Liver Disease and Pregnancy

Liver disease that occurs during pregnancy can present a challenge for healthcare providers. Certain liver diseases are uniquely associated with pregnancy, whereas others are unrelated. The liver diseases unique to pregnancy include hyperemesis gravidarum, acute fatty liver of pregnancy (AFLP), intrahepatic cholestasis of pregnancy (ICP), and hemolysis and elevated liver enzymes and low platelets (HELLP) syndrome. ^[1] Liver disease such as acute viral hepatitis can occur in pregnancy, and pregnancy may occur in a patient with underlying chronic liver disease, including patients with cirrhosis and portal hypertension, and patients who have undergone liver transplantation.

In the initial evaluation of a pregnant patient with abnormal liver tests, the American College of Gastroenterology (ACG) recommends these women undergo the same standard workup as that of nonpregnant individuals. ^[2]  With regard to imaging studies and/or endoscopy in pregnant women, the ACG has the following recommendations ^[2] :

• Ultrasonography is safe and the preferred imaging modality for the assessment of abnormal liver studies suggestive of biliary tract disease.
• Magnetic resonance imaging (MRI) with gadolinium can be used in the second and third trimester.
• Computed tomography (CT) scans carry a risk of teratogenesis and childhood hematologic malignancies but may be used judiciously with minimized radiation protocols (2-5 rads).
• Endoscopy is safe in pregnancy but should be deferred until the second trimester if possible.
• Meperidine and propofol can be used for endoscopic sedation.

Approximately 50%-80% of pregnant women experience nausea, and an estimated 50% suffer from retching. ^{[3, 4]}  Hyperemesis gravidarum—in which persistent vomiting is associated with a 5% or more loss of prepregnancy body weight, dehydration, and ketosis—occurs in up to 3% pregnancies. ^{[2, 5]}

Pregnancy-related diseases are the most frequent causes of liver dysfunction during pregnancy and exhibit a trimester-specific occurrence during pregnancy. ^[5]  Hyperemesis gravidarum occurs early in the first trimester and often resolves by 20 weeks' gestation. ^[2]

The differential diagnosis of hyperemesis gravidarum includes uncomplicated nausea and vomiting of pregnancy, gastric ulcers, gastroenteritis, viral hepatitis, pyelonephritis, nephrolithiasis, ovarian torsion, hyperthyroidism, diabetic ketoacidosis, and migraines.

Risk factors

Risk factors for hyperemesis gravidarum include past history of the disease, hyperthyroidism, psychiatric illness, molar pregnancy, preexisting diabetes, multiple gestations, multiparity, increased body mass index, and high daily intake of saturated fat before pregnancy. One study also identified female sex of the fetus as a risk factor. ^[6] An association between Helicobacter pylori infection and hyperemesis has also been identified. ^[7]

Etiology

The cause of hyperemesis gravidarum remains unknown. Multiple theories exist, from psychologic predisposition, including conversion disorders, to evolutionary adaptation to protect a mother and her fetus from certain potentially harmful foods. Certain hormone levels also seem to play a role, as nausea and vomiting symptoms peak when human chorionic gonadotropin and estradiol levels are higher. Furthermore, cigarette smokers with lower estradiol levels also have a lower incidence of hyperemesis. ^[8]

Symptoms

Symptoms of hyperemesis gravidarum include severe nausea and vomiting, at times requiring hospitalization. Patients often present with dehydration and may show evidence of malnutrition with poor weight gain.

Diagnosis

The diagnosis is based upon the clinical presentation. Although no standard diagnostic criteria exist, some commonly used ones include persistent vomiting with no other cause, evidence of acute starvation (usually with ketonuria), and evidence of acute weight loss (≥5%). ^{[2, 9]} Up to half of these hospitalized women have abnormal liver enzymes. Aminotransferase levels may rise up to 200 IU/L but are generally below 300 IU/L, ^[10] and alkaline phosphatase may rise to twice the normal value. Both direct and indirect bilirubin values may rise to 4 mg/dL, ^{[10, 11]} and serum amylase and lipase levels may rise up to five times the normal values. ^[9]

Although usually not necessary, a liver biopsy may be performed if a more serious liver disease must be ruled out. The biopsy often reveals a normal histologic appearance or bland cholestasis. ^[12]

Treatment

Treatment of hyperemesis gravidarum consists of nonpharmacologic and pharmacologic interventions. A Cochrane review found that no specific intervention was superior to others for the treatment of nausea and vomiting in early pregnancy. ^[13]

American College of Gastroenterology (ACG) and American College of Obstetricians and Gynecologists (ACOG) guidelines

The 2016 ACG  guidelines indicate use of supportive treatment for hyperemesis gravidarum, which may require hospitalization. ^[2]

The 2015 updated ACOG guidelines on the treatment of nausea/vomiting in pregnancy included the following recommendations ^[14] :

• Nausea or vomiting almost always presents before 9 weeks of gestation. When nausea or vomiting begins for the first time after 9 weeks, other conditions should be considered.
• In patients with hyperemesis gravidarum who also have suppressed thyroid-stimulating hormone levels, treatment of hyperthyroidism should not begin without evidence (eg, goiter, thyroid autoantibodies, or both) of thyroid disease.

The 2018 updated ACOG guidelines recommend the following ^{[3, 4]} :

• Use vitamin B ₆ (pyridoxine) alone or in combination with doxylamine as first-line pharmacotherapy, as they are safe and effective.
• Clinicians should encourage women to take prenatal vitamins for 1 month before fertilization, as it may decrease the incidence and severity of nausea and vomiting during pregnancy.
• Supportive therapy is recommended for abnormal maternal thyroid tests caused by gestational transient thyrotoxicosis or hyperemesis gravidarum, or both, but ACOG recommends against antithyroid medications.
• Intravenous (IV) hydration should be administered to patients who are unable to tolerate oral (PO) fluids for a prolonged period and if clinical signs of dehydration develop.
• Strongly consider correction of ketosis and vitamin deficiency. Include dextrose and vitamins in therapy in cases of prolonged vomiting; consider administering thiamine before dextrose infusion to prevent Wernicke encephalopathy.
• Begin enteral tube feeding (nasogastric or nasoduodenal) as first-line treatment to support nutrition for women with hyperemesis gravidarum who do not respond to medical therapy and who are unable to maintain their weight.
• Use peripherally inserted central catheters only as a last resort in women with hyperemesis gravidarum, as significant complications are associated with this intervention, and there is the potential for severe maternal morbidity.

Both the 2015 and 2018 ACOG guidelinesnote the following ^{[3, 14]} :

• Early treatment of nausea and vomiting of pregnancy can help control symptoms and prevent more serious complications (eg, hospitalization) and may help prevent it from progressing to hyperemesis gravidarum.
• Ginger may be used as a nonpharmacologic option, as it has had some beneficial effects in the treatment of nausea and vomiting of pregnancy.
• Treatment of severe nausea and vomiting of pregnancy or hyperemesis gravidarum with methylprednisolone may be effective in some refractory cases; however, it should be considered a last-resort treatment as a result of its risk profile.

Nonpharmacologic interventions

Nonpharmacologic interventions include avoiding nausea-inducing triggers such as odors from perfume, smoke, cooking foods, and chemicals. One study by Heinrichs et al demonstrated that none of the women with anosmia from congenital olfactory deficiency experienced nausea and vomiting of pregnancy, whereas 54% of pregnant women with intact olfaction had nausea and vomiting of pregnancy, although not necessarily hyperemesis gravidarum. ^[15]

Other triggers that may stimulate nausea include eating certain foods, especially spicy, salty, or fatty ones; therefore low-fat, frequent small meals may help to improve symptoms. Crystallized ginger or ginger capsules (250 mg by mouth 4 times per day) have also been used with some success.

Acupuncture and wristbands that apply pressure to the volar aspect of the wrist is another common intervention. In a Cochrane review, the wristband demonstrated no benefit over placebo, but all of the studies had a large placebo effect, and no risk of adverse effects was associated with the treatment. ^[16] Another treatment option that has proven successful is multivitamin use at the time of conception; thus, any patient with a history of hyperemesis should be encouraged to start taking multivitamins prior to conception.

Pharmacologic treatment

According to the ACOG practice bulletin algorithm for pharmacologic treatment of nausea and vomiting in pregnancy, 10-25 mg of vitamin B6 given 3-4 times per day is the initial treatment of choice. ^[14] It may also be used in conjunction with doxylamine, an H1 receptor blocker, given as 12.5 mg by mouth 3-4 times per day. This combination has demonstrated success and been proven safe to take in pregnancy.

If these two medications prove insufficient, the next step is to add promethazine 12.5 mg PO or rectally (PR) every 4 hours, or another H1 blocker, dimenhydramine, 50-100 mg PO or PR every 4-6 hours. If additional treatment is required, the algorithm splits depending upon the absence or presence of dehydration. If dehydration is not evident, another agent can be added, such as metaclopramide 5-10 mg intramuscularly (IM) or PO every 8 hours; promethazine 12.5-25 mg IM, PO, or PR every 4 hours; or trimethobenzamide 200 mg PR every 6-8 hours.

If dehydration is present, IV fluids should be started, as well as either dimenhydrinate 50 mg IV every 4-6 hours, metoclopramide 5-10 mg IV every 8 hours, or promethazine 12.5-25 mg IV every 4 hours. Finally, if all of the above are insufficient, methylprednisolone 16 mg every 8 hours PO or IV for 3 days, followed by a 2-week taper or ondansetron 8 mg IV every 12 hours can be added. Methylprednisolone has a demonstrated association with oral clefts when used in the first 10 weeks of gestation, therefore exercise great caution with its use.

Hospital admission should be considered if a patient has persistent vomiting and cannot tolerate any liquids. In addition, any patient with a change in vital signs, mental status changes, or continued weight loss should be admitted, evaluated, and treated appropriately. IV fluids along with the necessary electrolytes and vitamins, especially thiamine, should be administered to patients who cannot tolerate liquids for a prolonged time period or who have evidence of dehydration. If antiemetics allow, diets should be advanced as tolerated, but in severe cases, tube feeds and parenteral nutrition may be necessary.

Prognosis

Maternal outcomes of women with hyperemesis gravidarum are generally similar to those in the general population with minor complications, including acid-base and electrolyte disturbances. Although rare, more serious complications can include esophageal rupture, retinal hemorrhage, pneumothorax, renal damage, and Wernicke encephalopathy. ^[17]

Wernicke encephalopathy, usually associated with alcohol abuse, is due to thiamine deficiency and is characterized by ataxia, ophthalmoplegia, and confusion. It is associated with a 10%-20% mortality, and many patients have long-term neurologic deficits. Treatment includes prompt thiamine replacement, initially 100 mg IV prior to the administration of any glucose-containing fluids, and may be continued until a normal diet is tolerated. Some authors recommend that thiamine supplementation should be the standard of care for any patient with longer than 3-4 weeks of vomiting. ^[18] In addition to physical complications, some patients can experience significant psychological morbidity, including depression.

In terms of fetal outcome in patients with hyperemesis gravidarum, the results have been mixed. Some studies have demonstrated that with prompt treatment and continued antiemetic use, fetal outcomes are unchanged from those in the general population, ^[19] except in cases of severe disease in which the mean birth weight is significantly lower than those with mild disease.

Other studies have demonstrated an increased incidence of low-birth-weight infants, preterm birth, preeclampsia, and placental abruption, especially in patients with second trimester hyperemesis gravidarum. ^{[9, 20, 21]} No evidence of increased risk of fetal malformations exists. ^[21] Cases of fetal death have been reported, but these are extremely rare and have only been seen in the setting of severe disease.

Relatively recently, attention has been directed toward the long-term effects of hyperemesis gravidarum on the offspring. A study demonstrated decreased insulin sensitivity and increased baseline cortisol levels in the children of mothers with severe hyperemesis compared to those in the control group. ^[22] The lifelong effect of this difference in still unknown, but it may place these children at higher risk for type 2 diabetes and cardiovascular disease.

The prevalence of acute fatty liver of pregnancy (AFLP), in which microvesicular fatty infiltration of the liver can lead to liver failure, ^[2] is 1 per 10,000-15,000 pregnancies. This life-threatening condition often develops in the second half of pregnancy (range: 27-40 weeks' gestation), usually close to term, with a reported mean gestational age of 36 weeks (see the Gestational Age from Estimated Date of Delivery [EDD] calculator), but AFLP may not be diagnosed until the postpartum period.

The differential diagnosis includes fulminant viral hepatitis, drug-induced hepatic toxicity, idiopathic cholestasis of pregnancy, adult-onset Reye syndrome, and hemolysis and elevated liver enzymes and low platelets (HELLP) syndrome.

Risk factors

No clear geographic or racial predisposition for AFLP exists. Risk factors include older maternal age, primiparity, multiple gestations, preeclampsia, male fetus, being underweight, and a history of AFLP. Studies have revealed a higher incidence of AFLP in women who (1) have a genetic mutation that affects their mitochondrial fatty acid oxidation pathway and (2) carry a fetus with a long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency.

Etiology

AFLP is in the family of microvesicular fatty liver diseases, along with Reye syndrome and valproate toxicity. In many cases, the condition is linked to mutations in LCHAD, which is one of four enzymes that break down long-chain fatty acids in the liver. A deficiency leads to accumulation of these fatty acids in the liver.

Studies have demonstrated an 18-fold increase in maternal liver disease, either AFLP or HELLP syndrome, in mothers carrying infants with fatty acid oxidation (FAO) deficiencies. However, because not all mothers carrying infants with LCHAD mutations develop liver disease, some investigators have speculated that maternal heterozygosity places these mothers at risk for developing AFLP because they cannot oxidize the increased load of long-chain fatty acids from the fetus. These fatty acids eventually accumulate within the liver, causing impaired function and eventual liver failure. ^[23]

Symptoms

Symptoms usually develop over several days to weeks and include nausea, vomiting, anorexia, lethargy, abdominal pain, ascites, and progressive jaundice. Transient polyuria and polydipsia may also occur due to the development of transient diabetes insipidus. Acute renal failure occurs in 50% of patients, and hepatic encephalopathy occurs in 60% of patients. Approximately 50% of patients also have hypertension, proteinuria, and edema suggestive of preeclampsia.

Diagnosis

The diagnosis of AFLP is usually made based on patient presentation and laboratory findings. The serum aminotransferase levels are moderately elevated (typically 300-500 U/L). Bilirubin levels are usually below 5 mg/dL but can be higher in severe cases of AFLP. Other typical abnormalities include leukocytosis, hypoglycemia, elevated ammonia levels, thrombocytopenia, neutrophilia, coagulopathy, and renal dysfunction. ^{[24, 25]}

Imaging such as computed tomography (CT) scanning may demonstrate diffuse low-density signals in the liver and ascites. However, ultrasonography of the liver usually yields findings that are interpreted as normal because the fat deposits are microvesicular. A definitive diagnosis can be obtained with a liver biopsy, but a biopsy is rarely performed because of the need for prompt therapy as well as owing to the presence of coagulopathy. When performed, the liver biopsy reveals microvesicular steatosis, fat droplets surrounding a centrally placed nucleus.

Treatment

American College of Gastroenterology (ACG) guidelines ^[2]

• Women with AFLP should be delivered promptly; expectant management is not appropriate.
• All women with AFLP and their children should undergo molecular testing for LCHAD.
• The offspring of women affected by AFLP should be monitored carefully for manifestations of LCHAD, including hypokinetic hypoglycemia and fatty liver.

Any patient with a possible diagnosis of AFLP should be immediately admitted, as the disease is characterized by progressive and sudden deterioration. Continuous fetal monitoring should be initiated and laboratory tests should be drawn immediately. Supportive measures should be instituted to stabilize the mother; these often include glucose infusion and blood products as needed, with careful attention paid to the patient’s fluid status.

The primary treatment is prompt delivery of the fetus, which stops the overload of fatty acids on the mother’s liver, as well as supportive measures to stabilize the mother. Recovery before delivery has not been reported.

Although induction of labor is a viable option if a rapid vaginal delivery is probable (26 </ref>as it can hasten resolution of the disease secondary to earlier delivery. However, cesarean delivery may increase the risk of maternal morbidity and the need for blood products. The route of anesthesia must also be discussed between the obstetric and anesthesia teams. Some patients may require general anesthesia due to coagulopathy and concern for hematoma formation with regional anesthesia.

Most patients start to improve within 48-72 hours after delivery and demonstrate an improvement in their levels of aminotransferases, ^[24] but those with evidence of coagulopathy, encephalopathy, or hypoglycemia on admission often require continued intensive care level monitoring and possible transfer to centers capable of liver transplantations.

Prognosis

Liver function usually normalizes within 1 week but may be delayed for months. Complete recovery is generally anticipated. The maternal mortality has been as high as 70%, but more recent estimates range from 7% to 18%, secondary to advances in supportive management of these patients. ^{[26, 27]} Maternal complications include postpartum hemorrhage, renal failure, hypoglycemia, disseminated intravascular coagulation (DIC), pancreatitis, and pulmonary edema.

Perinatal mortality has been as high as 85%, and more recent rates range from 9% to 23%. ^[28] Because of the urgent need for immediate delivery, approximately 75% of deliveries are preterm, with an average gestational age at delivery of 34 weeks. All infants of mothers with AFLP are tested for defects in FAO because prompt recognition and treatment can decrease mortality and morbidity.

Recurrence of AFLP in subsequent pregnancies is rare but has occurred, often in carriers of LCHAD mutations. Affected patients should be closely monitored by maternal-fetal medicine specialists.

Intrahepatic cholestasis of pregnancy (ICP) occurs in approximately 1-2 per 1,000 pregnancies in the United States. ^[29] ICP generally manifests in the third trimester, with a mean onset at 30 weeks of gestation, and symptoms resolve after delivery. The differential diagnosis includes viral hepatitis, autoimmune hepatitis, primary biliary cholangitis, and cholelithiasis.

Risk factors

Geographic variability exists, with an increased incidence in South America, especially Chile. Early reported rates in this population are as high as 10%, but more recent reports suggest rates of 1.5%-4%. ^[30] Additional risk factors include advanced maternal age, multiparity, personal or family history of the disease, preexisting liver disease, and a history of cholestasis while taking oral contraceptives. ^{[31, 32]}

Etiology

The etiology of ICP is multifactorial, including genetic, hormonal, and exogenous factors. This condition is due to abnormal biliary transport resulting in saturation of the hepatic transport system. Recurrent familial ICP has been described as a heritable defect in the multidrug resistance 3 (MDR3) gene, which encodes for a canalicular phospholipid translocator involved in bile duct secretion of phospholipids. A study demonstrated that the heterozygote genotype for the MDR3 gene predisposes women to developing ICP, but the expression of the disease is influenced by female sex hormone levels and metabolites. ^[33] Mutations in the MDR3 gene may account for up to 15% of cases of ICP.

Female sex hormones play an important role, as almost all cases are seen in the third trimester, when estrogen levels are rising. Estrogens are known to be cholestatic, and administration to nonpregnant women with a history of ICP has been shown to induce signs of cholestasis. Abnormal progesterone metabolism may also play a role in developing ICP, as elevated levels have been found in patients with ICP.

Exogenous progesterone also has a role in ICP. A study showed that 64% of patients who developed ICP were taking oral micronized progesterone to reduce the risk of premature delivery. In patients who experienced a relief of pruritus before delivery, 70% experienced relief after withdrawal of progesterone and another 10% did so after a decrease in their progesterone dose. ^[34] Seasonal variations have also been found, with increased rates of ICP in the winter months in Scandinavia and Chile.

Symptoms

Patients with ICP usually experience generalized pruritus that begins in the periphery, often worse on the palms and soles, and then moves centrally to the trunk and face. The pruritus persists and worsens as the pregnancy continues and resolves within 48 hours of delivery. The pruritus is often worse at night and may be so severe that it causes sleep disturbance, irritability, and psychiatric disturbances. Approximately 10%-25% of patients develop jaundice, usually 1-4 weeks after the onset of pruritus. No rash is associated with ICP. Some patients, however, may have excoriations caused by scratching. Patients may occasionally develop constitutional symptoms such as chills and abdominal pain, and other patients may develop diarrhea or steatorrhea.

Diagnosis

ICP can be diagnosed based on clinical symptoms, but common laboratory values include elevated bilirubin levels, usually less than 6 mg/dL, and elevated transaminases, varying from a minimal rise to 20 times the normal values. The most sensitive laboratory value is that of serum bile acids, which may be the first or only laboratory abnormality and is used as confirmation of the diagnosis. Patients with ICP generally have levels of bile acids above 10 μmol/L and they may be as high as 100-fold of the normal. The laboratory abnormalities often resolve within 2-8 weeks of delivery.

Liver biopsy is rarely needed, usually only in cases in which a more serious liver disease needs to be excluded. If biopsy is performed, it reveals cholestasis with minimal or no inflammatory changes. ^[35]

Treatment

American College of Gastroenterology (ACG) guidelines

The ACG recommends the following for ICP ^[2] :

• Owing to an increased risk of fetal complications with ICP, early delivery at 37 weeks is recommended.
• Ursodeoxycholic acid (UDCA), at 10-15 mg/kg, should be administered to women with ICP for symptomatic improvement.

ICP has the potential for severe fetal consequences, including fetal distress, prematurity, and stillbirth, ^[36]  thus, patients should be treated at centers capable of treating premature infants. Management includes symptomatic treatment of the patient as well as close monitoring and possibly early delivery of the fetus.

The medical treatment of choice is UDCA, with doses of 1 g/day. A Cochrane review found that UDCA improves pruritus over placebo, ^[37] and some trials have demonstrated improvement in levels of liver enzymes as well as shown enablement of delivery to occur closer to term. ^[38] Cholestyramine may be also used to reduce pruritus in total divided doses of 10-12 g/day, but it is less effective than UDCA and has more side effects. ^{[39, 40]}

Fetal mortality in patients with ICP has been recorded to be as high as 11%, ^[41]  and the cause of mortality is still unknown. Fetal mortality does not seem to be due to chronic uteroplacental insufficiency, but rather to an acute anoxic injury. Some believe that meconium, which complicates up to 45% of these pregnancies, causes umbilical vein constriction, thereby leading to fetal death and hypoxia. The cause of increased meconium passage remains unknown. Animal studies have demonstrated that high maternal bile acid levels increase colonic motility in sheep, but the level of bile acids in maternal or umbilical cord serum does not seem to correlate with the rate of meconium stained fluid.

Once-weekly nonstress tests are a common method of fetal surveillance, often begun at 34 weeks of gestation or as soon as the diagnosis of ICP is made, but these are not necessarily a good predictor of fetal outcome. ^[42] With active management of ICP (including maternal record of fetal movement, once-weekly nonstress tests starting at 34 weeks with a contraction stress test if the nonstress test is nonreactive), no increased rate of perinatal mortality versus control exists. In a study, all but one fetal death in the treatment group occurred within 1 week of a reactive nonstress test. ^[41]

There is no consensus on the timing of delivery in women with ICP, but the ACG recommends early delivery at 37 weeks' gestation. ^[2] Some authors recommend delivery once fetal lung maturity is confirmed, with a study demonstrating good fetal and neonatal outcome with amniocentesis for fetal lung maturity at 36 weeks. ^[43]  Separately, a small, prospective, randomized study of 69 patients found that those randomized to deliver after 38 weeks with active management, versus after 37 weeks, demonstrated lower rates (although not statistically significant) of cesarean delivery, neonatal intensive care unit (NICU) admission, and neonatal jaundice. ^[44]  In this study, there was only one neonatal death, occurring between 37 and 38 weeks’ gestation, in a neonate with hyaline membrane disease. In another study, Wikstrom Shemer et al did not find an increased risk of stillbirth compared to control patients with active management, including induction of labor before 38 weeks. ^[45]

Prognosis

Maternal outcome is good, with symptom resolution after delivery. There is a small risk of persistence after delivery, in some rare familial forms of ICP. A study demonstrated that ICP may be an indicator of susceptibility to developing more serious liver diseases, including chronic hepatitis, nonalcoholic liver fibrosis/cirrhosis, hepatitis C, gallstones, cholecystitis, and nonalcoholic pancreatitis. ^{[32, 46]} ICP recurs in 45%-70% of subsequent pregnancies.

As mentioned above, ICP is associated with spontaneous preterm labor (19%-60%), meconium-stained fluid, and perinatal mortality. A study demonstrated that with every 1 µmol/L increase in serum bile acids, fetal complications increased by 1%-2%. ^[39] The same study also demonstrated no increase in preterm labor, meconium-stained fluid, or perinatal mortality versus uncomplicated pregnancies with levels of maternal fasting serum bile acids below 40 μmol/L. ^[39] Rates of spontaneous preterm labor in patients with ICP range from 30% to 40%. The cause of preterm labor remains unknown, but in vitro studies have demonstrated that the myometrium in patients with ICP has a more intense response to oxytocin than that in normal women.

As would be expected, elevated rates of respiratory distress syndrome (RDS) exist in preterm infants, but RDS rates are also elevated in ICP patients delivered at term, suggesting that a mechanism exists through which ICP itself contributes to RDS. Early studies demonstrated rates of perinatal mortality between 10% and 15%, which now has largely decreased due to active management, with current rates of up to 3.5%. Rates of stillbirth increase after 37 weeks' gestation, thus supporting active management of delivery at 37 weeks, but case reports of fetal death from 31 weeks still exist.

Hemolysis, elevated liver enzymes, and low platelets (HELLP) usually presents as a complication of preeclampsia, but it can also occur independently. HELLP syndrome affects 1-6 per 1,000 pregnancies and 5%-20% of patients with preeclampsia. ^[47] Preeclampsia is characterized by hypertension, proteinuria, and edema, with an onset in the second or third trimester, and it affects 5%-7% of pregnancies. About 70% of patients with HELLP syndrome present before delivery, with the remaining 30% developing in the postpartum period.

The differential diagnosis includes hepatitis, pancreatitis, peptic ulcer, appendicitis, cholelithiasis, liver hematoma, acute fatty liver of pregnancy, immune thrombocytopenic purpura, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, and systemic lupus erythematosus.

Risk factors

Risk factors for HELLP syndrome include white race/ethnicity, nulliparity, and older age. ^[48] As most women who develop HELLP syndrome have preeclampsia, it is also a risk factor.

Etiology

HELLP syndrome is caused by several mechanisms that, when combined, result in hemolysis, liver necrosis with elevated transaminases, and thrombocytopenia. The initial source of the insult is unknown, but all patients have evidence of endothelial injury with fibrin deposit that causes a microangiopathic hemolytic anemia and platelet activation and consumption, leading to thrombocytopenia. The fibrin deposits cause obstruction in the hepatic sinusoids, which results in areas of hemorrhage and eventual necrosis in the liver, leading to elevated liver enzymes. The hemorrhage can eventually develop into large hematomas and cause liver capsule tears.

Symptoms

Patients with HELLP syndrome often present with right upper quadrant or epigastric pain, nausea and vomiting, malaise, and nonspecific viral-like symptoms. Some patients also experience headache (30%-60%), but fewer experience visual symptoms (17%). ^[49]

Diagnosis

Physical examination findings include right upper quadrant or epigastrium tenderness and generalized edema. Hypertension and proteinuria are common, as most of the patients have preeclampsia, but these are not always present. Hypertension is absent in up to 20% of patients, and proteinuria is absent in up to 13% of cases.

Laboratory abnormalities assist in confirming the diagnosis of HELLP syndrome, but no standardized diagnostic laboratory criteria currently exist. Commonly used laboratory values include platelet counts below 100,000/μL, serum aspartate aminotransferase (AST) levels above 70 U/L, and serum lactic dehydrogenase levels (LDH) over 600 U/L. A peripheral blood smear may also assist in the diagnosis and often demonstrates schistocytes, burr cells, and echinocytes.

Studies have revealed that about 50% of patients diagnosed with HELLP syndrome do not have all the diagnostic criteria, but of those that do, they have more severe disease with increased rates of blood transfusions and disseminated intravascular coagulation (DIC) than women with only partially abnormal laboratory criteria. ^[49]

Some studies have found that maternal morbidity varies depending upon the degree of thrombocytopenia; thus, subtype classifications of HELLP syndrome have been developed, such as the Mississippi 3 class classification ^[50] :

• Class 1: Platelet count of 50,000/µL or less
• Class 2: Platelet count above 50,000 but less than or equal to 100,000/µL
• Class 3: Platelet count less than or equal to 150,000/µL

Liver biopsy is not necessary for the diagnosis of HELLP, but if performed, it generally demonstrates sinusoidal fibrin thrombi, hemorrhage, and hepatocellular necrosis. ^[51]

Treatment

The American College of Gastroenterology (ACG) recommends the following ^[2] :

• HELLP syndrome should be managed by prompt delivery, especially after 34 weeks' gestation.
• Platelet transfusion to 40,000-50,000 cells/μL should be considered before delivery, especially if cesarean section is likely.

After the initial diagnosis of HELLP syndrome, the disease often continues to progress and can sometimes have sudden and severe advancement, eventually compromising maternal and fetal outcome. If the diagnosis of HELLP syndrome is still in question, the women should be stabilized initially with good blood pressure control. Intravenous (IV) hydralazine or labetalol may be used to maintain the systolic blood pressure below 160 mm Hg and the diastolic blood pressure below 105 mm Hg.

After the diagnosis is confirmed or highly suspected, stable patients should be transferred to tertiary care facilities for both maternal and possible neonatal treatment. Delivery is the definitive treatment for HELLP syndrome.

Controversy exists regarding the treatment of patients with HELLP syndrome at less than 34 weeks' gestation. Generally, if a reassuring fetal and maternal status exists, delivery may be delayed for a steroid course of betamethasone 12 mg intramuscularly (IM) every 24 hours for two doses, with delivery 24 hours after the last dose. During the steroid course, the patient and fetus are continually monitored, and any sign of distress or deterioration of condition should prompt immediate delivery.

A published case report described the administration of eculizumab, an inhibitor of complement protein 5, to a 25-year-old nulliparous woman at 26-3/7 weeks' gestation with HELLP syndrome. ^[52] In addition to a course of betamethasone, she was administered eculizumab three times over a course of weeks, with normalization of her laboratory parameters within a few days. Delivery was performed at 29-2/7 weeks' gestation when her condition worsened. ^[52] Although improvement from bed rest and corticosteroids cannot be excluded, more research on the use of eculizumab is required.

Delivery is indicated for women with HELLP syndrome at greater than 34 weeks’ gestation. During labor and for 24 hours postpartum, patients should receive IV magnesium sulfate for seizure prophylaxis, usually with a 4-gram loading dose, followed by 2 g/h. If the patient is already in labor, a vaginal delivery may proceed, as long as no evidence exists of fetal distress or DIC. Any evidence of the above, multiorgan dysfunction, renal failure, or abruption should prompt immediate delivery, usually by cesarean section. Induction of labor is not indicated in these patients, as the induction process can take several hours to days and therefore places the patient and neonate in danger.

Platelets are generally transfused when the platelet count is below 20,000/μL ^[53] ; if it is less than 50,000/μL and cesarean delivery is necessary; or in the setting of any significant bleeding. Multiple platelet transfusions are generally unnecessary without significant bleeding, as delivery eventually leads to improvement in thrombocytopenia.

Controversy also exists regarding the method of analgesia. Epidural analgesia is generally contraindicated with a platelet count less than 75,000/μL, but it is also up to the discretion of the anesthesiologist. Intermittent doses of systemic opioids are often used, and local infiltration for lacerations and episiotomies are another option.

Patients should be monitored very carefully for at least 48 hours in the postpartum period for evidence of pulmonary edema due to fluid shifts or renal or hepatic dysfunction. Laboratory abnormalities usually tend to nadir 24 hours postpartum and begin to recover 48 hours postpartum. IV steroids have been studied for use in the postpartum period to expedite recovery. A small retrospective study demonstrated a faster recovery time with earlier discharge, less transfusions, less invasive hemodynamic monitoring, and invasive respiratory therapy versus that of controls, ^[50] but a more recent Cochrane review demonstrated no difference in severe maternal morbidity or mortality, or fetal mortality with the administration of steroids. ^[54]

Prognosis

HELLP syndrome is associated with increased maternal and fetal morbidity and mortality. The risk of maternal death is approximately 1%. Multiple maternal complications are associated with HELLP syndrome, including pulmonary edema, acute renal failure, DIC, abruptio placenta, liver hemorrhage or failure, acute respiratory distress syndrome, retinal detachment, and stroke. Patients with HELLP syndrome also have higher rates of blood transfusion.

A history of HELLP syndrome is a risk factor for preterm delivery, preeclampsia (5%-22%) and HELLP syndrome (3%-27%) in subsequent pregnancies, especially if diagnosed before 28 weeks of gestation. In addition, a study demonstrated that 33% of affected women developed essential hypertension, with a greater proportion developing in those who were diagnosed at less than 28 weeks' gestation, ^[55] although other historical studies have found a smaller proportion (6%-8%). ^[56]

HELLP syndrome not only increases morbidity and mortality in the mother but also in the fetus. The rate of perinatal death has been demonstrated to range from 7.4% to 20.4% and is largely dependent upon the gestational age and any additional complicating factors related to the pregnancy or delivery (see the Gestational Age from Estimated Date of Delivery [EDD] calculator). The highest morbidity and mortality rates are associated with earlier gestations (<28 weeks), and studies have demonstrated that the rates are not any higher than those found at the same gestational age in women diagnosed only with preeclampsia. Most perinatal morbidity is due to prematurity with common complications, including respiratory distress syndrome, bronchopulmonary dysplasia, intracerebral hemorrhage, and necrotizing enterocolitis.

Subcapsular hematoma formation and liver capsular rupture was first described by Abercrombie in 1884. They both carry a very high maternal and perinatal mortality. Fortunately, these are rare complications of pregnancy, with respective incidences of 1 in 40,000 and 1 in 250,000 deliveries. Less than 200 cases are reported in the worldwide literature. Subcapsular hematoma formation and liver capsular rupture are most often complications of preeclampsia/eclampsia and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome and, therefore, often present in the second or third trimester, with 30% occurring postpartum, usually within 48 hours of delivery.

Although most cases are associated with HELLP syndrome, case reports and reviews exist in which up to 14% of patients with liver hematomas and capsule ruptures had no clear diagnosis of preeclampsia or HELLP syndrome. ^[57]

The differential diagnosis includes trauma, hepatic adenoma, hemangioma, acute fatty liver of pregnancy, cocaine use, and hepatocellular carcinoma.

Risk factors

Although HELLP syndrome seems to be more common in nulliparous women, multiparous women older than 30 years with HELLP syndrome seem to be at greater risk for liver hematomas. ^[58] Additional risk factors include cocaine abuse and trauma in patients with HELLP syndrome.

Etiology

The initial insult in the cascade of events leading to hematoma formation is believed to be endothelial injury, which causes vasospasm. In addition to vasospasm, fibrin deposits cause vascular congestion, sinusoidal obstruction with increased pressure ultimately causing hepatic necrosis, and intrahepatic hemorrhage. Hematomas predominantly affect the right hepatic lobe (75%) but can be seen in the left lobe (11%) and both lobes (14%). It is believed that any trauma to the abdomen, either external or internal, including uterine contractions, is a risk factor for hepatic rupture.

Symptoms

Patients with subcapsular hematomas or liver rupture often present with severe right upper quadrant or epigastric pain, nausea, vomiting, shoulder pain, abdominal distention with hepatomegaly, peritoneal signs, hypotension, and even hypovolemic shock. Some patients may have ascites and right-sided pleural effusions.

Diagnosis

Subcapsular hematomas and liver rupture can be diagnosed by clinical presentation, laboratory values, and/or imaging. Abnormal laboratory values include demonstration of severe anemia, elevated transaminases (often >3000 u/L), thrombocytopenia, and abnormal coagulation results. Patients that are hemodynamically unstable are often diagnosed at the time of laparoscopy and/or laparotomy.

If patients are hemodynamically stable, several different imaging modalities can be used, including transabdominal ultrasonography, computed tomography (CT) scanning, magnetic resonance imaging (MRI), selective angiography, and technetium-99m scanning. CT scanning with contrast is the best imaging modality for detecting hepatic hematomas, as they can efficiently and accurately detect acute hemorrhage.

Treatment

Treatment generally consists of either conservative or operative management. In cases of liver hematomas without capsule rupture, a patient may be managed conservatively with supportive measures as long as she remains hemodynamically stable. ^[2] If the patient is antepartum, immediate delivery is indicated, often by cesarean delivery with a vertical skin incision so that the liver may be inspected.

Additional management includes blood, plasma, and platelet transfusions as needed; close hemodynamic monitoring, often in an intensive care unit; and serial abdominal examinations and abdominal imaging with either ultrasonography or CT scanning, to monitor expansion of the hematoma and integrity of the Glissen capsule. Some patients may also be candidates for hepatic artery embolization, which is a good option for patients with multiple intrahepatic hematomas who are poor surgical candidates, or it may be done in conjunction with surgery. Any sign of hemodynamic instability, continued bleeding, expanding hematoma, or infection are indications to proceed with surgery.

Surgical treatment depends upon the condition of the liver, and it is often best handled by general surgeons and/or liver transplant surgeons. Intervention is indicated in the setting of enlarging hematomas or evidence of rupture with hemodynamic instability. ^[2] Most surgeons believe that any evidence of a ruptured liver capsule requires emergent surgery. One study demonstrated a maternal mortality rate of 96% with a ruptured liver capsule and conservative treatment, versus a 33% mortality rate with surgical treatment. ^[59]

Treatment includes evacuation of the hematoma and packing the liver with collagen sponges, absorbable mesh, or fibrin glue with concurrent drain placement. If this is insufficient in controlling bleeding, direct hepatic pressure, oversewing lacerations, application of Gelfoam or collagenated materials, hepatic artery ligation, and compression of the porta hepatis using the Pringle maneuver may be beneficial.

If these techniques are not successful at controlling hemorrhage or a lobe or segment is completely disrupted, lobectomies and segmentectomies have also been performed. The last operative treatment option is a liver resection, with plans for liver transplantation; liver transplantation can be an effective salvage in the setting of continued decompensation despite standard interventions. ^[2] Multiple case reports have described successful liver transplantations performed for uncontrollable hemorrhage. A case report by Hunter et al details a liver resection due to uncontrollable hemorrhage with a successful liver transplant procedure 8 hours later. ^[60]

Prognosis

The maternal mortality rate has significantly decreased over time. Before the 1970s, it was reported to be has high as 100%. This has steadily declined each decade thereafter, but maternal mortality remains approximately 12%. ^[61]

A literature review found that the lowest maternal mortality rate, 10%, was seen in the those that underwent arterial embolization, with or without laparotomy, ^[61] versus maternal mortality of at least 30% in all other treatment groups. A case review demonstrated no mortalities out of seven women treated with embolization, alone or in addition to surgery. ^[62]

One theory behind the improved outcome is that arterial embolization involves less handling of the liver and less iatrogenic trauma. As maternal mortality has decreased, so has perinatal mortality. The 1960s-1970s demonstrated a perinatal mortality of approximately 80%, with a marked decrease to approximately 40% perinatal mortality. ^[61] This improvement is likely due to both improved maternal care and care of the preterm and very ill neonate. ^[61] Most patients who survive the event have complete resolution, with normal CT scans approximately 4-6 months later. A case of recurrent hepatic rupture in a subsequent pregnancy has been reported.

The incidence of viral hepatitis A, B, and C is the same in pregnancy as it is for the general population, but the incidence of hepatitis E is much higher in pregnancy.

The American College of Gastroenterology (ACG) has the following recommendations for infection with hepatitis A virus (HAV), hepatitis E virus (HEV), and/or herpes simplex virus (HSV) in pregnancy ^[2] :

• Pregnant women presenting with acute hepatitis should be tested for common etiologies of acute liver injury including viral hepatitis, HAV, hepatitis B (HBV), HEV, and HSV.
• Pregnant women with acute hepatitis suspected from HSV should be initiated on acyclovir.

Hepatitis A

In the United States, the incidence of hepatitis A is 9/100,000. It is transmitted through oral-fecal exposure, and children play a key role in transmission, as many have asymptomatic and unrecognized infections. The virus can remain in the environment for several months and may contaminate food after cooking, often after unhygienic handling of food.

Symptoms

Symptoms in pregnancy are the same as those seen in nonpregnant patients, including malaise, fatigue, nausea, vomiting, right upper quadrant pain, and pruritus, which may be more severe in pregnancy (secondary to elevated levels of estrogen).

Diagnosis

The diagnosis of acute hepatitis A infection is made with the detection of hepatitis A immunoglobulin M (IgM) antibodies. Intrauterine transmission with infection during the first trimester has been reported; this was diagnosed by elevated levels of hepatitis A IgG in the infant at 6 months of life. ^[63]

Treatment

The hepatitis A vaccine is not contraindicated in pregnancy, and those with prolonged contact in areas with high rates of hepatitis A infection should receive prevaccination testing in order to determine existing exposure and immunity. ^[64]

Any patient with close personal or sexual contact with someone known to have an acute hepatitis A infection should receive postexposure prophylaxis with a one-time 0.02 mL/kg intramuscular (IM) dose of immune globulin and the hepatitis A vaccine. ^[64]  The immunoglobulin provides protection for up to 3 months and is 80%-90% effective. If it is given 2 or more weeks after exposure, it is not effective in preventing the infection or improving symptoms. If the patient is infected in the third trimester, the newborn should receive passive immunoprophylaxis within 48 hours of delivery. ^[65]

Hepatitis A does not lead to chronic infection and rarely leads to serious complications. The overall case fatality rate is less than 1%. ^[64]

Hepatitis B

The incidence of acute hepatitis B is 1-2 per 1000 population; for chronic hepatitis B, it is 1 per 100 population. The virus is transmitted through multiple routes, including mucosal, parenteral, sexual, and vertical exposure. Although the virus has been detected in multiple body fluids, it is only infectious in saliva, serum, and semen. Sexual contact is an efficient method of spreading the virus. The likelihood of developing a chronic infection is inversely related to the age at which the infection is acquired. The risk of chronic infection is 90% in neonates, versus approximately 2%-6% in adults. ^[66]  Chronic hepatitis B may lead to liver cirrhosis and hepatocellular carcinoma.

Risk factors

Risk factors for hepatitis B infection include unprotected sex with an affected partner, multiple sexual partners, intravenous (IV)/injection drug use, men who have sex with men, and a history of sexually transmitted infection(s) (STIs). ^[66]

Symptoms

Patients with acute hepatitis present with nausea, vomiting, fevers, and fatigue. They may also present with jaundice and pruritus, and they often have elevated transaminase levels, usually over 1000 U/L.

Diagnosis

Diagnosis of acute hepatitis B infection is made with detection of hepatitis B surface antigen (HBsAg) and IgM antibodies to hepatitis B core antigen (HbcAg). Patients who clear the initial infection develop anti-hepatitis Bs antibodies (anti-HBs) when they are clearing HbsAg. During this “window” phase, infection can be detected by testing for anti-hepatitis B core antigen (anti-HBc). The chronic carrier state is represented by the presence of HbsAg and the absence of anti-HBs. Another indicator of not only active infection but also increased infectivity is the presence of hepatitis B e antigen (HBeAg).

All pregnant women should be screened for hepatitis B by testing for HBsAg in the first trimester. ^[67]  A patient with any risk factors, including a recent or remote history of injection drug use, having had multiple sexual partners in the previous 6 months, having a sexual partner who is positive for HBsAg, or previous treatment for an STI in pregnancy should be tested upon admission to labor and delivery. Women who test positive should be reported to the state or local health department as per the local law requirements. The patient should be counseled about the modes of transmission and the prevention of hepatitis B, neonatal concerns, and understand that all household contacts should be immunized.

ACP/CDC, ACG, and AASLD guidelines

The American College of Physicians (ACP) and the Centers for Disease Control and Prevention (CDC) jointly recommend vaccination against chronic HBV in unvaccinated adults, including pregnant women who are at risk for HBV infection during pregnancy (eg, having more than one sex partner during the previous 6 months, having been evaluated or treated for an STI, recent or current injection drug use, or having an HBsAg-positive sex partner). ^{[67, 68]}

The ACG has the following recommendations ^[2] :

• Active-passive immunoprophylaxis with hepatitis B immunoglobulin (HBIg) and the HBV vaccination series should be administered to all infants born to HBV-infected mothers to prevent perinatal transmission.
• Women chronically infected with HBV and who have high viral load (>10 ⁶ log copies/mL [200,000 IU/mL] and higher) should be offered antiviral medication with tenofovir or telbivudine in the third trimester to reduce perinatal transmission of HBV
• Cesarean section should not be performed electively in HBV-positive mothers to prevent fetal infection.
• Women chronically infected with HBV should be allowed to breastfeed as recommended for infant health.

The American Association for the study of Liver Diseases (AASLD) suggests antiviral therapy to reduce the risk of perinatal transmission of hepatitis B in HBsAg-positive women with an HBV DNA level above 200,000 IU/mL, but it is not recommended in HBsAg-positive women with an HBV DNA level up to 200,000 IU/mL. ^[69]

Treatment

No specific treatment exists for acute hepatitis B, but supportive care is recommended. All women who are HbsAg positive should be enrolled in an appropriate case management program to ensure that the neonate is treated appropriately. The risk of perinatal transmission from mothers who are HbsAg positive is 10%-20% in the absence of neonatal immunoprophylaxis. In the presence of HBeAg, the neonatal transmission risk without neonatal prophylaxis is 90%. The risk of perinatal transmission also depends upon when the infection occurred during pregnancy. The risk is greatest during the third trimester, likely due to peripartum transmission, and is approximately 90%, whereas in the second trimester the risk of transmission to the fetus is 10%.

Postexposure immunoprophylaxis with HBIg and HBV vaccine can help prevent 85%-95% of cases of perinatal transmission. ^[64]  According to the CDC, all infants born to mothers who are HBsAg positive or whose status is unknown should receive single-agent HBV and HBIg within 12 hours of birth, and the vaccine series should be completed in the first 6 months of life. Preterm infants weighing less than 2000 g born to mothers who are HbsAg positive require an additional vaccine dose, and the first dose should not be counted due to the potentially reduced immunogenicity in these patients.

All infants should be tested for anti-HBsAg and HBsAg 9-18 months after delivery. ^[70]  The efficacy of passive-active immunization has been shown to vary depending upon maternal viral loads. One study demonstrated a 100% efficacy rate for maternal viral loads below 150 pg/mL versus 68% in patients with a viral load above 150 pg/mL. ^[71]

In addition to passive-active immunization at birth, some studies have demonstrated that the addition of antivirals, including lamivudine or telbivudine, can decrease the transmission of hepatitis B in pregnancy. Lamivudine is an antiviral medication that decreases viral replication in the mother, but there is concern that antiviral monotherapy can predispose to viral mutations and thus resistance to therapy. ^[51]

A study in the Netherlands demonstrated that in women with high hepatitis B viral loads (>1.2 X 10⁹), the addition of lamivudine 150 mg daily from 34 weeks' gestation versus untreated historical controls decreased the transmission rate by a factor of 2.9. ^[72]  Although the study was small, with only eight subjects, no adverse effects were noted, and when used in treatment to prevent transmission of human immunodeficiency virus (HIV), the most frequently reported adverse events were mild anemia and prematurity. ^[72]

Lamivudine treatment is generally reserved for the second or third trimester because of the risks of birth defects if used in the first trimester, but a study in China investigated the efficacy and safety of lamivudine, 100 mg/day, initiated prior to pregnancy or in the first trimester. Ninety-two subjects delivered 73 live infants. Of the 68 infants that completed the study, there were two episodes of HBV transmission, and the only adverse effect likely directly attributed to lamivudine was an elevation in serum creatinine kinase levels in one patient. ^[73]

In an open-label prospective study, telbivudine 600 mg daily was given to women in their second or third trimester with chronic hepatitis B, with viral loads greater than 6¹⁰, who were HBeAg positive, and had elevated alanine aminotransferase (ALT) levels. ^[74]  The results were compared to a control group receiving no treatment. The mothers in the treatment group experienced a significant decrease in HBV viral load greater than 4¹⁰ and a 0% maternal to child transmission compared to a 9% transmission in the control group at 28 weeks. ^[74]

Because all infants born to HBsAg positive mothers receive postexposure prophylaxis, it is safe for chronic hepatitis B carriers to breastfeed.

Infection can be prevented by avoiding high risk behaviors, including sexual contact with multiple partners or those with known hepatitis B infection and IV/injection drug use. It can also be prevented with HBIg and hepatitis B vaccine. HBIg is used for postexposure prophylaxis and provides temporary protection for 3-6 months. It is generally given in a single dose of 0.06 mL/kg IM. It is not effective if given more than 2 weeks after exposure. Two approved vaccines with various dosing schedules exist, but, most commonly, adolescents and adults receive doses at 0, 1, and 6 months. ^[75]

Hepatitis C

The incidence of hepatitis C virus in pregnant women is the same as in the general population, 0.5%-1.4%. Risk factors for hepatitis C include transfusion of unscreened blood products and IV/injection drug use. The growing US opioid epidemic and its attendant rise in IV/injection drug users has contributed to a more than two-fold increase in the annual incidence rate of acute HCV infection over a decade (2004-2014), including a near four-fold increase in prescription opioid analgesic injection. ^[76] Less common routes of transmission include sexual contact, transmission from an infected mother, and needle-stick injuries. With the advent of screening of blood products, the risk of infection decreased to 1 per 1,000,000 units of blood. ^[64]  The incubation period is about 45 days.

Symptoms

Approximately 20%-30% of patients with a new infection develop symptoms of acute hepatitis, including fever, fatigue, nausea, vomiting, abdominal pain, and loss of appetite. The remainder of the patients have asymptomatic infections. Generally, 70%-80% of people develop chronic infection, which is associated with an increased risk of B-cell lymphomas and cryoglobulinemia. Of the patients who develop chronic disease, 60%-70% develop chronic liver disease, 5%-20% develop cirrhosis, and approximately 1%-5% die from cirrhosis or liver cancer. ^[77]

ACG and AASLD/IDSA guidelines

Please note that guidelines for the current diagnostic workup and management of HCV infection continue to rapidly evolve. Clinicians are advised to refer frequently to the most recent recommendations of the AASLD and Infectious Diseases Society of America (ISDA) at https://www.hcvguidelines.org/. Other resources can also be found at the IDSA website at http://www.idsociety.org/HCV_Clinical_Guidance/.

The ACG recommends the following for hepatitis C in pregnancy ^[2] :

• All pregnant women with risk factors for HCV should be screened with anti-HCV antibody. Screening should not be performed in women without risk factors for HCV acquisition.
• Invasive procedures (eg, amniocentesis, invasive fetal monitoring) should be minimized in infected mothers and their fetus to prevent vertical transmission of hepatitis C.
• Cesarean section should not be performed electively in HCV-positive mothers to prevent fetal infection.
• Women chronically infected with HCV should be allowed to breastfeed as indicated for infant health.
• Hepatitis C therapy should not be offered to pregnant women to either treat HCV or decrease the risk for vertical transmission.

The AASLD and IDSA have the following joint recommendations ^[78] :

• At present, no recommendation for universal HCV screening in pregnant women exists, but review is ongoing.
• Screening with an HCV antibody assay is recommended for pregnant women with known or suspected risk factors for HCV infection. Confirmatory HCV nucleic acid testing is recommended for women with a positive screening test.
• For women of reproductive age with known HCV infection, antiviral therapy is recommended BEFORE considering pregnancy, whenever practical and feasible, to reduce the risk of HCV transmission to future offspring.
• Treatment during pregnancy is not recommended due to the lack of safety and efficacy data.
• HCV RNA and routine liver function tests are recommended at the initiation of prenatal care for HCV-antibody–positive pregnant women to assess the risk of mother-to-child transmission (MTCT) and degree of liver disease.
• All pregnant women with HCV infection should receive prenatal and intrapartum care that is appropriate for their individual obstetric risk(s) as there is no currently known intervention to reduce MTCT.
• In HCV-infected pregnant women with pruritus or jaundice, there should be a high index of suspicion for intrahepatic cholestasis of pregnancy (ICP) with subsequent assessment of levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and serum bile acids.
• HCV-infected women with cirrhosis should be counseled about the increased risk of adverse maternal and perinatal outcomes. Antenatal and perinatal care should be coordinated with a maternal-fetal medicine (ie, high-risk pregnancy) obstetrician.
• Breastfeeding is not contraindicated in women with HCV infection, except when the mother has cracked, damaged, or bleeding nipples, or in the context of coinfection with human immunodeficiency virus (HIV)
• Women with HCV infection should have their HCV RNA reevaluated approximately 9 to 12 months after delivery to assess for spontaneous clearance.

Diagnosis

The diagnosis of hepatitis C is made with detection of the antibody to hepatitis C. The antibody may not be detected until 6-10 weeks after clinical illness, but hepatitis C RNA can be identified soon after infection. The presence of both anti-HCV and HCV RNA demonstrate the presence of a current infection. Chronic infection does not seem to alter the course of a pregnancy and does not place the mother at an increased risk of preterm labor, preeclampsia, or gestational diabetes.

Currently, screening all pregnant women for hepatitis C is not recommended. Only those with risk factors should be screened, including HIV infection, prior or current IV/injection drug use, a history of partners with IV/injection drug use, and blood transfusion or organ transplantation prior to 1992.

Patients who test positive should be counseled regarding methods to decrease the risk of transmission to others, including not donating any blood, semen, or serum, and covering all open wounds. According to the CDC, those involved in a monogamous relationship should be aware of the low, although possible, risk of transmission, but they do not necessarily need to change their practices. Patients with hepatitis C should also be counseled about the risk of chronic liver disease and the need for possible treatment, as well as about ways to protect their liver.

Treatment

No vaccine for hepatitis C exists; thus, primary prevention is necessary in order to avoid infection. Treatment of hepatitis C with ribavirin and α-interferon is contraindicated in pregnancy, as ribavirin is teratogenic and α-interferon causes severe neurotoxicity in those younger than age 2 years.

The risk of neonatal transmission is as high as 4.3%, especially if the mother has an elevated viral load (10⁶ copies/mL) during pregnancy. In pregnancies with no detectable levels of HCV RNA, vertical transmission is rare. Additional risk factors for neonatal transmission include HIV coinfection (19.4%) and current IV/injection drug use (8.6%). If coinfection with HIV is present, antiretroviral treatment of HIV can decrease the transmission rate of HCV to levels of those who are not coinfected. ^[79]  The risk of invasive prenatal procedures, including amniocentesis and chorionic villus sampling, is unclear, and noninvasive testing should be fully explored with the patient.

Although no current American College of Obstetricians and Gynecologists (ACOG) recommendations exist regarding management of labor, transmission rates have been reported to be increased with prolonged rupture of membranes during labor (>6 hours) and the use of internal fetal monitoring. No difference was found in the transmission rate between vaginal and cesarean deliveries, ^[80]  and infection should not influence the method of delivery. Although the virus can be detected in breast milk, a review for the United States Preventative Services Task Force (USPSTF) of 14 studies found no association between breastfeeding and transmission of the virus. ^[81]  Furthermore, ACOG and the American Association of Pediatrics (AAP) advise that breastfeeding is not contraindicated. ^[82]

Hepatitis D

Hepatitis D virus is an incomplete viral particle that depends on the presence of HBV for survival. It can either be acquired at the time of HBV infection (coinfection) or after HBV infection (superinfection). It is transmitted through percutaneous or mucosal contact with blood.

Chronic infection produces more severe disease than the other forms of hepatitis, as 70%-80% of patients with chronic hepatitis D develop cirrhosis and portal hypertension. It can progress very rapidly from infection to cirrhosis within 2 years. It can be transmitted at the time of delivery, but postexposure treatment of hepatitis B is effective in decreasing the transmission rates.

Hepatitis E

Hepatitis E has a higher incidence and mortality rate in pregnancy than in the nonpregnant state. It is rare in the United States but endemic in developing countries, including areas of Asia, Africa, and Central America. Similar to hepatitis A, HEV is primarily transmitted through oral-fecal exposure, often through contaminated water supplies. Person-to-person transmission is uncommon, but vertical transmission does occur.

Symptoms

The clinical presentation can range from asymptomatic infection to fulminant hepatitis with hepatic encephalopathy that can be confused with acute fatty liver of pregnancy (AFLP). The incubation period is approximately 40 days, ranging from 2 to 10 weeks, and in the general population usually produces a self-limited disease lasting 1-4 weeks. No association exists with chronic hepatitis or cirrhosis.

Pregnant women have higher infection rates than the general population during epidemics. In one epidemic, the attack rate of nonpregnant women and men was 2.1% versus 8.8%, 19.4%, and 18.6% in the first, second and third trimester, respectively. Infection during pregnancy is associated with a higher rate of fulminate hepatitis and mortality, up to 25%, versus 2.8% in the general population. A small study demonstrated fulminate disease in 63% of Indian patients with a 100% mortality. ^[83]  The same study also demonstrated an increased risk of fulminate hepatitis when the infection was acquired in the third trimester (64%) versus infection acquired in the second trimester (36%). ^[83] Infection during pregnancy is also associated with increased rates of abortion, stillbirth, and neonatal deaths.

Diagnosis

Hepatitis E is diagnosed by the presence of anti-hepatitis E antibody, and active infection is indicated in the presence of HEV RNA. One study demonstrated that up to 70% of patients with anti-HEV antibodies were asymptomatic, ^[84]  likely reflecting prior HEV infection.

Perinatal transmission does occur, but rates are still unknown. One study demonstrated mother-to-infant transmission from symptomatic, seropositive HEV RNA mothers to be 100%, whereas HEV-RNA negative mothers had a 0% transmission rate. Transmission does not differ depending on the route of delivery as long as no signs of acute maternal disease are present.

Treatment

Hepatitis E is best prevented by providing clean drinking water and following strict sewage disposal. Postexposure or preexposure anti-HEV immunoglobulins have demonstrated no benefit; one study demonstrated a decreased rate of total HEV infections but no change in the number of clinical cases when administered to pregnant patients during an outbreak. Although anti-HEV antibodies and HEV RNA have been found in colostrum of mothers, according to the ACOG, breastfeeding is not contraindicated.

Cirrhosis is not a contraindication to pregnancy, but women with decompensated cirrhosis are unlikely to conceive secondary to hypothalamic-pituitary dysfunction. Patients with cirrhosis are often anovulatory, but after treatment they may start to have regular menstrual cycles. Controversy remains regarding the effect of pregnancy on cirrhotic patients. Only one study used a control group of nonpregnant cirrhotic patients and found no significant difference in maternal morbidity and mortality, ^[85] but other studies have demonstrated increased maternal mortality. ^[86] Fetal and neonatal outcomes are affected by maternal cirrhosis, with increased rates of preterm deliveries, spontaneous abortions, stillbirths, and neonatal mortality.

Etiology

Cirrhosis is an irreversible disease characterized by damage to the liver and subsequent fibrosis that compromises its ability to metabolize toxins. Due to fibrosis, blood is shunted away from the liver, which eventually leads to elevated pressures in the portal system. In the United States, cirrhosis is primarily caused by heavy alcohol use (65%) and hepatitis B and C infections (10%-15%). Other less common causes include hepatotoxic medications and other infections. Cirrhosis is also the primary cause of portal hypertension, but portal hypertension can develop from other diseases that produce fibrosis of the liver or extrahepatic portal vein obstruction.

Complications of cirrhosis during pregnancy are similar to those that can occur in a nonpregnant patient with cirrhosis, including variceal bleeding, liver failure, encephalopathy, splenic artery aneurysm, and malnutrition.

Symptoms

Patients can have a range of symptoms depending upon the extent of their disease. Some patients may have essentially asymptomatic cirrhosis with mild portal hypertension, whereas others with more advanced disease can have complications including acute gastrointestinal hemorrhage, liver failure, and encephalopathy.

Esophageal variceal bleeding occurs in up to 24% of pregnant patients with cirrhosis and portal hypertension. It is more common during the second and third trimesters due to the increased pressure of the expanding uterus on the inferior vena cava. Maternal mortality with acute variceal bleeds ranges from 20% to 50%. ^[87]

Liver failure occurs in up to 24% of patients with cirrhosis during pregnancy. Patients may present with hypoglycemia, coagulopathy, confusion, severe mental deterioration, and even encephalopathic coma. Several case reports also describe spontaneous splenic artery aneurysm ruptures. ^[88]

Diagnosis

A diagnosis can often be made on the basis of the history, physical examination, and laboratory findings. Features of the physical examination may include the presence of spider angiomas, ascites, caput medusae, palmar erythema, and splenomegaly. Laboratory abnormalities include hypoalbuminemia, prolonged prothrombin time, and thrombocytopenia. A biopsy is often not necessary to make the diagnosis, but if it is performed, it will show nodules with connective tissue septations.

AASLD recommendations

The American Association for the study of Liver Diseases (AASLD) provides the following guidance for noninvasive testing for the diagnosis of clinically significant portal hypertension (CSPH) ^[89] :

• Hepatic venous pressure gradient (HVPG) measurement is the gold-standard method to assess the presence of CSPH, defined as an HVPG of at least 10 mm Hg.
• CSPH can be identified by noninvasive tests: Liver stiffness above 20-25 kPa, alone or combined with platelet count and spleen size. The presence of portosystemic collaterals on imaging studies is sufficient to diagnose CSPH.
• By definition, patients with gastroesophageal varices as demonstrated by endoscopy have CSPH.

The AASLD recommends the following for noninvasive testing for the diagnosis of gastroesophageal varices ^[89] :

• Patients with a liver stiffness below 20 kPa and a platelet count over 150,000/μL have a very low probability (<5%) of having high-risk varices, and esophagogastroduodenoscopy (EGD) can be circumvented.
• In patients who do not meet these criteria, screening endoscopy for the diagnosis of gastroesophageal varices is recommended when the diagnosis of cirrhosis is made.

Treatment

AASLD recommendations

In general, for individuals with compensated cirrhosis and mild portal hypertension, the AASLD provides the following guidance ^[89] :

• The treatment goal is to prevent the development of CSPH/decompensation and, perhaps, even to achieve regression of cirrhosis.
• Elimination of the etiologic agent is the current mainstay of therapy.
• Drugs that act on portal flow, such as nonselective beta-blockers, will be mostly ineffective in this substage, given that the hyperdynamic circulatory state is not fully developed.

For individuals with compensated cirrhosis and CSPH but without gastroesophageal varices, the AASLD recommends the following ^[89] :

• The goal of treatment should be to prevent clinical decompensation (ie, it is no longer the objective to prevent varices).
• No evidence exists at present to recommend the use of nonselective beta-blockers to prevent the formation of varices.

In patients with compensated cirrhosis and gastroesophageal varices, AASLD recommendations include the following ^[89] :

• Nonselective beta-blockers are the recommended therapy for patients with high-risk small esophageal varices (ie, primary prevention in patients with small esophageal varices).
• Either traditional nonselective beta-blockers (eg, propranolol, nadolol), carvedilol, or endoscopic variceal ligation (EVL) is recommended for the prevention of first variceal hemorrhage (VH) (primary prophylaxis) in patients with medium or large varices.
• Treatment selection should be based on patient preference and characteristics.
• Patients on nonselective beta-blockers or carvedilol for primary prophylaxis do not require monitoring with serial EGD.
• Not recommended in this setting: The combination therapy of nonselective beta-blockers plus EVL
• Not recommended in the prevention of first VH: Transjugular intrahepatic portosystemic shunt (TIPS) placement

Issues to consider

No published systematic reviews or meta-analyses regarding the management of cirrhosis or portal hypertension during pregnancy exist, which may be due to a low prevalence of cirrhosis in women of reproductive age and the reduced fertility of women with cirrhosis. ^[2]

All affected women should be monitored in the antenatal period with close surveillance of liver function, with laboratory tests every 2-4 weeks, including serum albumin levels and prothrombin time. Nonstress tests should be started at approximately 28 weeks' gestation. Additionally, patients with recurrent hematemesis or those on treatment with immunosuppressants should have ultrasonographic examinations in the third trimester to evaluate fetal growth owing to an increased risk of intrauterine growth restriction. ^[87]

Unless maternal deterioration or evidence of fetal distress is found, labor should be conducted as in pregnancies not complicated with cirrhosis. Once the patient is admitted to the labor and delivery unit, additional laboratory tests should be obtained, including liver, renal, and coagulation studies. Any laboratory abnormalities, especially coagulation, platelet, and hematocrit abnormalities, should be addressed and treated with blood products prior to delivery, if possible.

If the patient has known esophageal varices, a gastroenterologist should be consulted and alerted to the patient’s presence during labor and delivery, in case an emergent endoscopy or Sengstaken-Blakemore tube needs to be placed.

An early epidural is also helpful to reduce pain and intra-abdominal pressure, which increases the pressure on any varices. Some experts also recommend assisting the second stage of labor with the application of vacuum or forceps as well.

Treatment of complications

Variceal bleeding

For patients who present with acute esophageal VH, the AASLD guidelines indicate the following ^[89] :

• Conservative transfusion of packed red blood cell (PRBC): Starting to transfuse when the hemoglobin reaches a threshold of around 7 g/dL, with the goal of maintaining it between 7 and 9 g/dL.
• Short-term (maximum 7 days) antibiotic prophylaxis should be instituted in any patient with cirrhosis and gastrointestinal hemorrhage.
• Intravenous (IV) ceftriaxone 1 g/24 h is the antibiotic of choice and should be used for a maximum of 7 days (consider discontinuing when hemorrhage has resolved and vasoactive drugs discontinued).
• Vasoactive drugs (somatostatin or its analogue, octreotide; vasopressin or its analogue, terlipressin) should be initiated as soon as VH is suspected.
• EGD should be performed within 12 hours of admission and once the patient is hemodynamically stable.
• If a variceal source is confirmed/suspected, EVL should be performed.
• In patients at high risk of failure or rebleeding (Child-Turcotte-Pugh [CTP] class C cirrhosis or CTP class B with active bleeding on endoscopy) who have no contraindications for TIPS, an “early” (preemptive) TIPS within 72 hours from EGD/EVL may benefit selected patients.
• For patients in whom an early TIPS is not performed, IV vasoactive drugs should be continued for 2-5 days and nonselective beta-blockers initiated once vasoactive drugs are discontinued. Rescue TIPS is indicated in these patients if hemorrhage cannot be controlled or if bleeding recurs despite the use of vasoactive drugs plus EVL.
• In patients in whom TIPS is performed successfully, IV vasoactive drugs can be discontinued.

For individuals who have recovered from an episode of acute esophageal VH, the AASLD recommends the following ^[89] :

• First-line therapy in the prevention of rebleeding: The combination of nonselective beta-blockers plus EVL
• Patients who have had successful placement of a TIPS during the acute episode do not require nonselective beta-blockers or EVL.
• TIPS is the recommended rescue therapy in patients who experience recurrent hemorrhage despite the use of combination therapy nonselective beta-blockers plus EVL.

Known esophageal varices can be ligated or sclerosed endoscopically prior to pregnancy to prevent hemorrhage. A study by Aggarwal demonstrated that 8.6% of patients managed with endoscopic sclerotherapy prior to pregnancy had variceal bleeding during pregnancy, versus 93.3% of those without prior treatment. ^[90]

Acute treatment of variceal bleeding in pregnancy is similar to treatment in nonpregnant patients and includes continuous hemodynamic monitoring (in an intensive care unit as needed), transfusions, balloon tamponading, endoscopy, or pharmacologic treatment. Endoscopy with variceal ligation or sclerotherapy injection is considered safe in pregnancy.

IV vasoconstricting medications that reduce portal pressures, including octreotide, have been used. No evidence of teratogenicity has been found, but this agent has not yet been well studied in pregnancy. However, one medication commonly used in nonpregnant patients, vasopressin, is contraindicated in pregnant patients because it can cause arteriolar spasm that can lead to placental ischemia and abruption. Vasopressin has also been associated with fetal digit and limb reductions due to fetal ischemia.

Portasystemic shunts have been placed in pregnant patients and may decrease the risk of recurrent hemorrhage, but these procedures should be reserved for patients with bleeding refractory to other treatment methods.

Hepatic failure

Patients with hepatic failure should be carefully monitored in an intensive care setting. Treatment is similar to nonpregnant patients with hepatic failure, including blood products as needed to correct coagulopathies and mannitol diuresis with intubation and hyperventilation for cerebral edema. A neurosurgeon may be consulted if an intracranial pressure monitor needs to be placed. The only definitive treatment for cases of fulminant hepatic failure is a liver transplantation, which has been performed a few times in pregnant patients.

Prognosis

Maternal and fetal prognosis depend upon the severity of liver disease and the incidence of complications, especially variceal bleeding. One study demonstrated that 20% of patients with noncirrhotic portal hypertension had spontaneous abortion, ^[90] usually in the mid-trimester. About half of pregnancies with cirrhosis are complicated by preterm deliveries. ^[90] Maternal mortality ranges from 10% to 18% and is often due to acute gastrointestinal hemorrhage or hepatic failure.

Gallstones or cholelithiasis are common in pregnancy, with up to 10% of patients developing stones or bile duct sludge during pregnancy or in the 6-week postpartum period. Acute cholecystitis develops when a stone obstructs the cystic duct, often after a course of symptomatic cholelithiasis.

Risk factors

Risk factors for gallstone formation and biliary sludge include elevated body mass index (BMI) (>25 kg/m²), with one study demonstrating that 2.7% of women with normal prepregnancy BMI developed gallbladder disease, versus 11% in obese women. ^[91]

Etiology

Gallstones are more common during pregnancy because cholesterol secretion increases relative to bile acid and phospholipids, thereby causing supersaturated bile. Furthermore, gallbladder volume is larger with decreased emptying, thus leaving supersaturated bile in the gallbladder with eventual gallstone formation.

Symptoms

Despite the high prevalence of the disease, only approximately 0.1%-0.3% of gallstones are symptomatic. Gallstones can manifest with right upper quadrant pain, nausea, and vomiting. In addition to these symptoms, acute cholecystitis can manifest with low-grade fever and mild leukocytosis.

Diagnosis

Biliary sludge and gallstones are diagnosed by ultrasonographic studies. Biliary sludge, also known as microlithiasis, is described as low-level echoes that shift with change in position and have no acoustic shadow, whereas gallstones have high-level echoes larger than 2 mm in size with postacoustic shadowing. In addition to pain and evidence of gallstones on sonograms, patients with acute cholecystitis also have fever or elevated white blood cell counts. Patients with gallstone pancreatitis have gallstones and elevated levels of serum amylase and lipase. Choledocholithiasis is diagnosed with evidence of gallstones in the common bile duct on ultrasonographic studies or endoscopic retrograde cholangiopancreatography (ERCP), with a similar risk profile as that for nonpregnant women.

Treatment

Uncomplicated biliary colic and acute cholecystitis can often be treated with conservative therapy, including bowel rest, intravenous fluids, pain control, and antibiotics as needed. This is the primary treatment method in the first and third trimester and is successful 80% of the time. Because biliary colic recurs 50% of the time in pregnancy, readmission rates for those initially treated conservatively range from 38% to 70%, with each subsequent admission being more severe than the prior one.

A review comparing conservative versus surgical management of symptomatic cholelithiasis demonstrated multiple readmissions in the conservative group, with 27% of them eventually undergoing surgery, 19% in the first trimester, 60% in the second trimester, and 10% in the third trimester. ^[92] The rate of preterm deliveries (3.5% vs 6%) and fetal mortality (2.2% vs 1.2%) was similar for both groups. If performed, a cholecystectomy is recommended during the second trimester, due to the risk of abortion in the first trimester and the risk of preterm labor in the third trimester.

Surgical intervention is the primary treatment for acute cholecystitis that fails medical management, if obstructive jaundice or gallstone pancreatitis exists, or if peritonitis is suspected. Most of the procedures can be performed laparoscopically, especially if performed in the second trimester. Special considerations for laparoscopic surgery include the use of open cannulation by the Hasson technique for the umbilical port site, maintaining a pneumoperitoneal pressure between 10 and 12 mm Hg, ^[93] placing the patient in the left lateral position, and using electrocautery carefully and away from the uterus. ^[92]

With an impacted common bile duct stone, ERCP with sphincterotomy and stone extraction is safe to perform during pregnancy. Case reports thus far have not demonstrated serious harm to the mother or fetus. The major maternal risk is pancreatitis, with an incidence of approximately 5%. ^[92]

Successful pregnancies have occurred after orthotopic liver transplantations, and a few successful transplants during pregnancy have been reported. Almost all patients resume normal menstruation within 7 months of a successful liver transplant, but conception should be postponed 1 year and, potentially, up to 2 years, following transplantation because of the increased immunosuppression during this time, a higher risk of acute cellular rejection, and a greater risk of opportunistic infections within the first year. ^[2] Indeed, pregnancies during this period are associated with an increased risk of infection, especially from cytomegalovirus, and carry increased maternal and fetal morbidity and mortality. Pregnancies after liver transplant procedures are associated with higher risks of worsening chronic hypertension, gestational hypertension, preeclampsia, and preterm delivery.

Pregnancy complications

Whether the increased risks of hypertension and preeclampsia are due to the liver transplantation or the use of immunosuppressive medications is unclear. In a case series of eight patients, five pregnancies were complicated by worsening hypertension and three patients developed preeclampsia with normal baseline blood pressures. ^[94] Anemia is another common complication, often due to chronic renal insufficiency.

Pregnancy does not appear to increase the rate of allograft rejection. One patient in the same study experienced an acute graft rejection, which responded to conventional treatment with glucocorticoids. ^[94]

Treatment

Pregnant patients with liver transplantation should be managed by maternal-fetal medicine specialists and closely followed by their transplant surgeon during pregnancy. Baseline assessment includes complete blood cell counts, electrolyte levels, cytomegalovirus titers, and renal and liver function tests. Patients should receive routine anatomy scans at 18-20 weeks' gestation and growth scans every 4-6 weeks after 24 weeks' gestation. In addition, these women should undergo weekly fetal testing, either with a nonstress test or a biophysical profile after 26 weeks' gestation. ^[95]

Most of our experience with immunosuppressive medications during pregnancy comes from renal transplant patients. Medications are usually continued during pregnancy, and dosages may be adjusted according to changes in serum levels during pregnancy. The American College of Gastroenterology (ACG) recommends pregnant women with a history of liver transplantation continue their immunosuppression except for mycophenolic acid. ^[2]

Corticosteroids are safe in pregnancy but have been associated with fetal growth restriction, suppression of fetal adrenal axis, and premature rupture of membranes. Patients receiving prednisone during pregnancy should receive stress dose steroids during labor and delivery.

No controlled studies have examined the use of azathioprine during pregnancy. Although it does cross the placenta, it has not been associated with teratogenicity. However, it has been associated with fetal growth restriction, fetal immunosuppression, and fetal bone marrow toxicity. Neonatal bone marrow suppression is noted only when maternal leukopenia is recorded and can be avoided if maternal leukocytes are monitored closely. Azathioprine does not cross into breast milk, but experts should be consulted before proceeding with breastfeeding.

Cyclosporine inhibits T-cell clonal expansion. Maternal side effects include hypertension and nephrotoxicity. Although it has not been shown to be teratogenic, it is associated with growth retardation. Because cyclosporine binds to erythrocytes, fetal blood concentrations have been found to range from 37% to 64% of maternal concentrations. Cyclosporine levels should be checked during pregnancy because dosages may need to be adjusted.

The mode of delivery should proceed based on routine obstetric practices. Several studies have demonstrated increased rates of cesarean delivery,(≤50%), but this may be secondary to maternal indications, including worsening preeclampsia.

Most liver transplants in pregnancy occur prior to viability or in the periviable period (17.5-27 weeks' gestation). ^[96] Termination of a pregnancy may not be an option because of the risk of maternal complications, including hemorrhage and infection. If the fetus is viable, delivery prior to transplantation may be a reasonable option, especially because of the risk of fetal infection posttransplant during the immunosuppressed period, but delivery prior to transplantation should be weighed against the risks of prematurity. The gravid uterus may also make the procedure technically more difficult and interfere with optimal surgical and postoperative management.

Prognosis

Several hundred pregnancies after liver transplantations and several liver transplantations during pregnancy have been reported. As mentioned earlier, these pregnancies are complicated by increased rates of anemia, worsening chronic hypertension, and/or preeclampsia, as well as increased rates of preterm delivery, gestational hypertension, and intrauterine growth restriction.

Several studies have shown increased rates of complications in pregnancies occurring closer to the time of liver transplantation (97</ref> ^[98] Anemia affects up to 30% of these pregnancies and may be severe enough to necessitate transfusion. Rates of preterm deliveries range from 56% to 68%, ^[99] with a mean gestational age at delivery of 34.7 weeks, based on 27 pregnancies in 24 patients. ^[94] The most common indication for delivery in this group was pregnancy-induced hypertension (28%), with preterm premature rupture of the membranes (PPROM) being the second most common (21%). A systemic review of 450 pregnancies in 306 liver transplant patients found a higher live birth rate, 76.9%, compared to the general United States population, 66.7%, and a lower miscarriage rate. ^[100]

Pregnancy also does not seem to affect the rates of allograft rejection. In a study examining 27 pregnancies after liver transplantation, Laifer et al reported only one patient experienced an acute graft rejection (confirmed by liver biopsy), which responded to conventional treatment. ^[94]  Several studies have also demonstrated elevated transaminases in multiple pregnancies that may be secondary to hepatotoxic effects of cyclosporine and unrelated to graft rejection.

In addition to neonatal complications related to preterm delivery, including respiratory distress syndrome, an increased risk of intrauterine growth restriction (23%) also exists. ^[99] Increased risk of congenital anomalies is not documented, although data on long-term outcome after liver transplantation is limited; renal transplant outcomes have been reassuring. In pregnancies after transplantation, few neonatal deaths have been reported, and in one study all three neonatal deaths were due to congenital cytomegalovirus infections. ^[101]

Maternal outcomes with liver transplants that occur during pregnancy are overall good, but fetal outcome is less reassuring. In a case review by Laifer et al, all eight patients survived the transplant, two requiring retransplant for graft dysfunction, but only three of the eight fetuses survived. ^[96] All deaths occurred prior to 30 weeks' gestation, and two occurred in the immediate postoperative period.