Nausea, Vomiting, and Hyperemesis of Pregnancy
Nausea and vomiting of pregnancy (NVP) is quite common, affecting between 70% and 85% of pregnant women (Jewell & Young, 2003). Although typically a benign condition, NVP may lead to interruption of family life and the inability to attend work. The distress surrounding NVP commonly causes women to seek care in an emergency room or an obstetric triage unit, especially since symptoms may begin before a prenatal visit has taken place. In only 2% to 5% of pregnant women will the symptoms be severe enough to lead to the diagnosis of hyperemesis gravidarum (HG; Eliakim, Abulafia, & Sherer, 2000). Although there is no commonly agreed definition for HG, most diagnostic criteria include the following: severe nausea and persistent vomiting, resulting in dehydration (as indicated by ketonuria and elevated urine specific gravity), electrolyte abnormalities (e.g., hypokalemia), and 5% or greater weight loss. Hyperemesis can cause severe morbidity for both fetus and mother. Pregnancies complicated by HG are at higher risk for adverse outcomes, including premature birth and/or birth weight below the 10% for gestational age (Roseboom, Ravelli, van der Post, & Painter, 2011).
Attard and colleagues (2002) found that, in a sample of 223 women, those who suffered HG were slightly younger, more often primiparous, of lower socioeconomic status, and prone to substance abuse. They had more often conceived through assisted reproduction techniques, and more often had preexisting hypertension, metabolic conditions (e.g., diabetes mellitus), or psychologic conditions than women who did not suffer from HG.
Pregnant women may present with nausea, vomiting, retching, fatigue, mild abdominal pain, heartburn, dyspepsia, hyperptyalism, and lightheadedness if dehydration has occurred. These symptoms can persist throughout the day. Syncopal episodes or weight loss represents other common complaints that prompt patients to seek medical care. Abdominal pain not associated with retching or a fever must prompt the provider to search for a diagnosis other than NVP.
The symptoms of HG include significant maternal weight loss of 5 or greater pounds, dehydration, and electrolyte abnormalities, all of which require 108immediate medical attention and all of which may adversely affect the health of both the mother and infant. Extreme cases of HG have led to other medical complications including peripheral neuropathies secondary to vitamin B6 and B12 deficiencies, Wernicke’s encephalopathy (WE), splenic avulsion, esophageal rupture, pneumothorax, and acute tubular necrosis (American College of Obstetricians and Gynecologists [ACOG], 2009).
HISTORY AND DATA COLLECTION
A thorough history is taken relative to the onset of symptoms. Symptoms often begin as early as 4 weeks after the last menstrual period (LMP) and peak at 9 weeks from LMP. Sixty percent of symptoms resolve by the end of the first trimester and 91% resolve by 20 weeks gestation (Niebyl, 2010). Knowing the duration of symptoms is crucial, as WE has been reported after 4 or more weeks of chronic, intense vomiting. Wernicke’s is a neurologic condition that results from a depletion of vitamin B6. Women must be questioned about additional symptoms such as abdominal pain, fever, hematemesis, dysuria, hematuria, flank pain, diarrhea, and headache. Nausea and vomiting may cause mild upper abdominal pain from retching. Other, more severe types of pain will alert the clinician to seek an alternative diagnosis. Recent travel and exposure to food-borne illness must be documented, as well as remedies attempted and the results of such interventions.
The physical examination in the obstetric triage or emergency room setting for women with NVP is typically benign. Mild epigastric tenderness may be present due to retching; however, the abdominal examination is otherwise normal without guarding, rebound, or organomegaly. Costovertebral angle tenderness may indicate renal pathology as the primary cause of the symptoms. The patient is typically afebrile, with a normal neurologic examination and no goiter palpable. Mucous membranes and skin turgor are useful in determining the severity of dehydration. Orthostatic vital signs are recorded, as well as weight. An increase in pulse of 20 beats per minute or a drop in systolic blood pressure by more than 20 or 10 mmHg diastolic, associated with a change from a sitting to standing position, indicates a hypovolemic state. Orthostatic hypotension identifies those women who will benefit from intravenous (IV) fluid administration.
LABORATORY TESTING AND IMAGING STUDIES
Laboratory testing includes urinalysis and electrolyte evaluation. A complete blood count, liver function tests, amylase, lipase, and thyroid function tests are helpful in ruling out other causes of nausea and vomiting. Typical findings include suppressed thyroid stimulating hormone (TSH) levels and elevated free thyroxine, which resolves by 20 weeks gestation. These changes are likely due to stimulation of the thyroid gland by human chorionic gonadotropin. Elevated free thyroxine and free triiodothyronine can be measured to test for true hyperthyroidism. Other common blood work changes include elevated transaminases (usually <300 U/L); these mild elevations are likely due 109to a combination of dehydration, malnutrition, and lactic acidosis. Levels in the 1,000s are atypical and may indicate viral hepatitis as the primary diagnosis. Elevated bilirubin (<4 mg/dL) and elevated amylase (up to 5 times normal values) are common findings. Amylase levels may be increased due to increased secretion of saliva, not from pancreatic production. If levels are 5 to 10 times greater than normal, pancreatitis must be considered as a potential diagnosis. A significantly elevated lipase is another laboratory finding suggestive of pancreatitis. Hematocrit and hemoglobin levels may be elevated due to hypovolemia or decreased from vitamin deficiency anemia (vitamin B6 and B12). A leukocytosis may indicate that infection is the underlying cause. Cholecystitis, pancreatitis, or pyelonephritis all need to be carefully considered. Electrolyte imbalances are common including hypokalemia, hyponatremia, and hypochloremic alkalosis. Ultrasound may disclose conditions that contribute to symptoms, such as multiple pregnancy or molar pregnancy.
Nausea and vomiting of pregnancy (NVP) is a diagnosis of exclusion. Other causes of vomiting must be carefully considered. These include various infectious, neurologic, and gastrointestinal causes for nausea and vomiting. Table 10.1 notes the extensive list of differential diagnoses when considering NVP.
DIAGNOSES TO CONSIDER
Conditions related to pregnancy
Acute fatty liver of pregnancy, preeclampsia, premature contractions, hyperemesis gravidarum
Addison’s disease, diabetic ketoacidosis, hyperthyroidism, porphyria, thyrotoxicosis
Achalasia, appendicitis, biliary tract disease, diaphragmatic hernia, gastroenteritis, gastroparesis, cholecystitis, cholelithiasis, hepatitis, intestinal obstruction, pancreatitis, stomach cancer, stomach or duodenal ulcer, dumping syndrome (postgastric bypass)
Urogenital tract conditions
Degenerative uterine fibroids, nephrolithiasis, pyelonephritis, uremia, ovarian torsion
Acute alcohol withdrawal, migraine headache, vestibular disorders, central nervous system tumors, pseudotumor cerebri, Wernicke’s encephalopathy
Drug toxicities, food poisoning, iron imbalance, psychogenic causes
Sources: Adapted from ACOG (2009) and Jueckstock, Kaestner, and Mylonas (2010).
110CLINICAL MANAGEMENT AND FOLLOW-UP
The goal of therapy is to reduce symptoms, correct the consequences of vomiting such as dehydration and electrolyte imbalance, and prevent serious complications to the woman and fetus. If the patient has not already received education through the office setting, dietary interventions can be discussed with the patient such as multiple smaller meals as opposed to larger meals, avoidance of spicy foods, and taking prenatal vitamins at night. If conservative measures are unsuccessful or the pregnant woman’s symptoms are worsening, then antiemetics may be indicated. In more severe cases, rehydration with IV fluids may be necessary and vitamins and electrolytes may need to be repleted.
If a patient appears to be dehydrated either by elevated urine specific gravity, findings on physical examination, or orthostatic vital signs, IV fluids will need to be initiated. Sodium chloride 0.9% is the preferred IV solution; 1.8% sodium chloride is not advised, even in the setting of hyponatremia, as rapid correction may lead to central pontine myelinolysis. Thiamine must be administered along with glucose if vomiting has persisted for longer than 3 weeks as thiamine depletion can result in WE. Wernicke’s triad of symptoms includes ataxia, confusion, and ophthalmoplegia. This complication absolutely must be identified, as it carries a 10% to 20% mortality rate and can cause persistent neurologic findings. A dose of 100 mg of thiamine IV followed by daily oral supplementation is recommended. The shortest duration of vomiting that has been shown to result in WE is 4 weeks (Togay-Isikay, Yigit, & Mutluer, 2001).
The antiemetic Bendectin® was removed from the U.S. market in 1983 due to the cost of defending legal accusations of congenital malformations. The drug continued to be used in Canada, under the name Diclegis®. To date, none of these allegations has been confirmed. The combination of the antihistamine doxylamine and vitamin B6, the two ingredients in Bendectin, reduces nausea up to 70% (Niebyl, 2010). The attempts to duplicate Bendectin by using combinations of over-the-counter (OTC) medications are not exact, as OTC doxylamine is not time-released. In 2004, the U.S. Food and Drug Administration (FDA) approved the U.S. release of Diclectin®, which is a delayed-release formulation of 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride (HCl), for treatment of NVP. Diclectin remains a first-line treatment option recommended by the American College of Obstetricians and Gynecologists, when NVP does not respond to dietary or lifestyle changes (ACOG, 2015). The most common side effects are drowsiness, dry mouth, blurred vision, constipation, and urinary retention. Diclectin is taken twice at bedtime, once in the morning, and once in the afternoon. Women are encouraged to continue usage, as beneficial results may not occur for several days. Separate trials have also shown efficacy of using vitamin B6 alone to treat nausea with good results (Niebyl & Goodwin, 2002; Sahakian, Rouse, Sipes, Rose, & Niebyl, 1991). In some circumstances, the cost of Diclectin remains a barrier to its usage.
Several dopamine antagonists may also be used to treat NVP. Promethazine and prochlorperazine are two commonly used agents. Both agents have demonstrated efficacy, as well as little or no risk for major malformations to offspring (Magee, Mazzotta, & Koren, 2002). In a trial comparing promethazine with metoclopramide, both were found to have similar results in treating nausea and vomiting and increasing overall well-being; however, promethazine had more side effects, including drowsiness (83.6%), dry mouth (43.8%) , headaches 111(30.2%), and dystonia (19.2%), versus metoclopramide (Tan, Khine, Vallikkannu, & Omar, 2010). Compazine is available as a buccal tablet, which is associated with less drowsiness. Other side effects include extrapyramidal symptoms and Parkinsonian-like symptoms usually seen with higher doses or extended usage. These symptoms can be treated with diphenhydramine or lorazepam.
Metoclopramide is a dopamine antagonist with prokinetic properties. It is highly effective as described in the previous study and accepted by most pregnant women. Continuous use for more than 12 weeks has been linked to tardive dyskinesia. No increase in malformations or poor obstetric outcomes has been seen in studies performed to date, including an Israeli study of 3,458 women exposed to metoclopramide in the first trimester (Matok et al., 2009). Metoclopramide stimulates smooth muscle in the intestine and must be avoided in those women with bowel obstruction, perforation, or gastrointestinal bleeding.
Ondansetron is a HT3 antagonist commonly used to treat nausea and vomiting. This agent acts on both the peripheral vagal nerve terminals as well as centrally in the chemoreceptor trigger zone (Siminerio, Bodnar, Venkakataramanan, & Caritas, 2016). In recent years, published retrospective studies raise a controversial link between early exposure to ondansetron and birth defects, specifically cleft palate and cardiac anomalies (Einarsen, Maltepe, Navloz, Kennedy, Tan, & Koren, 2004). One of the largest studies to date, performed by using the Danish Birth Registry, also took into account family and maternal history and showed no evidence of increased risk for birth defects in infants exposed to ondansetron (Pasternak, Svanstrom, & Hviid, 2013). A subsequent review article suggests a possible small association between use of ondansetron in the first trimester of pregnancy and the increased incidence of neonatal cardiac septal defects and concludes ondansetron should only be used when other methods have failed (Carstairs, 2016). To summarize, current evidence suggests ondansetron is an option for treatment of nausea and vomiting when symptoms are unresponsive to first-line therapies. As always, risks and benefits must be discussed with pregnant women. Of note, ondansetron can prolong the QT complex and needs to be avoided in patients who have underlying heart problems, hypokalemia, hypomagnesemia, or are taking other medications such as anticholinergics, antihistamines, narcotics, metronidazole, or macrolide antibiotics. A summary of antiemetic treatment options is contained in Table 10.2.
A review of six controlled trials by Borrelli and Capasso (2005) supports ginger use as an efficacious treatment for emesis without any significant side effects. Ginger showed beneficial effects for women after admission for hyperemesis when compared to placebo. About 250 mg four times daily by tablet and syrup both showed beneficial effects. In syrup form, nausea decreased by 77% in the ginger group versus 20% in the placebo group. Sixty percent of the ginger group and 20% of the placebo group stopped vomiting after 6 days of usage. No negative outcomes for mother or fetus were reported. When compared to vitamin B6, ginger had equal reductions in nausea and number of vomiting episodes. Side effects of ginger were minor, including reflux and heartburn.
Acupressure is related to acupuncture and aims to heal by applying pressure to designated points throughout the body. Pressure to P6 or Neiguan is located three fingers or 4.5 cm above the wrist and is thought to treat nausea. Use of wristbands and electrical stimulation of P6 for treatment show conflicting results (Matthew, Dowswell, Haas, Doyle, & O’Mathuna, 2015). There are no consistent data to support acupuncture. A trial comparing acupuncture, sham acupuncture, 112and no acupuncture showed a decrease in nausea for both sham and acupuncture groups; however, no change occurred in vomiting (Smith, Crowther, & Bellby, 2002).