Hyperemesis Gravidarum 

Nausea and vomiting in pregnancy is extremely common. Hyperemesis gravidarum (HEG) is the most severe form of nausea and vomiting in pregnancy. 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 hyperemesis gravidarum.

Studies estimate that nausea and vomiting occurs in 50-90% of pregnancies. The nausea and vomiting associated with pregnancy usually begins by 9-10 weeks of gestation, peaks at 11-13 weeks, and resolves in most cases by 12-14 weeks. In 1-10% of pregnancies, symptoms may continue beyond 20-22 weeks.^{[1, 2]}

Normal nausea and vomiting may be an evolutionary protective mechanism—it may protect the pregnant woman and her embryo from harmful substances in food, such as pathogenic microorganisms in meat products and toxins in plants, with the effect being maximal during embryogenesis (the most vulnerable period of pregnancy). This is supported by studies showing that women who had nausea and vomiting were less likely to have miscarriages and stillbirth.^{[3, 4]}

Hyperemesis gravidarum is characterized by persistent nausea and vomiting associated with ketosis and weight loss (>5% of prepregnancy weight). Hyperemesis gravidarum may cause volume depletion, electrolytes and acid-base imbalances, nutritional deficiencies, and even death. Severe hyperemesis requiring hospital admission occurs in 0.3-2% of pregnancies.^[5]

The physiologic basis of hyperemesis gravidarum is controversial. Hyperemesis gravidarum appears to occur as a complex interaction of biological, psychological, and sociocultural factors. The following theories have been proposed:

Hormonal changes

Women with hyperemesis gravidarum often have high hCG levels that cause transient hyperthyroidism. hCG can physiologically stimulate the thyroid gland thyroid-stimulating hormone (TSH) receptor. hCG levels peak in the first trimester. Some women with hyperemesis gravidarum appear to have clinical hyperthyroidism. However, in a larger portion (50-70%), 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. In transient hyperthyroidism of hyperemesis gravidarum, thyroid function normalizes by the middle of the second trimester without antithyroid treatment. Clinically overt hyperthyroidism and thyroid antibodies are usually absent.^{[4, 6, 7, 5]}

A report on a unique family with recurrent gestational hyperthyroidism associated with hyperemesis gravidarum showed a mutation in the extracellular domain of the TSH receptor that made it responsive to normal levels of hCG. Thus, cases of hyperemesis gravidarum with a normal hCG may be due to varying hCG isotypes.^{[8, 9]}

A positive correlation between the serum hCG elevation level and free T4 levels has been found, and the severity of nausea appears to be related to the degree of thyroid stimulation. hCG may not be independently involved in the etiology of hyperemesis gravidarum but may be indirectly involved by its ability to stimulate the thyroid. For these patients, hCG levels were linked to increased levels of immunoglobulin M, complement, and lymphocytes. Thus, 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 (1) nausea and vomiting are not usual symptoms of hyperthyroidism, (2) signs of biochemical hyperthyroidism are not universal in cases of hyperemesis gravidarum, and (3) some studies have failed to correlate the severity of symptoms with biochemical abnormalities.^{[10, 11, 12]}

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 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. Lagiou et al studied prospectively 209 women with nausea and vomiting who showed that estradiol levels were positively correlated while prolactin levels were inversely associated with nausea and vomiting in pregnancy and no correlation existed with estriol, progesterone, or sex-hormone binding globulin.^[13]

Gastrointestinal dysfunction

The stomach pacemaker causes rhythmic peristaltic contractions of the stomach. Abnormal myoelectric activity may cause a variety of gastric dysrhythmias, including tachygastrias and bradygastrias. Gastric dysrhythmias have been associated with morning sickness. The presence of dysrhythmias was associated with nausea while normal myoelectrical activity was present in the absence of nausea. Mechanisms that cause gastric dysrhythmias include elevated estrogen or progesterone levels, thyroid disorders, abnormalities in vagal and sympathetic tone, and vasopressin secretion in response to intravascular volume perturbation. Many of these factors are present in early pregnancy. These pathophysiologic factors are hypothesized to be more severe or the gastrointestinal tract more sensitive to the neural/humoral changes in those who develop hyperemesis gravidarum.^[14]

Hepatic dysfunction

Liver disease, usually consisting of mild serum transaminase elevation, occurs in almost 50% of patients with hyperemesis gravidarum. Impairment of mitochondrial fatty acid oxidation (FAO) has been hypothesized to play a role in the pathogenesis of maternal liver disease associated with hyperemesis gravidarum. It has been suggested that women heterozygous for FAO defects develop hyperemesis gravidarum associated with liver disease while carrying fetuses with FAO defects due to accumulation of fatty acids in the placenta and subsequent generation of reactive oxygen species. Alternatively, it is possible that starvation leading to peripheral lipolysis and increased load of fatty acids in maternal-fetal circulation, combined with reduced capacity of the mitochondria to oxidize fatty acids in mothers heterozygous for FAO defects, can also cause hyperemesis gravidarum and liver injury while carrying nonaffected fetuses.

Lipid alterations

Jarnfelt-Samsioe et al found higher levels of triglycerides, total cholesterol, and phospholipids in women with hyperemesis gravidarum compared with matched, nonvomiting, pregnant and nonpregnant controls. This may be related to the abnormalities in hepatic function in pregnant women. However, Ustun et al found decreased levels of total cholesterol, LDL cholesterol, apoA and apoB in women with hyperemesis gravidarum compared with controls.^{[15, 16]}

Infection

Helicobacter pylori is a bacterium found in the stomach that may aggravate nausea and vomiting in pregnancy. Studies have found conflicting evidence of the role of H pylori in hyperemesis gravidarum. Recent studies in the United States have not shown association with hyperemesis gravidarum. However, persistent nausea and vomiting beyond the second trimester may be due to an active peptic ulcer caused by H pylori infection.^{[17, 18]}

Vestibular and olfaction

Hyperacuity of the olfactory system may be a contributing factor to nausea and vomiting during pregnancy. Many pregnant women report the smell of cooking food, particularly meats, as triggers to nausea. Striking similarities between hyperemesis gravidarum and motion sickness suggest that unmasking of subclinical vestibular disorders may account for some cases of hyperemesis gravidarum.^{[19, 20]}

Genetic

In studies examining the familial link of hyperemesis gravidarum, research suggests a possible genetic aspect to hyperemesis. A study was performed looking at 544,087 pregnancies from Norway’s mandatory birth registry from 1967-2005. This study demonstrated that daughters born from a pregnancy complicated by hyperemesis had a 3% risk of having hyperemesis in their own pregnancy. Women who were born after an unaffected pregnancy had a risk of 1.1%.^[21] In surveys administered to mothers who had pregnancies complicated by hyperemesis, higher rates of hyperemesis were reported among their relatives. This was particularly so in their sisters.^[22]

Overall, the data suggest that a genetic predisposition may play a role in the development of hyperemesis gravidarium.

Biochemical research

Hyperemesis gravidarum is associated with overactivation of sympathetic nerves and enhanced production of tumor necrosis factor (TNF)-alpha.^[23] Increased adenosine levels have also been noted; since adenosine is an established suppressor of excessive sympathetic nerves activation and cytokine production, the increase in plasma adenosine in hyperemesis gravidarum may be modulatory.^[24] Trophoblast-derived cytokines have been reported to induce secretion of hCG.

Immunoglobulins C3 and C4 and lymphocyte counts are significantly higher in women with hyperemesis gravidarum. T-helper 1/T-helper 2 balance is decreased in women with hyperemesis gravidarum, which results in increased humoral immunity. Increased fetal DNA has been found in the maternal plasma of women with hyperemesis gravidarum, and the increased DNA is speculated to be derived from trophoblasts that have been destroyed by the hyperactive maternal immune system. Thus, hyperemesis gravidarum may be mediated by immunologic aberrations in pregnancy.^{[25, 26, 27, 28]}

Psychological issues

Physiological changes associated with pregnancy interact with each woman's psychologic state and cultural values. Psychologic responses may interact with and exacerbate the physiology of nausea and vomiting during pregnancy. Nonetheless, hyperemesis gravidarum is typically the cause of, as opposed to the result of, psychologic stress. In very unusual instances, cases of hyperemesis gravidarum could represent psychiatric illness, including conversion or somatization disorder or major depression.^{[29, 30, 31]}

Frequency

United States

Of all pregnancies, 0.3-2% are affected by hyperemesis gravidarum (approximately 5 per 1000 pregnancies).

International

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

Mortality/Morbidity

Hyperemesis gravidarum was a significant cause of maternal death before 1940. In Great Britain, mortality decreased from 159 deaths per million births from 1931-1940 to 3 deaths per million births from 1951-1960. Charlotte Brontë is thought to have died of hyperemesis gravidarum in 1855. In the United States, 7 deaths from hyperemesis gravidarum were reported in the 1930s. Today, although hyperemesis gravidarum is still associated with significant morbidity, it is still a rare cause of maternal mortality.

• Many hours of productive work are lost because of nausea and vomiting during pregnancy. Nearly 50% of employed women believe that their work is affected, and up to 25% require time off from work.
• Hyperemesis gravidarum is a debilitating illness that can cause severe suffering, which profoundly affects both patients and their families. In about half of the women there is an adverse effect on spousal relationships, and 55% have feelings of depression. In one study of 140 women with hyperemesis gravidarum, 27% required multiple hospitalizations. The financial burden of hyperemesis gravidarum on the American health system has been estimated as approximately $130 million dollars per year, excluding physician fees.
• Women with hyperemesis gravidarum who have a low pregnancy weight gain (< 15.4 lb or 7 kg) have increased risk for delivering neonates of low birth weight, delivering neonates who are small for gestational age, preterm delivery, and a 5-minute Apgar score of less than 7.

Race

No clear racial predominance is noted for hyperemesis gravidarum.

• Hyperemesis gravidarum is less common in American Indian and Eskimo populations.
• Hyperemesis gravidarum is less common in African and some Asian populations (but not industrialized Japan).

Sex

Hyperemesis gravidarum affects females.

Age

The risk of hyperemesis gravidarum appears to decrease with advanced maternal age.