Herbal products have been used for gas pains in children for many years. However, the quality of herbal products used in children and the presence of contamination in the products are controversial. This study was conducted to evaluate the frequency of use of herbal products for gas pain in pediatric patients, the attitudes of parents towards the use of herbal products, and the pyrrolizidine alkaloid content of herbal products used for gas pain.

The survey part of the study was conducted between 15.06.2020–15.09.2020 at Gazi University Hospital Pediatrics Clinics. The surveys were conducted face to face with the parents. The Statistical Package for Social Sciences (SPSS) 23 program was used in the analysis of the data. In the other part of the study, 28 herbal products frequently used in gas pain were purchased from spice shops, markets and internet sites and their pyrrolizidine alkaloid content was evaluated by LC-QTOF-MS analysis.

31.5% of the participants had their children use herbal products for gas pains. When the plants used for gas pains in children were examined, fennel came first with a usage rate of 51.3%. The plants used in gas pains were purchased from spice shops by most of the participants (59%). The presence of pyrrolizidine alkaloids above 10 µg/kg concentration was detected in 75% of herbal products used in gas pains.

In all segments of society, children are given herbal products for gas pains. Parents mostly buy herbal products from spice shops. Products sold for gas pains may cause hepatotoxic effects in children when consumed for a long time and in high doses due to the pyrrolizidine alkaloids they contain. Herbal products to be used in gas pain should be used under the consultancy of a physician/pharmacist and should be obtained from pharmacies.

Gas, known as increased gastrointestinal air load, is a common complaint in both pediatric and adult patients. Gas in children and infants usually causes infantile colic [1]. In this case, nutritional changes, physical support, pharmacological and behavioral treatments are applied to the baby and mother [2]. Dicyclomine hydrochloride, which has a relaxing effect on smooth muscles, cimetropium bromide, which has spasmolytic activity, and simethicone, which disperses gas bubbles in the gastrointestinal tract, were found to be effective, but these drugs caused some side effect [3, 4]. Due to the side effects of medicines and various reasons, families use plants and herbal products to prevent gas pains in children [5, 6].

Plants have been used for many years for colic and gas problems in children and these effects of plants have been researched. Plants frequently used in gas pains in children include Foeniculum vulgare Mill. (fennel), Matricaria recutita L. (chamomile), Anethum graveolens L. (dill), Zingiber officinale Roscoe (ginger), Carum carvi L. (cumin), Pimpinella anisum L (anise) [2, 7, 8].

In our previous study, we reported that herbal products used in children in Turkey are used without consulting health professionals (doctors, pharmacists, etc.) and that these products are obtained from places other than pharmacies [9]. It is important that herbal products have a certain quality in order to be used. Problems occur in the quality of herbal products due to contamination of toxic substances in herbal products [10]. One of the contaminations causing these quality problems is pyrrolizidine alkaloid (PA) contamination [11]. PAs are naturally occurring chemical compounds, especially in plants of the Boraginaceae, Asteraceae and Fabaceae families, and PAs have been reported to be hepatotoxic [12]. Current available information has shown that PAs have adverse effects such as hepatotoxicity, developmental toxicity, genotoxicity and carcinogenicity [13]. Contamination with these alkaloids occurs in herbal teas and herbal products due to the presence of plants naturally containing PAs in agricultural areas [14].

This study was conducted to evaluate the frequency of use of herbal products in gas pain in children, parents’ attitudes towards the use of herbal products, and the PA content of herbal products used in gas pain. To the best of our knowledge, this is the first study in Turkey to evaluate in detail the use of herbal products for gas pain in children.

Study design

The survey part of this study was conducted between 15.06.2020–15.09.2020 in the Pediatric Clinics of Gazi University Hospital. Approval for the study was obtained from Gazi University Ethics Commission with research code number 2020 − 257 (date 07.04.2020 and numbered 04).

Inclusion and exclusion criteria

Parents of children aged 0–1 years were included in the study. There were no exclusion criteria.

Sample size

The sample size was determined as a minimum of 114 participants with the Raosoft Sample size calculator (95% confidence interval, 50% response rate and 5% margin of error) [15].

Data collection tools

Those who wanted to participate voluntarily were included in the study and a voluntary consent form was obtained from the participants. Participants were informed that they could withdraw from the study at any time. Data were collected through surveys and the questions in the survey were revised and prepared according to previous studies [16, 17]. The questionnaire form is given in the supplementary file. The questionnaires were completed by the researchers through face-to-face interviews with the families. The survey includes a total of 13 multiple-choice and open-ended questions. While the first part of the survey was about demographic information, the second part was prepared to determine the factors related to the use of herbal products in gas pain.

Data analysis

The data obtained were analyzed using the Statistical Package for Social Sciences (SPSS) 23 program. Descriptive statistics were represented by frequencies and percentages.Chi-square test was used for data comparison between categorical variables. A value of p < 0.05 was considered statistically significant.

Plant samples, chemicals and solvents

Acetonitrile used for stock solution preparation was purchased from Carlo Erba^®. C18 SPE cartridge (Copure^® C18) was used for solid phase extraction. Standard substances (Intermedine, lycopsamine, europine, retrorsine, seneciphylline, echimidine, lasiocarpine, erucifoline, heliotrine, senecivernine, jacobine, monocrotaline, senecionine, senkirkine, trichodesmine and N-oxide derivatives) were obtained from Phytolab^®. Samples of herbal teas sold to relieve gas pain in children (28 samples) were obtained from spice shops, markets and websites in Turkey. Information on the analyzed samples is shown in Table 1.

Preparation of samples and SPE

Modifications were made to the German Federal Institute for Risk Assessment (BfR) method protocol and SPE was performed using a vacuum chamber [18]. The samples were extracted with H₂SO₄ (20 mL, 0.05 M) solution and kept in an ultrasonic bath for 15 min. The mixture was then centrifuged at 4000 rpm for 10 min and the resulting supernatant was transferred into a tube. The same procedure was repeated a second time by adding 20 ml of 0.05 M H₂SO₄ solution to the remaining portion and the supernatants were combined after centrifugation. The combined supernatants were filtered and neutralized extracts were obtained by adding 6.4% (1 mL) aqueous ammonia solution. SPE was performed on the neutralized extracts. SPE was performed on neutralized extracts and LC-QTOF-MS analysis was performed on extract matrices.

Analysis parameters

Analyses were performed on an Agilent 1260 series HPLC system and Agilent 6550 iFunnel High Resolution Mass Spectrometer connected to the system (Agilent Technologies, Inc., CA, USA). The MS system was used in a dual-spray Agilent Jet Stream Electrospray ionization technique and analyses were performed in positive mode. MS operating mode: 2 GHz Extended Dynamic Range. Agilent TC C-18 (4.6 mm x 150 mm x 5 μm) column was used for chromatographic separation. Analysis parameters: Injection volume: 10 µL, column temperature: 30 °C, analysis time: 45 min, mobile phase A: 10 mM ammonium acetate, mobile phase B: methanol, flow: 0.6 mL/min, ionization mode: positive, dryer gas temperature: 200 °C, desiccant gas flow, N₂: 14 L/min, sheath gas temperature: 350 °C, sheath gas flow, N₂: 11 L/min, mass reading range: 40-1700 amu, reference ions: 922,0098. The flow program is shown in Table 2. Agilent MassHunter Software B06.00 and Metlin Metabolite database were used for analysis and data evaluation.

In this study, 124 out of 562 parents presenting to the pediatric clinics met the inclusion criteria. A total of 124 people participated in the study, and 81.5% of the participants were mothers and 18.5% were fathers. When the gender of the patients registered in the clinics was analyzed, it was observed that 51.6% were girls. In this study, mostly parents aged 18–30 years (59.7%) participated and 31.5% of the participants used herbal products for gas pains in their children. The relationship between parental gender, age and education level and herbal product use was not statistically significant (p > 0.05). The relationship between demographic characteristics and the use of herbal products for gas pain in children is shown in Table 3.

When herbal products used for gas pain in children were investigated, fennel ranked first with 51.3% (n = 20). This use was followed by herbal mixtures containing cumin and dill with 12.8% (n = 5) and herbal mixtures containing olive oil with 10.3% (n = 4). The plants used for gas pains in children are shown in Table 4.

The majority of the participants (59%) had purchased herbal products used for gas pain from spice shops. The shops where herbal products are purchased in case of gas pains are shown in Fig. 1.

Shops where herbal products for gas pain are purchased

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When the method of application of herbal products used in gas pains in pediatric patients by families was investigated, the majority of the participants (97.4%) used the products internally, while a small proportion (2.6%) used them externally.

Sources of information on the use of herbal products against gas pains were investigated and it was seen that the first people consulted were physicians (Fig. 2).

Sources of information on the use of herbal products and plants against gas pains

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Among the reasons for the preference of herbal products in gas pain, “Herbal products are useful when used correctly” was the most common answer (41%). 35.9% of the participants stated that they prefer herbal products because they think that they are natural and harmless, and 20.5% stated that they prefer herbal products because they think that herbal products reduce the use of chemical drugs. Those who prefer herbal products because they are easy and cheap to access constituted 2.6% of the participants.

Europin or senesifylline was detected above the limit of quantification (LOQ) value of 10 µg/kg in 21 (75%) of 28 herbal products used for gas pains. The amounts of europine and seneciphylline in the samples are shown in Tables 5 and 6.

It was noteworthy that europine was detected in all of the fennel samples investigated. The highest amount of europin was detected in cumin sample number 15.

The highest PA content among the samples examined was found in sample number 7. The amount of seneciphylline in plant products was between 35.363 and 434.067 µg/kg.

In many parts of the world, herbal products are used to support child health [19]. Herbal products are widely used in children in Turkey as they are used all over the world [20]. While cultural and traditional factors play a role in the use of herbal products, the belief that herbal medicines are beneficial by the public is also effective [17].

Gastrointestinal system problems such as gas pain, constipation, nausea and vomiting are common in childhood. Gas pains are one of the most common problems in newborns and children, especially in the first few months after birth. Anise, chamomile and fennel tea are reportedly used by mothers to prevent gas pains and constipation in children [6, 21].

In our study, the relationship between demographic characteristics of parents (age, gender and education level) and herbal product use was not statistically significant. In a study conducted in Turkey, Akkuş et al. [22], found no statistically significant difference between parents who used herbal products and those who did not in terms of gender, age and educational level. Similarly, Ustuner Top et al. [23], evaluated the use of complementary medicine for children in Turkey and found no statistically significant difference between the age and education levels of parents who practised complementary medicine and those who did not. However, there are contradictory results in the literature. In a study conducted in the United States of America, the use of herbal products in children was positively associated with parental education [24]. In a study conducted in Germany, it was reported that higher education and female gender had a positive effect on the use of complementary medicine in children [25]. This may be related to the fact that people with higher education level have higher health literacy levels and have more motivation to use herbal products [25]. Another reason for this may be that parents with a higher level of education are more exposed to herbal products and complementary medicine practices because they are more interested in the media [26]. Some studies have reported that young parents are more likely to use herbal products and complementary practices. This is explained by the fact that young parents are more influenced by their environment [23].

In the study conducted by Oshikoya et al. [27], it was reported that herbal products were used by 51.8% of families in case of colic. Plants used by families include Allium asalonicum L. leaves, Syzygium aromaticum L. seeds and Parinari spp. seeds. Gürol et al. [6], conducted a study on herbal supplements used to cope with common health problems in childhood. According to Gürol et al. [6], study, 28.2% of the participants reported that they had their children use herbal products for gas pains and digestive problems. When herbal products used for gas pain were examined, it was seen that fennel tea was the most preferred. Fennel tea was used by 77.2% of the participants for gas pain in children. Mothers also stated that they used fennel tea for children’s constipation and sleep problems. In a previous study conducted by us, we reported that 8.8% of families used herbal products for gas pains and abdominal pain in their children [9]. In a study conducted by Bülbül et al. [5], 14.8% of the participants used herbal products for gas pains in children. In a study by Akkuş et al. [22], investigating the use of herbal products in children, 30.90% of the participants used plants for gas pains. As a result of this research conducted by us, it was observed that the rate of families using herbal products for gas pains in their children was 31.5%. Our results are similar to the results of other studies. Similar to the study of Gürol et al. [6], fennel was most preferred by families for gas pains in our study. The use of plants other than fennel in the study by Oshikoya et al. [27], may be due to the fact that the study was conducted in a different region and therefore the plant diversity in that region was different.

The main compound of fennel fruit is trans- anethole, which is chemically similar to dopamine. Fennel may reduce flatulence and improve gastrointestinal motility function by exerting a relaxant effect on intestinal smooth muscles [28]. Fennel is useful in the treatment of digestive disorders such as gas and bloating with its antispasmodic effect [29]. The fact that fennel was the most preferred plant in our study may be due to its significant carminative effect.

It is important to consult doctors or pharmacists for accurate information before using herbal products [30]. Physicians should be informed about the herbal products used to prevent herb-drug interactions and complications [31]. In our study, it was observed that a significant proportion of parents received information from physicians about the products they used and were aware of this issue. In addition, according to literature data, personal experiences are also an important parameter in the use of herbal products. Positive experiences in the past make it possible to use herbal products again in case of illness [32]. In line with literature data, personal experiences were an important factor in the use of herbal products in our research.

As a result of our research, regardless of the level of education, it was observed that the participants mostly (59%) purchased herbal products used against gas pain from spice shops. In a study evaluating the use of complementary and alternative medicine in Australian children, herbalists (spice shops) were visited most frequently (30.4%) [33]. In a study examining the use of complementary and alternative therapies in patients applying to a pediatric outpatient clinic in Turkey, the participants mostly visited spice shops (65.2%) [34]. In this respect, our results are similar to other studies. The majority of plants and herbal products sold in spice shops in Turkey are stored in inappropriate conditions and these products often do not have label information. For this reason, herbal products sold in pharmacies in Turkey are safer [35]. Therefore, there may be problems in the quality of herbal products sold in places other than pharmacies.

Quality problems in herbal products pose significant safety risks for consumers. Contaminants and pollutants in herbal products can cause toxicity and adverse health consequences [36]. In this context, especially PA contamination in herbal products can cause serious toxic effects.

PA content analyzes were performed on 50 different tea samples from Polish local stores and supermarkets. When the results of the study were examined, it was seen that 78% of the analyzed samples contained PA. The PA content concentrations of these samples were determined to be in the range of 2–6498 µg/kg, and it was determined that 9 out of 50 teas may pose a high risk for adults and 17 for children [37]. Herbal teas used in Germany for infants and pregnant women were analyzed for PA content by Mädge et al. [38], of the 44 teas analyzed, 38 (86%) were found to contain PA and the PA content of the teas was reported to range from 0 to 391 µg retronesin equivalent/kg. Seventy commercial plant products commonly used in Ghana were analyzed for PA contamination and 60% of the plant products examined were found to contain PA. As a result of the study, it was reported that some products contained higher doses of hepatotoxic PA than the daily dose for children and that quality control tests should be performed on the products [39]. Similar to previous studies, PA content was detected in 75% of 28 samples in our study. In a study evaluating the content of PA, PA N-oxide and tropane alkaloids in herbal products sold in Turkey, it was reported that at least a few of the alkaloids were detected in all products examined [40]. Analysis of herbal products and honey sold in Germany to determine the amount of PA found that teas contain high amounts of PA. In the study, at least one PA content was detected in 83% of fennel teas, while the presence of PA was detected in all lemon balm and rooibos tea samples. It was stated that the detected PA contents could be a contamination caused by harvesting together with PA producing plants [41]. In a different study, total PA content in herbal teas was generally determined in the range of 0–5668 µg/kg. Three of the tea mixtures examined were found to have extremely high PA content at concentrations of 4227, 5137 and 5668 µg/kg. PA contamination was observed in 14.3% of the chamomile tea samples and 25% of the fennel samples. The maximum amount of PA content in fennel was 26.6 µg/kg, while the average value was around 5.7 µg/kg [42]. In the study conducted by Bodi et al. [41], PA content was detected in almost all of the fennel teas (83%), while in our study PA content was detected in all of the fennel samples. In our study, the highest PA concentration in fennel samples was 219.44 µg/kg. Unlike our study, Schulz et al. [42], found PA content in 25% of fennel samples and the highest PA content concentration in fennel was 26.6 µg/kg. This difference suggests that the PA content in fennel teas in our country is high, therefore caution should be exercised when using fennel teas in children and the use of these teas at high doses for a long time in pediatric patient groups may cause toxic effects. The PA contents we detected in herbal teas are probably due to contamination with other plants growing in the area and containing PA.

The maximum daily intake recommended by the German Federal Institute for Risk Assessment (BfR) and the UK Toxicity Committee is reported to be 0.007 µg/kg body weight [43]. In this context, the samples we analyzed (least and most contaminated) were evaluated according to the maximum recommended dose for children (0.007 µg per kg body weight). According to these data, the maximum safe limit for a child weighing 5 kg is 0.035 µg/day (5 × 0.007). If the child consumes 2 g of a product with a concentration of 31.163 µg/kg (in the least contaminated sample, sample number 27), the dose becomes approximately 0.062 µg, far exceeding the safe limit by a significant margin. Similarly, if a child consumes 2 g of a product with a concentration of 434.067 µg/kg (in the most contaminated sample, sample number 7), the dose would be about 0.868 µg, which is about 25 times higher than the safe limit (0.035 µg/day). The relevant calculations apply to a single consumption, but Mädge et al. [38], reported that herbal teas containing PA are usually consumed for more than 6 weeks. As the same brand of tea is often used, children are exposed to high concentrations of PAs over long periods of time [37, 38]. Therefore, the products in which we detected PA may have undesirable consequences for children in the long term. Similar to our study, Schulz et al. [42], reported that two of five tea infusions prepared from medicinal teas contained high amounts of PA (> 300 µg/kg) and that these teas exceeded the maximum recommended daily dose. Letsyo et al. [39], reported in their study on herbal products that a herbal product exceeded the daily tolerable PA limit 415 times in children. In another study, it was reported that consumption of the sample with the highest PA content would cause 36 times more exposure in children and this would pose a high risk in children [37].

Considering all these data, consumption of products containing high amounts of PA may be hepatotoxic for infants and children. Therefore, care should be taken to ensure that the amount of PA in herbal products and teas is within low limits [44].

The study is important in terms of providing information about PA content contamination of herbal products used in children’s gas pains, but there are some limitations in the study. Since the number of samples was limited, this should be taken into account when generalizing for Turkey. In addition, the data used in the evaluation of herbal product use behaviors in gas pain were based on parental statements, so this should be taken into consideration when making social evaluations, as the accuracy of the data may be limited. Survey research is valuable in that it was conducted by researchers in hospital during the coronavirus pandemic.

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Study concept and design: SB, DDO; Data Collection: SB, NMK; Analysis and interpretation of data: SB, NMK, AİA, DDO; Drafting of the manuscript: SB, DDO; Critical revision of the manuscript for important intellectual content: SB, NMK, AİA, DDO. All the authors read and approved the final manuscript.

Correspondence to Semih Bulut.

Ethics committee approval was given by the Gazi University Ethics Commission (Date 07.04.2020/No: 2020 − 257). We confirm that all methods were performed in accordance with the Declaration of Helsinki. Informed consent was obtained from each participant.

Not applicable.

The authors declare no competing interests.

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