Hyperemesis Gravidarum

INTRODUCTION

Background: Nausea and vomiting in pregnancy is extremely common. Studies estimate nausea occurs in 66-89% of pregnancies and vomiting in 38-57%. The nausea and vomiting associated with pregnancy almost always begins by 9-10 weeks of gestation, peaks at 11-13 weeks, and resolves (in 50% of cases) by 12-14 weeks of gestation. In 1-10% of pregnancies, symptoms may continue beyond 20-22 weeks.

The most severe form of nausea and vomiting in pregnancy is called hyperemesis gravidarum (HEG). A continuous spectrum of the severity of nausea and vomiting ranges from the nausea and vomiting that occurs in most pregnancies to the severe disorder of HEG.

HEG is characterized by persistent nausea and vomiting associated with ketosis and weight loss (>5% of prepregnancy weight). HEG may cause volume depletion, altered electrolytes, and even death. Hospitalization is not infrequent.

Pathophysiology: The physiologic basis of HEG is controversial. Theories are as follows:

Psychological abnormalities

Early work on the cause of both nausea and vomiting in pregnancy and HEG suggested that women with these symptoms were unable to accept pregnancy, had problems with their relationships with their mothers, or suffered from personality disorders and/or hysteria. However, nausea and vomiting in pregnancy now is recognized as affecting the majority of women. Retrospectively, many of the earlier studies appear flawed. Newer evidence is conflicting. Some cases of HEG may represent psychiatric illnesses, including Munchausen syndrome, conversion or somatization disorder, and major depression, or they may occur under situations of stress or ambivalence surrounding the pregnancy. However, HEG may occur in the absence of psychological illness or stress.

Hormonal changes

Homology exists between the human chorionic gonadotropin (HCG) molecule and its receptor and the thyroid-stimulating hormone (TSH) molecule and its receptor. HCG can physiologically stimulate the thyroid. HCG levels peak in the first trimester. Some women with HEG appear to be clinically hyperthyroid. However, in a larger proportion (50-60%), TSH is transiently suppressed and the free thyroxine (T4) index is elevated (40-73%) with no clinical signs of hyperthyroidism, circulating thyroid antibodies, or enlargement of the thyroid on exam.

Some investigators have found a positive correlation in cases of HEG between the level of serum HCG elevation and free T4 levels. In these studies, the severity of nausea also appeared to be related to the degree of thyroid stimulation. For these patients with HEG, HCG levels were linked to increased levels of immunoglobulin M (IgM), complement, and lymphocytes. An immune process may be responsible for increased circulating HCG or isoforms of HCG with a higher activity for the thyroid. Critics of this theory note that nausea and vomiting is not a usual symptom of hyperthyroidism, signs of biochemical hyperthyroidism are not universal in cases of HEG, and some studies have failed to correlate the severity of symptoms with biochemical abnormalities.

Some studies link high estradiol levels to the severity of nausea and vomiting in patients who are pregnant, while others find no correlation between estrogen levels and the severity of nausea and vomiting in pregnant women. Previous intolerance to oral contraceptives is noted to be associated with nausea and vomiting in pregnancy.

Progesterone also peaks in the first trimester and decreases smooth-muscle activity; however, studies have failed to show any connection between progesterone levels and symptoms of nausea and vomiting in pregnant women.

Gastrointestinal dysfunction

Elevations in female sex hormones during pregnancy may change esophageal, gastric, and small bowel motility. Although progesterone does appear to decrease lower-esophageal sphincter pressure, a number of studies have found no decrease in lower-esophageal sphincter pressure during pregnancy. Studies on gastric emptying demonstrate that it is unchanged in pregnancy. Some studies, however, have correlated alterations in gastric myoelectrical activity in the first trimester of pregnancy with nausea. Small bowel transit time increases in pregnancy, but only in the second and third trimester.

Hepatic dysfunction

Many investigators have targeted changes in liver function as a possible cause of HEG. Patients with HEG often demonstrate abnormalities of liver enzymes. Liver disease can cause symptoms of nausea and vomiting, and abnormalities have been found on liver biopsies of patients with pregnancies complicated by HEG. Theories either postulate an increased sensitivity of the liver to the hormonal alterations of pregnancy or abnormalities in steroid inactivation; however, not all patients with HEG show liver abnormalities. In one study by Jarnfelt-Samsioe, et al, pregnant women with vomiting had lower bilirubin and gamma-glutamyl transferase levels than women without vomiting.

Lipid alterations

In another study, Jarnfelt-Samsioe, et al, found higher levels of triglycerides, total cholesterol, and phospholipids in women with HEG than matched, nonvomiting, pregnant and nonpregnant controls. This may be related to the abnormalities in hepatic function in pregnant women.

Infection

Newer studies have found a relationship between infection with Helicobacter pylori and HEG. In a study by Kocak et al, of 95 patients with HEG and 116 matched controls, H pylori infection was found in 91% of patients with HEG, compared to 45% of patients in the control.

Frequency:
　

• In the US: Of all pregnancies, 0.3-2% are affected with HEG (about 5 per 1,000 pregnancies).

  HEG appears to be more common in westernized industrialized societies and urban areas than rural areas.

Mortality/Morbidity: HEG was a significant cause of maternal death before 1940. Mortality from HEG in Great Britain decreased from 159 deaths per million births in 1931-1940 to 3 deaths per million births in 1951-1960. Charlotte Bront?is said to have died of HEG in 1855.

• Many hours of productive work are lost because of nausea and vomiting during pregnancy. In one study of 200 pregnant women, 35% reported time lost from work.

• HEG is a debilitating illness that can cause severe suffering and profoundly affects both patients and their families. In one study of 140 women with HEG, 27% required multiple hospitalizations.

Race: HEG is less common in American Indian and Eskimo populations. HEG is less common in African and some Asian populations (but not industrialized Japan). No clear racial predominance is noted in HEG.

Sex: Female

CLINICAL

History: The defining symptoms of HEG are:

• Gastrointestinal

• Nausea

• Vomiting

• Also common are:

• Ptyalism (excessive salivation)

• Fatigue

• Weakness

• Dizziness

• Patients may experience:

• Sleep disturbance

• Hyperolfaction

• Dysgeusia

• Decreased gustatory discernment

• Depression

• Anxiety

  　

• Irritability

  　

• Mood changes

  　

• Decreased concentration

• When obtaining history from the patient, discuss present symptoms (as above). Obtain information pertaining to timing, onset, severity, pattern, and alleviating and exacerbating factors (eg, relationship to meals, medications, prenatal vitamins, stress, other triggers).

• A thorough review of systems for any symptoms that might suggest other gastrointestinal, renal, endocrine, and central nervous system disorders is vital.

• Review past medical history, placing emphasis on past medical conditions, surgeries, medications, allergies and adverse drug reactions, family history, social history including support system, employment, habits, and diet.

• Obtaining a thorough gynecologic history of symptoms, such as vaginal bleeding or spotting, past pregnancies, past use of oral contraceptives, and response to oral contraceptives used, is important.

Physical: The physical exam usually is unremarkable in patients with HEG.

• Physical exam may be more helpful when the patient has unusual complaints suggestive of other disorders (eg, bleeding, abdominal pain).

• Pay attention to the vital signs, including standing and lying blood pressure and pulse; volume status (mucous membrane condition, skin turgor, neck veins, mental status); general appearance (nutrition, weight); thyroid exam; abdominal exam; cardiac exam; and neurologic exam.

Causes: In some studies, women from low-to-middle socioeconomic class, women with lower levels of education, women with previous pregnancies with nausea and vomiting, women in their first pregnancies, and women with previous intolerance to oral contraceptives more commonly experience nausea and vomiting during pregnancy. Nausea and vomiting during pregnancy also is more common with multiple-gestation pregnancies.

• For HEG, risk factors may include the following:

• Previous pregnancies with HEG

• Greater body weight

• Multiple gestations

• Trophoblastic disease

• Nulliparity

WORKUP

Lab Studies:
　

• Initial lab studies for HEG should include the following:

• Urinalysis for ketones and specific gravity: A sign of starvation, ketones may be harmful to fetal development. High specific gravity occurs with volume depletion.

• Serum electrolytes: To evaluate for low potassium or sodium, identify hyperchloremic metabolic alkalosis or acidosis, and evaluate renal function and volume status.

• Liver enzymes and bilirubin: Elevated transaminases may occur in as many as 50% of patients with HEG.

• Amylase: This is elevated in about 10% of HEG cases.

• TSH: HEG is associated with hyperthyroidism and suppressed TSH in 50-60% of cases.

• Consider Ca⁺⁺: Some rare cases of hypercalcemia associated with HEG from hyperparathyroidism have been reported.

• Hematocrit: This may be elevated from volume contraction.

Imaging Studies:
　

• In patients with HEG, an ultrasound to evaluate for multiple gestations or trophoblastic disease is usually warranted.

• Additional imaging generally is not needed unless the clinical presentation is atypical (eg, nausea and/or vomiting beginning after 9-10 wk, nausea and/or vomiting persisting after 20-22 wk of gestation, acute severe exacerbation) or another disorder is suggested by history or physical exam.

• If indicated clinically, ultrasound for evaluation of the pancreas and/or biliary tree appears to be low risk.

Procedures:
　

• In patients with abdominal pain or upper gastrointestinal bleeding, upper gastrointestinal endoscopy appears to be safe in pregnancy, though careful monitoring is suggested.

• Acupressure has been shown in some studies to have a beneficial effect on nausea and vomiting during pregnancy; however, it has not been studied in patients with HEG.

• More controversy surrounds the benefit of hypnosis, but it has been studied in some cases of HEG and may be beneficial.

• Psychological counseling may be considered.

• Reserve pharmacologic therapy for severe and refractory cases. First-line outpatient drug therapy can include oral pyridoxine. If vomiting persists, doxylamine may be added to the pyridoxine, or conventional antiemetics may be administered.

  　

• Initiate a full laboratory workup in cases of severe refractory HEG (weight loss or > than trace urine ketones). Outpatient or home IV hydration should be considered. Failure of medications and outpatient hydration, or severe electrolyte disturbances may necessitate inpatient admission for intravenous hydration.

• If hypokalemia is severe or symptomatic, it should be replaced parenterally. Before administering IV potassium, renal function should be ascertained. Potassium is usually added to IV fluid to a concentration of 40 mEq/L (and not greater than 80 mEq/L). An infusion rate of 10 mEq of potassium per hour should be safe as long as urine output is adequate.

  　

• When administrating IV hydration to a patient who has severe volume depletion to prevent the development of Wernicke encephalopathy, avoid IV glucose until IV thiamine has been administered.

• If vomiting is recurrent with IV hydration and conventional medications fail, a trial of oral corticosteroids is appropriate. Failure of this regimen necessitates consideration of enteral nutrition (either central or peripheral total parenteral nutrition [TPN]).

Surgical Care: In some refractory severe cases of HEG, or if maternal survival is threatened, termination of the pregnancy should be considered as a last resort.

Consultations: Patients with HEG should be under the care of an obstetrician who is familiar with this disorder.

• Psychological assessment may be needed. In some cases, even supportive or focal psychotherapy or psychiatric medications may be indicated. Behavioral therapy may be beneficial early in the course of HEG.

MEDICATION

Antihistamines, antiemetics of the phenothiazine class, and promotility agents (eg, metoclopramide) have been used in the treatment of nausea and vomiting during pregnancy.

Vitamin B-6 (pyridoxine) also has been studied in the treatment of nausea and vomiting during pregnancy. In one study, nausea was decreased but vomiting was not. In another study, pyridoxine significantly reduced nausea scores, but only in patients with the most severe symptoms.

A number of randomized studies on the drug treatment of HEG have been performed.

Ondansetron (Zofran), a serotonin-receptor antagonist, showed no benefit over the antiemetic promethazine (Phenergan) at much greater cost.

In treating HEG, intramuscular adrenocorticotropic hormone (ACTH) had no benefit over the placebo.

A randomized, double-blind, crossover trial of a ginger extract was shown to be more beneficial than the placebo in reducing symptoms.

Promethazine (Phenergan) also has been compared to methylprednisolone in a randomized, double-blind, controlled trial. Methylprednisolone appeared to decrease the rate of readmission for HEG; however, the patients randomized to promethazine had a significantly longer duration of symptoms prior to treatment.

Diazepam (Valium) has been used in one randomized study and appeared to shorten hospitalization, significantly reduce nausea, and decrease readmission for HEG. No significant adverse effects or fetal abnormalities were observed.
　

Drug Category: Vitamin -- These agents are essential for normal DNA synthesis. They play a role in various metabolic processes.

Drug Category: Herbal medications -- These are non-FDA approved remedies believed to improve symptoms.

Drug Category: Antiemetics -- These agents are useful in the treatment of symptomatic nausea.

Drug Category: Antihistamine -- Studied in nausea and vomiting during pregnancy and in small numbers of patients with HEG, providing relief in 82% of patients. Appears to be as efficacious as pyridoxine in another study.

FOLLOW-UP

Further Inpatient Care:
　

MISCELLANEOUS

Medical/Legal Pitfalls:
　

• Considering other diagnoses in cases of severe refractory nausea and vomiting during pregnancy is important, especially if the presentation is atypical or other symptoms are present.

• Fully informing patients of the available evidence surrounding potential risks and benefits of all treatments administered for HEG is vital, especially regarding the effects of medications on the fetus. If not emergently required, avoid, if possible, the administration of drugs during the first 10 weeks of gestation.