Study data and population
This was a multinational, cross-sectional study conducted in 18 countries (Australia, Austria, Canada, Croatia, Finland, France, Iceland, Italy, Norway, Poland, Russia, Serbia, Slovenia, Sweden, Switzerland, The Netherlands, United Kingdom, and USA) between October 1st 2011 and February 29th 2012. Women were eligible to participate if they were pregnant or had at least one child less than 1 year of age. Women were recruited to complete an online-self-reported questionnaire via the placement of banners (invitation to participate in the study) on national websites and/or social networks frequently visited by pregnant women and new mothers. The banners contained information about the rationale behind the study and the criteria for partcipation such as: “Moms-to-be and new moms, share your thoughts in an international survey about your views on medication use in pregnancy. Click here to read more about the study and take part.” In each participating country, the online questionnaire was available for 2 months. The survey questionnaire was administered by Questback (
http://www.questback.com). A detailed description of the study design and methods has been published previously [
13].
Consent was obtained from each participant. When a woman clicked on the survey link, a description of the study was presented and she was asked whether she was willing to participate. Informed consent was given by ticking a Yes response. The Regional Ethic Committee, Region South-East in Norway, evaluated the study protocol in its multinational aspect and approved the study. Further approvals were provided from the Faculty of Medicine and Health Science Research Ethics Committee of the University of East Anglia in the UK, The National Bioethics Committee in Iceland and The Scientific Ethic Board, and Provincial Health Service of Trento in Italy. Permission to analyze the herbal medicine study data was also obtained from the Research Ethic Board of the Hospital for Sick Children, Toronto, Canada. All data were handled and stored anonymously.
The online questionnaire captured data on maternal health, socio-demographic, and lifestyle characteristics as well as use of herbal and conventional medicines in pregnancy. Maternal characteristics included age, marital status, educational level, mother tongue, employment status, parity, pregnancy intention, and information on use of assisted reproductive technology. Life-style characteristics included folic acid use and smoking status before and during pregnancy and alcohol consumption after awareness of pregnancy.
The following question about use of herbal medicine was posed to all study participants
“Did you take any herbal preparations during pregnancy (e.g. ginger, echinacea, valerian, cranberries)? If yes, please provide the name of all herbal preparations you have taken during pregnancy”. Herbal medicine use could also be reported under the specific questions about diseases and pregnancy-related health ailments throughout the questionnaire, as described in detail elsewhere [
13]. The names of all herbal medicines used during pregnancy were captured as free text. Herbal medicine were defined according to the World Health Organization’s definition: “any medicinal product based on herbs, herbal materials, herbal preparations and finished herbal products, that contain as active ingredients parts of plants, other plant materials, or combinations thereof ” [
17]. Medicinal products based on animal components, vitamins, minerals or homeopathic products were not considered herbal medicines.
A pre-determined herbal medicine classification list (common name and Latin name) was compiled by the study team and followed the format of the World Health Organization’s Anatomical Therapeutic Chemical (ATC) code convention as a means to standardize the coding in the questionnaire database. The free text responses were coded according to this pre-determined classification list by the national coordinator in each country. When a product name representing a multi-herbal combination or combination product was entered, an internet search on the product name was performed and the botanical ingredient(s) coded according to the pre-determined classification list. Any mineral supplement(s) and vitamins were recorded separately whenever present in the combination product and excluded from the estimation of herbal use. The form of the herbal medicine (tea, tablet, or tincture) was not specifically requested nor was the dose.
In the survey, women were asked to identify the source(s) of the recommendation to use the herbal medicine. The reported sources were then categorized into the following groups: informal (including the sources: own initiative, family/friends, internet, magazines/media and herbal shop personnel), healthcare provider (including the sources: physician, midwife/nurse and pharmacy personnel), and other (neither informal nor HCP). Women who had responses from both informal and HCP recommendation sources were classified into the “Both informal and HCP group”.
Determination of the safety classification of herbal medicines
Herbal medicines were categorized into one of four safety categories; safe, caution, contraindicated or unknown (Table
1) based on a summary of the literature, reference textbooks and monographs. The safety classifications were defined as shown in Table
1.
Table 1
Overview of herbal medicines used in pregnancy according to safety classification and number of users
| Total: | 126 (100.0) | 4,911 (100.00) |
Safe | Evidence for the safety of the herb in pregnancy. | 28 (22.2) | 2,347 (47.8) |
Caution | Caution regarding this herb in pregnancy because there is either no or limited human evidence or results suggest that this herb should be used under the supervision of a qualified health care practitioner. | 60 (47.6) | 1,902 (38.7) |
Contraindicated | The use of the herb in pregnancy has demonstrated negative impacts on the pregnancy or fetus. | 27 (21.4) | 609 (12.4) |
Unknown | No reference regarding the use of this herb in pregnancy was found. | 11 (8.7) | 55 (1.1) |
The safety classification was determined by recording the current classification of each herbal medicine from the available reference sources. Several reference sources were reviewed in order to capture different perspectives when classifying the individual herbal medicines: The Australian text book “The Essential Guide to Herbal Safety” [
18] The European Medicines Agency’s [
19] and North America (Herbal Medicines in Pregnancy & Lactation [
15], Botanical Safety Handbook [
20], and Botanical Medicine for Women’s Health [
21], and Natural Medicines database [
22]). If a particular herbal medicine was not listed in the above mentioned reference sources, additional sources were used; Handbook of Medicinal Herbs [
23] and PDR for Herbal Medicines [
24]. The Handbook of Medicinal Herbs identifies contraindications from multiple sources, often an earlier edition of the Botanical Safety Handbook.
For those herbal medicines which were not listed in any of the referenced books mentioned above, searches in Pubmed, and EBSCO (Alt HealthWatch, AMED, Biomedical Reference Collection, Psychology and Behavioral Sciences Collection, CINHAL Plus, MEDLINE) were performed using first the combination of the terms: “herbal common name and pregnancy” then the “Latin name and pregnancy”. In addition, we performed a search of NCBI’s PubMed database for each of the 125 individual herbal medications reported in the study to identify whether there was evidence of safety in pregnancy. Evidence from controlled studies in human pregnancy was considered first. If no evidence in human studies was available, then in vivo research was considered in the classification. The searches were performed from inception to July 2015.
Once the safety classification of each herbal medicine was compiled from the different sources, one author (DAK) reviewed the information and assigned the preliminary classification. The safety classification for each herbal medicine was reviewed by the co-authors (DAK, HN, and Gro Cecilie Havnen) and all discrepancies discussed until agreement was obtained.
We made two assumptions to the safety classifications; 1) that the classification is for the herbal medicine itself rather than a concentrated whole herbal extract form or concentrated isolated constituent of the plant, 2) the dose is assumed to be at therapeutic levels, suitable for oral administration, versus excessive consumption of the herbal medicine or an alternate route of administration. If an herbal medicinal product included several herbs, each herbal was assessed individually and classified.
Statistical analysis
Factors associated with the use of contraindicated herbal medicines in pregnancy (dichotomous variable: contraindicated herbal medicine user versus non-contraindicated herbal medicine user) were explored via the Generalized Estimating Equations (GEE) [
25]. The GEE method is often used to analyze correlated response data such as multiple observations over time for the same individual or clustered data where observations are grouped based on sharing some common characteristic. The use of the GEE in the current study permitted the results to account for any clustering on region of residency. Data are presented as adjusted odds ratios (aOR) with 95 % confidence intervals (CI). A two-tailed
p-value of <0.05 was considered statistically significant. The multivariate GEE model was developed by first selecting candidate variables whose results, in a univariate model, had a
p-value < 0.15. Variables with a
p-value >0.05, no effect, or those having less than a 20 % impact on the beta coefficients of the retained variables were not included in the multivariate model. The final multivariate model included statistically significant independent variables (i.e. employment status, education level, folic acid use during pregnancy, alcohol use during pregnancy, and recommendation source) and potential confounders (i.e. age as a continuous variable). All statistical analyses were performed by using the Statistical Package for the Social Sciences (SPSS) version 20.0 (IBM® SPSS® Statistics).