Hyperemesis gravidarum: clinical guidelines

List of Abbreviations

Terms and Definitions

Nausea and vomiting of pregnancy is a complication predominantly of the first half of pregnancy, characterized by dyspeptic disorders and impairments of all types of metabolism in severe cases, which reduces the patient's quality of life.

Transient gestational hyperthyroidism is a transient (temporary) decrease in thyroid-stimulating hormone (TSH) levels caused by the overproduction of human chorionic gonadotropin (hCG), without pronounced clinical manifestations of thyroid hyperfunction, and does not require medical treatment.

Wernicke's encephalopathy is an acute or subacute lesion of the midbrain and hypothalamus due to vitamin B₁ deficiency that occurs with excessive vomiting.

Ketonuria is the presence of acetone in the urine.

Hypokalemia is a decrease in blood potassium levels.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Nausea and vomiting of pregnancy occurring more than 2-3 times a day is a complication predominantly of the first half of pregnancy, characterized by dyspeptic disorders and impairments of all types of metabolism in severe cases, which reduces the patient's quality of life [1, 2].

Hyperemesis gravidarum is the extreme degree of nausea and vomiting of pregnancy, characterized by a prolonged course, weight loss of more than 5% of the baseline, and accompanied by marked electrolyte disturbances and dehydration [3].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Nausea and vomiting of pregnancy are multi-etiological in nature, affecting the course of pregnancy and the patient's quality of life [4, 5].

A significant contribution to the development of this obstetric complication is made by central nervous system (CNS) dysfunction, which is characterized by impaired regulation of internal organ activity against the background of hormonal changes. At the same time, excitation processes predominate in the subcortical structures of the CNS, including the reticular formation and the regulatory centers of the medulla oblongata, which house the vomiting, vasomotor, respiratory, and salivary centers, as well as the nuclei of the olfactory system of the brain.

Hormonal changes are associated with hCG overproduction, and certain isoforms of hCG are associated with nausea and vomiting of pregnancy [6]. In multiple pregnancies and trophoblastic diseases with high hCG levels, nausea and vomiting of pregnancy occur more frequently and are more severe [7]. In addition, hCG, acting as a TSH agonist, interacts with its receptors. Around the 8th week of pregnancy, at the peak of hCG secretion, the synthesis of thyroid hormones increases, which, via a negative feedback mechanism, suppresses TSH production, leading to the development of transient hyperthyroidism. By the end of the first trimester, as hCG levels decline, TSH levels return to baseline values [8]. Increased estradiol levels may also play a role in the genesis of nausea and vomiting of pregnancy. As estradiol levels rise, the frequency of vomiting increases [9].

A certain role is attributed to the specific features of gastrointestinal tract activity due to relaxation of the lower esophageal sphincter, which leads to reflux esophagitis or worsens symptoms of gastroesophageal reflux disease (GERD) during pregnancy [10].

Genetic predisposition is attributed to several factors: polymorphism/mutation of two genes, GDF15 and IGFBP7, involved in placentation and associated with appetite regulation and the development of cachexia [11]; hepatic carnitine palmitoyltransferase I deficiency (a mitochondrial enzyme), which may manifest during pregnancy and contribute to vomiting [12]. Cases of familial gestational hyperthyroidism caused by a TSH receptor mutation hypersensitive to hCG have been described [13].

An association between nausea and vomiting of pregnancy and Helicobacter pylori infection has been identified [14].

1.3 Epidemiology of the Disease or Condition

In a normal pregnancy, nausea and vomiting may occur in 50-80% of women, more often on an empty stomach and in the mornings, up to 2-3 times a day. The patient's general condition does not deteriorate, and medical treatment is not required [15, 17].

Hyperemesis gravidarum occurs in 0.3-3.6% of pregnant women. The incidence varies depending on the classification used and ethnic differences [3, 16].

In 3% of patients, vomiting may persist into the third trimester of pregnancy. In 10% of women with hyperemesis gravidarum, symptoms are observed throughout the entire pregnancy [17].

The recurrence rate of hyperemesis gravidarum in a subsequent pregnancy is 8-81% [18, 19].

1.4 Features of Coding the Disease or Condition

ICD-10:

O21 Excessive vomiting in pregnancy;

O21.0 Mild or moderate hyperemesis gravidarum;

O21.1 Excessive or severe hyperemesis gravidarum with metabolic disturbances;

O21.2 Late vomiting of pregnancy;

O21.8 Other forms of vomiting complicating pregnancy;

O21.9 Vomiting of pregnancy, unspecified.

1.5 Classification of the disease or condition

The classification of hyperemesis gravidarum is based on clinical presentation, general condition, physical examination, and laboratory parameters (Appendix A3.2).

1.6 Clinical presentation of the disease or condition

Nausea and vomiting typically begin at 5–6 weeks of gestation [20].

In addition to nausea and vomiting, the following symptoms are observed:

– dyspeptic symptoms: decreased or absent appetite, altered taste and smell, sialorrhea, heartburn, belching, bloating, constipation;

– central nervous system symptoms: headache, dizziness, weakness, apathy, drowsiness, irritability, delirium, euphoria, coma in severe cases, visual impairment;

– cardiovascular symptoms: tachycardia, hypotension;

– skin and mucous membranes: dryness, icterus;

– urinary system: decreased diuresis, ketonuria, dehydration;

– increased depression and anxiety [21, 22].

Complications of nausea and vomiting in pregnancy

Maternal and fetal complications typically develop in cases of prolonged and/or excessive vomiting.

1. Maternal complications.

• Wernicke's encephalopathy.

• Severe electrolyte disturbances, primarily hypokalemia, which can significantly complicate the woman's condition, potentially leading to a fatal outcome [23].

• Repeated intractable vomiting can lead to gastroesophageal reflux, esophagitis, or gastritis [24, 25].

• Rupture of the spleen, esophagus, or pneumothorax in cases of excessive prolonged vomiting [26–29].

• Acute kidney injury with tubular necrosis.

• Depression and psychiatric disorders [21].

2. Fetal complications.

Data regarding the rate of preterm births and perinatal or neonatal mortality are contradictory [30–33]. There is no reliable evidence of a correlation between hyperemesis gravidarum and the rate of congenital anomalies [31–33]. Some studies report a slightly higher incidence of low birth weight infants [34].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria for hyperemesis gravidarum.

• Persistent nausea and vomiting not attributable to other causes.

• Ketonuria associated with starvation.

• Weight loss of at least 5% of pre-pregnancy weight.

• Electrolyte disturbances.

• Hyperthyroidism.

• Liver dysfunction.

2.1 Complaints and Anamnesis

The primary complaints are dyspeptic symptoms: nausea, vomiting more than 2–3 times a day, decreased or absent appetite, altered taste and smell, hypersalivation, etc. In hyperemesis gravidarum, symptoms involving virtually all organs and systems may be observed. The most frequent complaints include: weight loss, dizziness, headache, weakness, apathy, drowsiness, insomnia, irritability, dry skin and mucous membranes, tachycardia, hypotension, hyperthermia, decreased diuresis, acetone breath, and stool irregularities.

When taking the medical history, it is necessary to assess family history, parity, extragenital diseases that could cause vomiting, and the course of previous pregnancies.

If vomiting first begins at a gestational age of 10 weeks and 6 days or later, it is caused by other factors and requires differential diagnosis.

2.2 Physical Examination

Physical examination during pregnancy must comply with the clinical guidelines "Normal Pregnancy" [1].

• As part of the physical examination for hyperemesis gravidarum, it is recommended to perform the following procedures in order to assess the severity of the patient's condition, conduct differential diagnosis, and timely identify hyperemesis gravidarum and its complications (see subsections 1.6 and 2.1):

– measurement of peripheral blood pressure, respiratory rate, and pulse,

– general thermometry,

– pulse oximetry (in cases of excessive vomiting),

– BMI calculation,

– assessment of skin turgor, condition of mucous membranes, signs of dehydration, muscle tone, and gastrointestinal function (presence of regular bowel movements).

– abdominal palpation,

– bimanual pelvic examination,

– inspection of the cervix using specula,

– visual general medical examination [1-3, 17, 37, 41, 132].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

2.3 Laboratory Diagnostics

The list of laboratory diagnostic tests for mild hyperemesis gravidarum must comply with the clinical guidelines "Normal Pregnancy".

– measurement of total and free (unconjugated) bilirubin in the blood, liver enzymes (determination of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and gamma-glutamyl transferase (GGT) activity in the blood), determination of amylase activity in the blood, blood urea nitrogen, electrolytes – potassium, sodium, chlorides, total calcium in the blood, and protein fraction ratios by electrophoresis;

– assessment of acid-base balance (ABB) and blood gases (in severe vomiting);

– detection of ketone bodies in the urine;

– determination of Helicobacter pylori antibodies in the blood in cases of excessive and/or prolonged vomiting unresponsive to treatment;

– daily diuresis, monitoring of the water balance (fluid intake, administration, and output).

GPP BLOE 3Grade of Recommendation B (Level of Evidence – 3).

Comment: In hyperemesis gravidarum, multi-organ changes are observed: hyperbilirubinemia (less than 4 mg/dL) without jaundice, metabolic hypochloremic alkalosis, acidemia, and an almost fivefold increase in serum amylase levels. Elevated hemoglobin or hematocrit may be associated with hemoconcentration due to dehydration. Electrolyte levels can be affected by prolonged bouts of vomiting and reduced oral fluid intake. Severe electrolyte disturbances, primarily hypokalemia, can significantly complicate the woman's condition, potentially leading to a fatal outcome [23]. Significant dehydration can lead to acute kidney injury, as evidenced by elevated serum creatinine, blood urea nitrogen, and decreased glomerular filtration rate.

Comment: Thyroid enlargement (goiter) is not among the symptoms observed in hyperemesis gravidarum (despite the frequently encountered transient hyperthyroidism in this condition) [30]. A decreased TSH level in 5–66% of pregnant women with vomiting – transient hyperthyroidism – does not require treatment. Thyroid function normalizes spontaneously by the 20th week of gestation [30].

2.4 Instrumental Diagnostics

The list of instrumental diagnostic procedures during pregnancy must comply with the clinical guidelines "Normal Pregnancy".

• In case of severe vomiting or an ambiguous ultrasound picture of the abdominal organs, if treatment is ineffective, magnetic resonance imaging (MRI) of the abdominal cavity is recommended to diagnose comorbid extragenital diseases [39, 40, 41, 132].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

Comments: Non-contrast MRI can be performed in the second and third trimesters of pregnancy.

• In cases of severe vomiting accompanied by neurological symptoms, magnetic resonance imaging (MRI) of the brain is recommended for the timely diagnosis of Wernicke's encephalopathy [61, 134, 136].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

• In severe cases (hematemesis or pronounced epigastric pain), esophagogastroduodenoscopy (EGD) is recommended to diagnose gastrointestinal diseases [24].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

Comments: EGD is safe during pregnancy and should be performed when clinically indicated—for example, in cases of hematemesis or severe epigastric pain—to rule out gastrointestinal bleeding [24].

Comments: Helicobacter pylori infection is associated with an increased risk of hyperemesis gravidarum; eradication of Helicobacter pylori may improve the patient's condition in some refractory cases [43].

2.5 Other Procedures

The list of other diagnostic tests during pregnancy must comply with the clinical guidelines «Normal Pregnancy» [1].

Comments: Hyperemesis gravidarum is a diagnosis of exclusion. Clinical symptoms are usually nonspecific, and it is important to rule out other causes of nausea and vomiting. Differential diagnosis is carried out with the following conditions (Appendix A3.4) [36, 49, 50].

• Gastrointestinal diseases: gastritis, pancreatitis, cholecystitis, hepatitis, cholelithiasis, reflux esophagitis, peptic ulcer disease, appendicitis, enteritis, colitis, intestinal obstruction, diaphragmatic hernia.

• Kidney and urinary tract diseases: pyelonephritis, chronic kidney disease (CKD), urolithiasis.

• Gynecologic diseases: ovarian torsion, uterine myoma with degeneration, trophoblastic disease, ectopic pregnancy.

• Endocrine and metabolic diseases: thyrotoxicosis, hyperparathyroidism, diabetes mellitus, adrenal insufficiency, porphyria.

• Infectious diseases: foodborne toxicoinfection, viral hepatitis.

• Central nervous system diseases: migraine, tumors, stroke, vestibular disorders.

• Pregnancy complications: acute fatty liver of pregnancy, preeclampsia.

• Other conditions: poisoning, intoxications, drug intolerance and side effects, psychiatric disorders.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Non-pharmacological and pharmacological methods for managing pregnancy-related dyspeptic symptoms, as well as the prescription of vitamins and dietary supplements during pregnancy, must comply with the clinical guidelines «Normal Pregnancy» [1].

3.1. Non-pharmacological treatment

Comment: Patients should consume any pregnancy-safe food that they find appealing. Protein-rich foods and dry crackers reduce nausea and vomiting during pregnancy [133].

Comments: Most systematic reviews have noted the efficacy and safety of oral ginger use for nausea and vomiting of pregnancy [55–59].

3.2. Pharmacological treatment

Basic principles.

Comments: It should be borne in mind that combinations of different medications may lead to adverse reactions and potentiate side effects. Many drugs with proven efficacy and safety in pregnant women with vomiting are registered in Russia with the label "contraindicated in pregnancy". However, they may be used in severe cases when conventional treatment fails, provided the benefit outweighs the risk according to the conclusion of a medical board.

• As 1st-line drugs for the treatment of mild to moderate nausea and vomiting of pregnancy, #pyridoxine** 10–25 mg orally 3–4 times a day is recommended. The daily dose should not exceed 100 mg/day [17, 41, 61–63].

GoR ALoE 2Grade of Recommendation A (Level of Evidence – 2).

Comments: The combination of #doxylamine+#pyridoxine** has been established as safe and effective in numerous epidemiological studies – #doxylamine 12.5 mg with #pyridoxine** 10–25 mg orally 3–4 times a day [62, 63], [64–66, 133].

• For acute and/or prolonged episodes of nausea and vomiting in pregnancy, it is recommended to use systemic antihistamines — #diphenhydramine 25–50 mg orally or IV 10–50 mg every 4–6 hours or #dimenhydrinate rectally 50–100 mg every 4–6 hours (no more than 400 mg/day and no more than 200 mg/day if the patient is taking #doxylamine) [16, 17, 68–73, 138].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comments: Dimenhydrinate is contraindicated in the first trimester of pregnancy. H1-receptor antagonists (Anatomical Therapeutic Chemical [ATC] classification: systemic antihistamines) are not approved as antiemetics and are therefore used off-label; their use requires a decision by a medical committee.

• As 2nd-line drugs for the treatment of moderate to severe nausea and vomiting of pregnancy, #thiamine** (vitamin B1) is recommended for the prevention of Wernicke's encephalopathy [74–87].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

Comment: Dosage regimens for #thiamine**:

– orally 25–50 mg 3 times a day [17],

– orally 100 mg 3 times a day (every 8 hours) [132]

– IV 100 mg (in 100 ml of 0.9% sodium chloride**) per day for 2–3, 7 days [17, 39]

Wernicke's encephalopathy develops due to vitamin B1 (thiamine**) deficiency secondary to severe hyperemesis gravidarum. It is characterized by visual disturbances, confusion, disorientation, apathy, ataxia, impaired coordination, memory impairment, somnolence, nystagmus, ophthalmoplegia, hyporeflexia, or areflexia. This condition develops insidiously, and symptoms are not always distinguishable. Wernicke's encephalopathy is potentially fatal but is reversible with timely medical care [74]. Full recovery is observed in only 29% of cases. Permanent neurological disability may develop subsequently [74, 75, 80, 81].

• As 2nd-line drugs for the treatment of moderate to severe nausea and vomiting of pregnancy, the use of gastrointestinal motility stimulants (dopamine and serotonin receptor antagonists) – metoclopramide** at a daily dose of 5–10 mg every 8 hours orally or IV is recommended [17, 73, 82, 132].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comments: The maximum dose is 30 mg over 24 hours. Intravenous administration must be performed slowly (at least 3 minutes) to minimize side effects [132]. Short-term use of metoclopramide** is justified by the high risk of adverse effects (extrapyramidal symptoms and oculomotor disorders) with prolonged treatment [82]. Metoclopramide** is contraindicated in the first trimester of pregnancy; therefore, if used off-label, a medical board approval is required prior to its administration.

• As 2nd-line drugs for the treatment of moderate and severe hyperemesis gravidarum, it is recommended to use a serotonin 5-HT3 receptor blocker (serotonin 5-hydroxytryptamine type 3 receptor antagonist) – #ondansetron**, preferably after 10 weeks of gestation [83-87].

GCR BLOE 2Grade of Recommendation B (Level of Evidence – 2).

Comments: Dosing regimens:

– orally 4 mg every 8 hours for 5 days or 8 mg every 12 hours [87];

– IV 8 mg over 15 minutes every 12 hours [87]

– rectally 16 mg per day [87]

#Ondansetron** has a more pronounced antiemetic effect and fewer adverse reactions compared to other drugs, including metoclopramide** and the #pyridoxine** + doxylamine combination. #Ondansetron** should be prescribed with caution prior to 10 weeks of pregnancy when other drug therapies are ineffective.

Studies have established a potential association with congenital malformations (CM) of the palate [76] and atrial septal defect [76–78, 85]. For these reasons, the use of #ondansetron** prior to 10 weeks should be restricted, justified, and recommended for patients who have failed to achieve an effect with other agents. Pregnant women should be counseled on the potential risks.

• As 3rd-line drugs for the treatment of moderate and severe vomiting, systemic corticosteroids are recommended in cases of ineffectiveness of other treatment methods, particularly in cases of intractable vomiting, the use of systemic corticosteroids [79, 88-90].

Leveled recommendation BLevel of evidence 2Level of recommendation validity B (level of evidentiary reliability – 2).

Comments: Systemic corticosteroids are effective in patients with intractable vomiting [88–90] when ongoing therapy fails. Systemic corticosteroids should be avoided during the first trimester up to 10 weeks due to a potentially increased risk of cleft palate (#methylprednisolone**), and should be used only in refractory cases [91, 92].

• In patients with no response to 1st- and 2nd-line therapy, the following systemic corticosteroid regimen is recommended – #methylprednisolone** at a dose of 16 mg 3 times a day (48 mg per day) for 3 days orally or IV [17, 39, 89].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comments: If no effect is observed, treatment should be discontinued. If a positive result is achieved, the dose is tapered over 2 weeks. Treatment may be continued for up to 6 weeks, and in individual cases – up to childbirth [89].

• In hyperemesis gravidarum, it is recommended to prescribe low-molecular-weight heparins (ATX Heparin group) in accordance with the "Clinical Guidelines for the Prevention of Venous Thromboembolic Complications in Pregnant Women" [53, 93-95, 139].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comments: The risk of venous thromboembolism in hyperemesis gravidarum is significantly increased [94]. After clinical improvement and cessation of vomiting, low-molecular-weight heparins (B01AB Heparin group) can be discontinued [95].

• As 3rd-line drugs for the treatment of intractable vomiting when other ongoing therapy is ineffective, it is recommended to prescribe aliphatic phenothiazine derivatives:

– #promethazine at a dose of 12.5–25 mg per day IV, IM, orally, or rectally every 4 hours [17, 39, 132],

– #chlorpromazine** i.m., i.v. 10–25 mg daily every 4 hours (Maximum dose is 40 mg/day) [17, 39, 132],

– perphenazine** at a dose of 4–24 mg daily orally), which may be recommended for the treatment of intractable vomiting in the absence of an effect from ongoing therapy [41, 133].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comments: Recommended by the RCOG as first-line agents for the treatment of hyperemesis gravidarum. In the Russian Federation, aliphatic phenothiazine derivatives are contraindicated in pregnant women and can be used only for life-saving indications by decision of a medical panel [96, 97]. These drugs are administered orally and parenterally in the form of intramuscular, intravenous injections, and suppositories [68].

Comments: There is no evidence regarding the preference for specific solutions. Given that most women develop hyponatremia, hypochloremia, hypokalemia, and ketonuria, sodium chloride** and potassium chloride** may be used. The total volume of infusion therapy is 1000–3000 ml/day. It is advisable to administer crystalloids (electrolyte solutions – ATX code B05XA) that act as reserve alkalinity carriers (e.g., compound sodium chloride solution** and analogs) on average for 3–5 days depending on the degree of dehydration and the patient's body weight, under the control of blood pressure, electrolyte levels (potassium, sodium, chlorides), hematocrit assessment, and diuresis (determination of urine volume). Parenteral nutrition solutions (dextrose** solutions, amino acids, and fat emulsions) are prescribed when enteral nutrition is impossible. Colloidal solutions are used for marked hypoproteinemia (protein less than 50 g/L) – 5–10% albumin** solution up to 200–400 ml per day.

3.3. Other treatment

3.3.1. Enteral or parenteral nutrition.

The decision to include these methods is made in the absence of an effect from ongoing therapy, necessarily with the participation of related specialists possessing sufficient knowledge and experience (clinical nutritionist, clinical pharmacologist, gastroenterologist).

Comments: Nasojejunal feeding is performed via a tube placed endoscopically. The condition of pregnant women may improve significantly within 48 hours, but constant regurgitation and vomiting can displace the tube [108]. Parenteral nutrition is performed when enteral nutrition is impossible [103, 104, 109, 110]. Prolonged parenteral nutrition is undesirable due to increased infectious and thrombotic risks [42, 100, 105, 111, 112].

This recommendation covers the following medical services in the nomenclature of medical services depending on the specific clinical situation:

– feeding via a nasogastric, duodenal, or nasojejunal tube;

– feeding via a gastrostomy;

– feeding via a jejunostomy.

Comments: Most studies have demonstrated efficacy and safety [16, 113–115]. Stimulation of the PC6 point is performed, located approximately 2.5 finger-widths above the wrist crease on the inner side of the forearm, between the tendons of the palmaris longus and flexor carpi radialis [116].

Comments: Hypnosis (A13.29.018 Hypnotherapy) may be effective in a number of patients due to induced deep relaxation, leading to a decrease in sympathetic nervous system arousal [117]. Given that hypnotherapy is safe, it can also be prescribed to pregnant women in mild cases of nausea and vomiting.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Not applicable.

5. Prevention and Dispensary Observation

• It should be recommended to follow a daily routine, get adequate rest, and avoid strong odors, overheating, humidity, harsh light, and noise for women at risk of developing hyperemesis gravidarum [61].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

6. Organization of Medical Care

Comments: Treatment in a day care setting is possible when outpatient treatment is ineffective and/or oral intake of medications and adequate fluid volume is not feasible (established clinical practice).

Indications for hospitalization in hyperemesis gravidarum.

• Ongoing or recurring nausea and vomiting not mitigated by oral antiemetics and/or inability to take them.

• Lack of response to outpatient treatment and inability to take oral fluids.

• Weight loss of more than 5% of baseline with ongoing vomiting and ketonuria.

• Hyperemesis gravidarum.

• Moderate vomiting accompanied by the following symptoms: tachycardia exceeding 100 bpm, icteric skin and sclera, hyperthermia, ketonuria, electrolyte imbalances.

• Vomiting persisting after 20 weeks of gestation.

• Hepatosplenomegaly, epigastric tenderness.

• Comorbidities (other extragenital diseases).

Indications for medical leave from work:

– mild hyperemesis gravidarum;

– moderate hyperemesis gravidarum in the absence of indications for hospitalization.

Indications for discharge from the hospital:

• positive dynamics of the general condition, cessation and/or reduction in the frequency of nausea and vomiting, normalization of laboratory parameters;

• after discharge, continuation of antiemetic therapy is recommended:

• if symptoms persist at the end of the 2nd and in the 3rd trimester, fetal growth monitoring is indicated [121].

• in case of symptom recurrence, treatment in a day care setting is possible [124].

7. Additional Information

Mild and moderate vomiting generally responds well to therapy and does not lead to complications.

Studies conducted have confirmed a lower rate of spontaneous miscarriage in women with vomiting [125].

The incidence of fetal congenital anomalies does not differ from the general population (meta-analysis).

There is evidence of an increased incidence of low birth weight (LBW) infants and preterm birth [34]. Therefore, if nausea and vomiting symptoms persist in the II and III trimesters, ultrasound monitoring of fetal growth is required.

Some studies have shown that women with low gestational weight gain (less than 7 kg during pregnancy) are at an increased risk of preterm birth [94, 124, 126].

Hyperemesis gravidarum can lead to multiple organ dysfunction syndrome (affecting two or more organs and systems) and serve as an indication for pregnancy termination – artificial abortion (according to several studies, performed in 10% of women with hyperemesis [129]). The decision to terminate a pregnancy is made by a medical board consisting of an obstetrician-gynecologist together with relevant specialists: a physician, a surgeon, and a neurologist, in the absence of response to all types of therapy in accordance with Order No. 736 of the Russian Ministry of Health [48, 127, 128].

Indications for artificial pregnancy termination (abortion) – a combination of 2 or more symptoms:

• unremitting vomiting for 3 days under ICU treatment conditions;

• decrease in diuresis to 300 ml per day;

• progressive acetonuria for 3–4 days;

• progressive weight loss;

• pronounced tachycardia (100–120 bpm);

• impairment of nervous system functions (adynamia, apathy, delirium, euphoria);

• jaundiced discoloration of the sclera and skin;

• acid-base balance (ABB) disturbances, hyperbilirubinemia (up to 100 µmol/L).

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Natalia I. Klimenchenko – PhD in Medical Sciences, Senior Research Fellow, Institute of Obstetrics, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health (Moscow). There is no conflict of interest.

2. Natalia V. Artymuk – MD, Professor, Head of the Department of Obstetrics and Gynecology named after Professor G.A. Ushakova, Kemerovo State Medical University of the Russian Ministry of Health, Chief Freelance Specialist in Obstetrics and Gynecology of the Russian Ministry of Health in the Siberian Federal District (Kemerovo). There is no conflict of interest.

3. Nadezhda V. Bashmakova – MD, Professor, Chief Research Fellow, Research Institute of Maternity and Infancy Care of the Russian Ministry of Health, Honored Doctor of the Russian Federation, Chief Freelance Specialist in Obstetrics and Gynecology of the Russian Ministry of Health in the Ural Federal District (Yekaterinburg). There is no conflict of interest.

4. Tatiana E. Belokrinitskaya – MD, Professor, Head of the Department of Obstetrics and Gynecology of the Faculty of Advanced Training and Professional Retraining, Chita State Medical Academy of the Russian Ministry of Health, Honored Doctor of the Russian Federation, Chief Freelance Specialist in Obstetrics and Gynecology of the Russian Ministry of Health in the Far Eastern Federal District (Chita). There is no conflict of interest.

5. Kristina A. Gladkova – PhD in Medical Sciences, Head of the 1st Obstetric Department of Pregnancy Pathology, Senior Research Fellow, Institute of Obstetrics, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health (Moscow). There is no conflict of interest.

6. Ksenia A. Gorina – Research Fellow, 1st Obstetric Department of Pregnancy Pathology, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health (Moscow). There is no conflict of interest.

7. Nataliia V. Dolgushina – MD, Professor, Deputy Director – Head of the Department of Scientific Activity Organization, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health (Moscow). There is no conflict of interest.

8. Roza M. Esayan – PhD in Medical Sciences, Head of the Therapeutic Department, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health (Moscow). There is no conflict of interest.

9. Marina V. Ipatova – MD, Head of the Rehabilitation Treatment Department, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health (Moscow). There is no conflict of interest.

10. Kirsanova Tatiana Valerievna – PhD in Medical Sciences, Senior Researcher, Department of Reproductive Hematology and Clinical Hemostasiology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Russian Ministry of Health (Moscow). No conflict of interest.

11. Malyshkina Anna Ivanovna – MD, Professor, Director of the V.N. Gorodkov Ivanovo Research Institute of Maternity and Childhood, Head of the Department of Obstetrics and Gynecology, Medical Genetics at the Faculty of Medicine, Ivanovo State Medical Academy, Russian Ministry of Health, Chief Freelance Specialist in Obstetrics and Gynecology of the Russian Ministry of Health in the Central Federal District (Ivanovo). No conflict of interest.

12. Muminova Camilla Timurovna – PhD in Medical Sciences, Junior Researcher, 1st Obstetric Department of Pregnancy Pathology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Russian Ministry of Health (Moscow). No conflict of interest.

13. Olenev Anton Sergeevich – PhD in Medical Sciences, Associate Professor, Chief Freelance Specialist in Obstetrics and Gynecology of the Moscow Healthcare Department, Head of the Perinatal Center, City Clinical Hospital No. 24 (Moscow). No conflict of interest.

14. Pyregov Alexey Viktorovich – MD, Professor, Director of the Institute of Anesthesiology, Resuscitation and Transfusiology, Head of the Department of Anesthesiology and Resuscitation, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Russian Ministry of Health, Chairman of the Committee on Anesthesiology and Resuscitation in Obstetrics and Gynecology of the Association of Anesthesiologists and Resuscitators (Moscow). No conflict of interest.

15. Radzinsky Viktor Evseevich – Honored Scientist of the Russian Federation, MD, Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Department of Obstetrics and Gynecology with a Course in Perinatology, Peoples' Friendship University of Russia under the Ministry of Education of Russia (Moscow). No conflict of interest.

16. Savelyeva Galina Mikhailovna – Academician of the Russian Academy of Sciences, MD, Professor, Hero of Labour of the Russian Federation, Honored Scientist of the RF, Honorary Professor of the Department of Obstetrics and Gynecology, Pediatric Faculty, Pirogov Russian National Research Medical University (Moscow). No conflict of interest.

17. Fatkullin Ildar Faridovich – MD, Professor, Honored Scientist of the Republic of Tatarstan, Honored Doctor of the Republic of Tatarstan, Head of the Prof. V.S. Gruzdev Department of Obstetrics and Gynecology, Kazan State Medical University, Russian Ministry of Health, Chief Freelance Specialist in Obstetrics and Gynecology of the Russian Ministry of Health in the Volga Federal District (Kazan). No conflict of interest.

18. Fedorova Tatyana Anatolyevna – MD, Professor, Deputy Director of the Institute of Anesthesiology, Resuscitation and Transfusiology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Russian Ministry of Health (Moscow). No conflict of interest.

19. Khodzhaeva Zulfiya Sagdullaevna – MD, Professor, Deputy Director for Science, Institute of Obstetrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Russian Ministry of Health (Moscow). No conflict of interest.

20. Shabanova Natalia Evgenievna – PhD in Medical Sciences, Senior Researcher, Department of Clinical Pharmacology of Antimicrobial and Immunobiological Drugs, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Russian Ministry of Health (Moscow). No conflict of interest.

21. Sheshko Elena Leonidovna – Director of the Department of Medical Care for Children, Maternity Services and Public Health, Ministry of Health of the Russian Federation (Moscow). No conflict of interest.

22. Shmakov Roman Georgievich – MD, Professor of the RAS, Director of the Institute of Obstetrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Russian Ministry of Health (Moscow). No conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. obstetrician-gynecologist, general practitioner, anesthesiologist-resuscitologist, neurologist, gastroenterologist.

2. midwife.

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing levels of reliable evidence (LRE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Appendix A3. Reference Materials

1. Obstetrics. National Guidelines. Moscow: GEOTAR-Media, 2015.

Appendix A3.1. Risk factors for vomiting in pregnancy [130].

• Increased placental mass (multiple pregnancy, trophoblastic disease).

• Heredity (genetic predisposition).

• Migraine.

• Vomiting in previous pregnancies. However, the recurrence rate decreases with a change of partner [18, 126].

• Daughters and sisters of women who experienced hyperemesis gravidarum are at risk of developing it, as well as those carrying a female fetus [20, 131].

Appendix A3.2. Clinical classification of vomiting in pregnancy (Obstetrics. National Guidelines. Moscow: GEOTAR-Media, 2015.).

Note: +, ++, +++ – severity grade.

Appendix B. Physician Action Algorithms

APPENDIX B2. Differential diagnosis of vomiting in pregnancy.

Note: -, -+, +, ++, +++ – severity grade.

Appendix C. Patient Information

Vomiting of pregnancy occurring more than 2-3 times a day is a complication developing in the first half of pregnancy. This condition is characterized by dyspeptic disorders and impairment of all types of metabolism in severe cases, dehydration, and weight loss, which reduce the quality of life. Hyperemesis gravidarum is the extreme degree of this condition, requiring inpatient medical care.

The causes of this complication often include endocrine system imbalance, CNS dysfunction, changes in gastrointestinal function during pregnancy, and genetic predisposition.

In normal pregnancy, nausea and vomiting up to 2-3 times a day occurs in 50-80% of women and is not a pathological condition requiring treatment. In such cases, the doctor provides recommendations on lifestyle modification, diet, and dietary regimen.

Symptoms of nausea and vomiting usually first appear at 5-6 weeks of gestation. Other complaints may be observed, namely: decreased or absent appetite, altered taste and smell, sialorrhea, heartburn, eructation, bloating, constipation, weight loss. Symptoms such as headache, dizziness, weakness, apathy, drowsiness, irritability, delirium, euphoria, coma in severe cases, visual impairment, palpitations, decreased blood pressure, decreased urination frequency, dryness, and icterus of the skin and mucous membranes also occur.

The danger of this condition is that in the absence of treatment, severe and sometimes irreversible complications can develop. These include CNS damage, electrolyte changes leading to cardiovascular system dysfunction, severe gastrointestinal damage, renal failure, and others.

If vomiting persists more than 2-3 times a day and/or other symptoms listed above occur, you should consult a doctor, who must prescribe an examination including laboratory and instrumental diagnostic methods, and consultations with relevant specialists. In severe cases, the pregnant woman is hospitalized, where a complex of necessary studies is also performed. Daily measurement of peripheral blood pressure, pulse, body weight, thermometry, and determination of daily urine volume are mandatory. In severe cases, additional instrumental research methods are prescribed, such as magnetic resonance imaging of the brain, abdominal organs, and gastroesophagogastroduodenoscopy.

Treatment includes several stages. Initially, it is necessary to follow a diet, work and rest regimen, and avoid bad habits, harsh light, odors, and other factors that worsen the condition.

Ginger can be included in the diet to relieve symptoms of nausea and vomiting.

If non-pharmacological treatment is ineffective, medications may be used. Monotherapy with drugs that are safe for the mother and fetus during pregnancy, have proven efficacy, and have no or minimal side effects is preferred.

Many drugs with proven efficacy and safety in pregnant women with vomiting are registered in Russia with the label "contraindicated during pregnancy." However, they can be used in severe cases when conventional treatment is ineffective, provided that the benefit outweighs the risk of use according to the medical board conclusion. In each specific case, the physician explains the necessity and justification for prescribing a particular medicinal product. It is necessary to timely inform the physician about potential comorbid conditions, adverse treatment effects, or side effects.

Self-medication is strictly not recommended.

In mild cases of hyperemesis gravidarum, treatment is carried out on an outpatient basis in accordance with the physician's recommendations and under their supervision. If parenteral administration of drugs is necessary, therapy in a day hospital setting is possible.

In cases of hyperemesis gravidarum and/or comorbid conditions and complications, hospitalization is indicated for intensive care and monitoring of the pregnant woman's condition.

If ongoing intensive therapy is ineffective and the woman's condition worsens, artificial termination of pregnancy (abortion) is indicated. The decision is made by a medical board taking into account the woman's condition and wishes.

Pregnancy planning, preconception examination and preparation, timely treatment of gynecological and extragenital diseases, and multivitamin intake at least 1 month before planned pregnancy have a preventive effect against the development of hyperemesis gravidarum.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

No.