Pregnancy in patients with advanced chronic liver disease

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Abbreviations

AIH

autoimmune hepatitis

CT

computer tomography

EVL

endoscopic band ligation

FNH

focal nodular hyperplasia

HA

hemangioma

HCA

hepatocellular adenomas

ICP

intrahepatic cholestasis of pregnancy

LT

liver transplantation

MELD

model for end‐stage liver disease

MMF

mycophenolate mofetil

NTPR

National Transplantation Pregnancy Registry.

Pregnancy in the Cirrhotic Patient: A Rare Event?

Pregnancy is not uncommon in patients with preexisting advanced liver disease. In the past, pregnancy in the setting of advanced liver disease was thought to be rare. This common misconception is based on two assumptions: 1) liver disease is more prevalent in a population older than reproductive age, and 2) liver disease is associated with infertility. Today, these are no longer true.

Currently, peak fertility occurs between 15 and 44 years of age. Chronic liver disease in women is a common disease, particularly in the third and fourth decades of life. Indeed, chronic liver disease in the United States ranks as fifth and sixth among all‐cause mortality of women in this age group (2009 CDC report).1

Infertility may be overestimated. With current advances in assisted reproduction techniques, as well as aggressive medical treatment of liver diseases, fertility in this population is maintained.

Thus, it is not uncommon to encounter pregnant patients with advanced chronic liver diseases. Such pregnancies are likely to increase in the years to come and present unique medical challenges for both patients and clinicians. More extensive studies and evidence‐based guidelines are needed to steer the management of these patients prior to conception, during pregnancy, and postpartum.

Before Conception

• Pregnancy in cirrhotic women is no longer discouraged.

• Infertile women can achieve pregnancy with assisted reproductive technology.

• Poor fetal outcome is increased and includes fetal demise, intrauterine growth retardation, prematurity, and high cesarean rate.

• Maternal mortality is increased.

• Poor pregnancy outcome is correlated to a model for end‐stage liver disease (MELD) score greater than 10.

In the last few decades, the attitude of the medical community toward pregnant patients with serious medical problems has changed. This is the result of the availability of better medical treatment and the training of many internists in the obstetric medicine discipline skilled in the management of complicate medical issues during gestation.

Consequently, pregnancy is no longer feared, nor is it considered absolutely contraindicated. Rather, the physician offers extensive counseling prior to the conception or at the beginning of the pregnancy. Key elements of the consultation are: effect of pregnancy on underlying disease, effect of disease on pregnancy outcomes, therapeutic option during gestation and their potential teratogenicity, and expected complications and their management.

For patients with advanced liver disease, the hepatologist plays an important role in explaining the maternal risks, including mortality, the fetal risks including premature birth resulting in long‐term disabilities, and the reasonable expectations for the future health of mother. Pregnancy outcomes are discussed in detail elsewhere in this article. Successful pregnancies have been described in many well compensated cirrhotic, and medical therapy is effective in treating common complications.

In contrast, patients with a MELD score above 10 are especially at risk for poor maternal and fetal outcomes, with increased chance of disease decompensation and mother mortality up to 7.8 %. In this group, in particular, a frank discussion should occur that includes considering elective termination of pregnancy on medical grounds and other options such as surrogacy and postponing pregnancy after liver transplantation (LT). Ultimately, the choice of starting a pregnancy as well as of having a therapeutic abortion is taken by the woman and her family

This is not an easy discussion and often the decision is made on the basis of cultural, religious, and socioeconomic as well as medical considerations.

The successful management of patients with advanced liver disease requires a multidisciplinary team of hepatologists, reproductive endocrinologists, anesthesiologists, neonatologists, and maternal fetal and obstetric medicine specialists. Ideally the high‐risk team discusses the case before conception and follows the patient throughout gestation and delivery.

The hepatologist plays an important role both in preconception consultation and the management of complications during the pregnancy.

Fertility

Fertility and fecundity are compromised in some patients with advanced or untreated liver disease. Fecundity is defined as the physical ability to get pregnant; fertility is the overall result of having offspring. Fertility in women with advanced liver disease depends not only on fecundity but on the pregnancy outcome and the voluntary decision to have children.

The overall fertility rate in this population is unknown and may be influenced by the etiology of the underlying liver disease. Fertility is maintained in patients with autoimmune hepatitis (AIH),2 primary biliary cirrhosis,3 and primary sclerosis cholangitis.4

Fecundity

Women with advanced liver disease may have anovulatory cycles or are amenorrheic due to an alteration of the hypothalamic‐pituitary‐ovarian axis. This leads to hormonal imbalances. For example, hypogonadotropic hypogonadism as well as elevated levels of estrogen are seen. These changes are reversible because fecundity is restored after LT. Successful pregnancies can be achieved in anovulatory cirrhotic patients with assisted reproductive technology. Concomitant diseases and nutritional deficiencies may also impair fecundity. Hypogonadism in chronic alcoholism, polycystic ovarian syndrome in nonalcoholic steatohepatitis, and vitamin K deficiency are prime examples.

Voluntary Childlessness

The patient's personal decision plays an important role in the previously observed overall low fertility rate. In the past, physicians considered pregnancy absolutely contraindicated in cirrhotic patients. This attitude might have contributed to voluntary childlessness.

Conception Outcome

It is estimated that half of all pregnancies in the setting of advanced liver disease will result in live births. In a recent retrospective review of 62 pregnancies in patients with cirrhosis, the live birth rate was 58%.5 Miscarriage and elective termination rates did not deviate from the average population rates of 19% and 15%, respectively. However, in this study, half of the elective terminations were advised for medical reasons. Stillbirth rate was 6%.

Fetal and Obstetric Outcome

Advanced liver disease is associated with poor pregnancy outcomes such as a significant increased risk of premature birth and intrauterine growth restriction. In one study, 18% of deliveries occurred before 30 weeks gestation and 64% before 37 weeks.5 Other studies confirm the same complications, citing higher rates of premature labor, intrauterine growth restriction, and infections compared to historical controls.6 In the same cohort, the stillbirth rate was increased by 6%. Whereas the cause of increased stillbirth is unknown, it is most likely multi‐factorial. In terms of obstetric outcome, the rate of cesarean is increased in this population, most likely due to physician preference.

Maternal Outcome

Pregnancy in the cirrhotic patient carries a significant risk of complications and mortality to the mother, although the degree is difficult to determine. In retrospective studies and case series, the rate of complications and maternal mortality varies greatly from 10% to 80%, reflecting the heterogeneity of subjects.6, 7 In a U.S. retrospective study conducted of 339 pregnant cirrhotic patients, Shaheen et al. describe a maternal mortality rate of 1.8; in other series mortality was as high as 7.8%.

Liver failure, ascites, hepatic encephalopathy, and variceal bleeding are common complications in patients with cirrhosis and may occur during pregnancy. Although pregnancy per se does not seem to exacerbate underlying liver disease or precipitate hepatic failure, some important exceptions include AIH and chronic hepatitis B, both of which will be discussed separately. These complications, along with postpartum hemorrhage and delivery complications, are responsible for the high maternal mortality rate that occurs in this group of patients.7

Recently, the first prospective study addressing the natural history of posthepatitis cirrhosis in pregnancy was published.7 The data confirmed poor maternal outcomes for pregnant patients with cirrhosis; in this study, the increased maternal morbidity in comparison to nonpregnant cirrhotic controls was secondary to variceal bleeding (78% vs. 19%). Maternal mortality was also increased overall (7.8 %). MELD predicts the likelihood of complications in pregnant patients with cirrhosis. In a retrospective study, a MELD score greater than 10 confirmed a correlation with the risk of maternal complications,5 whereas a MELD less than 6 was associated with good pregnancy outcome.

Maximizing Maternal Health Before Pregnancy

• Nutritional consult

• Review medications

• Preconception endoscopy for variceal surveillance and eradication

Maximizing maternal health, including nutritional status before and during pregnancy, may improve outcomes.

Nutrition

An optimal caloric intake for all pregnant patients is not established and should be tailored to individual need to achieve appropriate weight gain. In general, as the pregnancy progresses into the second and third trimester, calories should be increased by 300 to 500 kcal/daily. Malnutrition is a common complication in liver cirrhosis, and cirrhotic patients require the consumption of 25 to 40 kcal/kg body weight a day to improve their nutritional status. Protein restriction is no longer recommended. During pregnancy, protein intake should be targeted at 1.2 grams of protein/kg of body weight. Patients should be counseled to consume small, frequent meals as well as restrict sodium intake.

Patients with advanced liver disease are prone to deficiencies in minerals such as magnesium, phosphorus, and zinc. In addition, fat‐soluble vitamins such as vitamins D and K are often low. These nutrients are vital during pregnancy, and adequate levels should be carefully restored. Nutritional consult is beneficial to develop an individualized plan to address each of these components.

Medications

Common medications used in the cirrhotic patient are generally considered safe and do not contribute to poor fetal outcome, although there are some exceptions such as spironolactone, which causes feminization of the offspring. A list of common medications and their use in pregnancy is summarized in Table 1.

Table 1.

Common Medications Used in the Cirrhotic Patient

Medications	Use in Pregnancy
Lactulose (FDA category B)	Frequently used without adverse effects
Spironolactone (FDA category C)	Should be avoided; causes feminization of the male fetus
Hydrochlorothiazide (FDA category B)	Use if necessary; avoid hyponatremia
Furosemide (FDA category C)	Use if necessary; avoid hyponatremia
Ciprofloxacin (FDA category C)	Use only if absolutely necessary; associated with skeletal abnormalities
Metronidazole (FDA category B)	Use if necessary
Rifaxamin (FDA category C)	No data available
Nonselective beta blocker (Propranolol category C)	Use if necessary; caution associated with newborn bradycardia and growth restriction

Abbreviation: FDA, US Food and Drug Administration.

Management of Complications During Gestation and Delivery

• Medications should be continued during pregnancy.

• Monitor and treat protein malnutrition and fat‐soluble vitamin deficiencies.

• Variceal hemorrhage is the most common complication and cause of maternal morbidity and mortality.

• Primary prophylaxis with endoscopic band ligation (EVL) may be performed at 28 weeks.

• Correct coagulopathy and plan delivery

Hepatic decompensation, encephalopathy, and ascites can occur in pregnancy, and their treatment should follow the general guidelines established for the general population.

Management of Portal Hypertension and Variceal Bleeding in Pregnancy

Esophageal variceal rupture has been observed in up to half of cases of pregnant patients with severe underlying liver disease and carries a high maternal mortality rate of 10% to 50%.8 The worsening of portal hypertension is due to the systemic and intraabdominal physiological changes occurring in pregnancy.

During gestation, compensatory dilation of collateral veins connecting the portal circulation and the azygos vein occurs. This is aggravated by expanding circulating blood volume, which will increase by 50%, typically peaking between 28 and 32 weeks. Moreover, the expanding uterus compresses the inferior vena cava and increases intraabdominal pressure. Rupture of esophageal varices or splenic artery aneurysm may occur. Due to these physiologic changes during pregnancy, the major cause of maternal morbidity and mortality in pregnant patients with cirrhosis is increased portal hypertension and variceal bleeding, particularly in the third trimester and during labor and delivery. Bleeding is exacerbated by thrombocytopenia and coagulopathy secondary to underlying hepatic dysfunction and vitamin K malabsorption.

Successful management of acute variceal bleeding in pregnant patients does not differ from nonpregnant patients and includes EVL, transjugular intrahepatic portosystemic shunt, and endoscopic injection sclerotherapy.9, 10 However, the safety of octreotide infusion, which has not been established and carries a theoretical risk of uterine ischemia, should be used only if absolutely necessary.

Primary Prophylaxis

Many experts advocate the primary prevention of variceal bleeding in pregnancy. The efficacy of this strategy is not supported by evidence but is recommended given the high maternal mortality associated with acute variceal bleeding. Pregnant patients with cirrhosis, whether having undergone previous eradication or not, should undergo an upper endoscopy for detection and possible prophylactic EVL of high‐risk varices. Endoscopy should be timed to coincide with maximum volume expansion (28 weeks of gestational age).8, 11 EVL is preferred for primary prophylaxis during pregnancy. Alternatively, nonselective beta‐blockers can be used for primary and secondary prophylaxis. However, intrauterine growth restriction, bradycardia, and hypoglycemia have been reported during their use. Regardless of the indication for a nonselective beta blocker, this agent should be continued in pregnancy to avoid rebound variceal bleeding.

Management of Uncommon Complications During Gestation

Other rare maternal complications can occur during pregnancy in patients with underlying advanced liver disease.

Intrahepatic cholestasis of pregnancy (ICP) is characterized by intractable pruritus and the elevation of fasting biliary acids above 10 micromol/L. This occurs in healthy patients as a result of genetic mutations, but it also complicates pregnancy in a subset of patients with underlying chronic liver disease. It is believed that the hormonal changes related to pregnancy affect the expression of biliary acid transport protein in the biliary canaliculi, resulting in cholestasis and rising serum biliary acids. Hepatitis C is the most common underlying liver disease associated with ICP. Fetal demise after 37 weeks of gestation can occur when the level of biliary acids exceed 40. Ursodeoxycholic acid at 1.5 mg/kg is used to control pruritus and decrease serum biliary acids level, and it may improve fetal outcome.

Splenic Aneurysm

Splenic aneurysms are described in pregnancy and can rupture as a result of increased portal hypertension. This event presents with the sudden onset of left upper quadrant pain, followed by intraabdominal hemorrhage, hypovolemia, and shock. Treatment consists of emergency laparotomy, splenectomy, and arterial ligation or embolization when possible. Acute rupture in pregnancy is associated with high mother mortality. Incidentally discovered splenic artery aneurysms measuring 2 cm or larger, and those found in women of childbearing age, should be treated with endovascular coil embolization.

Portal vein thrombosis can complicate pregnancy and it is the result of underlying hypercoagulable status common in pregnancy. Portal vein thrombosis is an important cause of non cirrhotic portal hypertension in the pregnant population. Anticoagulation with low molecular weight heparin can be used.

Delivery

Delivery of the fetus in the pregnant patient with cirrhosis requires an individualized plan. Degree of liver dysfunction and the presence and/or treatment of esophageal varices, as well as patient and obstetric preferences, must be taken into consideration.

Coagulopathy is a major concern at this time. Due to cirrhosis, variceal bleeding and peripartum hemorrhage may complicate delivery. Variceal bleeding has been described in the setting of increased intraabdominal pressure during labor, subsequently leading to increased portal pressures. If the patient with cirrhosis has not undergone prophylactic EVL, elective cesarean should be advised to avoid the high risk of esophageal variceal bleeding during the final stages of labor. In addition, for those patients who undergo vaginal deliveries, consideration should be given for early epidural anesthesia, shortening of the second stage, and assisted delivery. Peripartum hemorrhage may occur as coagulopathy and thrombocytopenia may predispose to bleeding.

General anesthesia and surgery is poorly tolerated in the cirrhotic patient and risks, and the benefits of cesarean versus spontaneous vaginal delivery with or without regional anesthesia must be carefully evaluated. The observed rate of cesarean is high in the cirrhosis population. In addition, the anesthetic management during delivery is dictated by careful evaluation of type and severity of the liver dysfunction. Whereas surgery carries a high mortality rate in the cirrhotic patients, regional anesthesia is associated with an increased risk of intravascular injection and epidural hematoma, which can result in permanent neurological damages.

The threshold for using blood products varies from center to center. In general, a platelet count above 80,000 (however, in some centers it is as low as 50.000) and an international normalized ratio of less than 1.5 are considered adequate for surgical and/or anesthetic procedures.

Management of the patient with advanced liver disease in pregnancy is summarized in Table 2.

Table 2.

Management of Pregnant Patient With Underlying Advanced Liver Disease

Preconception Evaluation

• Assess liver disease function and portal hypertension and calculated MELD

• Advise patient with MELD > 10 of high maternal risk and poor outcome

• Nutrition consult

• Maximize nutrition: Replace fats soluble vitamins and minerals.

• Endoscopy for varices surveillance and endoscopic eradication of large varices

Pregnancy

• High‐risk team

• Frequent visits

• Monthly complete blood count with platelets, international normalized ratio, prealbumin, and liver function tests

• Continue nonselective B blockers

• Continue all medications

• Monitor nutritional status

• Upper endoscopy and endoscopic ligation of large varices at 28 weeks

Third trimester/delivery

• Monitor coagulopathy, nutritional status, and serum biliary acids

• High‐risk team delivery plan

• Ensure availability of platelets and blood products at time of delivery

• Cesarean or operative delivery if risk of esophageal rupture is present

• Antibiotic prophylaxis after cesarean

Special Considerations in Patients with Preexisting Liver Disease

The treatment of most common liver disease in pregnancy is summarized in Table 3. In general, pregnancy does not alter the course or treatment of preexisting liver diseases.

Table 3.

Common Causes of Chronic Liver Disease and Their Therapy in Pregnancy

Common Chronic Liver Disease	Pregnancy Considerations	Therapy
Alcoholic liver disease	Causes fetal alcohol syndrome in the newborn	Abstinence; nutritional support
Nonalcoholic fatty liver disease	Increased prevalence with gestational diabetes	Glucose control; diet and exercise
AIH	Pregnancy affects the disease course; may present de novo in pregnancy	Prednisolone/azathioprine
Wilson's disease	May present de novo in pregnancy	Zinc therapy is effective and well tolerated; continue chelators
Primary biliary cirrhosis	Course not altered by pregnancy; monitor serum biliary acid	Ursodeoxycholic acid is well tolerated; replace fat soluble vitamins
Primary sclerosis cholangitis	Course not altered by pregnancy; monitor serum biliary acid	Ursodeoxycholic is well tolerated; replace fat soluble vitamins
Hemochromatosis	Rare in fertile years; decreasing iron storages improves disease
Biliary atresia	Pregnancy common in patient on waiting list for LT; monitor serum biliary acid	Replace fat soluble therapy
Budd‐Chiari syndrome	15% of cases present in pregnancy; most common in hereditary or acquired thrombophilia	Anticoagulation; LT
Portal vein thrombosis	Important cause of noncirrhotic portal hypertension in pregnancy; important cause of portal hypertension in pregnancy	Anticoagulation

Wilson's Disease

Wilson's disease presents in the first four decades of life and affects women during the peak age of fertility. Accumulation of copper in the liver leads to progressive liver damage or acute fulminant hepatitis. In fact, women are four times more likely to develop fulminant hepatitis compared to men. When presenting acutely as fulminant hepatitis during pregnancy, concomitant hemolytic anemia, thrombocytopenia, and liver failure make it easily mistaken for hemolysis, elevated liver enzymes, low platelets syndrome. Ultimately, liver biopsy might be necessary for the diagnosis. Untreated Wilson's may lead to spontaneous abortion, fetal demise, and recurrent miscarriage; however, with of life‐long administration of copper chelators such as penicillamine, trientine, and tetrathiomolybdate, fertility is restored. Several cases of successful pregnancy in patients with Wilson's disease are described in the literature.12, 13 Limited data exists regarding the safety of chelators in pregnancy. The European Association for the Study of Liver Diseases recent guidelines recommend continuing medications in pregnancy to avoid the risk of rebound liver damage upon discontinuation. Reduction and optimization of dosage of chelators is required in the third trimester to maintain adequate copper supply to the growing fetus. Zinc salt is also prescribed to treat this condition and is considered the first line treatment in pregnancy and for women wishing to conceive.14

Autoimmune Hepatitis

Autoimmune hepatitis is a common disease occurring in 100,000 to 200,000 patients per year in the United States. It is more common in women than in men and often presents in patients during their childbearing age. Thus, AIH in pregnancy is a common condition. Spontaneous remissions have been described in pregnancy; however, liver decompensation and poor maternal outcomes have been reported as well.2 A recent case series showed an increase in risk of adverse outcomes, including prematurity and maternal hepatic decompensation. Poor outcome has been associated with poor disease control prior to conception.15 Postpartum, the disease may flare with the return of normal immunity after pregnancy, and patients should be followed with care for the first 4 to 6 months postpartum while the immune system reconstitutes. The mainstay of treatment for AIH is immunosuppression, usually with prednisone/prednisolone alone or in combination with azathioprine.16 Therapy should be continued because relapse is associated with progression of the liver disease.

Mycophenolate mofetil (MMF) is among the newest therapy commonly prescribed for treatment of AIH. It is US Food and Drug Administration category D, and its use has been associated with fetal malformations in animals and humans as well pregnancy loss, spontaneous abortion, and severe infections in the expectant mother. Thus, it is contraindicated in pregnancy. Use of MMF is limited to situations in which no other choice is available. Pregnancy should not be attempted before 6 weeks after discontinuation of the drug, and two forms of birth control are recommended for women of childbearing age who take this medication.

Liver Masses

The incidental discovery of mass‐like defects in pregnancy is common. Indeed, benign liver lesions are common in women of childbearing age, and they are found in more than 20% of the general population. The most common are benign hemangioma (HA), focal nodular hyperplasia (FNH), and hepatocellular adenomas (HCA).

The diagnostic algorithm for these lesions is the same in the pregnant patients as it is in the nonpregnant counterpart. Ultrasound and noncontrast magnetic resonance (MRI) are safe at any time during pregnancy. Computer tomography (CT) with contrast is used routinely in pregnancy when its potential benefit outweighs the risk. If possible, CT scan should be delayed after 14 weeks of gestation, at which time organogenesis is completed. The safety of contrast media for MRI and ultrasound has not been determined, but their use is justifiable if absolutely necessary. Liver biopsy is performed safely in pregnancy when indicated; however, liver biopsy can precipitate rupture of HCA in pregnancy and is generally avoided.

HA and FNH are benign lesions and rarely lead to complications. Thus, routine serial follow‐up imaging is not necessary. In a recent case report, 20 pregnant patients with FNH carried their pregnancies to term without complications. Moreover, the FNH lesions followed by serial ultrasound were not changed in size throughout pregnancy.17 The effect of pregnancy on HA size is debated but overall felt to be modest. Rare complications of HA reported in pregnancy include consumption coagulopathy and intracavernous HA bleeding.

On the other hand, the natural history of HCA in pregnancy is controversial. HCAs carry a risk of hormone‐induced growth and rupture associated with high maternal and fetal mortality. Some experts advocate preventive angioembolization and formal resection during pregnancy for any HCA larger than 5 cm, even in the absence of complications.18 Noels et al.19 reported a series of 17 pregnancies occurring in 12 patients with HCA. All of the pregnancies were successful and resulted in a live newborn. In four cases, the HCA grew requiring either cesarean or radiofrequency ablation as a preventive measure to avoid possible rupture. The author suggested a conservative approach in all HCA, reserving intervention only in case of size changes or rupture. In the absence of an evidence‐based algorithm, serial abdominal ultrasound should monitor HCAs through pregnancy, and intervention should be considered if growth progression is demonstrated.

Pregnancy After Liver Transplantation

After successful orthotopic LT, fertility is restored promptly in as early as 3 months posttransplant. Women who resume normal menstruation may become pregnant and deliver normal infants. The National Transplantation Pregnancy Registry (NTPR) established in 1991 is a questionnaire‐based registry investigating pregnancy outcomes in North American transplant recipients. In the 2009 report, the NTPR investigated 128 pregnancies occurring in LT recipients and20 demonstrated that a transplant to conception interval > 2 years was associated with a reduction in the rates of low birth weight newborns, rejection during pregnancy, and graft loss. The American Society of Transplantation recommended at least 1 year prior to conception to stabilize graft function and immunosuppressive therapy. Thus although there are no established ideal intervals, patients should be advised to wait more than 1 year before attempting pregnancy.

Effect of Pregnancy on Liver Allograft

The rate of acute rejection in LT recipients is not altered by pregnancy. The NTPR reported that 7% of patients20 developed acute rejection during pregnancy, and 8% suffered graft loss within 2 years of delivery. This risk was highest in women who conceived within 6 months of their transplant. Similar rates were reported in other large series.

Pregnancy Outcomes

LT recipients and their infants are at risk of maternal and fetal complications. Poor fetal outcome was reported in several studies and include growth restriction, prematurity, and low birth weight. In a large population‐based analysis of transplant recipients and matched controls, fetal mortality was also increased (6.3% vs. 2.0%; P = 0.0006).21 These findings were only partially confirmed by a recent meta‐analysis of 450 pregnancies in 306 patients from the United States and Europe.22 In this study, a live birth rate exceeded the national average in this population. However the rate of preterm delivery and cesarean was significantly increased.

Maternal complications during pregnancy are common and include gestational hypertension, preeclampsia, and postpartum hemorrhage. Maternal mortality is not affected.

Immunosuppressive Therapy

After LT, mothers should continue immunosuppressive therapy during pregnancy. Teratogenicity has not been associated with any treatment regimen, with the exception of MMF.

Medications may contribute to maternal morbidity. For example, calcineurine inhibitors including cyclosporine and tacrolimus may lead to adverse effects such as maternal hypertension, preeclampsia, renal dysfunction, and gestational diabetes.