What is fetal ketonuria

Summary
Introduction: Around 50 to 90% of all pregnant women suffer from nausea and vomiting during pregnancy. As a rule, the symptoms cease in the first 20 weeks of pregnancy, although in up to 20% of cases these symptoms can persist throughout the pregnancy. Methods: Review based on a selective selection of literature. Results: The symptoms are often unspecific. The focus is usually on excessive, frequent and all-day vomiting.
Particularly trend-setting are the laboratory diagnostics of the peripheral blood, including electrolyte imbalance, increased hematocrit, and the urine status (especially ketonuria). The initial treatment consists of extensive nutritional advice. Vitamin B6 (pyridoxine), antihistamines and anticholinergics, other low-dose anti-emetics and gastrointestinal drugs can be administered as medication. In-patient admission should take place in severe cases with electrolyte imbalance. Discussion: The etiology of vomiting and hyperemesis gravidarum has not yet been finally clarified. It is assumed that physiological as well as psychological factors play a decisive role. In the case of persistent vomiting and pronounced symptoms, other causes should also be considered in the differential diagnosis.
Dtsch Arztebl 2007; 104 (25): A 1821-6.
Key words: nausea, vomiting, pregnancy, diagnosis, therapy concept

Summary
Nausea and vomiting in pregnancy
Introduction: About 50 to 90% 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 (pyrodixine), 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 1821-6.
Key words: emesis, vomiting, pregnancy, diagnosis, treatment



Around 50 to 90% of all pregnant women experience nausea and vomiting during pregnancy (1). Only around 2% of pregnant women suffer from isolated morning sickness, whereas in over 80% of those affected the symptoms occur throughout the day. As a rule, nausea and vomiting cease in the first 20 weeks of pregnancy; in up to 20% of cases, the symptoms can persist throughout pregnancy (1, 2).
In addition to nausea, vomiting caused by pregnancy is also referred to as emesis gravidarum, but without any feeling of illness or impairment of wellbeing. An important distinction to this is the transition to persistent vomiting with a frequency of more than five times a day, weight loss of more than 5% and difficult food and fluid intake, this is called hyperemesis gravidarum (synonyms: excessive vomiting during pregnancy, premature gestosis ) designated. Under certain circumstances, this disease can be life-threatening for the patient and must be recognized and treated immediately. Hyperemesis gravidarum is vomiting with threatening symptoms during pregnancy with dehydration, acidosis due to insufficient food intake, alkalosis due to HCl loss and hypokalemia. Hyperemesis gravidarum can be divided clinically into grade 1 with a feeling of illness without metabolic derailment and grade 2 with a pronounced feeling of illness with metabolic derailment, dehydration and electrolyte imbalance. The incidence of hyperemesis gravidarum is between 0.5% and 2% worldwide (3, 4); there are regional, social and temporal differences (5).
This review article, based on a selective review of the literature, presents the etiology, pathophysiology, clinical features, diagnostics and therapy.
Etiology and pathophysiology
The etiology of vomiting and hyperemesis gravidarum is still largely unclear. Both physiological and psychological factors are likely to be involved.
Possible risk factors for developing hyperemesis gravidarum include: migration background, obesity, multiple pregnancy, trophoblastic disease, hyperemesis gravidarum in a previous pregnancy, nulliparity, metabolic causes (such as hyperthyroidism, hyperparathyroidism, liver dysfunction such as lipid metabolism disorders) (2, 6, 7).
Psychosomatic causes
A psychosomatic disorder is often assumed to be the cause of hyperemesis gravidarum in the first trimester, which can be explained by fear of parenthood. In addition, this often occurs in pregnant women with stress and emotional tension. However, there is little scientific evidence to support this theory. In what is probably the most famous study, the psychological Cornell Medical Index was determined on 44 pregnant patients with hyperemesis gravidarum and 49 pregnant women without hyperemesis. The Minnesota Multiphasic Personality Inventory (MMPI) psychological test was only used on pregnant women with hyperemesis gravidarum. Both studies with different question scores showed that hyperemesis patients had excessive attachment to their mother and suffered more from hysterical attacks and an infantile personality (8, 9).
Hyperemesis gravidarum occurs more frequently in personality disorders and depressive moods, although this has not been adequately investigated (10).
Human chorionic gonadotropin
A connection between nausea, vomiting and increased production of human chorionic gonadotropin (hCG) is assumed because hyperemesis is often associated with multiple pregnancies and trophoblastic diseases, and hCG levels are increased in both (11, e1, e2, e3, e4, e5) . However, this has not yet been clearly confirmed. Many women with high hCG do not have nausea and vomiting. In addition, patients with chorionic cancer who also have elevated hCG levels do not feel nausea.
Hormones
Estrogen, progesterone, adrenal and pituitary hormones could also trigger hyperemesis. However, the data situation for this is not clear (12). Progesterone is decreased (13) or increased (14) in patients with hyperemesis. Other researchers found no connection between hyperemesis and progesterone concentrations (e5, 15). Progesterone therapy does not improve symptoms (8, 9). Estrogen is associated with nausea during estrogen treatment, so a connection between estrogen and hyperemesis is assumed. However, some prospective studies found an increase in the estrogen concentration in connection with hyperemesis (14, 16), whereas other studies showed no connection (9, e6). Interestingly, hyperemesis gravidarum is more often associated with a female fetus and could therefore be an indication of an increased estrogen level in utero (17). Patients with hyperemesis probably react more sensitively to the effects of estrogen than asymptomatic pregnant women (13).
Helicobacter pylori
Chronic Helicobacter pylori infection could also be responsible for hyperemesis gravidarum (18). In a histological evaluation of the gastric mucosa, this pathogen was detectable in almost 95% of the hyperemesis patients, in the control group in 50% (19). In another study, the H. pylori genome was found in the saliva in 61.8% of cases with hyperemesis gravidarum (21 of 34 patients) compared to 27.6% in the group of normal pregnant women (20). This connection seems to be confirmed by the fact that in 2 observational studies with a total of 5 patients there was no improvement in symptoms with standard drug treatment, with antibiotic therapy against H. pylori leading to a significant improvement in symptoms (21, e7).
Changes in gastrointestinal motility
Gastrointestinal motility is restricted during pregnancy due to progesterone (22). Gastric dysrhythmias also occur (23). The restricted motility could thus contribute to hyperemesis gravidarum.
Hyperthyroidism
Hyperthyroidism has also been associated with hyperemesis gravidarum (24). While fT3 and fT4 were in the normal range, there was a reduction in the expression of thyroid-stimulating hormone (TSH). It is believed that a self-limiting transient hyperthyroidism of hyperemesis gravidarum (THHG) exists. THHG can exist up to the 18th week of pregnancy and does not require therapy. The prerequisite for the diagnosis of a THHG are
- that pathological serological findings are established during hyperemesis,
- there was no overactive thyroid gland before pregnancy,
- there are no clinical signs of hyperthyroidism and
- a negative antibody titer is present.
Clinic and diagnostics
The clinical symptoms are mostly unspecific and uncharacteristic. The focus is on excessive, frequent and all-day vomiting. Clinical signs of volume depleted desiccosis, weight loss, and metabolic ketoacidosis, and ketonemia (fruity bad breath) may also occur. A rise in temperature and liver affections with jaundice can be side effects. Drowsiness and mental slowness, which can lead to delirium, are rare. In addition to the clinical symptoms, laboratory tests are crucial for the diagnosis (Figure 1). The laboratory diagnostics (hematocrit, electrolytes, transaminases, bilirubin, thyroid values) and the urine status (positive ketone bodies, specific gravity, aciduria) are trend-setting. Sonography to confirm intact intrauterine pregnancy and, if necessary, to rule out multiple pregnancy, trophoblastic disease and neoplasia should also be performed (Figure 1). In the case of prolonged vomiting and pronounced symptoms, differential diagnostic causes should be considered (Table 1).
therapy
Nausea and vomiting in early pregnancy are mostly self-limiting and often only require symptomatic therapy. Treatment is dependent
of the respective symptoms and ranges from a change in diet, for example with many small meals and avoiding strongly acidic fruits or fruit juices, to inpatient admission with parenteral nutrition. An outpatient change in diet with the addition of low anti-emetics if necessary appears to be sensible. With hyperemesis gravidarum grade 2, the patient should be admitted to the hospital.
Outpatient therapy
Detailed nutritional advice is the initial treatment step. The desired diet should be high in carbohydrates, low in fat and eaten in frequent small meals. You should also avoid unpleasant smells that can cause nausea and vomiting (such as the smell of meat). The emotional support and, if necessary, psychosomatic care from a psychologist or doctor with additional psychosomatic training is also important. Depending on the severity of the clinical picture, supportive discussions, crisis interventions or psychosomatic or psychiatric treatment may be necessary. A more precise description of the therapy options would lead too far in this context. For drug treatment, vitamin B6 (pyridoxine), antihistamines, anticholinergics, other low-dose antiemetics and gastrointestinal substances can be administered. An analysis of 28 randomized studies on the treatment of hyperemesis gravidarum found that antiemetics reduced the frequency of nausea in early pregnancy and were more effective than placebo. However, some drugs have side effects, most notably fatigue. Vitamin B6 (pyridoxine) was shown to be more effective than a placebo for treating nausea and vomiting in pregnant women (25). At a dose of 10 to 25 mg three times a day, pyridoxine reduces symptoms; a low dose should be started with (e8).
Antihistamines and anticholinergics such as meclozine, dimenhydrinate, and diphenhydramine are primarily used to treat nausea and vomiting during pregnancy (Table 2). These substances are more effective than a placebo in treating vomiting and hyperemesis (e9). If necessary, ondansetron and promethazine can also be used in severe cases of hyperemesis gravidarum (Table 2). Metoclopramide, for example, can also be administered without any problems to improve gastrointestinal motility. Acupressure and ginger extracts can be used as additional alternatives. Acupressure, especially at the P6 point (Neiguan) on the wrist, has also been suggested for the treatment of pregnancy-related nausea (e10). However, there is a lack of sufficient scientific evidence to confirm the effectiveness of this measure. A popular therapeutic alternative is ginger (e11), which can be consumed in a number of dosage forms (e.g. tea). Ginger powder (1 g / d) has proven to be more effective than a placebo in treating hyperemesis gravidarum (e12). Although ginger does not appear to be teratogenic, possible side effects and the optimal dose are not yet known (e8, e13).
Inpatient therapy
In-patient admission should be provided in severe cases of hyperemesis gravidarum with electrolyte imbalance. The primary treatment consists of complete abstinence from food, volume and electrolyte substitution (at least 3,000 mL / d), correction of the electrolyte balance, administration of vitamins and antiemetics as well as parenteral administration of carbohydrate and amino acid solutions (approx. 8,400 to 10,500 kJ / d ). Treatment should continue until vomiting stops or occurs less than three times a day. A subsequent, slow increase in diet should be aimed for (Figure 2). Diazepam also has a positive effect on hyperemesis (e14), probably due to the sedative component. When using it, however, a possible development of dependency must be taken into account. The indication for diazepam during pregnancy should also be strict with regard to possible side effects for the child. Corticoids (e.g. hydrocortisone) can also be used in therapy-resistant hyperemesis (e15). Although corticosteroids are considered safe during pregnancy, a meta-analysis showed a slightly increased risk of fetal malformation, especially during the first trimester (e16). If the symptoms persist, relevant diseases should be excluded from the differential diagnosis. Continuous psychosomatic care and emotional support should also be aimed for (10). Often only inpatient admission improves the symptoms. This confirms the therapeutic approach of Thure von Uexküll, who primarily calls for sustaining, supportive care for these pregnant women (e17). However, if a psychotic component of the disease is suspected, a psychiatrist must be consulted.
Maternal and fetal prognosis
Women with uncomplicated vomiting gravidarum have a better fetal prognosis compared to the normal collective, including a lower tendency to abort, intrauterine growth retardation, and premature birth (2, 4, e18). In contrast, hyperemesis gravidarum is associated with an increased incidence of esophageal ruptures (severe vomiting), Mallory-Weiss syndrome (acute increase in pressure due to vomiting), pneumothorax, neuropathy, preeclampsia, and fetal growth retardation (2, 4, e19).
Conclusion
Although the occurrence of hyperemesis gravidarum is now very rare, in contrast to the frequent mild vomiting, both the clinical and the socio-economic aspect are important. This disease goes hand in hand with a serious impact on the quality of life of the patient concerned and, in individual cases, with high costs for the health system. Since the pathogenesis of hyperemesis gravidarum is still largely unknown, therapy is usually symptomatic and often suboptimal.

Conflict of interest
The authors declare that there is no conflict of interest within the meaning of the guidelines of the International Committee of Medical Journal Editors.

Manuscript dates
submitted: August 28, 2006, revised version accepted: January 17, 2007


Address for the authors
Dr. med.Ioannis Mylonas
1. Women's Clinic - Inner City Clinic
Ludwig Maximilian University of Munich
Maistraße 11
80337 Munich
Email: [email protected]


Literature marked with "e":
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1. Gadsby R, Barnie-Adshead AM, Jagger C: A prospective study of nausea and vomiting during pregnancy. Br J Gen Pract 1993; 43: 245-8. MEDLINE
2. Broussard CN, Judge JE: Nausea and vomiting of pregnancy. Gastroenterol Clin North Am 1998; 27: 123-51. MEDLINE
3. Kallen B: Hyperemesis during pregnancy and delivery outcome: a registry study. Eur J Obstet Gynecol Reprod Biol 1987; 26: 291-302. MEDLINE
4. Tsang IS, Katz VL, Wells SD: Maternal and fetal outcomes in hyperemesis gravidarum. Int J Gynaecol Obstet 1996; 55: 231-5. MEDLINE
5. Jordan V, MacDonald J, Crichton S, Stone P, Ford H: The incidence of hyperemesis gravidarum is increased among Pacific Islanders living in Wellington. N Z Med J 1995; 108: 342-4. MEDLINE
6. Abell TL. Nausea and vomiting of pregnancy and the electrogastrogram: old disease, new technology. Am J Gastroenterol 1992; 87: 689-91. MEDLINE
7. Abell TL, Riely CA: Hyperemesis gravidarum. Gastroenterol Clin North Am 1992; 21: 835-49. MEDLINE
8. Fairweather DV: Nausea and vomiting during pregnancy. Obstet Gynecol Annu 1978; 7: 91-105. MEDLINE
9. Fairweather D: Nausea and vomiting in pregnancy. Am J Obstet Gynecol 1968; 102: 135-75. MEDLINE
10. Munch S: Chicken or the egg? The biological-psychological controversy surrounding hyperemesis gravidarum. Soc Sci Med 2002; 55: 1267-78. MEDLINE
11. James WH: The associated offspring sex ratios and cause (s) of hyperemesis gravidarum. Acta Obstet Gynecol Scand 2001; 80: 378-9. MEDLINE
12. Borgeat A, Fathi M, Valiton A: Hyperemesis gravidarum: is serotonin implicated? Am J Obstet Gynecol 1997; 176: 476-7. MEDLINE
13. Jarnfelt-Samsioe A: Nausea and vomiting in pregnancy: a review. Obstet Gynecol Surv 1987; 42: 422-7. MEDLINE
14. Yoneyama Y, Suzuki S, Sawa R, Yoneyama K, Doi D, Otsubo Y, Araki T: The T-helper 1 / T-helper 2 balance in peripheral blood of women with hyperemesis gravidarum. Am J Obstet Gynecol 2002; 187: 1631-5. MEDLINE
15. Lagiou P, Tamimi R, Mucci LA, Trichopoulos D, Adami HO, Hsieh CC: Nausea and vomiting in pregnancy in relation to prolactin, estrogens, and progesterone: a prospective study. Obstet Gynecol 2003; 101: 639-44. MEDLINE
16. Depue RH, Bernstein L, Ross RK, Judd HL, Henderson BE: Hyperemesis gravidarum in relation to estradiol levels, pregnancy outcome, and other maternal factors: a seroepidemiologic study. Am J Obstet Gynecol 1987; 156: 1137-41. MEDLINE
17. Schiff MA, Reed SD, Daling JR: The sex ratio of pregnancies complicated by hospitalization for hyperemesis gravidarum. BJOG 2004; 111: 27-30. MEDLINE
18. Kazerooni T, Taallom M, Ghaderi AA: Helicobacter pylori seropositivity in patients with hyperemesis gravidarum. Int J Gynaecol Obstet 2002; 79: 217-20. MEDLINE
19. Bagis T, Gumurdulu Y, Kayaselcuk F, Yilmaz ES, Killicadag E, Tarim E: Endoscopy in hyperemesis gravidarum and Helicobacter pylori infection. Int J Gynaecol Obstet 2002; 79: 105-9. MEDLINE
20.