NORD gratefully acknowledges Marlena S. Fejzo, PhD, Associate Researcher, Department of Maternal-Fetal Medicine, USC, Department of Medicine, UCLA, for assistance in the preparation of this report.
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 5% 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. Affected individuals can progress from mild or moderate nausea and vomiting to hyperemesis gravidarum. While the cause of HG is likely multifactorial, currently, the most evidence exists for the placenta and appetite hormone GDF15 as playing an important role in the etiology of HG.
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 5% of their original body weight. In addition, frequent vomiting may 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). Some affected women 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 or care for young children and 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 systematic review and meta-analysis of existing studies show that infants of women who experienced hyperemesis gravidarum are significantly more likely to have a lower birth weight, be small for gestational age, and to be born prematurely. 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. Adverse birth outcomes have also been associated with low maternal weight gain and/or prolonged symptoms.
Mounting evidence suggests there can be long-term effects of hyperemesis gravidarum on exposed offspring. One such study showed children whose mothers reported nausea in middle or late pregnancy had lower task persistence at age 5 which is a marker of attention span, and at age 12 were viewed by teachers as having more attention and learning problems. 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. More recent studies suggest exposure in utero to HG is associated with an increased risk in offspring for neurodevelopmental delay including autism spectrum disorder, attention deficit disorder, learning difficulty or delay, depression, anxiety and sensory integration or processing disorders.
Currently, the most evidence exists for the placenta and appetite hormone GDF15 as playing a role in the etiology of HG. Genetic evidence also supports a role for the hormone receptors GFRAL and PGR, and for IGFBP7. Outdated theories concerning the cause of hyperemesis gravidarum include the pregnancy hormone hCG, 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 and it is not yet clear if they cause hyperemesis or result from HG. 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 explanations 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 they 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. In addition, many women with no or normal nausea in pregnancy have H. Pylori infections and/or abnormally high levels of the pregnancy hormone hCG. The studies of these past theories, some researched for decades, have led to contradictory conclusions and are unlikely to play major roles in the causation of HG.
Recent studies using a genetic approach have identified factors that are more likely to be involved in the etiology of HG. In particular, a study of over 53,000 23andMe research participants identified an association between genetic variants in the placenta and appetite genes GDF15 and IGFBP7 and HG. These findings were replicated in a separate cohort in whom variants in other genes were also found to be associated with HG including the GDF15 gene, the GDF15 receptor gene, GFRAL, localized to the vomiting center of the brain, and the progesterone receptor gene PGR. It is important to note that no association was found between HG and the hCG receptor. Additionally, studies have detected abnormally high blood levels of GDF15 (and IGFBP7 in one study) but not hCG in women with HG. Hyperthyroidism, nutrient deprivation, long-term fasting, potassium depletion and infection are all associated with HG pregnancies, and result in increasing GDF15 levels. Thus, there may be a cyclical effect whereby genetic factors contribute initially to abnormal levels of GDF15, which is then increased further by these other contributing factors.
Reports of additional factors that 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. In addition, rare mutations in genes coding for the serotonin receptor, thyroid-stimulating hormone receptor, and the ryanodine receptor 2 in families with HG suggest these receptors may also play a role in a subset of patients with familial HG.
While nausea and vomiting of pregnancy in general is estimated to occur in 50 to 90% of all pregnancies, hyperemesis gravidarum is estimated to occur in .5 to 2% of pregnant women. Over 192,000 hospital visits and/or admissions occur in the US annually for HG 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. HG is the second leading cause of hospitalization in early pregnancy and is more common in non-white and Asian populations. In addition, emergency department visits for HG are on the rise with over 285,000 visits per year in United States in 2014.
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 HG patients, symptoms resolve before 20 weeks. However, cases have been reported in which symptoms persisted after 20 weeks and as many as 22% 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 the woman’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 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.
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). Some antiemetics used to treat HG include doxylamine/pyridoxine, diphenhydramine, metoclopramide, ondansetron and corticosteroids. In a 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 recent reviews find it is either not significantly associated or minimally associated with increased risk of adverse fetal outcome. More studies are needed to determine whether this unconfirmed minimal risk is greater than the risk to the mother/offspring if left untreated.
A clinical trial is currently underway comparing the effectiveness of ondansetron to gabapentin for treating hyperemesis gravidarum. It should be noted that a case of maternal intestinal obstruction and ondansetron has been reported and stool softeners may be recommended with use in cases of severe constipation. 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 women discontinuing drug therapies. There is also increasing use of cannabis to self-treat HG. 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 and dehydration 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.
A free HG Care App for iphone https://apps.apple.com/us/app/hg-care/id1148105670 developed to track HG symptoms and share a report with providers has been shown to improve communication and care. A trial is currently being conducted to determine whether it improves outcomes.
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:
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