NORD gratefully acknowledges 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.
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.
A recent systematic review and meta-analysis of existing studies showed that infants of women who experienced hyperemesis gravidarum are significantly more likely to exhibit a lower birth weight, be small for gestational age, and to be born prematurely. 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.
Only a few studies exist in the medical literature examining the long-term effects hyperemesis gravidarum may have on exposed offspring. One such study showed 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. Additionally, another study showed 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. And a third study concluded adult offspring exposed to HG in utero were 3.6 times more likely to have a psychological and behavioral disorder with diagnoses primarily of depression, bipolar disorder and anxiety when compared to non-exposed offspring.
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. Studies suggest familial aggregation of hyperemesis gravidarum as there is a remarkably high prevalence of affected siblings and mothers of patients affected with nausea and vomiting of pregnancy and hyperemesis gravidarum, and a significantly increased risk to daughters and sisters of women with a history of HG. 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 or increasing the duration of hyperemesis gravidarum including a history of hyperemesis gravidarum in a previous pregnancy, a family history of severe nausea/vomiting in pregnancy, younger maternal age, high body weight (obesity), no previous completed pregnancies (nulliparity), carrying multiples, a first-time pregnancy, allergies, and a restrictive diet.
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. Over 192,000 hospital visits and/or admissions occur in the US annually and approximately 4,000 Canadian women a year experience hyperemesis gravidarum, according to estimates from the U.S. Healthcare Cost and Utilization Project, and the Society of Obstetricians and Gynecologists of Canada. 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.
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.
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.
In some persistent cases of hyperemesis gravidarum, drugs that may lessen nausea and vomiting can be prescribed (antiemetic drug therapy). In a recent study of 254 women with HG in the US, 36 different medications/treatments were administered and among the most common (antacids, antihistamines, intravenous fluids, promethazine, metoclopramide, sea-bands, special diet, vitamins, and ondansetron) patients self-reported that ondansetron and/or intravenous fluids were the most effective (approximately 50%) in treating HG. A recent clinical trial of ondansetron compared to doxylamine/pyridoxine also found ondansetron to be superior in the treatment of nausea and vomiting of pregnancy, and a recent review found it was not significantly associated with increased risk of adverse fetal outcome.
Currently a clinical trial is underway comparing the effectiveness of ondansetron to gabapentin for treating hyperemesis gravidarum. However, it should be noted that a case of maternal intestinal obstruction and ondansetron has been reported. Importantly, most medications/treatments have not been studied thoroughly in pregnant women with HG, and their FDA approval labeling may caution that they are not approved for pregnant or nursing women. Because most medications are not very effective in treating severe hyperemesis and/or many women fear medication in pregnancy, there is a high rate of therapeutic termination. While the long-term effect on the mother and exposed child are currently unknown, it is also important to consider that 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: [email protected]
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
For more information on the Genetics and Epidemiology of Hyperemesis Gravidarum Study, please contact Dr. Marlena Fejzo at [email protected] or read more at http://www.helpher.org/HER-Research/opportunities.php
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