Usage of Tacrolimus and Mycophenolic Acid During Conception, Pregnancy, and Lactation, and Its Implications for Therapeutic Drug Monitoring: A Systematic Critical Review

Abstract

Background: Conception, pregnancy, and lactation following solid organ transplantation require appropriate management. The most frequently used immunosuppressive drug combination after solid organ transplantation consists of tacrolimus (Tac) plus mycophenolic acid (MPA). Here, the effects of Tac and MPA on fertility, pregnancy, and lactation are systematically reviewed, and their implications for therapeutic drug monitoring (TDM) are discussed. Methods: A systematic literature search was performed (August 19, 2019) using Ovid MEDLINE, EMBASE, the Cochrane Central Register of controlled trials, Google Scholar, and Web of Science, and 102 studies were included. Another 60 were included from the reference list of the published articles. Results: As MPA is teratogenic, women who are trying to conceive are strongly recommended to switch from MPA to azathioprine. MPA treatment in men during conception seems to have no adverse effect on pregnancy outcomes. Nevertheless, in 2015, the drug label was updated with additional risk minimization measures in a pregnancy prevention program. Data on MPA pharmacokinetics during pregnancy and lactation are limited. Tac treatment during conception, pregnancy, and lactation seems to be safe in terms of the health of the mother, (unborn) child, and allograft. However, Tac may increase the risk of hypertension, preeclampsia, preterm birth, and low birth weight. Infants will ingest very small amounts of Tac via breast milk from mothers treated with Tac. However, no adverse outcomes have been reported in children exposed to Tac during lactation. During pregnancy, changes in Tac pharmacokinetics result in increased unbound to whole-blood Tac concentration ratio. To maintain Tac concentrations within the target range, increased Tac dose and intensified TDM may be required. However, it is unclear if dose adjustments during pregnancy are necessary, considering the higher concentration of (active) unbound Tac. Conclusions: Tac treatment during conception, pregnancy and lactation seems to be relatively safe. Due to pharmacokinetic changes during pregnancy, a higher Tac dose might be indicated to maintain target concentrations. However, more evidence is needed to make recommendations on both Tac dose adjustments and alternative matrices than whole-blood for TDM of Tac during pregnancy. MPA treatment in men during conception seems to have no adverse effect on pregnancy outcomes, whereas MPA use in women during conception and pregnancy is strongly discouraged.

Paternity in male kidney transplant recipients: A French national survey, the PATeRNAL study.

“…They found no difference in malformations nor pre-term deliveries in children fathered by MMF/MPA exposed compared to KT recipients not exposed [24]. The outcomes of pregnancies fathered by male transplant recipients appear similar to those of the general population and MPA embryopathies have not been noted in pregnancies fathered by those patients [21,54]. Our results add to the available data in the literature, that pregnancies fathered by patients under MMF/MPA at the time of conception do not seem to have more complications than pregnancies in the general population…”

“…Of the 330 participants who never had a child, 105 (32%, 95% CI [27][28][29][30][31][32][33][34][35][36][37]) declared that they did not want to conceive after transplantation, 6 (2%, 95% CI [0.7-4]) male KT recipients were concerned about the risk of transmission of polycystic kidney disease (PKD), whereas 55 (17%, 95% CI [13][14][15][16][17][18][19][20][21]) suffered from infertility (Table 1). Childless participants seemed to be younger than the ones who had fathered children before KT (Table 2).…”

“…Rejection episode before or during pregnancy 80 (20%, [16][17][18][19][20][21][22][23][24] Intellectual disability 3 (1%, [0.…”

Paternity in male kidney transplant recipients: A French national survey, the PATeRNAL study.

“…Of the 5 pregnancies within the partnerships of the participants treated by everolimus, there was one therapeutic abortion due to multiple malformations. The proportion of therapeutic abortions and malformations according to the immunosuppressive agents taken by the father were: 6 of 59 (10%, 95% CI [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] As before the pregnancies the male patients were exposed to co-medication, one outcome can be declared in several columns.…”

“…MMF/MPA and sirolimus should be discontinued and replaced by another drug at least six weeks prior to conception [5,7,12,[19][20][21].…”