Description of the condition
While nausea and vomiting in early pregnancy are very common, affecting approximately 80% of pregnancies, hyperemesis gravidarum is a severe form affecting 0.3% to 1.0% of pregnancies (Gadsby 1993; Niebyl 2010). The definition of hyperemesis gravidarum varies but generally includes intractable nausea/vomiting, signs of dehydration such as ketonuria, high urine specific gravity, electrolyte imbalances, and weight loss of at least 5% of pre-pregnancy weight, excluding other diagnoses (ACOG 2004; Mella 2011). The onset is generally in the first trimester at six to eight weeks, peaking by 12 weeks, with most women having resolution of symptoms by 20 weeks' gestation (Jarvis 2011). The lack of standard criteria has implications for inclusion criteria and outcome measurements of controlled studies. For example, requirement of at least 5% weight loss is not always used as an inclusion criteria in studies of interventions for hyperemesis gravidarum, but one study found that the efficacy of corticosteroids may vary depending on this criterion (Moran 2002).
It is important to exclude other causes of severe nausea and vomiting before arriving at the diagnosis of hyperemesis gravidarum. Other causes include gastrointestinal (GI) etiologies such as infection, gastritis, cholecystitis, hepatitis, appendicitis, and pancreatitis. Neurological causes include migraines or other central nervous system disease. Genitourinary etiologies include urinary tract infection/pyelonephritis. Metabolic or endocrine disturbances include hypercalcemia, Addisons's disease, thyrotoxicosis. Psychological disorders include the spectrum of eating disorders. Finally, other pregnancy associated conditions such as molar pregnancy must also be excluded (Ismail 2007; Mella 2011).
The epidemiology of hyperemesis gravidarum is generally young women, primiparous, non smokers, and non Caucasian (Bailit 2005; Klebanoff 1985; Niebyl 2010). Other risk factors include prior history of hyperemesis, pre-existing diabetes, hyperthyroid disorder, depression or psychiatric illness, asthma, and GI disorders (Fell 2006). Fetal abnormalities such as triploidy and hydrops have also been associated with hyperemesis (Kelly 2009). The etiology of hyperemesis gravidarum is poorly understood, although it is generally thought to be associated with hormonal changes associated with pregnancy. Postulated mechanisms include human chorionic gonadotropin stimulating secretory processes in the upper GI tract and/or stimulation of the thyroid stimulating hormone receptor. Estrogen levels have also been positively associated with nausea and vomiting in pregnancy, perhaps through delayed GI motility and gastric emptying. Physiological stimulation of the thyroid gland in early pregnancy causes a transient thyrotoxicosis that may lead to hyperemesis. Several studies have found a significant increase in Helicobacter pylori (H. pylori) infection in hyperemesis patients, although whether this is a cause, risk factor, or consequence of hyperemesis is not well established (Ismail 2007; Kelly 2009).
Hyperemesis gravidarum has both maternal and fetal complications. Although hyperemesis gravidarum is rarely a source of mortality, it is a significant source of morbidity. It is the most common indication for hospitalization in early pregnancy, and the second most common indication for hospitalization in pregnancy (ACOG 2004). Malnutrition and vitamin deficiencies may lead to anemia and peripheral neuropathies, or more serious, but rare, complications such as Wernicke's encephalopathy and central pontine myelinolysis. Prolonged vomiting may lead to esophageal trauma such as Mallory-Weiss tears. Nausea and vomiting in early pregnancy are associated with psychiatric morbidity. Although a causal relationship is uncertain, the severity of nausea and vomiting has been correlated with somatic symptoms, social dysfunction, anxiety, insomnia, and severe depression (Ismail 2007; Kramer 2013; Mella 2011; Swallow 2004). There may also be significant psychosocial morbidity associated with hyperemesis. Multiple studies have demonstrated an association with decreased psychosocial well being, depression, and anxiety (ACOG 2004; Munch 2011; Poursharif 2008). The physical and psychological/social burden of hyperemesis gravidarum has also been associated with elective termination of the pregnancy (ACOG 2004; Poursharif 2007). Fetal complications include preterm birth (delivery less than 37 weeks' gestation), low birthweight (generally less than 2.5 kg), and small-for-gestational age (less than 10% of expected weight for gestational age). There does not appear to be an increased risk of spontaneous abortion (usually defined as less than 20 weeks), still birth (death of a fetus >= 20 weeks' gestation or greater than 500 g), or neonatal death (death of a baby born live within 28 days of birth) (Bailit 2005; Dodds 2006). The socioeconomic costs of hyperemesis are also significant, stemming from individual expense in paying for treatment, lost job productivity from time off work, and high healthcare costs related to provision of services and hospital admissions. One study found that the cost of hyperemesis was about $200,000,000 per year for the United States (Bailit 2005). Studies in Canada have estimated that severe nausea and vomiting in pregnancy result in as many as 14 hospitalizations/1000 births, and has a cost of $653/woman/week (Neutel 2000; Piwko 2007).
Description of the interventions and how they might work
A range of interventions are commonly used for the treatment of hyperemesis gravidarum. These include dietary and lifestyle modifications, complementary therapies (i.e. acupuncture, herbal remedies), pharmaceutical therapies including a variety of classes of anti-emetics and corticosteroids, and enteral/parenteral nutrition. The goals of therapy are generally to reduce nausea and vomiting, minimize hospitalization, prevent progression of symptom severity, and improve quality of life. Prior studies examining intervention efficacy have used qualitative measures of nausea/vomiting such as visual analog scales (Sullivan 1996; Tan 2009) and the Rhodes Index of Nausea, Vomiting, and Retching (Rhodes 1984; Rhodes 1999; Rosen 2003; Shin 2007), quantitative measures such as days of hospital admission and readmission rates, and quality of life measures such as the General Health Questionnaire (Swallow 2004) and the Edinburgh Postpartum Depression Screen (Bown 2008; Cox 1987; Kramer 2013). Secondary outcomes often include adverse maternal and fetal outcomes. It can be difficult to extrapolate safety data from trials designed to examine efficacy because they may not be powered to detect such outcomes, and it is difficult to determine whether certain outcomes, such as preterm delivery, are related to the intervention or the condition of hyperemesis. However, given that some adverse outcomes, such as congenital abnormalities, are not associated with hyperemesis, data on some specific outcomes may be used to draw conclusions on safety.
Dietary and lifestyle modifications
Dietary modifications include recommendations to have small and frequent meals, avoid spicy or fatty foods, and drink fluids regularly. Lifestyle modifications include avoiding noxious sensory stimuli, eating crackers in the morning after waking, and increasing rest. Although these are common recommendations, there are few published studies evaluating the efficacy of these changes for prevention or treatment of either nausea/vomiting of pregnancy or hyperemesis gravidarum (ACOG 2004; Arsenault 2002; Matthews 2010).
There are a number of non-pharmacological therapies that have been used for the treatment of nausea and vomiting in pregnancy and hyperemesis gravidarum. Acupressure and electrical stimulation wrist bands have been associated with benefit for nausea/vomiting of early pregnancy, although the evidence is mixed and limited (Heazell 2006; Ismail 2007; Matthews 2010; Mella 2011; Rosen 2003; Shin 2007). Acupuncture has also been shown to have some benefit in the treatment of nausea and vomiting in pregnancy and in the treatment of hyperemesis gravidarum, although again the evidence is limited (ACOG 2004; Carlsson 2000; Mella 2011), and the Cochrane review evaluating its efficacy in nausea and vomiting in early pregnancy found no benefit (Matthews 2010). These methods are based on traditional Chinese medicine that specifies a point PC6 5 cm proximal to the wrist crease that is associated with decreasing nausea. Acupuncture and other stimulation at this point has been suggested to reduce opioid related post operative nausea as well as chemotherapy-associated nausea (Carlsson 2000).
Ginger is another commonly recommended non-pharmacological intervention for the treatment of nausea and vomiting in pregnancy. The active ingredient in ginger responsible for its therapeutic effect is not well understood but it has long been used as a herbal medicine in Asian culture for the treatment of nausea and vomiting in pregnancy. Several randomized controlled trials have demonstrated a benefit to ginger in nausea and vomiting of pregnancy without any demonstrable adverse pregnancy outcomes. There are also studies demonstrating benefit in hyperemesis gravidarum (Arsenault 2002; Fischer-Rasmussen 1991; Matthews 2010; Mella 2011).
Intravenous fluids/enteral nutrition/parenteral nutrition
Hyperemesis gravidarum is commonly characterized by metabolic and electrolyte disturbance requiring hospital admission, with the initial therapy frequently being intravenous rehydration/repletion of electrolytes. Although intravenous rehydration is often a mainstay of treatment, there are few studies examining specific fluid regimens (ACOG 2004). One study in 2013 did compare a dextrose/saline solution with normal saline solution and found that there was no benefit in rehydration with dextrose. However, there remains a theoretical increased risk of Wernicke's encephalopathy as a result of glucose metabolism in a thiamine deficient state, which suggests that normal saline is preferable (Tan 2013).
Both enteral and parenteral nutrition are used in refractory hyperemesis gravidarum, although few studies have been done. There are case studies demonstrating that enteral nutrition is a relatively well tolerated and effective treatment strategy for refractory hyperemesis gravidarum. Complications can include infection, bleeding, tube dislodgement, preterm labor, and patient discomfort (ACOG 2004; Saha 2009). Parenteral nutrition is associated with a high incidence of complications including infection, thrombosis, and mechanical failure, and therefore is recommended only in the failure of medical management and enteral nutrition (ACOG 2004; Holmgren 2008).
A number of different classes of pharmaceutical agents have been evaluated for the treatment of hyperemesis gravidarum.
Vitamin B6 or pyridoxine is commonly used as a first line treatment for nausea and vomiting in pregnancy. It is a water soluble vitamin used as a cofactor in a wide array of metabolic processes and in the synthesis of nucleic acids and some neurotransmitters. Used on its own, it is associated with a decrease in nausea but not in vomiting (Mella 2011). In one study of women hospitalized with hyperemesis gravidarum, it did not seem to have any effect (Tan 2009). Vitamin B6 has not been shown to cause increased risk in major or minor congenital malformations (Arsenault 2002; Mazzotta 2000).
Antihistamines may act through different mechanisms. Doxylamine is a H-1 receptor antagonist that had been used frequently in combination with B6. When the combination B6 and doxylamine was available in the United States there was an association with decreased admissions for hyperemesis, however it was removed from the market secondary to safety concerns that were later unfounded (ACOG 2004; Ismail 2007). The combination of doxylamine/B6 has been found to be both safe, with no evidence of teratogenicity, and effective in the treatment of nausea and vomiting in pregnancy (Arsenault 2002; Mazzotta 2000; Mella 2011).
H1-receptor antagonists such as doxylamine, hydroxyzine, and diphenhydramine are thought centrally to reduce vestibular symptoms. There is one randomized controlled trial showing that diphenhydrinate is as effective as ginger in the treatment of nausea and vomiting of pregnancy (Pongrojpaw 2007). Antihistamines have not been well studied in hyperemesis (Mella 2011).
H2-receptor antagonists such as famotidine and ranitidine act peripherally in reducing reflux, which may help with reducing symptoms of nausea and vomiting, although this has not been well studied either.
Dopamine-2 antagonists such as metoclopramide stimulate GI motility and have been shown to be effective in decreasing vomiting. Limited studies have demonstrated its safety in pregnancy (Arsenault 2002; Mella 2011). Phenothiazines, such as promethazine, are dopamine 2-receptor antagonists that act centrally to suppress the chemoreceptor trigger zone (CTZ) that is responsible for stimulating vomiting. These have been shown to be both effective in treating hyperemesis and safe in pregnancy with regards to teratogenicity (Arsenault 2002).
Benzodiazepines such as diazepam have also shown some benefit in hyperemesis gravidarum, presumably through alleviating psychosomatic symptoms such as anxiety. However, the safety of these medications in pregnancy is still controversial with some studies demonstrating a positive association between neonatal exposure to diazepam and prematurity and low birth weight (Mella 2011; Tasci 2009).
Seratonin antagonists such as ondansetron also act centrally to suppress the CTZ. Limited data are available on the efficacy of ondansetron in hyperemesis gravidarum; one randomized controlled trial found no benefit over promethazine (Sullivan 1996). Safety data are also limited, animal studies and small case studies have not demonstrated any teratogenic effect (Mazzotta 2000). Recently, a large retrospective cohort study in Denmark found no association between ondansetron and adverse fetal outcome (Pasternak 2013). Despite the limited safety and efficacy data, its efficacy in treating chemotherapy-associated nausea/vomiting has led to increased use of this medication (ACOG 2004).
Corticosteroids are often used as a last resort for treatment of refractory hyperemesis. They have been used for the treatment of chemotherapy-associated nausea and are postulated to modify the CTZ. Studies are conflicting regarding the efficacy of steroids in hyperemesis gravidarum. However, their use in early pregnancy is associated with oral cleft malformations, so it is generally reserved as a last resort intervention (ACOG 2004; Arsenault 2002; Ismail 2007; Mazzotta 2000).
Adrenocorticotropic hormone has also been studied but generally has not been found to be effective for hyperemesis (Mella 2011).
Why it is important to do this review
Although there has been a recent Cochrane review in 2010 examining the efficacy and safety of many of these interventions for nausea/vomiting of early pregnancy (Matthews 2010), there has not yet been a review assessing interventions for the more severe condition of hyperemesis gravidarum.