OVERVIEW: What every practitioner needs to know

Are you sure your patient has hyperemesis? What are the typical findings for this disease?

Any reproductive age female with nausea, vomiting and general fatigue should be evaluated for pregnancy, including hyperemesis gravidarum (HG) in the differential diagnosis. As many adolescents will not be aware or actively present to their medical provider reporting suspected or known pregnancy, a thorough sexual history, LMP, and urine pregnancy test is critical for early diagnosis of HG.

Pregnant women of all ages with HG present with persistent vomiting, dehydration, and weight loss of more than 5%. Patients typically also have fluid and electrolyte abnormalities (elevated BUN and creatinine, hyponatremic hypochloremic hypokalemic metabolic alkalosis), ketonuria, and often require hospitalization for intravenous hydration and antiemetic therapy.

HG is a clinical diagnosis of excessive nausea, vomiting and clinical dehydration. HG is a diagnosis of exclusion once more serious and significant pathology is eliminated from the differential. In general, there may be a range of severity for HG but clinical criteria include: persistent nausea and vomiting, and dehydration with at least fluid and weight loss of more than 5%. Patients present with electrolyte abnormalities (elevated BUN and creatinine, hyponatremic hypochloremic hypokalemic metabolic alkalosis) and ketonuria.

• Historical features

  • Nausea and vomiting typically begin approximately 4 weeks after last menstrual period and reach a peak around 9 weeks of gestation

  • Consider other diagnoses if symptoms begin after 9 weeks of gestation, since symptoms being prior to that time in virtually all cases

  • For most patients, symptoms resolve by the end of the first trimester, but 10% continue to have symptoms after 20 weeks

  • Diagnosis also less likely in patients who were vomiting prior to pregnancy or complain of abdominal pain/fever/headache

• Physical exam findings

  • Fever, goiter, abdominal tenderness, back pain, abnormal neurologic exam make other diagnoses more likely

    • Abnormal neurologic exam may be present in rare complications of HG: central pontine myelinolysis, Wernicke's encephalopathy

  • Signs of dehydration consistent with chronic vomiting, e.g., tachycardia, hypotension, orthostatic changes

What other disease/condition shares some of these symptoms?

The evaluation for HG requires that other etiologies, both related to pregnancy and related to other organ systems be eliminated from the differential. See the list below and Figure 1 (Differential Diagnosis of Nausea and Vomiting in Pregnancy).

Figure 1

Differential diagnosis of nausea and vomiting in pregnancy

• Endocrine

  • Diabetic ketoacidosis

  • Addison's disease

  • Porphyria

  • Hyperthyroidism/hypothyroidism

• Gastrointestinal

  • Appendicitis

  • Infectious gastroenteritis

  • Helicobacter pylori

  • Biliary disease

  • Pancreatitis

  • Hepatitis

  • Peptic ulcer disease

  • Gastroparesis

  • Gastroparesis

  • Intestinal obstruction

  • Achalasia

  • Diaphragmatic hernia

• Genitourinary

  • Pyelonephritis

  • Uremia

  • Kidney stones

  • Degenerating uterine leiomyoma

  • Ovarian torsion

• Neurologic

  • Pseudotumor cerebri

  • Migraines

  • Vestibular lesions

  • Other conditions which increase intracranial pressure, e.g., tumor, bleeding

• Others

  • Eating disorder

  • Conversion/somatization disorder

  • Acute fatty liver of pregnancy

  • Preeclampsia

  • Premature contractions

  • Drug toxicity/intolerance, including iron

  • Food poisoning

What caused this disease to develop at this time?

Epidemiology

• 50-90% of women have nausea and vomiting in early pregnancy

• 1% of pregnant women suffer from more severe symptoms consistent with HG

• Women at higher risk of HG include those with

  • multiple fetuses

  • female fetus(es)

  • trophoblastic disease

  • first pregnancy

  • underlying endocrinologic or metabolic disease

  • obesity

  • history of motion sickness or migraines

  • history of HG in past pregnancies

  • first degree relatives who have had HG

  • low educational level/socioeconomic status

• HG is the most common indication for hospitalization during early pregnancy, and the second most common indication for hospitalization during all of pregnancy

  • Hospitalization typically lasts 3-4 days and readmission is relatively common

• Etiology: largely obscure, but there are a number of factors which appear to be associated with HG

  • HCG: Nausea and vomiting is associated temporally with increasing HCG levels, which raises estrogen levels, a known emetogen

    • Pregnancies with higher levels of HCG and increased placental mass, e.g., molar or multiple gestation, are at higher risk for HG

    • HCG increases thyroid hormone levels, which do not cause vomiting per se but elevated levels are associated with HG

  • Estrogen: a known cause of nausea and vomiting

  • Progesterone: a known cause of gastroparesis

  • Vitamin B deficiency: Nausea and vomiting improves when treated with vitamin B6, yet vitamin B6 levels do not predict response to vitamin B6 therapy

  • Psychological factors: Women who have poor coping mechanisms for dealing with excessive stress have been suggested to be more likely to experience excessive nausea and vomiting, but there are no good data which proves this. It has been suggested that HG is a conversion disorder but this also has not been proven. It is more likely that psychologic distress results from hyperemesis and chronic dehydration.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

• Urinalysis

  • Presence of ketones

  • High specific gravity

• Metabolic panel

  • Elevated BUN and creatinine associated with dehydration

  • Hypochloremic hypokalemic metabolic alkalosis associated with vomiting

  • Sodium changes

• Vitamins

  • Thiamine levels if considering treatment with IV fluids

• Liver function panel

  • Transaminases may be elevated (usually <300 U/L) and bilirubin may be high (<4 mg/dL)

• Amylase, lipase

  • May be mildy elevated. Higher levels indicate pancreatitis more likely

• TSH and free T4

  • TSH can be low and free T4 can be normal/high. Thyroid antibodies are not present. When T4 high, no hyperthyroid treatment necessary and repeat T4 after 20 weeks gestation if no other concerns for Graves' disease (e.g., bulging eyes, goiter)

• Helictobacter pylori

  • Consider testing prior to treating for heartburn or reflux symptoms, as its presence has been associated with HG

Would imaging studies be helpful? If so, which ones?

Pelvic ultrasound is used to confirm pregnancy and evaluate for multiple gestation/abnormal pregnancy.

If you are able to confirm that the patient has hyperemesis, what treatment should be initiated?

Earlier treatment can reduce risk of hospitalization and severity of disease.

Lifestyle/Dietary Changes

Early treatment for mild HG should include dietary and lifestyle changes which are generally low risk and potentially effective ways to reduce nausea and vomiting, maintain hydration, and improve nutrition. Patients should be advised to get adequate rest, with at least 8 hours of sleep every night. Dietary changes are not well studied regarding efficacy, but are a relatively easy first step in treatment. Patients may need to tailor a diet specific to their tastes and needs, often by trial and error.

Women should avoid substances which provoke nausea and vomiting, which may include fatty, heavy, spicy foods. Encouraging frequent, small, protein-rich meals every 1-2 hours may reduce nausea and vomiting. Iron-containing prenatal vitamins may be discontinued or switched to children's chewable tablets with folic acid supplements for the first 12 weeks of pregnancy when anemia is less likely. Sucking on popsicles or ice chips may ameliorate the metallic taste some women complain of which provokes vomiting. Patients should drink at least 2 liters of water daily to maintain hydration; drinking small quantities at a time throughout the day may help prevent vomiting. Additionally, drinking liquids at separate times from meals and maintaining an upright position after meals also may help prevent vomiting.

Pharmacotherapy

See Table I, Selected Agents Used to Treat Nausea and Vomiting of Pregnancy.

Table I

Providers should initiate pharmacotherapy with oral pyroxidine (vitamin B6), which has been proven to be effective and carries no risk of harm. Oral doxylamine may be added to pyridoxine as needed.

If there is no response to these modalities, promethazine (PO/PR) or dimenhydrinate (PO/PR) can be added.

Providers may also opt to stop doxylamine when adding these medications.

If there continues to be no response, metoclopromide (IM/PO) or trimethobenzamide (PR) can be added.

If the patient is not dehydrated, metochlorpramide (IM/PO), promethazine (IM/PO/PR), or trimethobenzamide (PR) can be added. If the patient is dehydrated, intravenous hydration should be initiated (see below, "Nutritional supplementation/rehydration"), and dimenhydrinate IV, metochlopramide IV, or promethazine IV should be added to therapy. If there is still no response, zofran IV can be started. Methylprednisolone (PO/IV) should be used only as a last resort when other pharmacotherapy is not effective. If used at all, it should be used after 10 weeks gestation due to increased risk of oral clefts when used earlier in the first trimester.

Complementary therapies may also be helpful in treatment. Ginger has been documented to be effective in the treatment of nausea and vomiting of pregnancy, and is low risk; it may be added at any time in treatment. P6 acupressure may also be effective.

Nausea and vomiting is more frequent in patients with pregnancy-related heartburn. It may be effective in some patients to add acid reflux pharmacotherapy as adjunct therapy. Antacids, H2-histamine blockers, and proton pump inhibitors are well studied to be safe in pregnancy. In addition, consider testing for helicobacter pylori, as treatment may help ameliorate reflux symptoms.

Nutritional Supplementation/Rehydration

Nutritional supplementation and rehydration therapy may be considered for any patient with dehydration or persistent weight loss, in order to help ensure normal fetal growth and development and restore adequate maternal nutritional stores.

Dehydrated patients should be treated with intravenous fluid replacement, e.g., 500 ml 5% dextrose normal saline at 50 ml/hour. Patients who have vomited for more than 3 weeks should be treated with thiamine 100 mg IV daily for 2-3 days and providers should consider checking thiamine levels in order to avoid Wernicke's encephalopathy. Then, a multivitamin supplement should be considered, consisting of vitamins B1 (thiaminchloride) 200 mg, B6 (pyridoxine) 200 mg, B12 (cyanocobalamine) 200 mg, C (ascorbic acid) 2000 mg.

Placement of a nastogastric feeding tube should be attempted prior to parenteral nutrition. Refractory cases of HG may benefit from jejunostomy tubes, which have shown to be well tolerated and safe in one small case series. Patients intolerant of enteral nutrition should be treated with parenteral nutrition. This is typically a last resort treatment in life threatening cases of HG with no tolerance for food and with concerns for maternal nutrition and fetal growth. Peripheral nutrition with high lipid formulation best for short term supplementation.

Patients with higher caloric needs or longer term treatment may need total parenteral nutrition. Central and peripheral placement of lines are associated with high maternal morbidity, including line sepsis, thrombosis, and metabolic abnormalities, relegating this modality as a last resort.

What are the adverse effects associated with each treatment option?

Total parenteral nutrition can be associated with line sepsis/thromboembolic disease (25% of cases in one study of central line placement in obstetric patients, and 66% of HG patients with a peripheral line placed for nutrition), steatohepatitis.

See Table I for adverse effects of medication and complementary therapies.

What are the possible outcomes of hyperemesis?

• Patients with HG should be advised that safe and effective treatment is available and can reduce the risk of complications (See Table I for risks/benefits of specific agents)

  • If one agent is not effective, there are others available to try

• Parenteral/enteral nutritional supplementation may be indicated

• Symptoms generally improve/resolve around the end of the first trimester, but some women continue to have symptoms

• Pregnancy outcome is generally good

  • There is an increased chance of having a baby with low birth weight

  • Fetal demise is extremely rare

• More common complications include hospitalization, depression, and stress. Occasionally, maternal stress is so high that patients opt to terminate pregnancy

• There are some rare but serious maternal complications, including Wernicke's encephalopathy, acute tubular necrosis, and esophageal rupture

What causes this disease and how frequent is it?

Epidemiology

• 50-90% of women have nausea and vomiting in early pregnancy

• 1% of pregnant women suffer from more severe symptoms consistent with HG

• Women at higher risk of HG include those with

  • multiple fetuses

  • female fetus(es)

  • trophoblastic disease

  • first pregnancy

  • underlying endocrinologic or metabolic disease

  • obesity

  • history of motion sickness or migraines

  • history of HG in past pregnancies

  • first degree relatives who have had HG

  • low educational level/socioeconomic status

• HG is the most common indication for hospitalization during early pregnancy, and the second most common indication for hospitalization during all of pregnancy

  • Hospitalization typically lasts 3-4 days and readmission is relatively common

• Etiology: largely obscure, but there are a number of factors which appear to be associated with HG

  • HCG: Nausea and vomiting is associated temporally with increasing HCG levels, which raises estrogen levels, a known emetogen

    • Pregnancies with higher levels of HCG and increased placental mass, e.g., molar or multiple gestation, are at higher risk for HG

    • HCG increases thyroid hormone levels, which do not cause vomiting per se but elevated levels are associated with HG

  • Estrogen: a known cause of nausea and vomiting

  • Progesterone: a known cause of gastroparesis

  • Vitamin B deficiency: Nausea and vomiting improves when treated with vitamin B6, yet vitamin B6 levels do not predict response to vitamin B6 therapy

  • Psychological factors: Women who have poor coping mechanisms for dealing with excessive stress have been suggested to be more likely to experience excessive nausea and vomiting, but there are no good data which proves this. It has been suggested that HG is a conversion disorder but this also has not been proven. It is more likely that psychologic distress results from hyperemesis and chronic dehydration.

Women who have sisters or mothers who have had HG in pregnancy are more likely to suffer from the disease.

How do these pathogens/genes/exposures cause the disease?

Maternal genotype appears to play a larger role than fetal genotype in a recent large population-based study. Women who were exposed to HG in utero were more likely to experience hyperemesis when they were pregnant. Exposed men were not more likely to have offspring who had HG.

Other clinical manifestations that might help with diagnosis and management

• Patients with HG might present with the following rare neurologic presentations:

  • Wernicke's encephalopathy: ataxia, opthalmoplegia, confusion, and impaired short term memory

  • Korsakoff's syndrome: anterograde amnesia, retrograde amnesia, confabulation, meager content in conversation, apathy, difficulty with insight

• High index of suspicion is crucial because disease can have permanent neurologic consequences, including death

What complications might you expect from the disease or treatment of the disease?

Common complications

• Hospitalization for antiemetic therapy and nutritional supplementation/hydration

• Psychological sequelae

  • Associated with anxiety and depression, probably as a consequence of symptoms and not a cause

  • Many patients feel they do not have support from their partner and feel their complaints are undervalued by their health care providers

  • Strained family relationships

  • Impaired job performance

  • Some women terminate pregnancy due to severity of symptoms

Rare, serious maternal complications

• Medication side effects such as

  • Antihistamines, promethazine, metoclopramide: decreased level of consciousness, seizures, cardiac rhythm changes, hallucinations

  • Doxylamine, dimenhydrinate, promethazine, metoclopramide, prochlorperazine, methylprednisolone: headache, myalgias, tremor, fevers

• Wernicke's encephalopathy, due to thiamine deficiency

  • Presents with ataxia, ophthalmoplegia, confusion, impaired short term memory

  • Generally occurs after hyperemesis symptoms lasting > 3 weeks

  • Can also be triggered by IV dextrose in setting of low thiamine levels

  • Patients may suffer permanent neurologic damage/death

• Central pontine myelinolysis

  • Occurs following too rapid correction of hyponatremia

• Esophageal rupture

• Pneumothorax

• Splenic avulsion

• Peptic ulcer disease

• Refeeding syndrome

• Complications due to parenteral nutrition as stated above

Postpartum complications

• Women with weight loss may have longer postpartum recovery times and postpartum persistence of psychological and physical symptoms

  • Post traumatic stress disorder symptoms

  • Food aversions

  • Muscle pain

  • Nausea

• Infants are more likely to have lower birth weight

How can hyperemesis be prevented?

Taking a multivitamin around the time of conception may reduce the severity of nausea and vomiting.

Early treatment of nausea and vomiting can prevent HG and its complications.

Avoiding stimuli which cause vomiting can reduce severity of disease.

What is the evidence?

"Guideline summary: Nausea and vomiting of pregnancy". National Guideline Clearinghouse (NGC). 2011 Mar 18. http://www.guideline.gov.

(Based upon guidelines released by the American College of Obstetricians and Gynecologists in 2004 and reaffirmed in 2009: Source: American College of Obstetricians and Gynecologists (ACOG). Nausea and vomiting of pregnancy. ACOG Practice bulletin 52. Obstetrics and Gynecology 103 (4): 803-815. The College of Family Physicians of Canada published similar recommendations in 2002:)

Levicheck, L, Atanackovic, G, Oepkes, D. "Nausea and vomiting of pregnancy: Evidence-based treatment algorithm". Canadian Family Physician. vol. 48. pp. 267-277.

(Level A Recommendations based on good and consistent scientific evidence: Multivitamin use around conception time may reduce the severity of nausea and vomiting. Firstline pharmacologic treatment for nausea and vomiting includes vitamin B6 +/- doxylamine, which is safe and effective in pregnancy. Without other evidence of thyroid disease, HG patients who have low TSH levels should not be treated for hyperthyroidism. Level B Recommendations based on limited or inconsistent scientific evidence: Ginger can be considered as a treatment option for nausea and vomiting in pregancy. Antihistamine H1 receptor blockers, phenothiazines, and benzamides are safe and effective in the treatment of nausea and vomiting requiring pharmacotherapy. Treatment with methylprednisolone may be beneficial as a last resort in HG because of its associated risk. Early treatment of nausea and vomiting can help prevent hyperemesis. Level C Recommendations based primarily on consensus and expert opinion: Patients who are dehydrated or who cannot tolerate oral hydration should be treated with IV hydration. Providers should strongly consider correction of ketosis and vitamin deficiencies. Patients who have had prolonged vomiting should be administered dextrose and vitamins, especially thiamine. Patients who lose weight due to vomiting should be given enteral or parenteral nutrition.)

Additional references and reviews:

Matthews, A, Dowswell, T, Haas, DM, Doyle, M, O'Mathuna, DP. "Interventions for nausea and vomiting in early pregnancy". Cochrane Database Syst Rev. 2010 Sep 8.

(Reviewed 27 trials (4041 women) that evaluated a variety of pharmacologic and nonpharmacologic treatment. Ginger, vitamin B6, and anti-emetic drugs had limited inconsistent evidence. P6 acupressure had limited evidence with no demonstration of effectiveness but no harm. There was little evidence on adverse outcomes (fetal as well as maternal, including psychosocial). They conclude that high quality evidence is lacking for this high pr to support that advice. The difficulties in interpreting the results of the studies included in this review highlight the need for specific, consistent and clearly justified outcomes and approaches to measurement in research studies.)

Ebrahimi, N, Maltepe, C, Einarson, A. "Optimal management of nausea and vomiting of pregnancy". International Journal of Women's Health.. vol. 4. 2010. pp. 241-248.

(Canadian medical societies 2010 review of current management of HG with easy to use treatment algorithm.)

Jueckstock, JK, Kaestner, R, Mylonas, I. "Managing hyperemesis gravidarum: a multimodal challenge". BMC Medicine. vol. 8. 2010. pp. 46.

(British perspective on HG.)

Niebyl, JR. "Nausea and vomiting in pregnancy". NEJM. vol. 363. 2010. pp. 1544-1550.

(New England Journal of Medicine case vignette with overview of current US formal guidelines.)

Ongoing controversies regarding etiology, diagnosis, treatment

The cause of nausea and vomiting of pregnancy and HG remains unclear.

Predictive factors regarding patient response to therapy are obscure.

The efficacy of complementary therapies continues to be investigated.

The role of Helicobacter pylori in hyperemesis is controversial.

The psychosocial and economic implications of HG continue to be investigated.