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Gastrointestinal and Hepatic Disorders in the Pregnant Patient
Gastrointestinal and Hepatic Function in Normal Pregnancy
The GI tract undergoes dramatic modifications during pregnancy. Intra-abdominal organs must move to accommodate uterine growth, hormonal factors alter motility, and the immunologic adaptation to pregnancy affects response to disease. Heartburn, nausea, abdominal cramps, and altered bowel habits, the most common GI symptoms of pregnant women, are caused by normal physiologic changes in gut motility. These symptoms are usually transitory and easily treated with conservative measures. It may be a challenge, however, to distinguish between symptoms of altered motility and those that signal the onset or worsening of problems that require immediate medical attention.
Esophageal Function
The amplitude and duration of esophageal muscle contractions in pregnant and nonpregnant women are similar. 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. In contrast, resting lower esophageal sphincter tone progressively declines during gestation, most likely a consequence of inhibition of smooth muscle contraction by progesterone. This effect coupled with increased abdominal pressure during gestation is responsible for the gastroesophageal reflux symptoms that occur in 70% of pregnant women.
GI Function
The effects of pregnancy on gastric motility are unclear. Delayed gastric emptying has been demonstrated by some authors, especially during delivery, whereas no effect on gastric emptying has been found by others. Pregnant women have normal gastric secretion. Intestinal transit time is prolonged during gestation. Delayed small-bowel transit is most pronounced during the third trimester and is associated with slowing of the migrating motor complex. Colonic transit time is prolonged in pregnant animals. Progesterone is thought to have a direct inhibitory effect on gut smooth muscle cells that slows motility. A role for endogenous opioids has also been suggested. 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. Animal experiments have revealed pregnancy-induced increases in small intestinal weight and villous height in conjunction with mucosal hypertrophy. The activity of some brush border enzymes increases during lactation and then decreases after weaning.
Immune Function and the Intestinal Microbiota
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. There is a shift from cellular to humoral responses, with downregulation of Th1 and upregulation of Th2 cytokines. Pregnancy modulates natural killer cell cytotoxicity and induces T-regulatory cells that affect the maternal immune response. Unfortunately, we still do not understand the effects of pregnancy on the mechanisms responsible for autoimmune diseases such as autoimmune hepatitis and Crohn disease well enough to allow us to predict clinical outcomes during pregnancy. The maternal intestinal flora changes during pregnancy, potentially altering the host-microbial interaction in a beneficial fashion. Bacteria from the mother colonize the neonate’s gut, establishing the microbiota with potential long-lasting health consequences. Although the establishment of the human GI microbiota previously was thought to begin at birth, the finding of bacterial products in meconium, placenta, and amniotic fluid suggests that seeding occurs in utero.
Gallbladder Function
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. 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.
Hepatic Function
During pregnancy, maternal blood volume increases progressively until week 30 of gestation when it is 50% greater than normal and remains so until confinement. 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); thus, total serum protein concentrations diminish 20% by mid-pregnancy, largely as a result of a reduced serum albumin level. Maternal proteins passively diffuse across the placenta to the fetal circulation. Similarly, fetal AFP moves across the placenta from the fetal to the maternal circulation, raising maternal serum levels. Active transport may be involved in the transplacental movement of some macromolecules.
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 the products of the cytochrome P-450 gene superfamily and other proteins at an accelerated rate, including coagulation factors, binding globulins, and ceruloplasmin. Maternal serum alkaline phosphatase levels are normally 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. Mild leukocytosis and increased erythrocyte sedimentation rates are also common in normal pregnancy.
Drug Safety in Pregnant Patients
Patients and physicians tend to avoid treatment with medications during pregnancy because they fear harming the fetus. Withholding medical intervention, however, 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 drug therapy should be discussed with the patient and known and unknown risks of treatments must be carefully evaluated. For this reason, the FDA in 2014 required a change in the content and format of prescription-drug labels required by the Physician Labeling Rule. Letter categories (A, B, C, D, X) are no longer used. Instead, the FDA now requires labels to contain a narrative explanation of risk and supporting data.
Endoscopy During Pregnancy
It is estimated that 20,000 pregnant women undergo endoscopy each year. 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. Pregnant women have safely undergone EGD, colonoscopy, sigmoidoscopy, ERCP, and percutaneous gastroscopy. Although a recent large Swedish cohort study found endoscopy during pregnancy to be associated with an increased risk of preterm birth or small-for-gestational-age neonates, the authors concluded that the risks were small and likely due to intrafamilial factors or disease activity and not because of endoscopy alone. 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.
Several precautions should be observed to avoid complications when performing endoscopy in a pregnant patient. Given the extreme sensitivity of the fetus to maternal hypoxia, pregnant women should receive supplemental O 2 with continuous saturation monitoring. When the fetus is capable of surviving outside the uterus, usually around 24 weeks of gestation, maternal monitoring for contractions 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, and every effort should be made to avoid fetal radiation (see later). Opioid (narcotic) analgesics cross the placenta, and benefits during endoscopy must be weighed against risks for the mother (see Chapter 42 ) and the fetus. Sedation with benzodiazepines should be avoided, especially during the first trimester, because diazepam has been reported to cause fetal malformations. Extensive experience with propofol is lacking, and its high lipid solubility is a reason for concern. Lactating patients are advised to avoid breastfeeding and to discard breast milk for 4 hours after a procedure requiring sedation.
Imaging and Radiation Exposure During Pregnancy
The National Commission on Radiation Protection recommends limiting exposure to ionizing radiation during pregnancy to less than 5cGy. Well-referenced guidelines for imaging of pregnant women with ionizing radiation have been published by the American College of Radiology Guidelines and Standards Committee and by the American College of Obstetricians and Gynecologists Committee on Obstetric Practice. The potential for radiation damage to the fetus is determined by dose and gestational age at the time of exposure ( Table 40.1 ).
TABLE 40.1
Fetal Effects of Radiation During Gestation ∗
| Gestational Age (Days) | Effects of Radiation |
|---|---|
| 0-9 | Death |
| 13-50 | Teratogenesis |
| Growth restriction | |
| 51-280 | Growth restriction |
| CNS abnormalities | |
| Possible cancer risk |
CT should be performed only when its potential benefits clearly outweigh its risks and should be done, if possible, after completion of organogenesis. Helical CT may be associated with less fetal radiation exposure than conventional CT. MRI is often 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. There is a theoretical risk of thermal injury to the fetus from MRI in early pregnancy and thus MRI is not recommended during the first 12 weeks of gestation. Contrast agents may cross the placenta, and their safety in pregnant women has not been formally assessed. Neonatal hypothyroidism has been associated with use of some iodinated agents. Paramagnetic contrast agents used during MRI (e.g., gadolinium) have not been studied in pregnant women. Less than 0.04% of a dose of gadolinium-labeled contrast is excreted in breast milk during the first 24 hours after administration and a negligible amount of this is absorbed from the infant GI tract. Therefore, breastfeeding should not be interrupted after imaging with gadolinium. US is widely used and safe during pregnancy.
GI Disorders and Pregnancy
Nausea, Vomiting, and Hyperemesis Gravidarum (See Chapter 15 )
In their first trimester, 60% to 70% of pregnant women report having some nausea, and more than 40% report vomiting. Onset of these symptoms is typically in the 4th to 6th week of gestation, with a peak occurrence in the 8th to 12th week and resolution by week 20. Although nausea and vomiting may vary from mild to severe, most affected individuals are still able to obtain adequate oral nutrition and hydration, in some cases by eating frequent small meals of dry starchy foods. Hp infection in pregnant women may contribute to the development of vomiting.
Severe persistent vomiting demanding medical intervention, or hyperemesis gravidarum , is less common, occurring in 2% or less of pregnancies. Hyperemesis is accompanied by fluid, electrolyte, and acid-base imbalances, nutritional deficiency, and weight loss and is defined by the presence of ketonuria and a 5% decrease from pre-pregnancy weight. It may be associated with pyrosis, hematemesis, and hypersalivation (ptyalism). 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. Hyperemesis frequently recurs in subsequent pregnancies. 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 Hp infection.
The etiology of hyperemesis gravidarum is likely multifactorial, including contributions by hormonal changes, GI dysmotility, Hp infection, and psychosocial factors. A genetic predisposition is suggested by familial clusters of the disease. Pregnancy-related hormones, specifically HCG and estrogen, have been implicated as important causes of hyperemesis. Symptoms worsen during periods of peak HCG concentrations, and conditions associated with higher serum HCG levels, such as multiple gestation, trophoblastic disease, and trisomy 21, are associated with an increased incidence of hyperemesis. Elevated serum estrogen concentrations, as seen in obese patients, have also been associated with this disorder. Estrogen and progesterone are thought to cause nausea and vomiting by altering gastric motility and slowing GI transit time. Other hormones implicated in the pathogenesis of hyperemesis include thyroid hormones and gut-derived hormones, ghrelin, and leptin. Abnormal thyroid function test results are found in two thirds of patients with hyperemesis gravidarum. The alpha subunit of HCG has thyroid-stimulating hormone-like activity that suppresses endogenous thyroid-stimulating hormone release and causes a slight rise in free thyroxine (T 4 ) levels. Despite these findings, this transient gestational thyrotoxicosis is not associated with unfavorable pregnancy outcomes and does not usually require treatment. An increased risk of hyperemesis has been found in 2 meta-analyses of Hp infection during pregnancy. , Some authors have documented symptomatic improvement in pregnant patients with vomiting after Hp eradication.
Vomiting in patients with hyperemesis gravidarum is often 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. Hospital admission for IV 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, seen in a quarter of affected patients, is caused by excessive salivary gland production stimulated by prolonged vomiting.
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. These findings were confirmed by a recent meta-analysis. Severe, albeit rare, maternal complications of hyperemesis include Mallory-Weiss tears with upper GI bleeding, Boerhaave syndrome, Wernicke encephalopathy with or without Korsakoff psychosis, central pontine myelinolysis, retinal hemorrhage, and spontaneous pneumomediastinum. Patients with hyperemesis may have depression and post-traumatic stress disorder during pregnancy and postpartum. Lastly, severe depression after elective termination of pregnancy has been reported.
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 ingestion of solid and liquid foods, and consumption of a high-carbohydrate diet may be helpful. Antiemetic and antireflux medications are first-line pharmacologic therapy for outpatients who have failed dietary modifications. Ginger, phenothiazines (chlorpromazine, prochlorperazine), the dopamine antagonist metoclopramide, and pyridoxine (vitamin B 6 ) have proved beneficial in this setting. Extensive data show lack of teratogenesis and good fetal safety for many of these drugs. Treatment with ondansetron, a 5-hydroxytryptamine-3 (5-HT 3 ) 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, case reports, and widespread clinical experience. Glucocorticoids may benefit individuals with severe symptoms. Failure of oral medical therapy can be managed in the home setting with IV fluid replacement, medications, and multivitamins. It should be noted, however, that as many as 50% of pregnant patients treated through central venous catheters, including those peripherally inserted, have catheter-related complications, most likely as a result of the relative hypercoagulable state and increased susceptibility to infections seen in pregnant women. Enteral feeding through a nasoenteric tube or surgically placed feeding tube is sometimes required to maintain maternal nutrition.
GERD (See Chapter 46 )
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. Pyrosis, however, is rarely accompanied by overt esophagitis or its complications. Pregnant women with heartburn may also have regurgitation and, as already mentioned, nausea and vomiting, as well as atypical reflux symptoms, such as persistent cough and wheezing. Symptoms may develop at any time during pregnancy, with a peak incidence in the third trimester, may persist until delivery, and may be predictive of recurrent GERD later in life. Risk factors for reflux include multiparity, older maternal age, and reflux complicating a prior pregnancy. The contributions of pre-pregnancy BMI and excessive weight gain are controversial.
The pathogenesis of GERD in pregnant women is related to the effects of gestational hormones on esophageal motility, lower esophageal sphincter 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.
EGD is rarely required for the assessment of pregnant women with symptoms of GERD. There are no data assessing the use of 24-hour ambulatory pH monitoring in this setting, and use of a barium esophagogram is undesirable because it entails fetal radiation 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 can often be controlled by modifications of diet and lifestyle. Liquid antacids and sucralfate are prescribed as first-line pharmacologic therapy. Magnesium-containing antacids should be avoided during the late third trimester because they theoretically may impair labor. Ranitidine remains the treatment of choice for patients who have persistent heartburn despite liquid antacid therapy. PPIs should be reserved for refractory cases. A large population study and 2 meta-analyses have found no significant risk of fetal malformations in babies exposed to PPIs during the first trimester of pregnancy. Omeprazole, however, has caused fetal toxicity in animals. An association between use of PPIs or H2RAs by pregnant women and development of childhood asthma in their offspring has been noted in a survey of Danish medical registries, but the significance of this observation is unclear. The pro-motility agent metoclopramide has not been used extensively to treat GERD during gestation, although it is used during obstetric anesthesia and to treat hyperemesis gravidarum.
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