at <35 weeks. However, rates of perinatal mortality and preterm birth at <24 weeks were significantly lower in women treated with 17 OHP-C in the no-cerclage group [43]. The 2011 Guidelines from the European Association of Perinatal Medicine noted the promising evidence for preterm birth prophylaxis with either micronized progesterone or 17 OHP-C for singleton pregnancies in nulliparous women who had an asymptomatic cervical shortening (15 mm) detected on transvaginal ultrasound. However, they stated that further research was required before this intervention could be recommended in clinical practice [19]. An algorithm for the management of incidentally detected short cervical length in pregnant women has recently been proposed by the American College of Obstetricians and Gynecologists (Figure 3) [44]. The first study to randomize women to vaginal progesterone (200 mg/day) or placebo based on cervical length was reported by Fonseca et al.; of 24,620 unselected women screened between 22 and 25 weeks gestation, 413 (1.7%) had a cervical length 15 mm on transvaginal ultrasound and 300 were subsequently randomized. Progesterone treatment conferred a 44% relative risk reduction for spontaneous preterm birth at <34 weeks compared with placebo and a nonsignificant reduction in neonatal mortality and morbidity (8.15 vs. 13.8%; p = 0.17) [45]. More recently, Hassan et al. analysed data from an international, multicenter study comparing the effects of vaginal progesterone (90mg/day) versus placebo in 465 women randomized from a sample of 733 women with cervical length of 1020 mm detected on sonography between 19 and 24 weeks gestation (total screened population: 32,091 women). Women treated with progesterone were 45% less likely to deliver before 33 weeks (8.9 vs. 13.1%), 50% less likely to deliver before 28 weeks (5.1 vs. 10.3%), and 47% less likely to deliver a low-birth weight infant (6.4 vs. 13.6%) than women in the placebo group. Respiratory distress syndrome and

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930 G. C. Di Renzo et al.

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Figure 3. American College of Obstetricians and Gynecologists algorithm for the management of incidentally detected short cervical length [44].

a composite endpoint of neonatal morbidity indices were also significantly reduced with progesterone treatment [46]. Unlike Fonseca and colleagues, Hassan et al. excluded women with a cervical length of 010mm and twin pregnancies, which may explain the 50% higher incidence of preterm births seen in the placebo arm of the Fonseca study [47]. Both studies were included in a recent meta-analysis of pregnancy outcomes in women with short cervical length treated with progesterone [48]. An additional 95 women with short cervix were included from secondary analyses of studies in women with a history of spontaneous preterm birth in the immediately preceding pregnancy [49], women with a twin pregnancy (PREDICT study) [40], and women with a history of spontaneous preterm birth, twin pregnancy or uterine malformation [36]. Individual patient data meta-analysis showed that treatment with vaginal progesterone was associated with relative risk reductions for preterm birth of 42% at <33 weeks (relative risk [RR] 0.58, 95% confidence interval [CI] 0.420.80), 31% at <35 weeks (RR 0.69, 95% CI 0.550.88), and 50% at <28 weeks (RR 0.50, 95% CI 0.300.81) [48].

Safety
Natural progesterone has an established safety profile in the first trimester of pregnancy with >15 years of continued use in infertility. Vaginal administration of natural progesterone keeps undesirable systemic effects of treatment to a minimum, and does not affect either maternal weight or embryo-fetal viability, or cause malformation [30,50]. However, synthetic progestogens, such as 17 OHP-C, have been associated with a less favorable tolerability profile [51,52]. Side effects reported in the literature include pain, swelling, pruritis and nodule formation at the injection site, urticaria, nausea and vomiting, mood swings, bloating, abdominal

pain, depression, nervousness, sleep disorder and tiredness, dizziness, fever, flu-like symptoms, upper respiratory infection, urinary tract infection, yeast infection, asthma, acne and pain in the joints, back and leg [29,52]. Weekly 17 OHP-C prophylaxis has also been linked with an increased risk of gestational diabetes mellitus in women with a history of spontaneous preterm birth (odds ratio 2.9, 95% CI 2.14.1) [53]. Few studies have reported good follow-up data on neonatal safety in pregnancies where mothers have been treated with either progesterone or 17 OHP-C. The meta-analysis by Romero et al. supported earlier findings that progesterone treatment reduces the incidence of composite neonatal morbidity and mortality, low birth weight, respiratory distress syndrome, admission to neonatal intensive care unit, and requirement for mechanical ventilation (relative risk reductions of 43, 45, 52, 25 and 34%, respectively). The authors also confirmed that progesterone treatment has no effect on the incidence of adverse maternal events or on congenital abnormalities [48]. Furthermore, OBrien et al. reported a significantly shorter mean length of stay in the neonatal intensive care unit for neonates of progesterone-treated women with cervical length <28mm at enrolment compared with the placebo group (1.1 days vs. 16.5 days; p = 0.013). Complications of pregnancy leading to hospitalization (e.g. preterm labor, preterm birth and premature rupture of the membranes) accounted for 85 and 91% of the serious adverse events in the progesterone and placebo groups, respectively [49]. While there are no identified global safety issues with vaginal delivery of natural progesterone, some concerns remain surrounding the use of 17 OHP-C [54]. Reporting on a mean follow-up of 48 months in 278 surviving children of mothers who participated in a multicenter placebo-controlled trial of 17 OHP-C, the National Institute of Child Health and Human

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Role of progesterone931 Development indicated no major fetal safety concerns with 17 OHP-C treatment in the second and third trimesters of pregnancy [55]. However, in a randomized controlled trial by Combs et al., fetal death cause by midtrimester loss was significantly more common with 17 OHP-C [56], while a meta-analysis by OBrien and Lewis indicated a possible link between 17 OHP-C treatment and second-trimester miscarriage [57].
5. Di Renzo GC, Rosati A, Mattei A, Gojnic M, Gerli S. The changing role of progesterone in preterm labour. BJOG 2005;112 Suppl 1:5760. 6. Bulletti C, de Ziegler D, Flamigni C, Giacomucci E, Polli V, Bolelli G, Franceschetti F. Targeted drug delivery in gynaecology: the first uterine pass effect. Hum Reprod 1997;12:10731079. 7. Cicinelli E, de Ziegler D, Bulletti C, Matteo MG, Schonauer LM, Galantino P. Direct transport of progesterone from vagina to uterus. Obstet Gynecol 2000;95:403406. 8. Tita AT, Rouse DJ. Progesterone for preterm birth prevention: an evolving intervention. Am J Obstet Gynecol 2009;200:219224. 9. Kurjak A, Chervenak FA. Management of preterm labor: pharmacological and non-pharmacological aspects. Textbook of Perinatal Medicine. 2nd Edition. Cap. 130. UK, London: Informa Healthcare; 2006. pp 13941400. 10. Nakamura O. Childrens immunology, what can we learn from animal studies (1): Decidual cells induce specific immune system of fetomaternal interface. J Toxicol Sci 2009;34 Suppl 2:SP331SP339. 11. Raghupathy R, Al-Mutawa E, Al-Azemi M, Makhseed M, Azizieh F, Szekeres-Bartho J. Progesterone-induced blocking factor (PIBF) modulates cytokine production by lymphocytes from women with recurrent miscarriage or preterm delivery. J Reprod Immunol 2009;80:9199. 12. Szekeres-Bartho J. Progesterone-mediated immunomodulation in pregnancy: its relevance to leukocyte immunotherapy of recurrent miscarriage. Immunotherapy 2009;1:873882. 13. Raghupathy R. Manipulation of cytokine production profiles as a therapeutic approach for immunologic pregnancy loss. Indian J Biochem Biophys 2008;45:229236. 14. Druckmann R, Druckmann MA. Progesterone and the immunology of pregnancy. J Steroid Biochem Mol Biol 2005;97:389396. 15. Szekeres-Bartho J, Par G, Dombay G, Smart YC, Volgyi Z. The antiabortive effect of progesterone-induced blocking factor in mice is manifested by modulating NK activity. Cell Immunol 1997;177:194199. 16. Szekeres-Bartho J. Immunological relationship between the mother and the fetus. Int Rev Immunol 2002;21:471495. 17. Daya S. Luteal support: progestogens for pregnancy protection. Maturitas 2009;65 Suppl 1:S29S34. 18. Walch KT, Huber JC. Progesterone for recurrent miscarriage: truth and deceptions. Best Pract Res Clin Obstet Gynaecol 2008;22:375389. 19. Liu J, Matsuo H, Laoag-Fernandez JB, Xu Q, Maruo T. The effects of progesterone on apoptosis in the human trophoblast-derived HTR-8/ SV neo cells. Mol Hum Reprod 2007;13:869874. 20. Devoto L, Kohen P, Muoz A, Strauss JF 3rd. Human corpus luteum physiology and the luteal-phase dysfunction associated with ovarian stimulation. Reprod Biomed Online 2009;18 Suppl 2:1924. 21. Ruddock NK, Shi SQ, Jain S, Moore G, Hankins GD, Romero R, Garfield RE. Progesterone, but not 17--hydroxyprogesterone caproate, inhibits human myometrial contractions. Am J Obstet Gynecol 2008;199:391. e1391.e7. 22. Haas DM, Ramsey PS. Progestogen for preventing miscarriage. Cochrane Database Syst Rev 2008;CD003511. 23. Sotiriadis A, Papatheodorou S, Makrydimas G. Threatened miscarriage: evaluation and management. BMJ 2004;329:152155. 24. Kalinka J, Szekeres-Bartho J. The impact of dydrogesterone supplementation on hormonal profile and progesterone-induced blocking factor concentrations in women with threatened abortion. Am J Reprod Immunol 2005;53:166171. 25. Czajkowski K, Sienko J, Mogilinski M, Bros M, Szczecina R, Czajkowska A. Uteroplacental circulation in early pregnancy complicated by threatened abortion supplemented with vaginal micronized progesterone or oral dydrogesterone. Fertil Steril 2007;87:613618. 26. Goldstein P, Berrier J, Rosen S, Sacks HS, Chalmers TC. A meta-analysis of randomized control trials of progestational agents in pregnancy. Br J Obstet Gynaecol 1989;96:265274. 27. Daya S. Efficacy of progesterone support for pregnancy in women with recurrent miscarriage. A meta-analysis of controlled trials. Br J Obstet Gynaecol 1989;96:275280. 28. Walch K, Hefler L, Nagele F. Oral dydrogesterone treatment during the first trimester of pregnancy: the prevention of miscarriage study (PROMIS). A double-blind, prospectively randomized, placebocontrolled, parallel group trial. J Matern Fetal Neonatal Med 2005;18:265269. 29. Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B, Moawad AH, Spong CY, et al.; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Prevention of recurrent preterm delivery by 17 -hydroxyprogesterone caproate. N Engl J Med 2003;348:23792385.

Discussion
In January 2012, the US Food and Drug Administration refused to license the use of vaginal progesterone gel for the prevention of preterm birth in women with a short cervix, calling for further clinical trials in the American population. The European Medicines Agency has yet to make a decision in this indication, but there is strongly supportive evidence on a global basis that prophylactic daily application of vaginal progesterone gel, combined with routine transvaginal cervical-length screening in the second trimester, in women with singleton (but not multiple) pregnancies, prevents spontaneous preterm birth (Romero et al. report a 45% reduction in early preterm birth at <33 weeks gestation [48]) and reduces neonatal morbidity and mortality [30]. Furthermore, cost-effectiveness analyses of routine screening and subsequent vaginal progesterone prophylaxis for preterm birth in women with cervical length 15 mm have consistently shown the potential for substantial cost savings compared with no screening/no treatment [58,59]. However, there are no clinical data to support the effectiveness of routine screening for short cervix followed by vaginal progesterone treatment for women found to have a short cervix, compared with no screening. There is also no guarantee that universal screening in clinical practice would produce results consistent with those of a controlled trial, nor that screening would be truly universal as some practices may not have the resources to perform transvaginal ultrasound routinely. New guidance from the Society for MaternalFetal Medicine reviews these considerations in more depth [60]. Given that compliance with vaginal application of progesterone is >90% and that there appear to be no maternal side effects associated with this formulation, as Stuart Campbell wrote in his 2011 editorial for Ultrasound in Obstetrics & Gynecology, doing nothing is no longer an option [47]. To address the paucity of neonatal outcomes data, efforts are being made to include neonatal follow-up in new and ongoing trials of progesterone, and postmarketing surveillance would be prudent following regulatory approval [30]. The use of 17 OHP-C as prophylaxis for preterm birth remains more controversial. Although it has comparable effectiveness with natural progesterone, there is both biological plausibility and empirical evidence for undesirable systemic side effects attributable to the drug that requires further exploration [54]. Declaration of Interest: The authors report no conflicts of interest.

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Gynecological Endocrinology