About 50% of pregnant women experience nausea and vomiting in early pregnancy, 25% experience nausea without vomiting, and 25% have no symptoms. These symptoms mostly start at 4 weeks of gestation and are most severe at 9 weeks of gestation; 60% of pregnant women have their symptoms resolve on their own after 12 weeks of gestation, 91% after 20 weeks of gestation, and about 10% of pregnant women have persistent nausea and vomiting throughout pregnancy [1-2]. The recurrence rate of nausea and vomiting in repeat pregnancies ranges from 15.2% to 81.0%. Hyperemesis gravidarum is the most severe stage of pregnancy vomiting and often results in delayed consultation or inadequate treatment due to doctor-patient concerns about the safety of medications used in early pregnancy leading to serious complications or even life-threatening conditions for the mother and forced termination of pregnancy. Therefore, early recognition and proper management are of great clinical significance.
The Obstetrics and Gynecology Group of the Obstetrics and Gynecology Branch of the Chinese Medical Association organized domestic experts to formulate the “Expert Consensus on the Diagnosis and Clinical Management of Hyperemesis Gravidarum (2015)” with reference to the international guidelines on the treatment of hyperemesis gravidarum and the latest evidence-based evidence on the application of antiemetic drugs in early pregnancy, and combined with domestic clinical practice, with the aim of standardizing and guiding The aim is to standardize and guide obstetricians and gynecologists in the clinical management of hyperemesis gravidarum, improve pregnancy outcomes, and reduce unnecessary medically induced pregnancy terminations.
I. Definition
Hyperemesis gravidarum refers to severe and persistent nausea and vomiting in early pregnancy that causes dehydration, ketosis and even acidosis and requires hospitalization. Only 0.3% to 1.0% of pregnant women with nausea and vomiting usually develop hyperemesis gravidarum, and the need for hospitalization is often used as one of the important bases for clinical judgment of hyperemesis gravidarum.
Diagnosis
1.Clinical manifestations.
(1) Medical history: hyperemesis gravidarum is a diagnosis of exclusion. Careful medical history should be taken to exclude other diseases that may cause vomiting, such as gastrointestinal infection (with diarrhea), cholecystitis, biliary ascariasis, pancreatitis (with abdominal pain and elevated plasma amylase levels of 5 to 10 times the normal value), urinary tract infection (with difficulty urinating or lumbar pain), viral hepatitis (positive hepatitis virology, elevated liver enzyme levels of 1,000 U/L or more) or pre-pregnancy illnesses (e.g. vomiting due to diabetes, Addison’s disease). Special questions should be asked about the presence of epigastric pain and vomiting of blood or symptoms caused by other pathologies (e.g. gastric ulcer). (2) Symptoms: Almost all cases of hyperemesis gravidarum occur before 9 weeks of gestation, which is particularly important for the differential diagnosis [1]. The typical presentation is nausea and vomiting around 6 weeks of gestation, which gradually worsens with the progress of pregnancy and develops into persistent vomiting around 8 weeks of gestation, with inability to eat and, in extremely severe cases, drowsiness, confusion, delirium or even coma and death.
2. Physical signs.
The pregnant woman’s body mass decreases, and the decrease even exceeds 5% of that before the onset of the disease, with symptoms such as obvious emaciation, extreme fatigue, dry lips, dry skin, sunken eyes and reduced urine output.
3.Auxiliary examination.
(1) urine examination: the body mobilizes adipose tissue to supply energy in the starvation state, so that the intermediate product of fat metabolism, ketone bodies, accumulate, positive urine ketone body test; at the same time to determine the volume of urine, urine specific gravity, pay attention to the presence of proteinuria and tubular urine; midstream urine bacterial culture to exclude urinary tract infection.
(2) Routine blood tests: the hemoglobin level will be increased due to blood concentration, up to 150 g/L or more, and the erythrocyte volume will be 45% or more.
(3) Biochemical indices: serum potassium, sodium and chloride levels are reduced, showing metabolic hypochlorhydria alkalosis; 67% of pregnant women with severe pregnancy vomiting have elevated liver enzyme levels, but usually not more than 4 times the upper limit of normal or 300 U/L; serum bilirubin levels are elevated, but not more than 4 mg/dl (1 mg/dl = 17.1 μmol/L); plasma amylase and lipase levels are elevated up to 5 times the normal value If renal insufficiency is present, urea nitrogen and creatinine levels are elevated.
(4) Arterial blood gas analysis: carbon dioxide binding capacity decreases to <22 mmol/L. These abnormalities usually return to normal rapidly after correction of dehydration and resumption of feeding.
(5) Fundus examination: optic neuritis and retinal hemorrhage may occur in severe cases of severe pregnancy vomiting.
Special complications
1. Hyperthyroidism.
The reason is that the β-subunit structure of β-hCG is similar to the chemical structure of TSH, and the β-hCG level increases after pregnancy, stimulating the thyroid gland to secrete thyroid hormone, which in turn suppresses the TSH level by feedback. It is often temporary, most of which is not serious and usually does not require the use of antithyroid drugs. Patients with primary hyperthyroidism rarely experience vomiting, and pregnant women with severe pregnancy vomiting without clinical manifestations of hyperthyroidism (e.g., goiter) or thyroid antibodies should have their thyroid function rechecked at 20 weeks of pregnancy, and thyroid hormone levels usually return to normal.
2. Wernicke’s encephalopathy.
It usually develops after 3 weeks of severe pregnancy vomiting and is caused by severe vitamin B1 deficiency due to severe vomiting. About 10% of patients with severe pregnancy vomiting have this disease, which is characterized by oculomotor paralysis, trunk ataxia and amnestic psychiatric symptoms. Clinical manifestations include nystagmus, visual impairment, impaired gait and standing posture, and in some cases, xerosis or coma. The mortality rate of treated patients is still 10%, and the mortality rate of untreated patients is up to 50%.
IV. Treatment
Pregnant women with persistent vomiting and ketosis need to be hospitalized, including intravenous rehydration, multivitamin supplementation, correction of dehydration and electrolyte disorders, rational use of antiemetic drugs, and prevention and treatment of complications.
1. General management and psychological support treatment.
Exposure to odors, foods or additives that tend to induce vomiting should be avoided as much as possible. Avoid fasting in the morning, encourage small and frequent meals, drink water between meals, and eat light, dry and high-protein food. Medical staff and family members should give psychological guidance to the patients and inform them that after 2-3 days of active treatment, the condition will improve rapidly, and only a few pregnant women will have a relapse of symptoms after discharge and need to be re-admitted to the hospital.
2. Correct dehydration and electrolyte disorders.
(1) Daily intravenous infusion of glucose solution, glucose saline, saline and balance solution totaling about 3,000 ml, including vitamin B6 100 mg, vitamin B1 100 mg, vitamin C 2-3 g, continuous infusion for at least 3 d (depending on the degree of relief of vomiting and feeding), maintaining daily urine output ≥ 1,000 ml. can be in accordance with glucose 4-5 g + insulin 1 U + 10% KCl 1.0-1.5 g formulated as a polarized solution infusion for energy supplementation, but care should be taken to supplement vitamin B1 before glucose infusion to prevent the development of Wernicke’s encephalopathy [1]. Enteral nutrition by nasogastric tube can be considered for those who cannot maintain normal body mass with conventional treatment. Parenteral intravenous nutrition can only be used as the last supportive treatment when the aforementioned treatment is ineffective due to its potential serious complications in mothers.
(2) Generally, potassium supplementation should be 3-4 g/d, or 6-8 g/d in case of severe hypokalemia, and pay attention to the urine volume, in principle, it is safer to supplement 1 g of potassium per 500 ml of urine volume. According to the blood carbon dioxide level, supplement sodium bicarbonate or sodium lactate solution appropriately to correct metabolic acidosis, commonly used amount is 125~250 ml/time.
3.Antiemetic treatment.
(1) The safety of antiemetic drugs: Since severe pregnancy emesis occurs in early pregnancy, which is the most teratogenic and sensitive period for the fetus, the safety of antiemetic drugs is of great concern.
①Vitamin B6 or vitamin B6-doxylamine combination.
Studies have confirmed that it is safe and effective for application in early pregnancy hyperemesis, and it was approved by the U.S. Food and Drug Administration (FDA) in 2013 and recommended as a first-line drug [7], but doxylamine is not yet available in China.
②Metoclopramide (other name: Gastrofluan).
A multicenter prospective study showed that the application of metoclopramide during early pregnancy did not increase the risk of fetal malformation or spontaneous abortion, and there was no significant difference in neonatal birth mass compared with normal controls [8]. Another study with a large sample size showed that metoclopramide application during early pregnancy did not increase the risk of neonatal birth defects, low birth mass, preterm delivery, or perinatal death [9].
A recent study evaluating the safety of metoclopramide application during pregnancy in a very large sample size (more than 1.2 million cases) further confirmed that the drug did not increase the risk of birth defects (including neural tube abnormalities, transposition of great vessels, ventricular septal defect, atrial septal defect, tetralogy of Fallot, aortic constriction, cleft lip, cleft palate, anal atresia or stenosis, and short limbs) as well as preterm delivery and stillbirth [10].
(iii) Ondansetron (other name: Endansetron):
A 5-hydroxytryptamine type 3 receptor antagonist, the largest sample size to date (more than 600,000 cases) of safety studies of ondansetron in singleton pregnancies and early pregnancy showed no increased risk of spontaneous abortion, intrauterine death, neonatal birth defects, preterm birth, low birth mass of the newborn, or the occurrence of infants younger than gestational age, although an association with fetal cleft lip has been reported. The American College of Obstetricians and Gynecologists (ACOG) recently concluded that although there is insufficient evidence to confirm the safety of ondansetron in the fetus, the absolute risk is low and should be used on a balance of benefits and harms. On the other hand, ondansetron has the potential to increase the risk of prolonged cardiac QT interval leading to tip-twist ventricular tachycardia, so the FDA recommends that single doses should not exceed 16 mg and that patients with a personal and family history of prolonged QT interval, cardiac failure, hypokalemia, and hypomagnesemia should have their electrolytes and electrocardiogram monitored when ondansetron is administered. Meanwhile, another randomized controlled double-blind study confirmed that the antiemetic effect of intravenous metoclopramide was similar to that of ondansetron, but the incidence of side effects such as drowsiness, dry mouth, and urinary ketosis of the latter was lower than that of metoclopramide, which has become an alternative choice for pregnant women with hyperemesis gravidarum because it is safer for the fetus, has good antiemetic effect, and is inexpensive.
iv) Promethazine.
The results of a randomized controlled double-blind study showed that the antiemetic efficacy of promethazine was essentially similar to that of metoclopramide, but the incidence of side effects was lower with metoclopramide than with promethazine [15]. In addition, it has been reported in the literature that although the application of isoprostanes for antiemetic in early pregnancy did not increase the incidence of birth defects, their continued use in late pregnancy can cause withdrawal effects and extrapyramidal reactions in neonates [4].
⑤ Glucocorticoids.
Studies have reported that methylprednisolone may alleviate the symptoms of hyperemesis gravidarum, but given the association of early pregnancy application with fetal cleft lip [16-18], the ACOG recommends that it should be avoided as a first-line agent before 10 weeks of gestation and only as a last antiemetic option for patients with intractable hyperemesis gravidarum [1].
(2) Commonly used antiemetic medications for hyperemesis gravidarum: see Table 1.
4. Indications for termination of pregnancy.
(1) Persistent body temperature above 38 °C;
(2) Heart rate >120 beats/min at bed rest;
(3) persistent jaundice or proteinuria;
(4) The presence of polyneuritis and neurological signs;
(5) Intracranial or fundus bleeding that does not improve with treatment;
(6) The presence of Wernicke’s encephalopathy.
V. The medication process of hyperemesis gravidarum
The process of medication administration for hyperemesis gravidarum.
VI. Prognosis and prevention
Some studies have concluded that pregnant women with hyperemesis gravidarum are not at increased risk of low birth mass in their offspring and that there are no significant differences in perinatal outcomes compared with those without hyperemesis gravidarum. A recent study with a large sample size reported a slightly increased risk of preeclampsia in pregnant women with early-onset hyperemesis and a 2-fold increased risk of preeclampsia by 37 weeks of gestation, a 3-fold increased risk of placental abruption, and a 39% increased risk for children younger than gestational age in those admitted to the hospital with midtrimester hyperemesis (12 to 21 weeks), suggesting that persistent hyperemesis in midtrimester may be associated with abnormal placental function. However, in the majority of cases, the clinical course is mostly benign, and with aggressive and correct treatment, the condition improves quickly and subsides spontaneously as the pregnancy progresses, with a good overall maternal and child prognosis.
Treatment of vomiting begins with prevention, and studies have found that multivitamins taken at the time of conception may reduce the need for medical management of vomiting, and therefore a multivitamin regimen is recommended for the first 3 months of pregnancy to potentially reduce the incidence and severity of vomiting.