CHAPTER 38 Gastrointestinal and Hepatic Disorders in the Pregnant Patient
GASTROINTESTINAL AND HEPATIC FUNCTION IN NORMAL PREGANCY
GASTROINTESTINAL FUNCTION
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
DRUG SAFETY IN PREGNANT PATIENTS
Patients and physicians tend to withhold pharmacologic treatment with medications during pregnancy because they fear harming the fetus. Nevertheless, avoidance of medical interventions may adversely affect the mother’s health and the pregnancy outcome. Having stated this, no medication or other therapeutic intervention can be considered definitely safe during pregnancy. Indeed, the placenta is not a reliable barrier to the passage of most drugs, the distribution of a drug within the fetal compartment cannot be accurately predicted, and data on long-term effects of in utero fetal drug exposure are practically impossible to collect. The necessity of any proposed therapy should be discussed with the patient, and known and unknown risks of treatments must be carefully evaluated. The U.S. Food and Drug Administration (FDA) categorizes drugs based on their potential fetal toxicity during pregnancy (Tables 38-1 and 38-2). The FDA classification, however, is of limited practical value because it is based on very few data. A recent publication of the American College of Physicians28 makes recommendations concerning drug therapy in pregnant women.
Table 38-1 Food and Drug Administration Categories of Fetal Risk from Medicines*
| CATEGORY | CRITERIA |
|---|---|
| A | Adequate well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities. |
| B | Animal studies have revealed no evidence of harm to the fetus; however, there are no adequate and well-controlled studies in pregnant women. |
| Or | |
| Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus. | |
| C | Animal studies have shown an adverse effect and there are no adequate and well-controlled studies in pregnant women. |
| Or | |
| No animal studies have been conducted and there are no adequate and well-controlled studies in pregnant women. | |
| D | Adequate well-controlled or observational studies in pregnant women have demonstrated a risk to the fetus. The benefits of therapy, however, may outweigh its potential risk. |
| X | Adequate well-controlled or observational studies in animals or pregnant women have demonstrated evidence of fetal abnormalities. The use of the product is contraindicated in women who are or may become pregnant. |
* U.S. Food and Drug Administration. FDA Consumer Magazine. May-Jun 2001; 35:3.
Table 38-2 Food and Drug Administration Categories of Fetal Risk for Some Medications Used to Treat Gastrointestinal and Hepatic Diseases
| MEDICATION | INDICATION | FDA CATEGORY |
|---|---|---|
| Adalimumab | IBD | B |
| Adefovir | Hepatitis B | C |
| Amoxicillin | Infection | B |
| Azathioprine | IBD; autoimmune hepatitis | D |
| Balsalazide | IBD | C |
| Benzodiazepines | Sedation | D |
| Bismuth | Helicobacter pylori infection | C |
| Budesonide | IBD | B |
| Certolizumab pegol | IBD | B |
| Cimetidine | GERD; PUD | B |
| Clarithromycin | Infection | C |
| Cyclosporine | Transplantation | C |
| Entecavir | Hepatitis B | C |
| Esomeprazole | GERD; PUD | B |
| Famotidine | GERD; PUD | B |
| Fentanyl | Sedation, analgesia | C |
| Infliximab | IBD | B |
| Interferon alpha | Hepatitis B, C | C |
| Lamivudine | Hepatitis B | C |
| Lansoprazole | GERD; PUD | B |
| Meperidine | Sedation, analgesia | B |
| Mesalamine | IBD | B |
| Methotrexate | IBD | X |
| Metoclopramide | Nausea; GERD | B |
| Metronidazole | Infection | B* |
| Nizatidine | GERD; PUD | B |
| Olsalazine | IBD | C |
| Omeprazole | GERD; PUD | C |
| Ondansetron | Nausea, vomiting | B |
| Pantoprazole | GERD; PUD | B |
| Penicillin | Infection | B |
| Prednisone | IBD; autoimmune hepatitis | B |
| Prednisolone | IBD; autoimmune hepatitis | C |
| Propofol | Sedation | B |
| Rabeprazole | GERD; PUD | B |
| Ranitidine | GERD; PUD | B |
| Ribavirin | Hepatitis C | X |
| Sucralfate | PUD | B |
| Sulfasalazine | IBD | B |
| Telbivudine | Hepatitis B | B |
| Tenofovir | Hepatitis B | B |
| Tetracycline | Antibiotic | D |
| Thalidomide | Sedative; myeloma | X |
B, no evidence of risk in humans; C, possible risk; D, evidence of fetal risk; X, definite fetal risk; GERD, gastroesophageal reflux disease; IBD, inflammatory bowel disease; PUD, peptic ulcer disease.
ENDOSCOPY DURING PREGNANCY
It is estimated that 20,000 pregnant women undergo endoscopy each year.29 Recommendations concerning endoscopy in this setting are largely based on expert opinion and case reports. Although the safety of endoscopy during pregnancy has not been completely established, it is performed routinely if there is a clear indication.30 Pregnant women have undergone upper gastrointestinal tract endoscopy, colonoscopy, sigmoidoscopy, endoscopic retrograde colangiopancreatograpy (ERCP), and percutaneous gastroscopy safely.31 In addition to general contraindications to endoscopic procedures, specific contraindications during pregnancy include imminent or threatened delivery, ruptured membranes, placental abruption, and pregnancy-induced hypertension.32
Several precautions should be observed to avoid complications when endoscoping a pregnant patient.32 Given the extreme sensitivity of the fetus to maternal hypoxia, pregnant women should receive supplemental oxygen with continuous blood-saturation monitoring. When the fetus is capable of surviving outside the uterus, usually around 24 weeks of gestation, external fetal heart monitoring before, during, and after invasive procedures is advisable to enable prompt delivery if fetal distress occurs. In the second and third trimesters, the supine position and external abdominal pressure should be avoided because resulting compression of the vena cava and aorta may cause hypotension and placental hypoperfusion. ERCP should be performed only with therapeutic intent and by expert endoscopists; every effort should be made to avoid fetal radiation.31 Sedation with meperidine (pregnancy category B), which crosses the blood-brain barrier more slowly than fentanyl (pregnancy category C) and morphine (pregnancy category C), is preferred, although fentanyl may be superior during lactation because it is poorly excreted in breast milk. Sedation with benzodiazepines (pregnancy category D) should be avoided, especially during the first trimester, because diazepam has been reported to cause fetal malformations.33,34 Extensive experience with propofol (pregnancy category B) is lacking, and its high lipid solubility is a reason for concern.35 Patients are advised to avoid breast-feeding and to discard breast milk for 24 hours after a procedure requiring sedation.32
IMAGING AND RADIATION EXPOSURE DURING PREGNANCY
The National Commission on Radiation Protection recommends limiting exposure to ionizing radiation during pregnancy to less than 5 cGy.36,37 The potential for radiation damage to the fetus is determined by dose and gestational age at the time of exposure (Table 38-3).
| GESTATIONAL AGE (DAYS) | EFFECTS OF RADIATION |
|---|---|
| 0-9 | Death |
| 13-50 | Teratogenesis |
| Growth restriction | |
| 51-280 | Growth restriction |
| CNS abnormalities | |
| Possible cancer risk |
CNS, central nervous system.
Computed tomography (CT) should be performed only when its potential benefits clearly outweigh its risks and should be done, if possible, after completion of organogenesis.38 Helical CT may be associated with less fetal radiation exposure than plain CT. Magnetic resonance imaging (MRI) often is a superior alternative to CT; MRI without contrast has not been associated with adverse pregnancy outcomes and magnetic fields are not considered harmful to living organisms.39 There is a theoretical risk of thermal injury to the fetus from MRI in early pregnancy, and MRI is not recommended during the first 12 weeks of gestation. Gadolinium crosses the placenta and its safety in pregnant women has not been formally assessed. Ultrasonography is widely used and safe during pregnancy.
GASTROINTESTINAL DISORDERS AND PREGNANCY
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
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
BILIARY AND PANCREATIC DISORDERS AND PREGNANCY
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.
HEPATIC DISORDERS UNIQUE TO PREGNANCY
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
