MEDICINE

REVIEW ARTICLE

Nausea and Vomiting in Pregnancy

Ioannis Mylonas, Andrea Gingelmaier, Franz Kainer

SUMMARY
Introduction: About 5090% of all pregnant women experience nausea and vomiting. Generally, these symptoms discontinue within the first 20 weeks of pregnancy. However, in up to 20% symptoms persist for the duration of pregnancy. Methods: Selective literature review. Results: Symptoms are often nonspecific. Most women suffer from frequent or constant vomiting. Blood results (for example urea and electrolyte disturbance, hematocrit elevation) and urinalysis (in particular ketonuria) are helpful diagnostic indicators. First treatment should be dietary advice. Vitamin B6 (pyridoxine), antihistamines and anticholinergics as well as other low-dose antiemetics and gastrointestinal agents, may be given. Inpatient treatment is advisable for severe cases with electrolyte imbalance. Discussion: The etiology of emesis and hyperemesis gravidarum are not fully understood. It is likely that physiological as well as psychological causes play a part in its development. If vomiting persists and symptoms are severe alternative differential diagnoses should be considered. Dtsch Arztebl 2007; 104(25): A 18216.
Key words: emesis, vomiting, pregnancy, diagnosis, treatment

ome 5090% of pregnant women develop nausea and vomiting during pregnancy (1). Isolated morning sickness affects only about 2% of pregnant women, whereas over 80% suffer from symptoms throughout the entire day. As a rule, nausea and vomiting cease in the first 20 weeks of pregnancy; in up to 20% of cases, symptoms may last for the entire pregnancy (1, 2). Emesis gravidarum is the term used for nausea as well as pregnancy-related vomiting, but without feelings of sickness and impairment to wellbeing. An important distinction needs to be made for the transition to persistent vomiting with a frequency of more than five times a day, weight loss of more than 5%, and impaired intake of food and fluids; this is known as hyperemesis gravidarum (synonyms: excessive vomiting during pregnancy, early gestosis). The condition can be life threatening for the patient and has to be diagnosed and treated at once. Hyperemesis gravidarum is vomiting with threatening symptoms during pregnancy, accompanied by dehydration, acidosis due to lack of nutrition, alkalosis due to loss of hydrochloride, and hypokalemia. Clinically, hyperemesis gravidarum is differentiated into grade 1, with feelings of sickness without metabolic imbalance and grade 2 with pronounced feelings of sickness and metabolic imbalance. The incidence of hyperemesis is 0.52% worldwide; regional, social, and temporal differences exist (5). This review article presents etiology, pathophysiology, clinical presentation, diagnosis, and therapy, on the basis of a selective literature review.

Etiology and pathophysiology

The etiology of emesis and hyperemesis gravidarum is not clear. Physiological as well as psychological factors are likely to be involved. Likely risk factors for hyperemesis gravidarum to develop include: a background of migration, obesity, multiple pregnancy, trophoblastic disorders, hyperemesis gravidarum in previous pregnancy, nulliparity, metabolic causes (e.g., hyperthyroidism, hyperparathyroidism, hepatic dysfunction, impaired lipid metabolism), and eating disorders such as bulimia or anorexia (2, 6, 7).
1. Frauenklinik Klinikum Innenstadt, Ludwig-Maximilian-Universitt Mnchen, Mnchen: Dr. med. Mylonas, Dr. med. Gingelmaier, Prof. Dr. med. Kainer

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DIAGRAM 1

Algorithm for diagnosis of hyperemesis gravidarum, according to (e20) GOT, glutamatoxalacetate transaminase; GPT, glutamatpyruvate transaminase

Psychosomatic causes
The often assumed cause of hyperemesis gravidarum during the first trimester is a psychosomatic disorder, which may be explained with fear of becoming a parent. Pregnant women with stress and emotional tensions often have this condition. But only few scientific data confirm this theory. In the best known study, the psychological Cornell Medical Index was measured in 44 pregnant patients with, and 49 pregnant women without, hyperemesis gravidarum. The psychological test Minnesota Multiphasic Personality Inventory (MMPI) was applied only to the pregnant women with hyperemesis gravidarum. Both studies with different question scores showed that patients with hyperemesis had an excessive bond with their mothers and more frequently had hysterical fits and infantile personalities (8, 9). Hyperemesis gravidarum occurs more often in personality disorders and depressive disorders, but the association has not been studied to a sufficient extent (10).

Human chorionic gonadotropin

An association between nausea, vomiting, and an increased production of human chorionic gonadotropin (hCG) is assumed because hyperemesis is often associated with multiple pregnancies and trophoblastic disorders, with hCG concentrations being elevated in both (11, e1e5). However, this has not been proven conclusively up to now. Many women with elevated hCG do not suffer from nausea and vomiting. And patients with chorionic carcinoma, who also have raised hCG measurements, have not nausea either. Dtsch Arztebl 2007; 104(25): A 18216 www.aerzteblatt.de

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Hormones
Estrogen, progesterone, adrenal, and pituitary hormones may also trigger hyperemesis. The data situation is not straightforward, however (12). In patients with hyperemesis, progesterone levels are lower (13) or elevated (14). Other researchers found no association between hyperemesis and progesterone concentrations (e5, 15). Progesterone treatment does not improve the complaints (8, 9). The fact that nausea is known to occur during estrogen treatment suggests that estrogen may play a role in hyperemesis. Several prospective studies found raised estrogen concentrations in association with hyperemesis (14, 16), whereas others found no association (9, e6). Interestingly, hyperemesis gravidarum is more often associated with a female fetus and might thus hint at a higher concentration of estrogen in utero (17). Patients with hyperemesis probably react more sensitively to estrogen effects than asymptomatic pregnant women (13).

TABLE 1
Differential diagnosis in sustained nausea and vomiting in pregnancy

Causes Pregnancy associated

Differential diagnosis Emesis gravidarum (< 5 x/d) Hyperemesis gravidarum (> 5 x/d) Pre-eclampsia Acute fatty liver

Diagnostic pointers Mostly in the morning, watchful waiting Ketonuria, ketonemia Prodromal stage of eclampsia in 2nd and 3rd trimester Clinical symptoms, serology, ultrasonography Clinical symptoms, watchful waiting, stool culture Raised transaminases Early pregnancy: typical points for pain on pressure Late pregnancy: no typical leading symptoms (caution!) Clinical symptoms, serology, amylases, lipases Clinical symptoms, plain abdominal radiography (even in pregnancy) Serology, ultrasonography of upper abdomen Gastroscopy Gastroscopy Gastroscopy Clinical symptoms, urinary status, creatinine Ultrasonography Ultrasonography Urinary status, creatinine Clinical symptoms, urinary status Serology Clinical symptoms, serology fT3, fT4, TSH Clinical symptoms, serology Medical history, clinical course, if required magnetic resonance imaging Nystagmus, impaired hearing Medical history, clinical course Medical history Medical history Medical history Medical history

Gastrointestinal

Gastroenteritis Hepatitis Appendicitis Pancreatitis Ileus and subileus Hepatic or cholecystic disorders Stomach ulcer or duodenal ulcer Stomach cancer Diaphragmatic hernia

Urogenital

Pyelonephritis Nephrolithiasis Degenerative uterine fibroids Uremia

Metabolic

Diabetic ketoacidosis Porphyria Addison's disease Hyperthyroidism Thyrotoxicosis

Neurological

Wernickes encephalopathy Vestibular disorders Korsakoff's psychosis Migraine

Other causes

Food poisoning Iron medication Drug poisoning

fT3, free triiodothyronine; fT4, free tretraiodothyronine; TSH, thyreoid stimulating hormone Adapted from e20, in: Facharzt Geburtsmedizin, Urban und Fischer Verlag, with kind permission of Elsevier GmbH

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Helicobacter pylori
Chronic infection with Helicobacter pylori is also a possible cause of hyperemesis gravidarum (18). Histological evaluation of the stomach mucosa showed that this causative agent was present in almost 95% of patients with hyperemesis and in 50% of controls (19). Another study found the H pylori genome in the saliva of 61.8% of patients with hyperemesis gravidarum (21 of 34 patients), compared with 27.6% of pregnant women without symptoms (20). This association seems confirmed by the fact that in two observational studies with a total of five patients, no improvement in symptoms occurred after standard drug treatment, whereas antibiotic treatment for H pylori resulted in a clear improvement of symptoms (21, e7).

Changes in gastrointestinal motility

During pregnancy, a woman's gastrointestinal motility is limited owing to progesterone (22). Gastric dysrythmias may also occur (23). The impaired motility may therefore contribute to hyperemesis gravidarum.

Hyperthyroidism
Hyperthyroidism has also been linked to hyperemesis gravidarum (24). While fT3 and fT4 were in the normal range, the expression of thyroid stimulating hormone (TSH) was decreased. The assumption is that a self limiting, transient hyperthyroidism of hyperemesis gravidarum (THHG) exists. THHG may prevail up to the 18th week of gestation and does not require treatment. The conditions for the diagnosis of THHG are: > That pathological serology results are confirmed during hyperemesis, > That no hyperthyroidism existed before the pregnancy, > That no clinical signs of hyperthyroidism exist, and > That a negative antibody is present.

Clinical presentation and diagnosis

The clinical symptoms are mostly unspecific and uncharacteristic. The main symptom is excessive, frequent vomiting that lasts all day. Clinical signs of desiccation with a loss in volume, weight loss, and metabolic ketoacidosis and ketonemia (fruity smell on the breath) may also be present. This may be associated with pyrexia and hepatic symptoms such as jaundice. Rare symptoms include drowsiness and intellectual slowness, which may result in delirium. Further to the clinical symptoms, chemical laboratory tests (hematocrit, electrolytes, transaminases, bilirubin, thyroid function) and urinary status (positive ketone bodies, specific weight, aciduria) are pointers (diagram 1). Ultrasonography to confirm an

TABLE 2
Antiemetics and dosages in hyperemesis gravidarum

FDA Effective substance Dosage category A B Pyridoxone (vitamin B6) 20 mg p.o.; 3 x daily Dimenhydrinate 62 mg IV; 2 x daily 50 mg p.o.; 34 x daily Supp.: 13 x daily 2550 mg IV/p.o.; Every 68 hours 25100 mg p.o.; 24 x daily; Supp.: 1 x daily 10 mg p.o.; 4 x daily 24 mg IV every 68 hours 12.525 mg p.o./IV up to 6 x daily

Diphenhydramine Meclozine Metoclopramide Ondansetron C Promethazine

Adapted from e20: Facharzt Geburtsmedizin, Urban und Fischer Verlag, with kind permission of Elsevier GmbH

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intact, intrauterine pregnancy and to rule out a multiple pregnancy, trophoblastic disorders, and neoplasia should also be conducted (diagram 1). If the vomiting is sustained and the symptoms are striking, differential diagnostic causes should be considered (table 1).

Treatment
Nausea and vomiting in early pregnancy are mostly self limiting and often need merely symptomatic treatment. The therapy depends on the respective symptoms, and the range of treatments includes dietary changes, e.g., with several, small meals and avoidance of acidic fruit or fruit juices, to inpatient admission with parenteral feeding. Primarily, dietary changes on an outpatient basis seem advisable; if necessary, antiemetics may be added in small dosages. In hyperemesis gravidarum grade 2, the woman should be admitted as an inpatient.
DIAGRAM 2

Inpatient procedure in hyperemesis gravidarum, adapted from e20

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Outpatient treatment The first therapeutic step should be extensive dietary advice. The desirable foods should be rich in carbohydrates and low in fat and should be consumed in many small meals. Disagreeable smells that might trigger nausea and vomiting should be avoided (e.g., the smell of meat). Emotional support and, if needed, psychosomatic care administered by a psychologist or a doctor with additional psychosomatic training is also important. Depending on the severity of the patient's illness, supportive counselling, crisis interventions, or psychosomatic or psychiatric care might be required. A more extensive explanation of the therapeutic options would lead too far in this context. Drug treatments include vitamin B6 (pyridoxine), antihistamines, anticholinergics, further low-dosage antiemetics, and gastrointestinally effective substances. An analysis of 28 randomized trials into the treatment of hyperemesis gravidarum showed that antiemetics reduce the frequency of nausea in early pregnancy and are more effective than placebo. But some drugs had side effects, especially fatigue. Vitamin B6 (pyridoxine) was more effective than placebo on treating nausea and vomiting in pregnant women (25). At a dosage of 1025 mg, thrice daily, pyridoxine reduces symptoms; treatment should be started using a low dose (e8). Antihistamines and anticholinergics such as meclozine, dimenhydrinate, and diphenhydramine are used primarily to treat nausea and vomiting in pregnancy (table 2). These substances are more effective than placebo in treating emesis and hyperemesis (e9). If needed, ondansetron and promethazine can also be used in severe cases of hyperemesis gravidarum (table 2). To improve gastrointestinal motility, metoclopramide may also be used without problems. Additional alternatives include acupressure and ginger extracts. Acupressure, especially on the P6 point (Neiguan) on the wrist, has also been suggested for the treatment of pregnancy related nausea (e10). But sufficient scientific proof is absent, which confirms the efficacy of this method. A popular therapeutic alternative is ginger (e11), which may be administered in several ways (e.g., as tea). Powdered ginger (1 g/d) has been found to be more effective than placebo in hyperemesis gravidarum (e12). Although ginger is apparently not teratogenic, possible side effects and the optimal dosage are unknown (e8, e13). Inpatient treatment Pregnant women with severe hyperemesis gravidarum and electrolyte imbalances should be admitted as inpatients. The primary treatment is total food withdrawal, accompanied by substitution of volume and electrolytes (at least 3 000 ml/d), correction of the electrolyte imbalance, administration of vitamins and antiemetics, and parenteral administration of carbohydrate and amino acid solutions (about 8 400 to 10 500 kJ/d). Treatment should be continued until the vomiting ceases or occurs less than three times daily. Subsequently, food should be slowly reintroduced (diagram 2). Diazepam is also positive in hyperemesis (e14), probably because of its sedative component. If this is used, however, possible dependency problems should be taken into consideration. Diazepam should be used with caution in pregnancy due to possible fetal side effects. Corticoids (e.g., hydrocortisone) may also be used in hyperemesis that is refractory to treatment (e15). Although corticosteroids during pregnancy are classed as safe, a meta-analysis showed a slightly increased risk of fetal malformations, especially during the first trimester (e16). If symptoms persist, relevant disorders should be excluded by differential diagnosis. Continuing psychosomatic care and emotional support are also desirable (10). Often, symptoms are improved merely by inpatient admission. This confirms the therapeutic approach used by Thure von Uexkll, who demanded primarily supportive, embracing attention for such pregnant women (e17). If a psychotic component to the disorder is suspected, however, a psychiatrist needs to be consulted.

Maternal and fetal prognosis

Women with uncomplicated emesis gravidarum have a better fetal prognosis than the normal cohort, including a lower tendency to miscarry, to retarded intrauterine growth, and premature birth (2, 4, e18). Hyperemesis gravidarum, however, is associated with increased esophageal rupture (severe vomiting), Mallory-Weiss syndrome (acute pressure increase owing to vomiting), pneumothorax, neuropathy, pre-eclampsia, and fetal growth retardation (2, 4, e19). Dtsch Arztebl 2007; 104(25): A 18216 www.aerzteblatt.de

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Conclusion
Although hyperemesis gravidarum is very rare compared with frequent mild vomiting during pregnancy, its clinical and socioeconomic aspects are important. The disorder is accompanied by a severely impaired quality of life for the patient and with high costs to the healthcare system. Since the pathogenesis of hyperemesis gravidarum is thus far unknown, treatment is mostly symptomatic and often suboptimal.
Conflict of Interest Statement The authors declare that no conflict of interest exists according to the Guidelines of the International Committee of Medical Journal Editors. Manuscript received on 28 August 2006, final version accepted on 17 January 2007. Translated from the original German by Dr Birte Twisselmann.

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Corresponding author Dr. med. Ioannis Mylonas 1. Frauenklinik Klinikum Innenstadt Ludwig-Maximilian-Universitt Mnchen Maistr. 11 80337 Mnchen, Germany ioannis.mylonas@med.uni-muenchen.de

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