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

Abstract

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 therefore, further studies need to be conducted to the of progesterone in live births in women with recurrent miscarriage. of the publications for these Good Practice Recommendations treatment after pregnancy was therefore, progestogens be more administered during the luteal phase of the confirmation of pregnancy. There may also be a role for synthetic progestogens in reducing recurrent pregnancy loss; however, such evidence is available on the and duration of progesterone the current recommendations are based on the recent randomized trial available to There is evidence to the use of progesterone to live in women with recurrent miscarriage. natural vaginal progesterone at positive pregnancy test is not in women with a of unexplained recurrent miscarriage. However, there may be a role for synthetic oral trials and duration are Progesterone has an role in a pregnancy. It is produced by the of the corpus luteum in the of the menstrual a pregnancy is during the early weeks it to be produced from the corpus luteum and from the placenta. Progesterone also has a role in the endometrium for implantation of the this the corpus luteum to help the pregnancy weeks of after this time the over the of progesterone production and this role for the duration of the The role of progesterone in a pregnancy is not However, it has been that progesterone may in an in These include and which have been to have a role in the It is therefore thought that of these is essential to a successful pregnancy and progesterone in to have a role in The physiological of progesterone in the early of pregnancy has to the role and effect of progesterone treatment in the first trimester of pregnancy in women with a of recurrent miscarriage. to was first to the role of progesterone in This that the total of luteal weeks of resulted in a in progesterone concentration and pregnancy studies have the low progesterone and recurrent However, despite evidence of an low progesterone levels with miscarriage in and recurrent miscarriage to be the studies that have evaluated the use of progesterone to recurrent pregnancy loss have produced and This has it to a on its effect on recurrent miscarriage. the in the may also be to the in including the use of different delivery and Numerous studies in the have the effect of progesterone treatment in with recurrent miscarriage, as as However, these studies were had methodological not the or used different of This has led to which has it for bodies and to provide recommendations on the use of progesterone for the treatment of this In this review two studies the the quality was a multicenter, double-blind, randomized trial of women with unexplained recurrent miscarriage that were with vaginal micronized progesterone or from the time of a positive pregnancy the of 12 weeks of gestation. This not show a of live births among women with a of unexplained recurrent miscarriage. In the other randomized trial that included with unexplained recurrent miscarriage, progestogen that is like endogenous and had no from confirmation of pregnancy and the of gestation. that there was a in miscarriage live 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 therefore, further studies need to be conducted to the of progesterone in live births in women with recurrent miscarriage. In a recent Cochrane review in trials the 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. and duration of progestogen treatment the with trials at low risk of for 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 trials and different of administration no for miscarriage. the other there appears to be a difference for miscarriage women with three or more compared with women with two or more miscarriages, with a more effect in women with three or more miscarriages. 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The of administration are in the that progesterone administered the vaginal route was used in the by Coomarasamy et al.13 the not show that this treatment had a on women with recurrent miscarriage. In the other included in the oral was This 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 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 with recurrent miscarriage. two studies the for this progesterone was used in one and this not show any effect on with recurrent The other used oral This a role for oral progesterone treatment in women with recurrent miscarriage. However, after review of this it be at more trials are Progesterone supplementation given the vaginal, and of administration however, the oral route is to be more as it is and it is to progesterone this the two studies included in this one the supplementation of progesterone the oral route in women with recurrent pregnancy This be at in more in In conducted a randomized trial The two treatment either 10 oral or intramuscular four from the pregnancy was to the of The group no The miscarriage was in the group compared to the group This difference was not treatment were The methodology in this had certain including a process and the of that the of bias. the two studies included in this one oral for the of recurrent pregnancy This highlights the need for more studies with to there is a effect of oral progesterone supplementation on recurrent first-trimester miscarriage. a comprehensive review of the not evidence to progesterone supplementation for of first-trimester recurrent pregnancy It is the authors' view that giving oral progesterone may show compared to 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 by of the women in the pregnancies to two had one of and one of This was not significant compared to in the one randomized trial was identified from the available in which oral progesterone supplementation in the first trimester was in the form of This a dose of oral which was given as a dose of 10 Therefore, a dose of would to be however, the of this and the of studies in this be into women vaginal micronized progesterone have vaginal from an pregnancy by a and a of a However, it is to that the purpose of these Good Practice Recommendations is to recurrent miscarriage. The vaginal route was in a trial with the to a of the to the the administration appears to a of progesterone to the uterus, which the of the uterine The multicenter, double-blind, randomized trial by Coomarasamy et al.13 included 836 women with unexplained recurrent miscarriage were with vaginal micronized progesterone or The treatment was from the time of a positive pregnancy the of 12 weeks of and no difference in live births in women with unexplained recurrent miscarriage given vaginal progesterone. 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However, a by et reported a randomized trial that was conducted to the effect of early in the luteal phase confirmation of pregnancy, in miscarriage in women with a of unexplained recurrent miscarriage. No be as the was the studies included in the Coomarasamy et al.13 no difference in anomalies the progesterone group and the placebo 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 with recurrent miscarriage. In the Coomarasamy et al.13 were in a to vaginal containing either micronized progesterone or placebo from after positive on a pregnancy This not show a of the treatment on women with recurrent miscarriage. The dose used a dose at the of the also in with it is the authors' view that there is currently evidence to 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 rectal administration of progesterone for the management or of including two randomized trials on the of using administered progesterone in and two randomized 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 was identified in the in which rectal progesterone was 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 in concentration is with the oral route due mainly to first-pass metabolism in the and rectal are with variation in however, this is dependent on and administration there is of 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 not show pregnancy with the intramuscular progesterone A systematic review and meta-analysis by Saccone et a significant in delivery at than weeks of in women vaginal progesterone compared to those were administered intramuscular progesterone. No from the available this route of administration for of recurrent first-trimester miscarriage. No 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 in the of No evidence was to support this from the available for Progesterone appears to be essential for a pregnancy by either the endometrium for implantation of the or its role in of the immune However, its role in a pregnancy is not Evidence on the use of progesterone no difference in live compared to There to be positive for the use of synthetic oral progesterone. trials on treatment of recurrent miscarriage with progesterone have used in of route and of administration. A different type of progesterone as well as of administration to in the luteal more

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