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Hyperemesis Gravidarum
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Copyright 1999, 2002, 2003, 2006, 2009
NORD is grateful to Marlena S. Fejzo, PhD, Assistant Professor of Research, Department of Maternal-Fetal Medicine, USC, Department of Medicine, UCLA, for assistance in the preparation of this report.
Synonyms of Hyperemesis Gravidarum
Disorder Subdivisions
General Discussion
Hyperemesis gravidarum (HG) is a rare disorder characterized by severe and persistent nausea and vomiting during pregnancy that may necessitate hospitalization. As a result of frequent nausea and vomiting, affected women experience dehydration, vitamin and mineral deficit, and the loss of greater than five percent of their original body weight.
Nausea and vomiting of pregnancy (NVP), more widely known as morning sickness, is a common condition of pregnancy. Many researchers believe that NVP should be regarded as a continuum of symptoms that may impact an affected woman's physical, mental and social well-being to varying degrees. Hyperemesis gravidarum represents the severe end of the continuum. No specific line exists that separates hyperemesis gravidarum from NVP; in most cases, affected individuals progress from mild or moderate nausea and vomiting to hyperemesis gravidarum. The exact cause of hyperemesis gravidarum is not known.
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Symptoms
Hyperemesis gravidarum may develop rapidly within a few weeks or gradually over a few months. Individuals with hyperemesis gravidarum experience severe and persistent nausea and vomiting that occur before the 20th week of pregnancy (gestation) and are severe enough to result in progressive weight loss of greater than five percent of their original body weight. In addition, frequent vomiting may also lead to dehydration and vitamin and mineral deficit. Hyperemesis gravidarum often leads to hospitalization to restore lost fluids and nutrients to affected women.
Additional symptoms associated with hyperemesis gravidarum may include rising pulse rate, excessive salivation (ptyalism), and a rapid heartbeat (tachycardia). In some cases, affected individuals may have a distinct odor to their breath (ketonic odor). Symptoms associated with the disorder may subside and recur ("wax and wane") resulting in affected individuals being hospitalized more than once during their pregnancy.
Quality of life is also affected. Individuals are often unable to work, complete daily household tasks and routines, care for young children and, in some cases, may elect to skip social activities and functions. Persistent and severe nausea and vomiting associated with hyperemesis gravidarum may put a strain on various family relationships as well.
Few studies exist in the medical literature as to the effect hyperemesis gravidarum may have on exposed offspring. Most studies fail to demonstrate any difference between infants of women who experience hyperemesis gravidarum during pregnancy, and women who do not. However, some researchers have reported that infants of women who experienced hyperemesis gravidarum often exhibit a lower birth weight than infants of women who did not have the disorder. In addition, some research has shown that low birth weight was more common in infants of women who were repeatedly hospitalized for hyperemesis gravidarum than infants of women who were hospitalized only once.
A few studies on children born to mothers with persistent nausea have shown possible long-term effects. Children whose mothers reported nausea in middle or late pregnancy had lower (task persistence) at age 5 (a marker of attention span) and were viewed by teachers as having more attention and learning problems at age 12. Approximately 9% of women with extreme weight loss in pregnancy (greater than 15% of pre-pregnancy weight) due to hyperemesis report having a child with a behavioral disorder.
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Causes
The exact cause of hyperemesis gravidarum is not known. Some theories concerning the cause of hyperemesis gravidarum include pregnancy hormone imbalances, vitamin B deficiency; hyperthyroidism; gastroesophageal reflux occurring in association with abnormalities in the electrical properties of muscles affecting the stomach (gastric dysrhythmias); Helicobacter Pylori infections; psychological factors; and disturbances in carbohydrate metabolism.
Many of these theories are based on symptoms coexisting with hyperemesis gravidarum that are just as likely to be caused by hyperemesis as they are to be causal. For example, many affected women are unable to tolerate vitamins and normal nutrition in pregnancy and therefore may develop vitamin deficiencies, thyroid, and other metabolic disturbances. Additionally, while in the first half of the 1900s theories for hyperemesis were dominated by far-fetched psychological proposals such as rejection of pregnancy due to embarrassment about sexual relations or fear of childbirth and motherhood, more recently, scientific studies have shown that 94% of women with hyperemesis have no prior psychiatric history and although women may be depressed or anxious during pregnancy when they are too nauseous to eat healthfully or care for their families, they revert back to normal when their extreme physical symptoms subside.
Finally, many women with no or normal nausea in pregnancy have H. Pylori infections and/or abnormally high levels of pregnancy hormones such as hCG and estrogen. Thus, despite several clinical studies, researchers have been unable to definitively determine why hyperemesis gravidarum occurs.
Several lines of evidence support a genetic predisposition to nausea and vomiting in pregnancy. In a study of nausea and vomiting of pregnancy in twins, concordance rates were more than twice as high for monozygotic compared to dizygotic twins. There is a remarkably high prevalence of affected siblings and mothers of patients affected with nausea and vomiting of pregnancy and hyperemesis gravidarum. Additionally, a biologic component to the condition has been suggested from animal studies. There are also data suggestive of a role for genetic predisposition in the development of nausea and vomiting of pregnancy. However, the cause of hyperemesis gravidarum is currently unknown and the rationale for maintenance of genes that predispose to dehydration and malnutrition in pregnancy remains an evolutionary enigma. One would think that a condition that commonly resulted in maternal and fetal death before the introduction of intra venous fluids in the 1950s would have been strongly selected against in nature. Studies are currently being done to identify the cause of hyperemesis gravidarum and more information can be found at http://www.helpher.org/HER-Research/opportunities.php.
Some researchers have reported that certain factors may be associated with an increased risk of developing hyperemesis gravidarum including younger maternal age, high body weight (obesity), no previous completed pregnancies (nulliparity), carrying twins, a first-time pregnancy, a family history, and/or a history of hyperemesis gravidarum in previous pregnancies.
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Affected Populations
While nausea and vomiting of pregnancy in general is estimated to occur in 50 to 90 percent of all pregnancies, hyperemesis gravidarum is estimated to occur in .5 to two percent of pregnant women. Approximately 60,000 women in the United States and 4,000 Canadian women a year experience hyperemesis gravidarum, according to estimates from the Center for Disease Control and the Society of Obstetricians and Gynecologists of Canada, based upon American data. It is the second leading cause of hospitalization in early pregnancy and is more common in non-white and Asian populations.
Hyperemesis gravidarum, like nausea and vomiting of pregnancy, usually occurs before the 20th week of pregnancy often between the fourth and tenth week. In many cases, as with mild or moderate nausea and vomiting of pregnancy, symptoms resolve before 20 weeks. However, cases have been reported in which symptoms persisted after 20 weeks, and as many as 22 percent of cases may have symptoms that last until term. Hyperemesis gravidarum often occurs during first pregnancies and usually recurs in subsequent pregnancies.
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Related Disorders
Symptoms of the following disorders can be similar to those of hyperemesis gravidarum. Comparisons may be useful for a differential diagnosis:
Many disorders and conditions affecting the digestive tract (gastrointestinal disorders) are associated with nausea and vomiting. Such disorders and conditions include acute inflammation of the appendix (appendicitis), inflammation of the pancreas (pancreatitis), bowel obstruction, peptic disorders and a flu-like illness that is characterized by nausea, vomiting, fever, and diarrhea and is caused by a virus (viral gastroenteritis) (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
Many disorders and conditions affecting the reproductive and urinary systems (genitourinary tract) may also be associated with nausea and vomiting. Such disorders or conditions include inflammation of the kidneys and pelvis (pyelonephritis), degeneration of abnormal growths of fibrous tissue (fibroid degeneration), and a twisted ovarian cyst (ovarian torsion). (For more information on these disorders, choose the specific disorder as your search term in the Rare Disease Database.)
Hepatitis is an inflammation of the liver that, in some cases, may cause temporary or permanent damage. At least six forms of hepatitis have been identified (i.e., hepatitis types A, B, C, D, E, and G). Common symptoms associated with hepatitis include fatigue, mild fever and gastrointestinal problems such as nausea and vomiting and a general feeling of discomfort in the stomach. Hepatitis is usually caused by viruses. However, other causes have been identified, including bacteria, certain chemicals, alcoholism, and other medical disorders. (For more information on this disorder, choose "hepatitis" as your search term in the Rare Disease Database.)
Additional disorders and conditions associated with nausea and vomiting include diabetes, lesions of the central nervous system, thyroid dysfunction, toxic effects of certain drugs (drug toxicity) and disorders affecting the ear and/or ear canal (vestibular disorders). Certain conditions associated with pregnancy may also cause nausea and vomiting, including carrying twins, high blood pressure caused by pregnancy (pregnancy-induced hypertension), excess amniotic fluid (hydramnios) and hydatidiform mole (a condition in which a mass of cysts develops in the fertilized egg). (For more information on these disorders, choose the specific disorder as your search term in the Rare Disease Database.)
The following disorder may be associated with hyperemesis gravidarum as a secondary characteristic. It is not necessary for a differential diagnosis:
Wernicke's encephalopathy is a neurological disorder characterized by confusion, an impaired ability to coordinate voluntary movements (ataxia), and paralysis of certain eye muscles (ophthalmoplegia). Additional symptoms may include drowsiness, lack of emotions (apathy) and rapid, involuntary eye movements (nystagmus). Wernicke's encephalopathy is caused by a deficiency of vitamin B1 (thiamine). (For more information on this disorder, choose "Wernicke " as your search term in the Rare Disease Database.)
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Standard Therapies
The diagnosis of hyperemesis gravidarum may be confirmed by a thorough clinical evaluation, detailed patient history, and the identification of characteristic symptoms (e.g., persistent and severe nausea and vomiting, dehydration, and weight loss). The diagnosis is one of exclusion as other causes of nausea and vomiting during pregnancy must be ruled out. Physicians should determine the frequency of nausea and vomiting and the extent to which they affect an affected individual's daily life.
Treatment
The diagnosis of hyperemesis gravidarum should lead to immediate hospitalization of an affected individual in order to restore fluids and replace electrolytes by infusing medication and fluids through veins (intravenously). Food should not be given through the mouth (orally) until vomiting stops and dehydration has been corrected. Instead, food may be supplied by way of the intestines (enteral feeding) or by injection through some other route (parenteral feeding).
Vitamin supplementation (particularly vitamins B6, C and thiamine) may also be recommended. Thiamine supplementation is specifically recommended to prevent the development of Wernicke's encephalopathy.
With these treatments, in many cases, vomiting may stop. If vomiting continues, antiemetic drug therapy may be recommended. (For more information on antiemetic drugs, see the Investigational Therapies section of this report.)
After vomiting stops, affected individuals should receive enteral nutritional supplementation as needed to calm nausea. Physicians should then slowly and carefully reintroduce fluids and small, frequent meals into an affected individual's diet. Meals should consist of foods that are high in carbohydrates and low in fat.
In some cases, counseling may be recommended for women to help deal with the complications of hyperemesis gravidarum. In addition, treatments for mild or moderate nausea and vomiting in pregnancy may also be of benefit. These common treatments include plenty of bed rest, avoiding odors that may trigger an episode of nausea or vomiting, and dietary changes (i.e., avoiding foods that worsen nausea and vomiting). However, no clinical data exist to prove the effectiveness of these treatments.
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Investigational Therapies
In some persistent cases of hyperemesis gravidarum, drugs that prevent or lessen nausea and vomiting may be prescribed (antiemetic drug therapy). In Canada, the drug diclectin, which contains an antihistamine (doxylamine succinate) and vitamin B6 (pyridoxine), is approved for treatment of nausea and vomiting of pregnancy. Diclectin is the only drug in Canada labeled as safe and effective to treat nausea and vomiting of pregnancy. It is not currently available in the United States, but papers presented at a May 2002 conference on Understanding and Treating Nausea and Vomiting of Pregnancy, sponsored by the National Institute of Child Health and Human Development and The Office of Rare Diseases, National Institutes of Health, proposed that its possible use in the U.S. be studied.
The ingredients of diclectin are the same as those of bendectin, a drug used to treat nausea and vomiting in pregnancy in the United States from 1956 to 1983. After numerous lawsuits were filed claiming bendectin caused various birth defects, the drug’s manufacturer voluntarily withdrew it from the market, citing rising legal costs and negative publicity. However, despite bendectin’s becoming the most studied drug in regard to pregnancy, no research has ever demonstrated an increased incidence of birth defects in association with the use of bendectin. In fact, the Food and Drug Administration (FDA) has determined that bendectin was not withdrawn from the market for reasons of safety or effectiveness.
Other antihistamines have been used to treat nausea and vomiting in pregnancy, sometimes in conjunction with diclectin. These include dimenhydrinate (Gravol), hydroxyzine (Atarax), and promethazine (Phenergan). Most medications are not very effective in treating severe hyperemesis, leading to a high rate of therapeutic termination. In the U.S., serotonin inhibitors such as Ondansetron (Zofran), intravenous fluids, and steroids are reported by patients to be the most effective in treating nausea and vomiting, but none are cures. Importantly, these drugs have not been studied thoroughly in pregnant women, and their FDA approval labeling cautions that they are not approved for pregnant or nursing women. While these drugs have been studied in pregnant women and have not been shown to increase the risk of congenital anomalies (with the exception of first trimester exposure to steroids), the long-term effect on the mother and exposed child are currently unknown. However, the long-term effects of nutritional disturbances caused by untreated hyperemesis are equally understudied. Meanwhile the link between poor diet in otherwise normal pregnancies and cross-generational effects are well known and are likely to be mimicked in some cases of hyperemesis gravidarum.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For more information on the Genetics and Epidemiology of Hyperemesis Gravidarum Study, please contact Dr. Marlena Fejzo at nvpstudy@usc.edu or read more at http://www.helpher.org/HER-Research/opportunities.php.
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Organizations related to Hyperemesis Gravidarum
- Genetic and Rare Diseases (GARD) Information Center
PO Box 8126
Gaithersburg MD 20898-8126
Phone #: 301-251-4925
800 #: 888-205-2311
e-mail: http://rarediseases.info.nih.gov/GARD/EmailForm.aspx
Home page: http://rarediseases.info.nih.gov/GARD
- NIH/National Institute of Child Health and Human Development
31 Center Dr
Building 31, Room 2A32
MSC2425
Bethesda MD 20892
Phone #: 301-496-5133
800 #: --
e-mail: N/A
Home page: http://www.nichd.nih.gov/
- NIH/Office of Research on Women's Health
6707 Democracy Blvd.
Suite 400
Bethesda MD 20892-5484
Phone #: 301-402-1770
800 #: --
e-mail: N/A
Home page: http://www.4.od.nih.gov/orwh
- National Healthy Mothers, Healthy Babies Coalition
2000 N. Beauregard Street
6th Floor
Alexandria VA 22311
Phone #: 703-836-6110
800 #: --
e-mail: info@hmhb.org
Home page: http://www.hmhb.org
- National Women's Health Network
514 10th Street NW
Suite 400
Washington D.C. 20004
Phone #: 202-628-7814
800 #: --
e-mail: nwhn@nwhn.org
Home page: http://www.womenshealthnetwork.org
- National Women's Health Resource Center
157 Broad Street
Suite 315
Red Bank NJ 07701
Phone #: 732-530-3425
800 #: 877-986-9472
e-mail: mchin@healthywomen.org
Home page: http://www.healthywomen.org
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