The first successful childbirth after LT took place in 1978 and, despite the decreased birth weight, was accompanied by optimal fetal and maternal outcomes[34]. Since then, several reports have demonstrated the feasibility of pregnancy after LT[35-47]. Notably, the restoration of menstruation and childbearing potential is successful in around 97% of previously fertile female LT recipients[48, 49]. It has been reported that within some months after LT (in a significant number of cases even within 1 mo[6]), sex hormone levels and sexual function normalize either partially or completely with amenorrhea reported in 26%, irregular bleeding in 26%, and regular menses restoration in 48% of the female LT recipients of childbearing age[50, 51]. While the resumption of normal cycle is commonly seen in a few months after LT, recipients are recommended to avoid conception up until a year due to potentially worse outcomes[52, 53]. Hence, family planning and consultation by a multidisciplinary team including a transplant hepatologist are pivotal for the well-being of these patients. Consultation should begin before LT. Naturally, these patients are prescribed combined oral contraceptives and transdermal contraceptive patches, which have traditionally resulted in no pregnancies and no overall changes in biochemistries, rendering them safe post-LT[54, 55]. Asingle-center cross-sectional survey study demonstrated that only 35% (n = 28/80) of the women received appropriate recommendations for effective contraception post-transplant and only 28% of them (n = 8/28) did use effective birth controlafter consultation[56]. Although the study showed no important change in the distribution of contraceptive methods used post-LT, it revealed an increase in the rate of hormonal contraception (pre-LT: 2% vs post-LT: 10%, P = 0.044), and the most common contraceptive method was condoms both pre- and post-LT (pre-LT: 66% vs post-LT: 55%, P = 0.223)[56]. Although barrier methods are easy to use and decrease the risk of transmission of sexually transmitted diseases and fertility is immediately restored with cessation, the failure rate is quite high. Hormonal contraception is more effective but may take a few months for fertility to restore after cessation, may induce withdrawal symptoms, and increase the risk of venous thromboembolism (if combined estrogen/progestin). The maindifferences between the oral contraceptive pills and the transdermal patches include lower effectiveness in women weighing ≥ 90kg, local reaction or visibility, and a higher rate of dysmenorrhea and breast pain[57]. Lastly, intrauterine devices offer the highest level of effectiveness with a low incidence of uterus perforation but have not been well-studied in LT recipients to date.

Mass et al[10] showed that the percentage of women being sexually active after LT slightly decreased from 77% to 72% post-LT. Notably, a cross-sectional study failed to show any significant differences in the incidence of sexual activity, dyspareunia, satisfaction with sex life, amenorrhea, and dysmenorrhea when comparing female patients pre- and post-LT[58]. A meta-analysis investigating the effect of LT on post-transplant quality of life reported significant improvements in sexual function after LT compared to the pre-LT state[59].

All LT recipients are on post-transplant immunosuppression in order to decrease the risk of organ rejection. All immunosuppressive agents are known to cross theplacenta and can enter thefetal circulation, with a possibility of resulting in deleterious fetal outcomes. However, there is evidencesuggesting that the use of immunosuppressive agents, such as asazathioprine and cyclosporine, during pregnancy was not associatedwith a significantly increased risk of birth defects[42, 60]. In fact, an analysis of the National Transplantation Pregnancy Registry showed that the incidence of birth defects among live births with cyclosporine exposure was 4.9% and with tacrolimus exposure was 4.2%, which are comparable to the 3%-5% incidence in the general population of the United States[61]. On the other hand, data support that exposure to mycophenolic acid in utero resulted in a 24% incidence of birth defects and in a significant increase of spontaneous abortions[62, 63]. Common immunosuppression medication regimens used after LT and their potential adverse maternal and fetal outcomes are shown in Table 2[64, 65]. In a recent meta-analysis[66], the most commonly used immunosuppressive agents after LT in pregnant womenwere tacrolimus (60%), sirolimus (27%), cyclosporine (20%), azathioprine (16%), and mycophenolate mofetil (3%). On meta-regression, the authors showed that sirolimus was less likely to lead to a live birth[66].

Mycophenolate mofetil is a commonly administered anti-proliferative agent that is used mostly as a second-line immunosuppressant in adults. There is a growing body of evidence suggesting that the use of mycophenolate mofetil in the first trimester can lead to spontaneous abortion (33%-45%) and congenital malformations (e.g., cleft lip and palate)[67]. Therefore, mycophenolate mofetil and sirolimus are currently contraindicated in pregnancy[5]. A study showed that patients on cyclosporine were more likely to develop renal dysfunction than patients on tacrolimus[42], while another study showed that premature delivery and cesarean section were more commonly reported in patients on tacrolimus than on cyclosporine[68]. Calcineurin inhibitors (cyclosporine and tacrolimus) are generally considered safe during pregnancy, but the data in LT recipients are scarce[69-71]. The decision on the immunosuppressive regimen for the pregnant LT recipient is challenging and should always be made in accordance to maternal allograft function and after a thorough risk-benefit analysis. Regardless of the choice of immunosuppression regimen, it is recommended that maternal and fetal care is prioritized by obtaining frequent serial medication levels to assure therapeutic levels and to assess hepatic function, while avoiding toxicity. The Food and Drug Administration has graded the commonly used immunosuppressive regimens as shown in Table 2[72]. Since there is a risk of pregnancy while an LT recipient is still on immunosuppressive therapy, it is very important for the patient to be well-informed about the detrimental effects of these medications on the fetus and the mother[73].

According to the available evidence, LT recipients have not been reported to experience higher rates of maternal mortality compared to the non-transplant population[64]. Studies examining the outcomes of pregnancy post-LT reported that the rate of graft rejection during pregnancy varies between 0%-20%[47, 64]. Data have suggested the following to besignificant predictors of graft rejection during pregnancy: Age < 18 years at LT, Caucasian race, anddiagnosis of viral hepatitis[53]. Although there is no compelling evidence to date, studies suggest that a minimum of 1 year should pass after LT before considering pregnancy to allow for stabilization of graft function and immunosuppression requirements[67, 74].

In a review article by Parhar et al[64], pregnancy-induced hypertension was reported in 2%-43%, pre-eclampsia in2%-22%, and gestational diabetes mellitus in 0%-37.5%. In a more recent meta-analysis, the respective rates were 18.2%, 12.8%, and 7%, while eclampsia was observed in 2% of all post-LT pregnancies[66].

Generally, the rate of cesarean delivery is higher in LT recipients compared to the general non-transplant population (20%-100%), and a plausible explanation may be the higher rates of hypertension and pre-eclampsia during pregnancy[64]. Data from a meta-analysis showed that cesarean delivery and vaginal delivery are performed at similar rates in LT recipients (42.2% and 42.4%, respectively)[66]. Moreover, pre-term birth is seen in 27.8% of post-LT pregnancies[66] and ranges between 12.5%-50%[64].

The majority of pregnancies in LT recipients have a positive outcome, with a high rate of live births (fixed-effects meta-analysis: 77%, random-effects meta-analysis: 86%)[66]. Evidence suggests that the indication for LT is generally not associated with adverse pregnancy outcomes, except for Wilson’s disease, which has been associated with lower live birth rates[66]. However, 7.8% of LT recipients experience miscarriage, 5.7% abortion, 3.3% stillbirth, and 1.7% ectopic pregnancy[66]. Fetal distress is more often seen in LT recipients (10.3%-40%), while low birth weight (< 2500 g) is anotherfrequent complication (4.8%-57%)[64]. On the other hand, congenital abnormalities are relatively uncommon, and the rate is only slightly increased compared to that of the non-transplant population (0%-16.7%)[64].

As expected, designing a study evaluating the long-term outcomes of children born to LT recipients is challenging, and thus the data on long-term pediatric outcomes are scarce. Wu et al[43] followed six children until the age of 4 years, and reported that all of them had achieved all appropriate milestones and had normal physical and psychological development. Ville et al[75] followed children for longer varied periods (3 mo to 5 years post-partum), andno abnormal physical development, adrenal or respiratory insufficiency, or lymphopeniawas reported.

The data from the National Transplantation Pregnancy Registry for about 2000 solid organ transplant recipients indicate favorable outcomes forLT recipients compared to other solid organ transplant recipients (Table 3)[76].

The benefits of breastfeeding are well-described, particularly regarding the immunologic components of colostrum and breast milk. However, certain factors should be considered in LT recipients, as immunosuppressive medication are present in breast milk[77]. The levels of such medication in breast milk arelower than those during pregnancy, and hence the risk is slightly decreased (i.e. only 0.1% of each steroid dose reaches the breast milk)[78]. In fact, maternal use of prednisone during breast-feeding is allowed according to the American Academy of Pediatrics[79]. An analysis of the National Transplantation Pregnancy Registry showed that among 23 breast-feeding mothers of 29 infants (22 exposed to tacrolimus, three exposed to cyclosporine, four exposed to cyclosporine USP) gestational age was 26-41 wk and birth weight was 680-4097 g, while no serious adverse events were reported[77]. Currently, breast-feeding is not contraindicated in LT recipients on tacrolimus or cyclosporine. Additionally, there is not sufficient evidence to suggest that breast-feeding should be contraindicated in LT recipients on azathioprine[78, 79]. Nevertheless, it is advised that when the mother is on tacrolimus, cyclosporine, corticosteroids, or azathioprine, the infant’s serum levels be monitored after the initial 1-2 wk of breast-feeding, as earlier may be due to in utero exposure or levels from colostrum, and if significantly high, breastfeeding should cease[77]. Lastly, caution is warranted for medication of uncertain safety profile, including betalacept, sirolimus, and everolimus[77].