Chewing Gum Containing Vitamin-c to Treat Emesis Gravidarum
Chewing Gum Containing Vitamin-c to Treat Emesis Gravidarum
Nausea and vomiting is a common complication of pregnancy and occurs in 70-80% of all
 pregnancies. The symptoms usually start 2-4 weeks after fertilization and peak between the
 9th and 16th week of gestation. In the 22nd week of pregnancy, the symptoms usually resolve.
 In up to 10% of all pregnancies nausea and vomiting may persist until delivery, which is
 called emesis gravidarum. In 0.3-2% of all pregnancies, nausea and vomiting occur with a
 pathological intensity called hyperemesis gravidarum. The cause of nausea and vomiting during
 pregnancy is unknown, but it is believed that the stimulus is the placenta and not the fetus.
 Antihistamines have proven to be an effective therapy. Histamine is increasingly produced
 during pregnancy by mast cells in the endometrium and myometrium, but also by mast cells in
 the placenta and in the decidua. High expression of the histamine-producing enzyme
 histamine-decarboxylase (HDC) in the placenta and many histamine receptors at the
 feto-maternal transition in the decidua indicate a physiological role of the histamine during
 pregnancy. The antidote is diamine oxidase (DAO), which is produced in the decidua and
 trophoblast and breaks down histamine. DAO acts as a barrier to prevent excessive passage of
 histamine into the maternal and fetal circulation. DAO levels increase exponentially in the
 first 20 weeks of pregnancy to 1000 times the baseline before pregnancy. It has been shown
 that intravenous vitamin C significantly reduces blood histamine levels in both allergic and
 non-allergic disorders. Another study with the German Navy also proved that oral vitamin C
 administration can reduce nausea in seasickness. In an Australian study in 2016, it was shown
 that chewing gum was not inferior to ondansetron therapy in patients with postoperative
 nausea and vomiting (PONV). From the available literature, we conclude that high maternal
 histamine concentrations in early pregnancy may be a cause of nausea and vomiting, whereas
 DAO is not sufficiently expressed by the transfer of histamine from the decidua and
 trophoblast into the maternal circulation prevent. Vitamin C has been identified in
 controlled clinical trials as a way to lower blood histamine levels. Furthermore, chewing gum
 was already described as a treatment option for nausea and vomiting. The aim of this study is
 therefore to test whether chewing gum containing vitamin C in pregnant women with emesis
 gravidarum has the potential to reduce nausea and vomiting.
The following 3 groups of patients should be compared: (1) patients with emesis gravidarum
 who take a chewing gum with vitamin C (verum) "ad libitum" several times daily for 2 weeks;
 (2.) patients with emesis gravidarum who take chewing gum without vitamin C (placebo) "ad
 libitum" several times daily for 2 weeks; (3.) patients with emesis gravidarum who do not use
 chewing gum during the study phase. The enrollment will take place at the Department of
 Obstetrics and Gynecology, Division of Obstetrics and Feto-Maternal Medicine, at the Medical
 University of Vienna. All pregnant women in the first trimester, who present for triage and
 birth registration between 6 to 9 gestational weeks, complaining of nausea and meeting the
 inclusion criteria, will be offered to participate in the study. If they agree to
 participate, patients will be randomized to one of the 3 study groups. In case of enrollment,
 patients are not allowed to take any other nausea therapy during the study period, otherwise
 the results could be distorted. Both the vitamin C-containing chewing gums (verum) and the
 non-vitamin C-containing chewing gums (placebo) are manufactured by the company Frey AG
 (Migros-Genossenschafts-Bund, 8031 Zurich, CH). Both chewing gums are not distinguishable
 from each other in taste. The only difference between verum and placebo is the proportion of
 150mg vitamin C per chewing gum (for verum) or no vitamin C (for placebo). The other
 ingredients are as follows: sweeteners isomalt, sorbitol, maltisirup, sucralose, acesulfame
 K, chewing gum (with antioxidant E306), sodium L-ascorbate, flavorings, acidifier (apple and
 citric acid), thickener gum arabic, dye E171, humectant E422 and E1518, coating agents E903
 and E553b. The randomization takes place by means of the GCP-compliant web-based randomizer
 of the Institute of Medical Informatics, Statistics and Documentation (IMI) of the Medical
 University of Graz (license Meduni Vienna). The ratio of the allocation to the 3 groups is
 1:1:1. Furthermore, as co-variable nicotine abuse is included in the randomization, since
 smoking with a lower risk correlates with suffering from hyperemesis gravidarum. Study
 patients are asked to complete a validated questionnaire (modified PUQE-Score) on their
 condition. In addition, there is a blood sample for the determination of diamine oxidase
 (DAO) and the histamine concentration in the blood of the patient. Patients are subsequently
 evaluated at two further follow-up appointments, one in the course of routine retesting for
 cervical crease measurement (between 11-14 weeks of gestation) and 2nd time during routine
 organ screening (between 20-24 weeks of gestation). At these appointments, a blood sample for
 the determination of DAO and the evaluation of well-being using the Modified PUQE
 questionnaire are carried out again. With the second control appointment the supervision ends
 within the study. The study phase is thus completed at the latest at the time of the organ
 screening at the Department of Obstetrics and Gynecology, at the latest until the 24th week
 of pregnancy. For the determination of DAO and histamine, the following tubes (a total of
 16mL blood) are necessary: 1 serum tube of 8mL with separating gel (DAO) + 1 EDTA tube of 8mL
 (histamine). In addition, it is planned to store the material that has not been used for the
 determination of DAO and histamine in order to answer future questions in the field of
 biomedical research in the MedUni Vienna Biobank. The legal basis for this can be found in
 the Research Organization Act 2018 §2d. For each additional project that uses samples and /
 or data from this study, a separate report will be sent to the Ethics Committee of the
 Medical University of Vienna. The analysis of the DAO levels takes place in the Allergy
 Center Floridsdorf, which has many years of experience in the measurement of DAO and is
 considered a reliable partner. The samples are pseudonymized and stored at -80°C. The
 measurement of histamine concentration is carried out by the Clinical Institute for
 Laboratory Medicine at the Medical University of Vienna. The samples are taken directly after
 acceptance by means of a cooled transport container on site for analysis (coordinated
 preanalytics). The design of the planned study is prospective, randomized, double-blind,
 placebo-controlled. Blinding is provided between verum and placebo chewing gum (groups 1-2).
 The taste of verum and placebo chewing gum is identical. The non-inferiority of chewing gum
 cooking against doing nothing should also be proved. In addition to the course of objective
 parameters such as DAO and histamine, the personal condition of the affected patient should
 be assessed on the basis of the modified PUQE score. The number of ingested chewing gum is
 determined by means of the number of used packs on the 1st inspection date. In addition,
 maternal characteristics are collected, which should be descriptive and should be included in
 the multivariate model: age, pregnancy, parity, gestational age at diagnosis, comorbidities,
 long-term medication, complications in this or previous pregnancies, previous hyperemesis
 gravidarum, nicotine abuse, educational level. In addition, the pregnancy outcome is
 retrospectively assessed in order to evaluate any influence of the chewing gum containing
 vitamin C on the pregnancy outcome. The primary endpoint is the modified PUQE score for the
 1st control appointment. Secondary endpoints are the PUQE score at the 2nd control
 appointment, as well as DAO and histamine concentrations for the 1st and 2nd control
 appointment. About the statistical methods: Based on the work of Birkeland E et al., a
 standard deviation of 3 points or less can be assumed for each Modified PUQE score group.
 With a caseload of 45 patients per group, the ANCOVA has a power of> 80% to find a difference
 between the three groups if two groups differ by at least 2 points. For the pairwise
 comparisons, the same difference results in a power of 88%. With a correction for a drop-out
 rate of 10%, this results in a case number of 50 patients per group. Descriptive statistics
 (number, mean, standard deviation, median, minimum and maximum) should be given separately
 for the 3 target variables Modified PUQE score, DAO and histamine values for the 3
 measurement times. The data is also displayed graphically using box plots and trajectories.
 Further metric variables are also described by mean, standard deviation, median, minimum and
 maximum, categorical variables are described by absolute and relative frequencies. As a
 primary analysis, a mean value comparison of the Modified PUQE scores is performed between
 the 3 groups for the measurements at the 2nd control date. For this, an ANCOVA model is
 calculated, to which the respective initial values at birth registration and the week in
 which the second measurement takes place are considered as covariates. From the ANCOVA model,
 the null hypothesis that there are no group differences on average is tested with an F-test
 at the 5% significance level. If this global null hypothesis is discarded, all pairwise group
 comparisons are performed by T tests for the corresponding model coefficients of the ANCOVA
 model at the 5% significance level. This test procedure does not require any further
 correction for multiple testing when comparing 3 groups. In another exploratory model, the
 maternal characteristics listed in the preceding section are additionally included as
 covariates to investigate the potential influence of these variables on the Modified PUQE
 score and to calculate adjusted group differences. The secondary endpoints are compared to
 the primary endpoint using ANCOVA models between the three groups. As a further secondary
 analysis, the Spearman correlations between the Modified PUQE scores, DAO and histamine
 levels at the three different time points will be determined.
Inclusion Criteria:

 -  age ≥18 years

 -  singleton pregnancy

 -  signed information sheet

 -  symptoms of nausea and / or vomiting in early pregnancy

 -  no pre-existing medication for nausea and vomiting

 Exclusion criteria:

 -  age <18 years

 -  multiple pregnancy

 -  patients with gastric band or in Z.n. bariatric surgery

 -  preexisting diabetes mellitus or gestational diabetes

 -  inability to consent to participation in the study

 -  already started therapy against the emesis gravidarum

 -  taking any antiemetic drugs during the study phase