We investigated the efficacy and safety of tacrolimus (TAC) by monitoring its serum concentration for mothers and infants in pregnant patients with systemic lupus erythematosus (SLE).
Methods
We measured trough concentrations of TAC in 25 pregnant patients with SLE to assess influence of TAC on the disease activity. Additionally, we measured the concentrations of TAC in umbilical arterial blood, breast milk, and breastfed infants to investigate the safety of TAC for the mothers and infants.
Results
The trough concentrations of TAC in the mothers significantly decreased in the second trimester as compared with those before pregnancy. However, the decrease in the trough concentrations of TAC did not lead to the deterioration of SLE. When examined, the doses of TAC were significantly lower in the second trimester and postpartum in the deteriorating group than those in the non-deteriorating group. There were no adverse events by TAC in mothers and fetuses. The concentrations of TAC in the umbilical cord blood were lower than those in the maternal blood. The relative infant dose in breastfed infants of TAC was < 1%. The level of TAC in infant bloods was below detectable limits.
Conclusion
These findings suggest that TAC is one of the most effective and safest immunosuppressive drugs for use in pregnant patients with SLE.
HardyCJPalmerBPMortonSJMuirKRPowellRJ. Pregnancy outcome and family size in systemic lupus erythematosus: a case-control study. Rheumatology (Oxford)1999; 38: 559–563.
2.
LateefAPetriM. Management of pregnancy in systemic lupus erythematosus. Nat Rev Rheumatol2012; 8: 710–718.
3.
KwokLWTamLSZhuTLeungYYLiE. Predictors of maternal and fetal outcomes in pregnancies of patients with systemic lupus erythematosus. Lupus2011; 20: 829–836.
4.
AndreoliLBertsiasKGAgmon-LevinNet al.EULAR recommendations for women’s health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. Ann Rheum Dis2017; 76: 476–485.
5.
WangYHWuXXTanJPZhangJP. Influential factors of systemic lupus erythematosus activity during pregnancy and its relationship with pregnancy outcome. Zhonghua Fu Chan Ke Za Zhi2006; 41: 601–604. in Chinese).
6.
HarwardLEMitchellKPieperCCoplandSCriscione-SchreiberLGClowseME. The impact of cyclophosphamide on menstruation and pregnancy in women with rheumatologic disease. Lupus2013; 22: 81–86.
7.
Perez-AytesAMarin-ReinaPBosoVLedoACareyJCVentoM. Mycophenolate mofetil embryopathy: a newly recognized teratogenic syndrome. Eur J Med Genet2017; 60: 16–21.
8.
SaavedraMÁSánchezAMoralesSÁngelesUJaraLJ. Azathioprine during pregnancy in systemic lupus erythematosus patients is not associated with poor fetal outcome. Clin Rheumatol2015; 34: 1211–1216.
9.
SaavedraMACruz-ReyesCVera-LastraOet al.Impact of previous lupus nephritis on maternal and fetal outcomes during pregnancy. Clin Rheumatol2012; 31: 813–819.
10.
DumontFJ. FK506, an immunosuppressant targeting calcineurin function. Curr Med Chem2000; 7: 731–748.
11.
KondoHAbeTHashimotoHet al.Efficacy and safety of tacrolimus (FK506) in treatment of rheumatoid arthritis: a randomized, double blind, placebo controlled dose-finding study. J Rheumatol2004; 31: 243–251.
12.
HannahJCasianAD’CruzD. Tacrolimus use in lupus nephritis: a systematic review and meta-analysis. Autoimmun Rev2016; 15: 93–101.
13.
ZhangXJiLYangLTangXQinW. The effect of calcineurin inhibitors in the induction and maintenance treatment of lupus nephritis: a systematic review and meta-analysis. Int Urol Nephrol2016; 48: 731–743.
14.
KainzAHarabaczICowlrickISGadgilSDHagiwaraD. Review of the course and outcome of 100 pregnancies in 84 women treated with tacrolimus. Transplantation2000; 70: 1718–1721.
15.
Ruiz-IrastorzaGKhamashtaMA. Evaluation of systemic lupus erythematosus activity during pregnancy. Lupus2004; 13: 679–682.
16.
BogenDLPerelJMHelselJCHanusaBHThompsonMWisnerKL. Estimated infant exposure to enantiomer-specific methadone levels in breastmilk. Breastfeed Med2011; 6: 377–384.
17.
YoonKH. Efficacy and cytokine modulating effects of tacrolimus in systemic lupus erythematosus: a review. J Biomed Biotechnol2010; 2010: 686480–686480.
18.
WebsterPWardleABramhamKWebsterLNelson-PiercyCLightstoneL. Tacrolimus is an effective treatment for lupus nephritis in pregnancy. Lupus2014; 23: 1192–1196.
19.
IzumiYMiyashitaTMigitaK. Safety of tacrolimus treatment during pregnancy and lactation in systemic lupus erythematosus: a report of two patients. Tohoku J Exp Med2014; 234: 51–56.
20.
OktemOGuzelYAksoySAydinEUrmanB. Ovarian function and reproductive outcomes of female patients with systemic lupus erythematosus and the strategies to preserve their fertility. Obstet Gynecol Surv2015; 70: 196–210.
21.
AktürkSÇelebiZKErdoğmuşŞet al.Pregnancy after kidney transplantation: outcomes, tacrolimus doses, and trough levels. Transplant Proc2015; 47: 1442–1444.
22.
ZhengSEasterlingTRUmansJGet al.Pharmacokinetics of tacrolimus during pregnancy. Ther Drug Monit2012; 34: 660–670.
23.
KroeseSJAbheidenCNHBlomjousBSet al.Maternal and perinatal outcome in women with systemic lupus erythematosus: a retrospective bicenter cohort study. J Immunol Res2017; 2017: 8245879–8245879.
24.
Yan YuenSKrizovaAOuimetJMPopeJE. Pregnancy outcome in systemic lupus erythematosus (SLE) is improving: results from a case control study and literature review. Open Rheumatol J2008; 2: 89–98.
25.
ClarkCASpitzerKANadlerJNLaskinCA. Preterm deliveries in women with systemic lupus erythematosus. J Rheumatol2003; 30: 2127–2132.
26.
BuyonJPKimMYGuerraMMet al.Predictors of pregnancy outcome in a prospective, multiethnic cohort of lupus patients. Ann Intern Med2015; 163: 153–163.
27.
HebertMFZhengSHaysKet al.Interpreting tacrolimus concentrations during pregnancy and postpartum. Transplantation2013; 95: 908–915.
28.
ZhengSEasterlingTRHaysKet al.Tacrolimus placental transfer at delivery and neonatal exposure through breast milk. Br J Clin Pharmacol2013; 76: 988–996.
29.
FrenchAESoldinSJSoldinOPKorenG. Milk transfer and neonatal safety of tacrolimus. Ann Pharmacother2003; 37: 815–818.
30.
GardinerSJBeggEJ. Breastfeeding during tacrolimus therapy. Obstet Gynecol2006; 107: 453–455.
31.
BramhamKChusneyGLeeJLightstoneLNelson-PiercyC. Breastfeeding and tacrolimus: serial monitoring in breast-fed and bottle-fed infants. Clin J Am Soc Nephrol2013; 8: 563–567.
