This continuing education activity aims to update the participant on current knowledge regarding hyperemesis gravidarum, including modifiable risk factors, diagnostic testing, and pharmacological and nonpharmacological interventions.
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Thyroid function is altered during healthy pregnancies. The rise in thyroxine-binding globulin, induced by estrogens, leads to decreased free thyroxine concentration. This negative feedback on the pituitary incites an increase in thyroid-stimulating hormone (TSH) secretion and hyperstimulation of the thyroid. Thyrotoxic crisis during pregnancy is rare, but the physiological processes described previously can place the pregnant patient and fetus at risk, especially in patients with preexisting hyperthyroidism. Additionally, high hCG levels cause activation of the TSH receptors on the thyroid gland, increasing activity in the gland. Stimulation of the thyroid gland can lead to symptoms of hyperthyroidism, such as palpitations, shortness of breath, nausea, vomiting, and diarrhea due to the increased metabolic rate. Another mechanism present is an increase in iodine clearance; this leads to hyperstimulation of the thyroid gland to compensate for a perceived deficiency. HCG levels usually peak in the first trimester, and thyroid function typically normalizes by 18 weeks with no further intervention. While not the only cause of HG, hCG may be indirectly involved due to thyroid stimulation (Jee & Sawal, 2024; Zimmerman et al., 2022).
Recent research supports a genetic predisposition to HG. An abnormal elevation of the growth and differentiation factor 15 (GDF-15) hormone, along with increased sensitivity, was found in a 2017 study to be a major contributing factor to the development of HG. High levels of GDF-15 are produced by the placenta during early pregnancy. A study of over 50,000 participants using 23andMe, Inc., identified an association between HG and variants in the placenta and appetite genes GDF-15 and insulinlike growth factor binding protein 7 (IGFBP7). Fejzo and colleagues replicated these results in a second cohort study in 2023. An additional study also found that HG included variants in the GDF-15 receptor gene, glial cell line–derived neurotrophic factor family receptor alphalike (GFRAL) gene, located in the brain's vomiting center. Research findings on the GDF-15, IGFBP7, and GFRAL genes associated with HG provide clear guidance for developing new treatment and prevention strategies (Fejzo, 2024; Fejzo et al., 2023; HER Foundation, 2024; van der Minnen et al., 2025).
Adverse Outcomes
Adverse outcomes related to HG are significant. Potential consequences for the pregnant patient include weight loss, nutrient deficiencies, Wernicke’s encephalopathy, Korsakoff's syndrome, loss of pregnancy, hemorrhage, venous thromboembolism during pregnancy, delivery, and postpartum, acute kidney injury, placental abruption, preeclampsia, depression, anxiety, posttraumatic stress disorder, and suicidal ideation. The severity of vomiting is linked with social dysfunction, anxiety, sleep disorders, and severe depression. The psychological and social effects of hyperemesis are likely underestimated. Pregnant individuals with HG, particularly severe HG, are at risk for psychological stress. A study in 2021 described the self-reported psychological impact of HG as being “deprived of my autonomy” through feelings of disempowerment, being unprioritized, and dependence (Lindgren et al., 2025, para. 13). One systematic review of 61 studies and another meta-analysis of over 1 million offspring identified potential adverse consequences for the fetus, which include low birth weight, preterm birth, neonatal intensive care stay, resuscitation, anxiety and sleep issues, cardiovascular events, elevated BMI, psychiatric disorders (e.g., autism spectrum disorder and ADHD), and cancer. Additionally, the risk for neural tube defects doubles due to nutrient deficiencies in the birthing parent. However, the long-term effects of HG on offspring have not been well studied and remain unclear (Fejzo, 2024; Lindgren et al., 2025; van der Minnen et al., 2025).
Risk Factors
Family history is a well-documented, significant risk factor for HG. Family history increases the risk for children and siblings of a person with HG. Children and siblings of an affected individual have a 30% higher risk of experiencing HG than the general population. The history of HG in a previous pregnancy increases the risk of developing HG by 24% to 80%. Underlying medical conditions (e.g., thyroid or parathyroid dysfunction, hypercholesterolemia, type 1 diabetes mellitus) also put a patient at elevated risk of HG. Additionally, evidence supports an increased risk of developing HG when multiple fetuses are present during pregnancy; the fetal sex is female; molar pregnancy is present; primiparity; or when the pregnant individual has younger age or a BMI over 30 or less than 20. Other risk factors for developing HG include tobacco use, asthma or allergies, history of urinary tract infections, dysmenorrhea, and peptic ulceration. People of Asian/Pacific Islander, White, and African American ethnicities had higher rates of HG recurrence in subsequent pregnancies (de Tejada et al., 2025; Fassett et al., 2023; Jansen et al., 2024).
Signs and Symptoms
HG can develop rapidly or slowly over several weeks with a gradual increase in the severity of symptoms. Individuals with HG experience severe and persistent NVP. Due to the inability to tolerate oral intake, HG can cause dehydration, resulting in tachycardia, hypotension, weight loss, decreased skin turgor, ptyalism (excessive salivation), dizziness, and dry mucous membranes. The lack of caloric intake often causes extreme fatigue and ketosis with the characteristic fruity breath due to metabolic changes. When symptoms are severe, many individuals cannot complete ADLs (Jansen et al., 2024; Smith et al., 2024a).
Diagnosis
The HCP should ask about symptoms, take a medical history, and perform a physical exam to assess for HG's most common signs and manifestations. The patient should be asked about the onset, duration, frequency of nausea and vomiting, loss of appetite, feeling lightheaded or dizzy, and weight loss. Diagnosis can be difficult due to the cyclic nature and waxing and waning of symptoms of HG. Due to the variability and complexity of symptoms and patient presentation, the HER Foundation created the hyperemesis level prediction (HELP) score assessment. The HELP assessment includes a patient self-report of symptoms using a Likert scale. Also included is the percentage of overall body weight lost since the last visit and the number of prescriptions the patient takes to manage symptoms. Patient response trends can help detect symptom changes. A HELP score greater than 32 indicates a need for more aggressive interventions. HG diagnostic criteria include significant dehydration and weight loss that are not attributed to another underlying cause. Significant weight loss related to HG is defined as the loss of 5% or more of the individual's prepregnancy weight. The physical exam should include urine ketones, CBC, TSH, complete metabolic panel, and liver function tests. Some individuals may not produce ketones, and others may not lose weight, but they may still experience HG. Ketonuria or serum electrolyte imbalances indicate significant dehydration. An ultrasound should also be completed to rule out a hydatidiform mole or multifetal pregnancy (Dulay, 2024; Jennings & Mahdy, 2023; van der Minnen et al., 2025).
Treatment
The goal of treatment is to reduce symptoms, prevent dehydration and malnutrition, and improve the patient's quality of life. This is accomplished through dietary and lifestyle modifications, followed by pharmacological therapy if needed. It is important to initiate treatment early, before serious complications occur, to minimize adverse effects for both pregnant patient and fetus (Smith et al., 2024b; van der Minnen et al., 2025).
Dietary Management
The initial intervention recommended for patients experiencing NVP is to switch prenatal vitamins, as the iron in most of these vitamins can cause nausea. The pregnant patient should continue to take folic acid (vitamin B9) and thiamine (vitamin B1) supplementation (Jansen et al., 2024). Other interventions for self-management of HG include:
- Avoid an empty stomach and eat small, frequent meals every 2 to 3 hours.
- Eat a high-protein snack before going to bed and before getting out of bed in the morning.
- Consume cold food instead of hot food.
- Eat dry, bland, low-fat, high-protein foods.
- Eat what sounds good and can be tolerated instead of focusing on a balanced diet.
- Eat protein after eating sweets.
- Drink liquids from a cup with a lid or use a straw and wait at least 30 minutes before or after meals to minimize the feeling of a full stomach.
- Suck on a popsicle or peppermint candies if vomiting occurs on an empty stomach.
- Drink cold, clear, carbonated, or sour liquids (most likely to be tolerated), such as ginger ale (without artificial sweetener), ginger tea, or water with lemon.
- Eliminate coffee and spicy, high-fat, acidic, odorous, and very sweet foods (de Tejada et al., 2025; Hollier, 2021; Smith et al., 2024b; Wong et al., 2022).
Ginger acts on the gastrointestinal tract to increase motility, and its absorbent property may decrease stimuli to chemoreceptors in the medulla that send impulses to the emetic center of the brainstem. Ginger may also block nausea feedback and has been successfully described as an adjunct treatment for NVP (Shareef, 2022; Smith et al., 2024b; Wong et al., 2022).
Lifestyle Changes
It is helpful to identify and avoid situations that may exacerbate the symptoms of HG. Once trigger foods are identified, they should be avoided, even beyond consumption. For example, being in the same room while trigger foods are prepared or cooked can cause nausea and vomiting. Other common triggers include being in a stuffy room with minimal airflow; strong odors from perfume, candles, air fresheners, chemicals, or smoke; heat; high humidity; excessive noise or visual stimulation; and physical motion such as driving or riding in a car. Keeping upright after eating can promote gastric emptying, decreasing fullness and nausea after eating. Brushing teeth after eating or changing toothpaste to one with less flavor may reduce nausea. It is also important to rest and get adequate sleep, as being tired or sleep deprived can aggravate symptoms (Smith et al., 2024b).
Alternative Therapies
Complementary and alternative medicine (CAM) can be beneficial for treating NVP that is less severe, possibly preventing progression to HG. Measures to treat nausea can include applying pressure to the pericardium 6 (P6) acupuncture point by hand or wristband. The P6 pressure point is located on the palmar side of the wrist, between two tendons, three finger breadths from the wrist crease. Compared to placebo groups, research has shown that applying pressure to this point can help patients cope with NVP and anesthesia. Acupuncture may also be offered as an adjunct to conventional treatment. Acupuncture therapy has no documented teratogenic side effects, and patients may appreciate the avoidance of medications. Some patients have found light therapy and hypnosis helpful in reducing NVP. While not CAM, psychotherapy is another nonpharmacological method that can also be effective for individuals with anxiety-related nausea and vomiting. Potentially harmful and unproven treatments that are not recommended include cannabis and Nzu, a traditional African morning-sickness remedy that is also referred to as La Craie, Calabar stone, Mabele, Argile, and Calabash clay (Elder et al., 2025; HER Foundation, n.d.; Mohd Nafiah et al., 2022; Smith et al., 2024b).
Pharmacological Management
If NVP persists despite the use of dietary and lifestyle changes, CAM, and psychotherapeutic strategies, antiemetic medication therapy is the next step. When using medications to treat HG, the following strategies are advised (HER Foundation, 2019; Ogunyemi, 2024).
- Monitor weight at each visit.
- Replace electrolytes and nutritional deficiencies.
- Prevent and proactively manage side effects.
- Wean over 2 weeks in the second trimester after 2 or more weeks without symptoms (Kimber’s Rule of 2s).
Medications to prevent nausea are used when persistent vomiting poses possible risks to the pregnant individual or fetus and nonpharmacological interventions have been unsuccessful. Taking medications during pregnancy can be distressing due to concerns about potential harm to the fetus. These concerns may need to be addressed to avoid adherence issues. When patients avoid pharmacological intervention when indicated, it may worsen their or their fetus’s condition. HCPs should explain the risks of untreated HG on the pregnant patient and their unborn child, including dehydration, malnutrition, metabolic abnormalities, electrolyte imbalances, emotional stress, and reduced mobility. Several medications are used to control NVP. The safety and benefits of any medication prescribed should be weighed carefully and collaboratively with the HCP. The inherent risks of leaving the condition untreated should be weighed against the risks of the treatment. In 2014, the Food and Drug Administration (FDA) removed the previous system of ranking medications for pregnant persons (Category A, B, C, D, and X) and now requires detailed specific information about pregnancy safety (including during labor and delivery), safety while breastfeeding, and protection for individuals of reproductive potential (HER Foundation, n.d., 2019; Leek & Arif, 2023; US FDA Center for Drug Evaluation and Research, 2024).
Initial treatment for HG without hypovolemia involves pyridoxine (vitamin B6). This first-line treatment safely improves nausea with minimal side effects. If ineffective, doxylamine (Unisom) should be added, which is available separately or in combination (pyridoxine/doxylamine succinate [Diclegis, Bonjesta]). Doxylamine is classified as an antihistamine and is used for the relief of allergy symptoms, including hay fever, as well as the common cold. Its mechanism of action is to block specific natural substances produced in the body (histamine, acetylcholine). Doxylamine (Unisom) is also sold as a sleep aid and has been found to help with NVP. Both medications have minimal side effects and a good safety profile for the pregnant patient and fetus. The primary mechanism of action of antihistamines in treating NVP is direct inhibition of histamine at the H1 receptor. The secondary mechanism is indirectly affecting the vestibular system by decreasing the stimulation of the vomiting center. Doxylamine succinate (Unisom) can cause drowsiness, and patients are cautioned to avoid driving after taking this medication. Antihistamines can also cause dry mouth and dry nasal passages. Additionally, antihistamines should not be combined with ondansetron (Zofran) or other medications that prolong the QT interval. If symptoms do not resolve, pyridoxine/doxylamine succinate (Diclegis, Bonjesta) should be discontinued, and a different antihistamine such as dimenhydrinate (Dramamine), diphenhydramine (Benadryl), meclizine (Bonine), or scopolamine (Maldemar) can be trialed. These are generally safe during early pregnancy, but scopolamine (Maldemar) should not be given to patients with preeclampsia (Jennings & Mahdy, 2023; Smith et al., 2024b).
Second-line medications include dopamine receptor antagonists. Several classes of dopamine receptor antagonists can be used for NVP, but the most common include benzamides (metoclopramide [Reglan]), phenothiazines (promethazine [Phenergan], prochlorperazine [Compazine]), and butyrophenones (droperidol [Inapsine]). These medications are thought to stimulate gastric motility and emptying, resulting in antiemetic effects. Blockage of dopamine2 receptors is also believed to block emetic signaling. Metoclopramide (Reglan) is one of the most prescribed medications for NVP (off-label use), but it can cause extrapyramidal reactions such as dystonia, akathisia, parkinsonism, and tardive dyskinesia. Other common side effects of these medications include drowsiness, dizziness, headaches, and urinary retention. They are not connected with a significantly increased risk for major congenital anomalies (HER Foundation, 2019; Smith et al., 2024b; UpToDate Lexidrug, n.d.-a).
If symptoms continue despite treatment, a serotonin antagonist can be added. Ondansetron (Zofran) is a selective antagonist at the 5-hydroxytryptamine-3 serotonin receptor. Although commonly used off label in nonpregnant individuals, the use of ondansetron (Zofran) during early pregnancy is controversial. The American Family Physicians and European Medicines Agency recommend not initiating ondansetron (Zofran) until the second trimester due to an increased risk of oral cleft palate and ventricular septal defects, although these findings are not consistent. Common side effects include headache, fatigue, constipation, and drowsiness (Gregory et al., 2018; HER Foundation, 2019; Jansen et al., 2024; Michie & Hodson, 2020; Smith et al., 2024b; UpToDate Lexidrug, n.d.-b).
If those measures fail, an abbreviated course of corticosteroids can be added as a last resort for severe NVP. Although the symptoms can improve dramatically with corticosteroids, this therapy should not be initiated before 10 weeks of gestation, secondary to associated congenital malformations like cleft palate in neonates. Hydrocortisone (Cortef) and prednisone (Deltasone), which are inactivated by the placenta, are preferred for use during pregnancy (HER Foundation, 2019; Jansen et al., 2024; Ogunyemi, 2024; Smith et al., 2024b; Wong et al., 2022).
Acid-reducing medications may be helpful for patients who have heartburn and acid reflux. Preferred medications considered safe during pregnancy are those containing aluminum or calcium. Histamine2 receptor antagonists (H2 blockers) can be considered (cimetidine [Tagamet] is the preferred H2 blocker). It has a good profile for safety of both pregnant patient and fetus. These medications will sometimes work for NVP if the nausea is triggered by stomach or intestinal problems (HER Foundation, n.d., 2019; Ogunyemi, 2024; Smith et al., 2024b).
Medications may need to be administered parenterally, subcutaneously, or transdermally if the individual cannot take medications by mouth due to severe HG. The IM route is not recommended for patients with HG due to sensitivity to pain and low muscle mass (HER Foundation, 2019; Ogunyemi, 2024; Smith et al., 2024b; Wong et al., 2022).
Tracking tools are helpful to monitor improvements in symptoms after treatment. The Pregnancy-Unique Quantification of Emesis 24 score has been validated and is short and easy to use. The newer HELP score (also used in diagnosis) developed by the HER Foundation is promising, but needs further validation (van der Minnen et al., 2025).
Restoring Homeostasis
A pregnant person needs consistent fluid intake to maintain or restore homeostasis. Pregnancy increases the demand for hydration to form amniotic fluid, increase blood volume, build new tissues, transport nutrients, improve digestion, and eliminate waste or toxins. For those individuals diagnosed with HG and demonstrating compromised physical functioning, treatment to restore fluids and replace electrolytes by infusing IV medication and fluids is indicated. Food should not be given orally until vomiting stops and dehydration has been corrected. Instead, nutrition may be provided by enteral or parenteral routes (Elkins et al., 2022; Jennings & Mahdy, 2023; van der Minnen et al., 2025).
Treatment is based on the care setting and severity of HG (including laboratory results; van der Minnen et al., 2025).
- Outpatient (mild and moderate cases): Primary care diagnosis and minimal treatment (e.g., oral hydration, dietary counseling, sick days out of work, and one transient antiemetic medication); with moderate cases, care is more extensive, including mild dehydration (e.g., multiple medications, IV rehydration in office)
- Inpatient (severe): Hospital admission with pronounced dehydration and lack of ability to tolerate any oral food or fluids (hospital admission should also be considered for persons with electrolyte imbalance or comorbidity that precludes the use of or timely administration or uptake of medications such as UTI, seizure disorder, HIV, type 1 diabetes, and psychiatric disorder)
IV fluid resuscitation is indicated when vomiting cannot be controlled and correction of fluid and electrolyte imbalances is needed. In the past, patients would need to be admitted to the hospital for IV fluid administration. However, this can now be managed in an office or the patient's home. In severe cases requiring close monitoring of laboratory values, hospitalization is indicated. Fluid resuscitation and the replacement of electrolytes are crucial in treating hyperemesis. Normal saline or lactated Ringer's are suitable solutions; potassium chloride can be added as needed to correct hypokalemia (common in HG). After prolonged and persistent vomiting, vitamins and minerals may also be depleted and require replacement. The optimum fluid replacement protocol has not been established. However, IV fluids with dextrose should be avoided without first administering 100 mg of thiamine IV due to the risk of inducing Wernicke’s encephalopathy, a degenerative brain disease affecting the thalamus and hypothalamus caused by a lack of thiamine. IV fluids may be discontinued once the patient is able to tolerate oral intake (Dulay, 2024; Elkins et al., 2022; Smith et al., 2024b).
Medical Nutrition Therapy
If dietary modifications and pharmacological interventions are ineffective, the patient may need medical nutrition therapy through either enteral or parenteral supplementation. Enteral therapy is the first choice. However, if the patient does not respond to enteral nutrition, then parenteral nutrition is used as a last resort (Hollier, 2021; Jansen et al., 2024; Wong et al., 2022).
Enteral feedings via nasogastric tube can provide needed fluids and nutrients to patients experiencing HG, but the literature is mixed regarding overall efficacy. For example, Grooten and colleagues (2017) found that early enteral tube feeding in pregnant individuals diagnosed with HG did not improve birth weight or overall fetal outcomes. Many individuals requested that tube feedings be discontinued due to discomfort, indicating that it was poorly tolerated as an early treatment of HG. Nijsten and colleagues (2022) verified the lack of benefits. While no definitive information was found to support the benefits outweighing the risks or inconvenience of enteral feedings, it remains a treatment option for individuals experiencing nutritional deficiencies related to HG (Elkins et al., 2022; Grooten et al., 2017; Jansen et al., 2024; Nijsten et al., 2022; van Vliet et al., 2018).
The most severe cases of HG might require total parenteral nutrition (TPN), a complex, balanced solution of nutrients to be given via IV throughout pregnancy. This treatment is indicated in prolonged cases of HG when there is a concern for long-term outcomes due to hypovolemia and nutritional deficits. TPN support during early pregnancy is associated with a decreased risk for perinatal morbidity in patients experiencing HG. Vitamin supplementation (particularly vitamins B6 and C and thiamine) is also recommended. If not already given, thiamine supplementation is critical to prevent Wernicke’s encephalopathy; 100 mg IV should be administered daily until laboratory values are stable and dietary intake returns to baseline (Elkins et al., 2022; Smith et al., 2024b).
Nursing Implications
Wong and colleagues (2022) reviewed multiple clinical practice guidelines and recommended improvements in treatment for patients experiencing NVP. Through research, they concluded that there is no international consensus on guidelines for HG treatment. Strategies for improvement include better awareness of the impact this condition has on a pregnant person's quality of life and educating care providers regarding medication best practices to relieve symptoms earlier. It is important to decide on the correct regimen and ensure the medication is tolerated and taken correctly for optimal effectiveness. Early pregnancy symptoms are challenging to manage, as symptoms generally worsen until the end of the first trimester. Many variables affect responsiveness to medications, such as hydration and nutritional status, duration of symptoms, and medication interactions. These must be considered when assessing a pregnant individual's response. Additionally, minimizing changes to doses and regimens when symptoms improve can prevent relapse, especially during initial recovery (Elder et al., 2025; Smith et al., 2024b; Wong et al., 2022).
Elder and colleagues (2025) interviewed individuals affected by HG. Research identified four main themes: HG’s impact, lack of recognition and understanding of HG, impact of HG programs, and improved need for education and resources. Participants also reported that individually tailored holistic support and education is valuable. Additionally, psychosocial support and interprofessional care based on a holistic approach have been highlighted in other studies. The need for consensus on international guidelines for HG treatment is evident (Elder et al., 2025; van der Minnen et al., 2025).
Future Research
New insights into the causes of HG can lead to new treatments, such as GDF-15 receptor antagonists or therapies that address increased GDF-15 levels before conception. However, because HG occurs during critical stages of embryonic development, any new treatments must be carefully tested for safety, effectiveness, and side effects. Early intervention could greatly affect the incidence, severity, and duration of HG. A phase 2 trial of NGM120, a GFRAL antagonist antibody, is currently being conducted by NGM Pharmaceuticals to determine its safety and effectiveness for treating HG. This could be the first treatment based on understanding GDF-15 (van der Minnen et al., 2025).
Further recommendations for future research include:
- Ways to enhance the nutritional intake of HG patients
- Exploring the role of nutrients in adverse outcomes
- Developing and evaluating new therapeutics for prevention and treatment based on recent genetic discoveries
- Investigating the mechanism behind GDF-15 desensitization and assessing if the hormone plays a secondary role in pregnancy
- Evaluating the applicability of genetic findings across diverse populations
- Identifying and clarifying the role of additional risk genes (Fejzo, 2024)
In addition, more effective antiemetic medications approved for NVP would assist pregnant individuals in maintaining adequate hydration and nutrition throughout their pregnancy. There is a need for new, effective, and safe medications to improve patient outcomes. The association between HG and adverse pregnancy outcomes remains an issue of considerable controversy. Given this lack of clarity, research is needed on the association between HG and long-term adverse pregnancy outcomes. The degree of severity associated with HG diagnosis needs to be better defined, and investigating whether the severity of the disorder is clinically significant and related to outcomes with consistent guidelines is another essential step (HER Foundation, 2024; van der Minnen et al., 2025).
References
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