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MINIREVIEWS

Liver diseases in pregnancy: Liver transplantation in

pregnancy

Ghassan M Hammoud, Ashraf A Almashhrawi, Khulood T Ahmed, Rubayat Rahman, Jamal A Ibdah

Ghassan M Hammoud, Ashraf A Almashhrawi, Khulood T transplantation minimizes fetal exposure to high doses
Ahmed, Rubayat Rahman, Jamal A Ibdah, Division of Gas- of immunosuppressants. Pregnant female liver trans-
troenterology and Hepatology, University of Missouri, Columbia, plant patients have a high rate of cesarean delivery
MO 65212, United States likely due to the high rate of prematurity in this popula-
Author contributions: Hammoud GM wrote and revised the tion. Recent reports suggest that with close monitoring
manuscript; Almashhrawi AA, Ahmed KT and Rahman R were
and multidisciplinary team approach, most female liver
involved in reviewing the literature and collecting data; Ibdah JA
provided the overall conceptual design and finalized the manuscript. transplant recipient of childbearing age will lead a suc-
Correspondence to: Jamal A Ibdah, MD, PhD, Professor, cessful pregnancy.
Director, Division of Gastroenterology and Hepatology, Univer-
sity of Missouri, 319 jesse hall, Columbia, MO 65212, © 2013 Baishideng Publishing Group Co., Limited. All rights
United States. ibdahj@health.missouri.edu reserved.
Telephone: +1-573-8827349 Fax: +1-573-8844595
Received: June 17, 2013  Revised: July 30, 2013 Key words: Liver; Pregnancy; Liver transplantation;
Accepted: August 16, 2013 Hemolysis elevated liver low platelets; Acute fatty liver;
Published online: November 21, 2013 Cirrhosis

Core tip: This review provides an up-to-date summary

of literature in the field of liver transplantation and
Abstract pregnancy. It outlines the outcomes of pregnancy prior
Pregnancy in patients with advanced liver disease is to and after orthotopic liver transplantation. Further-
uncommon as most women with decompensated cir- more, it provides input on preconception counseling
rhosis are infertile and have high rate of anovulation. for mothers contemplating pregnancy after liver trans-
However, if gestation ensued; it is very challenging and plantation, risks of immunosuppression, and safety of
carries high risks for both the mother and the baby breastfeeding.
such as higher rates of spontaneous abortion, prematu-
rity, pulmonary hypertension, splenic artery aneurysm
rupture, postpartum hemorrhage, and a potential for Hammoud GM, Almashhrawi AA, Ahmed KT, Rahman R, Ibdah
life-threatening variceal hemorrhage and hepatic de- JA. Liver diseases in pregnancy: Liver transplantation in preg-
compensation. In contrary, with orthotopic liver trans- nancy. World J Gastroenterol 2013; 19(43): 7647-7651 Avail-
plantation, menstruation resumes and most women of able from: URL: http://www.wjgnet.com/1007-9327/full/v19/
childbearing age are able to conceive, give birth and i43/7647.htm DOI: http://dx.doi.org/10.3748/wjg.v19.i43.7647
lead a better quality of life. Women with orthotopic liver
transplantation seeking pregnancy should be managed
carefully by a team consultation with transplant hepa-
tologist, maternal-fetal medicine specialist and other INTRODUCTION
specialists. Pregnant liver transplant recipients need to
stay on immunosuppression medication to prevent al- Liver transplantation is considered to be the treatment
lograft rejection. Furthermore, these medications need of choice for patients with advanced liver disease. Since
to be monitored carefully and continued throughout the first pregnancy in a transplant recipient in 1958, preg-
pregnancy to avoid potential adverse effects to mother nancy in recipients of solid organ transplants has become
and baby. Thus delaying pregnancy 1 to 2 years after increasingly common. In the setting of decompensated

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 Hammoud GM et al . Liver transplantation in pregnancy

cirrhosis, pregnancy is very uncommon as most women MATERNAL AND FETAL OUTCOMES IN
are infertile and have anovulation and secondary amenor-
rhea. However, once liver transplantation is performed, PREGNANT FEMALE LIVER TRANSPLANT
liver transplant recipients possess an improved quality of RECIPIENTS
life, their hormonal imbalance return to a normal state,
ovulation resumes and pregnancy may ensue if con- Most outcome data on pregnancy during and after liver
templated. The first successful pregnancy in a liver graft transplantation are obtained from the NTPR. The NTPR
recipient was reported in 1978[1]. Given the improving was established in 1991 at Thomas Jefferson University
success of liver transplantation over the past two decades in Philadelphia, Pennsylvania, to study the outcomes of
and decreasing levels of immunosuppression, most solid pregnancies in transplant recipients in North America, in-
organ transplant recipients lead happy and healthy lives cluding female transplant recipients and those fathered by
with an average 1-year survival rate of greater than 85% male transplant recipients. Since then many other reports
for most indications. and case series have been reported and published. A ret-
rospective study from a single institution evaluated a total
of 115 gestations in 37 women with liver transplant (LT)
PATHOGENESIS and in 34 women with kidney transplant. The authors
Women with decompensated liver disease commonly found 81 (70%) of all gestations were successful, 15 (13%)
have menstrual dysfunction. In fact, menstrual abnor- were terminated, and there were 19 (17%) spontaneous
malities may be the first signs of chronic liver disease abortions and 2 (2%) intrauterine deaths[8]. Deshpande
in females with chronic liver disease. In cirrhotic state, et al[9] reported in a systematic review and meta-analysis
hypothalamic-pituitary dysfunction is associated with outcome of 450 pregnancies in 306 LT recipients in com-
an inadequate response to the gonadotropin-releasing parisons with the general United States population as well
hormone agonists and clomiphene citrates as well as di- as kidney transplant recipients. The post-LT live birth
minished gonadotrophin release relative to the reduced rate was higher than the live birth rate for the US general
levels of circulating sex steroids[2]. Furthermore, serum population (76.9% vs 66.7%, 95%CI: 72.7%-80.7%). The
post-LT miscarriage rate was lower than the miscarriage
levels of estradiol and testosterone are increased in pa-
rate for the general population (15.6% vs 17.1%, 95%CI:
tients with portosystemic shunts. Thus pregnancy in
12.3%-19.2%). Moreover, these rates were similar to the
decompensated cirrhosis is very uncommon. Obstetrical
post-kidney transplant rates. The rates of pre-eclampsia,
syndromes associated with transplantation may depend
cesarean section delivery and preterm delivery were higher
on several factors such as defective deep placentation,
than the rates for the US general population (21.9% vs
underlying maternal diseases, uterine vascular bed and
3.8%, 95%CI: 17.7%-26.4%; 44.6% vs 31.9%, 95%CI:
effect of immunosuppressive therapy on uteroplacental 39.2%-50.1%; and 39.4% vs 12.5%, 95%CI: 33.1%-46.0%)
arteries[3]. Reports from the the National Transplantation respectively. Moreover, these rates were lower than those
Pregnancy Registry (NTPR) revealed that immunosup- for post-kidney transplant recipients. The overall mean
pressive medication is associated with an increased risk birth weight for newborns of LT recipients was less than
of miscarriage, prematurity, intrauterine growth retarda- the birth weight for the United States general population
tion, and low birth weight[4]. (2866 g vs 3298 g). More notably, the authors found that
the mean gestational age and mean birth weight seems
MATERNAL AND FETAL OUTCOMES IN significantly greater for liver transplant versus kidney
transplant recipients and the risk of hypertension during
PREGNANT FEMALE PATIENTS WITH pregnancy seems also lower for liver transplant than kid-
ADVANCED LIVER DISEASE ney transplant recipients[9]. In another recently published
study by Alvaro et al[10] from a single center in Spain, the
Pregnancy is associated with increase in portal pressure. authors analyzed the impact of pregnancy among 1341
During pregnancy, a hypervolemic state develops lead- liver transplant recipients from April 1986 to April 2011.
ing to an increase in portal flow and elevation of portal Thirty pregnancies commenced among 18 liver transplant
venous pressure transmitted to the collateral veins with recipients during the follow-up. Sixteen patients (88%) be-
increased risk of esophageal variceal bleeding[5,6]. The came pregnant beyond a year after orthotopic liver trans-
outcome of pregnancy in 339 patients with cirrhosis was plantation. The post-LT live birth was 66.6% and the
reported in a large population-based study from 1993 to post-LT abortions were 26.6%. There were no maternal
2005[7]. Maternal and fetal mortality were much higher deaths encountered during pregnancy or the postpartum
than the general population (1.8% vs 0%, P < 0.0001; 5.2% period. However, fetal deaths were observed in 6% of
vs 2.1%, P < 0.0001) respectively. The rate of hepatic de- LT recipients. The most common maternal complications
compensation occurred in 15% and patients with cirrho- during pregnancy were preeclampsia (15%), viral reacti-
sis were more likely to deliver by cesarean delivery (42% vation (15%), acute rejection episodes (10%), infections
vs 28%; adjusted OR = 1.41; 95%CI: 1.06-1.88). Similarly, (10%), and high blood pressure (5%)[10]. Table 1 shows a
the spontaneous abortion rate in cirrhotic patients is ap- summary of maternal and fetal outcomes in female liver
proximately 15%-20%. transplant recipients from selected reports and studies[11].

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 Hammoud GM et al . Liver transplantation in pregnancy

Table 1 Summary of important fetal and maternal outcomes in liver transplant recipients from selected publications

Author, reference, number Live birth Preterm (%) Graft Cesarean Spontaneous Low birth weight Maternal/neonatal
of pregnancies rate (%) dysfunction (%) section rate (%) abortions (%) < 2500 g (%) deaths (%)
Nagy et al[12], n = 38 63 29 17 46 NA 17 17/0
Jain et al[13], n = 49 100 4 25 47 0 9 10/6
Armenti et al[14], n = 205 73 35 7 35 19 34 /0
Christopher et al[15], n = 71 71 NA 17 40 19 20 4/0
Dei Malatesta et al[16], n = 285 78 31 10 43 NA 23 /4
Sibanda et al[17], n = 16 69 50 NA 62 13 57 NA
Coffin et al[18], n = 206 70 27 5 38 5 NA 0/6
Jabiry-Zieniewicz et al[19], n = 39 100 31 8 80 0 20 /0
Dashpande et al[9], n = 450 76.9 39.4 NA 44.6 6.2 (including NA NA
intrauterine
fetal death)
Alvaro et al[10], n = 30 66.6 NA 10 42 26.6 NA 0/6

NA: Not available.

Table 2 Food and drug administration pregnancy categories

potential infection complications. Furthermore, oral
of common immunosuppressive therapy contraceptives did not appear to impair liver function or
glucose metabolism after its introduction within 6 mo to
Medicine Pregnancy category 7 years post transplantation[23].
Corticosteroids B
Azathioprine D
Cyclosporin C IMMUNOSUPPRESSION IN LIVER
Mycophenolate mofetil D
Tacrolimus C TRANSPLANT PREGNANT RECIPIENTS
Sirolimus C
There is no consensus on the optimal maintenance regi-
men for transplant recipients. The use of immunosup-
pressive therapy after liver transplantation is unavoidable.
PRECONCEPTION COUNSELING Therefore, women planning to conceive after transplan-
Pregnancy after liver transplant should be considered as a tation should be counseled about the risks such therapy
high-risk pregnancy and should be monitored closely by may pose on them and their fetuses. All immunosup-
a team of a transplant hepatologist and experts in obstet- pressive medication cross the placenta and enter fetal
rics and fetal medicine. Female liver transplant recipients circulation and could potentially have deleterious effects
who are planning of becoming pregnant should be coun- in utero. Despite the fact that immunosuppressive agents
seled on optimal timing of pregnancy, mode of delivery such as Azathioprine, Cyclosporine, and Mycophenolic
and risks associated with immunosuppressive therapy. acid, were teratogenic in animals, the risk of birth de-
Furthermore, they should also be counseled on methods fects was not statistically different between those who
of contraception if pregnancy is not contemplated. Im- received immunosuppressive medications and those who
munosuppressive agents are at their nadir one-year post did not. Birth defects have been reported with Calcineu-
liver transplantation and thus risk of allograft rejection rin inhibitors[8,12,19]. Renal dysfunction and rates of pre-
is low. Furthermore, renal and liver functions tend to eclampsia appears higher with cyclosporine therapy[12,24].
stabilized during that period and thus it is ideal to delay No matter what immunosuppressive therapy is chosen
pregnancy till patient is on a maintenance immunosup- based on maternal allograft function and laboratory as-
pression 1 to 2 years after transplantation to minimizes say, patients treated with either calcineurin inhibitors
fetal exposure to high doses of immunosuppressants[14,20]. cyclosporine or tacrolimus should have serial blood tests
As per mode of delivery, vaginal delivery appears to in pregnancy to follow medication levels and to assess
be safe. However, high rates of cesarean section have hepatic and renal function while avoiding unnecessary
been reported in female liver transplant patients (45.8%[12], toxicity. Table 2 shows the food and drug administration
71%[21], 35%[22], 38%[18] and 44.6%[9]) signifying the high classification of risk of medication and their categories
rates of prematurity in this population. It is not known in pregnancy[25].
whether a particular immunosuppressive therapy is as-
sociated with increased rate of cesarean section. If preg-
nancy is not contemplated in young females of childbear- BREASTFEEDING IN FEMALE LIVER
ing age, contraceptive method is advised particularly in TRANSPLANT RECIPIENTS ON
the first few months post liver transplantation. Barrier
methods possess low risk of systemic side effects. In- IMMUNOSUPPRESSIVE THERAPY
trauterine devices are generally discouraged due to their The American academy of pediatrics advises that breast-

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 Hammoud GM et al . Liver transplantation in pregnancy

feeding mothers can use prednisone and other gluco- Garonzik-Wang JM, Cameron AM, Singer AL, Dagher NN,
corticoids safely. Infant exposure to tacrolimus in milk Segev DL. Pregnancy outcomes of liver transplant recipients:
a systematic review and meta-analysis. Liver Transpl 2012;
is very low and that maternal tacrolimus therapy may be 18: 621-629 [PMID: 22344967 DOI: 10.1002/lt.23416]
compatible with breastfeeding. Data collected from the 10 Alvaro E, Jimenez LC, Palomo I, Manrique A, Alegre C, Gar-
NTPR indicated no adverse outcomes in infants who cia M, Justo I, Abradelo M, Calvo J, Garcia-Sesma A, Cam-
were breastfed during maternal cyclosporine use. There bra F, Loinaz C, Moreno E. Pregnancy and orthotopic liver
is insufficient evidence in the literature to suggest that transplantation. Transplant Proc 2013; 45: 1966-1968 [PMID:
23769084 DOI: 10.1016/j.transproceed.2013.01.013]
women taking azathioprine should refrain from breast- 11 Hammoud GM, Choudhary A, Ibdah JA. Pregnancy and
feeding. Nevertheless, mothers may be discourage to liver transplantation. In: Ibdah JA: Maternal liver disease.
breast feed in the first few months post transplantation Austin (TX): Landes Bioscience, 2012: 119-136
where immunosuppressive therapy is at high serum level. 12 Nagy S, Bush MC, Berkowitz R, Fishbein TM, Gomez-Lobo
V. Pregnancy outcome in liver transplant recipients. Obstet
Gynecol 2003; 102: 121-128 [PMID: 12850617 DOI: 10.1016/
CONCLUSION S0029-7844(03)00369-7]
13 Jain AB, Reyes J, Marcos A, Mazariegos G, Eghtesad B,
Pregnancy after liver transplantation, although considered Fontes PA, Cacciarelli TV, Marsh JW, de Vera ME, Rafail A,
a high risk pregnancy, has an acceptable outcome for Starzl TE, Fung JJ. Pregnancy after liver transplantation with
both mother and baby. With the return of fertility follow- tacrolimus immunosuppression: a single center’s experience
update at 13 years. Transplantation 2003; 76: 827-832 [PMID:
ing transplantation, accurate family planning advice is es-
14501862 DOI: 10.1097/01.TP.0000084823.89528.89]
sential. To date there is no evidence of specific structural 14 Armenti VT, Daller JA, Constantinescu S, Silva P, Radomski
malformations among children born to female liver trans- JS, Moritz MJ, Gaughan WJ, McGrory CH, Coscia LA. Report
plant recipients, but there appears to be increased risk of from the National Transplantation Pregnancy Registry: out-
prematurity and low birth weight after solid organ trans- comes of pregnancy after transplantation. Clin Transpl 2006;
57-70 [PMID: 18368705]
plantation. Multidisciplinary team approach is of utmost
15 Christopher V, Al-Chalabi T, Richardson PD, Muiesan P,
importance to ensure smooth pregnancy. The NTPR data Rela M, Heaton ND, O’Grady JG, Heneghan MA. Pregnancy
and others have revolutionized our understanding of the outcome after liver transplantation: a single-center experi-
outcomes of pregnancy in this high risk population. We ence of 71 pregnancies in 45 recipients. Liver Transpl 2006; 12:
encourage physicians in the field to continue to report 1138-1143 [PMID: 16799943 DOI: 10.1002/lt.20810]
their outcome to the transplant registry. 16 Dei Malatesta MF, Rossi M, Rocca B, Iappelli M, Giorno MP,
Berloco P, Cortesini R. Pregnancy after liver transplantation:
report of 8 new cases and review of the literature. Transpl
Immunol 2006; 15: 297-302 [PMID: 16635752 DOI: 10.1016/
REFERENCES j.trim.2006.01.001]
1 Walcott WO, Derick DE, Jolley JJ, Snyder DL. Successful 17 Sibanda N, Briggs JD, Davison JM, Johnson RJ, Rudge
pregnancy in a liver transplant patient. Am J Obstet Gynecol CJ. Pregnancy after organ transplantation: a report from
1978; 132: 340-341 [PMID: 360844] the UK Transplant pregnancy registry. Transplantation
2 Van Thiel DH, Lester R. The effect of chronic alcohol abuse 2007; 83: 1301-1307 [PMID: 17519778 DOI: 10.1097/01.
on sexual function. Clin Endocrinol Metab 1979; 8: 499-510 tp.0000263357.44975.d0]
[PMID: 389488 DOI: 10.1016/S0300-595X(79)80028-6] 18 Coffin CS, Shaheen AA, Burak KW, Myers RP. Pregnancy
3 Brosens I, Pijnenborg R, Benagiano G. Risk of obstetrical outcomes among liver transplant recipients in the United
complications in organ transplant recipient pregnancies. States: a nationwide case-control analysis. Liver Transpl 2010;
Transplantation 2013; 96: 227-233 [PMID: 23466636 DOI: 16: 56-63 [PMID: 20035524 DOI: 10.1002/lt.21906]
10.1097/TP.0b013e318289216e] 19 Jabiry-Zieniewicz Z, Szpotanska-Sikorska M, Pietrzak B,
4 Coscia LA, Constantinescu S, Moritz MJ, Frank AM, Ramirez Kociszewska-Najman B, Foroncewicz B, Mucha K, Zien-
CB, Maley WR, Doria C, McGrory CH, Armenti VT. Report iewicz K, Krawczyk M, Wielgos M. Pregnancy outcomes
from the National Transplantation Pregnancy Registry among female recipients after liver transplantation: further
(NTPR): outcomes of pregnancy after transplantation. Clin experience. Transplant Proc 2011; 43: 3043-3047 [PMID:
Transpl 2010; 65-85 [PMID: 21698831] 21996220 DOI: 10.1016/j.transproceed.2011.08.070]
5 d’Alteroche L, Perarnau JM, Perrotin F, Bacq Y. Portal hy- 20 Mastrobattista JM, Katz AR. Pregnancy after organ trans-
pertension and pregnancy. Gastroenterol Clin Biol 2008; 32: plant. Obstet Gynecol Clin North Am 2004; 31: 415-428, vii
541-546 [PMID: 18472375 DOI: 10.1016/j.gcb.2008.02.028] [PMID: 15200970 DOI: 10.1016/j.ogc.2004.03.005]
6 Britton RC. Pregnancy and esophageal varices. Am J Surg 21 Jabiry-Zieniewicz Z, Bobrowska K, Pietrzak B, Kaminski
1982; 143: 421-425 [PMID: 6978619 DOI: 10.1016/0002-9610(8 P, Wielgos M, Durlik M, Zieniewicz K. Mode of delivery in
2)90190-8] women after liver transplantation. Transplant Proc 2007; 39:
7 Shaheen AA, Myers RP. The outcomes of pregnancy 2796-2799 [PMID: 18021990 DOI: 10.1016/j.transproceed.200
in patients with cirrhosis: a population-based study. 7.09.011]
Liver Int 2010; 30: 275-283 [PMID: 19874491 DOI: 10.1111/ 22 Armenti VT, Constantinescu S, Moritz MJ, Davison JM.
j.1478-3231.2009.02153.x] Pregnancy after transplantation. Transplant Rev (Or-
8 Blume C, Sensoy A, Gross MM, Guenter HH, Haller H, lando) 2008; 22: 223-240 [PMID: 18693108 DOI: 10.1016/
Manns MP, Schwarz A, Lehner F, Klempnauer J, Pischke j.trre.2008.05.001]
S, Strassburg CP. A comparison of the outcome of preg- 23 Jabiry-Zieniewicz Z, Bobrowska K, Kaminski P, Wielgos
nancies after liver and kidney transplantation. Transplan- M, Zieniewicz K, Krawczyk M. Low-dose hormonal contra-
tation 2013; 95: 222-227 [PMID: 23222883 DOI: 10.1097/ ception after liver transplantation. Transplant Proc 2007; 39:
TP.0b013e318277e318] 1530-1532 [PMID: 17580181 DOI: 10.1016/j.transproceed.200
9 Deshpande NA, James NT, Kucirka LM, Boyarsky BJ, 7.02.063]

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 Hammoud GM et al . Liver transplantation in pregnancy

24 Coscia LA, Constantinescu S, Moritz MJ, Frank A, Ramirez 25 Hammoud GM, Ibdah JA. The liver in pregnancy. In: Boyer,
CB, Maley WL, Doria C, McGrory CH, Armenti VT. Report TD, Manns MP, Sanyal AJ. Zakim and Boyer’s Hepatology:
from the National Transplantation Pregnancy Registry A Textbook of Liver Disease. Philadelphia (PA): Elsevier
(NTPR): outcomes of pregnancy after transplantation. Clin Saunders, 2012: 919-940 [DOI: 10.1016/B978-1-4377-0881-3.0
Transpl 2009; 103-122 [PMID: 20524279] 0052-8]

P- Reviewers: Muratori L, Yamagiwa S S- Editor: Wen LL

L- Editor: A E- Editor: Wang CH

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