PREGNANCY OUTCOME AFTER

LIVER TRANSPLANT

Gen.Dr Amgad .M.G. Moustafa , MSc,FRCOG.Head of Obstetrics and Gynecology department

International Medical Center

When we have to manage a liver problem with pregnancy ?

•IS IT BAD NEWS ?

HELLP syndrome

HELLP syndrome was named by Dr. Louis Weinstein in 1982 after its characteristics:H (hemolysis, which is the breaking down of red blood cells)EL (elevated liver enzymes)LP (low platelet count)The global mortality rate of HELLP syndrome has been reported to be as high as 25%.

Acute fatty liver of pregnancy (AFLP) is a rare, potentially fatal complication that occurs in the third trimester or early postpartum period

• The mortality from AFLP is approximately 18% and deaths are usually secondary to sepsis, renal failure, circulatory collapse, pancreatitis or gastrointestinal bleeding

Viral hepatitis with pregnancy virus A,B,C,D,E

• Acute viral hepatitis ( Virus E ) during pregnancy is associated with 20-30 % mortality .

Child-Pugh classification (Child-Turcotte-Pugh score)

Measure 1 point 2 points 3 points

Total bilirubin, μmol/l (mg/dl) <34 (<2) 34-50 (2-3) >50 (>3)

Serum albumin, g/dl >3.5 2.8-3.5 <2.8

Prothrombin time, prolongation (secs) <4.0 4.0-6.0 > 6.0

Ascites None Mild Moderate to Severe

Hepatic encephalopathy None Grade I-II (or suppressed with medication) Grade III-IV (or refractory)

Points Class One year survival Two year survival

5-6 A 100% 85%

7-9 B 81% 57%

10-15 C 45% 35%

Child-Pugh classification (Child-Turcotte-Pugh score)• Mortality rates for patients undergoing surgery were • 10% for those with Child class A, • 30% for those with Child class B, and • 76–82% for those with Child class C cirrhosis

Liver Transplantation and Pregnancy FIRST REPORTED 1960s• Liver transplant is the treatment of choice for end-stage liver disease.• Advances in surgical technique and immunosuppressive therapy have

helped to increase the number of women in the child bearing age who undergo LIVER TRANSPLANT each year.

IN 1987,• First successful pregnancy in a liver transplant recipient was reported.

Liver Transplantation and Pregnancy • In U.S.A. ,approximately 14,000 women of reproductive age

are currently living after liver transplantation, and another 500 undergo LT each year.

• IN EGYPT ?• IN International medical center• 2 females ( age reproductive period) out of 200

Liver Transplantation and Pregnancy

• Many times , a transplanted liver normalizes a woman’s hormone imbalance and restores fertility.

How are we going to manage a young lady? ( female liver transplant recipients )

• Preconception counselling ?• Contraception After Transplant ?• Management during pregnancy ?• Immunosuppression during pregnancy ?• Mode of delivery ?• Postpartum and Breast feeding ? • What is the outcome ?

Preconception counselling ?• A woman of childbearing age who receives a transplant is

typically advised to avoid pregnancy for at least 1 year after transplantation, based on data that show an increased risk of potential graft dysfunction, rejection, or loss, and adversely affect fetal well being.

• The American Society of Transplantation (AST)

• National Transplantation Pregnancy Registry (NTPR).

Preconception counselling ?

• The American Society of Transplantation (AST) recommends that pregnancy is allowable if there has been:

1. No rejection within the past year.2. There is adequate and stable graft function 3. No acute infections that may impact fetal growth and well-

being particularly cytomegalovirus infection4. Maintenance immunosuppression is at stable dosing.

Contraception After Transplant ?

• Ovulatory cycles may begin as soon as 1 month after transplantation. Thus, prior to transplantation, gynecologists and transplant professionals should counsel women on potential methods of contraception to avoid unplanned pregnancy.

• But what method of contraception are we going to use?• What are the advantages and disadvantages of each method?

There is limited evidence regarding the safest and most effective method of contraception following liver transplantation for prevention of an unplanned pregnancy:Barrier methods:• Lowest risk but probably lowest effectiveness

Combined hormonal methods (estrogen + progestin):• contraindicated in women with active liver disease.• In addition, combined oral contraceptives are relatively

contraindicated in women with hypertension, (especially in combination).

• They may also increase the blood levels of immunosuppressants such as corticosteroids, cyclosporine, tacrolimus, and sirolimus. Thus, blood levels of immunosuppressants must be monitored to ensure safety.

• Liver dysfunction can also interfere with estrogen metabolism that may adversely alter the efficacy of combined oral contraceptives.

Intrauterine devices (IUDs)• Perhaps the best contraceptive option for the transplant

population • It is long-acting reversible contraception.• No drug interaction, are highly efficacious, are reversible, and

have minimal risk to the recipient.• Furthermore, recent studies have shown that they are safe to

use in immunocompetent and immunocompromised patients. • Although the American Society of Transplantation recommends

against offering IUDs as first-line contraceptive therapy in this population, this remains an area of debate because IUDs have been reported to be an effective approach in some patients?

Management during pregnancy ?

• Routine monitoring of pregnancy and careful ultrasound examination to diagnose congenital malformations and growth restriction.

• Liver transplant recipients often have comorbidities, such as hypertension and diabetes, which add additional risk to a pregnancy.

• Aggressive management of hypertension: The drug of choice is methyldopa.

• In cases of acute rejection, steroids are the preferred drugs

Immunosuppression during pregnancy ?

• Overview and management of immunosuppression in liver transplanted female candidates for pregnancy need expertise to balance the risk of rejection and maternal and fetal complications.

Immunosuppression during pregnancy ?

Corticosteroids: • If the patient is maintained on a low dose of corticosteroids

due to the underlying liver disease etiology, like autoimmune disease, or because she has experienced episodes of rejection, there might be a need for an increased dose of steroid during pregnancy.

Immunosuppression during pregnancy ?Corticosteroids:

The Maternal Risk :• Gestational hypertension and gestational diabetes mellitus

(GDM) and increased rates of premature rupture of membranes.THE FETAL RISK: • The overall fetal- neonatal complication is low.• Increased cleft-palate and lip in animal studies.• Rare reports of fetal adrenal insufficiency. In summary,• Prednisone is classified as a category B medication for safe use

in pregnancy based on the US FDA classification system.

Immunosuppression during pregnancy ?

Calcineurin inhibitors – cyclosporine and tacrolimus• Calcineurin inhibitors suppress T cell function through

inhibition of cytokines such as interleukin-2.

Immunosuppression during pregnancy ?

Calcineurin inhibitors – cyclosporine and tacrolimusMaternal Risk :• hypertension, diabetes, renal insufficiency and neurotoxicity. FETAL RISK :• There are also reports of an increased incidence of transient neonatal

hyperkalemia. In summary :• Cyclosporine and tacrolimus are classified as United States Food and

Drug Administration (US FDA) category C medications and, overall, deemed as safe to use during pregnancy.

Immunosuppression during pregnancy ?

Azathioprine• It inhibits purine metabolism, resulting in suppression of cell-mediated immunity.

Immunosuppression during pregnancy ?AzathioprineMaternal Risk :• Preterm delivery FETAL RISK :• There are also reports of fetal anemia, thrombocytopenia, neonatal

infection and sepsis, and low birth weight In summary :• Azathioprine is classified as a US FDA category D medication, based

mainly on reports of animal studies with teratogenic effects, but this has not been corroborated with all of the human data. In general, most transplant physicians are quite comfortable continuing azathioprine throughout pregnancy in women who require it.

Immunosuppression during pregnancy ?Mycophenolate mofetil• Mycophenolate mofetil (MMF) is a purine biosynthesis inhibitor that

works by inhibiting B and T cell function.• In the first trimester, MMF has been associated with pregnancy loss

ranging from 33% to 45%.• There is multiple malformation reported that involve cleft lip and

palate, microtia and the absence of auditory canals.In summary: As a result of this significant teratogenic risk, MMF is classified as a US FDA category D medication and should not be used during pregnancy.  It is advised to stop MMF in patients on this medication who wish to get pregnant at least 6 weeks before conception.

Immunosuppression during pregnancy ?

Sirolimus• It acts through blocking signal 3 of cell activation from IL-2

receptors in T-cells and B-cells. • It has been considered a non-nephrotoxic immunosuppressant

agent that might replace Calcineurin inhibitors in liver recipients with renal dysfunction.

• Data on the safety of sirolimus during pregnancy and its teratogenicity is limited, although no significant fetal malformation has been reported.

Mode of delivery ?

Vaginal delivery (preferred):Usually delayed until labor onset unless maternal/fetal indications for induction exist Cesarean delivery:It is only indicated for obstetric reasons.

• Antibiotic prophylaxis for all surgical procedures.• Increased steroid dose at labor onset to overcome the stress of labor

and prevent postpartum transplant rejection.

Postpartum and Breast feeding ?

• Immunosuppressive drug levels should be monitored, as blood levels will vary due to changing gastrointestinal function and absorption, loss of effects of fetal liver metabolism , and reconstitution of the maternal immune system.

• It is essential to continue monitoring organ function for potential graft rejection.

Postpartum and Breast feeding ? • Breastfeeding by transplant recipient mothers remains a

controversial issue requiring further investigation.• Although recent reports have been supportive of the practice. The

national transplantation pregnancy registry (NTPR) has reports from 98 recipients who have breastfed their 126 children while taking a variety of immunosuppressive agents and regimens. There were no specific problems reported in the children related to breastfeeding.

• It is advisable to check the infant’s blood level of the maternal medications for which levels are available-a measurable level in the infant may be a substantial reason to discontinue breastfeeding.

What is the outcome ?

• Reports show a good success rate of pregnancy in liver transplant recipients compared to general population :

• Live birth rate reported to be 77%• Miscarriage rate reported to be 17%• However , complications were at higher rate compared to general

population• Preeclampsia reported to be 22%• C.S. rate 45%• Preterm delivery 39%

Conclusion• Successful pregnancy is becoming an expectation for both the

patient and their care providers. • Return of menstrual function is common in the months after

transplantation and, thus, preconception counselling is an essential part of pregnancy planning in the liver transplant recipient of childbearing age.

• A multidisciplinary team should be involved in the management of the transplant recipient before, during, and after pregnancy. obstetrician ( high risk Pregnancy , fetal medicine in conjunction with their transplant team ).

Conclusion• A woman of childbearing age who receives a transplant is typically

advised to avoid pregnancy for at least 1 year after transplantation. • Perhaps the best contraceptive option for the transplant population

is long-acting reversible contraception, more specifically, intrauterine devices. However individualization is important.

• Most immunosuppressive medications are considered relatively safe as they have not been shown to cause either an increase in the incidence of or a pattern of birth defects. These relatively safe medications include prednisone, azathioprine, the calcineurin inhibitors, cyclosporine, and tacrolimus. Mycophenolate mofetil (MMF) should not be used during pregnancy.