The exact etiology of HG is unknown. Whether HG is an extreme form of gestational vomiting or a distinct entity has also not been determined. Many possible causes have been investigated including hormonal changes, thyroid dysfunction, gastrointestinal tract dysmotility, H. pylori infection and psychologic factors.

The pregnancy-related hormones, specifically human chorionic gonadotropin (HCG) and estrogen, have been suggested to be the stimulus for nausea and vomiting of pregnancy [10]. It is well recognized that the peak symptoms of HG occur during periods of peak HCG concentration.

States of high estrogen concentration such as low parity and high maternal Body Mass Index have also been associated with higher incidence of HG [11]. Estrogen is thought to contribute to HG by slowing gastric intestinal transit time and gastric emptying. Among the estrogens, estradiol has been found in some studies to correlate with nausea and vomiting of pregnancy and higher rates of HG, whereas estriol has not [12,13]. It is unlikely that estrogens are the sole cause of HG, especially considering that estrogen levels peak in the third trimester of pregnancy while HG tends to improve during late pregnancy [1].

Nonpregnancy-related hormones implicated in the pathogenesis of HG include the thyroid hormones (thyroid-stimulating hormone (TSH), free tri-iodothyronine (FT3), and free thyroxine (FT4)) and leptin. Abnormal results on thyroid function tests are common in HG, occurring in two-thirds of women [14]. “Biochemical thyrotoxicosis” characterized by suppressed TSH and slightly elevated FT4 may be seen due to the mild thyroid-stimulating activity of HCG. Despite these laboratory abnormalities, women with HG are generally euthyroid with no history of prior thyroid diseases, absent goiter and negative antithyroid antibodies [7]. Treatment is generally not necessary as the thyroid function tests normalize in most patients by 18 weeks [15].

Recently, a relationship between the hormone leptin and HG has been proposed. Increased serum leptin levels during pregnancy, possibly the result of increased total fat mass and placental production have been found to be significantly higher in patients with HG when compared to healthy pregnant controls [16,17].

The role of the gram-negative spiral bacterium H. pylori in HG remains controversial. Several studies have found H. pylori seropositivity to be significantly associated with HG [8,18], whereas others could not determine any relationship between the two conditions [19]. In the single study which used endoscopy with gastric mucosal biopsies to identify active H. pylori infection, 95% of women with HG were positive for H. pylori infection compared with 50% of healthy pregnant controls [20]. A small case series of the effect of treatment of H. pylori infection in patients with HG reported dramatic improvement in symptoms after eradication [21]. Currently, there are no guidelines regarding whom or how to check for H. pylori infection in pregnancy; however, in severe cases of HG, H. pylori infection should be considered a contributing cause and should be treated.

Early studies proposed that HG may be a psychosomatic illness [1]. Recent studies, however, have not found definite psychogenic causes of HG [22,23]. It is likely that sociocultural factors rather than scientific evidence have led to the labeling of HG as a psychologically based condition and that psychologic disturbances are the result rather than the cause of HG [24].

Hyperemesis gravidarum presents in the first trimester of pregnancy, usually starting at 4–5 weeks gestation. In addition to severe nausea and vomiting, patients may report ptyalism, spitting and retching. Patients may also complain of gastroesophageal reflux symptoms such as retrosternal discomfort and heartburn. The initial evaluation of patients with HG is reviewed in Box 48.1. A pregnancy unique quantification of emesis and nausea (PUQE) score that is calculated using the number of hours of nausea per day, number of episodes of emesis per day and number of episodes of retching per day can be used to track the severity of symptoms [25] (Box 48.2).

On physical exam, patients may have evidence of volume depletion with dry mucous membranes, tachycardia and postural hypotension. Weight loss of greater than 5% of pre-pregnancy bodyweight or inadequate weight gain are viewed by many experts to be the features that distinguish HG from nausea and vomiting of pregnancy. Severely affected patients may have muscle wasting and weakness.

Laboratory studies that are useful in diagnosing and managing patients with HG include urinalysis to assess for specific gravity, ketonuria and infection. Electrolytes and renal function should also be assessed to evaluate for hyponatremia, hypokalemia, and metabolic alkalosis from severe dehydration. Complete blood count testing may reveal an elevated hemoglobin due to hemoconcentration and volume depletion. Prealbumin (plasma transthyretin) levels may be low, reflecting poor protein nutrition status in the mother and possibly predicting lower fetal birthweights [26].

Liver function tests may be abnormal in up to 50% of hospitalized patients [27]. Mild hyperbilirubinemia (bilirubin <4 mg/dL) and/or a rise in alkaline phosphatase to twice the upper limit of normal may be seen [28]. A moderate transaminitis is the most common liver function test abnormality, with alanine aminotransferase (ALT) levels generally greater than aspartate aminotranferase (AST) levels. The transaminase elevation is usually 2–3 times the upper limit of normal; however, levels greater than 1000 U/mL have been reported [29]. The abnormal liver tests are likely related to starvation and resolve promptly upon resolution of the vomiting.

Hyperamylasemia is common in HG. One study found elevated amylase levels in 24% of patients with HG [30]. This is likely due to excessive salivary gland production of amylase rather than pancreatic secretion and a result rather than a cause of HG [1].

Thyroid stimulating hormone levels may be low in HG, as mentioned above, due to cross-reaction between the alpha-subunit of HCG with the TSH receptor. In the majority of cases, this biochemical thyrotoxicosis is not clinically relevant as patients are euthyroid. Thyroid hormone levels generally normalize without treatment by 18 weeks gestation. In cases where it is hard to exclude thyrotoxicosis, thyroid autoantibodies (TSH receptor antibodies suggestive of Graves’ disease and thyroid peroxidase and thyroglobulin antibodies most commonly seen in Hashimoto’s thyroiditis) may be of value. In HG the raised liver transaminases and abnormal thyroid function tests should improve as the disease resolves and if they do not, further investigation should be undertaken to exclude other liver disease or hyperthyroidism.