GASTROINTESTINAL FUNCTION

The gastrointestinal tract undergoes dramatic modifications during pregnancy. Intra-abdominal organs must move to accommodate uterine growth, hormonal and humoral factors alter motility, and the immunologic adaptation to pregnancy affects response to disease. Heartburn, nausea, abdominal cramps, and altered bowel habits, the most common gastrointestinal symptoms of pregnant women, are caused by normal physiologic changes in gut motility. These symptoms usually are transitory and easily treated with conservative measures. However, it may be a challenge to distinguish among symptoms of altered motility and those that signal the onset or worsening of problems that require immediate medical attention.

The amplitude and duration of esophageal muscle contractions in pregnant and nonpregnant women are similar.¹ In the distal esophagus, the velocity of peristaltic waves has been found to decrease by approximately one third during pregnancy, but remains within the normal range.² In contrast, resting lower esophageal sphincter tone progressively declines during gestation, most likely as consequence of inhibition of smooth muscle contraction by progesterone.^2–4 This effect coupled with increased abdominal pressure during gestation is responsible for the gastroesophageal reflux symptoms that occur in 70% of pregnant women.⁵

The effects of pregnancy on gastric motility are unclear. Delayed gastric empting has been demonstrated by some authors, especially during delivery,⁶ whereas no effect on gastric emptying has been found by others.⁷ Pregnant women appear to have normal basal and stimulated gastric secretion.⁸ Transit time of intestinal contents is prolonged during gestation; delayed small-bowel transit is most pronounced during the third trimester and is associated with slowing of the migratory motor complex.^9,10 Colonic transit time is prolonged in pregnant animals. Progesterone is thought to have a direct inhibitory effect on smooth muscle cells that slows motility.¹¹ A role for endogenous opioids also has been suggested.¹² Together, these changes often result in mild physiologic constipation.

The absorptive capacity of the small intestine increases during pregnancy to meet the metabolic demands of the fetus; increased absorption of calcium, amino acids, and vitamins has been demonstrated.^13–16 Animal experiments have revealed pregnancy-induced increases in small-intestinal weight and villous height in conjunction with mucosal hypertrophy.^17,18 The activity of some brush border enzymes increases during lactation and then decreases after weaning.^19,20

During pregnancy the maternal immune system must adapt to the presence of the fetus. Adaptive changes can influence the response to infection and modulate the course of underlying autoimmune disease. Although many pregnancy-induced immunologic changes remain obscure, it has been proven that during pregnancy there is a shift from cellular to humoral responses with down-regulation of Th1 and up-regulation of Th2 cytokines. Pregnancy modulates natural killer (NK) cell cytotoxicity and induces T-regulatory cells that affect the maternal immune response.^21,22 Unfortunately, we still do not understand the affects of pregnancy on the mechanisms responsible for autoimmune diseases such as Crohn’s disease and autoimmune hepatitis well enough to allow us to predict clinical events.

Pregnancy causes an alteration in bile composition, including cholesterol supersaturation, decreased chenodeoxycholic acid and increased cholic acid concentrations, and an increase in the size of the bile acid pool.²³ These changes are associated with greater residual gallbladder volumes in the fasting as well as fed states. Sex-steroid hormones may inhibit gallbladder contraction in pregnant women, promoting precipitation of cholesterol crystals and stone formation.^24,25

HEPATIC FUNCTION AND LIVER BIOCHEMICAL TESTS

During pregnancy, maternal blood volume increases progressively until, by the thirtieth week of gestation, it is 50% greater than normal, remaining so until confinement.²⁶ This volume expansion, attributed to the effects of steroid hormones and elevated plasma levels of aldosterone and renin, is responsible for dilution of some blood constituents, such as red blood cells (physiologic anemia). Total serum protein concentration diminishes 20% by mid-pregnancy, largely as a result of a reduced serum albumin level. A reciprocal relationship between falling serum albumin and rising serum alpha-fetoprotein concentrations in pregnant women has been proposed.²⁷

Despite increases in maternal blood volume, the levels of many serum proteins measured to assess hepatic injury are unchanged or even increased during gestation. Progesterone causes a proliferation of smooth endoplasmic reticulum, whereas estrogens promote formation of rough endoplasmic reticulum and associated protein synthesis. Pregnant women synthesize at an accelerated rate the products of the cytochrome P-450 gene superfamily and other proteins, including coagulation factors, binding globulins, and ceruloplasmin. Maternal serum alkaline phosphatase levels normally are elevated during the third trimester of pregnancy, largely due to placental production; for this reason, measurement of alkaline phosphatase in pregnant women is only of clinical use early in gestation. Alterations in maternal concentrations of plasma proteins may persist for several months postpartum.

NAUSEA, VOMITING, AND HYPEREMESIS GRAVIDARUM (see Chapter 14)

Sixty percent to 70% of pregnant women report having some nausea in their first trimester, and more than 40% report vomiting.⁴⁰ Onset of these symptoms typically is in the fourth to sixth week of gestation, with a peak occurrence in the eighth to twelfth week and resolution by week 20. Although nausea and vomiting may vary from mild to severe, most affected individuals still are able to obtain adequate oral nutrition and hydration, in some cases by eating frequent small meals of dry starchy foods.

Severe persistent vomiting demanding medical intervention, or hyperemesis gravidarum, is less common, occurring in 2% or less of all pregnancies.^41,42 Hyperemesis is associated with fluid, electrolyte, and acid-base imbalances; nutritional deficiency; and weight loss, and is defined by the presence of ketonuria and a 5% decrease from prepregnancy weight. Although the prognosis of hyperemesis gravidarum is generally favorable, severe untreated disease may lead to significant maternal and fetal morbidity. Symptoms usually begin at weeks 4 to 5 and improve by weeks 14 to 16 of gestation. In up to 20% of affected patients, however, vomiting persists until delivery.⁴³ Reported risk factors for hyperemesis include a personal or family history of the disorder, a female fetus or multiple gestation, gestational trophoblastic disease, fetal trisomy 21, hydrops fetalis, and maternal Helicobacter pylori infection.⁴⁴

The etiology of hyperemesis gravidarum is likely multifactorial, including contributions by hormonal changes, gastrointestinal dysmotility, H. pylori infection, and psychosocial factors. Pregnancy-related hormones, specifically human chorionic gonadotropin (HCG) and estrogen, have been implicated as important causes of hyperemesis.⁴⁵ Symptoms worsen during periods of peak HCG concentrations, and conditions associated with higher serum HCG levels, for example, multiple gestation, trophoblastic disease, and trisomy 21, are associated with an increased incidence of hyperemesis.⁴⁶ Elevated serum estrogen concentrations, as seen in obese patients, also have been associated with this disorder.⁴⁷ Estrogen and progesterone are thought to cause nausea and vomiting by altering gastric motility and slowing gastrointestinal transit time.⁴⁸ Other hormones implicated in the pathogenesis of hyperemesis include the thyroid hormones and leptin.⁴⁹ Abnormal thyroid function test results are found in two thirds of patients with hyperemesis gravidarum.⁵⁰ The alpha-subunit of HCG has thyroid-stimulating hormone (TSH)–like activity that suppresses TSH release and causes a slight rise in free thyroxine (T₄) levels⁵¹ but, despite these findings, this gestational transient thyrotoxicosis is not associated with unfavorable pregnancy outcomes and usually does not require treatment. The role of H. pylori as an etiology of hyperemesis is controversial. Several studies have found H. pylori infection to be significantly associated with the disorder,^44,52 whereas others could not establish any relationship between the two conditions.⁵³ A small study of the effect of H. pylori eradication in pregnant patients with vomiting showed symptomatic improvement.⁵⁴

Vomiting in patients with hyperemesis gravidarum often is triggered by olfactory, and even auditory and visual stimuli. A pregnancy-unique quantification of nausea and emesis (PUQE score) can be used to evaluate the number of hours of nausea and the number of episodes of emesis and retching per day in affected women, and is helpful in tailoring therapy.⁵⁵ Hospital admission for intravenous fluid and electrolyte replacement and, sometimes, nutritional support is indicated when affected individuals develop hypotension, tachycardia, ketosis, weight loss, or muscle wasting. Abnormal laboratory test results in such patients include hypokalemia, hyponatremia, and ketonuria. Hyperemesis is associated with slight increases in serum aminotransferase and bilirubin levels in 25% to 40% of cases. Hyperamylasemia is seen in a quarter of affected patients due to excessive salivary gland production stimulated by prolonged vomiting.⁵⁶

Severe hyperemesis gravidarum is associated with poor maternal and fetal outcomes. In a study of more than 150,000 singleton pregnancies, infants born to women with hyperemesis who had gained less than 7 kg of weight during pregnancy were more likely to have low birth weights, be premature and small for gestational age, and to have low Apgar scores.⁴¹ Severe, albeit rare, maternal complications of hyperemesis include Mallory-Weiss tears with upper gastrointestinal bleeding, Boerhaave’s syndrome, Wernicke’s encephalopathy with or without Korsakoff’s psychosis, central pontine myelinolysis, retinal hemorrhage, and spontaneous pneumomediastinum.⁵⁷ Lastly, severe depression after elective termination of pregnancy has been reported.⁵⁸

Given the potential for morbidity and mortality in hyperemesis gravidarum, affected individuals should be treated aggressively. Obstetric management should be overseen, if possible, by physicians qualified in maternal-fetal medicine. The goals of therapy are maintenance of adequate maternal fluid intake and nutrition as well as symptom control. Patients should be advised to eat multiple small meals as tolerated and to avoid an empty stomach, which may trigger nausea. Also avoidance of offensive odors, separation of solid and liquid foods, and consumption of a high-carbohydrate diet may be helpful.⁵⁹ Antiemetics and antireflux medications are first-line pharmacologic therapy for outpatients who have failed dietary modifications (see Table 38-2). Phenothiazines (chlorpromazine, prochlorperazine), the dopamine antagonist metoclopramide, and pyridoxine (vitamin B₆) have proven beneficial in this setting.⁶⁰ Extensive data show lack of teratogenesis and good fetal safety for many of these drugs.^61,62 Treatment with ondansetron (pregnancy category B), a 5-hydroxytryptamine-3 (5-HT₃) receptor antagonist, should be considered in patients who do not respond to the above measures. The safety of ondansetron therapy during pregnancy is supported by a recent controlled trial,⁶³ case reports, and widespread clinical experience. Failure of oral medical therapy can be managed in the home setting with intravenous fluid replacement, medications, and multivitamins. As many as 50% of pregnant patients treated through central intravenous catheters, including those inserted peripherally, have catheter-related complications,⁶⁴ most likely as result of the relative hypercoagulable state and increased susceptibility to infections seen in pregnant women. Enteral feeding through a nasoenteric tube or even total parenteral nutrition is sometimes required to maintain maternal nutrition.⁶⁵

GASTROESOPHAGEAL REFLUX DISEASE (see Chapter 43)

At least as many women experience pyrosis as nausea during pregnancy; by the end of the third trimester, 50% to 80% of pregnant patients have had new, or an exacerbation of preexisting, heartburn.^66,67 Pyrosis, however, rarely is accompanied by overt esophagitis or its complications.⁶⁸ Pregnant women with heartburn also may have regurgitation and, as already mentioned, nausea and vomiting, as well as atypical symptoms, such as persistent cough and wheezing. Symptoms usually develop toward the end of the second trimester, persist until delivery, and may be predictive of recurrent gastroesophageal reflux disease (GERD) later in life.⁶⁶ Risk factors for reflux include multiparity, older maternal age, excessive weight gain, and reflux complicating a prior pregnancy.^5,66,69

The pathogenesis of GERD in pregnant women is related to the effects of gestational hormones on esophageal motility, lower esophageal sphincter muscle tone, and gastric emptying. Compression of the stomach and increased intra-abdominal pressure caused by the enlarging uterus also contribute to development of this disorder.

Esophagogastroduodenoscopy (EGD) is rarely required for the assessment of pregnant women with symptoms of GERD.⁷⁰ There are no data assessing the use of 24-hour ambulatory pH monitoring in this setting, and use of a barium esophagram is undesirable because it entails fetal x-ray exposure. Thus evaluation of suspected GERD in a pregnant woman depends on the clinical experience and judgment of the physician and requires due consideration of the patient’s history and all potential, reasonable causes for the patient’s present symptoms.

Mild reflux symptoms often can be controlled by modifications of diet and lifestyle. Liquid antacids and sucralfate (FDA category B) often are prescribed as first-line pharmacologic therapy.⁷¹ Alginic acid (FDA category B) also is effective.⁷² Magnesium-containing antacids should be avoided during the late third trimester because they theoretically may impair labor. Ranitidine (FDA category B) remains the treatment of choice for patients who have persistent heartburn despite liquid antacid therapy.⁷³ Proton pump inhibitors should be reserved for the most refractory cases, given their more recent introduction to the market. A recent meta-analysis found no significant risk of fetal malformations in babies exposed to proton pump inhibitors in utero.⁷⁴ Omeprazole is a pregnancy class C drug because it has caused fetal toxicity in animals; all other available proton pump inhibitors are pregnancy category B drugs. The promotility agent, metoclopramide, has not been used extensively to treat GERD during gestation, although it is used during obstetric anesthesia.

GASTRIC AND DUODENAL ULCER DISEASE (see Chapters 52 and 53)

Case studies and retrospective series suggest that the incidence of peptic ulcer disease (PUD) is lower in pregnant women than in nonpregnant individuals.^75,76 This impression, if it is valid, may be related to decreased use of nonsteroidal anti-inflammatory drugs (NSAIDs) by cautious patients or possibly to increased use of antacid medications to treat nausea or heartburn. It is conceivable, but equally unproven, that gestational steroids promote gastrointestinal mucosal cytoprotection. PUD is likely underdiagnosed during pregnancy, given the reluctance of physicians to perform diagnostic tests on pregnant women. Gastric acid secretion and the natural history of H. pylori infection, as far as we know, are not altered by gestation.

The dyspeptic symptoms that often accompany pregnancy, especially nausea, vomiting, and heartburn, may make diagnosis of PUD in this setting difficult. Because PUD is exceedingly common in the population as a whole, physicians who care for pregnant women should be vigilant for its occurrence in their patients. A trial of empirical acid suppression may be useful in women with suspected PUD, both as a diagnostic and a therapeutic maneuver, and is thought to be safe.^77–80 First-line therapies include ranitidine and sucralfate. In confusing cases, diagnostic EGD is indicated (see earlier). Patients with H. pylori infection may be given antibiotics during pregnancy or after delivery.

INFLAMMATORY BOWEL DISEASE (see Chapters 111 and 112)

Physicians who treat patients with inflammatory bowel disease (IBD) are likely to encounter the disorder in pregnant women. The majority of cases of IBD first present in women younger than age 30 years, the years of peak fertility.^81,82 Ulcerative colitis and Crohn’s disease may be more common in women than in men; some authors report women to have an approximately 30% greater risk than men of developing IBD.⁸²

There is controversy regarding the effects of IBD on fertility. Pregnancy rates in IBD patients may be spuriously low because of self-image problems that result in sexual avoidance and voluntary childlessness.⁸³ Fear of IBD in offspring and fear of fetal malformation secondary to maternal therapy are often cited as major causes of childlessness by affected women.⁸⁴ Female fertility itself, however, does not appear to be impaired by uncomplicated IBD.^85,86 A notable exception is fertility in ulcerative colitis patients treated with total colectomy and ileoanal J-pouch anastomosis.^87,88 A recent meta-analysis found a three-fold increase in the risk of infertility in IBD patients who had undergone this procedure.⁸⁸ Infertility in these individuals most likely is caused by pelvic adhesions and fallopian tube scarring. Potential infertility should be discussed with patients of childbearing age who are considering this operation. Male fertility is impaired by sulfasalazine treatment, which causes decreased sperm counts that usually return to normal within six months of discontinuing the drug.⁸⁹

An initial presentation of IBD during pregnancy is unusual; when IBD first develops in a pregnant woman, it most often does so during the first trimester.^90,91 Cases of this type are no more severe than those in nonpregnant individuals. Likewise, pregnancy does not appear to increase the severity of, or morbidity due to, preexisting IBD; disease activity prior to conception seems to be the most important factor determining the cause of the illness during gestation.⁹² Some authors have suggested that pregnancy might even have a beneficial effect on the disease.⁹³ Disease activity does appear to determine the effect of IBD on pregnancy outcome, although pregnancy is not contraindicated in patients with even the most severe disease.

The goals of the treating physician are thus to minimize IBD symptoms and morbidity prior to conception. Most experts agree that during gestation affected patients should continue optimized prepregnancy therapy to avoid possible flares resulting from medication withdrawal. Exacerbations of IBD that do occur during pregnancy should be managed aggressively because they may result in fulminant colitis and have serious consequences, including hemorrhage, perforation, sepsis, fetal demise, and premature labor. Treatment of fulminant colitis is the same as in nonpregnant individuals, namely high-dose glucocorticoids, intravenous antibiotics, cyclosporine, and salvage biological therapies (see Table 38-2). The indications for bowel surgery likewise are the same as in nonpregnant patients, although bowel surgery is associated with premature labor as well as maternal and fetal mortality.^94,95 A Turnbull-Blowhole colostomy to achieve colonic decompression and fecal diversion may be safer than total colectomy.⁹⁶ Synchronous cesarean section and subtotal colectomy have been advocated for patients with fulminant colitis after 28 weeks of gestation.⁹⁷ IBD patients are at risk for poor pregnancy outcomes, even if they have mild or inactive disease.⁹⁸ Major complications include premature birth, low-birth-weight and small-for-gestational-age infants, and increased cesarean section rates.⁹⁹ The risk of fetal malformations in this setting is unclear.¹⁰⁰

The majority of IBD patients require several medications to remain symptom-free. Limited reliable safety data are available on most commonly used IBD drugs, thus it is important to carefully review the possible risks and known benefits of therapy with patients before conception. Potentially teratogenic drugs should be discontinued before conception, if at all possible. Methotrexate and thalidomide (pregnancy category X) are known teratogens and abortifacients, and should be used with caution in patients of childbearing age. The optimum period of abstinence from these medications before conception is unknown; a minimum of six months is recommended. The 5-aminosalicylates (all pregnancy category B except osalazine, which is pregnancy category C) are widely used during pregnancy to treat mild IBD. A prospective study of pregnant patients treated with mesalamine, as well as a large case series, did not show any increased risk of teratogenicity from this therapy.^101,102 Azathioprine and its metabolite, 6-mercaptopurine (pregnancy category D), also are commonly used as maintenance treatments in patients with mild to moderate IBD. They both cross the placenta and are excreted in breast milk; however, data concerning use of these agents in the transplant setting have failed to confirm the teratogenicity that had been seen in animal studies.¹⁰³ A study of pregnant IBD patients treated with 6-mercaptopurine failed to demonstrate an increase in preterm delivery, spontaneous abortion, congenital abnormalities, or childhood neoplasia.¹⁰⁴ Based on these data and extensive experience with this drug and its metabolites in pregnant women, experts concur that their discontinuation before or during pregnancy is not advisable. Instead, dose reduction and careful monitoring of metabolite levels in the mother are recommended.¹⁰⁵

Glucocorticoids (pregnancy category C) have been used for decades to treat pregnant patients with moderate to severe IBD as well as other more common glucocorticoid-responsive diseases, such as asthma. Early reports suggested an increased risk of congenital malformations in the infants of treated mothers.¹⁰² Subsequent prospective studies and substantial experience with drugs in this class confirm that the risk of malformations secondary to their use is extremely low. Glucocorticoid treatment during pregnancy is, however, associated with other complications including maternal glucose intolerance, macrosomia, and fetal adrenal suppression.¹⁰⁶ Prednisolone (pregnancy category C) is more efficiently metabolized by the placenta than other glucocorticoids and may pose less risk of adrenal suppression.¹⁰⁷ Adverse outcomes have not been reported after use of oral budesonide (pregnancy category C) during pregnancy.¹⁰⁸

Many organ transplant recipients have been treated with cyclosporine (pregnancy category C) without reports of significant teratogenicity. At present, there are very few data concerning the safety of treatment with other immunomodulatory agents in pregnant women. These compounds are immunoglobulins and as such are capable of reaching the fetal compartment, especially during the third trimester, when they are actively transported across the placenta. High levels of infliximab (pregnancy category B) were detected in infants exposed to the drug in utero.¹⁰⁹ Post-marketing registries of safety data and small case series have not identified an increased incidence of fetal malformations or miscarriage in women treated during pregnancy with infliximab or adalimumab.¹¹⁰ Experts have suggested that therapy with antibodies against tumor necrosis factor-α (TNF-α) be discontinued early in the third trimester to avoid significant fetal exposure until better data on the safety of these agents are available; when necessary glucocorticoids may be substituted.⁸⁷

APPENDICITIS (see Chapter 116)

Suspected acute appendicitis is the most common nonobstetric indication for exploratory laparotomy in pregnant women.^111,112 Appendicitis complicates approximately 1 in 1500 pregnancies, and may develop at any time during the course of gestation.¹¹² Diagnosis may be difficult because the enlarging uterus displaces the cecum cephalad, altering the location of pain caused by appendiceal inflammation, and resulting in increasingly delayed detection as pregnancy progresses.¹¹³ Late diagnosis of an inflamed appendix is responsible for complications that are associated with excess maternal and fetal morbidity and mortality.¹¹⁴ During all three trimesters of pregnancy, right lower quadrant pain is the most common presenting symptom of appendicitis.¹¹⁵ In addition to pain, affected individuals frequently complain of nausea, but this symptom often is difficult to interpret during gestation. Graded-compression ultrasonography is the diagnostic test of choice for pregnant patients suspected of having appendicitis.¹¹⁵ Helical CT also has been reported to be helpful in this setting.¹¹² Pregnant patients with appendicitis during any trimester may be treated with laparoscopic appendectomy,¹¹⁶ although potential interference by the gravid uterus may be a relative contraindication to this procedure during the third trimester.¹¹⁷ Appropriate supportive care can prevent fetal loss associated with appendiceal perforation.¹¹⁸

GALLSTONE DISEASE (see Chapter 65)

Pregnant women tend to form gallstones because of changes in gallbladder function and bile composition (see earlier). Gallstones frequently are noted during gestation when ultrasonographic examination is performed to evaluate the fetus¹¹⁹; the prevalence of gallstones in asymptomatic pregnant women is reported to be between 2.5% and 12%. Despite this high prevalence, the incidence of acute cholecystitis is not increased by pregnancy. Cholecystitis is probably more common in the postpartum period than during gestation.¹²⁰ Other complications of cholelithiasis, including choledocholithiasis and pancreatitis (discussed later), also are rare in pregnant women.

Initial conservative management of suspected gallstone-related disease with intravenous fluids, analgesia, and antibiotics has been recommended to reduce maternal and fetal morbidity incident to surgery.¹²¹ A more aggressive operative approach, however, may be associated with superior outcomes. Open cholecystectomy in the first trimester of pregnancy can precipitate abortion, whereas in the third trimester it can induce premature labor. Many experts believe that laparoscopic cholecystectomy is the preferred approach when surgery is indicated in cases of acute cholecystitis, even near term when the uterus is very large.^122–125 Endoscopic extraction of bile duct stones with minimal use of fluoroscopy and appropriate maternal shielding is acceptable when necessary to treat choledocholithiasis in pregnant women.¹²⁵

PANCREATITIS (see Chapter 58)

Acute pancreatitis is uncommon during gestation, occurring once in every 1066 to 3300 pregnancies.^126,127 Most cases are due to gallstones and present during the third trimester or the puerperium. The hypertriglyceridemia normally seen in pregnant women may be more severe in persons with familial hyperlipidemia, predisposing them to develop pancreatitis on this basis.¹²⁸ The clinical characteristics of acute pancreatitis during gestation are similar to those in nonpregnant women.

CHOLESTASIS OF PREGNANCY

Cholestasis of pregnancy is a form of intrahepatic cholestasis associated with pruritus, elevated serum bile acid levels, and the findings of bland cholestasis on liver biopsy.¹²⁹ This disorder may have a variable course, making it difficult to diagnose.¹³⁰ It nevertheless has serious implications for fetal well-being, and cases must be identified as promptly as possible.¹³¹

Cholestasis of pregnancy usually presents in the third trimester, but may be seen earlier in gestation, even in the first trimester. Its first and most characteristic symptom is pruritus, and as a result patients may be referred to a dermatologist for initial evaluation. As in other forms of cholestasis, the pruritus of cholestasis of pregnancy is most severe in the skin of the palms and soles and experienced most intensely at night. Only 10% to 25% of affected individuals later develop jaundice. Elevated serum bile acid levels (>10 µmol/L) confirm the presence of cholestasis; some patients with the disorder also have bilirubinuria and even mild hyperbilirubinemia.¹³² Serum alkaline phosphatase concentrations are modestly increased, but gamma glutamyl transpeptidase (GGTP) levels are normal or only marginally elevated.¹³² The latter pattern of test results is atypical of adult cholestasis, but is seen in pediatric patients with progressive familial intrahepatic cholestasis, as in Byler’s syndrome.¹³³ Serum aminotransferase levels are elevated in affected women, sometimes to values of 1000 U/L or higher, making it difficult, on occasion, to distinguish cholestasis of pregnancy from hepatitis.¹³⁴ Symptoms and laboratory test abnormalities of patients may wax and wane. Intense cholestasis is associated with steatorrhea that usually is subclinical but can cause fat-soluble vitamin deficiencies, most notably deficiency of vitamin K.

Improvement of symptoms and laboratory test results begins with delivery of the infant, and usually, although not invariably, is prompt and complete. Rare patients experience prolonged cholestasis that may be indicative of underlying biliary tract disease, such as primary biliary cirrhosis or sclerosing cholangitis.^135,136 Women with ordinary cholestasis of pregnancy have no residual hepatic defect after resolution of the disorder, but they are at increased risk for development of gallstones, cholecystitis, and pancreatitis.¹³⁷ In addition, 60% to 70% of affected individuals develop cholestasis during subsequent pregnancies (although recurrent episodes may be less severe than the initial one) or with use of oral contraceptives. The risk of recurrence with subsequent pregnancy is increased by interval cholecystectomy.¹³⁸

Cholestasis of pregnancy has serious implications for fetal well-being. There are many reports of increased frequencies of fetal distress, unexplained stillbirth, and need for premature delivery in the babies of women with this disorder.¹³⁹ Fetal hypoxia and meconium staining have been reported at delivery in 19% of Swedish women with cholestasis of pregnancy.¹⁴⁰ These complications were shown to correlate with maternal bile acid levels greater than 40 µmol/L. Although the risk to the fetus may be reduced by close monitoring of affected mothers, it cannot be eliminated completely.^141–144 Planned early elective delivery as soon as the fetal lungs have matured has been recommended for this reason.

As discussed in Chapter 64, a number of the molecular mechanisms of bile formation have been elucidated in recent years, resulting in a more sophisticated understanding of many cholestatic disorders.¹⁴⁵ Mutations of the MDR3 (ABCB4) gene are likely responsible for approximately 15% of cases of cholestasis of pregnancy.^146–148 The MDR3 gene product is a phospholipid flippase that translocates phosphatidylcholine from the inner to the outer leaflet of the canalicular hepatocyte membrane where it is solubilized by bile acids to form mixed micelles. There is, however, no relationship of cholestasis of pregnancy to human leukocyte antigen (HLA) type.¹⁴⁹

Environmental and hormonal factors likely also contribute to development of cholestasis in pregnant women. In Chile and Scandinavia, where cholestasis of pregnancy is common, the disorder occurs most often during colder months. The incidence of cholestasis of pregnancy in Chile has declined, possibly due to a fall in mean plasma selenium levels.¹⁵⁰ An increased sensitivity to the cholestatic effects of exogenous estrogen has been demonstrated in family members, including male relatives, of patients who develop cholestasis while pregnant.¹⁵¹ Therapeutic or experimental administration of estrogen compounds to susceptible women can precipitate the disorder.^152,153 Similarly, progesterone therapy during gestation is associated with development of cholestasis.¹⁵⁴ The finding that ursodeoxycholic acid alters the metabolism of progesterone may explain its therapeutic effect in this setting.¹⁵⁵ It is possible that some women with cholestasis of pregnancy have inherited an enhanced sensitivity to estrogen or a variation in the metabolism of progesterone that causes cholestasis in response to a variety of stimuli, including some medications and dietary factors.

The differential diagnosis of cholestasis of pregnancy includes other cholestatic disorders such as primary biliary cirrhosis, primary sclerosing cholangitis, benign recurrent intrahepatic cholestasis, viral hepatitis, toxic liver injury, and bile duct obstruction. Liver biopsy specimens of affected individuals reveal bland changes typical of cholestasis due to a variety of etiologies, but biopsy usually is not necessary to make the diagnosis. It is important to remember that pregnancy may exacerbate a preexisting subclinical cholestatic disorder. For example, a family of sisters with progressive liver disease who also developed recurrent severe cholestasis of pregnancy was described in 1997.¹³⁵

Management of cholestasis of pregnancy is primarily palliative. Ursodeoxycholic acid is helpful in relieving symptoms, may reduce fetal complication rates,¹⁴⁶ and is well tolerated by mother and fetus.^131,156,157 Studies of treated individuals have demonstrated a change in the bile acid content of maternal serum and amniotic fluid, as well as increased placental bile acid transport.^158–160 Most investigators have prescribed a conventional dose (15 mg/kg/day), although one report suggests that a higher dose (20 to 25 mg/kg/day) is more effective.¹⁵³ Treatment with bile-acid binders such as cholestyramine¹⁵⁷ and guar gum also may relieve symptoms,¹⁶¹ but it is important to keep in mind that therapy with these agents worsens steatorrhea and resultant fat-soluble vitamin deficiencies.¹⁶² Administration of S-adenosyl-l-methionine (SAMe) to patients with cholestasis of pregnancy has had mixed therapeutic results^{131,163–165}; use in combination with ursodeoxycholic acid may increase its benefit.¹⁶⁶ A short course of oral dexamethasone (12 mg/day for 7 days) has been reported to reduce itching and serum bile acid levels in persons with this disorder¹⁶⁷ but also was associated with clinical deterioration in one case.¹⁶⁸ Sedatives, such as phenobarbital, may relieve itching in cholestasis patients, but may adversely affect the fetus. Exposure to ultraviolet B light has been suggested as therapy in this setting. As in other cholestatic syndromes, no treatment is always and completely effective in women with cholestasis of pregnancy, with the usual exception of delivery.

LIVER DISEASE OF PREECLAMPSIA

Preeclampsia is a disease of unclear etiology that remains difficult to define and, on occasion, to diagnose.¹⁶⁹ In broad terms, preeclampsia is a form of pregnancy-related hypertension that is associated with damage and dysfunction of one or more maternal organs, possibly including the liver, that may produce severe, even life-threatening, complications and affect pregnancy outcome. Preeclampsia complicates 3% to 10% of pregnancies, occurring in the second half of pregnancy or the puerperium and most commonly, but not exclusively, in primiparous women or women with multiple gestations.¹⁷⁰ Usual criteria for making the diagnosis include a sustained blood pressure of 140/90 mm Hg or greater after the twentieth week of pregnancy in a previously normotensive woman, accompanied by proteinuria (≥300 mg/24 hr), which is approximately equivalent to a urine protein concentration of 30 mg/dL (“1+ dipstick”) on random testing.¹⁶⁹ Many patients also are hyperreflexic and have edema.

Liver disease is recognized as a common and potentially ominous complication of preeclampsia. The HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count), first described by Weinstein in 1982,¹⁷¹ is the most usual form of preeclamptic liver disease and is presumed to underlie development of hepatic hematoma, rupture, and infarction in some women with this disorder.^172–174 Recent evidence, however, suggests that there are different preeclampsia phenotypes and that HELLP syndrome may be a distinct genetic and clinical entity.¹⁷⁵ Although preeclampsia is common in patients with acute fatty liver of pregnancy (AFLP) and may play a role in the pathogenesis of this disorder, AFLP usually is not classified as a preeclamptic liver disease.¹⁷⁶

HEMOLYSIS, ELEVATED LIVER ENZYMES, AND LOW PLATELET COUNT (HELLP) SYNDROME

HELLP syndrome is seen in up to 12% of women with severe preeclampsia.^177–179 In addition to the diagnostic abnormalities of hemolysis, elevated serum aminotransferase levels, and thrombocytopenia in conjunction with hypertension and proteinuria, patients with typical HELLP syndrome frequently have complaints of chest, epigastric, and right upper quadrant abdominal pain (Table 38-4). These symptoms often are accompanied by nausea, vomiting, headache, and blurred vision in varying combinations. Some pregnant patients, however, may present with an asymptomatic fall in the platelet count during observation for preeclampsia, or initially have no hypertension or proteinuria.¹⁸⁰ Other women may complain of malaise, suggesting the diagnosis of a viral syndrome.¹⁸¹ Most affected individuals seek treatment after the twenty-seventh week of gestation, but up to 11% may do so earlier. It is important to note that presentation of HELLP syndrome after delivery, despite absence of signs of preeclampsia at delivery, occurs in up to 30% of cases.^177,182

Table 38-4 Clinical Characteristics of Hemolysis, Elevated Liver Enzymes, and Low Platelet Count (HELLP) Syndrome

From Sibai BH, Ramadan MK, Usta I, et al. Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. Am J Obstet Gynecol 1993; 169:100-6.

The diagnosis of HELLP syndrome is based on an assessment of the clinical circumstances and features of the illness at the time of presentation; there is no single diagnostic test that confirms the presence of the disorder.^179,183 Hemolysis in patients with HELLP is mild. Fragmented red-blood cells (schistocytes) are seen on smears, and the serum lactate dehydrogenase (LDH) level is elevated. Serum aminotransferase levels also are elevated, sometimes minimally and other times greater than 1000 U/L in association with laboratory signs of cholestasis.^177,184 Serum bilirubin levels often are elevated, but in most patients to low levels compatible with the finding of hemolysis. Elevated serum levels of glutathione S-transferase alpha,¹⁸⁵ d-dimer,¹⁸⁶ tissue polypeptide antigen (TPA),¹⁸⁷ and fibronectin¹⁸⁸ have been described in persons with HELLP syndrome, and these tests may have some use in predicting the presence or severity of liver disease.

Cross-sectional abdominal imaging, especially CT and MRI, may be useful in making the diagnosis of HELLP syndrome and detecting cases of intrahepatic hemorrhage and infarction. Imaging should be performed in patients with complaints of severe abdominal pain, neck or shoulder pain, or a sudden drop in blood pressure. One report documented abnormal findings in 45% of such patients.¹⁷²

Liver biopsy specimens demonstrate periportal hemorrhage, intrasinusoidal fibrin deposition and irregular areas of liver cell necrosis with mild reactive hepatitis, findings characteristic of preeclampsia (Fig. 38-1). If steatosis is present, it is modest and does not have the appearance of the extensive pericentral microvesicular fat accumulation that occurs in patients with AFLP (discussed later). There is little if any correlation between the severity of liver biopsy lesions and laboratory test abnormalities in patients with HELLP syndrome; mild thrombocytopenia and mild increases in serum aminotransferase levels do not connote insignificant liver damage.¹⁸⁹ Liver biopsy, however, rarely is necessary to make a diagnosis in these patients, and possibly may precipitate development of intraparenchymal hepatic hematoma or contained hepatic rupture.

Figure 38-1. Histology of hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome. The portal triad on the left of the figure (the horizontal arrow points to an interlobular bile duct in the portal triad) is surrounded by pockets of hemorrhage (vertical arrows) and by an area of fibrin deposition (to the left of the portal triad).

Although most pregnant women with low platelet counts and preeclampsia have HELLP syndrome, the differential diagnosis includes other causes of thrombocytopenia, including immune thrombocytopenic purpura, thrombotic thrombocytopenic purpura,¹⁹⁰ and the antiphospholipid antibody syndrome.¹⁹¹ Elevated serum aminotransferase levels in patients with preeclampsia are most frequently misdiagnosed as being caused by viral hepatitis.¹⁹² A diagnosis of AFLP also should be considered in patients with clinical findings of HELLP syndrome, but AFLP usually is associated with signs of more significant liver disease and possibly liver failure, albeit with lower serum aminotransferase levels, and is not necessarily associated with thrombocytopenia.

Any hypothesis concerning the pathophysiology of preeclampsia must explain the known characteristics of the disorder, in particular the inappropriately high systemic vascular resistance and low plasma volume seen in affected individuals. Preeclampsia follows, and presumably is a consequence of, an abnormality of placental formation in which a failure of both trophoblast invasion of the uterine lining and dilation of the spiral arteries result in the physiologic inability to increase uteroplacental perfusion appropriately as gestation progresses.¹⁹³ Female relatives, including the mothers of patients with preeclampsia, often have a history of the disorder, and evidence exists in some populations for its inheritance as either an autosomal recessive trait or an autosomal dominant trait with variable penetrance.^175,194,195 Women with a circulating procoagulant, for example factor V Leiden or anticardiolipin antibody, are at risk for developing early and severe preeclampsia.^196,197 There is convincing evidence that development of this disorder is mediated by excessive production of soluble fms-like tyrosine kinase 1 (sFlt1), a potent antagonist of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), and of soluble endoglin (sEng), an inhibitor of capillary formation.^198,199 Pregnant rats that overexpress both sEng and sFlt1 develop proteinuria, severe hypertension, laboratory findings of HELLP syndrome, and intrauterine growth restriction.²⁰⁰ Women with preeclampsia similarly produce excessive amounts of sFlt1 and sEng.¹⁹⁹ The events responsible for abnormal production of these factors in this setting have yet to be elucidated.

Preeclampsia frequently is diagnosed in patients with AFLP. Although the latter disorder is not formally classified as a hepatic complication of preeclampsia, these two disease entities may share a common pathogenesis. Women with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, a cause of defective intramitochondrial beta oxidation of fatty acids, have been reported to develop preeclampsia and HELLP syndrome while pregnant with an affected fetus.^201,202 Abnormal mitochondrial fatty-acid metabolism also may play a role in the pathogenesis of AFLP (see following). Other studies, however, have not demonstrated LCHAD deficiency in women with HELLP syndrome.²⁰³ Additional hypotheses advanced to explain the pathogenesis of preeclampsia include lipid peroxidation and oxidative stress in response to an unknown primary insult, endothelial dysfunction,^188,204 abnormal fluidity of the endothelial cell membrane, abnormal cell permeability to calcium, or inheritance of a molecular variant of angiotensin known to be associated with hypertension.²⁰⁵ Interestingly there is no animal model for the human syndrome of preeclampsia. Furthermore, the histologic characteristics of this condition are unique and are not similar to those of any other known liver disease in humans or animals.

The clinical abnormalities that characterize HELLP syndrome usually resolve rapidly after childbirth.²⁰⁶ Transient postpartum diabetes insipidus has been reported in women with the disorder.²⁰⁷ Rarely, HELLP syndrome becomes gradually worse prior to delivery with subsequent development of postpartum liver failure, sepsis, consumptive coagulopathy, and, rarely, even death.²⁰⁸ In the absence of appropriate supportive therapy and expedited delivery, affected patients may progress to renal failure, hepatic hematoma, and hepatic rupture. Neither serum aminotransferase levels nor platelet counts are predictive of outcome in women with HELLP syndrome.²⁰⁹ The disorder can recur during subsequent pregnancies but usually does not.^210,211

Management of HELLP syndrome is primarily supportive; patients should be treated in an intensive care setting prior to delivery, preferably by an obstetrician qualified in the practice of maternal-fetal medicine. Some affected patients may have a decline in serum aminotransferase levels and a rise in platelet counts with supportive care.²¹² Under such circumstances, a delay in delivery may be appropriate in cases of fetal immaturity, but the fetus usually fails to grow in the setting of preeclampsia. Patients with severe preeclampsia and HELLP syndrome may require antepartum platelet transfusions and hemodialysis. Plasmapheresis after delivery has been advocated by some authorities but has not been proven to alter disease outcome.^182,213 Glucocorticoid therapy also has been used in this setting. Many affected women receive glucocorticoids before delivery, not as disease treatment, but to promote fetal lung maturity²¹⁴; glucocorticoid therapy of HELLP syndrome per se has not been evaluated in a controlled clinical trial.^215–217 Orthotopic liver transplantation may be appropriate treatment for some HELLP-syndrome patients,^218,219 but early diagnosis and prompt delivery almost always make this and other extreme therapeutic measures unnecessary in these individuals. Full recovery without sequelae is anticipated for the vast majority of affected patients.

HEPATIC RUPTURE, HEMATOMA, AND INFARCT

Spontaneous rupture of the liver may complicate preeclampsia and HELLP syndrome, usually in the third trimester of pregnancy close to term or in the early postpartum period. Patients with this often fatal disorder present with abdominal distention and pain, and cardiovascular collapse.^220,221 In contrast to other patients with preeclampsia, women with spontaneous hepatic rupture tend to be older and to have had multiple previous pregnancies. Diagnosis is made by signs of liver rupture on ultrasonography, CT, or MRI in conjunction with aspiration of blood on paracentesis.^172,222 Imaging studies often show that affected patients have a partially contained subcapsular hematoma (Fig. 38-2).²²³ Management must be aggressive, with rapid delivery of the fetus by the obstetrician and repair of the liver, preferably by an experienced liver surgeon. Postoperatively, patients have a protracted course that may include disseminated intravascular coagulation and hepatic failure. A few patients with hepatic rupture have undergone orthotopic liver transplantation after emergent hepatectomy and interval portosystemic shunt as a temporizing measure while a donor graft is sought.^219,224,225 Rarely, a hemodynamically stable patient with a ruptured liver can be successfully treated without surgery.²²⁶ Survivors of hepatic rupture may have uneventful subsequent pregnancies,²²⁷ but recurrence of hematoma and rupture also have been reported.²²⁸

Figure 38-2. Subcapsular hepatic hematoma in a patient with preeclampsia. This coronal section of a T1-weighted magnetic resonance imaging scan demonstrates the subcapsular clot or hemorrhage (horizontal arrows) adjacent to the liver (vertical arrow).

(From Barton JR, Sibai BM. Hepatic imaging in HELLP syndrome [hemolysis, elevated liver enzymes, and low platelet count]. Am J Obstet Gynecol 1996; 174:1820.)

Some pregnant women with preeclampsia, HELLP syndrome, and abdominal pain have contained subcapsular hematoma. In this circumstance, patients can be observed with serial CT imaging and managed without surgery.^172,228 Experts have recommended angiographic embolization of hepatic artery branches supplying blood to the affected portion of the liver in such cases.

Hepatic hematoma and rupture complicating preeclampsia presumably result from extravasation of blood from one or several microscopic areas of periportal hemorrhage under Glisson’s capsule. Periportal hemorrhage is a typical pathologic finding in the livers of patients with preeclampsia and HELLP syndrome.²²⁹ The capsule is believed to be stretched and torn away from the surface of the liver by the enlarging hematoma. Ultimately, the capsule ruptures, allowing the liver surface to bleed freely into the peritoneal cavity.

Necrotic hepatic infarcts also may complicate preeclampsia. Affected individuals present with fever, leukocytosis, anemia, and marked elevation of serum aminotransferase levels,^172,174,226 and in the most severe cases develop multiorgan failure, including liver failure. Cross-sectional imaging demonstrates confluent hepatic infarcts. Needle aspiration of these areas yields blood and necrotic tissue; immediately adjacent liver parenchyma contains periportal hemorrhage and fibrin deposition typical of preeclampsia and HELLP syndrome. Hepatic infarction sometimes is associated with the presence of a hypercoagulable condition such as factor V Leiden or antiphospholipid antibody.²³⁰

ACUTE FATTY LIVER OF PREGNANCY

AFLP is a form of microvesicular fatty liver disease unique to human gestation that presents late in pregnancy, often as fulminant hepatic failure with sudden onset of coagulopathy and encephalopathy in a woman without a prior history of liver disease.^231,232 AFLP is diagnosed on the basis of typical clinical and pathologic manifestations in approximately 1 of 6700 third-trimester pregnancies,²³³ but it also is recognized that subclinical cases exist.²³⁴ The pathophysiologic mechanisms underlying development of this disorder are unknown, although at least some patients with AFLP have an inherited LCHAD deficiency that also affects the fetus.^235,236

AFLP presents late in pregnancy; in the majority of cases, symptoms develop between 34 and 37 weeks of gestation, although cases beginning as early as 19 to 20 weeks of gestation have been reported. Rarely, the onset of AFLP is after delivery. Initial symptoms usually include nausea and vomiting, often associated with abdominal pain. Pruritus may be an early complaint; overlap with cholestasis of pregnancy has occurred but is rare.²³⁷ Patients with AFLP frequently are confused, and have pregnancy-related complications, such as premature labor, vaginal bleeding, and decreased fetal movement. The disorder is most common in primiparous women and in women with multiple gestations.²³⁸ Affected individuals have a much greater than expected number of male fetuses (2.7 : 1).²³⁹ Of note is the fact that preeclampsia, an accompanying diagnosis in 21% to 64% of cases,^233,240 also is associated with first pregnancies, twin pregnancies, and male fetuses.

On laboratory evaluation, women with AFLP often have prolonged prothrombin times and decreased serum fibrinogen levels as well as leukocytosis. Their serum aminotransferase levels usually are moderately elevated (≈750 U/L), but rarely may be very high or even normal. Jaundice is common but not invariable. Initial blood tests often reflect renal dysfunction with elevations of the serum creatinine, uric acid, and blood urea nitrogen levels.

The course of AFLP is quite variable. Hypoglycemia and hyperammonemia occur and should be suspected when at-risk patients exhibit signs of altered central nervous system function. Other complications of liver failure, including ascites, pleural effusion, acute pancreatitis, respiratory failure, renal failure, and infection may develop in patients with AFLP; vaginal bleeding or post–cesarean section bleeding is common in these individuals. Transient diabetes insipidus sometimes is seen²⁴¹; more rarely, affected patients have myocardial infarction²⁴² or pulmonary fat emboli.²⁴³

Diagnosis of AFLP almost always is based on the appearance of typical clinical features of the disorder, including laboratory test results, during the later stages of pregnancy. Hepatic imaging is not reliable in confirming the presence of AFLP,²⁴⁴ but plays a crucial role in identifying hepatic hematoma, rupture and infarction.

Liver biopsy usually is unnecessary to make the diagnosis, but histologic results may be pathognomonic and therefore useful if the obstetrician has reservations about delivery. However, transjugular sampling of liver tissue may be necessitated by coagulopathy. The histologic hallmark of AFLP is microvesicular fatty infiltration of the liver that is most prominent in hepatocytes surrounding central veins (zone three) and spares those surrounding portal areas (Fig. 38-3). Microvesicular steatosis of this type has a relatively homogeneous appearance on light microscopy and may be difficult to discern on examination of ordinary hematoxylin and eosin–stained specimens. To confirm the diagnosis, special techniques must be used; frozen tissue may be stained for fat with oil-red O, or electron microscopy can be used to examine a glutaraldehyde-fixed specimen. Plans must be made prior to the biopsy for appropriate handling of the liver tissue. Other histologic findings in affected patients can be misleading; they may include lobular disarray suggestive of viral hepatitis and biliary ductular proliferation and inflammation suggestive of cholangitis.^234,245 Patients with AFLP do not have the periportal hemorrhage and fibrin deposition seen in the livers of individuals with preeclampsia and HELLP syndrome.

Figure 38-3. Histology of acute fatty liver of pregnancy. The perivenular hepatocytes are pleomorphic and vacuolated, and there is lobular disarray. Large fat droplets are not seen.

The differential diagnosis in suspected cases of AFLP includes those causes of acute hepatic failure not associated with pregnancy, especially viral hepatitis and toxic liver injury. Uncommon types of viral hepatitis, such as hepatitis E and herpes simplex hepatitis, may be more severe in pregnant than in nonpregnant individuals.^246,247 These viral agents can be identified by appropriate serologic tests. A more difficult problem is distinguishing AFLP from other liver diseases that complicate pregnancy, particularly the preeclamptic liver diseases, namely HELLP syndrome and hemorrhagic or ischemic liver injury. For example, patients with AFLP may develop preeclampsia and disseminated intravascular coagulation with attendant thrombocytopenia, thereby meeting the diagnostic criteria for HELLP syndrome. Fortunately it is not usually necessary to distinguish among these various diagnoses because AFLP, HELLP syndrome, and preeclampsia are treated by expedited delivery of the infant. It is, however, of crucial importance to recognize hepatic hematoma and rupture rapidly.

The pathogenesis of AFLP, like that of preeclampsia, has not been elucidated. Initially AFLP was thought to be caused by exposure to a toxin; microvesicular steatosis of the liver is known, for example, to be caused by treatment with sodium valproate or intravenous tetracycline. Despite an intensive search, however, no toxin that might be responsible for development of AFLP has been identified. Because of the coincidental occurrence of preeclampsia and AFLP in many patients, the disorder has been considered by some experts to be a severe form of preeclamptic liver disease.^234,248,249 Arguing against this conclusion are the absence of the usual histologic features of preeclampsia in liver biopsy specimens from patients with AFLP and the absence of the usual clinical features of preeclampsia in many patients with AFLP.

There is a well-established association between AFLP and inherited defects in beta oxidation of fatty acids.^202,236,250 This connection is empirically supported by similar clinical and histologic findings in patients with AFLP and those with Jamaican vomiting sickness, a liver disease caused by a toxin in unripe akee fruit that disables intramitochondrial beta oxidation of fatty acids. Maternal liver disease (HELLP or AFLP) has been reported in 62% of the mothers of infants with defects of fatty-acid oxidation.²³⁶ AFLP may develop regardless of maternal genotype if the fetus is deficient in LCHAD and carries at least one allele for the G1528C LCHAD mutation.²³⁵ Another beta oxidation defect, carnitine palmitoyltransferase I deficiency, also has been associated with AFLP.²⁵¹ Prenatal genetic diagnosis based on chorionic villus sampling has proved to be feasible and accurate in pregnant members of affected families.^252,253 Not every investigator, however, has been able to confirm the association between AFLP and beta oxidation defects,²⁵⁴ and other as yet unknown mechanisms may play a role in the pathogenesis of this disorder.

Patients with AFLP should be managed in an intensive care setting, preferably by obstetricians qualified in the practice of maternal-fetal medicine in cooperation with other appropriate specialists. Early diagnosis and prompt delivery of the infant are imperative to minimize maternal and fetal morbidity and mortality. Affected individuals may be very ill post-partum until the physiologic defects responsible for their clinical abnormalities resolve and the livers recover. Supportive care may include infusion of blood products, mechanical ventilation, hemodialysis, and antibiotic therapy. Hepatic encephalopathy is treated as indicated by measures intended to evacuate feces and bacteria from the colon. Infusion of concentrated glucose solution may be required to treat or prevent hypoglycemia. Although many patients with AFLP have disseminated intravascular coagulation and depressed antithrombin III levels, treatment with heparin or antithrombin III is not recommended.²⁵⁵ Patients with diabetes insipidus may be managed with 1-deamino-8-d-arginine-vasopressin (DDAVP).²⁴¹ Some individuals with liver failure secondary to AFLP require emergency orthotopic liver transplantation as a potentially life-saving measure.^256,257 Most affected women, however, recover completely with appropriate supportive care. Persistent or even increasing hyperbilirubinemia and multiple complications after delivery do not necessarily indicate the need for liver transplantation.

Survival of patients with AFLP has been reported to be 100% with prompt diagnosis, delivery of the infant, and intensive care.^233,240,258 Infants of affected women have perinatal mortality rates of less than 7%; the surviving baby may have LCHAD deficiency and develop nonketotic hypoglycemia and obtundation. Recurrence of AFLP has been documented, particularly in women with LCHAD deficiency.^259,260 In cases of AFLP the mother, father, and child should be tested for the G1528C LCHAD mutation.²³⁵

VIRAL HEPATITIS

Viral hepatitis is the most common form of liver disease worldwide, and frequently affects women of childbearing age, either as an acute infection or as a chronic disease. Hepatitis A does not appear to alter the normal course of pregnancy, nor does pregnancy appear to influence the natural history of hepatitis A. Acute and chronic viral hepatitis of other types, however, may have implications for maternal well-being as well as the outcome of gestation.

CHRONIC LIVER DISEASE AND PORTAL HYPERTENSION (see Chapter 90)

Women with chronic liver disease and resultant cirrhosis often have anovulatory menstrual cycles or are amenorrheic and therefore unlikely to become pregnant. Portal hypertension, ascites, and compensatory dilation of submucosal esophageal veins connecting the portal circulation and the azygos vein can occur in pregnant women with noncirrhotic portal hypertension aggravated by increased circulating blood volume. Even in the absence of pathologic causes of portal hypertension, these esophageal venous collaterals may become engorged during gestation due to normal circulatory changes, including increased blood flow and compression of the inferior vena cava by the enlarging uterus, and may be seen on endoscopy. Enlarged veins of the latter type do not bleed spontaneously.

The effect of pregnancy on the risk of variceal bleeding in women with underlying portal hypertension is unknown. Furthermore, the most appropriate method for treating esophageal varices during pregnancy is controversial. β-Adrenergic receptor antagonists are tocolytic, but these drugs do not prevent normal labor in chronically treated pregnant patients. Use of beta blockers as primary prophylaxis against variceal bleeding in pregnant women has not been formally evaluated. Vasopressin and octreotide infusions to treat acute variceal hemorrhage may cause uterine ischemia and induce premature labor. Some authors have suggested prophylactic band ligation, portosystemic shunt procedures, and cesarean section to decrease the risk of bleeding from varices during gestation.

Ascites and hepatic encephalopathy are no more common in pregnant than in nonpregnant women with chronic liver disease, and when they occur are managed in the customary manner.

WILSON DISEASE (see Chapter 75)

Wilson disease in women of childbearing age is associated with amenorrhea and infertility. Treatment of affected individuals to remove excess copper may result in resumption of ovulatory cycles and a subsequent pregnancy. Pregnant patients must remain on medication to treat Wilson disease because discontinuation of therapy can cause sudden copper release, hemolysis, acute liver failure, and death.²⁸⁰ D-penicillamine is potentially teratogenic in humans,²⁸¹ but has been used safely during pregnancy at doses necessary for copper chelation.²⁸² Similarly, trientine is teratogenic in animals but appears to be safe in humans as treatment for copper overload. Zinc is not teratogenic, and some experts favor its use during pregnancy as therapy for Wilson disease for this reason.²⁸³

AUTOIMMUNE LIVER DISEASES (see Chapters 88 and 89)

Autoimmune diseases of all types, including autoimmune hepatitis, are more common in women than in men. In women, classic (type 1) autoimmune hepatitis typically presents around the expected time of menarche but is associated with amenorrhea. Immunosuppressive therapy is highly effective in controlling the disease in most patients; treated women who subsequently conceive a child should continue taking immunosuppressive medications during pregnancy. The doses of azathioprine prescribed as part of standard treatment regimens are not thought to be teratogenic. Occasionally autoimmune liver disease will worsen during the postpartum period when the physiologic immunosuppression of pregnancy resolves. For this reason, affected patients should have frequent measurements of serum aminotransferase levels for approximately six months after delivery.

Primary biliary cirrhosis is much more common in postmenopausal women than it is in their fertile counterparts. Pregnant women with primary biliary cirrhosis may experience an exacerbation of pruritus²⁸⁴ that can be ameliorated by treatment with ursodeoxycholic acid,²⁸⁵ although the safety of this therapy during pregnancy has not been formally proven.

HEPATIC NEOPLASIA AND MASS LESIONS (see Chapter 94)

Mass-like defects of the hepatic parenchyma may be discovered during pregnancy, usually as an incidental finding on ultrasonography. Benign liver lesions found commonly in women of childbearing age include adenomas, focal nodular hyperplasia, and hemangiomas. Hepatic adenomas are associated with oral contraceptive use and may enlarge during pregnancy; growing lesions can bleed and rupture into the abdominal cavity. Focal nodular hyperplasia and hemangiomas in pregnant patients also have been reported to hemorrhage. Women known to have a benign hepatic nodular defect should be evaluated with serial ultrasonography to measure mass size and look for evidence of intralesional bleeding.

Hepatocellular carcinoma occurs almost exclusively in persons with chronic liver disease and may present in the absence of cirrhosis in young people with chronic hepatitis B virus infection. At-risk patients should have standard screening for liver cancer during pregnancy. It must be borne in mind that maternal serum alpha-fetoprotein levels always are modestly elevated during normal pregnancy,²⁸⁶ and can further increase in cases of fetal Down syndrome, neural tube defects, and hydatidiform mole, thus limiting the positive predictive value for diagnosing hepatocellular carcinoma.

Hepatic fibrolamellar carcinoma has been reported to occur in pregnant women.²⁸⁷ Fibrolamellar carcinoma is a slow-growing cancer usually found in young adults; the median age of affected persons is 25 years.²⁸⁸ Unlike typical primary liver cancer, this neoplasm has no known association with cirrhosis or chronic liver disease and is not a cause of increased serum alpha-fetoprotein levels.

Although hepatic metastases are approximately 30 times more common than primary liver cancer, most malignant tumors are rare in women of childbearing age.

HEPATIC VEIN THROMBOSIS (BUDD-CHIARI SYNDROME) (see Chapter 83)

Pregnancy is a predisposing factor for the development of venous thrombosis. Hepatic vein thrombosis may occur in association with HELLP syndrome²⁸⁹ and with preeclampsia in women who have antiphospholipid antibody.²⁹⁰ Pregnant women who develop hepatic vein thrombosis should be evaluated for the presence of antiphospholipid antibody and other circulating procoagulants, for example factor V Leiden.²⁹¹

PREGNANCY AFTER LIVER TRANSPLANTATION

After successful orthotopic liver transplantation, women of childbearing age may become pregnant and deliver normal infants.^103,292 Delaying pregnancy until the second post-transplant year may be associated with a lower risk of prematurity. Transplant patients should continue immunosuppressive therapy during gestation; treatment regimens used to prevent graft rejection have not been associated with teratogenicity. Adverse effects of these medications, however, including hypertension and hyperglycemia, may increase the incidence of fetal distress and preeclampsia in liver transplant recipients who are pregnant. In rare instances, pregnancy has been complicated by organ rejection.