Gastrointestinal Diseases Complicating Pregnancy
Cornelia R. Graves
Washington C. Hill
Michelle Y. Owens
Maria Jacqueline Small
Introduction
Pregnancy can complicate almost any gastrointestinal (GI) disease. The pregnant woman may enter pregnancy with a GI disorder, or it may develop during pregnancy. The physiologic effects of pregnancy may cause GI disturbances such as nausea, vomiting, hyperemesis gravidarum (HG), and esophageal reflux. Conversely, GI disorders, such as ruptured appendix and inflammatory bowel disease (IBD), may affect the course of pregnancy. New findings and diagnostic advances warrant revisiting key features of acute nonobstetric abdominal pain in pregnancy. This chapter discusses the various GI diseases complicating pregnancy and their possible effects on the fetus and mother.
GI Alterations During Normal Pregnancy
There are both mechanical and physiologic alterations in the GI tract with the progression of pregnancy, which can pose significant challenges to the practitioner attempting a differential diagnosis of normal versus pathologic findings.1 From a mechanical standpoint, the expanding uterus displaces the GI organs, particularly the intestines and the stomach. These mechanical changes contribute to common aches, discomforts, and pains of pregnancy such as heartburn and gastric reflux due to displacement of the stomach and abdominal pain due to stretching of the peritoneum. However, it is vital for the practitioner to recognize that these symptoms can also indicate problems. For example, an abdominal mass can easily be missed depending on the gestational age of the fetus and the size of the uterus. In addition, the mechanical alterations of pregnancy can complicate medical interventions—ie, as the uterus expands, it causes the appendix to migrate upward, which would affect the site of a surgical incision should appendicitis be diagnosed in a pregnant patient.
From a physiologic standpoint, a major contributor to the GI changes seen in pregnancy is progesterone. An increase in progesterone levels throughout gestation leads to physiologic changes that result in a delay in gastric and gallbladder emptying; prolonged small bowel transit time; a decrease in gastric acid secretion; lower tone of the esophageal sphincter and in the urinary tract muscles; an increase in cholesterol synthesis and serum alkaline phosphatase concentration; changes in drug metabolism and clearance; and an increased risk for cholelithiasis, hydroureter, and hydronephrosis. All of these can result in symptoms for the pregnant woman, including reflux, dehydration, and constipation, among other sequelae.1,2,3
A newly recognized contributor to the physiologic changes of the GI system seen during pregnancy is the maternal gut microbiome.4,5,6 The microbiome encompasses the microorganisms living in and on the body, which react with the host and are essential for normal immune and metabolic health. Although we are still in the early stages of discovering the importance of the maternal gut microbiome during all aspects of pregnancy and prenatal disease, several studies indicate that host-microbial interactions that impact host metabolism may be beneficial in pregnancy. Edwards et al reviewed the normal hormonal, metabolic, and immunologic changes to the maternal gut microbiome throughout the prenatal period in addition to relevant implications for those providing care for pregnant women.7 Goodrich and colleagues8 characterized fecal bacteria of 91 pregnant women of
varying prepregnancy body mass indexes (BMIs) and gestational diabetes status and that of their infants7 and found that gut microbiota changed dramatically from first-to-third trimesters.
varying prepregnancy body mass indexes (BMIs) and gestational diabetes status and that of their infants7 and found that gut microbiota changed dramatically from first-to-third trimesters.
Differential Diagnosis of Abdominal Pain During Pregnancy
An understanding of the innervation of the GI tract is key to understanding the pathologies triggering pain responses9 (Table 33.1). Cappell et al provide an excellent summary of the neurophysiologic pathways provoking GI pain.10 Three levels of fibers provide affective autonomic feedback to the cerebral cortex. C and A delta fibers are first- and second-order fibers, whereas the third-order fibers travel to the limbic and sensory cortex to affect the perception of noxious stimuli.1 C fibers are unmyelinated slower pathways associated with dull, nonspecific pain; they cross midline to the contralateral spinal location and travel through the spinothalamic and spinoreticular tracts to the pons and medulla. Delta fibers are partially myelinated, faster conducting fibers with afferent neurons that synapse in the spinal cord. These fibers provoke sharp, focused pain identification.
The perception of abdominal pain is characterized by the type of innervation pathways. Visceral pain is produced by slow, C fibers that provide afferent innervation to the spinal cord and result in dull, unfocused pain. Visceral pain may trigger autonomic responses such as nausea or diaphoresis.10 Stretching the wall of abdominal viscera, as occurs with bowel overdistention, can provoke this sensation. Alternatively, faster C and A delta fibers transmit the pain of parietal inflammation and produce a severe, localized pain. This pain may be worsened by movement, or inspiration. Pain from skin tissue is also A delta-mediated and, therefore, more localized and may be perceived as sharp. Referred pain results from visceral and somatic afferent neurons meeting in the spinal cord at the same location and subsequently traveling via the same second-order neural pathways.10 This process may explain how inflammation of organs or from diaphragmatic irritation may radiate or refer to the back.
Emotions and stress may impact pain perception through both central and peripheral mechanisms.10 The neuro-GI axis may provoke or inhibit the perception of abdominal pain. Neural pathways from the cortex, thalamus, and brainstem inhibit painful stimuli through spinal cord pathways. Stress and emotions may trigger abdominal pain in response to cytokines and hormones that lower an individual’s threshold for pain. Functional pain, such as that which is experienced in irritable bowel syndrome (IBS), is associated with a history of traumatic events and psychological stress.10,11
Nonobstetric Causes of Abdominal Pain
Clinical Presentation and Etiology
The causes of nonobstetric abdominal pain in the pregnant patient are identical to those found in the nonpregnant patient; however, clinicians must consider physiologic changes in pregnancy that increase some pathologies during pregnancy as well as the changes in laboratory and physical exam findings.9 The physiologic leukocytosis of pregnancy resulting in a normal white blood cell (WBC) count of 10 to 14,000 cells/mm3 during pregnancy and up to 30,000 cells/mm3 postpartum may cloud the diagnosis of infectious etiologies for abdominal pain. The presence of bands, however, is not a physiologic feature of pregnancy and suggests infectious processes.9
Clinical Assessment
Although diagnostic testing and management should consider the developing fetus, delay should not occur due to concerns for exposure to radiation. Most options available to the nonpregnant patient are also appropriate for the pregnant patient, and delays may increase maternal morbidity and mortality. Radiation exposure from computed tomography (CT) scans and nuclear medicine procedures are typically at doses well under the threshold to cause fetal harm.12 An excess of 1000 mGy or 100 rad (1000 mGy = 1 Gy) is considered an extremely high level of ionizing radiation exposure, which would adversely affect the fetus. In the period of organogenesis, these effects may result in lethality, while high exposures later in gestation may be associated with conditions like growth restriction, microcephaly, and intellectual disability.12 Abdominal plain films are 0.1 to 10 mGy, chest radiographs (two views) are 0.0005 to 0.01 mGy, and CT scans of the abdomen are 1.3 to 35 mGy.8 Adverse fetal outcomes have not been seen at doses below 50 mGy.12
One of the initial steps in the evaluation of nonobstetric abdominal pain is the distinction between
the acute and chronic life-threatening conditions. In the acute setting, particularly after a trauma, point-of-care ultrasound may prove useful to facilitate evaluation for abdominal free fluid suggestive of hemoperitoneum or hematoma.
the acute and chronic life-threatening conditions. In the acute setting, particularly after a trauma, point-of-care ultrasound may prove useful to facilitate evaluation for abdominal free fluid suggestive of hemoperitoneum or hematoma.
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Acute, Life-Threatening Conditions
Bowel Obstruction
Bowel obstruction resulting from volvulus and adhesive disease are the most common causes of obstruction in pregnancy. Hernias and intussusception may also occur. Pregnant patients with prior history of gastric bypass surgery are particularly at risk and should be seen promptly by a surgical service when they present with abdominal pain. These patients are at high risk for hernias, volvulus, gastric rupture, and obstruction.13 These patients may present with cramp-like pain, nausea/vomiting (N/V), and obstipation. The classic finding of peritoneal signs may be obscured due to the enlarged uterus and the relaxation of the maternal abdominal wall. Evaluation, management, and treatment are the same as in the nonpregnant state.
Perforated Peptic Ulcers
Perforated peptic ulcers are less common in pregnancy but may be found more commonly in patients following gastric surgery or those with prolonged risk factors like steroid exposure.9,10 Clinical presentations include N/V and epigastric pain, which is often worse in the evening and postprandial. Acute, diffuse abdominal pain and associated low-grade temperature, tachycardia, and peritoneal signs should raise a high suspicion for perforated peptic ulcer. Plain upright abdominal radiograph is a fast modality for diagnosis; however, 10% to 20% of perforated duodenal ulcers will not demonstrate free air under the diaphragm.9,10
Ruptured Aneurysm
Visceral artery aneurysm rupture is rare in pregnancy. If they occur, the most commonly involved vessel is the splenic artery. The classic appearance/presentation occurs in the setting of third trimester circulatory collapse.14,15 Approximately 25% of patients may initially present with diffuse, abdominal pain that may radiate to the tip of the left shoulder (Kehr sign). Imaging may demonstrate the calcification in the area of aneurysmal dilation.15
Nausea, Vomiting, and Hyperemesis Gravidarum
Clinical Presentation
Nausea with or without vomiting is an especially common symptom during early pregnancy and the most common GI complaint, occurring in approximately 50% to 80% of pregnancies. It usually begins before 9 weeks’ gestation. By mid-second trimester, most women no longer complain of these symptoms, but approximately 1 to 2 per 1000 pregnant patients may experience some symptoms throughout their entire pregnancy.16
In its mildest form, nausea is referred to as morning sickness as most patients experience it in the morning. Symptoms are unpleasant and distressing, both physically and psychologically, but usually do not require any particular therapy. It is unknown why some patients experience no morning sickness and others are bothered by it all the time.
HG is the abnormal condition of pregnancy associated with pernicious nausea and vomiting. No single accepted definition of HG exists. The American College of Obstetricians and Gynecologists (ACOG) suggests that it is a clinical diagnosis of exclusion based on a typical presentation in the absence of other diseases that could explain the clinical findings.17 The most commonly cited criteria include persistent vomiting not related to other causes, a measure of acute starvation (usually large ketonuria), and some discrete measure of weight loss; most often at least 5% of prepregnancy weight is present.17
HG, although it is both infrequent and uncommon, can be very distressing to the patient and her family. These patients experience persistent intractable nausea and vomiting associated with weight loss, fluid and electrolyte imbalance, ketonuria, and ketonemia. Electrolyte imbalance may include decreased sodium, potassium, and chloride, and metabolic alkalosis. The patient usually becomes clinically dehydrated and may even develop jaundice, hyperpyrexia, and peripheral neuritis.
Serious adverse maternal or infant outcomes can occur as a result of persistent nausea and vomiting or hyperemesis, including significant psychosocial morbidity, significant financial burden, and worry about doing harm to the baby. Most patients with HG improve with appropriate medical therapy described above. Serious maternal morbidity or
mortality is rare, but occurs when severe metabolic abnormalities go untreated; esophageal rupture and esophageal tears (Mallory-Weiss syndrome) can occur; acute tubular necrosis, pneumothorax, splenic avulsion, hematemesis, or Wernicke encephalopathy can develop.18,19,75
mortality is rare, but occurs when severe metabolic abnormalities go untreated; esophageal rupture and esophageal tears (Mallory-Weiss syndrome) can occur; acute tubular necrosis, pneumothorax, splenic avulsion, hematemesis, or Wernicke encephalopathy can develop.18,19,75
Wernicke encephalopathy is a rare but serious maternal complication of prolonged nausea and vomiting of pregnancy (NVP); it is rarely reported but can cause significant permanent neurological disability, prolonged maternal morbidity, and even maternal death due to vitamin B1 deficiency. It can be underrecognized and has been reported in patients with HG. Lavin believes it is a predictable complication, due to prolonged intravenous and nutritional deficiency, but can be prevented by the timely administration of parenteral thiamine.20,21 It is a rare but serious maternal complication of prolonged NVP.
An extensive systemic review of Wernicke encephalopathy by Oudman et al22 points out that pregnant women have an increased demand for thiamine, and that in HG thiamine rapidly depletes, which can lead to this disorder. In their study of 146 patients reporting on 177 cases, thiamine supplementation was insufficient or absent from the treatment plan. The authors conclude to prevent Wernicke encephalopathy in pregnancy, it is necessary to give 100 mg of intravenous or intramuscular thiamine in HG patients with persistent or severe late-onset vomiting to prevent them from developing morbidity and mortality from Wernicke encephalopathy.
The association of mild or moderate nausea and vomiting in pregnancy with fetal outcomes has been investigated by several authors. Most studies show no adverse effect on fetal growth.23 Several studies have reported an increase in intrauterine growth restriction with severe nausea and vomiting during pregnancy although severe is not clearly defined.24,25
Clinical Assessment
The differential diagnosis of more serious NVP indicative of HG or other severe conditions should include evaluations of the genitourinary and GI tracts, metabolic conditions, neurological disorders, and pregnancy-related conditions such as preeclampsia. The clinician should remember that headache, fever, abdominal pain, and tenderness are not typically seen with morning sickness.
Although most patients with serious nausea and vomiting and a few patients with HG have transient hyperthyroidism and a low thyroid-stimulating hormone (TSH) or elevated free thyroxine thyroid, evaluation of thyroid function should not be part of the workup of these patients unless they have a history of thyroid disease.26 The TSH is low because of cross reaction between the alpha-subunit of HCG with the TSH receptor not due to true thyrotoxicosis. Whether the hyperthyroidism is a cause of hyperemesis or is present because of the condition is controversial and a difficult differential diagnosis. Antithyroid medications are not necessary to treat the biochemical or transient hyperthyroidism occurring in hyperemetic pregnancies. Goodwin and coworkers, in one of the largest series of subjects with HG concluded that hyperthyroidism in these patients is common, self-limited, and requires no therapy. Values return to normal when the nausea and vomiting or hyperemesis resolves or after delivery.27
The Pregnancy-Unique Quantification of Emesis (PUQE) is a validated scoring system to quantify the severity of NVP. A patient’s evaluation measured by the PUQE has had significant positive predictive value and has been proven beneficial in determining (1) a pregnant woman’s ability to take multivitamins, (2) rates of emergency room visits and hospitalization for NVP, (3) health costs of NVP, and (4) a woman’s self-scores of well-being in NVP. The index is useful in some centers clinically.28,29
Etiology
The exact etiology of nausea and vomiting during pregnancy and HG is unknown. The smooth muscles of the stomach relax during pregnancy due to hormonal changes, and this physiologic adaptation may play some role. Various other theories have been proposed, including a hormonal stimulus, evolutionary adaptation, and psychologic stressors and predisposition. The role of any or all of these has been studied, but a clear correlation between them individually or together in the occurrence and severity of nausea and vomiting during pregnancy has not been demonstrated.30,31,32
Increased placental mass, a history of motion sickness, migraine headaches, family history, HG in a previous pregnancy, advanced molar gestation, and multifetal gestation are some of the risk factors for both nausea and vomiting during pregnancy and HG.17,33 Another theory centers on the role of
Helicobacter pylori in causing or predisposing a patient to the spectrum of disease from nausea and vomiting to HG; however, more research is needed to show a causal relationship between H. pylori and hyperemesis.30,34
Helicobacter pylori in causing or predisposing a patient to the spectrum of disease from nausea and vomiting to HG; however, more research is needed to show a causal relationship between H. pylori and hyperemesis.30,34
A history of nausea or vomiting or HG in a prior pregnancy also appears to influence these conditions in subsequent pregnancies. A prospective study by Gadsby35 found that approximately two-thirds of women who described their vomiting as severe in one pregnancy had similar symptoms in their next pregnancy, and one-half of women who described their symptoms as mild in one pregnancy found that the symptoms worsened in their next.
One etiology, initially described by Allen and colleagues in 2004, is the cannabinoid hyperemesis syndrome or CHS.36,37 The prevalence of this syndrome and other cannabis use disorders (ie, cannabis dependence, cannabis abuse) has continued to rise, especially with the legalization of medical marijuana in the United States. CHS is characterized by chronic cannabis use, cyclic episodes of nausea and vomiting, and the learned behavior of hot bathing. This complication occurs by an unknown mechanism and can also occur during pregnancy. Despite the well-established antiemetic properties of marijuana, there is increasing evidence of its paradoxical effects on the GI tract and central nervous system. Tetrahydrocannabinol, cannabidiol (CBD), and cannabigerol are found in the cannabis plant and have opposing effects on the emesis response. Treatment of CHS is difficult but some success with stopping use of marijuana, which should never be used in any form during pregnancy, frequent hot bathing, and haloperidol.37 Metz and the group from Colorado38 conclude CHS should be considered in pregnant women with intractable nausea relieved by frequent hot bathing. By considering this diagnosis, extensive diagnostic testing can be avoided and the correct therapy, abstaining from cannabis use, can be recommended. More research is needed on the unknowns of this syndrome such as the duration, strength, dose, and route of marijuana to produce it.
Management of Nausea, Vomiting, and HG in Pregnancy
The ACOG has recommended an evidence-based algorithm of therapeutic treatment of NVP emphasizing if no improvement to move on to the next treatment option.17
The initial management of nausea and vomiting, whether nonpharmacologic or pharmacologic, is primarily supportive. Treatment early may prevent progression to the more serious HG, especially if the patient had it in a previous pregnancy.39
There are a number of accepted treatment protocols for nausea and vomiting during pregnancy and HG. The ACOG17 in its treatment algorithm of NVP also recommends thiamine, intravenously, 100 mg with the initial rehydration fluid and 100 mg daily for the next 2 to 3 days (followed by intravenous multivitamins) for women who require further intravenous hydration and have vomited for more than 3 weeks to prevent Wernicke encephalopathy.22
If the patient is not appropriately managed, there may be a failure of the mother and fetus to gain weight. Outpatient, hospital, or home therapy consisting of intravenous fluid hydration with 100 mL/L pyridoxine can be sufficient, along with supportive care. The management of hyperemesis in the home, although rare, can be both safe and efficacious. Furthermore, successful therapy can be achieved at a significantly reduced cost.40
However, when the patient’s condition does not improve, hospitalization with appropriate electrolyte, caloric, and fluid management is necessary, if not mandatory. A patient with HG who has abnormal electrolyte, renal, or liver test results should be promptly hospitalized for fluid and nutrition management. Experts emphasize nutritional support therapy is an important part of the management of nausea and vomiting.17,41 Rehydration with intravenous fluids should be used for the patient who cannot tolerate oral fluids or when dehydration occurs. Correction of ketosis and vitamin deficiency should be strongly considered. Dextrose and vitamins should be included in the therapy when prolonged vomiting is present, and thiamine should be administered before dextrose infusion to prevent Wernicke encephalopathy.
Nasogastric or nasoduodenal enteral tube feeding should be initiated as a first-line treatment to provide nutritional support to the woman with HG who is not responsive to medical therapy and cannot maintain her weight. Total parenteral nutrition (TPN) is used when enteral tube feeding is ineffective or not tolerated. Peripherally inserted central catheters (PICCs) or lines once used frequently for TPN should not be used routinely due to the significant complications of infection and thrombosis. PICCs should be utilized only as a last resort for
nutrition because of the potential of severe maternal morbidity. Other adverse effects of persistent nausea and vomiting on pregnant women include significant psychosocial morbidity, significant financial burden, and worry about doing harm to the baby.
nutrition because of the potential of severe maternal morbidity. Other adverse effects of persistent nausea and vomiting on pregnant women include significant psychosocial morbidity, significant financial burden, and worry about doing harm to the baby.
Nonpharmacologic Treatment
There are numerous nonpharmacologic regimens available to treat NVP. These include reassurance, physical and psychological support, frequent small meals, 250 mg of ginger four times daily, kava tea, eating bland or dry foods, avoidance of foods that are unpleasant or that may trigger symptoms, adequate hydration and fluid intake, acupressure and acustimulation, and cannabis and CBD use. Many of these “treatment modalities” have been studied with conflicting results and some not at all.
Cannabis is also a nonpharmacologic herbal therapy that is used by pregnant women to treat their nausea and vomiting. A 2019 study showed that self-reported prevalence of cannabis use during pregnancy is 1.95% to 3.38%.42 Smoking marijuana has been tried for years by patients because of its known antiemetic effects. However, its increasing use during pregnancy and lactation for nausea and vomiting should be discouraged. Marijuana crosses the placenta and passes into breast milk, resulting in fetal and neonatal exposure. Use during pregnancy may be associated with perinatal growth restriction, long-term neurobehavioral outcomes, stillbirth, spontaneous preterm birth, and neonatal intensive care unit admission. Corsi and colleagues43 studied an association between self-reported prenatal cannabis use and maternal, perinatal, and neonatal outcomes. The study concluded that, although there may be confounding variables, pregnant women who used cannabis had a significantly increased risk of preterm birth (12% vs 6%) compared with nonusers.
CBD is a component and active ingredient of marijuana and medical marijuana. Although CBD has been promoted as an oil, a boost in coffee, an ingredient in food, a workout drink, or an effective antianxiety or antistress therapy, it is an unregulated nonpharmacologic dietary supplement. As of this printing, there are no studies or scientific evidence that indicates that CBD is either safe or effective for nausea, vomiting, hyperemesis, or any other disorder during pregnancy and, indeed, CBD may have an opposing effect on the emesis response.
Pharmacologic Treatment
Pharmacological therapy should be used when supportive and nonpharmacological measures are not effective. There is no ideal antiemetic currently available for the treatment of morning sickness.
A study by Czeizel and colleagues suggested that women who were taking a multivitamin that included vitamin B6 (pyridoxine) at the time of conception were less likely to need medical attention for vomiting.44 It hypothesized that this may be because of an optimization of the patient’s nutritional status or/and because increasing levels of vitamin B6 may reduce vomiting subsequently. Therefore, the standard ACOG recommendation to take prenatal vitamins containing B6 for 1 month before pregnancy, primarily in an effort to decrease neural tube defects, may also reduce the incidence and severity of NVP.17,45
Until 1983, bendectin, a combination of doxylamine succinate (10 mg) and pyridoxine (10 mg), was used to treat morning sickness. Although there was no evidence that bendectin was teratogenic or caused congenital anomalies, it was taken off the market. However, several studies have shown that either pyridoxine or doxylamine when used alone may be effective in treating patients with nausea and vomiting in pregnancy,30 and women did and still can make their own “bendectin” preparations by combining 10 mg of pyridoxine with a half-tablet of 25 mg of doxylamine, which are both available as over-the-counter medications. When morning sickness symptoms require pharmacologic treatment, the ACOG states pyridoxine and doxylamine should be considered first-line therapy.17
Diclectin is a delayed-release tablet of pyridoxine and doxylamine and has been shown to be safe and effective in treating nausea and vomiting in pregnancy, although its use is associated with drowsiness, tiredness, or feeling sleepy. Other antiemetics include trimethobenzamide, metoclopramide, diphenhydramine, and the phenothiazines. However, caution should be exercised when the phenothiazines are used together with a dopamine antagonist because of an increased risk of extrapyramidal effects.
McGee46 reported on the safety and efficacy of the phenothiazine antiemetic medications (promethazine, prochlorperazine, or chlorpromazine) in the treatment and relief of nausea and vomiting during pregnancy. These drugs are both histamine H1 antagonists and weak dopamine antagonists. Their
advantage clinically is that they can be administered orally, intramuscularly, intravenously, or rectally, which can be very helpful when the patient cannot tolerate anything orally. When used they may cause a dry mouth, dystonia, sleepiness, drowsiness, and dizziness. Although there are conflicting data from older studies, recent studies show there is no increased risk from their use for congenital anomalies.
advantage clinically is that they can be administered orally, intramuscularly, intravenously, or rectally, which can be very helpful when the patient cannot tolerate anything orally. When used they may cause a dry mouth, dystonia, sleepiness, drowsiness, and dizziness. Although there are conflicting data from older studies, recent studies show there is no increased risk from their use for congenital anomalies.
Metoclopramide, a dopamine receptor antagonist, is commonly used in the management of the spectrum of nausea and vomiting and HG during pregnancy. Tan, in a double-blind randomized controlled trial of 10 mg of metoclopramide given every 8 hours compared with 25 mg of promethazine given every 8 hours for 24 hours, in women with HG found that both medications had similar efficacy in reducing nausea and vomiting symptoms at 24 hours, but there were less reports of drowsiness, dizziness, and dystonia from the use of metoclopramide use making metoclopramide more desirable in some cases than the phenothiazines.47
The use of metoclopramide during pregnancy increasing the risk of congenital malformations has been of concern. A Danish study of 309 pregnant women taking metoclopramide found no increased risk.48 Matox also concluded that exposure to metoclopramide in the first trimester was not associated with significantly increased risks of any of several adverse outcomes, including major congenital malformations, low birth weight, preterm delivery, or perinatal death.48 However, metoclopramide use is limited because of maternal side effects, including dystonia, restlessness, and somnolence, and also carries a U.S. Food and Drug Administration (FDA) black box warning due to the risks of tardive dyskinesia (repetitive and involuntary movements of the body) resulting from long-term use greater than 12 weeks.
Antihistamines have antiemetic effects through their effect on the vomiting center. Diphenhydramine, dimenhydrinate, and meclizine have been frequently used for years in the treatment of pregnant patients with nausea and vomiting. Magee46 and Etwel49 in their studies and reports regarding the use of antihistamines during pregnancy concluded that the antihistamines are both safe and shown effective with minimal adverse effects. These studies also showed no increased risk of poor perinatal outcome. The usual antihistamine side effects including dry mouth, sedation, and lightheadedness can occur.
Ondansetron is a serotonin 5-hydroxy-tryptamine type 3 receptor antagonist frequently used in the nonpregnant patient in the treatment of nausea and vomiting from chemotherapy and after surgery. Data on its use in pregnancy for the same indications are limited. However, a number of studies have found ondansetron when compared with metoclopramide having less side effects, and better improvement at controlling nausea and vomiting than metoclopramide or vitamin B6 combined with doxylamine.50,51,52
Adverse maternal drug-related side effects (fatigue, constipation, headache, drowsiness) are common with ondansetron, especially when used intravenously in bolus doses. There is a risk of maternal cardiac arrhythmias when this drug is used in patients who have underlying cardiac disease. The ACOG points out that, among the other listed adverse effects, prolongation of the QT interval, especially in patients with underlying heart problems, hypokalemia, or hypomagnesemia, is associated with ondansetron use.53 The FDA recommends that ondansetron not be given intravenously in multiple doses or doses greater than 16 mg to pregnant women. Electrolyte and electrocardiogram (ECG) screening or monitoring are not recommended in all patients but in those being treated who have risk factors for arrhythmia or use concomitant medications that lead to prolongation of the QT interval.54 Current evidence does not support routine ECG and electrolyte screening before single oral ondansetron dose administration to individuals without known risk factors.54
There are several conflicting studies examining the fetal safety of using ondansetron for nausea and vomiting during pregnancy. Carstairs55 conducted a systematic review and concluded that the overall risk of birth defects associated with ondansetron exposure appears to be low. However, there may be a small increase in the incidence of cardiac abnormalities in ondansetron-exposed neonates. Therefore, use of ondansetron in pregnancy, especially less than 10 weeks, should be reserved for those women whose symptoms have not been adequately controlled by other methods.55
One of the issues for patients experiencing prolonged or severe nausea and vomiting in pregnancy is they often cannot take oral medications. Drug administration must be through the intravenous, transdermal, or rectal routes. Although initially promising, subcutaneous microinfusion pumps of
antiemetic drugs have not proven cost effective,56,57 and intermittent subcutaneous dosing remains the more frequent method.
antiemetic drugs have not proven cost effective,56,57 and intermittent subcutaneous dosing remains the more frequent method.
Droperidol (Inapsine) is a dopamine antagonist used as an antiemetic for postoperative nausea and vomiting and during chemotherapy. There is limited current information on its use during pregnancy. It can also cause QT prolongation and cardiac dysrhythmias, and use during pregnancy as an antiemetic for nausea and vomiting is not recommended. The heartburn and acid reflux experienced by patients with nausea and vomiting can be treated with acid-reducing medications and antacids containing calcium and aluminum, and this is discussed later in this chapter.
Refractory HG has been successfully treated with corticosteroid therapy, but data are mixed and the exact mechanism of action remains unclear. Trials have shown statistically significant benefit,58 no benefit,59 and some benefit60 of steroid use. Results are not consistent and regimens differ from study-to-study, making any meta-analysis and conclusions challenging.
The safety of corticosteroid therapy early in pregnancy has been established by its use in other disorders. Corticosteroid therapy should not be considered a first-line therapy except in cases when (1) all other causes of vomiting have been excluded; (2) vomiting has been prolonged and associated with dehydration; (3) the risks and benefits of the treatment have been clearly explained to the patient; and (4) intravenous fluid replacement and conventional antiemetics have failed. Studies have established the efficacy and safety of corticosteroid therapy for refractory hyperemesis. Methylprednisolone in tapering doses is the drug of choice.58,59,60
Although there are no established guidelines for the use of steroids, a frequently used regimen is 48 mg of methylprednisolone given orally or intravenously in three divided doses for 2 or 3 days. The ACOG and experts using this protocol recommend if there is no positive response seen within 72 hours that treatment be stopped as improvement is unlikely.17,58,61
There are mixed and controversial data on the teratogenic effect of steroids when used early in pregnancy particularly in causing cleft lip or palate. Park-Wyllie,62 in a prospective cohort study and meta-analysis, and Carmichael,63 in a population-based case-controlled study, both reported an increased risk of cleft lip or palate among women who used corticosteroids during early pregnancy. A large study by Hviid did not show an increased risk of orofacial clefts with the use of corticosteroids during pregnancy.64
Diffuse Abdominal Pain
Colonic Pseudoobstruction (Ogilvie Syndrome)
Ogilvie syndrome is a life-threatening condition that may cause colonic distention and symptoms suggestive of obstruction in the absence of an actual mechanic al obstruction. The diagnosis is one of exclusion of mechanical obstruction or toxic megacolon. The severe colonic dilation can result in perforation. Treatment consists of neostigmine (contraindicated in pregnancy), colonoscopy, or surgery. Conservative measures are as effective as other treatments.65,66,67
Hemoperitoneum
Spontaneous hemoperitoneum is a rare life-threatening condition that may occur during pregnancy; the condition has been associated with endometriosis.68
Hereditary Angioedema
Patients with hereditary angioedema resulting from C1-inhibitor deficiency may experience severe episodes of debilitating subcutaneous and submucosal edema that may mimic an acute abdomen. Bowel wall edema may result in GI colic, NV, and diarrhea in the absence of hives. Approximately one-third of parturients will experience worsening symptom. C1-inhibitor replacement therapy is effective for acute exacerbations.69 Androgen therapies (not recommended in pregnancy) and ultrasound may aid in the diagnosis and demonstrate bowel wall edema or ascites.69,70
Substance Abuse
Opioid withdrawal may result in cramp-like abdominal pain, vomiting, and diarrhea.71
Chronic marijuana use may result in syndrome of cannabinoid hyperemesis, characterized by cyclic vomiting and abdominal pain. Patients may report relief of symptoms with hot showers or baths.36
Vasoocclusive Crises
Vasoocclusive crises in sickle cell anemia may occur in response to obstruction of arterioles and splenic
or mesenteric infarction. Cholelithiasis and cholecystitis are also more common in the parturient with sickle cell disease.72
or mesenteric infarction. Cholelithiasis and cholecystitis are also more common in the parturient with sickle cell disease.72
Right Upper Quadrant Pain
Gallbladder Disease
Gallbladder disease is the second most common cause for surgery in pregnancy, following appendectomy.8 Pregnancy increases the formation of gallstones, and pain is typically in the right upper quadrant, colicky, and associated with fat ingestion. Acute cholecystitis may result in fever, tachycardia, and leukocytosis. The presence of transaminitis and direct bilirubin suggest obstruction of the common bile duct or cholangitis. Ultrasound is the best initial diagnostic imaging tool.12
Hepatitis
Viral hepatitis symptoms are generally mild; however, hepatitis E may proceed to fulminant hepatic failure in pregnancy and is a global contributor to maternal mortality.9,10,73 Other viruses such as cytomegalovirus, Epstein-Barr virus, and adenovirus may also cause maternal anorexia, nausea, jaundice, and right upper quadrant pain and should be considered in the diagnostic evaluation.
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