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. 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.
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. 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 activation and controlling cytokine production during pregnancy. 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.
Progestogens available on the market are classified as either natural or synthetic. 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. 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, SubSaharan Africa, the Middle East, and Latin America.
