Many disorders of the gastrointestinal tract are common in pregnancy. Elevated levels of progesterone may lead to alterations in gastrointestinal motility which could contribute to nausea, vomiting, and/or GERD. Pregnancy-induced diarrhea may be due to elevated levels prostaglandins. This article reviews the normal physiologic and structural changes associated with pregnancy that could contribute to many of the common gastrointestinal complaints in pregnant patients. Additionally, the appropriate clinical and laboratory evaluations, other pathologic conditions that should be included in the differential, as well as the nonpharmacologic and pharmacologic therapies for each of these conditions is discussed.
Key points
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Pregnant women are susceptible to nausea, vomiting, gastroesophageal reflux, constipation, and diarrhea at rates similar to or higher than the general population.
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Many of the pregnancy-induced gastrointestinal (GI) disorders result from the normal hormonal and structural changes associated with pregnancy.
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Although a vast majority of GI complaints are caused by normal pregnancy-related changes, other pathologic conditions and causes should be considered.
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When symptomatic remission cannot be achieved with nonpharmacologic therapy, pharmacologic treatment may be instituted, but the potential teratogenic side effects must be considered.
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Starting June 2015, the Food and Drug Administration (FDA) began replacing pregnancy categories A, B, C, D, and X with narrative statements regarding safety studies for all biological products and prescription drugs, which may result in improved understanding of fetal and maternal risk.
Nausea, vomiting, and hyperemesis gravidarum
A majority of pregnant women experience nausea and vomiting during pregnancy. The prevalence of nausea in this group is between 50% and 80% and for vomiting 50%. These are the most common medical conditions during gestation, usually beginning between weeks 4 and 6, peaking at approximately weeks 8 to 12, and often ceasing by week 20.
Hyperemesis gravidarum (HG) is a severe and persistent form of nausea and vomiting. Fortunately, it only affects approximately 1.2% of pregnant women. Currently, there is no standard definition or diagnostic criteria for HG. Accepted definitions, however, combine the symptoms of protracted vomiting and nausea with the following findings: weight loss, ketonuria, electrolyte disturbances, dehydration, and/or hospitalization.
Evaluation
In the setting of significant nausea and vomiting, other pathologic causes should be excluded. Box 1 outlines other causes that may be considered. If the work-up for other causes is negative, a diagnosis of nausea and vomiting associated with pregnancy may be assigned.
Gastrointestinal
Gastroenteritis
Biliary disease
Gastroparesis
Peptic ulcers
Pancreatitis
Hepatitis
Appendicitis
IBS
Genitourinary
Pyelonephritis
Uremia
Kidney stones
Miscellaneous
Drugs
Psychological
Metabolic
Diabetic ketoacidosis
Addison disease
Hyperthyroidism
Neurologic
Pseudotumor cerebri
Vestibular
Central nervous system tumors
Pregnancy Associated
Multifetal gestation
Gestational trophoblastic disease
Preeclampsia/HELLP
Acute fatty liver of pregnancy
Abbreviation: HELLP, Hemolysis, Elevated Liver Enzymes, and Low Platelets.
Pathophysiology
The exact cause of nausea and vomiting during pregnancy is not fully understood. Permeations in gastric tone and gastric motility due to elevations in progesterone are, however, thought to be involved. Studies have shown that progesterone has an inhibitory effect on the smooth muscle of both the pylorus and the small bowel, which results in decreased GI contractility. Other studies comparing the gastric emptying rates of premenopausal women to men and postmenopausal women have detected slower gastric emptying rates in the former, which further suggest a hormone-induced delayed gastric emptying.
There are a few studies evaluating gastric function during pregnancy. However, studies have documented the presence of both tachygastria and bradygastria in pregnant women. Both of these gastric dysrhythmias have been associated with reports of nausea.
Delayed small bowel transit may also contribute to nausea and vomiting. In humans, lactulose breath testing has confirmed delayed small bowel transit in the third trimester, which returns to normal after delivery. Similarly, animals studied have shown delayed gastric emptying in the third trimester that persists until postpartum day 4. Gastric emptying then returns to normal, suggesting that the motor dysfunction associated with pregnancy is not solely due to the presence of an enlarged uterus.
Psychological factors may also have a role. Multiple studies report that nausea and vomiting can be worse in women who experience negative relationships with their mothers and in undesired pregnancies. Other studies suggest a link between somatization and/or conversion disorders with nausea and vomiting. Also, anxiety and depression, which complicate up to one-third of pregnancies, are more common in patients with HG.
Hyperemesis Gravidarum
As discussed previously, HG is a more severe form of nausea and vomiting. It is associated with a higher risk of negative pregnancy outcomes: preterm birth, low birth weight, and small-for-gestational-age infants. Risk factors for HG include female gender infant, young maternal age, previous pregnancy, and non-European heritage. Body mass index, smoking, and socioeconomic status are not risk factors for HG.
Pathophysiology
The current body of literature suggests 3 pathoetiologies for HG: placental growth and function as reflected by free human chorionic gonadotropin (hCG), maternal endocrine function, and preexisting GI disease. An observational study showed higher levels of free hCG in women with HG compared with controls. Higher maternal serum concentrations of hCG are seen in the first trimester when HG symptoms are often at their worse. Additionally, HG symptoms are more severe in molar pregnancies and multigestational pregnancy, conditions known to be associated with higher than normal hCG levels. The exact mechanism, however, for how elevated levels of hCG leads to HG is unclear. One proposed mechanism involves the stimulatory effect of hCG on the secretory pathways in the upper GI tract.
Other sex hormones and endocrine factors have been implicated in HG. A list of these hormones and their associated alterations is shown in Table 1 . Theories on how these alterations lead to HG include higher levels of these hormones during early pregnancy, an increased sensitivity to these hormones in patients with HG, and/or a different subtype or isoform of these hormones in women with HG.
| Factor | Alteration |
|---|---|
| Sex hormones | |
| Estrogens | Increased |
| Progesterone | Increased |
| Endocrine hormones | |
| Thyroid-stimulating hormone and thyroxine | Increased |
| Hypothalamic-pituitary-adrenal axis | Overactivity |
| Human growth hormone | Abnormal levels |
| Prolactin | Abnormal levels |
Multiple studies have also noted an association between Helicobacter pylori infection and HG. One study found that 95% of HG patients tested positive for H pylori , whereas only 50% of controls were positive. Additionally, the density of infection was higher in women with HG and correlated with the severity of symptoms. The cause for the increased incidence of H pylori in patients with HG is unclear and no causal relationship between HG and H pylori has been established.
Management
After other physiologic causes for nausea and vomiting have been eliminated, nonpharmacologic treatment options should be instituted. These includes reassurance, dietary changes, and lifestyle modifications. Additionally, patients should be counseled to reduce stress and get adequate rest. To prevent dehydration, daily consumption of 1 L to 1.5 L of either sports drinks or broth containing salt, glucose, and potassium is advised. Diet recommendations include small, frequent meals and the avoidance of fatty foods and fresh vegetables that may delay gastric emptying or have difficulty emptying from the stomach. High-protein liquid beverages have been shown to reduce gastric dysrhythmias and nausea in the first trimester.
Given the concern for teratogenic effects of pharmacologic therapy, alternative therapies have been explored. Studies have shown that both thiamine (vitamin B 1 ) and pyridoxine (vitamin B 6 ) are efficacious in reducing nausea and vomiting. Therefore, both are indicated as routine supplements in patients with protracted vomiting.
Zingiber officinale , the root of ginger, has also been studied in the treatment of nausea and vomiting. The antiemetic properties of ginger are due to the presence of gingerols and shogaols, which increase gastric motility, stimulate gastric antral contractions, and block the cholinergic M receptors as well as the serotonin receptor. Multiple studies have reported a subjective decrease in nausea and an objective decrease in vomiting after daily consumption of 1 g of ginger.
Due to the concern for teratogenic effects, judicious use of all pharmacologic therapy in pregnant women is indicated. Health care professionals should have thorough conversations with their patients regarding the potential risk and possible outcomes prior to starting medical therapy. To aid in this discussion, the Food and Drug Administration (FDA) has classified many supplements as well as over-the-counter and prescription medications in 1 of 5 pregnancy categories (A, B, C, D, or X) based on the risk of developmental and reproductive adverse effects compared with the potential benefit ( Table 2 ).
| Class | Definition |
|---|---|
| A | Appropriately designed studies in pregnant women have not demonstrated fetal risk. |
| B | No fetal risk in animal reproduction studies; no well-controlled studies in pregnant women OR Adverse effect in animal studies, but studies in pregnant women failed to demonstrate fetal risk |
| C | Animal reproduction studies show adverse fetal effect but no well-controlled studies in humans. OR No animal reproduction studies and well-controlled studies in humans |
| D | Evidence of human fetal risk in investigational or marketing experience or studies in humans |
| X | Animals or humans studies have demonstrated fetal abnormalities. OR Evidence of fetal risk based on investigational and/or marketing experience |
This system has been in place since 1979, but both patients and heath care professionals found the pregnancy categories confusing and ineffective at communicating varying degrees of fetal risk. Therefore, the FDA issued a final rule in December 2014 to replace the pregnancy categories with a narrative structure to better convey potential teratogenic and reproductive risk based on human and/or animal safety data. Biological products and prescription drugs submitted after June 30, 2015, will immediately use the new format, whereas prescription drug labeling approved after or on June 30, 2001 will be gradually introduced. Labeling for over-the-counter medications will not change. For historical purposes, subsequent tables regarding pharmacologic management of GI disease in pregnancy will contain the FDA pregnancy classification.
Regarding the pharmacologic treatment of nausea and vomiting, antiemetics should be used cautiously in pregnancy and should not be used before 12 to 14 weeks of gestation. The most commonly used agents include phenothiazines, histamine receptor blockers, and dopamine antagonists. Of these, phenothiazines are considered the least safe in pregnancy due to their known ability to cross the placenta and their comparatively slower excretion from neonatal and fetal tissue. Ondansetron, a 5-HT 3 antagonist, is particularly useful in the treatment of chemotherapy-induced nausea and vomiting. Studies have shown, however, an increased risk of congenital heart defects when used in the first trimester. Steroids, which are thought to relieve nausea via a central mechanism, are not routinely recommended in pregnancy due to concern for fetal growth impairment and increased risk of cleft palate.
Metoclopramide, a dopamine antagonist, may be used in the treatment of nausea and vomiting during pregnancy. Although it crosses the placenta, there are no reported teratogenetic effects in animals or humans. Studies have shown that metoclopramide and promethazine (a phenothiazine) have similar therapeutic effects, but metoclopramide has fewer side effects: less drowsiness, dizziness, and dystonia.
Oral histamine receptor blockers, such as over-the-counter doxylamine, have proved efficacy and are considered first-line pharmacologic therapy in the treatment of pregnancy-associated nausea and vomiting. There is no evidence of adverse fetal effects associated with the use of histamine antagonists. A list of antiemetic medications, dosages, and their FDA classifications is in Table 3 .
| Medication | Dosage | Food and Drug Administration Classification a |
|---|---|---|
| Alternative therapy | ||
| Pyridoxine | 10–25 mg Q8H | A |
| Thiamine | 100 mg QD | A |
| Ginger | 1 g QD | Not assigned |
| Histamine receptor blocker | ||
| Doxylamine | 12.5–25 mg Q4–6H | B |
| Dopamine antagonist | ||
| Metoclopramide | 10 mg Q8H | B |
| Phenothiazines | ||
| Promethazine | 25 mg Q8H | C |
| 5-HT 3 antagonist | ||
| Ondansetron | 4 mg Q8H | C |
| Steroids | ||
| Prednisone | 40 mg QD | C |
a Discontinued June 30, 2015, for biological products and prescription drugs; to be replaced by risk narratives based on human or animal studies.
Management of HG may require intravenous fluids to correct or prevent dehydration and restore electrolyte balance. Additional nutritional support via nasogastric or enteral route may be considered for those with severe, intractable symptoms and/or weight loss in spite of appropriate therapy. These modalities, however, pose significant risk to both mother as well as fetus and should be reserved for the most severe cases.
Nausea, vomiting, and hyperemesis gravidarum
A majority of pregnant women experience nausea and vomiting during pregnancy. The prevalence of nausea in this group is between 50% and 80% and for vomiting 50%. These are the most common medical conditions during gestation, usually beginning between weeks 4 and 6, peaking at approximately weeks 8 to 12, and often ceasing by week 20.
Hyperemesis gravidarum (HG) is a severe and persistent form of nausea and vomiting. Fortunately, it only affects approximately 1.2% of pregnant women. Currently, there is no standard definition or diagnostic criteria for HG. Accepted definitions, however, combine the symptoms of protracted vomiting and nausea with the following findings: weight loss, ketonuria, electrolyte disturbances, dehydration, and/or hospitalization.
Evaluation
In the setting of significant nausea and vomiting, other pathologic causes should be excluded. Box 1 outlines other causes that may be considered. If the work-up for other causes is negative, a diagnosis of nausea and vomiting associated with pregnancy may be assigned.
Gastrointestinal
Gastroenteritis
Biliary disease
Gastroparesis
Peptic ulcers
Pancreatitis
Hepatitis
Appendicitis
IBS
Genitourinary
Pyelonephritis
Uremia
Kidney stones
Miscellaneous
Drugs
Psychological
Metabolic
Diabetic ketoacidosis
Addison disease
Hyperthyroidism
Neurologic
Pseudotumor cerebri
Vestibular
Central nervous system tumors
Pregnancy Associated
Multifetal gestation
Gestational trophoblastic disease
Preeclampsia/HELLP
Acute fatty liver of pregnancy
Abbreviation: HELLP, Hemolysis, Elevated Liver Enzymes, and Low Platelets.
Pathophysiology
The exact cause of nausea and vomiting during pregnancy is not fully understood. Permeations in gastric tone and gastric motility due to elevations in progesterone are, however, thought to be involved. Studies have shown that progesterone has an inhibitory effect on the smooth muscle of both the pylorus and the small bowel, which results in decreased GI contractility. Other studies comparing the gastric emptying rates of premenopausal women to men and postmenopausal women have detected slower gastric emptying rates in the former, which further suggest a hormone-induced delayed gastric emptying.
There are a few studies evaluating gastric function during pregnancy. However, studies have documented the presence of both tachygastria and bradygastria in pregnant women. Both of these gastric dysrhythmias have been associated with reports of nausea.
Delayed small bowel transit may also contribute to nausea and vomiting. In humans, lactulose breath testing has confirmed delayed small bowel transit in the third trimester, which returns to normal after delivery. Similarly, animals studied have shown delayed gastric emptying in the third trimester that persists until postpartum day 4. Gastric emptying then returns to normal, suggesting that the motor dysfunction associated with pregnancy is not solely due to the presence of an enlarged uterus.
Psychological factors may also have a role. Multiple studies report that nausea and vomiting can be worse in women who experience negative relationships with their mothers and in undesired pregnancies. Other studies suggest a link between somatization and/or conversion disorders with nausea and vomiting. Also, anxiety and depression, which complicate up to one-third of pregnancies, are more common in patients with HG.
Hyperemesis Gravidarum
As discussed previously, HG is a more severe form of nausea and vomiting. It is associated with a higher risk of negative pregnancy outcomes: preterm birth, low birth weight, and small-for-gestational-age infants. Risk factors for HG include female gender infant, young maternal age, previous pregnancy, and non-European heritage. Body mass index, smoking, and socioeconomic status are not risk factors for HG.
Pathophysiology
The current body of literature suggests 3 pathoetiologies for HG: placental growth and function as reflected by free human chorionic gonadotropin (hCG), maternal endocrine function, and preexisting GI disease. An observational study showed higher levels of free hCG in women with HG compared with controls. Higher maternal serum concentrations of hCG are seen in the first trimester when HG symptoms are often at their worse. Additionally, HG symptoms are more severe in molar pregnancies and multigestational pregnancy, conditions known to be associated with higher than normal hCG levels. The exact mechanism, however, for how elevated levels of hCG leads to HG is unclear. One proposed mechanism involves the stimulatory effect of hCG on the secretory pathways in the upper GI tract.
Other sex hormones and endocrine factors have been implicated in HG. A list of these hormones and their associated alterations is shown in Table 1 . Theories on how these alterations lead to HG include higher levels of these hormones during early pregnancy, an increased sensitivity to these hormones in patients with HG, and/or a different subtype or isoform of these hormones in women with HG.
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