Traditionally, the World Health Organization (WHO) defines recurrent miscarriage (RM) as the occurrence of three or more consecutive spontaneous abortions (World Health Organization, 1977). In 2009, the International Committee for Monitoring Assisted Reproductive Technology and WHO updated the definition of RM as the occurrence of two or more miscarriages (Zegers-Hochschild et al., 2009). This condition affects 0.5%–2.5% of couples of reproductive age (Ford and Schust, 2009, Christiansen, 2021). Lifestyle factors, parental chromosomal disorders, uterine anatomy abnormalities, antiphospholipid syndrome, endocrinopathies, and high sperm DNA fragmentation are the frequently observed causes in RM cases (Regan et al.; Bender Atik et al., 2023). However, the main guideline recommendations indicate that only approximately half of the RM couples have identifiable reason for RM (Regan et al.; Bender Atik et al., 2023).

Implantation failure is observed in women undergoing assisted reproductive technology (ART) (Cimadomo et al., 2023). It occurs when a good-quality embryo is transferred into the uterine cavity but does not result in a clinical pregnancy, as evidenced by ultrasound visualization of an intrauterine gestational sac (Cimadomo et al., 2023). The definition of recurrent implantation failures (RIF) has no consensus (Cimadomo et al., 2023, Pirtea et al., 2023). Recently, the European Society of Human Reproduction and Embryology (ESHRE) recommended a new definition of RIF based on the estimated cumulative clinical pregnancy rate (CPR) of a patient who underwent an ART using her eggs (Cimadomo et al., 2023).

Thus, RIF is defined when a patient, submitted to at least two embryo transfers (ET), reaches an estimated cumulative CPR of ≥60%. This occurs after the transfer of ≥3 euploid embryos without successful implantation, regardless of the patient’s age. However, RIF may be defined as the lack of clinical pregnancy after 3, 4, or 6 ET in women aged <35, 35–39, and ≥40 years, respectively, when previously transferred embryos have not undergone preimplantation genetic investigation (Cimadomo et al., 2023). The number of couples with RIF remains unknown. RIF occurs in approximately 10% of couples undergoing ART. The etiology is multifactorial, including male, female, and embryorelated factors associated. However, a large number of RIF cases remain with an unknown cause (Cimadomo et al., 2023, Pirtea et al., 2023).

Embryo implantation is a biological phenomenon that requires maternal immune system involvement (Mor and Cardenas, 2010). Maternal immune cells recognize embryo alloantigens and trigger a systemic and intrauterine immune response characterized by allotolerance (Mor and Cardenas, 2010). Several studies indicate the role of an inadequate maternal immune response in reproductive failure cases, including RM and RIF. High pro-inflammatory interleukin (IL) levels, such as IL-2, IL-6, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ), increased peripheral natural killer (NK) cells cytotoxicity, reduced number of regulatory T cells (Treg), and imbalanced T helper (Th) 1/Th2 and Treg/Th17 immune response are often seen in women with unexplained RM (uRM) and RIF (uRIF) (Yang et al., 2010, Lee et al., 2013, Wang et al., 2020, Cavalcante et al., 2023b).

The use of immunomodulatory therapies in RM and RIF management has been proposed since the beginning of the 1980s (Taylor and Faulk, 1981, Mueller-Eckhardt et al., 1989). Several immunotherapies for the management of couples with reproductive failure have been investigated, such as immunization with lymphocytes, intravenous immunoglobulin (IVIG), lipid emulsions, corticosteroids, anti-TNF drugs, and granulocyte colony-stimulating factor. Several authors have reported an improvement in pregnancy outcomes in couples with a history of reproductive failures who have undergone immunological interventions, but the efficacy and safety of some immunotherapies still have no consensus (Cavalcante et al., 2021, Ma et al., 2022, Bender Atik et al., 2023, Cavalcante et al., 2023a, Cimadomo et al., 2023, Ma et al., 2023). Recently, ESHRE recognized that the use of repeated and high IVIG doses can increase the live birth rate (LBR) in women with four or more previous uRM (Bender Atik et al., 2023). However, ESHRE and the American Society for Reproductive Medicine do not recommend any immunological intervention intended to improve LBR in uRIF cases, except in research protocols (Cimadomo et al., 2023, Pirtea et al., 2023).

Calcineurin is a cytoplasmic protein involved in T lymphocyte activation, proliferation, and differentiation, acting as a mediator of inflammatory factor transcription and translation (Hogan, 2017, Park et al., 2020). Calcineurin is calcium- and calmodulin-dependent serine/threonine protein phosphatase. Calcineurin is responsible for the nuclear factor dephosphorylation of activated T-cell cytoplasmic (NFATc). NFATc is translocated to the nucleus and regulates the production of IL-2 and other ILs, such as IL-3, IL-4, and TNF-α, after its activation in the cytoplasm (Fig. 1) (Hogan, 2017, Park et al., 2020).

Calcineurin inhibitors (CNIs) are drugs with immunosuppressive action frequently used to prevent transplanted organ rejection. CNIs are prescribed for the treatment of some rheumatic diseases and severe atopic dermatitis. The two main CNIs are cyclosporine (CsA) and tacrolimus (TAC). Voclosporin and pimecrolimus are other drugs that are part of the CNIs group (Karolin et al., 2021, Safarini et al., 2023).

CsA, which is a decapeptide extracted from the fungus Tolypocladium inflatum, was the first CNI approved for post-transplant organ rejection treatment in the early 1980s. Problems associated with drug pharmacokinetics (dose, absorption, and narrow therapeutic window), in addition to side effects, especially nephrotoxicity, stimulated the production of new drugs (Engwenyu and Anderson, 2022, Safarini et al., 2023). A new CNI called TAC (a macrolide derived from the bacterium Streptomyces tsukubaensis) was later approved as an immunosuppressive drug for liver transplantation in the 1990s (Engwenyu and Anderson, 2022, Safarini et al., 2023). CsA and TAC bind to cytoplasmic receptors (cyclophilin [CpN] and the FK506 binding protein [FKBP]) and inhibit calcineurin activity. Consequently, NFATc dephosphorylation and translocation are inhibited, thereby reducing inflammatory ILs gene transcriptional activation (Fig. 1) (Engwenyu and Anderson, 2022, Safarini et al., 2023).

Fu et al. (2015) proposed the use of CsA for treating RM of immune etiology (Fu, 2015). Simultaneously, Nakagawa et al. (2015) revealed that immunosuppression with TAC increased the LBR of patients with RIF who had a high Th1/Th2 ratio (Nakagawa et al., 2015). Since then, several authors have evaluated the efficacy and safety of CNIs in treating women with reproductive failures, especially those with associated immune disorders.

Thus, this systematic review and meta-analysis (SRMA) aimed (1) to evaluate the effectiveness of the use of CNIs on the pregnancy outcomes of women with RM and RIF and (2) to evaluate the occurrence of side effects and obstetric and neonatal complications of women with RM and RIF treated with CNIs.