Introduction

Hyperemesis gravidarum refers to intractable vomiting during pregnancy that leads to weight loss and volume depletion, resulting in ketonuria and/or ketonemia.[1][2] There is no consensus on specific diagnostic criteria, but it generally refers to the severe end of the spectrum regarding nausea and vomiting in pregnancy. It occurs in approximately two percent of all pregnancies in the United States.[3] It can cause a significant impact on the quality of life of patients and, unfortunately, may be difficult to treat.[4]

Etiology

The etiology of hyperemesis gravidarum is largely unknown, but several theories exist (see pathophysiology). There are, however, risk factors associated with the development of hyperemesis during pregnancy. Increased placental mass in the setting of a molar or multiple gestations has been associated with a higher risk of hyperemesis gravidarum. Additionally, women who experience nausea and vomiting outside of pregnancy due to the consumption of estrogen-containing medications, exposure to motion, or have a history of migraines are at higher risk of experiencing nausea and vomiting during pregnancy. Some studies also suggest a higher risk of hyperemesis in women whose immediate family members, such as mothers or sisters, who also experienced hyperemesis gravidarum.[5]

Protective factors include the use of multivitamins before 6 weeks of gestational age and maternal cigarette smoking.[6][7][8][9][10]

Epidemiology

Up to ninety percent of women experience nausea during pregnancy. Studies show that approximately 27% to 30% of women experience only nausea, while vomiting may be seen in 28% to 52% of all pregnancies.[11][12] The incidence of hyperemesis gravidarum ranges from 0.3% to 3% depending on the literature source. Geographically, hyperemesis appears to be more common in western counties.[13]

Pathophysiology

The exact cause of hyperemesis gravidarum remains unclear. However, there are several theories for what may contribute to the development of this disease process.

Hormone Changes

• Levels of human chorionic gonadotropin (hCG) have been implicated. hCG levels peak during the first trimester, corresponding to the typical onset of hyperemesis symptoms. Some studies show a correlation between higher hCG concentrations and hyperemesis.[14][15] However, this data has not been consistent.[16]
• Estrogen is also thought to contribute to nausea and vomiting in pregnancy. Estradiol levels increase early in pregnancy and decrease later, mirroring the typical course of nausea and vomiting in pregnancy. Additionally, nausea and vomiting are the known side effects of estrogen-containing medications. As the level of estrogen increases, so does the incidence of vomiting.[17]

Changes in the Gastrointestinal System

• It is well-known that the lower esophageal sphincter relaxes during pregnancy due to the elevations in estrogen and progesterone. This leads to an increased incidence of gastroesophageal reflux disease (GERD) symptoms in pregnancy, and one symptom of GERD is nausea.[18] Studies examining the relationship between GERD and emesis in pregnancy report conflicting results.

Genetics

• An increased risk of hyperemesis gravidarum has been demonstrated among women with family members who also experienced hyperemesis gravidarum.
• Two genes, GDF15 and IGFBP7, have been potentially linked to the development of hyperemesis gravidarum.[19]

History and Physical

The history of a patient with suspected hyperemesis gravidarum should include their pregnancy status, estimated gestational age, history of complications during prior pregnancies, the frequency of nausea and vomiting, any interventions during which the patient has already tried to treat symptoms, and the outcomes of the attempted interventions. The average onset of symptoms happens approximately 5 to 6 weeks into gestation.[12]

The physical exam should include fetal heart rate (depending on gestational age) and an examination of fluid status, which should include an examination of blood pressure, heart rate, mucous membrane dryness, capillary refill, and skin turgor. A patient weight should be obtained for comparison to previous and future weights. Abdominal examination, as well as pelvic examination, if indicated, should occur to determine the presence or absence of tenderness to palpation.

Evaluation

There is no single accepted definition for hyperemesis gravidarum. However, it generally refers to extreme cases of nausea and vomiting during pregnancy. It is a clinical diagnosis. The criteria for diagnosis include vomiting that causes significant dehydration (as evidenced by ketonuria or electrolyte abnormalities) and weight loss (the most commonly cited marker for this is the loss of at least five percent of the patient’s pre-pregnancy weight) in the setting of pregnancy without any other underlying pathological cause for vomiting. Significant abdominal tenderness, pelvic tenderness, or vaginal bleeding should prompt a workup for alternative diagnoses.

The evaluation should include urinalysis to check for ketonuria and specific gravity, in addition to a complete blood count and electrolyte evaluation. An elevation in hemoglobin or hematocrit may be due to hemoconcentration in the setting of dehydration. Significant dehydration may result in acute kidney injury as evidenced by an elevation in serum creatinine, blood urea nitrogen, and a reduced glomerular filtration. Potassium, calcium, magnesium, sodium, and bicarbonate may be affected by prolonged bouts of vomiting and reduced oral intake of fluids. Thyroid tests, lipase, and liver function testing may also be completed to evaluate for alternate diagnoses.

Radiographic studies may be appropriate to rule out alternate diagnoses. Obstetrical ultrasounds may be considered to rule out multiple gestations, ectopic pregnancy, and gestational trophoblastic disease depending on the patient’s history and prior obstetrical evaluations. Magnetic resonance imaging (MRI) may be used to assess alternative diagnoses, such as appendicitis.

Treatment / Management

Treatment should be guided by the American College of Obstetrics and Gynecology (ACOG) Nausea and Vomiting in Pregnancy guidelines. Initial treatment should begin with non-pharmacologic interventions such as switching the patient’s prenatal vitamins to folic acid supplementation only, using ginger supplementation (250 mg orally 4 times daily) as needed, and by applying acupressure wristbands.[20][21] If the patient continues to experience significant symptoms, the first-line pharmacologic therapy should include a combination of vitamin B6 (pyridoxine) and doxylamine. Three dosing regiments are endorsed by ACOG, including pyridoxine 10 to 25 mg orally with 12.5 mg of doxylamine 3 or 4 times per day, 10 mg of pyridoxine and 10 mg of doxylamine up to 4 times per day, or 20 mg of pyridoxine and 20 mg of doxylamine up to 2 times per day. As demonstrated in multi-center randomized controlled trials, these first-line medications demonstrate efficacy in the treatment of nausea and vomiting, preserved good fetal and maternal safety profiles and are listed as one of the few FDA pregnancy category A medications.[22][23][24]

Second-line medications include antihistamines and dopamine antagonists such as dimenhydrinate 25 to 50 mg every 4 to 6 hours orally, diphenhydramine 25 to 50 mg every 4 to 6 hours orally, prochlorperazine 25 mg every 12 hours rectally, or promethazine 12.5 to 25 mg every 4 to 6 hours orally or rectally. If the patient continues to experience significant symptoms without exhibiting signs of dehydration, metoclopramide, ondansetron, or promethazine may be given orally. In the case of dehydration, intravenous fluid boluses or continuous infusions of normal saline should be given in addition to intravenous metoclopramide, ondansetron, or promethazine. Electrolytes should be replaced as needed. Severe refractory cases of hyperemesis gravidarum may respond to intravenous or intramuscular chlorpromazine 25 to 50 mg or methylprednisolone 16 mg every 8 hours, orally or intravenously.[25]

Differential Diagnosis

The diagnosis of hyperemesis gravidarum is clinical and largely a diagnosis of exclusion. The list of potential differential diagnoses for patients with similar symptoms is quite extensive. It can include:

• Gestational trophoblastic disease
• Multiple gestations
• Ectopic pregnancy
• Preeclampsia
• Hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome
• Gastroenteritis
• Gastroparesis
• Small bowel obstruction
• Cholecystitis
• Pyelonephritis
• Ovarian torsion

It is important to evaluate patients for gestational trophoblastic disease and multiple gestations as they may also include severe nausea and vomiting in the first trimester of pregnancy. The workup may begin with an obstetrical ultrasound, which will confirm the diagnosis in most cases. Other first-trimester obstetrical concerns include ectopic pregnancy, which is more likely to include abdominal pain, syncope, or vaginal bleeding and can again be evaluated by obstetrical ultrasound and B-hCG levels.

The onset of nausea and vomiting after nine weeks should spark concern for alternative diagnoses. Preeclampsia, HELLP (hemolysis, elevated liver enzymes, and low platelets), and acute fatty liver of pregnancy typically present themselves during the late second or third trimester of pregnancy.

Non-obstetrical causes for nausea and vomiting can also occur during pregnancy and should always remain on the differential, keeping in mind that pregnant patients are considered to be at higher risk of blood clotting; therefore diagnoses that result in ischemia or thrombus formation may be more common during pregnancy. Gastrointestinal causes such as gastroenteritis, small bowel obstruction, gastroparesis, peptic ulcer disease, cholecystitis, pancreatitis, hepatitis, and appendicitis should be considered. Pyelonephritis, urinary tract infections, renal stones, and ovarian torsion may also include vomiting. Metabolic derangements such as diabetic ketoacidosis, hyperthyroidism, and hyperparathyroidism may also have similar symptoms. Neurologic disorders such as migraine, intracranial hemorrhage, pseudotumor cerebri, and venous sinus thrombosis can also cause vomiting but are likely to have associated headaches or neurologic deficits. Psychiatric disorders such as anxiety and depression may also result in vomiting, as can toxic ingestions and myocardial ischemia.

Prognosis

Nausea and vomiting in pregnancy are common. Symptoms usually begin prior to 9 weeks gestation and the majority of cases are resolved by week 20 of gestation. A minority of patients, approximately 3%, will continue to experience vomiting during the third trimester. Approximately 10% of patients with hyperemesis gravidarum will be affected throughout the pregnancy.[26]

Complications

As hyperemesis gravidarum involves 2 patients, both must be considered when discussing complications.

Maternal Complications

In severe cases of hyperemesis, complications include vitamin deficiency, dehydration, and malnutrition, if not treated appropriately. Wernicke’s encephalopathy, caused by vitamin-B1 deficiency, can lead to death and permanent disability if it goes untreated.[27][28][29] Additionally, there have been case reports of injuries secondary to forceful and frequent vomiting, including esophageal rupture and pneumothorax.[30][31][32] Electrolyte abnormalities such as hypokalemia can also cause significant morbidity and mortality.[33] Additionally, patients with hyperemesis may have higher rates of depression and anxiety during pregnancy.[34]

Fetal Complications

Studies report conflicting information regarding the incidence of low birth weight and premature infants in the setting of nausea and vomiting in pregnancy.[35][36][37][38] However, studies have not shown an association between hyperemesis and perinatal or neonatal mortality.[38] The frequency of congenital anomalies does not appear to increase in patients with hyperemesis.[35]

Consultations

Obstetrics consultation is indicated in the setting of hyperemesis gravidarum as it is the most severe form of nausea and vomiting in pregnancy. Admission is indicated for intravenous antiemetics and fluids in the setting of refractory symptoms, failed outpatient treatment, severe dehydration, or electrolyte disturbance.

Deterrence and Patient Education

Daily intake of a multivitamin with folic acid at least one month prior to conception not only reduces the risk of congenital anomalies such as neural tube defects but has also been associated with reduced frequency and severity of nausea and vomiting in pregnancy.

Enhancing Healthcare Team Outcomes

An interprofessional team that provides comprehensive care and an integrated approach to the treatment of nausea and vomiting in pregnancy can lead to the best patient-centered outcomes. [Level V]