Approximately one million couples receive in vitro fertilisation (IVF) treatment every year worldwide . Luteal phase support (LPS) has routinely been applied as part of this treatment. The use of agonistic or antagonistic gonadotropin-releasing hormone (GnRH) protocols in stimulated IVF/intracytoplasmic sperm injection (ICSI) cycles cause disruptions to the luteal phase, leading to inadequate development of the endometrium and asynchrony between endometrial receptiveness and embryo transfer. The most plausible cause of this condition is the development of multiple follicles upon ovarian stimulation, which results in superphysiological steroid concentrations and consequent inhibition of luteinising hormone (LH) secretion by the pituitary via negative feedback at the level of the hypothalamic-pituitary axis . Despite the rapid recovery of the pituitary in GnRH-antagonist protocols, luteolysisis also prematurely induced after GnRH-antagonist co-treatment, resulting in a significant reduction in luteal phase length and a compromised reproductive outcome. For this reason, LPS remains mandatory in GnRH antagonist protocols used for IVF [3–5]. A large number of studies have shown that LPS improves the clinical pregnancy rate and thus the live birth rate, but the ideal LPS method remains unclear . Although luteal human chorionic gonadotropin (hCG) supplementation has proven to be an effective way to overcome luteal phase defects, this treatment is frequently associated with an increased risk of ovarian hyperstimulation syndrome (OHSS) , so the current most widely used form of LPS is progesterone (P).
The use of P supplementation after oocyte retrieval (OR) is almost universal, but the optimal duration of P administration remains controversial. A recent large survey of 84 IVF centres in 35 countries, encompassing 51,155 cycles, found that P was continued until 10–12weeks of gestation in 67% of the cycles, whereas it was discontinued in 22% and 12% when foetal heart pulsations were recognised or when the β-hCG test was positive, respectively . In the existing literature, P supplementation is variously terminated on or near the day of a positive β-hCG test [9–12] or extended to the day of the first ultrasound (5–7 weeks) , to the 8th week [14–16], or as late as the 12th week of pregnancy [17–21]. Until recently, the available data have been insufficient to determine the optimal duration of therapy, and prolonged P protocols have been the rule, with most clinicians following the dictum, “better safe than sorry” . A growing body of evidence, however, has challenged this concept and adds to the increasing concern that P supplementation of early pregnancy after IVF/ICSI might be unnecessary [10–14, 22, 23].
Four formulations of P are currently used for assisted reproduction, including vaginal, intramuscular (i.m.), oral and rectal preparations. Vaginal P was used for LPS as a single agent in 64% of cycles and in another 16% of cycles in combination with either i.m. (15%) or oral P (1%). As single agents, i.m. P was used in 13% of cycles, oral P in another 2% and hCG in 5% . Vaginal P can result in similar pregnancy rates as i.m. P and is more comfortable and tolerable to patients [24, 25], but it is more expensive. Conversely, i.m. P is often associated with a number of side effects, including painful injections, severe inflammatory reactions, and sterile abscesses . Prolonged and repeated i.m. injections of P in oil may also lead to delayed forms of hypersensitivity reactions, with leukocytosis, marked eosinophilia and compromised pulmonary activity [27, 28]. Orally administered P has a first-pass effect in which a high concentration is sent to the portal circulation, which, in turn, results in the production of many liver metabolites of P, some of which may be teratogenic. Despite the available literature on the teratogenic effects of prenatal oral P use [29, 30], this agent is still used routinely by many practitioners. Therefore, taking into consideration the burden of LPS treatment, the adverse reactions to P and updated results suggesting that P supplementation during early pregnancy after IVF/ICSI might be unnecessary, we questioned whether the practice of early pregnancy P supplementation in IVF/ICSI patients should be discontinued.
The aim of this study was to perform a meta-analysis of all available randomised controlled trials (RCT) comparing early P cessation with P continuation after assisted conception in IVF/ICSI cycles to investigate potential differences in live birth, miscarriage and ongoing pregnancy rates. This review was performed in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement principles .