FIGO Good Practice Recommendations on the use of progesterone in the management of recurrent first‐trimester miscarriage

Recurrent miscarriage, which affects 1% of couples trying to conceive, is defined as the loss of three or more consecutive pregnancies from the time of conception up to 24 completed weeks of gestation.1 However, for this review the definition is restricted to the first trimester up to 12 completed weeks of gestation. Professional bodies differ in their recommendations regarding the definition of recurrent miscarriage, with some requiring two or more clinical pregnancies with ultrasound or histological confirmation of pregnancy loss, whereas others require three or more losses after a positive pregnancy test with no specification of the need for clinical confirmation.1, 2 Many factors have been studied as possible causes of recurrent miscarriage, such as anatomical, endocrine, immunological, genetic, and thrombophilia (inherited and acquired) disorders. Endocrine abnormalities include thyroid disorders, polycystic ovarian syndrome, and possibly progesterone deficiencies. Numerous studies have been conducted to assess the use of progesterone in the management of pregnancy loss; however, there is variation in the type and dose of progesterone used and in the methodology of these studies, which has resulted in inconclusive findings. Progesterone is essential for secretory transformation of the endometrium that permits implantation and maintenance of early pregnancy. Luteal phase insufficiency is one of the reasons for implantation failure and is considered to be responsible for miscarriage.3 In addition to its well-known role in preparation of the endometrium for implantation, endometrial decidualization, and inhibition of uterine contractility, progesterone also has an immunomodulatory effect by suppression of T-cell activation4, 5 and controlling cytokine production during pregnancy.6 These characteristics have led to its current widespread use in managing recurrent miscarriage. Therefore, support with progesterone may help to establish a sufficient immune response in early pregnancy and prevent miscarriage.7 Progestogens available on the market are classified as either natural or synthetic.8, 9 Synthetic progestogens (progestins) do not correlate with natural progesterone and are artificially manufactured in a laboratory. Natural progesterone suppresses myometrial contractility, unlike the progestin 17-alpha hydroxyprogesterone caproate (17-OHPC) which does not have this effect and at high concentration may stimulate myometrial contractility.10 No trial has reported long-term follow-up of the use of progesterone for recurrent miscarriage, therefore the safety of progesterone supplementation is still not well known.11 However, there is no evidence that progesterone causes anatomical or physiological abnormalities in the fetus. This article highlights agreements based on current research on the use of progesterone in recurrent first-trimester miscarriage and the areas that need more research to provide further evidence to support recommendations. The purpose of this article is to provide a comprehensive summary of available evidence along with practical recommendations concerning the use of progesterone supplementation in women with recurrent first-trimester miscarriage. To achieve these goals, FIGO brought together international experts to review and summarize current knowledge of the subject. These Good Practice Recommendations are directed at multiple stakeholders, including healthcare providers, healthcare delivery organizations and providers, FIGO member societies, and professional organizations. Recognizing the variation in the resources and expertise available for the management of recurrent first-trimester miscarriage in different countries or regions, this article attempts to take into consideration the unique aspects of first-trimester pregnancy care in low-resource settings (labelled “LRS” in the recommendations). This was achieved by collaboration with authors and FIGO member societies from low-resource settings such as India, Sub-Saharan Africa, the Middle East, and Latin America. This article is directed at multiple stakeholders with the intention of bringing attention to supplementation of progesterone in women with recurrent first-trimester miscarriage. This article proposes to standardize and provide guidance for the use and supplementation of progesterone in women with three or more consecutive first-trimester miscarriages. We evaluated the quality of available and eligible evidence using the GRADE criteria. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach is a systematic and transparent approach for rating the certainty of evidence in systematic reviews and clinical practice guidelines.12 The certainty of evidence can be rated according to five domains: risk of bias, inconsistency, indirectness, imprecision, or publication bias. The process includes an overall rating of the certainty of evidence for each outcome. Evidence was evaluated and rated by four co-authors (HS, SD, MZ, and AE) and any disagreements were resolved by consensus of all authors. Historically, trials assessing the use of progesterone in early pregnancy had small numbers and significant methodological flaws. More recent good-quality studies, despite some variations in the gestational age, duration of treatment, and type of progesterone used, have not enabled health authorities to draw conclusions and make clinical recommendations. Searches identified 1045 Ovid MEDLINE papers, 40 review articles from the Cochrane Library, 32 publications from ClinicalTrials.gov, and 181 publications from the International Clinical Trials Registry Platform (ICTRP) giving a total of 1298 papers, which were then reviewed. Fifty-six duplicate papers were identified (Figure 1). Recurrent first-trimester miscarriage affects 1% of couples trying to conceive. Professional bodies differ in their recommendations regarding the definition of recurrent miscarriage. Numerous studies have been conducted to assess the use of progesterone in the management of pregnancy loss; however, there is variation in the type and dose of progesterone used and in the methodology of these studies, which has resulted in inconclusive findings. Progesterone was discovered in the urine of pregnant mares in the 1930 s,15 and over the following decades, natural and synthetic progestogens were introduced into the market in pessary, gel, oral, and injectable preparations.16 Progesterone is essential for secretory transformation of the endometrium that permits implantation and maintenance of early pregnancy. Luteal phase insufficiency is one of the reasons for implantation failure and is considered to be responsible for miscarriage.3 In addition to its well-known role in preparation of the endometrium for implantation, endometrial decidualization, and inhibition of uterine contractility, progesterone also has an immunomodulatory effect by suppression of T-cell activation4, 5 and controlling cytokine production during pregnancy.6 These characteristics have led to its current widespread use in managing recurrent miscarriage. Therefore, support with progesterone may help to establish a sufficient immune response in early pregnancy and prevent miscarriage.7 Recurrent miscarriage is defined as the loss of three or more consecutive pregnancies from the time of conception up to 24 completed weeks of gestation. However, for this review the definition is restricted to the first trimester up to 12 completed weeks of gestation. Progesterone is an endogenous steroid and progestogen sex hormone. It belongs to a group of steroid hormones called the progestogens and is the major progestogen in the body. Progesterone is produced by the ovarian corpus luteum during the luteal phase of the menstrual cycle. During pregnancy, progesterone is produced by the corpus luteum and/or the placenta. Progesterone also has antimineralocorticoid and inhibitory neurosteroid activity, whereas it appears to have little or no glucocorticoid or antiandrogenic activity and no androgenic activity.17 Because of its progestogenic activity, progesterone has functional antiestrogenic effects in certain tissues such as the uterus, cervix, and vagina.17 In addition, progesterone has antigonadotropic effects due to its progestogenic activity and can inhibit fertility and suppress sex hormone production.17 Progesterone differs from progestins (synthetic progestogens) such as medroxyprogesterone acetate and norethisterone, with implications for pharmacodynamics and pharmacokinetics as well as efficacy, tolerability, and safety.17 Route of administration of progesterone can be oral, vaginal, and by injection into muscle or fat, among other routes.17 The pharmacokinetics of progesterone is dependent on its route of administration. The medication is approved in the form of oil-filled capsules containing micronized progesterone for oral administration, termed oral micronized progesterone (OMP) or simply oral progesterone.18 It is also available as vaginal or rectal suppositories, vaginal gels, oil solutions for intramuscular injection, and aqueous solutions for subcutaneous injection, among others.18, 19 Recurrent miscarriage, which affects 1% of couples trying to conceive, is defined as the loss of three or more consecutive pregnancies from the time of conception up to 24 completed weeks of gestation.1 However, for this review the definition is restricted to the first trimester up to 12 completed weeks of gestation. There is currently no consensus-based definition of progesterone supplementation. Many factors have been studied as possible causes of recurrent miscarriage, such as anatomical, endocrine, immunological, genetic, and thrombophilia (inherited and acquired) disorders. The anatomical causes primarily include major uterine anomalies such as uterine septa; however, it is the authors' view that such causes would mainly contribute to second-trimester losses rather than in the first trimester. Endocrine abnormalities include thyroid disorders, polycystic ovarian syndrome, and possibly progesterone deficiencies. Immune causes are also thought to contribute to miscarriages, namely natural killer cells, cytokines, thyroid and antinuclear antibodies, lupus, and other immune syndromes. Inherited thrombophilia includes causes such as the presence of factor V Leiden (FVL), prothrombin G20210A mutation (PGM), and antithrombin and protein C and S deficiencies, whereas acquired thrombophilia includes the presence of lupus anticoagulant (LA), anticardiolipin (ACL), and anti-beta 2 glycoprotein antibodies.20 Progestogens available on the market are classified as either natural or synthetic.8, 9 Natural progesterone has chemical structures that are like those produced by the body and is available as a micronized vaginal gel or pessary. Synthetic progestogens (progestins) do not correlate with natural progesterone and are artificially manufactured in a laboratory. Examples of progestins include injectable 17-alpha hydroxyprogesterone caproate (17-OHPC) and oral dydrogesterone. Natural progesterone suppresses myometrial contractility, unlike 17-OHPC which does not have this effect and at high concentration may stimulate myometrial contractility. Although intramuscular progestogens bypass first-pass metabolism in the intestines and liver and achieve very high circulating progesterone levels where the level is maintained for a longer duration compared with vaginally administered progesterone,21 there is no clear evidence to show improvement in successful pregnancy rate. No trial has reported long-term follow-up of progesterone treatment in recurrent miscarriage; therefore, the long-term safety of progesterone supplementation is still not well known.11 However, there is no evidence that progesterone causes anatomical or physiological abnormalities in the fetus. A multicenter, double-blind, placebo-controlled, randomized trial of 836 women by Coomarasamy et al.13 concluded that there was no difference in live births in women with unexplained recurrent miscarriage given vaginal progesterone from positive pregnancy test (65.8%) compared to placebo (63.3%) (RR 1.04; 95% CI, 0.94–1.15). A recent systematic review and meta-analysis by Saccone et al.11 which included 10 trials with a total of 1580 women, concluded that the effect of progesterone in reducing pregnancy loss differs by the type of progestogen and that there may be benefit with synthetic progestogens compared to natural progesterone. This meta-analysis is limited because it included old trials that were of low quality and had small numbers; therefore, further direct like-for-like studies need to be conducted to determine the efficacy of progesterone in increasing live births in women with recurrent miscarriage. Most of the publications reviewed for these Good Practice Recommendations initiated treatment after pregnancy was confirmed; therefore, we cannot address whether progestogens could be more effective if administered during the luteal phase of the cycle, before confirmation of pregnancy. There may also be a role for synthetic progestogens in reducing recurrent pregnancy loss; however, until such evidence is available on the type, timing, and duration of progesterone supplementation, the current recommendations are based on the largest most recent randomized controlled trial available to date.13 Conclusion: There is insufficient evidence to recommend the use of progesterone to improve live birth rate in women with recurrent miscarriage. Recommendation: Commencing natural vaginal progesterone at positive pregnancy test is not recommended in asymptomatic women with a history of unexplained recurrent miscarriage. However, there may be a role for synthetic oral progesterone, but large placebo-controlled trials addressing timing, dosage, and duration are needed. Progesterone has an important role in maintaining a healthy pregnancy. It is produced by the granulosa lutein cells of the corpus luteum in the latter half of the menstrual cycle and, if a pregnancy is achieved, during the early weeks it continues to be produced from the corpus luteum and from the placenta. Progesterone also has a vital role in preparing the endometrium for implantation of the embryo. If this occurs, the corpus luteum continues to help sustain the pregnancy until about 8–12 weeks of gestation, whereby after this time the placenta takes over the vast proportion of progesterone production and continues this role for the duration of the pregnancy.22 The exact role of progesterone in maintaining a pregnancy is not fully understood. However, it has been shown that progesterone deficiency may result in an increase in inflammatory mediators.23 These include cyclo-oxygenase-2, proinflammatory interleukin 8 (IL-8), and monocyte chemoattractant protein-1, which have been shown to have a role in destabilizing the endometrium.24 It is therefore thought that regulation of these inflammatory mediators is essential to achieving a successful pregnancy and progesterone in speculated to have a role in this.25 The physiological importance of progesterone in the early part of pregnancy has prompted researchers to evaluate the role and effect of progesterone treatment in the first trimester of pregnancy in women with a history of recurrent miscarriage. Research dating back to 1972 was first to demonstrate the vital role of progesterone in maintaining pregnancy.26 This study showed that the total removal of luteal tissue before 7 weeks of gestation resulted in a fall in progesterone concentration and subsequent pregnancy loss. Successive studies have shown the association between low serum progesterone concentrations and recurrent miscarriage.27, 28 However, despite strong evidence of an association between low progesterone levels with miscarriage in general, and recurrent miscarriage to be specific, the few robust studies that have evaluated the use of progesterone treatments to reduce recurrent pregnancy loss have produced widely disparate and variable results. This has made it challenging to formulate a conclusive assessment on its effect on recurrent miscarriage. Furthermore, the variability in the results may also be attributed to the diversity in study parameters, including the use of different progestogens, doses, delivery routes, and protocols. Numerous studies in the past have investigated the effect of progesterone treatment in patients with recurrent miscarriage, dating as far back as 1953.29 However, these studies were small, had weak methodological protocols, did not meet the recommended inclusion criteria, or used different types of progestogens. This has led to unreliable results, which has made it difficult for governing bodies and decision makers to provide clear, evidence-based recommendations on the use of progesterone for the treatment of this patient group. In this review only two studies met the inclusion criteria.13, 14 Of these, the highest quality study was a large multicenter, double-blind, randomized controlled trial of 838 women with unexplained recurrent miscarriage that were treated with vaginal micronized progesterone or placebo.13 Treatment began from the time of a positive pregnancy result until the end of 12 weeks of gestation. This did not show a significantly higher rate of live births among women with a history of unexplained recurrent miscarriage. In the other randomized controlled trial that included patients with unexplained recurrent miscarriage, 82 received dydrogesterone (an orally active progestogen that is like endogenous progesterone) and 48 patients had no additional treatment.14 Treatment began from confirmation of pregnancy and continued until the 12th week of gestation. showed that there was a in subsequent miscarriage but live birth were not A recent systematic review and meta-analysis by Saccone et al.11 which included the Coomarasamy et al.13 publication and other trials with a total of 1580 women, concluded that the effect of progesterone in reducing pregnancy loss differs by the type of progestogen and that there may be benefit with synthetic progestogens compared to natural progesterone. This meta-analysis is limited because it included old trials that were of low quality and had small numbers; therefore, further direct like-for-like studies need to be conducted to determine the efficacy of progesterone in increasing live births in women with recurrent miscarriage. In a recent Cochrane review in trials met the inclusion of the trials compared treatment with placebo the four trials compared progestogen administration with no The trials were a of and In trials women had had three or more consecutive and in trials women had two or more consecutive miscarriages. dosage, and duration of progestogen treatment the with most trials at low risk of for most The meta-analysis of all women that there is a in the of for women given progestogen supplementation compared to risk 95% CI, women, A placebo-controlled trials and different of administration showed no between for miscarriage. the other there appears to be a difference for miscarriage between women with three or more compared with women with two or more miscarriages, with a more effect in women with three or more miscarriages. However, it be that there was high in the of women with three or more miscarriages, it difficult to any to recommend supplementation of progesterone. study by et investigated women with recurrent miscarriage to have early pregnancy progesterone defined by serum progesterone on the of positive pregnancy test and 48 The patients were treated with natural progesterone vaginal There was no group and were compared with No significant in subsequent miscarriage in women with three was for women with four the results a possible significant in the subsequent miscarriage rate. There were regarding the results of this study including the of a clear group and the results not a between live birth between the two it difficult to any Furthermore, the study only included a group of patients based on their progesterone levels and therefore cannot be to the overall recurrent miscarriage patient a comprehensive review of the only two studies met the inclusion by the 14 these studies do not show whether progesterone can reduce the risk of miscarriage and increase the rate of live There may be a role for oral progesterone treatment, its use is not recommended at until more robust placebo-controlled trials are Evaluation of the long-term effects of progesterone treatment during pregnancy, during the first is difficult primarily due to factors and loss to To no studies have reported any long-term according to progesterone or progestogens given in the first Of the studies included in the Coomarasamy et al.13 showed no difference in anomalies between the progesterone group and the placebo group. Furthermore, to no evidence or that used in the study included in this review is with a risk of To the of no publications have studied the effect of progesterone on safety in patients with recurrent miscarriage; however, evidence of its safety in other areas including and is well where progesterone is considered This is based on a of and its use in a large of patients over the all the identified papers and the two publications included in this there was no clear evidence of benefit of a dose in any of the administered to patients with recurrent miscarriage. The of administration are in the that progesterone administered the vaginal route was used in the study by Coomarasamy et al.13 the results did not show that this treatment had a on women with recurrent miscarriage. In the other study included in the oral dydrogesterone was This active progestogen is considered to produced progesterone in its and also has a high for progesterone may have a effect on women with recurrent miscarriage to improve pregnancy however, to no randomized studies have trials are to help make a clear all the identified papers and the three included in this there was no clear evidence of benefit of a route administered to patients with recurrent miscarriage. two studies met the inclusion for this progesterone was used in one study and this did not show any effect on patients with recurrent The other study used oral This a role for oral progesterone treatment in women with recurrent miscarriage. However, after review of this it cannot be recommended at until more robust placebo-controlled trials are Progesterone supplementation given the vaginal, and of administration higher however, the oral route is to be more as it is and it is to progesterone this Of the two studies included in this only one the supplementation of progesterone the oral route in women with recurrent pregnancy This study be at in more in subsequent In conducted a randomized controlled trial The two treatment received either 10 oral dydrogesterone or intramuscular four from the pregnancy was to the 12th week of The group received no additional The miscarriage rate was significantly in the dydrogesterone group compared to the group This difference was not treatment were The methodology in this study had certain including a process and the of that increase the of bias. Of the two studies included in this only one oral dydrogesterone for the of recurrent pregnancy loss. This highlights the need for more robust studies with to if there is a effect of oral progesterone supplementation on recurrent first-trimester miscarriage. a comprehensive review of the we could not evidence to progesterone supplementation for of first-trimester recurrent pregnancy loss. It is the authors' view that giving oral progesterone may show compared to only supplementation at positive pregnancy is a and its for the progesterone is very It is not to androgenic in the and does not progesterone In the study by of the women in the dydrogesterone pregnancies to two had one of and one of This was not significant compared to in the only one randomized controlled trial was identified from the available in which oral progesterone supplementation in the first trimester was in the form of This study a dose of oral which was given as a dose of 10 Therefore, a dose of would to be however, the of this study and the of studies in this be into women vaginal micronized progesterone if have vaginal from an pregnancy by a and a history of a However, it is important to that the purpose of these Good Practice Recommendations is to address recurrent miscarriage. The vaginal route was in a trial with the to a proportion of the to the the administration appears to a of progesterone to the uterus, which the of the uterine The large multicenter, double-blind, randomized trial by Coomarasamy et al.13 included 836 women with unexplained recurrent miscarriage were treated with vaginal micronized progesterone or The treatment was from the time of a positive pregnancy result until the end of 12 weeks of gestation and showed no difference in live births in women with unexplained recurrent miscarriage given vaginal progesterone. In an the rate of live births was of in the progesterone group and of in the placebo group rate 1.04; 95% CI, rate difference 95% CI, to There were no significant in the rate of These results were not in with of a Cochrane which a benefit of progesterone in the first trimester of However, that review was based on the results of small studies with methodological The authors of the trial that the results were based on a dose of and it is possible that the results with this are not and may not be with different and The study by et which is not included in the showed evidence from women with recurrent miscarriage to have early pregnancy progesterone defined by serum progesterone on the of positive pregnancy test and 48 The patients were treated with natural progesterone vaginal There was no group included in the study and were compared with The study showed no significant in subsequent miscarriage in women with three miscarriages, for women with four the results a possible significant in the subsequent miscarriage rate. regarding the results of this publication are in No study has investigated vaginal supplementation of progesterone. However, a by et reported a randomized controlled trial that was conducted to evaluate the effect of progesterone, early in the luteal phase before confirmation of pregnancy, in miscarriage in women with a history of unexplained recurrent miscarriage. No could be as the was Of the studies included in the Coomarasamy et al.13 showed no difference in anomalies between the progesterone group and the placebo group. Progestogens available on the market are classified as either natural or Natural progesterone has chemical structures that are like those produced by the body and is available as a micronized vaginal gel or pessary. no clear evidence of benefit of a dose in any of the administered to patients with recurrent miscarriage. In the Coomarasamy et al.13 were in a to vaginal containing either micronized progesterone or placebo from after positive results on a pregnancy This study did not show a of the treatment on women with recurrent miscarriage. The dose used a dose at the end of the also in patients with but it is the authors' view that there is currently insufficient evidence to recommend the use of vaginal progesterone for recurrent miscarriage. Although progesterone can be administered oral, vaginal, and intramuscular 40 administration of progesterone the rectal route for the of recurrent first-trimester miscarriage was not identified in the available This some studies have investigated rectal administration of progesterone for the management or of including two randomized controlled trials on the of birth using administered progesterone in and two randomized controlled trials where rectal progesterone was used as luteal phase support following injection and in and in addition to and rectal were with the rectal No study was identified in the in which rectal progesterone was investigated for of first-trimester recurrent miscarriage. the available there was no evidence of use of rectal progesterone in the to prevent recurrent first-trimester miscarriage. Although there was no evidence available on the use of rectal progesterone for recurrent first-trimester miscarriage, where it was used as luteal phase support and in of of the of abnormalities was not No studies were from the available in this The of progesterone after administration is dependent on the route used for administration. The highest variability in serum concentration is with the oral route due mainly to first-pass metabolism in the and rectal are with variation in serum however, this is dependent on and administration there is of serum concentration and It is the authors' view that injectable progesterone may not be considered in due to and of recurrent first-trimester miscarriage, no studies were identified from the available that intramuscular progesterone. where intramuscular progesterone was used in of miscarriage compared to or vaginal progesterone) did not show pregnancy with the intramuscular progesterone A systematic review and meta-analysis by Saccone et a significant in delivery at than weeks of gestation in women received vaginal progesterone compared to those were administered intramuscular progesterone. No study from the available this route of administration for of recurrent first-trimester miscarriage. No study from the available where intramuscular progesterone was used for this purpose was Although there were no studies from the available using intramuscular progesterone for of recurrent first-trimester miscarriage, where it was used in miscarriage and of there was no increase in the of No evidence was to support this from the available for Progesterone appears to be essential for maintaining a healthy pregnancy by either preparing the endometrium for implantation of the or its role in of the immune However, its exact role in maintaining a pregnancy is not fully understood. Evidence on the use of progesterone no difference in live birth compared to There to be positive for the use of synthetic oral progesterone. most trials on treatment of recurrent miscarriage with progesterone have used study in of route and of administration. A different type of progesterone as well as of administration to in the luteal could more