H. Guler Sahin, MD, Department of Obstetrics and Gynecology
Huseyin Avni Sahin, MD, Department of Family Medicine
Kevser Onbasi, MD, Department of Internal Medicine
Idris Sahin, MD, Department of Internal Medicine
University of Yuzuncu Yil, Medical Faculty, Van, Turkey

Key words: Helicobacter pylori, Hyperemesis gravidarum

Assistant Professor Guler Sahin
Yuzuncu Yil Universitesi Tip Fakultesi
Kadin Hastaliklarive Do_um Anabilim Dali
Telephone : 001190 532 3252526
Fax : 001190 432 2162329
e-mail :

Routine Helicobacter pylori IgG screening is not practical in Hyperemesis gravidarum but in refractory cases it should be included in the differential diagnosis.

Objective: To investigate whether Helicobacter pylori infection is a contributory factor for hyperemesis gravidarum and to elucidate the risk factors associated with Helicobacter pylori infection.
Methods: 60 pregnant patient with Hyperemesis gravidarum and 60 women with asymptomatic pregnancies were enrolled for a prospective study. The sero prevalence of antibodies against Helicobacter pylori in nature of IgG were detected using a commercial ELISA method, and the incidence, risk factors associated with the infection has been investigated. Chi-Square tests were used for the statistical analysis
Results: Positive IgG concentrations were. 61.67 % and 53.33 % in the study and the control group respectively. The statistical analysis showed no significant association between Helicobacter pylori infection and Hyperemesis gravidarum, but in refractory cases Helicobacter pylori infection should take its place in the differential diagnosis. (p>0.05) The risk factors positively associated with the infection were age, gravida, household size and later in the course of the pregnancy with the symptoms of dyspepsia.
Conclusion: Routine Helicobacter pylori IgG screening is not practical in Hyperemesis gravidarum but in refractory cases it should be included in the differential diagnosis

Almost half of the adult population has serological evidence of infection with Helicobacter pylori, a contributor to gastritis, peptic ulcer and gastric cancer. (1) Helicobacter pylori is a gram negative, spiral shaped, microaerofilic bacteria. The prevalence rate is higher in developing countries than the developed country. (2) Gastric colonisation with Helicobacter pylori has been reported in 90 to 95 percent of patients with duodenal ulcer and in 60-70 percent of patients with gastric ulcer. (3) The possible transmission routes may be oral-oral, faecal-oral, iatrogenic transmission and vectorial spread. (4) The only known reservoir is human itself. (5) Although half of the population is infected with this bacterium only a proportion of these people have clinically significant diseases like as gastritis, duodenal or gastric ulcer, gastric cancer and mucosa associated lymphoid tissue lymphoma. The reason may be host factors. (6)
Helicobacter pylori produce a variety of proteins that appear to mediate or facilitate its damaging effect on the gastric mucosa. Urease produced by Helicobacter pylori catalyses the hydrolysis of urea to ammonia and carbon dioxide. Ammonia can neutralise the hydrochloric acid and with the neutralisation of the acid in the stomach the bacteria can reach the gastric epithelium across the mucus layer. (7) Urease is one of Helicobacter pyloriˇÕs important enzymes, essential for pathogenicity, a potential immunogen for vaccine development and the basis of many recommended diagnostic tests. (8) Toxic oxygen metabolites can be cleared with the enzyme catalyse and superoxide dismutase that are produced by the bacteria. (7) Also the IgA protease enzyme which is secreted by Helicobacter pylori can degrade secretory IgA. Other enzymes like musin protease, lipase and phospholipase are contributory factors for pathogenicity. (9)
Hyperemesis gravidarum is the most severe spectrum of Gastro intestinal complaints in pregnant women. It is characterised by prolonged severe nausea, vomiting dehydration, ketosis and body weight loss. Investigations may show electrolyte imbalance (hyponatremia, hypokalaemia) metabolic hypochloraemic alkalosis and ketonuria. The haemotochrit is raised and abnormal liver function test may be associated with abnormal thyroid function tests. The phatophysiology is poorly understood. Various hormonal mechanical and physiological factors have been implicated. Studies have demonstrated are relationship between high or rapidly rising levels of HCG and estrogens. But still the etiopathogenesis is unclear. Our purpose was to investigate whether a subclinical Helicobacter pylori infection with the changes it causes in the gastric mucosa was a contributory factor for hyperemesis gravidarum. Because it was easy cheap and reliable serologic tests were used for investigation. (10)

Materials and methods:
60 pregnant patients with Hyperemesis gravidarum and 60 healthy pregnant women without any systemic disease were included in the study. The Hyperemesis gravidarum study group were aged between 17 to 42 and had gestations between 6-16 weeks. The criteria for inclusion for the study group were prolonged severe, dehydration, vomiting, more than 5% body weight loss ketone in the urine, exclusion of diseases such as hyperthyroidism, psychological disorders, urinary tract infections, gastro intestinal disorders, intracranial disorders, hepatic disorders and etc that can cause vomiting. Inclusion criteria for the control group were same as for the study group except there were no symptoms of hyperemesis gravidarum. They were recruited from our out patient clinic during their routine examination in pregnancy. The characteristics of the patient in both groups are presented in table I. All patients gave written informed consent. Patients were excluded if they had received antibiotics or bismuth components in the preceding month. A venous blood sample was taken for serology from each patient.
Serology was performed using a commercial ELISA method. Sera were stored at 200C until tested. Antibodies to Helicobacter pylori in nature of IgG were detected using commercial ELISA kit (ENZYWELL). The sensitivity for this test is 95.8 % specificity is 98.4 %.
The results were tested for statistical significance with Chi-Square tests, p<0.05 was regarded as statistically significant.

The IgG antibodies against Helicobacter pylori was positive in 37 of 60 patients in the hyperemesis group and it was positive in 32 of 60 patients in the control group with a sero prevalence of 61.67 % in the study group and 53.33 % in the control group. Although the sero prevalence of Helicobacter pylori was higher in the Hyperemesis gravidarum group the statistical evaluation showed no significant differences between the groups. (p>0.05) The association between positive Helicobacter pylori antibody status and possible risk factors are shown in Figure I to III
Positive Helicobacter pylori IgG status increased with age reaching to peak at the 40-43 age group. It increased with the number of pregnancies peaking at the 5th-6th pregnancies and reaching to its peak in a household size of 11-12. These variables were significantly associated with positive Helicobacter pylori IgG status.
During the follow up the patients were also interviewed about the symptoms of dyspepsia and reflux. Dyspepsia was significantly associated with positive Helicobacter pylori IgG status with 73.91 % positive results while reflux symptoms did not have a significant association with positive Helicobacter pylori titre.
In the hyperemesis study group 2 patients had multiple admissions with one also having positive Helicobacter pylori IgG status. She was 31 years old Gravida=3, Parity=2, had had an endoscopy performed and duodenal ulcer diagnosed a week before the time she learned that she was pregnant. She did not use the prescribed medication with the fear of teratogenity and did not have symptoms and signs of hyperemesis gravidarum in her first and second pregnancy. But she was hospitalised twice with hyperemesis gravidarum, upper abdominal discomfort and did not get complete relief from the routine hyperemesis gravidarum treatment in this pregnancy. On the 11th week of pregnancy she was hospitalised for the third time. She had also symptoms of hematemesis and Ranitidine ( Ranitab 150 mg ) bid, clarithromycin ( Klacid 500 mg ) bid, antiacid (Calcium carbonate 680mg+Magnezyum carbonate, Rennie 80 mg) qid was added to the treatment for two weeks. Within a week she improved, but the dyspepsia and infrequent vomiting lasted until the end of the pregnancy. The second patient had marital dispute and was hospitalised several times until the 20th week but on every admission with the help of psychotherapy she improved and was discharged.

Helicobacter pylori is one of the most common infectious disease on earth. Its prevalence varies among different populations. Higher prevalence rates are found in developing countries with lower prevalence rates in developed countries. We detected 61.67 % positive Helicobacter pylori IgG in the study group which is lower than what is detected in more crowded cities such as Istanbul. (11) This could be a consequence of lower population density in this region. As it has been reported with a study performed in Australia that having lived on a farm has been identified to be protective against Helicobacter pylori infection. (12) In this study, there was significant association between positive Helicobacter pylori IgG status and age, number of pregnancies and household size. This again shows the effect of living under overcrowded conditions and close contact, which are probably the most important factors in transmission of the infection. Similar results have been reported by other studies in the literature. (9,13)
Helicobacter Pylori causes a non-invasive infection of the gastric epithelium and the mucous layer that coats this epithelium. It can cause duodenal ulcer, gastric ulcer, chronic gastritis, gastric adenocarcinoma, mucosa associated lymphoid tissue lymphoma and a few other rare upper gastrointestinal disorders. (14) It is reported that Gastric Mucosa infected by Helicobacter pylori almost always shows a combination of inflammation and epithelial changes. The classical feature caused by this organism is chronic active gastritis. The infiltrate generally consists of monocytes and neutrophils. The degree of inflammation varies in severity from a minimal inflammatory infiltrate in the lamina propria with preserved architecture to severe gastritis with dense inflammation. In very severe cases intraepithelial neutrophils can be detected in both the surface epithelium and in the gastric pits as micro abscess. (15) Our purpose with this study was to investigate whether Helicobacter pylori infection with the changes it causes in the gastric mucosa has a relationship with Hyperemesis Gravidarum. Peter Frigo, et al with his study has reported 90.5 % Helicobacter pylori seropositivity associated with Hyperemesis Gravidarum. (16) Our findings suggest no association between infection with Helicobacter pylori and Hyperemesis Gravidarum. We found 61.67 % seropositivity in the study group and 53.33 % in the control group. The difference was statistically not significant (p>0.05)
During the follow up the patient were also interviewed about symptoms of dyspepsia and reflux. In agreement with other studies in the literature Helicobacter pylori seropositivity was 73.91 % in patients with symptom of dyspepsia and the statistical analysis showed significant association while reflux symptoms were not significantly associated with positive Helicobacter pylori status. (17)
In the study group there were 2 patients with multiple hospital admissions. One of these patients also had positive Helicobacter pylori IgG and dyspepsia. She didnˇÕt improve completely with the conventional management of Hyperemesis gravidarum. The conventional management consists of intravenous fluids, electrolyte replacement, vitamin supplementation (pyridoxine), and antiemetics. Antiacid, antibiotic and H2 receptor antagonist were added to the treatment. She improved within a week but symptoms of dyspepsia and occasional vomiting continued until term.
In conclusion the etiopathogenesis of Hyperemesis gravidarum is still obscure. Nausea and vomiting during pregnancy affect approximately 50% to 70% of all pregnant women. (18) Most of the cases are mild and do not require treatment. In only 0.6 % or less of patients is the vomiting severe enough to warrant hospitalisation. Symptoms of hyperemesis gravidarum are usually seen between 6-16th week of the gestation. There is no significant association between hyperemesis and Helicobacter pylori infection in our study. Therefore routine screening during this period for Helicobacter pylori is not practical but Helicobacter pylori infection should take its place in the differential diagnosis, especially in prolonged conditions that are refractory to conventional management and cases that extend to second trimester. Gastro-enteritis, cholecystitis, pancreatitis, hepatitis, pyelonephritis, fatty liver of pregnancy, hyperthyroidism, conditions that cause increased intracranial pressure, psychological factors, peptic ulcer with or without Helicobacter pylori infection should be included in the differential diagnosis. Then screening for Helicobacter pylori infections should be performed. If Helicobacter pylori infection is detected as a cause H2 receptor antagonist , antibiotics can be added to the treatment.

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Table I : Clinical Characteristics
________________________________________________________________ Study Group (n=60) Control Group (n=60)
Mean Standard Deviation Mean Standard Deviation
Age (years) 26.98 5.24 25.97 5.25
Gravida 2.92 2.16 3.05 2.53
Household size 4.22 3.27 4.38 2.52

Nagoya City University
Medical School