Liver Disease and Pregnancy 

Liver disease that occurs during pregnancy can present a challenge for health care 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, intrahepatic cholestasis of pregnancy, and hemolysis and elevated liver enzymes and low platelets (HELLP) syndrome. 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.

Hyperemesis gravidarum occurs in 1-20 patients per 1,000 pregnancies.^[1] It generally occurs in the first trimester, usually between 4-10 weeks of gestation, but may occur as late as 20 weeks gestation. 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 history of the disease, hyperthyroidism, psychiatric illness, molar pregnancy, preexisting diabetes, multiple gestations, multiparity, and high daily intake of saturated fat before pregnancy. One study also identified female gender of the fetus as a risk factor.^[2]

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.^[3]

Symptoms

Symptoms 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 clinical presentation. Although no standard diagnostic criteria exist, some commonly used include persistent vomiting with no other cause, evidence of acute starvation (usually with ketonuria), and evidence of acute weight loss.^[4] Up to half of hospitalized patients have abnormal liver enzymes. Aminotransferase levels may rise up to 200 IU/L but are generally less than 300IU/L,^[5] and alkaline phosphatase may rise to twice the normal value. Both direct and indirect bilirubin values may rise to 4mg/dL,^{[5, 6]} and serum amylase and lipase may rise up to 5 times normal values.^[4]

Although usually not necessary, if a more serious liver disease must be ruled out, a liver biopsy may be performed. The biopsy often reveals a normal histologic appearance or bland cholestasis.^[7]

Treatment

Treatment of hyperemesis gravidarum consists of non-pharmacologic and pharmacologic interventions.

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.^[8] 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.^[9] Another treatment option that has proven successful is multivitamin use at the time of conception, so 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. 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 great success and has proven safe to take in pregnancy.

If these 2 medications prove insufficient, the next step is to add promethazine 12.5 mg orally or rectally every 4 hours, or another H1 blocker, dimenhydramine, 50-100 mg orally or rectally every 4-6 hours. If additional treatment is required the algorithm splits depending upon absence or presence of dehydration. If dehydration is not evident, metaclopramide 5-10 mg intramuscularly or orally every 8 hours; promethazine 12.5-25 mg intramuscularly, orally, or rectally every 4 hours; or trimethobenzamide 200 mg rectally every 6-8 hours can be added.

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

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

Prognosis

Maternal outcomes are generally similar to those in the general population with minor complications, including acid-base and electrolyte disturbance. Although rare, more serious complications can include esophageal rupture, retinal hemorrhage, pneumothorax, renal damage, and Wernicke encephalopathy.^[10]

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 rate and many patients have long-term neurologic deficits. Treatment includes prompt thiamine replacement, initially 100 mg intravenously prior to the administration of any glucose-containing fluids and may be continued until a normal diet is tolerated. Some recommend that thiamine supplementation should be the standard of care for any patient with greater than 3-4 weeks of vomiting.^[11] In addition to physical complications, some patients can experience significant psychological morbidity, including depression.

In terms of fetal outcome in patients with hyperemesis gravidarum, mixed results can be found. With prompt treatment and continued anti-emetic use, some studies have demonstrated that fetal outcomes are unchanged from those in the general population,^[12] except in cases of severe disease in which mean birth weight is significantly lower than those with mild disease. But other studies have demonstrated increased incidence of low birth weight in women with hyperemesis gravidarum.^[4] No evidence of increased risk of fetal malformations exists. Cases of fetal death have been reported, but these are extremely rare and have only been seen in cases of severe disease.

The prevalence of acute fatty liver of pregnancy (AFLP) is 1 per 10,000-15,000 pregnancies. The condition often develops in the second half of pregnancy (ranges from 27-40 weeks gestation), usually close to term, with a mean gestational age reported at 36 weeks, but it 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 HELLP syndrome.

Risk Factors

No clear geographical or racial predisposition to 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 fat diseases, along with Reye syndrome and valproate toxicity. In many cases, the condition is linked to mutations in LCHAD, which is 1 of 4 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. But because not all mothers carrying infants with LCHAD mutations develop liver disease, some 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.^[13]

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 patient also have hypertension, proteinuria, and edema suggestive of preeclampsia.

Diagnosis

The diagnosis is usually made based on patient presentation and laboratory findings. In AFLP, serum aminotransferase levels are moderately elevated (typically 300-500 U/L). Bilirubin is usually less than 5 mg/dL but can be higher in severe cases of AFLP. Other typical abnormalities include hypoglycemia, elevated ammonia levels, thrombocytopenia, neutrophilia, coagulopathy, and renal dysfunction.^[14]

Imaging such as CT scanning may demonstrate diffuse low-density signals in the liver and ascites. However, ultrasonography of the liver usually yields findings that are read 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 the presence of coagulopathy. The liver biopsy reveals microvesicular steatosis, fat droplets surrounding a centrally placed nucleus.

Treatment

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 labs 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 (less than 24 hours), studies have demonstrated a cesarean delivery rate of up to 75%,^[15] 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 be discussed between the obstetric and anesthesia team. 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 improvement in their aminotransferases, 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 transplants.

Prognosis

Liver function usually normalizes within a week but may be delayed for months. Complete recovery is generally anticipated. The maternal mortality rate has been as high as 70%, but more recent estimates range from 7-18%, secondary to advances in supportive management of these patients.^[16] Maternal complications include postpartum hemorrhage, renal failure, hypoglycemia, DIC, pancreatitis, and pulmonary edema.

Perinatal mortality rates have been as high as 85%, and more recent rates range from 9-23%.^[17] 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 fatty acid oxidation 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, and these 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.^[18] It generally manifests in the third trimester, with a mean onset at 30 weeks gestation, and symptoms resolve after delivery. The differential diagnosis includes viral hepatitis, autoimmune hepatitis, primary biliary cirrhosis, and cholelithiasis.

Risk factors

A geographic variability exists, with increased incidence in South America, especially Chile. Early reported rates in his population are as high as 10%, but more recent reports suggest rates of 1.5-4%.^[19] Additional risk factors include advanced maternal age, multiparity, personal or family history of the disease, and a history of cholestasis while taking oral contraceptives.^[20]

Etiology

The etiology of ICP is multifactorial, including genetic, hormonal, and exogenous factors. ICP is due to abnormal biliary transport resulting in saturation of the hepatic transport system. Recurrent familial intrahepatic cholestasis of pregnancy 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. One 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.^[21] 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 has also demonstrated a role in ICP. One study demonstrated that 64% of patients who developed ICP were taking oral micronized progesterone for risk of premature delivery. In patients who experienced a relief of pruritus before delivery, 70% experienced relief after withdrawal of progesterone and another 10% after decrease in dose of progesterone.^[22] Seasonal variation has also been found, with increased rates of ICP in the winter months in Scandanavia and Chile.

Symptoms

Patients with ICP generally experience generalized pruritus that begins in the periphery, often worse on the palms and soles, and moves centrally to the trunk and face. The pruritus persists and worsens as pregnancy continues and resolves within 48 hours of delivery. 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 6mg/dL, and elevated transaminases from a minimal rise to 20 times normal values. The most sensitive laboratory value is serum bile acids, which may be the first or only lab abnormality and is used as confirmation of the diagnosis. Patients with ICP generally have bile acids greater than 10μmol/L and may be as high as 100 fold of normal. 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.^[23]

Treatment

ICP has the potential for severe fetal consequences including prematurity and stillbirth, so 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 ursodeoxycholic acid (UDCA), with doses of 1 gram per day. Several trials have demonstrated that compared with placebo, UDCA improved pruritus and liver enzymes and enabled delivery to occur closer to term.^[24] Cholestyramine may be 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.^{[25, 26]}

Fetal mortality in patients with ICP has been recorded to be as high as 11%,^[27] 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 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 gestation or as soon as the diagnosis of ICP is made, but these are not necessarily a good predictor for fetal outcome.^[28] 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. Again, all but one fetal death in the treatment group occurred within a week of a reactive nonstress test.^[27] Delivery is recommended when fetal lung maturity is confirmed. Although no consensus exists regarding when to begin testing for fetal lung maturity, one study demonstrated good fetal and neonatal outcome with amniocentesis for fetal lung maturity at 36 weeks.^[29]

Prognosis

Maternal outcome is good, with symptom resolution after delivery. One study demonstrated that ICP may be an indicator of susceptibility to developing more serious liver diseases, including gallstones and cholecystitis, nonalcoholic pancreatitis, and nonalcoholic cirrhosis.^[30] 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. One study demonstrated that with every 1µmol/L increase in serum bile acids, fetal complications increased by 1-2%.^[25] The same study also demonstrated no increase in preterm labor, meconium-stained fluid, or perinatal mortality versus uncomplicated pregnancies with maternal fasting serum bile acids less than 40 μmol/L.^[25] Rates of spontaneous preterm labor in patients with ICP range from 30-40%. The cause of preterm labor is still unknown, but in vitro studies have demonstrated that the myometrium in patients with ICP has a more intense response to oxytocin than 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 10-15%, 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 preeclampsiapreeclampsia, but it can also occur independently. HELLP syndrome affects 1-6 per 1,000 pregnancies and 4-12% of patients with severe preeclampsia. Preeclampsia is characterized by hypertension, proteinuria, and edema with onset in the second or third trimester and affects 5-7% of pregnancies. Seventy percent of patients with HELLP syndrome present before delivery, with the other 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, multiparous, and older patients. As most patients who develop HELLP syndrome have preeclampsia, it too is 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 leads to areas of hemorrhage and eventual necrosis in the liver, causing 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%), and fewer experience visual symptoms (17%).^[31]

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 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 currently no standardized diagnostic laboratory criteria exist. Commonly used lab values include platelet count of less than 100,000, serum aspartate aminotransferase (AST) greater than70 U/L, and serum lactic dehydrogenase greater than 600 U/L. A peripheral blood smear may also assist in the diagnosis and often demonstrates schistocytes, burr cells, and echinocytes.

Studies have demonstrated that about 50% of patients diagnosed with HELLP syndrome do not have all diagnostic criteria, but those that do have more severe disease with increased rates of blood transfusions and disseminated intravascular coagulation than those with only partially abnormal laboratory criteria.^[31] 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: class 1 with platelet count less than or equal to 50,000/µL, class 2 with platelet count greater than 50,000 but less than or equal to 100,000/µL, and class 3 with platelet count less than or equal to 150,000/µL.^[32]

Treatment

After 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, women should be stabilized initially with good blood pressure control. Intravenous hydralazine or labetalol may be used to maintain systolic blood pressure less than 160 mm Hg and diastolic blood pressure less than 105 mm Hg.

After 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 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 every 24 hours for 2 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.

Delivery is indicated for women with HELLP syndrome at greater than 34 weeks’ gestation. During labor and for 24 hours postpartum, patients should receive intravenous 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 disseminated intravascular coagulopathy. 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 places the patient and neonate in danger.

Platelets are generally transfused when the platelet count is less than 20,000/mm³,^[33] if less than 50,000/mm³ and cesarean delivery necessary, or with any significant bleeding. Multiple platelet transfusions are generally unnecessary without significant bleeding, as delivery eventually leads to improvement in thrombocytopenia.

Controversy also exists regarding method of analgesia. Epidural analgesia is generally contraindicated with a platelet count less than 75,000/mm³ but 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 post-partum 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. Intravenous steroids have been studied for use in the postpartum period to expedite recovery. One small retrospective study demonstrated a faster recovery time with earlier discharge, less transfusions, less invasive hemodynamic monitoring, and invasive respiratory therapy versus controls.^[32]

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, and stroke. Patients with HELLP syndrome also have higher rates of blood transfusion.

HELLP syndrome not only increases maternal morbidity and mortality but also that of the fetus. The rate of perinatal death has been demonstrated to range from 7.4-20.4% and is largely dependent upon gestational age and any additional complicating factors to the pregnancy or delivery. The highest morbidity and mortality rates are associated with the earlier gestations (less than 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. Luckily, they are rare complications of pregnancy, with incidences of 1 in 40,000 and 1 in 250,000 deliveries. Less than 200 cases are reported in the worldwide literature. They are most often complications of preeclampsia/eclampsia and 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.^[34]

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

Risk factors

Similar to risk factors for HELLP syndrome, patients that are over 30 years old and multiparous seem to be at greater risk for liver hematomas. 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 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 liver rupture or subcapsular hematomas often present with severe right upper quadrant or epigastric pain, nausea, vomiting, shoulder pain, abdominal distension with hepatomegaly, peritoneal signs, hypotension, and even hypovolemic shock. Some may have ascites and right-sided pleural effusions.

Diagnosis

Subcapsular hematomas and liver rupture can be diagnosed by clinical presentation, laboratory values, or imaging. Abnormal laboratory values include severe anemia, elevated transaminases, thrombocytopenia, and abnormal coagulation values. Patients that are hemodynamically unstable are often diagnosed at time of laparoscopy and/or laparotomy. If patients are hemodynamically stable, several different imaging modalities can be used, including transabdominal ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), selective angiography, and technetium-99m scan. CT 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 as long as she remains hemodynamically stable. If the patient is antepartum, immediate delivery is indicated, often by cesarean section 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 exams and abdominal imaging with either ultrasound or CT, to monitor expansion of the hematoma and integrity of Glissen’s 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. 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 is often best handled by general surgeons and/or liver transplant surgeons. 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.^[35]

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 at 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 the prior 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 a liver transplantation. Multiple case reports have described successful liver transplantations performed for uncontrollable hemorrhage. One case report by Hunter details a liver resection due to uncontrollable hemorrhage with a successful liver transplant 8 hours later.^[36]

Prognosis

The maternal mortality rate has significantly decreased over time. Before the 1970s, it was reported to be has high as 100%. It has steadily declined each decade, but it remains approximately 12%.^[37] One literature review found that the lowest maternal mortality rate, 10%, was in the group that underwent arterial embolization, with or without laparotomy,^[37] versus maternal mortality rates of at least 30% for all other treatment groups. 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.^[37] This improvement is likely due to both improved maternal care and care of the preterm and very ill neonate.^[37]

Most patients who survive the event have complete resolution, with normal CT scans approximately 4-6 months later. One 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.

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 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. The diagnosis of acute hepatitis A infection is made with detection of hepatitis A 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.^[38]

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 pre-vaccination testing in order to determine existing exposure and immunity.^[39]

Any patient with close personal or sexual contact with someone known to have an acute hepatitis A infection should receive postexposure prophylaxis with a 1-time 0.02 mL/kg intramuscular dose of immune globulin and the hepatitis A vaccine.^[39] The immunoglobulin provides protection for up to 3 months and is 80-90% effective. It 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.^[40]

Hepatitis A does not lead to chronic infection and rarely leads to serious complications. The overall case fatality rate is less than 1%.^[39]

Hepatitis B

The incidence of acute hepatitis B is 1-2 per 1000 population and chronic hepatitis B is 1 per 100 population. It 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.^[41] Chronic hepatitis B may lead to liver cirrhosis and hepatocellular carcinoma.

Risk factors for hepatitis B infection include unprotected sex with an affected partner, multiple sexual partners, intravenous drug use, men who have sex with men, and a history of sexually transmitted disease.^[41]

Patients with acute hepatitis present with nausea, vomiting, fevers, and fatigue. Patients may also present with jaundice and pruritus. Patients often have elevated transaminase levels, usually greater than 1000U/L. 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). In patients who clear the initial infection, they develop anti-hepatitis Bs while they are clearing HbsAg. During this “window” phase, infection can be detected by testing for anti-hepatitis B core antigen. 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. A patient with any risk factors, including injection drug use, multiple sexual partners in the previous 6 months, partner who is positive for HBsAg, treatment for a sexually transmitted disease in pregnancy, or a recent or remote history of injection drug use should be tested upon admission to labor and delivery. Patients who test positive should be reported to the state or local health department as per local law. The patient should be counseled about modes of transmission, prevention of hepatitis B, neonatal concerns, and all household contacts should be immunized.

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 hepatitis B immunoglobulin and hepatitis B virus vaccine can help prevent 85-95% of cases of perinatal transmission.^[39] According to the Center for Disease Control, all infants born to mothers who are HbsAg positive or whose status is unknown should receive single agent hepatitis B vaccine 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-HepBsAg and HepBsAg 9-18 months after delivery.^[42] 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 less than 150 pg/mL versus 68% in patients with a viral load greater than 150pg/mL.^[43]

In addition to passive-active immunization at birth, some studies have demonstrated that the addition of lamivudine can decrease the transmission of hepatitis B in pregnancy. Lamivudine is an anti-viral medication that decreases viral replication in the mother. A small 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. Although the study was small, with only 8 subjects, no adverse effects were noted, and when used in treatment to prevent transmission of HIV, the most frequently reported adverse events were mild anemia and prematurity.^[44]

Because all infants born to HepBsAg 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 intravenous drug use. It can also be prevented with hepatitis B immunoglobulin 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 intramuscularly. It is not effective if given more than 2 weeks after exposure. Two approved vaccinations with various dosing schedules exist, but, most commonly, adolescents and adults receive doses at 0, 1, and 6 months.^[45]

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 intravenous drug use. Less common routes of transmission include sexual contact, transmission from an infected mother, and needle-stick injuries. With screening of blood products, the risk of infection has decreased to 1 per 1,000,000 units of blood.^[39] The incubation period is approximately 45 days.

Approximately 20-30% of new infections develop symptoms of acute hepatitis, including fever, fatigue, nausea, vomiting, abdominal pain, and loss of appetite. The remainder of patients have asymptomatic infections. Generally, 75-85% 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.^[46]

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 detected soon after infection. Presence of both anti-HCV and HCV RNA demonstrate a current infection. Chronic infection does not seem to alter the course of a pregnancy and does not place the mother at 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 intravenous drug use, a history of partners with intravenous 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, semens, or serum and covering all open wounds. According to the CDC, those involved in a monogamous relationship should discuss the low, although possible, risk of transmission but 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 ways to protect their liver.

No vaccine for hepatitis C exists, and 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 under the age of 2.

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 co-infection (19.4%) and current intravenous drug use (8.6%). If co-infection with HIV isn’t present, anti-retroviral treatment of HIV can decrease the transmission rate of HCV to levels of those who are not co-infected.^[47] 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 ACOG recommendations exist regarding management of labor, transmission rates were also increased with prolonged rupture of membranes during labor (>6 hours) and use of internal fetal monitoring. No difference was found in the transmission rate between vaginal and cesarean deliveries,^[48] and infection should not influence the method of delivery. Although the virus can be detected in breastmilk, the ACOG and the American Association of Pediatrics (AAP) advise that breastfeeding is not contraindicated.^[49]

Hepatitis D

Hepatitis D virus is an incomplete viral particle that depends on the presence of hepatitis B virus for survival. It can either be acquired at the time of HBV infection (co-infection) or after HBV infection (super-infection). 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 for hepatitis B is effective at decreasing 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, it is primarily transmitted through oral-fecal exposure, often through contaminated water supplies. Person-to-person transmission is uncommon, but vertical transmission does occur.

Clinical presentation can range from asymptomatic infection to fulminant hepatitis with hepatic encephalopathy that can be confused with acute fatty liver of pregnancy. The incubation period is approximately 40 days, ranging from 2-10 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. One small study out of India demonstrated fulminate disease in 63% of patients with a 100% mortality.^[50] . 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%). Infection during pregnancy is also associated with increased rates of abortion, stillbirth, and neonatal deaths.

It is diagnosed by the presence of anti-hepatitis E antibody, and active infection is indicated with HEV-RNA. One study demonstrated that up to 70% of patients with Anti-HEV antibodies were asymptomatic,^[51] 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%, while HEV-RNA negative mothers had a 0% transmission rate. Transmission does not differ depending on route of delivery as long as no signs of acute maternal disease are present.

Hepatitis E is best prevented by providing clean drinking water and following strict sewage disposal. Postexposure or pre-exposure anti-HEV immunoglobulins have demonstrated no benefit, and 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 patients with decompensated cirrhosis are unlikely to conceive secondary to hypothalamic pituitary dysfunction. Patients with cirrhosis are often anovulatory, but after treatment may start to have regular menstrual cycles. Controversy still 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,^[52] but other studies have demonstrated increased maternal mortality.^[53] 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 be caused by other diseases that cause fibrosis of the liver or extra-hepatic portal vein obstruction.

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

Diagnosis

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

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, while 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 increased pressure of the expanding uterus on the inferior vena cava. Maternal mortality with acute variceal bleeds ranges from 20-50%.^[54]

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.

Treatment

All patients should be monitored in the antenatal period with close surveillance of liver function with laboratory tests every 2-4 weeks, including serum albumin and prothrombin time. Nonstress tests should be started at approximately 28 weeks. Additionally, any patients with recurrent hematemesis or on immunosuppressants should have ultrasounds in the third trimester to evaluate fetal growth, as they have been associated with intrauterine growth restriction.^[54]

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 on labor and delivery, in the case that an emergent endoscopy or Sengstaken-Blakemore tube needs to be placed.

An early epidural is also helpful in order to decrease pain and intra-abdominal pressure, which increases the pressure on any varices.

Treatment of Complications

Variceal bleeding

Known esophageal varices can be 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.^[55]

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 pharmacological treatment. Endoscopy with variceal ligation or sclerotherapy injection is considered safe in pregnancy.

Intravenous vasoconstricting medications that decrease portal pressures, including octreotide, have been used. No evidence of teratogenicity has been found, but it has not yet been well studied in pregnancy. 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 incidence of complications, especially variceal bleeding. One study demonstrated that 20% of patients with noncirrhotic portal hypertension had a spontaneous abortion,^[55] usually in the mid-trimester. About half of pregnancies with cirrhosis are complicated by preterm deliveries.^[55] Maternal mortality ranges from 10-18% 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 BMI (>25 kg/m²), with one study demonstrating that 2.7% of women with normal pre-pregnancy BMI developed gallbladder disease, versus 11% in obese women.^[56]

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 ultrasound. 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 greater than 2 mm in size with postacoustic shadowing. In addition to pain and evidence of gallstones on ultrasound, 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 ultrasound or endoscopic retrograde cholangiopancreatography (ERCP).

Treatment

Uncomplicated biliary colic and acute cholecystitis can often be treated with conservative therapy, including bowel rest, intravenous fluid, 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 38-70%, with each subsequent admission being more severe than prior.

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%, 60%, and 10% in the first, second, and third trimesters, respectively.^[57] 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, or 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, pneumoperitoneal pressure between 10 and 12 mm Hg,^[58] placing the patient in left lateral position and using electrocautery carefully and away from the uterus.^[57]

With an impacted common bile duct stone, an endoscopic retrograde cholangiopancreatography (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%.^[57]

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 transplant, but conception should be postponed 6 months to 1 year post-transplant because of increased immunosuppression during this time. 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 transplants are associated with increased 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 immunosuppressive medications is unclear. In one case series by Laifer, over half of the patients’ pregnancies were complicated by worsening hypertension and another was complicated by preeclampsia with normal baseline blood pressures.^[59] Anemia is another common complication, often due to chronic renal insufficiency.

Pregnancy does not appear to increase rates of allograft rejection. One patient in Laifer’s study experienced an acute graft rejection, which responded to conventional treatment with glucocorticoids.^[59]

Treatment

Pregnant patients with liver transplantation should be managed by maternal fetal medicine specialists and closely followed by their transplant surgeon during pregnancy. Baseline assessments include complete blood counts, electrolytes, cytomegalovirus titers, and renal and liver function tests. Patients should receive routine anatomy scans at 18-20 weeks and growth scans every 4-6 weeks after 24 weeks’ gestation. In addition, they should undergo weekly fetal testing, either with a nonstress test or biophysical profile after 26 weeks.^[60]

Most 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. 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. 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 breastmilk, 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 it binds to erythrocytes, fetal blood concentrations have been found to range from 37-64% of maternal concentrations. Levels should be checked during pregnancy because dosages may need to be adjusted.

Mode of delivery should proceed based on routine obstetric practices. Several studies have demonstrated increased rates of cesarean delivery, up to 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).^[61] 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 post-transplant 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 above, these pregnancies are complicated by increased rates of anemia, worsening chronic hypertension, and/or preeclampsia, increased rates of preterm delivery, and intrauterine growth restriction. Anemia affects up to 30% of these pregnancies and may be severe enough to necessitate transfusion. Rates of preterm deliveries range from 56-68%,^[62] with a mean gestational age at delivery of 34.7 weeks, based on 27 pregnancies in 24 patients.^[59] The most common indication for delivery in this group was pregnancy-induced hypertension (28%), with PPROM being second most common (21%).

Pregnancy also does not seem to affect rates of allograft rejection. In the study examining 27 pregnancies after liver transplantation by Laifer, only 1 patient experienced an acute graft rejection confirmed by liver biopsy, which responded to conventional treatment.^[62] Several studies have also demonstrated elevated transaminases in multiple pregnancies that may be secondary to hepatotoxic effects of cyclosporine and are 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.^[62] Increased risk of congenital anomalies is not document, 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 3 neonatal deaths were due to congenital cytomegalovirus infections.^[63]

Maternal outcomes with liver transplants that occur during pregnancy are overall good, but fetal outcome is less reassuring. In a case review by Laifer, all 8 patients survived the transplant, 2 requiring re-transplant for graft dysfunction, but only 3 of 8 fetuses survived.^[61] All deaths occurred prior to 30 weeks’ gestation, and 2 occurred in the immediate postoperative period.