tacrolimus and Abortion--Spontaneous

Infertility is estimated to affect 8% to 12% of reproductive-aged couples worldwide. While approximately 85% of infertile couples have an identified cause, the remaining 15% suffer physically and emotionally from unexplained intractable infertility. In recent years, maternal-to-fetal immunological abnormalities have attracted attention as mechanisms that differ from the conventional factors contributing to infertility and pregnancy loss. A T-helper 2 (Th2)-dominant immune state has been proposed as a maternal immune alteration to eliminate rejection and induce tolerance to a semi-allogeneic fetus. An imbalance in Th1 responses would not induce adequate maternal immune tolerance to the fetus or early embryos. Tacrolimus, widely used as an immunosuppressant agent in solid organ transplant recipients, is expected to suppress maternal rejection and promote tolerance to early embryos after assisted reproductive technology by modulating the immunological environment of the preimplantation endometrium. We planned an exploratory clinical trial to determine the efficacy, safety, and dosage of tacrolimus in women with intractable infertility.. This is a multicenter, 2-dose, single-group controlled trial in infertile women who failed to achieve a chemical pregnancy despite multiple in vitro fertilization (IVF) and embryo transfer (ET) treatment cycles. The following 2 key selection criteria were set: no underlying factors of infertility despite appropriate evaluation and presence of Th1-dominant immune state, defined as a Th1/Th2 cell ratio ≥ 10.3 in the peripheral blood. A total of 26 eligible participants are randomly assigned (in a 2:1 ratio) to receive immunosuppressive therapy with oral tacrolimus at a daily dose of 2 mg or 4 mg. Tacrolimus is administered for 16 days starting from 2 days before ET. The primary endpoint is the presence of clinical pregnancy 3 weeks after IVF/ET treatment, and the secondary endpoint is the presence of biochemical pregnancy 2 weeks after IVF/ET treatment. Safety evaluation and biomarker discovery for tacrolimus treatment in infertile women will be conducted simultaneously.. Japan Registry of Clinical Trials (jRCT; jRCTs031220235).

Topics: Abortion, Spontaneous; Adult; Embryo Transfer; Female; Fertilization in Vitro; Humans; Infertility, Female; Pregnancy; Pregnancy Rate; Reproductive Techniques, Assisted; Tacrolimus

To investigate the therapeutic effect of co-administration of tacrolimus (TAC) and low-molecular-weight heparin (LMWH) or LMWH only on pregnancy outcomes in the female with a history of implantation failure and elevated peripheral blood natural killer (pNK) cell proportion in frozen-thawed embryo transfer cycles.. To evaluate the pregnancy parameters for 249 patients with ≥2 implantation failures and pNK cell proportion ≥12% by analyzing a retrospective observational cohort study. Sixty patients had received the co-administration TAC and LMWH (TAC & LMWH group), 85 others had only taken LMWH (LWMH group), and the rest did not take any particular drugs (control group).. The experimental finding indicated that the TAC & LMWH group and the LMWH group showed higher clinical pregnancy rates than the control group (p < 0.05), and TAC & LMWH group had a much higher live birth rate. According to the binary logistic regression analysis, the combination of TAC and LMWH was conducive to clinical pregnancy and live birth rate and reduced the possibility of miscarriage. It would not affect the result of spontaneous abortion and live birth, although the LMWH was only beneficial to clinical pregnancy. In addition, these findings were similar for these three groups' obstetrical and neonatal outcomes.. The combination of TAC and LMWH can improve clinical pregnancy and live birth rates and reduce the risk of spontaneous miscarriage in patients with a history of implantation failure and elevated pNK ratio. LMWH is also beneficial to clinical pregnancy.

Topics: Abortion, Spontaneous; Female; Heparin, Low-Molecular-Weight; Humans; Infant, Newborn; Killer Cells, Natural; Live Birth; Pregnancy; Pregnancy Rate; Retrospective Studies; Tacrolimus

Some of obstetrical complications such as unexplained pregnancy loss and preeclampsia (PE) are associated with maternal-fetal immune abnormalities, leading to uteroplacental dysfunction, insufficient fetal immune tolerance, or fetal rejection. Immunosuppressants with calcineurin inhibitors could be useful for the prevention of these complications by modulating the cellular immune balance by directly inhibiting activated T-helper (Th) 1 and natural killer (NK)/NKT cells. We present our experience with the immunosuppressant tacrolimus in five pregnant women who had a previous pregnancy history of unexplained or preeclamptic stillbirth. Th1 and Th2 cell populations and NK cell activities in peripheral blood were measured as clinical parameters during pregnancy. Case 1-3 achieved suppressions of predominant Th1 immunity and live births without pregnancy-related complications. In case 4, increased tacrolimus dose after a miscarriage resulted in her first live birth; however, she developed PE and severe fetal growth restriction with elevated Th1/Th2 cell ratios at 26 weeks of gestation. Case 5 had a previous history of early onset PE and the hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, and an emergency cesarean section was needed for maternal safety at 20 weeks of gestation. The course of the next pregnancy was stable under tacrolimus treatment; however, the HELLP syndrome recurred after PE at 33 weeks of gestation. Although an imbalance in the Th1/Th2 cell ratio was not observed during pregnancy, NK cell activity was markedly elevated before delivery. In conclusion, tacrolimus is a potential drug candidate for the prevention of unexplained or preeclamptic stillbirth with Th1-dominant immune states.

Topics: Abortion, Spontaneous; Cesarean Section; Female; HELLP Syndrome; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Pharmaceutical Preparations; Pre-Eclampsia; Pregnancy; Stillbirth; Tacrolimus

We evaluated the clinical efficacy of immunosuppressive treatment with tacrolimus for repeated implantation failure (RIF) patients who have elevated in T helper (Th1)/Th2 cytokine producing cell ratios.. This was a prospective cohort study of treatment for RIF patients (n = 42) with elevated peripheral blood Th1 (CD4(+) /IFN-γ(+) )/Th2 (CD4(+) /IL-4(+) ) cell ratios at the Sugiyama clinic between November 2011 and October 2013. Twenty-five patients were treated with tacrolimus (treatment group) and 17 received no treatment (control group). Treatment group received tacrolimus 2 days before embryo transfer and continued until the day of the pregnancy test, for a total of 16 days. The daily dose of tacrolimus (1-3 mg) was determined based on the degree of the Th1/Th2 cell ratio.. The clinical pregnancy rate of the treatment group was 64.0%, which was significantly higher than that of the control group (0%) (P < 0.0001). In the treatment group, the miscarriage rate was 6.3%, the live birthrate was 60.0% (P < 0.0001). There was no significant side-effect from tacrolimus in treatment group. No one developed obstetrical complications during pregnancy.. An immunosuppressive treatment using tacrolimus improved pregnancy outcome of repeated implantation failure patients with elevated Th1/Th2 ratios.

Topics: Abortion, Habitual; Abortion, Spontaneous; Adult; Case-Control Studies; Embryo Implantation; Embryo Transfer; Female; Fertilization in Vitro; Humans; Immune Tolerance; Immunosuppression Therapy; Interferon-gamma; Interleukin-4; Pregnancy; Pregnancy Outcome; Pregnancy Rate; Prospective Studies; Reproduction; Tacrolimus; Th1 Cells; Th2 Cells

To report the pregnancy outcomes in Irish female renal transplant recipients on modern maintenance immunosuppression.. The Republic of Ireland transplant database was accessed to identify the patient cohort in question. All female renal transplant recipients whose transplantation was in Ireland before or during their reproductive years were included. A questionnaire was sent to the identified women. A chart review was performed for those women who reported a pregnancy following renal transplantation.. Two hundred and ten women met the inclusion criteria. There was a response rate of 70% (n = 148). Eighteen women reported 29 pregnancies. The live birth rate was 76%. The mean gestation of the live births was 36.2 weeks with a mean birth weight of 3.0 kg. There were six cases of pre-eclampsia. Twin pregnancies and those entering pregnancy with a creatinine greater than 135 µmol/l had particularly complicated clinical courses. Four women had not conceived post transplant despite actively trying for over 1 year. Two women utilised assisted fertility methods (in vitro fertilisation), one of whom became pregnant.. A significant proportion of women who attempt to conceive following renal transplantation are successful, without the use of assisted fertility. Pregnancy in this setting warrants meticulous multidisciplinary care.

Topics: Abortion, Spontaneous; Adult; Birth Weight; Female; Gestational Age; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Ireland; Kidney Transplantation; Live Birth; Pre-Eclampsia; Pregnancy; Pregnancy Rate; Reproductive Techniques, Assisted; Tacrolimus; Young Adult

To assess maternal, neonatal and graft outcomes after pregnancy in patients with kidney transplantation, and to compare the immunosuppressive therapies used.. Review of 29 pregnancies in 23 patients with kidney transplantation, managed at La Fe University Hospital, Valencia. Immunosuppressive therapies with Cyclosporine-A, Tacrolimus, Mycophenolate mofetil and Azathioprine were compared.. No statistical differences were found in perinatal or maternal complications, with respect to the immunosuppressive therapy used. There were no differences between therapy and graft survival. Maternal complications occurred in 25 out of 28 deliveries. The most common were anemia (75%) and hypertension (53.6%). Of the 29 pregnancies, 26 were live deliveries, two were stillbirths and one was a miscarriage. The median birth weight of newborns was 2650 g (900-4350 g). From the 28 deliveries, maternal complications were reported in 25 patients. Perinatal complications were recorded in 55.6% of the patients, with prematurity being the most common (44.4%) type. One malformation was reported, this was a cleft palate in a 25 year old patient who was treated with mycophenolate mofetil.. Pregnancies in patients with kidney transplantation should be considered high-risk pregnancies because of the higher rate of maternal and perinatal complications. Immunosuppressive therapies have not shown differences in maternal or perinatal outcomes.

Topics: Abortion, Spontaneous; Adult; Azathioprine; Cyclosporine; Female; Graft Survival; Humans; Immunosuppressive Agents; Infant, Newborn; Kidney Transplantation; Mycophenolic Acid; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Stillbirth; Tacrolimus; Transplantation Conditioning; Young Adult