Use of Progestagens During Early Pregnancy
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09-dante-_Opmaak 1 4/12/12 09:19 Pagina 61 FVV in ObGyn , 2012, M OnOGraph : 61-66 preterm birth Use of progestagens during early pregnancy G. D ante , V. V accarO , F. F acchinetti Mother-Infant Department, Unit of Obstetrics, University of Modena and Reggio Emilia, Italy. correspondence at: [email protected] Abstract The term “progestagens” covers a group of molecules including both the natural female sex hormones Progesterone and 17-hydroxy Progesterone as well as several synthetic forms, all displaying the ability to bind Progesterone receptors. Several studies have used Progesterone and related steroids in the attempt to prevent spontaneous miscarriage, and treat recurrent miscarriage. The present paper aims to provide a comprehensive review of the literature on progestagens effects during early pregnancy. We looked only at the results from randomized controlled trials. We found and analyzed 15 trials on the prevention of recurrent miscarriage and 2 trials on the treatment of miscarriage. The results demonstrated that there is no evidence to support the routine use of progestagens for the treatment of threatened miscarriage. Key words: Miscarriage, progestagens, Progesterone, 17 α OH Progesterone, 17 α OH Progesterone Caproate, recurrent miscarriage. Introduction to increase the embryo implantation rates in assisted reproduction programmes. the term “progestagens” progesterone (Fig. 1) is a steroid hormone which cover a group of molecules including both the plays a crucial role in each step of human pregnancy. natural female sex hormones progesterone and 17- in early pregnancy progesterone is produced by the hydroxy progesterone (17p) as well as several corpus luteum whose duration has been estimated synthetic forms, all displaying the ability to bind 12 ± 2 days. this organ is fundamental for preg - progesterone receptors. nancy maintenance until the placenta (syncytiotro - although pharmacokinetics and pharmacodynam - phoblast) takes over its function at 7-9 th week of ics features of progestagens have been studied, their gestation, just after the expression of major histo - use in human pregnancy remains controversial, i.e. compatiblity complex antigens is suppressed in the way of administration. indeed, progestagens extra-embryonic fetal tissue. could be administered by three routes: orally, progesterone is an essential hormone in the vaginally or intramuscularly. Oral administration process of reproduction. indeed, it induces secretory guarantees optimal compliance by patients but changes in the lining of the uterus and is essential shows many disadvantages; this route also results in for a successful implantation of the embryo. More - side effects such as nausea, headache and sleepiness. over, progesterone modulates the immune response the vaginal route results in higher concentrations in of the mother to prevent rejection of the embryo, and the uterus but does not reach high and constant blood enhances uterine quiescence and suppresses uterine levels. the drug administered intramuscularly occa - contractions. therefore it is theoretically plausible sionally induces non-septic abscesses, although it is that p supplementation may reduce the risk of the only route which results in optimal blood levels miscarriage in women with a history of recurrent (Whitehead et al., 1990; Szabo and Szilagyi, 1996; miscarriages. Several studies have used proges - cunningham, 2001; Di renzo et al., 2005; christian terone and related steroids (progestagens- Fig. 1) in et al., 2007). Several reports hypothesized an the attempt to prevent spontaneous miscarriage and association between intrauterine exposure to 61 09-dante-_Opmaak 1 4/12/12 09:19 Pagina 62 Progesterone 17 α OH Progesterone 17 α OH Progesterone Caproate Fig. 1. — progesterone and progestagens progestagens in the first trimester of pregnancy and More than 80% of miscarriages occur before the genital abnormalities in male and female fetuses. 12 th week, and the rate decreases rapidly thereafter. this was due to the possible up-regulation of andro - it is a common complication of pregnancy occurring gen receptor operated by pharmacological doses of in 15% to 20% of all clinically recognized pregnan - these steroids. however, maternal safety of progesta - cies with 1% to 2% of couples suffering a recurrent gens has been reported in different trials. neonatal early loss. it is thought, however, that the true inci - safety has been evaluated in only one trial where dence of early spontaneous miscarriage may be mothers have been treated with 17 progesterone. no much higher. indeed, after implementation of as - effects of general health status, external genitalia, sisted reproduction techniques we are able to detect and psychomotor development have been reported biochemical pregnancies and therefore to conclude at follow-up. Since the paucity of data, ongoing trials that the rate of early spontaneous miscarriage in the are encouraged to include the follow-up of neonates first trimester is higher than expected (everett, in their study design (Mosby, 2001). 1997). the present paper aims to provide a comprehen - chromosomal anomalies cause at least half of sive view of the literature on the effects of progesta - these early miscarriages. the risk increases with par - gens during early pregnancy. We describe the effects ity and at the extremes of maternal age (>34 years of progestagens for preventing recurrent miscar - and <20 years old). Other risk factors for miscarriage riages and managing threatened miscarriage. include maternal infections (such as vaginitis, uri - Miscarriage is defined as pregnancy loss before nary tract infections), endocrine abnormalities (dia - 23 weeks’ gestation, based on the first day of the last betes mellitus, hypothyroidism, pituitary adenoma), menstrual period. Miscarriage is associated with insufficient production of progesterone by the cor - considerable physical and psychological morbidity, pus luteum (short and/or abnormal luteal phase), particularly in developing countries (World health polycystic ovary syndrome, drug use, environmental Organization, 1992). haemorrhage into the decidua factors, maternal autoimmune disorders (such as basalis and necrotic changes in the tissues adjacent anti-phospholipids antibodies), previous history of to the bleeding usually accompany abortion; the two or more miscarriages and acquired or inherited ovum becomes detached and stimulates uterine con - uterine malformations (Szabo and Szilagyi, 1996). tractions that result in expulsion (cunningham, Despite all the above recognised or supposed factors, 2001). the cause of miscarriage cannot be identified in recurrent miscarriage has been defined as 3 or almost 50% of cases. threatened miscarriage mani - more consecutive episodes of spontaneous preg - fests itself through vaginal bleeding, with or without nancy losses with the same biological father (World abdominal pain, while the cervix is closed and the health Organization, 1992). extensive investigation fetus is viable inside the uterine cavity. the intro - of women involved will fail to find a recognisable duction of ultrasound scans in the management of cause in up to half of the cases. Luteal phase defects, bleeding in early pregnancy has improved the diag - immunotolerance derangements, chromosomal nosis tremendously (hemminki, 1998). anomalies and endocrine disorders are the most com - During the past 50 years several trials investigated mon recognisable causes. accepting an independent the use of progestagens for the prevention of miscar - risk of miscarriage to be 15%, a second loss could riage. actually the therapeutic value of progestagens be calculated to occur at a rate of 2-3% while a third remains to be established. this might be due to the loss is expected in 0.34% of women. poor design of the studies which evaluated hormone 62 FVV in ObGyn 09-dante-_Opmaak 1 4/12/12 09:19 Pagina 63 effectiveness. Moreover, a lot of different aetiologies trolled trials published between 1966 and 2006. they are associated with threatened miscarriages and included all types of progestagens in the prevention heterogeneity of studies has not been accounted for. of miscarriage (haas and ramsey, 2009) and for the treatment of threatened miscarriage (Wahabi et al., Methods 2011), regardless of the dose, duration or route of administration and compared with placebo, no treat - Literature searches were performed in the cochrane ment or other interventions. no further rcts were Library, only randomized controlled trials (rcts) published after those included in the cochrane re - were considered. the search terms were as follows: view . “progestagens”, “miscarriage”, “recurrent miscar - Wahabi et al. (2011) selected the trials published riage”. We performed a search about all types of in 7 databases and references from relevant articles. progestagens, their applications and potential effects the authors included only the trials where the for preventing recurrent miscarriage and for manag - administration of progestagens started before preg - ing miscarriage, regardless of the dose, duration or nancy and continued during pregnancy. twenty-nine route of administration compared with placebo, no studies were potentially eligible for inclusion, of treatment or other intervention. these, 15 studies were included after applying the all sources of information were read and evalu - inclusion criteria. the characteristics of these rcts ated by one of the authors (GD), and were later in - are described in table 1. dependentely