INTRODUCTION — Morning sickness and hyperemesis gravidarum are terms used to describe mild versus severe nausea and vomiting of pregnancy. Nausea is so common that it can be considered a normal physiological sign of early pregnancy. Nevertheless, the presence and severity of nausea and vomiting may significantly impact the pregnant woman's quality of life [1].

The definition, clinical manifestations, and diagnostic evaluation of women with nausea and vomiting of pregnancy will be reviewed here. Treatment of this disorder is discussed separately. (See "Treatment of nausea and vomiting of pregnancy (hyperemesis gravidarum and morning sickness)".)

DEFINITIONS

Morning sickness — Some degree of nausea with or without vomiting occurs in 50 to 90 percent of all pregnancies. The mean onset of symptoms is at 5 to 6 weeks of gestation, peaking at 9 weeks, and usually abating by 16 to 18 weeks of gestation; however, symptoms may continue until the third trimester in 15 to 20 percent of gravida and until delivery in 5 percent [2,3]. Sixty percent of women are asymptomatic six weeks from onset of nausea [3]. Although the lay term for mild pregnancy-related nausea and vomiting is "morning sickness," the symptoms may occur at any time of day and often (80 percent) persist throughout the day.

Interestingly, women with mild nausea and vomiting during pregnancy experience fewer miscarriages and stillbirths than women without these symptoms [2,4]. In one meta-analysis, the odds of miscarriage in women with nausea and vomiting in the first 20 weeks of pregnancy was OR 0.36 (95% CI 0.2-0.42) [5].

Hyperemesis gravidarum — Hyperemesis gravidarum is considered the severe end of the spectrum of nausea and vomiting, although there is no clear demarcation between common pregnancy-related "morning sickness" and the infrequent pathologic disorder. An objective definition of hyperemesis that is often used is persistent vomiting accompanied by weight loss exceeding 5 percent of prepregnancy body weight and ketonuria unrelated to other causes [6]. The incidence of woman with severe symptoms is not well-documented; reports vary from 0.3 to 2 percent [7-11]. Ethnic differences and differences in the definition of the disease may account, in part, for this variability. Hyperemesis tends to improve in the last half of pregnancy, but may persist until delivery. If vomiting persists beyond a few days postpartum [12], other etiologies should be investigated.

PATHOGENESIS — The pathogenesis of hyperemesis is unknown. The predominant theories that have been proposed are described below.

• Psychologic factors — Two general theories are that hyperemesis reflects (1) a conversion or somatization disorder or (2) a response to stress [13]. In particular, a feeling of ambivalence about the pregnancy has been offered as an etiologic or contributing factor. However, no study has definitively demonstrated that the psychologic makeup of patients with hyperemesis gravidarum differs from those without the disorder, although the psychological response to persistent nausea and vomiting may exacerbate symptoms [13,14].
• Hormonal changes — No single hormonal profile can accurately predict the presence of hyperemesis gravidarum. Elevated serum concentrations of estrogen and progesterone have long been implicated in the pathogenesis of this disorder. Although several lines of evidence support a role, especially for estrogen, the fact that sex hormone levels peak in the third trimester, long after symptoms of hyperemesis gravidarum have typically resolved, is inconsistent with this theory [15,16].

By comparison, serum concentrations of human chorionic gonadotropin (hCG) peak during the first trimester, the time when hyperemesis gravidarum is typically seen. The observation that serum hCG concentration is higher in women with hyperemesis than in other pregnant women also supports a possible etiologic role for this hormone [17,18]. In addition, their hCG has more thyroid-stimulating activity because more of it is desialylated [17,19]. An increased prevalence of hyperemesis in women with gestational trophoblastic disease, which is characterized by very high hCG levels, has been well-described. Nevertheless, an association between hCG levels and hyperemesis gravidarum has not been firmly established.

• Abnormal gastric motility — Gastric motility may be abnormal (delayed or dysrhythmic) in hyperemesis gravidarum. Studies addressing motility disturbances have shown conflicting results, suggesting that these abnormalities are not highly predictive of the disease. (See "Pathogenesis of delayed gastric emptying".)

Women with diabetes may have gastroparesis. (See "Diabetic autonomic neuropathy of the gastrointestinal tract".)

• Other — Several other theories to explain hyperemesis have been suggested, including specific nutrient deficiencies (eg, zinc), alterations in lipid levels, changes in the autonomic nervous system, genetic factors, and infection with Helicobacter pylori [20,21]. None is consistently associated with, or highly predictive of, the disease.

RISK FACTORS — Studies of risk factors for hyperemesis gravidarum have generally included only a small number of affected women, and results have not been definitive [20,22-24]. Nonpregnant women who experience nausea and vomiting after estrogen exposure, from motion sickness, with migraine, or with exposure to certain tastes (supertasters) are more likely to have pregnancy-related nausea and vomiting [2]. In contrast, anosmic women appear to be at low risk for this disorder [25]. Psychiatric illness and pregestational diabetes are other purported risk factors, but these are controversial [26,27]. Two prospective studies reported an association between increased vomiting and absence of multivitamin supplementation either prior to six weeks of gestation or during the peri-conceptional period [28,29]. Another prospective study found that heartburn and acid reflux were associated with increased severity of nausea and vomiting of pregnancy, and suggested that managing these disorders might improve symptoms [30]. Interestingly, studies consistently report a preponderance of female fetuses among pregnancies complicated by hyperemesis [22,26,31-34].

Advanced maternal age (age >35) and cigarette smoking (perhaps due to the effect of nicotine) appear to be protective.

CLINICAL FEATURES AND DIAGNOSIS — Hyperemesis gravidarum is a clinical diagnosis, without uniform criteria. As discussed above, the diagnosis can be made in a woman with persistent vomiting, weight loss exceeding 5 percent of prepregnancy body weight, and ketonuria beginning in the first trimester, after other causes have been excluded [6]. The onset of symptoms is typically at 4 to 10 weeks of gestation. Hospitalization rates peak at about 9 weeks, then fall, plateauing at around 20 weeks of gestation [26]. Abdominal pain is infrequent.

Laboratory abnormalities — Laboratory abnormalities may or may not be present:

• Electrolyte derangements, such as hypokalemia and metabolic alkalosis.
• An increase in hematocrit, indicating hemoconcentration due to plasma volume depletion. The degree of hemoconcentration may be underestimated unless the physiologic decline in hematocrit seen in normal pregnancies is considered.
• Abnormal liver enzyme values occur in approximately 50 percent of patients who are hospitalized with hyperemesis [35]. The most striking abnormality is an increase in serum aminotransferases. Alanine aminotransferase (ALT) is typically elevated to a greater degree than aspartate aminotransferase (AST). Values for both are typically only mildly elevated, eg, in the low hundreds, and rarely as high as 1000 U/L. Hyperbilirubinemia also can occur, but rarely exceeds 4 mg/dL [36]. Serum amylase and lipase may increase as much as five-fold (as opposed to a 5- to 10-fold increase in acute pancreatitis) and are of salivary rather than pancreatic origin [37]. The degree of abnormality in liver tests correlates with the vomiting; the highest elevations are seen in patients with the most severe or protracted vomiting. Abnormal liver biochemical tests resolve promptly upon resolution of the vomiting.
• Mild hyperthyroidism, possibly due to high serum concentrations of human chorionic gonadotropin which has thyroid-stimulating activity [17]. One report noted low serum TSH concentrations more often in women with hyperemesis gravidarum than in normal pregnant women; TSH was suppressed in 60 percent of hyperemesis patients versus 9 percent of controls [18]. Some of these women had elevated serum free T4 concentrations and therefore met the definition of hyperthyroidism. (See "Diagnosis and treatment of hyperthyroidism during pregnancy".)

Features that distinguish the transient hyperthyroidism of hyperemesis gravidarum from hyperthyroidism of other causes (which in a pregnant woman is most likely to be due to Graves' disease) are the vomiting, absence of goiter and ophthalmopathy, and absence of the common symptoms and signs of hyperthyroidism (heat intolerance, muscle weakness, tremor). In addition, serum free T4 concentrations are only minimally elevated and serum T3 concentrations are not elevated in women with hyperemesis gravidarum, whereas both are usually unequivocally elevated in pregnant women with true hyperthyroidism. Treatment of hyperthyroidism should NOT be undertaken without clear evidence of a primary thyroid disorder (eg, goiter, elevated free thyroid hormone or elevated TSH receptor antibody levels). (See "Diagnosis and treatment of hyperthyroidism during pregnancy".)

• Hypercalcemia due to hyperparathyroidism [38,39]. This is uncommon, but should be considered, as hypercalcemia may contribute to the vomiting.

DIAGNOSTIC EVALUATION — The standard initial evaluation of pregnant women with persistent vomiting includes measurement of weight, orthostatic blood pressures, serum electrolytes, and urine ketones. An ultrasound examination is performed to exclude gestational trophoblastic disease and multiple gestation, both of which are associated with hyperemesis.

Given the characteristic clinical manifestations of hyperemesis gravidarum, a liver biopsy is not needed in women with abnormal liver function tests to exclude other causes for the laboratory findings. When a liver biopsy has been performed, it was either normal or showed nonspecific findings. Inflammation was absent, but necrosis with cell drop out, steatosis centrilobular vacuolization, and rare bile plugs have been seen [36,40,41]. These changes help to explain the mechanism for the liver test abnormalities.

Differential diagnosis — Hyperemesis is generally a diagnosis of exclusion, based on its first occurrence in early pregnancy, with gradual resolution over weeks. Nausea and vomiting that develop after 10 weeks of gestation are not likely due to hyperemesis gravidarum. The presence of associated symptoms, such as abdominal pain, fever, headache, goiter, abnormal neurologic findings, diarrhea, constipation, or hypertension, also suggests another diagnosis is likely; many conditions unrelated to pregnancy can cause persistent nausea and vomiting (table 1A-B). These conditions are reviewed separately. (See "Approach to the adult with nausea and vomiting" and "Cyclic vomiting syndrome".)

Preeclampsia, HELLP syndrome (Hemolysis, Elevated Liver function tests, Low Platelets), and fatty liver of pregnancy are also causes of pregnancy-related nausea and vomiting, but onset is typically in the latter half of pregnancy. (See "Clinical features, diagnosis, and long-term prognosis of preeclampsia" and "HELLP syndrome" and "Acute fatty liver of pregnancy".)

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Nausea and vomiting of pregnancy".) We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.

SUMMARY AND RECOMMENDATIONS

• Some degree of nausea with or without vomiting occurs in most pregnancies, typically with onset at 5 to 6 weeks of gestation, then peaking at 9 weeks, and usually abating by 16 to 18 weeks of gestation. Hyperemesis gravidarum represents the severe end of the spectrum of symptoms. (See 'Definitions' above.)

• Nonpregnant women who experience nausea and vomiting after estrogen exposure, from motion sickness, with migraine, or with exposure to certain tastes (supertasters) are more likely to have pregnancy-related nausea and vomiting. (See 'Risk factors' above.)

• The diagnosis of hyperemesis gravidarum is made clinically in a woman with onset of persistent vomiting accompanied by weight loss exceeding 5 percent of prepregnancy body weight and ketonuria in the first trimester, unrelated to other causes. (See 'Clinical features and diagnosis' above.)

• The standard initial evaluation of pregnant women with persistent vomiting includes measurement of weight, orthostatic blood pressures, serum electrolytes, urine ketones, and an ultrasound examination to exclude gestational trophoblastic disease and multiple gestation. (See 'Diagnostic evaluation' above.)

ACKNOWLEDGMENT — The author and UpToDate would like to acknowledge Dr. Edmund F Funai, who contributed to earlier versions of this topic review.