Hyperemesis Gravidarum (Hyperemesis gravidarum)

Hyperemesis Gravidarum (HG) is a clinical condition characterized by persistent and severe nausea and vomiting during pregnancy. It is defined as a serious pregnancy complication that often requires hospitalization, leading to weight loss of more than 5% of pre-pregnancy body weight, dehydration (fluid loss), electrolyte imbalance, and ketonuria (presence of ketones in urine).^【1】

The historical management and outcomes of hyperemesis gravidarum have evolved over time. According to United Kingdom data, between 1931 and 1940, there were 159 maternal deaths per million pregnancies, whereas between 1951 and 1960, this rate decreased to three maternal deaths per million pregnancies.^【2】

Today, with advances in supportive therapies, maternal death is almost unheard of. Historically, one of the earliest theories regarding the etiology of the condition was psychological factors. Researchers suggested that women with HG exhibited hysteric or infantile personality traits, but these theories are now reported to lack robust evidence.^【3】

Globally, 70 to 80 percent of women experience nausea and vomiting at some point during pregnancy. However, hyperemesis gravidarum accounts for only a small fraction of these cases. The incidence of HG varies according to ethnic origin and socioeconomic status, generally ranging from 0.3 to 2 percent of pregnancies, though some sources report figures between 0.5 and 14 percent.^【4】

For example, incidence rates are reported as 0.3 percent in Sweden, 0.8 percent in Canada, and 1.2 percent in the United States, while in some Asian populations such as Japan, the rate can reach 3.6 percent, and in China, as high as 10.8 percent.^【5】

Various risk factors have been identified for the development of HG. These include young maternal age, primigravida status (first pregnancy), multiple gestations, hydatidiform mole (molar pregnancy), obesity or extreme low body weight, a history of HG in previous pregnancies, and a family history of HG. Additionally, carrying a female fetus, hyperthyroidism (overactive thyroid gland), a history of psychiatric illness, gastrointestinal disorders, and a history of migraine are also associated with increased risk. Smoking has been reported to reduce the risk.^【6】

The exact cause of the condition remains unknown, but its etiology is widely accepted as multifactorial. Key contributing factors include:

• Hormonal Factors: Elevated levels of human chorionic gonadotropin (hCG), estrogen, and progesterone during pregnancy are implicated. Symptoms tend to peak between weeks 8 and 12, coinciding with the highest hCG levels, supporting this association. It has also been reported that hCG’s thyrotropic effect may contribute to thyroid function changes.^【7】
• Infection: Helicobacter pylori infection has been associated with HG, with studies reporting increased frequency of HG in the presence of this infection. A meta-analysis found that the prevalence of H. pylori infection was 3.2 times higher in the HG group compared to the control group.^【8】
• Psychological Factors: Psychological conditions such as anxiety and depression may play a role in the etiology of HG, but evidence remains limited regarding whether these are causes or consequences of the condition.
• Genetic and Other Factors: Familial predisposition, vestibular system sensitivity, and gastrointestinal motility disorders are also recognized as contributing factors.

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The pathophysiology of hyperemesis gravidarum involves complex mechanisms. Current evidence highlights the following key processes:

• Endocrine Mechanisms: High hCG levels can stimulate TSH receptors, leading to gestational transient thyrotoxicosis (transient thyroid toxicity during pregnancy). In HG patients, elevated free T4 and suppressed TSH levels may be observed, though this typically does not require thyroid-suppressing treatment and resolves spontaneously. Additionally, increased estrogen and progesterone can exacerbate symptoms by delaying gastric emptying and slowing intestinal motility, contributing to gastroparesis.
• Inflammatory Processes: Immune and inflammatory factors have been reported to play a role in HG etiology. In HG patients, inflammatory markers such as white blood cell count, monocyte/lymphocyte ratio (MLR), neutrophil/lymphocyte ratio (NLR), and platelet/lymphocyte ratio (PLR) are significantly higher compared to healthy pregnant women. Elevated levels of proinflammatory cytokines such as interleukin-6 and TNF-alpha have also been detected, potentially linked to excessive activation of the maternal immune system.
• Fasting Metabolism: Persistent vomiting leads to inadequate nutrition, prompting the body to use fat stores for energy instead of glucose. This results in ketone bodies appearing in the urine. Fasting and low-calorie diets have been reported to increase insulin resistance.

The clinical course typically begins between weeks 4 and 6 of pregnancy, peaks between weeks 9 and 13, and resolves by week 20 in most cases; however, it persists until delivery in 5 to 15 percent of cases.^【9】

• Gastrointestinal: More than three vomiting episodes per day, persistent nausea, retching, epigastric pain (upper abdominal pain), and ptyalism (excessive salivation).
• Systemic: Fatigue, dizziness, syncope (fainting), and significant weight loss.
• Fluid Loss: Reduced skin turgor, dry mouth, and decreased urine output due to prolonged vomiting.

• Weight Loss: Loss of more than 5% of pre-pregnancy body weight is a diagnostic criterion.^【10】
• Urine Analysis: Ketonuria was detected in 31.3 percent of patients as (+), 26.2 percent as (++), and 42.4 percent as (+++).^【11】
• Electrolytes and Renal Function: Hypokalemia (low potassium), hyponatremia (low sodium), and chloride loss may lead to metabolic alkalosis. Increased blood urea nitrogen and hematocrit levels may occur due to fluid loss.
• Liver Enzymes: Mild elevations in liver enzymes are observed in approximately 50 percent of patients.^【12】

The diagnosis of HG is primarily based on clinical findings and exclusion of other causes. Diagnostic criteria include:

1. Persistent nausea and vomiting beginning in early pregnancy.
2. Weight loss exceeding 5% of pre-pregnancy body weight.
3. Ketonuria on urine analysis.
4. Evidence of fluid loss and electrolyte disturbances.

During diagnosis, other conditions that may cause vomiting—such as thyroid disorders, gastrointestinal infections, pancreatitis, hepatitis, and pyelonephritis—must be excluded. The PUQE score may be used to assess disease severity.

Treatment follows a stepwise approach tailored to symptom severity. The goals are to correct fluid loss, restore electrolyte balance, and support nutrition.

1. Diet and Lifestyle Modifications: Eating small, frequent meals; avoiding fatty and spicy foods; adopting a high-protein diet; and avoiding triggering odors are the most commonly recommended approaches. Although evidence is limited, ginger use has been reported to alleviate symptoms.
2. Fluid and Electrolyte Replacement: Intravenous (IV) fluid therapy is administered to patients unable to tolerate oral intake. Isotonic 0.9 percent sodium chloride solution is typically preferred. Before administering dextrose-containing fluids, thiamine supplementation must be provided to prevent Wernicke encephalopathy.
3. Pharmacological Treatment:
4. • Vitamins: Vitamin B6 alone or combined with doxylamine is first-line therapy.
   • Antiemetics: Antihistamines, dopamine antagonists, and serotonin antagonists are used. Ondansetron and metoclopramide have shown similar efficacy.
   • Corticosteroids: Methylprednisolone may be used after week 12 in refractory cases unresponsive to other treatments.
4. Nutritional Support: In persistent cases, enteral feeding (via tube) or total parenteral nutrition (intravenous complete nutrition) may be required.

The condition is generally self-limiting. With effective treatment, maternal mortality is now virtually nonexistent. However, untreated cases have been associated with serious maternal and fetal complications.

• Neurological: Wernicke encephalopathy due to thiamine deficiency and central pontine myelinolysis due to rapid correction of hyponatremia have been reported.
• Gastrointestinal: Esophageal rupture and organ dysfunction may occur due to severe vomiting.
• Psychological: Prolonged symptoms have been reported to increase the risk of anxiety and mood disorders.

• Inadequate maternal weight gain may increase the risk of low birth weight and preterm delivery.
• Offspring exposed to HG may have an increased long-term risk of metabolic disease and neurodevelopmental delays. However, no definitive association has been established between HG and congenital anomalies.

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